Complications in Anesthesia, Second Edition

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Section Editors JOHN L. ATLEE, MD

TERRI G. MONK, MD

Professor of Anesthesiology Department of Anesthesiology Medical College of Wisconsin Milwaukee, Wisconsin

Professor Department of Anesthesiology Duke University Medical Center Durham, North Carolina

BRENDA A. BUCKLIN, MD

TIMOTHY E. MOREY, MD

Associate Professor of Anesthesiology Department of Anesthesiology University of Colorado Health Sciences Center Denver, Colorado

Associate Professor of Anesthesiology Department of Anesthesiology University of Florida College of Medicine Gainesville, Florida

MARK A. CHANEY, MD

MICHAEL J. MURRAY, MD, PHD

Associate Professor of Anesthesiology Department of Anesthesia and Critical Care University of Chicago Pritzker School of Medicine Chicago, Illinois

DONN M. DENNIS, MD, FAHA Joachim S. Gravenstein, MD, Professor of Anesthesiology Department of Anesthesiology University of Florida College of Medicine Gainesville, Florida Vice President-Pharmacology, ARYx Therapeutics, Inc. Santa Clara, California

JOHN ELLIS, MD Professor of Anesthesiology Department of Anesthesia and Critical Care University of Chicago Pritzker School of Medicine Chicago, Illinois

JOEL M. GUNTER, MD Professor of Clinical Anesthesia and Pediatrics Department of Anesthesia University of Cincinnati School of Medicine Attending Anesthesiologist Department of Anesthesia Children’s Hospital Medical Center Cincinnati, Ohio

ROSEMARY HICKEY, MD

Professor of Anesthesiology and Chair Department of Anesthesiology Mayo Clinic College of Medicine Jacksonville, Florida

NADER D. NADER, MD Associate Professor of Anesthesiology, Surgery and Pathology State University of New York at Buffalo School of Medicine Buffalo, New York

MICHAEL F. O’CONNOR, MD Associate Professor Department of Anesthesia and Critical Care University of Chicago Pritzker School of Medicine Chicago, Illinois

KERRI M. ROBERTSON, MD Associate Clinical Professor of Anesthesiology Chief, General, Vascular, High-Risk Transplant and Surgical Critical Care Medicine Division Chief, Transplant Services Duke University School of Medicine Department of Anesthesiology Durham, North Carolina

SCOTT R. SPRINGMAN, MD

Professor and Program Director Department of Anesthesiology University of Texas Health Science Center at San Antonio San Antonio, Texas

Professor Departments of Anesthesiology and Surgery University of Wisconsin Medical School Madison, Wisconsin

BRIAN M. ILFELD, MD

KEVIN K. TREMPER, MD

Associate Professor Department of Anesthesia University of California, San Diego San Diego, California

Professor and Chairman Department of Anesthesiology University of Michigan Medical Center Ann Arbor, Michigan

DONALD A. KROLL, MD, PHD

B. CRAIG WELDON, MD

Staff Anesthesiologist Department of Surgery Veterans Affairs Medical Center Biloxi, Mississippi

Associate Professor Department of Anesthesiology and Pediatrics Duke University School of Medicine Durham, North Carolina

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1600 John F. Kennedy Blvd. Ste 1800 Philadelphia, PA 19103-2899

COMPLICATIONS IN ANESTHESIA, 2nd edition

ISBN-13: 978-1-4160-2215-2 ISBN-10: 1-4160-2215-5

Copyright © 2007, 1999 by Saunders, an imprint of Elsevier Inc. All rights reserved. No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopying, recording, or any information storage and retrieval system, without permission in writing from the publisher. Permissions may be sought directly from Elsevier’s Health Sciences Rights Department in Philadelphia, PA, USA: phone: (+1) 215 239 3804, fax: (+1) 215 239 3805, e-mail: [email protected]. You may also complete your request on-line via the Elsevier homepage (http://www.elsevier.com), by selecting ‘Customer Support’ and then ‘Obtaining Permissions’.

Notice Knowledge and best practice in this field are constantly changing. As new research and experience broaden our knowledge, changes in practice, treatment, and drug therapy may become necessary or appropriate. Readers are advised to check the most current information provided (i) on procedures featured or (ii) by the manufacturer of each product to be administered, to verify the recommended dose or formula, the method and duration of administration, and contraindications. It is the responsibility of the practitioner, relying on his or her own experience and knowledge of the patient, to make diagnoses, to determine dosages and the best treatment for each individual patient, and to take all appropriate safety precautions. To the fullest extent of the law, neither the Publisher nor the Editors assumes any liability for any injury and/or damage to persons or property arising out of or related to any use of the material contained in this book. The Publisher

Library of Congress Cataloging-in-Publication Data Complications in anesthesia / [edited by] John L. Atlee. -- 2nd ed. p. ; cm. Includes bibliographical references and index. ISBN 1-4160-2215-5 1. Anesthesia--Complications. I. Atlee, John L. [DNLM: 1. Anesthesia--adverse effects. 2. Anesthetics--adverse effects. WO 245 C7369 2007] RD82.5.C63 2007 617.9′6041--dc22 2006040549

Executive Publisher: Natasha Andjelkovic Developmental Editor: Jean Nevius Publishing Services Manager: Tina Rebane Project Manager: Amy Norwitz Marketing Manager: Dana Butler

Printed in the United States of America Last digit is the print number: 9 8 7 6 5 4 3 2 1

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To all who have contributed to this work, and to the patients we serve.

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Preface An ounce of prevention is worth a pound of cure. –ANONYMOUS The second edition of Complications in Anesthesia, like its first edition, is intended to provide all practitioners of anesthesia and critical care medicine with a comprehensive source of information for most complications that might be faced in clinical practice. Topics are addressed in ten sections: Pharmacology; General Anesthesia; Regional Anesthesia and Pain Management; Cardiothoracic and Vascular Surgery; Physiologic Imbalance and Coexisting Disease; Equipment and Monitoring; Pediatrics and Neonatology; Neurosurgery, Ophthalmology, and ENT; Other Surgical Subspecialties (subdivided into Obstetrics and Gynecology, General Surgery, Urologic Surgery, and Orthopedic Surgery); and Special Topics (subdivided into Postanesthesia Care Unit, Diagnostic or Therapeutic Intervention, and Medicolegal Aspects). Section Editors were selected based on their special expertise and knowledge of the topics addressed in each section. Each chapter is presented in a highly structured format (in accordance with problem-based learning) under the following headings and subheadings: Case Synopsis, Problem Analysis (divided into Definition, Recognition, Risk Assessment, Implications), Management, and Prevention; in chapters with more than one topic, each topic is addressed

using the same headings. Schematics, figures, and tables are used liberally to illustrate key points or to summarize important information. Key references are listed at the end of each chapter under “Further Reading,” avoiding in-text citations that might distract the reader. Some chapters contain footnotes that provide further explanations. In this way, the reader can gain useful insight into a topic of interest in the minimal amount of time and with maximal retention. Also, thumb indexing and liberal cross-referencing are intended to reduce the need for time-consuming index searches. Finally, under Further Reading, in text, or in footnotes, there are references to Web sites for more or updated information. In that way, the reader can keep abreast of new developments. I hope this unconventional treatment of complications in anesthesia and critical care will serve several purposes: first, to permit quick location and researching of topics of interest to busy practitioners in the least amount of time; second, to organize the thought processes involved in medical decisionmaking in an attractive format—i.e., akin to Sherlock Holmes’ “who done it?”; and third and most importantly, to reduce the risk to our patients for unexpected and untoward events. John L. Atlee, MD

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Contributors Mark Abel, MD

Lori A. Aronson, MD, FAAP

Clinical Assistant Professor, Department of Anesthesiology, Mount Sinai Medical Center, New York, New York Vaporizers

Assistant Professor of Clinical Anesthesia and Pediatrics, Department of Anesthesia, University of Cincinnati College of Medicine; Assistant Professor, Clinical Anesthesia and Pediatrics, Department of Anesthesia, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio Hypoxemia

Gaury S. Adhikary, MD, FRCA Assistant Professor, Department of Anesthesiology, University of Michigan Hospitals, Ann Arbor, Michigan Carbon Dioxide Absorbers

Maurice S. Albin, MD, MSc (Anes) Professor of Anesthesiology, Department of Anesthesiology, University of Alabama School of Medicine, Birmingham, Alabama Venous Air Embolism

Stacey L. Allen, MD Assistant Professor of Anesthesiology, Department of Anesthesiology, University of Texas Health Science Center at San Antonio, San Antonio, Texas Corneal Injury; Open Globe Injury

Steven J. Allen, MD Professor of Anesthesiology, Ohio State University College of Medicine; Chief Executive Officer, Columbus Children’s Hospital, Columbus, Ohio Autonomic Hyperreflexia

Jonathan M. Anagnostou, MD Associate Professor of Clinical Anesthesia, Department of Anesthesia, Indiana University School of Medicine; Staff Anesthesiologist, Medical Director of Respiratory Care, Department of Anesthesia, Respiratory Care, Indiana University Hospital, Indianapolis, Indiana Blood and Blood Products: Hepatitis and HIV

Maged Argalious, MD

John L. Atlee, MD Professor of Anesthesiology, Department of Anesthesiology, Medical College of Wisconsin, Milwaukee, Wisconsin Adenosine; Disorders of Potassium Balance; Nonbarbiturate Anesthetics; Chemotherapeutic Agents; Cardiac Risk Assessment; Postobstruction Pulmonary Edema; Perioperative Tachyarrhythmias; Tachyarrhythmias with Ventricular Preexcitation; Long QT Syndromes and Ventricular Arrhythmias; Patients with Cardiac Rhythm Management Devices; Disorders of Water Homeostasis: Hyponatremia and Hypernatremia

Michael S. Avidan, MD Associate Professor of Anesthesiology and Surgery; Division Chief, CT Anesthesiology and CT Intensive Care, Washington University School of Medicine, St. Louis, Missouri HIV Infection and AIDS

Isaac Azar, MD Professor of Anesthesiology, Albert Einstein College of Medicine; Consultant, Department of Anesthesiology, Beth Israel Medical Center, New York, New York Scavenging Systems

James E. Baker, MD, FRCPC Assistant Professor and Anesthesiologist, Department of Anesthesia and Perioperative Care, University of California, San Francisco, San Francisco, California Postoperative Pulmonary Hypertension

Staff Anesthesiologist, Departments of General Anesthesiology and Critical Care Medicine, Cleveland Clinic Foundation, Cleveland, Ohio Complications of Trauma Surgery

Narayan Baliga, MD

George A. Arndt, MD

Shahar Bar-Yosef, MD

Professor (CHS), Department of Anesthesiology, University of Wisconsin Medical School, Madison, Wisconsin Difficult Airway: Cannot Ventilate, Cannot Intubate

Assistant Professor, Department of Anesthesiology and Critical Care, Duke University School of Medicine, Durham, North Carolina Complications of Laparoscopic Surgery

Staff Anesthesiologist, Kenosha Hospital and Medical Center, Kenosha, Wisconsin Difficult Airway: Opiate-Induced Muscle Rigidity

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Contributors

Juliana Barr, MD

Lois L. Bready, MD

Associate Professor, Department of Anesthesiology, Stanford University School of Medicine, Stanford, California; Staff Intensivist and Anesthesiologist, Veterans Affairs Palo Alto Health Care System, Anesthesiology Service, Palo Alto, California Reversal Agents: Naloxone and Flumazenil

Professor and Vice Chair, Department of Anesthesiology, University of Texas Health Science Center at San Antonio, San Antonio, Texas Corneal Injury

Curtis L. Baysinger, MD Associate Professor, Department of Anesthesiology, Vanderbilt University School of Medicine, Nashville, Tennessee Hypertensive Disorders of Pregnancy

Eric Bedell, MD Associate Professor, Department of Anesthesiology, University of Texas Medical Branch, Galveston, Texas Posterior Fossa Surgery

Joan Benca, MD Associate Professor, Department of Anesthesiology, University of Wisconsin Hospital and Clinics, Madison, Wisconsin Bronchospasm

Patrick E. Benedict, MD Assistant Professor of Anesthesiology, University of Michigan Medical School, Ann Arbor, Michigan Transesophageal Echocardiography

Thomas P. Broderick, MD Assistant Professor, Department of Anesthesiology, University of Wisconsin Hospital and Clinics, Madison, Wisconsin Preanesthetic Evaluation: Inadequate or Missing Test Result

David L. Brown, MD Edward Rotan Distinguished Professor and Chairman, Department of Anesthesiology and Pain Medicine, M.D. Anderson Cancer Center, Houston, Texas Celiac Plexus Block: Side Effects and Complications

Adrie Bruijinzeel, MD Assistant Professor, Department of Psychiatry, Evelyn and William McKnight Brain Institute, University of Florida College of Medicine, Gainesville, Florida Chemical Dependency: Opioids

Brenda A. Bucklin, MD Associate Professor of Anesthesiology, Department of Anesthesiology, University of Colorado Health Sciences Center, Denver, Colorado Fetal Distress

Matthew D. Caldwell, MD David G. Bjoraker, MD Associate Professor, Department of Anesthesiology, University of Florida College of Medicine, Gainesville, Florida Anaphylaxis and Anaphylactoid Reactions

Assistant Professor, Department of Anesthesiology, University of Michigan Medical School, Ann Arbor, Michigan Pulmonary Artery Pressure Monitoring

William R. Camann, MD Susan Black, MD Professor, Department of Anesthesiology, University of Alabama School of Medicine, Birmingham, Alabama Antidepressants

Associate Professor, Department of Anesthesia, Harvard Medical School; Director of Obstetric Anesthesia, Brigham and Women’s Hospital, Boston, Massachusetts Pulmonary Aspiration in the Parturient

Maria I. Castro, PhD William S. Blau, MD, PhD Associate Professor of Anesthesiology, University of North Carolina School of Medicine, Chapel Hill, North Carolina Opioid Tolerance

Assistant Professor, Department of Anesthesiology, University of Arkansas for Medical Sciences, Little Rock, Arkansas Class II Antiarrhythmic Drugs: β-Blockers—Heart Block or Bradycardia

Steffan Blumenthal, MD

Kevin P. Chan, MD

Assistant Professor, Department of Anesthesiology and Reanimation, Orthopedic University Clinic Balgrist/Zurich, Zurich, Switzerland Interscalene Nerve Block: Potential Severe Complications

Fellow in Cardiovascular Anesthesia, Stanford University School of Medicine, Stanford, California Nonbarbiturate Anesthetics

Mark A. Chaney, MD John C. Boncyk, MD Assistant Professor, Department of Anesthesiology, University of Wisconsin Hospital and Clinics, Madison, Wisconsin Perioperative Hypoxia

Associate Professor of Anesthesiology, Department of Anesthesia and Critical Care, University of Chicago Pritzker School of Medicine, Chicago, Illinois Perioperative Myocardial Ischemia and Infarction; Adverse Neurologic Sequelae: Central Neurologic Impairment; Hypercoagulable States: Thrombosis and Embolism

Alain Borgeat, MD Professor and Chief of Staff, Department of Anesthesiology and Reanimation, Orthopedic University Clinic Balgrist/Zurich, Zurich, Switzerland Interscalene Nerve Block: Potential Severe Complications

Amit V. Chawla, MD Consultant, Department of Anesthesia, Guy’s Hospital, London, United Kingdom Inspiratory and Expiratory Gas Monitoring

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David C. H. Cheng, MD, MSc, FRCPC

James C. Crews, MD

Professor and Chair, Department of Anesthesia and Perioperative Medicine, University of Western Ontario; Anesthesiologist in Chief, London Health Sciences Center and St. Joseph’s Health Care, London, Ontario, Canada Fast-Track Cardiac Surgery

Associate Professor of Anesthesiology, Section of Regional Anesthesia and Acute Pain Management, Department of Anesthesiology, Wake Forest University School of Medicine, Winston-Salem, North Carolina Infectious Complications of Central Neuraxial Block

Deborah A. Davis, MD S. Devi Chiravuri, MD Assistant Professor, Department of Anesthesiology, University of Michigan Medical School, Ann Arbor, Michigan Rapid Fluid and Blood Delivery Systems

Gordon Lee Collins, MD Clinical Fellow, Department of Anesthesiology, Washington University School of Medicine, St. Louis, Missouri Complications after Pneumonectomy

Lois A. Connolly, MD Associate Professor, Department of Anesthesiology, Medical College of Wisconsin, Froedtert Memorial Lutheran Hospital, Milwaukee, Wisconsin Unstable Cervical Spine, Atlantoaxial Subluxation

D. Ryan Cook, MD Professor of Anesthesiology, Department of Anesthesiology, Children’s Hospital of Pittsburgh, Pittsburgh, Pennsylvania Hypoglycemia and Hyperglycemia

Clinical Professor of Anesthesiology, Department of Anesthesiology, Thomas Jefferson University – Jefferson Medical College, Philadelphia, Pennsylvania; Pediatric Anesthesiologist/Intensivist, Nemours Cardiac Center, A.I. duPont Hospital for Children, Wilmington, Delaware Pulmonary Hypertension

Martin L. De Ruyter, MD Associate Professor of Anesthesiology, Department of Anesthesiology, Kansas University School of Medicine, Kansas City, Kansas Hyperglycemia and Diabetic Ketoacidosis; Sarcoidosis

Hernando De Soto, MD Associate Professor, Department of Pediatric Anesthesia, University of Florida Health Science Center; Staff Anesthesiologist/Medical Director of the OR, Department of Anesthesiology, SHANDS Jacksonville, Jacksonville, Florida Difficult Pediatric Airway

Donn M. Dennis, MD, FAHA

Assistant Professor of Anesthesia, Department of Anesthesiology and Critical Care Medicine, University of Pennsylvania School of Medicine; Associate Anesthesiologist, Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania Ophthalmic Problems and Complications

Joachim S. Gravenstein, MD, Professor of Anesthesiology, Department of Anesthesiology, University of Florida College of Medicine, Gainesville, Florida; Vice PresidentPharmacology, ARYx Therapeutics, Inc., Santa Clara, California Class III Antiarrhythmic Drugs: Potassium Channel Blockers; Class IV Antiarrhythmic Drugs: Calcium Channel Blockers

Victoria Coon, CRNA, MS

Ronak Desai, DO

Scott D. Cook-Sather, MD

Perioperative Director and Anesthesiology Department Administrator, Kaiser Permanente, West Los Angeles, Los Angeles, California Quality Assurance; Cost Containment

Resident, CA-2, Department of Anesthesia and Critical Care, University of Chicago Pritzker School of Medicine, Chicago, Illinois Peripheral Vascular Surgery

John R. Cooper, Jr., MD

Cheryl DeSimone, MD

Clinical Associate Professor of Anesthesiology, University of Texas Health Science Center; Associate Chief, Cardiovascular Anesthesia; Co-Director, Cullen Cardiovascular Research Laboratories, Texas Heart Institute, Houston, Texas Troubleshooting Common Problems during Cardiopulmonary Bypass

Cyrus DeSouza, MB,BS, FANZCA

Associate Professor of Anesthesiology, Obstetrics and Gynecology, Department of Anesthesiology, Albany Medical College; Director of Obstetric Anesthesia, Albany Medical Center, Albany, New York Embolic Events of Pregnancy

Director of Clinical Research in Pediatric Anesthesia, Department of Anesthesiology, Massachusetts General Hospital, Boston, Massachusetts Sedation of Pediatric Patients

Acting Assistant Professor, Cardiothoracic Anesthesiologist, Department of Anesthesiology, University of Washington Medical Center, Seattle, Washington; Staff Specialist Anaesthetist, Department of Anaesthetics, St. Georges Hospital, Sydney, NSW, Australia Chronotropic Drugs

Douglas B. Coursin, MD

Clifford S. Deutschman, MD

Professor of Anesthesiology and Internal Medicine, Department of Anesthesiology, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin Adrenal Insufficiency

Professor, Department of Anesthesia and Surgery, Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania Sepsis, Systemic Inflammatory Response Syndrome, and Multiple Organ Dysfunction Syndrome

Charles J. Coté, MD

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Pema Dorje, MD

Brenda G. Fahy, MD, FCCP, FCCM

Clinical Assistant Professor, Department of Anesthesiology, University of Michigan Medical School, Ann Arbor, Michigan Arterial Blood Pressure Monitoring

Professor, Department of Anesthesiology, University of Kentucky; Director of Critical Care, Department of Anesthesiology, AB Chandler Medical Center, Lexington, Kentucky Disorders of Water Homeostasis: Hyponatremia and Hypernatremia

Anthony R. Doyle, BSc, MB,BS, FRCA Formerly, Visiting Instructor in Anesthesiology, University of Michigan Medical School, Ann Arbor, Michigan; Consultant Anaesthetist, Dorset County Hospital, Dorchester, United Kingdom Fires in the Operating Room

Kenneth Drasner, MD Professor, Department of Anesthesiology and Perioperative Care, University of California, San Francisco, San Francisco, California Local Anesthetic Neurotoxicity: Cauda Equina Syndrome

Catherine Drexler, MD Vice Chair, Department of Anesthesiology, ColumbiaSt. Mary’s-Milwaukee Campus, Milwaukee, Wisconsin Angioedema and Urticaria

Zhuang T. Fang, MD, MSPH Assistant Clinical Professor, Department of Anesthesiology, David Geffen School of Medicine at University of California, Los Angeles, Los Angeles, California Unanticipated Hospital Admission and Readmission

Doron Feldman, MD Associate Professor of Clinical Anesthesiology, State University of New York at Buffalo School of Medicine; Attending in Anesthesiology, Children’s Hospital of Buffalo, Buffalo, New York The Hostile-Combative Patient

Lynne R. Ferrari, MD

Ellen Duncan, MD

Associate Professor, Department of Anesthesia, Harvard Medical School; Medical Director, Perioperative Services, Children’s Hospital, Boston, Massachusetts Adenotonsillectomy

Tejas Anesthesia, San Antonio, Texas Open Globe Injury

Matthew P. Feuer, MD

Martin W. Dünser, MD Resident in Anesthesiology and Critical Care Medicine, Department of Anesthesiology and Critical Care Medicine, Medical University Innsbruck, Innsbruck, Austria Vasopressors: Vasoconstrictor Drugs

Jörg Dziersk, MD, FRCA Assistant Professor of Anesthesiology, Department of Anesthesiology, University of Washington School of Medicine, Seattle, Washington Vasodilator Drugs

Michael P. Eaton, MD Associate Professor, Department of Anesthesiology, University of Rochester School of Medicine and Dentistry, Rochester, New York Proportioning Systems; Patient Warming Systems

Charles E. Edmiston, Jr., MS, PhD Associate Professor, Department of Surgery; Director, Surgical Microbiology Research Laboratory, Medical College of Wisconsin, Milwaukee, Wisconsin Nosocomial Infections: Bacterial Pneumonia

Staff Anesthesiologist, Department of Anesthesiology, Virginia Mason Medical Center, Seattle, Washington Spinal Anesthesia: Post–Dural Puncture Headache

Stephanie S. F. Fischer, MD Visiting Associate in Cardiothoracic and Critical Care, Division of Pediatric Anesthesiology, Duke University School of Medicine, Durham, North Carolina Cardiomyopathies

M. Pamela Fish, MB,ChB Associate Professor, Department of Anesthesiology, Stanford University School of Medicine, Stanford, California; Staff Physician, Veterans Affairs Palo Alto Health Care System, Palo Alto, California Antiemetic Drugs

Randall Flick, MD, MPH Assistant Professor of Anesthesiology and Pediatrics, Department of Anesthesiology and Pediatrics, Mayo Clinic College of Medicine; Chair, Section of Pediatric Anesthesiology, Mayo Clinic, Rochester, Minnesota Anterior Mediastinal Mass

Michael P. Ford, MD

Professor of Anesthesiology, Mount Sinai School of Medicine, New York, New York Vaporizers

Assistant Professor of Anesthesiology, Department of Anesthesiology, University of Wisconsin Medical School, Madison, Wisconsin Preanesthetic Evaluation: False-Positive Tests; Difficult Airway: Cannot Ventilate, Cannot Intubate

John Ellis, MD

Jennifer T. Fortney, MD

Professor of Anesthesiology, Department of Anesthesia and Critical Care, University of Chicago Pritzker School of Medicine, Chicago, Illinois Carotid Endarterectomy; Thoracic Aortic Aneurysm

Assistant Clinical Professor, Department of Anesthesiology, Duke University School of Medicine, Durham, North Carolina Fat Embolism Syndrome

James B. Eisenkraft, MD

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James M. T. Foster, MD

Mark S. Gold, MD

Clinical Assistant Professor of Anesthesiology, Department of Anesthesiology, State University of New York at Buffalo School of Medicine; Director of Anesthesiology Services, Kaleida Health, Buffalo, New York The Hostile-Combative Patient

Distinguished Professor and Chief, Departments of Psychiatry, Neuroscience, Anesthesiology, Community Health and Family Medicine, Evelyn and William McKnight Brain Institute, University of Florida College of Medicine, Gainesville, Florida Chemical Dependency: Opioids; Chemical Dependency: Nonopioids

Melissa Franckowiak, MD Resident, Department of Anesthesiology, State University of New York at Buffalo School of Medicine, Buffalo, New York Cardioversion

Eugene B. Freid, MD Associate Professor, Departments of Anesthesiology and Pediatrics, University of North Carolina Hospitals, Chapel Hill, North Carolina Succinylcholine

Kimberly Frost-Pineda, MD Assistant in Psychiatry, Department of Psychiatry, Director of Public Health Research, University of Florida College of Medicine, Gainesville, Florida Chemical Dependency: Opioids; Chemical Dependency: Nonopioids

Jeffrey L. Galinkin, MD Associate Professor, Department of Anesthesia, Children’s Hospital, Denver, Colorado Fetal Intrauterine Surgery

Arjunan Ganesh, MD Assistant Professor of Anesthesia, Department of Anesthesia, University of Pennsylvania School of Medicine; Assistant Anesthesiologist, Department of Anesthesiology and Critical Care Medicine, Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania Upper Respiratory Tract Infection

Hind M. Gautam, MD Clinical Assistant Professor, Department of Anesthesiology, Veterans Affairs Medical Center, Buffalo, New York Magnetic Resonance Imaging

Rodolfo Gebhardt, MD

Stuart Grant, MD Assistant Professor, Department of Anesthesiology, Duke University School of Medicine, Durham, North Carolina Continuous Nerve Blocks: Perineural Local Anesthetic Infusion

Glenn P. Gravlee, MD Professor, Department of Anesthesiology, Ohio State University Hospitals, Columbus, Ohio Hemodilution and Blood Conservation

Ivar Gunnarsson, MD Landspítali—háskólasjúkrahús, Reykjavik, Iceland Oxygen Flush Valve

Mary Ann Gurkowski, MD Professor of Anesthesiology, University of Texas Health Science Center at San Antonio; Clinical Staff/Director of Medical Students, Department of Anesthesiology/Crossappointed to Otorhinolaryngology, University Hospital; Attending Staff, Department of Anesthesiology, Audie Murphy Veterans Affairs Hospital, San Antonio, Texas Foreign Body Aspiration

Jacob Gutsche, MD Physician, Department of Anesthesia, Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania Sepsis, Systemic Inflammatory Response Syndrome, and Multiple Organ Dysfunction Syndrome

Thomas S. Guyton, MD Staff Anesthesiologist, Methodist Healthcare of Memphis, Memphis, Tennessee Magnesium; Antibiotics

Assistant Professor of Clinical Anesthesiology, Department of Anesthesiology, Department of Clinical Anesthesiology, Veterans Affairs Medical Center, Buffalo New York Uncontrolled Pain

Ali Habibi, MD

Jeremy M. Geiduschek, MD

Saeed Habibi, MD

Clinical Professor, Department of Anesthesiology, University of Washington School of Medicine; Director, Clinical Anesthesia Services, Department of Anesthesiology, Children’s Hospital and Regional Medical Center, Seattle, Washington Intraoperative Cardiac Arrest

J. C. Gerancher, MD Associate Professor and Section Head, Regional Anesthesia and Acute Pain Management, Department of Anesthesiology, Wake Forest University School of Medicine, Winston-Salem, North Carolina Epidural Anesthesia: Unintended Intrathecal Injection; Epidural Anesthesia: Unintended Subdural Injection

Adjunct Clinical Faculty, Anesthesiology, Stanford University School of Medicine, Stanford, California Antihistamines: H1- and H2-Blockers Chair, Department of Anesthesiology, Columbia– St. Mary’s–Milwaukee Campus, Milwaukee, Wisconsin Angioedema and Urticaria

Charles B. Hantler, MD Professor, Department of Anesthesiology, Washington University School of Medicine, St. Louis, Missouri Bradyarrhythmias

H. David Hardman, MD, MBA Assistant Clinical Professor, Department of Anesthesiology, Duke University School of Medicine, Durham, North Carolina Extremity Tourniquets

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Contributors

Barry A. Harrison, MB,BS

Liana Hosu, MD

Assistant Professor of Anesthesiology, Department of Anesthesiology, Mayo Clinic College of Medicine, Jacksonville, Florida Hyperglycemia and Diabetic Ketoacidosis; Sarcoidosis

Assistant Professor of Anesthesia and Pediatrics, Department of Anesthesiology, University of Cincinnati College of Medicine; Staff Anesthesiologist, Department of Anesthesiology, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio Postoperative Apnea in Infants

Joy L. Hawkins, MD Professor of Anesthesiology and Director of Obstetric Anesthesia, University of Colorado School of Medicine, Denver, Colorado Nonobstetric Surgery during Pregnancy

Christopher M. B. Heard, MB,ChB, FRCA Research Assistant Professor, Department of Anesthesiology and Division of Pediatric Critical Care, State University of New York at Buffalo School of Medicine; Assistant Attending, Children’s Hospital of Buffalo, Buffalo, New York Magnetic Resonance Imaging; Alleged Malpractice; The HostileCombative Patient

Stephen O. Heard, MD Interim Chair, Professor of Anesthesiology and Surgery, University of Massachusetts Medical School, Worcester, Massachusetts Perioperative Care of Immunocompromised Patients

James R. Hebl, MD Assistant Professor, Department of Anesthesiology, Mayo Clinic College of Medicine, Rochester, Minnesota Anticoagulants and Peripheral Nerve Block

Robert F. Helfand, MD Associate Professor, Cleveland Clinic Lerner College of Medicine; Staff Anesthesiologist; Vice Chairman, Department of General Anesthesiology; Section Head of Orthopedic Anesthesia, Glickman Urological Center, Cleveland Clinic Foundation, Cleveland, Ohio Thromboembolic Complications

Rosemary Hickey, MD Professor and Program Director, Department of Anesthesiology, University of Texas Health Science Center at San Antonio, San Antonio, Texas Intracranial Hypertension

Kate Huncke, MD Clinical Associate Professor, Department of Anesthesiology, New York University School of Medicine, New York, New York Radiation Oncology

Samuel A. Irefin, MD Associate Professor of Anesthesiology, Cleveland Clinic Lerner College of Medicine; Staff Anesthesiologist, Department of Anesthesiology and Critical Care Medicine, Cleveland Clinic Foundation, Cleveland, Ohio Complications of Thyroid Surgery

William Jacobs, MD Associate Professor, Departments of Psychiatry and Anesthesiology, University of Florida College of Medicine, Gainesville, Florida Chemical Dependency: Opioids; Chemical Dependency: Nonopioids

Eric Jacobsohn, MB,ChB, MHPE, FRCPC Associate Professor of Anesthesiology, Department of Anesthesiology, Washington University School of Medicine, St. Louis, Missouri Complications after Pneumonectomy

J. Michael Jaeger, MD, PhD Associate Professor of Anesthesiology and Neurological Surgery; Director, Thoracic Anesthesia, Department of Anesthesiology, University of Virginia Health Sciences Center, Charlottesville, Virginia Class IV Antiarrhythmic Drugs: Calcium Channel Blockers

George A. Higgins, BSN, MS, CRNA Adjunct Faculty, Department of Nursing, University of Southern California; Senior Nurse Anesthetist, Department of Anesthesiology, Department of Veterans Affairs Medical Center, Los Angeles, California Embolization Procedures

Scott Holliday, MD Resident, Department of Anesthesiology, University of Texas Health Science Center at San Antonio, San Antonio, Texas Foreign Body Aspiration

William Hope, MD, PhD Assistant Professor, Department of Anesthesiology, Medical College of Wisconsin, Froedtert Memorial Lutheran Hospital East, Milwaukee, Wisconsin Laryngeal and Tracheal Injury

Michael F. M. James, MB,ChB, PhD, FRCA, FCA(SA) Professor and Head, Department of Anesthesia, University of Cape Town; Professor and Chief Anaesthetist, Department of Anaesthesia, Groote Schuur Hospital, Cape Town, Western Cape, South Africa Complications of Adrenal Surgery

Gregory M. Janelle, MD Assistant Professor, Chief of Cardiovascular Anesthesia, Department of Anesthesiology, University of Florida College of Medicine, Gainesville, Florida Phosphodiesterase Inhibitors

David R. Jobes, MD Terese T. Horlocker, MD Professor, Department of Anesthesiology, Mayo Clinic College of Medicine, Rochester, Minnesota Spinal Hematoma; Persistent Paresthesia

Professor of Anesthesia, Department of Anesthesia and Critical Care Medicine, Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania Complications of Massive Transfusion

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Nicola Jones, MA, MB,BS, DTM&H, MRCP, MRCPath, PhD Consultant in Microbiology and Infectious Diseases, Departments of Microbiology and Infectious Diseases, Nuffield Department of Clinical Laboratory Sciences, John Radcliffe Hospital, University of Oxford, Oxford, United Kingdom HIV Infection and AIDS

Shailendra Joshi, MD Assistant Professor of Anesthesiology, Department of Anesthesiology, College of Physicians and Surgeons of Columbia University, New York, New York Arteriovenous Malformation: Normal Perfusion Pressure Breakthrough

Zeev N. Kain, MD Professor of Anesthesiology, Department of Anesthesiology, Yale University School of Medicine, New Haven, Connecticut Perioperative Psychological Trauma

Wendy B. Kang, MD Associate Professor and Chair, Residency Education Committee, Department of Anesthesiology, University of Texas Health Science Center at San Antonio, San Antonio, Texas Retrobulbar Block

Shubjeet Kaur, MD Clinical Vice Chair, Department of Anesthesiology, University of Massachussets Memorial Medical Center, Worcester, Massachusetts Perioperative Care of Immunocompromised Patients

Robert D. Kaye, MD Assistant Professor of Clinical Anesthesiology and Pediatrics, State University of New York at Buffalo School of Medicine; Attending Anesthesiologist, Children’s Hospital of Buffalo, Buffalo, New York Alleged Malpractice

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Jonathan T. Ketzler, MD Associate Professor of Anesthesiology; Associate Director, Trauma and Life Support Center, Department of Anesthesiology, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin Adrenal Insufficiency

Evan D. Kharasch, MD, PhD Assistant Dean for Clinical Research; Professor and Research Director, Department of Anesthesiology, University of Washington School of Medicine, Seattle, Washington Volatile Anesthetics: Organ Toxicity

M. Sean Kincaid, MD Resident, Department of Anesthesiology, University of Washington Medical Center, Seattle, Washington Head Injury

Kathryn P. King, MD Associate Clinical Professor, Department of Anesthesiology, Duke University School of Medicine, Durham, North Carolina Methylmethacrylate

Kai T. Kiviluoma, MD, PhD Associate Professor, Department of Anaesthesiology, University of Oulu Faculty of Medicine; Head of the Department, Paediatric Anaesthesia, Oulu University Hospital, Oulu, Finland Disorders of Potassium Balance

Jerome M. Klafta, MD Associate Professor and Associate Chair for Education, Department of Anesthesia and Critical Care, University of Chicago Pritzker School of Medicine, Chicago, Illinois Mediastinal Masses

Pattricia S. Klarr, MD Paul E. Kazanjian, MD Clinical Assistant Professor, Department of Anesthesiology, University of Michigan Medical School, Ann Arbor, Michigan Fires in the Operating Room; Pulmonary Artery Pressure Monitoring

Clinical Assistant Professor, Department of Anesthesiology, University of Michigan Medical School; Associate Clinical Director, Department of Anesthesiology, University of Michigan Medical Center, Ann Arbor, Michigan Laser Complications

Jeffrey S. Kelly, MD

Sandra L. Kopp, MD

Associate Professor of Anesthesiology, Section of Critical Care, Wake Forest University School of Medicine, Winston-Salem, North Carolina Complications from Toxic Ingestion

Kevin J. Kelly, MD Professor and Chair, Department of Pediatrics; Associate Dean, School of Medicine, Children’s Mercy Hospital and Clinics, University of Missouri, Kansas City, Missouri Latex Reactions in Health Care Personnel

Instructor, Department of Anesthesiology, Mayo Clinic College of Medicine, Rochester, Minnesota Supraclavicular and Infraclavicular Block: Pneumothorax

Donald A. Kroll, MD, PhD Staff Anesthesiologist, Department of Surgery, Veterans Affairs Medical Center, Biloxi, Mississippi Quality Assurance; Cost Containment; Adverse Outcomes: Withheld Information or Misinformation

Robert E. Kettler, MD

Kenneth Kuchta, MD

Associate Professor, Department of Anesthesiology, Medical College of Wisconsin, Froedtert Memorial Lutheran Hospital East, Milwaukee, Wisconsin Patients with Seizure Disorders; Latex Reactions in Health Care Personnel

Assistant Clinical Professor, Department of Anesthesiology, David Geffen School of Medicine at University of California, Los Angeles, Los Angeles, California Misidentification of a Patient

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C. Dean Kurth, MD

Ray P. Liao, MD

Professor of Anesthesia and Pediatrics, University of Cincinnati College of Medicine, Anesthesiologist-in-Chief; Chair, Institute for Pediatric Research; Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio Postoperative Apnea in Infants

Acting Assistant Professor, Department of Anesthesiology, University of Washington School of Medicine, Seattle, Washington Inotropic Drugs

Spencer S. Liu, MD Arthur M. Lam, MD, FRCPC Professor of Anesthesiology, Department of Anesthesiology, University of Washington School of Medicine; Head of Neuroanesthesia, Harborview Medical Center, Seattle, Washington Head Injury

Jeffrey L. Lane, MD Assistant Professor of Clinical Anesthesia and Director, Human Simulation Laboratory, Department of Anesthesia, Indiana University School of Medicine; Staff Anesthesiologist, Clarian Health Partners, Indianapolis, Indiana Postoperative Respiratory Insufficiency

Clinical Professor of Anesthesiology, Department of Anesthesiology, Virginia Mason Medical Center, Seattle, Washington Spinal Anesthesia: Post–Dural Puncture Headache

Emilio B. Lobato, MD Professor of Anesthesiology, Department of Anesthesiology, University of Florida College of Medicine; Chief, Cardiovascular Anesthesia, Department of Anesthesia Service, Malcom Randall Veterans Affairs Hospital, Gainesville, Florida Digitalis

Robert G. Loeb, MD Paul B. Langevin, MD Associate Professor, Department of Anesthesiology, Veterans Affairs–West Haven, West Haven, Connecticut Chemotherapeutic Agents

Associate Professor of Anesthesiology, University of Arizona College of Medicine, Tucson, Arizona Flowmeters

Celeste M. Lombardi, MD Melissa A. Laxton, MD Assistant Professor of Anesthesiology, Wake Forest University School of Medicine, Winston-Salem, North Carolina Pituitary Tumors: Diabetes Insipidus

Fellow in Interventional Pain Medicine, Department of Anesthesiology, University of Florida College of Medicine, Gainesville, Florida Chronic Nonsteroidal Anti-inflammatory Drug Use

Prashant Lotlikar, MD Marcia M. Lee, MD, MBA Assistant Chief, Department of Anesthesiology, Kaiser Permanente–South Bay, Harbor City, California Awareness under Anesthesia

Clinical Assistant Professor, Department of Anesthesiology, University of Texas Health Science Center, Texas Heart Institute, Houston, Texas Troubleshooting Common Problems during Cardiopulmonary Bypass

Mijin Lee, MD Assistant Clinical Professor, Department of Anesthesiology, David Geffen School of Medicine at University of California, Los Angeles, Los Angeles, California Anesthesia for Electroconvulsive Therapy

Peter J. Lee, MD, MPH Formerly, Assistant Professor, Department of Anesthesiology, University of Michigan Medical School, Ann Arbor, Michigan Central Venous Pressure Monitoring

Philip Levin, MD Associate Professor, Department of Anesthesiology, David Geffen School of Medicine at University of California, Los Angeles, Los Angeles, California Postoperative Delirium

Jerrold H. Levy, MD Professor and Department Chair/Research, Department of Anesthesiology, Emory University School of Medicine, Atlanta, Georgia Perioperative Hypertension

Ian Lewis, MB,BS, MRCP, FRCA Associate Professor, Department of Anesthesiology, University of Michigan Medical School, Ann Arbor, Michigan Surgical Diathermy and Electrocautery

Michelle L. Lotto, MD Assistant Professor of Anesthesiology, Department of General Anesthesiology and Critical Care Medicine, Cleveland Clinic Lerner College of Medicine; Associate Staff Anesthesiologist, Cleveland Clinic Foundation, Cleveland, Ohio Complications of Spinal Surgery

Katarzyna Luba, MD Assistant Professor of Clinical Anesthesiology, Department of Anesthesia and Critical Care, University of Chicago Pritzker School of Medicine, Chicago, Illinois Perioperative Management of Patients with Muscular Dystrophy

Stewart J. Lustik, MD Associate Professor of Anesthesiology, University of Rochester School of Medicine and Dentistry, Rochester, New York Proportioning Systems; Patient Warming Systems

Vinod Malhotra, MD Professor and Vice Chair for Clinical Affairs, Department of Anesthesiology, Weill Medical College of Cornell University, New York–Presbyterian Hospital, New York, New York Complications of Transurethral Surgery

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Christina M. Matadial, MD

Terri G. Monk, MD

Assistant Professor, Department of Anesthesiology, Leonard M. Miller School of Medicine at the University of Miami; Staff Physician, Department of Anesthesiology, Jackson Memorial Hospital, Miami, Florida Surgery in the Morbidly Obese

Professor, Department of Anesthesiology, Duke University Medical Center, Durham, North Carolina Intraoperative Penile Erection; Complications of Radical Urologic Surgery

Lisa M. Montenegro, MD Viktoria D. Mayr, MD Resident in Anesthesiology and Critical Care Medicine, Department of Anesthesiology and Critical Care Medicine, Medical University Innsbruck, Innsbruck, Austria Vasopressors: Vasoconstrictor Drugs

Assistant Professor of Anesthesiology, University of Pennsylvania School of Medicine and Children’s Hospital of Philadelphia; Attending Anesthesiologist, Department of Anesthesiology, Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania Complications of Massive Transfusion

Deborah A. McClain, MD Chief, Anesthesiology Section, Veterans Affairs Medical Center, Biloxi, Mississippi Delayed Emergence

Thomas McCutchen, MD Assistant Professor, Department of Anesthesiology, Wake Forest University School of Medicine, Winston-Salem, North Carolina Epidural Anesthesia: Unintended Intrathecal Injection; Epidural Anesthesia: Unintended Subdural Injection

David L. McDonagh, MD Resident, Department of Anesthesiology, Duke University School of Medicine, Durham, North Carolina Autonomic Dysreflexia

Susan B. McDonald, MD Staff Anesthesiologist, Department of Anesthesiology, Virginia Mason Medical Center, Seattle, Washington Side Effects of Neuraxial Opioids

Lynda J. Means, MD Professor of Anesthesia and Surgery, Department of Anesthesia, Indiana University School of Medicine, Indianapolis, Indiana Postobstruction Pulmonary Edema in Pediatric Patients

Mark Meyer, MD Assistant Professor of Clinical Anesthesia, Department of Anesthesia, University of Cincinnati College of Medicine; Assistant Professor, Clinical Pediatrics, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio Perioperative Aspiration Pneumonitis

Mohammed Minhaj, MD Assistant Professor, Department of Anesthesia and Critical Care, University of Chicago Pritzker School of Medicine, Chicago, Illinois Adverse Neurologic Sequelae: Peripheral Nerve Injury

Vivek Moitra, MD Assistant Professor of Anesthesiology, Department of Anesthesiology, College of Physicians and Surgeons of Columbia University, New York, New York Carotid Endarterectomy

Timothy E. Morey, MD Associate Professor of Anesthesiology, Department of Anesthesiology, University of Florida College of Medicine, Gainesville, Florida Magnesium; Antibiotics

Lucille A. Mostello, MD Assistant Professor of Anesthesiology and Pediatrics, Department of Anesthesiology, George Washington University School of Medicine; Staff Anesthesiologist, Department of Anesthesiology, Children’s National Medical Center, Washington, DC Latex Allergy

Isobel Muhiudeen-Russell, MD Professor, Department of Anesthesia, University of California, San Francisco, San Francisco, California Postoperative Pulmonary Hypertension

J. Thomas Murphy, MD, FRCPC Associate Professor, Department of Anesthesiology, University of Kentucky College of Medicine, Lexington, Kentucky Disorders of Water Homeostasis: Hyponatremia and Hypernatremia

Catherine Friederich Murray Research Associate, Department of Anesthesiology, Mayo Clinic College of Medicine, Jacksonville, Florida Parkinson’s Disease; Alzheimer’s Disease

Michael J. Murray, MD, PhD Professor of Anesthesiology and Chair, Department of Anesthesiology, Mayo Clinic College of Medicine, Jacksonville, Florida Parkinson’s Disease; Alzheimer’s Disease

David Muzic, MD Fellow in Cardiac Anesthesia, Department of Anesthesia and Critical Care, University of Chicago Pritzker School of Medicine, Chicago, Illinois Adverse Neurologic Sequelae: Central Neurologic Impairment

Nader D. Nader, MD Constance L. Monitto, MD Assistant Professor of Anesthesiology, Department of Anesthesiology and Critical Care Medicine, Johns Hopkins Medical Institute, Baltimore, Maryland Muscle Relaxants

Associate Professor of Anesthesiology, Surgery and Pathology, State University of New York at Buffalo School of Medicine, Buffalo, New York Uncontrolled Pain; Hemodynamic Instability; Cardioversion

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Contributors

Carsten Nadjat-Haiem, MD

Hector F. Nicodemus, MD

Assistant Professor, Department of Anesthesiology, David Geffen School of Medicine at University of California, Los Angeles, Los Angeles, California Syringe Swaps

Pediatric Anesthesiologist, Department of Anesthesiology, Holy Cross Hospital, Silver Spring, Maryland Delayed Emergence in Pediatric Patients

Susan C. Nicolson, MD Mohamed Naguib, MB,Bch, MSc, FFARCSI, MD Professor, Department of Anesthesia, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, Iowa Myasthenic Disorders

Professor of Anesthesia, Department of Anesthesia, University of Pennsylvania School of Medicine; Division Director, Cardiothoracic Anesthesia, Department of Anesthesiology and Critical Care Medicine, Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania Upper Respiratory Tract Infection

Bhiken Naik, MD Fellow, Department of Anesthesiology, University of Florida College of Medicine, Gainesville, Florida Intrathecal Opiates; Ketamine; Steroids

David A. Nakata, MD Associate Clinical Professor and Vice Chair, Residency Development, Department of Anesthesia, Indiana University School of Medicine, Indianapolis, Indiana Postoperative Peripheral Neuropathy; Intractable Nausea and Vomiting

Charles A. Napolitano, MD, PhD Associate Professor; Director, Division of Cardiothoracic Anesthesia; Co-Director, Residency Program, Department of Anesthesiology, University of Arkansas for Medical Sciences, Little Rock, Arkansas Class II Antiarrhythmic Drugs: β-Blockers—Heart Block or Bradycardia

Susan H. Noorily, MD Clinical Professor, Department of Anesthesiology, University of Texas Health Science Center at San Antonio, San Antonio, Texas Laryngoscopy and Microlaryngoscopy

Mark Nunnally, MD Assistant Professor, Department of Anesthesia and Critical Care, University of Chicago Pritzker School of Medicine, Chicago, Illinois Postoperative Acute Renal Failure; Metabolic Acidosis and Alkalosis

Christopher J. O’Connor, MD Associate Professor, Department of Anesthesiology, Rush University Medical Center, Chicago, Illinois Abdominal Aortic Aneurysm Repair

Michael F. O’Connor, MD Bradly J. Narr, MD Associate Professor and Chair, Department of Anesthesiology, Mayo Clinic College of Medicine, Rochester, Minnesota Porphyrias

Associate Professor, Department of Anesthesia and Critical Care, University of Chicago Pritzker School of Medicine, Chicago, Illinois Thermally Injured Patients

Jerome F. O’Hara, Jr., MD Krishna M. Natrajan, MB,BS, FRCA Assistant Professor of Adult and Pediatric Cardiothoracic Anesthesiology, Department of Anesthesiology, University of Washington School of Medicine; Attending Anesthesiologist, Department of Anesthesiology, University of Washington Medical Center, Seattle, Washington Inotropic Drugs

Norah Naughton, MD Associate Professor of Anesthesiology and Associate Professor of Obstetrics and Gynecology, University of Michigan Medical School, Ann Arbor, Michigan Intracranial Pressure Monitoring

Patrick Neligan, MD Assistant Professor, Department of Anesthesia, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania Metabolic Acidosis and Alkalosis

Philippa Newfield, MD Assistant Clinical Professor of Anesthesia and Neurosurgery, University of California, San Francisco, School of Medicine; Attending Anesthesiologist, Department of Anesthesiology, California Pacific Medical Center, San Francisco, California Intracranial Aneurysms: Rebleeding; Intracranial Aneurysms: Vasospasm and Other Issues

Associate Professor, College of Medicine, Case Western Reserve University; Vice Chairman, Department of General Anesthesiology; Section Head of Anesthesia, Glickman Urological Center, Urology Department, Cleveland Clinic Foundation, Cleveland, Ohio Complications of Lithotripsy ..

Maria A. K. Ohrn, MD Anesthesiology Associates of North Florida, PA, North Florida Regional Medical Center, Gainesville, Florida Nondepolarizing Neuromuscular Relaxants

Nollag O’Rourke, MD Fellow in Obstetric Anesthesia, Department of Anesthesia, Brigham and Women’s Hospital, Boston, Massachusetts Pulmonary Aspiration in the Parturient

Sheela S. Pai, MD Assistant Professor, Department of Anesthesiology, Baylor College of Medicine; Staff Anesthesiologist, Department of Anesthesiology and Critical Care, Michael E. DeBakey Veterans Affairs Medical Center, Houston, Texas Mechanical Assist Devices

Craig M. Palmer, MD Professor of Clinical Anesthesiology; Director, Obstetric Anesthesia, University of Arizona College of Medicine, Tucson, Arizona Preterm Labor

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C. Lee Parmley, MD, JD

William Prince, MD

Professor of Anesthesiology, Department of Anesthesiology, Vanderbilt University Medical Center, Nashville, Tennessee Autonomic Hyperreflexia

Department of Anesthesiology, Kaiser Permanente Oakland Medical Center, Oakland, California Central Venous Pressure Monitoring

Lester T. Proctor, MD Komal Patel, MD Fellow in Cardiac Anesthesia, Department of Anesthesia and Critical Care, University of Chicago Pritzker School of Medicine, Chicago, Illinois Hypercoagulable States: Thrombosis and Embolism

D. Janet Pavlin, MD Professor, Department of Anesthesiology, University of Washington School of Medicine; Head of Teaching and Research in Ambulatory Anesthesia, Department of Anesthesia, University of Washington Medical Center, Seattle, Washington Postoperative Urinary Retention

Padmavathi Perala, MD Anesthesiologist, Department of Anesthesiology, Veterans Affairs Medical Center, Buffalo, New York Hemodynamic Instability

Patricia H. Petrozza, MD Professor of Anesthesiology, Associate Dean for Graduate Medical Education, Wake Forest University School of Medicine, Winston-Salem, North Carolina Pituitary Tumors: Diabetes Insipidus

Linda S. Polley, MD

Professor, Departments of Anesthesiology and Pediatrics, University of Wisconsin Medical School, Madison, Wisconsin Blood and Blood Products: Transfusion Reaction

Donald S. Prough, MD Professor and Chair, Department of Anesthesiology, University of Texas Medical Branch, Galveston, Texas Perioperative Fluid Management; Posterior Fossa Surgery

M. J. Pekka Raatikainen, MD Division of Cardiology, Oulu University Central Hospital, Oulu, Finland Adenosine; Class III Antiarrhythmic Drugs: Potassium Channel Blockers

Lee M. Radke, DDS Assistant Professor, Oral and Maxillofacial Surgery, Medical College of Wisconsin, Froedtert Memorial Lutheran Hospital, Milwaukee, Wisconsin Dental Injuries

Sivam Ramanathan, MD

Associate Professor, Department of Anesthesiology, University of Michigan Medical School, Ann Arbor, Michigan Postpartum Hemorrhage

Professor of Anesthesiology, University of Pittsburgh School of Medicine, Magee-Womens Hospital, Pittsburgh, Pennsylvania Humidifiers; Peripartum Neurologic Complications

David Porembka, FCCM

James G. Ramsay, MD

Professor of Anesthesia, Surgery and Internal Medicine (Cardiology), Department of Anesthesiology; Associate Director of Surgical Intensive Care; Director of Perioperative Echocardiography, University of Cincinnati College of Medicine, Cincinnati, Ohio Postoperative Respiratory Failure

Professor of Anesthesiology, Program Director, Anesthesiology Critical Care Medicine, Department of Anesthesia, Emory University School of Medicine; Anesthesiology Service Chief, Department of Anesthesiology, Emory University Hospital, Atlanta, Georgia Central Venous Pressure Monitoring

Claudia Praetel, MD

Monica N. Riesner, MD

Research Fellow, Department of Anesthesiology, College of Physicians and Surgeons of Columbia University, New York, New York Nitrous Oxide: Neurotoxicity

Joseph Previte, MD Associate Professor of Pediatrics and Anesthesiology, Project Leader of Anesthesia Centricity IS, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio Anesthetic Complications of Fetal Surgery: EXIT Procedures; Perioperative Aspiration Pneumonitis

Lecturer, Obstetric Anesthesia, Department of Anesthesiology, University of Michigan Medical School, Ann Arbor, Michigan Postpartum Hemorrhage

Edward T. Riley, MD Associate Professor, Department of Anesthesia, Stanford University School of Medicine, Stanford, California Antihistamines: H1- and H2-Blockers

Pamela R. Roberts, MD, FCCM, FCCP Richard C. Prielipp, MD, FCCM JJ Buckley Professor and Chair, Department of Anesthesiology, University of Minnesota Medical School, Minneapolis, Minnesota Hypothyroidism: Myxedema Coma; Hyperthyroidism: Thyroid Storm

Professor and Division Chief, Critical Care Medicine, John A. Moffitt Endowed Chair, Department of Anesthesiology, University of Oklahama Health Science Center, Oklahoma City, Oklahoma Hypothyroidism: Myxedema Coma; Hyperthyroidism: Thyroid Storm

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Kerri M. Robertson, MD

Ramachandran Satya-Krishna, MD, FRCA

Associate Clinical Professor of Anesthesiology; Chief, General, Vascular, High-Risk Transplant and Surgical Critical Care Medicine Division; Chief, Transplant Services, Duke University School of Medicine, Department of Anesthesiology, Durham, North Carolina Postoperative Hepatic Dysfunction; Complications of Carcinoid Tumors; Complications of Deliberate Hypotension: Visual Loss

Lecturer, Department of Anesthesiology, University of Michigan Medical School, Ann Arbor, Michigan; Consultant, Department of Anaesthesia, John Radcliffe Hospital, Oxford, United Kingdom Anesthesia Circuit

Marnie Robinson, MD Assistant Professor of Anesthesiology and Pediatrics, Department of Anesthesiology, University of Cincinnati College of Medicine, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio Anesthetic Complications of Fetal Surgery: EXIT Procedures

John B. Rose, MD Director, Pain Management Service, Department of Anesthesiology and Critical Care Medicine, Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania Delayed Emergence in Pediatric Patients

Mark I. Rossberg, MD Assistant Professor of Anesthesiology, Department of Anesthesia and Critical Care Medicine, Johns Hopkins Medical Institute, Baltimore, Maryland Postintubation Croup

Scott R. Schulman, MD Associate Professor of Anesthesiology and Pediatrics, Division of Pediatric Anesthesia and Critical Care Medicine, Duke University Medical Center, Durham, North Carolina Malignant Hyperthermia

Annette Schure, MD Anesthesiologist and Pediatric Anesthesiologist, Department of Anesthesia, Tufts-New England Medical Center, Boston, Massachusetts Thoracic Aortic Aneurysm

Jeffrey J. Schwartz, MD Associate Professor, Department of Anesthesiology, Yale University School of Medicine; Attending Physician, Department of Anesthesiology, Yale-New Haven Hospital, New Haven, Connecticut Electrical Safety

Christian Seefelder, MD David M. Rothenberg, MD Professor of Anesthesiology; Associate Dean, Academic Affiliations; Co-Medical Director, Surgical Intensive Care Unit, Rush University Medical Center, Chicago, Illinois Acute Pancreatitis

Assistant in Anaesthesia, Harvard Medical School; Instructor in Anaesthesia, Department of Anaesthesiology, Perioperative and Pain Medicine, Children’s Hospital, Boston, Massachusetts Air Emboli

Daniel D. Rubens, MB,BS, FANZCA

Rajamani Sethuraman, MD, FRCA

Assistant Professor, Department of Anesthesia, University of Washington School of Medicine, Children’s Hospital and Regional Medical Center, Seattle, Washington Intraoperative Cardiac Arrest

Consultant Anaesthetist, Department of Anaesthesia, Princess Alexandra Hospital, Essex, United Kingdom Intravenous Drug Delivery Systems

Christoph N. Seubert, MD Senthilkumar Sadhasivam, MD Assistant Professor in Anesthesia and Pediatrics, Department of Anesthesia, University of Cincinnati College of Medicine, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio Postoperative Nausea and Vomiting

Tetsuro Sakai, MD, PhD Resident, Department of Anesthesiology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania Complications in Orthopedic Outpatients Not Receiving Peripheral Nerve Blocks

Francis V. Salinas, MD Clinical Assistant Professor, Department of Anesthesiology, University of Washington School of Medicine; Staff Anesthesiologist, Department of Anesthesiology, Virginia Mason Medical Center, Seattle, Washington Local Anesthetic Systemic Toxicity

Theodore J. Sanford, Jr., MD Clinical Professor of Anesthesiology, Department of Anesthesiology, University of Michigan Medical School, Ann Arbor, Michigan Difficult Airway: Opiate-Induced Muscle Rigidity

Assistant Professor, Department of Anesthesiology, University of Florida College of Medicine, Gainesville, Florida Barbiturates: Porphyrias

Jack S. Shanewise, MD Chief, Division of Cardiothoracic Anesthesiology, Department of Anesthesiology, College of Physicians and Surgeons of Columbia University, New York, New York Transesophageal Echocardiography

Kelly T. Shannon, MD Associate Professor of Anesthesiology, University of Pittsburgh School of Medicine; Associate Chief, Department of Anesthesiology, Magee-Womens Hospital, Pittsburgh, Pennsylvania Humidifiers

Gauhar Sharih, MD, FRCA Formerly, Visiting Instructor, Department of Anesthesiology, University of Michigan Medical School, Ann Arbor, Michigan; Specialist Registrar, Department of Anaesthetics, City Hospital, Birmingham, West Midlands, United Kingdom Inspiratory and Expiratory Gas Monitoring

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Aarti Sharma, MD, DA(UK)

Mark D. Stoneham, MD, FRCA

Assistant Professor of Anesthesiology, Department of Anesthesiology, Weill Medical College of Cornell University; Attending Anesthesiologist, Department of Anesthesiology, New York–Presbyterian Hospital, New York, New York Complications of Deliberate Hypotension: Visual Loss

Honorary Senior Clinical Lecturer, Nuffield Department of Anaesthesia, John Radcliffe Hospital, Oxford, United Kingdom Pulse Oximetry

Robert N. Sladen, MD Professor and Vice Chair, Department of Anesthesiology; Chief, Division of Critical Care, College of Physicians and Surgeons of Columbia University, New York, New York Postoperative Acute Renal Failure; Hypothermia

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E. Price Stover, MD* Clinical Assistant Professor, Department of Anesthesia, Stanford University Medical Center, Stanford, California Nonbarbiturate Anesthetics

Laura Stover, MD, MASc, FRCP(C)

Professor of Anesthesia, Department of Anesthesiology, Toronto General Hospital, Toronto, Ontario, Canada One-Lung Ventilation

Acting Instructor, Department of Anesthesiology, University of Washington School of Medicine; Acting Instructor, Department of Cardiothoracic Anesthesiology, University of Washington Medical Center, Seattle, Washington; Assistant Professor of Anesthesiology, Hamilton Health Sciences, Hamilton, Ontario, Canada Drugs Affecting the Renin-Angiotensin System

Tod B. Sloan, MD

Vijayendra Sudheendra, MD

Professor of Anesthesiology, University of Colorado Health Sciences Center, Denver, Colorado Spinal Cord Injury

Clinical Instructor, Department of Surgery and Anesthesiology, Brown University School of Medicine; Staff Anesthesiologist, Miriam Hospital, Providence, Rhode Island; Chief of Anesthesia, East Bay Surgery Center, Swansea, Massachusetts Complications of Transurethral Surgery

Peter D. Slinger, MD

Jonathan H. Slonin, MD Chief Resident, Department of Anesthesiology, Leonard M. Miller School of Medicine at the University of Miami, Miami, Florida Surgery in the Morbidly Obese

Paul Smythe, MD Assistant Professor of Anesthesiology, University of Michigan Medical School; Adjunct Clinical Lecturer in Dentistry, Department of Oral and Maxillofacial Surgery/Hospital Dentistry, University of Michigan School of Dentistry, Ann Arbor, Michigan Intracranial Pressure Monitoring

Jennifer E. Souders, MD Clinical Associate Professor, Department of Anesthesiology, University of Washington School of Medicine, Seattle, Washington Venous Air Embolism

Scott R. Springman, MD Professor, Departments of Anesthesiology and Surgery, University of Wisconsin Medical School, Madison, Wisconsin Preanesthetic Evaluation: False-Positive Tests; Preanesthetic Evaluation: Inadequate or Missing Test Result

James M. Steven, MD Associate Professor of Anesthesia and Pediatrics, Department of Anesthesia, University of Pennsylvania School of Medicine; Chief Medical Officer, Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania Upper Respiratory Tract Infection

Robert K. Stoelting, MD Emeritus Professor and Chair, Department of Anesthesia, Indiana University School of Medicine, Indianapolis, Indiana Postoperative Peripheral Neuropathy; Intractable Nausea and Vomiting

Kevin J. Sullivan, MD Assistant Professor of Anesthesiology, Mayo Clinic College of Medicine; Clinical Assistant Professor of Pediatrics, University of Florida College of Medicine, Jacksonville; Staff Member, Department of Anesthesiology, Nemours Children’s Clinic; Staff Pediatric Anesthesiologist and Intensivist, Department of Anesthesia and Critical Care Medicine, Wolfson Children’s Hospital, Jacksonville, Florida Anticholinergics; Hypothermia in Pediatric Patients

Christer H. Svensén, MD Associate Professor, Department of Anesthesiology, University of Texas Medical Branch, Galveston, Texas Perioperative Fluid Management

James F. Szocik, MD Associate Professor, Department of Anesthesiology, University of Michigan Medical School; Chair, Technical Support Committee, Department of Anesthesiology, University of Michigan Medical Center, Ann Arbor, Michigan Pipeline Source Failure

Kenichi A. Tanaka, MD Assistant Professor, Department of Anesthesiology, Emory University School of Medicine, Atlanta, Georgia Perioperative Hypertension

Mark D. Tasch, MD Associate Professor of Clinical Anesthesia, Department of Anesthesia, Indiana University School of Medicine, Indianapolis, Indiana Pulmonary Aspiration

*Deceased

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Peter Tassani-Prell, MD

Karen M. Van Tassel, MD

Professor of Cardiac Anesthesia, Department of Anesthesia, German Heart Center Munich, München, Germany Anticoagulation Initiation and Reversal for Cardiac Surgery; Bleeding after Cardiac Surgery

Chief Resident, Department of Anesthesiology, Duke University Medical Center, Durham, North Carolina Malignant Hyperthermia

Lisa Thannikary, MD

Gurinder M. S. Vasdev, MB,BS

Adjunct Assistant Professor, Department of Anesthesiology, University of Florida College of Medicine, Gainesville, Florida Intrathecal Opiates; Ketamine; Steroids

Klaus D. Torp, MD Assistant Professor of Anesthesiology, Department of Anesthesiology, Mayo Clinic College of Medicine, Jacksonville, Florida Perioperative Management of Dialysis-Dependent Patients

Laurence C. Torsher, MD Assistant Professor of Anesthesiology, Department of Anesthesiology, Mayo Clinic College of Medicine, Rochester, Minnesota Perioperative Care for Patients with Hepatic Insufficiency (Cirrhosis)

Mark F. Trankina, MD Staff Anesthesiologist, Carraway Methodist Medical Center and University of Alabama Hospital at Birmingham, Birmingham, Alabama Class I Antiarrhythmic Drugs: Ventricular Proarrhythmia

Kenneth W. Travis, MD Associate Professor Emeritus, Department of Anesthesiology, Dartmouth-Hitchcock Medical Center, Lebanon, New Hampshire Postobstruction Pulmonary Edema

Lawrence C. Tsen, MD Associate Professor of Anesthesia, Department of Anesthesia, Harvard Medical School; Director of Anesthesia, Center for Reproductive Medicine, Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women’s Hospital, Boston, Massachusetts Antepartum Hemorrhage

Avery Tung, MD Associate Professor, Department of Anesthesia and Critical Care, University of Chicago Pritzker School of Medicine, Chicago, Illinois Major Organ System Dysfunction after Cardiopulmonary Bypass; Mechanical Assist Devices; Thermally Injured Patients

Manuel C. Vallejo, MD, DMD Associate Professor, Department of Anesthesiology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania Peripartum Neurologic Complications

Gail A. Van Norman, MD Clinical Associate Professor of Anesthesiology, Affiliate Associate Professor of Medical History and Ethics, University of Washington School of Medicine, Seattle, Washington; Physician, Department of Anesthesiology, St. Joseph Medical Center, Tacoma, Washington Patient Confidentiality; Do-Not-Resuscitate Orders in the Operating Room; The Jehovah’s Witness Patient

Assistant Professor of Anesthesiology, Department of Anesthesiology, Mayo Clinic College of Medicine, Rochester, Minnesota Cardiopulmonary Bypass in Pregnancy

Melissa M. Vu, MD Instructor of Anesthesiology, Department of Anesthesiology, Mayo Clinic College of Medicine, Jacksonville, Florida Hyperthermia

Mehernoor F. Watcha, MD Associate Professor of Anesthesia, Department of Anesthesiology and Critical Care Medicine, University of Pennsylvania School of Medicine, Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania Postoperative Nausea and Vomiting

Eileen Watson, MD Clinical Assistant Professor, Department of Anesthesiology, State University of New York at Buffalo; Attending Anesthesiologist, Children’s Hospital of Buffalo, Buffalo, New York Hemodynamic Instability

B. Craig Weldon, MD Associate Professor, Department of Anesthesiology and Pediatrics, Duke University School of Medicine, Durham, North Carolina Cardiomyopathies; Emergence Agitation

Robert S. Weller, MD Associate Professor of Anesthesiology, Department of Anesthesiology, Wake Forest University School of Medicine; Staff Anesthesiologist, Department of Anesthesiology, North Carolina Baptist Hospitals, Inc., Winston-Salem, North Carolina Psoas Compartment Block: Potential Complications

Lynda Wells, MD Associate Professor of Anesthesiology, University of Virginia Health System, Charlottesville, Virginia Pediatric Neurosurgery

Volker Wenzel, MD, MSc Associate Professor of Anesthesiology and Critical Care Medicine, Department of Anesthesiology and Critical Care Medicine, Medical University of Innsbruck, Innsbruck, Austria Vasopressors: Vasoconstrictor Drugs

Harshdeep Wilkhu, MD Clinical Assistant Professor, Department of Anesthesiology, University of Florida College of Medicine, Gainesville, Florida Nonbarbiturate Anesthetics

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Contributors

Brian A. Williams, MD

Brian J. Woodcock, MD

Associate Professor, Department of Anesthesiology, University of Pittsburgh School of Medicine; Director of Outpatient Regional Anesthesia Service, Department of Anesthesiology, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania Complications in Orthopedic Outpatients Not Receiving Peripheral Nerve Blocks

Assistant Professor of Anesthesiology, Department of Anesthesiology, University of Michigan Medical School, Ann Arbor, Michigan Mechanical Ventilators

Glyn D. Williams, MB,ChB, FFA Associate Professor, Department of Anesthesia, Stanford University School of Medicine, Lucile Packard Children’s Hospital, Palo Alto, California Catheter Ablation for Arrhythmias

xxiii

Christopher C. Young, MD, FCCM Assistant Clinical Professor of Surgery, Associate Clinical Professor of Anesthesiology, Chief of Critical Care Medicine Division, Department of Anesthesiology, Duke University School of Medicine, Durham, North Carolina Hypothermia

William L. Young, MD

Assistant Professor, Departments of Anesthesiology and Pediatrics, University of Colorado School of Medicine, Denver, Colorado Antidepressants; Air Emboli

James P. Livingston Professor and Vice Chair, Department of Anesthesia and Perioperative Care, University of California, San Francisco, San Francisco General Hospital, San Francisco, California Arteriovenous Malformation: Normal Perfusion Pressure Breakthrough

Eric P. Wittkugel, MD

Christine M. Zainer, MD

Associate Professor of Clinical Anesthesia and Critical Care; Staff Anesthesiologist; Director, Preoperative Services, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio Pediatric Laryngospasm

Assistant Professor of Anethesiology, Department of Anesthesiology, Medical College of Wisconsin, Froedtert Memorial Lutheran Hospital East, Milwaukee, Wisconsin Herbals and Alternative Medicine

Lisa Wise-Faberowski, MD

Mark A. Zakowski, MD David J. Wlody, MD Clinical Associate Professor of Anesthesiology and Vice Chair for Clinical Affairs, Department of Anesthesiology, State University of New York-Downstate Medical Center; Interim Chair, Department of Anesthesiology, Long Island College Hospital, Brooklyn, New York Postpartum Headache Other Than Post–Dural Puncture Headache

Gilbert Y. Wong, MD Assistant Professor of Anesthesiology and Consultant Physician, Division of Pain Medicine, Department of Anesthesiology, Mayo Clinic College of Medicine, Rochester, Minnesota Celiac Plexus Block: Side Effects and Complications

Chief, Section of Obstetric Anesthesia, Department of Anesthesiology, Cedars-Sinai Medical Center, Los Angeles, California Peripartum Neurologic Complications

Paul B. Zanaboni, MD, PhD Anesthesiologist, St. John’s Mercy Health Care, St. Louis, Missouri Bradyarrhythmias

R. Victor Zhang, MD, PhD Assistant Professor, Department of Anesthesiology, University of Florida College of Medicine, Gainesville, Florida a2-Adrenoreceptor Agonists

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Acknowledgments First, I wish to acknowledge the contributions to this work of my wife Barbara, my in-house administrative and editorial assistant. Thank you, Barbara! Your literary skills (you did major in English and minor in Philosophy) were much needed and greatly appreciated! I am deeply indebted to the Section Editors for this edition of Complications in Anesthesia, some of whom were Section Editors for the first edition as well. Organizing the topics for their sections or subsections, recruiting contributors, and seeing to it that the chapter manuscripts were submitted and pre-edited in a timely fashion were some of their tasks. Special appreciation goes to Natasha Andjelkovic (Executive Publisher), Jean Nevius (Senior Developmental Editor), and Amy Norwitz (Senior Project Manager). Once again, I salute Lewis Reines (former President of WB Saunders) and Leslie Day (former Medical Editor at WB Saunders), who in 1996-1997 convinced me of the need for this conceptually new work as a resource for busy practitioners in anesthesia and critical care. Finally, I express my sincere appreciation to John P. Kampine, MD, PhD, former Professor and Chair of the Department of Anesthesiology at the Medical College of Wisconsin, and to my colleagues in that department (some of whom have contributed to this work) for providing me the time and encouragement for yet again undertaking this work. John L. Atlee, MD

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PHARMACOLOGY

VASOACTIVE DRUGS

1

Vasodilator Drugs Jörg Dziersk Case Synopsis A 90-year-old man with severe aortic stenosis, stable angina, and pulmonary hypertension has surgery under general anesthesia for a femoral neck fracture. Owing to the associated cardiac morbidities, the anesthesiologist inserts a pulmonary artery catheter. Despite maintenance of normoxemia and mild hypocapnia, the patient’s pulmonary artery pressure rises from 60/25 to 70/35 mm Hg and is associated with signs of right ventricular strain. A nitroglycerin infusion is started at 0.2 μg/kg per minute. The pulmonary artery pressure returns to near baseline values, and the systemic blood pressure decreases from 125/90 to 75/30 mm Hg.

PROBLEM ANALYSIS Definition Left-sided heart disease (e.g., mitral valve disease, aortic stenosis, left ventricular failure) often causes significant pulmonary venous pressure elevation and leads to compensatory pulmonary artery (PA) hypertension. Chronic elevation of PA pressure promotes compensatory right ventricular (RV) hypertrophy and pulmonary vascular remodeling. This, in turn, results in increased pulmonary vascular resistance (PVR). For such patients, acute (or acute-on-chronic) increases in PA pressure are often poorly tolerated. The consequences are RV dilatation, significant tricuspid regurgitation, and reduced cardiac output secondary to reduced venous return and impaired left ventricular filling. Together, they may lead to a “downward spiral.” When RV systolic pressure exceeds aortic blood pressure, RV coronary perfusion is limited to diastole, which may further impair RV performance. Vasodilating drugs act by reducing the contraction of vascular smooth muscle cells through a reduction in cytoplasmic Ca2+ concentration [Ca2+]. Vascular smooth muscle relaxation may be mediated by the following: ●

●

●

● ●

●

Increased intracellular cyclic adenosine monophosphate (e.g., β2-adrenoceptor agonists, epoprostenol) Increased intracellular cyclic guanosine monophosphate (e.g., nitric oxide, nitroglycerin, sodium nitroprusside, brain natriuretic peptide) KATP channel-opening-related hyperpolarization (e.g., diazoxide) α1-Adrenoceptor antagonism (e.g., phentolamine) Ca2+ channel blockade (e.g., diltiazem, nicardipine, verapamil) Reduction of central sympathetic tone (e.g., clonidine)

Properties of an ideal vasodilator for perioperative use include (1) short onset time, (2) short to intermediate duration of action, (3) elimination independent of organ function (i.e., renal or hepatic), and (4) lack of serious side

effects or toxicity. At this time, there is no single drug that meets all these criteria. Clinical actions, mechanisms of action, and side effects of vasodilators currently available for intravenous or inhalational administration are listed in Table 1-1.

Recognition Systemic vasodilatation causes a decline in systemic blood pressure, the extent of which depends on circulating blood volume and venous return (cardiac preload), the adequacy of compensatory mechanisms (i.e., reflex increase in heart rate and contractility), and the cardiac ejection fraction (normal or reduced). The skin appears warm and may be flushed, with a shortened capillary refill time. Organ dysfunction may occur if systemic blood pressure is below the respective autoregulation threshold or if flow in a vascular territory is pressure dependent (e.g., in the presence of coronary artery disease, renal artery stenosis, head injury). Myocardial injury, acute renal failure, or neurologic deficits are typical examples of complications of systemic hypotension. Computation of systemic vascular resistance quantifies the average degree of vasodilatation (or vasoconstriction) in the whole body, but it requires a precise measurement of mean arterial pressure and central venous pressure, as well as a determination of cardiac output. A PA catheter equipped for thermodilution cardiac output is necessary. In the presence of PA hypertension, systemic vasodilatation may allow right-to-left shunting of blood through a patent foramen ovale, leading to a diminished arterial oxygen saturation. Reduced RV preload due to venous pooling and RV myocardial perfusion pressure may compromise RV performance and result in a low cardiac output state.

Risk Assessment Vasodilator therapy has an increased potential to cause complications in patients with the following conditions: ● ● ●

Hypovolemia Stenotic valvular lesions (especially severe aortic stenosis) Hypertrophic-obstructive cardiomyopathy 3

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Pharmacology

Vasodilators Available for Intravenous or Inhalational Administration

Drug Class and Drug*

Terminal Half-life

α1-Antagonists Labetalol

5-8 hr

Phentolamine

19 min (IV)

Urapidil†

2.7 hr

α2-Adrenoceptor Agonists Clonidine

8-16 hr

Donors Nitric oxide

6 sec

Nitroglycerin

2-8 min

Sodium nitroprusside

3-4 min

Blockers Diltiazem

3-6 hr

Nicardipine

8.6 hr (infusions ≥48 hr)

Verapamil

2-8 hr

Angiotensin-Converting 11 hr

Venous > arterial vasodilatation NO or S-nitrosothiol release by metabolism ⇒ activation of guanylyl cyclase Arterial ª venous vasodilatation NO release by red cell metabolism ⇒ activation of guanylyl cyclase

Bradycardia Drug fever Reflex tachycardia Hypoglycemia

Bradycardia Potentiates anesthetic/narcotic sedation Slow IV onset (30-60 min)

Arterial vasodilatation Vascular remodeling Inhibits generation of angiotensin II Stimulates kallikrein-kinin system

18 min

Cyanide toxicity, especially with higher doses and lengthy infusions Thiocyanate toxicity (lengthy infusions) Methemoglobinemia Reflex tachycardia

Vasodilatation unpredictable Little effect in PA HTN

Possibly severe (first dose) Acute renal failure ↑ K+, especially with renal failure No effect on PA HTN (given acutely) Slow IV onset (>15 min)

Severe systemic hypotension with IV dosing (common) Inhibition of platelet aggregation and adhesion Stimulates coughing (inhalational use)

5-10 min 3-5 min 13-30 min

Natriuretic Peptides

Inhibits platelet aggregation Pulmonary edema secondary to contaminants (NO2) and metabolites (peroxynitrite) Methemoglobinemia Tachyphylaxis Methemoglobinemia

Moderate negative inotrope AV conduction blockade Does not block L-type cardiac Ca2+ channels (little or no effect on contractility or AV conduction) Significant negative inotrope Depresses sinus node Blocks AV node conduction Longer half-life with chronic use

Activation of adenylyl cyclase ⇒↑cAMP

Prostaglandins with VSM Relaxing Effect

Brain natriuretic peptide

↓ Central sympathetic vasomotor tone Inhibits peripheral NE release

Block L-type Ca2+ channels Primary arterial dilators (no venodilatation at therapeutic doses)

Calcium Channel

Alprostadil (PGE1) Epoprostenol (PGI2) Iloprost

Arterial > venous vasodilatation Competitive adrenoceptor blockade (α1:β = 1:7) Competitive α1- = α2-adrenoceptor blockade Direct action on VSM Competitive α1-adrenoceptor blockade Competitive α2-adrenoceptor block

Side Effects and Problems

Activation of guanylyl cyclase ⇒↑cGMP

Nitric Oxide and

Enzyme Inhibitors Enalaprilat

Principal Action and Mechanism of Action

Arterial and venous vasodilatation Stimulation of natriuretic peptide receptor A ⇒ activation of guanylyl cyclase domain ⇒ ↑cGMP Inhibits renin-aldosterone axis

Miscellaneous Agents Adenosine

<10 sec

Stimulation of adenosine receptors ⇒ Direct vasodilatation (A2a, A2b, A3) Reduces central sympathetic vasomotor tone (A2a) Inhibits peripheral NE release (A1)

Bradycardia Bronchoconstriction Decreased glomerular filtration rate

Table continued on following page

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Vasodilators Available for Intravenous or Inhalational Administration—cont’d

Drug Class and Drug*

Terminal Half-life

Diazoxide

20-45 hr

Fenoldopam

5-10 min

Hydralazine

2-4 min

Principal Action and Mechanism of Action

Side Effects and Problems

Opens KATP channels ⇒ hyperpolarization and arteriolar vasodilatation Dopamine (DA1) agonist ⇒ arteriolar vasodilatation Arterial vasodilatation only

Sodium and water retention Hyperglycemia Reflex tachycardia Hypokalemia Nausea Slow IV onset (5-15 min) Reflex tachycardia (quite common) Sodium and water retention Lupus-like syndrome (slow acetylators)

*Drugs with vasodilator activity used principally for their sympathomimetic effects (e.g., β2-adrenoceptor agonists, phosphodiesterase-3 inhibitors) are not included. † Urapidil is widely used in Europe but is currently not available in the United States. AV, atrioventricular; cAMP, cyclic adenosine monophosphate; cGMP, cyclic guanosine monophosphate; HTN, hypertension; IV, intravenous; NE, norepinephrine; NO, nitric oxide; NO2, nitrogen dioxide; PA, pulmonary artery; PG, prostaglandin; VSM, vascular smooth muscle.

● ●

●

Intracardiac shunts Altered organ blood flow autoregulation (e.g., systemic hypertension, head injury) Perfusion territories with pressure-dependent blood flow (e.g., coronary artery disease, renal artery stenosis, aortic coarctation)

Besides their potential to cause inappropriate systemic hypotension, many vasodilators have other undesirable physiologic effects or toxicities (summarized in Table 1-1).

Implications Systemically administered vasodilators inhibit hypoxic pulmonary vasoconstriction. They may cause or aggravate hypoxemia during one-lung ventilation or in the presence of lung pathology (e.g., atelectasis, lung contusion, pneumonia), leading to increased ventilation-perfusion mismatch or intrapulmonary shunting. Pulmonary hypertension is associated with increased perioperative morbidity and mortality in cardiac surgery. The most recent ACC/AHA guidelines on Perioperative Evaluation for Noncardiac Surgery (2002) state: “although most experts agree that pulmonary hypertension poses an increased risk for noncardiac surgery, no organized study of the problem has been performed.”

MANAGEMENT Avoidance of vasodilator drug overdose is based on titration to effect with an intravenous infusion or repeated small bolus doses, depending on pharmacokinetics. Vasodilatorinduced hypotension can be treated by the following means: ●

● ●

●

Dose adjustment or (temporary) discontinuation of the responsible vasodilator Intravascular volume loading Head-down positioning or leg elevation (circumstances permitting) Judicious application of a (short-acting) vasoconstrictor

Management of PA hypertension begins with the elimination or modulation of factors known to increase PVR: ● ●

Hypoxemia Acidemia

● ●

High sympathetic tone High intrathoracic pressure

There is evidence that PVR begins to increase significantly when arterial PO2 falls below 60 mm Hg. Conversely, the existence of pulmonary vasodilatation with hyperoxia is controversial. However, there may be circumstances when the application of a high fraction of inspired oxygen (even 1.0) is indicated, if only to increase the margin of safety against hypoxemia. Pulmonary vasoconstriction occurs with an arterial pH of less than 7.35, irrespective of the cause of acidemia (respiratory versus metabolic). Moderate hyperventilation to an arterial PCO2 of 30 to 35 mm Hg and aggressive correction of any metabolic acidosis with sodium bicarbonate or tris(hydroxymethy) aminomethane (THAM) are advised. Extreme alkalosis (pH >7.5) may produce further pulmonary vasorelaxation but adversely affects oxygen delivery and enzyme function. High endogenous catecholamine levels cause pulmonary vasoconstriction through the stimulation of α1adrenoceptors. These high levels can be avoided or treated by providing adequate anesthetic depth and postoperative analgesia. Finally, it should be remembered that lung inflation above functional residual capacity causes a progressive increase in PVR. Ventilator settings should be adjusted, based on the patient’s pulmonary function, to provide adequate oxygenation and carbon dioxide elimination while keeping mean intrathoracic pressure to a minimum. Pharmacologic pulmonary vasodilatation without concomitant systemic vasodilatation, as was required in the case described here, can be attained in two ways: 1. Inhalation of a short-acting vasodilator, such as nitric oxide (NO) or prostacyclin (epoprostenol) 2. Coadministration of an intravenous pulmonary vasodilator (e.g., nitroglycerin, nitroprusside, epoprostenol) and a pulmonary vasculature-sparing vasoconstrictor (e.g., vasopressin or its synthetic analogue terlipressin). NO activates soluble guanylyl cyclase to increase cyclic guanosine monophosphate levels in vascular smooth muscle. It is inactivated by the heme moiety of hemoglobin and superoxide anions and has a blood half-life of approximately 6 seconds. Therefore, inhaled NO affects predominantly

PHARMACOLOGY

Table 1–1

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the tone of pulmonary vessels in ventilated lung areas but has negligible effects on systemic vascular resistance. Broader application is currently limited by its very high cost and the special equipment required for its administration. Prostacyclin (PGI2, epoprostenol) and its synthetic analogue iloprost are the most potent pulmonary vasodilators known. Their main application is continuous infusion in cases of severe pulmonary hypertension. Their vasodilator action is mediated by cyclic adenosine monophosphate. Intravenous administration frequently causes prohibitive systemic hypotension, but when administered via inhalation, the effectiveness is comparable to that of inhaled NO. Arginine vasopressin is a vasoactive nonapeptide produced in the hypothalamus. It is an agonist at three specific receptor types. Stimulation of the V1a receptor results in contraction of systemic vascular smooth muscle by means of an intracellular activation pathway shared with angiotensin II. Successful use of arginine vasopressin in vasodilatory shock after cardiopulmonary bypass and in hyperdynamic septic shock has been reported. The advanced cardiovascular life support guidelines of 2000 recommend vasopressin as an alternative to epinephrine in patients with refractory ventricular fibrillation. In contradistinction to the pulmonary vascular effects of other vasoconstrictors (e.g., α1adrenoceptor agonists, angiotensin II), vasopressin has been shown to cause pulmonary and cerebral artery vasodilatation, possibly through receptor-mediated local NO release. It may be the vasopressor drug of choice in patients with significantly elevated PVR or RV failure.

PREVENTION Preventing the complications of vasodilator use is based on an understanding of the patient’s pathophysiology and the pharmacology of available drugs. Vasodilators are used to advantage based on their specific profiles, always keeping in mind any undesired or dangerous side effects. For instance, in a patient with aortic stenosis and coronary artery disease, both systemic hypotension and tachycardia must be avoided. In the case described in this chapter, nitroglycerin would be a reasonable choice for treatment of

pulmonary hypertension, because it produces less relaxation of systemic resistance vessels than do other pulmonary vasodilators and does not cause a reflex tachycardia. Use of vasodilators in the perioperative period should take into account the common occurrence of hypovolemia due to preoperative fluid restriction, intraoperative fluid shifts or blood loss, and globally or regionally reduced sympathetic tone in anesthetized patients. Careful dose titration of vasodilators is advisable and is facilitated by using drugs with short half-lives. Vasodilator therapy for pulmonary hypertension coincides with the appropriate manipulation of physiologic factors known to affect PVR. Inhalational administration of NO or epoprostenol, if feasible, may help avoid unwanted systemic venodilatation or arterial vasodilatation effects. Finally, always keep in mind that adrenoceptor antagonists and vasodilators attenuate sympathetic responses, possibly masking the clinical signs of inadequate depth of anesthesia. The use of a depth-of-anesthesia monitor is encouraged, especially when neuromuscular blockers are used.

Further Reading Balser JR, Butterworth J: Cardiovascular drugs. In Hensley FA Jr, Martin DE, Gravlee GP (eds): A Practical Approach to Cardiac Anesthesia, 3rd ed. Philadelphia, JB Lippincott–Williams & Wilkins, 2003. Barnes PJ, Liu SF: Regulation of pulmonary vascular tone. Pharmacol Rev 47:87-131, 1995. Eagle KA, Berger PB, Calkins H, et al: ACC/AHA Guideline Update on Perioperative Cardiovascular Evaluation for Noncardiac Surgery, 2002. American College of Cardiology Web site available at http://www.acc.org/ clinical/ guidelines/perio/dirIndex.htm Frishman WH, Sonnenblick EH, Sica DH (eds): Cardiovascular Pharmacotherapeutics, 2nd ed. New York, McGraw-Hill, 2003. Katzung BG (ed): Basic & Clinical Pharmacology, 9th ed. New York, Lange Medical Books/McGraw-Hill, 2004. Malouf JF, Enriquez-Sarano M, Pellikka PA, et al: Severe pulmonary hypertension in patients with severe aortic valve stenosis: Clinical profile and prognostic implications. J Am Coll Cardiol 40:789-795, 2002. Olschewski H, Rose F, Schermuly R, et al: Prostacyclin and its analogues in the treatment of pulmonary hypertension. Pharmacol Ther 102:139-153, 2004. Reich DL, Bodian CA, Krol M, et al: Intraoperative hemodynamic predictors of mortality, stroke, and myocardial infarction after coronary artery bypass surgery. Anesth Analg 89:814-822, 1999.

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REGIONAL ANESTHESIA & PAIN PHARMACOLOGY MANAGMENT

Vasopressors: Vasoconstrictor Drugs

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Viktoria D. Mayr, Volker Wenzel, and Martin W. Dünser Case Synopsis A 73-year-old woman with a history of chronic arterial hypertension and coronary heart disease undergoes surgery for an infected hip prosthesis. Etomidate, fentanyl, and rocuronium are used to induce anesthesia. After induction, the patient’s arterial blood pressure (BP) suddenly drops to 60/40/30 mm Hg (systolic/mean/diastolic). Infusion of 1 L normal saline and two 5-mg intravenous bolus injections of ephedrine have no significant effect on BP. Continuous infusion of norepinephrine restores BP to a more normal range (105/74/58 mm Hg); however, simultaneously, the patient develops tachycardia with ventricular ectopic beats. After norepinephrine is increased to 0.35 μg/kg per minute, atrial fibrillation with a rapid ventricular response develops and results in a sustained reduction in arterial BP.

PROBLEM ANALYSIS Definition The first priority of perioperative cardiovascular care is to maintain adequate perfusion of vital organs. In addition to sufficient cardiac output, mean arterial BP must be maintained to secure organ perfusion pressure. Accordingly, arterial hypotension is either a mean arterial pressure (MAP) less than 60 mm Hg or a drop in MAP of more than 30% from preoperative values. Below a MAP of about 60 mm Hg, vascular autoregulation1 declines in the brain, kidneys, and parts of the gastrointestinal tract. For the heart, autoregulation is lost below a diastolic BP of 50 to 55 mm Hg, presuming a normal left ventricular end-diastolic pressure. With loss of autoregulation, vital organ perfusion becomes compromised. Fluids, inotropes, and vasopressors are used to treat hypotension in perioperative and critical care settings. After restoration of normovolemia and adequate cardiac output with intravenous fluids and inotropes, ongoing hypotension may require the use of vasopressors. Commonly used vasopressors in the perioperative setting are dopamine, norepinephrine, epinephrine, phenylephrine, ephedrine, and vasopressin (Table 2-1). All these drugs exert their effects by stimulating α-adrenergic and β-adrenergic receptors. These receptors are found not only in vascular and cardiac smooth muscle but also in the liver, platelets, leukocytes, bronchiolar smooth muscle, fat, and muscle.

1 The autoregulatory (AR) curve is shifted upward and to the right in chronic hypertension. In normotensives, flow is constant over the MAP range of 60 to 160 mm Hg. With chronic hypertension, the AR range is 80 to 180 mm Hg or higher. Below or above this, flow is directly proportional to MAP: flow increases for MAP values above the upper AR setpoint, and it decreases for values below the lower setpoint. For the heart, the AR curve is a diastolic BP of 50 to 150 mm Hg, presuming a normal left ventricular end-diastolic pressure (0 to 3 mm Hg). If the left ventricular enddiastolic pressure increases, the AR curve shifts upward and to the right.

Systemic inflammation or sepsis leads to high cytokine concentrations, with overproduction of nitric oxide. In turn, both membranous and cytosolic adrenergic receptor complexes are quantitatively and qualitatively down-regulated. These pathophysiologic adaptive mechanisms lead to reduced effects of endogenous or exogenous catecholamines, often necessitating the infusion of even higher catecholamine doses to ensure adequate vital organ perfusion. However, such high-dose catecholamine infusions may adversely affect the risk-benefit ratio of adrenergic vasopressor therapy beyond clinically acceptable ranges.

Recognition Institution of vasopressor therapy may have a number of untoward effects on major organ systems. Among the more common side effects of catecholamines are α1- and primarily β-adrenergic-mediated ventricular ectopy and tachyarrhythmia.2 High-dose vasopressor therapy with primary α-adrenergic agonists may increase pulmonary artery pressure. Aside from these effects, some catecholamine derivatives have specific side effects that may have an adverse impact on patient outcomes. For example, dopamine is known to reduce mucosal perfusion in the gastrointestinal tract. Although mesenteric blood flow significantly increases during therapy with dopamine, mucosal oxygenation deteriorates. This paradoxical effect is likely due to an intervillus shunt (i.e., shift of intestinal wall blood flow to the submucosa). Dopamine also influences the production and release of several hormones. Lengthy infusions may lead to reduced serum concentrations of prolactin, human growth hormone, and thyroid hormones.

2 A synergistic interaction between α1- and β-adrenoceptors has been implicated in the genesis of catecholamine-anesthetic ventricular arrhythmias: a1A-mediated slowing of Purkinje fiber conduction, with enhanced conduction at the Purkinje fiber–ventricular muscle fiber junction.

7

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Pharmacology

Effects of Vasopressor Drugs

Drug

Negative Effects

Positive Effects

Dopamine

Tachycardia Tachyarrhythmia Pulmonary artery vasoconstriction ↓ PaO2 (↑ O2 demand) ↑ Systemic vascular resistance Tachycardia Tachyarrhythmias ↑ O2 consumption Tachycardia Tachyarrhythmias ↑ O2 consumption Hyperglycemia ↑ Systemic vascular resistance ↑ O2 consumption

↑ Myocardial contractility ↑ Glomerular filtration rate

Norepinephrine

Epinephrine

Phenylephrine

Ephedrine

Tachycardia Indirectly mediated effects†

Vasopressin

Ischemic skin lesions Gut ischemia

↑ Myocardial contractility

↑ Cardiac index ↑ Stroke volume ↑ O2 delivery ↑ Cardiac index* ↑ Stroke volume* ↑ Cardiac output* ↑ O2 delivery ↑ Heart rate ↑ Cardiac output ↑ Mean arterial pressure ↑ O2 delivery ↑ Mean arterial pressure Heart rate‡ ↑ Mean pulmonary artery pressure ↑ Catecholamine requirements

*Venous constriction in venous capacitance bed augments venous return and cardiac preload, thereby increasing cardiac output. † Effects largely mediated by endogenous catecholamine release. ‡ No effect, or decrease due to baroreceptor stimulation caused by increased blood pressure.

Apart from reduced gastrointestinal blood flow, phenylephrine may reduce cardiac output. Although this is not a consistent finding, it may be explained by a baroreceptormediated reduced heart rate and possibly reduced contractility. Aside from substantial tachycardia and proarrhythmia potential, both epinephrine and norepinephrine may have significant metabolic side effects, including sustained hyperglycemia due to β-adrenergic stimulation of hepatic gluconeogenesis and down-regulation of peripheral insulin receptors. Further, epinephrine may lead to significant hyperlactatemia via the stimulation of muscular β receptors. Consequently, excessive stimulation of glycoclysis leads to the overproduction of lactate. Epinephrine is also known to cause a significant reduction in the hepatosplanchnic oxygen supply. Catecholamines stimulate α receptors to activate platelets and induce a hypercoagulable state. Such hypercoagulability may be aggravated by α-adrenergic-mediated vasoconstriction. Consequent thrombosis or vasoconstriction could further impair vital organ perfusion. Also, adrenergic receptor stimulation exerts several immune-modulating effects. Whereas α receptors mediate immune-suppressive effects by increasing tumor necrosis factor α, stimulation of β receptors improves immune function by releasing interleukin-10 to reduce dendritic cell migration. This influences antigen expression and contact hypersensitivity responses. Thus, a number of complications involving multiple organ systems may occur when administering catecholamines to support BP.

Risk Assessment The occurrence of adverse effects during vasopressor therapy with catecholamines depends not only on the doses used but

also on individual patient characteristics. Patients with coronary heart disease or congestive heart failure are more prone to develop tachyarrhythmias, myocardial ischemia, or myocardial infarction during therapy with catecholamine vasopressors. Owing to a reduced arrhythmogenic threshold in the elderly, catecholamine-induced tachyarrhythmias occur at much lower doses in older patients than in younger ones. Moreover, the α-receptor-mediated increase in pulmonary vascular resistance may significantly impair right heart function in patients suffering from chronic pulmonary hypertension or right ventricular failure. If fluids and inotropic therapy fail to restore normovolemia and sufficient cardiac output, complications caused by catecholamine vasopressor therapy may occur sooner and with greater severity than would otherwise be the case. In this circumstance, catecholamine vasopressors may produce tissue hypoxia by aggravating peripheral vasoconstriction and significantly interfering with vital organ perfusion. Thus, ensuring adequate cardiac output with fluids and inotropic support is the mainstay of cardiovascular therapy, before initiating any vasopressor treatment.

Implications Adverse effects of high-dose catecholamine therapy substantially alter the risk-benefit ratio of any vasopressor therapy. Further, they increase the risk for adverse perioperative outcomes. Especially in elderly patients and those with cardiac dysfunction, catecholamine-induced tachycardia may significantly increase myocardial oxygen demand, thereby causing ischemia or myocardial infarction. Vasopressor-induced increased myocardial oxygen consumption not only compromises oxygen availability but also significantly reduces cardiac output and systemic oxygen delivery.

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Chapter 2

Vasopressors: Vasoconstrictor Drugs

9

of new tachyarrhythmias (8.3%) compared with high-dose norepinephrine alone (54.3%). Although arginine vasopressin has no antiarrhythmic activity by itself, adding it to high-dose norepinephrine in patients with advanced vasodilatory shock after cardiopulmonary bypass can significantly reduce norepinephrine needs and facilitate spontaneous conversion of about 50% of new-onset tachyarrhythmias independent of antiarrhythmic therapy. In contrast to high-dose norepinephrine, the significantly lower heart rates after arginine vasopressin therapy in patients with advanced vasodilatory shock can substantially reduce myocardial oxygen demand. There is now evidence of improved myocardial performance with norepinephrine–arginine vasopressin, likely owing to the reduced need for norepinephrine. Adverse effects of arginine vasopressin include possible deterioration of hepatic function and reduced platelet counts; however, reduced platelet counts do not appear to lead to increased clinical bleeding. Effects of arginine vasopressin on gastrointestinal blood flow have been inadequately studied. Although some authorities fear gastrointestinal hypoperfusion, there is evidence that arginine vasopressin may actually improve gastrointestinal perfusion when given continuously at doses of 4 units/hour in patients with advanced vasodilatory shock. At present, because there are no data supporting a beneficial effect on patient outcomes with the administration of supplementary arginine vasopressin in cases of advanced vasodilatory shock, its use with catecholamine vasopressors to reduce the latter’s toxicity can be advised only as a last resort.

MANAGEMENT If vasopressors are not necessary, do not use them. However, do assure normovolemia and adequate inotropic therapy. If cardiac output is still inadequate, administer catecholamine vasopressors in the lowest possible doses. In patients with significant cardiovascular dysfunction, even this may not be possible. If this is the case, symptomatic therapy, such as that for new-onset tachyarrhythmias, is the only therapy for catecholamine-induced complications. Striking recent evidence suggests that supraphysiologic doses of hydrocortisone (200 to 300 mg/day) not only significantly improve cardiovascular function and reduce catecholamine requirements but also reduce mortality in patients with septic shock. Possible mechanisms include relief of relative adrenal insufficiency as well as unspecific, permissive effects leading to up-regulation of adrenergic receptors. Also, hydrocortisone may favorably alter several pathophysiologically relevant inflammatory pathways that contribute to cardiovascular failure. Adverse hydrocortisone effects appear to occur independent of the dosage used and include hypernatremia and hyperglycemia. It is unknown whether hydrocortisone-mediated immune modulation or aggravation of catabolic metabolism is clinically relevant. Arginine vasopressin is used as a supplementary vasopressor in the treatment of advanced vasodilatory shock. Several studies show that continuous arginine vasopressin (4 units/hour) significantly improves hemodynamic variables and reduces catecholamine vasopressor requirements. In these cases, combined arginine vasopressin–norepinephrine infusion leads to a significant reduction in the incidence

PREVENTION Assurance of adequate volume and inotropic therapy to guarantee sufficient cardiac output are the most important preventive measures to avoid catecholamine vasopressormediated complications. Infusion of high dosages of hydrocortisone may reduce the need for high-dose norepinephrine therapy and thus reduce catecholamine-associated complications. Also, recent evidence suggests that a supplementary continuous infusion of arginine vasopressin (4 units/hour) might contribute to improved hemodynamic stability, fewer norepinephrine-related complications, and higher survival rates, but only when started before norepinephrine doses exceed 0.6 μg/kg per minute.

Further Reading Annane D, Sebille V, Charpentier C, et al: Effect of treatment with low doses of hydrocortisone and fludrocortisone on mortality in patients with septic shock. JAMA 288:862-871, 2002. Dellinger RP: Cardiovascular management of septic shock. Crit Care Med 31:946-955, 2003. Dunser MW, Mayr AJ, Ulmer H, et al: Arginine vasopressin in advanced vasodilatory shock: A prospective, randomized, controlled study. Circulation 107:2313-2319, 2003. Heyndrickx GR, Boettcher DH, Vatner SF: Effects of angiotensin, vasopressin, and methoxamine on cardiac function and blood flow distribution in conscious dogs. Am J Physiol 231:1579-1587, 1976. James JH, Luchette FA, McCarter FD, Fischer JE: Lactate is an unreliable indicator of tissue hypoxia in injury or sepsis. Lancet 354:505-508, 1999.

PHARMACOLOGY

Catecholamine-induced tachyarrhythmias may further aggravate myocardial ischemia. In particular, the development of atrial fibrillation with a rapid ventricular response—the most common tachyarrhythmia with catecholamine therapy— exacerbates cardiovascular dysfunction due to a loss of atrial transport function and reduced ventricular filling. This can cause a substantial reduction in cardiac output, with a subsequent backward increase in pulmonary vascular resistance, leading to right ventricular failure and further deterioration of cardiovascular function. Reduced hepatic, splanchnic, or intestinal mucosal oxygen delivery with prolonged epinephrine or dopamine infusions can increase organ damage, facilitate endotoxin production, and exacerbate systemic inflammation and multiple organ dysfunction. Arterial lactate concentrations correlate with patient outcome, because hyperlactatemia may increase perioperative mortality irrespective of metabolic acidosis. Moreover, elevated serum glucose concentrations significantly contribute to adverse patient outcomes, especially among the critically ill. Theoretically, catecholamine-induced hypercoagulability may facilitate thrombus formation at the microcirculatory level, thus precipitating multiorgan system damage; however, there is no clinical evidence of this. Such hypercoagulability may also facilitate the evolution of perioperative myocardial infarction. Further, it is unknown whether adrenergic vasopressor-mediated immune modulation influences immune responses in the perioperative setting.

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Lorton D, Lubahn C, Bellinger DL: Potential use of drugs that target neuralimmune pathways in the treatment of rheumatoid arthritis and other autoimmune diseases. Curr Drug Targets Inflamm Allergy 2:1-30, 2003. Luckner G, Dunser MW, Jochberger S, et al: Arginine vasopressin in 316 patients with advanced vasodilatory shock. Crit Care Med 33:2659-2666, 2005. Maestroni GJ, Mazzola P: Langerhans cells beta 2-adrenoceptors: Role in migration, cytokine production, Th priming and contact hypersensitivity. J Neuroimmunol 144:91-99, 2003. Marik PE, Varon J: The hemodynamic derangements in sepsis: Implications for treatment strategies. Chest 114:854-860, 1998. Meier-Hellmann A, Reinhart K, Bredle DL, et al: Epinephrine impairs splanchnic perfusion in septic shock. Crit Care Med 25:399-404, 1997. Practice parameters for hemodynamic support of sepsis in adult patients in sepsis. Task Force of the American College of Critical Care

Medicine, Society of Critical Care Medicine. Crit Care Med 27: 639-660, 1999. Rudis MI, Basha MA, Zarowitz BJ: Is it time to reposition vasopressors and inotropes in sepsis? Crit Care Med 24:525-537, 1996. Schutz W, Anhaupl T, Gauss A: Principles of catecholamine therapy. 1. Characterization of clinically relevant sympathomimetics. Anasthesiol Intensivmed Notfallmed Schmerzther 35:67-81, 2000. Trager K, DeBacker D, Radermacher P: Metabolic alterations in sepsis and vasoactive drug-related metabolic effects. Curr Opin Crit Care 9:271-278, 2003. van den Berghe G, Wouters P, Weekers F, et al: Intensive insulin therapy in the critically ill patient. N Engl J Med 345:1359-1367, 2001. Zhang H, De Jongh R, DeBacker D, et al: Effects of alpha- and beta-adrenergic stimulation on hepatosplanchnic perfusion and oxygen extraction in endotoxic shock. Crit Care Med 29:581-588, 2001.

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Krishna M. Natrajan and Ray P. Liao

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3

Inotropic Drugs Case Synopsis A 72-year-old man with mitral regurgitation has mitral valve replacement. His preoperative transesophageal echocardiogram (TEE) reveals reduced left ventricular function and moderate pulmonary hypertension. Just before separation from cardiopulmonary bypass (CPB), a 50 μg/kg bolus of milrinone is given, followed by an infusion at 0.5 μg/kg per minute, along with epinephrine at 0.03 μg/kg per minute. The TEE reveals good left ventricular function with adequate filling after release of the aortic cross-clamp, but the patient cannot be weaned from CPB owing to low mean arterial pressure. Pulmonary artery catheter data show a cardiac index of 2.8 L/min/m2 and systemic vascular resistance of 550 dyne . sec . cm–5. The addition of vasopressin (4 units/hour) enables weaning from CPB, after which the heart rate is 94 beats per minute and the mean arterial pressure is 72 mm Hg.

PROBLEM ANALYSIS Definition Inotropic drugs (Table 3-1) are classified as (1) naturally occurring catecholamines (e.g., dopamine, epinephrine, norepinephrine), (2) synthetic catecholamines (e.g., dobutamine, isoproterenol), or (3) phosphodiesterase-3 inhibitors (e.g., amrinone, milrinone). They are commonly administered solely or used in combination to treat low-output syndromes that are frequently encountered in congestive heart failure and myocardial infarction and following openheart surgery. The primary effect of inotropic drugs is to increase contractility, which ultimately increases cardiac output and promotes tissue perfusion.

Recognition The case synopsis illustrates the need to tailor appropriate therapy. Depressed left ventricular function with elevated pulmonary artery pressure suggests the need for inotropic

Table 3–1

■

Inotropic Drugs

Digitalis Digoxin Digitoxin Ouabain Catecholamines Natural Epinephrine Norepinephrine Dopamine Synthetic Dobutamine Dopexamine Isoproterenol Synthetic noncatecholamines Indirect acting Ephedrine

Mephentermine Amphetamines Metaraminol Direct acting Phenylephrine Methoxamine Phosphodiesterase-3 inhibitors Amrinone Milrinone Enoximone Miscellaneous Calcium Glucagon Thyroid hormone

support, but with a drug that does not increase pulmonary vascular resistance (PVR). Milrinone is one option because it increases cardiac output and lowers PVR. However, it also significantly lowers systemic vascular resistance (SVR), which can jeopardize perfusion of the heart and other vital organs. Reduced SVR with milrinone may require therapy with a vasopressor, such as norepinephrine, epinephrine, phenylephrine, or vasopressin. Notably, vasopressin increases SVR without increasing pulmonary artery pressure.

Risk Assessment The primary goal of inotropic drugs is to improve myocardial contractility and increase cardiac output, vital organ perfusion, and tissue oxygen delivery (Table 3-2). However, these drugs have other effects that can be useful or problematic, depending on the circumstances. Their effects on SVR are important and can be used to divide the drugs into two groups: vasoconstrictors (epinephrine, norepinephrine, dopamine) and vasodilators (dobutamine, isoproterenol, milrinone). Epinephrine and norepinephrine are naturally occurring catecholamines used in cardiac emergencies. The inotropic and vasoconstrictive responses are mediated by the activation of adrenergic receptors. The effects of these drugs can be titrated to the desired level owing to their linear dose response, rapid (almost immediate) onset of action, and fast elimination. Dopamine is another inotrope with vasoconstrictive properties. Its positive inotropic effect is mediated by the release of norepinephrine from nerve terminals. Dopamine’s pharmacodynamic effect is dose dependent, and the hemodynamic profile with low, medium, and high doses can vary greatly among individuals, with higher doses commonly producing an increase in SVR. Dopamine has the theoretical advantage of selective renal and mesenteric vascular dilatation, thus enhancing renal blood flow and natriuresis while preventing mesenteric ischemia in low cardiac output states. However, the clinical value of this effect remains uncertain. Isoproterenol and its chemical derivative dobutamine are vasodilators. They act directly on β-adrenergic receptors 11

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Hemodynamic Profile of Inotropic Drugs

Drug

CO

HR

MAP

VR

SVR

PVR

MCO

Epinephrine Norepinephrine Dopamine Dobutamine Isoproterenol Milrinone

↑↑↑ ↑↑ ↑↑ ↑↑ ↑↑ ↑↑

↑↑↑ ↑↑ ↑↑ ↑↑ ↑↑↑ ←→

↑ ↑↑ ↑ ↓ ↓↓ ↓↓

↑ ↑↑↑ ↑ ↓ ↓ ↓↓

↑↑↑ ↑↑↑ ↑↑ ↓ ↓↓↓ ↓↓↓

↑ ↑↑ ↑↑ ↓↓ ↓↓ ↓↓↓

↑↑↑ ↑↑↑ ↑↑ ↑↑ ↑↑↑ ←→

CO, cardiac output; HR, heart rate; MAP, mean arterial pressure; MCO, myocardial oxygen consumption; PVR, pulmonary vascular resistance; SVR, systemic vascular resistance; VR, venous return (preload). ↑, increase; ↓, decrease; ←→, unchanged.

to cause a positive inotropic response while decreasing SVR. Hypotension resulting from their use may require treatment with vasoconstrictors. Milrinone is a phosphodiesterase-3 inhibitor and prevents cyclic adenosine monophosphate (cAMP) degradation. It increases myocardial contractility in a linear doseresponse relationship without increasing myocardial oxygen consumption. The onset of action is slower than that of catecholamines, and its elimination half-life is longer, causing a prolonged duration of effect. Rapid administration produces vascular smooth muscle relaxation to reduce SVR and venous return. This can lead to hypotension, especially in hypovolemic patients. Concomitant use of volume loading and vasoconstrictors (e.g., phenylephrine, epinephrine, norepinephrine, vasopressin) attenuates milrinone’s potential for vasodilatation and hypotension. These inotropes are routinely used to treat the low cardiac output states often seen after CPB. The unique hemodynamic profile of each agent needs to be considered when deciding which inotrope, alone or in combination, will best facilitate a particular patient’s separation from CPB.

Implications Low cardiac output and hypotension following separation from CPB can reduce tissue perfusion and lead to vital organ dysfunction. The use of hemodynamic parameters and TEE identifies its cause. Treatment must be prompt and may require the administration of combined inotropes. The use of inotropes with vasodilator properties may necessitate the addition of a vasoconstrictor. Of the available vasoconstricting agents, vasopressin has the advantage of not increasing PVR. Arrhythmias resulting from inotropes can occur and should be monitored closely.

CPB is often complicated by post-CPB low cardiac output states that require inotropic support. Combined epinephrine and milrinone, which have different actions, increase cardiac contractility better than either agent alone. Epinephrine increases the formation of cAMP by activating adrenergic receptors, while milrinone reduces the rate of cAMP degradation by inhibiting the phosphodiesterase-3 enzyme. The cardiovascular actions and other effects of each of these drugs must be taken into consideration. At low doses, epinephrine has predominant β-adrenergic actions: positive inotropy and chronotropy. Milrinone is also a positive inotrope, and a systemic and pulmonary arterial vasodilator as well. A reduction in PVR may benefit patients with pulmonary artery hypertension. However, reduced SVR and systemic hypotension may require substantial volume loading and use of a vasoconstrictor, such as vasopressin, which has minimal effects on the pulmonary and splanchnic vasculature. Also, a reduction in either PVR or SVR may lead to a reflex increase in heart rate, mediated by pulmonary mechanoreceptors or aortic barorecptors, respectively. Phosphodiesterase-3 inhibitors (e.g., amrinone) have been associated with thrombocytopenia, possibly due to a metabolite-mediated toxic effect on platelets. However, milrinone appears to have a better safety profile. Further, like all positive inotropic agents, milrinone and epinephrine have the potential to initiate or aggravate troublesome arrhythmias. Causative or provocative factors, such as a concurrent physiologic imbalance and (perhaps) even the inotrope itself, must be quickly identified and corrected before significant hemodynamic compromise occurs.

PREVENTION ● ●

MANAGEMENT ●

●

●

●

TEE to assess left ventricular filling and function and maintain adequate preload and afterload Careful titration of inotropes to achieve adequate cardiac output and arterial pressure Vasoconstrictors as needed for low perfusion pressure due to vasodilator effects of inotropes Prompt correction of acid-base and electrolyte abnormalities

●

Ensure adequate preload and afterload Normalize metabolic parameters Titrate inotropic drugs precisely

TEE to assess left ventricular filling and function, preload, and afterload is often useful when weaning patients from CPB. Volume depletion should be corrected by the judicious use of fluids or blood products. It is also important to correct metabolic abnormalities, especially acidosis and hypokalemia. Inotropic support is commonly necessary for separation from CPB. The choice of inotropic agent or agents depends on surgical and patient factors. Precise titration of

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Further Reading Lehtonen LA, Antila S, Pentikainen PJ: Pharmacokinetics and pharmacodynamics of intravenous inotropic agents. Clin Pharmacokinet 43: 187-203, 2004.

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13

Levy JH, Bailey JM, Deeb GM: Intravenous milrinone in cardiac surgery. Ann Thorac Surg 73:325-330, 2002. Stoelting RK: Sympathomimetics: Pharmacology and Physiology in Anesthetic Practice, 3rd ed. Philadelphia, JB Lippincott, 1999, pp 259-277. Tisdale JE, Patel R, Webb CR, et al: Electrophysiologic and proarrhythmic effects of intravenous inotropic agents. Prog Cardiovasc Dis 38: 167-180, 1995.

PHARMACOLOGY

inotropic drugs is needed, especially when several drugs are used in combination.

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Case Synopsis Five years after heart transplantation, a 44-year-old man has laparoscopic cholecystectomy. After induction of anesthesia, the electrocardiogram (ECG) rhythm strip shows absent P waves and a wide QRS rhythm at a rate of 38 beats per minute (Fig. 4-1). Neither intravenous (IV) atropine (1.0 mg) nor ephedrine (10 mg) affects the rhythm or increases its rate. IV bolus epinephrine (200 μg) is given, followed by an IV infusion at 0.25 μg/kg per minute. The heart rate increases to 130 beats per minute, accompanied by frequent ventricular ectopic beats.

PROBLEM ANALYSIS Definition Epinephrine and other positive chronotropes, especially when given in large doses, can have deleterious effects in patients with cardiovascular disease. These effects include the following: ● ● ●

Untoward tachycardia and hypertension Generation of new or worse atrial or ventricular arrhythmias Increased myocardial oxygen consumption and ischemia due to increased heart rate and contractility and left ventricular wall stress

As the case synopsis illustrates, the effects in cardiac transplant patients are even more unpredictable or may be nonexistent owing to cardiac denervation. Consequently, only drugs that act directly on cardiac receptors should be used. Drugs such as atropine and ephedrine may be ineffective or unpredictable because they act indirectly to increase heart rate. Moreover, coronary atherosclerosis can occur in transplant recipients, with an incidence of up to 50% at 5 years. Without cardiac afferent innervation, ischemia in heart transplant recipients may be silent.

Recognition Bradycardia with absent P waves on the ECG can have many causes, including the following: ●

● ● ●

Sinoatrial (SA) exit block, sinus arrest, or sick sinus syndrome Atrioventricular (AV) junctional rhythm Idioventricular rhythm Slow atrial fibrillation or flutter

Also, P waves may be “buried” within the QRS complex with AV dissociation, such as in advanced second degree or third degree (complete) AV heart block. With third degree SA exit block, P waves are absent or have an altered morphology if a subsidiary atrial pacemaker has usurped atrial control. If so, they will be bifid, inverted, or flattened in leads with SA node origin (upright) P waves. On the surface ECG, third degree SA exit block is indistinguishable from sinus arrest. A subsidiary atrial, junctional, or ventricular pacemaker usually usurps ventricular control. Third degree SA exit block is distinguished from third degree AV block, which has the following features on ECG: ● ●

●

P waves present but with no relation to QRS complexes QRS complexes wide (ventricular origin or with ventricular aberration) or of normal width (AV junctional origin above bifurcation of bundle of His [common]) Slow ventricular escape rate (≈30 to 45 beats per minute)

Intraoperative bradycardia that is severe or that compromises the patient’s cardiac output or blood pressure must be treated aggressively. Assessment for reversible causes is important (Fig. 4-2) and must occur simultaneously with treatment. Temporary pacing and drug therapy are the two main options. Two different classes of drugs are commonly used to increase the heart rate: anticholinergics (e.g., atropine, glycopyrrolate) and adrenergic receptor agonists (e.g., ephedrine, epinephrine, isoproterenol, dopamine). Direct adrenergic agonists are more reliable than ephedrine. Isoproterenol is a nonselective β agonist with chronotropic, inotropic, and vasodilatory effects. It is usually recommended to treat bradycardia after heart transplantation, but care must be exercised in the presence of coronary artery disease. Isoproterenol increases myocardial osygen consumption and may reduce coronary perfusion pressure, worsening ischemia. Thus, isoproterenol is no longer part of

Figure 4–1 ■ Bradycardia and absent P waves with ventricular escape rhythm. (From Conover MB: Understanding Electrocardiography, 8th ed. St. Louis, Mosby, 2003.)

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Chronotropic Drugs

15 PHARMACOLOGY

Figure 4–2 ■ Algorithm for the management of intraoperative bradycardia. AV, atrioventricular. (Modified from Guidelines 2000 for cardiopulmonary resuscitation and emergency cardiovascular care. Part 6: Advanced cardiovascular life support. Section 7: Algorithm approach to ACLS emergencies. 7C: A guide to the international ACLS algorithms. Circulation 102 [8 Suppl]: I142-I157, 2000.)

the advanced cardiovascular life support algorithms for the emergency treatment of bradycardia. The side effects of atropine are as follows: ● ● ● ●

Excessive tachycardia; arrhythmias Pupillary dilatation, blurred vision, dry mouth Difficulty in micturition; decreased intestinal peristalsis Central anticholinergic crisis (e.g., ataxia, restlessness, delirium, coma) (This cannot occur with glycopyrrolate because it does not cross the blood-brain barrier.)

Atropine is ineffective in heart transplant patients owing to the lack of vagal innervation. In fact, in some cases, it may provoke bradyarrhythmias. Ephedrine acts predominantly by a presynaptic mechanism (i.e., indirect release of catecholamines) and may be unpredictable or ineffective owing to cardiac sympathetic denervation in heart transplant recipients. However, it offers some protection against many reflex-mediated causes of bradycardia and produces a high resting heart rate. Bradyarrhythmias occurring late

after heart transplantation, without an obvious reversible cause, may be a sign of ischemia or chronic rejection.

Risk Assessment ●

●

●

Heart transplant patients have denervated hearts and are prone to accelerated coronary vasculopathy. Effects of chronotropic drugs are unpredictable or nonexistent owing to cardiac denervation in heart transient recipients. Epinephrine can exacerbate ischemia by causing tachycardia, hypertension, increased contractility, and arrhythmias in patients with intact hearts, whether diseased or not.

Epinephrine is given as an IV bolus or infusion in emergencies. Typical starting infusion rates are 0.03 to 0.2 μg/kg per minute, with titration to the desired effect. The goal should be to restore the heart rate to greater than 60 beats per minute while avoiding excess tachycardia.

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However, temporary pacing is often the preferred treatment for nontransient, severe bradycardia and can be rapidly instituted via the noninvasive transcutaneous or transesophageal (atrial pacing only; requires intact AV conduction) route. Pacing is more predictable (i.e., precision titration of rate, can be turned “on” or “off ” as needed) than treatment with positive chronotropic drugs, which have the following disadvantages: ● ●

● ●

May cause excess tachycardia or arrhythmias May cause myocardial ischemia or decompensation (i.e., heart failure) May take time or fail to produce the desired effect May produce adverse drug effects that are compounded by the drugs used to treat them

Implications Tachycardia associated with severe ventricular ectopy must be treated urgently, because it may degenerate into ventricular tachycardia-fibrillation. Also, the potential for myocardial ischemia exists if myocardial oxygen consumption exceeds demand.

MANAGEMENT ●

● ●

Cease the epinephrine infusion and allow its plasma concentration to decrease. Prepare for temporary pacing if the bradycardia recurs. Assess for reversible causes of intraoperative bradycardia (see Fig. 4-2).

Low-dose epinephrine infusions may restore the heart rate without adverse effects. If drug therapy is ineffective, is contraindicated, or causes complications, pacing should be instituted. Temporary transcutaneous pacing is a class I therapy for the emergency treatment of severe bradycardia. If available, transesophageal atrial pacing is useful (with intact AV conduction). Arrangements should be made for the insertion of a temporary pacing pulmonary artery catheter or transvenous pacing catheter.

PREVENTION ●

●

Suspect coronary artery disease in heart transplant recipients more than 2 years post transplant. Recognize the implications of cardiac denervation for treating bradycardia with drugs.

●

●

●

Anticipate and avoid common reversible causes of intraoperative bradycardia. Avoid high doses of chronotropic drugs by carefully titrating smaller doses to effect. Use temporary pacing for severe bradycardia or when drugs fail.

Careful preoperative evaluation is important to identify patients at increased risk for bradycardia. Pretreatment with a chronotrope and avoidance of known causes of bradycardia may prevent tachycardia or arrhythmias from occurring. In some cases, pacing therapy is required preoperatively, depending on the underlying rhythm (e.g., advanced second degree or complete AV heart block). There are special considerations for heart transplant recipients who develop intraoperative bradycardia.

Further Reading Atlee JL, Pattison CZ, Mathews EL, et al: Transesophageal atrial pacing for intraoperative sinus bradycardia or AV junctional rhythm: Feasibility as prophylaxis in 200 anesthetized adults and hemodynamic effects of treatment. J Cardiothorac Vasc Anesth 7:436-441, 1993. Bernheim A, Fatio R, Kiowski W, et al: Atropine often results in complete atrioventricular block or sinus arrest after cardiac transplantation: An unpredictable and dose-independent phenomenon. Transplantation 77:1181-1185, 2004. Brawn JH, Taylor P: Muscarinic receptor agonists and antagonists. In Hardman JG, Limbird LE (eds): Goodman and Gilman’s The Pharmacological Basis of Therapeutics, 10th ed. New York, McGrawHill, 2001, pp 155-174. Conover MB: Understanding Electrocardiography, 7th ed. St. Louis, Mosby, 1996. Gao SZ, Schroeder JS, Alderman EL, et al: Prevalence of accelerated coronary artery disease in heart transplant survivors: Comparison of cyclosporine and azathioprine regimens. Circulation 80:100-105, 1989. Guidelines 2000 for cardiopulmonary resuscitation and emergency cardiovascular care. Part 6: Advanced cardiovascular life support. Section 5: Pharmacology. I: Agents for arrhythmias. Circulation 102 (8 Suppl): I112-I128, 2000. Guidelines 2000 for cardiopulmonary resuscitation and emergency cardiovascular care. Part 6: Advanced cardiovascular life support. Section 7: Algorithm approach to ACLS emergencies. 7C: A guide to the international ACLS algorithms. Circulation 102(8 Suppl):I142-I157, 2000. Hoffman BB: Catecholamines, sympathomimetic drugs, and adrenergic receptor antagonists. In Hardman JG, Limbird LE (eds): Goodman and Gilman’s The Pharmacological Basis of Therapeutics, 10th ed. New York, McGraw-Hill, 2001, pp 215-268. Quinlan JJ, Firestone S, Firestone LL: Anesthesia for heart, lung, and heartlung transplantation. In Kaplan JA, Reich DL, Konstadt SN (eds): Cardiac Anesthesia, 4th ed. Philadelphia, WB Saunders, 1999. Weinfeld MS, Kartashov A, Piana R, et al: Bradycardia: A late complication following cardiac transplantation. Am J Cardiol 78:969-971, 1996.

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5

Drugs Affecting the Renin-Angiotensin System Laura Stover Case Synopsis A 95-kg, 70-year-old man is scheduled to have left internal carotid endarterectomy. He takes nicardipine (50 mg/day) and irbesartan (150 mg/day), an angiotensin II receptor antagonist, for hypertension. He took his usual doses of both medications on the morning of surgery. Preoperative tests included a transthoracic echocardiogram that showed normal left ventricular systolic function and septal hypertrophy. Blood pressure and heart rate immediately before induction of anesthesia were 150/70 mm Hg and 56 beats per minute, respectively. After receiving 900 mL of crystalloid, he was induced slowly with sufentanil (45 μg), propofol (140 mg), and vecuronium (7 mg), with subsequent endotracheal intubation and anesthetic maintenance with oxygen and nitrous oxide (50:50) and a propofol infusion. Three minutes after induction, his blood pressure fell to 92/44 mm Hg. Despite repeated intravenous boluses of ephedrine (20 mg total), his blood pressure was 47/30 mm Hg 5 minutes after induction.

PROBLEM ANALYSIS Definition Renin-angiotensin system (RAS) antagonists include both angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor antagonists. These drugs are used with increasing frequency to treat hypertension and heart failure in selected patients. ACE inhibitors and angiotensin II receptor antagonists cause a blockage of the RAS that can adversely affect hemodynamics during anesthesia and surgery. Although anesthesia is not invariably associated with hemodynamic instability in RAS-blocked patients, unexpected episodes of refractory hypotension have been reported. Also, RAS antagonists, specifically ACE inhibitors, have been associated with potentially life-threatening angioedema of the head and neck. The RAS plays an essential role in the regulation of vascular tone and extracellular fluid volume. As shown in Figure 5-1, sympathetic stimulation via β1-adrenergic receptors, renal artery hypotension, and decreased sodium delivery to the distal tubules stimulate the release of renin by the kidney. Renin is a proteolytic enzyme that cleaves to the circulating substrate angiotensinogen to form angiotensin I, which has little intrinsic pharmacologic activity. Angiotensin I is converted immediately to angiotensin II via a reaction catalyzed by ACE, which is present in vascular endothelium and lung tissue. In the short term (e.g., intraoperatively), angiotensin II contributes to vascular homeostasis by increasing vascular (especially arteriolar) tone. It acts directly on angiotensin II receptors and indirectly by enhancing sympathetic adrenergic function to increase vascular tone, which is necessary to maintain adequate perfusion pressure in patients with hypovolemia or reduced cardiac output. In the longer term (e.g., hours to days), angiotensin II contributes to vascular

homeostasis by its effect on extracellular fluid volume. It causes the adrenal cortex to release aldosterone, a hormone that acts on the kidneys to increase sodium and fluid retention. Angiotensin II also stimulates the release of vasopressin (i.e., antidiuretic hormone) from the posterior pituitary, which causes the kidneys to increase fluid retention. Blocking angiotensin II–mediated increased vascular tone and relative reductions in intravascular volume in patients receiving RAS antagonists chronically may cause refractory hypotension following the induction of anesthesia. Angioedema of the oropharynx or larynx has been recognized as an unusual complication of ACE inhibitor therapy. ACE-induced angioedema usually manifests spontaneously within hours to days of the initiation of treatment and has been described in association with anesthesia and Sympathetic stimulation Hypotension Decreased sodium delivery Angiotensinogen

Kidneys

Renin

Angiotensin I

Cardiac and vascular hypertrophy

ACE

Adrenal cortex

Angiotensin II

Pituitary

Aldosterone

ADH Thirst Systemic vasoconstriction

Renal sodium and fluid retention

Increased blood volume

Figure 5–1 ■ The renin-angiotensin system. ACE, angiotensin-converting enzyme; ADH, antidiuretic hormone.

17

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endotracheal intubation. Edema of the tongue is commonly the presenting symptom, with involvement of the face, lips, floor of the mouth, pharynx, glottis, or larynx frequently observed. The precise mechanism of angioedema formation is uncertain. Because it is likely mediated by the kallikreinbradykinin system, it is probably a biochemical rather than an immunologic phenomenon. Bradykinin is a potent vasodilator that increases vascular permeability and produces tissue edema. Kinase II (which is identical to ACE) is the major tissue enzyme responsible for the breakdown of bradykinin. ACE inhibitors inhibit kinase II to prevent bradykinin breakdown. Angioedema associated with ACE inhibitor therapy may therefore be a result of inhibition of bradykinin inactivation by kinase II.

Recognition HYPOTENSION Recognition of RAS antagonist therapy as a contributor to hypotension relies on the exclusion of other intraoperative events that may produce hypotension. A heightened index of suspicion in patients chronically treated with these drugs, especially those with a history of severe hypotension or left ventricular diastolic dysfunction, is justified. The temporal relationship between cardiovascular instability and induction of anesthesia in patients chronically treated with RAS antagonists, along with the failure of ephedrine in usual doses (10 to 20 mg IV in adult patients) to resolve the hypotension, makes RAS antagonism a likely cause of hypotension. ANGIOEDEMA Recognition of ACE inhibition as the cause of angioedema relies on the exclusion of other perioperative events associated with swelling of the head and neck (e.g., allergy, anaphylaxis), as well as the knowledge that angioedema can occur (though infrequently) with ACE inhibitors. When it does occur, angioedema is usually temporally related to the initiation of ACE inhibitor therapy.

Risk Assessment HYPOTENSION A number of patient factors modify the risk of severe hypotension with the induction of anesthesia in those treated with RAS antagonists. Patients treated with other antihypertensive agents in combination with a RAS antagonist are more likely to have refractory hypotension on induction. Likewise, the combination of RAS antagonists and other vasodilator drugs (e.g., amiodarone) increases the risk for hypotension. Patients with “complete” RAS blockade, which is associated with high doses and recent administration, are more likely to be unstable on induction. Patients with a history of severe hypertension, especially those with left ventricular diastolic dysfunction (which amplifies the dependence of blood pressure on intravascular volume in patients receiving ACE inhibitors), are also at increased risk for refractory hypotension. Short-term preoperative RAS inhibition (1 to 2 days) in normotensive or mildly hypertensive subjects

is less likely to result in refractory hypotension on induction. Patients who continue therapy until the day of surgery are also at increased risk. One review found that the incidence of hypotension on induction of anesthesia in patients with a history of severe hypertension was 75% to 100% when ACE inhibitors were continued until the day of surgery. ANGIOEDEMA Angioedema involving the oropharynx or larynx is an unusual complication of ACE inhibitor therapy, occurring on average in 0.1% of patients taking captopril, lisinopril, or enalapril; the incidence in patients taking enalapril may be slightly higher (0.2%) than in those taking the other two drugs. Patients are at highest risk within the first week of starting an ACE inhibitor; a retrospective study of 36,000 patients receiving enalapril showed that 60% to 70% of cases of angioedema occurred within this period. However, angioedema has occurred suddenly after months to years of therapy, and about 20% of known cases of angioedema occurring in this context may involve severe symptoms (e.g., dyspnea, stridor, laryngospasm). Unfortunately, there are no characteristics to predict which patients will progress to lifethreatening airway compromise.

Implications Concerning the risk for refractory hypotension on induction of anesthesia in patients taking RAS antagonists, there is no consensus on continuing or discontinuing the drug in the immediate preoperative period. For this class of drugs, the elimination half-life does not necessarily predict the duration of action, making recommendations with respect to perioperative dosing difficult.

MANAGEMENT Hypotension If RAS blockade contributes significantly to refractory hypotension after induction of anesthesia, therapy relies on the prompt restoration of adequate systemic vascular resistance and venous tone1 with phenylephrine or vasopressin, as well as increased intravenous fluid administration. Remedial actions for managing hypotension related to RAS antagonists include discontinuing or reducing the dose of other agents that might contribute to hypotension. Advanced cardiovascular life support protocols should be invoked in the event of cardiovascular collapse.

Angioedema Most occurrences of ACE inhibitor–induced angioedema are mild and resolve spontaneously or with discontinuation of the drug. However, swelling may progress rapidly to include the posterior pharynx or larynx, causing partial or complete 1 Venoconstriction (venous capacitance bed) indirectly increases venous return and preload.

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Chapter 5

Drugs Affecting the Renin-Angiotensin System

19

time to allow the return of RAS activity. However, any risk reduction might be at the expense of optimal therapy for hypertension or heart failure. Identifying patients at the greatest risk for severe hypotension (those with severe hypertension or those receiving high doses of RAS antagonists, RAS antagonists in combination with other antihypertensives, or RAS antagonists chronically), along with intravenous fluid loading before the induction of anesthesia, may reduce the risk for refractory hypotension. Such pretreatment combined with the early use of vasopressors for hypotension believed to be caused by RAS blockade will shorten the duration of hypotension. Consistent with the foregoing, frequent blood pressure measurement immediately after induction (direct arterial pressure monitoring may be necessary) contributes to the earlier detection of severe hypotension.

Further Reading PREVENTION As noted earlier, there is no consensus regarding the management of patients receiving RAS antagonist therapy in the immediate preoperative period. Discontinuation of RAS antagonists during this period reduces the risk for hypotension with anesthesia induction, provided there is sufficient

Colson P, Ryckwaert F, Coriat P: Renin angiotensin antagonists and anesthesia. Anesth Analg 89:1143-1155, 1999. Dean DE, Schultz DL, Powers RH: Asphyxia due to angiotensin converting enzyme (ACE) inhibitor mediated angioedema of the tongue during the treatment of hypertensive heart disease. J Forensic Sci 46: 1239-1243, 2001. Kharash ED: Angiotensin-converting enzyme inhibitor–induced angioedema associated with endotracheal intubation. Anesth Analg 74:602-604, 1992.

PHARMACOLOGY

upper airway obstruction. The symptoms may progress despite aggressive therapy and may recur hours after apparent resolution. Angioedema caused by ACE inhibitors can be fatal. Management ranges from simply stopping the ACE inhibitor to endotracheal intubation or tracheostomy. Mild cases confined to the anterior tongue or lips generally resolve with discontinuation of the drug and administration of intravenous diphenhydramine and corticosteroids. More severe cases involving the pharynx and associated with dysphagia may require subcutaneous epinephrine, tracheal intubation, or both. As with any evolving process involving the airway, the potential for life-threatening airway obstruction dictates close observation and prompt intervention. Following resolution of the acute process, a note should be made in the patient’s medical record of this potentially lifethreatening adverse reaction to ACE inhibitor therapy, and the patient should receive appropriate counseling.

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CARDIAC DRUGS

Phosphodiesterase Inhibitors

6

Gregory M. Janelle Case Synopsis A 56-year-old man presents for emergent repair of an open olecranon fracture sustained in a motorcycle accident. There are no other signs of trauma. His past medical history is significant for hypertension, dyslipidemia, gastroesophageal reflux disease, and a 40-pack-year history of tobacco use. His father died from a myocardial infarction at age 60. He has no allergies and denies alcohol or other illicit drug use. Medications prior to admission include atorvastatin, ramipril, and esomeprazole. Baseline vital signs include blood pressure, 148/74 mm Hg; heart rate, 86 beats per minute; and respiration, 18 breaths per minute and nonlabored. An electrocardiogram (ECG) in the emergency room shows normal sinus rhythm with no evidence of ischemic changes. The patient refuses regional anesthesia. Preoperative medications include midazolam 2 mg and sodium bicitrate 30 mL. After uneventful induction of general anesthesia (thiopental, fentanyl, and succinylcholine), anesthesia is continued with isoflurane. After surgical stimulation, the patient has hypertension (180/100 mm Hg) and tachycardia (115 beats per minute). Concomitantly, there is 2-mm downsloping ST depression in lead V5 of a calibrated, monitored ECG. The end-tidal isoflurane concentration is increased from 0.8% to 1.2%, and intravenous esmolol (20 mg) and sublingual nitroglycerin spray (0.4 mg × 2) are also given. Within minutes, the patient’s blood pressure drops to 60/40 mm Hg and his heart rate increases to 90 beats per minute. While treating this, the anesthesiologist has the circulating nurse call the patient’s wife to inquire about unreported drug use. He learns that the patient was taking sildenafil for erectile dysfunction along with his other medications.

PROBLEM ANALYSIS Definition Intraoperative myocardial ischemia is potentially life threatening, especially if it is not recognized and promptly treated. It demands utmost vigilance on the part of the anesthesiologist. Intraoperative ischemia is defined as ST deviation, relative to the preoperative, reference ECG, of 0.2 mV or greater in one lead or 0.1 mV or greater in two contiguous leads and lasting at least 10 minutes. Once ischemia is diagnosed, the anesthesiologist must identify and aggressively treat the cause. Based on this definition of intraoperative myocardial ischemia, the patient described in the case synopsis had at least demand ischemia and likely significant underlying coronary artery disease (CAD) as well. The case synopsis also illustrates that aggressive treatment of hypertension, tachycardia, and myocardial ischemia by increasing the end-tidal concentration of isoflurane, along with esmolol and sublingual nitroglycerin, can lead to profound hypotension in patients also taking phosphodiesterase-5 (PDE-5) inhibitors. This hypotension may further aggravate myocardial ischemia by reducing coronary perfusion pressure. In this case, the anesthesiologist was not expecting 20

the sudden, profound hypotension that resulted from his treatment, which was quite reasonable given the ECG evidence, the circulatory changes, and the patient’s past medical history. Unfortunately, the patient had failed to report his use of sildenafil. Only further (indirect) inquiry by an astute and knowledgeable anesthesiologist led to the discovery of the likely proximate cause of the patient’s hypotension. Sildenafil citrate is a highly selective PDE-5 inhibitor that interacts with organic nitrates such as nitroglycerin to potentiate vascular smooth muscle relaxation, with the potential to cause profound blood pressure reduction. For this reason, organic nitrates are contraindicated if sildenafil has been taken in the preceding 24 hours.

Recognition PDE-5 breaks down cyclic guanosine monophosphate (cGMP). Therefore, PDE-5 inhibitors such as sildenafil are expected to increase available cGMP. The formation of cGMP is stimulated by guanylate cyclase, which in turn is stimulated by nitric oxide (NO). Nitroglycerin is a potent NO donor, although its effects are more prominent in the venous capacitance bed, except in very high doses. Nonetheless, nitroglycerin does dilate epicardial coronary

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Chapter 6

Risk Assessment Although the intraoperative hypotension experienced by the patient described in the case synopsis was probably due to an adverse interaction between nitroglycerin and the PDE-5 inhibitor sildenafil, intraoperative hypotension has many other causes unrelated to this interaction (Table 6-1) that are discussed elsewhere in this book. In addition, for this patient, increasing the end-tidal isoflurane concentration and giving intravenous esmolol compounded his hypotension. Refractory hypotension is also associated with angiotensin-converting enzyme (ACE) inhibitors and selective antagonists of angiotensin II receptors, such as olmesartan (see Chapter 5). Patients with preoperative sympathetic blockade or volume depletion due to fasting, blood loss, or diuretic therapy have a reduced venous capacitance. This reduces venous return and cardiac output and often compounds hypotension with the induction of anesthesia. For patients on ACE inhibitors, angiotensin II (a potent vasoconstrictor) does not counter such hypotension.

Table 6–1

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Causes of Intraoperative Hypotension Unrelated to Phosphodiesterase-5 and Nitroglycerin Interactions

Anesthetics (IV and volatile agents) Central neuraxial anesthesia (spinal, epidural) Myocardial ischemia and reperfusion injury Heart failure (systolic or diastolic) Cardiac rhythm disturbances Chronic adrenocortical insufficiency Overly aggressive use of diuretics Recent hemo- or peritoneal dialysis Volume depletion related to third-space loss Inadequate fluid resuscitation Severe hemorrhage; hemorrhagic shock Hemothorax; hemopericardium Reduced venous return secondary to caval compression Restrictive pericarditis; pericardial effusion Tumors compressing or restricting heart Tumors compressing or restricting great vessels Severe bronchospasm; pneumothorax Increased intrathoracic pressure Excessive tidal volumes or airway pressures Sepsis and septic shock Anaphylactic and anaphylactoid reactions Carcinoid syndrome Monitoring artifacts Angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers

Phosphodiesterase Inhibitors

21

However, the timing of this patient’s hypotension makes it less likely that ramipril (an ACE inhibitor) was the primary agent that precipitated the profound decrease in blood pressure. The patient also had multiple risk factors for CAD: ● ● ● ● ●

Hypertension Age older than 50 years Dyslipidemia Tobacco abuse Strongly positive family history

Further, erectile dysfunction disproportionately affects patients with cardiovascular disease. Thus, one must consider that these patients may be receiving sildenafil or similar potent PDE inhibitors. As the case synopsis illustrates, patients may fail to report the use of these drugs. Finally, this patient had objective evidence of CAD: ECG changes consistent with ischemia associated with tachycardia and hypertension with surgical stimulation.

Implications The clinical effects of sildenafil and other PDE-5 inhibitors (e.g., tidalafil, vardenafil) are mediated by a local increase in available cGMP. This, in turn, leads directly to smooth muscle relaxation in the arteries, arterioles, and sinusoids of the corpus cavernosum. The net result with sildenafil alone is vasodilatation and enhanced erectile function. The reduction in systolic and diastolic blood pressure is modest (≈8 and 5.5 mm Hg, respectively). When given to healthy volunteers, sildenafil had no apparent orthostatic effects. Sildenafil has also been investigated as a potential treatment for pulmonary hypertension. In patients with severe congestive heart failure, sildenafil reduces mean pulmonary artery pressure and arteriolar resistance by 20% and 45%, respectively. However, the drug has no significant effect on the cardiac index, ejection fraction, or pulmonary capillary wedge pressure. The safety of sildenafil in patients with documented CAD has been the subject of numerous reports. In one recent controlled trial, patients with CAD receiving sildenafil reported improved erections and sexual performance but experienced more side effects (e.g., transient headache, hypertension, flushing, dyspepsia) compared with placebo. However, there were no serious drug-related cardiovascular effects. An American College of Cardiology–American Heart Association consensus statement asserts that the available evidence supports the general safety of sildenafil in patients with CAD. Patients should not receive PDE-5 inhibitors and nitrates concomitantly. In fact, the current sildenafil product label states that the use of nitrates with sildenafil is strictly contraindicated. The simultaneous administration of nitric oxide donors (e.g., nitroglycerin) results in a marked accumulation of cGMP. This occurs because nitrates increase the production of cGMP, whereas sildenafil prevents its breakdown. The net result is a pronounced reduction in blood pressure with symptomatic hypotension. Other drugs that attenuate or block compensatory hemodynamic responses, including β- or α-adrenergic blockers, ACE inhibitors, and angiotensin II receptor antagonists, can also dramatically

PHARMACOLOGY

arteries; also important to the anti-ischemic action of nitroglycerin are reduced venous return and decreased cardiac preload, which lessen myocardial wall stress and reduce oxygen consumption. Sildenafil is prescribed for erectile dysfunction because sexual stimulation normally results in the release of NO from nerves and endothelial cells in the corpus cavernosum and systemic blood vessels, and NO stimulates guanylate cyclase to promote the formation of cGMP. Both aging and peripheral vascular disease interfere with this process; hence, the rationale for prescribing sildenafil or other PGE-5 inhibitors.

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Pharmacology

exaggerate the adverse drug interaction between organic nitrates and PDE-5 inhibitors, especially when there is preexisting cardiovascular compromise. Twenty-one PDE genes have been cloned and belong to 11 PDE families based on their homology sequence and biochemical and pharmacologic properties. Table 6-2 depicts both experimental and clinical PDE inhibitors and their relative selectivity as inhibitors of PDE-1 through -11. Among these families, the PDE-3 inhibitors (e.g., enoximone, amrinone, milrinone, imazodan) are the most extensively studied group. By blocking the breakdown of cyclic adenosine monophosphate (cAMP), PDE-3 inhibitors reduce systemic and pulmonary arterial pressures. They also increase cardiac cAMP and Ca2+-induced Ca2+ release to increase myocardial contractility and the cardiac index, but without increasing myocardial oxygen consumption. Thus, PDE-3 inhibitors are considered positive inotropes and vasodilator agents. They have been used successfully in patients with advanced heart failure (both acutely and chronically) and as a bridge to cardiac transplantation. Thrombocytopenia limits the long-term use of amrinone, and the chronic use of milrinone has been associated with increased mortality in patients with New York Heart Association class III and IV heart failure. This mortality increase may be due to QTc prolongation with intravenous milrinone. The addition of a β-adrenergic blocking agent to low-dose milrinone therapy has been shown to reduce QTc prolongation and is associated with an improvement in patients’ functional status; however, sudden death was a relatively uncommon occurrence. Also, milrinone has been used to treat cerebral vasospasm associated with subarachnoid hemorrhage.

Table 6–2

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Experimental and Clinical Inhibitors of Phosphodiesterase and Their Relative Selectivity

Phosphodiesterase Inhibitor

Phosphodiesterase Selectivity (IC50)

IBMAX Papaverine EHNA Rolipram Dipyridamole

Nonselective (2-50 μM) Nonselective (5-25 μM) PDE-2 (1.0 μM) PDE-4 (2.0 μM) PDE-5 (0.9 μM) PDE-6 (0.38 μM) PDE-7 (9.0 μM) PDE-8 (4.5 μM) PDE-10 (1.1 μM) PDE-1 and -5 (0.1 μM) PDE-7 (35 μM) PDE-9 (1.15 μM) PDE-10 (1.0 μM) PDE-3 (1.0 μM) PDE-5 (3.9 nM) PDE-5 (0.76 μM) PDE-6 (0.15 μM) Nonselective (45-150 nM)

SCH51866

Enoximone Sildenafil Zaprinast Pentoxifylline

EHNA, erythro-9-[3-(2-hydroxynonyl)]adenine; IBMAX, 3-isobutyl-1-methylxanthine; IC50, concentration of PDE inhibitor with 50% activity against PDE; PDE, phosphodiesterase; SCH, succinylcholine. Adapted from Hetman JM, Robas N, Baxendale R, et al: Cloning and characterization of two splice variants of human phosphodiesterase 11A. Proc Natl Acad Sci U S A 97:12891-12895, 2000.

Inhibition of PDE-3 and PDE-4 may have therapeutic utility in reactive airway disease and for ameliorating pulmonary hypertension. PDE-4 inhibitors, such as compound A, cilomilast, and rolipram, also have anti-inflammatory and uterorelaxant effects. Finally, several commonly used drugs (e.g., papaverine, dipyridamole, pentoxifylline) appear to have significant nonselective PDE-inhibiting properties. Clinical effects of inhibition of the various PDE subtypes require further elucidation.

MANAGEMENT The management of perioperative myocardial ischemia and infarction is discussed in Chapter 76. Treatment for perioperative hypotension includes correction of the underlying pathophysiology and the administration of vasopressors if needed. For the patient described in the case synopsis, knowledge of all his preoperative medications would have permitted the recognition of potential drug-drug interactions (i.e., sildenafil-nitroglycerin) and prevented his profound hypotension. Therapy to counter nitroglycerin’s potentiation of sildenafil’s vasodilatory effect includes restoring intravascular volume by fluid resuscitation and increasing blood pressure with a vasoconstrictor such as phenylephrine, vasopressin, norepinephrine, epinephrine, or ephedrine. All are systemic arterial and venous vasoconstrictors, but phenylephrine and vasopressin have no β-adrenergic effects and would be the most judicious primary therapy in light of the patient’s predisposition for developing demand myocardial ischemia. Further, and importantly, by constricting the venous capacitance bed, α1 agonists such as phenylephrine and vasopressin increase venous return to augment preload and cardiac output. Refractory hypotension may necessitate the use of an intraaortic balloon counterpulsation device (see Chapter 98). Finally, administration of subsequent nitroglycerin doses is absolutely contraindicated.

PREVENTION Awareness is the key factor in preventing potentially lifethreatening drug-drug interactions. Unfortunately, erectile dysfunction still represents a social stigma in many cultures, which may prevent patients from reporting the problem and its treatment to their physicians and sexual partners. Sildenafil use increased by approximately 84% between 1998 and 2002. It was estimated that more than 14 million patients in the United States were taking sildenafil by 2001. With the advent of novel formulations of PDE-5 inhibitors and the reported growth in use among females and males between 18 and 45 years of age, it is likely that this number will well exceed 20 million patients by 2006. Although sildenafil is safe when taken by healthy patients, it should be administered with extreme caution in patients with cardiovascular disease. It is absolutely contraindicated in patients taking organic nitrates and those with hemodynamically significant aortic stenosis or hypertrophic obstructive cardiomyopathy. The cytochrome P-450 2C9 and 3A4

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Chapter 6

Further Reading Cheitlin MD, Hutter AM Jr, Brindis RG, et al: Use of sildenafil (Viagra) in patients with cardiovascular disease: ACC/AHA expert consensus document. Circulation 99:168-177, 1999. Hermann HC, Chang G, Klugherz BD, et al: Hemodynamic effects of sildenafil in men with severe coronary artery disease. N Engl J Med 342:1622-1626, 2000.

Phosphodiesterase Inhibitors

23

Hetman JM, Robas N, Baxendale R, et al: Cloning and characterization of two splice variants of human phosphodiesterase 11A. Proc Natl Acad Sci U S A 97:12891-12895, 2000. Jaski BE, Fifer MA, Wright RF, et al: Positive inotropic and vasodilator actions of milrinone in patients with severe congestive heart failure: Dose-response relationships and comparison to nitroprusside. J Clin Invest 75:643-649, 1985. Kulkarni SK, Patil CS: Phosphodiesterase 5 enzyme and its inhibitors: Update on pharmacological and therapeutical aspects. Methods Find Exp Clin Pharmacol 26:789-799, 2004. Landesberg G, Mosseri M, Wolf Y, et al: Perioperative myocardial ischemia and infarction: Identification by continuous 12-lead electrocardiogram with online ST-segment monitoring. Anesthesiology 96:264-270, 2002. Viagra (sildenafil citrate): US prescribing information. In Physicians’ Desk Reference, 57th ed. Montvale, NJ, Medical Economics, 2003, pp 2653-2656. Zusman RM, Morales A, Glasser DB, et al: Overall cardiovascular profile of sildenafil citrate. Am J Cardiol 83(Suppl):35C-44C, 1999.

PHARMACOLOGY

pathways are the primary pathways for the metabolism of sildenafil. Thus, potent inhibitors of the these cytochromes (e.g., cimetidine, erythromycin, digoxin, some statins) may increase sildenafil’s plasma concentration. In such patients, and in those with severely compromised renal or hepatic function, reduced starting doses of sildenafil have been advocated to reduce the incidence of significant untoward effects.

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7

Digitalis Emilio B. Lobato Case Synopsis A 70-year-old man is scheduled for a subtotal colectomy under general anesthesia. He has a history of anterior myocardial infarction and intermittent atrial fibrillation and is receiving digoxin. His preoperative serum digoxin and potassium concentrations are 1.5 ng/dL and 3.9 mEq/L, respectively. Preparation for surgery includes colonic enemas (given until clear). His digoxin is withheld. Soon after the patient is placed on mechanical ventilation, he develops atrioventricular junctional tachycardia (AVJT) at 95 to 100 beats per minute (Fig. 7-1). Pulse oximetry reveals an arterial blood oxygen saturation of 100%. The end-tidal carbon dioxide partial pressure is 22 mm Hg, and the serum potassium concentration is 3.0 mEq/L. Digitalis toxicity is the suspected cause of the AVJT. Intravenous potassium chloride is given, and ventilation is reduced. Eventually, AVJT gives way to sinus rhythm, and the surgical procedure continues uneventfully.

PROBLEM ANALYSIS

●

●

Definition The use of digitalis to treat congestive heart failure (CHF) has been eclipsed by the current widespread use of angiotensinconverting enzyme (ACE) inhibitors and β-blockers to treat this condition. Prospective, randomized clinical trials have shown conclusively that both ACE inhibitors and β-blockers reduce mortality, whereas digoxin does not. However, one meta-analysis of available clinical trials (2001) showed that digoxin had beneficial effects, even in patients treated with ACE inhibitors; these findings may extend to β-blockers, but specific data were lacking. The results of this meta-analysis strengthen the concept that digoxin still has beneficial clinical effects in symptomatic patients with CHF, including the ability to reduce hospitalizations. Further, most patients in these reviewed trials were also receiving diuretics. Thus, clinicians still offer digoxin to symptomatic patients or those at appreciable risk for hospitalization for CHF, with a reasonable expectation of some benefit. Digitalis increases myocardial contractility in patients with heart failure and reduces the ventricular rate in those with atrial fibrillation. Cardiac complications can result from therapeutic or toxic effects of digitalis, primarily due to inhibition of membrane Na+,K+-ATPase. Extracardiac complications usually involve the central nervous system and gastrointestinal tract. Monitoring serum concentrations of digoxin (normally, 0.9 to 2.0 ng/dL) may help prevent toxic effects; however, there is considerable overlap between digoxin’s toxic and therapeutic effects, especially with hypokalemia or increased sensitivity to its effects (e.g., patients with severe cardiac disease or hypothyroidism). To avoid sampling errors due to slow digoxin equilibration, blood must be drawn at least 4 hours after intravenous dosing or 12 hours after oral dosing. Elevated serum digoxin concentrations may be due to the following: ● ●

Overdose or increased bioavailability (e.g., digitalis gel caps) Reduced volume of distribution (especially in elderly patients)

24

Reduced excretion (e.g., renal failure, patients receiving quinidine) Displacement from binding sites (e.g., with calcium channel blockers)

Recognition Digitalis toxicity may be immediately apparent or difficult to recognize, especially if cardiac manifestations are due to underlying heart disease. The presenting signs and symptoms depend on whether the digitalis toxicity is acute or chronic. If acute, gastrointestinal symptoms may be prominent. If chronic, patients may present with nonspecific symptoms (e.g., weakness and malaise). However, the sole evidence of chronic toxicity may be new arrhythmias. CARDIAC MANIFESTATIONS Cardiac manifestations of digitalis toxicity (primarily arrhythmias) include the following: ● ● ● ● ● ● ●

Sinus bradycardia Ventricular premature beats Nonparoxysmal AVJT Wenckebach atrioventricular (AV) block Atrial tachycardia with varying AV block Bidirectional ventricular tachycardia Ventricular fibrillation

When interpreting electrocardiogram (ECG) findings in patients receiving digitalis, one must distinguish between

Figure 7–1 ■ Nonparoxysmal atrioventricular junctional tachycardia at 100 beats per minute. Negative P waves after each QRS complex indicate retrograde atrial capture.

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Chapter 7

●

● ●

●

T-wave changes (often the earliest sign), ranging from flattening to inversion or peaking of the terminal portion of the T wave Shortening of the Q-T interval ST-T segment flattening or depression, resulting in the classic concave (“scooped”) appearance (often more pronounced in ECG leads with tall R waves) Increased U-wave amplitude

Also, a slowed but irregular ventricular rate in atrial fibrillation implies a therapeutic digitalis effect. Regularization of the ventricular rate suggests toxicity and is usually due to the development of AV junctional rhythm (rate ≤70 beats per minute) or AVJT (rate >70 beats per minute). Cardiac complications can also result from the therapeutic effects of digitalis and include the following: ●

●

●

Increased risk for ventricular tachycardia and ventricular fibrillation in patients with Wolff-Parkinson-White syndrome and atrial fibrillation. Digitalis shortens refractoriness and speeds conduction in accessory AV conducting pathways. This may lead to preferential accessory pathway conduction and a greatly increased ventricular rate with atrial fibrillation (see Chapter 80). The latter can exceed 300 beats per minute and is limited solely by accessory pathway refractoriness. If this rate is sustained, there is a strong potential for early degeneration into ventricular tachycardia or ventricular fibrillation. Increased ventricular outflow tract obstruction in patients with asymmetrical ventricular septal hypertrophy, due to the positive inotropic effects of digitalis. Aggravation of myocardial ischemia in patients with coronary artery disease; this is “demand” ischemia due to digitalis-increased myocardial oxygen consumption.

Digitalis is ill-advised in any of these circumstances. The associated risks outweigh any potential benefits. ECG signs of toxicity occur in 5% to 20% of patients receiving digitalis. Almost any arrhythmia can result from the direct toxic or neurally mediated electrophysiologic effects of digitalis on cardiac muscle or the specialized conducting tissues (Table 7-1). The most common arrhythmia

Table 7–1

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Digitalis

in patients with sinus rhythm is the appearance of ventricular extrasystoles. With atrial fibrillation, regularization of the ventricular rate occurs due to the development of AV junctional rhythm or AVJT; this may be the first manifestation of digitalis toxicity. In fact, the development of accelerated AV junctional rhythm or idioventricular rhythm in patients with AV heart block is highly suggestive of digitalis toxicity. Two other arrhythmias are characteristically identified with digitalis toxicity: 1. Paroxysmal atrial tachycardia with AV heart block. This is due to increased atrial conduction time and reduced refractoriness, along with AV node conduction block. 2. Bidirectional ventricular tachycardia. In this case, QRS complexes alternate between two distinctly different morphologies. In some leads, distinct R and S waves alternate between each other. Table 7-2 lists arrhythmias associated with digitalis toxicity in decreasing order of frequency. Worsening of preexisting CHF is often the first symptom of digitalis-induced arrhythmias and should alert the clinician to possible toxicity. EXTRACARDIAC MANIFESTATIONS Extracardiac manifestations of digitalis toxicity include the following: ●

●

●

Gastrointestinal symptoms, including nausea, vomiting, diarrhea, and increased salivation, from stimulation of central vagal nuclei Central nervous system manifestations (more common in the elderly), including blurred vision, abnormal color perception (e.g., green halos), hallucinations, and frank delirium Acute life-threatening hyperkalemia, occurring with severe digitalis overdose and caused by paralysis of the Na+-K+ pump and outward intracellular K+ leak

Risk Assessment Knowledge of factors that may alter digitalis pharmacokinetics or myocardial sensitivity and thus predispose patients to digitalis toxicity is of paramount importance (Table 7-3). Elderly patients are at greater risk than younger ones, and

Electrophysiologic Effects of Therapeutic and Toxic Digitalis

Tissue

Therapeutic Effects

Clinical Manifestations

Toxic Effects

Clinical Manifestations

Sinus node

Slows sinus rate

Sinus bradycardia

Sinus pause; SA conduction block

Atrium

None

None

AV node/AVJ

↓ Conduction time

Purkinje fibers

↓ Refractoriness; ↑ repolarization ↓ Refractoriness

↓ Ventricular rate; ↑ P-R interval None; ST-T segment depression ↓ Q-T interval

Sinus pause or arrest; SA conduction block ↑ Conduction; ↓ refractoriness AV heart block; ↑ AVJ automaticity ↑ Automaticity; DADtriggered activity ↑ Automaticity; DADtriggered activity

Ventricle

25

↑ Atrial rate (atrial flutter/fibrillation) Mobitz type I-II second or third degree heart block; AVJR or AVJT VPB; VT VPB; VT

AV, atrioventricular; AVJ, atrioventricular junction; AVJR, atrioventricular junctional rhythm; AVJT, atrioventricular junctional tachycardia; DAD, delayed after depolarization; SA, sinoatrial; VPB, ventricular premature beats; VT, ventricular tachycardia.

PHARMACOLOGY

normal and toxic effects. Normal ECG changes with therapeutic levels of digitalis include the following:

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Table 7–2

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Digitalis-Caused Arrhythmias in Decreasing Order of Frequency

Premature ventricular beats Accelerated AV junctional rhythm or tachycardia Wenckebach (Mobitz type I) AV block Sinus bradycardia or arrest Atrial tachycardia with variable AV block* Bidirectional ventricular tachycardia* Atrial flutter Ventricular fibrillation *Almost always due to the toxic effects of digitalis. AV, atrioventricular.

reduced body mass lowers the volume of distribution for digitalis. Other drugs administered concomitantly may interact with digoxin and affect serum concentrations. Also, a progressive decline in renal function and reduced serum albumin may elevate serum digoxin concentrations, as does reduced creatinine clearance if no adjustment in dosage is made. Importantly, dialysis is not effective for clearing digoxin. In hypothyroidism, the activity of membrane Na+,K+ATPase is reduced, which means that lower digoxin doses are needed to achieve a therapeutic effect, and toxicity can occur with usual doses. Hypoxemia enhances digitalis’s acceleration of lower pacemaker activity and may trigger arrhythmias from delayed afterpotentials. In patients receiving digitalis, ectopic beats or tachycardia can be exacerbated by the concomitant use of β-adrenergic agonists and diuretics. Hypokalemia potentiates the effects of digitalis owing to impaired Na+-K+ pump function. Low serum K+ concentrations increase the binding of digitalis to myocardium. Hypomagnesemia reduces the activity of membrane Na+,K+ATPase and may increase kaliuresis and cause hypokalemia. Hypercalcemia increases digitalis activity by increasing intracellular Ca2+. In addition, many drugs and other factors interact with digoxin to alter its pharmacokinetics, displace it from tissue binding sites, or reduce its clearance to increase serum drug concentrations (see Table 7-3).

Table 7–3

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Factors that Predispose to Digitalis Toxicity

Older age Electrolyte imbalance (hypokalemia, hypomagnesemia, hypercalcemia) Renal insufficiency Severity of heart disease Hypoxemia Hypothyroidism Drug interactions Angiotensin-converting enzyme inhibitors Benzodiazepines Quinidine or quinine Calcium channel blockers Erythromycin Cyclosporine Amiodarone

Implications Digitalis toxicity constitutes a serious condition that merits hospitalization. Hemodynamic deterioration with associated arrhythmias in patients with significantly impaired cardiac function may cause acute hemodynamic decompensation. In addition to hemodynamic compromise, some arrhythmias themselves are life threatening. Therefore, early recognition of the toxic effects of digitalis is imperative. Some extracardiac manifestations may be debilitating and may, in fact, precipitate arrhythmias. In surgical candidates, all but the most urgent procedures should be postponed until the digitalis toxicity has been resolved.

MANAGEMENT The treatment of digitalis toxicity depends on the severity of the clinical manifestations (Table 7-4). However, all patients suspected of digitalis intoxication should have an assessment of serum electrolytes, potassium, magnesium, and calcium, as well as a determination of serum digoxin concentration. For patients with mild symptoms, temporary discontinuation of the drug, cardiac monitoring, and supportive measures are sufficient. For patients with severe or lifethreatening arrhythmias (complete heart block, ventricular tachyarrhythmias), in addition to discontinuing digitalis, the administration of potassium chloride (in the absence of hyperkalemia) and magnesium sulfate should be considered. For heart block, 1 mg of atropine is usually effective in counteracting the vagal effects of digoxin. For ventricular arrhythmias, in addition to monitoring serum levels, lidocaine is the drug of choice, with a loading dose of 1 to 2 mg/kg, followed by an infusion of 1 to 2 mg/minute. Phenytoin was used in the past but, owing to its myocardial depressant properties and its tendency to produce hypotension when given intravenously, has largely been replaced by digoxin-specific antibodies (Digibind). There is no evidence to support the use of amiodarone to treat ventricular tachycardia or to prevent recurrences of ventricular fibrillation in patients with digitalis toxicity. At least in theory, the complementary electrophysiologic actions of amiodarone and digitalis to promote sinus bradycardia and increase sinoatrial and AV node conduction times and refractoriness might promote or precipitate asystole. More important is that amiodarone is known to

Table 7–4

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Management of Digitalis Toxicity

Withhold further digitalis Assess electrolytes (K+, Ca2+, Mg2+) Administer potassium chloride in the absence of hyperkalemia Administer magnesium sulfate Treat bradyarrhythmias Atropine Temporary or (possibly) permanent artificial pacing Treat ventricular arrhythmias Lidocaine Phenytoin (diphenylhydantoin) Digoxin-specific antibodies (Digibind)

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PREVENTION Knowledge of the multiple factors that affect digoxin pharmacokinetics and pharmacodynamics is important to avoid

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its toxic effects. Regular determination of serum digoxin concentrations and dose adjustments in patients with conditions that increase the risk of digitalis toxicity are important measures, especially in the elderly.

Further Reading Antman EM, Wenger TL, Butler VP Jr, et al: Treatment of 150 cases of life-threatening digitalis intoxication with specific Fab antibody fragments: Final report of a multicenter study. Circulation 81:1744-1750, 1990. Fenster PE, White NW Jr, Hanson CD: Pharmacokinetic evaluation of the digoxin-amiodarone interaction. J Am Coll Cardiol 5:108-112, 1985. Hauptman PJ, Kelly RA: Digitalis. Circulation 99:1265-1270, 1999. Hood WB Jr, Dans AL, Guyatt GH, et al: Digitalis for treatment of congestive heart failure in patients in sinus rhythm. Update of Cochrane Database Syst Rev 3:CD002901, 2001; PMID: 11687032. Kelly RA, Smith TW: Recognition and management of digitalis toxicity. Am J Cardiol 69:108G-119G, 1992. Ma G, Brady WJ, Pollack M, et al: Electrocardiographic manifestations: Digitalis toxicity. J Emerg Med 20:145-152, 2000. Ooi H, Colucci WS: Pharmacological treatment of heart failure. In Hardman JG, Limbird LE (eds): Goodman and Gilman’s The Pharmacological Basis of Therapeutics, 10th ed. New York, McGrawHill, 2001, pp 901-932. Spratt KA, Doherty JE: Principles and practice of digitalis. In Messerli FH (ed): Cardiovascular Drug Therapy, 2nd ed. Philadelphia, WB Saunders, 1996, pp 1136-1146.

PHARMACOLOGY

increase serum digoxin levels. Systemic clearance of digoxin is significantly prolonged owing to reduced renal and nonrenal clearance, which lengthens its half-life of elimination by approximately 20%. However, amiodarone does not appear to affect the volume of distribution for digoxin. Electrical countershock (direct-current cardioversion) is contraindicated because it can exacerbate the severity of arrhythmias. Administration of digoxin-specific antibodies (Digibind) is the treatment of choice for life-threatening arrhythmias and for digoxin-induced refractory hyperkalemia. The use of an antibody rapidly reduces the percentage of unbound digoxin in the serum from 75% to less than 5%. The antibody-digoxin complex then undergoes renal excretion. Side effects are infrequent but include allergic reactions and rebound toxic digoxin effects in patients treated with inadequate doses of Digibind. Importantly, conventional serum assays for digoxin cannot distinguish between free and bound digoxin; thus, serum digoxin concentrations appear markedly elevated following Digibind treatment. The results of treatment are monitored by manifestations of clinical improvement; however, free digoxin determinations can be obtained in patients who show a poor response to treatment.

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Anticholinergics Kevin J. Sullivan Case Synopsis A 1-year-old child weighing 10 kg is in the pediatric intensive care unit with respiratory failure and a difficult airway. Prior attempts at laryngoscopy and endotracheal intubation have been unsuccessful, and mask ventilation is difficult. The infant, who becomes hypoxic and bradycardic during resuscitation efforts, is unintentionally given 4 mg of intravenous atropine, instead of the 0.2 mg that was ordered. Endotracheal intubation is performed to reverse the respiratory failure and hypoxia. Shortly thereafter, the patient is noted to be tachycardic (225 beats per minute), with warm, red, dry skin and fever (39°C). He appears disoriented, agitated, and inconsolable.

PROBLEM ANALYSIS Definition Because infants and young children have a relatively enhanced vagal tone compared with adults, vagotonic physiologic perturbations, such as airway instrumentation, can result in bradycardia. Thus, in pediatric anesthesia and critical care settings, bradycardia can be seen during laryngoscopy and induction of anesthesia with volatile inhalational agents (most commonly halothane), as well as with hypoxemia and elevated intracranial pressure. Bradycardia and the consequent reduced cardiac output can be prevented by premedication with oral, intravenous, or intramuscular anticholinergic drugs. In the case synopsis, an inadvertently high dose of atropine (about 20-fold too high) was given to increase the patient’s heart rate during bradycardia. Anticholinergic (antimuscarinic) toxicity is commonly seen in infants and young children after the accidental ingestion of belladonna alkaloids and their synthetic congeners, antiparkinson medications, histamine receptor antagonists, tricyclic antidepressants, and phenothiazines. For persons of all ages, the ingestion of plants that contain large quantities of belladonna alkaloids can cause anticholinergic toxicity. Such plants include deadly nightshade (Atropa belladonna), jimsonweed (Datura stramonium), and angel’s trumpet (Brugmansia candida). Anticholinergics used in anesthesia include atropine, glycopyrrolate, and scopolamine. They compete with neurally released acetylcholine to attach to muscarinic cholinergic receptors and block the effects of acetylcholine, and they antagonize muscarinic agonist actions at noninnervated muscarinic cholinergic receptors. Further, presynaptic muscarinic receptors on adrenergic nerve terminals inhibit norepinephrine release. Thus, muscarinic antagonists (anticholinergics) can enhance sympathetic activity. Except for the fact that quaternary ammonium compounds (glycopyrrolate) do not readily cross the blood-brain barrier to exert central nervous system (CNS) actions, there is little difference in the qualitative actions of atropine, glycopyrrolate, and scopolamine. However, some quantitative differences in effect may be seen. For example, both atropine and scopolamine have a shorter duration of action than glycopyrrolate. Further, the 28

antisialagogue effects of glycopyrrolate and scopolamine are greater than those of atropine. In addition, heart rate is most increased by atropine, then by glycopyrrolate, and least by scopolamine. Finally, although both atropine and scopolamine are tertiary amines that readily cross the blood-brain barrier, they differ in CNS effects: atropine causes CNS stimulation, whereas scopolamine produces sedation and amnesia. Human tissues vary with respect to both the density and the type of muscarinic receptors present. Five subtypes of muscarinic receptors have been identified (M1, M2, M3, M4, M5), each with a different location and function. For example, M1 receptors are found in the cerebral cortex, sympathetic ganglia and postganglionic neurons, and some presynaptic sites. M2 receptors are present in myocardium, smooth muscle cells, and some presynaptic sites. M3 receptors are found in exocrine glands, and M4 receptors in heart. M5 receptors are found mostly in brain. All muscarinic receptor subtypes interact with heterotrimeric, guanine nucleotide-binding regulatory proteins (G proteins) linked to cellular effectors. Although selectivity is not absolute, stimulation of M1 or M3 receptors causes hydrolysis of polyphosphoinositides and mobilization of intracellular Ca2+, which is due to interaction with a G protein (Gq) that activates phospholipase C. The latter causes a variety of Ca2+-mediated events, either directly or via phosphorylation of target proteins. In contrast, M2 and M4 muscarinic receptors inhibit adenylyl cyclase and regulate specific ion channels (e.g., enhancement of K+ conductance in cardiac atrial tissue) through subunits released from pertussis toxinsensitive G proteins (G1 and G0). These are distinct from the G proteins used by the M1 and M3 receptors. Finally, M5 receptors may inhibit M-type (KCNQ2/KCNQ3) K+ channels via the activation of a common G protein.

Recognition Table 8-1 lists the effects of anticholinergics in various organ systems. Appreciation of the range of organ systems affected by anticholinergic drugs is required to maximize their benefits while minimizing side effects. Drugs in common use (atropine, scopolamine, glycopyrrolate) are nonselective muscarinic receptor antagonists. They have similar side effects, but to a varying extent. As stated earlier, atropine and

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Clinical Effects of Anticholinergic Drugs

Cardiovascular effects (observed at moderate doses) Increased rate of sinoatrial (SA) node discharge Decreased rate of SA node discharge (low doses of atropine) Enhanced atrioventricular node conduction Little or no effect on ventricular function Little effect on peripheral vasculature Cutaneous vasodilatation in high doses Respiratory effects (observed at low doses) Drying of respiratory secretions Relaxation of bronchial smooth muscle Increased anatomic dead space Central nervous system effects (observed at larger doses) Wide range of symptoms, from sedation and depression to agitation and delirium Gastrointestinal effects (observed at larger doses) Decreased salivation Reduced gastric secretions and motility Decreased lower esophageal sphincter tone Ophthalmic effects (observed at moderate doses) Mydriasis Cycloplegia Genitourinary effects (observed at larger doses) Decreased ureter and bladder tone Urinary retention Thermoregulation effects (observed at small doses) Inhibition of sweat gland secretions (function most sensitive to anticholinergics) Elevated temperature

scopolamine cross the blood-brain barrier, whereas glycopyrrolate does not. Scopolamine is more sedating than atropine but causes less of a heart rate increase; similar to atropine, it is a moderately potent antisialagogue. Glycopyrrolate is the most potent antisialagogue, causes moderate tachycardia, and is nonsedating. The pharmacologic effects of anticholinergics used in anesthesia are summarized in Table 8-2. Another anticholinergic agent, ipratropium (Atrovent), is used primarily in pulmonary care. This drug was introduced

Table 8–2

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Pharmacologic Effects of Anticholinergics Used in Anesthesia

Atropine Causes greater vagolysis than glycopyrrolate Increases heart rate and enhances atrioventricular node conduction Paradoxical slowing of heart rate at low doses Little sedation Moderately potent antisialagogue Glycopyrrolate Moderate vagolytic effect on heart, but less than that of atropine No sedation (charged quaternary amine; does not cross blood-brain barrier) Highly potent antisialagogue Scopolamine Marked sedation-amnesia (tertiary amine structure; lipid soluble; crosses blood-brain barrier) Most likely to cause central anticholinergic syndrome (easily reversed with physostigmine) Moderately potent antisialagogue

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in the 1980s and reestablished anticholinergics as a therapy for bronchospastic disorders. Although ipratropium is structurally similar to atropine and has similar actions if given parenterally, it is a quaternary ammonium compound. Ipratropium is poorly absorbed when inhaled and has few extrapulmonary effects, even with very large inhaled doses. When inhaled, 90% of ipratropium is swallowed, and only 1% of the total dose is absorbed systemically. When given to normal volunteers, the drug provides almost complete protection against bronchospasm induced by a variety of provocative agents. However, in asthmatics, the results can vary. Whereas the bronchospastic effects of some agents (e.g., methacholine, sulfur dioxide) are completely blocked, there is little blocking of leukotriene-induced bronchoconstriction. Also, unlike atropine, ipratropium has no negative effect on ciliary clearance. In general, this drug and other anticholinergics are more effective in chronic obstructive pulmonary disease, especially when cholinergic tone is high. The development of new drugs that affect specific muscarinic receptor subtypes will provide more effective therapy with fewer adverse or troublesome side effects than the drugs used today. The child in the case synopsis displayed many of the signs and symptoms of anticholinergic toxicity, which can be divided into two types: CNS and peripheral antimuscarinic. CNS toxicity can manifest as agitation, delirium, seizures, or coma. Systemic anticholinergic effects are most prominent in tissues or organs with dense parasympathetic innervation and include tachycardia; dry mucous membranes; urinary retention; dry, flushed skin; dilated pupils with cycloplegia; fever; and ileus. The child in the case illustrated the typical findings accompanying anticholinergic overdose in pediatric patients. Although the cause of his condition was known, the differential diagnosis includes other potentially lifethreatening conditions (Table 8-3). Physical examination and the natural history of the disease process should allow the clinician to differentiate among these conditions. Physical and laboratory findings of anticholinergic toxicity that help exclude other conditions are summarized in Table 8-4. Although the conditions in the differential diagnosis share overlapping features with anticholinergic toxicity, the combination of abolition of pupillary responses and sweating is very specific for anticholinergic toxicity. Many clinicians confuse anticholinergic toxicity with the diametrically opposed toxidrome associated with anticholinesterase poisoning, which results in excessive cholinergic tone. Physician familiarity with toxic syndromes due to anticholinesterase poisoning has increased dramatically with the proliferation of chemical weapons of mass destruction. In contrast to the symptoms and signs of anticholinergic

Table 8–3

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Differential Diagnosis of Anticholinergic Toxicity

Hypoxemia and/or hypercarbia Sepsis Malignant hyperthermia Thyroid storm (crisis) Pheochromocytoma Carcinoid syndrome

PHARMACOLOGY

Table 8–1

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Pharmacology

Distinguishing Features of Anticholinergic Toxicity*

Relatively normal arterial O2 and CO2 tensions (rules out hypoxemia and hypercarbia) Cycloplegia (pupillary light reflexes remain intact for most other conditions) Mydriasis (pupils may also be dilated in MH due to elevated circulating catecholamines) Anhidrosis; warm, red skin (sweating is preserved in other disorders within the differential diagnosis; see Table 8-3) Lack of muscle rigidity (commonly seen with MH) No ventricular arrhythmias (not characteristic of carcinoid syndrome, but common with MH, pheochromocytoma, and thyrotoxicosis) Minimal to modest increase in end-tidal CO2 due to hyperthermia (usually far greater with MH or thyrotoxicosis) Mild (or no) hypertension (as in MH), or paroxysmal, severe hypertension (thyroid storm, pheochromocytoma, or carcinoid tumor†), especially with gland or tumor manipulation Mild to no metabolic acidosis (far more severe in MH) *In anesthetized patients, the modulatory effects of anesthesia must be considered. † Serotonin released by carcinoid tumors has little if any direct effect on the heart. However, positive chronotropic and inotropic effects, and possibly arrhythmias, may occur with the release of norepinephrine. Effects of serotonin on the peripheral vasculature include both vasoconstriction and vasodilatation. MH, malignant hyperthermia.

overdose, poisoning with carbamate insecticides or organophosphates leads to CNS excitation and excessive nicotinic and muscarinic receptor activation. CNS signs include ataxia, restlessness, agitation, convulsions, and coma. Muscarinic signs include excessive salivation, perspiration, vomiting, diarrhea, abdominal cramps, tenesmus, bradycardia or heart block, pupillary constriction, lacrimation, wheezing, hypotension, blurred vision, and urinary and fecal incontinence. Nicotinic signs include muscle twitching, fasciculations, cramping, paralysis, respiratory compromise, and subsequent cardiac arrest.

Risk Assessment Patients with heart disease are at far greater risk for anticholinergic complications. In this respect, atropine and glycopyrrolate produce more vagolysis than scopolamine does, causing a much greater increase in the sinus rate and speed of atrioventricular (AV) node conduction. An increased heart rate is more dangerous in patients with coronary artery disease and valvular or subvalvular restrictive cardiac lesions (e.g., aortic and mitral valve stenosis, idiopathic hypertrophic subaortic stenosis). Further, in patients with functional accessory AV pathways and a history of AV reciprocating tachycardia or atrial flutter or fibrillation (e.g., WolffParkinson-White syndrome), atropine or glycopyrrolate (especially in a relative overdose) may precipitate dangerously fast tachyarrhythmias (see Chapter 80). Also, because both drugs facilitate AV node conduction, they are contraindicated in patients with supraventricular tachyarrhythmias, especially atrial flutter or fibrillation.

Implications Anticholinergics exert their effects in many organ systems (see Table 8-1). Therapeutic effects in one organ system may be accompanied by undesirable side effects in others. Careful selection of the anticholinergic agent and its dose allows the clinician to target the appropriate organ system and simultaneously minimize undesirable side effects in other organ systems (see Table 8-2). Although atropine is considered relatively safe and benign in adults, an atropine overdose is very dangerous in pediatric

patients, especially infants. Deaths due to anticholinergic poisoning have been reported with doses as low as 2 mg of atropine in infants. Anticholinergics have complex gastrointestinal actions. Salivary gland secretions are reduced and are the most sensitive to cholinergic block. Gastric secretions are also reduced, but this requires larger doses. Both gastrointestinal motility and lower esophageal sphincter tone are reduced. However, it is important to remember that anticholinergic premedication does not confer protection against aspiration of gastric contents and chemical or bacterial pneumonitis. Also, the function of a number of other organs can be impaired by anticholinergic therapy. In the eye, anticholinergic drugs can precipitate narrow-angle glaucoma. Individuals with a shallow anterior chamber can suffer acute increased intraocular pressure due to impaired drainage via the canal of Schlemm. Postsurgical patients, especially elderly men with prostatic hypertrophy, are at risk for severe urinary retention after taking anticholinergics. Further, confusion, agitation, and delirium are CNS side effects of anticholinergics that cross the blood-brain barrier (scopolamine, atropine). Patients at greatest risk for mental status changes are those at the extremes of age, those with preexisting abnormalities of mental status, and those taking drugs with significant anticholinergic properties (e.g., antiparkinson drugs, phenothiazines, tricyclic antidepressants, butyrophenones, antihistamines, cycloplegics, antispasmodics). Impaired thermoregulation due to the inability to sweat can result in hyperpyrexia. Children and infants are especially vulnerable owing to their high metabolic rate and immature thermoregulatory mechanisms. It is clear that hyperpyrexia involves an impaired ability to dissipate heat through sweating. Whether there is a central effect on thermal regulation remains unclear. Finally, atropine and glycopyrrolate are commonly given with or prior to anticholinesterase drugs to reverse nondepolarizing neuromuscular blockade. Because of similarities in onset of drug action, atropine is commonly administered with edrophonium, which has a very rapid onset. Similarly, glycopyrrolate is often administered with neostigmine because both have a slower onset and a longer duration of action. By selecting an anticholinergic that matches the anticholinesterase drug’s onset and duration of action, heart

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MANAGEMENT Most complications related to anticholinergic drugs are self-limited and can be effectively treated with supportive care. For example, urinary retention in elderly men may require short-term or intermittent bladder catheterization. However, some complications, such as fast sinus or nonparoxysmal atrial tachycardias in patients with myocardial ischemia or infarction, aortic or mitral valve stenosis, or idiopathic hypertrophic subaortic stenosis, require prompt treatment. Therapeutic options include β-blockers and calcium channel antagonists. If paroxysmal supraventricular tachycardia is likely, adenosine is useful. However, the current advanced cardiovascular life support guidelines advise early cardioversion for most hemodynamically disadvantageous tachyarrhythmias, rather than a trial of drugs (see Chapter 79). Likewise, severe hyperthermia should be treated aggressively with cooling blankets and, if needed, immersion in ice water and irrigation of body cavities with cold saline. With careful consideration of the underlying medical history and the pharmacodynamics of the various anticholinergics, it is possible to maximize the benefits of this class of medications while minimizing undesirable side effects of therapy.

PREVENTION Prevention of the side effects of anticholinergic drugs begins with an appreciation of the fact that they affect different

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organ systems with different intensities (see Tables 8-1 and 8-2) but do so in a predictable, dose-related fashion. To avoid complications, it is most important to recognize that certain subsets of patients are at greater risk for morbidity related to the use of anticholinergic drugs. Therefore, it is crucial to evaluate the specific vulnerabilities of the patient, delineate the goals of anticholinergic therapy, and select a drug with a pharmacodynamic profile that most closely suits the goals of therapy.

Further Reading Brown JH, Taylor P: Muscarinic receptor agonists and antagonists. In Hardman JG, Limbird LE (eds): Goodman and Gilman’s The Pharmacological Basis of Therapeutics, 10th ed. New York, McGrawHill, 2001, pp 155-173. Das G: Therapeutic review: Cardiac effects of atropine in man: An update. Int J Clin Pharmacol 27:473-477, 1989. Feldman MD: The syndrome of anticholinergic intoxication. Am Fam Physician 34:113-116, 1986. Friesen RH, Lichtor JL: Cardiovascular depression during halothane anesthesia in infants: A study of three induction techniques. Anesth Analg 61:42-45, 1982. Goyal RK: Muscarinic receptor subtypes: Physiology and clinical implications. N Engl J Med 321:1022, 1989. Gross NJ: Ipratropium bromide. N Engl J Med 319:486-494, 1988. Guo J, Schofield GG: Activation of muscarinic M5 receptors inhibits recombinant KCNQ2/KCNQ3 K+ channels expressed in HEK293T cells. Eur J Pharmacol 462:25-32, 2003. Mirakhur RK: Antagonism of the muscarinic effects of edrophonium with atropine or glycopyrrolate. Br J Anaesth 57:1213-1216, 1985. Moss J, Glick D: The autonomic nervous system. In Miller RD (ed): Miller’s Anesthesia, 6th ed. Philadelphia, Churchill Livingstone, 2005, pp 617-677. Patton WDM: The principles of drug action. Proc R Soc Med 53:815-820, 1965. Polak RL: Effects of hyoscine on the output of acetylcholine into preferred cerebral ventricles on cats. J Physiol 181:317-323, 1965.

PHARMACOLOGY

rates that are too fast or too slow can be avoided. It also appears that lower doses of anticholinergics are required to antagonize the weaker and shorter-lived muscarinic effects of edrophonium compared with those of neostigmine.

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Adenosine M. J. Pekka Raatikainen and John L. Atlee Case Synopsis A 63-year-old man with a history of transient ischemic attacks is admitted to the hospital for elective surgery. His medications include aspirin 250 mg/day orally and dipyridamole 75 mg orally three times a day. During the operation under regional anesthesia, a regular supraventricular tachycardia (SVT) is observed. The tachycardia terminates after intravenous bolus adenosine (12 mg) and is followed by a long sinus pause and angina-like pain (Fig. 9-1).

PROBLEM ANALYSIS Definition The first step is to determine whether the signs or symptoms are due to tachycardia. If they are, the existing advanced cardiovascular life support guidelines advise immediate cardioversion rather than a trial of antiarrhythmic drugs. If cardioversion is not indicated (e.g., ectopic atrial tachycardia), the guidelines stress making a specific diagnosis and identifying patients with impaired cardiac function (ejection fraction <40%). Importantly, the 2000 guidelines downplay the use of adenosine to differentiate wide QRS tachycardia due to ventricular aberration versus ectopy. This unnecessarily exposes patients to adenosine’s unpleasant side effects, possibly worsens arrhythmias, and may destabilize heart rate and pressure. However, given the history of the patient described in the case synopsis, the circumstances, and the apparent suddenness of onset, it was reasonable to administer adenosine to terminate this regular, narrow QRS complex tachycardia, especially because it was associated with apparent ST segment

depression in the lead depicted. The advantage of adenosine (versus intravenous calcium channel antagonists, such as verapamil or diltiazem, or β-blockers) for the chemical conversion of sudden-onset, narrow QRS tachycardia is related to its rapid action and ultrashort half-life. Although adenosine rarely causes severe side effects, minor adverse effects such as facial flushing and chest discomfort are frequently observed. In the majority of patients, these are well tolerated and resolve rapidly without intervention. However, the concomitant administration of drugs that inhibit the elimination of adenosine from blood, and the presence of some clinical conditions (e.g., asthma), may render some patients more susceptible to the development of severe adverse effects with adenosine.

Recognition Endogenous adenosine is involved in numerous physiologic and pathophysiologic processes in mammalian organs and tissues. Most, if not all, of these actions are mediated by specific cell surface receptors (A1-, A2A-, A2B-, and A3-adenosine receptors). Because of the ubiquitous nature and distribution of these receptors, administration of adenosine to terminate SVT may cause adverse effects unrelated to the heart. Following are the most common patient complaints after the administration of adenosine: ● ●

A

B

Rhythm strip during the tachycardia

20 sec after 12 mg adenosine bolus

●

5.5 s

Figure 9–1 ■ A, Intraoperative rhythm strip from the patient described in the case synopsis (paper speed, 25 mm/second). It shows a regular, narrow QRS tachycardia (180 beats per minute). B, Rhythm strip 20 seconds after the administration of intravenous bolus adenosine (12 mg). Sinus arrest lasting 5.5 seconds occurs after termination of the tachycardia. The patient was receiving dipyridamole, which is a potent nucleoside transport blocker and likely potentiated adenosine’s effects. In later ambulatory electrocardiographic recordings and electrophysiologic testing, there was no evidence of sinoatrial node dysfunction.

32

Facial flushing Dyspnea Chest discomfort

Less common side effects are nausea, lightheadedness, headache, dizziness, and palpitations. These adverse side effects often occur concomitantly with tachycardia termination and persist for 2 to 3 minutes. Many, but not all, of these effects are attributable to vasodilatation with activation of the A2adenosine receptors. For example, facial flushing is caused by cutaneous vasodilatation. Direct stimulation of carotid chemoreceptors and cardiac pain receptors may explain respiratory stimulation and the sensation of dyspnea and chest discomfort (angina-like pain), respectively. Adenosine may also cause bronchoconstriction, especially in asthmatics. Like all antiarrhythmics, adenosine may be proarrhythmic, provoking new or worse arrhythmias. Given the potent depressant effects of adenosine in the sinoatrial (SA) and atrioventricular (AV) nodes, it is not surprising that adenosine

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● ● ● ● ● ● ● ●

Sinus bradycardia; transient sinus arrest Transient AV block Supraventricular premature beats Atrial flutter Atrial fibrillation Ventricular premature beats Nonsustained VT Torsades de pointes–type polymorphic VT

The potent negative chronotropic (slowed sinus rate) and dromotropic (slowed AV node conduction) effects of adenosine explain its ability to cause pronounced bradycardia or sinus arrest or AV heart block. The induction of atrial flutter or fibrillation by adenosine appears to be due to shortening of atrial repolarization and refractoriness. Although the drug effectively terminates most paroxysmal SVT, some reports have demonstrated its proarrhythmic potential, including the induction of VT. However, the mechanisms of adenosine-induced ventricular premature beats and nonsustained or even sustained VT are less clear. Adenosine has no known direct effect on ventricular myocytes. Thus, it seems unlikely that adenosine exerts a direct proarrhythmic effect, at least in normal ventricles. Further, ventricular premature beats are not specific for adenosine but may also be seen after termination of SVT by calcium channel blockers (e.g., verapamil, diltiazem) or AV node ablation. Some reports suggest that termination of SVT by adenosine may occasionally lead to the development of torsades de pointes polymorphic VT. Adenosine markedly slows the sinus and ventricular rates and, when given intravenously, leads to increased sympathetic discharge. In fact, adenosine has been used to reproduce clinical torsades de pointes in patients with congenital long Q-T interval syndrome during electrophysiologic testing. Thus, one might speculate that an adenosineslowed ventricular rate and an increased sympathetic discharge interact adversely to facilitate early afterdepolarizations, the proximate cause of ventricular tachyarrhythmias in experimental models. One group attempted to define the proarrhythmic effects of adenosine used to terminate 187 episodes of SVT in 127 patients admitted to the emergency room over a 5-year period. In two thirds of cases, adenosine induced ventricular ectopy after successful termination of SVT, including premature ventricular beats and nonsustained VT, both of which were transient and self-terminating. Based on morphologic criteria, more than half the arrhythmias appeared to originate in the inferior left ventricular septum, which may be more susceptible to adenosine’s proarrhythmic effects. Although this high incidence of ventricular arrhythmias was surprising, no further intervention was required. These proarrhythmic

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33

effects may be due to abnormal electrophysiologic mechanisms facilitated by adenosine-increased sympathetic discharge. To recognize transient or sustained ventricular proarrhythmias after the administration of adenosine for the treatment of paroxysmal SVT, one should monitor the electrocardiogram (ECG) continuously for at least 2 minutes following each intravenous adenosine bolus.

Risk Assessment The reported incidence of adverse extracardiac symptoms after an intravenous bolus injection of adenosine ranges from less than 30% to more than 70%. Proarrhythmic effects are less common; for example, the incidence of atrial fibrillation is 1% to 5%, and the incidence of ventricular premature beats is approximately 10% to 30%. Only occasionally do case reports describe more severe proarrhythmic actions. However, it is known that interactions with drugs inhibiting adenosine metabolism and some clinical conditions may sensitize patients to the effects of adenosine and thus render them susceptible to more severe adverse effects. For example, in patients receiving dipyridamole, the cellular uptake of adenosine is blocked, and the half-life of the nucleoside is markedly prolonged. Consequently, these patients are much more vulnerable to the development of prolonged bradycardia, AV node conduction disturbances, and extracardiac adverse effects. Likewise, patients with preexisting AV node conduction disturbances, sick sinus syndrome, myocardial ischemia, and cardiac allografts are more sensitized to the cardiac effects of adenosine, and asthmatic patients are more susceptible to adenosine-induced bronchoconstriction. In view of the finding that abrupt slowing of the heart rate may cause torsades de pointes VT, adenosine, like any other agent that promotes the development of sudden bradycardia, may be arrhythmogenic in patients with long QT syndrome. Factors and clinical conditions that predispose patients to the adverse effects of adenosine include the following: ●

●

● ● ● ●

Medications that inhibit the elimination of adenosine from blood (e.g., dipyridamole) Myocardial ischemia (especially inferior myocardial infarction or ischemia) Heart transplantation Preexisting AV node conduction disturbances Preexisting SA node disease Acquired or congenital long QT syndrome

Nevertheless, compared with calcium channel antagonists, β-blockers, and other antiarrhythmic agents, adenosine has many important advantages related to its rapid onset of action and less severe and shorter-lived adverse effects. Initial experience also indicates that adenosine can be relatively safely administered to patients in whom the use of calcium channel antagonists may be hazardous (e.g., those with heart failure, ischemic heart disease, WolffParkinson-White syndrome, or wide-complex tachycardia or those taking β-blockers). In addition, adenosine may still have utility for differentiating wide QRS complex SVT from VT and for identifying the arrhythmogenic mechanism of a variety of tachycardias, especially in the cardiac catheterization laboratory during electrophysiologic testing (Fig. 9-2). However, as stated earlier, for arrhythmias involving

PHARMACOLOGY

often causes transient sinus bradycardia and AV block. In fact, adenosine’s efficacy in terminating AV nodal reentrant tachycardia and AV reciprocating tachycardia depends on the production of transient AV block. In addition to commonly associated bradyarrhythmias, clinicians report that adenosine occasionally induces atrial fibrillation, ventricular premature beats, brief episodes of nonsustained ventricular tachycardia (VT), and torsades de pointes VT (a polymorphic VT in association with Q-T interval prolongation; see Chapter 81). The following proarrhythmias have been observed after the intravenous administration of adenosine:

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Tachycardia Adenosine Termination • • • •

Transient suppression

AVNRT, AVRT cAMP-dependent VT SNRT Atrial tachycardia

• Sinus tachycardia • Atrial tachycardia

No effect • • • •

Reentrant and automatic VT Atrial flutter Atrial fibrillation Atrial tachycardia

Figure 9–2 ■ Possible effects of adenosine on cardiac arrhythmias. Because important diagnostic information can be obtained during the drug’s peak effect, the cardiac rhythm should be monitored by electrocardiogram for at least 2 minutes after each adenosine bolus. Rapid intravenous bolus adenosine (6 mg, followed by 12 mg if necessary) terminates more than 90% of supraventricular tachycardias that involve the atrioventricular (AV) node, including AV nodal reentrant tachycardia (AVNRT) and AV reentrant tachycardia (AVRT) involving the AV node and accessory AV conduction pathways. Some catecholamine-dependent (e.g., cyclic adenosine monophosphate [cAMP]) ventricular tachycardia (VT) and sinoatrial node reentrant tachycardia (SNRT) are also terminated by adenosine. Depending on the tachycardia mechanism and the location of the arrhythmogenic focus, the effect of adenosine on atrial tachycardias can vary considerably. Although adenosine may terminate some atrial tachyarrhythmias, it can also precipitate atrial fibrillation or flutter.

severe hemodynamic compromise, immediate cardioversion is recommended rather than a trial of antiarrhythmic drugs.

Implications Among the drugs used for the acute treatment of paroxysmal SVT, adenosine appears to be the least likely to cause significant adverse hemodynamic effects. It can also be used safely throughout the perioperative period. However, caution is necessary when administrating adenosine to patients receiving dipyridamole or other agents that inhibit the elimination of adenosine. Likewise, patients with myocardial ischemia, SA or AV node dysfunction, and cardiac allografts seem to be sensitized to both the therapeutic and the adverse effects of adenosine.

restore sinus rhythm in patients with ischemia-induced AV node block during the early phase of inferior myocardial infarction. They can also relieve angina-like pain in patients treated with adenosine. The principles for the management of proarrhythmias associated with adenosine administration are outlined in Figure 9-3. With hemodynamically unstable AV heart block or bradyarrhythmias, cardiopulmonary resuscitation must be started without delay. Likewise, patients with adenosineinduced tachyarrhythmias and hemodynamic compromise require emergency direct-current cardioversion. Otherwise, an adenosine receptor antagonist (e.g., theophylline, aminophylline) is the initial drug of choice. The recommended dose of theophylline is 150 to 250 mg as a slow intravenous bolus injection (approximately 100 mg/minute). If bradycardia or AV block does not respond to theophylline, adrenergic drugs, atropine, or cardiac pacing may be effective. If antiarrhythmic drugs are used to treat adenosine-induced tachyarrhythmias, they should be selected according to the type or mechanism of tachycardia. However, cardioversion is generally preferred to drugs.

PREVENTION There are only a few absolute contraindications for the use of adenosine. Adenosine should not be administered to patients with second or third degree AV block or sick sinus syndrome unless the patient has a pacemaker. In addition, patients with asthma or severe obstructive pulmonary disease probably should not be given adenosine. When administering adenosine therapeutically, physicians should be aware of important drug interactions. Drugs that inhibit the metabolism of adenosine, either by blocking the nucleoside transporter or by directly inhibiting adenosine-metabolizing enzymes (adenosine kinase and adenosine deaminase), significantly prolong the half-life of the adenosine and dramatically potentiate its effects. For example, the concurrent use of dipyridamole potentiates the effects of adenosine by a factor of four. Accordingly, clinicians

Adenosine-induced proarrhythmia

Bradyarrhythmia

MANAGEMENT Because of adenosine’s extremely short half-life, any adverse effects caused by its intravenous bolus injection are usually transient and require observation only. Again, to recognize transient or sustained ventricular proarrhythmias after the administration of adenosine for paroxysmal SVT, the ECG must be monitored continuously for at least 2 minutes after each injection. The nonselective A1- and A2-adenosine receptor antagonists aminophylline and theophylline are highly effective in reversing any unfavorable side effects of adenosine injection or infusion. In addition, these agents have been used to

Tachyarrhythmia

Hemodynamically stable?

Hemodynamically stable?

NO YES

NO YES

Theophylline

Theophylline CPR Theophylline Adrenergic drugs Cardiac pacing Atropine

Sinus rhythm?

Immediate DC shock; CPR

Sinus rhythm? NO YES

NO YES Successful

Antiarrhythmic drugs DC shock

Successful

Monitor for further arrhythmias Figure 9–3 ■ Algorithm for the management of proarrhythmias associated with the administration of adenosine. CPR, cardiopulmonary resuscitation; DC, direct current.

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●

●

● ●

●

●

Identify and correct factors that may predispose patients to proarrhythmia and other adverse effects. Reduce the dosage in patients receiving dipyridamole or other agents that inhibit the elimination of adenosine. Reduce the dose when using central vascular access. Always use incremental adenosine dosing, starting with a low initial dose. An unnecessarily large initial dose will not improve adenosine’s efficacy in terminating SVT but will certainly increase the risk for adverse effects. Warn patients about adenosine’s common side effects and reassure them that these effects will resolve within 2 minutes. Monitor the ECG continuously for several minutes after each intravenous bolus of adenosine. This facilitates early diagnosis and treatment of proarrhythmia and may provide valuable diagnostic information.

In summary, an understanding of the pharmacologic basis of adenosine’s actions (pharmacokinetics and drug

Adenosine

35

interactions), combined with meticulous attention to minimizing the factors predisposing to adverse effects, is crucial to this drug’s safe and effective use.

Further Reading Bertolet BD, McMurtrie EB, Hill JA: Theophylline for the treatment of atrioventricular block after myocardial infarction. Ann Intern Med 123:509-511, 1995. Blomström-Lundqvist C, Scheinman MM, Aliot EM, et al: ACC/AHA/ESC guidelines for the management of patients with supraventricular arrhythmias—executive summary. J Am Coll Cardiol 42:1493-1531, 2003. Camm AJ, Garratt CJ: Adenosine and supraventricular tachycardia. N Engl J Med 325:1621-1629, 1991. Celiker A, Tokel K, Cil E, et al: Adenosine induced torsades de pointes in a child with congenital long QT syndrome. Pacing Clin Electrophysiol 17:1814-1817, 1994. Guidelines 2000 for cardiopulmonary resuscitation and emergency cardiovascular care. Part 6: Advanced cardiovascular life support. Section 5: Pharmacology. I: Agents for arrhythmias. The American Heart Association in collaboration with the International Liaison Committee on Resuscitation. Circulation 102(8 Suppl):I112-I128, 2000. Guidelines 2000 for cardiopulmonary resuscitation and emergency cardiovascular care. Part 6: Advanced cardiovascular life support. 7D: The tachycardia algorithms. The American Heart Association in collaboration with the International Liaison Committee on Resuscitation. Circulation 102(8 Suppl):I158-I165, 2000. Harrington GR, Froelich EG: Adenosine-induced torsades de pointes. Chest 103:1299-1301, 1993. Pelleg A, Pennock RS, Kutalek SP: Proarrhythmic effects of adenosine: One decade of clinical data. Am J Ther 9:141-147, 2002. Raatikainen MJP, Dennis DM, Belardinelli L: Cardiac electrophysiology of adenosine: Cellular basis and clinical implications. In Pelleg A, Belardinelli L (eds): Effects of Extracellular Adenosine and ATP on Cardiomyocytes. Austin, Tex, RG Landes, 1998, pp 87-132. Sylven C: Mechanisms of pain in angina pectoris: Critical review of the adenosine hypothesis. Cardiovasc Drug Ther 7:745-759, 1993. Tan HL, Spekhorst HH, Peters RJ, et al: Adenosine induced ventricular arrhythmias in the emergency room. Pacing Clin Electrophysiol 24:450-455, 2001. Wesley RC Jr, Turnquest P: Torsades de pointe after intravenous adenosine in the presence of prolonged QT syndrome. Am Heart J 123:794-796, 1992.

PHARMACOLOGY

recommend that the initial dose of adenosine in patients receiving dipyridamole should not exceed 1 mg, compared with the typical initial dose of 6 mg rapidly administered via a peripheral vein. It is also advisable to use lower-than-usual doses if adenosine is given via a central vein or to patients with myocardial ischemia or to cardiac transplant recipients. In contrast, larger doses (≥12 mg) may be needed to terminate SVT in patients receiving adenosine receptor antagonists such as aminophylline or theophylline. The response to adenosine may be attenuated in patients who consume food or drink containing methylxanthines (e.g., coffee, cola, chocolate). Although no severe interactions with anesthetic drugs have been reported, it may be important to recognize that benzodiazepines block nucleoside transport in the brain, albeit to a lesser extent than dipyridamole. Adenosine may also lower anesthetic requirements (reduced minimum alveolar concentration) and potentiate nondepolarizing neuromuscular blockade. The following actions may help prevent adverse effects associated with the use of adenosine:

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Class I Antiarrhythmic Drugs: Ventricular Proarrhythmia

10

Mark F. Trankina Case Synopsis A 56-year-old man with stable angina and paroxysmal atrial fibrillation is scheduled for ambulatory inguinal hernia repair. He takes sublingual nitroglycerin as needed, quinidine (400 mg four times a day), and metoprolol (50 mg/day). His preoperative electrocardiogram (ECG) shows normal sinus rhythm at 60 beats per minute, with a corrected Q-T interval of 490 msec and possible left atrial enlargement. He refuses regional anesthesia. He is induced with fentanyl (150 μg), thiopental (350 mg), and succinylcholine (100 mg). His airway is secured without difficulty. However, the pulse oximeter malfunctions within minutes of induction. A sporadic carotid pulse is felt, and the ECG shows twisting of QRS complexes around the isoelectric baseline (Fig. 10-1).

PROBLEM ANALYSIS Definition The Cardiac Arrhythmia Suppression Trial (CAST) in 1989 and CAST II in 1992 tested the idea that chronic suppression of lesser ventricular arrhythmias (e.g., ventricular premature beats and nonsustained ventricular tachycardia) by class I antiarrhythmics would reduce mortality in survivors of myocardial infarction. Such arrhythmias were believed to be the inciting events for lethal (malignant) ventricular arrhythmias such as sustained ventricular tachycardia (VT) or ventricular fibrillation. Although encainide and flecainide reduced the incidence of lesser ventricular arrhythmias, they also conferred excess mortality (7.7% in the treatment group versus 3.0% in placebo groups). This excess mortality was attributed to proarrhythmia. Further, deaths in the treatment group were equally distributed throughout the treatment period, suggesting that the proarrhythmic response could occur any time after the start of drug therapy. Proarrhythmia is defined as the provocation of new or worse arrhythmias by antiarrhythmic drugs. The incidence can be as high as 9% to 10% with some class IA, IB, IC, or III drugs and is lowest (2% to 3%) with amiodarone (a class III antiarrhythmic that also has class I, II, and IV actions). Ventricular proarrhythmia manifests as (1) incessant monomorphic VT or polymorphic VT without Q-T interval prolongation or (2) polymorphic VT with Q-T interval prolongation, or torsades de pointes (TDP). Because the patient in the case synopsis had Q-T prolongation, his arrhythmia was TDP (see Fig. 10-1). Early afterdepolarizations (EADs) are believed to be the inciting mechanism for TDP. EADs are oscillations in the transmembrane potential of ventricular myocytes that occur during the repolarization phase. EADs are caused by the blockage of outward potassium (K+) 36

repolarization currents; however, this blockage also leads to Q-T interval prolongation and increased ventricular refractoriness. This is conducive to reentry of excitation, the likely sustaining mechanism for TDP. However, because the increase in refractoriness is uneven (greater in some ventricular fibers than in others), VT induced by EADs has a multiform rather than a uniform morphology. Ischemia-related regional differences in cardiac conduction delay and refractoriness promote ventricular reentry. Ischemia also leads to heterogeneity in antiarrhythmic drug concentrations in myocardium, which augments ischemic cellular electrophysiologic changes. However, the reentry circuits are larger (i.e., macroreentry versus microreentry), and the associated VT is often monomorphic as opposed to polymorphic. When polymorphic VT occurs in patients without Q-T interval prolongation, it is simply polymorphic VT; in association with Q-T interval prolongation, it is TDP. Both have the same ECG appearance (see Fig. 10-1). Mechanisms for the development of clinical arrhythmias include automaticity, which refers to spontaneous cardiac impulse formation without the need for prior stimulation; it can be normal or abnormal. Normal automaticity occurs in the sinoatrial node (the primary pacemaker) or in latent pacemakers (e.g., subsidiary atrial or Purkinje fibers). Abnormal automaticity can occur in any myocardial fiber type, although it usually occurs in fibers that do not normally exhibit automaticity, such as atrial and working ventricular muscle fibers. Such fibers manifest automaticity only if their cell membrane potentials become depressed by the effects of disease, drugs, or imbalance (i.e., the loss of cell membrane potential). At these low cell membrane potentials, ionic currents responsible for automaticity become activated. Arrhythmias ascribed to enhanced normal automaticity are atrioventricular (AV) junctional and ventricular escape rhythms with advanced second degree or complete (third degree) AV heart block or increased AV node refractoriness.

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Class I Antiarrhythmic Drugs: Ventricular Proarrhythmia

37 PHARMACOLOGY

Figure 10–1

■

Torsades de pointes after induction of general anesthesia. Note “twisting” of the QRS complexes around the isoelectric baseline.

Those ascribed to abnormal automaticity include automatic atrial and AV junctional tachycardia, as well as accelerated idioventricular rhythm or tachycardia following cardiopulmonary bypass or in patients with acute coronary syndromes. Triggered activity is initiated by depolarizing oscillations in the cell transmembrane potential (afterdepolarizations) that occur before EADs or after full cell repolarization (delayed afterdepolarizations). Thus, triggered activity is the result of a preceding impulse or series of impulses, without which electrical quiescence occurs. Not all afterdepolarizations reach the threshold potential for a regenerative action potential. However, if they do, they can trigger further afterdepolarizations and thus become self-perpetuating. Arrhythmias caused by digitalis toxicity are triggered by delayed afterdepolarizations. Some ectopic atrial tachycardia may also be triggered. As already noted, there is strong evidence that EADs and EAD-triggered activity are the cause of polymorphic VT associated with congenital or acquired long QT syndromes (e.g., TDP). Some causes of EADs are listed in Table 10-1. In addition, there has been a great deal of controversy over the Food and Drug Administration’s “black box” warning about the clinical significance of Q-T prolongation due to droperidol, a drug that has been used safely for decades by anesthesiologists and other health care providers. A more comprehensive listing of drugs associated with TDP (and thus likely causes of EADs) can be found in Chapter 81 or on the Web site http.//www.torsades.org.

Table 10–1

■

Causes of Early Afterdepolarizations and Triggered Activity

α-Adrenergic stimulation Imbalance Hypoxia Hypercarbia Acidosis Hypokalemia Anitarrhythmic drugs Quinidine Ibutilide Sotalol Local anesthetics Bupivacaine Etidocaine Miscellaneous Cesium

Recognition The Vaughan-Williams antiarrhythmic drug classification divides drugs into four classes based on their principal mode of action: class I, sodium channel blockers; class II, β-adrenergic blockers; class III, potassium channel blockers; and class IV, calcium channel blockers. Class I antiarrhythmic drugs are further subdivided into classes IA, IB, and IC. Signs of toxicity caused by class I antiarrhythmics include the following: ●

●

● ●

●

Lengthened Q-T interval (class IA) or widened QRS complexes (class IC) manifesting as proarrhythmia Long Q-T interval (corrected Q-T interval of 440 to 450 msec) History of dizziness or syncope preoperatively Change in dosing or the recent initiation of antiarrhythmic therapy Occurrence of TDP (see Fig. 10-1)

Class IA Antiarrhythmic Drugs. All class I antiarrhythmics are sodium channel blockers, and some also affect the currents involved in action potential repolarization. Class IA drugs (e.g., quinidine, procainamide, disopyramide) reduce action potential upstroke velocity and prolong its duration. The kinetics of these drugs’ onset and offset of effect are of intermediate rapidity (<5 seconds). Class IB Antiarrhythmic Drugs. Class IB drugs (e.g., mexiletine, phenytoin, lidocaine) do not reduce upstroke velocity, but they do shorten action potential duration. They have fast onset and offset kinetics (<500 msec). Class IC Antiarrhythmic Drugs. Class IC drugs (e.g., flecainide, propafenone, moricizine) reduce upstroke velocity (primarily by slowing conduction) and also prolong refractoriness somewhat. They have slow onset and offset kinetics (10 to 20 seconds). The Vaughan-Williams classification is still widely used, but it has many limitations because of the complexity of drug actions. The “Sicilian gambit’’ (see Further Reading) provides a more realistic view. Some drugs exert greater effects at slow rates than at fast rates (reverse use dependence); this is particularly true of drugs that lengthen repolarization (class IA). Thus, the Q-T interval becomes prolonged at slow rates rather than at fast rates, which is exactly the opposite of what an ideal antiarrhythmic drug should do. Prolongation of refractoriness should be increased at fast rates to interrupt or prevent a reentrant tachycardia and minimal at slow rates to avoid precipitating TDP.

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Finally, it is important to remember that anesthesiologists must evaluate the patient with a rhythm disturbance, not the rhythm disturbance itself. Some arrhythmias are hazardous to the patient regardless of the clinical setting, whereas others are hazardous because of the clinical setting (e.g., anesthesia and surgery, acute coronary syndromes, post cardiopulmonary bypass).

Risk Assessment Conditions associated with Q-T interval prolongation and thus predisposition to TDP are listed in Table 10-2. A variety of commonly prescribed drugs belonging to many different therapeutic classes, including antiarrhythmics, antibiotics, antihistamines, and prokinetic drugs, can adversely prolong cardiac repolarization. However, arrhythmias related to drug-induced Q-T prolongation do not occur in every patient treated with such drugs; they occur only in susceptible patients. It has been postulated that these individuals may be silent carriers of genes responsible for congenital long QT syndromes. Up to 70% of these patients have normal Q-Tc intervals until exposed to a Q-T interval–prolonging drug. The primary objective of pharmacologic therapy for a patient with a cardiac arrhythmia is to achieve an effective and well-tolerated plasma drug concentration as quickly as possible and to maintain that concentration for as long as required without producing adverse effects. In many circumstances (but not with all drugs), the plasma concentration after equilibration correlates with the pharmacodynamic and adverse effects of the drug. However, the therapeutic concentration for any given patient is the amount of drug required to suppress or terminate the specific cardiac arrhythmia without producing adverse side effects.

Table 10–2

■

Factors that Predispose to Q-T Interval Prolongation

Congenital or acquired long QT syndromes Coexisting disease Hypothyroidism Cardiomyopathies Bradycardia Physiologic imbalance Hypokalemia Hypomagnesemia Hypocalcemia Antiarrhythmics Class IA, IC, and III drugs Combined class IA and III drugs Other drugs Potassium-wasting diuretics Tricyclic antidepressants Phenothiazines Erythromycin Terfenadine Astemizole Liquid protein diets For a more complete listing, see Chapter 81 or go to http.//www.torsades.org.

Given the fact that automaticity, triggered activity, or reentry can cause cardiac arrhythmias, the mechanisms by which antiarrhythmic agents suppress cardiac arrhythmias can be postulated. Antiarrhythmic agents can slow the spontaneous discharge frequency of an automatic pacemaker by depressing the slope of diastolic depolarization, shifting the threshold voltage toward zero, or hyperpolarizing the resting membrane potential. Mechanisms by which different drugs suppress normal or abnormal automaticity may not be the same. In general, most antiarrhythmic drugs in therapeutic doses depress automaticity at ectopic sites while minimally affecting automaticity of the sinus node. However, calcium channel blockers (e.g., verapamil) and β-blockers (e.g., propranolol) can depress the sinus rate, and drugs that exert vagolytic effects (e.g., disopyramide, quinidine) can increase the sinus rate. Drugs can also suppress early or delayed afterdepolarizations to eliminate triggered arrhythmias. Proarrhythmia with antiarrhythmic drugs is an important clinical problem. Electrophysiologic mechanisms include prolongation of repolarization, development of delayed after depolarizations (e.g., arrhythmias with digitalis toxicity) or EADs (to initiate TDP), or alterations in conduction and refractoriness that are conducive to reentry and the initiation or maintenance of VT or ventricular fibrillation. The acquired form of Q-T interval prolongation (see Table 10-2) is caused by various agents and conditions that reduce the magnitude of outward repolarizing K+ currents, enhance inward depolarizing Na+ or Ca2+ currents, or both, which leads to the development of EADs that initiate TDP. Proarrhythmic events can occur in as many as 5% to 10% of patients. Congestive heart failure increases proarrhythmic risk. In one recent study, patients with atrial fibrillation receiving antiarrhythmic drugs had a 4.7 relative risk of cardiac death if they had a history of heart failure, compared with a 3.7 relative risk among those not receiving antiarrhythmic drugs. Patients without a history of congestive heart failure had no increased risk of cardiac mortality during antiarrhythmic drug therapy. Reduced left ventricular function, treatment with digitalis and diuretics, and longer pretreatment Q-T interval are often seen in patients who develop drug-induced ventricular fibrillation. Usually the proarrhythmic events occur within several days of beginning drug therapy or after a change in dosage and are manifest by the development of VT, Q-T interval prolongation, or TDP (long QT syndrome). Doses for class I antiarrhythmic drugs are listed in Table 10-3. Proarrhythmic effects are likely additive when multiple drugs are used. Mortality with TDP is approximately 30%. With acquired long QT syndromes, the therapeutic challenge is to maintain prolonged repolarization but interrupt the arrhythmogenic cascade.

MANAGEMENT It is possible that multiple drugs have a cumulative effect in provoking EADs and TDP. Antiarrhythmics may paradoxically produce malignant ventricular tachyarrhythmias via proarrhythmia, and preoperative antiarrhythmic treatment does not preclude the generation of more ominous perioperative arrhythmias. The ECG should be carefully scrutinized

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Dosing for Class I Antiarrhythmic Agents

Drug

IV Loading

IV Maintenance

PO Loading

PO Maintenance

Quinidine Procainamide Disopyramide Lidocaine Mexiletine Tocainide Phenytoin Flecainide Propafenone Moricizine

6-10 mg/kg at 0.3-0.5 mg/kg/min 6-13 mg/kg at 0.2-0.5 mg/kg/min 1-2 mg/kg over 15-45 min 1-3 mg/kg at 20-50 mg/min 500 mg 750 mg 100 mg q5min to <1000 mg 2 mg/kg 1-2 mg/kg

600-1000 mg 2-6 mg/min 1 mg/kg/hr 1-4 mg/min 0.5-1.0 g/24 hr

300-600 mg q6h 500-1000 mg NA 400-600 mg 400-600 mg 1000 mg

300-600 mg q6h 350-1000 mg q3-6h 100-400 mg q6-8h NA 150-300 mg q6-8h 400-600 mg q8-12h 100-400 mg q12-24h

600-900 mg 300 mg

150-300 mg q8-12h 100-400 q8h

100-200 mg q12h

NA, not applicable.

preoperatively for signs of toxic effects caused by drugs (e.g., prolonged Q-Tc interval or widened QRS complex). Specific management for TDP includes the following: ●

● ●

●

●

Atrial or ventricular pacing to increase the K+ current and shorten refractoriness at faster heart rates Intravenous bolus magnesium sulfate Lidocaine by intravenous bolus (does not prolong the Q-T interval) Calcium channel blocker by intravenous bolus (if other interventions fail) Cautious use of isoproterenol to increase the heart rate if pacing is not available

PREVENTION Prevention includes providing a stress-free perioperative period (to the extent possible) to reduce myocardial ischemia and related increased dispersion of myocardial refractoriness. In addition, the following points should be noted: ● ●

●

●

Regional anesthesia is advised. Consider cardiology reevaluation for drug dosing and appropriateness. Consider stopping quinidine before anesthesia administration. Avoid conditions that prolong the Q-T interval (see Table 10-2).

Booker and colleagues have provided a comprehensive review of anesthetic management for patients with

congenital and acquired long QT syndromes, including specific recommendations for the perioperative management of such patients.

Further Reading Atlee JL: Drug treatment for arrhythmias. In Atlee JL (ed): Arrhythmias and Pacemakers: Practical Management for Anesthesia and Critical Care Medicine. Philadelphia, WB Saunders, 1996, pp 154-204. Atlee JL: Overview of mechanisms for arrhythmias. In Atlee JL (ed): Arrhythmias and Pacemakers: Practical Management for Anesthesia and Critical Care Medicine. Philadelphia, WB Saunders, 1996, pp 25-58. Booker PD, Whyte SD, Ladusans EJ: Long QT syndrome and anaesthesia. Br J Anaesth 90:349-366, 2003. Charbit B, Albaladejo P, Funck-Brentano C, et al: Prolongation of QTc interval after postoperative nausea and vomiting treatment by droperidol or ondansetron. Anesthesiology 102:1094-1100, 2005. Effect of the antiarrhythmic agent moricizine on survival after myocardial infarction. The Cardiac Arrhythmia Suppression Trial II investigators. N Engl J Med 327:227-233, 1992. Preliminary report: Effect of encainide and flecainide on mortality in a randomized trial of arrhythmia suppression after myocardial infarction. The Cardiac Arrhythmia Suppression Trial (CAST) investigators. N Engl J Med 321:406-412, 1989. Soroker D, Ezri T, Szmuki P, et al: Perioperative torsades de pointes ventricular tachycardia induced by hypocalcemia and hypokalemia. Anesth Analg 80:630-633, 1995. Tan HL, Hou CJ, Laver MR, et al: Electrophysiologic mechanisms of the long QT interval syndromes and torsades de pointes. Ann Intern Med 122:701-714, 1995. Task Force of the Working Group on Arrhythmias of the European Society of Cardiology: The Sicilian gambit: A new approach to the classification of antiarrhythmic drugs based on their actions on arrhythmogenic mechanisms. Circulation 84:1831-1851, 1991.

PHARMACOLOGY

Table 10–3

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Class II Antiarrhythmic Drugs: β-Blockers—Heart Block or Bradycardia

11

Charles A. Napolitano and Maria I. Castro Case Synopsis A 60-year-old woman with a history of mitral valve stenosis and atrial fibrillation is scheduled for abdominal hysterectomy. Her current medications include verapamil and digoxin. Following induction of anesthesia with etomidate and maintenance with sevoflurane, oxygen, fentanyl, and vecuronium, her ventricular rate increases acutely to 140 beats per minute. Esmolol therapy results in acute bradycardia (30 beats per minute). Electrocardiogram (ECG) monitoring reveals third degree atrioventricular (AV) heart block with regular, wide QRS complexes.

PROBLEM ANALYSIS Definition β-Blockers are commonly used in the management of arrhythmias, hypertension, and heart failure. However, by producing β-adrenergic block, they have the potential to cause sinus bradycardia or sinoatrial (SA) or AV heart block at the AV node. These effects can be aggravated by drugs used during anesthesia (e.g., potent volatile anesthetics, high-dose opiates, local anesthetic toxicity, succinylcholine). Some β-blockers also have vasodilator activity (e.g., carvedilol, labetalol) and may be better tolerated in patients with heart failure. Sinus bradycardia in adults is a heart rate less than 60 beats per minute with a rhythm that originates in the SA node. Third degree AV heart block is the complete absence of impulses conducted from the atria to the ventricles, with the ventricles controlled by impulses originating in subsidiary (latent) cardiac pacemakers located distal to the site of block. If the site of conduction block is perinodal (SA exit block or AV node block), the heart rate typically ranges from 45 to 55 beats per minute, and the QRS interval is of normal duration (~−120 msec). Infranodal block (below the AV node) is characterized by a ventricular rate of 30 to 40 beats per minute and wide QRS complexes. The conduction defect depicted in the case synopsis represents infranodal third degree block with slow secondary pacemaker activity; this can lead to cardiac arrest. Although the third degree AV heart block in this case likely resulted from synergistic depression of AV node function by esmolol (a class II antiarrhythmic) and verapamil (a class IV antiarrhythmic), the other drugs, including digoxin, sevoflurane, and fentanyl, likely contributed. Esmolol, a shortacting β1-selective adrenergic antagonist (β-blocker), is indicated when immediate control of the heart rate or blood pressure is needed and prolonged β-blockade is undesirable. The peak onset of action (6 to 10 minutes) and short halflife (8 minutes) make esmolol appropriate for the management 40

of perioperative tachyarrhythmias. Like all β-blockers, esmolol reduces the sinus rate and AV node conduction time while increasing AV node functional refractoriness. Owing to its inhibitory effects on AV node conduction, verapamil, a calcium channel antagonist, is also useful for reducing the ventricular rate in patients with atrial flutter or fibrillation. However, the effects of verapamil can be potentiated by the concomitant use of β-blockers. As mentioned, the use of sevoflurane, digoxin, and fentanyl, and possibly the surgical procedure itself, likely contributed to the development of heart block in this case. To maintain cardiac output and prevent left ventricular failure or pulmonary edema, tight control of left ventricular preload, heart rate, and systemic vascular resistance is critical for patients with mitral or aortic stenosis and restrictive cardiomyopathies. Thus, the selection of etomidate as an anesthetic induction agent was, at least in theory, a good choice, because etomidate minimizes reflex increases in heart rate and generally maintains systemic vascular resistance and blood pressure within normal limits. However, like other potent inhalational agents, sevoflurane reduces systemic vascular resistance and preload (by dilating the venous capacitance bed to decrease venous return) and may have contributed to the intraoperative increase in ventricular rate via a reflex increase in adrenergic tone. Further, it may have contributed to the third degree AV block and bradycardia by direct effects on AV node conduction and refractoriness. Other potent volatile anesthetics, with the possible exception of desflurane, may also decrease the rate of AV node conduction and SA node discharge. Digoxin’s central actions stimulate vagal tone to reduce heart rate and increase AV node conduction time and refractoriness. Fentanyl, especially at high doses, may inhibit AV node function by causing centrally increased parasympathomimetic and reduced sympathomimetic tone. Finally, peritoneal retraction slows the heart rate and AV node conduction by increasing vagal tone. Thus, any of these factors could have exacerbated the effects of verapamil and esmolol on SA and AV node function.

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Recognition ECG monitoring is the definitive means of detecting bradycardia or AV conduction block. Sinus bradycardia (<60 beats per minute) or asystole is easily recognized on ECG. AV node or infranodal third degree conduction block requires closer ECG inspection (Fig. 11-1). With AV node or perinodal heart block, P waves are dissociated from the QRS complex, but with an AV junctional pacemaker and normal conduction through the ventricles. The QRS complex is of normal ~120 msec duration). In contrast, with infranodal width (~ block, conduction from latent pacemakers below the AV node or His bundle leads to wide QRS complexes. Other, less reliable methods of detecting bradycardia or heart block include the following: ●

●

●

Pulse oximetry plethysmographs reveal a reduced heart rate and possibly reduced arterial oxygen saturation. Capnography may show low end-tidal carbon dioxide values due to reduced pulmonary flow. Noninvasive blood pressure monitoring may reveal hypotension and a reduced heart rate or may simply provide a default “error” message.

Figure 11–1 ■ Atrioventricular (AV) block. Diagrammatic representation of the conduction pathology and resultant electrocardiogram. S-A, sinoatrial. (Adapted with permission from the American Heart Association: Textbook of Advanced Cardiac Life Support, 2nd ed. New York, AHA, 1990; and Netter FH: CIBA Collection of Medical Illustrations. West Caldwell, New Jersey, CIBA Medical Education Division, 1987.)

●

●

Invasive blood pressure monitoring reveals reduced frequency and possibly amplitude of the arterial waveform. Palpation of peripheral pulses indicates decreased frequency and intensity of the pulses.

Although these modalities can assist in assessing the hemodynamic impact of bradycardia, only ECG allows definitive diagnosis of its cause.

Risk Assessment Although the incidence of new intraoperative heart block is unknown, its incidence in animal and prospective clinical studies appears to be greater when antagonists and β-blockers are used in combination. The potential risk of developing bradyarrhythmias and AV node conduction disturbances in patients receiving β-blockers varies. It is greatest with verapamil, somewhat less with diltiazem, and least with dihydropyridine (DHP) calcium channel antagonists such as nicardipine, amlodipine, and nifedipine. DHP calcium channel antagonists have a much higher affinity for L-type Ca2+ channels in vascular smooth muscle as opposed to cardiac myocytes. Animal studies show synergism between the cardiac electrophysiologic effects of β-blockers and calcium channel antagonists (e.g., verapamil, diltiazem). When the latter are given at low doses, propranolol enhances their effect on heart rate and AV node conduction. When given at high doses

PHARMACOLOGY

Although this patient had third degree AV heart block and severe bradycardia, any condition within the spectrum of bradycardia (including asystole) could have occurred. Anesthesiologists must be prepared for this possibility with the appearance of severe bradycardia.

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with verapamil or diltiazem, propranolol causes significant heart block, hypotension, or left ventricular dysfunction. Clinical studies support the findings in animal models. In patients with chronic stable angina, therapy with a β-blocker and verapamil (versus diltiazem or nifedipine) causes a significant (10% to 15%) increase in the incidence of adverse cardiac or hemodynamic effects (bradycardia, heart block, hypotension, syncope, or congestive heart failure). However, diltiazem in combination with various β-blockers does not cause significant AV heart block, although it does increase the risk for P-R interval prolongation and bradycardia. Also, intraoperative bradycardia, first degree AV block, and AV junctional rhythms occurred more often in patients having coronary artery bypass graft surgery who took nonDHP calcium channel antagonists and β-blockers before surgery. Finally, transient AV block after aortic cross-clamp release during coronary artery bypass surgery was significantly increased in patients receiving preoperative propranolol (5% higher) or propranolol-nifedipine (15% higher). Patients whose medical treatment may include a β-blocker, calcium channel antagonist, or both are listed in Table 11-1. Other preoperative and intraoperative factors that place patients at increased risk for heart block during anesthesia and surgery are listed in Tables 11-2 and 11-3.

Implications Bradycardia with AV heart block can lead to severe hemodynamic compromise. In the absence of SA node activity, cardiac arrest is possible if perinodal or ventricular escape rhythms do not occur promptly. Severe hypotension due to reduced heart rate and lack of AV synchrony may cause myocardial ischemia. Heart failure may follow if cardiac output is not maintained by a compensatory increase in stroke volume. Hypotension, increased pulmonary artery pressure, and increased left ventricular end-diastolic pressure

Table 11–2

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Patient Populations Managed with β-Blockers or Calcium Channel Blockers

Coronary Artery Disease Chronic stable angina or previous myocardial infarction Native coronary arteries or autografts prone to spasm Perioperative management of myocardial ischemia in selected patients

Arrhythmias Prevention or treatment of supraventricular tachyarrhythmias (especially paroxysmal supraventricular tachycardia) Prevention or treatment of focal ventricular tachycardia in patients without structural heart disease (e.g., right ventricular outflow tract tachycardia, idiopathic left ventricular tachycardia*)

Cardiovascular Disease Hypertension Heart failure (β-blockers along with other drugs, such as angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers) Symptomatic patients treated with β-blockers for mitral valve prolapse *Focal ventricular tachycardias that originate in the left ventricular outflow tract, epicardium, or midseptum.

Preoperative Risk Factors for the Development of Intraoperative Heart Block

Age older than 60 years Chronic administration of β-blockers, calcium channel antagonists, amiodarone, or other drugs that prolong AV node or AV conduction (e.g., class IC antiarrhythmics, long-acting local anesthetics) Underlying conduction system disease (e.g., congenital heart disease, repair of atrial secundum defects, repair of transposition of the great vessels) Electrolyte or metabolic imbalance (e.g., hyperkalemia, hypothermia) Systemic disease (e.g., hypothyroidism-myxedema, intracardiac rheumatoid nodules, rheumatic heart disease) Preexisting heart disease (e.g., coronary artery disease, idiopathic degeneration or fibrosis, aortic or mitral valve surgery, Lyme disease, bacterial endocarditis, chagasic myocarditis,* calcific aortic stenosis) Preoperative bradycardia (<60 beats per minute) Myocardial infiltrative processes (e.g., sarcoidosis, amyloidosis, scleroderma) *Common in Central and South America. AV, atrioventricular.

have been observed in both animal and clinical studies of combined β-blocker and non-DHP calcium channel antagonist therapy.

MANAGEMENT After verification of third degree AV heart block and hemodynamic assessment, optimal oxygenation, ventilation, and perfusion are ensured by increasing the fraction of inspired

Table 11–3 Table 11–1

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Intraoperative Risk Factors Associated with the Development of Atrioventricular Heart Block

Drugs β-blockers Calcium channel antagonists High-dose volatile anesthetics or opiates IV anesthetic drugs (e.g., propofol, high-dose opiates, succinylcholine) Anticholinesterase therapy Digitalis glycosides IV amiodarone or sotalol Class IA or IB antiarrhythmic drugs, especially high IV doses

Increased Vagal Tone or Stimulation Peritoneal retraction or retraction of ocular muscles Direct laryngoscopy and endotracheal intubation Urinary bladder catheterization Esophageal instrumentation Baroreceptor reflex activation with acute hypertensive episodes (e.g., aortic cross-clamp application) Rectal or cervical dilatation

Imbalance Hypoxia Hypothermia Hyperkalemia

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● ●

● ● ● ●

●

● ● ● ● ●

Ephedrine 5 to 10 mg intravenously (IV); repeat if necessary Atropine 0.4 mg IV or glycopyrrolate 0.2 mg IV (up to a total of 2 or 1 mg IV, respectively, if necessary) Calcium 250 mg IV; repeat up to a total of 1 g if necessary Epinephrine 10 mg IV; repeat with increased doses as needed Isoproterenol 1 to 10 mg/minute IV Perform noninvasive (transcutaneous) pacing before instituting invasive transvenous pacing; noninvasive esophageal atrial pacing is ineffective in third degree AV block. Perform cardiopulmonary resuscitation if systolic blood pressure is 40 to 50 mm Hg (while attempting or repeating the above measures). Anticipate adverse drug interactions. Maintain hemodynamic stability. Perform intraoperative hemodynamic monitoring. Select drugs to treat tachycardia. Consider cardioversion in place of drugs for symptomatic supraventricular tachycardia.

PREVENTION The patient in the case synopsis developed third degree AV heart block after esmolol was given to control a rapid ventricular rate with atrial fibrillation. Her preexisting heart disease required the avoidance of extreme increases or decreases in heart rate to maintain hemodynamic stability and vital organ perfusion. Prevention of hemodynamic instability in such patients requires careful preoperative assessment, anticipation of adverse drug interactions, and attention to surgical or procedure-related interventions that might lead to wide fluctuations in heart rate or blood pressure. In addition to a thorough history and physical examination and the necessary laboratory tests, the preoperative assessment should include knowledge of the patient’s baseline heart rate, blood pressure, and intravascular volume status. Anesthesiologists should be able to anticipate adverse events and must be prepared to manage them early to minimize complications. Intraoperatively, care should be taken to ensure an adequate depth of anesthesia and analgesia and to maintain appropriate hydration. The placement of a Swan-Ganz catheter or intraoperative transesophageal echocardiography to monitor cardiac hemodynamic parameters should be considered for high-risk patients. If significant tachycardia develops in a patient receiving a non-DHP calcium channel antagonist, a reduced dose of esmolol (0.1 to 0.25 mg/kg) can be given to minimize any synergistic effect. To terminate

reentrant supraventricular tachycardia involving the AV node, adenosine (6 to 12 mg IV) can be used; it is an ultra-shortacting nucleoside with an efficacy equal to or better than that of the DHP calcium channel antagonists. Other alternatives are diltiazem (0.25 to 0.35 mg/kg IV), neostigmine (1 mg IV), edrophonium (10 mg IV), or phenylephrine (50 to 100 μg IV); vagal maneuvers (e.g., carotid sinus massage, Valsalva’s maneuver, ocular massage); or medications the patient is already receiving (e.g., verapamil 1.25 to 2.5 mg or digoxin 0.125 to 0.5 mg IV). Although synergistic effects with β-blockers are most often reported with verapamil, heart block is a theoretical possibility with any of the previously mentioned drugs, particularly when they depress AV node function by different cellular mechanisms. Finally, early direct-current cardioversion is the treatment of choice for atrial fibrillation or flutter causing hemodynamic compromise due to a rapid ventricular response.

Further Reading Atlee JL: Perioperative cardiac dysrhythmias: Diagnosis and management. Anesthesiology 86:1397-1424, 1997. Auerbach AD, Goldman L: Beta-blockers and reduction of cardiac events in noncardiac surgery: Scientific review. JAMA 287:1435-1444, 2002. Baraka AS, Taha SK, Yasbeck VK, et al: Transient atrioventricular block after release of aortic cross-clamp. Anesth Analg 80:54-57, 1995. Devereaux PJ, Beattie WS, Choi PT, et al: How strong is the evidence for the use of perioperative beta-blockers in non-cardiac surgery? Systematic review and meta-analysis of randomised controlled trials. BMJ 331:313-321, 2005. Henling CE, Slogoff S, Kodal SV, et al: Heart block after coronary artery bypass: Effects of chronic administration of calcium-entry blockers and β-blockers. Anesth Analg 63:515-520, 1984. Hoffman BB: Catecholamines, sympathomimetic drugs, and adrenergic receptor antagonists. In Hardman JG, Limbird LE (eds): Goodman and Gilman’s The Pharmacological Basis of Therapeutics, 10th ed. New York, McGraw-Hill, 2001, pp 215-268. Kapur PA, Matarazzo DA, Fung OM, et al: The cardiovascular and adrenergic actions of verapamil or diltiazem in combination with propranolol during halothane anesthesia in the dog. Anesthesiology 66:122-129, 1987. Kerins DM, Robertson RM, Robertson D: Drugs used for the treatment of myocardial ischemia. In Hardman JG, Limbird LE (eds): Goodman and Gilman’s The Pharmacological Basis of Therapeutics, 10th ed. New York, McGraw-Hill, 2001, pp 843-870. Krum H: Tolerability of carvedilol in heart failure: Clinical trials experience. Am J Cardiol 93:58B-63B, 2004. Lopez-Sendon J, Swedberg K, McMurray J, et al: Task Force on BetaBlockers of the European Society of Cardiology. Expert consensus document on beta-adrenergic receptor blockers. Eur Heart J 25: 1341-1362, 2004. McMurray JJ, Pfeffer MA: Heart failure. Lancet 365:1877-1889, 2005. Messerli FH, Grossman E: Beta-blockers in hypertension: Is carvedilol different? Am J Cardiol 93:7B-12B, 2004. Oates JA, Brown NJ: Antihypertensive agents and the drug therapy of hypertension. In Hardman JG, Limbird LE (eds): Goodman and Gilman’s The Pharmacological Basis of Therapeutics, 10th ed. New York, McGraw-Hill, 2001, pp 871-900. Priebe HJ: Perioperative myocardial infarction—aetiology and prevention. Br J Anaesth 95:3-19, 2005. Schwartz AB, Moskowitz RM, Klausner SC: The electrophysiological effects of nicardipine hydrochloride in man. Can J Cardiol 3:14-17, 1987. Strauss WE, Parisi AF: Combined use of calcium-channel and beta-adrenergic blockers for the treatment of chronic stable angina: Rationale, efficacy, and adverse effects. Ann Intern Med 109:570-581, 1988.

PHARMACOLOGY

oxygen to 1.0 and discontinuing the use of volatile anesthetics. If the blood pressure and cardiac output are not adequate, cardiopulmonary resuscitation should be started immediately. The surgeon should discontinue any maneuvers that could increase vagal tone (e.g., peritoneal retraction) until the condition has been resolved. The treatment of mild (sinus bradycardia) to severe (asystole) complications includes the following:

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12

M. J. Pekka Raatikainen and Donn M. Dennis Case Synopsis A 76-year-old woman with a history of paroxysmal atrial fibrillation is admitted to the hospital for elective surgery. Her antiarrhythmic medication is 80 mg of sotalol twice daily. Before the operation, she has a sudden syncopal attack, and an electrocardiogram (ECG) shows a wide QRS self-terminating tachycardia.

PROBLEM ANALYSIS Definition The patient’s medical history and ECG (Fig. 12-1) are consistent with drug-induced Q-T prolongation and proarrhythmia. It is well known that prolongation of ventricular repolarization (i.e., long Q-T interval), the electrophysiologic basis for class III antiarrhythmic drug action, can paradoxically cause polymorphic torsades de pointes (TDP). TDP is a polymorphic ventricular tachycardia (VT) that occurs in the setting of Q-T interval prolongation; in the absence of Q-T prolongation, it is known as simply polymorphic VT. With TDP or polymorphic VT, the distinctive ECG pattern is characterized by a continuous twisting of the QRS axis around the isoelectric ECG baseline.

Although the precise mechanisms underlying TDP are unclear, most experimental and clinical evidence suggests that triggered activity initiated by early afterdepolarizations, along with delayed ventricular repolarization, provokes the onset of TDP. In general, TDP manifests as brief, repetitive episodes of self-terminating VT. Unabated, it can deteriorate into ventricular fibrillation.

Recognition The diagnosis of drug-induced long QT syndrome and TDP (see also Chapter 81) is based on the characteristic ECG findings and the patient’s medical history. In particular, special attention should be focused on concurrent use of other Q-T–prolonging drugs, including class IA antiarrhythmics (e.g., quinidine), macrolide antibiotics (e.g., erythromycin), nonsedating antihistamines (e.g., terfenadine), and psychotropic drugs (e.g., antipsychotics, tricyclic antidepressants). A more complete listing can be found at http:// www.torsades.org. ECG features of long QT syndrome include the following: ●

0.80 s

A Rhythm strip during the tachycardia

● ●

Prolonged ventricular repolarization (Q-Tc >0.44 second) Alternating T waves or prominent U waves Increased dispersion of ventricular repolarization (Q-T dispersion) ECG features of drug-induced TDP include the following:

●

0.56 s

B ECG (lead II) before the syncope Figure 12–1 A, Electrocardiogram (ECG) rhythm strip obtained from a 76-year-old woman immediately after syncope. Note the extremely long Q-T interval (0.80 second) immediately before the onset of the arrhythmia and twisting of the QRS axis around the isoelectric baseline during the tachycardia (220 beats per minute) (paper speed 25 mm/second). B, ECG (lead II) from the same patient showing a significant prolongation of the Q-T interval (Q-Tc = 0.56 second) during normal sinus rhythm (62 beats per minute) (paper speed 25 mm/second). After cessation of class III antiarrhythmic drugs (sotalol 80 mg twice daily), the Q-Tc interval returned to a value of 0.40 second.

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Polymorphic tachycardia (160 to 250 beats per minute), with characteristic twisting of the QRS axis around the isoelectric ECG baseline Characteristic “short-long-short” initiation sequence (i.e., R-R intervals) Initiation frequently caused by extra systoles with a long coupling interval

In patients with acquired long QT syndrome, TDP typically follows long pauses, whereas in patients with congenital (idiopathic) long QT syndrome, the initiation of TDP is commonly associated with an increase in catecholamines and heart rate (e.g., stress, fright, physical exercise).

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Risk Assessment Experience with the perioperative use of class III antiarrhythmic agents is limited, and there is little information on interactions between these drugs and anesthetic agents. The major perioperative complications related to long-term therapy with class III antiarrhythmics include proarrhythmia (e.g., TDP) and noncardiac amiodarone interactions and toxicity. The latter is discussed in more detail later in this chapter.

studies have yet to be conducted, one could speculate that anesthetics that reduce heart rate, depress atrioventricular (AV) node conduction, and lengthen ventricular repolarization might increase the proarrhythmic effects of class III antiarrhythmic drugs during surgery. Given the data indicating that patients with acquired long QT syndrome may suffer from variant forms of the congenital syndrome (e.g., electrically silent gene defects that manifest only with Q-T interval–prolonging drugs), genetic analyses of genes encoding the cardiac sodium and potassium channels may provide valuable information about the risk of drug-induced proarrhythmias. The following ECG findings before anesthesia indicate an increased risk for perioperative proarrhythmia: ● ● ● ● ● ●

Excessive prolongation of the Q-T interval Increased Q-T interval dispersion T-wave alternans or prominent U waves Polymorphic premature ventricular complexes Sinus bradycardia and AV conduction disturbances Abrupt slowing of the heart rate (e.g., conversion of atrial fibrillation to normal sinus rhythm)

PROARRHYTHMIC RISK

AMIODARONE INTERACTIONS

The following factors predispose to the development of class III antiarrhythmic drug-induced TDP during anesthesia:

Several groups have noted a greater incidence of cardiac rhythm and conduction disturbances (e.g., atropineresistant bradycardia, slow AV junctional rhythms, complete AV heart block, pacemaker dependency), an increased need for perioperative circulatory support (including inotropes or intra-aortic balloon counterpulsation), and more noncardiac complications in patients receiving amiodarone. However, perioperative hemodynamic instability with amiodarone and a poor response to inotropic drugs may be explained, in part, by the drug’s antiarrhythmic actions. In addition to class III activity, these include sodium channel blockade (class I), noncompetitive blockade of β- and α-adrenergic receptors (class II), and inhibition of calcium channels (class IV). The reader is referred to Chapters 10, 11, and 13, respectively, for complications related to these antiarrhythmic classes of drugs. The role of general anesthetic agents in the development of amiodarone’s pulmonary toxicity remains controversial. Although some groups have found a higher incidence of postoperative acute respiratory distress syndrome and other pulmonary disorders in patients receiving amiodarone, others have been unable to show this relationship. Nonetheless, pulmonary toxicity is the most feared long-term complication of amiodarone therapy and should not be forgotten in the risk assessment of patients receiving this drug.

● ●

● ● ●

●

Female gender Electrolyte disturbances (e.g., hypokalemia, hypomagnesemia, severe hypocalcemia) Structural heart disease and myocardial ischemia Excessive dosing Genetic defects behind the enzymes metabolizing the drug or defective cardiac ion channels responsible for congenital long QT syndrome (see Chapter 81) Drug interactions or simultaneous use of drugs that prolong ventricular repolarization

Critical values for Q-T prolongation are lacking. Available data indicate that Q-T dispersion (i.e., difference between the longest and shortest Q-T intervals assessed by 12-lead ECG) may predict the proarrhythmia more accurately than absolute Q-T interval prolongation or the latter corrected for heart rate (Q-Tc interval). For example, amiodarone—which, unlike the other class III agents, prolongs the Q-T interval uniformly (i.e., does not increase Q-T interval dispersion)—has a significantly lower proarrhythmic risk (2% to 3%) than the other class III antiarrhythmics (5% to 10%). Other factors that may explain amiodarone’s lower proarrhythmic risk compared with “pure” class III antiarrhythmics (which selectively inhibit cardiac potassium channels) include a heart rate–independent action on ventricular repolarization, and β-adrenergic blocking, α-adrenergic blocking, and calcium channel blocking properties. The incidence of TDP with amiodarone is only 0.7%, whereas sotalol and quinidine induce TDP in about 5% and 8% of cases, respectively. Further, in contrast to sotalol and ibutilide (a class III antiarrhythmic), acute intravenous amiodarone seldom if ever prolongs the Q-T interval. However, in the setting of electrolyte abnormalities, bradycardia, or abrupt changes in the heart rate, the proarrhythmic risk increases significantly. Thus, although definitive clinical

AND

TOXICITY

Implications Owing to their potent cardiac electrophysiologic properties, class III drugs not only exhibit important antiarrhythmic actions but also have the potential to induce life-threatening proarrhythmias, typically TDP. Therefore, anesthesiologists should be familiar with the adverse effects of these drugs and their interactions with other Q-T interval–prolonging drugs and anesthetics. Also, amiodarone has special implications in terms of pulmonary complications.

PHARMACOLOGY

Although TDP may present as a monomorphic VT in a single monitored ECG lead, confusion with monomorphic ventricular arrhythmias is rare when a 12-lead ECG is obtained. The characteristic “short-long-short” initiation sequence and the patient’s medical history help distinguish TDP from other forms of polymorphic VT. Importantly, these other forms of polymorphic VT occur without ECG evidence of Q-T interval prolongation, and often in the setting of an acute coronary syndrome (e.g., myocardial ischemia or infarction, reperfusion injury).

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MANAGEMENT Actions to take when treating drug-induced TDP include the following: ●

● ●

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Immediate electrical cardioversion in hemodynamically unstable patients Infusion of magnesium sulfate (MgSO4) Interventions that shorten the Q-T interval and prevent pause-dependent bradycardia (preferably atrial or ventricular overdrive pacing, or atropine or isoproterenol) Alleviation of electrolyte disturbances and bradycardia (preferably with temporary pacing) and other permissive factors Withdrawal of any offending drugs, along with correction of imbalance

Therapy of drug-induced TDP must focus on immediate TDP termination and the prevention of early recurrence. If TDP causes early hemodynamic collapse, it must be treated with prompt direct-current cardioversion or defibrillation, depending on whether the ECG R or S waves are distinct (cardioversion) or not (defibrillation). Other therapy includes intravenous MgSO4, which is effective against TDP even in patients with normal serum magnesium levels. MgSO4 is given as a 1- to 2-g intravenous bolus. If necessary, it is repeated after 10 to 15 minutes, followed by continuous intravenous infusion at 3 to 20 mg/minute for 24 to 48 hours. If this is ineffective, atropine, isoproterenol, or overdrive pacing is used to prevent long sinus pauses to shorten the Q-T interval. Isoproterenol infused at a dose that maintains the ventricular rate at about 90 beats per minute (1 to 8 μg/minute) may suppress TDP within minutes. However, given this drug’s proarrhythmic actions and other adverse effects, isoproterenol should be used only while pacing is instituted, especially in patients with ischemic heart disease. Preferably, temporary atrial or ventricular overdrive pacing is initiated at a rate of 120 to 130 beats per minute and adjusted to the lowest effective rate. Temporary pacing should be continued until the offending drug is completely eliminated. The role of antiarrhythmic drugs in the treatment of TDP is controversial. In experimental preparations and in some patients, calcium channel blockers, lidocaine, mexiletine, and recently developed potassium channel openers (e.g., nicorandil, pinacidil) have been effective. However, the clinical evidence is marginal and has yet to be verified in large prospective clinical studies. Drugs that prolong ventricular repolarization should be avoided in the therapy of acquired long QT syndrome. Once acute TDP episodes have been controlled, attention should focus on identifying and correcting predisposing metabolic and electrolyte factors and eliminating causative drugs. In patients with congenital long QT syndrome, β-blockers are the drugs of choice, and catecholamines must be avoided. Patients receiving class III antiarrhythmics, especially amiodarone, may be more vulnerable to the development of perioperative bradycardia, AV node conduction disturbances, and circulatory failure. If these conditions do not respond

to atropine, adrenergics, or other positive chronotropes, cardiac pacing or intra-aortic counterpulsation should be instituted.

PREVENTION Prevention includes the following measures: ●

●

●

●

●

Identify and correct any factors that predispose patients to proarrhythmia (e.g., electrolyte imbalance, bradycardia, myocardial ischemia). Stop any drugs that prolong the Q-T interval (e.g., macrolide antibiotics, nonsedating antihistamines, tricyclic antidepressants). Consider reassessing the dosage or withdrawing class III antiarrhythmics and postponing elective operations, especially if the Q-Tc is greater than 0.60 second. Consider regional anesthesia in patients receiving amiodarone. Monitor hemodynamic and respiratory functions throughout the perioperative period.

Q-T prolongation with class III antiarrhythmic drugs is a therapeutic end point. Mechanisms by which this effect becomes proarrhythmic are not easily separated from antiarrhythmic actions. Thus, the cornerstone of preoperative risk reduction in patients receiving class III antiarrhythmics is identification and elimination of predisposing risk factors. Of special importance is correction of electrolyte imbalance and withdrawal of drugs that cause additional Q-T interval prolongation (e.g., macrolide antibiotics, nonsedating antihistamines, tricyclic antidepressants). Likewise, patient reassurance and adequate sedation and analgesia can eliminate preoperative catecholamine increases and help prevent abrupt changes in heart rate during the induction of anesthesia. Amiodarone is the most effective intravenous antiarrhythmic for life-threatening arrhythmias. However, its extremely long elimination half-life and serious adverse extracardiac effects (especially with chronic therapy) make it the most complicated of the class III agents. Importantly, amiodarone significantly augments the cardiac depressant effects of general anesthesia. In addition, amiodaroneassociated pulmonary toxicity may become apparent during emergence and recovery from general anesthesia. Attention to these shortcomings and careful intraoperative monitoring of respiratory and hemodynamic parameters should help anesthesiologists avoid these severe complications. Some case reports suggest that regional anesthesia is preferable in patients receiving amiodarone, but this remains to be confirmed in controlled clinical studies. Likewise, although some experimental data suggest that intravenous anesthetics have different effects on ventricular repolarization in acquired (drug-induced) long QT syndrome, until clinical trials are completed, no specific advice can be given on the selection of general anesthetics for patients receiving class III antiarrhythmics. Finally, because most patients receiving class III agents have severe arrhythmias and other cardiac disease, it is prudent to consult a cardiologist before anesthesia and surgery.

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Atlee JL: Perioperative cardiac dysrhythmias: Diagnosis and management. Anesthesiology 86:1397-1424, 1997. Balser JR: The rational use of intravenous amiodarone in the perioperative period. Anesthesiology 84:974-987, 1997. Belardinelli L, Antzelevitch C, Vos MA: Assessing predictors of drug-induced torsades de pointes. Trends Pharmacol Sci 24:619-625, 2003. Haverkamp W, Breithardt G, Camm AJ, et al: The potential for QT prolongation and proarrhythmia by non-antiarrhythmic drugs: Clinical and regulatory implications. Report on a policy conference of the European Society of Cardiology. Eur Heart J 21:1216-1231, 2000.

Priori SG, Napolitano C: Genetic defects of cardiac ion channels: The hidden substrate for torsades de pointes. Cardiovasc Drugs Ther 16: 89-92, 2002. Roden DM: Drug-induced prolongation of the QT interval. N Engl J Med 350:1013-1022, 2004. Shah RR: Pharmacogenetic aspects of drug-induced torsades de pointes: Potential tool for improving clinical drug development and prescribing. Drug Saf 27:145-172, 2004. Viskin S, Justo D, Halkin A, et al: Long QT syndrome caused by noncardiac drugs. Prog Cardiovasc Dis 45:415-427, 2003. Wolbrette DL: Risk of proarrhythmia with class III antiarrhythmic agents: Sex-based differences and other issues. Am J Cardiol 91:39D-44D, 2003.

PHARMACOLOGY

Further Reading

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13

J. Michael Jaeger and Donn M. Dennis Case Synopsis An obese 48-year-old woman with a history of hypertension treated with diltiazem undergoes a laparoscopic cholecystectomy. Following insufflation of the abdomen with carbon dioxide, she becomes hypertensive and develops sinus tachycardia at a rate of 110 beats per minute; the tachycardia is unresponsive to deepening the level of anesthesia with isoflurane and fentanyl. Propranolol 1 mg is administered intravenously. The patient develops a marked sinus bradycardia, with a P-R interval of 0.24 second on the electrocardiogram (ECG), and becomes hypotensive.

PROBLEM ANALYSIS Definition This case illustrates many of the common toxic effects of L-type (long-lasting) calcium channel antagonists (specifically the class IV antiarrhythmic drugs verapamil and diltiazem) or of interactions between calcium channel antagonists and other cardiodepressant drugs. The marked bradycardia, first degree atrioventricular (AV) node block, and hypotension are manifestations of the pharmacologic interaction of several drugs, most notably diltiazem and propranolol. Each drug has a depressive effect on conduction in both the sinoatrial (SA) node and the AV node, although by different cellular mechanisms. However, both diltiazem and propranolol have little effect on ventricular conduction (Fig. 13-1). Although therapeutic doses of diltiazem and propranolol by themselves generally do not produce this magnitude of response, the concurrent use of a calcium channel antagonist and a β-receptor antagonist can lead to cardiovascular collapse, particularly when other cardiac depressants (e.g., volatile inhalational anesthetics) are involved. Such patients require heightened vigilance by anesthesiologists because AV node conduction blockade can reduce the compensatory reflex increase in cardiac output observed with pathophysiologic conditions (e.g., hypercarbia, hypoxemia, hypovolemia, anemia). In addition to SA and AV node conduction block, this drug combination can precipitate acute heart failure in patients with cardiac disease and limited functional reserve. Both L-type (e.g., verapamil, diltiazem, nifedipine) and T-type (transient) calcium channel antagonists (e.g., mibefradil) have been implicated as the cause of adverse drug interactions. They alter the pharmacokinetics and pharmacodynamics of a wide variety of drugs, including carbamazepine, neuromuscular blockers, digoxin, quinidine, statins, theophylline, and volatile inhalational anesthetics (Table 13-1). 48

Recognition The toxic effects of class IV antiarrhythmic drugs, or their interactions with other depressants of cardiac conduction, can be recognized by the following ECG features: ● ●

● ●

Sinus bradycardia (<60 beats per minute) P-R intervals greater than 0.2 second (first degree block) or P waves not always followed by QRS complexes (second degree block) Normal QRS complex duration (£ 0.1 second) Normal Q-T interval relationships and ST segment configurations unless myocardial ischemia is present

Note that the QRS complex and ST segment remain normal in duration and configuration. This distinguishes direct toxicity by class IV antiarrhythmics or indirect toxicity through their interaction with other depressants of myocardial conduction (e.g., β-blockers) from other disturbances of conduction (e.g., bundle branch or fascicular block, myocardial ischemia). In addition, the interaction of calcium channel antagonists with other drugs should not be confused with preexisting conditions that can have a similar clinical presentation. For example, sick sinus syndrome, preexisting AV node block of varying degrees, amyloidosis, myotonic dystrophy, or cardiomyopathy may confound the ECG diagnosis, although the clinical history and presentation should allow clarification.

Risk Assessment The following factors influence the risk of toxicity: ● ● ●

Therapeutic spectrum Clinical pharmacology Mechanism of action

Verapamil and diltiazem are widely used to treat and prevent supraventricular tachycardias, to limit ventricular rates with atrial fluttter or fibrillation, and as adjuncts for the

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SA Node Action Potential Purkinje Fiber Action Potential (Bundle Branch)

SA Node ↓ conduction

Verapamil & AV Node Diltiazem ↓↓ conduction His Bundle/Bundle Branches AV Node Action Potential

↓ contractility

Table 13–1

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Verapamil & Diltiazem

Selected Drug Interactions with Calcium Channel Antagonists

Drug Antiarrhythmics Amiodarone (AM)

Adenosine Quinidine β-Blockers Atenolol Metoprolol Propranolol Carbamazepine Clonidine Cyclosporine Digoxin Lithium Magnesium sulfate Midazolam Phenytoin Quinidine Rifampin Statin drugs Succinylcholine Theophylline Vecuronium Volatile anesthetics Desflurane Enflurane Halothane Isoflurane Sevoflurane

49

Nature of Interaction

Effect of Interaction

Possible potentiation of AM class IV activity at SA and AV nodes* Possible increase in L-type Ca2+ channel block by AM in vascular smooth muscle* Additive effect ↓ Clearance

AV node block and hypotension; possible bradycardia Prolonged bradycardia AV node block

Noncompetitive Potentiation Potentiation ↓ Clearance Additive effect ↑ Serum concentration Modest ↑ serum concentration Synergism Potentiation ↓ Clearance ↑ Serum concentration ↑ Serum concentration ↑ Clearance of verapamil ↑ Serum concentration Potentiation ↓ Clearance Potentiation

Hypotension; AV node block Hypotension; AV node block Hypotension; AV node block Neurotoxicity; Hypotension; AV node block Nephrotoxicity AV node block Muscle weakness, ataxia Muscle weakness, hypotension Profound and prolonged sedation Neurotoxicity Potentiate hypotensive effects Supraventricular tachycardia Rhabdomyolysis Possible prolonged effect Theophylline toxic effects Prolonged neuromuscular block

Unknown† (possible ↓ heart rate?) Potentiation Potentiation Potentiation Unknown

No reported interactions in humans† Rare AV node block ↓ Cardiac output, AV node block No significant interactions in humans No reported interactions in humans†

*Speculation. † MEDLINE database search Sept 27, 2005: no reports of adverse interactions in animal models or humans. AV, atrioventricular; SA, sinoatrial.

PHARMACOLOGY

Figure 13–1 ■ Cardiac conduction system, with examples of “slow-response” action potentials recorded from the sinoatrial (SA) and atrioventricular (AV) nodes and a “fast-response” action potential recorded from a Purkinje fiber in a bundle branch. Note the smaller action potential upstrokes characteristic of slow-conducting SA and AV node (i.e., slow-response) cells versus the much faster and larger action potential upstroke typical of fast-conducting (i.e., fast-response) Purkinje fibers. Atrial and ventricular muscle fibers also have fast-response action potentials (not shown), similar to those of Purkinje fibers. Verapamil and diltiazem have a greater impact on the conduction of slow-response action potentials in the heart. Contractility is also reduced because of the reduced influx of calcium ions during the cardiac action potential plateau.

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treatment of vasospastic angina and essential hypertension. Although the probability of having to administer an anesthetic to a patient taking either of these calcium channel antagonists is high, actual clinical experience reveals that doing so is generally not a significant problem for anesthesiologists. Nonetheless, the potential for problems exists, and vigilance is important. In large clinical trials, verapamil and diltiazem caused the following cardiovascular abnormalities, in decreasing order of frequency: first degree AV block (2.4%), bradycardia (1.7%), second or third degree AV block (0.8%), and congestive heart failure (<1% to 1.8%). Understanding the clinical problem and identifying patients at risk for complications require an appreciation of the relevant cardiac electrophysiology and pharmacology of all classes of calcium channel antagonists. Six types (T, L, N, P/Q, and R) of mammalian voltage-dependent calcium channels (VDCCs) have been identified. They are distinguishable by location and electrophysiologic characteristics (voltage thresholds for activation; kinetics of channel opening and closing). VDCCs have been classified into two general groups: (1) high-voltage-activated (HVA) calcium channels (threshold activation = −40 to −10 mV), and (2) low-voltage-activated (LVA) calcium channels (threshold activation = −60 to −70 mV). HVA channels include calcium channels of the L, N, P/Q, and R types, whereas LVA channels include only the T type. At times, the R-type channel is classified as an intermediate voltage activated (IVA) calcium channel with threshold activation voltages being intermediate between those of HVA and LVA. Key characteristics of the different types of calcium channels include the following: ●

●

●

●

●

●

T-type calcium channels include a heterogeneous group of Transient (or low voltage) activated–type calcium channels, which are primarily located in the SA and AV nodes, cardiac Purkinje cells, and central nervous system. L-type calcium channels are Long-lasting voltage-gated channels located in both excitable and nonexcitable tissue, which are responsible for normal myocardial and vascular smooth muscle contractility. The alpha-1 subunit of L-type calcium channel is the binding site for calcium channel blockers (e.g., dihydropyridine [DHP]-based calcium channel antagonists. N-type calcium channels are widely distributed in Neural tissue. Omega toxins inhibit the function of these types of calcium channels by changing their voltage dependence. P-type calcium channels were first identified within the Purkinje cells of the cerebellum. They play a role in regulating neuronal stimulation-secretion coupling. Q-type calcium channels are located in neurons. Because Q- (letter derived from the following letter of P) type current is rapidly inactivated, it requires prior blockade of P- and N-type calcium current components to isolate this current for study. R-type calcium channels are located in neurons. They are inhibited by the marine snail toxin, omega conotoxin MVIIC. A notable feature of the R-type channels is their resistance to all known calcium channel blockers. The R-type current (which was named after the following letter of Q, or Remaining channel) is defined as the residual

HVA calcium current observed after the application of toxins that selectively block N, L, P, and Q-type currents. Calcium channels in cardiac muscle and vascular smooth muscle cells are generally of the T and L types, which impart distinct characteristics to the cardiac action potential and influx of calcium into the cell. The T-type channel contributes significantly to the slow upstroke of the action potential found in the SA and AV nodes and, therefore, controls one of the pacemaker currents responsible for the initiation of the heartbeat. This channel exists in ventricular muscle but plays a less significant role in initiating the action potential. The L-type calcium channel produces the plateau of the cardiac action potential and is responsible for the influx of extracellular Ca2+ into the cell. This influx of extracellular Ca2+ is thought to serve as the trigger for the release of internally stored (sarcolemmal) Ca2+. The latter leads to cardiac contraction. The entire process is known as excitation-contraction coupling. Verapamil and diltiazem alter the function of L-type but not T-type calcium channels. Hence, they have a greater impact on the conduction and repolarization of cardiac action potentials (especially within the SA and AV nodes) and on the influx of extracellular Ca2+ than they do on the initiation of cardiac (or smooth) muscle action potentials (see Fig. 13-1). At first, this might seem counterintuitive, given that sinus bradycardia is occasionally observed with verapamil (less often with diltiazem). However, for heartbeats to occur, the SA node must first generate an action potential. In turn, it must be propagated to surrounding atrial muscle and the rest of the heart in a properly synchronized fashion. As more and more L-type calcium channels become blocked, SA node impulse formation slows, and SA conduction and refractoriness increase. Together, these lead to failure of SA node impulse formation and propagation. Reduction of the magnitude of extracellular Ca2+ influx— through fewer functional L-type calcium channels or a shorter duration of their open state—also reduces the strength of cardiac contraction. Because L-type calcium channels are also found in vascular smooth muscle, inhibition of excitation-contraction coupling here leads to vasodilatation. Whereas verapamil affects primarily cardiac L-type calcium channels, diltiazem affects L-type calcium channels in both cardiac and vascular smooth muscle. Finally, the dihydropyridine (DHP) calcium channel blockers (e.g., nifedipine, nicardipine, nimodipine) are highly selective for L-type calcium channels in vascular smooth muscle. Among the L-type calcium channel blockers, verapamil (a diphenylalkylamine) and diltiazem (a benzothiazepine) markedly depress AV node conduction and increase refractoriness, whereas the DHP calcium channel blockers mentioned earlier are primarily vasodilators and have minimal to no effect on SA or AV node tissue or cardiac contractility. Verapamil and diltiazem are useful for treating reentrant supraventricular tachycardias involving the AV node and for achieving ventricular rate control in most patients with atrial flutter or fibrillation. They are also used as therapy for essential hypertension and chronic stable angina, especially vasospastic angina. However, DHP calcium channel blockers are increasingly used in these conditions, especially for patients who are also receiving β-blockers.

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Increased AV node refractoriness with non-DHP calcium channel blockers increases the risk for high-degree AV block when combined with other drugs that also slow AV node conduction. Although this list is lengthy, it includes any drugs that are vagomimetic (e.g., opioids, anticholinesterases, digoxin) or sympatholytic (β-receptor antagonists, clonidine), as well as other drugs (e.g., adenosine, amiodarone, volatile inhalational anesthetics). Accentuation of high-degree AV heart block can lead to cardiovascular collapse. Also, because non-DHP calcium channel blockers have the potential to increase the ventricular rate with atrial flutter or fibrillation and precipitate fatal ventricular tachyarrhythmias, diltiazem or verapamil should not be used in patients with Wolff-Parkinson-White syndrome or its variants, especially when the state of accessory pathway refractoriness is unknown. Essentially, accessory pathways are extensions of atrial muscle and have similar electrophysiologic properties (i.e., they are “fast-response” fibers). Thus, accessory pathway conduction is not blocked, nor is its refractoriness increased. However, both conduction and refractoriness at the AV node are impaired by diltiazem or verapamil. Because low-dose non-DHP calcium channel blockers (diltiazem more so than verapamil) cause vascular relaxation and hypotension before significant AV node block, reflex tachycardia can occur and cause angina in susceptible patients with nonvasospastic (fixed) coronary artery disease. Also, patients with limited cardiovascular reserve (i.e., cardiomyopathy) are at risk for acute worsening of heart failure when subjected to the additional negative inotropic effect of non-DHP calcium channel blockers. Last, aside from their cardiac effects, calcium channel blockers may significantly inhibit hepatic cytochrome enzymes and alter hepatic or renal blood flow and drug binding. Thus, the pharmacologic properties of a wide variety of drugs may be affected (see Table 13-1). This problem was most pronounced with mibefradil, a T-type calcium channel blocker that was developed for the treatment of hypertension and chronic stable angina. Because mibefradil was a very potent inhibitor of CYP3A4, the single most important P-450 enzyme for metabolizing therapeutic agents, it caused many severe adverse drug reactions and was removed from the market. One interesting drug-drug interaction with mibefradil was increased blood levels of HMG-CoA reductase inhibitors (statin cholesterol-lowering agents) that depended on CYP3A4 for metabolic clearance (e.g., lovastatin, simvastatin, atorvastatin), leading to severe rhabdomyolysis.

MANAGEMENT Because bradycardia, AV block, and hypotension can occur in patients receiving regional or general anesthesia, the first step is to determine the level of consciousness and then the adequacy of the airway and ventilation. Administer 100% oxygen and, if bradycardia is hemodynamically significant, immediately send for a transcutaneous or transvenous pacing device. Transesophageal atrial pacing is ineffective with

high-degree (second or third degree) AV node block. Secure the airway if necessary. In the interim, attempt to reduce as many negative chronotropic, dromotropic, and inotropic influences as possible by decreasing (or turning off) the inspired concentration of volatile inhalational agents and ceasing the manipulation of any organs (e.g., bowel, reproductive organs, eyes) known to elicit vagal responses. Atropine can be given as a first-line drug to reduce vagal tone and enhance SA and AV node conduction. If the patient remains hypotensive and does not respond to atropine, β-sympathomimetic drugs, such as epinephrine or isoproterenol, are used to enhance SA and AV node conduction if pacing is not yet available, especially if reduced myocardial contractility is evident. Intravenous calcium chloride has been used successfully in cases of deliberate verapamil overdose. In some cases, high-degree AV heart block resistant to pharmacologic intervention may require cardiac pacing. Once stabilized, the patient requires prolonged monitoring because the α-elimination half-life of calcium channel blockers ranges from 10 to 35 minutes (depending on age), and the β-elimination half-life is 5 to 12 hours. Depending on the duration of calcium channel blocker therapy, the latter parameter is variable and may increase to 16 hours or more with hepatic insufficiency.

PREVENTION Prevention relies on a full understanding of the patient’s underlying pathophysiology and the effects of all concurrent drugs, including antiarrhythmics, calcium channel blockers, β-adrenergic blockers, opiates, and digitalis; automaticity of the sinus node; subsidiary atrial, AV junctional, or ventricular escape pacemakers; electrophysiologic properties of specialized atrial, AV, and ventricular conducting tissues (i.e., conduction times and refractoriness); and potential interactions with any drugs used during anesthesia or in perioperative settings. Take the following specific precautions: ●

●

●

●

●

Assess the patient’s history (duration of drug use, dose, side effects, response). Determine the presence of heart failure or arrhythmias by a focused cardiac and pulmonary examination, and assess a 12-lead ECG for arrhythmias and AV conduction abnormalities. Use caution if block of the cardioaccelerator nerves is anticipated (e.g., activation of vagal, cardioinhibitory reflexes), and evaluate whether regional anesthesia might be preferable to intravenous or inhalation general anesthesia. If inhalation anesthesia is chosen, isoflurane, sevoflurane, or desflurane is preferable to enflurane or halothane in patients receiving calcium channel blockers (or β-adrenergic blockers). Use careful opiate dosing. Use of muscle relaxants must be guided by neuromuscular function monitoring.

Many patients receiving calcium channel blockers have successfully undergone a variety of surgical procedures under both regional and general anesthesia. Although the

PHARMACOLOGY

Implications

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safety of these drugs in perioperative settings is supported by the paucity of reports of adverse outcomes, calcium channel blockers have a recognized potential to cause significant adverse events in perioperative settings. Given recent clinical trials showing the safety and efficacy of calcium channel blockers for the treatment of cardiovascular disease, anesthesiologists can expect to see a substantial increase in the number of patients receiving these drugs. Large prospective, controlled clinical trials (e.g., the INVEST trial) have shown that (1) for patients with hypertension, therapy with calcium channel blockers, angiotensin-converting enzyme inhibitors, or angiotensin receptor blockers reduces the risk for diabetes more effectively than does therapy with β-blockers and diuretics; and (2) for patients with hypertension and coronary artery disease, therapy with sustainedrelease verapamil or trandolapril was as clinically effective as atenolol-hydrochlorothiazide.

Further Reading Altier C, Zamponi GW: Targeting Ca2+ channels to treat pain: T-type versus N-type. Trends Pharmacol Sci 25:465-470, 2004. Atlee JL: Perioperative cardiac dysrhythmias: Diagnosis and management. Anesthesiology 86:1397-1424, 1997.

Atlee JL, Hamann SR, Brownlee SW, et al: Conscious state comparisons of the effects of the inhalation anesthetics and diltiazem, nifedipine, or verapamil on specialized atrioventricular conduction times in spontaneously beating dog hearts. Anesthesiology 68:519-528, 1988. Bakris GL, Gaxiola E, Messerli FH, et al: Clinical outcomes in the diabetes cohort of the International Verapamil SR-Trandolapril [INVEST] study. Hypertension 44:637-642, 2004. Durant NN, Nguyen N, Katz R, et al: Potentiation of neuromuscular blockade by verapamil. Anesthesiology 60:298-303, 1984. Elmslie KS: Neurotransmitter modulation of neuronal calcium channels. J Bioenerg Biomembr 35:477-489, 2003. Opie L: Calcium channel antagonists in the treatment of coronary artery disease: Fundamental pharmacological properties relevant to clinical use. Prog Cardiovasc Dis 38:273-290, 1996. Packer M, Meller J, Medina N, et al: Hemodynamic consequences of combined beta-adrenergic and slow calcium channel blockade in man. Circulation 65:660-668, 1982. Pepine CJ, Cooper-Dehoff RM: Cardiovascular therapies and risk for development of diabetes. J Am Coll Cardiol. 44:509-512, 2004. Reves JG, Kissin I, Lell W, et al: Calcium entry blockers: Uses and implications for anesthesiologists. Anesthesiology 57:504-518, 1985. Rosenthal T, Ezra D: Calcium antagonists: Drug interactions of clinical significance. Drug Saf 13:157-187, 1995.

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Disorders of Potassium Balance

REGIONAL ANESTHESIA & PAIN PHARMACOLOGY MANAGMENT

ADJUNCT THERAPY

14

John L. Atlee and Kai T. Kiviluoma Case Synopses Hypokalemia A 56-year-old man with chronic renal failure underwent cardiopulmonary bypass (CPB) for coronary artery revascularization. His pre-CPB serum potassium (K+) concentrations ranged between 5.5 and 6.6 mEq/L. After separation from CPB, the patient had frequent premature atrial beats and nonsustained ectopic atrial tachycardia (≤15 seconds). Lead II of the monitored electrocardiogram (ECG) revealed prominent U waves (Fig. 14-1). Repeated post-CPB serum K+ concentrations were 4.5 and 4.7 mEq/L. Hyperkalemia A 74-year-old man with severe coronary artery disease had coronary artery bypass grafting with five distal anastomoses. Because of impaired myocardial function (ejection fraction 22%), a high-dose glucose-insulin-potassium infusion was started intraoperatively. Postoperatively the patient was hemodynamically stable, and he was extubated 12 hours after surgery. However, 2 days later, ventricular arrhythmias, peaked T waves, and transient second degree atrioventricular (AV) block developed.

PROBLEM ANALYSIS Definition HYPOKALEMIA There is a lack of consensus over what constitutes hypokalemia. Although a number of studies have addressed this issue, many fall short because (1) a single K+ value is not confirmed, (2) there is no information regarding the patient’s usual range of K+ values (i.e., is the hypokalemia acute or chronic?), and (3) possible confounding effects of concurrent diseases and other metabolic imbalances are not considered. As the case synopsis illustrates, the reported “normal” serum K+ values may be misleading unless interpreted within the context of the patient’s history and clinical status. Notably, the patient has ECG changes and arrhythmias consistent with hypokalemia, despite seemingly “normal” serum K+ concentrations of 4.5 and 4.7 mEq/L.

speed of repolarization and reduce action potential duration. In moderate hyperkalemia, these actions may even reduce the likelihood for arrhythmias. The increase in K+ permeability with hyperkalemia decreases the rate of spontaneous diastolic (phase 4) depolarization in the sinus node and subsidiary pacemakers to cause bradycardia and even asystole at very high extracellular K+ concentrations. AV and intraventricular conduction abnormalities are also observed with severe hyperkalemia. This latter group of patients has

ECG

ECG

ART

HYPERKALEMIA With regard to the patient described in the case synopsis, it is probable that after stopping glucose-insulin treatment, a new balance between intracellular and extracellular K+ concentrations was established. Because up to 98% of the total body potassium pool is located intracellularly, dramatic changes in serum K+ may be observed. Normal values for serum K+ range from 3.5 to 5.3 mEq/L. Hyperkalemia increases myocardial membrane permeability to K+ to increase the

PAP

Figure 14–1 ■ Electrocardiogram changes after separation from cardiopulmonary bypass. Note the prominent U waves (arrows). (From Atlee JL: Arrhythmias and Pacemakers. Philadelphia, WB Saunders, 1996, p 90.)

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a very high risk of developing fatal arrhythmias, including persistent ventricular fibrillation or asystole. Excessive serum K+ concentrations not only profoundly affect the electrical properties of the heart but also cause severely depressed myocardial contractility. These myocardial effects of hyperkalemia are potentiated in patients with concomitant hypocalcemia or hyponatremia.

Recognition HYPOKALEMIA Low serum K+ concentrations can exist without significant associated ECG changes. The following are common ECG changes with acute hypokalemia (serum K+ ≤ 3.0 mEq/L) in normokalemic patients (serum K+ 3.5 to 4.5 mEq/L): ●

●

● ● ●

The appearance of U waves (see Fig. 14-1, lead II), which may fuse with T waves to cause apparent Q-T interval prolongation “Bowl-shaped” (concave or scooped) ST segment depression (see the last four QRS complexes in Fig. 14-1, lead II) Increased amplitude of QRS complexes (see Fig. 14-1, lead II) Flattened or inverted T waves Arrhythmias: atrial or ventricular extrasystoles or ectopic atrial tachycardia

plasma K+ concentrations exceed 5.5 mEq/L (Fig. 14-2). These T-wave changes are seen most clearly in the precordial leads of the ECG. With more severe hyperkalemia, the P-Q interval is prolonged, the QRS amplitude is decreased, and the QRS interval widens (usually seen at potassium concentrations > 6.5 mEq/L). Ultimately, the P wave disappears. With preterminal hyperkalemia, the markedly widened QRS complex merges with the T wave, giving the ECG a “sine-wave” appearance (see Fig. 14-2). Ventricular flutter, fibrillation, or asystole usually ensues shortly thereafter. The correlation between the degree of hyperkalemia and tissue effects is better at higher K+ concentrations than at lower ones. Thus, widening of the QRS complex more reliably predicts serum K+ levels than does peaking of the T wave. Although ECG changes can be detected during the early phase of hyperkalemia, a high index of clinical suspicion and serial measurement of serum K+ concentrations are essential for the definitive diagnosis of hyperkalemia and to avoid the morbidity and mortality associated with it.

Aside from arrhythmias and ECG changes, hypokalemia can affect cardiovascular, central nervous system, neuromuscular, renal, or metabolic function (Table 14-1). HYPERKALEMIA To recognize hyperkalemia, one must be aware of the possibility. It is confirmed by measuring serial serum K+ concentrations. Also, the ECG is analyzed for the following features: ● ●

●

Peaking and narrowing of the T wave Progressive widening of the QRS complex as hyperkalemia worsens Prolongation of the P-Q and disappearance of P waves

The earliest manifestation of hyperkalemia is peaking and narrowing of the T wave. This is usually observed when Table 14–1

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Effects of Hypokalemia

Cardiovascular Autonomic neuropathy with postural hypotension Impaired contractility and vasopressor responses Potentiation of toxic effects of digitalis

Neuromuscular and Central Nervous System Potentiation of neuromuscular blockade Weakness and lethargy Peripheral neuropathy and hyporeflexia Respiratory depression Confusion and depression

Renal and Gastrointestinal Polyuria; reduced urine concentrating ability Hypoperistalsis

Metabolic Glucose intolerance Potentiation of hypomagnesemia and hypocalcemia

Figure 14–2 ■ Schematized electrocardiogram (ECG) changes accompanying acute changes in serum potassium (K+) concentration. Note flattening of the T wave and prominent U waves with hypokalemia. As the serum K+ increases toward hyperkalemia, there is a small reduction in the QRS amplitude, QRS complex widening, P-R interval prolongation, reduced P-wave amplitude, and increased T-wave amplitude. Finally, the QRS and T waves merge, giving the ECG a sine-wave appearance. (From Sandøe E, Sigurd B: Arrhythmia. St. Galen, Belgium, Fachmed AG, 1984, p 403.)

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Table 14–2

HYPOKALEMIA Hypokalemia is more likely than hyperkalemia to cause clinically important arrhythmias. It often results from excessive dialysis, thiazide or loop diuretics, mechanical hyperventilation, or therapy with insulin or β-adrenergic agonists. Cellular repolarization abnormalities and loss of transmembrane potential with hypokalemia alter cardiac conduction and refractoriness to facilitate reentry. They are also conducive to disturbed automaticity or triggered activity. Arrhythmias caused by severe hypokalemia resemble those accompanying digitalis toxicity (see Chapter 7) and likely have similar mechanisms. Arrhythmias include atrial and ventricular extrasystoles, ectopic atrial tachycardia, reentrant (paroxysmal) supraventricular tachycardia, and AV heart block. These are not caused by changes in serum K+ concentration per se, but rather by changes in the ratio between intra- and extracellular K+. This is the most important determinant of resting cell membrane potential and cellular electrophysiologic properties. Only extreme extracellular K+ changes (<2.7 or >10 mEq/L) significantly depolarize cell transmembrane potential in atrial, Purkinje, or ventricular muscle fibers. However, loss of transmembrane potential is conducive to automatic, triggered, or reentrant arrhythmias. Between these values, transmembrane potential increases toward more normal values. Further, electrophysiologic changes due to K+ imbalance are likely heterogeneous, with some cells or tissues affected more than others. Thus, the patient described in the first case synopsis was likely relatively hypokalemic, because his pre-CPB serum K+ concentrations ranged from 5.5 to 6.5 mEq/L. Indeed, treatment with intravenous potassium chloride (KCl) restored this patient’s serum K+ concentration to his normal range and abolished the U waves, ectopic atrial beats, and nonsustained ectopic atrial tachycardia. HYPERKALEMIA Causes of hyperkalemia are listed in Table 14-2. Surgery or underlying pathophysiology can cause large changes in potassium excretion and balance. Patients receiving potassium therapy or potassium-sparing diuretics preoperatively are at risk for the development of intra- and postoperative hyperkalemia. Renal failure also renders patients extremely susceptible to hyperkalemia. Patients with advanced renal failure do not respond normally to aldosterone. Thus, their ability to excrete potassium is impaired. Cell disruption of any kind causes intracellular potassium leak and is often associated with hyperkalemia. Hyperkalemia is commonly associated with major trauma, large surface area third-degree burns, and rhabdomyolysis. During hemolytic processes, massive amounts of potassium are liberated over a short period. Reperfusion of ischemic areas can mobilize potassium, and hyperkalemia is worsened by ischemic acidosis. Anesthesiologists commonly encounter these problems in patients having vascular surgery that requires the application of an aortic cross-clamp. Succinylcholine muscle depolarization causes transient increases in serum K+ that are especially dangerous in the setting of chronic hyperkalemia. Owing to a proliferation in

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Causes of Hyperkalemia

Potassium supplementation and potassium-sparing diuretics Acute or chronic renal insufficiency Trauma and large burns Succinylcholine Neuromuscular disorders, myopathies, muscle denervation, massive muscle injury, tetanus Hemiplegia or paraplegia Diffuse head injury and encephalitis Rhabdomyolysis, hemolysis, or massive blood transfusions Primary or secondary hypoaldosteronism Addison’s disease (chronic adrenocortical insufficiency) Angiotensin-converting enzyme inhibitors Prostaglandin synthetase inhibitors Heparin therapy or digitalis poisoning Respiratory or metabolic acidosis

the number of nicotinic receptors or alterations in the kinetics of potassium channel opening (i.e., the channels remain open longer), succinylcholine may cause life-threatening increases in serum K+ concentrations in a variety of disorders, especially large surface area third-degree burns, spinal cord injury leading to hemi- or quadriplegia, and neuromuscular diseases. Potassium distribution between the intra- and extracellular spaces is strongly pH dependent. A 0.1 decrease in pH causes about a 1.0 mEq/L increase in serum K+. Thus, acidemia of metabolic or respiratory origin can cause severe hyperkalemia by moving intracellular K+ out of the cell. Hypoventilation and respiratory acidosis are important causes of hyperkalemia during anesthesia. Likewise, diabetic ketoacidosis due to insulin-dependent diabetes, especially when compounded by acidosis due to circulatory or hemorrhagic shock, is a common cause of hyperkalemia in emergency rooms. However, despite seeming hyperkalemia, these patients actually have total body K+ depletion. A number of other conditions can cause clinically significant hyperkalemia, albeit more rarely. Massive blood transfusion can cause hyperkalemia by liberating potassium accumulated during blood preservation. Massive amounts of citrate can also bind calcium and worsen the cardiac effects of hyperkalemia. In addition, digitalis preparations have the potential to cause clinically significant hyperkalemia by inhibiting the Na+,K+-ATPase pump.

Implications HYPOKALEMIA There is no unequivocal serum K+ concentration below which the risk for arrhythmias is certain. The development of clinically significant hypokalemia is context sensitive and depends on the following factors: ● ●

●

Concurrent disease and associated pathophysiology Nature of the planned surgery or other therapeutic intervention Acute imbalance imposed by the circumstances of anesthesia and surgery

The last can include stress-induced catecholamine surges, exaggerated temperature changes, impaired ventilation and oxygenation, and the effects of drugs and other interventions.

PHARMACOLOGY

Risk Assessment

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Therefore, the decision to proceed with elective surgery in the face of chemical evidence of hypokalemia depends on many factors: whether the condition is acute or chronic, its effect on perioperative risk, the urgency of the planned surgery or intervention, and the implications of the associated imbalance and the patient’s current medications.

●

●

●

HYPERKALEMIA Concerns about anesthesia and surgery in a patient with hyperkalemia (especially if acute) involve the risk of cardiac electrical and mechanical dysfunction: ● ● ● ● ●

First, second, and third degree AV heart block Potential for bradycardia and asystole Ventricular and AV junctional escape rhythms Ventricular fibrillation Decreased contractility

Hyperkalemia can impair cardiac function by causing disturbances of cardiac rhythm or mechanical dysfunction. Although cardiac electrophysiologic abnormalities related to hyperkalemia can cause many different types of arrhythmias, heart block and bradycardia are most common. However, ventricular extrasystolic beats, ventricular fibrillation, and asystole are also possible. Importantly, far more adverse events occur with rapid changes in serum K+ concentration than with chronic hyperkalemia.

Based on the available evidence and the realization that context-sensitive and adequately powered outcome studies are lacking, we suggest the following guidelines for patients with hypokalemia. WHETHER ●

●

MANAGEMENT The decision to proceed with surgery or other major therapeutic interventions requiring anesthesia in patients with hypo- or hyperkalemia remains controversial. However, it is now clear that the duration of hypo- or hyperkalemia is more important than some arbitrary serum K+ value. Chronic imbalances are much better tolerated than their acute counterparts. Other considerations before proceeding with surgery in patients with hypokalemia or hyperkalemia include the following: ●

● ●

● ●

Severity and urgency of the planned surgery or therapeutic intervention Presence of associated physiologic or metabolic imbalances Presence of concurrent systemic disease that may be aggravated by acute hypokalemia or hyperkalemia, especially cardiovascular and central nervous system afflictions Presence of uncontrolled hypertension Presence of renal insufficiency, heart failure, or coronary heart disease

Hypokalemia Roizen and Fleisher addressed some unresolved issues concerning the perioperative management of patients with hypokalemia: ●

●

In patients with modest hypokalemia, should surgery be delayed to subject them to the risks of intravenous or even oral K+ supplementation therapy? What is the definition of modest hypokalemia: less than 3.4 mEq/L? less than 3.0 mEq/L?

Is modest hypokalemia context sensitive? That is, is modest hypokalemia (however defined) safe for some surgeries but not for others (e.g., coronary artery bypass grafting)? Are some individuals more sensitive than others to even minor K+ depletion? Are risk measures for modest hypokalemia (e.g., ventricular premature beats per hour) appropriate and context sensitive? (Such frequency might be more meaningful for patients with evolving myocardial infarction or following cardiopulmonary bypass.)

●

TO

PROCEED

WITH

ANESTHESIA

AND

SURGERY

Serum K+ below 2.5 mEq/L: Confirmed serum K+ values less than 2.5 mEq/L, especially if associated with ECG changes or arrhythmias, justify the delay of all but truly emergency interventions requiring anesthesia, owing to the increased risk of periprocedural complications. This delay provides the time needed to determine the cause and chronicity of the imbalance and to correct it. Serum K+ between 2.5 and 3.0 mEq/L: Confirmed values in this range, especially when associated with ECG changes consistent with hypokalemia or the anticipated presence of other factors that increase the risk for perioperative arrhythmias (Table 14-3), justify the postponement of elective surgery in order to identify the cause of hypokalemia and correct the imbalance. Emergent and urgent procedures can proceed as the imbalance is being corrected. Serum K+ between 3.1 and 3.5 mEq/L: With serum K+ values in this range, provided there has not been an acute decrease of 1.5 mEq/L or more, there is little risk of significant arrhythmias without overt digitalis toxicity, catecholamine excess, acute myocardial infarction, heart

Table 14–3

■

Risk Factors for Perioperative Arrhythmias

Unstable coronary artery disease Chronic pulmonary disease Hypertensive urgencies* or emergencies† NYHA class III or IV or ACC/AHA stage C or D heart failure‡ Acute or chronic renal failure Morbid obesity Malnutrition or cachexia Excess catecholamines Autonomic dysfunction Sick sinus syndrome Increased intracranial pressure *Subacute or chronic stage 2 blood pressure increase to ≥160/100 mm Hg; no end-organ damage. † Acute stage 2 blood pressure increase with evidence of end-organ damage. ‡ New York Heart Association (NYHA): class I—no symptoms of heart failure (HF) at rest; class II—HF symptoms with ordinary exertion; class III—HF symptoms with less than ordinary exertion; class IV—HF symptoms at rest. The American College of Cardiology/American Heart Association (ACC/AHA) staging emphasizes the evolution and progression of HF: stage A—high risk for developing HF, but no structural heart disease; stage B—structural heart disease (SHD), but no HF symptoms; stage C—SHD and past or current HF symptoms; stage D—end-stage heart disease and need for advanced HF treatment (continuous inotropes, mechanical circulatory support, cardiac transplantation, hospice care).

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POTASSIUM REPLACEMENT Treatment for hypokalemia, especially with arrhythmias, consists of K+ repletion, correction of alkalosis, and removal of drugs that are likely to exaggerate its effects (e.g., insulin, potassium-wasting diuretics, β2-adrenergic agonists, catecholamines). If total body K+ is depleted, as with chronic hypokalemia, oral repletion is prudent. For intravenous repletion, KCl is used because coexisting chloride depletion may limit the ability of the kidney to conserve K+. KCl is administered cautiously (no more than 10 to 20 mEq/hour), especially if the absolute deficit and its acuteness are not known. However, if the deficit is known to be acute and large (e.g., the result of massive diuresis or overly aggressive dialysis), intravenous KCl can be administered more rapidly; however, this should be done with simultaneous ECG monitoring. Special care should be exercised during K+ repletion in patients with diabetes, acidemia, and renal tubular acidosis and in those receiving angiotensin-converting enzyme inhibitors, β-adrenergic blockers, or nonsteroidal anti-inflammatory agents. All these conditions and drugs delay the movement of K+ into cells and could lead to significant hyperkalemia. Finally, keep in mind that hypomagnesemia is commonly associated with hypokalemia; it aggravates the effects of the latter by impairing K+ conservation. Hypomagnesemia is common in critically ill patients with chronic ethanolism, acute myocardial infarction, diarrhea, cachexia, malnutrition, and starvation. It is also common following CPB and dialysis and in patients receiving digitalis or chronic diuretic therapy.

Hyperkalemia It is unknown what a safe concentration of K+ is in patients with hyperkalemia. In experimental hyperkalemia, there is good correlation between the magnitude of serum K+ increases and ECG changes (see Fig. 14-2). In clinical hyperkalemia, however, abnormalities of impulse formation and propagation may occur at lower K+ concentrations than in experimental hyperkalemia; in addition, the correlation between serum K+ concentration and ECG changes is not as reliable. However, if hyperkalemia is associated with conduction disturbances, arrhythmias, or reduced contractility, acute therapy is warranted, as follows: ●

●

●

●

Antagonize the cardiac effects of K+ with intravenous calcium gluconate or chloride. Redistribute K+ into the cells with β-adrenergic agonists, sodium bicarbonate, hyperventilation, or glucose-insulin. Remove K+ from the body with furosemide or potassiumbinding resin (Kayexalate). Use hemo- or peritoneal dialysis.

In emergencies, one must rapidly reduce the extracellular concentration of K+ to counteract its effects on myocardial function. Although normalizing total body K+ is the long-term goal of therapy, calcium gluconate or chloride is used acutely to antagonize the effects of increased K+ on cardiac cell membranes. Insulin and β-adrenergic agents redistribute K+ intracellularly and produce a positive inotropic effect.

Disorders of Potassium Balance

57

Correction of acid-base imbalance and moderate alkalosis have the same effect. Sodium bicarbonate (1 to 2 mEq/kg) and moderate hyperventilation (pH 7.45 to 7.50) are also effective for acutely lowering serum K+. Infusion of glucose (1.5 g/kg) and insulin (1 unit/3 g glucose) are relatively rapid means of moving K+ intracellularly. One must measure serum K+ repeatedly, because marked hypokalemia can result from overly rapid intracellular K+ shifts. Total body K+ content is reduced with loop diuretics (e.g., furosemide) or cation exchange resins (e.g., Kayexalate). The latter bind K+ in the gut. Although both therapies are effective, their actions develop more slowly. Thus, they are used after initial treatment in emergencies. Dialysis (hemodialysis or peritoneal dialysis) or hemofiltration (our preference) is indicated in patients with severe renal insufficiency or when physiologic stability cannot be achieved by other means.

PREVENTION In the critically ill patient, sequential perioperative measurement of serum K+ and arterial blood gases for acid-base status is important. Although hypokalemia can be easily treated by giving potassium, the principles of potassium homeostasis must be kept in mind. Before and during anesthesia, it is often wise not to treat mild hypokalemia (K+ ≤ 3.0 to 3.4 mEq/L), or to do so very slowly (≤10 mEq KCl/hour). Circulatory insufficiency can cause tissue hypoperfusion and severe metabolic acidosis, which in turn moves intracellular K+ to the extracellular space. Respiratory acidosis acts similarly. In hyperkalemic patients, succinylcholine should be avoided because it causes a transient rise in serum K+. This rise can be dramatic and potentially lethal if succinylcholine is given to patients with large surface area burns, certain neuromuscular disorders (see Chapters 23 and 153), or a large mass of denervated muscle (i.e., spinal hemiplegia or paraplegia).

Hypokalemia One must be knowledgeable about the causes of hypokalemia and its associated conditions. Also, one must have a high index of suspicion for this condition in critically ill patients or those receiving chronic therapy with potassium-wasting diuretics (e.g., patients with hypertension or heart failure). Finally, one must be able to recognize the ECG signs of hypokalemia and monitor the ECG for evidence of its development.

Hyperkalemia Clinical awareness of the possibility of hyperkalemia is the most important factor in preventing it and its complications. To this end, take the following steps: ● ● ● ● ● ●

Identify patients at risk. Monitor the ECG for signs of hyperkalemia. Measure serial serum K+ concentrations. Monitor acid-base status. Avoid unnecessary potassium supplementation. Avoid respiratory or metabolic acidosis and succinylcholine.

PHARMACOLOGY

failure, or other significant comorbidities. In other words, there is no compelling reason to delay elective surgery or other therapeutic interventions to correct the imbalance.

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Preoperative use of potassium supplementation or the use of potassium-sparing diuretics must be kept in mind. During anesthesia, continuous ECG monitoring and end-tidal carbon dioxide monitoring are essential; with the latter, respiratory acidosis can be avoided. With suspected hyperkalemia, T-wave changes usually manifest well before heart block, bradycardia, escape rhythms, or deterioration in myocardial contractile function. Widening of the QRS complex indicates more severe changes. Asystole or ventricular fibrillation occurs with extreme hyperkalemia or after inadvertent intracardiac administration of potassium.

Further Reading Atlee JL: Perioperative cardiac arrhythmias. Anesthesiology 86:1397-1425, 1997. Atlee JL: Perioperative Cardiac Dysrhythmias, 2nd ed. Chicago, Year Book Medical Publishers, 1990, pp 128-129.

Cox M: The renal system and metabolic function. In Carlson RW, Geheb MA (eds): Principles and Practice of Medical Intensive Care, 3rd ed. Philadelphia, WB Saunders, 1993, pp 1155-1334. Davis RF: Etiology and treatment of perioperative cardiac arrhythmias. In Kaplan JA, Reich DL, Konstadt SN (eds): Cardiac Anesthesia, 4th ed. Philadelphia, WB Saunders, 1999, pp 177-213. Juurlink DN, Mamdani MM, Lee DS, et al: Rates of hyperkalemia after publication of the randomized aldactone evaluation study. N Engl J Med 351:543-551, 2004. Roizen MF, Fleisher LA: Anesthetic implications of concurrent diseases. In Miller RD (ed): Miller’s Anesthesia, 6th ed. Philadelphia, Churchill Livingstone, 2005, pp 1017-1149. Winkler AW, Hoff HE, Smith PK: Electrocardiographic changes and concentration of potassium in serum following intravenous injection of potassium chloride. Am J Physiol 124:478-483, 1948.

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REGIONAL ANESTHESIA & PAIN PHARMACOLOGY MANAGMENT

15

Magnesium Thomas S. Guyton and Timothy E. Morey Case Synopsis While recovering from hip surgery, a 54-year-old man suffering from alcoholism experiences recurrent episodes of ventricular tachycardia that are resistant to therapy with lidocaine. His serum magnesium level is 1.1 mEq/L. While receiving intravenous magnesium sulfate replacement, the patient complains of feeling hot and has difficulty breathing. Within 15 minutes of initiating replacement therapy, the patient has a respiratory arrest.

PROBLEM ANALYSIS Definition MAGNESIUM HOMEOSTASIS Magnesium is the fourth most abundant cation in the body, with total body stores of about 2000 mEq. Normal serum magnesium (Mg2+) concentrations are between 1.4 and 2.1 mEq/L, equivalent to 1.7 and 2.5 mg/dL, respectively (see Table 15-1 for unit conversions). Serum Mg2+ concentrations correlate poorly with total body stores, reflecting less than 1% of the amount stored. Gastrointestinal absorption in the duodenum and jejunum represents the principal source of Mg2+ (8 to 9 mEq/day). The amount of Mg2+ lost from the body via gastrointestinal secretions is relatively constant (2 mEq/day). In contrast, the kidney can dramatically affect losses in response to lowered serum Mg2+ concentrations due to reabsorption of Mg2+ in the proximal renal tubules and the loop of Henle. ROLE

IN

CELLULAR FUNCTION

Magnesium serves as an essential cofactor for many important cellular enzymes (e.g., adenylyl cyclase, Na+,K+-ATPase). In addition, the magnesium complex with adenosine triphosphate serves as a substrate for the enzymatic reaction mediating muscle contraction and relaxation. Magnesium also regulates cellular function by antagonizing the cellular effects of calcium and modulating several potassium currents (Table 15-2).

Increased serum Mg2+ concentrations cause vascular smooth muscle relaxation by directly competing with Ca2+ to inhibit muscle contraction. Alterations in serum Mg2+ concentrations affect multiple organ systems. For example, hypermagnesemia produces relaxation of vascular smooth muscle by directly competing with Ca2+ to inhibit smooth muscle contraction, increasing the release of prostacyclin and decreasing catecholamine release after sympathetic stimulation. At the motor neuromuscular junction, increased Mg2+ causes presynaptic inhibition of Ca2+ release; this facilitates acetylcholine release, which depresses sarcolemmic excitability. In the heart, reduced Mg2+ slows the heart rate owing to suppressed automaticity and depressed atrioventricular conduction. Hypermagnesemia also reduces the amplitude of early afterdepolarizations to oppose triggered arrhythmias (see later). In the brain, increased Mg2+ serves as an anticonvulsant by blocking neuronal Ca2+ channels associated with the N-methyl-D-aspartate receptor. ROLE

IN

THERAPEUTICS

Magnesium infusions may be therapeutic in the case of triggered ventricular arrhythmias. They are also used as adjunct therapy for atrial fibrillation in cardiac surgery, as tocolytic agents in preterm labor, and to prevent seizures with preeclampsia. The frequency of automatic or triggered ventricular arrhythmias with hypomagnesemia (e.g., torsades de pointes, digitalis ventricular arrhythmias) is reduced by intravenous magnesium infusions that double the serum Mg2+ concentration. Thus, such infusions may increase inwardly

Table 15–2 Table 15–1

■

Unit Conversions for Magnesium Compounds and Serum Concentrations

Compound

Unit Conversions

Magnesium sulfate (MgSO4) Magnesium oxide (MgO) Magnesium acetate (MgC4H6O4) Magnesium chloride (MgCl2) Serum concentrations (all compounds)

1 1 1 1 1

g = 8.13 mEq of Mg2+ g = 46 mEq of Mg2+ g = 9.35 mEq of Mg2+ g = 9.75 mEq of Mg2+ mg/dL = 0.83 mEq/L = 0.415 mmol/L

■

Mechanisms for Magnesium’s Effect on Cellular Function

Ca2+ Antagonism Modulates handling of Ca2+ by sarcoplasmic reticulum Inhibits Ca2+ influx into myocyte through sarcolemmal channels Modulates second messenger system (i.e., adenyl cyclase– adenosine monophosphate) Competes with Ca2+ for high affinity site on actin

K+ Current Enhances function of Na+,K+-ATPase Blocks outward K+ current to result in an increase in inward rectifying K+ current Mediates inwardly rectifying properties

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rectifying potassium currents to reduce the amplitude of the early afterdepolarizations that serve as the triggers for torsades de pointes. Proposed mechanisms for magnesium’s effect on digitalisinduced ventricular arrhythmias include improved function of the Na+,K+-ATPase pump and reduction in the amplitude of delayed afterdepolarizations owing to a reduction in the intracellular rise of Ca2+. However, most ventricular arrhythmias are due to reentry and do not respond to intravenous magnesium. In contrast, preoperative β-blockers and calcium channel antagonists with adjunct Mg2+ therapy can reduce the occurrence of atrial fibrillation in postoperative cardiac surgery patients. Hypomagnesemia can result from hemodilution with cardiopulmonary bypass and diuretic therapy. Finally, increasing the serum Mg2+ concentration by 4 to 6 mEq/L has been used to decrease uterine activity in preterm labor and to prevent seizure activity in women diagnosed with preeclampsia.

Recognition HYPOMAGNESEMIA Alterations in serum Mg2+ concentrations are often occult and occur along with alterations in other serum electrolytes, such as calcium and potassium. Hypomagnesemia is best diagnosed by recognizing those conditions associated with it (e.g., chronic ethanol abuse, diuretic or digitalis therapy). Hypomagnesemia alone does not result in electrocardiogram changes; however, the associated disturbances in calcium and potassium may do so. HYPERMAGNESEMIA Hypermagnesemia is most often diagnosed by associating the timing of adverse effects with the administration of magnesium. In patients with gastrointestinal diseases leading to increased absorption or renal failure leading to decreased excretion, large doses of cathartics, antacids, or analgesics containing magnesium salts may result in significant hypermagnesemia. Under these conditions, the temporal association with magnesium administration is often not apparent. Hypermagnesemia is also diagnosed by recognizing the progressive pattern of its adverse effects and then confirming that suspicion with serum Mg2+ measurements. Hypermagnesemia can produce the following adverse effects: ● ● ● ● ● ● ●

Generalized vasodilatation Lethargy Muscle weakness Respiratory depression Sinus bradycardia Atrioventricular block Asystole

Table 15-3 lists common adverse effects of hypermagnesemia and the associated serum Mg2+ concentration at which these effects first appear. It is noteworthy that the serum concentration at which a particular adverse reaction occurs in a given individual varies considerably, depending on the associated metabolic disturbances.

Table 15–3

■

Correlation between Serum Magnesium Concentration and Systemic Effects

Concentration (mEq/L)

Systemic Effects

<0.8

1.4-2.1 3-4

5-6

10 20 >25

Arrhythmias may be resistant to therapy When associated with hypocalcemia: disorientation, muscle twitching, choreiform movements, seizures Normal range Flushing 7%-13% increase in PR interval 0%-11% increase in QRS interval No change in Q-T interval Slight reduction in blood pressure Slight increase in heart rate 10% reduction in FEV1 and FVC Blurred vision from diminished accommodation and convergence Lethargy Loss of deep tendon reflexes Respiratory arrest Atrioventricular conduction block Progressive QRS widening and bradycardia Cardiac arrest

FEV1, forced expiratory volume in 1 second; FVC, forced vital capacity.

Risk Assessment HYPOMAGNESEMIA Hypomagnesemia has an incidence of 470 per 1000 individuals suspected of having serum electrolyte abnormalities. Persons with congestive heart failure who are treated with diuretics and digitalis have a 7% to 37% incidence of hypomagnesemia. Alcoholics have a 30% to 40% incidence of hypomagnesemia. HYPERMAGNESEMIA Hypermagnesemia has an incidence of 57 per 1000 individuals suspected of having serum electrolyte abnormalities. Because of the kidney’s remarkable ability to reduce the reabsorption of magnesium, respiratory and cardiac arrests are extremely rare during continuous magnesium infusions for arrhythmias, tocolysis, or seizure prevention in preeclampsia. To prevent the adverse effects of hypermagnesemia, it is best to avoid administering magnesium to individuals with renal failure. In individuals with congestive heart failure, a therapeutic regimen consisting of 0.3 mEq/kg of magnesium given as an intravenous bolus over 10 minutes, followed by a continuous infusion of 0.08 mEq/kg per hour, resulted in serum Mg2+ concentrations of 3.5 mEq/L. In women with preeclampsia, an intravenous bolus of 32 mEq of magnesium sulfate over 20 minutes, followed by 16 mEq/hour, resulted in average serum Mg2+ levels of 4 to 6 mEq/L.

Implications Ventricular arrhythmias resulting from increased automaticity or triggered activity due to magnesium deficits

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The best prevention for hypermagnesemia is to not give magnesium-containing salts or compounds to patients with renal failure. Magnesium-containing compounds include the following: ● ● ●

The key to the management of both hypomagnesemia and hypermagnesemia is recognition. Hypomagnesemia can be treated either orally or parenterally. Table 15-1 gives the elemental content of the various magnesium-containing formulations used to treat hypomagnesemia. In patients with normal renal function, 16 to 32 mEq of magnesium sulfate can be infused intravenously over 30 minutes to 1 hour for rapid correction or over 8 to 24 hours for slower correction. As stated earlier, serum Mg2+ represents less than 1% of the total body stores of magnesium. Thus, achieving sustained elevations in serum Mg2+ concentrations with hypomagnesemia involves multiple doses to replete total body stores. In contrast, the treatment of hypermagnesemia includes any or all of the following: ● ●

●

●

●

Removal of all potential ex vivo sources of magnesium In cases of respiratory arrest, intubation and support of ventilation Administration of furosemide and magnesium-free salt solutions to increase the renal excretion of magnesium Calcium chloride (5 to 10 mEq every 5 to 10 minutes) to antagonize hypermagnesemia Dialysis with magnesium-poor dialysate

61

PREVENTION

●

MANAGEMENT

Magnesium

Cathartics (e.g., magnesium citrate) Antacids (e.g., magnesium oxide) Analgesics (e.g., buffered aspirin) Magnesium supplements

During the administration of cathartics to individuals with gastrointestinal disturbances (e.g., paralytic ileus, ulcerative colitis, perforated duodenal ulcer), massive amounts of magnesium absorption can occur.

Further Reading Dube L, Granry JC: The therapeutic use of magnesium in anesthesiology, intensive care and emergency medicine: A review. Can J Anaesth 50: 732-746, 2003. Ducceschi V, Di Micco G, Sarubbi B, et al: Ionic mechanisms of ischemiarelated ventricular arrhythmias. Clin Cardiol 19:325-331, 1996. Hazelrigg SR, Boley TM, Cetindag IB, et al: The efficacy of supplemental magnesium in reducing atrial fibrillation after coronary artery bypass grafting. Ann Thorac Surg 77:824-830, 2004. Kelepouris E, Agus ZS: Hypomagnesemia: Renal magnesium handling. Semin Nephrol 18:58-73, 1998. Sibai BM: Magnesium sulfate prophylaxis in preeclampsia: Lessons learned from recent trials. Am J Obstet Gynecol 190:1520-1526, 2004. Surawicz B: The interrelationship of electrolyte abnormalities and arrhythmias. In Mandel WJ (ed): Cardiac Arrhythmias: Their Mechanisms, Diagnosis, and Management. Philadelphia, JB Lippincott, 1995, pp 89-109.

PHARMACOLOGY

clearly warrant the replacement of those deficits. The use of magnesium infusions to reduce the risk of acute myocardial infarction is controversial and is still under investigation. The use of magnesium for preterm labor tocolysis seems to be a safe alternative to β-sympathomimetics. In comparison to phenytoin, magnesium appears to be more efficacious in preventing seizures in women with preeclampsia.

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Perioperative Fluid Management

16

Donald S. Prough and Christer H. Svensén Case Synopses Case 1 A 72-year-old man is scheduled to undergo transverse colectomy and primary reanastomosis for a nonobstructing carcinoma. He has a history of hypertension that is well controlled by a diuretic and is otherwise healthy. Case 2 A 35-year-old woman is scheduled to undergo laparoscopic cholecystectomy for cholelithiasis. Other than mild obesity (preoperative weight, 88 kg), she is healthy.

PROBLEM ANALYSIS Definition Complications are related to either insufficient or excessive fluid therapy, and in both instances, complications can range from relatively minor to life threatening. Recent studies strongly suggest that both the frequency and the importance of complications of perioperative fluid therapy have been underestimated in the past. Life-threatening complications of insufficient fluid therapy are hypoperfusion and related vital organ system complications. Acute renal failure and multisystem organ failure are associated with the worst outcomes. Less serious complications are postoperative thirst, dizziness, nausea, vomiting, fatigue, and drowsiness. Postoperative exercise capacity and pulmonary function may be transiently impaired by insufficient fluid therapy. The most feared complication of excessive fluid therapy is primary or secondary pulmonary edema. With primary pulmonary edema, there is increased venous return and right ventricular preload. This leads to increased right ventricular outflow and pulmonary artery flow and, ultimately, increased pulmonary capillary hydrostatic pressure. If this increase is sufficient and sustained, it can cause pulmonary alveolar capillary leak and alveolar flooding. This mechanism is similar to that associated with naloxone overreversal of opiates (see Chapter 33). Secondary pulmonary edema is due to left ventricular overload and “forward” (cardiogenic) failure. This is more likely in patients with at least some left ventricular functional impairment. Less threatening but still bothersome late complications related to excessive fluid therapy include peripheral edema, periorbital edema, and impaired gastrointestinal function or wound healing. These occur after discharge from the postanesthesia care unit or in the intensive care unit and are thus less readily apparent to anesthesia personnel.

complications of insufficient fluid administration have been emphasized for the past 40 years. In the 1960s, Shires and colleagues emphasized the concept that extracellular fluid volume was decreased during hemorrhage or major surgery and required replacement with crystalloid fluids. As a consequence of their studies, infusion of large amounts of crystalloids became the standard of care for combat casualties during the Vietnam conflict. This new treatment method was associated with an apparent reduction in the rate of renal failure and was subsequently adopted for the perioperative management of civilian surgical patients. Morris and associates reported in 1991 that of 72,757 admissions to nine regional trauma centers, only 78 patients (0.11%) required dialysis for acute renal failure, perhaps as a result of more liberal fluid therapy. Yet as the perioperative administration of larger crystalloid volumes became more prevalent, “shock lung” or the “Da Nang lung syndrome,” now termed acute respiratory distress syndrome (ARDS), was clinically recognized. Although a strict cause-and-effect relationship between increased fluid resuscitation and ARDS has never been established, the possible association has troubled clinicians. In 1999, Arieff reported 13 patients who developed postoperative pulmonary edema. Of these, 10 were generally healthy, and 3 had serious medical comorbidities. However, collectively, the group had a net fluid retention of 67 mL/kg within the first 24 intraoperative and postoperative hours. An accompanying retrospective review of the surgical experience during 1 year at a major teaching hospital found that among 8195 patients having major inpatient surgery, 7.6% developed postoperative pulmonary edema. One third of these patients had no preexisting comorbidity. The overall mortality rate was 11.9%, and the mortality rate among those without comorbidities was 3.9%. Based on this single-institution experience, Arieff projected that between 8300 and 74,000 patients die from perioperative pulmonary edema in the United States each year.

Historical Perspective

Recognition

Because fluid restriction was the predominant strategy of perioperative fluid management until the mid-1960s, the

Clinicians can easily recognize the extremes of insufficient or excessive fluid therapy. Hypotension, tachycardia, and oliguria

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Perioperative Fluid Management

63

Urine output often declines precipitously during moderate to severe hypovolemia. Therefore, in the absence of glycosuria or diuretic administration, a urine output of 0.5 to 1.0 mL kg−1 hr−1 during anesthesia suggests adequate renal perfusion. Arterial pH may decrease only when tissue hypoperfusion becomes severe. Cardiac output may remain normal, despite severely reduced regional blood flow. Mixed venous oxygen saturation is a specific indicator of poor systemic tissue and vital perfusion; however, it reflects average perfusion in multiple organs and cannot supplant regional monitors such as urine output.

·

·

Risk Assessment Anesthesia personnel have considerable experience and expertise in recognizing patients at high risk for the extremes of perioperative hypovolemia and hypervolemia. Preoperative determination of the patient’s American Society of Anesthesiologists (ASA) physical status and assessment of the likely duration and magnitude of physiologic stress imposed by the planned surgery can be accomplished quickly. However, to date, anesthesia training has not adequately emphasized the relationship between intraoperative fluid therapy and (1) mild symptomatic outcomes (e.g., nausea, vomiting, drowsiness) or (2) less immediate but more important outcomes (e.g., integrity of bowel anastomosis, likelihood of satisfactory wound healing or postoperative wound infection). As further evidence accumulates, anesthesia personnel should approach fluid management for all patients with the expectation that careful attention to the rate and volume of fluid administration will improve the postoperative course.

Implications The potential complications of improper perioperative fluid management suggest that additional studies in certain patient populations are needed to develop specific and comprehensive fluid management algorithms. The input needed to develop such algorithms is now available for patients undergoing colon surgery or laparoscopic cholecystectomy. Brandstrup and colleagues randomized 172 elective colon surgery patients to restrictive or standard perioperative fluid management. In the fluid-restricted group, the primary measure was maintenance of preoperative body weight. All patients underwent combined epidural and general anesthesia. Important details of the standard (liberal) and restrictive protocols are detailed in Table 16-1. By design, the fluidrestricted group received less perioperative fluid and acutely gained less than 1 kg, in contrast to more than 3 kg in the standard fluid therapy group. More important, total postoperative complications were 33% in the fluid-restricted group and 51% in the standard fluid therapy group. Cardiopulmonary complications were also significantly reduced in association with fluid restriction (7% in the restricted group versus 24% in the liberal group), as were tissue healing complications (16% in the restricted group versus 31% in the liberal group). Holte and coworkers randomized 48 ASA I to II patients having laparoscopic cholecystectomy to receive either 15 or 40 mL/kg of lactated Ringer’s solution intraoperatively. They found that the higher dose was associated with improved

PHARMACOLOGY

are obvious, though not specific, signs of hypovolemia; pulmonary edema is an obvious but not specific sign of hypervolemia. Recognition of subtle hypovolemia or hypervolemia is often more difficult. The clinical assessment of blood and extracellular volume begins with the recognition of deficit-generating situations, such as bowel obstruction, preoperative bowel preparation, chronic diuretic use, sepsis, burns, and trauma. Physical signs suggesting hypovolemia include oliguria, supine hypotension, and a positive tilt test. Although oliguria implies hypovolemia, hypovolemic patients may be nonoliguric, and normovolemic patients may be oliguric because of renal failure or stressinduced endocrine responses. Supine hypotension implies a blood volume deficit of more than 30%, although a normal arterial blood pressure could represent relative hypotension in an elderly or chronically hypertensive patient. A positive tilt test is defined as an increase in heart rate of at least 20 beats per minute and a decrease in systolic blood pressure of 20 mm Hg or more when a patient assumes the upright position. However, young, healthy subjects can withstand acute loss of 20% of blood volume while exhibiting only postural tachycardia. In contrast, orthostasis may occur in 20% to 30% of elderly patients, despite normal blood volume. Laboratory evidence that suggests hypovolemia or extracellular volume depletion includes azotemia, low urinary sodium, metabolic alkalosis (if hypovolemia is mild), and lactic acidosis (if hypovolemia is severe). Hematocrit is virtually unchanged by acute hemorrhage until fluids are administered or fluid shifts from the interstitial to the intravascular space occur. Blood urea nitrogen (BUN), normally 8 to 20 mg/dL, is increased by hypovolemia, high protein intake, gastrointestinal bleeding, or accelerated catabolism; it is reduced by severe hepatic dysfunction. Serum creatinine (SCr), a product of muscle catabolism, may be misleadingly low in elderly adults, females, and debilitated or malnourished patients; however, in muscular or acutely catabolic patients, it may exceed the normal range (0.5 to 1.5 mg/dL). A BUN/SCr ratio exceeding the normal range (10 to 20) suggests dehydration. In prerenal oliguria, enhanced sodium reabsorption should reduce urinary [Na+] to 20 mEq/L or less. Enhanced water reabsorption should increase the urine concentration (urine osmolality >400; urine-plasma creatinine ratio >40:1). However, sensitivity and specificity of these urinary variables may be misleading. Assessment of the adequacy of intraoperative fluid resuscitation integrates multiple clinical variables, including sodium concentrations, estimates of intraoperative blood loss and monitoring of heart rate, blood pressure, urine output, arterial oxygenation, and pH. Visual estimation of intraoperative blood loss is notoriously inaccurate. Moreover, tachycardia is an insensitive, nonspecific indicator of hypovolemia. In patients receiving potent inhalational anesthetics, maintenance of a satisfactory blood pressure implies adequate intravascular volume, as does a central venous or pulmonary artery occlusion pressure within the normal range (6 to 12 mm Hg). However, during profound hypovolemia, indirect blood pressure measurements may underestimate direct arterial pressure. Another advantage of direct arterial pressure monitoring may be the recognition of increased systolic blood pressure variation accompanying positive-pressure ventilation with hypovolemia.

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Restricted versus Liberal Perioperative Fluids

Group

Restricted Fluids

Liberal Fluids

Preload Maintenance Third-space fluid replacement Blood replacement

None 5% dextrose in water None Hydroxyethyl starch 1:1 for blood loss ≤1500 mL; components for blood loss >1500 mL

Hydroxyethyl starch 0.9% normal saline 0.9% normal saline 0.9% normal saline or hydroxyethyl starch for blood loss £1500 mL; components for blood loss >1500 mL

From Brandstrup B, Tonnesen H, Beier-Holgersen R, et al: Effects of intravenous fluid restriction on postoperative complications: Comparison of two perioperative fluid regimens—a randomized assessor-blinded multicenter trial. Ann Surg 238:641-648, 2003.

postoperative pulmonary function and exercise capacity, reduced neurohormonal stress response, and improvements in nausea, general sense of well-being, thirst, dizziness, drowsiness, fatigue, and balance function.

MANAGEMENT For the patients described in the case synopses, there is enough class I evidence from randomized clinical trials to propose appropriate approaches to perioperative fluid therapy (although one clinical trial for each condition would be insufficient to support formal standards or guidelines). For the 72-year-old man having transverse colectomy, a reasonable option is to manage fluids as in the trial conducted by Brandstrup and colleagues. Using that approach, the patient would receive no preload and minimal crystalloid during induction. Postinduction hypotension, if it developed, would be treated with a pressor while awaiting the onset of surgical stimulation. Maintenance fluids would consist of 5% dextrose in water, and no additional fluid would be given to cover third-space losses. All blood loss would be replaced with 6% hydroxyethyl starch in a ratio of 1:1 unless blood loss exceeded 1500 mL, in which case blood components would be given as appropriate. (For details on the management of changes in blood pressure unrelated to blood loss and other perturbations, such as oliguria, the original publication by Brandstrup’s group should be consulted.) In addition, it is essential to note that in patients undergoing colon surgery, laparoscopic cholecystectomy, or other surgery, it may be necessary to modify the preoperative fluid management plan. For the 35-year-old woman undergoing laparoscopic cholecystectomy, the fluid strategy would be diametrically opposite. Infusing 40 mL/kg of crystalloid over the course of the case would likely exceed what such patients typically receive, but the available evidence suggests that this approach is associated with improved postoperative symptoms. Also, there are important differences between laparoscopic cholecystectomy and colon surgery: ●

Postoperative cardiovascular, pulmonary, infectious, and wound complications occur much less commonly with laparoscopic cholecystectomy than with colon surgery. Thus, the goals of fluid therapy may be quite different for the two types of surgery.

●

In contrast to colon surgery, in which fluid sequestration and blood loss are common, laparoscopic cholecystectomy is associated with minimal fluid sequestration and usually minimal blood loss. Also, based on Brandstrup’s study, it is likely that replacement of blood loss with colloid limits postoperative hypovolemia.

So far, clinical trials have examined the influence of relative extremes of fluid therapy in only two types of surgery. It is likely that subsequent trials will examine more intermediate fluid restriction in colon surgery and less liberal fluid administration in laparoscopic cholecystectomy.

PREVENTION Prevention of the complications of insufficient or excessive perioperative fluid administration requires a multifaceted, flexible approach. A reasonable starting point for the fluid management of individual patients is to plan to replicate a strategy that has been effective in a prospective, randomized clinical trial in a similar population of patients undergoing the same procedure. In addition, each perioperative fluid plan must take into account the physiologic status of the individual patient. If no trials are available for identical surgical procedures, fluid management is based on trials in similar patients and adjusted for the invasiveness of the planned surgery (e.g., amount of tissue manipulation and trauma leading to increased third-space losses, amount of associated bleeding). Also, ambulatory patients without cardiovascular, pulmonary, or renal disease could reasonably be managed with a strategy similar to that used by Holte and coworkers in patients undergoing laparoscopic cholecystectomy. Data reported by Yogendran and associates suggest that such a strategy is advantageous, although improved outcomes in their trial were attained with less isotonic crystalloid preload (20 mL/kg). In patients undergoing major surgical procedures other than bowel surgery, the fluid strategy used by Brandstrup’s group might be used; bowel surgery may impose some procedure-specific constraints. One possible refinement of fluid management in major surgical procedures is better monitoring of fluid requirements. In that regard, studies in which esophageal Doppler monitoring (EDM) was used to measure descending aortic flow are provocative. EDM also quantifies the percentage of time that the descending aortic flow is systolic (i.e., corrected

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Further Reading Arieff AI: Fatal postoperative pulmonary edema: Pathogenesis and literature review. Chest 115:1371-1377, 1999. Brandstrup B, Tonnesen H, Beier-Holgersen R, et al: Effects of intravenous fluid restriction on postoperative complications: Comparison of two perioperative fluid regimens—a randomized assessor-blinded multicenter trial. Ann Surg 238:641-648, 2003. Gan TJ, Soppitt A, Maroof M, et al: Goal-directed intraoperative fluid administration reduces length of hospital stay after major surgery. Anesthesiology 97:820-826, 2002. Hirsch EF: United States Navy surgical research Republic of Vietnam 19661970: A retrospective review. Mil Med 152:236-240, 1987.

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65

Holte K, Klarskov B, Christensen DS, et al: Liberal versus restrictive fluid administration to improve recovery after laparoscopic cholecystectomy: A randomized, double-blind study. Ann Surg 240:892-899, 2004. Knight RJ: Resuscitation of battle casualties in South Vietnam: Experiences at the First Australian Field Hospital. Resuscitation 2:17-31, 1973. Lipsitz LA: Orthostatic hypotension in the elderly. N Engl J Med 321: 952-957, 1989. Morris JA Jr, Mucha P Jr, Ross SE, et al: Acute posttraumatic renal failure: A multicenter perspective. J Trauma 31:1584-1590, 1991. Perel A: Assessing fluid responsiveness by the systolic pressure variation in mechanically ventilated patients. Anesthesiology 89:1309-1310, 1998. Rooke GA, Schwid HA, Shapira Y: The effect of graded hemorrhage and intravascular volume replacement on systolic pressure variation in humans during mechanical and spontaneous ventilation. Anesth Analg 80:925-932, 1995. Shires GT, Brown FT, Canizaro PC: Distributional changes in extracellular fluid during acute hemorrhagic shock. Surg Forum 11:115, 1960. Shires GT, Coln D, Carrico J, et al: Fluid therapy in hemorrhagic shock. Arch Surg 88:688-693, 1964. Shires GT, Williams J, Brown F: Acute changes in extracellular fluid associated with major surgical procedures. Ann Surg 154:803-810, 1961. Stoneham MD: Less is more . . . using systolic pressure variation to assess hypovolaemia. Br J Anaesth 83:550-551, 1999. Tavernier B, Makhotine O, Lebuffe G, et al: Systolic pressure variation as a guide to fluid therapy in patients with sepsis-induced hypotension. Anesthesiology 89:1313-1321, 1998. Venn R, Steele A, Richardson P, et al: Randomized controlled trial to investigate influence of the fluid challenge on duration of hospital stay and perioperative morbidity in patients with hip fractures. Br J Anaesth 88:65-71, 2002. Yogendran S, Asokumar B, Cheng DC, et al: A prospective randomized double-blinded study of the effect of intravenous fluid therapy on adverse outcomes on outpatient surgery. Anesth Analg 80:682-686, 1995. Zaloga GP, Hughes SS: Oliguria in patients with normal renal function. Anesthesiology 72:598-602, 1990.

PHARMACOLOGY

flow time). For example, Gan and colleagues randomized 100 patients undergoing surgery in which the predicted blood loss was greater than 500 mL to fluid management based on conventional criteria versus EDM (the treatment group). In the latter, 6% hydroxyethyl starch was given in 200-mL increments to increase corrected flow time if it was less than 0.35 second. The treatment group had a shorter hospital length of stay and resumed eating solid food more quickly. Venn and associates randomized 90 patients having repair of proximal femoral fractures to one control and two treatment groups: (1) conventional fluid management (control), (2) repeated challenges with colloid guided by central venous pressure monitoring, or (3) the same colloid challenges guided by EDM. Both treatment groups had significantly fewer episodes of intraoperative hypotension and were discharged from the hospital sooner than the controls. Importantly, noninvasive EDM was equivalent to more invasive central venous pressure monitoring for assessing intraoperative fluid requirements.

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Volatile Anesthetics: Organ Toxicity

17

Evan D. Kharasch Case Synopsis A 53-year-old woman has laser excision of vocal cord papillomas under anesthesia with halothane and spontaneous ventilation. She has had several prior excisions, including one a month earlier, all with halothane; all were uneventful. However, 1 week after this surgery, she develops fever, nausea, and malaise, along with severe jaundice and markedly elevated serum transaminase concentrations.

PROBLEM ANALYSIS Definition Organ toxicity caused by volatile anesthetics is the result of alterations in cellular structure or function that persist beyond the period of anesthetic administration and elimination. Of greatest concern with volatile anesthetics are hepatic toxicity and renal toxicity. Not discussed here, but worthy of mention, is the potential for volatile inhalational anesthetics to interact with desiccated carbon dioxide absorbents to form potentially toxic compounds, such as carbon monoxide and compound A. Pulmonary and renal toxicity can occur, and fires and explosions have also been reported. (For more details, see the works by Baum and Woehlck listed under “Further Reading.”) HEPATIC TOXICITY Hepatic toxicity occurs most commonly after halothane administration, but it has also been observed with less frequency after enflurane, isoflurane, sevoflurane, and desflurane. Halothane causes two types of liver damage: ● ●

Fulminant hepatic necrosis (“halothane hepatitis”) Mild subclinical hepatotoxicity

Fulminant hepatic necrosis is clinically characterized by fever and jaundice, with grossly elevated serum transaminase levels. Liver biopsies show massive centrilobular necrosis. Today, fulminant hepatic necrosis is considered an immune phenomenon that is initiated by oxidative metabolism of halothane to an intermediate. This subsequently binds to liver proteins and induces trifluoroacetylation, which renders the proteins antigenic. These antigens stimulate the formation of antibodies that, on re-exposure to halothane (or enflurane, isoflurane, or desflurane), initiate immunemediated hepatic necrosis. Such necrosis is rare, occurring in 1 in 6000 to 35,000 persons after halothane administration and in 2 in 1 million persons after enflurane; there have been a few reports of cases after isoflurane and one confirmed case after desflurane. Hepatic dysfunction after sevoflurane 66

administration has also been reported, but it is not thought to represent immune-mediated necrosis, and the relationship to anesthesia is unknown. Mild hepatotoxicity occurs commonly after halothane administration (approximately 25% of cases) but not after the administration of other volatile anesthetics. It is characterized by mild, transient elevations in serum transaminase and glutathione-S-transferase concentrations and altered postoperative drug metabolism. However, clinically evident hepatocellular disease is not a characteristic of mild hepatic toxicity. Rather, it is attributed to reductive (anaerobic) halothane metabolism, with reactive metabolites causing lipid peroxidation and binding to cytochrome P-450. The two forms of hepatic anesthetic toxicity are thought to be unrelated. ACUTE RENAL FAILURE Acute renal failure is a common perioperative problem, but it is now rarely the direct result of volatile anesthetics. Several terms require definition: ●

●

●

●

●

Renal failure is a reduction in renal function sufficient to cause alterations in serum biochemistry; it may be oliguric, nonoliguric, or polyuric. Renal insufficiency is a lesser reduction in renal function with normal serum biochemistry. Oliguria is urine output less than 20 mL/hour (in a 70-kg adult) and implies renal failure. Nonoliguric renal failure is more common than oliguric failure, and it is thought to represent a milder renal insult. Polyuria is urine output greater than 100 mL/hour (in a 70-kg adult).

Both oliguric and nonoliguric renal failure may be postrenal (obstructive), prerenal (renal hypoperfusion due to hypovolemia, hypotension, decreased renal blood flow, or cardiovascular surgery), or intrinsic (caused by nephrotoxins such as aminoglycosides, myoglobin, hemoglobin, radiocontrast media, or nonsteroidal anti-inflammatory agents). Polyuric renal failure with reduced concentrating ability is due to either central diabetes insipidus (insufficient antidiuretic

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Recognition Fulminant hepatic necrosis manifests clinically as fever, nausea, anorexia, chills, malaise, and rash that appear 3 to 6 days postoperatively, followed by severe jaundice that occurs 6 to 10 days postoperatively. Laboratory manifestations include grossly elevated serum transaminase levels, hyperbilirubinemia, and prolonged prothrombin time, but these are not specific for the disease. Pathologic findings include centrilobular and midzonal necrosis, but again, these findings are not specific. Mild hepatotoxicity after halothane is usually clinically silent, consisting of only mild, reversible increases in liver enzymes (aspartate aminotransferase, alanine aminotransferase, γ-glutamyl transferase, and glutathione-S-transferase) on laboratory studies. These elevations appear 1 to 2 days postoperatively and usually resolve within days. However, levels may remain elevated for up to 2 weeks. A specific diagnosis of anesthetic-related hepatitis is difficult at best. Both the clinical presentation and the morphologic features strongly resemble those of viral hepatitis. Indeed, the incidence of occult perioperative hepatitis (viral, infectious, alcoholic) is 1 in 700, and in 30% of these cases, postoperative jaundice develops; this is far greater than the incidence of anesthetic-related fulminant hepatitis. Positive serologic markers for hepatitis A, B, C, or D or other infectious agents (e.g., cytomegalovirus, Epstein-Barr virus) may help exclude anesthesia as the cause of postoperative hepatitis, but negative serologic findings are inconclusive, especially if infection is recent. A few laboratories can detect antitrifluoroacetylated protein antibodies in serum, which favors a diagnosis of anesthetic-related hepatitis. However, the assay lacks sufficient specificity and is not routinely available. Hepatitis C is the most common cause of postoperative hepatitis, but hepatic ischemia, other drugs, transfusion, and cholestasis should also be excluded. The clinical characteristics of renal insufficiency and acute renal failure were listed earlier. Differentiation of central and nephrogenic diabetes insipidus is based on response to water deprivation and vasopressin. The cause of oliguric

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67

renal failure is determined by the BUN-creatinine ratio, urine sodium and osmolality, urine-plasma osmolality, urineplasma creatinine, fractional excretion of sodium, and response to volume challenge. The diagnosis of renal failure specific to a volatile anesthetic is extremely rare in the postmethoxyflurane era.

Risk Assessment Clinical risk factors for fulminant hepatic necrosis include the following: ● ● ● ● ●

Repeated halothane exposure Prior history of postanesthetic fever or jaundice Obesity Female sex Middle age

Halothane is oxidatively metabolized by cytochrome P-450 2E1. Thus, enzyme induction (alcohol, isoniazid, obesity) increases antigen formation and increases risk, whereas enzyme inhibition (disulfiram) reduces metabolism. Multiple, repeated exposures at short intervals (<6 weeks) is the greatest risk factor for halothane hepatitis. Children are at greatly diminished risk, for unknown reasons, even after repeated halothane exposure. Liver disease itself is not a risk factor for halothane hepatitis. Clinical risk factors for mild hepatotoxicity are those that increase reductive halothane metabolism. Halothane is reduced anaerobically by P-450 3A4 and 2A6; thus, enzyme induction (e.g., by barbiturates, phenytoin, valproic acid) increases metabolism, as does reduced hepatic blood flow. The latter is further reduced by halothane. Although enflurane, isoflurane, and desflurane also cause neoantigen formation, the degree of such formation is far less than with halothane, so the risk of hepatitis with these agents in halothane-sensitized patients is far less. The only clearly identified clinical risk factors for postoperative renal failure are the following: ●

● ●

Poor preoperative renal function (increased BUN or creatinine levels) Advanced age Cardiac failure

Treatment and prevention of hypovolemia and preoperative hydration are primary goals in ameliorating the cardiovascular and renal blood flow effects of volatile anesthetics in general. Mechanical ventilation and positive endexpiratory pressure are other factors peripherally related to volatile anesthetics that diminish renal function. Although not pertinent to contemporary anesthesia, certain inducers of drug metabolism (barbiturates, isoniazid, ethanol) potentiate methoxyflurane metabolism and toxicity.

Implications Fulminant hepatic necrosis after halothane is fatal in nearly half of all cases. There are no known clinical implications of mild hepatotoxicity. Perioperative acute renal failure accounts for half of all patients who require acute dialysis and is associated with a 50% mortality rate. This has remained unchanged for decades.

PHARMACOLOGY

hormone secretion, usually due to pituitary dysfunction) or nephrogenic diabetes insipidus (renal unresponsiveness to antidiuretic hormone). Anesthesia-related renal insufficiency is often prerenal and is caused by hypotension or altered renal perfusion. It is limited to the duration of the anesthetic and is reversible. Renal failure specifically attributable to anesthetic agents has been observed only with methoxyflurane, which can cause vasopressin-resistant polyuria, hypernatremia, hyperosmolality, and dehydration; it also increases blood urea nitrogen (BUN) and creatinine levels. Methoxyflurane nephrotoxicity is due to dose-related methoxyflurane metabolism. Associated plasma fluoride concentrations range from greater than 50 to 80 μM. A mild but reversible concentrating defect following prolonged enflurane use has been noted. Direct nephrotoxicity has not been observed with enflurane, isoflurane, desflurane, or sevoflurane, even with systemic fluoride concentrations far exceeding 50 μM. The role of systemic fluoride concentrations as a factor in nephrotoxicity has been discounted.

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MANAGEMENT There is no specific management for either fulminant hepatic necrosis or mild hepatotoxicity. No therapy is needed for mild hepatotoxicity, whereas only supportive therapy and orthotopic liver transplantation are available for hepatic necrosis. Treatment for acute renal dysfunction includes restoration of normovolemia and renal blood flow; administration of mannitol, loop diuretics (controversial), dopamine, and fenoldopam (experimental); and dialysis.

PREVENTION No measures for the prevention of mild hepatotoxicity are necessary. The only fail-safe method of preventing fulminant hepatic necrosis is total avoidance of halothane, enflurane, isoflurane, and desflurane in patients previously exposed to halothane. Hepatitis is rare in children and in adults with only a single exposure to halothane. A conservative approach is to avoid halothane in patients with known risk factors for fulminant necrosis, especially recent halothane anesthesia. The ultraconservative approach is to avoid halothane altogether. The single most effective measure to prevent postoperative renal failure is to minimize renal ischemia by maintaining

renal perfusion. Maintenance of adequate hydration is essential. Mannitol may be an effective prophylactic.

Further Reading Baden JM, Mazze RI: Polyuria. In Gravenstein N, Kirby RR (eds): Complications in Anesthesiology, 2nd ed. Philadelphia, LippincottRaven, 1996, pp 493-498. Baum JA, Woehlck HJ: Interaction of inhalational anaesthetics with CO2 absorbents. Best Pract Res Clin Anaesthesiol 17:63-76, 2003. Brown BR: Inhalation anesthesia and hepatic injury. In Gravenstein N, Kirby RR (eds): Complications in Anesthesiology, 2nd ed. Philadelphia, Lippincott-Raven, 1996, pp 701-710. Dooley JR, Mazze RI: Oliguria. In Gravenstein N, Kirby RR (eds): Complications in Anesthesiology, 2nd ed. Philadelphia, LippincottRaven, 1996, pp 479-491. Gut J, Christen V, Frey N, et al: Molecular mimicry in halothane hepatitis: Biochemical and structural characterization of lipoylated autoantigens. Toxicology 97:199-224, 1995. Novis BK, Roizen MF, Aronson S, et al: Association of preoperative risk factors with postoperative acute renal failure. Anesth Analg 78: 143-149, 1994. Pearson JD, Gelman S: Liver complications after anesthesia. In Benumof JL, Saidman LJ (eds): Anesthesia and Perioperative Complications. St. Louis, Mosby–Year Book, 1992, pp 413-433. Prough DS, Zaloga G: Hypovolemia and renal dysfunction. In Benumof JL, Saidman LJ (eds): Anesthesia and Perioperative Complications. St. Louis, Mosby–Year Book, 1992, pp 434-465. Ray DC, Drummond GB: Halothane hepatitis. Br J Anaesth 67:84-99, 1991. Woehlck HJ: Sleeping with uncertainty: Anesthetics and desiccated absorbent. Anesthesiology 101:276-278, 2004.

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18

Nitrous Oxide: Neurotoxicity Claudia Praetel Case Synopsis Two weeks after surgery for prostate adenoma, a 69-year-old man developed ascending paresthesia of the limbs, severe ataxia, tactile sensory loss in the limbs and trunk, and absent tendon reflexes. After a second surgical intervention, the patient became confused. Four months after onset, the patient demonstrated paraplegia, severe weakness of the upper limbs, cutaneous anesthesia sparing the head, and confusion.

PROBLEM ANALYSIS Definition Nitrous oxide (N2O) has been safely used for anesthesia for almost 140 years, since it first became available in compressed gas cylinders in 1868. However, there are increasing reports of the neurotoxic potential of N2O associated with recreational use, with chronic occupational exposure in unscavenged environments, and after exposure during general anesthesia. A small subset of patients routinely seen during preoperative anesthetic assessment may indeed be at high risk for postoperative neurologic deterioration if exposed to N2O. Schilling postulated that N2O may precipitate neurologic disease in patients with unrecognized vitamin B12 deficiency. The patient described in the case synopsis was diagnosed with previously unrecognized pernicious anemia with subacute combined degeneration of the spinal cord after exposure to N2O anesthesia. Marié and coworkers published this case report in 2000. During the past 20 years, numerous welldocumented case reports have substantiated this potentially devastating complication. Table 18-1 highlights recent reports of neurologic complications after N2O in both children and adults.

Lack of methionine can also result in defective myelination and demyelination. Neurologic sequelae include paresthesias, peripheral neuropathy, and subacute combined degeneration of both the posterior and lateral columns of the spinal cord. Subacute combined degeneration is reversible if diagnosed and treated early with cobalamin. Psychological symptoms such as memory loss, disorientation, and depression have been described. These conditions may be observed with or without macrocytic changes in erythrocytes.

Risk Assessment Inhibition of methionine synthase by N2O anesthesia does not cause a problem in healthy individuals with sufficient vitamin B12 stores. However, any patient with even subclinical deficits of vitamin B12 is at increased risk for the development of myeloneuropathy because occult cobalamin deficiency, combined with subsequent N2O exposure, compounds inhibition of the methionine synthesis pathway. Insufficient availability of cobalamin may have the following causes: ●

●

Recognition N2O is a potent oxidant. It irreversibly oxidizes methylcobalamin through inhibition of the methionine synthesis pathway, thereby inactivating the active form of vitamin B12. The latter is essential for methionine synthase, the key enzyme for converting homocysteine to methionine (an essential amino acid) using tetrahydrofolate (the bioactive form of folate) as the methyl source. Therefore, insufficient availability of either cobalamin1 or folate results in a decrease of methionine, with the accumulation of homocysteine. N2O also directly inactivates methionine synthase, possibly due to the production of free radicals. Inhibition of methionine synthase activity has deleterious consequences for DNA synthesis, leading to megaloblastic changes in all rapidly dividing cells, macrocytosis in erythroid precursors, and ineffective erythropoiesis.

●

Inadequate intake (e.g., alcoholics, long-term strict vegetarians, breast-fed infants of vitamin B12-deficient mothers) Impaired absorption (e.g., gastric atrophy, long-term use of drugs that interfere with acid production, Crohn’s disease, lack of intrinsic factor due to autoimmune destruction of parietal cells or after surgery such as gastrectomy and gastric bypass) Rare congenital disorders (e.g., deficiencies of transcobalamin II, familial selective vitamin B12 malabsorption)

Folate deficiency is very rare due to the dietary fortification of wheat and corn grains with folic acid. Inherited defects in folate metabolism (5,10-methylenetetrahydrofolate reductase deficiency) are a contraindication to N2O exposure. 1 The terms cobalamin and vitamin B12 are used interchangeably as generic terms for all the cobalamides active in human beings. Preparations of vitamin B12 for therapeutic use contain either cyanocobalamin or hydroxocobalamin, because only these derivatives remain active following storage.

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Selected Case Reports of Neurologic Complications after Nitrous Oxide (N2O) Anesthesia

Reference

Demographics

Onset Time and Symptoms

Findings

Selzer et al

3 mo old; excisional biopsy (45 min); 4 days later, tumor resection (270 min), for a total N2O exposure time of 315 min 8 mo old; laparoscopic orchiopexy; N2O exposure of 180 min

25 days: hypotonia, ataxic ventilation, absent reflexes

Methylenetetrahydrofolate reductase deficiency; died 46 days postoperatively

6 days: hypotonia, fine motor tremor, athetoid movements

Profound dietary cobalamin deficiency (<20 pg/mL); hyperhomocysteinemia; normal folate levels; megaloblastic abnormalities in bone marrow Severe dietary cobalamin deficiency (<45 pg/mL); normal folate levels; MRI revealed diffuse cerebral atrophy Cobalamin deficiency (135 pmol/L); borderline anemia; abnormal Schilling test; MRI revealed signal changes of posterior spinal columns; SSEP showed severe spinal cord conduction disturbance; EMG and NCS showed mixed polyneuropathy Normal cobalamin level (<166 pmol/L); low folate; macrocytic, hyperchromic anemia; bone marrow exam revealed megaloblastic hematopoiesis; MRI showed signal changes in posterior columns along cervical cord segments: EMG and NCS showed mild demyelinative polyneuropathy Macrocytic anemia; MRI revealed signal changes in posterior and lateral spinal columns

Felmet et al

McNeely et al

4 mo old; repair of cranisynostosis; N2O exposure of 80 min

3 wk: hypotonia, lethargy, feeding difficulty, severe acidosis, dehydration 2 mo: gait imbalance, lower extremity paresthesias

Ilnicziky et al (case 1)

57-yr-old man; cranial artery bypass; duration of N2O exposure unspecified

Ilnicziky et al (case 2)

52-yr-old man; gallbladder removal; duration of N2O exposure unknown

1 wk: paresthesias in both feet, ascending to trunk and upper extremities; weakness and clumsiness in all limbs

Sesso et al

63-yr-old woman; gallbladder removal; N2O exposure of 80 min

1 day: rapidly ascending paresthesias in hands/feet 2 mo: moderate tabetic-spastic gait, with impaired proprioception and sensation

EMG, electromyography; MRI, magnetic resonance imaging; NCS, nerve conduction velocity study; SSEP, somatosensory evoked potentials.

Implications A recently published multicenter study in Great Britain examined blood samples of 1562 patients aged 65 to 74 years and 75 years or older. Among men, 11% and 24%, respectively, were at high risk of vitamin B12 deficiency; the corresponding numbers were slightly lower for women (9% and 17%, respectively). Similar results were reported for the United States. This high prevalence of borderline or low vitamin B12 concentrations in the elderly (due to the decline in digestive efficiency, atrophic gastritis, and the ubiquitous use of acid-reducing drugs) is particularly worrisome because the clinical presentation varies considerably and rarely includes all the classic features. Hematologic signs of macrocytosis and anemia are often missing. Apparently, a dissociation of neurologic and hematologic findings is common. Cobalamin deficiency in young adults is uncommon, except among strict long-term vegetarians. The potential risks of N2O are increased in children with enzyme disorders and noncompliance with vitamin supplements, as described in a patient with phenylketonuria. There is growing evidence that markers such as holotranscobalamin II, methylmalonic

acid, and total serum homocysteine constitute a better index of early cobalamin deficiency and allow the differentiation between storage depletion and functional deficiency. Presently, these tests are very expensive and are not used as routine assays to investigate functional vitamin B12 status. Low cobalamin status is significantly correlated to increased plasma homocysteine, which is recognized as an independent atherothrombotic risk factor. The latency in onset of neurologic symptoms following exposure to N2O may confound the true incidence of this anesthesia-related complication.

MANAGEMENT The preoperative risk assessment should include careful attention to the following: ● ●

● ●

Hematologic abnormalities (e.g., anemia, macrocytosis) Increased prevalence of subclinical vitamin B12 deficiency in the elderly Rare genetic enzyme disorders Diet (strict vegetarian or vegan)

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● ● ●

●

History of gastric or small bowel surgery (e.g., gastric bypass in the morbidly obese, resection of the terminal ileum in Crohn’s disease) Inflammatory bowel disease Long-term use of antacids, histamine (H2) receptor antagonists, or proton pump inhibitors (e.g., aluminum and magnesium hydroxide, ranitidine, omeprazole) Severe depression in the elderly Unexplained neurologic symptoms Previous exposure to inhaled anesthesia (including N2O) that was associated with postoperative neurologic complications Increased prevalence of folate deficiency in patients with chronic liver disease or malabsorption syndromes, longterm use of anticonvulsants (e.g., valproic acid, phenytoin), and antimetabolite therapy (e.g., methotrexate)

PREVENTION Avoidance of N2O anesthesia in patients with an elevated risk of cobalamin deficiency appears prudent in view of the possibly serious neurologic sequelae. The fact that subclinical or clinical deficits are not always accompanied by hematologic changes deserves special emphasis. Routine N2O use may be detrimental to patients with marginal cobalamin status. Vitamin pretreatment of at-risk patients is an option, but an impractical one, because anesthesiologists generally see patients immediately before surgery. Optimal management of patients with confirmed or suspected cobalamin deficiency includes an anesthetic regime devoid of N2O. N2O-induced postoperative neurologic complications are preventable with

Nitrous Oxide: Neurotoxicity

71

a proper focus on the recognition of preexisting vitamin B12 deficiency as outlined here.

Further Reading Badner NH, Freeman D, Spence JD: Preoperative oral B vitamins prevent nitrous oxide-induced postoperative plasma homocysteine increase. Anesth Analg 95:787, 2002. Clarke R, Refsum H, Birks J, et al: Screening for vitamin B12 and folate deficiency in older persons. Am J Clin Nutr 77:1241-1247, 2003. Deleu D, Hanssens Y, Louon A: Nitrous oxide-induced cobalamin deficiency. Arch Neurol 58:134-135, 2001. Felmet K, Robins B, Tilford D, Haflick SJ: Acute neurologic decompensation in an infant with cobalamin deficiency exposed to nitrous oxide. J Pediatr 137:427-428, 2000. Hadzic A, Glab K, Sanborn KV, Thys DM: Severe neurologic deficit after nitrous oxide anesthesia. Anesthesiology 83:863-866, 1995. Herrmann W, Geisel J: Vegetarian lifestyle and monitoring of vitamin B12 status. Clin Chim Acta 326:47-59, 2002. Ilniczky S, Jelencsik, Kenéz J, Szirmai I: MR findings in subacute combined degeneration of the spinal cord caused by nitrous oxide anaesthesia— two cases. Eur J Neurol 9:101-104, 2002. Marié RM, Le Biez E, Busson P, et al: Nitrous oxide anesthesia-associated myelopathy. Arch Neurol 57:380-382, 2000. McNeely JK, Buczulinski B, Rosner DR: Severe neurological impairment in an infant after nitrous oxide anesthesia. Anesthesiology 93:1549-1550, 2000. Nunn JF: Clinical aspects of the interaction between nitrous oxide and vitamin B12. Br J Anaesth 59:3-13, 1987. Royston BD, Nunn JF, Weinbren HK, et al: Rate of inactivation of human and rodent methionine synthase by nitrous oxide. Anesthesiology 68:213-216, 1988. Schilling RF: Is nitrous oxide a dangerous anesthetic for vitamin B12-deficient subjects? JAMA 255:1605-1606, 1986. Selzer RR, Rosenblatt DS, Laxova R, Hogan K: Adverse effect of nitrous oxide in a child with 5,10-methylenetetrahydrofolate reductase deficiency. N Engl J Med 349:45-50, 2003. Sesso RM, Iunes Y, Melo AC: Neuropathy following nitrous oxide anesthesia in a patient with macrocytic anaemia. Neuroradiology 41:588-590, 1999.

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Intrathecal Opiates Lisa Thannikary and Bhiken Naik Case Synopsis An otherwise healthy 26-year-old woman undergoes cesarean section for delivery of a breech infant. Spinal anesthesia is used, consisting of hyperbaric bupivacaine (12 mg) with preservative-free morphine (0.3 mg). The surgery is uneventful, and the infant has Apgar scores of 9 and 9 at 5 and 10 minutes, respectively. The patient remains in the recovery room for 2 hours and is then transferred to the floor. She is treated with diphenhydramine 50 mg intravenously (IV) for generalized pruritus 4 hours after surgery and promethazine 25 mg IV for vomiting 7 hours after surgery. Ten hours after surgery, she is found to be somnolent, with a respiratory rate of 6 breaths per minute, and is minimally responsive to deep tactile stimulation.

PROBLEM ANALYSIS Definition Intrathecal administration of opioids is an effective means of providing analgesia. A combination of opioids and local anesthetics is often administered intrathecally in an effort to reduce drug dosages while limiting the side effects of both classes of drugs. Morphine is commonly chosen for intrathecal administration, because a single dose may provide analgesia for up to 24 hours. Side effects of intrathecal opioids include early and late respiratory depression, nausea and vomiting, pruritus, sedation, and urinary retention (Table 19-1). Early respiratory depression occurs in the first 2 hours after intrathecal administration and is believed to be due to vascular uptake and redistribution. This occurs more often with lipophilic opioids such as fentanyl and sufentanil than with less lipophilic opioids such as morphine. Delayed respiratory depression occurs 6 to 12 hours after intrathecal administration and is believed to be the result of rostral spread of the opioid in the cerebrospinal fluid. The target receptors are likely located in the respiratory center of the brainstem. However, the occurrence of clinically significant respiratory depression is very low, typically less than 0.5%. Pruritus, either generalized or localized, occurs frequently in patients receiving intrathecal opioids. Although

Table 19–1

■

the mechanism is not fully understood, histamine release is not postulated to be a causative factor. Nausea and vomiting are believed to be due to rostral spread of the opioid in the cerebrospinal fluid. The opioid stimulates the vomiting center and the chemoreceptor trigger zone in the fourth ventricle. Sedation is believed to result from opioid spread through the cerebrospinal fluid to the thalamus, limbic system, or cerebral cortex. Sedation may be exacerbated by hypercarbia with carbon dioxide narcosis. Urinary retention is believed to be due to inhibition of sacral parasympathetic outflow. This results in relaxation of the bladder detrusor muscle and the concomitant inability to relax the sphincter.

Recognition The most serious complication of intrathecal opioid administration is delayed respiratory depression because it usually occurs when the patient is no longer under an anesthesiologist’s or intensivist’s care. In the operating room, labor suite, recovery room, or critical care unit, patients are more closely monitored than they are on the floor. It is also important to recognize that respiratory depression is often a late finding. Increasing somnolence, bradypnea, and smaller tidal volumes are early signs of respiratory compromise. Late signs are hypoxia, unresponsiveness, and cardiopulmonary arrest.

Cause and Treatment of Complications of Intrathecal Medications

Complication

Cause

Treatment

Early respiratory depression Late respiratory depression Pruritus Nausea, vomiting

Rapid vascular uptake and redistribution Rostral CSF spread to brainstem respiratory center Unknown (unlikely due to histamine release) Rostral CSF spread to vomiting center or chemoreceptor trigger zone in fourth ventricle Inhibited sacral parasympathetic outflow Rostral spread in CSF to thalamus, limbic system, or cortex; hypercarbia

Ventilatory support, naloxone Ventilatory support, naloxone Naloxone, antihistamines, propofol Naloxone, antiemetics, droperidol, transdermal scopolamine Naloxone (large doses), urinary catheterization Naloxone

Urinary retention Sedation

CSF, cerebrospinal fluid.

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Risk Assessment Careful selection of patients for the administration of intrathecal opioids is important. Patients at increased risk for respiratory depression include those who are debilitated or elderly, suffer from coexisting respiratory disease, and are placed in Trendelenburg’s position following intrathecal opioid injection. Also, patients receiving hydrophilic opioids, large or frequent doses of opioids, large-volume injections, and concomitant parenteral or oral sedatives are at increased risk for respiratory depression.

Implications Anesthesiologists commonly administer intrathecal opioids to provide postoperative analgesia. It is important to remember that side effects of intrathecal opioids can occur after the patient has left the anesthesiologist’s care. Good communication with the nursing staff caring for the patient is crucial for the prevention of many complications.

MANAGEMENT The immediate treatment for neuraxial opiate-induced respiratory depression is ventilatory support until the opiate is metabolized or pharmacologically antagonized. The patient must be ventilated with positive-pressure mask ventilation and 100% oxygen. Tracheal intubation and mechanical ventilation may be necessary in some patients. Opiate reversal is accomplished with small doses (40 to 80 μg) of parenteral naloxone. Repeated naloxone doses or infusions may be necessary because its half-life is shorter than that of intrathecal morphine. Also, advanced cardiovascular life support is required for patients with cardiac arrest due to narcotic-caused respiratory depression. Arterial blood gas measurements for carbon dioxide concentrations are helpful to ascertain the degree of inhibition of respiration or the adequacy of ventilation. Finally, narcotics administered by other routes (intravenous, oral, epidural, intramuscular) must be discontinued.

Intrathecal Opiates

73

PREVENTION The best way to prevent delayed respiratory depression in patients receiving spinal opioids is to not give parenteral opioids or other sedating medications until at least 24 hours after intrathecal administration. Pruritus and nausea are common side effects of intrathecal opioids and can be treated effectively with naloxone. If other drugs are used for the treatment of pain or side effects, it is important to use nonsedating ones, such as nonsteroidal anti-inflammatory drugs for patients with pain. Good communication between anesthesia and nursing personnel is essential to prevent and treat adverse sequelae of intrathecal opioid administration. Nursing staff must be educated about intrathecal opioid side effects and their appropriate management. One effective measure is to use a preprinted order signed by the anesthesiologist stating that the patient received intrathecal opioids and should not receive further sedating drugs for at least 24 hours without clearance from the anesthesia staff. Signs posted above the head of the patient’s bed indicating that intrathecal opioids have been used may also be helpful. Monitoring the patient at frequent intervals is critical to prevent significant respiratory depression. The patient must be assessed for rate and quality of respirations and level of sedation. For very high-risk patients, the usual floormonitoring interval may not be adequate. If so, the patient may have to be admitted to a unit where more staff are available to monitor the patient more closely. Pulse oximetry monitoring with data telemetry to a centralized nursing station is also helpful but may not be available to all patients or in all hospitals.

Further Reading Ballantyne JC, Loach AB, Carr DB: Itching after epidural and spinal opiates. Pain 33:149-160, 1988. Brill S, Gurman GM, Fisher A: A history of neuraxial administration of local analgesics and opioids. Eur J Anaesthesiol 20:682-689, 2003. Gustafsson LL, Schildt B, Jacobsen K: Adverse effects of extradural and intrathecal opiates: Report of a nationwide survey in Sweden. Br J Anaesth 54:479-485, 1982. Ready LB: Acute perioperative pain. In Miller RD (ed): Anesthesia, 5th ed. Philadelphia, Churchill Livingstone, 2000, pp 2323-2350. Reiz S, Westberg M: Side effects of epidural morphine. Lancet 2:203-204, 1980. Sinatra RS: Acute pain management and acute pain services. In Cousins MJ, Bridenbaugh PO (eds): Neural Blockade in Clinical Anesthesia and Management of Pain, 3rd ed. Philadelphia, Lippincott-Raven, 1998, pp 793-835.

PHARMACOLOGY

Further, intrathecal opioids can impair the ventilatory response to carbon dioxide, which can exacerbate respiratory depression. A high index of suspicion and early recognition of delayed respiratory depression are paramount to timely and effective management. Otherwise, there may be fatal or permanent injuries.

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Barbiturates: Porphyrias Christoph N. Seubert Case Synopsis An anxious 24-year-old woman presents with nausea, vomiting, and abdominal pain and is scheduled for an exploratory laparotomy. The past medical history indicates a negative exploratory laparotomy 2 years ago. The patient’s blood pressure is 150/90 mm Hg and pulse is 105 beats per minute. The physical examination reveals abdominal tenderness. Electrolyte levels and white blood cell count are normal. With direct questioning about family history, the patient declares that her mother may have had porphyria.

PROBLEM ANALYSIS Definition Although barbiturates are widely used in anesthetic practice, they may cause an acute attack in susceptible patients with inducible porphyria. Porphyrias are a heterogeneous group of genetic disorders wherein genetic, physiologic, and environmental factors interact to cause disease. Although porphyrias can be classified on the basis of the underlying genetic defects involved in hemoglobin synthesis, the simple clinical division into inducible-acute and noninduciblechronic forms remains useful. An example of the latter is porphyria cutanea tarda (PCT), the most common form of porphyria. Apart from the friability of the patient’s skin and the association with hepatitis C, human immunodeficiency virus (HIV), and alcohol abuse, PCT presents no anesthetic concerns and does not restrict the choice of drugs. In contrast, all patients with acute porphyrias are at risk for porphyric crisis, particularly in the perioperative period. Drugs administered in the perioperative period for the condition requiring surgery, stress, or fasting may precipitate acute attacks of porphyria. If the attack goes untreated or unrecognized, it may be fatal. Conversely, control of precipitating factors or prompt treatment can avert or mitigate the attack and allow the safe conduct of surgery. Acute porphyrias, therefore, present important anesthetic concerns. Porphyrin synthesis occurs in all cells and is of particular importance in the bone marrow and liver. Porphyrins are essential components of proteins involved in the utilization, transport, and storage of oxygen. These proteins include the ubiquitous cytochrome oxidases of the respiratory chain, the hepatic cytochrome P-450 enzymes, and transport proteins such as hemoglobin. Synthesis of porphyrins involves a series of enzymes (Fig. 20-1). Genes for key enzymes of porphyrin synthesis are duplicated in the genome, allowing for separate regulation of heme synthesis in the bone marrow and the liver. In the liver, most heme is used for the production of cytochrome P-450 enzymes. Heme synthesis and P-450 production are regulated in a coordinated fashion. The four acute porphyrias are acute intermittent porphyria (AIP), variegate porphyria (VP), hereditary coproporphyria (HCP), and δ-aminolevulinic acid dehydratasedeficient porphyria (ADP) (Table 20-1). The gene defects 74

that underlie the acute porphyrias are loss-of-function mutations and typically reduce enzyme activity by half. This reduction results in a pattern of inheritance that is either recessive for the rare ADP or dominant with variable penetrance for the three more frequent acute porphyrias. Although the location of the defective hepatic enzyme in the synthetic pathway for heme varies among the acute porphyrias (see Fig. 20-1), all four may present with acute attacks that are similar in terms of symptoms and treatment. It is not known why enzymatic defects in chronic or erythropoietic porphyrias do not lead to acute attacks. HCP and VP may cause accumulation of excess porphyrins in the skin, where excitation by ultraviolet light causes blistering and scarring skin lesions.

Recognition Acute attacks of inducible porphyria are difficult to recognize in the perioperative setting because symptoms may be nonspecific and varied. Typical symptoms are summarized in Table 20-2. Attacks rarely occur before puberty and seldom recur throughout adult life. They last for several days and are characterized by intense abdominal pain that is steady and poorly localized. The pain intensity contrasts sharply with the paucity of physical findings, sometimes resulting in emergent exploratory laparotomy. Nausea, vomiting, and decreased bowel sounds are common but do not dominate

Glycine + Succinyl CoA ALA Synthetase

negative feedback

Aminolevulinic Acid (ALA)

Heme

Porphobilinogen

Protoporphyrin

Hydroxymethylbilane

Protoporphyrinogen

Uroporphyrinogen

Coproporphyrinogen

Figure 20–1

■

Heme synthesis.

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75

Barbiturates: Porphyrias

Acute-Inducible Porphyrias Neurovisceral Symptoms

Photosensitivity

Autosomal recessive

++

–

Autosomal dominant Autosomal dominant Autosomal dominant

+++ ++ ++

– + +

Type

Incidence

Inheritance

δ-Aminolevulinic acid dehydratasedeficient porphyria (ADP) Acute intermittent porphyria (AIP) Hereditary coproporphyria (HCP) Variegate porphyria (VP)

Exceedingly rare (only 7 cases reported) 1:10,000 (higher in Scandinavia) Rare (1:1 million) 1:300,000 (higher in South Africa)

the clinical picture; fever, leukocytosis, and abdominal tenderness are usually absent. Acute attacks of inducible porphyria may involve the peripheral nervous system in the form of a proximally accentuated motor weakness. This weakness occasionally occurs after resolution of the abdominal pain and may resemble Guillain-Barré syndrome, without the characteristic albumin increase in cerebrospinal fluid. Cranial nerves and sensory nerves may be affected, and progression of neurologic involvement to respiratory and bulbar paralysis and death is possible. In a quarter of patients the central nervous system may be involved, resulting in psychiatric symptoms such as anxiety, hallucinations, and paranoia. Generalized seizures may occur as a neurologic manifestation of central nervous system involvement or as a manifestation of severe hyponatremia caused by inappropriate secretion of antidiuretic hormone or vomiting. If acute porphyria is suspected, the diagnosis can be confirmed by screening for and quantifying the porphyrin precursors δ-aminolevulinic acid and porphobilinogen in urine. Daylight can convert the colorless porphobilinogen to porphyrins, causing a darkening and red to purple discoloration of the urine. Resolution of symptoms is usually rapid, but weakness may persist for days or months. In asymptomatic patients, the perioperative diagnosis of acute porphyria relies on a detailed family history. Because the more frequent forms are all inherited as autosomal

dominant diseases, many susceptible patients know of blood relatives with a diagnosis of acute porphyria. In contrast, laboratory investigations may be negative because the patient’s metabolic situation is compensated. Positive diagnosis of porphyria therefore belongs in the hands of a specialist.1

Risk Assessment The prevalence of acute porphyrias (see Table 20-1) is difficult to estimate because as many as 80% of affected patients may never experience an acute attack in their lifetimes. The prevalence of AIP is estimated to be about 1 in 10,000 in North America but may be as high as 1 in 1000 in Scandinavia or in people of Scandinavian descent. Clinically, AIP accounts for three quarters of acute attacks. VP is less prevalent, except in South Africans of Dutch descent; more than 20,000 cases have been traced to a single immigrant couple. HCP is rare, with an estimated prevalence of 1 in 1 million. Only seven cases of ADP have been reported. More important to risk assessment than prevalence data is the fact that acute attacks are always multifactorial. Even prior uneventful exposure to porphyrinogenic drugs does not rule out a diagnosis of acute porphyria. A high index of suspicion is therefore justified if the constellation of symptoms (see Table 20-2) fits that of an acute attack of porphyria.

Implications Table 20–2

■

Symptoms of a Porphyric Crisis

Parameter Peripheral nervous system Sensory Motor Autonomic Central nervous system Psychiatric Endocrine Neurologic Miscellaneous Laboratory

Symptom

Failure to diagnose and treat an acute attack of porphyria confers up to a 10% risk of mortality. Such failure not only prolongs the attack but also puts the patient at risk of further morbidity from the following: ●

Abdominal pain Proximally accentuated weakness; may involve cranial nerves and respiratory muscles Tachycardia; hypertension Anxiety; hallucinations; paranoia SIADH Seizures Nausea, vomiting Increased ALA and PBG in urine; light-exposed urine turns dark red or pink

ALA, δ-aminolevulinic acid; PBG, porphobilinogen; SIADH, syndrome of inappropriate secretion of antidiuretic hormone.

●

●

●

●

●

Further up-regulation of hepatic heme synthesis, because of decreased glucose intake Progression of motor involvement to include respiratory muscles and cranial nerves Residual paresis that persists even after resolution of the attack Seizures, which may be treated with porphyrinogenic drugs Exposure to porphyrinogenic drugs for other supportive treatment Unwarranted surgery

1 Information can be found on the American Porphyria Foundation Web site: www.porphyriafoundation.com.

PHARMACOLOGY

Table 20–1

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MANAGEMENT Perioperative care of patients with porphyria involves more than the avoidance of barbiturates. Preoperative assessment should identify whether symptoms of an acute attack are present. In the absence of an acute attack, the anesthetic prescription should consist of nonporphyrinogenic drugs. Details, as well as additional measures to minimize the risk of an acute attack, are discussed later. If the preoperative assessment suggests an acute attack of porphyria, both symptomatic and specific therapies should be instituted in an appropriate inpatient setting.

Acute Attack of Porphyria in the Perioperative Period Therapy for acute attacks of porphyria consists of three interventions: (1) administration of hematin and (2) administration of glucose, both of which inhibit δ-aminolevulinic acid synthase and thus correct the metabolic abnormality; and (3) identification and removal of the precipitating factor to decrease enzyme induction. Hematin (Panhematin, Ovation Pharmaceuticals, Deerfield, Ill) contains alkaline heme from processed human red blood cells. It is a lyophilized powder that is best reconstituted in albumin to form a stable solution and minimize thrombophlebitis and anticoagulation. Depending on the severity of an attack, hematin is given at a dose of 3 to 4 mg/kg for up to 4 days. Hematin replenishes the hepatic heme pool and normalizes the activity of the heme synthesis pathway by providing negative feedback (see Fig. 20-1). Given the mortality risk and the potential for severe or protracted neurologic symptoms with acute attacks of porphyria, hematin therapy should be initiated as early as possible. Glucose, at a dose of 300 to 400 g/day, is less effective than hematin but has been shown to decrease the excretion of porphyrin precursors. Furthermore, fasting and lowcarbohydrate diets can precipitate acute attacks. Although glucose is effective when administered enterally, the nausea and decreased intestinal motility accompanying an acute attack make parenteral administration more feasible. Finally, identification and removal of precipitating factors should include a careful assessment of the patient’s drug therapy to determine the safety implications of such drugs in a patient with suspected acute porphyria (Table 20-3). Given that the causes of an acute attack may be multifactorial, complete removal of all precipitating factors may not be possible. Supportive therapy focuses on the symptoms associated with the attack. Pain is treated with opiates, and electrolyte imbalances are corrected. Cranial nerve involvement may require aspiration prophylaxis, whereas involvement of respiratory muscles may require mechanical ventilation or close monitoring in an intensive care unit. Seizures present a particular challenge because barbiturates, phenytoin, and some other antiseizure drugs are potent triggers for an acute attack. Hyponatremia should be excluded as a cause of seizures, and midazolam or clonazepam can be used safely to stop seizure activity.

Table 20–3

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Unsafe/Avoid Barbiturates Etomidate Phenytoin Valproic acid Succinimides Pyrazolones Clindamycin Erythromycin Doxycycline Sulfonamides Amiodarone

Safety of Drugs in Patients with Acute Porphyria Use with Caution/ Avoid Ketorolac Macrolides Tetracyclines Quinolones Hydralazine Calcium channel blockers

Probably Safe Opiates Neuromuscular blockers Glycopyrrolate Atropine Neostigmine Naloxone Midazolam Flumazenil Nitrous oxide Halothane Local anesthetics Procainamide β-Blockers Scopolamine Diphenhydramine Chlorpromazine

This list is incomplete, and unlisted drugs cannot be assumed to be safe. These categories are intended to provide guidance and not to replace the clinical judgment of the prescribing physician. Some drugs are categorized based on clinical experience, irrespective of the presence or absence of warnings in the package insert. Porphyrics should be treated with the minimum number of drugs necessary.

Anesthetic Management of Patients with Acute Porphyria Assessment of the safety profile of drugs in porphyria is difficult. On the one hand, drugs are the most frequent precipitating factor of acute attacks. On the other hand, not every exposure of susceptible patients to porphyrinogenic drugs results in an acute attack. Information about drug safety in porphyria is derived from three sources, listed in order of decreasing clinical applicability: (1) actual human cases that suggest a temporal or causal relationship, (2) animal models of induced porphyria, and (3) cell culture. The last two sources tend to overstate the risks to patients and frequently provide conflicting information.2 Volatile anesthetics, for example, are porphyrinogenic in animal models, but clinical experience with halothane and isoflurane suggests that they are safe to use. Many drugs can be used with caution, provided they are indicated and the potential benefits outweigh the risks. The anesthetic plan for patients with porphyria should avoid agents that are known to precipitate acute attacks (see Table 20-3). For general anesthesia, propofol is considered the induction agent of choice, whereas barbiturates and etomidate should be avoided. Muscle relaxants and opioids are safe. As stated earlier, volatile agents appear safe, although data on sevoflurane and desflurane are limited. Local and regional anesthesia can be used safely in patients with porphyria, but during an acute attack, autonomic instability, psychiatric symptoms, weakness, and hypovolemia

2 More detailed drug information and lists of safe and potentially unsafe drugs can be found on the following Web sites: http://web.uct.ac.za/depts/porphyria/professional/prof%20index.htm and http://www.porphyries.com.fr.

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PREVENTION Perioperative prevention of acute attacks in patients with acute porphyria requires careful planning and good communication among all caregivers. Admission on the night before surgery allows prophylactic administration of glucose, thus minimizing the impact of the preoperative fast. Reassurance and premedication can relieve anxiety and stress. Drug administration should be minimized, and each drug should be assessed for its risk of precipitating an acute attack. Because a delayed porphyric crisis may develop 3 to

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5 days after the precipitating event, discharge instructions should stress the symptoms of a porphyric crisis as reportable postoperative complaints. The workup for symptoms should include screening for and quantification of the urinary porphyrin precursors δ-aminolevulinic acid and porphobilinogen. Such an integrated approach allows for the safe conduct of surgery in patients with acute porphyria.

Further Reading Dover SB, Plenderleith L, Moore MR, et al: Safety of general anesthesia and surgery in acute hepatic porphyria. Gut 35:1112-1115, 1994. Elder GH, Hift RJ, Meissner PN: The acute porphyrias. Lancet 349:1613-1617, 1997. Harrison GG, Meissner PN, Hift RJ: Anesthesia for the porphyric patient. Anaesthesia 48:417-421, 1993. James MFM, Hift RJ: Porphyrias. Br J Anaesth 85:143-153, 2000. Palmieri C, Vigushin DM, Peters TJ: Managing malignant disease in patients with porphyria. Q J Med 97:115-126, 2004.

PHARMACOLOGY

may present relative contraindications. Clinical experience suggests that both amide- and ester-type local anesthetics are safe, even though lidocaine increases δ-aminolevulinic acid synthase activity in tissue culture.

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Ketamine Lisa Thannikary and Bhiken Naik Case Synopsis A 68-year-old man is brought to the operating room emergently for exploratory laparotomy after suffering a gunshot wound to the abdomen. He is tachycardiac with a heart rate of 114 beats per minute and hypotensive with a blood pressure of 86/47 mm Hg. He was resuscitated with 2 L of crystalloid in the emergency room. Although he was not intubated, he was unable to give any history owing to acute ethanol intoxication. A rapid-sequence induction with cricoid pressure is performed with intravenous ketamine (3 mg/kg) and succinylcholine (1.5 mg/kg). Intubation occurs without difficulty. Following intubation, the patient’s blood pressure decreases precipitously to 65/33, and an ST segment depression of 2 mm is noted in lead V5. The patient is treated with intravenous fluids and ephedrine, with minimal improvement in blood pressure. A transesophageal echocardiogram shows decreased myocardial contractility.

PROBLEM ANALYSIS Definition Ketamine is a phencyclidine derivative used for the induction of anesthesia; it provides anterograde amnesia as well as intense analgesia. It is the only induction agent that stimulates the sympathetic nervous system centrally, which can lead to an increase in blood pressure and heart rate of approximately 30% from baseline values. These hemodynamic effects are seen after 3 to 5 minutes of intravenous injection and slowly decrease to predrug levels after about 20 minutes. The cardiovascular stimulating effects can be blunted by the prior administration of benzodiazepines or concomitant use of inhalation agents. The mechanisms for the increase in hemodynamic variables are complex. Ketamine is believed to stimulate the central nervous system directly, leading to increased sympathetic outflow. Increased plasma levels of epinephrine and norepinephrine that occur after injection of the drug are also believed to play a role in increasing the heart rate and blood pressure. Ketamine has direct negative inotropic effects, however, that are usually overshadowed by the sympathetic stimulation. These negative inotropic effects are usually seen with depletion of endogenous catecholamine stores or with exhaustion of the sympathetic nervous system compensatory mechanisms in patients who are critically ill or in shock.

Recognition If a patient has an attenuated or blunted response to an induction dose of ketamine, the possibility of depleted catecholamine stores or exhausted sympathetic nervous system compensatory mechanisms, with unmasking of the direct myocardial depressant effects of ketamine, must be considered.

Risk Assessment Clinical scenarios in which the negative inotropic effects of ketamine can be unmasked include the following: ● ●

Prolonged critical illness Uncompensated shock

78

● ● ● ●

Inadequate volume resuscitation Underlying ischemic heart disease Chronic β-blocker therapy Cocaine use

Implications Ketamine antagonizes N-methyl-D-aspartate receptors. It also interacts with μ, δ, and κ opioid receptors, as well as with monoaminergic receptors, muscarinic receptors, and voltage-sensitive calcium channels. It produces dissociative anesthesia resembling a cataleptic state in which the patient is noncommunicative but appears awake. Because ketamine is a phencyclidine derivative, emergence delirium is possible, but this can be reduced with concomitant use of benzodiazepines. Ketamine has a rapid onset of action, a relatively short duration of action, and high lipid solubility. It does not bind significantly to plasma proteins and is initially distributed to highly perfused tissues, such as the brain. Ketamine rapidly crosses the blood-brain barrier owing to its high lipid solubility. Ketamine’s pharmacokinetic characteristics (Table 21-1), coupled with its sympathomimetic effects, make it an ideal induction agent for patients who are hemodynamically unstable.

Table 21–1

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Pharmacokinetic Properties of Intravenous Ketamine

Parameter

Value

pKa Protein binding (%) Distribution half-life (min) Distribution volume at steady state (L/kg) Clearance (mL/kg/min) Elimination half-life (hr) Breakdown product

7.5 12 11-16 2.5-3.5

Elimination

12-17 2-4 Norketamine (20%-30% potency of ketamine) Renal

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Ketamine

79

PREVENTION

MANAGEMENT

It is important to recognize risk factors that may lead to hypotension with the use of ketamine. In these patients, an alternative induction agent should be used.

Before induction of anesthesia, anesthesiologists should attempt to identify patients who might be at risk for developing a hypotensive response to ketamine. Patients with hypovolemic or hemorrhagic shock should be volume-resuscitated before induction, if possible. Invasive monitoring, including central venous pressure, pulmonary artery catheter, or transesophageal echocardiography, can be used in the perioperative period to optimize filling pressures and contractility. If the patient remains hypotensive after induction—despite adequate fluid resuscitation—an inotropic agent or pressor (or both) may be needed to ensure adequate perfusion pressure to the vital organs. The optimal inotropic agent in these patients is a direct-acting sympathomimetic, such as epinephrine or norepinephrine.

Further Reading Reich DL, Silvay G: Ketamine: An update on the first 25 years of clinical experience. Can J Anaesth 36:186-197, 1989. Rogers RJ: Intravenous anesthetic agents. In Kirby RR, Gravenstein N, Lobato EB, et al (eds): Clinical Anesthesia Practice. Philadelphia, WB Saunders, 2002, pp 636-637. Stoelting RK: Nonbarbiturate induction drugs. In Stoelting RK (ed): Pharmacology and Physiology in Anesthetic Practice. Philadelphia, Lippincott-Raven, 1999, pp 148-155. Tweed WA, Minuck MS, Mymin D: Circulatory response to ketamine anesthesia. Anesthesiology 37:613-619, 1972.

PHARMACOLOGY

Caution should be exercised, however, when using ketamine in the aforementioned high-risk patients.

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Nonbarbiturate Anesthetics Harshdeep Wilkhu, Kevin P. Chan, E. Price Stover, and John L. Atlee Case Synopsis A 53-year-old, 75-kg man with no significant past medical history or allergies is scheduled for a screening colonoscopy. During anesthetic induction he receives a bolus of propofol (80 mg) with additional propofol (170 mg) titrated in divided doses over the course of the procedure. The patient maintains spontaneous ventilation throughout the procedure. Upon completion of the procedure, the patient is responsive to verbal commands and is transferred to the recovery room. Ten minutes after arrival, the patient develops gross arrhythmic jerking of all limbs that appears to be a grand mal seizure.

PROBLEM ANALYSIS Definition In addition to ketamine (see Chapter 21), nonbarbiturate anesthetics include midazolam, etomidate, and propofol. Midazolam is more commonly used as a sedative-anxiolytic than as an intravenous (IV) anesthetic induction agent. Both etomidate and propofol are used as IV induction agents; the former is often preferred for patients with or at risk for hemodynamic instability.

Recognition MECHANISM

OF

ACTION

Midazolam is a benzodiazepine that increases the frequency of chloride channel opening by facilitating γ-aminobutyric acid (GABA) receptor binding, and it has an inhibitory effect on neural function. GABA is the principal central nervous system neuroinhibitory transmitter.

Table 22–1

■

Etomidate is an imidazole derivative. It inactivates the reticular activating system and may also increase GABA receptor availability. Propofol is an alkylphenol. It is presumed to act on GABA receptors in the central nervous system to increase the frequency of chloride channel opening. Thus, propofol too has a neuroinhibitory action. PHARMACOKINETICS Midazolam is water soluble in a buffered acid medium (pH = 3.5) and highly lipophilic at physiologic pH. Other pharmacokinetic data for propofol, etomidate, and midazolam are listed in Table 22-1. Etomidate is water soluble and is dissolved in 35% propylene glycol. Its short duration of action is the result of redistribution after an initial distribution time of 3 minutes. It is metabolized by the liver into inactive metabolites that are excreted by the kidneys (85%) and in the bile (13%). Age decreases its clearance, whereas in cirrhosis, clearance is normal but the volume of distribution and elimination half-time are doubled.

Pharmacokinetic Data for Propofol, Etomidate, and Midazolam Drug

Parameter

Propofol

Etomidate

Midazolam

Distribution half-life (min)

2-8

3-10

Elimination half-life (hr) Biotransformation Metabolites Excretion IV induction dose IV sedation dose IV maintenance dose

0.5-1.5 Hepatic; extrahepatic (lungs) Inactive Renal 1-2.5 mg/kg 10-75 μg/kg/min 50-150 μg/kg/min

Initial: 3 Late: 29 2-5 Hepatic Very weakly active Renal (85%); bile (13%) 0.2-0.5 mg/kg 5-8 μg/kg/min 10 μg/kg/min (with N2O-opiate)

80

1-4 Hepatic Inactive Renal 0.1-0.2 mg/kg 0.5-1 mg incremental dosing 0.05-0.1 μg/kg/min

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HEMODYNAMIC

AND

OTHER EFFECTS

Midazolam has little effect on hemodynamic parameters (Table 22-2). At a dose of 0.2 mg/kg, midazolam appears to be safe in patients with cardiovascular disease. Any increase in heart rate is likely a reflex-caused response to modestly decreased stroke volume and blood pressure, with reduced sympathetic tone secondary to anxiolysis. Hypovolemia accentuates these effects. In contrast, midazolam can cause apnea and decrease the ventilatory response to carbon dioxide (CO2), especially after bolus dosing. Also, midazolam is commonly given with an opiate (e.g., fentanyl, alfentanil) for sedation in the preoperative or ambulatory surgery holding area. Such opiates potentiate midazolam’s effect on respiration, so patients receiving this combination of drugs must be closely monitored for signs of respiratory insufficiency. Etomidate does not affect sympathetic activity or baroreflex function. It confers reliable hemodynamic stability in patients with or without cardiac disease. The myocardial oxygen (O2) supply-demand ratio is maintained. A slightly negative inotropic effect occurs with its solvent (propylene glycol), which likely explains any observed hemodynamic changes (see Table 22-2). In hemorrhagic shock models,

Table 22–2

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Nonbarbiturate Anesthetics

etomidate is associated with increased survival compared with thiopental. However, some studies suggest that the cardiovascular depression with etomidate is similar to that with propofol. Finally, etomidate is less likely to cause apnea or decrease the ventilatory response to CO2 than is midazolam. Propofol has potent cardiovascular depressant effects. It decreases mean arterial pressure by as much as 40% due to myocardial depression and vasodilatation. Preload and afterload are reduced secondary to decreased venous return and systemic vascular resistance, respectively. This is brought about by propofol’s action to reduce sympathetic tone and directly relax vascular smooth muscle. However, the myocardial O2 supply-demand balance is maintained. Propofol also impairs the vasoconstrictor reflex in acute hemorrhage. Propofol has neuroexcitatory side effects that range from mild, involuntary myoclonic limb movements to grand mal seizures; their timing is quite variable and may occur with induction, in the recovery room, or even many days afterward. However, most neuroexcitatory events related to propofol occur during induction or emergence from anesthesia, when both plasma and cerebral concentrations of the drug are in a dynamic state of flux. They also occur in a variety of scenarios: lengthy or short, major or minor surgical procedures; with or without a prior history of neurologic events.

Risk Assessment When choosing a nonbarbiturate anesthetic for short outpatient procedures, there are several options, including midazolam, etomidate, propofol, and ketamine (see Chapter 21). The most commonly used drug is propofol, owing to its rapid onset of action and recovery and lack of serious side effects. However, when choosing among these nonbarbiturates as IV induction agents, one must consider whether any of the following is present or possible: ● ●

Hypovolemia or circulatory shock Cardiovascular disease

Hemodynamic, Respiratory, and Other Effects of Propofol, Etomidate, and Midazolam Drug

Parameter

Propofol

Etomidate

Midazolam

Heart rate Mean arterial pressure Systemic vascular resistance Mean pulmonary artery pressure Cardiac index Stroke volume Myocardial contractility Apnea Ventilatory response to CO2 Bronchodilatation Nausea and vomiting Analgesia Pain on injection

↓ ↓↓ ↓↓ 0 ↓↓ ↓↓ 0/↓ ↑↑↑ ↓↓↓ + in COPD Decrease Minimal Severe

0/↑ 0/↓ 0/↓ 0/↑ 0/↑ 0/↓ 0/↓ ↑ ↓ 0 Increase Minimal Possible

0/↑ 0/↓ 0/↓ 0 0/↓ 0/↓ 0/↓ ↑↑ ↓↓ 0 Minimal Minimal Minimal

COPD, chronic obstructive pulmonary disease.

81 PHARMACOLOGY

Propofol is highly lipophilic and is formulated in a soybean oil–egg yolk–lecithin emulsion. Pharmacodynamic properties of propofol are dependent on the plasma concentration of the drug. The induction dose of propofol in adults is 1 to 2.5 mg/kg, producing blood concentrations of 2 to 6 μg/mL. Awakening is rapid even after prolonged infusions and typically occurs at plasma concentrations of 1.0 to 1.5 μg/mL. Steady-state propofol blood concentrations are generally proportional to infusion rates. The context-sensitive half-time of propofol is minimally influenced by infusion duration, owing to rapid metabolic clearance. Biotransformation occurs in the liver. Clearance exceeds hepatic blood flow, suggesting the existence of extrahepatic metabolism. Metabolites are secreted in the urine. Hepatic or renal dysfunction does not reduce the clearance of the parent drug.

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Respiratory insufficiency Central nervous system injury or impairment Hepatic or renal impairment and any related pharmacokinetic implications Drug interactions Full stomach or history of acid reflux

MIDAZOLAM As earlier noted, midazolam has minimal adverse cardiovascular effects and appears to be safe in patients with coronary or heart disease (at doses of 0.2 mg/kg); however, it has the potential to aggravate respiratory insufficiency (see Table 22-2). Other considerations include the following: ●

●

●

●

●

●

Hepatic biotransformation with inactive metabolites; renal excretion Slight reduction in cerebral O2 consumption, with little or no decrease in cerebral blood flow Small decrease in intracranial pressure (ICP); small increase in seizure threshold Maintains cerebral autoregulation; large decrease in intraocular pressure (IOP) Slower loss of consciousness and longer recovery period for return of cognitive functions Potential for coughing, hiccups, or involuntary skeletal muscle movements when used for induction of anesthesia

ETOMIDATE Etomidate has generally supportive and beneficial effects on both cardiovascular and cerebral function. However, as noted earlier, there is a slightly negative inotropic effect with its solvent (propylene glycol). Etomidate has minimal effects on ventilation and does not trigger histamine release. It is not an analgesic. Similar to the effects of midazolam, coughing, hiccups, or involuntary skeletal muscle movements (nonepileptogenic) may occur if etomidate is used for anesthetic induction. Although grand mal seizures have occurred with etomidate, it induces electroencephalographic burst suppression at high doses. Other considerations are the following: ● ● ●

●

●

● ●

●

Increased incidence of nausea and vomiting Irritation at peripheral vein injection site Clinically significant adrenocortical inhibition with prolonged infusions May reduce IOP, but this is counteracted by myoclonus, mydriasis, or coughing Unlikely to cause apnea or impair the ventilatory response to CO2 Hepatic metabolism; inactive metabolites; renal elimination Initial distribution half-life of 3 minutes and redistribution half-life of about 30 minutes Elimination half-life of 3 to 5 hours

inotropic effects are due to reduced myocardial intracellular calcium availability, caused by Ca2+ influx inhibition. Overall, propofol decreases sympathetic more than parasympathetic activity, leading to parasympathetic dominance. Propofol produces dose-dependent respiratory depression that acts in synergy with opioids and benzodiazepines. Further, it has a high potential to impair the ventilatory response to CO2 and cause apnea (see Table 22-2). Continuous infusions reduce both the tidal volume and the frequency of breathing; opiates potentiate this effect. Propofol has a bronchodilating effect, and it decreases the intraoperative incidence of bronchospasm with reactive airways disease. In February 2001 the Food and Drug Administration noted that abrupt discontinuation of propofol after prolonged infusion may result in agitation, tremulousness, and hyperirritability in pediatric patients. This led to a pediatric exclusivity labeling change: propofol is not indicated for prolonged use in the pediatric intensive care unit. Other effects to consider are the following: ●

●

● ●

●

●

●

●

Coughing, hiccups, and involuntary skeletal muscle movements with induction Vein irritation and pain on injection (lidocaine helps reduce this, but slow, incremental, “desensitizing” injections are more reliable)1 Antiemetic, antipruritic, and anxiolytic properties Reports of delayed seizures, hallucinations, and opisthotonos Formerly, anaphylactic reactions and bacterial growth were possible with the lipid solvent (less of a problem with the current formulation) Hepatic and possible extrahepatic biotransformation, with inactive metabolites and renal (85%) and bile (13%) excretion Reduction in cerebral O2 consumption, blood flow, and ICP and IOP No effect on seizure threshold, and not an analgesic

Implications The delayed onset of neurologic excitatory events (especially with etomidate or propofol) has serious implications for ambulatory surgery (outpatient) anesthesia practice. When patients are discharged home 1 to 2 hours after surgery or other procedures, they are at serious risk of harm to themselves or others. The patient or family can be traumatized during a seizure, and loss of the airway during this event can have dire consequences. Adverse neurologic sequelae also increase health care costs because many of these patients must be admitted to an intensive care unit to rule out serious pathology and undergo costly diagnostic studies (e.g., magnetic resonance imaging, computed tomography, electroencephalography). In addition, consultant care may be requested for these events.

PROPOFOL Propofol reduces systemic blood pressure by vasodilatation and negative inotropic effects. The inhibition of efferent sympathetic activity results in vascular smooth muscle relaxation and blood pressure reduction. Propofol’s negative

1 We have found that 1-, 2-, and 3-mL “desensitizing” increments of propofol spaced 30 to 45 seconds apart, followed by an IV “push” of the remaining induction dose, are effective at reducing the discomfort associated with propofol induction. Lidocaine (50 mg) can be either mixed with or given before propofol.

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Chapter 22

MANAGEMENT Selection of an appropriate nonbarbiturate IV induction agent must take the following issues into consideration: ●

Hypovolemia or hypotension due to hemorrhage ● Restore intravascular volume (preload) and use blood or blood products as needed. ● Optimize ventilation and oxygenation. ● Restore acid-base balance. ● Consider the use of vasoactive drugs. ● Initiate invasive monitoring, transesophageal echocardiography, or both, if needed. ● Choose a nonbarbiturate anesthetic and method of delivery according to the aforementioned considerations.

●

Airway management ● Use awake intubation followed by an IV induction agent or inhalational anesthetic. ● Assess the need for rapid or modified rapid-sequence intubation.

●

Increased ICP ● Choose an IV induction agent accordingly (propofol or etomidate decreases ICP). ● Consider hypocapnia, mannitol, and corticosteroids (see also Chapters 174 and 182).

Neuroexcitatory Events Initially, no treatment may be necessary because the majority of neuroexcitatory events resolve spontaneously. Benzodiazepines are the drugs of choice for events that do not resolve spontaneously. They depress spinal reflexes and reduce the spontaneous electrical activity in all regions of the brain and spinal cord. All benzodiazepines elevate the seizure threshold and thus are considered anticonvulsants. These drugs are quite safe and are rarely fatal, unless taken concomitantly with other sedatives. Second-line therapy for neuroexcitatory events is a barbiturate. This family of drugs depresses the activity of all excitable central nervous system tissue. In general, barbiturates possess a low therapeutic index, along with low selectivity. Hence, they must be dosed cautiously.

PREVENTION Avoidance of complications with nonbarbiturate IV induction agents requires attention to the following issues: ●

●

Hypovolemia and Airway Management

Increased Intracranial or Intraocular Pressure Midazolam, etomidate, and propofol exert a beneficial decrease in ICP, in contrast to ketamine, which increases

83

ICP and can produce emergence delirium. However, slower emergence with midazolam can hinder early postoperative neurologic assessment. Both midazolam and propofol decrease IOP. Etomidate has the same effect, but it can be counteracted by myoclonic activity, mydriasis, and cough caused by etomidate. Ketamine increases IOP.

●

Resuscitation begins with securing a compromised airway, optimizing O2 delivery, restoring intravascular volume, and correcting acidosis. A rapid-sequence induction is usually necessary to minimize the risk of aspiration. In the case of a difficult airway or an unstable cervical spine, awake intubation is indicated in a cooperative patient. The choice of an IV anesthetic is dictated by its cardiovascular, cerebrovascular, and pharmacokinetic effects (see Tables 22-1 and 22-2). Of the agents discussed here, etomidate is probably the safest agent for patients with significant hypovolemia or blood loss. However, regardless of which agent is selected, its dose must be reduced in the presence of significant hemorrhage or reduced intravascular volume, because either of these conditions will increase the amount of drug delivered to the heart or brain due to redistribution of blood flow to vital organs.

Nonbarbiturate Anesthetics

●

Volume repletion and administration of blood or blood products, if indicated Appropriate selection of the IV anesthetic induction agent. Consider time of onset and emergence, amnesia, analgesia, coronary and cerebral perfusion, systemic blood pressure, myocardial and cerebral O2 consumption, onset of apnea, and effects on ICP and IOP. Slow titration and adjustment of induction doses. Careful titration to effect generally prevents abrupt, deleterious changes in blood pressure, unless a rapid-sequence induction is indicated. If so, a vasopressor may be needed for the patient to tolerate the induction. Doses of IV induction agents should be adjusted based on the patient’s age, ideal weight, and hepatic and renal function. Side effects of and relative contraindications to the various IV anesthetic induction agents

For the patient described in the case synopsis, prevention of future neuroexcitatory events suggests that propofol (or etomidate) should not be administered to him in the future. This advice might also apply to patients with a history of neuroexcitatory events. However, no single diagnosis or combination of diagnoses has been implicated as the cause of such events. The seeming rarity of major neuroexcitatory events with administration of propofol or etomidate, along with the lack of reported long-term adverse sequelae, has resulted in their continued use in ambulatory and inpatient settings, especially propofol. The overall risk-benefit ratio for propofol is extremely low, and the decision whether to use the drug should not be based on reports of rare associated neurologic phenomena.

PHARMACOLOGY

Patients with cardiovascular disease or hypovolemia are at increased risk for cardiovascular collapse and myocardial ischemia or infarction after IV anesthesia induction (greatest risk with propofol, followed by midazolam and then etomidate). Hemorrhagic shock results in lactic acidosis, and hepatorenal lactate clearance must be maintained. End-organ perfusion in general must be preserved. Also, the risk of irreversible brain or ocular injury must be carefully evaluated during the selection of a rapid IV induction agent.

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Further Reading Dearlove JC, Dearlove OR: Cortical reflex myoclonus after propofol anaesthesia. Anaesthesia 57:834-835, 2002. Reves JG, Glass PSA, Lubarsky DA, et al: Intravenous nonopioid anesthetics. In Miller RD (ed): Miller’s Anesthesia, 6th ed. Philadelphia, Churchill Livingstone, 2005, pp 317-378.

Strachan AN, Raithatha HH: Propofol myoclonus. Can J Anaesth 43:536-537, 1996. Sutherland MJ, Burt P: Propofol and seizures. Anaesth Intensive Care 22:733-737, 1994. Walder B, Tramer MR, Seeck M: Seizure-like phenomena and propofol: A systematic review. Neurology 58:1327-1332, 2002.

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ANESTHETIC ADJUNCTS

23

Succinylcholine Eugene B. Freid Case Synopsis A 32-year-old woman undergoes emergent open reduction of bilateral femoral fractures sustained in a fall. Past history is pertinent only for mild, hemiparetic, static encephalopathy as a result of meningitis in infancy. Rapid-sequence induction of anesthesia with 20 mg of etomidate and 80 mg of succinylcholine is uneventful. At the end of the 2-hour procedure, she is clinically weak, with four diminished twitches and moderate fade on a train-of-four. She is extubated 1 hour after completion of surgery. Evaluation reveals a pseudocholinesterase activity of 95% and a dibucaine number of 25, which is consistent with an abnormal genetic variant of pseudocholinesterase.

PROBLEM ANALYSIS Definition The onset and offset characteristics of succinylcholine provide distinct advantages over other neuromuscular blocking drugs. Unfortunately, succinylcholine also has a number of well-described complications related to its mechanism of action or pharmacokinetics or that occur as an idiosyncratic effect (Table 23-1). Observations show that hyperkalemia and cardiac arrest develop soon after succinylcholine administration to patients with thermal injury, trauma, upper and lower motor neuron injuries, and various myopathies (Table 23-2). Prolonged relaxation may occur after succinylcholine administration because of the development of a phase II blockade or decreased metabolism. After a single large dose, repeated doses, or a prolonged continuous infusion of succinylcholine, the postjunctional receptor may not respond

normally to acetylcholine, even after the receptor-nicotinic channel has repolarized. This is termed a phase II block and is preferred to the terms dual block and nondepolarization block because phase II block does not imply a specific mechanism. Under normal circumstances, the short duration of the effect of succinylcholine is the result of rapid hydrolysis by pseudocholinesterase. Ninety percent of an intravenous dose of succinylcholine is rapidly hydrolyzed to a nearly inactive metabolite in the plasma and liver by pseudocholinesterase. Neuromuscular blockade terminates by the diffusion of succinylcholine from the end plate into the extracellular fluid because there is no pseudocholinesterase at the motor end plate. Pseudocholinesterase influences the onset and duration of action by controlling the rate of hydrolysis in plasma. A prolonged duration of succinylcholine neuromuscular block may occur when quantities of normal pseudocholinesterase are decreased or when an atypical or abnormal variant of pseudocholinesterase is present.

˜

Table 23–1

■

Complications of Succinylcholine Administration

Cardiovascular Tachycardia (ganglionic stimulation) Bradycardia, sinus arrest, junctional rhythm Hyperkalemia Fasciculations; myalgia* Myoglobinuria, elevated plasma creatine phosphokinase Sustained muscle contraction (myotonic dystrophy, congenital myotonia) Malignant hyperpyrexia Masseter muscle rigidity Prolonged relaxation Phase II block Inadequate pseudocholinesterase activity Increased intraocular pressure* Increased intracranial pressure Increased intragastric pressure* Histamine release

Table 23–2

■

Conditions Predisposing to Exaggerated Potassium Release with Succinylcholine

Thermal injury Traumatic injury Neurologic disease Spinal cord trauma Hemiparesis, lower motor neuron lesions Multiple sclerosis Stroke Guillain-Barré disease Encephalitis Central nervous system trauma Myopathy, muscular dystrophy Disuse atrophy Tetanus

*May be reduced with succinylcholine pretreatment (defasciculation).

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Recognition T-wave elevation, QRS complex prolongation and a sinusoidal QRS waveform (see Chapter 14, Fig. 14-2), and arrhythmias (ventricular tachycardia or fibrillation) occurring shortly after succinylcholine administration are the characteristic alterations seen on the electrocardiogram (ECG) in patients with hyperkalemia and exaggerated potassium (K+) release. Measurement of serum K+ concentrations confirms hyperkalemia. However, if the ECG is abnormal, treatment should precede confirmation of serum K+ concentrations. Prolonged relaxation after succinylcholine is indicated by apnea and neuromuscular weakness or paresis. The diagnosis is confirmed by characteristic findings on peripheral nerve stimulation, including a train-of-four (T4/T1) of less than 0.3 and the presence of fade and post-tetanic facilitation. The presence of low levels of normal pseudocholinesterase, or atypical or abnormal forms of pseudocholinesterase, leads to variable prolongation of neuromuscular blockade (Table 23-3). The presence of abnormal pseudocholinesterase is frequently recognized only after moderately or very prolonged blockade occurs in an otherwise healthy patient who received a normal dose of succinylcholine. Nerve monitoring characteristics typical of a phase II block should be expected when abnormal pseudocholinesterase is present due to the large concentration of unmetabolized succinylcholine at the neuromuscular junction.

Risk Assessment POTASSIUM RELEASE Under normal conditions, depolarization of skeletal muscle occurs at acetylcholine receptors at the motor end plate. Fluxes in sodium (Na+) and K+ after succinylcholine typically lead to an increase in serum K+ concentrations of up to 0.5 mEq/dL. In a number of pathologic conditions, however, exaggerated K+ release following succinycholine causes plasma K+ concentrations to rise excessively (see Table 23-2). In patients with denervation states, up-regulation of acetylcholine receptors leads to muscle supersensitivity. In effect, the entire muscle membrane acts as a motor end plate.

Table 23–3

■

The increased zone of permeability to Na+ and K+ leads to exaggerated movement of these ions after the administration of succinylcholine and consequent increased efflux of K+ from the myocytes into the extracellular fluid. The timing of the development of exaggerated K+ release with succinylcholine administration depends on the nature of the injury and follows the timing of the development of acetylcholine receptor supersensitivity. Typically, it begins 5 to 15 days after thermal injury or trauma, peaks at 20 to 60 days, and persists for up to 3 months. In patients with upper and lower motor neuron disease, it begins at 7 days and persists for about 6 months. Pretreatment with a nondepolarizing relaxant does not reliably abolish the hyperkalemic response. In infants and children, myopathy may be clinically unapparent and may be diagnosed only after succinylcholine-hyperkalemic cardiac arrest. In contrast, patients with static encephalopathies (e.g., cerebral palsy) typically do not have exaggerated K+ release after succinylcholine, because their nervous system damage is remote and stable. PHASE II BLOCK Clinically relevant phase II block can occur with total succinylcholine doses as low as 4 mg/kg in some patients, with either repeat dosing or continuous infusions. Such block may be evident with tetanic stimulation in highly sensitive (“fine”) muscle groups (e.g., extraocular muscles) before it occurs in the larger muscles involved in respiration. Development of tachyphylaxis, which manifests as an increase in the amount of infused succinylcholine, often occurs concurrently with the development of clinically relevant phase II block. PSEUDOCHOLINESTERASE Low pseudocholinesterase activity occurs in the newborn and the elderly; with pregnancy, liver disease, malignancy, or thermal injury; and with the use of certain medications (glucocorticoids, estrogens, echothiophate, bambuterol, phenelzine, and cyclophosphamide) and organophosphate pesticides. Pseudocholinesterase levels may drop precipitously

Characteristics of Normal, Atypical, and Abnormal Pseudocholinesterase

Pseudocholinesterase Type

Genotype

Duration of Clinical Block

Homozygous normal Heterozygous dibucaine Heterozygous fluoride Heterozygous silent Dibucaine fluoride Dibucaine silent Fluoride silent Homozygous dibucaine (atypical) Homozygous fluoride Homozygous silent

Eu Eu Eu Ea Eu Ef Eu Es Ea Ef Ea Es Ef Es Ea Ea Ef Ef Es Es

Normal Slightly prolonged Slightly prolonged Slightly prolonged Moderately prolonged Very prolonged Moderately prolonged Very prolonged Slightly prolonged Very prolonged

Dibucaine No.

Fluoride No.

80 60 75 80 50 20 65 20 65 —

60 50 50 60 50 20 35 20 35 —

Adapted from Pantuck EJ, Pantuck CB: Prolonged apnea following succinylcholine administration. In Azar I (ed): Muscle Relaxants. New York, Marcel Dekker, 1987, pp 206-229.

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Succinylcholine

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medicine specialist for an occult myopathy should be performed.

Prolonged Block Treatment for prolonged relaxation includes ensuring an adequate airway and gas exchange until phase II block is no longer evident (neuromuscular function monitoring) and adequate muscle strength is present. Pure phase II block is reversible with anticholinesterase. However, the block caused by succinylcholine overdose or with atypical or abnormal pseudocholinesterase is mixed (phase I and phase II block). In this case, anticholinesterase therapy may lengthen the duration of phase I block. Most practitioners simply continue ventilatory support until the block wanes and muscle strength has returned to its baseline level. With prolonged block due to atypical or abnormal pseudocholinesterase, ventilatory support must be continued until muscle strength returns. Although banked blood and plasma contain active pseudocholinesterase, the risk associated with their transfusion outweighs the possible benefit of reversing prolonged block. Patients suspected of having atypical or abnormal pseudocholinesterase should be tested for pseudocholinesterase activity and type and made aware of their condition. There should be a note in the patient’s chart indicating an “allergy” to succinylcholine, and the patient should wear a MedicAlert bracelet.

Implications The consequences of succinylcholine-induced hyperkalemia include arrhythmias and cardiac arrest. Prolonged relaxation after succinylcholine requires airway management and mechanical ventilation (with sedation) until the neuromuscular weakness subsides. Patients with atypical or abnormal pseudocholinesterase also demonstrate prolonged metabolism of mivacurium and ester local anesthetics. Because red blood cell esterase hydrolyzes esmolol, its metabolism is unaffected in patients with atypical or abnormal pseudocholinesterase.

MANAGEMENT Hyperkalemia Ventricular tachyarrhythmias and fibrillation are treated with standard advanced cardiovascular life support protocols. In addition, hyperkalemia must be aggressively treated with hyperventilation, calcium salts (chloride or gluconate), sodium bicarbonate, and epinephrine. Hyperventilation, bicarbonate, and β-adrenergic receptor agonists help drive K+ intracellularly, and calcium reduces the cellular effects of high K+ concentrations in the heart. Milder degrees of hyperkalemia are treated with hyperventilation, calcium salts, sodium bicarbonate, and parenteral or inhaled β-adrenergic receptor agonist therapy (albuterol or terbutaline). Glucose and insulin can also be used, but because their effects are more delayed, they are not considered first-line therapy. For children with hyperkalemic cardiac arrest, a postoperative evaluation by a neurologist or physical and rehabilitation

PREVENTION One way to prevent complications with succinylcholine is to avoid it altogether, unless there is a compelling indication for or advantage to its use. This is especially true in young children, who might have clinically unapparent myopathies. Rarely, an unexpected hyperkalemic response may occur, but with the avoidance of succinylcholine in at-risk patients, this should be quite unusual. With the availability of short- and intermediate-acting nondepolarizing agents, the need for large doses or infusions of succinylcholine should be uncommon. If repeated doses or infusions of succinylcholine are used, keeping the total dose under 5 to 6 mg/kg will help. During the preoperative evaluation, a family history of prolonged weakness or delay in awakening from anesthesia should be elicited. There are some geographic regions in which pseudocholinesterase exists because of its hereditary nature. In these regions, preoperative laboratory screening for pseudocholinesterase activity may be useful.

Further Reading Goldhill DR, Martyn JA Jr: Succinylcholine-induced hyperkalemia. In Azar I (ed): Muscle Relaxants. New York, Marcel Dekker, 1987, pp 93-113. Jensen FS, Viby-Mogensen J: Plasma cholinesterase and abnormal reaction to succinylcholine: Twenty years’ experience with the Danish Cholinesterase Research Unit. Acta Anaesth Scand 39:150-156, 1995. Larach MG, Rosenberg H, Gronert GA, et al: Hyperkalemic cardiac arrest during anesthesia in infants and children with occult myopathies. Am J Anesth 24:241-247, 1997.

PHARMACOLOGY

after plasmapheresis. Low levels of normal pseudocholinesterase generally do not prolong succinylcholine block to a clinically significant degree; this occurs only when normal pseudocholinesterase activity is reduced by at least 75% (normal, 4.9 to 12 IU/mL). In contrast, in patients with genetically atypical or abnormal pseudocholinesterase, the delay in return of normal neuromuscular function can range from mild (10 to 15 minutes) to severe (2 to 4 hours), depending on the variant. The difference among normal, atypical, and abnormal pseudocholinesterase variants is shown in the laboratory with compounds (e.g., dibucaine, fluoride) that inhibit benzoylcholine hydrolysis by pseudocholinesterase. The most common forms of abnormal pseudocholinesterase are the dibucaine-resistant and atypical variants (Eu Ea and Ea Ea, respectively). The homozygous atypical form (Ea Ea) occurs in 1 in 3200 patients, and the heterozygous form (Eu Ea) occurs in 1 in 480 patients. Dibucaine inhibits benzoylcholine hydrolysis by normal pseudocholinesterase by more than 70%; it inhibits benzoylcholine hydrolysis by the atypical (Ea Ea) form by less than 30%. Other forms of pseudocholinesterase include fluoride-resistant variants and a “silent” variant that shows neither dibucainenor fluoride-induced inhibition. Table 23-3 summarizes the characteristics of normal, atypical, and abnormal pseudocholinesterase variants.

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Levano S, Ginz H, Siegemund M, et al: Genotyping the butyrylcholinesterase in patients with prolonged neuromuscular block after succinylcholine. Anesthesiology 102:531-535, 2005. Martyn JA Jr, White DA, Gronert GA, et al: Up-and-down regulation of skeletal muscle acetylcholine receptors. Anesthesiology 76:822-843, 1992. Pantuck EJ: Plasma cholinesterase: Gene and variations. Anesth Analg 77:380-386, 1993.

Pantuck EJ, Pantuck CB: Prolonged apnea following succinylcholine administration. In Azar I (ed): Muscle Relaxants. New York, Marcel Dekker, 1987, pp 206-229. Viby-Mogensen J: Correlation of succinylcholine duration of action with plasma cholinesterase activity in subjects with the genotypically normal enzyme. Anesthesiology 53:517-520, 1980.

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PHARMACOLOGY

Nondepolarizing Neuromuscular Relaxants ..

Maria A. K. Ohrn Case Synopsis Following emergence and extubation after general anesthesia, a 52-year-old woman with a history of chronic renal insufficiency has a labored breathing pattern, including paradoxical movement of the chest wall and abdomen and intermittent upper airway obstruction.

peripheral nerve stimulation for 5 seconds or more, evidence exists of significant block at the neuromuscular junction. To prevent the overaccumulation of NDMR at the neuromuscular junction, one must consider the following:

PROBLEM ANALYSIS Definition Prolonged (residual) neuromuscular relaxant blockade is due to the presence of a nondepolarizing muscle relaxant (NDMR) at the neuromuscular junction beyond its expected duration of action. Residual neuromuscular relaxant block must be sufficient to cause motor weakness in response to peripheral nerve stimulation or to cause clinical signs of impaired muscle function. Unrecognized, residual neuromuscular relaxant block may cause respiratory insufficiency or arrest. Under controlled circumstances, each NDMR is metabolized, excreted, or both at a rate that can be predicted based on its pharmacokinetic profile. Clinically, however, it is important to recognize that coexisting disease processes, intraoperative events, and some concurrent drug therapy may prolong the duration of action of all NDMRs.

Recognition

■

●

●

Coexisting diseases or conditions that may affect any particular NDMR’s route of elimination or metabolism Expected recovery times with low or high doses of NDMRs (Table 24-1) Routine monitoring of neuromuscular function with a peripheral nerve stimulator

With train-of-four (T1/T4) stimulation, titration of twitch responses, and knowledge of the usual recovery time for specific NDMRs, clinicians can detect early evidence of impaired drug metabolism or excretion.

Risk Assessment Whether by known, unknown, or postulated mechanisms, all the following agents can potentiate the actions of NDMRs: ●

After anesthesia, if the patient is unable to sustain a head lift for at least 5 seconds or has fade with 50-Hz tetanic Table 24–1

●

● ●

Antibiotics (especially aminoglycosides) Loop diuretics (e.g., furosemide) Magnesium sulfate

Approximate Recovery Time to Baseline Twitch Height with Nondepolarizing Muscle Relaxants (NDMRs) Dose Range (mg/kg)

Recovery Time from Low Dose* (min)

Recovery Time from High Dose* (min)

0.1 0.05-0.08

50-130 (mean 91)

40-60 74-268 (mean 177)

Long-acting NDMRs Pancuronium† Doxacurium

Intermediate-acting NDMRs Vecuronium Rocuronium Atracurium† Cisatracurium‡

0.10 0.6-1.2 0.5 0.15-0.20

28-65 (mean 46)

0.25

11-29 (mean 19)

15-85 (mean 31)

25-45 38-160 (mean 67) 20-45 31-103 (mean 59)

Short-acting NDMRs Mivacurium†

*Approximate duration of recovery based on package inserts and variability in manufacturers’ definitions of recovery. Unless otherwise specified, the value given is for recovery to 25% of twitch height. † Range for recovery time from high dose is that until a first maintenance dose is needed. ‡ Value for recovery to 5% of twitch height.

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Lithium salts Calcium channel blockers Quinidine or procainamide

Along with drugs that may potentiate NDMR actions, there are patient factors that impair the metabolism or excretion of NDMRs. Renal or hepatic insufficiency can alter the duration of action of some NDMRs (Table 24-2). Intraoperative temperature fluctuations and acid-base imbalance also affect the pharmacokinetic and pharmacodynamic properties of NDMRs, which can make their duration of action and effects unpredictable.

avoid subsequent recall of unpleasant events due to partial or complete paralysis. Unrecognized residual neuromuscular blockade can cause further complications. With partial block, patients may have insufficient motor strength to protect the airway, increasing the risk for pulmonary aspiration. This can also cause respiratory insufficiency, hypercarbia, and hypoxemia. Collectively, these conditions may cause hemodynamic instability, arrhythmias, or respiratory arrest.

MANAGEMENT Implications It is known that some NDMRs (e.g., D-tubocurarine, atracurium, cisatracurium, doxacurium, metocurine, mivacurium) may cause nonimmunologic histamine release. The magnitude of this response is species dependent (e.g., greater in cats than in rats or dogs) and varies with the dose, the rapidity of injection, and, in clinical situations, the individual patient. Although the response may at first appear anaphylactic, any histamine release is more direct (anaphylactoid), often self-limited, and easily managed with judicious use of short-lived vasoconstrictors to counter the associated vasodilatation. Recent studies indicate that NDMRs account for more than half of all anaphylactoid reactions during general anesthesia. NDMRs, collectively, cause more such reactions than any other class of drugs commonly given during general anesthesia. However, the incidence of true anaphylaxis during anesthesia is quite low (estimated at 1 in 5000 to 1 in 25,000 cases). Concerning other NDMR complications, if these are recognized early enough, prolonged block can be managed without incident. If not (e.g., those that occur at the end of anesthesia), the need for patient care and the health care costs increase. Prolonged block can also increase operating room times, especially if patients must be extubated before admission to the postanesthetic care unit, as required in some ambulatory surgery centers. With severe NDMR overdose, postoperative mechanical ventilatory support may be needed for some time. If so, the patient must be sedated to

Table 24–2

■

Use of smaller NDMR doses titrated to twitch, train-of-four, and tetanic responses and early recognition of prolonged NDMR block are important for expectant management. If prolonged recovery from the initial intubating NDMR dose is detected, the cause of the drug’s reduced elimination or potentiation must be sought and corrected, if possible. Alternatively, in longer cases, subsequent use of shorteracting NDMRs with a different route of elimination may help address the problem, assuming that the cause of reduced metabolism or elimination of the first drug is known. Even so, at least initially, the kinetics of the second NDMR will be more like those of a longer-acting agent. For example, changing from pancuronium (a long-acting drug) to mivacurium (a short-acting drug) will not immediately alter the pharmacokinetics to those of mivacurium. Instead, mivacurium’s duration of action will be more similar to that of pancuronium. Not until several pancuronium halflives have passed will the pharmacokinetics resemble those of mivacurium. Also, combining steroid-derivative NDMRs (identified by the suffix “curonium”) with benzylisoquinolonederivative NDMRs (identified by the suffix “curium”) may have an initial supra-additive effect on the duration of action. If prolonged neuromuscular block is not detected until the case’s conclusion, the patient is kept sedated with nitrous oxide or low-dose volatile inhalation anesthesia. If the patient continues to show weakness, even with evidence for adequate neuromuscular relaxant reversal by head lift or peripheral nerve stimulation, an amnestic is given while arrangements are made for postoperative ventilatory support

Routes of Metabolism or Elimination for Neuromuscular Blocking Agents Route

Drug

Renal

Hepatic

Ester Hydrolysis*

Hoffman Eliminationt†

Pancuronium Doxacurium Vecuronium Rocuronium Atracurium Cisatracurium Mivacurium

Major Major Minor Minor Negligible Minor Minor

Intermediate Major Major Major Negligible Minor Minor

Negligible Negligible Negligible Negligible Major Negligible Major

Negligible Negligible Negligible Negligible Major Major Negligible

All categories were derived from data on elimination and metabolism from package inserts. ∗Plasma (pseudo) cholinesterase. † Butyrylcholinesterase and spontaneous (nonenzymatic) degradation.

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While in the postanesthesia care unit, the patient should remain sedated until head lift or results of peripheral nerve stimulation indicate adequate recovery of motor strength. An unfortunate occurrence is the one described in the case synopsis. Apparently, the patient was not adequately assessed before extubation, so the clinician was confronted with a patient struggling to breathe. Prompt action was needed to ensure adequate oxygenation and ventilation, which could be achieved with a face or laryngeal mask, while preparing for reintubation. The patient did not need additional muscle relaxation for reintubation, but she did require an amnestic agent.

of direct muscle stimulation is acceptable, bearing in mind that there are slight differences in recovery times among the various muscle groups. For example, the diaphragm and pharyngeal muscles recover relatively more quickly than the other muscle groups. The train-of-four response, which is preferred for intraoperative monitoring, poorly predicts adequate recovery from blockade. For clinical recovery of respiratory muscle function to occur, the T4/T1 ratio should be at least 0.7. Experienced clinicians, however, are unable to detect any fade with T4/T1 ratios as low as 0.3. Therefore, many patients are still significantly weak, based solely on train-of-four responses. Selecting double-burst stimulation or 5-second, 50-Hz tetanus, combined with clinical signs, provides far greater sensitivity for the detection of residual block. Even with anticholinesterase therapy, the time to full recovery is dependent on full metabolism and elimination of the NDMR. Further, there may be active metabolites. If these or the parent drug have slow metabolism or elimination, the recovery time can be even more delayed.

PREVENTION

Further Reading

Preventing prolonged neuromuscular blockade begins with the selection of an appropriate NDMR. An understanding of the comorbidities affecting hepatic or renal elimination of various NDMRs will help clinicians choose one that is not overly dependent on the liver or kidneys for its metabolism or elimination. Continual intraoperative surveillance of the magnitude of neuromuscular block requires a peripheral nerve stimulator and documentation of the time course for recovery of twitch, double-burst, train-of-four, and tetanic responses. This allows early detection of block prolongation. Ideally, the train-of-four response is measured after induction of anesthesia, but before giving a neuromuscular relaxant, whether succinylcholine or an NDMR. The peripheral nerve stimulator must be tested for adequate battery voltage, and it should display the current (amperes) delivered to the patient. Ballelectrode, hand-held peripheral nerve stimulators are not as reliable as those secured at one site with electrode gel adhesive pads. Any monitoring site that avoids misleading effects

Bevan DR, Donati F: Muscle relaxants. In Barash PG (ed): Clinical Anesthesia, 2nd ed. Philadelphia, Lippincott-Raven, 1996, pp 481-508. Erkola O, Rautoma P, Meretoja OA, et al: Mivacurium when preceded by pancuronium becomes a long-acting muscle relaxant. Anesthesiology 84:562-565, 1996. Goudsouzian NG: Muscle relaxants in children. In Coté CJ, Todres ID, Goudsouzian N, Ryan J (eds): A Practice of Anesthesia for Infants and Children, 3rd ed. Philadelphia, WB Saunders, 2001, pp 196-215. Mertes PM, Laxenaire MC, Alia F: Groupe d’Etudes des Reactions Anaphylactoides Peranesthesiques. Anaphylactic and anaphylactoid reactions occurring during anesthesia in France in 1999-2000. Anesthesiology 99:536-545, 2003. Naguib M, Lien CA: Pharmacology of muscle relaxants and their antagonists. In Miller RD (ed): Miller’s Anesthesia, 6th ed. New York, Churchill Livingstone, 2005, pp 481-572. Nejman AM: Muscle relaxants. In Kirby R, Gravenstein N, Lobato E, Gravenstein J (eds): Clinical Anesthesia Practice, 2nd ed. Philadelphia, WB Saunders, 2002, pp 707-714. Plaud B, Debaene B, Lequeau F, et al: Mivacurium neuromuscular block at the adductor muscles of the larynx and adductor pollicis in humans. Anesthesiology 85:77-81, 1996. Viby-Mogensen J: Neuromuscular monitoring. In Miller RD (ed): Anesthesia, 4th ed. New York, Churchill Livingstone, 1994, pp 1345-1361.

● ●

●

Inability to sustain a head lift for at least 5 seconds Fade with 50-Hz tetanic stimulation lasting 5 seconds (the patient must be sedated, because this is extremely painful) Detectable difference in two responses elicited by doubleburst stimulation

PHARMACOLOGY

in the postanesthesia care unit. Evidence that a problem exists includes the following:

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Ali Habibi and Edward T. Riley Case Synopsis A 75-year-old man presents with acute urinary retention, tremors, blurred vision, and confusion. His past medical history is significant for allergic rhinitis, chronic renal failure, and hypertension. He is currently taking diphenhydramine and diltiazem.

Recognition

PROBLEM ANALYSIS Definition Antihistamines (H1-blockers) are a family of drugs used for hypersensitivity reactions of various types. Antihistamines are easily obtained, even without a prescription, but are not free of adverse side effects. Also, most first-generation H1-antagonists, such as diphenhydramine, inhibit muscarinic receptors to cause anticholinergic effects; the elderly are especially prone to these side effects of H1-blockers. Common side effects of first-generation antihistamines are sedation, confusion, tremors, blurred vision, diplopia, nervousness, insomnia, tinnitus, dry mouth, and dilated pupils. Second-generation H1-blockers (e.g., terfenadine, astemizole) can cause Q-T interval prolongation and torsades de pointes (see Chapter 81). H2-blockers can have significant effects on the hepatic metabolism of drugs and alcohol absorption.

Table 25–1

■

An overview of the side effects associated with antihistamines is provided in Table 25-1. A more detailed description of the physiology behind these effects follows. H1-BLOCKERS H1-receptor antagonists competitively inhibit the interaction of histamine with the H1-receptor, thereby inhibiting the vasodilator effects of histamine and preventing the occurrence of edema, flare, and wheal. H1-antagonists are taken primarily for acute allergies that present as rhinitis, urticaria, congestion, or conjunctivitis. However, H1-receptor antagonists may not oppose histamine-induced allergic bronchoconstriction, anaphylaxis, laryngeal edema, or angioedema. This is probably due to the involvement of other mediators (e.g., leukotriene, platelet-activating factor). H1-antagonists are well absorbed from the gastrointestinal tract, and they are metabolized by the hepatic microsomal

Adverse Reactions to Antihistamines First-Generation H1-Blockers

Second-Generation H1-Blockers

Cardiovascular

Tachycardia; no vasodilatation or vasoconstriction

Long Q-T interval; torsades de pointes

Nervous system

Adults: sedation, dry mouth, seizures, tremors, confusion Children: fixed, dilated pupils; flushed face; fever; possible coma Urinary retention; diarrhea, nausea, vomiting, constipation; no endocrine effects; allergic dermatitis (topical application)

Minimal

Reaction Type

Genitourinary, gastrointestinal, endocrine, skin, miscellaneous

Interactions

92

Potentiated by alcohol

Minimal genitourinary or endocrine effects; diarrhea or constipation

Potentiated by cytochrome P-450 inhibitors

H2-Blockers With rapid IV administration: decreased blood pressure, bradycardia, potential asystole Coma, headaches (famotidine), dizziness, drowsiness, confusion, seizures, agitation Transient ↑ serum creatinine; constipation or diarrhea; ↓ hepatic blood flow, gastric acidity; rare hepatotoxicity (ranitidine); gynecomastia; impotence (cimetidine); can facilitate bacterial infection Cimetidine inhibits cytochrome P-450; ↑ alcohol absorption

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H2-BLOCKERS Histamine binds to the H2-receptors located on the acidsecreting gastric parietal cells. This initiates a cascade that eventually increases the intracellular cyclic adenosine monophosphate (cAMP). Cyclic AMP activates the hydrogenpotassium pump, causing secretion of hydrogen ions. H2receptor antagonists are competitive inhibitors of histamine at H2-receptors, thereby reducing acid secretion. Currently there are several H2-blockers approved in the United States for the treatment of duodenal and gastric ulcer disease. They are all orally absorbed but have different degrees of bioavailability. Cimetidine and ranitidine are eliminated primarily by hepatic metabolism through cytochrome P-450 enzymes. Famotidine and nizatidine are primarily renally excreted.

Risk Assessment and Implications H1-BLOCKERS As noted earlier, the elderly are especially prone to the anticholinergic side effects of older H1-blockers. Urinary retention, confusion, hallucinations, tremors, dry mouth, and tachycardia may occur in older patients, even with moderate amounts of first-generation antihistamines. At higher doses, the central excitatory effects may cause convulsions. Concurrent ingestion of alcohol can potentiate the sedative effects of older H1-blockers. In contrast, second-generation H1-blockers have a minimal effect on muscarinic receptors. They do not cross the blood-brain barrier and thus have a less sedating effect. However, the second-generation H1-blockers (terfenadine, astemizole) can prolong the Q-Tc interval, which on rare occasion can cause polymorphic ventricular tachycardia. The latter in association with Q-Tc interval prolongation is known as torsades de pointes (see Chapter 81). Hepatic dysfunction or the coadministration of drugs that inhibit cytochrome P-450 (e.g., erythromycin, clarithromycin, ketoconazole, itraconazole) can also prolong the Q-Tc interval and trigger torsades de pointes. H2-BLOCKERS H2-blockers are relatively safe when the manufacturer’s prescribing guidelines are followed. Cimetidine inhibits cytochrome P-450. This can impair the metabolism and potentiate the actions of certain drugs (e.g., phenytoin,

Antihistamines: H1- and H2-Blockers

93

carbamazepine, quinidine, nifedipine, theophylline, warfarin, tricyclic antidepressants). Cimetidine and ranitidine inhibit the renal excretion of procainamide and its metabolite N-acylprocainamide to increase their plasma concentrations. Further, cimetidine, ranitidine, and nizatidine may potentiate the absorption of alcohol by inhibiting gastric alcohol dehydrogenase. Renal dysfunction can potentially increase the plasma levels of H2-blockers, which may contribute to a lower threshold for adverse effects.

MANAGEMENT Therapy for anticholinergic side effects of first-generation H1-blocking antihistamines is supportive. Each adverse effect must be addressed and treated separately. The drug causing the adverse side effects must be stopped immediately. With urinary retention, a Foley catheter should be inserted. If the patient has coronary artery disease or cardiovascular instability, tachycardia is treated with β-blockers or calcium channel blockers. The patient should be reassured about the transient central nervous system effects of diphenhydramine and closely monitored. Management for torsades de pointes with second-generation H1-blockers is discussed in Chapter 81.

PREVENTION Avoid giving antihistamines to patients at increased risk for their adverse side effects. First-generation H1-blockers should be avoided in the elderly. Patients receiving firstgeneration H1-blockers and H2-blockers should avoid alcohol. Second-generation H1-blockers should not be given to persons with Q-Tc interval prolongation; this advice may apply to those susceptible to ventricular tachyarrhythmias (or with a history thereof) as well, although there is no concrete evidence to back this recommendation. One must consider potential drug interactions (see Table 25-1), and doses should be adjusted on the basis of underlying renal or hepatic diseases.

Further Reading Feldman M: Pros and cons of over-the-counter availability of histamine-2 receptor antagonists. Arch Intern Med 153:2415-2418, 1993. Kosoglou T, Vlasses PH: Drug interactions involving renal transport mechanisms: An overview. Ann Pharmacother 23:116-122, 1989. Sax MJ: Clinically important adverse effects and drug interactions with H-2 antagonists: An update. Pharmacotherapy 7:110S-115S, 1987. Simons FER, Simons KJ: H1-receptor antagonist treatment of chronic rhinitis. J Allergy Clin Immunol 81:975-980, 1988. Simons FER, Simons KJ: The pharmacology and use of H1 receptorantagonist drugs. N Engl J Med 330:1663-1670, 1994. Woosley RL, Chen Y, Freiman JP: Mechanism of the cardiotoxic actions of terfenadine. JAMA 269:1532-1536, 1993.

PHARMACOLOGY

P-450 system. Most H1-antagonists induce hepatic microsomal enzymes to facilitate their metabolism. The metabolites, whether active or inactive, are renally excreted. The newer types of H1-receptor antagonists (secondgeneration or specific H1-blockers) were designed to eliminate the unwanted central nervous system and anticholinergic side effects of older H1-blockers.

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R. Victor Zhang Case Synopsis A 44-year-old woman presents for an abdominal incisional hernia repair. She is on several medications for hypertension, including oral clonidine (0.3 mg twice daily), which she did not take on the day of surgery. On preoperative examination, her blood pressure is 195/95 mm Hg, and her heart rate is 86 beats per minute. Surgery under general anesthesia proceeds uneventfully. On awakening, the patient has excellent pain control with narcotics, but her blood pressure has increased to 230/120 mm Hg, with a heart rate of 110 to 120 beats per minute. She is treated with intravenous (IV) boluses of labetalol and hydralazine and an IV infusion of esmolol. An IV bolus of clonidine 100 μg is also given but does not provide immediate hemodynamic improvement.

Mild respiratory depression Rebound hypertension on abrupt withdrawal

PROBLEM ANALYSIS

●

Definition

Hypotension and bradycardia during anesthesia are caused by the sympatholytic and anesthetic-sparing properties of α2-agonists. They often occur when dosages of other anesthetic agents and adjuncts are not properly adjusted in patients receiving α2-agonists. Transient hypertension after rapid IV injection of α2-agonists is due to direct binding with postsynaptic, vascular smooth muscle α2-adrenergic receptors. This causes vasoconstriction in peripheral resistance vessels via an endothelium-independent process. α2-Agonist-mediated respiratory depression is often mild, except at high doses or in association with other sedatives or narcotics. Rebound hypertension after abrupt cessation of α2-agonists is due to sympathetic hyperactivity. It occurs most often with clonidine, especially after prolonged use. It may produce a hypertensive crisis that is accompanied by other signs of sympathetic hyperactivity, such as nervousness, tachycardia, headache, and sweating.

The case synopsis typifies rebound hypertension after the abrupt withdrawal of clonidine in a patient with hypertension. The stress response associated with surgery under general anesthesia makes clonidine withdrawal more pronounced and difficult to control. Clonidine is a centrally acting α2-adrenoreceptor agonist (α2-agonist). It is commonly used by anesthesiologists and critical care physicians to treat patients with hypertension. In addition, it is used as a preanesthesia medication owing to its sedative, anxiolytic, hemodynamic, analgesic, antisialagogic, and anesthetic-sparing properties. A newer, more selective, and shorter acting α2-agonist, dexmedetomidine, has a similar pharmacologic profile to clonidine and is increasingly used in general anesthesia and intensive care settings. α2-Agonists reduce sympathetic tone, as well as plasma aldosterone and catecholamine concentrations and plasma renin activity. Perioperatively, these agents reduce heart rate, cardiac output, hypertension, and myocardial ischemia. They also improve survival in high-risk patients undergoing noncardiac surgery. Also, clonidine is used in conjunction with local anesthetics in neuraxial and peripheral nerve blocks to enhance and prolong analgesia. α2-Agonists are becoming more important as anesthetic adjuncts and analgesics. Clonidine is also used in therapy for withdrawal from alcohol, nicotine, and benzodiazepines, as well as in narcotic detoxification. Further, it has been used successfully in the treatment of migraine headaches, Tourette’s syndrome, attention-deficit disorder, premenstrual tension, and diabetic diarrhea. Perioperative use of α2-agonists is associated with adverse effects, including the following: ●

●

Increased incidence of hypotension and bradycardia during anesthesia Transient hypertension following rapid IV administration

94

●

Recognition Adverse effects of α2-agonists are related primarily to the extension of their pharmacologic activities, especially when compounded by the effects of anesthetics and anesthetic adjuncts. Thus, knowledge of potentially untoward perioperative physiologic effects is necessary for the recognition, management, and prevention of adverse effects of α2-agonists. These drugs exert their effects mainly via activation of presynaptic α2-adrenoreceptors in various locations in the central nervous system, especially within the brainstem. This results in a decreased efferent sympathetic outflow, with reduced blood pressure and heart rate, along with sedative, anxiolytic, and anesthetic-sparing effects that are often desirable during the perioperative period. Most adverse effects from α2-agonists are hemodynamic. In this case, early detection relies on close monitoring of blood pressure, heart rate, and electrocardiogram (ECG).

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Implications Bradycardia or hypotension from α2-agonists is usually mild. These conditions can be treated effectively with anticholinergics or positive chronotropes and therefore do not present serious problems. In contrast, severe bradycardia and hypotension are associated with a significant reduction in cardiac output and compromised perfusion to vital organs. Owing to the prevalence of hypertension and coronary artery disease in the elderly, these patients are at increased risk for myocardial and cerebral ischemia. Clonidine withdrawal is especially worrisome in the elderly. Rebound hypertension increases the risk of cerebral hemorrhage. Hypertension and tachycardia increase myocardial oxygen consumption, possibly leading to myocardial ischemia or infarction. Hypertension after rapid IV boluses of α2-agonists can be more pronounced in patients with hypertension. Although transient, this too increases the risk for adverse cardiovascular events. Mild sedation and respiratory depression can be well tolerated in healthy patients. However, those with hypertension or coronary artery disease are at increased risk for myocardial and cerebral ischemia.

Risk Assessment All α2-agonists cause sympatholysis, which results in decreased sympathetic outflow. Patients whose hemodynamic stability depends on increased sympathetic tone are at increased risk for severe hypotension with α2-agonists, especially those with anemia, hypovolemia, or heart failure. Patients with sinus node dysfunction or AV conduction delay or block are also at increased risk for severe bradycardia or complete AV block when treated with α2-agonists. Anesthetic adjuncts with sympatholytic properties, such as high doses of a potent narcotic, also increase the risk of bradycardia in patients receiving α2-agonists, especially during anesthesia induction. The risk of hypotension and bradycardia is also significantly increased if the anesthesiologist fails to take into account the anesthetic-sparing effect of α2-agonists and properly reduce the dose of IV or volatile anesthetic agents. Another risk factor for hypotension and bradycardia is renal insufficiency, which reduces the renal clearance of α2-agonists. Patients older than 65 years are also at increased risk for hypotension and bradycardia due to age-related renal insufficiency and reduced cardiovascular compensation. Transient hypertension after rapid IV injection of α2-agonists is enhanced in patients with hypertension, who are more sensitive to vasoconstrictors. Avoiding such rapid IV injections can reduce transient hypertension. Sudden cessation of clonidine can cause worrisome and sometimes severe rebound hypertension. The risk of this withdrawal response is higher in patients who have been chronically treated with clonidine, especially at high doses. It can occur from 8 to 36 hours after the last dose. Rebound hypertension is also possible after stopping guanfacine, another α2-agonist, but it occurs later (2 to 4 days) and with less frequency, presumably owing to its longer half-life. Respiratory depression from α2-agonists is often mild. However, at high doses or with other sedative-narcotics, deep sedation and respiratory depression can occur, especially in the elderly.

MANAGEMENT Bradycardia is treated effectively with IV anticholinergics (e.g., atropine, glycopyrrolate). IV ephedrine is also useful, especially with associated hypotension. However, ephedrine’s action is brief, so it may not be effective for bradycardia of long duration. Vasoconstrictors and IV fluids are used for α2-agonist-mediated hypotension. Because this is due to sympatholysis, α1-adrenergic agonists, especially phenylephrine, can reverse hypotension. Ephedrine has both α1and β-agonist effects and is sometimes used to reverse α2-agonist-mediated hypotension. The anesthetic-sparing effect of α2-agonists likely contributes to hypotension and bradycardia during induction or maintenance of general anesthesia. Hemodynamics are stabilized with IV fluids and vasoconstrictors, along with readjustment of anesthetic dosing. Transient hypertension from overly rapid IV injection of α2-agonists is often mild and followed by hypotension from central α2-adrenoreceptor activation. Treatment with long-acting antihypertensive agents can result in undesired hypotension. For rebound hypertension, labetalol is a good choice owing to its ability to block α- and β-adrenergic receptors. Labetalol alone might be inadequate to control hypertension and tachycardia; more selective β-blockers (e.g., metoprolol, esmolol, atenolol) are often needed to control tachycardia. β-Blockers should not be used alone, however, because they can worsen hypertension due to unopposed vasoconstriction from peripheral α-adrenergic activity. β-Blockers may even increase the risk of rebound hypertension with abrupt clonidine withdrawal. Vasodilators (e.g., hydralazine, dihydropyridine calcium channel blockers) are often required to control hypertension. Also, IV infusions of nitroglycerine or sodium nitroprusside are options for uncontrolled

PHARMACOLOGY

Sinus bradycardia is the most common form of bradycardia caused by α2-agonists. However, atrioventricular (AV) junctional and ventricular escape rhythms (bradycardia) and highdegree AV heart block can also occur. Therefore, the ECG is important for its ability to detect cardiac rhythm changes. Blood pressure and heart rate should be closely monitored in patients receiving α2-agonists, especially during induction and maintenance of anesthesia. For patients with poorly controlled hypertension, especially those on clonidine, an arterial line should be considered for perioperative blood pressure monitoring. The preoperative interview should focus on the patient’s history of hypertension and medications to control it, to identify those at high risk for clonidine withdrawal. Close monitoring of blood pressure and heart rate should continue for several hours postoperatively in such patients. In awake patients, other signs of clonidine withdrawal, such as nervousness, headache, and sweating, can aid in the diagnosis. Respiratory depression from α2-agonists is normally mild. Nevertheless, for patients sedated with an α2-agonist, respiratory rate and pulse oximetry must be monitored.

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severe hypertension. IV clonidine is another option, but it does not offer immediate relief for rebound hypertension and has the potential to aggravate hypertension transiently; subsequently, it may cause hypotension and bradycardia.

PREVENTION Awareness of the potential adverse effects of α2-agonists and their proper management is the key to preventing complications associated with their use. Dosages for IV anesthetic induction agents and volatile anesthetics must be adjusted downward. For patients at increased risk for bradycardia and hypotension, α2-agonists should not be used at all or should be given in smaller doses. Avoiding the rapid IV injection of clonidine or high doses of dexmedetomidine helps prevent transient hypertension with α2-agonists. To prevent adrenergic hyperactivity with withdrawal, patients receiving α2-agonists should continue therapy throughout the perioperative period. If the α2-agonist must be discontinued, this should be done over 1 week. For patients at risk for rebound hypertension, a transdermal clonidine patch may be applied preoperatively to abate perioperative sympathetic hyperactivity. Parenteral agents are also used to prevent rebound hypertension (e.g., labetalol, esmolol, propranolol, hydralazine, diltiazem, dihydropyridine calcium channel blockers, nitrates). Finally, severe respiratory depression is rare with therapeutic α2-agonist doses. For patients receiving other sedatives

or narcotics, these must be used with caution to avoid overly deep sedation or severe respiratory depression.

Further Reading Ghignone M, Calvillo O, Quintin L: Anesthesia and hypertension: The effect of clonidine on perioperative hemodynamics and isoflurane requirements. Anesthesiology 67:3-10, 1987. Ghignone M, Quintin L, Duke PC, et al: Effects of clonidine on narcotic requirements and hemodynamic response during induction of fentanyl anesthesia. Anesthesiology 64:36-42, 1986. Husserl FE, Messerli FH: Adverse effects of antihypertensive drugs. Drugs 22:188-210, 1981. Kamibayashi T, Maze M: Clinical uses of α2-adrenergic agonists. Anesthesiology 93:1345-1349, 2000. Levitan D, Massry SG, Romoff M, et al: Plasma catecholamines and autonomic nervous system function in patients with early renal insufficiency and hypertension: Effect of clonidine. Nephron 36:24-29,1984. Manhem P, Paalzow L, Hökfelt B: Plasma clonidine in relation to blood pressure, catecholamines, and renin activity during long-term treatment of hypertension. Clin Pharmacol Ther 31:445-451, 1982. Mercado DL, Petty BG: Perioperative medication management. Med Clin North Am 87:41-57, 2003. Talke P, Lobo E, Brown R: Systemically administered α2-agonist-induced peripheral vasoconstriction in humans. Anesthesiology 99:65-70, 2003. Talke PO, Lobo EP, Brown R, et al: Clonidine-induced vasoconstriction in awake volunteers. Anesth Analg 93:271-276, 2001. Weber MA: Discontinuation syndrome following cessation of treatment with clonidine and other antihypertensive agents. J Cardiovasc Pharmacol 2(Suppl 1):S73-S89, 1980. Weitz HH: Perioperative cardiac complications. Med Clin North Am 85:1151-1169, 2001. Wijeysundera DN, Naik JS, Beattie WS: Alpha-2 adrenergic agonists to prevent perioperative cardiovascular complications: A meta-analysis. Am J Med 114:742-752, 2003.

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MISCELLANEOUS DRUGS AND RELATED TOPICS

27

Anaphylaxis and Anaphylactoid Reactions David G. Bjoraker Case Synopsis A 40-year-old man has brachial plexus block with a lidocaine-tetracaine mixture containing a 1:200,000 concentration of epinephrine. Initially he complains of dizziness, difficulty breathing, and retrosternal chest discomfort. He rapidly develops acute respiratory distress and pulmonary edema, urticaria over the blocked extremity and shoulder, and marked hypotension.

another drug. Allergic drug reactions are generally not predictable, not dose dependent, and not related to the pharmacology of the drug.

PROBLEM ANALYSIS Definition Parenteral medications may cause anaphylaxis. Although it varies in severity, anaphylaxis is the most severe of the immediate hypersensitivity reactions. Anaphylactic shock refers to the complete cardiovascular collapse that may result. The classic anaphylactic reaction is mediated by immunoglobulin E (IgE) antibodies formed in response to prior exposure to a foreign antigen. In many cases, low-molecular-weight drugs are too small to be antigenic alone, but they may combine as haptens with endogenous protein carriers to form an antigenic complex. In the early 20th century, Richet and Portier administered large doses of sea anemone toxin to dogs. The animals survived the initial dose but died within minutes when given a minute dose weeks later. They termed this phenomenon anaphylaxis, indicating that attempted immunization failed to provide prophylaxis against sea anemone toxin. Anaphylactoid reactions may be clinically indistinguishable from anaphylactic reactions. The same chemical mediators released via the IgE-antigen pathway in anaphylaxis are also released by nonimmunologic mechanisms in anaphylactoid reactions.

CLINICAL MANIFESTATIONS

DRUG REACTIONS: ALLERGIC

AND

NONALLERGIC

Drug reactions are common during anesthesia, but less than 10% are true allergic reactions. Nonallergic drug reactions are generally predictable, dose dependent, and related to the known properties of the drug. Often the reactions are either enhanced desired effects or side effects of the drug resulting from overdosage, inadvertent route of administration, impaired elimination, low individual tolerance, or interaction with

ANAPHYLAXIS

The clinical manifestations of anaphylaxis depend on the route of administration of the antigen or hapten, as well as the exact type, quantity, and anatomic site of the various physiologic mediators released (Table 27-1) and the end-organ responses to them. These mediators result from the initial degranulation of mast cells and basophils and the ensuing biochemical events. Symptoms of anaphylaxis occur within 2 to 20 minutes of exposure to the antigen or hapten and may persist for up to 36 hours. Before induction and during regional anesthesia and monitored anesthesia care, both symptoms (Table 27-2) and signs (Table 27-3) of an allergic reaction can facilitate an early diagnosis. After the induction of general anesthesia, however, the patient cannot express symptoms and is hidden from view by the surgical drapes; in this case, serious respiratory and cardiovascular signs are often the first indicators of anaphylaxis. In addition, many signs, such as tachypnea, laryngeal edema, small increases in

Table 27–1

Recognition

OF

■

Mediators Released during Anaphylaxis

Complement (C3a, C5a anaphylatoxins) Heparin Histamine Kinins Leukoagglutinins Leukotrienes Lysosomal enzymes Platelet-activating factor Prostaglandins and other arachidonic acid metabolites Serotonin

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Symptoms of Anaphylaxis

Cutaneous Pruritus Burning Tingling Respiratory Nasal stuffiness Breathing difficulty Chest tightness, discomfort Cardiovascular Dizziness Malaise; confusion Retrosternal oppression Other Organ Systems Aura Nausea Abdominal pain

bronchial tone, and early decreases in systemic vascular resistance, may be obscured by anesthetic drugs and management. DIFFERENTIAL

AND

LABORATORY DIAGNOSES

Generally, the differential diagnosis of anaphylaxis is not difficult owing to the immediacy of the response after exposure to a foreign antigen or hapten. Because anaphylaxis is a systemic condition, signs in multiple organ systems differentiate it from a primary cardiac event or sudden exacerbation of bronchospasm in patients with asthma. Differentiation of anaphylactic and anaphylactoid reactions is academic, because the immediate medical management is identical.

Table 27–3

■

Signs of Anaphylaxis

Cutaneous Urticaria (hives); angioedema Erythema (flushing) Periorbital, facial edema Respiratory Coughing; sneezing Hoarseness Perioral and intraoral edema Laryngeal edema; stridor Intercostal and substernal retractions Cyanosis Tachypnea Wheezing Reduced pulmonary compliance Pulmonary edema Acute respiratory distress Cardiovascular Diaphoresis Hypotension Tachycardia Arrhythmias Reduced systemic vascular resistance Pulmonary hypertension Other Organ Systems Vomiting Diarrhea Acute intravascular coagulation

Laboratory diagnosis of anaphylaxis is retrospective, owing to the rapidity of its onset; after a reaction, however, several uncommon tests may substantiate its diagnosis. Circulating complement C3 and C5 activation products (C3a, C3d, and C5a) may be increased. IgE blood concentrations may be reduced, and plasma histamine concentrations may be briefly elevated. In addition, the concentration of tryptase, a protease released from mast cells, may be increased. If multiple drug exposures occur in close temporal proximity to an anaphylactic reaction, these tests will not assist in differentiating the causative agent.

Risk Assessment All patients receiving parenteral drugs are at risk for anaphylaxis, but those with a notable allergic history or atopy have a greater risk. The risk of an allergic reaction to a drug is approximately 1% to 3%. Anaphylaxis occurs in about 1 of 4000 to 25,000 anesthetic administrations. Table 27-4 lists drugs and other agents frequently used in the perioperative period that may cause anaphylactic or anaphylactoid reactions. For induction agents used in the United States, severe allergic reactions are uncommon. Neuromuscular relaxants are the most common cause of allergic reactions (about two thirds) during anesthesia. Neuromuscular relaxants such as atracurium, cisatracurium, tubocurarine, doxacurium, metocurine, and mivacurium occasionally cause signs of an allergic response due to nonimmunologic histamine release. Morphine, meperidine, and codeine also may release sufficient amounts of histamine to be confused with an allergic reaction. Other materials that come into contact with the patient, such as vascular graft material, methylmethacrylate bone cement, chlorhexidine, and latex rubber, have been implicated in anaphylactoid reactions. Latex allergy is the second most common cause of anaphylaxis during anesthesia (approximately one eighth of cases), and antibiotics are the third most common cause.

Implications An allergic reaction during anesthesia is usually unexpected and may range from a mild urticarial reaction to anaphylactic shock with cardiorespiratory arrest. Although a patient’s preexisting medical conditions may affect or otherwise complicate therapy, a fatal outcome can also occur in patients classified as status I or II by the American Society of Anesthesiologists (ASA) system.

MANAGEMENT Management of anaphylaxis and anaphylactoid reactions includes the following: ● ● ● ●

Removal or reduction of the offending agent Aggressive airway management Circulatory management: volume, epinephrine Adjunct pharmacologic management

If an anaphylactic or anaphylactoid reaction is suspected, the administration of any possible causative agents should

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Perioperative Drugs and Other Factors Associated with Anaphylactic or Anaphylactoid Reactions

Anesthetic Agents

Other Drugs and Miscellaneous Products

Induction agents used in the United States Barbiturates Benzodiazepines Etomidate Ketamine Propofol Induction agents not approved in the United States but used elsewhere Althesin Propanidid Neuromuscular relaxants Succinylcholine (see Chapter 23) Nondepolarizing neuromuscular relaxants (see Chapter 24) Opioids True allergic reactions and systemic anaphylactoid reactions to opioids are rare Anaphylactoid reactions have been reported after IV morphine or codeine (rare) Local anesthetics Para-aminobenzoic ester local anesthetics Amide local anesthetics (rare) Methylparaben or propylparaben preservatives Sulfite, bisulfite, or metabisulfite antioxidants

Antibiotics Aminoglycosides Amphotericin B Cephalosporins Nitrofurantoin Penicillin Tetracycline Vancomycin Intravenous fluids, blood products, volume expanders, hemostatics Albumin, dextran, hetastarch, purified protein fraction Aprotinin, protamine, vitamin K (phytonadione) Blood and blood products (all) Hypertonic solutions*: mannitol, sodium bicarbonate Dyes Isosulfan blue, methylene blue, iodinated radiopaque contrast dyes* Hormones Corticosteroids Insulin Vasopressin Immunosuppressive agents Cyclosporin FK-506 Antithymocyte globulin Latex Nonsteroidal anti-inflammatory drugs* Acetylsalicylic acid Aminopyrine Indomethacin Other drugs Chlorhexidine Chymopapain Streptokinase Tetanus antitoxin

*Usually anaphylactoid reactions.

be stopped immediately. Although a reaction is not strictly dose dependent, the less antigen or triggering agent administered, the better the situation. Also, use of a venous extremity tourniquet can prevent subcutaneously and intramuscularly administered antigenic or triggering material from reaching the central circulation. Oxygenation is monitored by pulse oximetry, and supplemental oxygen is used if necessary. Airway edema can progress rapidly, so the airway must be carefully and continuously monitored. Anesthesiologists should be predisposed to early endotracheal intubation. Discontinuation of general anesthesia is advised to help stabilize the circulatory dynamics, and rapid intravascular volume expansion should be started. Epinephrine is the drug of choice for hypotension because it attenuates associated mediator release and counters bronchospasm. In selecting a dose, the patient’s current hemodynamic state must be considered; doses range from an initial intravenous bolus of 0.2 to 1 μg/kg for moderate hypotension to 3 to 15 μg/kg intravenously for circulatory collapse. Repeated administration or an infusion is appropriate and often necessary. Other adjunct therapy may help after initial stability is achieved. If further antigen will likely be introduced into the

central circulation, antihistamines (e.g., diphenhydramine 0.5 to 0.7 mg/kg or cimetidine 4 to 6 mg/kg) and corticosteroids (e.g., methylprednisolone 15 to 25 mg/kg or hydrocortisone 4 to 15 mg/kg) should be considered. For bronchospasm, along with β-adrenergic aerosols (e.g., albuterol), aminophylline 5 to 6 mg/kg over 20 minutes, followed by an infusion at 0.5 to 1 mg/kg per hour, may be useful. Sodium bicarbonate is used to correct measured acidosis. The Joint Task Force on Practice Parameters has published diagnostic and management guidelines for anaphylaxis (see “Further Reading”). Although not limited to intraoperative anaphylaxis, these guidelines recognize that anaphylaxis is a significant perioperative problem, and they provide a broader context for patient care both before and after anesthesia.

PREVENTION Prevention includes avoiding risky practice patterns, as well as the following measures: ● ●

Intradermal skin testing Radioallergosorbent test (RAST)

PHARMACOLOGY

Table 27–4

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Leukocyte histamine release test Pharmacologic prophylaxis

The ultimate prevention of anaphylaxis and anaphylactoid reactions would be the elimination of exposure to all foreign materials, substances, and drugs, which of course is absurd. The practical approach is to prevent re-exposure to known allergens and to avoid risky patterns of practice, such as the repeated use of aprotinin or dextran infusions without the prior use of dextran 1 (Promit) or the use of a nonsteroidal anti-inflammatory drug when another such drug has caused a serious reaction. A careful history of prior incidents should be obtained, including review of the medical records and discussion with medical personnel who treated a previous reaction. If avoidance of a reactive drug compromises medical treatment, pretesting should be performed before actual use. Fortunately, an acceptable anesthetic regimen can almost always be formulated that excludes any questionable agents. Skin testing is the least expensive and most widely used method for pretesting anesthetic drugs. Fisher and Doig described intradermal skin testing for anesthetic agents and recommended dilution—usually a 1:1000 to 1:10,000 dilution of the commercial concentration. However, the irritant effect of the injection or direct histamine release by opioids or muscle relaxants may result in false-positive findings. Falsenegative findings are also possible, especially if the patient uses antihistamines or sympathomimetic preparations. Because anaphylaxis can occur in response to even small quantities (0.02 mL) of an agent, even when diluted 1000-fold, resuscitation agents and skilled personnel must be readily available. In vitro testing is much more convenient and completely safe for the patient. RAST is the most useful test and involves exposure of the patient’s serum to the questionable allergen. The latter is bound to an insoluble, drug allergen-matrix complex, and if the patient is capable of reacting to the allergen, his or her serum IgE will bind to the drug allergenmatrix complex as well. To measure the quantity of the patient’s serum IgE bound to the drug allergen-matrix complex, they are combined with radiolabeled antihuman IgE, and the radioactivity is measured. A low level of radioactivity indicates high occupation of the drug allergen-matrix complex by the patient’s serum IgE, or true allergy. Conversely, a high level of radioactivity indicates unlikely allergy. However, a deficiency of RAST is that many drug allergenmatrix complexes are not available commercially. Another in vitro test, the leukocyte histamine release test, does not require commercial allergen-matrix complexes. This test is conducted through direct exposure of a suspension of the patient’s leukocytes to the allergen. Histamine release is measured fluorometrically or with a radioenzymatic assay. For patients requiring treatment with a drug that has previously caused an allergic or anaphylactoid response, or

for atopic patients with multiple drug allergies, pharmacologic prophylaxis may be required. For anaphylactoid reactions to iodinated radiopaque contrast material, Greenberger and colleagues recommended the following protocol: ●

●

●

Ephedrine 25 mg and H1-receptor blockade (diphenhydramine 50 mg orally or intramuscularly) 1 hour before exposure Prednisone 50 mg 13 hours, 7 hours, and 1 hour before exposure Another 25 mg of oral ephedrine just before exposure, unless contraindicated

H2-blockade with cimetidine also was examined but was not found to be helpful. Recommendations for drug pretreatment in other situations are anecdotal and similar to those for radiocontrast material. H2-blockade in other circumstances can be achieved with 4 to 6 mg/kg of cimetidine or 1 to 2 mg/kg of ranitidine, preferably started 24 hours before exposure. Terbutaline, a β2-adrenergic agonist, and cromolyn sodium (which blocks the release of histamine and other autacoids from basophils and mast cells) have been proposed as prophylactic treatment, but their role in preventing anaphylactic or anaphylactoid reactions is unproved.

Further Reading Ebo DG, Hagendorens MM, Bridts CH, et al: Allergic reactions occurring during anaesthesia: Diagnostic approach. Acta Clin Belg 59:34-43, 2004. Fisher MM, Doig GS: Prevention of anaphylactic reactions to anaesthetic drugs. Drug Saf 27:393-410, 2004. Fukuda K: Intravenous opioid anesthetics. In Miller RD (ed): Miller’s Anesthesia, 6th ed. Philadelphia, Churchill Livingstone, 2005, pp 379-437. Greenberger PA, Patterson R, Tapio CM: Prophylaxis against repeated radiocontrast media reactions in 857 cases: Adverse experience with cimetidine and safety of β-adrenergic antagonists. Arch Intern Med 145:2197-2200, 1985. Gutstein HB, Akil H: Opioid analgesics. In Hardman JG, Limbird LE (eds): Goodman and Gilman’s The Pharmacological Basis of Therapeutics, 10th ed. New York, McGraw-Hill, 2001, pp 569-619. Joint Task Force on Practice Parameters, American Academy of Allergy, Asthma and Immunology; American College of Allergy, Asthma and Immunology; Joint Council of Allergy, Asthma and Immunology: The diagnosis and management of anaphylaxis: An updated practice parameter. J Allergy Clin Immunol 115:S483-S523, 2005. Levy JH: Anaphylactic Reactions in Anesthesia and Intensive Care, 2nd ed. Stoneham, Mass, Butterworth-Heinemann, 1992. Mertes PM, Laxenaire MC: Allergic reactions occurring during anaesthesia. Eur J Anaesthesiol 19:240-262, 2002. Moneret-Vautrin DA, Kanny G: Anaphylaxis to muscle relaxants: Rationale for skin tests. Allerg Immunol (Paris) 34:233-240, 2002. Pepys J, Whitwam JG, Baldo BA, et al: Anaphylactic/anaphylactoid reactions to anaesthetic and associated agents: Skin prick tests in aetiological diagnosis. Anaesthesia 49:470-475, 1994. Soetens FM: Anaphylaxis during anaesthesia: Diagnosis and treatment. Acta Anaesthesiol Belg 55:229-237, 2004. Terr AI: In vitro tests for immediate hypersensitivity. Annu Rev Med 39: 135-145, 1988.

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28

Antibiotics Case Synopsis A 23-year-old man presents for reduction and fixation of an open tibial fracture after falling off a horse. Following thiopental and succinylcholine administration and successful endotracheal intubation, anesthesia is maintained with isoflurane, nitrous oxide 50% and oxygen 50%, and fentanyl 2 μg/kg per hour. The surgeon requests that the patient be given vancomycin 1 g before incision. Three minutes after vancomycin is given, the patient suffers cardiovascular collapse.

PROBLEM ANALYSIS

●

●

Definition Anesthesiologists frequently administer antibiotic prophylaxis to surgical patients and should be knowledgeable about the indications, dosages, complications, and interactions between antibiotics and anesthetics and other medications used in the perioperative period. Antibiotics possess a diverse spectrum of side effects (Table 28-1) and interact with a number of anesthetic adjuvants. For these reasons, anesthesiologists must understand and anticipate possible complications associated with antibiotic administration. Vancomycin is a glycopeptide antibiotic commonly used for bacterial prophylaxis in orthopedic, neurologic, and vascular surgery and as an alternative antibiotic for patients who are allergic to penicillins and cephalosporins. An unusual feature of vancomycin is its ability to nearly double histamine release from basophils and cutaneous mast cells through a poorly understood dose-dependent mechanism that is neither immunologic nor cytotoxic. The liberated histamine causes dilatation of peripheral blood vessels and simultaneously increases cardiac output, stroke volume, and pulmonary artery pressure. However, peripheral vascular dilatation is the most prominent physiologic feature and may induce severe hypotension and cardiovascular collapse. There have been several reports of hypotension and cardiac arrest during concurrent vancomycin and anesthesia administration, but cardiovascular collapse can also occur in unanesthetized patients receiving vancomycin.

Recognition Recognition of vancomycin as the cause of hypotension relies primarily on the exclusion of other intraoperative events as the cause, the temporal relationship between cardiovascular instability and vancomycin infusion, and the observation of other manifestations of histamine release. Signs of elevated plasma levels of histamine include the following: ●

●

“Red neck” or “red man” syndrome, consisting of cutaneous flushing, erythema, urticaria, pruritus, and maculopapular rash primarily on the face, neck, arms, and chest Perioral, periocular, and facial edema

● ●

Bronchospasm due to stimulation of bronchial histamine receptors Hypoxia caused by histamine-induced inhibition of pulmonary vasoconstriction and subsequent formation of pulmonary shunts Systemic hypotension Pulseless electrical activity cardiac arrest (electromechanical dissociation)

In addition, a “pain and spasm” syndrome has been described following vancomycin infusion, but it is unknown whether this is a histamine-mediated complication or whether another mechanism is responsible. Anesthesiologists must be cognizant that contaminants in the vancomycin solution may cause a true anaphylactic reaction, although hypotension is much more likely to result from vancomycininduced histamine release.

Risk Assessment Because vancomycin-induced histamine release results from nonspecific degranulation of basophils or mast cells, it is classified as an anaphylactoid reaction, not anaphylaxis. That is, histamine liberation is mediated not by an immune system response but by an unclear mechanism. Consequently, a patient’s risk for hypotension and cardiovascular collapse is independent of previous exposure to vancomycin, may occur with the first dose, and does not increase with multiple administrations of the antibiotic. Hence, a patient with a history of “red man” syndrome or vancomycin-induced hypotension can safely receive this antibiotic if it is administered appropriately. Anesthesiologists may be concerned about a greater risk of hypotension when vancomycin and a volatile anesthetic are administered concurrently (i.e., vancomycin infusion after anesthetic induction), because both agents can potentially depress blood pressure. Although hypotension during vancomycin administration is more common in anesthetized than in nonanesthetized patients, this difference is probably due to more intensive monitoring and observer vigilance during anesthesia rather than an actual interaction between vancomycin and anesthetics. In one study investigating hypotension during concurrent vancomycin and anesthetic administration in adult patients undergoing orthopedic surgery (see Von Kaenel under “Further Reading”), no difference was noted (either before 101

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Complications of Antibiotics Used for Prophylaxis

Antibiotic

Common

Occasional

Rare

Aminoglycosides

Nephrotoxicity Ototoxicity

Peripheral neuritis Anaphylaxis Electrolyte disturbances

Cephalosporins

Painful when given IM

Rash Nausea, vomiting Potentiation of neuromuscular blockade Nausea Drug fever Diarrhea Phlebitis

Clindamycin

Erythromycin

Phlebitis when given IV Painful when given IM

Metronidazole

Nausea, vomiting Metallic taste Disulfiram-like reaction if alcohol consumed

Diarrhea Pseudomembranous colitis Rash Metallic taste Inhibition of neuromuscular transmission Potentiation of neuromuscular blockade Nausea, vomiting Diarrhea Pseudomembranous colitis Burning tongue Urethral/vaginal burning Dark urine Rash

Penicillin G, ampicillin

Rash Drug fever Diarrhea Leukopenia

Trimethoprim-sulfamethoxazole

Rash

Vancomycin

Phlebitis Severe pain when given IM

“Red man” syndrome “Pain and spasm” syndrome Hypotension Anaphylaxis Nephrotoxicity Ototoxicity

Anaphylaxis Hypotension Bronchospasm Angioedema Urticaria Anaphylaxis Cardiac arrest Erythema Granulocytopenia Thrombocytopenia

Long QT syndrome Fever Rash Eosinophilia Convulsions Ataxia Peripheral neuropathy Encephalopathy Cerebellar dysfunction Anaphylaxis Bronchospasm Angioedema Electrolyte disturbances Interstitial nephritis Erythema multiforme Diarrhea Aplastic anemia Neutropenia Thrombocytopenia Neutropenia

Adapted from Cheng EY, Nimphius N, Hennen CR: Antibiotic therapy and the anesthesiologist. J Clin Anesth 7:425-439, 1995.

or after anesthetic induction) in hemodynamic parameters, anesthetic depth, ephedrine use, or volume of intravenous fluid administration following an infusion of either vancomycin or a saline carrier solution over 30 to 60 minutes (Table 28-2). In contrast, children and patients undergoing cardiopulmonary bypass and coronary bypass grafting are apparently more sensitive to the vasodilating effects of vancomycin. Anesthetized pediatric patients demonstrated a 35% incidence of hypotension following vancomycin infusion. Likewise, 30% of adults undergoing cardiopulmonary bypass required a postbypass infusion of norepinephrine following the addition of vancomycin 500 mg to the cardiopulmonary bypass pump prime solution, compared with 7% in a control group given saline. However, vancomycin administration via aortic cannula using flow rates necessary for cardiopulmonary bypass (60 to 70 mL/kg per minute) is probably too rapid

to maintain hemodynamic stability even in some healthy patients. Critically ill patients have a diminished risk of vancomycininduced reactions compared with healthy patients presenting for elective procedures. Vancomycin 1 g infused over 30 minutes did not affect cardiac index, heart rate, blood pressure, pulmonary venous pressure, central venous pressure, systemic vascular resistance, or pulmonary vascular resistance in 16 hemodynamically stable patients who were given the antibiotic within 24 hours of coronary artery bypass grafting or cardiac valve replacement. Remarkably, little rise in histamine concentrations occurred, despite substantially elevated vancomycin concentrations. Failure to develop cardiovascular side effects may be explained in part by the depletion of histamine from its previous liberation in response to illness, perioperative stress, and protamine administration.

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Complications of Vancomycin Administration before or after Induction of Anesthesia in Studies Noting Adverse Events

Study (Year)

Subjects

No. Preinduction

No. Postinduction

Blomstedt et al (1988) Von Kaenel et al (1993)

Adults

—

169

Adults

17

19

Odio et al (1984) Romanelli et al (1993)

Children Adults

— 30*

20 30*

End Points (No. of Patients) “Red man” syndrome (6), hypotension (5), bronchospasm (1), hypoxia (1) No differences in HR, BP, end-tidal enflurane concentration, ephedrine use, IV fluid administration compared with placebo “Red man” syndrome (7), hypotension (1) No differences in HR, SBP, CVP, CO, SVR, or intraoperative fluid balance after anesthetic induction and before cardiopulmonary bypass, but higher HR and CO combined with lower BP, CVP, and SVR after cardiopulmonary bypass and surgery in patients receiving vancomycin compared with placebo; also, 9 of 30 patients receiving vancomycin required norepinephrine infusion, compared with 2 of 28 patients in the control group

*Patients received vancomycin both before anesthetic induction and at the initiation of cardiopulmonary bypass for coronary artery bypass grafting. BP, blood pressure; CO, cardiac output; CVP, central venous pressure; HR, heart rate; SBP, systemic blood pressure; SVR, systemic vascular resistance.

Consistent with this hypothesis is an investigation that demonstrated significantly elevated histamine concentrations in 28 patients who were studied immediately after multiple traumatic injuries and compared with a control group. Alternatively, critically or chronically ill patients may possess a diminished response to histamine stimulation when compared with the response of healthy volunteers or patients presenting for ambulatory surgery. For example, patients with cancer exhibit less pruritus and diminished wheal and flare responses following an intradermal histamine challenge. Regardless, anesthesiologists would be prudent to carefully monitor such patients during vancomycin administration, because even mild or moderate hypotension may be poorly tolerated in critically ill patients.

That is, treatment options should become more aggressive with later detection, greater histamine release, and more severe hypotension. Management options include the following: ● ● ●

● ● ●

●

Discontinue or slow the vancomycin infusion. Administer an intravenous fluid bolus. Discontinue or decrease concentrations of other agents that are capable of inducing hypotension (e.g., anesthetics, sodium nitroprusside). Administer H1-antihistamines (e.g., diphenhydramine). Consider inhaled β-agonists if bronchospasm is present. Administer vasopressors (e.g., ephedrine, phenylephrine, epinephrine) for severe hypotension. Initiate advanced cardiovascular life support maneuvers in the event of cardiac arrest.

Implications Vancomycin can be safely administered to patients in the perioperative period either before or after induction of anesthesia. Prudent anesthesiologists follow the manufacturer’s recommendations regarding the duration of vancomycin infusion, especially in patients at greater risk (e.g., children) or who poorly tolerate even mild hypotension (e.g., patients with aortic stenosis). Hemodynamic depression requires prompt detection and treatment to avoid potentially lifethreatening cardiovascular collapse.

MANAGEMENT Managing vancomycin-induced hypotension grows progressively more difficult the longer it takes to detect the drug’s toxic effects, and detecting the toxic effects grows progressively more difficult the longer the drug is administered.

PREVENTION Histamine release and the severity of reactions during vancomycin administration are directly dependent on the rate of infusion. Consequently, vancomycin should be infused over 60 minutes to minimize adverse reactions, as recommended by the manufacturer. In a study of nonanesthetized patients, rapid vancomycin infusion (1 g over 10 minutes) caused a 25% to 50% decrease in systolic blood pressure lasting 2 to 3 minutes in 11 of 56 patients, whereas no hypotension was observed in patients receiving a slow vancomycin infusion (1 g over 30 minutes). The key element is slow administration over 30 to 60 minutes, which may be impractical when attempting to complete a dose before surgical incision or tourniquet inflation. In this situation, preoperative infusion may be warranted if there is insufficient time to safely infuse vancomycin. Regardless, frequent monitoring

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of blood pressure; observation of skin color of the head, neck, and trunk; and auscultation of breath sounds are necessary for prompt detection and treatment of vancomycin’s toxic effects. Finally, some patients with extreme sensitivity to vancomycin may require this antibiotic to treat infections with multidrug-resistant organisms. In this situation, protocols for vancomycin desensitization have been developed to allow this patient population to safely receive intravenous vancomycin. This treatment revolves around gradual desensitization of mast cells by gradually increasing the serum concentration of vancomycin. This can be accomplished in as little as 24 hours for acutely ill patients. This preventive protocol is, of course, reserved for patients in duress and requires planning before the day of surgery if operative prophylactic vancomycin administration is envisioned.

Further Reading Cheng EY, Nimphius N, Hennen CR: Antibiotic therapy and the anesthesiologist. J Clin Anesth 7:425-439, 1995.

Levy JH, Kettlekamp N, Goertz P, et al: Histamine release by vancomycin: A mechanism for hypotension in man. Anesthesiology 67:122-125, 1987. Polk RE: Anaphylactoid reactions to glycopeptide antibiotics. J Antimicrob Chemother 27B:17-29, 1991. Romanelli VA, Howie MB, Myerowitz PD, et al: Intraoperative and postoperative effects of vancomycin administration in cardiac surgery patients: A prospective, double-blind, randomized trial. Crit Care Med 21:1124-1131, 1993. Sokoll MD, Gergis SD: Antibiotics and neuromuscular function. Anesthesiology 55:148, 1981. Stier GR, McGory RW, Spotnitz WD, Schwenzer KJ: Hemodynamic effects of rapid vancomycin infusion in critically ill patients. Anesth Analg 71:394-399, 1990. Von Kaenel WE, Bloomfield EL, Amaranath L, Wilde AA: Vancomycin does not enhance hypotension under anesthesia. Anesth Analg 76:809-811, 1993. Wazny LD, Daghigh B: Desensitization protocols for vancomycin hypersensitivity. Ann Pharmacother 35:1458-1464, 2001.

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Antidepressants MONOAMINE OXIDASE INHIBITORS Case Synopsis A 32-year-old woman with a 38-week intrauterine pregnancy presents for cesarean section due to failure to progress. The patient has a 2-year history of depression and is currently taking 15 mg of phenelzine orally, twice daily. The patient refuses general anesthesia. A lumbar epidural block is placed without complication, and a T6 level of anesthesia is achieved. The surgical procedure proceeds and is uneventful. In the recovery room, the nurse requests intravenous meperidine for postoperative shivering. Later, the anesthesiologist is informed that the patient is tachycardic, hypertensive, and hyperpyrexic.

PROBLEM ANALYSIS Definition Monoamine oxidase inhibitors (MAOIs) block oxidative deamination to cause the accumulation of endogenous catecholamines (serotonin, norepinephrine, and dopamine) at adrenergically active tissue sites (e.g., brain). This is the proposed mechanism for the antidepressant actions of MAOIs. Meperidine increases serotonin (5-hydroxytryptamine) and catecholamine concentrations in synaptic clefts by inhibiting their uptake. In combination, meperidine and MAOIs can lead to increased serotonin and catecholamine levels in brain and peripheral tissue sites, causing signs of sympathetic nervous system overactivity (e.g., hypertension, tachycardia, hyperpyrexia) and potentially coma.

Recognition Use of narcotics in patients receiving MAOIs can lead to one of three clinical presentations: 1. No adverse effects 2. Hypertension, hyperpyrexia, and tachycardia—a more common clinical presentation, especially with meperidine 3. Hypotension and loss of consciousness—reported with morphine sulfate

Risk Assessment Inhibition of approximately 80% of monoamine oxidase (MAO) activity is necessary to achieve a therapeutic antidepressant effect with MAOIs. There are two MAO enzymes (A and B), which differ in their tissue distribution (active sites) and preference for substrates. Because the brain contains predominantly MAO A (approximately 60% of the total), selective inhibitors could potentially minimize (or eliminate) the side effects associated with MAOIs. Two types of MAOI derivatives (hydrazine and nonhydrazine analogues) exist.

Implications The use of narcotics in the setting of MAOI treatment remains controversial. Morphine has been reported to cause adverse outcomes in patients taking MAOIs, presumably via histaminemediated release of catecholamines. In addition, MAOIs reduce intrahepatic enzyme function and thus can prolong the effects of other drugs. The most well-known adverse interactions, however, are those between MAOIs and meperidine; such adverse outcomes have been reported from at least 12 independent sources. Even the use of synthetic narcotics (e.g., fentanyl) that do not release histamine has been questioned. The synthetic opioids increase norepinephrine release and inhibit its reuptake in sympathetic nerve terminals. Fentanyl may also increase the release of serotonin. Despite three reports of adverse outcomes with fentanyl-based anesthesia in patients receiving MAOIs and having cardiac surgery, many other reports have described the safety of high-dose fentanyl in that setting. The newer selective MAOI moclobemide has not been associated with adverse outcomes in patients receiving morphine or synthetic opioids. Volatile anesthetics and intravenous agents, including ketamine, have also been used safely in patients receiving moclobemide. Although there is some concern about the use of local anesthetic solutions containing epinephrine in patients receiving moclobemide, data to support or refute this concern are unavailable. Hyperdynamic circulatory responses have been reported in patients receiving MAOIs who are given indirect-acting vasopressors such as ephedrine. Indirect-acting adrenergic agonists can cause an unpredictable release of catecholamines from presynaptic stores into the nerve terminal and lead to a grossly exaggerated sympathetic response. Therefore, these drugs are best avoided in patients receiving MAOIs. In contrast, MAOIs do not significantly alter the hemodynamic effects of exogenously administered direct-acting vasopressors such as phenylephrine.

MANAGEMENT The hyperdynamic circulatory responses elicited with the use of meperidine and indirect-acting sympathomimetic 105

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agents in patients receiving MAOIs can be controlled with the use of arterial vasodilators such as nitroprusside and nicardipine. In comatose patients, supportive care, including airway management, is imperative. Hypotensive episodes during surgery are best treated with reduced intravenous doses of phenylephrine or other direct-acting sympathomimetic agents.

PREVENTION The preceding considerations suggest the discontinuance of MAOIs 2 weeks before elective surgery to permit the synthesis of new MAO enzyme. However, the pharmacologic effects of nonhydrazine MAOIs are absent after the drug has been discontinued for 24 hours. The nonhydrazine MAOIs are reversible inhibitors of MAO and are not associated with

adverse outcomes during anesthesia and surgery. Thus, discontinuing such therapy is generally not warranted and must be carefully weighed against exacerbations of the underlying psychiatric illness. Neither general nor regional anesthesia is contraindicated in patients receiving nonhydrazine MAOIs. If central neuraxial regional anesthesia is chosen, however, volume loading before the introduction of sympathectomy is advised. Further, with hypotension, the use of direct-acting vasopressors is recommended. MAOIs have a minor role in terminating the release and action of norepinephrine at nerve terminals. For cardiac surgical patients, some authors recommend the use of benzodiazepines and β-adrenergic blockers with highdose narcotic anesthesia, whereas others recommend the use of etomidate or thiopental in doses appropriate to the patient’s hemodynamic status.

TRICYCLIC ANTIDEPRESSANTS Case Synopsis A 24-year-old man presents emergently to the operating room for surgical exploration of the abdomen after a motor vehicle accident. In the emergency room, the patient is very difficult to arouse and is intubated. Vital signs are stable except for mild tachycardia. The head computed tomography scan is normal, and no other injuries are noted. During induction of anesthesia with low-dose thiopental and pancuronium, the patient becomes extremely hypotensive and bradycardic, with wide QRS complexes on the electrocardiogram (ECG). Epinephrine (100 μg) is given, and profound sustained hypertension and tachycardia ensue. An attempt at arterial line placement reveals severe scarring on both wrists. Intravenous fluid resuscitation is initiated, and sodium nitroprusside 1 μg/kg per minute is administered. Later, the family reveals that the patient has had suicidal depression for at least 3 months and is taking imipramine.

PROBLEM ANALYSIS Definition Reduced concentrations of norepinephrine and serotonin in the central nervous system (CNS) are thought to underlie depression. Thus, the condition is effectively treated by agents that block catecholamine reuptake in the CNS. Although tricyclic antidepressants (TCAs) do this, they also bind to other CNS receptors (γ-aminobutyric acid [GABA], muscarinic, α-adrenergic, and histamine). In addition to CNS actions, TCAs have important cardiac implications. Depending on serum TCA concentrations, these drugs may exert proarrhythmic or antiarrhythmic properties. However, TCAs have not been implicated as a direct cause of left ventricular dysfunction.

Recognition The width of the QRS complex represents the relatively brief duration of phase 0 and phase I of the cardiac action potential (AP) relative to phases II, III, and IV (plateau, repolarization, and isoelectric phases, respectively). Phase 0 is the rapid depolarization phase that results from the influx of sodium

ions into the cardiac muscle and conducting fibers. Phase I is early, rapid depolarization that precedes the AP plateau phase (phase II). Phase I is believed to be due to several potassium repolarizing currents and to sodium “window” and calcium currents. Blockage of voltage-gated sodium channels that generate fast inward current required for AP phase 0 depends on the heart rate. Profound block, especially with toxic TCA concentrations, occurs at fast heart rates. However, such block accumulates over time and eventually leads to bradycardia with widened QRS complexes. Early signs of TCA toxicity are PR interval prolongation and T-wave flattening. Also, most patients display anticholinergic effects with TCAs, leading to an early increase in heart rate. However, bradycardia with wide QRS complexes may follow.

Risk Assessment QRS complex widening is the harbinger of seizures and cardiac arrhythmias with acute TCA intoxication. With therapeutic TCA concentrations, most patients show a 10% to 20% increase above their baseline heart rate due to TCAs’ anticholinergic effects. Further, PR and Q-Tc interval prolongation is not infrequent with therapeutic concentrations of TCAs.

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With TCAs, hypotension can occur due to bradycardia, volume depletion, or vasodilatation secondary to α-adrenergic receptor blockade. One’s first impulse might be to administer a direct-acting vasoconstrictor, such as phenylephrine or even epinephrine. However, the use of epinephrine can lead to profound hypertension and tachycardia (as illustrated in the case synopsis) in the presence of increased circulating concentrations of catecholamines with TCAs. Use of epinephrine in local anesthetic solutions should also be avoided. Increased circulating catecholamines may lead to ventricular tachycardia and arrest in the presence of halothane and pancuronium. Ketamine should also be avoided owing to its potential sympathomimetic effects. ECG evidence of Q-T interval prolongation precludes the use of stellate ganglion blocks for treating reflex sympathetic dystrophy. In fact, TCAs are an alternative but often overlooked therapy for these patients.

MANAGEMENT In the presence of ventricular arrhythmias, class IA antiarrhythmic agents (e.g., quinidine, procainamide, disopyramide) are of no benefit and in fact should not be used. TCAs and class IA antiarrhythmics have similar effects on the myocardium that are compounded by combined use, especially the risk for Q-T interval prolongation and proarrhythmia (i.e., torsades de pointes). In cardiac arrest, resuscitation should proceed as usual with intravenous lidocaine (a class IB agent) or amiodarone (the class III agent with the lowest proarrhythmia risk) and direct-current cardioversion for ventricular tachycardia or defibrillation for

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ventricular fibrillation. If cardiac arrest is due to ventricular tachycardia or fibrillation, epinephrine should be avoided. Assurance of ventilation and oxygenation, mechanical chest compressions, and early cardioversion or defibrillation are mandatory. If a vasopressor is needed, the best alternative may be vasopressin in reduced dosages. Then, attention should be directed toward the correction of acidosis and hypokalemia and the replacement of intravascular volume. Bradycardia or asystole may respond to atropine, but if not, temporary transcutaneous pacing is used. In a comatose patient, airway management is the primary concern, not only to ensure adequate ventilation and oxygenation but also to protect against pulmonary aspiration.

PREVENTION In the case of elective surgery, a preoperative ECG should be obtained in all patients receiving TCAs. Unless the history or physical examination reveals significant heart disease or heart failure, a preoperative echocardiogram is generally not necessary, because left ventricular function is usually well preserved in patients taking TCAs. Further, the preoperative discontinuation of TCAs is not warranted. However, close observation of the intraoperative ECG and knowledge and awareness of the drug’s cardiac implications are of utmost importance in the care of these patients. Drugs to avoid include direct-acting catecholamines, sensitizing inhalation agents (e.g., halothane more than enflurane; but sensitization unlikely with desflurane or sevofurane), induction agents that facilitate this interaction (e.g., thiopental), and intravenous agents such as ketamine (owing to its sympathomimetic actions).

SELECTIVE SEROTONIN REUPTAKE INHIBITORS Case Synopsis After an orthopedic procedure performed with an axillary block and sedation, a 28-year-old woman develops hyperthermia, hyperreflexia, and agitation in the recovery room. She is currently being treated with sertraline because of postpartum depression.

PROBLEM ANALYSIS

pathways) and channels (e.g., sodium, potassium), they have a significantly better safety profile than TCAs.

Definition

Recognition

Selective serotonin reuptake inhibitors (SSRIs) inhibit the presynaptic 5-hydroxytryptamine reuptake transport system. This leads to an acute increase in serotonin concentrations at the synaptic cleft. The therapeutic effects, which take approximately 2 weeks to develop, are the result of neuroadaptive changes that result in increased serotonin release and transmission. Because SSRIs are highly specific for serotonin and have less effect on other neurotransmitter systems (e.g., adrenergic, muscarinic, histamine, and dopaminergic

In patients receiving SSRIs, concurrent nonanesthetic drugs and some anesthetic drugs may cause adverse reactions, including the serotonin syndrome, which is identified by any three of the following symptoms: mental status changes, including agitation; hyperreflexia; diaphoresis; shivering; tremor; hypertension; oculogyric crisis (i.e., extreme eyeball rotation); diarrhea; and hyperthermia. Drugs that can cause adverse reactions or the serotonin syndrome in concert with SSRIs include the following:

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Nonanesthetic drugs: L-dopa, lithium, bromocriptine, fenfluramine, dextromethorphan, pethidine, and pentazocine can increase serotonin activity by blocking the reuptake or increasing the presynaptic release of serotonin. Anesthetic drugs: highly protein-bound anesthetic drugs (e.g., fentanyl, midazolam, local anesthetics) may increase the free (unbound) fraction of sertraline (Zoloft).

Risk Assessment SSRIs are the most frequently used antidepressants in the United States. Fluoxetine (Prozac) is the least specific of the SSRIs, especially at higher doses, and may be associated with greater CNS effects. Paroxetine (Paxil) is more specific but also has mild antimuscarinic effects. Sertraline (Zoloft) is the most specific SSRI.

Implications SSRIs inhibit cytochrome P-450 enzymes. Their use with drugs that have narrow therapeutic windows, including phenytoin, TCAs, tolbutamide, carbamazepine, clozapine, haloperidol, class IC antiarrhythmics (see Chapter 10), and warfarin, can cause clinically significant adverse drug interactions. Thus, for some surgeries, preoperative evaluation of coagulation status may be warranted. The syndrome of inappropriate antidiuretic hormone secretion (SIADH) may occur in geriatric patients

and warrants preoperative evaluation for hyponatremia. Postoperative delirium can be confused with neuroleptic malignant syndrome, SIADH, and withdrawal of SSRIs.

MANAGEMENT Most adverse events associated with SSRIs are due to drug interactions. If this is the case, the preferred initial therapy is to discontinue the inciting drug. Supportive measures include cooling for hyperthermia, artificial ventilation for inadequate ventilation, clonazepam for myoclonus, anticonvulsants for seizures, and chlorpromazine for its antipyretic and sedative properties.

PREVENTION SSRIs should be continued perioperatively to prevent a withdrawal syndrome. Neither general nor regional anesthesia is contraindicated. SSRIs are metabolized by hepatic transformation involving the cytochrome P-450 enzyme and can potentially inhibit the metabolism of other drugs similarly metabolized. For example, prolonged sedation with midazolam has been observed in patients receiving SSRIs. Decreased analgesic effects of μ opioids, such as morphine, have also been noted with fluoxetine.

ST. JOHN’S WORT Case Synopsis A 19-year-old, otherwise healthy man undergoes general anesthesia with midazolam, propofol, fentanyl, rocuronium, and nitrous oxide for an appendectomy. The intraoperative course is uncomplicated, with a total anesthesia time of 1 hour. Later, in the recovery room, the patient is difficult to arouse. His pupils are equal and reactive but constricted. Despite the administration of naloxone and flumazenil, and normal electrolytes and arterial blood gas measures, he remains difficult to arouse. An hour and a half later, he is arousable and purposeful. Upon subsequent interview, he states that he uses St. John’s wort for depression.

PROBLEM ANALYSIS Definition Increasing numbers of surgical patients are taking herbal remedies that can complicate the perioperative period (see also Chapter 39). A survey of the general U.S. population reported a 380% increase in the use of herbal preparations over the past decade. Up to 22% of all surgical patients use homeopathic medications. St. John’s wort is an extract from the flowers and leaves of the plant Hypericum perforatum. It is used for the short-term treatment of mild to moderate depression but is not effective for major depression. Although St. John’s wort is used for other psychiatric conditions (e.g., anxiety), there is little

evidence to support its use outside of depression, and even then, its efficacy for clinical depression is controversial. Metaanalyses of some studies have reported response rates similar to those for placebo; others have shown efficacy comparable to that of conventional antidepressants. St. John’s wort appears to have fewer side effects than conventional antidepressants.

Recognition Six classes of compounds in St. John’s wort extracts are believed to be its active components: 1. 2. 3. 4.

Naphthodianthones (i.e., hypericin, pseudohypericin) Acylphloroglucinols (i.e., hyperforin, adhyperforin) Proanthocyanidins Flavanol glycosides

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Although hypericin was formerly believed to be the principal active compound in St. John’s wort, more recent evidence suggests that hyperforin is more important for its antidepressant effects. Hyperforin has the following actions: ● ●

● ●

●

Inhibition of serotonin reuptake Weak in vitro inhibition of MAO A and B (demonstrated in one report but not confirmed in several others) Inhibition of norepinephrine and dopamine reuptake High affinity for GABAA and GABAB receptors, as well as adenosine, dopamine, and benzodiazepine receptors Significant increase in the metabolism of many concurrently used drugs by induction of cytochrome P-450 microsomal enzymes to nearly double their metabolic activity

The most affected enzyme appears to be CYP3A4, which is responsible for the metabolism of more than half of clinical drugs subject to cytochrome P-450 oxidative metabolism. Interactions with the CYP3A4 substrates indinavir, ethinyl estradiol, and cyclosporin have been reported. This interaction led to a 50% reduction in cyclosporin concentrations in one series of organ transplant recipients. There have also been reports of acute heart transplant rejection. Other CYP3A4 substrates in perioperative use are alfentanil, midazolam, lidocaine, calcium channel blockers, and SSRIs. It is likely that metabolism of these drugs is also increased. Further, St. John’s wort induces CYP2C9. Its clinical substrates include nonsteroidal anti-inflammatory drugs, diphenylhydantoin (phenytoin), and, importantly, warfarin. Finally, St. John’s wort lowers digoxin serum concentrations by induction of the P-glycoprotein transporter. St. John’s wort can be associated with adverse drug reactions in patients undergoing anesthesia and surgery, including the development of serotonin syndrome. Because it increases serotonin levels, serotonin syndrome is most commonly seen in patients also taking TCAs and is even more problematic with MAOIs. Delayed emergence from anesthesia is a relatively common occurrence with St. John’s wort and is often due to potentiation of the effects of other drugs used in anesthesia. Less common is thromboembolic stroke in patients on warfarin. Metabolic imbalance is rare.

Risk Assessment Because the most active ingredient in St. John’s wort was formerly believed to be hypericin, most preparations are still standardized to hypericin content. However, extracts contain other active constituents, especially hyperforin. Because herbals such as St. John’s wort are not subject to stringent licensing regulations, the hypericin percentage does not guarantee the amounts or pharmacologic biopotential of any other components.

Implications The antidepressant effects of St. John’s wort are believed to be a synergistic combination of MAO inhibition, decreased serotonin reuptake, and GABA activity. The anesthetic

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implications are mostly theoretical, with rare case reports. Of greatest concern is the potential for a decreased response to inotropic agents, because long-term use of St. John’s wort alters G-protein coupling mechanisms and down-regulates adrenergic receptors.

MANAGEMENT Because of its effect on anesthetics and other drugs used in perioperative settings, the preoperative discontinuation of St. John’s wort is important. This is critical in certain organ transplant patients owing to the increased risk of rejection. Also included are patients receiving warfarin for prophylaxis of thromboembolic events. Further, delayed emergence from anesthesia has been associated with St. John’s wort. In particular, the sedative effects of agents acting at GABA receptors are potentiated by the preoperative use of St. John’s wort. Also, it inhibits norepinephrine reuptake and downregulates adrenergic receptors, thus increasing the risk of cardiovascular collapse.

PREVENTION The use of herbal medications cannot be discounted and must be addressed in the preoperative assessment. Because of the long median elimination half-lives of hyperphorin (9 hours), hypericin (43 hours), and pseudohypericin (25 hours), patients should be advised to discontinue the use of St. John’s wort 5 to 7 days before anesthesia and surgery, if possible.

Further Reading Ang-Lee M, Yuan C-S, Moss J: Complementary and alternative therapies. In Miller RD (ed): Miller’s Anesthesia, 6th ed. Philadelphia, Churchill Livingstone, 2005, pp 605-615. Atlee JL: Management of perioperative dysrhythmias. Anesthesiology 86:1397-1424, 1997. Atlee JL, Bosnjak ZJ: Mechanisms for cardiac dysrhythmias during anesthesia. Anesthesiology 72:347-374, 1990. Boehnert MT, Lovejoy FH: Value of the QRS duration versus the serum drug level in predicting seizures and ventricular arrhythmias after an acute overdose of tricyclic antidepressants. N Engl J Med 313:474-479, 1985. El-Ganzouri AR, Ivankovich AD, Braverman B, et al: Monoamine oxidase inhibitors: Should they be discontinued preoperatively? Anesth Analg 64:592-596, 1985. Glassman AH, Bigger JT: Cardiovascular effects of therapeutic doses of tricyclic antidepressants: A review. Arch Gen Psychiatry 38:815-820, 1981. Hodges PJ, Kam PC: The perioperative implications of herbal medicines. Anaesthesia 57:889-899, 2002. Kam PC, Chang GW: Selective serotonin reuptake inhibitors: Pharmacology and implications in anaesthesia and critical care medicine. Anaesthesia 52:982-988, 1997. Kudoh A, Katagai H, Takazawa T: Antidepressant treatment for chronic depressed patients should not be discontinued prior to anesthesia. Can J Anaesth 49:132-136, 2002. Mcfarlane HJ: Anesthesia and the new generation monoamine oxidase inhibitors. Anaesthesia 49:597-599, 1994. Scher CS, Anwar M: The self-reporting of psychiatric medications in patients scheduled for elective surgery. J Clin Anesth 11:619-621, 1999. Stack CG, Rogers P, Linter SPK: Monoamine oxidase inhibitors and anesthesia. Br J Anaesth 60:222-227, 1988.

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Case Synopsis A 45-year-old woman presents for elective cholecystectomy. During the preoperative consultation, she states that she had a lump removed from her breast 10 years earlier after “they found cancer under my arm.” She underwent six cycles of chemotherapy with radiation therapy, and the cancer has not recurred. She feels fine and denies any cardiac history.

modifiers (interleukin-2, granulocyte colony-stimulating factor [filgrastin], granulocyte-macrophage colonystimulating factor [sargramostim]); monoclonal antibodies (trastuzumab, rituximab, tositumomab)

PROBLEM ANALYSIS Definition CLASSIFICATION

AND

USE

There are numerous chemotherapeutic agents in use today. The major classes, along with their subclasses and some specific agents, are as follows: ●

●

●

● ●

● ●

Alkylating agents: nitrogen mustards (mechlorethamine, cyclophosphamide, ifosfamide, melphalan, chlorambucil); ethylenimines and methylmelamines (triethylenemelamine [TEM], thiotepa [triethylene thiophosphoramide], altretamine [hexamethylmelamine]); alkyl sulfonates (busulfan); nitrosoureas (carmustine [BCNU], streptozocin); triazenes (dacarbazine) Antimetabolites: folic acid analogues (methotrexate); pyrimidine analogues (fluorouracil, floxuridine, cytarabine, gemcitabine); purine analogues (mercaptopurine, azathioprine, thioguanine, fludarabine phosphate, pentostatin, cladribine) Natural products and synthetic congeners: antimitotics (vinca alkaloids, paclitaxel and its more potent analogue docetaxel); epipodophyllotoxins (etoposide, teniposide); camptothecin analogues (the parent compound [camptothecin] had significant antitumor activity but was subsequently discarded in favor of analogues with less severe and more predictable toxicity, such as irinotrecan and topotecan); antibiotics (dactinomycin [actinomycin D], daunorubicin, doxorubicin, idarubicin), newer synthetic analogues of doxorubicin (valrubicin, epirubicin, mitoxantrone), bleomycins (bleomycin sulfate, mitomycin) Enzymes (L-asparaginase) Miscellaneous agents: platinum coordination complexes (cisplatin, carboplatin, oxaliplatin); hydroxyurea; procarbazine; mitotane Hormones: adrenocorticosteroids Aminoglutethimide and two newer classes of aromatase inhibitors (the enzyme that converts androgens to estrogens): analogues that block this conversion (formestane, exemestane) and the imidazole inhibitors (anastrozole, vorozole, letrozole); steroidals (progestins, estrogens and androgens, antiestrogens [tamoxifen, raloxifene], antiandrogens [flutamide, nilutamide, bicalutamide]); gonadotropin-releasing hormone analogues (leuprolide, goserelin, triptorelin, buserelin); biologic response

110

The potential perioperative complications associated with all chemotherapeutics cannot be addressed here. This chapter focuses on two commonly used anthracycline antibiotics and a synthetic analogue. Information about other important, representative chemotherapeutic agents is provided in Table 30-1. Anthracycline antibiotics and their derivatives are among the principal chemotherapeutics in use today. Daunorubicin (Cerubidine, daunomycin, rubidomycin) and doxorubicin (Rubex, Adriamycin) were first isolated from the fungus Streptomyces peucetius. Synthetic derivatives are available (e.g., idarubicin [Idamycin]). Although they differ slightly in chemical structure, daunorubicin and idarubicin are used, along with cytarabine (see Table 30-1), against acute myelogenous and lymphocytic leukemias. In fact, daunorubicin is among the most active drugs against acute myelogenous leukemia in adults. A daunorubicin citrate liposomal drug preparation (DaunoXome) is used to treat Kaposi’s sarcoma related to acquired immunodeficiency syndrome (AIDS). Doxorubicin has activity against acute leukemias, malignant lymphomas, and other human neoplasms. A doxorubicin liposomal product (Doxil) is used against AIDS-related Kaposi’s sarcoma. In contrast to daunorubicin, doxorubicin has activity against solid tumors. Along with cyclophosphamide, procarbazine, and vincristine (or others), it is critical for the successful treatment of Hodgkin’s and non-Hodgkin’s lymphomas. Doxorubicin is also used in regimens against breast and small cell lung carcinomas; adult and pediatric sarcomas (osteogenic, Ewing’s, soft tissue); cancer of the cervix or endometrium, prostate, testes, and head and neck; and plasma cell myeloma. However, the clinical value of these “parent” anthracycline antibiotics (daunorubicin, doxorubicin) is limited by an unusual and often irreversible cardiomyopathy that is directly related to the total amount of agent received. Thus, in the search for agents with higher antineoplastic activity but less cardiotoxicity, numerous derivatives have been prepared, some of which have shown promise in clinical studies: ● ● ●

Idarubicin (leukemia) Epirubicin (solid tumor chemotherapy) Mitoxantrone (prostate cancer, leukemia, high-dose chemotherapy)

Catalyzes the hydrolysis of L-asparagine (required by some neoplastic cells—e.g., acute lymphoblastic leukemia—for protein synthesis) to aspartic acid and ammonia, which deprives neoplastic cells of an essential amino acid, leading to cell death Antibiotic; cleaves DNA The drug in clinical use is a mixture of two copper-chelating peptides (bleomycin A2 and B2); interactions with O2 and Fe2+ lead to scission of DNA

L-Asparaginase

Busulfan Alkylating agent; few actions other (Myleran,Busulfex) than myelosuppression at conventional doses; at low doses, selective depression of granulocytopoiesis

Bleomycin (Blenoxane)

(Oncaspar, Elspar)

Anastrozole (Arimidex)

Antibiotic; binds to DNA to form highly stable drug-DNA complexes that block DNA transcription by RNA polymerase; this inhibits any rapidly proliferating cells Nonsteroidal; inhibits imidazole aromatase; effectively blocks the biosynthesis of estrogen

Mechanism of Antineoplastic Effect

Highly effective for ovarian or testicular germ cell tumors With cisplatin and vinblastine or etoposide, curative for testicular cancer With cisplatin and other agents, highly active for GU tract squamous cell, esophageal, and head and neck carcinomas Sometimes used as a component of therapy for Hodgkin’s and non-Hodgkin’s lymphomas For chronic granulocytic leukemia, expect remission in 85%-90% of patients after initial therapy; however, the drug has largely been replaced by interferon-α and hydroxyurea

Useful component of therapy for acute lymphoblastic leukemia and other lymphoid malignancies

Pediatric tumors: Wilms’ and Ewing’s tumors Additional activities: Kaposi’s sarcoma, choriocarcinoma, metastatic testicular sarcoma Primary therapy: estrogen or unknown receptor Postmenopausal, advanced, or metastatic breast cancer; recurrence of disease after tamoxifen

Important Indications

No androgenic effects; metabolized in liver; dosing unaffected by renal dysfunction; long half-life (50 hr); can be given orally once daily; suppresses estrogen to below detectable concentrations; has a favorable toxicity profile Hypoalbuminemia; hyperglycemia; thrombosis; less often, hemorrhagic events Most thromboses are in patients with gene defects: factor V Leiden; protein S, C, or AT III; low or ↑ homocysteine

With SC extravasation, marked local inflammation; very potent immunosuppressant

Clinical Considerations

Continued

Pulmonary toxicity (dry cough, fine Little myelosuppression; avoid high FiO2; rales, diffuse infiltrates leading judicious IV fluids in patients with to possibly fatal pulmonary fibrosis), pulmonary toxicity, especially with worsened by ↑ FiO2 fibrosis Skin toxicity: erythema, hyperkeratoses, hyperpigmentation, ulcerations, N/V Unusual toxicity in patients with lymphomas: severe hyperthermia and hypotension; then sustained cardiorespiratory arrest Nonimmune? Endogenous pyrogen? Low doses: cytotoxic action does not Allopurinol reduces renal damage from appear to extend to lymphoid or urate deposits GI tissues Expect lower leukocyte counts by High-dose regimens: pulmonary 3 wk, then a reduction in spleen fibrosis and hepatic veno-occlusive size in CML disease

Few effects on bone marrow or GI mucosa; severe toxicity due to antigenicity and protein synthesis inhibition; hypersensitivity reactions in 5%-20% of patients (may be fatal); deficient insulin or clotting factors

Reduced toxicity: acne (“androgenic skin”), alopecia, N/V

Myelosuppression (pancytopenia), N/V, anorexia, diarrhea, proctitis, cheilitis, ulcerations (oral and GI mucosa, skin), alopecia

Clinical Toxicities

Mechanisms, Uses, and Toxicities of Selected Chemotherapeutic Agents Other than Anthracycline Antibiotics

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Dactinomycin or actinomycin D (Cosmegen)

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Table 30–1

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112

Enters cells by diffusion – Replacement of Cl by water yields a positively charged molecule that may be responsible for drug activity; this can react with nucleic acids and proteins – Acquation is favored at low [Cl ]; – high [Cl ] stabilizes cisplatin Platinum complexes react with DNA, forming intra- and interstrand cross-links; DNA adducts inhibit replication and transcription of DNA breaks and miscoding; ability to form these adducts predicts efficacy Cyclophosphamide Most widely used alkylating drug; (Cytoxan, converted by liver P-450 enzymes Neosar) to acyclic aldophosphamide and 4-hydroxycyclophosphamide (tautomers that are in steady-state equilibration with each other); the latter is metabolized to inactive metabolites that may limit liver damage; aldophosphamide is converted in malignant cells to phosphoramide mustard and acrolein; the former, an alkylating agent, is antineoplastic Pretreatment with phenobarbital (which induces liver P-450 enzymes) enhances drug activation but does not affect its toxicity or therapeutic efficacy

Mechanism of Antineoplastic Effect Thrombocytopenia (prolonged) is possible Initially, rapid cell destruction leads to extensive purine catabolism and renal damage from precipitation of urates N/V in almost all patients Nephroxicity can be mostly prevented with hydration and diuresis Tinnitus and high-frequency hearing loss more frequent or severe with repeat dosing in children Peripheral neuropathy may worsen after repeated cycles of therapy Electrolyte imbalance (↓ Ca2+, Mg2+, K+, PO4) common and can cause tetany or promote arrhythmias Hemolytic anemia, hyeruricemia, and seizures Cardiac abnormalities have been reported Myelosuppression (platelet sparing), N/V, alopecia, SIADH, GI mucosal ulcerations and (less common) interstitial pulmonary fibrosis With high-dose IV therapy, renal, hepatic, and cardiac toxicities may occur; sterile hemorrhagic cystitis occurs in 5%-10% of patients secondary to acrolein

In AML, busulfan (high doses) + cyclophosphamide is given for bone marrow transplants Also used in polycythemia vera and myeloid fibrosis-metaplasia

Alone, for susceptible lymphomas and chronic leukemia Higher doses with other drugs: breast cancer, lymphomas Key drug in non-Hodgkin’s or Burkitt’s lymphoma Used with methotrexate (or doxorubicin) + fluorouracil after breast cancer surgery Other uses: multiple myeloma; lung cancers; cancer of the breast, ovaries, or cervix; childhood neuroblastoma or retinoblastoma As immunosuppressant: organ transplants, Wegener’s granulomatosis, rheumatoid arthritis, pediatric nephrotic syndrome

Combined chemotherapy with cisplatin, bleomycin, etoposide, and vinblastine is 85% curative for advanced testicular carcinoma If combined with paclitaxel, doxorubicin, or cyclophosphamide, it is beneficial in ovarian carcinoma Also produces responses in cancers of the head and neck, endometrium, small cell lung carcinoma, and some childhood neoplasms Sensitizes cells to cytotoxic effects of radiation therapy

Clinical Toxicities

Important Indications

No SC extravasation reactions or thrombophlebitis Reduce cystitis incidence with mesna + diuresis Stop drug if dysuria or hematuria occurs Hepatic P-450 required for activation; may be less effective with liver dysfunction Caution: renal dysfunction is possible; ample fluids advised, but water intoxication is possible Cyclophosphamide and others (mechlorethamine) prolong block with some muscle relaxants (i.e., act as anticholinesterases)

Prevent N/V with ondansetron and high-dose corticosteroids For electrolyte imbalance, use K+, Mg2+ repletion therapy Anaphylactic-like reactions may occur minutes after administration (facial edema, bronchospasm, tachycardia, hypotension) and are treated with IV epinephrine + corticosteroids or antihistamines.

Clinical Considerations

Mechanisms, Uses, and Toxicities of Selected Chemotherapeutic Agents Other than Anthracycline Antibiotics—cont’d

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Metabolism by cytochrome P-450 system (primarily by CYP3A4) mandates careful surveillance for possible drug-drug interactions

Periorbital and leg edema, muscle cramping, GI hemorrhage

Major toxicity: GI epithelium, bone marrow Patients possibly at risk for spontaneous hemorrhage or severe infections Side effects often last for weeks Chronic bone marrow suppression with renal dysfunction due to slow MTX excretion Other toxicities: alopecia, dermatitis, lung (interstitial pneumonitis), kidneys, defective oogenesis or spermatogenesis, teratogenesis or abortion

CML (with bcr-abl translocation); some GISTs (mostly stomach) and lymphoid CML; possibly some activity against other solid tumors As a single agent, imatinib has remarkable remission-inducing activity Some GIST subsets have mutations that confer in vitro resistance to imatinib Acute lymphoblastic leukemia in high doses in children Valuable for remission induction or consolidation and for maintaining remissions in leukemia; less valuable for adult leukemia, except for treatment or prevention of leukemic meningitis Intrathecal MTX: therapy or prophylaxis of meningeal leukemia, lymphoma, or carcinomas Proven value in choriocarcinoma and related trophoblastic tumors in women

Continued

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Potent immune suppressant that reduces platelets, hemoglobin, and leukocytes Eliminated renally via glomerular filtration and tubular secretion; ensure adequate hydration to avoid MTX precipitation in renal tubules; also, avoid drugs that decrease renal flow or are weak acids or direct nephrotoxins (NSAIDs, piperacillin, aspirin, cisplatin) Half of MTX is bound to plasma proteins and is displaced from plasma albumin by salicylates, chloramphenicol, sulfonamides, tetracyclines, and phenytoin

Response to therapy affected by proportion of drug converted to ara-CTP, which depends on relative activities of a number of anabolic or catabolic enzymes (see Chabner under “Further Reading”) Relationships exist between ara-CTP synthesis and its retention in leukemic cells, and remission duration in AML; cells’ ability to transport ara-CTP is another important factor in determining clinical response Owing to a rapid fall in plasma drug concentrations to levels less than those needed to saturate drug transport or activation processes, many clinicians use high-dose regimens to attain 20- to 50-fold higher serum levels; this has improved the induction of remissions

Best agent for inducing remissions As a potent myelosuppressant, in AML in children and adults; toxicity includes thrombocytopenia, as single therapy, remission rates severe leukopenia, and anemia with of 20%-40% reported, but more striking megaloblastic changes effective with anthracyclines or Causes fever, GI disturbances, mitoxantrone stomatitis, mild reversible hepatic Given as a single IV injection or by dysfunction, pneumonitis, and continuous infusion (varying dosage); dermatitis children may tolerate higher doses After intrathecal administration, than adults seizures and other neurotoxic Intrathecal ara-C has been used against manifestations can occur; also meningeal leukemia possible when high IV doses Liposomal ara-C (DepoCyt) appears (>3 g/m2) are given to patients to be as effective as IV ara-C ≥40 yr and/or with renal Especially useful for adult, acute dysfunction or abnormal alkaline nonlymphocytic leukemia phosphatase Used in aggressive non-Hodgkin’s lymphomas and for acute lymphocytic leukemia relapses in patients of all ages

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Cytarabine or ara-C Antimetabolite, pyrimidine analogue; (Cytosar-U, penetrates cells by a carrierTarabine PFS) mediated process; activated by conversion to ara-CMP (a 5′-monophosphate nucleotide), which reacts with nucleotide kinases to form diphosphatetriphosphate nucleotide residues (ara-CDP, ara-CTP), potent inhibitors of DNA polymerase; effects extend not only to DNA synthesis but also to repair Precise mechanism of cellular death is not understood; fragmentation of DNA is observed in ara-C–treated cells, and there is evidence of apoptosis in tumor and normal cells Kinetic properties also affect results of therapy Intracellular concentrations of araCTP must be at inhibitory levels for ≥1 cell cycle Response to ara-C is strongly affected by proportion of drug converted to ara-CTP Imatinib mesylate FMS-like TK 3 (FLT3) receptor exists (Gleevec) in myeloid and some lymphoid leukemias The bcr-abl translocation in CML encodes for abnormal TK, needed for cell proliferation and survival; it causes the Philadelphia chromosome abnormality in CML GISTs may harbor oncogenic TK mutations and are targets for TK receptor inhibitors such as imatinib Methotrexate Folic acid is an essential dietary (Folex, Mexate, factor; from it are derived Rheumatrex, tetrahydrofolate (TH4) cofactors others) that provide single carbon groups for the synthesis of precursors of DNA (thymidylate and purines) and RNA (purines) The enzyme DHFR is the primary site of action for MTX and most other folate analogues; MTX’s inhibition of DHFR leads to toxic effects via (1) partial depletion of TH4 cofactors needed for synthesis of purines and

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114 Natural antibiotic derived from Streptomyces acromogenes; also a nitrosourea alkylating agent that affects all stages of the mammalian cell cycle MNU has high affinity for insulinproducing β cells of pancreatic islets of Langerhans and causes diabetes in animal models

Important vinca alkaloids; cell cycle– specific agents that block cells in mitosis—specifically, binding to tubulin to block its ability to polymerize into microtubules; this disrupts microtubules of the mitotic apparatus to arrest cell

Vincristine (Oncovin, Vincasar PFS, others) and vinblastine (Velban)

thymidylate, (2) inhibition of folate-dependent enzymes required in thymidylate-purine metabolism, and (3) accumulation of a toxic DHFR inhibitory substrate—FH2 polyglutamate

Mechanism of Antineoplastic Effect

Vincristine and corticosteroids are first-line therapy for inducing remission of leukemia in children Adults with lymphomas (Hodgkin’s or non-Hodgkin’s) usually receive vincristine as part of a combined protocol

Also used in osteosarcoma and mycosis fungoides Part of combined therapy in Burkitt’s and non-Hodgkin’s lymphomas and in carcinomas of the breast, lung, head and neck, ovary, and bladder Also used in therapy of severe and disabling psoriasis Advanced and metastatic pancreatic islet cell tumors; beneficial response results in significant increase in 1-yr survival rate and doubling of median survival time Also shows promise as therapy with fluorouracil or dacarbazine for advanced carcinoid tumors

Important Indications

Liver dysfunction is often reversible but may lead to cirrhosis (e.g., chronic continuous therapy, as in psoriasis) Intrathecal use often causes inflammatory response in CSF or meningismus Seizures, coma, and death (rare occurrences) Nausea (common) Renal or hepatic toxicity in about two thirds of patients; renal toxicity is usually reversible, dose related, and cumulative, but may be fatal; proximal tubular damage is the most important effect; urinary protein assays are used to detect early toxicity; not given with nephrotoxic drugs Hematologic toxicity occurs in 20% of patients and includes anemia, leukopenia, and thrombocytopenia Vincristine: toxicity is predictable, cumulative, and mostly neurologic—extremity numbness or tingling and loss of deep tendon reflexes (early, common), followed by motor weakness; the former usually do not warrant an

Clinical Toxicities

Neurologic toxicity is avoided or reversed by stopping therapy or reducing the dosage when motor dysfunction first occurs Severe constipation or obstipation is prevented with laxatives or hydrophilic agents

Unmodified MNU (active moiety) causes delayed myelosuppression; streptozocin does not Also, MNU carbamoylates lysine residues of proteins; it is attached to these to alter specificity, distribution, and toxicity (e.g., carmustine and lomustine are lipophilic and cross the blood-brain barrier and are used for brain tumors; unlike streptozocin, they cause profound, cumulative myelosuppression)

Folinic acid (Leukovorin) does not reverse neurotoxicity

Clinical Considerations

Mechanisms, Uses, and Toxicities of Selected Chemotherapeutic Agents Other than Anthracycline Antibiotics—cont’d

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Vinblastine was once used with bleomycin and cisplatin to cure metastatic testicular tumors, but etoposide has largely replaced it Other indications for vinblastine are breast cancer, Hodgkin’s disease, Kaposi’s sarcoma, histiocytosis, neuroblastoma, and choriocarcinoma

immediate dose reduction, but motor loss dictates re-evaluation of therapy; vocal cord paralysis or extraocular muscle function loss is rare In high doses, vincristine can cause severe constipation or obstipation; intrathecal injection causes fatal CNS toxicity; SIADH occurs rarely Vinblastine: nadir of leukopenia occurs by 7-10 days, with recovery by 7 days; other toxicities include neurotoxicity (as for vincristine), GI disturbances, and SIADH; alopecia, oral mucositis, and dermatitis are rare; extravasation during injection may lead to cellulitis and phlebitis

Alopecia occurs in about 20% of patients but is always reversible (often without stopping therapy) Myelodepression (leukopenia, anemia, thrombocytopenia) is more common with vincristine than vinblastine Hyponatremia, high urinary Na+, and SIADH are occasionally seen In view of the rapid action of vinca alkaloids, one must prevent hyperuricemia with allopurinol Vinca alkaloids are extensively metabolized by the liver, so caution is advised in patients with decreased hepatic function Vinca alkaloids are very irritating to tissues

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PHARMACOLOGY

AML, acute myelogenous leukemia; AT, antithrombin; CML, chronic myelogenous leukemia; CSF, cerebrospinal fluid; DHFR, dihydrofolate reductase; FiO2, fractional inspired oxygen; GI, gastrointestinal; GIST, gastrointestinal stromal tumor; GU, genitourinary; IV, intravenous; MNU, methylated nitrosourea; MTX, methotrexate; N/V, nausea or vomiting; NSAIDs, nonsteroidal anti-inflammatory drugs; SC, subcutaneous; SIADH, syndrome of inappropriate antidiuretic hormone secretion; TK, tyrosine kinase. From Chabner BA, Ryan DP, Paz-Ares L, et al: Antineoplastic agents. In Hardman JG, Limbird LE (eds): Goodman and Gilman’s The Pharmacological Basis of Therapeutics, 10th ed. New York, McGraw-Hill, 2001, pp 1389-1459; and www.pdr.net.

division in metaphase (microtubules are important for other cell functions as well: movement, axonal transport, phagocytosis) Without an intact mitotic spindle, chromosomes disperse throughout the cytoplasm (“exploded mitosis”) or cluster oddly Incorrect chromosomal segregation during mitosis causes cell death Normal and malignant cells exposed to these agents undergo changes characteristic of apoptosis

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Mitoxantrone (an anthracenedione) has significantly less cardiotoxicity than the anthracyclines. MECHANISM

OF

ACTION

The anthracycline antibiotics have three major biochemical effects that may explain their antineoplastic efficacy (if not their toxicity). First, they function as electron-accepting and electron-donating agents. They intercalate with the DNA helix to affect many of its functions. Single- and double-strand breaks and sister chromatid exchanges interfere with the transcription of RNA and the replication of DNA. As a result, toxicity occurs in the S phase of the cell cycle, but the cell dies on entering the G2 phase. Genetic material is exchanged between chromatids, which, in addition to causing breaks in the DNA strand, renders this material mutagenic and carcinogenic. Breaks in the helix occur because intercalation disturbs the action of topoisomerase II. Second, the anthracycline antibiotics produce free radicals, giving rise to potent alkylating agents. For example, with reduced NADPH, they react with cytochrome P-450 reductase to generate semiquinone radical intermediates. In the presence of oxygen, superoxide anion radicals form to generate reactive species (e.g., H2O2, NO, and OH–) that attack DNA. At least with doxorubicin, iron catalyzes free radical production. Insertion of these free radicals into the DNA helix may also cause breaks in the DNA sequence. Third, anthracycline antibiotics interact with cell membranes to form lipid peroxides. Peroxides alter cell membrane function and, therefore, cell function. Which of these three diverse actions is primarily responsible for the efficacy or toxicity of the anthracyclines is still a matter of speculation.

Recognition Patients almost invariably know their primary tumor type but may not know or recall exactly what drugs they received or their dosages. This is especially true when patients received complex chemotherapeutic regimens or were treated in the distant past. In addition, many patients now receive their chemotherapy as outpatients, and the specific protocol used may not be included in the medical record. As a result, anesthesiologists should at least be aware of the agents used to treat the more common malignancies and the side effects of some typically used antineoplastics. The goal of chemotherapy is to administer a dose of drug that maximizes the cytotoxic effect on neoplastic cells or tissues without impairing the patient’s lifestyle when the course of therapy is completed. However, these drugs may significantly reduce the patient’s functional reserve, which becomes apparent only in the perioperative period when the patient is physiologically stressed. Anesthesiologists should maintain a high index of suspicion that such a patient’s physiologic reserve may be significantly impaired (in spite of a healthy appearance) and be prepared to evaluate this condition appropriately and initiate the indicated remedial therapy.

Risk Assessment CLINICAL CONSIDERATIONS Daunorubicin, doxorubicin, epirubicin, and idarubicin are usually administered intravenously and are cleared by hepatic

metabolism and biliary excretion. Doxorubicin has biphasic clearance, with 3- and 30-hour half-lives of elimination. Idarubicin has monophasic clearance and a half-life of elimination of 15 hours. The clearance of all anthracyclines is delayed in patients with hepatic dysfunction, and at least a 50% reduction in dose should be considered in patients with abnormal serum bilirubin concentrations. Daunorubicin and doxorubicin are converted to a variety of less active or inactive products. Idarubicin is metabolized primarily to idarubicinol, which accumulates in plasma and resembles the parent compound in activity. Daunorubicin and doxorubicin are converted to their alcohols, aglycons, and other derivatives. Rapid uptake of these anthracyclines occurs in the heart, kidneys, lungs, liver, and spleen. The anthracyclines do not cross the blood-brain barrier. Superoxide dismutase and catalase help protect against anthracycline toxicity, an effect increased by exogenous antioxidants. Both daunorubicin and doxorubicin may impart a red color to urine. Appropriate care is exercised to prevent inadvertent extravasation during intravenous administration of anthracyclines because a severe local vesicant action and tissue necrosis may result. TOXICITY The anthracycline antibiotics cause myelosuppression. This results in leukopenia and, to a lesser degree, anemia and thrombocytopenia, reaching a nadir around 10 to 14 days after beginning therapy. Stomatitis, alopecia, and gastrointestinal symptoms are also common. The anthracycline antibiotics produce a dose-dependent cardiotoxicity that is unique to this class of drugs. This cardiotoxicity may be acute or chronic and is resistant to digitalis. Acute myocardial damage is often revealed by electrocardiogram (ECG), showing flattened T waves, ST segment depression, or cardiac rhythm disturbances (notably, sinus tachycardia and extrasystoles). Often, these are selflimited and rarely cause serious complications. However, life-threatening arrhythmias have occurred within hours of doxorubicin administration in some patients. Further, the cardiac ejection fraction may be depressed within 24 hours of a single dose of these agents, but even this is often transient and rarely problematic. The pericarditis-myocarditis syndrome is a potentially life-threatening manifestation of acute cardiotoxicity with anthracycline antibiotics. Features include severe conduction disturbances or arrhythmias and frank congestive heart failure (CHF), often associated with pericardial effusion. Although this usually occurs outside of perioperative settings, it may first manifest after anesthetic induction, with surgical stress, or in the postanesthetic or intensive care unit after anesthesia and surgery. Fortunately, pericarditismyocarditis syndrome is an uncommon occurrence. CHF that is unresponsive to cardiac glycosides is the hallmark of chronic cardiac toxicity with anthracycline antibiotics. It may develop years after the completion of chemotherapy but often develops within 6 months. Electron microscopy reveals cardiac mitochondrial changes, a reduction in myocardial fibrils, and cellular cardiac degeneration after the administration of these agents. On ECG, the QRS voltage is reduced, and the systolic time interval is prolonged. The extent of myocardial damage is directly proportional to

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EVALUATION

AND

WORKUP

The first and most important element when assessing risk in patients who are receiving (or have received) anthracycline antibiotic chemotherapeutics is a high index of suspicion for associated cardiotoxicity. This cannot be overemphasized. Often, these patients do not appear physically handicapped based on their history, physical examination, and routine laboratory test results. Only when their cardiac functional reserve is tested (e.g., during exercise stress testing) does it become apparent that further (i.e., perioperative) cardiac stress will be poorly tolerated. Once the anesthesiologist suspects that a patient has received a chemotherapeutic agent that could compromise cardiopulmonary function, every effort must be made to determine the regimen used, including the dose and pathway of concurrent or subsequent irradiation therapy. The drugs, their associated toxicities, and therapeutic implications (see Table 30-1) must be carefully assessed. This includes defining the patient’s baseline physiologic functional status and the anticipated insult from any surgical or other intervention requiring anesthesia. Radionuclide-gated blood pool studies may be the most sensitive test for detecting CHF, but an echocardiogram is a reasonable alternative. The patient should have an ECG and evaluation of the cardiac ejection fraction before the initiation of anthracycline chemotherapy and before each cycle of such therapy after cumulative doses of 400 mg/m2. No test can predict which patients will develop CHF with therapy. Acute or chronic toxicity is unpredictable. Common sense suggests reducing the cumulative dose in patients with preexisting heart disease. The preoperative evaluation should include the following: ● ● ● ●

Cumulative dose of drugs administered Date of final administration Associated therapy (e.g., irradiation? if so, how directed?) Results of cardiac functional evaluation (ECG, echocardiogram, multiple gated image analysis, exercise stress testing, or a combination) before therapy was initiated and 6 months after the last cycle of chemotherapy

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117

Because myocardial injury may progress for years after therapy, ideally, cardiac function should be evaluated within 1 month of interventions requiring anesthesia. However, given current cost concerns, this may not be justified unless the patient’s history suggests a deteriorating functional status. CONFOUNDING ISSUES

AND

VARIABLES

Irradiation of the mediastinum; exposure to cyclophosphamide, vincristine, or fluorouracil; or the addition of another drug can exacerbate the toxicity associated with these drugs. Indeed, in one study, all cases of CHF in patients who had received radiation therapy to the mediastinum occurred after anthracycline antibiotic doses of less than 315 mg/m2. Calcium channel blockers also may increase the risk for cardiotoxicity. As noted earlier, when CHF does develop, the mortality rate can exceed 50%. Dexrazoxane appears to reduce cardiotoxicity with the anthracycline antibiotics. Its addition to the regimen may allow higher cumulative doses of these agents. Newer anthracycline analogues (e.g., epirubicin, mitoxantrone, idarubicin) may have less cardiotoxicity but retain near full cytotoxic potential against some malignant cells. Thus, although they may have a narrower spectrum of action, they may be inherently safer. Finally, doxorubicin can cause red streaks near the infusion site (i.e., Adriamycin flare), even without extravasation of the vesicant. Also, doxorubicin can cause severe local toxic effects in irradiated tissues, even when chemotherapy and irradiation therapy are not concurrent.

Implications Cancer has now surpassed heart disease as the leading cause of death in the United States. Patients with cancer live longer and, increasingly, present to hospitals or ambulatory care facilities for treatment requiring an anesthesiologist’s services— anesthesia for surgical or other painful interventions, pain management, critical care, or treatment for disease progression, a new malignancy, or another problem. Regardless, patients who have received anthracycline antibiotics tolerate anesthetics or other myocardial depressants poorly, even without evidence of loss of myocardial function (e.g., reduced ejection fraction). Invariably, these patients have reduced inotropy that is difficult to assess with echocardiography or cardiac catheterization. If anesthesia is required for such patients, the anesthesiologist must give serious consideration to a regional anesthetic technique, if suitable. Perioperative care should include the following: ● ● ● ● ● ●

Limiting intravenous fluids Improving the inotropic state Reducing afterload to optimize cardiac output Careful selection of the intravenous induction agent Judicious use of invasive cardiovascular monitoring Availability of mechanical circulatory assistance, if needed (however, this intervention often proves minimally beneficial)

Although this chapter focuses on anthracycline-induced cardiotoxicity, anesthesiologists should be aware of the mechanisms of action, important indications, and clinical

PHARMACOLOGY

the cumulative dose of the anthracycline antibiotic or synthetic congeners. Although practical and completely reliable tests are unavailable, serious cardiomyopathy with doxorubicin occurs in 1% to 10% of patients with total doses less than 450 mg/m2 of body surface area (BSA). This risk increases to more than 20% of patients with total doses greater than 550 mg/m2 BSA. Such total dosage should rarely be exceeded, and then only with the concomitant administration of dexrazoxane (Zinecard), a cardioprotective, intracellular chelating agent (see “Confounding Issues and Variables”). The mortality rate with significant anthracycline-related cardiomyopathy can exceed 50%. Total doses as low as 250 mg/m2 can cause myocardial toxicity, as revealed by subendocardial biopsies. Children appear to be at even greater risk, because anthracyclines impair myocardial growth. Among pediatric patients, 5% to 10% will have overt CHF by the time they become adults, and subclinical cardiac dysfunction will develop in 40%. Finally, cardiac irradiation or the coadministration of high doses of cyclophosphamide or other anthracyclines may increase the risk of cardiotoxicity.

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toxicities and indications of other important and widely used chemotherapeutic agents (see Table 30-1).

the anesthesiologist will be able to tailor any anesthetics or drugs used for pain management to the needs of the patient.

MANAGEMENT

Further Reading

Therapy for anthracycline-induced CHF includes the following: ● ● ● ●

Diuretics Afterload reduction Low-sodium diet Bed rest

Therapy should also include cardiac glycosides, despite their limited benefit (anthracycline-induced cardiotoxicity is resistant to digitalis). Although these interventions may provide some symptomatic and functional improvement, the direct effects of cardiotoxicity are irreversible. Finally, because of the loss of contractile elements, mitochondrial damage, and unsatisfactory geometry of a dilated ventricle, the response to nondigitalis inotropes may be quite limited. An intensive care unit should be available postoperatively to receive the patient if needed.

PREVENTION There is no acceptable therapeutic alternative to chemotherapeutic drugs in many patients. Even after a successful course of chemotherapy, a patient may continue to require the services of an anesthesiologist for related or nonrelated surgery or other painful interventions or for chronic pain management. With the anthracycline antibiotics, prevention focuses on how best to minimize the risk for further depression of myocardial function. Thus, awareness that some myocardial injury has occurred and evaluation of its severity are critical to anesthetic or pain management. With such knowledge,

Capizzi RL: Principles of treatment of cancer. In Stein JH (ed): Internal Medicine, 4th ed. New York, Mosby–Year Book, 1994, pp 707-729. Chabner BA, Ryan DP, Paz-Ares L, et al: Antineoplastic agents. In Hardman JG, Limbird LE (eds): Goodman and Gilman’s The Pharmacological Basis of Therapeutics, 10th ed. New York, McGraw-Hill, 2001, pp 1389-1459. Corless CL, Schroeder A, Griffith D, et al: PDGFRA mutations in gastrointestinal stromal tumors: Frequency, spectrum and in vitro sensitivity to imatinib. J Clin Oncol 23:5357-5364, 2005. de Mestier P, des Guetz G: Treatment of gastrointestinal stromal tumors with imatinib mesylate: A major breakthrough in the understanding of tumor-specific molecular characteristics. World J Surg 29:357-361, 2005. Di Cosimo S, Ferretti G, Fazio N, et al: Docetaxel in advanced gastric cancer—review of the main clinical trials. Acta Oncol 42:693-700, 2003. Kouvaraki MA, Ajani JA, Hoff P, et al: Fluorouracil, doxorubicin, and streptozocin in the treatment of patients with locally advanced and metastatic pancreatic endocrine carcinomas. J Clin Oncol 22: 4762-4771, 2004. Kvolik S, Glavas-Obrovac L, Sakic K, et al: Anaesthetic implications of anticancer chemotherapy. Eur J Anaesthesiol 20:859-871, 2003. McCollum AD, Kulke MH, Ryan DP, et al: Lack of efficacy of streptozocin and doxorubicin in patients with advanced pancreatic endocrine tumors. Am J Clin Oncol 27:485-488, 2004. Roizen MF, Fleisher LA: Anesthetic implications of concurrent disease. In Miller RD (ed): Miller’s Anesthesia, 6th ed. New York, Churchill Livingstone, 2005, pp 1017-1149. Selvin BL: Cancer chemotherapy: Implications for the anesthesiologist. Anesth Analg 60:425-434, 1981. Sternberg DW, Licht JD: Therapeutic intervention in leukemias that express the activated FMS-like tyrosine kinase 3 (FLT3): Opportunities and challenges. Curr Opin Hematol 12:7-13, 2005. Sun W, Lipsitz S, Catalano P, et al: Phase II/III study of doxorubicin with fluorouracil compared with streptozocin with fluorouracil or dacarbazine in the treatment of advanced carcinoid tumors: Eastern Cooperative Oncology Group Study E1281. J Clin Oncol 23: 4897-4904, 2005.

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Chemical Dependency: Opioids Mark S. Gold, Adrie Bruijnzeel, Kimberly Frost-Pineda, and William Jacobs Case Synopsis A 38-year-old anesthesiologist is found unresponsive and cyanotic in the call room after failing to return from a break in the case of a patient undergoing a craniotomy for tumor. Both fresh and recent venipuncture sites are found on his left forearm, along with a 1-mL insulin syringe and a rubber tourniquet.

PROBLEM ANALYSIS Definitions The American Medical Association defines an impaired physician as “one unable to fulfill professional or personal responsibilities due to psychiatric illness, alcoholism or drug dependency.” This definition is in stark contrast to that for a professional athlete or a pilot, who is defined as impaired if “he or she is unfit for duty, shows up at work underthe-influence, or with residual effects.” As defined in the Diagnostic and Statistical Manual of Mental Disorders, drug dependence is a maladaptive pattern of substance use leading to clinically significant distress or impairment. Individuals are considered to be drug dependent when three or more of the following behaviors exist within the same 12-month period: ●

●

●

●

●

●

●

Tolerance, which is the need for more of the drug to achieve intoxication or the desired effect, or a decreased effect with continued use of the same amount of the drug. Withdrawal, in which a characteristic withdrawal syndrome appears without the substance, or the same or similar substance is taken to relieve or avoid withdrawal. The drug is taken in larger quantities or over a longer period than was intended. There is a persistent desire or unsuccessful efforts to cut down or control use. A significant amount of time is spent in obtaining, using, or recovering from use. Important social, occupational, or recreational activities are reduced or stopped because of use. Use continues despite adverse consequences.

and denial are part of the disease of addiction. Naturally, the intensity of withdrawal depends on whether a tolerant and dependent person is given an antagonist (e.g., naloxone, naltrexone) to provoke withdrawal or whether opiates are slowly discontinued. Abrupt withdrawal from opiates often results in nausea, vomiting, diarrhea, goose flesh, dilated pupils, perspiration, increased vital signs (pulse rate, respiratory rate, blood pressure), bone and muscle aches, and a delusional fear that death will occur without opiates. These symptoms are associated with a very strong drive for the drug. Track marks and other physical evidence of parenteral use may be found during examination of a chemically dependent anesthesiologist. Most anesthesiologists, however, are quite adept at using needles and finding discreet intravenous injection sites. Patients, physician colleagues, and loved ones often recognize the drug seeking, acquisition, and consumption after it becomes clear that addiction is the cause of observed problems. Clinicians and experienced addicts recognize that a protracted syndrome, which may last for months and include episodes of sweats, night terrors, dysphoria, drug craving, and malaise, generally follows the acute withdrawal phase with its dramatic symptoms. Laboratory diagnosis is the gold standard. Drug testing is available and reliable when the correct methodology is used and the correct body fluid for the particular opioid being abused is tested. Thin-layer chromatography is the most inexpensive and commonly used comprehensive test. Enzyme-linked immunoassays can detect opiates, methadone, and propoxyphene even in the microgram or picogram per milliliter range. Gas chromatography with mass spectroscopy is a gold standard for testing. Blood testing using this method or radioimmunoassay is necessary for some very potent opioids (e.g., fentanyl).

Recognition

Risk Assessment

Although drug testing is used in emergencies because clinical diagnosis is so unreliable, a medical history and physical examination coupled with confirmatory laboratory testing are useful for diagnosing drug dependence. Direct observation of a health professional using drugs, inappropriately carrying or procuring drugs, or having withdrawal symptoms makes the diagnosis possible. This is so because lying

Opiates have been important analgesics and drugs of abuse for centuries. With the availability of parenterally administered opiates and the invention of the hypodermic syringe, opiate addiction and withdrawal distress are now major, worldwide public health problems. Drug dependence is a disorder characterized by compulsive drug use, tolerance, and withdrawal symptoms with cessation of drug use. 119

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The concept of drug tolerance was originally based on the observation that opioids lose their physiologic effects with repeated use. As tolerance develops, drug-dependent subjects progressively increase the dose of the drug to achieve the originally experienced euphoric effects. In the psychopharmacologic context, tolerance is an organism’s adaptive response to supraphysiologic levels of an exogenous substance. A major drawback of this adaptation is that on cessation of drug use, the physiologic adaptations remain unopposed and induce a physiologic withdrawal syndrome. After chronic opioid use, cessation can induce a severe physical withdrawal syndrome including diarrhea, hypertension, vomiting, and muscle cramps. Depression, dysphoria, or negative affective symptoms (e.g., anhedonia) are associated with the cessation of almost all drugs of abuse. Depression and suicide are common comorbidities with drug abuse and dependence. In contrast to drug use, drug dependence is characterized by loss of control over drug intake and the development of tolerance and withdrawal. Addiction among health professionals is a significant public health problem. Without treatment, impaired professionals harm themselves, their families, and their patients. Although treatment outcomes for physician addicts are remarkably positive, there is a dearth of research on the primary prevention of substance abuse and dependence in this population. Researchers have studied opioid-addicted physicians for decades, reported on the use of clonidine and naltrexone in this population, and followed them for many years after detoxification. Although physicians are overrepresented among prescription drug addicts, their rates of alcohol abuse and dependence are similar to those of appropriately matched controls. All medical schools and hospitals encounter cases of physician opioid abuse, dependence, and overdose. However, they attribute these events to poor self-regulation or ease of drug access. Substance abuse appears to be an occupational hazard among physicians, but why is this so? To become a physician, one must be a high achiever throughout high school and college to obtain the required grades and test scores for medical school admission. Additionally, potential physicians must continue to excel throughout medical school to gain internships and residencies. Physicians seem unlikely candidates for opioid injection and self-administration. However, they are 30 to 100 times more likely to become addicted to narcotics than the general population. One study estimated that 12.5% of male physicians are drug dependent, compared with 0.1% of men in the general population. Although alcohol-related disorders and cigarette smoking rates were comparable between physicians and other Harvard University graduates, physicians had higher rates of drug use and prescription drug abuse, depression, depression with substance abuse, and suicide than other age- and sex-matched professionals. At least 15% of all physicians will become markedly impaired during their careers. Stress and access have dominated the theories for physician use and dependence, but basic scientists who conduct research with cocaine or narcotics do not usually use these drugs themselves. Further, not all medical subspecialties are equally represented among physicians with substance use disorders (Fig. 31-1). Perhaps anesthesiologists suffer a high rate of drug abuse because they administer

Anesthesiologists

Psychiatrists

25% 20% 15% 10% 5% 0%

Florida MDs

Florida MDs with SUDs

Figure 31–1 ■ Substance use disorders (SUDs) among anesthesiologists and psychiatrists in Florida.

highly potent anesthetics or other drugs to patients; they also work in a confined space around the patient’s head and are exposed in the workplace to discarded drugs (e.g., narcotics, benzodiazepines) that can affect the brain, emotions, and behavior. This intriguing hypothesis merits further consideration in future investigations. Fentanyl and its analogues deserve special mention as a risk to anesthesiologists. Fentanyl abuse, overdose deaths, and dependence have been limited to health care professionals for many years. Fentanyl is a narcotic analgesic developed in the early 1960s by Janssen Pharmaceutica in Belgium. Like morphine, fentanyl is an opioid receptor agonist that preferentially binds μ-opioid receptors. Fentanyl’s chemical structure, however, is distinct from that of morphine analogues. Also, new and more potent fentanyl analogues have been developed. The most potent is 3-methylfentanyl, which is about 6000 times as potent as morphine and 600 times as potent as heroin. Unfortunately, these potent analgesics also have an extremely high abuse potential and have been associated with a large number of drug overdose deaths. Between 1979 and 1988, 108 drug overdose deaths were related to fentanyl analogues in California alone. The respiratory depressant effects of fentanyl, combined with its extreme potency, may account for the high number of overdose deaths. It has been reported that fentanyl concentrations vary between 1 and 10 ng/mL in the body fluids of those dying of fentanyl overdose, which is very low compared with the concentrations of other abused opioids. For example, free morphine concentrations in heroin overdose deaths vary between 462 and 1350 ng/mL. In 2004, prescription methadone, OxyContin-like analgesics, and fentanyl were more likely to cause an overdose death in Florida than was heroin.

Implications At the onset of therapy, a full medical and psychiatric evaluation helps predict the outcome of therapy. Intravenous drug abuse is associated with a number of medical conditions, including bacterial or viral endocarditis, hepatitis, acquired immunodeficiency syndrome, tuberculosis, cellulitis, cerebritis, wound abscess, sepsis, arterial thrombosis, renal infarction, and thrombophlebitis. The most common severe complications from intravenous drug use, however, are accidents, head injuries, memory failure, sexually transmitted diseases, seizures, depression, suicidal thinking, and suicide attempts. Opioid dependence is associated with a

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MANAGEMENT Detoxification and abstinence are the treatment of choice for physician addicts; replacement or maintenance treatments (e.g., methadone) are not used for this class of addicts. In the detoxification phase, clonidine not only provides an effective nonopiate treatment for opiate withdrawal but also allows a rapid progression from opiate dependence to maintenance, especially when coupled with naltrexone. Together, clonidine and naltrexone reduce the detoxification process from 14 days to 8 to 24 hours. This combination has rapidly become a new standard of treatment, along with opiate maintenance, detoxification and abstinence, 12-step fellowships, and therapeutic communities. Clonidine and naltrexone, however, also reveal the limitations of pharmacologic advances in the prevention and treatment of opiate addiction, for none of these treatments has greatly impacted the long-term natural history of the disease. Nevertheless, the treatment of physicians in specialized physician programs has been remarkably efficacious. Whereas most treatment programs for addicts have been shortened, physician and health care provider treatment programs have been extended to include inpatient, residential, and rehabilitation phases. Using these techniques, long-term treatment outcomes for physicians are far better than those reported for similarly diagnosed addicts in the general population. In the most recent study of randomly selected Physician Recovery Network physician addicts at 5 years, 91.4% had returned to work. This rate is comparable to the results of other studies of physician addicts. In summary, good management options exist to care for physicians addicted to narcotics and allow them to obtain meaningful recovery and return to their professional duties.

PREVENTION Our research confirms other studies’ findings that anesthesiologists have an increased rate of opiate abuse and dependence. Left untreated, addiction has numerous adverse health consequences for anesthesiologists, as well as their patients and families. Early detection is critical and makes outpatient treatment more successful. For prevention and early detection,

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consideration should be given to random testing until the cause is identified and remedied.

Further Reading Aach RD, Girard DE, Humphrey H, et al: Alcohol and other substance abuse and impairment among physicians in residency training. Ann Intern Med 116:245-254, 1992. American Psychiatric Association Diagnostic and Statistical Manual of Mental Disorders. Washington, DC, American Psychiatric Press, 1994. Bohigian GM, Croughan JL, Sanders K: Substance abuse and dependence in physicians: An overview of the effects of alcohol and drug abuse. Mo Med 91:233-238, 1994. Gold MS: Opiate addiction and the locus coeruleus. Psychiatr Clin North Am 16:61-73, 1993. Gold MS, Frost-Pineda K, Pomm R: Is addiction an occupational hazard for anesthesiologists? College on Problems of Drug Dependence, 2004. Available online at http://biopsych.com:81/CPDD04_Web/ MeetProgAbSearch_04.html Gold MS, Miller NS: Intoxication and withdrawal from opiates and inhalants. In Miller NS, Gold MS, Smith DE (eds): Manual of Therapeutics for Addictions. New York, Wiley-Liss, 1992, pp 72-86. Gold MS, Redmond DE Jr, Kleber HD: Clonidine may relieve opiate withdrawal symptoms. JAMA 240:25-27, 1978. Goldberger BA, Merves ML, Frost-Pineda K, et al: Use, misuse and diversion of methadone and hydrocodone: The deaths continue to increase J Clin Pharmacol 43:83, 2003. Henderson GL: Blood concentrations of fentanyl and its analogs in overdose victims. Proc West Pharmacol Soc 26:287-290, 1983. Henderson GL: Designer drugs: Past history and future prospects. J Forensic Sci 33:569-575, 1988. Herridge P, Gold MS: Pharmacological adjuncts in the treatment of opioid and cocaine addicts. J Psychoactive Drugs 20:233-242, 1988. Jacobs WS, Hall JD, Pomm R: Prognostic factors for physician addiction outcomes at five years. J Addict Dis 22:140, 2003. Janssen PAJ: 1-Aralkyl-4-(n-aryl-carbonyl-amino)-piperidines and related compounds. US Patent Office No. 3,164,600, 1965. Koob GF: Neuroadaptive mechanisms of addiction: Studies on the extended amygdala. Eur Neuropsychopharmacol 13:442-452, 2003. Maguire P, Tsai N, Kamal J, et al: Pharmacological profiles of fentanyl analogs at mu, delta and kappa opiate receptors. Eur J Pharmacol 213:219-225, 1992. Miller NS, Mahler JC, Gold MS: Suicide risk associated with drug and alcohol dependence. J Addict Dis 10:49-61, 1991. Moriya F, Hashimoto Y: Distribution of free and conjugated morphine in body fluids and tissues in a fatal heroin overdose: Is conjugated morphine stable in postmortem specimens? J Forensic Sci 42:736-740, 1997. Repetto M, Frost-Pineda K, Gold MS: Pharmacological therapeutics for alcohol, cocaine and opioid intoxication and detoxification. In Miller NS, Wadland WC (eds): Addictions in Medicine: Principles and Practice. Hoboken, NJ, John Wiley & Sons, 2004. Shook JE, Watkins WD, Camporesi EM: Differential roles of opioid receptors in respiration, respiratory disease, and opiate-induced respiratory depression. Am Rev Respir Dis 142:895-909, 1990. Talbott GD, Richardson AC Jr, Mashburn JS, et al: The Medical Association of Georgia’s Disabled Doctors Program—a 5-year review. J Med Assoc Ga 70:545-549, 1981. Vaillant GE, Brighton JR, McArthur C: Physicians’ use of mood-altering drugs: A 20-year follow-up report. N Engl J Med 282:365-370, 1970. Van Bever WF, Niemegeers CJ, Janssen PA: Synthetic analgesics: Synthesis and pharmacology of the diastereoisomers of N-(3-methyl-1-(2phenylethyl)-4-piperidyl)-N-phenylpropanamide and N-(3-methyl1-(1-methyl-2-phenylethyl)-4-piperidyl)-N-phenylpropanamide. J Med Chem 17:1047-1051, 1974.

PHARMACOLOGY

very high death rate, with an annual incidence of about 10 per 1000 persons among those who are untreated. Death is most often due to overdose, accidents, injuries, or general medical complications. In some places, violence accounts for more opioid-related deaths than does overdose or human immunodeficiency virus infection. Beyond these medical issues, physician addicts are exposed to significant professional risk in medical credentialing and licensure, as well as marital and other personal problems.

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Chemical Dependency: Nonopioids Mark S. Gold, Kimberly Frost-Pineda, and William Jacobs Case Synopses Alcohol Dr. P is a 60-year-old white male anesthesiologist with a 40-year history of alcohol abuse. Five years ago, he was questioned about alcohol on his breath before starting an 8:00 AM case. He immediately took a blood alcohol concentration (BAC) test, which was below detectable limits, and proceeded with the case. Two years later, the operating room staff thought they detected the smell of alcohol on his breath; that time, his BAC was 0.12. Dr. P denied having had anything to drink since midnight but admitted to drinking vodka tonics the night before. He was referred to the state physician’s health program (PHP), where he was evaluated by an addictionologist certified by the American Society for Addictive Medicine. Dr. P successfully completed an intensive outpatient program and then entered into a monitoring agreement with the PHP. He actively participated in the facilitated group meetings and attended 12-step meetings but did not get a sponsor or work the steps. Random urine testing was negative until 1 month ago. Dr. P had had three drinks after his wife retired for the night and was selected for a random urine drug screen the following morning. He notified the PHP facilitator of his relapse before the positive result was reported. Tobacco Dr. K is a 62-year-old white male anesthesiologist with a 100 pack-year history of cigarette smoking. He has smoked two packs a day since age 12 and has suffered from chronic bronchitis and chronic obstructive pulmonary disease for at least the past 12 years. He has made numerous attempts to stop smoking—including cold turkey, hypnosis, and nicotine patch—without success. He now believes that he is “too old” to quit. He slipped on a wet floor in the operating room last week and fell against the anesthesia machine. Since then, he has had left-sided chest pain at the site of the impact and had a lateral chest film taken today. He reads the film himself and sees a cavitating lesion in the right upper lobe. Cannabis Dr. B is a 28-year-old black male anesthesiologist who joined a prestigious private practice after finishing his chief residency at a major university anesthesiology program. He immediately became a favorite of many surgeons and operating room staff. He was seen smoking cigars on his way home on a number of occasions. After 6 months in private practice, he purchased a new car that was valued at over $100,000. The following Friday, after finishing his cases and leaving the hospital, he was arrested for misdemeanor possession of marijuana and drug paraphernalia after a police officer saw his car pulled to the side of the road. Dr. B was caught with six rolled “joints.” The incident was discovered by his partners within 24 hours, and he was given no option but to self-report to the state PHP. He was evaluated and found to have a long history of polysubstance dependence that had evolved into cannabis dependence and alcohol abuse. He was treated in a long-term residential treatment program and entered into a 5-year monitoring agreement with the PHP. His license was placed on probation for 2 years after treatment and then restored to unencumbered active status. He returned to private practice after completing residential treatment. Cocaine Dr. W is a 44-year-old white male anesthetist who was reported to his state PHP after being seen snorting a white powder, presumed to be cocaine, in the men’s room during the hospital Christmas party. He was contacted 2 days after the party and denied any drug abuse. A urine drug screen was requested immediately, and Dr. W reluctantly complied. It was positive for benzyleconine, a cocaine metabolite. Dr. W was not allowed to continue working and, after an evaluation by an addiction psychiatrist, was admitted to a residential substance abuse treatment program. 122

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Definition Nonopiate abuse and dependence are common among health care professionals. Alcohol and tobacco are the most commonly abused chemical substances, but marijuana is the most commonly abused illicit chemical substance in the general population. It is widely believed that tobacco, alcohol, and marijuana are the most commonly abused substances among physicians. Alcohol dependence appears to be as common among physicians as among their age-, sex-, socioeconomicmatched controls. Cannabis abuse is quite common among medical students and younger physicians, and alcohol dependency is more common among older physicians. Although the abuse of other illicit or licit substances, such as cocaine, is not as prevalent, it may cause significant impairment and have detrimental effects on the lives of health care providers, their patients, and their families. Although the diversion and abuse of prescription drugs by physicians and other health care personnel are also a concern, this problem is not discussed here. Definitions for impairment and chemical (substance) dependence are found in Chapter 31. Substance dependence can have a number of negative impacts, including severe medical and legal implications. Chemical dependence can impair function in relation to acute intoxication, drug-seeking behavior, chronic dependence, and substance withdrawal. In this chapter, we focus on the recognition of nonopiate dependence—specifically, alcohol, tobacco, marijuana, and cocaine. Also, we consider behaviors associated with such substance use, the diagnosis of dependence, its implications, and the management and prevention of substance dependency.

Recognition and Risk Assessment DIAGNOSIS Several screening tests are available for the diagnosis of substance abuse, such as the CAGE and AUDIT programs for alcohol; these have now been modified for marijuana abuse. Clinical diagnosis of substance abuse is often difficult, because denial and lying are part of the disease of addiction. Denial is the hallmark of many initial clinical interviews. Physicians may admit to use, but only on occasion. They may quote the New York Times or High Times to defend their use, as opposed to a respected medical, addiction, or psychiatric text or journal. They may actually say that marijuana smoke is not dangerous to one’s health and deny any similarities to tobacco smoking or secondhand smoke. Among health care professionals, direct observation of drug use, possession, inappropriate procurement of drugs, or signs and symptoms of intoxication or withdrawal can help make the diagnosis. The diagnosis of abuse or dependence is based on Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) criteria (see Chapter 31). The medical history and physical examination, along with confirmatory laboratory testing, are useful for diagnosis. Although there could be other reasons for changes in personality, family problems, infertility (males), withdrawal from social activities, and impaired ability to perform professional duties, a positive

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drug test moves a substance use disorder to the top of the differential diagnosis. Physicians rarely refer themselves to addiction specialists for drug abuse or dependence problems. Laboratory testing is the gold standard for confirming substance use and is also helpful during treatment. Drug testing cannot detect all marijuana, cocaine, or other illicit drug users, however. Random testing does not detect all substances of abuse and may not detect infrequent use. For example, even daily users have only a 50-50 probability of testing positive in any given month when urine testing is done eight times per year. Urine testing is standard for the evaluation and treatment of substance abuse; detection times for some common drugs of abuse are given in Table 32-1. There have also been advances in the testing of other biologic substrates, including hair, sweat, and oral fluid. Thin-layer chromatography and enzyme-linked antibody testing are the most comprehensive, inexpensive, and widely used drug screening tests, but combined gas chromatography with mass spectroscopy is the gold standard for drug testing. Marijuana impairment must be diagnosed with blood tetrahydrocannabinol (THC) concentrations. Random drug testing should be a mandatory part of all health care provider health programs. Laboratory tests may also help in the diagnosis of a chronic substance abuse problem, but they are usually performed late in the course of the disease. Heavy consumption of alcohol (e.g., one bottle of wine a day) for a few months almost always results in macrocytosis (mean corpuscular volume between 100 and 110 fL), even before anemia occurs. Alcohol-related liver disease may be reflected in abnormal serum γ-glutamyltransferase, aspartate transaminase, and alanine transaminase levels. In fact, unlike in other liver diseases, aspartate transaminase may be more than two times greater than alanine transaminase when alcoholic hepatitis is present. The Food and Drug Administration has also approved a new test that measures serum carbohydrate-deficient transferrin to identify long-term excessive alcohol use. ALCOHOL

AND

TOBACCO

Symptoms of alcohol or tobacco dependence include the following: ● ● ● ●

● ●

Impaired control over use Preoccupation with obtaining the substance Continued use, despite adverse consequences Distorted thinking, especially denial of substance dependency Development of tolerance to the effects Withdrawal symptoms when use is discontinued

Table 32–1

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Substance Detection Time in Urine

Substance

Detection Times

Amphetamines Barbiturates Benzodiazepines Cannabinoids Cocaine Opiates Phencyclidine

Up to 24 hr 5-10 days 5-7 days 1-3 days; greater with chronic use 1-3 days 1-3 days Up to 3 days

PHARMACOLOGY

PROBLEM ANALYSIS

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Although no specific constellation of symptoms is specific for the diagnosis of alcohol abuse or dependence, physical examination findings consistent with alcohol abuse are elevated blood pressure, evidence of physical harm, tremors, obstructive lung disease (due to concurrent tobacco use), and unexplained tachycardia, hepatosplenomegaly, or peripheral neuropathy. In contrast to alcohol, the health consequences of tobacco dependence generally take years to develop and are related primarily to lung cancer or chronic pulmonary disease. Just quitting smoking has immediate positive health effects, reduces the risk for adverse consequences over time, and increases the smoker’s life expectancy. (see www.cancer.org for more details). COCAINE A number of clinical and behavioral signs and symptoms of cocaine use are usually evident. Some are related to acute intoxication, and others appear after chronic use or during withdrawal (Table 32-2). Although cocaine is more commonly abused as a “street drug” (snorted as powder or smoked as crack), it is also used medicinally as a topical anesthetic and vasoconstrictor (e.g., in awake oral or nasal intubation). If so, health care professionals may have access to unadulterated cocaine, similar to fentanyl and other highly potent narcotics (see Chapter 31). Street cocaine is often adulterated or “cut” with other substances that have the potential to cause additional harm. MARIJUANA In the 1960s and 1970s, marijuana was perceived as a safe and natural drug that produced a “high” (euphoria) without the risk of negative side effects or addiction. Some young physicians still do not believe that marijuana dependence is possible and may smoke marijuana more frequently

Table 32–2

■

than cigarettes. Dependence on marijuana is related to the THC concentration in its smoke and the duration of use; signs of marijuana withdrawal can be provoked by the administration of a THC antagonist. Today, the THC concentration in “street” marijuana has been increased to encourage repeat use. Researchers at Harvard and Columbia have shown that with this increased potency, chronic marijuana use can lead to tolerance, dependence (even subhuman animal species will self-administer THC), and a distinct withdrawal syndrome. Marijuana is now one of the leading substances of abuse in persons institutionalized for the treatment of substance abuse. As defined in DSM-IV, marijuana intoxication begins with a feeling of being “high.” Symptoms vary but generally include grandiosity, euphoria, and inappropriate laughter. Acute use also causes difficulty with concentration and complex thought processes; distorted sensory and time perception; lethargy and sedation; and impaired judgment, memory (especially short-term memory), and motor performance. Marijuana use sometimes provokes anxiety and panic, which may require treatment. During and after intoxication, there is generally increased appetite, red eyes, dry mouth, and increased heart rate. As these effects subside, there is often depressed mood, anger, irritability, or social withdrawal. Experimental cannabinoid antagonists, which are now in clinical trials, appear to be the most effective treatment for the overeating and memory problems related to chronic marijuana dependence. The long-term health effects of marijuana smoke are difficult to determine because persons who use marijuana often use tobacco products as well. Recent studies have shown, however, that there are many carcinogens in marijuana smoke, which actually has 50% higher levels of tar and carcinogens than tobacco smoke does. Also, case-control studies have linked marijuana smoke to head and neck cancers.

Signs and Symptoms of Acute Cocaine Intoxication and Chronic Cocaine Abuse or Dependence Acute Cocaine Intoxication

Chronic Cocaine Abuse or Dependence

Signs

Clinical Symptoms

Physical and Mental Symptoms

Behavioral and Social Signs

Sociability—most users become overly “chatty” at low doses Hypervigilance Impaired judgment Grandiose thinking and plans Increased anxiety and tension Quick mood changes Increased libido

Blood pressure changes Breathing difficulties Dilated pupils Mental confusion Muscle weakness Tachycardia, chest pain Nausea or vomiting Psychomotor agitation or retardation, seizures Sweating or chills

Anxiety, delirium, depression, hallucinations, insomnia, memory loss, confusion, slurred speech, reflex changes, blackouts, acute vision changes, incoordination, dizziness, tremors, impotence Hypertension, irregular heartbeat, bradycardia Bronchitis, lingering colds and flu symptoms, frequent respiratory tract infections Bumps and bruises due to falls Craving for sweets or avoidance, loss of appetite, poor nutrition, liver enlargement Increased or reduced alcohol or drug tolerance Red, puffy face; red, swollen nasal mucosa

Car and boat accidents Problems with family or job (e.g., tardiness, absenteeism) Legal or financial problems Increased reliance on drugs Passive-aggressive behavior, suicidal thoughts or gestures, violent or aggressive behavior, suspiciousness

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Implications Maladaptive behavior problems are usually the first sign of chemical dependency. However, these often are not attributed to drug abuse until after an addiction is recognized. Health care professionals are generally better equipped than others to hide and deny substance abuse. Most often, family and social problems related to use occur far in advance of problems on the job. Health care professionals who are using drugs may experience changes in mood, energy level, and the ability to concentrate. They also miss work or arrive late. They may use the drug more often and at inappropriate times, taking more frequent breaks than their colleagues. In addition, they may have alcohol on their breath or smell of tobacco or marijuana smoke. Often family and friends become aware of the drug-seeking, -acquiring, and -consuming behaviors before patients and other physicians recognize the problems. Chemical-dependent health care professionals often have problems in their interpersonal relationships, and they are exposed to significant professional risk in terms of medical credentialing and licensure, as well as criminal investigations. A physician might come to attention by propositioning a prostitute or experiencing money problems related to gambling or purchasing drugs. However, these are late-stage behaviors. Early detection requires a high degree of suspicion both at the workplace and at home. Common severe complications from drug abuse include accidents, head injuries, memory failure, financial collapse, sexually transmitted diseases, seizures, depression, impulsivity, suicidal thinking, and suicide attempts. Negative affective symptoms (e.g., anhedonia), depression, and dysphoria are symptoms associated with the cessation of almost all drugs of abuse (see also Chapter 31). The chemical withdrawal syndrome specific to the drug of choice may be another sign of chronic use and dependence. The desire for the drug is probably greatest during withdrawal, because the addicted person wishes to alleviate unpleasant withdrawal symptoms. Health care professionals who abuse or become dependent on drugs have higher rates of depression, which may lead to suicide without intervention and treatment.

ALCOHOL

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TOBACCO

Alcohol and tobacco are the most widely used drugs. Alcohol is generally considered safe and may even have a beneficial effect when used in moderation. However, there are no established moderate or safe levels of tobacco use. People who smoke often drink, and those who abuse alcohol usually use tobacco; thus, dependence on both alcohol and tobacco is common. Tobacco smoking is the leading cause of death among alcoholics. Alcohol can also be potent and dangerous, causing more death and personal destruction than any other drug except for tobacco. Each year, alcohol misuse causes more than 100,000 deaths and injury to more than 2 million people; tobacco is reportedly responsible for more than 400,000 deaths annually. COCAINE The pathologic attraction to cocaine can be intense, with many experts agreeing that it is the most intense among the substances of abuse. Although detoxification is usually unnecessary, discontinuation is clinically significant and difficult to manage outside of a hospital or highly controlled environment. Craving for cocaine, anhedonia, feelings of helplessness, and drive for the drug make relapse likely. Animal self-administration models suggest that the amount of work or punishment an animal will expend or endure for a dose of cocaine is greater than for most other drugs. Once the physician addict discontinues the drug, treatment begins. We have reported on cocaine sniffing, cocaine injecting, and even crack addiction among physicians. Cocaine addiction is so profound and relapse so common that the DSM had to change the diagnostic criteria to allow addiction to be diagnosed in the absence of significant signs and symptoms of withdrawal. Addicted physicians often sign contingency contracts, agree to random and at least biweekly urine testing, and are sent to inpatient and residential treatment facilities. MARIJUANA Possessing, smoking, growing, and purchasing marijuana are all illegal. Physicians who do so are a phone call or two away from losing their licenses. This usually does not occur, however. Their spouses, children, or angry patients may call an anonymous tip line to report their behavior. Marijuana use may bring doctors into contact with other illicit drugs, leading to further experimentation. Sometimes, marijuana smoking or the use of other illicit substances brings physicians into contact with drug dealers and other criminals. Physicians are usually undertrained for this social network and may be easily blackmailed or robbed by their dealers or new “friends.”

MANAGEMENT Changes in thinking and behavior, along with a positive drug test, are usually taken as definitive evidence of substance abuse by hospital staffs, physician employment groups, and state physician health monitoring programs. Detoxification and abstinence, followed by involvement in 12-step fellowships and therapeutic communities, remain the treatment of choice for professional health care addicts. It is important

PHARMACOLOGY

People who become dependent on marijuana usually use it daily, often for months or years. When they try to stop using it, they often cannot do so for longer than 30 days. They are also easily angered by questions about their marijuana use, because they are psychopathologically attached to the substance. Often, this has a negative impact on their health, families, and careers. Moreover, they may choose parties, social contacts, or friends on the basis of whether marijuana is going to be available, and they may spend many hours each day thinking about using marijuana and later recovering from the effects. Further, they may smoke cigarettes or take psychostimulants in an attempt to reverse the effects of marijuana on their memory or performance. Dependence interferes with family life and work, but use continues despite the development of chronic problems, such as a smoker’s cough or psychological problems (e.g., excessive sedation resulting from repeated use of high doses), or social consequences.

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to note that detoxification is not sufficient treatment. Numerous treatment programs are designed to meet the special needs of addicted health care professionals. There are also a number of pharmacologic therapies that may be useful in the treatment of alcohol, tobacco, marijuana, and cocaine dependence (Table 32-3). Physicians have the best outcomes when there is long-term follow-up, random routine drug testing, 12-step group attendance, and individual follow-up with a psychiatrist and treatment facilitator.

Alcohol and Tobacco Both psychosocial and pharmacologic therapies can help in overcoming alcohol and tobacco addiction. Some of these can be purchased over the counter (e.g., nicotine replacements), but others require a prescription. For alcohol, a number of pharmacologic therapies have been approved for use in the United States, including disulfiram (Antabuse), naltrexone, and acamprosate.

Cocaine Treatment for cocaine dependence includes both residential and outpatient approaches. One primary approach is behavioral intervention. After stabilization, recovery begins with a learning process of breaking old habits, breaking ties with cocaine-using friends, and identifying “triggers” that increase the desire to use cocaine; once these triggers are identified, patients are encouraged to restructure their lifestyles to avoid them. Cognitive-behavioral coping skills provide another alternative that, in the short term, focuses on helping cocaineaddicted individuals become abstinent through a learning process. This therapy is compatible with a range of other treatments, such as pharmacotherapy. Active membership in 12-step programs, such as Narcotics Anonymous and Cocaine Anonymous, is one of the most beneficial tools for continued abstinence from cocaine and other drugs of abuse. For addicted health care professionals, regular random drug testing, a contract, and chronic follow-up care improve the long-term success of treatment. It is imperative that any positive drug tests be promptly identified and that any necessary changes in treatment plans be made quickly. Waiting can be associated with a rapid and complete relapse. Finally, cocaine abstinence and long-term use are associated with depression,

Table 32–3

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suicidal ideation, and suicide attempts; thus, cocainedependent physicians must be closely monitored.

Marijuana Treatments under study include use of the synthetic marijuana dronabinol (Marinol). This is similar to the use of methadone for heroin addicts. Relapse prevention is an important factor in the successful treatment of marijuana dependence. Recovering addicts must change their behaviors and be able to resist social and environmental cues for continued drug use. Psychosocial treatments, such as cognitive-behavioral therapy, can be successful. Pharmacologic therapies under study may be useful as maintenance therapy.

PREVENTION Prevention of substance abuse and dependence starts with abstinence—that is, no experimentation. Physicians are well educated and are therefore used as examples of the limitations of knowledge as a protective factor against addiction. Drug use, abuse, and dependence are now observed in medical students and house staff, not just in older practicing physicians. Physicians who have learned to balance their lives and manage their stress, anxiety, and workplace problems without drugs should mentor medical students to help them learn to do the same. Addiction among health care professionals is a significant public health problem that requires intervention. Without treatment, addiction leads to harm to self, family, and patients. At least 15% of all physicians will become markedly impaired sometime during their careers; however, there continues to be a dearth of research on the primary prevention of substance abuse and dependence among health care providers. Generally, the best way to prevent drug dependence is to prevent drug use in the first place. For example, there is a strong genetic risk for alcohol dependence among those who have a positive family history, especially among first-degree relatives. Such persons should refrain from using alcohol. Prevention of exposure to drugs and drug use during early childhood and adolescence is key to reducing later dependence. Prevention efforts and appropriate training should also be a focus in medical schools and other

Pharmacologic Treatment for Nonopioid Dependency

Substance

Pharmacologic Treatment

Alcohol

Antabuse—deters drinking by causing painful symptoms when alcohol is used Naltrexone—likely reduces craving and may reduce pleasurable effects of alcohol Acamprosate—reduces craving for alcohol and prevents relapse Nicotine replacement: gum, patch, inhaler, spray Detoxification: bupropion (Zyban, Wellbutrin)—originally prescribed as an antidepressant but now used primarily for smoking cessation Maintenance: Marinol—in clinical trials Antagonist: Rimonblat—in clinical trials Definitive: none at present Supportive: antidepressants, mood stabilizers (e.g., lithium)

Tobacco

Marijuana Cocaine

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Further Reading Aach RD, Girard DE, Humphrey H, et al: Alcohol and other substance abuse and impairment among physicians in residency training. Ann Intern Med 116:245-254, 1992. American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders, 4th ed [DSM-IV]. Washington, DC, American Psychiatric Press, 1994. Bohigian GM, Croughan JL, Sanders K: Substance abuse and dependence in physicians: An overview of the effects of alcohol and drug abuse. Mo Med 91:233-238, 1994. Gold MS, Aronson MD: Screening and diagnosis of patients with alcohol problems, and treatment of alcohol abuse and dependence. Harvard University’s UpToDate Web site and CD-ROM Educational Program, 2005.

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Gold MS, Frost-Pineda K: Substance abuse and psychiatric dual disorders: Focus on tobacco. J Dual Diagnosis 1:15-36, 2005. Gold MS, Frost-Pineda K, Jacobs WS: In Galanter M, Klever HD (eds): Textbook of Substance Abuse Treatment, 3rd ed. New York, American Psychiatric Press, 2004, pp 167-188. Gold MS, Jacobs W: Cocaine (and crack): Clinical aspects. In Lowinson JH, Ruiz P, Millman RB (eds): Substance Abuse: A Clinical Textbook, 2nd ed. Baltimore, Williams & Wilkins, 2004, pp 218-251. Herridge P, Gold MS: Pharmacological adjuncts in the treatment of opioid and cocaine addicts. J Psychoactive Drugs 20:233-242, 1988. Jacobs WS, Hall JD, Pomm R, et al: Prognostic factors for physician addiction: Outcomes at five years. J Addict Dis 22:140, 2003. Jacobs WS, Repetto M, Vinson S: Random urine testing as an intervention for drug addiction. Psych Ann 34:781-785, 2004. Koob GF: Neuroadaptive mechanisms of addiction: Studies on the extended amygdala. Eur Neuropsychopharmacol 13:442-452, 2003. Miller NS, Mahler JC, Gold MS: Suicide risk associated with drug and alcohol dependence. J Addict Dis 10:49-61, 1991. Repetto M, Frost-Pineda K, Gold MS: Pharmacological therapeutics for alcohol, cocaine and opioid intoxication and detoxification. In Miller NS, Wadland WC (eds): Addictions in Medicine: Principles and Practice. Hoboken, NJ, John Wiley & Sons, 2004. Repetto M, Gold MS: Cocaine (and crack): Neurobiology In Lowinson JH, Ruiz P, Millman RB (eds): Substance Abuse: A Clinical Textbook, 2nd ed. Baltimore, Williams & Wilkins, 2004, pp 195-218. Robinson TE: Addicted rats. Science 305:951-953, 2004. Talbott GD, Richardson AC Jr, Mashburn JS, et al: The Medical Association of Georgia’s Disabled Doctors Program—a 5-year review. J Med Assoc Ga 70:545-549, 1981. Vaillant GE, Brighton JR, McArthur C: Physicians’ use of mood-altering drugs: A 20-year follow-up report. N Engl J Med 282:365-370, 1970.

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health care professional educational programs to minimize the risk of future chemical dependency problems. If primary prevention has failed, there is still the opportunity for early intervention. Even if dependence has developed, we know that treatment works, especially for physician addicts, who have remarkably positive 5-year outcomes. Treatment can prevent or reduce the incidence of a number of adverse health outcomes. Another method to detect and prevent drug use that is increasingly being used in training, workplace, and treatment settings is random drug testing. Some leading institutions, such as Massachusetts General Hospital, have incorporated random testing into their substance abuse policy and now routinely test residents and house staff.

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Juliana Barr Case Synopsis An otherwise healthy 65-year-old, 80-kg man with coronary artery disease is given fentanyl (2 mg), midazolam (20 mg), and vecuronium (15 mg) intravenously during a 3-hour coronary artery bypass grafting procedure. He remains intubated and mechanically ventilated after surgery and is transferred to the intensive care unit (ICU) in stable condition. The surgeons elect for early extubation, but the patient remains deeply sedated, does not respond to painful stimuli, and is not “fighting” the ventilator. He is given intravenous (IV) naloxone (2 mg) and flumazenil (1 mg) over 5 minutes. He becomes acutely hypoxemic, with increasing rales and frothy pulmonary secretions. A chest radiograph reveals acute pulmonary edema, and the electrocardiogram shows ventricular ectopy.

PROBLEM ANALYSIS Definition Naloxone. Naloxone (Narcan) is an opioid antagonist that competitively inhibits the sedative, analgesic, and cardiopulmonary depressant effects of opioids at various opioid receptors. Typically, it is used to reverse the sedative and respiratory depressant effects of opioids. Following a single IV bolus injection, the onset of naloxone is rapid, with a short duration of effect (Table 33-1). It is metabolized hepatically, with renal excretion of its inactive metabolites. Small IV doses of naloxone (e.g., 20 to 40 μg) may reverse the respiratory depressant and sedative effects of opioids, but with incomplete reversal of the analgesic effects (Table 33-2). Larger doses may cause acute cardiopulmonary instability, especially in critically ill patients. Hypertension, tachycardia, arrhythmias, or acute fulminant pulmonary edema may occur following the administration of naloxone, even with incomplete reversal of the opioid’s analgesic and sedative effects. Flumazenil. Flumazenil (Romazicon) is a benzodiazepine antagonist with weak agonist activity at the γ-aminobutyric

Table 33–1

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Clinical Parameters of Intravenous Reversal Agents

Drug

Onset (min)

Peak Effect (min)

Duration of Effect (min)

Elimination Half-life (min)

Naloxone∗ Flumazenil

1-2 1-2

5-15 2-10

60-240 45-90

40-60† 50‡

∗Can also be given intramuscularly, subcutaneously, or endotracheally, although time to onset, peak effect, and duration and magnitude of effect may vary considerably among patients. † Doubled in neonates. ‡ Halved in neonates and prolonged in patients with liver disease.

128

acid (GABA) receptor. It is given intravenously to reverse benzodiazepine-induced sedation, amnesia, disorientation, hypoventilation, or cardiovascular instability. After a single IV bolus dose, flumazenil’s onset of action and peak effect occur within minutes (see Table 33-1). Because of its rapid hepatic clearance, flumazenil is short acting. It has no active or toxic metabolites. Flumazenil’s duration of effect may be prolonged in patients with severe liver disease owing to reduced hepatic clearance. Unlike naloxone, flumazenil does not precipitate the acute onset of cardiopulmonary instability in critically ill patients, although it can cause signs of withdrawal or seizures in some patients.

Recognition Naloxone. The onset of naloxone’s cardiopulmonary side effects is rapid. Acute pulmonary edema results from increased hydrostatic pressure across the pulmonary capillary bed and increased pulmonary capillary permeability. This causes rapid extravasation of protein-rich fluid into the lung parenchyma. Hypertension is due to increased cardiac output, as well as increased systemic and pulmonary vascular resistance. The cardiovascular side effects of naloxone may resolve more quickly than the pulmonary edema and pulmonary hypertension. Flumazenil. Like naloxone, the onset of flumazenil action is rapid. Because of its short duration of action, flumazenil does not precipitate cardiopulmonary instability; however, resedation and respiratory depression may recur after its administration. The total dose of flumazenil needed to achieve a full and sustained reversal of the side effects of benzodiazepines may vary with the potency and residual plasma concentration of the benzodiazepine used. Respiratory depression may not be fully reversed, however, even with maximal doses of flumazenil. In patients with a history of chronic benzodiazepine use, those undergoing benzodiazepine withdrawal, or those with tricyclic antidepressant overdose, flumazenil can cause seizures or other

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Dosing Reversal Agents for Postoperative Sedation and Respiratory Depression

Drug

Intermittent IV Bolus Dosing*

Continuous IV Infusion*

Naloxone Flumazenil

20-40 μg q1-2 min (5-20 μg q1-2 min) 0.2 mg q2-5 min to ≤1 mg; may repeat q20 min; maximum dose 3 mg/hr (4-20 μg/kg)

4-8 μg/kg/hr (4-8 μg/kg/hr) 0.5-1 μg/kg/min to ≤3 mg/hr (0.5-1 μg/kg/min)

∗Pediatric doses are in parentheses.

signs of drug withdrawal. There are no reports of seizures following flumazenil administration to ICU patients who received benzodiazepines for chronic sedation.

Risk Assessment Naloxone. The incidence of cardiopulmonary instability after naloxone administration is not known. Although it appears to occur more commonly in patients with preexisting cardiopulmonary disease, it has also been reported in patients without such disorders. Cardiopulmonary instability is more likely in critically ill patients and after cardiac surgery, because much larger doses of highly potent opioids (e.g., alfentanil, fentanyl, sufentanil) are used in these patients. Patients with a history of opioid use and physical dependency also appear to be at increased risk for cardiopulmonary instability, as well as seizures and other symptoms of opioid withdrawal (e.g., nausea, vomiting, diaphoresis, agitation), after naloxone. The risk for cardiopulmonary instability is increased with rapid administration of high IV doses of naloxone (400 μg).1 Flumazenil. Flumazenil is an effective means of reversing the residual sedative or respiratory depressant effects of benzodiazepines following the small doses typically used for anesthesia or conscious sedation. However, owing to flumazenil’s short duration of action, ICU patients who receive chronic infusions or large doses of benzodiazepines may experience resedation and recurrent respiratory depression once flumazenil’s antagonistic effects wear off. Therefore, flumazenil should not be used to hasten the termination of benzodiazepine sedation in these patients. However, a trial of flumazenil may be diagnostically useful in critically ill patients who fail to awaken within a reasonable time after discontinuing benzodiazepines. If the patient fails to awaken after receiving the maximal dose of IV flumazenil (3 mg over 1 hour), other causes of the persistent sedation or respiratory depression should be considered. Patients who do respond to flumazenil should be carefully monitored for up to 2 hours after the last dose of flumazenil for signs of resedation or recurrent respiratory depression.

1 Over a period of 2 months, shortly after naloxone became available for the reversal of high-dose opioid effects, the editor saw three cases of acute fulminant pulmonary edema that developed within 15 to 20 minutes after IV bolus naloxone (400 μg) was given in the postanesthesia care unit to patients who had had lengthy, major noncardiac surgeries. ICU admissions were not planned.

Implications Acute-onset hypertension, tachycardia, arrhythmias, or pulmonary edema after naloxone, or seizures after flumazenil, may not be well tolerated, especially in critically ill patients with preexisting cardiopulmonary disease. Cardiac surgical patients appear to be at even greater risk for hemodynamic instability after naloxone due to compromised myocardial performance and postoperative arrhythmias. Also, hemodynamic profiles can fluctuate rapidly with rewarming or increased circulating catecholamines. Moreover, the pulmonary capillary bed becomes more permeable owing to systemic inflammatory mediators released during cardiopulmonary bypass. If so, early postoperative naloxone may trigger acute, life-threatening cardiopulmonary changes in cardiac surgical patients. In contrast, flumazenil does not precipitate acute anxiety, hypertension, tachycardia, myocardial ischemia, or ventricular dysfunction in postoperative cardiac surgical patients who do not take benzodiazepines chronically.

MANAGEMENT Avoid IV boluses and continuous naloxone infusions if cardiopulmonary instability occurs. Treat the patient symptomatically, as follows, until naloxone’s effects resolve: ●

● ● ●

●

● ●

Control blood pressure with short-acting IV antihypertensives (see Chapter 77). Treat myocardial ischemia with nitrates (see Chapter 76). Treat tachycardia with β-blockers (see Chapter 11). Treat arrhythmias with pacing, cardioversion, or defibrillation and antiarrhythmic drug therapy (see Chapters 10-13, 79-82, and 229). Minimize intravascular volume to minimize extravasation of fluid into lung tissues (see Chapter 16). Support oxygenation and ventilation. Provide treatment for exacerbating conditions or imbalances (e.g., acidosis, hypercarbia, hypoxia, hypokalemia, hypomagnesemia, agitation, pain).

Flumazenil can precipitate withdrawal symptoms (e.g., seizures, agitation, confusion) in patients with a physical dependence on benzodiazepines and can cause seizures in patients with tricyclic antidepressant overdose. Patients with any of these symptoms after flumazenil should be treated symptomatically, as follows: ●

Seizures: antiepileptics, including benzodiazepines, phenytoin, or barbiturates

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Table 33–2

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Acute agitation and delirium: short-acting anxiolytics, including benzodiazepines Observation: careful monitoring for resedation or recurrent respiratory depression for up to 2 hours after benzodiazepine reversal with flumazenil

PREVENTION Naloxone. Avoid high doses of naloxone, especially in critically ill patients. Small IV bolus doses (20 to 40 μg) or continuous infusions (4 to 8 μg/kg per hour) may reverse opioid-induced respiratory depression and sedation without reversing the analgesic effects of opioids or precipitating cardiopulmonary instability. The duration of naloxone’s effect is brief and variable. Resedation and respiratory depression may occur following a single dose of naloxone. Although naloxone can be given intramuscularly, subcutaneously, or endotracheally, IV dosing is preferred because of the variable uptake with other routes of administration. Further, the dose does not need to be adjusted in patients with hepatic or renal insufficiency, although the elimination half-life and duration of clinical effect may be prolonged in neonates. Naloxone readily crosses the placenta and may precipitate acute withdrawal symptoms or seizures in neonates or their opioid-dependent mothers. Flumazenil. Flumazenil is safe and effective for reversing short-term sedation and respiratory depression with benzodiazepines, but not for chronically dependent patients.

It should be given in small divided doses, and patients must be carefully observed for signs of resedation and respiratory depression for at least 2 hours. Small repeat IV boluses (0.2 mg) or a low-dose continuous IV infusion (0.5 to 1 μg/kg per minute, up to 3 mg/hour) can be titrated to the desired level of sedation and ventilation. This more reliably prevents resedation of postoperative patients and also avoids abrupt or complete reversal of anxiolysis. Finally, avoid flumazenil in patients with chronic dependence on benzodiazepines or suspected tricyclic antidepressant overdose.

Further Reading Bertaccini E, Geller E: Benzodiazepine antagonists and their role in anesthesia and critical care. Anaesth Pharmacol Rev 3:74-81, 1995. Murray MJ, DeRuyter ML, Harrison BA: Opioids and benzodiazepines. In Cheng EY (ed): Sedation of the critically ill patient. Crit Care Clin 11:849-874, 1995. Rudolph U, Crestani F, Möhler H, et al: Sedatives, anxiolytics, and amnestics. In Evers AS, Maze M (eds): Anesthetic Pharmacology: Physiologic Principles and Clinical Practice. Philadelphia, Churchill Livingstone, 2004, p 431. Sasada M, Smith S: Flumazenil. In Drugs in Anaesthesia and Intensive Care, 3rd ed. New York, Oxford University Press, 2003, pp 162-163. Sasada M, Smith S: Naloxone. In Drugs in Anaesthesia and Intensive Care, 3rd ed. New York, Oxford University Press, 2003, pp 266-267. Stoelting RK: Benzodiazepines. In Pharmacology and Physiology in Anesthetic Practice, 3rd ed. Philadelphia, JB Lippincott–Williams & Wilkins, 1999, p 138. Stoelting RK: Opioid agonists and antagonists. In Pharmacology and Physiology in Anesthetic Practice, 3rd ed. Philadelphia, JB Lippincott– Williams & Wilkins, 1999, pp 106-107. White PF, Shafer A, Boyle WA, et al: Benzodiazepine antagonism does not provoke a stress response. Anesthesiology 70:636-639, 1989.

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Bhiken Naik and Lisa Thannikary

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34

Steroids Case Synopsis A 55-year-old man with severe chronic obstructive airway disease and steroid dependence is taken to the operating room emergently for an acute abdomen due to a perforated colonic diverticulum. The patient has been maintained on this dose of steroids for 1 year. Intraoperatively, he demonstrates hemodynamic instability requiring largevolume fluid resuscitation and the use of vasopressors. Postoperatively, he is transferred to the intensive care unit, where he is intubated and ventilated and remains hemodynamically unstable.

PROBLEM ANALYSIS Definition Steroids are the mainstay of therapy for a variety of disorders, including autoimmune diseases, and for immune suppression following solid organ transplantation. With chronic steroid therapy, there is a risk of triggering an addisonian crisis if cortisol levels are insufficient to meet the increased physiologic, perioperative demands. Following surgery, peak plasma cortisol concentrations are achieved after 4 to 5 hours and may remain elevated for 48 to 72 hours, especially following major surgery. Minor surgery induces less than 50 mg of cortisol production during the first 24 hours, but after major surgery, 75 to 100 mg of cortisol is produced in the same period. With maximal stress (e.g., septic shock), the adrenals may produce as much as 300 to 500 mg of cortisol per day. Adrenal insufficiency is classified as primary, secondary, or tertiary, based on the anatomic level of impairment within the hypothalamic-pituitary-adrenal (HPA) axis. With primary adrenal insufficiency, the abnormality is in the adrenal gland. More than 90% of the adrenal gland must be destroyed before symptoms of glucocorticoid and mineralocorticoid deficiency are evident. The most common cause of primary adrenal insufficiency in the United States is autoimmune in nature. In secondary adrenal insufficiency, the abnormality is at the level of the pituitary gland. Such patients show symptoms of glucocorticoid deficiency but usually have intact mineralocorticoid function. Tertiary adrenal insufficiency is the most common type and is caused by suppression of the HPA axis by chronic exogenous steroids. However, there is a lack of prospective, randomized trials investigating perioperative steroid supplementation in patients receiving chronic steroids. Most available data are based on small case series and personal preference.

Recognition The clinical presentation of an addisonian crisis varies from mild, nonspecific constitutional symptoms to the presence of profound shock unresponsive to vasopressor therapy. Clinicians should maintain a high index of suspicion when caring for patients receiving chronic steroids during the perioperative period. Mild symptoms or signs of adrenal

insufficiency include nausea, vomiting, and abdominal pain. With associated hypoglycemia, there may be subtle neurologic symptoms (e.g., restlessness, lethargy). Mineralocorticoid deficiency occasionally accompanies an addisonian crisis and presents as hyponatremia and hyperkalemia with metabolic acidosis. With severe adrenal insufficiency, arterial hypotension with postural accentuation is common. Such hypotension may be refractory to fluid and vasopressor therapy.

Risk Assessment The following are important predictors of risk for the development of adrenal insufficiency during the perioperative period: ● ● ● ●

Total daily dose of steroids Duration of steroid therapy Type of surgery and degree of perioperative stress Response to short (rapid) adrenocorticotropic hormone (ACTH) stimulation test

It has been shown that the total daily dose of steroids determines the responsiveness of the HPA axis to stress. LaRochelle and colleagues demonstrated that when the total daily dose of prednisone was less than 5 mg, there was a normal response to the short ACTH test. With doses greater than 5 mg/day, however, responses to the short ACTH test varied widely. Although these authors reported that the duration of steroid therapy did not affect HPA axis recovery, there is evidence that HPA axis responsiveness may be impaired for up to 9 months after chronic steroid therapy. The nature of the surgery and the degree of perioperative stress are important determinants for steroid replacement therapy. Subjects undergoing major surgery have elevated glucocorticoid concentrations commensurate with the degree of stress and nature of the surgery. Finally, the response to the short ACTH test can help the clinician determine whether the HPA axis has returned to normal. It is sensitive for determining HPA axis impairment in subjects on chronic steroid therapy. Following measurement of baseline plasma cortisol concentrations, 250 μg of cosyntropin is administered intravenously (IV). Blood cortisol concentrations are then determined at 30 and 60 minutes. A normal response is a peak cortisol concentration greater than 18 μg/dL and a minimal increase of 7 μg/dL above baseline. 131

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Table 34–1

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Steroid Supplementation Guidelines

Dose and Duration of Steroid Therapy*

Perioperative Management

<5 mg/day >5 mg/day—minor surgery >5 mg/day—moderate surgery >5 mg/day—major surgery Steroids stopped <6 mo Steroids stopped >6 mo Septic shock with abnormal ACTH test Late fibroproliferative ARDS

Normal HPA axis; no supplemental steroids necessary Hydrocortisone 25 mg at anesthetic induction; resume oral steroids Hydrocortisone 75-100 mg/day; taper over 1-2 days to usual dose Hydrocortisone 100-150 mg/day; taper over 1-2 days to usual dose Assume HPA axis impaired; dose steroids according to type of surgery Assume HPA axis intact; no supplemental steroids necessary Hydrocortisone 100 mg q 8 h for 5-7 days Methylprednisolone 2 mg/kg/day tapered to 0.125 mg/kg/day over 32 days

*Based on dose of cortisol (hydrocortisone). For relative potencies of synthetic corticosteroids, see Table 34-2. ACTH, adrenocorticotropic hormone; ARDS, acute respiratory distress syndrome; HPA, hypothalamic-pituitary-adrenal.

Implications Although addisonian crisis secondary to inadequate steroid supplementation is rare, vigilance by the anesthesiologist for subtle signs of adrenal insufficiency is important. The cumulative daily dose, the duration of chronic steroid therapy, and the nature of surgery are important factors for determining the integrity and responsiveness of the HPA axis. Further, there is increasing evidence of the importance of physiologic replacement doses of steroids in patients with sepsis and septic shock. Although supraphysiologic steroid doses have not been shown to improve outcomes, studies by both Annane and Bollaert and their coworkers have shown the benefits of physiologic replacement doses of steroids in septic shock. There also appears to be a beneficial role for steroid therapy in the late fibroproliferative phase of acute respiratory distress syndrome (ARDS). Although this conclusion is based on a small study by Meduri and associates, a larger multicenter trial is being conducted by the ARDS Network.

MANAGEMENT As discussed earlier, the decision to supplement steroids in the perioperative period is based on the history of steroid intake and the severity of the planned surgery (Tables 34-1 and 34-2). A standard dose for all patients should be avoided. Supplemental doses should be individualized based on total

Table 34–2

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daily dose, duration of therapy, and severity of perioperative stressors. Although the short ACTH test is useful for determining the integrity of the HPA axis, it may be impractical to perform the test in all patients. When steroids have been stopped for at least 6 months, it can be assumed that the HPA axis has returned to normal. Although some data suggest that a minimum of 2 months is sufficient time for the resumption of normal cortisol production, it is prudent to assume that HPA axis function will be impaired for up to 6 months. Patients taking less than 5 mg/day of prednisone or its equivalent can be assumed to have an intact HPA axis and do not require supplemental doses of steroids; however, it is important to continue the daily dose of the steroid. With minor surgery, a supplemental dose of 25 mg of hydrocortisone should be given IV at induction of anesthesia; normal oral replacement therapy should be resumed postoperatively. With moderate surgical stress, the chronic daily steroid dose should be given IV preoperatively. Additional doses of hydrocortisone between 75 and 100 mg/day should be given IV. If there are no postoperative complications, the supplemental steroid should be weaned rapidly over 1 to 2 days, and the normal oral steroid dose should be restarted. With major surgery, the preoperative oral steroid dose should be followed by an additional 100 to 150 mg of intravenous hydrocortisone administered over 24 hours. In uncomplicated cases, this dose can be rapidly tapered within 24 to 48 hours. Patients with septic shock who are refractory to

Steroid Comparisons: Relative Glucocorticoid and Mineralocorticoid Potencies and Duration of Action

Steroid Cortisol* Prednisone Prednisolone Methylprednisolone Dexamethasone Fludrocortisone *Identical to hydrocortisone.

Glucocorticoid Potency 1 4 4 5 25-30 10

Mineralocorticoid Potency 1 0.8 0.8 0.5 0 120

Duration of Action (hr) 8-10 18-36 12-36 18-36 36-54 18-36

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PREVENTION The following steps are useful for preventing a steroidinduced crisis: ●

● ●

●

Identify patients who are at risk of developing adrenal insufficiency. Be vigilant for subtle signs of hypoadrenalism. Have a low threshold for treating patients with possible adrenal insufficiency. Use postoperative steroids in patients with septic shock, based on emerging evidence of their beneficial role in this patient subgroup.

●

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133

Consider the possible benefit of steroids for attenuating the late fibroproliferative phase of ARDS and reducing mortality.

Further Reading Annane D, Sebille V, Charpentier C, et al: Effect of treatment with low doses of hydrocortisone and fludrocortisone on mortality in patients with septic shock. JAMA 288:862-871, 2002. Bollaert PE, Charpentier C, Levy B, et al: Reversal of late septic shock with supraphysiologic doses of hydrocortisone. Crit Care Med 26:645-650, 1998. Friedman RJ, Schiff CF, Bromberg JS: Use of supplemental steroids in patients having orthopaedic operations. J Bone Joint Surg Am 77:1801-1806, 1995. LaRochelle GE Jr, LaRochelle AG, Ratner RE, et al: Recovery of the hypothalamic-pituitary-adrenal (HPA) axis in patients with rheumatic diseases receiving low-dose prednisone. Am J Med 95:258-264, 1993. Meduri GU, Headley AS, Golden E, et al: Effect of prolonged methylprednisolone therapy in unresolving acute respiratory distress syndrome: A randomized controlled trial. JAMA 280:159-165, 1998. Salem M, Tainsh RE Jr, Bromberg J, et al: Perioperative glucocorticoid coverage: A reassessment 42 years after emergence of a problem. Ann Surg 219:416-425, 1994.

PHARMACOLOGY

fluid and vasopressor therapy can be treated with hydrocortisone 100 mg IV every 8 hours or with a continuous infusion of 10 mg/hour. Before initiating therapy, a short ACTH test should be performed to document adrenal insufficiency. When surgery is urgent or emergent and time constraints prevent the performance of a short ACTH test, dexamethasone can be given, because this will not interfere with future tests to determine normal blood cortisol concentrations in response to a short ACTH test.

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Antiemetic Drugs M. Pamela Fish Case Synopsis A 21-year-old woman (American Society of Anesthesiologists [ASA] status 1) presents with a suspected ectopic pregnancy for outpatient laparoscopy. She has no history of previous psychiatric illness or drug use. Metoclopramide 10 mg and glycopyrrolate 0.2 mg are administered intravenously as premedication. The patient becomes severely agitated and verbally abusive and refuses to proceed with surgery. She returns the following day and receives no premedication. Anesthesia and surgery proceed uneventfully.

PROBLEM ANALYSIS Definition Complications of antiemetic therapy are undesirable effects resulting from the administration of medications to prevent or treat nausea and vomiting. Untreated, up to 30% of surgical patients will suffer postoperative nausea and vomiting (PONV). For high-risk patients, the incidence can be as high as 80%. Thus, antiemetic drugs are commonly used in the perioperative period.

Recognition Conditions such as hypotension, hypoxemia, hypoglycemia, raised intracranial pressure, and bowel obstruction should be considered in the differential diagnosis of PONV. Currently available antiemetics produce their effect by antagonizing neurotransmitters in the brainstem. The major

Table 35–1

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receptor sites at which these drugs act are listed in Table 35-1. Except for antiserotonin (5-HT3) antagonists, most antiemetics antagonize more than one neurotransmitter. The antiemetic action of the corticosteroids is not well understood; some of the proposed mechanisms include prostaglandin antagonism, tryptophan depletion, and reduced 5-HT3 concentrations. Common side effects with antiemetic therapy are provided in Table 35-2.

Risk Assessment All patients who receive antiemetic therapy are at risk for related side effects. The following factors increase the likelihood that a patient will require treatment with antiemetic drugs: PATIENT FACTORS ● ●

Female sex and children under the age of puberty Nonsmoking history

Receptor Site Affinity of Antiemetic Drugs

Drug

Dopamine Receptor

Cholinergic (Muscarinic) Receptor

Histamine Receptor

Serotonin Receptor

Phenothiazine Chlorpromazine (Thorazine) Prochlorperazine (Compazine)

+++ +++

++ +

+++ ++

+ +

+ ++

++ +++

+++ ++++

– –

++++

–

+

+

++

–

+

++

– – –

– – –

– – –

++++ ++++ ++++

+

++++

–

–

Antihistamine Diphenhydramine (Benadryl) Promethazine (Phenergan)

Butyrophenone Droperidol (Inapsine)

Benzamide Metoclopramide (Reglan)

Antiserotonin Ondansetron (Zofran) Dolasetron (Anzemet) Granisetron (Kytril)

Anticholinergic Scopolamine (Hyoscine)

The number of plus signs indicates the relative degree of activity from least (+) to most (++++); a minus sign indicates no activity. Adapted from Watcha MF, White PF: Postoperative nausea and vomiting. Anesthesiology 77:162-184, 1992.

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+

+ +

+ +

+

+

+ +

+ +

+ +

+ +

+ +

+ +

+

+

+

+

+

+

+

+

+

+

ECG Changes

Visual Effects/ Diplopia

Cutaneous Flushing/ Perineal Itching

Dry Mouth

+

Tachycardia

+

Hypotension

Diphenhydramine + Promethazine +

Dizziness

+ +

Headache

+ +

Disturbed Coordination

Extrapyramidal Movements

+ +

Drug

Dysphoria

Restlessness/ Agitation

Side Effects of Antiemetic Drugs

Sedation

■

135

Antiemetic Drugs

PHARMACOLOGY

Table 35–2

■

Neuroleptic Malignant Syndrome

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Hallucinations

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Phenothiazine Chlorpromazine Prochlorperazine

Antihistamine + +

+

Anticholinergic Scopolamine

+

+

+

+

+

+

+

+

+

+

+

Benzamide Metoclopramide

+

+

+

+

+

+

+

Butyrophenone Droperidol

+

+

Antiserotonin Ondansetron Dolasetron Granisetron

+ + +

+ + +

+ + +

Corticosteroid Dexamethasone

+

+

ECG, electrocardiogram.

● ● ●

Prior history of motion sickness or PONV Preoperative anxiety or pain Any disease process that delays gastric emptying

●

Overly early or aggressive fluid intake, or requirement of oral fluid intake before discharge home

Implications SURGICAL FACTORS ● ● ● ●

Strabismus repair, head and neck surgery, or dental surgery Laparoscopic gynecologic procedures, shoulder surgery Plastic surgery (especially breast augmentation) Adenotonsillectomy, hernia repair, orchiopexy, and penile surgery in children

The following list describes some considerations and potential complications with antiemetic therapy: ●

●

ANESTHESIA FACTORS ● ● ● ●

● ● ●

Inadequate fluid replacement Duration of surgery (risk increases for length up to 3 hours) General anesthesia with volatile anesthetic agents Nitrous oxide use, due to gastrointestinal distention or increased middle ear (labyrinthine, vestibular apparatus) pressure Use of narcotic analgesics Use of certain hypnotic agents (etomidate, ketamine) Use of neostigmine (>2.5 mg)

●

●

POSTOPERATIVE FACTORS ● ●

Pain Sudden motion

Sedation ● This is the most common side effect with all antiemetic drugs. Metoclopramide ● Causes an increased risk of extrapyramidal reactions in children and the elderly ● Avoid in patients with hypertension or those taking monoamine oxidase inhibitors ● Painful stimulation may provoke supraventricular tachycardia after administration. ● Use is contraindicated in patients with epilepsy ● Because of its short half-life, not effective when administered at start of surgery Antihistamines ● Often cause dizziness, sedation, and hypotension in elderly patients Serotonin receptor antagonists ● Headache (dose dependent), dizziness, blurred vision, and abnormal liver enzymes have been reported. ● Blockage of cardiac sodium and potassium channels can cause transient electrocardiogram (ECG) changes.

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Cross-reactive hypersensitivity (anaphylactic, anaphylactoid) reactions among different 5-HT3 receptor antagonists have been reported. Droperidol ● A Food and Drug Administration (FDA) advisory was issued concerning potential Q-T prolongation and fatal arrhythmias with droperidol use (see Chapter 81). ● Contraindicated in patients with Parkinson’s disease Phenothiazines ● Drug ampules contain sodium bisulfite and sodium sulfite, which may cause an allergic-type reaction, especially in patients with a history of asthma. ● Perphenazine, the most potent antiemetic among the phenothiazines, is reserved for intractable vomiting. Scopolamine ● Use of the transdermal route is limited by long onset time and excessive drowsiness. ● Psychosis may be seen in the elderly and has also occurred in pediatric patients. Dexamethasone ● Wound infection and adrenal suppression have not been noted after a single bolus dose in otherwise healthy patients. ● Phosphate (injectable solution) is linked to perineal itching and cutaneous flushing. ●

●

●

●

●

PREVENTION The following list describes measures to avoid complications with drugs used to treat or prevent PONV: ●

●

●

MANAGEMENT Management of the complications of antiemetic drugs can range from simple observation after discontinuing the drug to treatment with specific agents. Sedation is a common side effect of antiemetc drug therapy, frequently resulting in delayed transfer from the recovery room or discharge home after ambulatory surgery. There is no specific therapy other than continued observation. Hypotension usually responds to increased intravenous fluids. However, parenteral phenothiazines may produce hypotension, requiring therapy with a vasoconstrictor such as phenylephrine. As noted earlier, ECG changes with antiserotonin antagonists are usually temporary. Although there have been reports of Q-T interval prolongation and fatal arrhythmias (torsades de pointes) with larger doses of droperidol, there have been no reports in any peer-reviewed journal of Q-T prolongation, arrhythmias, or cardiac arrest associated with the much smaller intravenous doses (0.125 mg) used for the management of PONV. Extrapyramidal disorders can present as dystonic reactions (especially in children), motor restlessness (akathisia), or signs and symptoms of parkinsonism (especially in the elderly). Treatment of extrapyramidal effects involves the administration of benztropine (a centrally acting anticholinergic) or diphenhydramine. For akathisia, antiparkinsonian drugs, benzodiazepines, or propranolol may be useful. Clinical manifestations of the neuroleptic malignant syndrome include hyperpyrexia, muscle rigidity, altered mental status, and evidence of autonomic instability. Management is discontinuation of nonessential drugs, intensive correction of fluid and electrolyte imbalance, and therapy with dopamine agonists such as bromocriptine or dantrolene.

●

Prophylaxis for PONV ● In general, there is no rationale for routine prophylactic antiemetic therapy. ● Prophylaxis in some high-risk patients may be appropriate, however (see “Risk Assessment”). ● Dexamethasone requires 4 to 5 hours for an optimal effect, so it is best administered before induction of anesthesia. ● Low-dose dexamethasone or droperidol and a 5-HT 3 receptor antagonist have been shown to be effective prophylaxis for patients at high risk for PONV. Appropriate preoperative antiemetic management ● Use premedication with oral clonidine or benzodiazepines. ● In females, avoid elective laparoscopic surgery around the time of their menses. ● Acupressure or acupuncture at the P-6 (Neiguan) point should be considered. Anesthetic technique ● Use regional anesthesia when possible. ● Choose appropriate anesthetic agents (e.g., total intravenous anesthesia with propofol). ● Avoid gastric distention from high positive-pressure facemask ventilation. ● Consider prophylactic gastric decompression (oroor nasogastric tube) before endotracheal extubation (especially for patients having emergency surgery, with a history of PONV, or at high risk for PONV). ● Avoid ingestion of blood with throat packs, or insert an oro- or nasogastric tube. ● Ensure adequate fluid replacement. ● Provide effective postoperative analgesia (consider epidural analgesia, peripheral nerve blocks, or local anesthetic wound infiltration). This will reduce opiate needs and the associated increased risk for PONV. ● Use analgesics that are less likely to cause PONV (e.g., ketorolac, COX-2 inhibitors). Antiemetic therapy ● Should PONV occur, select the antiemetic agent most appropriate for the patient. ● Serotonin receptor antagonists are more effective against vomiting than nausea. ● Repeated low doses of droperidol (0.125 mg) increase the drug’s antinausea efficacy, with reduced side effects. However, current FDA guidelines require that ECG monitoring be performed before and continued for 2 to 3 hours after droperidol use, thus limiting its use in outpatient settings. ● Antihistamines are the agents of choice following middle ear surgery. ● Ephedrine, an indirect-acting sympathomimetic, is effective for treating emesis due to hypotension associated with spinal anesthesia. ● A new class of drugs, the neurokinin-1 (NK ) receptor 1 antagonists, is currently under investigation for the prevention of PONV.

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Apfel CC, Laara E, Koivuranta M, et al: A simplified risk score for predicting postoperative nausea and vomiting. Anesthesiology 91:693-700, 1999. Caldwell C, Rains G, McKiterick K: An unusual reaction to preoperative metoclopramide. Anesthesiology 67:854-855, 1987.

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137

Gan TJ, Meyer T, Apfel CC, et al: Consensus guidelines for managing postoperative nausea and vomiting. Anesth Analg 97:62-71, 2003. Sinclair DR, Chung F, Mezei G: Can postoperative nausea and vomiting be predicted? Anesthesiology 91:109-118, 1999. Watcha MF, White PF: Postoperative nausea and vomiting. Anesthesiology 77:162-184, 1992.

PHARMACOLOGY

Further Reading

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PREANESTHETIC ASSESSMENT

36

Preanesthetic Evaluation: False-Positive Tests

GENERAL ANESTHESIA

Michael P. Ford and Scott R. Springman Case Synopsis A 25-year-old male athlete presents for repair of the anterior cruciate ligament of his knee. He is taking no medications. He has a negative personal and family history of abnormal clotting or bleeding or easy bruising. Multiple tests, including prothrombin time and partial thromboplastin time (PTT), are ordered. The PTT results are reported as above normal. The surgery is postponed, and an extensive hematology workup is performed. The final report concludes, “normal variant, no coagulation defect.”

PROBLEM ANALYSIS Definition A test is useful only to the extent that clinicians can understand the implications of a positive or negative result. Few, if any, tests always correctly identify the presence or absence of disease in all patients. Clinicians can decide what to do with a “positive” test result only when they have a clear knowledge of the test’s characteristics and its statistical predictive value when applied to a specific patient population. Such “medical decision analysis” directly affects the clinical care of patients. Some tests provide a qualitative positive or negative result. Many test results, however, are quantitative and define a range of “normal” values around a mean. Therefore, a few members of any population will have an “abnormal” test result but not actually have a disease. This means that a test result may be misleading owing to variability in the patient population. The test itself can give an incorrect result due to (1) inaccuracy, (2) imprecision, or (3) incorrect performance. The accuracy of a test is the difference between the mean value of test results and the true result, as measured by a gold standard test. The precision of a test is the reproducibility of results between instruments or persons performing the test. An incorrectly performed test can invalidate any result. Test accuracy can be described in several ways. The sensitivity of a test measures the proportion of individuals who have a disease and are correctly identified as being positive for that disease, based on the test. Specificity measures the proportion of individuals who do not have a disease and are identified as being disease free, based on the test. False-positive results are more likely with tests that have a high sensitivity, low specificity, or both. Sensitivity and specificity are characteristics of the test and do not change with the prevalence (frequency) of disease in the population. Said another way: a test’s sensitivity and specificity do not affect the probability of a patient having a disease. The predictive value of tests, in contrast, depends on the prevalence of a disease in a population of patients.

The predictive value of a positive test indicates the proportion of those with a positive test who actually have the disease. Often, the predictive value of tests is expressed as the probability, or odds, that a condition is present. Likelihood ratios express the amount that the odds change when the results of the test are available (Table 36-1). In this respect, an important concept is Bayes’ theorem, which “relates the probability of an item (e.g., a patient) being a member of a particular group (e.g., clinical class), given the presence of an attribute (e.g., an abnormal test result), to the probability of known group members having the attribute and the probability of

Table 36–1

■

Accuracy and Predictive Value of Tests Target Disorder, Based on Gold Standard Test

Diagnostic Test Results Positive Negative Total

Present

Absent

a c a+c

b d b+d

Number of Patients with This Test Result a+b c+d

1. a/(a + c) = Sensitivity. 2. d/(b + d) = Specificity. 3. a/(a + b) = Positive predictive value, or post-test probability of having the target disorder among patients with positive test results. 4. d/(c + d) = Negative predictive value, or post-test probability of not having the target disorder among patients with negative test results. 5. c/(c + d) = Post-test probability of having the target disorder for patients with negative test results. 6. (a + c)/(a + b + c + d) = Prevalence or pretest probability of having the target disorder. 7. Sensitivity/(1 – Specificity) = Likelihood ratio (of having the target disorder) for a positive test result = [a/(a + c)]/[b/(b + d)]. 8. (1 – Sensitivity)/Specificity = Likelihood ratio (of having the target disorder) for a negative test result = [c/(a + c)]/[d/(b + d)]. 9. Post-test probability of the target disorder (expressed as odds) = Pretest probability of target disorder (expressed as odds) × Likelihood ratio for the test result. 10. Odds = Probability/[1 – Probability]. Adapted from Sackett DL: A primer on the precision and accuracy of the clinical examination. JAMA 267:2638-2644, 1992.

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obtaining a group member when picking at random an item from the universe of items.”1 It allows the calculation of changes in the probability of disease as new information (e.g., test results) becomes available. The post-test probability is calculated with the Fagan nomogram, similar to that shown in Figure 36-1. A Web-based interactive nomogram can be accessed at http://www.cebm.net/nomogram.asp.

Recognition A positive test result may turn out to be false if the test was performed incorrectly. Alternatively, a patient may not actually have a disease if the results of a gold standard test are normal. Other, non–gold standard tests may falsely indicate that a patient has a disease when he or she does not. Finally, because of population variability, a patient may truly test positive for a disease (be outside the “normal” range) yet be clinically normal.

Probability of at least one abnormal result

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1.0 0.8

PN = .90 P = .95 N PN = .98

0.6

PN = .99

0.4

PN = .995 0.2 0

10

20

30

40

50

60

70

80

No. of independent tests (Each with probability of normality = PN) Figure 36–2 ■ Probability of at least one falsely abnormal result for multiple tests, each with a probability of a normal result (PN), for selected values of PN. (From Berwick DM: Screening in health fairs. JAMA 254:1495, 1985.)

99

.1 .2

Risk Assessment .5 1 2

5 10 20

1000

95 90

500 200 100 50

80

20 10 5

60

2

30

Implications

20

In the preoperative setting, the most likely outcome of a false-positive test is the delay or cancellation of surgery. Physicians often repeat the test, hoping that the first result was due to an improperly performed test. Other tests to corroborate the diagnosis may be performed. However, both these options add to costs. Further, if the test is invasive, it adds to the risk of physical harm to the patient. Yet if elective surgery is not delayed and the test was not falsely positive, the providers run the risk of professional or medicolegal scrutiny. In addition, any unnecessary alteration in perioperative management may add cost and risk to the patient’s care. Finally, a false-positive result, such as for human immunodeficiency virus (HIV), may cause unnecessary psychological stress for the patient, as well as for providers.

70 50 40

1 30

.5

40

.2 .1 .05

50 60 70 80 90 95

.02 .01 .005 .002

.001

10 5

2 1 .5

.2 99 Pretest probability

If we assume that tests are being performed correctly and that their precision is high, then the accuracy of the test and the prevalence of the disease are the main factors that determine whether a test result will be “correct.” Patients who undergo multiple tests are likely to have at least one that is falsely positive. This is true especially if the tested patient population has a low prevalence of the condition. This scenario often occurs when asymptomatic patients undergo large numbers (a battery) of preoperative screening tests (Fig. 36-2).

Likelihood ratio

.1 Post-test probability

Figure 36–1 ■ Draw a line from the pretest probability through the likelihood ratio to determine the post-test probability. (Adapted from Fagan TJ: Nomogram for Bayes’s theorem. N Engl J Med 293:257, 1975.)

1 This definition is found in the 25th edition of Stedman’s Medical Dictionary, Baltimore, Williams & Wilkins, 1990.

MANAGEMENT The decision to accept a positive test result as “true” must depend on knowledge of the test’s characteristics and its performance pitfalls. The decision also depends on knowledge of the incidence of the tested condition in the patient population in question. Every test result should be examined to determine whether it fits the overall picture of the patient’s condition. If it does not, and if there are no corroborative

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findings, further investigation may be required before accepting the result as true. In many cases, a lone finding should be suspect unless it is known that the specificity of the test is high, the incidence of the condition is high, or both.

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Preanesthetic Evaluation: False-Positive Tests

143

analysis may help decide whether a test should be performed at all, in spite of the complexity of such evaluations and the need for subjective value judgments.

Further Reading

Clearly, the best way to minimize the chances of a false-positive test result is to avoid any unnecessary testing. Appropriate guidelines may take into account available scientific studies and local and national expert medical opinion. Selection of tests with a high specificity can also reduce the number of false-positive results. However, both physicians and patients abhor adverse outcomes, and the consequences of missing a true-positive result may be serious; therefore, testing and the acceptance of a certain incidence of false-positive results are commonplace. The use of cost-benefit and risk-benefit

Pasternak LR: Preoperative laboratory testing: General issues and considerations. Anesthesiol Clin North Am 22:13-25, 2004. Practice Advisory for Preanesthesia Evaluation: A Report by the American Society of Anesthesiologists Task Force on Preanesthesia Evaluation. Anesthesiology 96:485-496, 2002. Roizen MF, Foss JF, Fischer SP: Preoperative evaluation. In Miller R (ed): Anesthesia. New York, Churchill Livingstone, 2000, pp 824-883. Ross AF, Tinker JH: Preoperative evaluation of the healthy patient. In Longnecker DE, Tinker JH, Morgan GE (eds): Principles and Practice of Anesthesiology. St. Louis, Mosby–Year Book, 1998, pp 3-51. Sackett DL: A primer on the precision and accuracy of the clinical examination. JAMA 267:2638-2644, 1992. Vitez TS: Principles of cost analysis. J Clin Anesth 6:357-363, 1994.

GENERAL ANESTHESIA

PREVENTION

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Preanesthetic Evaluation: Inadequate or Missing Test Result

37

Thomas P. Broderick and Scott R. Springman Case Synopsis A 44-year-old man with a history of hypertension, obesity, and episodes of epigastric pain is scheduled for elective laparoscopic cholecystectomy. No preoperative electrocardiogram is obtained. The patient subsequently sustains perioperative myocardial infarction secondary to undiagnosed coronary artery disease.

PROBLEM ANALYSIS Definition Effective preoperative test selection is best achieved by knowing how outcome is affected by the performance or omission of a test. The following are three important outcomes: 1. Adverse medical events 2. Cost of care 3. Litigation

However, if a patient has severe, unrecognized coronary disease and sustains a perioperative myocardial infarction, there will definitely be more medical care required, greater time spent in the hospital, increased costs, and possible long-term disability or risk of death. Further, emotional, professional, economic, and medicolegal risks for the providers will be increased.

MANAGEMENT

Patients are at risk for adverse outcomes when tests are not done owing to an oversight, inadequate history and physical examination, inadequate guidelines, or inappropriate emphasis on cost reduction. Process failures also occur when tests are done but the results are unavailable or lost or when providers fail to review the results before an anesthetic is administered.

If a test is found to be missing before an anesthetic is administered and the surgery is elective, the anesthesiologist and the surgeon must determine whether official internal or external policies absolutely mandate the test. If so, the test should be obtained, or the providers must justify in the medical record why they were willing to proceed with anesthesia or surgery without the test results. Of course, for emergent or urgent procedures, physicians should always weigh the expected benefits of a test against the risks of delay. If the test is discovered to be missing after anesthesia or surgery has commenced, the providers must determine whether obtaining the test result will make a real difference and whether the procedure should be terminated (fortunately, rare). Tests may, of course, be obtained during the provision of an anesthetic and serve the same purpose as a preoperative test. This is not true, however, if a preoperative test would have changed the decision to proceed with the procedure or if the test would have substantially affected the initial anesthetic plan. An example of this would be the finding of an elevated prothrombin time before the administration of a neuraxial anesthetic. If a test is discovered to be missing after surgery, is there a need to obtain the test? It may be wise to do so if postoperative or long-term medical management would be altered by the results.

Implications

PREVENTION

If a test is mandated by policy but is not done, the outcome may or may not be affected. For example, if a patient has a slightly elevated serum calcium level or is slightly anemic, for most operations, adverse perioperative outcomes are unlikely.

VALUE-BASED MEDICAL CARE

These may or may not be related. Simply knowing the result of a preoperative test cannot ensure a good outcome. Moreover, the accuracy and usefulness of a test depend greatly on its sensitivity and specificity, combined with the frequency of the condition in the patient population.

Recognition It is easy to determine whether a test was not done, not reviewed, or not available. A more difficult issue is whether a specific test was actually indicated. Hindsight may not be adequate to determine actual preoperative need. Only well-structured clinical studies and logical analysis can provide direction for clinicians who wish to provide evidenced-based care.

Risk Assessment

144

If the absence of a test leads to an adverse outcome, the system should be reexamined to prevent future problems.

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Preanesthetic Evaluation: Inadequate or Missing Test Result

EVIDENCE-BASED MEDICAL CARE Ideally, all tests should be ordered using the principle of evidence-based medical care. Many articles have been written about preoperative assessment, but few cite sufficient rigorous evidence to be of significant use. Recently, an American Society of Anesthesiologists task force found that there were insufficient scientific outcome studies to support a specific scheme for preoperative testing, other than sound medical practice based on a careful history and physical examination. The National Institute for Clinical Excellence (NICE) in the United Kingdom published a lengthy set of preoperative testing guidelines based on both patient disease and severity of surgery (www.nice.org.uk). The American College of Cardiology–American Heart Association guideline update (see also Chapter 38) can help determine the need for cardiac testing based on criteria that rely heavily on the history and physical examination. FOCUSED PREOPERATIVE TESTING The proper use of the history and physical examination is to focus further preoperative testing. However, it is important to note that many symptoms are sensitive but not highly specific indicators of problems. Interobserver variability also may be high. In addition, the value of the history depends on the adequacy of the past medical record and the patient’s reliability and communication skills.

Table 37–1

■

NONSELECTIVE

VERSUS

SELECTIVE TESTING

Pathology can exist without significant symptoms or signs. With that in mind, most schemes for preoperative testing distinguish between nonselective and selective testing. The former requires that every patient be tested or screened, even if asymptomatic. Although this approach was commonly used in the past, few recommend it today. Selective testing requires that certain groups of criteria be used to determine the need for testing. Patient Factors. The first group of criteria involves patient factors. These include, but are not limited to, symptoms, age, past medical history, gender, and physical findings. Other factors, such as the ability to obtain a reliable history or perform an adequate examination, should also be considered. Type of Surgery. The second group of criteria involves the type of surgery. Baseline values may be required because the surgery itself will alter these values or because of possible physiologic derangements caused by the surgery. Type of Anesthesia. The last group of criteria relates to the type of anesthesia. Although local or regional anesthesia may require a different testing scheme or perhaps fewer tests, there is always the possibility that local or regional anesthesia may be inadequate, and conversion to general anesthesia may be required. TESTING GUIDELINES Lacking rigorous outcome studies, criteria must be based on local and national experience. Policies or guidelines need to be constantly updated to be credible, and local consensus is an absolute necessity. Published guidelines may be simple (Table 37-1) or complex, such as the NICE guidelines. Others may simply recommend testing “as indicated by history and examination.” Experience has shown, however, that such nonspecific guidelines often result in many more or fewer tests than needed, especially when nonanesthesia providers are responsible for ordering the tests. Importantly, there are good reasons to omit nonindicated tests. Even if the tests cost nothing, they can do harm by leading to further testing, inappropriately altering case

Preanesthetic Testing and Type of Anesthesia

General or Major Conduction Anesthesia (Asymptomatic Individuals) Age

Men

Women

6 mo-<40 yr 40-<50 yr 50- <65 yr 65-74 yr

None ECG ECG HGB or HCT, ECG, BUN, GLU HGB or HCT, ECG, BUN, GLU, ± chest radiograph

HCT ± pregnancy test HCT ± pregnancy test HCT ± pregnancy test, ECG HGB or HCT, ECG, BUN, GLU HGB or HCT, ECG, BUN, GLU, ± chest radiograph

≥75 yr

Sedative-Hypnotics for IV Monitored Anesthesia

Peripheral Nerve Blocks

None None HCT (≤6 mo) HCT (≤6 mo), ECG (≤1 yr)

None None None HCT (≤6 mo)

HCT (≤6 mo), ECG (≤1 yr), BUN (≤6 mo), GLU (≤6 mo)

HCT (≤6 mo), ECG (≤1 yr)

BUN, blood urea nitrogen; ECG, electrocardiogram; GLU, glucose; HCT, hematocrit; HGB, hemoglobin; IV, intravenous. Adapted from Roizen MF, Fisher SP: Preoperative evaluation: Adults and children. In White PF (ed): Ambulatory Anesthesia and Surgery. Philadelphia, WB Saunders, 1997, p 164.

GENERAL ANESTHESIA

Caution should be used, however, in ascribing causality. Bad outcomes do not necessarily mean that more defensive testing is indicated. Consider whether testing really would have made a difference in the outcome. In addition, short-term and long-term benefits versus the potential harmful effects of testing must be considered. This is consistent with the concept of value-based anesthesia care. Complex cost-benefit analysis may be needed; time has actual value in medicine, and a seemingly more costly process may turn out to be less expensive in the long run than a less costly but lengthier process. A thoughtfully managed continuous quality improvement program may provide process and systems benefits, minimizing the pitfalls of arbitrarily assigning value based purely on cost to clinical decision making.

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management, giving the anesthesiologist and surgeon a false sense of security, and even distracting them from more important issues. Performing tests when there is no plan to review them before surgery is medically useless and legally dangerous. COMPUTERIZED PREOPERATIVE ASSESSMENT SYSTEMS PREANESTHETIC EVALUATION CLINICS

AND

A preanesthetic evaluation clinic can provide a systematic, logical, cost-effective, and streamlined approach to preoperative testing. Also, a well-structured computerized preoperative assessment system (which must comply with the Health Insurance Portability and Accountability Act) can both enhance the collection of patient data and reduce the volume of unnecessary or missed preoperative visits. Further, an electronic medical record employing integrated “decision support” may substantially improve both the quality and the availability of preoperative evaluation and testing. The anesthesiologist’s review of a patient’s workup is then more convenient, complete, and useful. Gaining consensus about the indications for testing, the timing of testing, who orders the tests, and who reviews the test results is the first step in optimizing a preoperative evaluation process.

Further Reading American Society of Anesthesiologists: Practice advisory for preanesthesia evaluation: A report by the American Society of Anesthesiologists Task Force on Preanesthesia Evaluation. Anesthesiology 96:485-496, 2002. Eagle KA, Berger PB, Calkins H, et al: ACC/AHA guideline update for perioperative cardiovascular evaluation for noncardiac surgery— executive summary: A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee to Update the 1996 Guidelines on Perioperative Cardiovascular Evaluation for Noncardiac Surgery). Anesth Analg 94:1052-1064, 2002. Ferrari LR: Preoperative evaluation of pediatric surgical patients with multisystem considerations. Anesth Analg 99:1058-1069, 2004. Fischer S: Development and effectiveness of an anesthesia preoperative evaluation clinic in a teaching hospital. Anesthesiology 85:196-206, 1996. Fisher S: Cost-effective preoperative evaluation and testing. Chest 115: 96S-100S, 1999. Gibby G: How preoperative assessment programs can be justified financially to hospital administrators. Int Anesthesiol Clin 40:17-30, 2002. Hildred W, Watkins L: The nearly good, the bad, and the ugly in cost effectiveness analysis of health care. J Econ Issues 30:755-775, 1996. Orkin FK: Moving toward value-based anesthesia care. J Clin Anesth 5: 91-98, 1993. Roizen MF, Fisher SP: Preoperative evaluation: Adults and children. In White PF (ed): Ambulatory Anesthesia and Surgery. Philadelphia, WB Saunders, 1997, pp 155-172.

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Cardiac Risk Assessment John L. Atlee

38

Case Synopsis GENERAL ANESTHESIA

A 70-year-old man with intermittent claudication, hypertension, non-insulin-dependent diabetes mellitus, and hyperlipidemia is admitted for same-day right axillary–bifemoral and right femoral–popliteal bypass surgery for arterial occlusive disease. His past medical history is significant for myocardial infarction (MI) 5 years ago and 50 pack-years of smoking before that. His left ventricular ejection fraction is 45%, but his exercise capacity is limited by claudication. The 12-lead electrocardiogram (ECG) shows sinus bradycardia (56 beats per minute), old anterior wall infarction, and occasional ventricular extrasystoles (VES). In the preoperative holding area, his blood pressure is 168/95 mm Hg, and the monitored ECG shows 4 to 6 VES/minute. His current medications include metoprolol, glyburide, atorvastatin, and a long-acting nitrate. His primary physician has cleared him for surgery.

PROBLEM ANALYSIS Definition Cardiovascular disease and all types of surgeries are increasing globally, both in prevalence and in number. Cardiovascular conditions that may affect the postoperative outcomes of cardiac and noncardiac surgery alike include hypertensive crisis,1 coronary artery disease, valvular heart disease, arrhythmias or conduction disturbances, and hypertrophic or dilated cardiomyopathy. Cardiomyopathies also increase the risk for perioperative congestive heart failure. Chronic pulmonary disease, hepatic or renal insufficiency, diabetes mellitus, and other severe systemic disease can also have an adverse impact on postoperative cardiovascular outcomes. The cardiovascular complication of most concern is perioperative acute MI. Others are acute heart failure, thromboembolism (e.g., stroke, pulmonary embolism), arrhythmias and conduction disturbances, and hypertensive crisis.

Recognition The initial history, physical examination, and ECG assessment should focus on identifying potentially serious cardiac disorders, including coronary artery disease (defined as previous MI or angina), heart failure, and symptomatic arrhythmias; the presence of an implanted cardiac rhythm management device, such as a pacemaker or internal cardioverter-defibrillator (see Chapter 97); or a history of orthostatic intolerance. The Framingham Heart Study identified major, predisposing, and conditional risk factors for coronary artery disease (Table 38-1). Although age per se is not a modifiable risk factor, it relates to the length of time a person is exposed to risk factors that increase the severity

1 Hypertensive crisis includes urgencies and emergencies. Both require severe (stage 2) blood pressure elevation above 160/100 mm Hg. For emergencies, end-organ damage is also evident.

of atherosclerosis; it is also an important index in the Framingham risk equation. Because obesity, family history of early coronary artery disease, and physical inactivity contribute to other risk factors, they too are considered major risk factors.

Risk Assessment Clinical predictors of increased risk for perioperative MI, heart failure, or death are listed in Table 38- 2. Major predictors

Table 38–1

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Risk Factors for Coronary Artery Disease

\

Major Cigarette smoking Elevated blood pressure Elevated serum total and LDL cholesterol Low serum HDL cholesterol Diabetes mellitus Advanced age

Other (Predisposing) Risk Factors Obesity Abdominal obesity Physical inactivity Family history of premature coronary heart disease Ethnic characteristics Psychosocial factors

Conditional Risk Factors Elevated serum triglycerides Small LDL particles Elevated serum homocysteine Elevated serum lipoproteins Prothrombogenic factors (e.g., fibrinogen) Inflammatory markers (e.g., C-reactive proteins) HDL, high-density lipoprotein; LDL, low-density lipoprotein. Adapted from Eagle KA, Brundage BH, Chaitman BR, et al: Guidelines for perioperative cardiovascular evaluation for noncardiac surgery. Circulation 93: 1278-1317, 1996; and Eagle KA, Berger PB, Calkins H, et al: ACC/AHA update for perioperative cardiovascular evaluation for noncardiac surgery. Circulation 105: 1257-1267, 2002.

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Clinical Predictors of Increased Risk for Perioperative Myocardial Infarction, Heart Failure, or Death

Major Unstable coronary syndromes Acute or recent MI* Unstable or severe angina† (Canadian class III or IV)‡ Evidence of large ischemic burden by clinical symptoms or noninvasive testing Decompensated heart failure Significant arrhythmias High-grade atrioventricular block Symptomatic ventricular arrhythmias in the presence of underlying heart disease Supraventricular arrhythmias with uncontrolled ventricular rate Severe valvular heart disease

Intermediate Mild angina pectoris Previous MI by history or pathologic Q waves Compensated or prior heart failure Diabetes (particularly insulin-dependent) Renal insufficiency

Minor Advanced age Abnormal ECG (left ventricular hypertrophy, left bundle branch block, ST-T abnormalities) Rhythm other than sinus (e.g., atrial fibrillation) Low functional capacity (e.g., inability to climb one flight of stairs with a bag of groceries) History of stroke Uncontrolled systemic hypertension *Acute MI is within 7 days; recent MI is >7 days but ≤30 days. † May include “stable” angina in patients who are unusually sedentary. ‡ See Campeau L: Grading of angina pectoris. Circulation 54:522-523, 1976. ECG, electrocardiogram; MI, myocardial infarction. Adapted from Eagle KA, Brundage BH, Chaitman BR, et al: Guidelines for perioperative cardiovascular evaluation for noncardiac surgery. Circulation 93: 1278-1317, 1996; and Eagle KA, Berger PB, Calkins H, et al: ACC/AHA update for perioperative cardiovascular evaluation for noncardiac surgery. Circulation 105: 1257-1267, 2002.

of increased risk are unstable coronary syndromes or evidence of large ischemic burden, decompensated heart failure, significant arrhythmias, or severe valvular heart disease. Evidence of such risk factors is found in clinical symptoms or results of noninvasive testing. Anemia also may increase the risk for perioperative cardiovascular events. Further, the patient’s underlying cardiac condition, which might be stable at present (e.g., angina, heart failure, valvular disease), may become manifest with perioperative stress (e.g., pain, high circulating catecholamines, hypoxia, hypercarbia, acute electrolyte imbalance). Also, one should identify serious comorbid conditions (e.g., diabetes, peripheral vascular disease, renal insufficiency, stroke, pulmonary disease), because these too may affect perioperative outcome. Intermediate predictors of increased risk for perioperative cardiovascular events are mild angina, more remote previous MI, compensated heart failure, creatinine 2.0 mg/dL or greater, and diabetes mellitus. Minor predictors are advanced age, abnormal ECG, low functional capacity, history of stroke, and uncontrolled systemic hypertension. Odds ratios for variables that

Table 38–3

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Factors that Increase the Risk for Perioperative Cardiac Events and Are Indications for β-Blocker Therapy

Risk Variables

Odds Ratio (95% CI)

β-Blocker Indicated

Clinical features Coronary artery disease (CAD)* Heart failure (HF) Diabetes melliltus†

2.4 (1.3-4.2)

Yes

1.9 (1.1-3.5) 3.0 (1.3-7.1)

Yes Yes

Renal insufficiency

3.0 (1.4-6.8)

Poor functional status‡

1.8 (0.9-3.5)

High-risk surgery§

2.8 (1.6-4.9)

Probably yes, if secondary to CAD or HF Probably yes, if secondary to CAD or HF Yes

∗Includes angina and prior myocardial infarction. † Especially if insulin required. ‡ Inability to walk four blocks or climb two flights of stairs. § See Table 38-4. CI, confidence interval. Adapted from Fleisher LA, Eagle KA: Clinical practice: Lowering cardiac risk in noncardiac surgery. N Engl J Med 345:1677-1682, 2001.

increase the risk of perioperative cardiac complications, as well as indications for perioperative β-blocker therapy, are listed in Table 38-3. Cardiac risk for various types of surgery is stratified in Table 38-4. Note that a remote history of MI or abnormal Q waves by ECG is an intermediate predictor of increased risk for perioperative cardiovascular events, whereas an acute MI (documented MI ≤7 days before preoperative evaluation) or recent MI (>7 but <30 days before preoperative evaluation),

Table 38–4

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Cardiac Risk Stratification for Various Types of Surgical Procedures

High risk (reported cardiac risk* ≥ 5%) Emergency major operations, especially in the elderly Aortic, major vascular, and peripheral vascular surgery Extensive operations with large volume shifts and/or blood loss

Intermediate risk (reported cardiac risk ≥ 1% but < 5%) Intraperitoneal surgery Intrathoracic surgery Carotid endarterectomy Head and neck surgery Orthopedic surgery Prostate surgery

Low risk (reported cardiac risk† < 1%) Endoscopic procedures Superficial biopsy Cataract surgery Breast surgery ∗Combined incidence of cardiac death and nonfatal MI † Does not generally require further preoperative cardiac testing Adapted from Eagle KA, Brundage BH, Chaitman BR, et al: Guidelines for perioperative cardiovascular evaluation for noncardiac surgery. Circulation 93:1278-1317, 1996.

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Implications Preoperative cardiac risk assessment is important for reducing perioperative morbidity and mortality, especially for patients having noncardiac surgery. Such risk is best evaluated by a multidisciplinary, integrated approach. This requires good communication among the patient, primary physician, consultant, anesthesiologist, and surgeon.

MANAGEMENT The goal of cardiac risk assessment and any remedial therapy is to improve intra- and postoperative and long-term outcomes. Optimization of associated medical conditions may include control of hypertension, coronary revascularization, treatment for congestive heart failure and other important systemic conditions (e.g., hepatic or renal insufficiency, pulmonary insufficiency), and management for coagulation or anticoagulation disorders.

PREVENTION Perioperative β-blockers are used to prevent postoperative atrial fibrillation and perioperative hypertension. Anticoagulation may be required to reduce the risk of thromboembolism and

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stroke in patients at increased risk (e.g., those with atrial fibrillation, hemoglobinopathies, coagulopathies, heart failure, prolonged bed rest). For patients with systemic anticoagulation or coagulopathies who are at increased risk for bleeding complications, special precautions must be taken if regional anesthesia will be used or is contemplated.

Further Reading Boersma E, Poldermans D, Bax JJ, et al: Predictors of cardiac events after major vascular surgery. JAMA 285:1865-1873, 2001. Dupuis J-Y, Wang F, Nathan H, et al: The cardiac anesthesia risk evaluation score. Anesthesiology 94:194-204, 2001. Eagle KA, Berger PB, Calkins H, et al: ACC/AHA update for perioperative cardiovascular evaluation for noncardiac surgery. Circulation 105:1257-1267, 2002. Eagle KA, Brundage BH, Chaitman BR, et al: Guidelines for perioperative cardiovascular evaluation for noncardiac surgery. Circulation 93:1278-1317, 1996. Fleisher LA, Eagle KA: Clinical practice: Lowering cardiac risk in noncardiac surgery. N Engl J Med 345:1677-1682, 2001. Grundy SM: Age as a risk factor: You are as old as your arteries. Am J Cardiol 83:1455-1457, 1999. Grundy SM, Pasternak R, Greenland P, et al: Assessment of cardiovascular risk by use of multiple-risk-factor assessment equations: A statement for healthcare professionals from the American Heart Association and the American College of Cardiology. Circulation 100:1481-1492, 1999. Lee TH, Marcantonio ER, Mangione CM, et al: Derivation and prospective validation of a simple index for prediction of cardiac risk of major noncardiac surgery. Circulation 100:1043-1049, 1999. Mukherjee D, Eagle KA: Perioperative cardiac assessment for noncardiac surgery. Circulation 107:2771-2774, 2003. Nashef SA, Roques F, Michel P, et al: European system for cardiac operative risk evaluation (EuroScore). Eur J Cardiothorac Surg 16:9-13, 1999. Ouattara A, Niculescu M, Ghazouani S, et al: Predictive performance and variability of the cardiac anesthesia risk score. Anesthesiology 100:405-410, 2004. Park KW: Preoperative cardiology consultation. Anesthesiology 98:754-762, 2003. Tu JV, Jaglal SB, Naylor D: The Steering Committee of the Provincial Adult Cardiac Care Network of Ontario: Multicenter validation of a risk index for mortality, intensive care unit stay, and overall hospital length of stay after cardiac surgery. Circulation 91:677-684, 1995. Wilson PWF, D’Agostino RB, Levy D: Prediction of coronary heart disease using risk factor categories. Circulation 97:1837-1847, 1998.

GENERAL ANESTHESIA

with evidence of important ischemic burden by symptoms or noninvasive study, is a major predictor. This definition of acute and recent MI was a consensus recommendation and avoids the traditional division of MI into 3-month and 6-month intervals. Finally, current management of MI provides for risk stratification during convalescence. If a recent stress test does not indicate residual myocardium at risk (ischemic burden), the likelihood of perioperative reinfarction with noncardiac surgery is low. Although there are no adequate clinical trials on which to base firm recommendations, it appears reasonable to wait 4 to 6 weeks after acute MI to perform elective surgery.

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Christine M. Zainer Case Synopsis A 47-year-old female executive with breast cancer is scheduled to have a lumpectomy and sentinel node biopsy under general anesthesia. She has a history of mild depression and a 1-week history of an upper respiratory infection that is resolving. The patient denies allergies and medications. Upon further questioning, she admits to taking St. John’s wort, Ginkgo biloba, dong quai, multivitamin and calcium supplements, and vitamin E. She also admits to taking ginseng and echinacea for the past week to treat her upper respiratory symptoms, because she did not want to postpone her surgery.

PROBLEM ANALYSIS Definition Many complementary and alternative medicine (CAM) systems rely on herbs or dietary supplements or modifications. These substances are also called nutraceuticals—anything that can be considered a food or part of a food and provides medical or health benefits, including the prevention and treatment of disease. Such CAM systems include Ayurveda (India), traditional Chinese medicine, homeopathy, and naturopathy. Other CAM systems do not necessarily include nutraceuticals but may involve manipulative, body-based, or energy therapies. These include the following: ● ● ● ● ● ●

Chiropractic Acupuncture Bioelectromagnetic field therapies Qi gong Reiki Therapeutic touch

Under the 1994 Dietary Supplement Health and Education Act, herbals are considered dietary supplements, not drugs. According to the Food and Drug Administration (FDA), dietary supplements are nutrients (vitamins, minerals, amino acids), botanicals (herbs or extracts from plants, including flowers, trees, shrubs, algae, ferns, fungi, seaweeds, and grasses), and glandular extracts from animal or synthetic sources. Manufacturers are allowed to state that their products affect the “structure or function” of the body, provided that there is a disclaimer that the product has not been evaluated by the FDA. Manufacturers are responsible for their products’ quality and safety, but the FDA does not require proof of efficacy or purity or reporting of adverse effects. The FDA may withdraw products shown to be harmful (e.g., fen-phen, cholestin, contaminated L-tryptophan, ephedra). Also, since 1998, FDA regulations require that dietary supplements that claim to “diagnose, treat, prevent, or cure disease” are to be regarded as drugs and must meet safety and efficacy 150

standards; hence the disclaimers on so many product labels. Homeopathic and parenteral nutritional products are registered by the FDA but are not approved as drugs.

Recognition Herbal medicines have been used for many thousands of years and are still used by 80% of the world’s population. Herbal medicines are prescribed in Europe, and the German Commission E monographs for over 400 herbs are a resource for physicians. One third of conventional drugs are plant derived; aspirin (willow bark), digoxin (foxglove), ephedrine (ma huang), and atropine (belladonna alkaloids) are some common examples. More than 5000 suspected herb-related adverse effects were reported to the World Health Organization prior to 1996. Between 1993 and 1998, the FDA received 2621 reports of adverse events, with 101 deaths associated with dietary supplements. In contrast, in 1995 the FDA received reports of 7000 deaths related to adverse prescription drug effects. One meta-analysis estimated that 100,000 deaths per year are associated with adverse drug reactions in hospitalized patients. Given the widespread use of herbals and other dietary supplements, reported adverse effects are relatively few. However, lack of recognition and underreporting are possible reasons for this disparity. Many reports of adverse effects lack documentation of temporal effects, concomitant drug use, and positive identification of the herb in question, and they exclude the possible effects of contaminants or adulterants. For any substance that may have pharmacologic effects, vigilance is prudent, especially during anesthesia and surgery. Consumers consider nutraceuticals to be safe, effective, and natural; as a result, their use is often not reported to physicians. As many as 20% of adults in the United States may use nutraceuticals, including herbs, and these numbers are increasing. One survey of more than 1000 adults undergoing preanesthetic evaluation revealed that about 40% were using at least one supplement, and 32% of these patients took herbals. More than 70% of these patients failed to report this use during routine preanesthetic assessment. A survey of more

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Risk Assessment Although mechanical and infectious complications have been reported after some CAM therapy, an extensive review is beyond the scope of this chapter. Given that there are more than 20,000 herbal products in the United States, this chapter focuses on those substances most commonly used or most likely to have adverse pharmacologic effects in the perioperative period. Assessment of risk is difficult, given the relative paucity of reports, incomplete information, and multiple patient and product variables. Dietary supplements, including vitamins, may contain a variety of substances with herbal ingredients. Product labels may not accurately reflect the contents or amounts. Also, lot-to-lot potency may vary owing to many factors, such as growing conditions, part of the plant used, time of harvest, preparation and extraction methods, and storage techniques. Standardization of compounds extracted from herbs is sometimes attempted, but the pharmacologic effects may be due to the combined or synergistic effects of the many compounds present in the herb. Further, products may be misused or adulterated with contaminants, such as misidentified botanical species, pesticides, herbicides, heavy metals, and conventional drugs. Asian products have a high rate of contamination (about 30%). For example, contaminants in L-tryptophan resulted in eosinophilia-myalgia syndrome. Also, substitution of Aristolochia fangchi (fang-ji, a known nephrotoxin) for Stephania tetrandra (huang-fang ji) in a Chinese weight-loss preparation sold in Belgium caused more than 100 cases of renal failure and urothelial carcinoma. The safety of raw animal glandular products (e.g., melatonin) is not known, especially those originating from the brains of animal species capable of transmitting spongiform encephalopathies. Synthetic sources are available for some of these substances. Possible adverse effects are often based on in vitro studies of isolated compounds in animal models, isolated case reports, or small observational clinical trials. Often, any observed adverse effects are assumed to be related to the active ingredients. Randomized, controlled trials of the effects of herbs in the perioperative period are lacking. Future risk assessment must distinguish a “no observed effect level” and a “no observed adverse effect level” similar to that adopted for food additives and contaminants. More study is definitely needed.

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Dietary substances affect enzyme systems and have clinical effects. For example, foods in the nightshade family (e.g., tomato, potato, eggplant) decrease acetylcholinesterase and pseudocholinesterase activity. These foods may influence the levels of drugs metabolized by these routes, including the neuromuscular blocking agent succinycholine. Dietary regimens that lead to subclinical vitamin deficiency states may predispose patients to complications. Neurologic complications after nitrous oxide anesthesia have been reported in patients with vitamin B12 deficiency, including one patient on a restricted vegan diet.

Implications Common side effects include gastrointestinal upset, allergic reactions, and dermatitis. Direct, indirect, synergistic, antagonistic, and toxic pharmacologic effects are possible when herbs are taken alone or in combination with conventional drugs. Herbs and nutraceuticals associated with organ system toxicity or physiologic effects are listed in Table 39-1. Table 39-2 summarizes the common uses for these herbs, the perioperative concerns, and other pertinent information. The risk of toxicity with conventional medications is increased for patients at the extremes of age, as well as those who are pregnant, have a chronic illness or metabolic dysfunction, or are receiving chronic drug treatment. These patients may also be at increased risk for adverse effects or drug interactions with some nutraceuticals.

MANAGEMENT There are no formal guidelines for the perioperative management of patients who are taking herbals or nutraceuticals. It may be reasonable to postpone elective surgery in those who are using nutraceuticals that may affect coagulation or cardiovascular, central nervous system, or other major organ function. The American Society of Anesthesiologists has made no formal statement about the known therapeutic properties of herbal medications, and it has no formal policy or standards of care that apply specifically to phytopharmaceuticals. It does advise, however, that patients inform their physicians if they are using phytopharmaceuticals, that physicians specifically ask their patients about such use, and that patients discontinue these products 2 to 3 weeks before anesthesia and surgery. Just as discontinuing some conventional medications is associated with increased morbidity and mortality, the discontinuation of herbal preparations may have similar effects. Abruptly stopping the use of some herbs may produce withdrawal symptoms. Individual management based on available pharmacokinetic data is recommended by some authors and may be the most practical approach in some clinical scenarios (Table 39-3). As for neuraxial blocks, herbal medicines alone are not thought to create a risk that would mandate the cancellation of surgery. Concurrent use of oral anticoagulants or heparin may increase the risk for bleeding. There are no wholly accepted tests for hemostasis in patients using

GENERAL ANESTHESIA

than 1000 preoperative pediatric patients showed that 12% used herbal remedies. Supplement use is more prevalent among the following groups: females, nonsmokers, those with higher incomes, those who exercise regularly, those educated beyond high school, those in generally good health (albeit with one or more health problems), presurgical patients, and patients with cancer, liver disease, human immunodeficiency virus (HIV), asthma, and rheumatologic disorders. By sales, the 10 top-ranked herbs in 2001 were echinacea, garlic, Ginkgo biloba, saw palmetto, ginseng, grapeseed extract, green tea, St. John’s wort, bilberry, and aloe. Studies have shown statistically significant efficacy in the case of garlic, Ginkgo biloba, saw palmetto, and St. John’s wort.

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Organ System or Pharmacologic Effects of Herbals and Nutraceuticals

Effects

Herbal/Nutraceutical

Abortifacient effects

Devil’s claw Dong quai Goldenseal Aromatherapy Salicylate sources: willow bark, meadowsweet Feverfew (↓ migraines) Fish oils (ω-3 fatty acids)

Analgesic effects

Anti-inflammatory effects

Blood pressure effects

Carcinogen Cardiac effects

Cardiac glycoside–like effects

Cardiac effects— ischemic preconditioning CNS effects Cognitive function Seizures Sedative effects

Ginseng (↓ opioid effects) Blueberry Devil’s claw Ginkgo biloba Ginger Green tea Milk thistle Red grapes Stinging nettle Turmeric Willow bark Yarrow Black cohosh (↓) Celery (↓) Fenugreek (↓) Garlic (↓) Hawthorn (↓) Horseradish (↓) Capsicum (↑) Ephedra (↑) Goldenseal (↑) Licorice (↑) Ginger (↓ or ↑) Ginkgo (↑ or ↓) Ginseng (↓ or ↑) St. John’s wort (↓ or ↑) Calamus Sassafras Aconite Black cohosh Ephedra Fenugreek Fish oils GBL, BD, GHB Ginger Ginkgo biloba Goldenseal Hawthorn

Other Names

Oxytocic

Withdrawal possible Decreases pain associated with migraines, sickle cell, rheumatoid arthritis Vaccinium myrtillus Harpagophytum procumbens Ginkgo biloba Zingiber officinale Camellia sinensis Silybum marianum Vitus vinifera Urtica dioica Curcuma longa Salix alba Achillea millefolium

Jimsonweed Licorice Lobelia Foxglove (yellow, purple) Digitalis lanata; purpurea Kyushin Milkweed Apocynum androsaemifolium Lily of the valley Plantain (adulterated with foxglove) Siberian ginseng Eleutherococcus senticosus Hawthorn berries Uzara root Antioxidants (free radicals are involved in ischemic preconditioning in animals) Melatonin Ginkgo toxin in seed and leaf Celery Chamomile

Specific Effects/Comments

Arrhythmias ↓ HR, vasodilator Arrhythmias ↑ HR ↓ Sudden death, ↓ lipids ↓ HR, death ↓ HR, inotrope in vitro Vasodilator, but HTN noted Cardiac stimulant, ↓ coronary blood flow Arrhythmias; potentiation of digitalis; possible β-blocker, ACE inhibitor properties ↑ HR, anticholinergic effects HTN, hypokalemia ↑ HR

Vitamin C–attenuated beneficial effect of ischemic preconditioning in pigs Case report—used to treat/prevent postoperative delirium Neurotoxin; decreased seizure threshold Unconsciousness, slow respirations Table continued on following page

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Organ System or Pharmacologic Effects of Herbals and Nutraceuticals—cont’d

Effects

Herbal/Nutraceutical

Coagulation effects

Drug interactions Digoxin Digoxin assay: interference/ without toxicity Dilantin MAOIs SSRIs Warfarin ↓ INR ↑ INR Potentiation of effect Drug metabolism Hepatic enzyme inducers ↓ drug concentrations (subtherapeutic) Hepatic enzyme inhibitors ↑drug levels (toxicity) Esterase inhibitors (↓ metabolism of cocaine, heroin, esmolol, local ester anesthetics, cholinesterase inhibitors, neuromuscular blocking drugs) Electrolyte abnormalities

Valerian Chinese herbs (most P) Dan-shen (P) Dong quai (P) Vitamin E (P) (>800 mg = 1200 IU/day) Feverfew (P) Fish oils (P) Garlic (P) Ginger (P) (inhibits thromboxane synthetase) Ginkgo biloba (P) (inhibits plateletactivating factor) Ginseng—Panax (P, F) (prolongs PT, PTT; but ↓ INR on warfarin) Ginseng—American (↓ INR) Kava kava (P) Hawthorn Licorice St. John’s wort Kyushin (false ↑) Siberian ginseng (false ↑) Shankhapushpi (Ayurvedic) Ginseng (Panax) Licorice St. John’s wort St. John’s wort St. John’s wort Coenzyme Q10 Ginseng (Panax, American) Dan-shen Dong quai Garlic Ginger Ginkgo

Specific Effects/Comments

Serotonergic syndrome with SSRIs (tremor, headache, myalgias, restlessness, mental status changes) Withdrawal syndrome Coumarin-containing plants: alfalfa, capsicum, celery, chamomile, fenugreek, ginseng, horseradish, licorice, passsionflower, red clover

↑ Toxicity ↓ Digoxin levels Traditional Chinese medicine “to save the heart” ↓ Plasma concentration

Serotonergic syndrome with concomitant use

Vitamin K analogue

St. John’s wort

Echinacea Grapefruit juice Glycoalkyloids of Solanaceae (nightshades—potato, tomato, eggplant)

Aloe Artichoke Celery Dandelion

Cathartic, hypokalemia Diuretic Diuretic Diuretic Table continued on following page

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GBL, BD, GHB Ginseng Goldenseal Hops Kava kava Passionflower St. John’s wort

Other Names

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Organ System or Pharmacologic Effects of Herbals and Nutraceuticals—cont’d

Effects

Herbal/Nutraceutical

Other Names

Glossypol Goldenseal Licorice Glucose blood levels Increased

Decreased

Hepatic toxicity

Immune function

Devil’s claw Ephedra Ginseng Licorice Chromium Cinnamon Fenugreek Garlic Ginseng Karela Sage Chaparral Comfrey Germander Kava kava Pennyroyal Yohimbe Echinacea

Nausea and vomiting Neuromuscular blockade

Ginger (↓ motion sickness) Potato glycoalkaloids Solanaceae (nightshade—tomato, potato, eggplant)

Renal toxicity Skin effects

Aristolochia fangchi Kava kava Dong quai St. John’s wort Valerian (GABAergic)

Withdrawal syndromes

Specific Effects/Comments Hypokalemia Aquaretic (water, not Na+, excreted; ↑ HTN, edema) Hypokalemia, pseudoaldosteronism

Momordica charantia

Need for liver transplant or death Multicomponent product Not recommended for patients with autoimmune diseases Inhibits pseudocholinesterase (in vitro, human; in vivo, rabbit) Inhibits pseudocholinesterase and acetylcholinesterases Urothelial carcinoma, renal failure Kava dermopathy (yellow, dry, flaky skin) Photosensitizer Photosensitizer Consider tapering over 2 wk; give benzodiazepines for withdrawal

ACE, angiotensin-converting enzyme; BD, 1,4-butanediol; CNS, central nervous system; F, fibrin formation inhibitor; GABA, γ-aminobutyric acid; GBL, γ-butyrolactone; GHB, γ-hydroxybutyrate; HR, heart rate; HTN, hypertension; INR, international normalized ratio; MAOI, monoamine oxidase inhibitor; P, platelet aggregation inhibitor; PT, prothrombin time; PTT, partial thromboplastin time; SSRI, selective serotonin reuptake inhibitor.

herbal preparations, nor are there specific concerns or recommendations regarding the timing of neuraxial block placement or catheter removal. Information and vigilance are key to recognizing potentially adverse reactions and responding to them appropriately. Also, the recognition of potentially advantageous effects may come with further research.

PREVENTION Physicians should be informed about and familiar with the effects of commonly used herbals and nutraceuticals, whether positive and negative. They should ask patients about their use and be willing to act as resource for them.

Patients should consult with their physicians before using herbals or nutraceuticals and then report any beneficial or adverse side effects. Consumers who use these substances should be cautious about product quality, especially with foreign manufacturers or distributors. They may want to consider requesting independent laboratory test results for product content and the presence of contaminants. Information about herbals and nutraceuticals is available from many public and private resources (Table 39-4). Suspected adverse effects should be reported to the FDA’s Center for Food Safety and Applied Nutrition (http://vm.cfsan.fda.gov/~dms/supplmnt.html) or to the FDA MedWatch Program (www.fda.gov/medwatch; 1-800FDA-1088).

Ginseng American (Panax quinquefolius) Asian (Panax ginseng) Sanchi (Panax pseudoginseng var notoginseng) Siberian (Eleutherococcus senticosus) GBL, BD, GHB

Ginkgo (Ginkgo biloba)

Ginger (Zingiber officinale)

Garlic (Allium sativum)

Illegally distributed (not approved by FDA) for bodybuilding, weight loss, sleep aid

HTN; hyperlipidemia; respiratory, digestive, liver complaints Nausea, vomiting; vertigo; motion sickness; antispasmodic; digestive complaints Dementia; claudication; increased mental acuity; tinnitus; vertigo Adaptogen; immunomodulation; tonic for many conditions

Weight loss; antitussive; asthma Antioxidant; antiaging; cardiovascular health and cancer prophylaxis; fibrocystic breast syndrome Migraines; fever

Ephedra, ma huang (Ephedra sinica) Vitamin E

Feverfew (Tanacetum parthenium)

Upper respiratory infections, flu

Echinacea (E. angustifolia, E. pallida, E. purpurea)

Yes Yes

Inhibits platelet-activating factor; seed and leaf contain a neurotoxin HTN; tachycardia; bleeding; ↓ INR with warfarin; CNS stimulation; hypoglycemic effects in type 2 diabetes

Yes

Yes

Inhibits platelet aggregation; ↑ INR with warfarin Inhibits thromboxane synthetase

Yes

Yes

Yes

Inhibits platelets

HTN, arrhythmias, sympathomimetic effects

Possible inhibition of platelet aggregation and cyclooxygenase; ↑ INR on warfarin Immunostimulant; inhibits CYP3A4, so risk of toxicity for drugs metabolized by CYP3A4 (alprazolam, calcium channel blockers, protease inhibitors)

Continued

Death; seizures; unconsciousness; bradycardia; slowed respirations requiring intubation

Spontaneous hyphema, subdural hematoma; no known interaction with cardiac glycosides or hypoglycemics Stevens-Johnson syndrome; epistaxis; vaginal bleeding; mastalgia Siberian ginseng interferes with digoxin assay— false elevation of digoxin levels without toxicity

Abrupt withdrawal can cause headache, insomnia, nervousness, arthralgias, fatigue, stiffness; aphthous ulcers Case of elderly man who developed spontaneous epidural hematoma while gardening—4 raw cloves/day Possible mutagenesis

Tachyphylaxis; autoimmune disease exacerbation; potentially hepatotoxic, but lacks 1,2 unsaturated necrine ring associated with other hepatotoxic pyrrolizidine alkaloids Banned by FDA in 2004; interactions with cardiac glycosides Possible bleeding with doses >800 mg = 1200 IU/day

Photosensitivity

Structurally related to vitamin K

↓ INR on warfarin

Congestive heart failure, cardiovascular health; used with statins Menopausal symptoms

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Dong quai (Angelica sinensis)

Cross-allergenicity with ragweed

Hypokalemia Sedation

Digestion, cathartic Insomnia

Other Concerns

Aloe Chamomile (Matricaria chamomilla) Coenzyme Q10 (ubiquinone, ubidecarenone)

Potential Bleeding

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Potential Perioperative Concerns

Common Uses of and Potential Problems with Herbals and Nutraceuticals Common Uses

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Herbal/Nutraceutical

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156 Depression; anxiety; sleep disorders Insomnia; sedation; anxiety

St. John’s wort (Hypericum perforatum)

Valerian (Valeriana officinalis)

Kava dermopathy (red eyes; dry, flaky, yellow skin and nails); inhibits cyclooxygenase Cross-reacts with digoxin assays Glycyrrhizic acid inhibits 11-β-hydroxysteroid dehydrogenase resulting in mineralocorticoid effects; transient myopathy (2 wk) Inhibits dihydrotestosterone binding and 5α-reductase activity; possible interaction with other hormone therapies Photosensitivity; induction of hepatic cytochromes P-450, 3A4; decreased digoxin levels; decreased HIV protease inhibitors and NNRTIs Withdrawal possible; treat with benzodiazepines

Coma with alprazolam; GABA effects; potentiates barbiturates and benzodiazepines; hepatotoxicity False elevations of digoxin levels without toxicity HTN; K+ loss; edema; pseudoaldosteronism

Prolongs barbiturate-induced sleep

Possible weak MAOI; possible SSRI (mechanism uncertain); use caution with β-sympathomimetic amines, SSRIs, MAOs

None known

Oxytocic; aquaretic, not diuretic (no Na+ excreted, just free water)

Other Concerns

HTN; edema; paralysis with overdosage

Potential Bleeding

BD, 1,4-butanediol; CNS, central nervous system; FDA, Food and Drug Administration; GABA, γ-aminobutyric acid; GBL, γ-butyrolactone; GHB, γ-hydroxybutyrate; HIV, human immunodeficiency virus; HTN, hypertension; INR, international normalized ratio; MAOI, monoamine oxidase inhibitor; NNRTI, non-nucleoside reverse transcriptase inhibitor; SSRI, selective serotonin reuptake inhibitor.

Benign prostatic hypertrophy

Saw palmetto (Serenoa repens)

Diuretic; antiinflammatory; laxative; hemostatic Insomnia; sedation; anxiety Chinese medicine “to save the heart” Licorice (Glycyrrhiza glabra) Digestion; ulcers

Goldenseal (Hydrastis canadensis)— turmeric root Kava kava (Piper methysticum) Kyushin

Potential Perioperative Concerns

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Common Uses of and Potential Problems with Herbals and Nutraceuticals—cont’d

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Herbals and Alternative Medicine

Recommended Preoperative Discontinuation of Herbs Preoperative Discontinuation

Aloe Echinacea Ephedra (banned) Garlic Ginkgo Ginseng Kava kava St. John’s wort Valerian

No data No data At least 24 hr At least 7 days At least 36 hr At least 7 days At least 24 hr At least 5 days No data (benzodiazepine-like acute withdrawal possible)

■

Herbal and Dietary Supplement Resources

Organization

Web Address/Phone

Information/Comments

Alternative Medicine Foundation

http://www.herbmed.org

American Botanical Council

www.herbalgram.org

Certificates of analysis

Various sources; available on request from manufacturers or distributors www.epocrates.com http://vm.cfsan.fda.gov/~dms/supplmnt.html 1-888-723-3366 www.fda.gov/medwatch 1-800-FDA-1088 www.cancer.gov

Research publication summaries; MEDLINE links News, information; German Commission E Monographs Amount of active ingredient in given lot; presence of contaminants Alternative medicine tables Report adverse events; safety, industry regulations Report adverse events Search “alternative medicine”

http://nccam.nih.gov 1-888-644-6226

Fact sheets, consensus reports, databases

Epocrates Rx Pro FDA, Center for Food Safety and Applied Nutrition FDA Medwatch NCI, Division of Cancer Prevention and Control, Chemoprevention Program NIH, National Center for Complementary and Alternative Medicine NIH, Office of Alternative Medicine and Office of Dietary Supplements NIH, Office of Dietary Supplements, International Bibliographic Information on Dietary Supplements (IBIDS) PDR for Herbal Medicines Quackwatch US Department of Health and Human Services US Pharmacopoeia

www.altmed.od.nih.gov www.ods.od.nih.gov

Abstracts of peer-reviewed literature

ISBN 1-56363-292-6; Medical Economics Co., Montvale, NJ http://www.quackwatch.com www.healthfinder.gov

General health care; CAM Search “alternative medicine”

www.usp.org

Private organization; quality standards

CAM, complementary and alternative medicine; FDA, Food and Drug Administration; NCI, National Cancer Institute; NIH, National Institutes of Health; PDR, Physicians’ Desk Reference.

Further Reading Abebe W: Herbal medication: Potential for adverse interactions with analgesic drugs. J Clin Pharm Ther 27:391-401, 2002. Adusumilli PS, Ben-Porat L, Pereira M, et al: The prevalence and predictors of herbal medicine use in surgical patients. J Am Coll Surg 198: 583-590, 2004. Anesthesiologists warn: If you’re taking herbal products, tell your doctor before surgery. Information for patients: http://www.asahq.org/ patientEducation/insiderherb.html. Information for doctors: http://www.asahq.org/patientEducation/herbal.html. Ang-Lee MK, Moss J, Yuan C: Herbal medicines and perioperative care. JAMA 286:208-216, 2001. Bent S, Ko R: Commonly used herbal medicines in the United States: A review. Am J Med 116:478-485, 2004.

Borins M: The dangers of using herbs—what your patient needs to know. Postgrad Med 104:91-100, 1998. Chagan L, Ioselovich A, Asherova L, Cheng JWM: Use of alternative pharmacotherapy in management of cardiovascular diseases. Am J Manag Care 8:270-285, 2002. Considerations for anesthesiologists—what you should know about your patients’ use of herbal medicines and other dietary supplements. American Society of Anesthesiologists brochure, 2003. Available at www.ASAhq.org. De Smet PAGM: Herbal remedies. N Engl J Med 347:2046-2056, 2002. Ernst E: The risk-benefit profile of commonly used herbal therapies: Ginkgo, St John’s wort, ginseng, echinacea, saw palmetto, and kava. Ann Intern Med 136:45-53, 2002. Ezzo J, Berman BM, Vickers AJ, et al: Complementary medicine and the Cochrane collaboration. JAMA 280:1628-1630, 1998.

GENERAL ANESTHESIA

Herb

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Fugh-Berman A: Herb-drug interactions. Lancet 355:134-138, 2000. Get the facts—what is complementary and alternative medicine (CAM). National Institutes of Health Center for Complementary and Alternative Medicine. Available at http://nccam.nih.gov/health/ whatiscam/index.htm. Hanania M, Kitain E: Melatonin for treatment and prevention of postoperative delirium. Anesth Analg 94:338-339, 2002. Horlocker TT, Wedel DJ, Benzon H, et al: Regional anesthesia in the anticoagulated patient: Defining the risks. Reg Anesth Pain Med 29:1-11, 2004. Izzo AA, Ernst E: Interactions between herbal medicines and prescribed drugs. Drugs 61:2163-2175, 2001. Kaye AD, Clarke RC, Sabar R, et al: Herbal medicines: Current trends in anesthesiology practice—a hospital survey. J Clin Anesth 12:468-471, 2000. Kaye AD, Kucera I, Sabar R: Perioperative anesthesia clinical considerations of alternative medicines. Anesthesiol Clin North Am 22:125-139, 2004. Kottke MK: Scientific and regulatory aspects of nutraceutical products in the United States. Drug Dev Indust Pharm 24:1177-1195, 1998. Lazarou J, Pomeranz BH, Corey PN: Incidence of adverse drug reactions in hospitalized patients. JAMA 279:1200-1205, 1998. Lee P, Smith I, Piesowicz A, Brenton D: Spastic paraparesis after anaesthesia. Lancet 353:554, 1999. Lin Y, Bioteau AB, Ferrari LR, Berde CB: The use of herbs and complementary and alternative medicine in pediatric preoperative patients. J Clin Anesth 16:4-6, 2004. McGehee DS, Krasowski MD, Fung DL, et al: Cholinesterase inhibition by potato glycoalkaloids slows mivacurium metabolism. Anesthesiology 93:510-519, 2000. Miller LG: Herbal medicinals—selected clinical consideration focusing on known or potential drug-herb interactions. Arch Intern Med 158:2200-2211, 1998. Murphy JM: Preoperative considerations with herbal medicines. AORN J 69:173-183, 1999.

Niggemann B, Gruber C: Side-effects of complementary and alternative medicine. Allergy 58:707-716, 2003. Norred CL: A follow-up survey of the use of complementary and alternative medicines by surgical patients. AANA J 70:119-125, 2002. Norred CL, Brinker F: Potential coagulation effects of preoperative complementary and alternative medicines. Altern Ther Health Med 7:58-67, 2001. Norred CL, Zamudio S, Palmer SK: Use of complementary and alternative medicines by surgical patients. AANA J 68:13-18, 2000. Pinn G: Adverse effects associated with herbal medicine. Aust Fam Physician 30:1070-1075, 2001. Pribitkin E, Boger G: Herbal therapy—what every plastic surgeon must know. Arch Facial Plast Surg 3:127-132, 2001. Rados C: Ephedra ban: No shortage of reasons. FDA Consumer Magazine, July 2004. Available at http//www.fda.gov/fdac/features/2004/ 204_ephedra.html. Rose KD, Croissant PD, Parliament CF, Levin MB: Spontaneous spinal epidural hematoma with associated platelet dysfunction from excessive garlic ingestion: A case report. Neurosurgery 26:880-882, 1990. Rosener M, Dichgans J: Severe combined degeneration of the spinal cord after nitrous oxide anaesthesia in a vegetarian. J Neurol Neurosurg Psychiatry 60:354, 1996. Sabar R, Kaye AD, Frost EAM: Perioperative considerations for the patient on herbal medicines. Middle East J Anesthesiol 16:287-314, 2001. Skyschally A, Schulz R, Gres P, et al: Attenuation of ischemic preconditioning in pigs by scavenging of free oxyradicals with ascorbic acid. Am J Physiol Heart Circ Physiol 284:698-708, 2003. Walker R: Criteria for risk assessment of botanical food supplements. Toxicol Lett 149:187-195, 2004. Yuan CS, Wei G, Dey L, et al: Brief communication: American ginseng reduces warfarin’s effect in healthy patients: A randomized controlled trial. Ann Intern Med 141:23-27, 2004.

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Difficult Airway: Cannot Ventilate, Cannot Intubate

40 GENERAL ANESTHESIA

Michael P. Ford and George A. Arndt Case Synopsis A moderately obese man with lung contusions and a closed head injury requires endotracheal intubation on admission to the hospital. Two days later, after neurologic and respiratory recovery, his trachea is extubated. The patient immediately develops respiratory difficulty. Attempts to ventilate the lungs via facemask are unsuccessful. As the patient loses consciousness, laryngoscopy is performed, but the laryngeal structures cannot be visualized. The patient’s oxygen saturation decreases rapidly.

PROBLEM ANALYSIS Definition CANNOT VENTILATE, CANNOT INTUBATE The cannot ventilate, cannot intubate (CVCI) situation is defined as the inability to ventilate the patient’s lungs via facemask despite multiple attempts, and the inability to intubate the patient’s trachea via conventional direct laryngoscopy. In 2003 the American Society of Anesthesiologists (ASA) Task Force on Management of the Difficult Airway updated the applicable practice guidelines. It is hoped that use of the ASA difficult airway algorithm (Fig. 40-1) will reduce the likelihood of adverse outcomes. The CVCI situation can develop quickly but often occurs after repeated attempts at direct laryngoscopy or after a failed rapid-sequence induction or intubation. No more than two or three attempts should be made at direct laryngoscopy, because repeated attempts may worsen the patient’s outcome. The CVCI portion of the ASA algorithm entails the use of rescue options with varying degrees of invasiveness. Before resorting to invasive airway rescue techniques, it is crucial that every effort be made to achieve oxygenation and ventilation through noninvasive techniques, such as optimal facemask ventilation (two-person mask technique, ensuring adequate jaw thrust and facemask seal, with an oral or nasal airway [or both]) or supraglottic ventilation using a laryngeal mask airway. Although potentially lethal, the CVCI situation is, fortunately, a rare occurrence. El-Ganzouri and colleagues evaluated the airways of 10,507 consecutive patients and found that 107 (1%) had a poor laryngoscopic view (grade 4—neither laryngeal structures nor epiglottis visualized), 535 (5.3%) patients had a grade 3 laryngeal view, and only 8 patients (0.07%) could not be adequately ventilated using a facemask. DIFFICULT AIRWAY A difficult airway is defined as a clinical situation in which a conventionally trained anesthesiologist experiences difficulty

with facemask ventilation of the airway, difficulty with tracheal intubation, or both. Intubation is difficult when multiple attempts, maneuvers, blades, and endoscopies are required. Some patients with a difficult airway for mask ventilation may be relatively easy to intubate, and vice versa. Reasons for the majority of airway complications and management failures are listed in Table 40-1. DIFFICULT FACEMASK VENTILATION Difficult facemask ventilation occurs when positive-pressure ventilation, by an unassisted anesthesiologist, fails to maintain oxygen saturation above 90% (with an inspired oxygen concentration of 100%) or the ventilation effort fails to prevent or reverse signs of inadequate gas exchange. Inadequate facemask ventilation is secondary to inadequate facemask seal, excessive gas leak, or excessive resistance to the ingress or egress of gas. Signs of inadequate facemask ventilation are listed in Table 40-2. The incidence of difficult facemask ventilation is approximately 5%. The incidence of difficult ventilation, despite optimization of the mask airway using supraglottic adjuncts, is less than 0.5%. All patients should be oxygenated before the induction of general anesthesia; doing so decreases the incidence of and prolongs the time interval to oxygen desaturation when facemask ventilation is inadequate or not attempted (rapidsequence induction). In pediatric and uncooperative patients, however, the effectiveness of preoxygenation may be limited. In obese patients, preoxygenation using continuous positive airway pressure and the reverse Trendelenburg position lengthens the time to decreased oxygen saturation after the onset of apnea or inadequate ventilation. Patient factors associated with difficult facemask ventilation, as well as some suggestions for dealing with them, are listed in Table 40-3. Multiple factors indicate a high likelihood of difficult facemask ventilation. Placing a laryngeal mask airway permits adequate positive-pressure ventilation to occur in most patients and should be used early when difficulty with facemask ventilation (or difficult intubation) is encountered. 159

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1. Assess the likelihood and clinical impact of basic management problems: A. Difficult ventilation B. Difficult intubation C. Difficulty with patient cooperation or consent D. Difficult tracheostomy 2. Actively pursue opportunities to deliver supplemental oxygen throughout the process of difficult airway management 3. Consider the relative merits and feasibility of basic management choices: A.

Awake intubation

vs.

Intubation attempts after induction of general anesthesia

B.

Noninvasive technique for initial approach to intubation

vs.

Invasive technique for initial approach to intubation

C.

Preservation of spontaneous ventilation

vs.

Ablation of spontaneous ventilation

4. Develop primary and alternative strategies: A.

AWAKE INTUBATION

Airway approach by noninvasive intubation

Succeed*

Cancel case

Invasive airway access(b)*

B.

INTUBATION ATTEMPTS AFTER INDUCTION OF GENERAL ANESTHESIA

Initial intubation attempts successful*

From this point onward consider: 1. Calling for help 2. Returning to spontaneous ventilation 3. Awakening the patient

FAIL

Consider feasibility of other options(a)

Initial intubation attempts UNSUCCESSFUL

Invasive airway access(b)*

FACEMASK VENTILATION ADEQUATE

FACEMASK VENTILATION NOT ADEQUATE

Consider / Attempt LMA

NONEMERGENCY PATHWAY Ventilation adequate, intubation unsuccessful

LMA ADEQUATE*

LMA NOT ADEQUATE OR NOT FEASIBLE

EMERGENCY PATHWAY Ventilation not adequate, intubation unsuccessful Alternative approaches to intubation(c)

Successful intubation*

FAIL after multiple attempts

IF BOTH FACEMASK AND LMA VENTILATION BECOME INADEQUATE

Call for help

Emergency noninvasive airway ventilation(e)

Successful ventilation*

Invasive airway access(b)*

Consider feasibility of other options(a)

Awaken patient(d)

FAIL

Emergency invasive airway access(b)*

* Confirm ventilation, tracheal intubation, or LMA placement with exhaled CO2. a. Other options include (but are not limited to): surgery utilizing facemask or LMA anesthesia, local anesthesia infiltration or regional nerve blockade. Pursuit of these options usually implies that mask ventilation will not be problematic. Therefore, these options may be of limited value if this step in the algorithm has been reached via the Emergency Pathway. b. Invasive airway access includes surgical or percutaneous tracheostomy or cricothyrotomy. c. Alternative noninvasive approaches to difficult intubation include (but are not limited to) use of different laryngoscope blades, LMA as an intubation conduit (with or without fiberoptic guidance), fiberoptic intubation, intubating stylet or tube changer, light wand, retrograde intubation, and blind oral or nasal intubation. d. Consider repreparation of the patient for awake intubation or canceling surgery. e. Options for emergency noninvasive airway ventilation include (but are not limited to) rigid bronchoscope, esophageal-tracheal Combitube ventilation, or transtracheal jet ventilation.

Figure 40–1 ■ American Society of Anesthesiologists difficult airway algorithm. LMA, laryngeal mask airway. (From Practice guidelines for management of the difficult airway—an updated report by the American Society of Anesthesiologists Task Force on Management of the Difficult Airway. Anesthesiology 98:1269-1277, 2003.)

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Reasons for Airway Complications and Management Failures

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Patient Factors Associated with Difficult Facemask Ventilation and Suggested Solutions

Facial Hair Place adhesive plastic sheet, with mouth and naris openings, over facial hair to achieve better mask seal Place oral, nasal, or laryngeal mask airway early

Edentulous Consider leaving dentures in place until laryngoscopy to improve facemask seal Place laryngeal mask airway early

Body Mass Index >26

DIFFICULT INTUBATION Difficult intubation occurs when endotracheal intubation requires multiple attempts. The ASA Task Force defines difficult intubation as more than three attempts at conventional direct laryngoscopy or more than 10 minutes to achieve intubation. Difficult laryngoscopy is the inability to visualize any portion of the vocal cords after multiple attempts using conventional rigid laryngoscopy. The incidence of difficult direct laryngoscopy (more than two attempts) is between 0.5% and 2%. The first attempt must be optimized, including adequate depth of anesthesia and muscle relaxation, proper positioning of the head and neck, use of a styletted tube, and application of laryngeal manipulation. External laryngeal pressure or manipulation by the laryngoscopist’s right hand (or by an assistant) may convert a grade 3 visualization of the larynx to a grade 2 (Fig. 40-2). Straight laryngoscope blades can be efficacious with “anterior” anatomy. Alternative, specialized laryngoscopes should be employed only by those experienced with their use. No more than two or three attempts should be made at direct laryngoscopy, because repeated attempts may worsen the patient’s outcome (e.g., conversion of a can-ventilate to a cannot-ventilate situation, or laryngeal edema causing glottic airway obstruction after tracheal extubation). Facemask ventilation must occur between attempts, and direct laryngoscopy must be stopped if oxygen saturation falls below 90% to 92% (maintenance of oxygenation takes precedence). The most experienced anesthesiologist available should perform the final attempt at direct laryngoscopy.

Table 40–2

■

Signs of Inadequate Facemask Ventilation

Insufficient or absent chest movement Absent or inadequate breath sounds Audible signs of airway obstruction, gastric air insufflation, or gastric dilatation Inadequate or decreasing oxygen saturation Cyanosis Absent, inadequate, or elevated end-tidal carbon dioxide Absent or inadequate exhaled gas flow (spirometry) Hemodynamic consequences of hypercarbia or hypoxemia (e.g., tachycardia, hypertension, dysrhythmias)

Preoxygenate patient with continuous positive airway pressure and use 20- to 30-degree reverse Trendelenburg position Increases time interval to desaturation after onset of apnea or difficult mask ventilation Reverse Trendelenburg “unloads” diaphragm, improving pulmonary compliance Use laryngeal mask airway early for positive-pressure mask ventilation

Snoring and Obstructive Sleep Apnea Place oral, nasal, or laryngeal mask airway early

Age >55 yr History of Smoking Supraglottic, Glottic, and Subglottic Pathology or Stridor Consider prospective placement of translaryngeal jet ventilation catheter Strongly consider awake airway management Avoid sedation if stridor is present

Bronchospasm (active or at risk for) Nebulize with bronchodilator before induction

Recognition The cause of the majority of difficult endotracheal intubations is limited oropharyngeal space, decreased atlantooccipital extension, decreased pharyngeal space, or decreased submandibular compliance. Recognition of potentially difficult direct laryngoscopy and endotracheal intubation is facilitated by a systematic search for abnormalities during the preoperative airway examination (Table 40-4). Unfortunately, airway examination findings have low and variable sensitivity and marginal specificity; however, worrisome findings, particularly in combination, suggest a difficult intubation. A Mallampati class higher than II (Fig. 40-3) in association with other airway findings signifies potential difficulty during traditional direct laryngoscopy. Reviewing the patient’s prior anesthetic history and previous records of airway management (if available) is extremely helpful when formulating the airway management plan. Anesthesiologists must accurately document the ease or difficulty of facemask ventilation, laryngoscopy attempts and blades used, the laryngoscopic view obtained (see Fig. 40-2), how intubation was ultimately achieved, and any special maneuvers or devices used. Assume high reliability if the patient selfreports a difficult airway. Consider any systemic diseases or congenital abnormalities that require special attention during airway management.

GENERAL ANESTHESIA

Inaccurate or incomplete preoperative airway assessment Incorrect prediction of: Easy mask airway Routine direct laryngoscopy-guided intubation Uncomplicated extubation Unwillingness to abandon failed airway management plan Failure to call for help early, when difficult airway is first apparent Incomplete preparation of backup plan Deterioration of performance under stress Failure in judgment

Difficult Airway: Cannot Ventilate, Cannot Intubate

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Figure 40–2 ■ Laryngoscopic view grading systems. A, Cormack-Lehane system: grade 1, visualization of the entire laryngeal aperture; grade 2, visualization of only the posterior portion of the laryngeal aperture; grade 3, visualization of only the epiglottis; grade 4, visualization of only the soft palate. B, Modified grading system of view at direct laryngoscopy: grade 1, most of cords visible (direct intubation); grade 2A, posterior cord visible (direct intubation); grade 2B, only arytenoids visible (indirect intubation); grade 3A, epiglottis visible and liftable (indirect intubation); grade 3B, epiglottis adherent to pharynx (specialist required for intubation); grade 4, no laryngeal structures seen (specialist required for intubation). (A, From Cormack RS, Lehane J: Difficult tracheal intubation in obstetrics. Anaesthesia 39:1105, 1984. B, From Cook TM: A new practical classification of laryngeal view. Anaesthesia 55:274-279, 2000.)

Laryngoscope

Epiglottis

A

1

2

3

4

Grade 1

B

Grade 2A

Grade 2B

Easy

Grade 3A

Restricted

ENDOTRACHEAL INTUBATION INTRODUCERS AND INTUBATING CATHETERS A malleable tracheal tube introducer (gum-elastic bougie [GEB], length 60 cm) or an intubating catheter can be placed blindly and gently under the epiglottis (or directed through partially visible, posterior vocal cords) into the trachea during one of the laryngoscopic attempts. The anesthesiologist will not see the GEB entering the larynx with a grade 3 or 4 laryngoscopic view. Tactile “clicking” may be felt as the angled (about 60 degrees), anteriorly directed tip of the GEB passes over (hits against) the tracheal rings. If clicks are not perceived, the GEB should be gently advanced to a maximum depth of 45 cm (in an adult patient). If distal hold-up is sensed, such as slight resistance to further advancement, the GEB is likely “caught up” in the bronchial tree, and the patient may cough if not completely paralyzed. If neither clicks, hold-up, nor coughing is evoked, the GEB is probably in the esophagus and should be removed. A second attempt at passing the GEB blindly into the trachea can be considered, unless there is a grade 4 laryngeal view or the epiglottis

Grade 3B

Grade 4

Difficult

cannot be elevated (the epiglottis is “adherent” to the pharynx). If the GEB is believed to be in the trachea, an internally lubricated endotracheal tube (ETT) is advanced (“railroaded”) over the GEB. Leaving the laryngoscope blade in the mouth and rotating the ETT 90 degrees counterclockwise facilitates ETT advancement (orientation of the Murphy eye at the 12 o’clock position prevents the ETT tip from hanging up on the right vocal cord or arytenoids during passage). Tracheal location is confirmed by auscultation of equal bilateral breath sounds and sustained end-tidal carbon dioxide waveforms. The rule is, “if in doubt, take the ETT out,” unless immediate flexible bronchoscopy via the ETT confirms a tracheal location. Optimal results achieving intubation with the GEB are dependent on experience and regular use. DIFFICULT EXTUBATION The risks for difficult facemask ventilation and difficult intubation, as well as other events, herald difficult extubation. Patients with a difficult airway should meet the usual criteria for extubation and be fully awake. They also should cough

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Airway Examination Predictors of Difficult Direct Laryngoscopy and Endotracheal Intubation

Interincisor Gap

Length of Upper Incisors Long incisors impede alignment of oral and pharyngeal axes during direct laryngoscopy Relatively long, protruding upper incisors are worrisome Mallampati Oropharyngeal Classification (see Fig. 40-3) With Mallampati class I or II, tongue should be easily retracted from the line of site during direct laryngoscopy Mallampati class >II is worrisome

Mandibular Space With hyomental and thyromental distances (estimates of mandibular space) >6 and 7 cm, respectively, larynx should be sufficiently posterior for favorable line of sight with direct laryngoscopy Distance <3 ordinary fingerbreadths (5 cm) is worrisome

Length and Thickness of Neck Short, thick neck reduces ability to align upper airway axes during direct laryngoscopy In obese patients, large neck circumference and Mallampati class >II are worrisome

Head and Neck Range of Motion Atlanto-occipital (AO) extension or neck flexion on chest of <35 degrees predicts difficult direct laryngoscopy; this amount of AO extension and neck flexion is required for proper alignment of oral, pharyngeal, and laryngeal axes Obese body habitus may preclude optimal alignment of oral, pharyngeal, and laryngeal axes Direct laryngoscopy in obese patients is facilitated when head, neck, and shoulders are elevated (“stacked”), bringing chin level with sternum; fiberoptic bronchoscopy intubation is rarely necessary with proper positioning Higher Mallampati class and large neck circumference are reliable predictors of difficult intubation in obese patients Inability to touch chin to chest is worrisome

Maxillary-Mandibular Overbite (Buck Teeth) Buck teeth reduce the ability to align oral and pharyngeal axes during direct laryngoscopy

Mandibular Translation Ability to protrude lower jaw by more than 1 cm often predicts good direct laryngoscopic view Ability to touch bottom incisors to the upper lip–skin border is reassuring

Mandibular Space Compliance Worrisome findings include stiffness, induration, and presence of mass

Palate Configuration Narrow or highly arched palate reduces oropharyngeal volume and ability to visualize glottis with both laryngoscope blade and endotracheal tube in mouth

Class I

Class II

Class III

Class IV

Figure 40–3 ■ Mallampati classification. With the patient seated and the head in the neutral position, the patient is asked to open the mouth as wide as possible and to protrude the tongue out as far as possible (the patient should not phonate during this evaluation). Class I, soft palate, fauces, uvula, and anterior and posterior tonsillar pillars are visible; class II, soft palate, fauces, and uvula are visible; class III, soft palate and base of uvula are visible; class IV, only hard palate is visible. (Modified from Mallampati S, Gatt S, Gugino L, et al: A clinical sign to predict difficult tracheal intubation: A prospective study. Can J Anaesth 32:429, 1985; and Samsoon GLT, Young JRB: Difficult tracheal intubation: A retrospective study. Anaesthesia 42:487, 1987.)

GENERAL ANESTHESIA

If distance between upper and lower incisors is less than 3-4 cm, direct laryngoscopy may be difficult because of: Insufficient space for blade insertion and blade “traction” without dental injury Less room for endotracheal tube passage and direction Possible obscured line of sight to glottic opening

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Factors to Consider When Formulating an Extubation Strategy

Relative advantages of awake extubation vs tracheal extubation before return of consciousness Was intubation difficult? Was facemask ventilation difficult? Is risk for aspiration high? Upper airway edema or bleeding may have adverse impact on effective ventilation after extubation Bleeding, tissue edema, or nerve injury can cause airway obstruction after neck surgery Edema risk may be higher with recent neck infection or prior irradiation Direct or indirect trauma to peritracheal, laryngeal, and supraglottic structures Manipulation during surgery increases potential for airway obstruction Edema may occur after difficult or multiple laryngoscopies but not be apparent until after extubation Recurrent laryngeal nerve injury Predetermined plan for airway management if patient is unable to maintain adequate ventilation after removal of endotracheal tube Extubation over previously inserted endotracheal tube exchange catheter Functions as a guide for rapid reintubation Can facilitate ventilation if tube exchanger has a lumen Extubation over flexible fiberoptic bronchoscope Endotracheal tube can be readvanced into trachea if necessary Trachea and glottic and supraglottic structures can be examined for abnormalities as bronchoscope is slowly removed Bronchoscope removal can be stopped if significant airway concerns are identified Bronchoscope may be readvanced into trachea, with subsequent passage of “loaded” endotracheal tube Wire can be inserted through fiberoptic bronchoscope suction channel before bronchoscope’s gradual removal to serve as guide for reintroduction of bronchoscope or airway exchange catheter into trachea

and phonate during ETT cuff deflation. Patients at high risk should have the ETT removed over an intubating stylet (bougie or exchange catheter), guidewire, or fiberoptic bronchoscope, with an experienced surgeon (for cricothyrotomy and tracheostomy) at the bedside. Factors to consider in formulating an extubation strategy are listed in Table 40-5.

Risk Assessment Risk assessment for a potentially difficult airway is multifactorial (Table 40-6). Reduction of risk with the CVCI situation begins with a thorough assessment of the patient’s airway before induction, predicting which patients may be difficult or impossible to ventilate via facemask (see Table 40-2) or intubate (see Table 40-4).

Table 40–6

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Risk Assessment of the Difficult Airway

Physical examination predictors suggestive of difficult facemask or supraglottic ventilation Physical examination predictors suggestive of difficult intubation Preexisting medical conditions and congenital abnormalities Actual difficulties with mask ventilation or laryngoscopy-guided intubation How was effective ventilation achieved? How was intubation achieved? Preexisting or current airway pathology Airway infection Tumor; prior head or neck surgery or radiation treatment Supraglottic or subglottic edema Presenting injuries of the airway, facial bones, and cervical spine Postoperative effects on airway From prior surgery From just-completed surgical procedure From multiple laryngoscopic attempts or traumatic intubation

Implications The inability to provide adequate ventilation to a patient may rapidly result in disability or death. ASA closed claims analysis revealed that the most common mechanisms of adverse respiratory events were inadequate ventilation, difficult intubation, and esophageal intubation. The airway sites most frequently injured were the larynx (33%), pharynx (19%), and esophagus (18%). Injuries to the trachea and esophagus were more commonly associated with difficult endotracheal intubation. Injuries to temporomandibular joint and the larynx were more frequently associated with intubations that were classified as “nondifficult.” Injuries to the esophagus were more devastating and resulted in larger payments to the plaintiffs than did claims for injuries to other locations. Although the CVCI situation is rare, the consequences can be devastating.

MANAGEMENT Optimal airway management requires recognition of the causes of a difficult airway and familiarity with the methods to secure it. Goals include maintenance of adequate oxygenation, ventilation, and protection of the airway from aspiration. Many airway management devices and techniques are available. The ASA difficult airway algorithm (see Fig. 40-1) favors no single method. It is unlikely that an individual anesthesiologist will be adept at all techniques and devices; each anesthesiologist should use the airway techniques at which he or she is adept. All anesthesiologists must have clinical familiarity with a number of airway devices and techniques, however, including (but not limited to) fiberoptic intubation, a method for emergency nonsurgical ventilation that allows blind supraglottic placement (laryngeal mask airway or esophageal-tracheal Combitube), and a method for emergency nonsurgical ventilation that allows subglottic

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From Sanchez A, Trivedi NS, Morrison DE: Preparation of the patient for awake intubation. In Benumof JL (ed): Airway Management: Principles and Practice. St. Louis, Mosby, 1996, pp 159-182.

placement (transtracheal jet ventilation or percutaneous dilatational cricothyrotomy). If there is any reason to believe that conventional facemask or supraglottic ventilation may be unsuccessful, awake management of the airway is indicated (Table 40-7). Recently, Rosenblatt published a decision tree for organizing preoperative airway information (Fig. 40-4). This approach asks a series of questions regarding management of the airway. A positive answer leads the operator to the next question, and a negative answer directs the clinician to the appropriate location in the ASA algorithm (see Fig. 40-1). Predicting specific difficulties with airway management prospectively (preoperatively) and integrating this information into the airway approach strategy may avoid the need to use the emergency branches of the ASA algorithm (e.g., encourage the anesthesiologist to use awake intubation initially rather than intubation after induction of general anesthesia, apnea, and paralysis). The CVCI situation, once recognized, must be managed quickly and decisively. “Rapid” options for management include the following: ● ● ● ● ●

Laryngeal mask airway Esophageal-tracheal Combitube Laryngeal tube Transtracheal jet ventilation Cricothyrotomy

The first three methods of establishing ventilation are supraglottic ventilatory mechanisms, and the latter two are subglottic ventilatory mechanisms. Only the most invasive method, cricothyrotomy with insertion of a cuffed airway device, is capable of definitively securing the airway, allowing positive-pressure ventilation, and preventing aspiration

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1) Must the airway be managed? (Is airway control necessary?) • If NO, is regional anesthesia or monitored anesthesia care an acceptable alternative for the patient, surgeon, and anesthesiologist? If NOT, continue on to question 2. – Regional anesthesia doesn’t always preclude airway management. 2) Is there potential for a difficult laryngoscopy? • If NO, enter ASA-DAA @ Intubation Attempts After Induction of General Anesthesia. 3) Can supraglottic ventilation be utilized? (LMA or Combitube for rescuing the airway, if the cannot-ventilate, cannot-intubate scenario occurs). • If NO, enter ASA-DAA @ Awake Intubation. 4) Is the stomach empty? (Is there an aspiration risk?) • If NO, enter ASA-DAA @ Awake Intubation. 5) Will the patient tolerate an apneic period if unable to ventilate? • If NO, enter ASA-DAA @ Awake Intubation. • If YES, enter ASA-DAA @ Intubation Attempts After Induction of General Anesthesia with supraglottic airway/ventilation device present. A “NO” answer to any of the AAA questions directs the anesthesiologist to a “root point” of the American Society of Anesthesiologists−Difficult Airway Algorithm (ASA-DAA). A “YES” answer leads the anesthesiologist to the subsequent question. The AAA does not suggest particular procedures or specific pathways, but rather is meant to organize the anesthesiologist’s own beliefs and choices along the lines of the ASA-DAA. Figure 40–4 ■ Airway approach algorithm (AAA). LMA, laryngeal mask airway. (Modified from Rosenblatt W: The airway approach algorithm: A decision tree for organizing preoperative airway information. J Clin Anesth 16:312-316, 2004.)

of gastric material. Regardless of the temporary measures taken to ventilate a patient in the CVCI situation, efforts should be made to definitively secure the airway as soon as possible. The following techniques are commonly employed in managing the difficult airway.

Fiberoptic Bronchoscopy and Endotracheal Intubation Many anesthesiologists prefer to use fiberoptic bronchoscopy (FOB) to manage a known or suspected difficult airway and for an unrecognized difficult intubation when supraglottic ventilation is achieved and maintained. FOB can be performed in awake or anesthetized patients. Success requires careful patient selection and preparation, as well as sufficient operator skill and experience. The decision to perform the procedure in an awake or sedated patient versus after the induction of general anesthesia depends on the patient’s ability to cooperate and the ability to maintain ventilation and oxygenation. Fiberoptic intubation under general anesthesia should be considered only if the anesthesiologist believes that adequate ventilation and oxygenation can be readily maintained. It is often better to maintain spontaneous ventilation and consciousness, especially in a patient with a difficult airway. INDICATIONS

AND

CONTRAINDICATIONS

Tumors, abscesses, maxillofacial trauma, and suspected or actual cervical spine injuries are indications for FOB intubation, provided the airway can be safely navigated.

GENERAL ANESTHESIA

History of difficult intubation Anticipated difficult airway Prominent protruding teeth Small mouth opening Narrow mandible Micrognathia Macroglossia Short, muscular neck Very long neck Limited neck extension Congenital airway anomalies Obesity Known airway pathology Known airway malignancy Upper airway obstruction Trauma Facial Upper airway Cervical spine Anticipated difficult mask ventilation Severe risk of aspiration Respiratory failure Severe hemodynamic instability

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Other indications include the following situations: (1) neck extension for optimal alignment of the oral, pharyngeal, and laryngeal axes is difficult or ill advised; (2) difficult direct laryngoscopy is predicted on the basis of airway risk assessment; (3) risk of aspiration is high; (4) patient who cannot tolerate a period of apnea; and (5) patient with an injury to or near the airway. Absolute contraindications to FOB intubation include (1) high risk of dislodging friable tissue or rupturing an abscess, (2) bleeding or swelling that prevents visualization of airway structures or passage of the bronchoscope, and (3) life-threatening airway obstruction or hemodynamic instability (lack of time). Relative contraindications include (1) copious secretions despite an anticholinergic drying agent, (2) friable tissues that cannot be navigated despite careful manipulation, (3) edema of the pharynx or tongue, (4) hematoma, (5) tracking infections, and (6) infiltrating masses. PATIENT PREPARATION Nasal FOB intubation is generally easier to perform than oral FOB intubation because the angle of curvature of the inserted ETT naturally approximates that of the patient’s upper airway. The ETT serves as a channel for the bronchoscope, and the gag reflex is less pronounced with the nasal approach. The sitting position is preferred to the supine position because it facilitates passage of the bronchoscope and drainage of secretions. Extension of the cervical spine (if not contraindicated) provides the optimal position for the performance of fiberoptic laryngoscopy. For awake or sedated patients, nasal or oral oxygen is administered, monitors are applied, and an anticholinergic drying agent (to increase the effectiveness of topical anesthetics and decrease secretions) and sedation are administered, according to the anesthesiologist’s preferences. Good topical anesthesia (with adequate time allowed) is essential for awake techniques. The naris and nasopharynx are anesthetized with cocaine or lidocaine-phenylephrine, if vasoconstrictors are not contraindicated. The superior laryngeal nerve (innervates the epiglottis, aryepiglottic folds, and laryngeal mucosa) is blocked by the advancement of cotton-tipped applicators into the pyriform fossa. The oropharynx, base of tongue, and larynx are sprayed with a topical anesthetic, or the patient can gargle with a topical anesthetic. A lidocaine and phenylephrine mixture can be nebulized via a facemask; lidocaine can also be sprayed onto the vocal cords and into the tracheal lumen via the bronchoscope as they are encountered or viewed. The use of transtracheal lidocaine, superior laryngeal nerve blocks, and glossopharyngeal blocks is optional. Insufflation of oxygen through the suction port of the bronchoscope serves as a defogging mechanism, blows secretions away from the tip of the bronchoscope, and provides supplemental oxygen during the procedure. When performing FOB in apneic patients, transnasal jet ventilation, via a nasal airway, often effectively oxygenates the patient for a short time.

side of the nose has a larger “passage,” which can be determined with trials of nasal airways of progressively increasing diameters. “Softened” ETTs (warmed in warm water) usually pass more easily. The largest ETT possible should be used— 8 mm internal diameter in adults, if a 34 French soft nasal airway readily passes. The ETT is positioned proximally over the bronchoscope. The most patent naris is intubated first, preventing it from exiting the Murphy eye of the ETT during bronchoscope advancement. If the ETT is inserted through the naris first, the bronchoscope should be visualized following the stripe on the ETT to the beveled tip. This prevents passage of the bronchoscope through the Murphy eye. Lidocaine is sprayed via the bronchoscope on or in airway structures as they are identified. Inflating the cuff of the ETT can create more space in the pharynx and directs the FOB channel (ETT) anteriorly. The bronchoscope is advanced until the epiglottis or glottis is identified, maneuvered past the glottis into the trachea, and advanced to the carina. Subsequently, the ETT is advanced into the trachea. The ETT may hang up on supraglottic structures as it is advanced over the bronchoscope. Rotation of the ETT 90 degrees counterclockwise may facilitate passage. The appropriate depth of the ETT can be determined by visualizing the distance between the carina and the tip of the ETT as the bronchoscope is removed. If the ETT does not advance or the bronchoscope cannot easily be removed from the ETT, both must be removed together (to avoid bronchoscope damage), and FOB intubation should be reattempted, possibly with a smaller ETT. Factors affecting the success of FOB-guided intubation are summarized in Table 40-8. Oral Intubation. Oral FOB intubation is well suited for apneic or anesthetized patients, as well as for awake or sedated patients who are well anesthetized topically. Preparation of the nasal passageway is unnecessary, and the oral route can be used in patients when the nasal route is contraindicated. Neck extension, if not contraindicated, reduces the angle between the oropharynx and larynx, facilitating advancement of the bronchoscope into the trachea. The bronchoscope can be advanced through a fiberoptic-compatible oral airway (FCOA) or advanced above and around a “pulled-out” or protruded tongue. The FCOA serves as a channel for the bronchoscope, prevents “bite” damage to it, and facilitates midline positioning by mechanically guiding the bronchoscope (Fig. 40-5). An FCOA with an “anterior channel” may be better at directing the bronchoscope toward the glottic opening. Performing a jaw thrust or pulling the tongue forward can be helpful. Oral FOB intubation can readily be accomplished by using a laryngeal mask as the channel for the bronchoscope. Ventilation is continuous via the laryngeal mask airway (LMA), either spontaneously or by positive pressure, as the bronchoscope is passed through a bronchoscope port adapter, through the LMA ventilating tube, and into the trachea.

TECHNIQUES

Blind Nasal Intubation

Nasal Intubation. Care must be taken to minimize the risk of epistaxis. Nasal intubation is contraindicated in patients with coagulation disorders, who cannot tolerate vasoconstrictors, and with facial or basilar skull trauma. Often one

Blind nasal intubation is much less stimulating than direct laryngoscopy. The patient must breathe spontaneously and be adequately sedated and cooperative. Topical anesthesia and nasal vasoconstriction precede the insertion of a

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Factors Affecting Successful Fiberoptic Bronchoscopy and Intubation

Factor

Comments and Possible Solutions

Patient Selection Frequent suctioning and topical vasoconstrictor will help reduce small amounts of bleeding Rarely a problem with elective FOB but may be in trauma or emergency situations Titrate sedation as indicated Amount of sedation inversely proportional to degree of airway difficulty Inadequate time to safely anesthetize patient and intubate trachea Skill and experience can decrease FOB intubation time

Unstable patient

Patient Preparation Topical anesthesia

Reduce and remove secretions so topical agents are in contact with mucosa Allow sufficient contact time Spray lidocaine (via suction port of bronchoscope) onto structures as they are identified Nerve blocks are often unnecessary Administer anticholinergic drying agent and vasoconstrictor Suction oral pharynx with tonsil tip suction before starting Connect O2 source to suction port of bronchoscope to blow away secretions Use nasal prongs or mask O2 during FOB Maintain spontaneous ventilation Attach O2 source to suction port of bronchoscope Instruct patient to breathe during procedure Avoid excessive sedation Ventilate with LMA Use LMA as channel or conduit for bronchoscope Jet-ventilate via nasal airway

Secretions, blood Decreased O2 saturation

Endoscopist Experience Abnormal anatomy

Full knowledge of normal anatomy necessary to negotiate abnormal anatomy with difficult airway Maintain spontaneous ventilation Use nasal route; allow sufficient laryngeal space Use channel for bronchoscope (ETT, FCOA) Awake patient: instruct patient to pant, say “ahh,” or stick out tongue Unconscious or anesthetized patient: jaw thrust, pull out tongue, use FCOA, use nasal route Warm and wipe bronchoscope lens with dilute detergent before use Insufflation of O2 via suction port decreases fogging Lubricate bronchoscope If tube becomes hung up, try rotating it counterclockwise 90 degrees May exit Murphy eye of ETT Remove tube and bronchoscope as unit and try again

Large, floppy epiglottis Fogging of objective Inability to advance ETT Inability to remove bronchoscope

ETT, endotracheal tube; FCOA, fiberoptic-compatible oral airway; FOB, fiberoptic bronchoscopy; LMA, laryngeal mask airway; O2, oxygen.

A

B

Figure 40–5 ■ Fiberoptic-compatible oral airways (FCOAs). A, Two FCOAs, with anterior versus posterior channels compared. On the left is the Williams airway intubator, with an anterior channel; on the right is a Luomanen FCOA, with a posterior channel. Note that an anterior channel may offer more immediate entry into an anteriorly oriented glottis. B, Berman and Ovassapian oral intubating airways. (A, From Atlas GM: A comparison of fiberoptic-compatible oral airways. J Clin Anesth 16:66-73, 2004. B, From Stackhouse R: Fiberoptic airway management. Anesthesiol Clin North Am 20:933-951, 2002.)

GENERAL ANESTHESIA

Oropharyngeal bleeding Uncooperative patient

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Endotracheal Tube Malpositioning and Corrective Measures during Blind Nasal Intubation

Table 40–10

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Lighted Stylet–Assisted Oral Intubation

Indications Vocal cords outside larynx Obstructed tube passage despite good detection of breath sounds Can often be corrected by gentle rotation Vallecula Often causes midline supralaryngeal bulge in neck Retract tube a few centimeters, followed by gentle pressure just above larynx or slight flexion of head Left or right pyriform fossa Often results in corresponding lateral bulge in neck Gently use tongue depressor or laryngoscope blade to see if endotracheal tube is in midline Correct this problem by: Displacing patient’s larynx slightly in direction of bulge Rotating tube Moving head toward side of displacement Using lighted stylet to transilluminate endotracheal tube tip location Esophagus Pull back endotracheal tube and try again

“warmed” ETT. The ETT is gently passed and advanced. Breath sounds (or air movement) heard through the ETT become louder as the tube tip nears the glottis. Tracheal passage is facilitated during patient inspiration. Palpation bilaterally under the patient’s mandible may detect passage of the ETT off the midline and guide redirection by rotation of the ETT. Other ETT tip locations outside the trachea and corrective measures that may enable successful blind nasal intubation are listed in Table 40-9. Multiple blind passages must be avoided. Bleeding can compromise subsequent attempts at FOB intubation or direct laryngoscopy. Switch to FOBguided intubation if blind passage is not successful.

Lighted Stylet Oral Intubation The lighted stylet (LS) or light wand is sometimes used for routine elective and difficult endotracheal intubations. The LS is inserted into the lumen of the ETT until its tip is within 5 mm from the end of the ETT. The LS and distal ETT tip are bent or curved about 90 degrees and advanced during tongue retraction (the LS tip must point anteriorly). Light transilluminates through the anterior neck tissue (darken the room if necessary), facilitating redirection of the ETT-LS tip toward and into the trachea. Once past the glottis, the LS transilluminates brightly through the trachea, producing a distinct jack-o’-lantern effect (well-circumscribed glow through the anterior neck if in the trachea; diffuse glow if in the esophagus). The ETT is stabilized while the LS is removed. Transillumination may be inadequate in obese patients. Indications for LS intubation and contraindications to blind passage of the LS are listed in Table 40-10.

Elective, asleep, oral intubation Patients with the following: Restricted movement of cervical spine (e.g., cervical spine instability) Limited mouth opening Capped teeth Severe overbite Poor dentition Facial trauma Direct “blind” passage of endotracheal tube through intubating laryngeal mask airway To facilitate intubation using direct laryngoscopy Difficult airway alternative in experienced hands Situations in which a fiberoptic bronchoscope is unavailable Situations in which fiberoptic bronchoscopy is difficult to perform (e.g., secretions, blood)

Contraindications Airway pathology Foreign body Laryngeal fracture Pharyngeal mass Retropharyngeal abscess

useful for emergency airway management unless the cause of airway obstruction is glottic or subglottic in nature. The recently introduced laryngeal tube has also been used to manage the difficult airway. LARYNGEAL MASK AIRWAY The LMA plays an important role in the management of the difficult airway, serving as an airway ventilating device, a conduit for achieving endotracheal intubation, or both. The incidence of the cannot-ventilate situation decreased dramatically after the adoption and widespread use of the LMA, which is now an integral part of the ASA difficult airway algorithm (see Fig. 40-1). The LMA is blindly inserted into the hypopharynx until the leading edge of the mask is behind the arytenoids and cricoid cartilage and lies just above the upper esophageal sphincter. The LMA “mask” is inflated to form a low-pressure seal (20 cm H2O or less; about 30 cm H2O with a ProSeal LMA) around the laryngeal inlet. Spontaneous or controlled positive-pressure ventilation can be used. Disadvantages of the LMA include the following: ●

●

●

●

SUPRAGLOTTIC AIRWAY DEVICES Many supraglottic airway devices are available, and they have changed our approach to airway management. Most, if not all anesthesiologists commonly use the laryngeal mask. Both the LMA and the esophageal-tracheal Combitube are

It is a supraglottic device and may be ineffective in the presence of glottic or subglottic pathology. It does not protect the trachea against pulmonary aspiration of gastric contents. It may be placed over the esophageal inlet, resulting in gastric distention, especially when positive-pressure ventilation is employed. It may not be able to achieve adequate airway sealing pressures in patients with poor pulmonary compliance who require positive-pressure ventilation.

The aperture of a properly positioned classic LMA aligns itself anatomically with the glottis and can serve as a conduit to endotracheal intubation. An FOB wire-guided

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exchange technique for achieving endotracheal intubation via a classic laryngeal mask is as follows: ● ●

●

● ●

●

●

The intubating LMA (ILMA) was specially designed to facilitate endotracheal intubation, either blindly or by fiberoptic guidance. In a recent study by Combs and associates using a treatment algorithm (the gum-elastic bougie [GEB] and ILMA were proposed as the first and second steps in the case of impossible laryngoscope-assisted tracheal intubation, respectively), 100 cases of unexpected difficult airway were recorded among 11,257 intubations (0.9%), with no cases of impossible ventilation. Deviation from the algorithm was recorded in three cases, and two patients were wakened before any alternative intubation technique was attempted. All remaining patients were successfully ventilated with either the facemask (89 of 95) or the ILMA (6 of 95). Six difficult-to-ventilate patients required the ILMA before completion of the first intubation step. Eighty patients were intubated using the GEB, and 13 required a blind intubation through the ILMA. Two patients ventilated with the ILMA were never intubated. In emergency situations, the ProSeal LMA may prove especially useful when positive-pressure ventilation is required and gastric distention or regurgitation is a major concern (e.g., cannot intubate in the obstetric patient). The ProSeal is not useful as a channel for FOB (smaller lumen for the bronchoscope; channel off the midline). ESOPHAGEAL-TRACHEAL COMBITUBE The esophageal-tracheal Combitube (ETC, Sheridan Catheter, Argyle, NY) was developed for emergency airway management. The ETC is a double-lumen airway containing a “tracheoesophageal” lumen with an open distal end. The second “pharyngeal” lumen, resembling an esophageal obturator-type airway, contains a distally blocked end and perforations in the lumen through which ventilation occurs. Dual standard airway connectors allow ventilation in either the esophageal or the tracheal position. The ETC comes in 37 and 41 French sizes for patients 4 to 6 feet tall and greater than 6 feet tall, respectively. With the neck in a neutral position (the sniffing position may hinder insertion), the ETC is inserted through the mouth. It is advanced over and beyond the tongue using a gentle, downward-curved, dorsocaudal movement and then advanced parallel to the patient’s horizontal plane until the proximal marker rings are at the upper incisors (or the

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alveolar ridge in edentulous patients). When inflated, the proximal, 100-mL, latex oropharyngeal balloon essentially seals the patient’s mouth and nose (some titrate the oropharyngeal balloon volume to air leak). The distal tracheoesophageal 15-mL balloon (use 10 to 15 mL air) seals either the esophagus or the trachea after insertion and inflation. Insertion results in esophageal intubation more than 96% of the time. Ventilation is initiated via tube 1 (the longer blue tube), with ventilation occurring via perforations in the “pharyngeal lumen” between the two balloons. Air is forced past the epiglottis into the trachea because the two balloons seal off all other “escape routes” (nose, mouth, esophagus). If there are no breath sounds or expired carbon dioxide (<4% of the time), tube 2 (the shorter clear tube) is ventilated (via the tracheoesophageal lumen), because the ETC has presumably entered the trachea. The ETC is an important method of out-of-hospital emergency airway management and can be used as a rescue ventilation device in the management of the difficult airway. When properly positioned, the ETC allows higher airway sealing pressures than a classic LMA. The distal balloon may prevent gastric distention and protect from gastric regurgitation and pulmonary aspiration. The risk of aspiration should theoretically be less than that with an LMA because the esophagus is sealed by the distal cuff. The ETC is a useful device to facilitate airway control in trauma patients with possible cervical spine injury because it is placed with the neck in the neutral position. In addition, the ETC is useful in patients with massive airway bleeding or regurgitation or limited access to the airway. Laryngoscopy can also be performed to ease placement of the ETC and may decrease soft tissue trauma compared with blind passage. The ETC has a good safety record, with only rare reports of esophageal injury. LARYNGEAL TUBE The laryngeal tube (LT) is a new supraglottic ventilatory device consisting of an airway tube and two low-pressure balloons (cuffs). When inserted, the LT lies along the length of the tongue with the distal tip (blind end; no gastric access) positioned in the upper esophagus. The distal (esophageal) balloon seals the airway distally, protecting from regurgitation. The proximal (pharyngeal) balloon seals both the oral and nasal cavities. The two balloons are inflated sequentially. Openings in the airway tube are situated between the two balloons and allow ventilation to occur. Fiberoptic tracheal intubation through the LT using an “exchange technique” is also possible. Recently, the LT was fitted with a second lumen for suctioning and free gastric drainage, but not for ventilation, as with the Combitube.

Invasive Airway Techniques RETROGRADE TRACHEAL INTUBATION Retrograde tracheal intubation has been used with good success to manage difficult airways and is a useful alternative in difficult (or anticipated to be difficult) intubations. The entry site for transtracheal puncture is made midline through the cricothyroid membrane. The risk of significant bleeding is low because the cricothyroid membrane is relatively avascular. The patient is placed supine—ideally, in the sniffing

GENERAL ANESTHESIA

●

Place a classic LMA while adequate ventilation is occurring. Pass a fiberoptic bronchoscope through a bronchoscope port adapter attached to the classic LMA ventilating tube. Guide the bronchoscope visually through the LMA aperture into the trachea, without interrupting ventilation. Pass a wire through the working channel of the bronchoscope into the trachea. Remove the bronchoscope. Place an airway exchange catheter over the wire into the trachea. Subsequently, remove the LMA over the airway exchange catheter. Pass an ETT over the airway exchange catheter into the trachea.

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position, if it is not contraindicated. Under sterile technique, an epidural needle or intravenous needle-catheter (18 gauge), with a saline (or lidocaine) half-filled syringe attached, is advanced in a 30- to 40-degree cephalad direction through the cricothyroid membrane. Upon air aspiration, lidocaine can be injected into the trachea. The patient’s tongue is pulled or protruded anteriorly. An epidural catheter, or spring guidewire, is passed “retrograde” back through the glottis into the mouth or naris. The guidewire needs to be long enough to pass out of the mouth or naris (a 100-cm wire is recommended to allow the use of adjunct equipment or manipulation of the ETT). An ETT is advanced over the epidural catheter or guidewire past the glottis into the trachea. The guidewire or epidural catheter is removed via the mouth (or naris) in the retrograde direction to prevent contamination of the cervical soft tissues at the puncture site. Unfortunately, the ETT may fall back into the hypopharynx upon release of the guide. Tracheal location of the ETT is confirmed using standard techniques. A guidewire technique using a commercially available retrograde intubation kit (Cook Critical Care, Bloomington, Ind) is shown in Figure 40-6. Indications, contraindications, and alternative methods for retrograde tracheal intubation are summarized in Table 40-11.

A

B

C

D

E

F

SURGICAL AIRWAY The rapid development of severe hypoxemia, especially if associated with bradycardia, is an indication for immediate intervention with an invasive technique, because rapid reoxygenation is essential. Surgical methods to secure the airway include cricothyrotomy and surgical tracheostomy. The cricothyroid membrane is the most accessible portion of the trachea below the level of the glottis. Cricothyrotomy is easier and preferred for transtracheal jet ventilation (TTJV). Contraindications to cricothyrotomy are listed in Table 40-12. Tracheostomy. The classic emergency surgical tracheostomy involves incision through the skin and platysma, division of the isthmus of the thyroid gland, hemostasis, incision of the tracheal cartilage, and insertion of a cuffed tracheostomy tube. Emergency tracheostomy can be very difficult to perform and may result in serious complications. Although a few surgeons may be able to perform a tracheostomy in 3 minutes or less, most take longer. Delay in completing a tracheostomy during the CVCI scenario may result in serious morbidity or death of the patient. Some patients require awake tracheostomy as the initial airway management method. Cannula Cricothyrotomy with Percutaneous Transtracheal Jet Ventilation. Compared with emergency surgical cricothyrotomy or tracheostomy, establishment of percutaneous TTJV via needle-cannula cricothyrotomy is quicker and simpler. TTJV permits continuous, uninterrupted ventilation and oxygenation in patients without an anatomic impediment to passive exhalation through the upper airway. This allows time to secure the patient’s airway by alternative techniques. Some anesthesiologists place a “prophylactic” TTJV catheter before intubation attempts in patients with suspected difficult airways so that a ready conduit is available in the event of difficulty with ventilation. The cricothyroid membrane is identified, and a 12- to 16-gauge over-the-needle catheter, attached to a partially

Figure 40–6 ■ Retrograde intubation using the guidewire technique. A, The J-tip of the guidewire and the guiding catheter. B, After standard preparation of the access site, advance the 18-gauge sheath needle (attached to a 6-mL disposable syringe) in a cephalad direction through the cricothyroid membrane and into the trachea. Free flow of air aspirated into the syringe confirms correct positioning. Remove the needle and syringe, leaving the sheath in place. C, Advance the J end of the guidewire through the sheath and up the trachea in a cephalad direction, until the tip of the guidewire can be retrieved through the mouth or nose. Note: The black proximal positioning mark of the guidewire should be visible at the access site, ensuring that enough guidewire is exposed orally or nasally for control of subsequent catheter introduction. Remove the sheath, leaving the guidewire in place. D, Advance the catheter antegrade over the guidewire by way of the mouth or nose and into the trachea until tenting is noted at the cricothyroid access site. E, With the catheter is position, advance the endotracheal tube over the catheter and into position below the level of the vocal cords. Note: Always maintain control and position of the guidewire during advancement of the endotracheal tube. F, Remove the guidewire and catheter from the endotracheal tube and inflate the balloon cuff of the endotracheal tube. Verify the position, and secure in a standard fashion. (From Behringer ED: Approaches to managing the upper airway. Anesthesiol Clin North Am 20:813-832, 2004; courtesy of Cook Critical Care, Bloomington, Ind.)

saline-filled syringe, is inserted at a 30- to 45-degree angle caudally into the “air vessel.” Easy aspiration of air into the syringe confirms placement (Fig. 40-7). Kink-resistant catheters are recommended because standard intravenous catheters are readily bent. The catheter hub is connected (preferably by a Luer-Lok connector) to a TTJV system. An alternative technique is to use a Seldinger catheter introducer set (8.5 French introducer kit commonly used for

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Indications

Contraindications Unfavorable anatomy in area of cricoid cartilage and cricothyroid membranes Nonpalpable landmarks Pretracheal mass Severe flexion deformity of neck Laryngotracheal pathologic condition Malignancy Tracheal stenosis Severe trauma to larynx or laryngotracheal separation Infection Significant coagulopathy Patients requiring immediate intubation and ventilation (can take up to 5 min to complete) Complete upper airway obstruction

Alternative Techniques Needle placement through infracricoid membrane instead of cricothyroid membrane (may increase success rate because it facilitates passage of ETT through larynx) Introduction of guidewire or epidural catheter (previously passed retrograde into mouth or naris) through hollow airway exchange catheter; passage of tube exchanger down over guidewire into trachea; subsequent advancement of ETT down over tube exchanger into trachea; guide lessens chance of dislodgment or hang-up of ETT tip in vocal cords, arytenoid cartilage, vallecula, or pyriform sinus Insertion of guide (previously passed retrograde into mouth or naris) through distal lateral eye of ETT before passing ETT over guide into trachea; can prevent entrapment of ETT tip in arytenoids or epiglottis Use of pulling techniques, either by creating loop around side eye or simply knotting epidural catheter with Murphy’s eye; can increase success rate of retrograde tracheal intubation Insertion of bronchoscope with preloaded ETT over guidewire via bronchoscope’s suction channel; allows visualization of airway structures as bronchoscope is advanced; wire is removed while observing bronchoscope remaining in trachea, with subsequent advancement of ETT into trachea ETT, endotracheal tube.

pulmonary artery catheters). The needle is used to make the initial puncture, air is aspirated, the guidewire is inserted into the distal trachea, and the catheter is threaded over the guidewire using the dilator. These 8.5 French catheters may allow some exhalation to take place via the catheter if the system can be vented. The TTJV system should provide 50 pounds per square inch of pressure (using an adjustable high-pressure device, driven by gas pipeline pressure) for adequate inspiratory gas flow. The oxygen flush systems of most modern anesthesia machines do not provide

Table 40–12

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Contraindications to Cricothyrotomy

Preexisting laryngeal disease Acute inflammation Chronic inflammation Malignancy Translaryngeal intubation >3 days Increased incidence of subglottic stenosis Coagulopathy Distortion of normal airway anatomy Infants and children <6 yr Inexperience in cricothyrotomy procedure (experience decreases complications)

sufficient pressure. Jaw thrust facilitates exhalation. The catheter must be stabilized during ventilation, or else the jet pressure may force it out of the trachea. TTJV should be considered a temporary measure because it can maintain adequate oxygenation for only about 30 to 60 minutes. Progressive hypercapnia is likely to occur because overall minute ventilation is usually inadequate. When air entry exceeds air exit during TTJV, lung hyperinflation, tension pneumothorax, pneumomediastinum, and subcutaneous emphysema will inevitably occur. Strategies to minimize barotrauma are listed in Table 40-13. Major changes in cardiovascular parameters should be assumed to be related to TTJV and possible barotrauma. TTJV can sometimes facilitate endotracheal intubation using standard methods because the high intratracheal pressure from TTJV can lift up and open the glottis. The escape of gas under high pressure causes the edges of the glottis to flutter, which may facilitate the identification of the glottic opening. If TTJV fails or surgical emphysema or another complication occurs, convert immediately to surgical cricothyrotomy. Surgical Cricothyrotomy. Surgical cricothyrotomy may allow the rapid restoration of oxygenation and ventilation in the CVCI scenario. Surgical cricothyrotomy is also indicated in the setting of severe maxillofacial trauma preventing oral intubation, known unstable cervical spine fracture,

GENERAL ANESTHESIA

Multiple intubation attempts have caused bleeding or edema Patients with limited mouth opening or neck movement Facial trauma Failed endotracheal intubation Elective management of difficult airway

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Figure 40–7 ■ Needle insertion for cricothyrotomy and transtracheal jet ventilation (TTJV). A, A 14-gauge (or larger) angiocatheter is directed caudad, using an angle of approximately 30 degrees to the skin, and passed through the cricothyroid membrane. B, The free return of air on aspiration through the syringe confirms the position of the tip of the needle in the tracheal lumen. The catheter is advanced over the needle into the tracheal lumen, the needle is removed, and the hub of the catheter is connected to the TTJV tubing (Luer-Lok connector recommended). (From Patel RG, Norman JR: The technique of transtracheal ventilation. J Crit Illness 11:803-808, 1996.)

laryngotracheal trauma (except for tracheal transection), complete upper airway obstruction, oropharyngeal obstruction, or inability to secure the airway by other intubation techniques. It is contraindicated in patients younger than 12 years and in the case of laryngotracheal separation or tracheal transection (the transected airway may be tenuously held together by cervical fascia), tracheal foreign body, or penetrating trauma to the neck (in either high zone 2 or zone 3) associated with an expanding hematoma. The surgical cricothyrotomy technique uses low-pressure ventilation through a cuffed tube placed in the trachea. A simplified cricothyrotomy technique (consisting of palpation, incision, insertion, and intubation) can be performed in approximately 30 seconds in experienced hands (Table 40-14). Invasive airway access is a temporary measure to restore oxygenation. Definitive airway management follows, such as surgical tracheostomy; alternatively, because oxygenation and ventilation have been established, there may be time to achieve tracheal intubation. Guidewire techniques of cricothyrotomy have been developed, and some claim that these techniques can restore the airway as quickly as the

Table 40–13

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Minimizing Barotrauma during Transtracheal Jet Ventilation

Preset jet ventilator to 25-50 psi by using additional in-line regulator Use lowest effective psi Limit inspiratory time to <1 sec Keep natural airway maximally patent with bilateral jaw thrust and oropharyngeal or nasopharyngeal airway (or both) If laryngeal mask airway was used, leave in place to facilitate exhalation Confirm ventilation of lungs and exhalation through upper airway psi, pounds per square inch.

standard surgical technique. Percutaneous dilatational cricothyrotomy (PDC) kits are commercially available. PDC is a rapid, relatively straightforward procedure that is touted as having a decreased operative time and lower late complication rate compared with surgical cricothyrotomy.

PREVENTION Prevention of complications related to difficult airway management requires the following: ● ●

● ●

Ability to recognize a potentially difficult airway Well-thought-out plan with suitable alternatives for all patients Willingness to call for help at the first sign of difficulty Availability of all necessary equipment (i.e., difficult airway cart)

Table 40–14

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Technique of Rapid Cricothyrotomy

Identify cricothyroid membrane (CTM) Palpate and stabilize larynx by bracing laryngeal cartilage with thumb and middle finger Maintain position of CTM with index finger Make horizontal stab incision through skin and CTM, just above cricoid cartilage Immediately insert tracheal hook (preferred), hemostat, or blade handle into opening Do not lose control of opening Apply caudal traction on CTM (if tracheal hook used) Intubate trachea with appropriately sized, preferably cuffed, endotracheal tube Tube insertion can be facilitated by passage of introducer (bougie) through incision or use of tracheal retractor Avoid excessive insertion depth (endobronchial tube placement) Confirm breath sounds and expired carbon dioxide

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●

●

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Adequate technical assistance (i.e., knowledgeable staff, dedicated to the task) Immediate availability of another anesthesiologist experienced with difficult airway management

Further Reading Agro F, Frass M, Benumof JL, Krafft P: Current status of the Combitube: A review of the literature. J Clin Anesth 14:307-314, 2002. Atlas GM: A comparison of fiberoptic-compatible oral airways. J Clin Anesth 16:66-73, 2004. Behringer EC: Approaches to managing the upper airway. Anesthesiol Clin North Am 20:813-832, 2002. Blanda M, Gallo UE: Emergency airway management. Emerg Med Clin North Am 21:1-26, 2003. Bogetz M: Using the laryngeal mask to manage the difficult airway. Anesthesiol Clin North Am 20:863-870, 2002. Cheney FW, Posner KL, Caplan RA: Adverse respiratory events infrequently leading to malpractice suits: A closed claims analysis. Anesthesiology 75:932-939, 1991. Combes X, Le Roux B, Suen P, et al: Unanticipated difficult airway in anesthetized patients: Prospective validation of a management algorithm. Anesthesiology 100:1146-1150, 2004. Cook TM: A new practical classification of laryngeal view. Anaesthesia 55:274-279, 2000. Davis L, Cook-Sather SD, Schreiner MS: Lighted stylet tracheal intubation: A review. Anesth Analg 90:745-756, 2000. Domino KB, Posner KL, Caplan RA, Cheney FW: Airway injury during anesthesia: A closed claims analysis. Anesthesiology 91:1703-1711, 1999. Dorges V, Ocker H, Wenzel V, et al: The Laryngeal Tube S: A modified simple airway device. Anesth Analg 96:618-622, 2003. el-Ganzouri AR, McCarthy RJ, Tuman KJ, , et al: Preoperative airway assessment: Predictive value of a multivariate risk. Anesth Analg 82:1197-1204, 1996. Ezri T, Szmuk P, Warters RD, et al: Difficult airway management practice patterns among anesthesiologists practicing in the United States: Have we made any progress? J Clin Anesth 15:418-422, 2003.

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Gaitini LA: The esophageal-tracheal Combitube. Anesthesiol Clin North Am 20:893-906, 2002. Genzwuerker H, Vollmer T, Ellinger K: Fibreoptic tracheal intubation after placement of the laryngeal tube. Br J Anaesth 89:733-738, 2002. Hagberg CA: Special devices and techniques. Anesthesiol Clin North Am 20:907-932, 2002. Hagberg CA: Current concepts in the management of the difficult airway. ASA Refresher Course, 2004. Henderson JJ, Popat MT, Latto IP, et al: Difficult Airway Society guidelines for management of the unanticipated difficult intubation. Anaesthesia 59:675-694, 2004. Langeron O, Masso E, Huraux C, et al: Prediction of difficult mask ventilation. Anesthesiology 92:1229-1236, 2000. Levitan RM: Patient safety in emergency airway management and rapid sequence intubation: Metaphorical lessons from skydiving. Ann Emerg Med. 42:81-87, 2003. Melker RJ, Florete OG: Cricothyrotomy: Review and debate. Anesthesiol Clin North Am 13:565, 1995. Mort TC: Emergency tracheal intubation: Complications associated with repeated laryngoscopic attempts. Anesth Analg 99:607-613, 2004. Patel RG, Norman JR: The technique of transtracheal ventilation. J Crit Illness 11:803-808, 1996. Practice guidelines for management of the difficult airway—an updated report by the American Society of Anesthesiologists Task Force on Management of the Difficult Airway. Anesthesiology 98:1269-1277, 2003. Rosenblatt W: The airway approach algorithm: A decision tree for organizing preoperative airway information. J Clin Anesth 16:312-316, 2004. Stackhouse R: Fiberoptic airway management. Anesthesiol Clin North Am 20:933-951, 2002. Weksler N, Klein M, Weksler D, et al: Retrograde tracheal intubation: Beyond fiberoptic endotracheal intubation. Acta Anaesthesiol Scand 48:412-416, 2004. Wilson WC: Emergency airway management. In Brown D (ed): Cardiac Intensive Care. Philadelphia, WB Saunders, 1998, pp 705-734. Wong EK, Bradrick JP: Surgical approaches to airway management for anesthesia practitioners. In Hagberg CA (ed): Handbook of Difficult Airway Management. Philadelphia, Churchill Livingstone, 2000, pp 209-210.

GENERAL ANESTHESIA

It is also incumbent on any clinician who is confronted with a difficult airway to enroll the patient in the MedicAlert system (1-800-344-3226) to apprise other clinicians of the patient’s history.

Difficult Airway: Cannot Ventilate, Cannot Intubate

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Difficult Airway: Opiate-Induced Muscle Rigidity Narayan Baliga and Theodore J. Sanford, Jr. Case Synopsis Anesthetic induction is being performed in a 70-kg, 65-year-old man undergoing elective coronary artery bypass graft surgery. Following 3 minutes of preoxygenation, fentanyl (3000 μg) is administered intravenously over 5 minutes. The chest and abdominal wall become rigid, and it becomes very difficult to ventilate the patient’s lungs with a mask and bag. The oxygen saturation drops rapidly, and the anesthesiologist cannot maintain the airway. It is difficult to open the patient’s mouth to insert an oropharyngeal airway.

PROBLEM ANALYSIS Definition Opioid-induced muscle rigidity usually occurs with large doses of potent opioids given intravenously. These include drugs such as fentanyl, alfentanil, sufentanil, and remifentanil. Morphine and meperidine can also cause such reactions, but this is not common with the doses used during balanced anesthesia. There have been published reports of muscle rigidity occurring with relatively small doses of highly potent opiates such as sufentanil and alfentanil. The phenomenon of muscle rigidity is usually seen during induction of anesthesia when opioids are the sole or primary anesthetic agent. All the skeletal muscles are involved. The rigidity starts within 1 or 2 minutes of opioid administration and typically lasts 10 to 20 minutes. The mechanism is thought to originate in the central nervous system. Rigidity of the torso muscles leads to a fall in chest wall compliance, hypoventilation, respiratory acidosis, and systemic arterial hypotension.

Recognition MUSCLE RIGIDITY The rigidity is immediate and occurs in all skeletal muscles. Sometimes the rigidity is accompanied by explosive myoclonus and vertical nystagmus, resembling seizures. There is an increase in electromyographic activity, but the electroencephalogram does not indicate seizure activity. It has been shown that this increase in muscle tone is most likely central in origin.

opioid is the causative agent. Chest wall rigidity makes it difficult to ventilate the patient with a mask and bag. Inability to open the mouth may make it impossible to insert an oropharyngeal or laryngeal mask airway. Although a nasopharyngeal airway can be inserted, airway obstruction caused by glottic closure may make it difficult to ventilate the patient manually. Chest wall rigidity leads to a rise in intrathoracic pressure, which causes an immediate rise in right atrial pressure. If sustained, this leads to a reduction in venous return and cardiac output and, ultimately, systemic arterial blood pressure.

Risk Assessment The differential diagnosis for inability to maintain the airway and oxygen desaturation includes the following: ● ●

●

Muscle rigidity from rapid narcotic administration Laryngospasm from a noxious stimulus during light anesthesia Seizures, if there is a history of epilepsy or an intracranial lesion

The incidence of muscular rigidity is between 50% and 100% in unpremedicated patients given large doses of the contemporary synthetic opioids (e.g., fentanyl, alfentanil, sufentanil, remifentanil). The doses noted to cause rigidity from various studies are as follows: fentanyl, 12 to 15 μg/kg; alfentanil, 175 μg/kg; sufentanil, 2.6 μg/kg. Much smaller doses may cause rigidity when given rapidly as an IV bolus. Little time is available for making a diagnosis. Rapid muscular paralysis and control of the airway are imperative and must be done immediately to prevent cerebral hypoxia.

CARDIORESPIRATORY EFFECTS The sudden onset of muscle rigidity immediately following the intravenous (IV) administration of opioids, accompanied by apnea and rapid oxygen desaturation, suggests that the 174

Implications Chest wall rigidity and respiratory insufficiency can lead to cardiovascular collapse and cerebral hypoxia. Unlike thiopental,

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opioids do not sufficiently reduce cerebral oxygen consumption to protect the brain during a global hypoxic event. Prompt intervention is required to prevent cerebral hypoxia. Patient awareness does not seem to be a problem; patients have no recall of the event when questioned postoperatively.

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Difficult Airway: Opiate-Induced Muscle Rigidity

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MANAGEMENT Attempts to manually ventilate the patient’s lungs without muscle relaxants are usually inadequate. Management consists of IV administration of either a depolarizing or a rapidly acting nondepolarizing neuromuscular blocking agent in the usual intubating doses (succinylcholine 1 mg/kg, vecuronium 150 μg/kg, or rocuronium 100 μg/kg). Manual ventilation is performed easily within 60 seconds after the administration of succinylcholine, and the airway can then be secured with an endotracheal tube. Once the airway has been secured, IV or inhaled anesthetics are administered to continue the anesthesia. A 7.6% incidence of delayed postoperative muscle rigidity has been reported when large doses (100 μg/kg) of fentanyl are used for induction of anesthesia. If this is severe enough to cause failure of ventilation, either a muscle relaxant or naloxone can be administered to reverse muscle rigidity.

PREVENTION Opioid-induced rigidity is difficult to prevent. The incidence can be reduced by slow injection of the opioid agent and

Further Reading Bailey PL, Wilbrink J, Zwanikken P, et al: Anesthetic induction with fentanyl. Anesth Analg 64:48-53, 1985. Benthuysen JL, Smith NT, Sanford TJ, et al: Physiology of alfentanil-induced rigidity. Anesthesiology 64:440-446, 1986. Janis KM: Acute rigidity with small intravenous dose of Innovar: A case report. Anesth Analg 51:375-376, 1972. Lui PW, Tsen LY, Fu MJ, et al: Involvement of locus coeruleus and noradrenergic neurotransmission in fentanyl-induced muscular rigidity in the rat. Neurosci Lett 96:114-119, 1989. Muller P, Vogtmann C: Three cases with different presentation of fentanylinduced muscle rigidity—a rare problem in intensive care of neonates. Am J Perinatol 17:23-26, 2000. Sanford TJ, Weinger MB, Smith NT, et al: Pretreatment with sedativehypnotics, but not with nondepolarizing muscle relaxants, attenuates alfentanil-induced muscle rigidity. J Clin Anesth 6:473-480, 1994. Streisand JB, Bailey PL, LeMaire L, et al: Fentanyl-induced rigidity and unconsciousness in human volunteers: Incidence, duration, and plasma concentrations. Anesthesiology 78:629-634, 1993. Weinger MB, Segal IS, Maze M: Dexmedetomidine, acting through central alpha2-adrenoceptors, prevents opiate-induced muscle rigidity in the rat. Anesthesiology 71:242-249, 1989. Weinger MB, Smith NT, Blasco TA, et al: Brain sites mediating opiate-induced muscle rigidity in the rat: Methylnaloxonium mapping study. Brain Res 544:181-190, 1991.

GENERAL ANESTHESIA

pretreatment with midazolam (0.1 mg/kg) or α2-agonists, such as clonidine and dexmedetomidine. Rigidity cannot be prevented or significantly reduced by pretreatment with small doses of nondepolarizing muscle relaxants. Careful attention to the time frame over which the newer synthetic opioids are administered and pretreatment with midazolam are the most important measures for prevention.

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Unstable Cervical Spine, Atlantoaxial Subluxation Lois A. Connolly Case Synopsis A 79-year-old man presents with C1 and odontoid fractures sustained in a fall down stairs while he was intoxicated. He was found at the bottom of the stairs 2 days after the injury. In addition to alcoholism, the patient has a history of hypertension and smokes 1 to 2 packs of cigarettes per day. The patient is not oriented to time, place, or person and has inappropriate verbal responses, but there is no apparent neurologic deficit.

PROBLEM ANALYSIS Definition Cervical spine stability is defined as the ability of the spine to maintain relationships between vertebrae during physiologic loading, so as not to damage contained neural structures. Cervical spine instability occurs when physiologic loading causes patterns of vertebral displacement that jeopardize the cervical spinal cord. The muscles of the neck, along with ligamentous structures, intervertebral disks, and osseous articulations, all play a role in cervical spine stability. Upper cervical spine stability may be affected by trauma, congenital disorders, and inflammatory diseases, all of which may result in atlantoaxial instability (Table 42-1). TRAUMATIC ATLANTOAXIAL INSTABILITY The transverse ligament normally allows no more than 3 mm of anteroposterior translation between the odontoid and the anterior arch of the atlas. If disruption of this ligament

Table 42–1

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occurs, displacement of the odontoid reduces the space available for the spinal cord (Fig. 42-1). In the normal spine, the space available for the spinal cord is about 20 mm. Cord compression does not occur when the space is greater than 18 mm, but it does occur if it is less than 14 mm. CONGENITAL ATLANTOAXIAL INSTABILITY Congenital or chromosomal anomalies may contribute to atlantoaxial instability by means of either odontoid hypoplasia or laxity of the transverse ligaments. The stabilizing action of the odontoid during extension is lost with odontoid hypoplasia, and subluxation of the atlas occurs on the axis anteriorly, reducing the space available for the spinal cord. Laxity of the transverse ligament is present in 14% to 22% of patients with trisomy 21. Excessive laxity of other joints correlates with the presence of atlantoaxial instability. INFLAMMATORY ATLANTOAXIAL INSTABILITY Cervical spine involvement is common in inflammatory arthropathies such as rheumatoid arthritis (RA). The pathophysiology involves pannus formation, with subsequent destruction of cartilage and subchondral bone, along with

Conditions Associated with Atlantoaxial Subluxation Anterior arch of atlas

Congenital Down’s syndrome Odontoid anomalies Mucopolysaccharidoses

Odontoid process of axis

Transverse ligament

Acquired Rheumatoid arthritis Juvenile rheumatoid arthritis Ankylosing spondylitis Psoriatic arthritis Enteropathic arthritis Crohn’s disease Ulcerative colitis Reiter’s syndrome Trauma Odontoid fracture Ligamentous disruption From Crosby ET: The adult cervical spine: Implications for airway management. Can J Anaesth 37:77-93, 1990.

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Space available for cord

Posterior arch Figure 42–1 ■ Atlantoaxial articulation—view from above. (From Crosby ET: The adult cervical spine: Implications for airway management. Can J Anaesth 37:77-93, 1990.)

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EPIDEMIOLOGY ●

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●

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●

●

Cervical spine injuries occur in 1.5% to 7.7% of all major trauma cases. The peak distribution of injury is at the C2 and C5-C6 levels. The highest prevalence is in 15- to 24-year-old males, with a smaller peak occurring in persons older than 55 years. Most cervical spine injuries result from motor vehicle accidents (42% to 56%), falls (19% to 30%), or gunshots and sports-related activities (6% to 7%). Motor vehicle accidents and sports-related activities account for the majority of cervical spine injuries in younger patients, whereas falls account for most cervical spine injuries in older patients. Young children are less susceptible to cervical spine injury because they weigh less and have more cartilage than adults do; vulnerability increases with age. Cervical spine injuries in children younger than 2 years are exclusively C1-C2 injuries, because facet joints at this level are more horizontal and the ligaments more lax.

Unstable Cervical Spine, Atlantoaxial Subluxation

Vertebral injury can occur without cord damage because the spinal canal is widest in the cervical region. Neurologic deficits are present in 46% of patients and are more frequent with injuries involving C5-C7. A thorough neurologic examination should enable classification and identification of the level of the spinal cord lesion. Autonomic instability may occur acutely and is termed spinal shock. With spinal shock, loss of sympathetic tone leads to generalized hemodynamic instability characterized by bradycardia, peripheral arterial and venous vasodilatation, hypotension, and arrhythmia. Respiratory compromise may occur acutely due to loss of intercostal muscle innervation or, with high cervical lesions, due to phrenic nerve loss. In normal individuals, expansion of the rib cage accounts for 60% of resting tidal volume. Therefore, alveolar ventilation and the ability to cough are decreased with loss of intercostal muscle innervation, even if phrenic nerve function remains intact. Thus, acute cervical cord injury may cause hypoxia, atelectasis, and respiratory failure. The possibility of aspiration pneumonitis may compound the situation. In addition, neurogenic pulmonary edema may be associated with spinal cord injury due to massive sympathetic discharge associated with trauma. RADIOGRAPHIC EVALUATION Radiographic evaluation of the cervical spine is indicated for all of the following patients: ●

The cervical spinal cord is particularly prone to injury because of spinal flexibility and the mass of the head. The spinal cord is injured when the ligaments, muscles, and osseous structures fail to dissipate the energy of impact. Transmission of this energy results in microhemorrhage in the spinal cord central gray matter and loss of neurotransmission in the surrounding white matter. A biochemical cascade that destabilizes the neurologic axon membrane and promotes vasospasm creates a secondary injury pattern after the initial insult. Also, primary cervical spinal cord injury leads to altered autonomic tone, loss of autoregulation, depressed cardiovascular function, and hypotension. Current pharmacologic treatment is concerned with minimizing the deleterious effects of secondary injury.

Recognition HISTORY

AND

PHYSICAL EXAMINATION

Recognition of a cervical spine injury begins with the history. High-risk causes (e.g., motor vehicle accident, fall, long-standing RA) or known chromosomal abnormalities may alert the clinician to the presence of an unstable cervical spine. For example, a patient with RA may complain of clicking on neck flexion and pain and stiffness of the neck. An alert trauma patient may complain of neck pain or tenderness. An alert patient without neck pain or neurologic deficit does not require further cervical spine evaluation, immobilization, or special precautions during airway manipulation. If the patient is not fully alert, complains of neck pain, has neurologic deficits, or has other painful injuries, cervical spine precautions should be maintained.

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Alert, sober patients who complain of neck pain or tenderness Patients who have neurologic deficits or multiple traumatic injuries, including craniofacial injuries Inebriated or unconscious patients

A missed cervical spine injury can have devastating longterm consequences. Therefore, coexistent cervical spine injury should be assumed until the diagnosis is excluded. Patients with no significant mechanism of injury and who are fully alert and oriented, with no evidence of head trauma or a distracting injury, may be cleared clinically if they have no neck pain or tenderness and have a normal neurologic examination. The most appropriate method for clearing the cervical spine in patients with mental status changes is controversial. There is no national or international consensus for the optimal approach to this patient population. The Eastern Association for the Surgery of Trauma’s 1998 practice management guidelines state that “trauma patients with altered levels of consciousness who are unable to complain of neck pain or neurological deficits for 24 hours or more may be considered to have a stable cervical spine if adequate threeview radiography and thin-cut CT images through C1 and C2 are read as normal.” Others recommend a passive extension-flexion examination under fluoroscopy to assess ligamentous stability. Ligamentous injury is the type most often missed on other radiographic studies, even though unstable cervical spine ligamentous injury without fracture is rare (<0.5%). Others suggest indefinite cervical immobilization. However, collar complications such as rash, skin breakdown, and pressure-related injuries; difficult central venous access; and delay in tracheostomy are possible when collars are left on for more than 72 hours.

GENERAL ANESTHESIA

ligamentous laxity and instability. Atlantoaxial subluxation occurs in about 25% of patients with RA. It occurs more frequently in men, in those with disease of long duration, in patients with subcutaneous nodules or seropositive disease, and in those receiving steroid therapy. Vertical subluxation of the odontoid process through the foramen magnum may also occur in patients with RA.

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A lateral cervical spine radiograph is assessed first. All seven cervical vertebrae should be evaluated, because 20% of cervical spine injuries are at C7. A swimmer’s view may be used if necessary to view C7. Alignment of the vertebral bodies, transverse processes, and spinous processes is best assessed on the lateral view (Fig. 42-2). Each vertebra should be examined for bony integrity, intervertebral disk spaces, facet joints, and interspinous distance. Sensitivity of the cross-table lateral view alone is 80%; that is, 20% of patients with cervical spine injury have a normal lateral view. The sensitivity increases to 93% by adding the anteroposterior and odontoid views. The cervical spine cannot be considered cleared on the basis of the lateral view alone. A diagnostic algorithm for the evaluation of cervical spine fractures is shown in Figure 42-3. Computed tomography (CT) is considered the gold standard for diagnosis. It is superior to plain films in evaluating injuries to C1-C2. Fractures in the axial plane may be difficult to identify by CT scan, and ligamentous injury may not be appreciated. Magnetic resonance imaging (MRI) provides excellent visualization of spinal soft tissue structures and clear definition of canal compromise. In an emergent situation, however, MRI may be impractical. In conditions associated with the possibility of atlantoaxial subluxation (e.g., RA, Down’s syndrome), lateral cervical spine films are obtained in neutral, flexed, and extended positions. Evidence of both anterior and vertical subluxation should be sought, and the space available for the spinal cord

Anterior vertebral line Spinous process line

Spinolaminar line Figure 42–2

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Lateral cervical spine.

MRI scan if: - Indirect reduction of facet dislocation - Abnormal neurology

Clear C-spine clinically? No pain/tenderness Alert and oriented No alcohol or drugs Pain-free active movement No distracting injury

Thoracolumbar spine films if: - Evidence of thoracolumbar injury - Unconscious - Cervical spine injury

No

Unconscious? No

Yes

Lateral, AP, and odontoid plain films Normal

Remove immobilization and reassess

Lateral and AP plain films + CT scan C0-C2 abnormalities, areas not seen

Abnormal

CT scan abnormalities, areas not seen

Regain consciousness within 24 hours?

Abnormal exams

Flexion-extension views

Yes

Leave immobilization and reassess

No

Dynamic fluoroscopy or MRI scan

Figure 42–3 ■ Algorithm for evaluation of cervical spine injury. AP, anteroposterior; CT, computed tomography; MRI, magnetic resonance imaging. (From Brohi K, Wilson-Macdonald J: Evaluation of unstable cervical spine injury: A 6-year experience. J Trauma 49:76-80, 2000.)

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should be measured. In patients with RA, the anteroposterior view may be examined for the presence of laryngeal deviation.

Risk Assessment

● ●

●

●

●

●

●

Evaluation of the cervical spine radiographically Determination of the adequacy of respiration (blood gas analysis or spirometry) Examination for evidence of spinal shock (blood pressure, heart rate, arrhythmia, electrocardiographic changes, need for vasopressors) Evaluation of the injury’s effect on the central nervous system (neurologic evaluation, evidence of closed cranial trauma) Examination of associated injuries (chest radiograph or CT and electrocardiogram to rule out chest injuries) Determination of hemoglobin, electrolyte levels, coagulation status, and creatinine level Assessment of temperature balance

Implications As discussed, multiple organs are affected by acute spinal cord trauma. Spinal shock requires invasive arterial monitoring, central venous pressure monitoring, and titration of vasopressors to ensure adequate perfusion pressure. If neurogenic pulmonary edema exists, further monitoring with a pulmonary artery catheter may be warranted. Acute spinal cord injuries are treated with high-dose methylprednisolone. This is believed to reduce edema, have anti-inflammatory effects, and protect neuronal membranes by scavenging free radicals. However, complications of such therapy include an increased rate of wound infection and a greater risk of gastrointestinal hemorrhage. Initial immobilization, with supervised reduction and realignment, is achieved with skeletal traction. Cervical immobilization is paramount and must be maintained during airway manipulation.

MANAGEMENT Intraoperative Concerns The primary intraoperative concerns are as follows: ● ● ● ● ●

Monitoring Airway management Positioning Administration of anesthetic drugs (succinylcholine) Fluid management, glucose administration

Intraoperative management requires tracheal intubation. The urgency of airway intervention is probably the most important factor in planning for airway management. Other factors include patient cooperation, assessment of the airway, and risk to the cord with neck movement. Direct laryngoscopy requires atlanto-occipitoaxial extension and mild inferior rotation of C3-C5, although there is minimal movement below C3. Accordingly, unstable C1-C2 injuries

Unstable Cervical Spine, Atlantoaxial Subluxation

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are most likely to cause neurologic damage. Manual in-line traction reduces atlanto-occipital extension during intubation, and several published series detail the use of direct laryngoscopy with in-line traction without evidence of neurologic deterioration. The use of a Miller-type blade results in less movement (i.e., axial distraction) than the use of curved (e.g., Macintosh) blades. Preintubation techniques, such as jaw-thrust and chin-lift maneuvers, cause the most motion and narrowing of the space available for the cord; therefore, great care must be taken when performing these maneuvers. Failed intubation is a danger, however, and the laryngoscopist’s view may be hindered by the stabilization. Direct laryngoscopy with in-line stabilization is most useful when it is vital to gain rapid control of the airway (e.g., patients with respiratory failure, hemodynamic instability, increased intracranial pressure). Use of a laryngeal mask airway is not advised because it can exert a great deal of pressure against the cervical vertebrae. Indeed, it may produce posterior displacement of the cervical spine (C2-C6) and possible rupture of the posterior longitudinal ligament. Awake tracheal intubation is probably the ideal way to secure the airway in a patient with an unstable cervical spine, although it may be inappropriate if rapid intubation is necessary. Use of the fiberoptic scope allows intubation under direct vision, but it may be difficult if the patient has pharyngeal bleeding or is uncooperative. Other awake techniques include blind nasal intubation or retrograde intubation over a wire. Cricothyrotomy or tracheotomy may be considered if attempts at placing an endotracheal tube by other means are unsuccessful. Once tracheal intubation is achieved in a conscious patient, positioning for surgery requires that continuous cervical spine stability be maintained. Often, the patient is positioned awake, so that any neurologic deterioration can be identified immediately. In addition to securing the airway and correct patient positioning, choice of anesthetic agents is paramount. Beyond the first 24 hours after injury, succinylcholine may cause hyperkalemia. In denervated muscle, motor end plates proliferate, and succinylcholine produces an exaggerated depolarizing response with a large release of potassium. This acute increase in potassium may lead to arrhythmia, cardiac arrest, and death. Anesthetic drugs are chosen based on preserved spinal cord perfusion and autoregulation and neuroprotective effects. If somatosensory evoked potential monitoring is done intraoperatively, anesthetic drugs may affect the latency or amplitude of evoked potentials. Hypotension and hypothermia may also affect somatosensory evoked potential monitoring. A drug regimen based on nitrous oxide, opiates, and nondepolarizing muscle relaxants, with minimal use of potent inhalational agents, appears most advantageous. Fluid management should balance the need to maintain intravascular volume to ensure adequate perfusion with the avoidance of interstitial edema. Avoidance of glucosecontaining solutions is important. Worsening neurologic outcomes have been demonstrated with transient spinal cord ischemia and exposure to modest elevations in plasma glucose concentrations.

GENERAL ANESTHESIA

Preoperative assessment in a patient with a known unstable cervical spine should include the following:

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Postoperative Concerns Extubation relies on the level of the neurologic lesion and the absence of associated injuries to the head and chest. Weaning criteria used for other patients, which include a maximum inspiratory force of –20 cm H2O, a vital capacity of 1000 mL, and a PaO2/FiO2 ratio greater than 250, may not be appropriate for a quadriplegic patient. If the surgical approach includes the anterior neck, a leak test around the endotracheal tube is helpful to rule out edema or airway compression from a neck hematoma. Both the recurrent laryngeal nerve and branches of the vagus may be damaged during neck dissection (more common on the right side than the left), leading to vocal cord paralysis and stridor on extubation, as well as dysphagia.

PREVENTION Prevention of neurologic deterioration with an unstable cervical spine requires the following: ●

●

●

● ●

Recognition of cervical spine injury and stabilization of the cervical spine during airway maneuvers and positioning Preservation of spinal cord perfusion by optimizing mean arterial pressure Minimization of spinal cord edema by careful attention to fluid management Use of high-dose steroids Prompt treatment of respiratory compromise to prevent hypoxia and further neurologic deterioration

In summary, the unstable cervical spine requires prompt recognition, evaluation of neurologic deficits, and evaluation and treatment of systemic effects, as well as meticulous airway management to ensure optimal outcome from the cervical spine injury.

Further Reading Ajani AE, Cooper DJ, Scheinkestel CD, et al: Optimal assessment of cervical spine trauma in critically ill patients: A prospective evaluation. Anaesth Intensive Care 26:487-491, 1998. Brohi K, Wilson-Macdonald J: Evaluation of unstable cervical spine injury: A 6-year experience. J Trauma 49:76-80, 2000.

Chin WC, Haan JM, Cushing BM, et al: Ligamentous injuries of the cervical spine in unreliable blunt trauma patients: Incidence, evaluation, and outcome. J Trauma 50:457-464, 2001. Cornelius RS, Leach JL: Imaging evaluation of the cervical spine trauma. Neuroimaging Clin N Am 5:451-463, 1995. Crosby ET, Lui A: The adult cervical spine: Implications for airway management. Can J Anaesth 37:77-93, 1990. Davis JW, Kaups KL, Cunningham MA, et al: Routine evaluation of the cervical spine in head-injured patients with dynamic fluoroscopy: A reappraisal. J Trauma 50:1044-1047, 2001. Donaldson WF, Heil BV, Donaldson VP, et al: The effect of airway maneuvers on the unstable C1-C2 segment: A cadaver study. Spine 22: 1215-1218, 1997. Edge CJ, Hyman N, Addy V, et al: Posterior spinal ligament rupture associated with laryngeal mask insertion in a patient with undisclosed unstable cervical spine. Br J Anaesth 89:514-517, 2002. Gerling MC, Davis DP, Hamilton RS, et al: Effects of cervical spine immobilization technique and laryngoscope blade selection on an unstable cervical spine in a cadaver model of intubation. Ann Emerg Med 36:293-300, 2000. Hastings RH, Marks JD: Airway management for trauma patients with potential cervical spine injuries. Anesth Analg 73:471-482, 1991. http://www.dhfs.state.wi.us/Disabilities/Physical/SCI.htm Keller C, Brimacombe J, Keller K: Pressures exerted against the cervical vertebrae by the standard and intubating laryngeal mask airways: A randomized, controlled, cross-over study in fresh cadavers. Anesth Analg 89:1296-1300, 1999. Laine FJ, Smoker WRK: Neuroradiology. In Cottrell JE, Smith DS (eds): Anesthesia and Neurosurgery, 4th ed. St. Louis, Mosby–Year Book, 2001, pp 151-156. Mackenzie CF, Geisler FH: Management of acute cervical spinal cord injury. In Albin MS (ed): Textbook of Neuroanesthesia. New York, McGrawHill, 1997, pp 1083-1136. Marshall WK, Mostrom JL: Neurosurgical diseases of the spine and spinal cord: Anesthetic considerations. In Cottrell JE, Smith DS (eds): Anesthesia and Neurosurgery, 4th ed. St. Louis, Mosby–Year Book, 2001, pp 557-590. Netterville JL, Koriwchak MJ, Winkle M, et al: Vocal fold paralysis following the anterior approach to the cervical spine. Ann Otol Rhinol Laryngol 105:85-91, 1996. Pasquale M, Fabian T: Practice management guidelines for trauma from the Eastern Association for the Surgery of Trauma. J Trauma 44:941-957, 1998. Short DJ, El Masry WS: High dose methylprednisolone in the management of acute spinal cord injury—a systematic review from a clinical perspective. Spinal Cord 38:273-286, 2000. Slucky AV, Eismont FJ: Treatment of acute injury of the cervical spine. Instr Course Lect 44:67-80, 1995. Stewart M, Johnston RA, Stewart I, et al: Swallowing performance following anterior cervical spine surgery. Br J Neurosurg 9:605-609, 1995. Walker DAJ: Management of the patient with spinal cord injury. In Fleisher LA, Prough DS (eds): Problems in Anesthesia: Traumacare, vol 13. Philadelphia, JB Lippincott–Williams & Wilkins, 2001, pp 340-347.

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Dental Injuries Lee M. Radke Case Synopsis

PROBLEM ANALYSIS Definition Most anesthesia references identify damage to teeth and dental prostheses as the most common complication of endotracheal intubation. In fact, dental complications are the most common reason for complaints against anesthesiologists. The incidence of dental trauma during general anesthesia has been reported to be as high as 12% and as low as 0.04%. A large survey in which more than 1 million endotracheal intubations were examined reported an incidence of approximately 1 dental injury per 1000 intubations.

Recognition Modern dental materials and techniques make dental injury difficult to recognize and diagnose. Restorations are often quite natural appearing, and to the untrained eye, it may be difficult to differentiate whether damage has occurred to a natural tooth or a restored tooth. Intubation-related dental injuries include fractured teeth, displaced restorations, subluxation, and avulsion. Individual teeth are numbered according to a system (Fig. 43-1), and damage to a tooth is classified in the following manner: ● ● ● ● ● ●

Class I: fracture confined to enamel Class II: fracture involving dentin layer Class III: fracture resulting in exposure of dental pulp Class IV: fracture of tooth root Class V: subluxation of tooth Class VI: tooth avulsion

Risk Assessment The greatest risk of dental injury occurs during laryngoscopy and tracheal intubation. The anterior maxillary teeth are most commonly damaged, with the left incisors affected most often. Damage to oral hard and soft tissues can usually be attributed to use of the maxillary anterior teeth as a fulcrum or resting place for the proximal laryngoscope blade during tracheal intubation. However, dental injuries occur in other ways as well. During airway maintenance, a poorly positioned airway or bite block can damage the dentition. During recovery, especially when volatile anesthetic agents have been used, powerful masseter muscle spasms can occur. If an oropharyngeal airway device has been left in place, the spastic biting and grinding forces against the airway can be sufficient to cause dental injury.

Patients with preexisting dental problems are at greater risk for dental injury during general anesthesia. During the preanesthetic evaluation, the anesthesiologist should note the patient’s risk for dental injury, especially the condition of the number 9 and 10 incisors (see Fig. 43-1), which are the teeth at highest risk for injury. Any potential dental problems should be noted in the patient’s chart: ●

●

●

●

●

●

Teeth that are decayed and not restored are susceptible to chipping or fracture. Teeth with dental restorations (e.g., large fillings or crowns), although strong and functional, can fracture when subjected to impact stresses. Endodontically treated teeth (e.g., root canal therapy) are weaker and more brittle than healthy, vital teeth. Periodontal disease results in decreased bony support. In this situation, laryngoscopy, tracheal intubation, or insertion of a laryngeal mask airway makes subluxation or avulsion of affected teeth more likely. Elderly patients may experience thinning of the tooth enamel due to aging and attrition. Such enamel is more easily damaged during instrumentation of the airway. Loose, exfoliating deciduous teeth are at risk for displacement in young patients.

Although deciduous teeth often are considered expendable, premature loss can result in problems. Deciduous teeth maintain space in the dental arch and help guide the permanent teeth into the proper position. If deciduous teeth are lost prematurely, the dental arch could collapse, with a resultant crowding of the permanent teeth. Further, any damage to a deciduous tooth may harm the underlying permanent tooth. Difficulty of endotracheal intubation can be a contributing factor to dental injury. Emergent, hurried intubations are more likely to result in tooth damage. Unfavorable anatomic features, such as mandibulofacial abnormalities or a short neck, complicate intubation, as do conditions that cause decreased mobility of the mandible or the neck. Although not well studied, another factor contributing to dental injury during general anesthesia is the experience level of the person performing the intubation.

Implications As stated, patients with preexisting dental problems are at the greatest risk for dental injuries related to intubation. If the patient is aware of dental problems or is informed of such risk before general anesthesia, liability is greatly diminished, even if damage occurs. Affected teeth should be noted 181

GENERAL ANESTHESIA

A 55-year-old man is taken to the operating room for hernia repair. He has cervical ankylosis, and intubation proves to be difficult. Two maxillary incisors are fractured. Hernia repair is completed, and the dental service is contacted for consultation.

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Molars Bicuspids Canine Lateral incisor Central incisors Lateral incisor Canine Bicuspids

1

2

32

31

3

4 30

5 29

6 28

7 27

8

9

10

26 25 24 23

11 22

12 21

13 20

14 19

Molars

15

16

18

17

Molars Bicuspids Canine Lateral incisor Central incisors Lateral incisor Canine Bicuspids Molars Figure 43–1

■

Nomenclature and universal numbering system for permanent (adult) dentition.

by number (see Fig. 43-1) during the preanesthetic airway evaluation. The consequences of dental trauma during general anesthesia can range from minor to severe. Many dental injuries can be repaired easily with standard restorative dental procedures, such as replacement of a displaced filling or repair of chipped enamel. More severe damage, such as dentoalveolar injury,“healthy” tooth loss, or damaged crowns or bridgework, is costly to rectify, causes substantial patient dissatisfaction and upset, and may result in litigation. Endobronchial aspiration of a natural, restored, or prosthetic tooth is the most serious adverse outcome of dental injury.

MANAGEMENT Ideally, management of an intubation-related dental injury is undertaken by a dental consultant shortly after the injury occurs. Because this service is not always immediately available, the anesthesia staff usually provides early management of such injuries. If a fragment of a tooth or restoration is displaced, the pieces must be located and recovered. If it is apparent that not all pieces have been retrieved, radiographs should be

obtained to ensure that the object has not passed through the glottic opening. Anteroposterior and lateral chest radiographs and lateral head and neck views should be taken. If a tooth is loosened but not avulsed, it should be returned to its original position as soon as possible. The inner and outer alveolar bone should be compressed with digital pressure to realign bone fragments. Temporary splinting should be done with tape or suture, especially if the tooth is very loose and aspiration is a concern. If a tooth is avulsed, it should be replanted immediately into its original position. Care must be taken not to wipe or dry the root surface. Tooth roots attach to the alveolar socket through a network of collagenous fibers, which form the periodontal ligament. Wiping or drying the root disrupts the attachment fibers, making successful replantation less likely. In addition, the less time a tooth is out of its socket, the more likely it is that replantation will be successful. Teeth replanted within 30 minutes can usually be retained. Temporary splinting with tape or suture is indicated. Often, a tooth cannot be safely replanted until the patient awakens because of concern about aspiration. If this is the case, the tooth should be handled carefully by the crown and placed in a suitable medium. Saline is readily available and works well, but milk is better. Milk may be available

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PREVENTION Preoperative Evaluation Prevention of anesthesia-related dental injuries begins during the preoperative anesthetic evaluation. Clinicians should determine whether the patient has any difficulty opening his or her mouth and whether any fixed or removable prostheses are present. The patient should be asked whether he or she is aware of any carious teeth or teeth that have been loosened by periodontal disease, especially any anterior teeth (numbers 6 to 11 and 21 to 27; see Fig. 43-1). Many patients do not receive regular dental care and may be totally unaware of their dental and periodontal status. If any teeth have periodontal disease (e.g., gingival recession, gingivitis, stain, calculus deposits, exudate), an evaluation for hypermobility should be done. This can be done using a tongue depressor blade or wooden cotton-tipped applicator to apply pressure to the facial aspect of the tooth while bracing the lingual aspect with the index finger of the other hand. Subtle, almost imperceptible movement is normal. Do not attempt to evaluate mobility by wiggling a tooth with the fingertips alone, because the sponginess of the fleshy part of the fingertip could be perceived as tooth movement. Accurate documentation of preexisting conditions (e.g., loose teeth, decay, restorations) and honest discussion of the risk of dental injury with the patient and his or her family

Dental Injuries

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members or representatives will greatly reduce liability if damage to the teeth should occur during anesthesia. If time permits (i.e., elective surgery) and there are serious concerns related to poor dental health, a dental consultation may be requested to thoroughly evaluate and possibly treat dental problems before the planned surgery. Tooth protection devices should always be considered for patients undergoing laryngoscopy or endoscopy, especially those who have known risk factors for dental injury. Prefabricated rubber or plastic protectors are available but are not universally used or accepted. Concerns that tooth protectors may hinder visualization during direct laryngoscopy may account for their limited use. Custom-made protectors can be fabricated by a dentist before surgery if the need exists and time permits. Custom-made protectors are somewhat expensive, but they offer a high degree of protection with minimal hindrance to visualization of the larynx. It has been reported that some degree of tooth protection may be provided by applying several layers of surgical adhesive tape to the teeth or the back of opposing surface of the laryngoscope blade. In an attempt to minimize contact between the teeth and the laryngoscope, many modifications to the shape of the blade have been proposed. It is suggested that an angulated straight blade with a low heel offers greater visualization between the posterior end of the blade and the upper teeth. Regardless, it is apparent that most anesthesia-related dental injuries can be prevented with a knowledge of dental factors that predispose teeth to such injury and the use of devices or strategies to protect the teeth.

Further Reading Burton JF, Baker AB: Dental damage during anaesthesia and surgery. Anaesth Intensive Care 15:262-268, 1987. Chadwick RG, Lindsay SM: Dental injuries during general anesthesia. Br Dental J 180:255-258, 1996. Givol N, Gershtansky Y, Halamish-Shani T, et al: Perianesthetic dental injuries: Analysis of incident reports. J Clin Anesth 16:173-176, 2004. Lockhart PB, Feldbau EV, Gabel RA, et al: Dental complications during and after tracheal intubation. J Am Dent Assoc 112:483, 1986. Skeie A, Schwartz O: Traumatic injuries of the teeth in connection with general anaesthesia and the effect of use of mouthguards. Endodont Dental Traumatol 15:33-36, 1999. Warner ME, Benenfeld SM, Warner MA, et al: Perianesthetic dental injuries: Frequency, outcomes, and risk factors. Anesthesiology 90:1302-1325, 1999. Watanabe S, Suga A, Asakura N, et al: Determination of the distance between the laryngoscope blade and the upper incisors during direct laryngscopy. Anesth Analg 79:638-641, 1994.

GENERAL ANESTHESIA

from the lunch bag of an understanding employee or from a nearby cafeteria. In the case of significant dental injury, arrangements should be made for immediate referral to a dentist for further evaluation. Loosened or avulsed teeth usually require splinting, and root canal therapy is often necessary if the teeth are to be retained. The circumstances of a dental injury should be documented in the patient’s chart and discussed with the patient as soon as he or she is able to understand the situation. Hospital policy usually requires that an incident report be filed. Administrative personnel from risk management or an equivalent department should become involved to help prevent public-relations, legal, or economic problems for the hospital and physicians involved. Responsibility for reimbursement of the patient for anesthesia-related dental injury could rest with the hospital, anesthesia department, or physician, depending on the hospital’s policy.

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Laryngeal and Tracheal Injury William Hope Case Synopsis A 65-year-old man describes persistent hoarseness and stridor after prolonged tracheal intubation and mechanical ventilation for treatment of respiratory insufficiency after emergent abdominal aortic aneurysm repair.

PROBLEM ANALYSIS Definition Acute and chronic injuries associated with laryngoscopy and tracheal intubation include but are not limited to the following: ● ● ● ● ● ● ●

Tracheobronchial laceration and rupture Laryngeal and tracheal edema and scarring Tracheal ulceration and stricture Subglottic and posterior glottic stenosis Dislocation of the arytenoid cartilages Vocal cord paralysis Ductal retention cysts

These complications can result in vocal cord dysfunction and airway obstruction of variable severity. In addition, laryngoscopy and placement of a tracheal tube may cause acute problems related to excessive autonomic stimulation and device malposition or malfunction. An endotracheal tube always lies in and exerts pressure on the posterior larynx, with potential damage to the arytenoid cartilages and cricoarytenoid joints, posterior glottis, and subglottis involving the inner surface of the cricoid cartilage. The degree of damage from intubation differs among patients. Damage has been shown to occur within a few hours and increases with the duration of intubation. Changes such as edema and hyperemia are seen initially. Progression to mucosal ulcerations and granuloma formation can lead to scar tissue formation and strictures, with chronic airway obstruction. Depending on the site of the injury and the presence of granulation or scar tissue, there can be stenosis and adhesions at, above, or below the level of the vocal cords, possibly with vocal cord dysfunction. Ductal retention cysts form due to irritation and obstruction of subglottic mucous gland ducts. Tracheal erosion caused by tracheal tube trauma may ultimately lead to tracheoesophageal fistula or tracheomalacia and potential tracheal collapse.

Recognition Laryngeal and tracheal injuries can be divided into those occurring after short-term or prolonged intubation. 184

SHORT-TERM TRACHEAL INTUBATION Acute injury, including mucosal and vocal cord edema, usually manifests within hours after extubation and may produce a barking, brassy cough and varying degrees of respiratory obstruction. Dyspnea, stridor, tachypnea, tachycardia, and suprasternal retraction are common presenting signs. Vocal cord dysfunction from recurrent laryngeal nerve injury or arytenoid dislocation presents as partial airway obstruction, dysphonia, and dysphagia. Although usually unilateral, bilateral vocal cord paralysis can present as complete airway obstruction necessitating emergency airway management. Tracheobronchial rupture is suspected with subcutaneous emphysema, respiratory distress, pneumomediastinum, and pneumothorax. Radiography and fiberoptic bronchoscopy confirm the diagnosis. PROLONGED TRACHEAL INTUBATION Chronic disorders often present weeks to months after prolonged intubation. Patients present with persistent voice dysfunction, dysphagia, and symptoms of airway obstruction. The lesion can be diagnosed endoscopically or radiographically. In the case of arytenoid dislocation, direct laryngoscopy with the patient under general anesthesia allows testing of the mobility of the cricoarytenoid joint. Flow-volume loops can be used to detect airway obstruction and provide valuable information about its location and functional importance. For example, in patients with airway obstruction, flows are reduced over the full range of lung volume from total lung capacity to residual volume (Fig. 44-1).

Risk Assessment Because late complications of tracheal intubation present weeks to months after the injury, the acute care practitioner is often unaware of the true incidence of the problem. There is evidence that even with short-term intubation, laryngoscopy results in radiographic and endoscopic evidence of laryngeal damage in a high percentage of patients. As many as 4% of young children experience symptomatic tracheal or laryngeal edema after intubation. The incidence of granuloma formation in adults reportedly ranges from 1 in 800 to 1 in 20,000 tracheal intubations. Granuloma formation occurs more commonly in women than in men and is relatively rare in children.

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Normal

MANAGEENT

4

Obstruction 2

1

2

3

4

TLC

5

6

RV Expired volume (L)

Figure 44–1 Hypothetical expiratory flow-volume curve for a patient with severe airway obstruction due to tracheal stenosis compared with that for a normal person. Note that flows are reduced over the full range of lung volumes, from total lung capacity (TLC) to residual volume (RV). ■

The following factors have been identified as contributing to intubation trauma:

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●

185

Laryngeal abnormalities (external trauma, inflammatory conditions) Difficult, traumatic, or repeated attempts at tracheal intubation Endotracheal tube movement (during coughing, swallowing, mechanical ventilation) Impairment of mucociliary clearance mechanisms or stasis of secretions Bacterial superinfection (prolongs healing and increases scar formation) Gastroesophageal reflux with spillover of acid into the laryngeal and subglottic region Nasogastric tube (increases the likelihood of gastroesophageal reflux and can cause pressure necrosis in the posterior cricoid region) Acute or chronic disease states with altered consciousness, poor tissue perfusion, or hypoxemia Long duration of intubation (5 to 7 days in adults and 1 to 2 weeks in children) Endotracheal tube characteristics (larger size, highpressure cuff)

Implications Laryngeal and tracheal injuries after laryngoscopy and tracheal intubation can be a significant cause for perioperative morbidity and, possibly, mortality. Tracheal rupture can lead to mediastinitis and pneumothorax. Acute airway edema can result in significant obstruction; this is especially

For acute laryngeal edema, nebulized racemic epinephrine (0.5 mL of a 2% solution diluted in a volume of 2 to 4 mL, given every 4 hours) can improve the symptoms of stridor. This dose should not be repeated more frequently than every 2 hours, and the patient must be observed for at least 4 to 6 hours after the last dose for possible rebound effects. Although its efficacy has not been proved, dexamethasone (0.2 to 0.4 mg/kg; maximum dose, 10 mg) may be beneficial. With prolonged intubation (adults, 5 to 7 days; children, 1 to 2 weeks), consultation for endoscopic laryngeal assessment is advised. Minor injuries usually resolve spontaneously after removal of the endotracheal tube. However, the finding of deep ulcerations calls for immediate extubation or tracheotomy, in addition to precautions to reduce the risk of infection (antibiotic therapy). If extubation is attempted in a patient with laryngeal edema, steroids can be administered in addition to the interim placement of a smaller endotracheal tube for 24 to 48 hours. The removal of granulation tissue may be required for successful extubation. Chronic injury secondary to intubation trauma may require laser ablation of scar tissue; tracheal dilatation, resection, reconstruction, or stents; or even anterior cricoid arch resection. Tracheal rupture usually requires emergent thoracotomy for repair.

PREVENTION Attempt to treat modifiable risk factors as follows: ● ●

● ●

Judicious use of intubating stylet Use of smallest endotracheal/tracheostomy tube diameter possible Aggressive gastroesophageal reflux treatment Antibiotic treatment for tracheostomy site infection

Further Reading Benjamin B: Prolonged intubation injuries of the larynx: Endoscopic diagnosis, classification, and treatment. Ann Otol Rhinol Laryngol Suppl 160:1-15, 1993. Flemming DC, Orkin FK, Kirby RR: Hazards of tracheal intubation. In Gravenstein N, Kirby RR (eds): Complications in Anesthesiology, 2nd ed. Philadelphia, Lippincott-Raven, 1996, pp 229-239. Reidenbach MM, Schmidt HM: Membranous tracheal rupture after endotracheal intubation. Ann Thorac Surg 60:1367-1371, 1995.

GENERAL ANESTHESIA

Flow (L/sec)

8

●

Laryngeal and Tracheal Injury

true in young children because of their small airway diameter. Sedatives, anesthetics, and muscle relaxants oppose the necessary compensatory increased activity of the accessory muscles of breathing in patients with severe airway obstruction to cause respiratory embarrassment. Bilateral recurrent laryngeal nerve palsy and flaps of granulation tissue can cause sudden and complete airway obstruction, necessitating the immediate establishment of an artificial airway.

10

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Case Synopsis An obese, agitated, 43-year-old man presents for exploratory laparotomy following a gunshot wound to the abdomen. He is uncooperative for examination of the airway. Following rapid-sequence induction of anesthesia, laryngoscopy is unexpectedly difficult. As neuromuscular function returns, the patient vomits a massive quantity of semidigested food.

PROBLEM ANALYSIS Definition The pulmonary aspiration of gastric contents can produce a variety of hazardous sequelae, depending on the nature of the aspirate. Aspirations may include the following: ●

●

● ●

●

Large food fragments, which can obstruct the airway, rapidly causing asphyxia Small particles (e.g., particulate antacids), which can produce severe granulomatous inflammation Gastric acids, which can induce chemical pneumonitis Blood and digestive enzymes, which are relatively innocuous Feculent material, which can cause severe infectious pneumonia

Recognition Unwanted materials can enter the lungs in either a subtle or a dramatic manner. Signs and symptoms (Table 45-1) can appear immediately or after several hours. Rales and rhonchi may be audible in affected lung regions, whereas wheezing may be prominent in only one third of patients with pulmonary aspiration. Dyspnea and tachypnea may develop in an awake patient. Both bronchial obstruction and pulmonary edema can induce profound hypoxemia. Pulmonary edema may also be associated with pink, frothy sputum. Tachycardia can result from respiratory distress as well as from intravascular hypovolemia. The latter can be due to a massive leakage of fluid through damaged pulmonary capillaries. Radiographic infiltrates may appear promptly or after a variable delay, and they may continue to worsen even as the clinical picture begins to improve. No particular radiographic

Table 45–1

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Signs and Symptoms of Pulmonary Aspiration

Rales and rhonchi Wheezing Dyspnea and tachypnea Hypoxemia Tachycardia Pulmonary infiltrates or edema

186

pattern is specific to pulmonary aspiration; it depends on the volume of material inhaled and the patient’s position during aspiration. In supine adult patients, the bronchial anatomy most commonly directs foreign matter into the right lower lobe and, less frequently, into the left upper lobe.

Risk Assessment Several large surveys have found that the incidence of clinically significant aspiration ranges from 0.5 to 4.7 per 10,000 cases. In some studies, the likelihood of pulmonary aspiration is three to four times greater for emergency surgery than for elective surgery. Children and the elderly are more likely to aspirate than are patients of intermediate ages. It may be troubling to note that whereas one third to one half of manifest pulmonary aspirations occur during anesthetic induction or laryngoscopy, one fifth to one third occur during emergence from anesthesia and extubation, when vigilance for this complication is lessened. The preoperative factor most often associated with aspiration is gastrointestinal obstruction. When aspiration occurs in the absence of known predisposing factors, two thirds of such episodes are complications of unanticipated difficulties in airway management. Pulmonary aspiration has two basic components. First, gastric contents must either escape or be propelled from the stomach into the oropharynx. Second, they must enter the lungs. Active vomiting can be provoked by opioids, cricoid pressure, gastrointestinal obstruction, or hypotension (Table 45-2). Passive regurgitation is promoted by increased intragastric volume or pressure or reduced lower esophageal sphincter (LES) tone. Failure of protective laryngeal reflexes can result from neurologic or neuromuscular disorders, sedative or narcotic medications, or general medical debility. Among the factors that influence the risk of pulmonary aspiration and its sequelae are the volume and character of gastric contents (Table 45-3). Increased volume alone may overcome any protection afforded by the strength of LES tone. Although the normal stomach apparently passes clear liquids within 2 to 3 hours, clearance of solids may require 6 hours or longer. Gastric acid secretion is thought to be stimulated by ethanol, hypoglycemia, and anxiety. In contrast, antegrade gastric emptying may be inhibited by diabetic gastroparesis, opioids, and pain. LES tone is weakened by nicotine, caffeine, fats, and gastric acid. Although a nasogastric tube permits gastric decompression, it also prevents LES closure. Finally, it is important to seek a history of gastroesophageal reflux

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Table 45–2

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Risk Factors for Pulmonary Aspiration: Escape of Gastric Contents

Vomiting

Regurgitation Gastrointestinal obstruction Diabetic gastroparesis Gastroesophageal reflux Increased intragastric pressure Decreased lower esophageal sphincter tone

Other Factors Impaired laryngeal protective reflexes Difficult airway management

from all patients and to recognize that elderly individuals may have feeble gag or cough reflexes. Some large clinical studies have failed to confirm conventional notions regarding the risk for aspiration. In these studies, patient factors that did not reliably predict gastric fluid acidity or volume were outpatient status, reflux history, anxiety, obesity, duration of fasting, and pregnancy. Similarly, the intake of alcohol, nicotine, or opioids had limited predictive value.

Implications When pulmonary aspiration of gastric contents occurs, the possible consequences range from benign to lethal. In one series of more than 200,000 operations, nearly two thirds of obvious aspirations produced no signs or symptoms within 2 hours. In this fortunate majority, no related complications ensued. For those patients who developed coughing, wheezing, infiltrates, or hypoxemia within 2 hours of aspiration, more than half required mechanical ventilation for at least several hours. Half the patients who required mechanical ventilation for more than 24 hours never fully recovered. In this and other large series, overall mortality from pulmonary aspiration was less than 5%; however, others reported much higher mortality rates. In two major surveys, pulmonary aspiration was never fatal in healthy patients after elective surgery. Even in Mendelson’s historic 1946 report of peripartum aspiration, the only fatalities resulted from rapid asphyxiation caused by food solids.

■

Risk Factors for Pulmonary Aspiration: Volume and Character of Gastric Contents

Increased volume of gastric contents Increased acidity of gastric contents Particulate matter in stomach Feculent matter in aspirate

187

MANAGEMENT When gastric contents enter the pharynx, the first priority is to clear the upper airway and prevent asphyxia. Tracheal intubation should follow promptly, even if difficult intubation precipitated the aspiration. Bronchoscopic suctioning of the lower airways may be indicated for pulmonary toilet. It is utterly useless, at best, to attempt to neutralize or dilute inhaled acids with an alkaline or saline chaser. Gastric acids experimentally instilled into the bronchi appear at the surface of the lung in less than 20 seconds. Thus, pulmonary parenchymal damage occurs almost immediately. It had been hoped that corticosteroids might interrupt the pulmonary inflammatory response to acid aspiration and ameliorate the subsequent clinical course. Unfortunately, after 3 decades of investigation, no beneficial effect has been shown. Although corticosteroids may attenuate inflammatory pneumonitis, the immunosuppressant effect of glucocorticoids may exacerbate any secondary bacterial pneumonia or sepsis. Also, prophylactic antibiotics are now considered useless in cases of pulmonary aspiration and may promote rather than prevent secondary infection with resistant pathogens. However, when the aspirate is feculent, antibiotic coverage may be indicated. The most important therapeutic measure after any pulmonary aspiration is maintenance of pulmonary gas exchange. Often, mechanical ventilation is instituted immediately after any major pulmonary aspiration. Although the prophylactic benefits of positive-pressure ventilation and positive endexpiratory pressure on the development of subsequent lung injury have been debated, such measures are often required merely to provide adequate arterial oxygenation.

PREVENTION Prevention of pulmonary aspiration includes careful, skilled airway management, as well as pharmacologic alteration of gastric contents and emptying with the following agents: ● ●

●

Nonparticulate antacids H2-receptor antagonists (or other suppressants of gastric acid secretion) Gastroprokinetic drugs

Several classes of drugs are used as chemoprophylaxis to alter gastric fluid volume and pH and to reduce both the likelihood of pulmonary aspiration and any associated complications (Table 45-4). Nonparticulate citrate antacids can Table 45–4

Table 45–3

Pulmonary Aspiration

■

Prophylaxis for Pulmonary Aspiration

Safe airway management Cricoid pressure Gastric tube decompression Chemoprophylaxis Clear citrate antacids H2-receptor histamine antagonists Proton pump inhibitors Gastroprokinetic agents

GENERAL ANESTHESIA

Gastrointestinal obstruction Opioids Cricoid pressure Hypotension

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elevate gastric pH in most patients, although gastric acids do reaccumulate. Commonly, 15 or 30 mL of sodium citrate or Bicitra is given before cesarean section and has been shown to raise gastric fluid pH to a presumably safe level in the vast majority of parturients. When given before nonobstetric emergency surgery in nonfasting patients, citrates reportedly have less consistent effects. In nonobstetric patients, 30 mL of citrate appears to be more reliable than 15 mL. However, the effects of citrates can never be presumed to persist through emergence and extubation. Particulate antacids are hazardous to the lungs and are therefore contraindicated preoperatively. Various H2-receptor histamine antagonists (e.g., cimetidine, ranitidine, famotidine) have been evaluated in many oral and parenteral regimens. Such drugs effectively suppress gastric acid secretion in most patients for several hours. However, they exert no effect on secretions already present in the stomach. Thus, their clinical utility is limited in truly emergent surgical patients. Proton pump inhibitors (e.g., omeprazole) are similarly effective in reducing further gastric acid production, but they have no demonstrable advantage over the H2-receptor histamine antagonists for aspiration prophylaxis. Gastroprokinetics (e.g., metoclopramide) may both facilitate antegrade gastric emptying and strengthen LES barrier pressure. However, their efficacy is somewhat inconsistent. Diabetics and others with known or suspected gastroparesis are likely the best candidates for gastroprokinetic medications. When preparing a patient for emergency surgery, a 10- or 20-mg intravenous dose of metoclopramide can empty the stomach within 10 to 20 minutes, whereas an oral dose takes 30 to 60 minutes. Erythromycin is also known to accelerate gastric emptying. Of course, individual responses vary, and it is potentially dangerous (and contraindicated) to attempt to increase gastrointestinal motility in the presence of intestinal obstruction. Prevention of pulmonary aspiration rests primarily on proper airway management. Chemoprophylaxis is useful, but it is only an adjunct. Although a variety of drugs can safely reduce the pulmonary threat imposed by gastric contents, their routine use is generally not advocated in otherwise healthy, nongravid surgical patients without apparent risk factors for aspiration. Owing to the infrequency of aspiration

pneumonitis in such patients, it is unlikely that these drugs will ever be shown to have a statistically significant effect on clinical outcome. Whenever possible, a difficult airway should be identified preoperatively. Gastrointestinal obstruction and airway morphology may warrant tracheal intubation before protective laryngeal reflexes are pharmacologically ablated. Although a gastric tube may not completely empty the stomach, it can provide a vent for increased intragastric pressure. Cricoid pressure (Sellick’s maneuver), when properly applied, can help prevent the passage of gastric contents into the oropharynx. However, it may also provoke active vomiting in an unanesthetized patient. In recent years, more authors have questioned the primary benefits of this maneuver. It is physically difficult to maintain cricoid pressure at the recommended level or force for more than a few minutes. In addition, backward pressure on the cricoid cartilage facilitates laryngoscopy in some patients but interferes with it in others. In fact, in some patients, pushing the larynx posteriorly, cephalad, and to the right provides the best view of the vocal cords. Cricoid pressure can also impede mask or laryngeal mask airway ventilation. Although Sellick’s maneuver remains a standard component of aspiration prophylaxis, oxygenation, ventilation, and securing the airway must always take precedence.

Further Reading ASA Task Force: Practice guidelines for preoperative fasting and the use of pharmacologic agents to reduce the risk of pulmonary aspiration: Application to healthy patients undergoing elective procedures: A report by the American Society of Anesthesiologists Task Force on Preoperative Fasting. Anesthesiology 90:896-905, 1999. Ljungqvist O, Soreide E: Preoperative fasting. Br J Surg 90:400-406, 2003. LoCicero J: Bronchopulmonary aspiration. Surg Clin North Am 69:71-76, 1989. Marik PE: Primary care: Aspiration pneumonitis and aspiration pneumonia. N Engl J Med 344:665-671, 2001. Mendelson CL: The aspiration of stomach contents into the lungs during obstetric anesthesia. Am J Obstet Gynecol 52:191-205, 1946. Ng A, Smith G: Gastroesophageal reflux and aspiration of gastric contents in anesthetic practice. Anesth Analg 93:494-513, 2001. Sellick BA: Cricoid pressure to control regurgitation of stomach contents during induction of anaesthesia. Lancet 2:404-406, 1961. Warner MA, Warner ME, Weber JG: Clinical significance of pulmonary aspiration during the perioperative period. Anesthesiology 78:56-62, 1993.

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46

Bronchospasm Joan Benca Case Synopsis

GENERAL ANESTHESIA

A 4-year-old boy with cerebral palsy has general anesthesia for repair of an inguinal hernia. Following intubation, peak inspiratory pressure increases acutely from 18 to 35 cm H2O. This is accompanied by a decrease in oxygen (O2) saturation from 100% to 82%, a decrease in blood pressure from 98/64 to 68/34 mm Hg, and an increase in heart rate from 90 to 140 beats per minute. Chest auscultation reveals diffuse bilateral expiratory wheezes.

PROBLEM ANALYSIS Definition In asthmatics, bronchospasm is caused by the spasmodic contraction of the bronchial smooth muscle. However, it occurs rarely during general anesthesia. In one series, wheezing occurred in only 0.17% of nonasthmatic and 0.8% of asthmatic patients. However, following induction with thiopental, wheezing has been reported in 6.7% to 8.1% of normal patients and in up to 45% of asthmatics. One review of a large number of asthmatic patients who received general anesthesia concluded that bronchospasm was a rare event and that associated adverse outcomes were uncommon. Thus, the relationship between intraoperative wheezing due to bronchospasm and severe adverse outcomes is unclear. However, data from the American Society of Anesthesiologists (ASA) closed claims study indicate that severe bronchospasm can result in death or brain injury. Patients who have bronchial asthma or chronic bronchitis may exhibit exaggerated responses to mechanical or chemical irritants or toxins, such as severe bronchoconstriction. Other factors can contribute to increased airway resistance with bronchospasm, such as mucosal edema, excessive mucus production and plugging, and desquamation of bronchial epithelium. Likely, all these in combination (bronchoconstriction, mucosal edema, mucus production, and inflammation) constitute bronchospasm, not just bronchial smooth muscle contraction. Normal airways are slightly constricted in their baseline condition. Bronchial smooth muscle tone is controlled by the parasympathetic nervous system via efferent vagal activity. Histamine also directly stimulates afferent parasympathetic pathways and directly increases bronchial smooth muscle tone. Muscarinic receptors can be blocked with atropine or glycopyrrolate. The parasympathetic nervous system is an important pathway in bronchoconstriction caused by inhaled irritants. Asthmatics have a smaller baseline airway caliber and hypertrophied bronchial smooth muscle, giving irritants greater access to receptors mediating bronchoconstriction. The smaller baseline airway caliber of asthmatic patients is significant; any further decrease in diameter will have a major effect on airway resistance, because laminar flow is proportional to the fourth power of the radius (Poiseuille’s law).

Large airways account for 80% of airflow resistance. The remaining 20% is accounted for by small airways and peripheral bronchioles. These smaller airways are sometimes referred to as the silent zone because their resistance can increase before there is a significant change in total airway resistance. Different factors trigger bronchospsasm in pediatric patients versus adult patients with obstructive airway disease. In pediatric patients, environmental allergens and viral respiratory illnesses are the most common causes of acute bronchospasm, whereas in adults, mechanical and chemical irritants are probably the most common causes. Further, viral illnesses can exacerbate symptoms in patients with asthma and can cause normal patients to exhibit increased airway reactivity. Thus, it is important to consider these mechanisms when tailoring therapy for individual patients.

Recognition Symptoms and signs of acute bronchospasm include wheezing, prolonged expiration, reduced breath sounds, and increased airway pressure during positive-pressure ventilation. O2 saturation may decrease, and the patient may become hypotensive. Owing to ventilation-perfusion mismatch, end-tidal carbon dioxide (CO2) concentration may decrease, even with an increased arterial CO2 concentration. End-tidal CO2 monitoring shows an upsloping curve, but this alone is not specific for bronchospasm; it indicates only obstruction to exhalation somewhere along the expiration pathway (i.e., from the patient’s alveolus to where the end-tidal CO2 sensor is positioned in the breathing circuit). Further, bronchospasm is not the only cause of wheezing. Table 46-1 lists other causes of wheezing in anesthetized, ventilated patients, and Table 46-2

Table 46–1

■

Causes of Nonbronchospastic (Asthmatic) Wheezing in Anesthetized Patients

Mechanical obstruction of endotracheal tube Negative-pressure expiration Tension pneumothorax Pulmonary edema Pulmonary aspiration of gastric contents Pulmonary embolism

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Causes of Increased Peak Airway Pressure during Ventilation

Increased inspiratory flow rate Excessive tidal volume: “alveolar overdistention” Increased intrapleural pressure Coughing Pleural effusion, ascites Abdominal gas insufflation, abdominal packs Restraints, bandages Head-down position Tension pneumothorax Increased resistance of endotracheal tube Small caliber, kinks, secretions Increased resistance of patient’s airway Secretions, bronchospasm* *If confronted with wheezing and increased peak inspiratory pressure, other causes must be ruled out before making the diagnosis of acute bronchospasm.

lists causes of increased peak inspiratory pressure during ventilation. Table 46- 3 lists causes of acute bronchospasm in anesthetized patients.

Risk Assessment Many patients with bronchospasm do not have a history of obstructive pulmonary disease. Also, most patients with obstructive pulmonary disease do not have bronchospasm under anesthesia. Factors that increase the risk for intraoperative bronchospasm are the following: ● ● ● ●

Recent viral upper respiratory infection Recent exacerbation of pulmonary symptoms Recent hospital admission for treatment of asthma Exposure to tobacco smoke

Bronchospasm may be more common in patients with tracheal intubation. One study showed a reversible component of increased airway system resistance after placement of an endotracheal tube, but not after placement of a laryngeal mask airway.

Implications Acute bronchospasm requires early diagnosis and treatment. Untreated, it causes hypoxemia, hypotension, and possibly brain damage or death. In the 1991 ASA closed claims study, 2% of the claims involved bronchospasm, and in 90% of these, the result was brain injury or death. The majority of these cases occurred during induction of general anesthesia and airway instrumentation. Airway instrumentation may precipitate acute bronchospasm, likely due to mechanical irritation and parasympathetic stimulation.

MANAGEMENT AND PREVENTION Acute bronchospasm is not limited to patients with a history of bronchial hyperreactivity. It is helpful, however, to make sure that patients with such a history receive bronchodilators and possibly steroids before the induction of general anesthesia. Patients with a history of asthma or chronic bronchitis who

Table 46–3

■

Causes of Acute Bronchospasm in Anesthetized Patients

Nonspecific bronchial hyperresponsiveness Allergic or anaphylactic reaction to drugs or blood transfusion Allergic or anaphylactic reaction to other allergens (e.g., latex) Exacerbation of asthma Pharmacologic factors (e.g., β-blockers, prostaglandin inhibitors, anticholinesterases) Stimulation of parasympathetic fibers and M2 and M3 muscarinic receptors Tracheal irritation from intubation

are scheduled for elective surgery should continue all their medications, and the chest examination should be at their baseline. Preoperative physical examination on the day of surgery must include chest auscultation. Active wheezing, worsening cough, more than usual sputum production, shortness of breath, and fever are reasons to delay anesthesia and surgery. A review of any previous anesthesia records may help in planning anesthetic management. For severe asthmatics, preoperative investigation may include a chest radiograph, 1-second forced expiratory volume (FEV1), and arterial blood gas analysis. For patients who are asymptomatic, no laboratory tests are necessary. Guidelines for the treatment of asthmatic patients were described by the 1997 National Heart, Lung, and Blood Institute’s Expert Panel on Asthma and include the use of steroids as anti-inflammatory agents (Table 46-4). It is unnecessary to treat all patients with a history of wheezing with steroids and bronchodilators, however. There is about an 8% incidence of asthma in the United States, so checking the FEV1 and starting all patients with asthma on steroids before anesthesia would be excessively costly. Those at highest risk for postoperative pulmonary complications (e.g., those having cardiac surgery, thoracotomy or airway surgery, or abdominal surgery, and those with a history of significant pulmonary symptoms) should probably receive steroids and have a baseline pulmonary function assessment. Interventions that may attenuate bronchial hyperreactivity during induction of anesthesia and airway manipulation include pretreatment with a nebulized β-agonist (e.g., albuterol, salbutamol, ipratroprium); intravenous (IV), nebulized, or intratracheal lidocaine; IV propofol induction; and preoperative oral or inhaled steroids. It is difficult to compare studies of interventions to attenuate bronchial hyperreactivity because some report airway resistance changes in response to tracheal intubation, others report responses to a histamine challenge, and still others report the incidence of perioperative clinical wheezing. Clearly, patients with significant bronchial hyperreactivity will benefit from the administration of steroids before anesthesia and surgery. A combination of steroids and β-agonists is clearly superior to either agent alone. For patients requiring general anesthesia, potent inhalational agents (at least equal to or greater than one minimum alveolar concentration) are the mainstays of anesthetic technique. All potent inhalational agents effectively reduce airway resistance. Using propofol as an induction agent, instead of thiopental or etomidate, reduces the incidence of postintubation wheezing in both

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Table 46–4

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■

Bronchospasm

191

Approach to Asthma Management in Adults and Children Older than Five Years Daily Medications

Step 4 Severe, persistent Asthma

Anti-inflammatory: inhaled steroid (high dose) and long-acting inhaled β2-agonist; possibly systemic steroids Short-acting bronchodilator: inhaled β2-agonist as needed for symptoms Anti-inflammatory: inhaled steroid (medium dose) or inhaled steroid (low to medium dose) and inhaled long-acting β2-agonist Short-acting bronchodilator: inhaled β2-agonist as needed for symptoms Anti-inflammatory: inhaled steroid (low dose) or cromolyn or nedrocromil Short-acting bronchodilator: inhaled β2-agonist as needed for symptoms Anti-inflammatory: no daily medication needed Short-acting bronchodilator: inhaled β2-agonist as needed for symptoms

Step 3 Moderate, persistent Asthma Step 2 Mild, persistent Asthma Step 1 Mild, intermittent Asthma

Adapted from National Heart, Lung, and Blood Institute National Asthma Education and Prevention Program EPR-2, 1997.

asthmatic and nonasthmatic patients. Both inhaled and IV lidocaine attenuate histamine-induced bronchospasm; however, the use of inhaled lidocaine attenuates histamineinduced bronchospasm at lower serum levels of local anesthetic than does IV lidocaine. This effect appears to be independent of topical airway anesthesia, because inhaled dyclonine provides excellent topical anesthesia but does not attenuate bronchial hyperreactivity to histamine. Laryngeal mask airways do not provoke bronchospasm and should be used if endotracheal intubation is not necessary, especially for pediatric patients with upper respiratory infections. Regional anesthesia is another option that avoids the problems associated with tracheal intubation. However, a neuraxial block may adversely affect pulmonary function. For patients with primarily reactive airway disease but without increased mucus production, the reduced ability to cough with a high neuraxial block is not a problem. Further, there is some evidence that a high epidural block does not exacerbate symptoms of asthma, but it is unclear whether it is the lack of tracheal intubation, serum concentration of local anesthetic, or some other effect of epidural anesthesia that contributes to the lower incidence of bronchospasm. Bronchospasm may still occur despite careful patient preparation and choice of an appropriate anesthetic technique. Treating bronchospasm under anesthesia can be difficult. One should administer100% O2 and use a potent inhalational anesthetic, but these steps are not always effective. With bronchospasm, it can be difficult to deepen anesthesia with an inhalational agent if ventilation is severely compromised.

Table 46–5

■

Adjunctive measures to treat the bronchospasm include IV lidocaine, IV propofol, subcutaneous (SC) terbutaline, SC or IV epinephrine, and a nebulized β-agonist. With severely impaired ventilation due to bronchospsam, SC or IV epinephrine should be given, and anesthesia should be deepened with an IV agent until effective ventilation is possible. Table 46-5 lists therapeutic steps for acute bronchospasm. β-Agonists given via a breathing circuit elbow adapter and a metered-dose inhaler are not as effective as those administered via a nebulizer or aerosol-enhancing chamber. Much of the delivered dose is contained in large (>5 μm) particles that do not reach the distal airways (a particle size of 1 to 5 μm is required for deposition in the distal airways). Therefore, only 10% to 20% of a dose delivered by a metered-dose inhaler reaches the small airways under optimal conditions in nonintubated patients. Delivery systems for intubated patients are even less effective, with as little as 1% to 2% of the delivered dose reaching the distal airways. Corticosteroids do not have an immediate beneficial effect in acute bronchospasm. However, they should be given to patients with acute bronchospasm to help reduce ongoing inflammatory changes that contribute to the problem. Finally, the most important factor in preventing bronchospasm during general anesthesia is to provide an adequate depth of anesthesia before and during airway manipulation and tracheal intubation, as well as during the surgical procedure itself. It is important to use anesthetic adjuncts, such as lidocaine and narcotics, in addition to potent inhalational agents to achieve this goal.

Therapy for Acute Bronchospasm

Deepen anesthesia with potent inhalational anesthetics or IV anesthetics Administer β-agonist bronchodilators (albuterol, metoproterenol, salbutamol, ipratroprium) using a metered-dose inhaler through an aerosolization chamber or by solution in a nebulizer placed in the anesthesia circuit Epinephrine Adult dose: 0.1 to 0.5 mL of 0.1% epinephrine solution SC Pediatric dose: 0.01 mL/kg of 0.1% epinephrine solution SC (maximum, 0.3 mL); 0.10 to 0.01 μg/kg/min infusion Isoproterenol Pediatric dose: 0.01 μg/kg SC up to a maximum of 0.3 mg; 0.01 to 0.1 μg/kg/min infusion Corticosteroids Hydrocortisone Methylprednisolone Dexamethasone

GENERAL ANESTHESIA

Step and Asthma Type

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Further Reading Berry A, Brimacombe J, Keller C, Verghese C: Pulmonary airway resistance with the endotracheal tube versus laryngeal mask airway in paralyzed anesthetized adult patients. Anesthesiology 90:395-397, 1999. Bishop MJ: Preoperative corticosteroids for reactive airway? Anesthesiology 100:1047-1049, 2004. Bishop MJ, Cheney FW: Anesthesia for patients with asthma: Low risk but not no risk. Anesthesiology 85:455-456, 1996. Cheney FW, Posner KL, Caplan RA: Adverse respiratory events infrequently leading to malpractice suits. Anesthesiology 75:932-939, 1991. Eames WO, Rooke GA, Wu RS, Bishop MJ: Comparison of the effects of etomidate, propofol, and thiopental on respiratory resistance after tracheal intubation. Anesthesiology 84:1307-1310, 1996. Gold MI, Helrich M: A study of the complications related to anesthesia in asthmatic patients. Anesth Analg 42:283-293, 1963. Groeben H, Grosswendt T, Silvanus M-T, et al: Airway anesthesia alone does not explain attenuation of histamine-induced bronchospasm by local anesthetics: A comparison of lidocaine, ropivicaine, and cyclonine. Anesthesiology 94:423-426, 2001. Groeben H, Silvanus M-T, Beste M, Peters J: Combined intravenous lidocaine and inhaled salbutamol protect against bronchial hyperreactivity more effectively than lidocaine or salbutamol alone. Anesthesiology 89:862-865, 1998. Kil H-K, Rooke GA, Ryan-Dykes MA, Bishop M: Effect of prophylactic bronchodilator treatment on lung resistance after tracheal intubation. Anesthesiology 81:43-46, 1994. Kim ES, Bishop MJ: Endotracheal intubation, but not laryngeal mask airway insertion, produces reversible bronchoconstriction. Anesthesiology 90:391-393, 1999.

National Institutes of Health Guidelines for the Diagnosis and Management of Asthma: Clinical Practice Guidelines Expert Panel Report-2. Bethesda, Md, National Institutes of Health, 1997. Olsson GL: Bronchospasm during anaesthesia: A computer aided incidence study of 136,929 patients. Acta Anaesthesiol Scand 31:244-252, 1987. Pizov R, Brown RH, Weiss YS, et al: Wheezing during induction of general anesthesia in patients with and without asthma: A randomized, blinded trial. Anesthesiology 82:1111-1114, 1995. Rooke GA, Choi J-H, Bishop M: The effect of isoflurane, halothane, sevoflurane, and thiopental/nitrous oxide on respiratory system resistance after tracheal intubation. Anesthesiology 86:1294-1297, 1997. Scalfaro P, Sly PD, Sims C, et al: Salbutamol prevents the increase of respiratory resistance caused by tracheal intubation during sevoflurane anesthesia in asthmatic children. Anesth Analg 93:888-890, 2001. Shnider SM, Papper EM: Anesthesia for the asthmatic patient. Anesthesiology 22:886-892, 1961. Silvanus M-T, Groeben H, Peters J: Corticosteroids and inhaled salbutamol in patients with reversible airway obstruction markedly decrease the incidence of bronchospasm after tracheal intubation. Anesthesiology 100:1052-1057, 2004. Tait AR, Pandit U, Voepel-Lewis T, et al: Use of the laryngeal mask airway in children with upper respiratory tract infections: A comparison with endotracheal intubation. Anesth Analg 86:706-709, 1998. Warner DO, Warner MA, Barnes RD, et al: Perioperative respiratory complications in patients with asthma. Anesthesiology 85:460-464, 1996.

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Perioperative Hypoxia John C. Boncyk

47

Case Synopsis GENERAL ANESTHESIA

A 70-year-old, 63-inch, 110-kg woman has laparoscopic cholecystectomy. After satisfactory anesthesia (nitrous oxide-oxygen, isoflurane, and a muscle relaxant) and surgery, she is transported to the postanesthesia care unit (PACU). Upon arrival in the PACU, the oxygen saturation of her arterial blood by pulse oximetry (SpO2) is 85% with 40% oxygen by facemask. She does not appear to be in any distress, and her other vital signs are stable. Over the next few minutes, her SpO2 trends down to 70%, and she becomes dyspneic.

PROBLEM ANALYSIS Definition Hypoxia is reduced oxygen (O2) tension within or outside the body; however, it is usually construed as reduced O2 tension at the tissue level. The oxygen cascade (Fig. 47-1) depicts the movement of O2 down its partial-pressure gradient from that of dry ambient air to the mitochondria. There are four categories of hypoxia: hypoxemia, anemic hypoxia, circulatory hypoxia, and histiocytic hypoxia. HYPOXEMIA Hypoxemia is decreased blood O2 tension. The lungs play a central role in all causes of hypoxemia: ● ● ● ● ●

Low fraction of inspired O2 (FiO2) Hypoventilation . . Alveolar ventilation-perfusion (VA/Q) mismatch Increased shunt Diffusion limitations

How these affect the alveolar-arterial O2 partial-pressure difference [P(A-a)O2], the response to breathing 100% O2, and the arterial partial pressure of carbon dioxide (CO2) is shown in Table 47-1. Low Inspired Oxygen Concentration. In addition to altitude and incorrect flowmeter settings, low FiO2 may be caused by faulty tank or hose connections, central gas distribution, or excessive inspired concentrations of nitrous oxide or nitrogen. The inspired partial pressure of O2 (PiO2) is directly related to atmospheric minus saturated water (H2O) vapor pressure (47 mm Hg at 37°C, regardless of altitude) and FiO2. Hypoventilation. With hypoventilation, alveolar ventila. tion (VA) cannot remove all produced CO2, so arterial and alveolar CO2 concentrations increase. With constant O2 consumption, hypoxia inevitably results. However, even a small increase in FiO2 will increase the arterial partial pressure of O2 (PaO2), as predicted by the alveolar gas equation: PAO2 = FiO2 • (PB – PiH2O) – (PACO2/RQ) where PAO2 and PACO2 are alveolar partial pressures of O2 and CO2, respectively; FiO2 is the fraction of inspired O2;

PB is atmospheric (barometric) pressure; PiH2O is saturated H2O vapor pressure; and RQ is the respiratory quotient (0.8). Assuming an FiO2 of 0.21, sea-level PB (760 mm Hg) and PiH2O (47 mm Hg), and variable PACO2, PAO2 decreases from 100 to 50 mm Hg as PACO2 increases from 40 to 80 mm Hg. Simply increasing FiO2 to 0.3 (PACO2 80 mm Hg) will increase PAO2 to 114 mm Hg. Ventilation-Perfusion Mismatch. Matching alveolar venti. . lation (VA) and perfusion (Q) involves many factors: ● ● ● ● ● ● ● ●

Ventilation volume Alveolar pressure Lung compliance Chest wall compliance Airway resistance Gravity (posture) Pulmonary blood flow Mode of ventilation

. . When ventilation and perfusion are matched, VA/Q . is. equal to 1.0. However, the lung does not have uniform VA/Q (Fig. 47-2). Dead space refers to ventilation without perfusion, and perfusion without ventilation is called shunt. Note in Figure 47-2 that the top of the lung has more dead-space ventilation (and higher PAO2) than the bottom, and the bottom of the lung has relatively more shunt . .(and lower PAO2). The reason PaO2 is decreased with . V. A/Q mismatch is that capillary blood leaving the high-VA/Q regions has higherthan-normal PO2 but only minimally enhanced O2 content (owing to the shape of the dissociation curve). . oxyhemoglobin . Blood leaving the low-VA/Q regions has both low PO2 and low O2 content;.this.situation reduces O2 transfer to blood far more than high-VA/Q regions . .can increase it, thereby increasing the P(A-a)O2 gradient. VA/Q mismatch also interferes with the uptake and elimination of anesthetic gases. Denitrogenation and the uptake and elimination of inhalational . . anesthetic agents are slowed in patients with significant VA/Q mismatch. . . Increased Shunt. Anatomic right-to-left shunt (Qs /Qt) is not considered here (see Chapter 157). Right-to-left transpulmonary shunt (i.e., mixed venous blood traverses the pulmonary capillary bed without being oxygenated) is the primary mechanism for hypoxia in anesthetized patients and in those with pneumonia and pulmonary edema. Right-to-left shunt (either anatomic or transpulmonary) is the only mechanism 193

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Inspired oxygen concentration FiO2 Alveolar ventilation • VA

Scatter of • • V/Q ratios

0

Venous admixture • • Qs/Qt

Arterial blood PaO2

Hemoglobin concentration Hb

Cell PO2

Cytoplasm

c

0 Vol. (%)

Table 47–1

Oxygen consumption • VO2

Alveolar gas PaO2

Mitochondria

5

Arterial blood –

50

Inspired gas FiO2

a

Mean capillary blood –

10

A ‘Ideal’ alveolar gas –

100

E′ End-expiratory gas –

15

PO2

I

150

Air humidified at 37°C –

20

Blood flow • Q

mm Hg Dry atmospheric air –

kPa

Figure 47–1 ■ Oxygen partialpressure cascade from dry atmospheric air (160 mm Hg) to the mitochondria (3 to 20 mm Hg). (From Lumb AB: Nunn’s Applied Respiratory Physiology, 5th ed. London, Butterworth-Heinemann, 2000, p 250.)

Barometric pressure PB

■

Causes of Hypoxemia and Their Effects on Alveolar-Arterial Oxygen Partial Pressure Difference, Response to 100% Oxygen, and Arterial Partial Pressure of Carbon Dioxide

Cause

P(A-a)O2

100% O2

PaCO2

Low FiO2 Hypoventilation . . VA/Q mismatch . . Shunt (Q s/Q t ) Diffusion limitation

Normal Normal Increased Increased Increased

Increased PaO2 Increased PaO2 Increased PaO2 No change Increased PaO2

Normal Increased Normal Normal Normal

FiO2, fraction of inspired oxygen; PaO2, arterial partial pressure of oxygen; P(A-a)O2, alveolar-arterial oxygen . . partial pressure difference; PaCO2, arterial partial pressure of carbon dioxide; VA/Q , alveolar ventilation-perfusion.

•

•

VA

Q

•

•

VA/Q

PO2

(L/min)

PCO2

PN2

(mm Hg)

7

.24

.07

3.3

132

28

553

11

.52

.50

1.0

108

39

566

13

.82

1.29

0.63

89

42

582

. . Figure 47–2 ■ Regional lung alveolar ventilation-perfusion (VA/Q ) ratios and gas composition for three zones of the upright lung. (From West JB: Pulmonary Pathophysiology: The Essentials. Baltimore, Williams & Wilkins, 1980.)

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500

ANEMIC HYPOXIA

400

Anemic hypoxia is caused by a low hemoglobin concentration or abnormal hemoglobin function. The following considerations are relevant to the discussion of anemic hypoxia:

% Shunt 0

● ●

10

Breathing air

● ●

20

0

30 50

20 40 60 80 Inspired O2 concentration (%)

100

Figure 47–3 ■ Relationship between arterial partial pressure of oxygen (PaO2) and fraction of inspired oxygen (FiO2) for shunts of various percentages (isoshunt diagram). Isoshunt lines hold for hemoglobin of 10 to 14 g/dL and arterial partial pressure of carbon dioxide (PaCO2) of 25 to 40 mm Hg. (Modified from Nunn JF: Applied Respiratory Physiology, 4th ed. London, Butterworth-Heinemann, 1993, p 184.)

for hypoxemia in which PaO2 stays well below PAO2, even with an FiO2 of 1.0 (Fig. 47-3). Diffusion Limitation. Alveolar-capillary gas exchange is limited by the diffusing capacity of a particular gas across the alveolar-capillary membrane (D). The normal resting diffusing capacity for O2 (DO2) is 21 mL/minute per mm Hg P(A-a)O2. During exercise, DO2 can increase to 65 mL/minute per mm Hg P(A-a) . O.2 owing to increased capillary exchange and improved VA/Q matching. Diffusion limitation is an unusual cause of clinical hypoxemia.

Oxygen-Hemoglobin Dissociation Curve. The O2-Hb dissociation curve is sigmoidal and describes the affinity of hemoglobin for O2. P50 is the value for PO2 when hemoglobin is 50% saturated with O2. For normal hemoglobin in adults, this is 26.6 mm Hg (see Fig. 47-4). A shift to the right means that hemoglobin unloads its O2 to tissues more easily, and a shift to the left means that hemoglobin unloads its O2 with more difficulty. Four factors regulate the affinity of hemoglobin for O2: 1. Hydrogen ion (Bohr effect) 2. 2,3-Diphosphoglycerate

Total 100 Hb ñ O2 80

20

15 60 10 Mixed venous

SaO2 (%)

Figure 47–4 ■ Oxyhemoglobin dissociation curve relates arterial oxygen saturation (SaO2; left ordinate) and content (CaO2 [mL/dL]; right ordinate) to tension (PaO2; abscissa). This assumes hemoglobin = 15 g/dL, CaO2 = 20 mL/dL, and arteriovenous CaO2 difference = 5 mL/dL. (From Luce JM, Pierson DJ, Tyler ML: Intensive Respiratory Care, 2nd ed. Philadelphia, WB Saunders, 1993, p 27.)

Hemoglobin Structure-Function Relationship. Hemoglobin is composed of four subunits to form a tetrameric molecule. There are several different subunits (denoted α through ε), but only two are contained in a single hemoglobin molecule. Normal adult hemoglobin has two α and two β subunits. Heme, the iron-containing moiety, fits into each hemoglobin subunit, allowing it to bind one molecule of O2 (oxygenation). Interactions between hemoglobin subunits (subunit cooperativity) are responsible for the increased O2 affinity that occurs as each successive O2 molecule is bound to hemoglobin. This property accounts for the sigmoid shape of the O2-Hb dissociation curve (Fig. 47-4).

40

20

5

Dissolved 0

0 0

20

40

60

80

PaO2 (mm Hg)

100

600

CaO2 (mL/dL)

100

Normal arterial

200

Hemoglobin structure-function relationship Oxygen-hemoglobin (O2-Hb) dissociation curve Oxygen content Other hemoglobin species Minimum hemoglobin concentration

●

300

GENERAL ANESTHESIA

Arterial PO2 (mm Hg)

Chapter 47

(a –v)O2 Difference

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3. CO2 (Haldane effect) 4. Temperature An increase in any of these factors decreases the affinity of hemoglobin for O2 and shifts the O2-Hb dissociation curve to the right (i.e., increases P50), with more O2 unloaded to tissues for a given PO2. A decrease shifts the O2Hb dissociation curve to the left, with less O2 unloaded to tissues at any given PO2. Oxygen Content. Four moles of O2 bind with each mole of hemoglobin. The O2 carrying capacity of hemoglobin is 1.39 mL O2/g; however, this is typically lower in patients (about 1.34 mL/g), owing to the small amounts of methemoglobin and carboxyhemoglobin that are normally present. In addition, there is physically dissolved O2 in plasma (0.003 mL/dL per mm Hg of PO2), so arterial O2 content (CaO2) is expressed as follows: CaO2 = SaO2 • [Hb] • 1.34 + PaO2 • 0.003 or 20 mL/dL (see Fig. 47-4). However, the amount of O2 given off to the tissues is dependent on O2 content and the P50 of the hemoglobin species. Other Hemoglobin Species. Myoglobin serves both as an O2 buffer and to store O2 in muscle. All known vertebrate

myoglobins and β-hemoglobin subunits are similar in structure, but myoglobin binds O2 more avidly at low PO2 (Fig. 47-5) because it is a monomer (i.e., it does not undergo a significant conformational change with oxygenation). Thus, myoglobin remains fully saturated at O2 tensions between 15 and 30 mm Hg and unloads its O2 to the muscle mitochondria only at very low O2 tensions. Note that fetal hemoglobin also functions at a lower PO2 than adult hemoglobin (see Fig. 47-5). Minimum Hemoglobin Concentration. The American Society of Anesthesiologists (ASA) addressed optimal hemoglobin concentrations in its Practice Guidelines for Blood Component Therapy. The ASA task force reviewed the pertinent literature and made the following recommendations: Transfusion is rarely indicated when hemoglobin values are greater than 10 g/dL and is almost always indicated when values are less than 6 g/dL. Determining whether a transfusion is indicated when the hemoglobin is between 6 and 10 g/dL is based on the risk of tissue hypoxia in the individual patient, as judged by the patient’s physician. The organ at highest risk during anemia is normally the heart, because it has a baseline O2 extraction ratio greater than 50%. In a study evaluating outcomes for critically ill patients transfused to hemoglobins of 7 to 9 g/dL versus greater than 10 g/dL, patients had better outcomes when maintained at the lower range, unless they had clinically significant cardiac disease.

Oxygen tension (mm Hg) 100

0

20

40

60

80

100

80

100

Carboxyhemoglobin Myoglobin A

Percentage saturation

80

Normal adult hemoglobin

60

Fetal blood 40

B

20

0 20

40

60

Oxygen tension (mm Hg)

Figure 47–5 ■ Oxyhemoglobin dissociation curves for adult and fetal hemoglobin and carboxyhemoglobin and myoglobin. Note that fetal hemoglobin and myoglobin function at much lower oxygen tension (PO2) levels than adult hemoglobin, and carboxyhemoglobin has a very left-shifted curve. (From Lumb AB: Nunn’s Applied Respiratory Physiology, 5th ed. London, Butterworth-Heinemann, 2000, p 266.)

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CIRCULATORY HYPOXIA

HISTIOCYTIC HYPOXIA Histiocytic hypoxia occurs if the cell is unable to use delivered O2. Cyanide (CN –) toxicity is a classic example and may occur with the administration of large amounts of sodium nitroprusside. CN – binds to mitochondrial cytochrome oxidase, disrupting aerobic metabolism and resulting in anaerobic metabolism. Early signs of CN – toxicity are tachycardia, increased mixed venous O2 saturation, bright red venous blood, and lactic acidosis. All are due to the inability of tissue to utilize O2. Carbon monoxide (CO), in addition to binding to hemoglobin and shifting the oxyhemoglobin curve to the left, binds to cytochrome c and interferes with oxidative metabolism at the mitochondrial level. The high affinity of CO for hemoglobin (200 times that of O2) requires a high concentration of O2 (100% at 1 to 3 atmospheres) to effectively treat CO poisoning. The subsequent regeneration of functional cytochrome c by the displacement of CO with O2 may be the mechanism by which neuronal death is prevented.

Recognition CYANOSIS Before the widespread use of pulse oximetry, the early recognition of hypoxemia (PaO2 <60 mm Hg) was difficult. The presence of cyanotic mucosal membranes or dark blood in the operative field often provided the earliest warning, because the anesthetic agents in use before the availability of SpO2 measurement tended to attenuate the physiologic (tachycardia, hypertension, tachypnea) and mental status (restlessness, somnolence) changes caused by hypoxia.

Table 47–2

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Perioperative Hypoxia

197

Even so, cyanosis is an imprecise monitor of O2 status, because hemoglobin saturation must be below 85% before cyanosis is clinically apparent. Anemia makes detection even more difficult. More than 50 years ago, Comroe and Botehlo used ear oximetry to assess whether hypoxia was invariably associated with clinical cyanosis. Of 1723 SpO2 measurements with values between 71% and 80%, 12% were said to be associated with a normal skin color. It is possible that anemia skewed the results in some patients, because 5 g of reduced hemoglobin must be present to allow the detection of cyanosis. ARTERIAL BLOOD GAS ANALYSIS The gold standard for the diagnosis of hypoxemia is direct PaO2 measurement with a Clark electrode; however, this is invasive and is rarely a continuous parameter. PULSE OXIMETRY Pulse oximetry provides an early warning of hypoxemia (for SpO2 from 70% to 100%), provided that reduced or oxyhemoglobin is the only hemoglobin present. Carboxyhemoglobin and methemoglobin have similar absorption spectra to oxyhemoglobin and may provide misinformation; in fact, carboxyhemoglobin and oxyhemoglobin are indistinguishable. Pulse oximetry readings are falsely high in the presence of carboxyhemoglobin. As methemoglobin concentrations increase, pulse oximetry readings tend to approach 85%. Fluorescent lighting can also cause a falsely elevated SpO2. Blue nail polish, tape adhesive, methylene blue, indigo carmine, and isosulfan blue may cause falsely low SpO2 measurements. A co-oximeter measures the amounts of deoxyhemoglobin, oxyhemoglobin, carboxyhemoglobin, and methemoglobin in a blood sample. Such testing is indicated if SpO2 readings are dubious (e.g., intravenous dyes have been injected or infiltrated for surgical mapping) or CO poisoning is suspected. One major manufacturer has developed a pulse co-oximeter using eight light wavelengths and capable of measuring deoxyhemoglobin, oxyhemoglobin, carboxyhemoglobin, and methemoglobin. SPECIFIC ORGANS Methods used to assess the adequacy of O2 delivery to organs and tissues are summarized in Table 47-2.

Methods to Assess the Adequacy of Organ and Tissue Oxygen Delivery

Organ/Tissue

Method

Brain

Cerebral perfusion pressure (CPP = MAP – ICP), transcranial Doppler monitoring, electroencephalography, jugular venous O2 saturation, near-infrared spectroscopy, SSEPs/MEPs Electrocardiography, transesophageal echocardiography, coronary sinus O2 saturation, pulmonary artery catheter PaO2/FiO2 ratio, lung injury score, pulmonary arterial pressures, airway pressures (lung compliance and resistance), bronchoalveolar lavage Lactate production, hepatic enzymes, urine output and specific gravity, blood urea nitrogen and creatinine, gastric tonometry

Heart Lungs Liver, kidneys, gut

CPP, cerebral perfusion pressure; FiO2, fraction of inspired oxygen; ICP, intracranial pressure; MAP, mean arterial pressure; MEP, motor evoked potential; PaO2, arterial partial pressure of oxygen; SSEP, somatosensory evoked potential.

GENERAL ANESTHESIA

Circulatory hypoxia results from insufficient cardiac output. All conditions that reduce heart rate or stroke volume also reduce cardiac output. However, cardiac output must increase with increased tissue O2 utilization (O2 demand). Basal O2 delivery (DO2) is about 200 mL O2 per liter of cardiac output per minute (or 1000 mL O2 for a cardiac output of 5 L/minute). But what is critical for survival? One study in conscious, resting volunteers reported a rate of 7.5 mL/kg per minute (525 mL/minute for a 70-kg adult). A case report of a Jehovah’s Witness patient found critical DO2 to be 184 mL/minute per square meter.

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Measures to Reduce the Risk of Perioperative Hypoxia Based on Cause

Cause

Measure

Hypoxemia

Verify O2 supply (check anesthesia machine), confirm fail-safe function; use in-line O2 analyzer; preoxygenate; increase FiO2 Confirm breath sounds and end-tidal CO2; increase FiO2; assess lung compliance; use bronchodilators; maintain bronchopulmonary toilet Increase FiO2; restrict volatile agents (inhibit hypoxic pulmonary vasoconstriction) Use larger tidal volumes (10-15 mL/kg), intermittent sighs, frequent suctioning; add PEEP in high-risk patients (low FRC, obesity, hypoalbuminemia) Increase FiO2 Evaluate hematocrit frequently; give transfusions; increase FiO2 Increase cardiac output (volume, inotropes, circulatory assist device); relieve surgical compression or traction; increase FiO2 Limit SNP to ≤1 mg/kg over 1-3 hr and 0.5 mg/kg/hr over 24 hr, use another vasodilator†, or combine another vasodilator or SNP with a β-blocker to reduce the need for SNP; increase FiO2 (especially with CO poisoning)

Hypoventilation . . VA/Q mismatch Shunt Diffusion limitation* Anemia Circulatory failure O2 utilization

*Uncommon cause in healthy patients; may contribute to hypoxia after lung resection in patients with a reduced alveolar capillary bed (emphysema) and high cardiac output (sepsis). † Nicardipine IV may be preferred to SNP owing to the possibility of cyanide toxicity with large doses of the latter (see Chapters 1 and 77). CO, carbon. monoxide; CO2, carbon dioxide; FiO2, fraction of inspired oxygen; FRC, functional residual capacity; PEEP, positive end-expiratory pressure; SNP, sodium . nitroprusside; VA/Q , alveolar ventilation-perfusion.

Risk Assessment Inhalational anesthetics reduce the slope of the CO2-ventilation response curve in direct proportion to dose. Intravenous anesthetics (except ketamine) have the same effect. Inhalational anesthetics and propofol have also been shown to depress the ventilatory response to hypoxia, even at low doses. Functional residual capacity decreases upon the induction of anesthesia and does not return to normal until hours after anesthesia has been.terminated. This contributes to atelectasis . in alveoli with low VA/Q ratios. Volatile (but not intravenous) anesthetic agents oppose hypoxic pulmonary . vasoconstric. tion and increase the risk of hypoxia due to VA/Q mismatch. During recovery, elimination of nitrous oxide lowers PAO2 for several minutes. Anesthetics also reduce the tone in muscles involved in maintaining pharyngeal patency, increasing the risk of partial or complete airway obstruction. For these reasons, any patient having an anesthetic is at risk for hypoxia. Patients at increased risk for hypoxia include those with significant cardiopulmonary disease, morbid obesity, major trauma, thromboembolism, sepsis, head injury, pulmonary aspiration, and drug overdose. Risk also increases when diagnostic or therapeutic procedures are performed with the patient under intravenous sedation and inattentive, untrained, or preoccupied personnel are responsible for patient monitoring (e.g., interventional radiology or cardiology, magnetic resonance imaging). The risk for postoperative hypoxia is increased with long-acting anesthetic agents or neuromuscular blockers and with hypothermia or impaired drug metabolism and elimination.

Implications Severe hypoxia leads to ischemia or death. The central nervous system is most vulnerable to hypoxia (tolerating ≤5 minutes of normothermic ischemia). With hypoxia, anaerobic metabolism replaces aerobic metabolism, with a consequent fall in intracellular high-energy compounds and acidosis.

Insufficient high-energy compounds leads to the failure of intracellular pumps and the release of calcium from intracellular stores, damaging the intracellular elements. Acidosis and consequent anaerobic metabolism of glucose (causing lactic acidosis) produce further cell damage. As noted, the brain is most vulnerable, followed by the heart, the liver, and the kidneys.

MANAGEMENT ● ● ● ●

●

●

Identify and correct the primary cause. Supply supplemental oxygen; increase FiO2. Increase . O.2 delivery (transfusion, inotropes, or both). Treat VA/Q mismatch (positive end-expiratory pressure, sighs, inhaled nitric oxide, patient posturing). Protect vital organs (hypothermia, drugs, spinal drainage, steroids). Administer amyl nitrate, sodium nitrite, or thiosulfate for CN – toxicity.

PREVENTION Measures to reduce the risk of perioperative hypoxia from the causes discussed herein are listed in Table 47-3.

Further Reading Comroe JH, Botehlo S: The unreliability of cyanosis in the recognition of arterial hypoxemia. Am J Med Sci 214:1, 1947. Comroe JH, Forster RE, Dubois AB, et al: Diffusion. In The Lung: Clinical Physiology and Pulmonary Function Tests, 2nd ed. Chicago, Year Book Medical Publishers, 1962, pp 111-139. Hall AH: Systemic asphyxiants. In Irwin RS, Rippe JM (eds): Intensive Care Medicine, 5th ed. Philadelphia, JB Lippincott–Williams & Wilkins, 2003, pp 1608-1616. Herbert PC, Wells G, Blajchman MA, et al: A multicenter, randomized, controlled clinical trial of transfusion requirements in critical care. N Engl J Med 340:409-417, 1999.

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Moon RE, Camporesi EM: Respiratory monitoring. In Miller RD (ed): Anesthesia, 5th ed. Philadelphia, Churchill Livingstone, 2000, pp 1255-1295. Stehling LC, Doherty DO, Faust RJ, et al: Practice guidelines for blood component therapy. Anesthesiology 84:732-747, 1996. van Woerkens ECSM, Trouwborst A, van Lanshot JJB: Profound hemodilution: What is the critical hemodilution at which oxygen deliverydependent oxygen consumption starts in an anesthetized human? Anesth Analg 75:818-821, 1992. Wilson WC, Shapiro B: Perioperative hypoxia: The clinical spectrum and current oxygen monitoring methodology. Anesth Clin North Am 19:769-812, 2001.

GENERAL ANESTHESIA

Kelly SD, Lieberman J, Feiner JR, et al: Critical oxygen delivery in resting conscious humans is less than 7.5 mL O2 /kg/min [abstract]. Anesthesiology 87:58, 1997. Lumb AB: Anaesthesia. In Nunn’s Applied Respiratory Physiology, 5th ed. London, Butterworth Heinemann, 2000, pp 420-459. Lundsgaard C, Van Slyke DD: Cyanosis. Medicine 2:1, 1923. Martin RL, Lloyd HGE, Cowan AI: The early events of oxygen and glucose deprivation: Setting the scene for neuronal death? Trends Neurosci 17:251-256, 1994. Moon RE, Camporesi EM: Clinical care at altered environmental pressure. In Miller RD (ed): Anesthesia, 5th ed. Philadelphia, Churchill Livingstone, 2000, pp 2271-2301.

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48

Robert E. Kettler Case Synopsis A 45-year-old man presents for repair of an inguinal hernia. Other than a history of epilepsy, his past medical history is unremarkable. Except for the inguinal hernia, his physical examination is also unremarkable.

PROBLEM ANALYSIS Definition Epilepsy presents clinically as sudden, usually spontaneous episodes of involuntary motor activity with an altered level of consciousness. Epilepsy is a chronic condition. It has an annual incidence of 30 to 55 per 100,000 persons and affects about 2 million people in the United States. In addition, many patients with chronic pain syndromes are treated with anticonvulsants. Thus, anesthesiologists have a high probability of managing patients receiving these drugs. Epilepsy is classified according to seizure type, which also determines which drug will be used to manage the epileptic syndrome. Partial seizures originate in part of one cerebral hemisphere, whereas more generalized seizures originate throughout the hemispheres. Partial seizures are further classified as follows: ●

●

●

Simple partial seizures (i.e., with no impairment of level of consciousness) Complex partial seizures (i.e., with impairment of level of consciousness) Partial seizures that progress to generalized seizures

Generalized seizures are associated with an altered level of consciousness and are further classified as follows: ● ● ● ●

Absence seizures Myoclonic seizures Tonic-clonic seizures Atonic seizures

Complex partial seizures are the most common type of seizures in both adult and pediatric epileptic populations, constituting 23% and 39% of seizures in these groups, respectively. Generalized tonic-clonic seizures are second in frequency; this seizure type accounts for 25% of adults and 19% of children with epilepsy. The pathologic mechanism of epilepsy is unknown; however, several mechanisms have been proposed. It is thought that absence seizures may result from disruption of normal thalamocortical activity. As a result, cortical activity typical of non–rapid eye movement sleep occurs during periods of wakefulness. Such activity may be due to the abnormal function of T-type calcium channel or γ-aminobutyric acid (GABA) receptors. Other more generalized seizures may be 200

caused by an abnormality of the sodium channel, resulting in frequent depolarization. Additional evidence suggests that there is a reduction in potassium channel activity, which also increases the frequency of depolarization. Partial seizures may be due to structural alterations that result in hyperexcitability and altered GABA receptor functioning. The result of these neuronal changes is a pool of neurons that have the following characteristics: ● ● ● ●

Increased excitability Increased excitatory input Increased effectiveness of excitatory input Decreased inhibition

Primary physicians caring for patients with epilepsy must evaluate such patients with the goals of (1) determining that the patient does indeed have a seizure disorder, (2) the cause of the disorder, and (3) the type of seizure disorder. Goals of pharmacotherapy are reduction in seizure frequency, maximization of overall function, and minimal adverse effects. Typically, patients who present with one seizure but have no family history of epilepsy, no history of brain injury or mass lesion, and a normal electroencephalogram (EEG) are not treated. Such patients have only a 24% rate of seizure recurrence in the subsequent 2 years. However, patients who have a second seizure should be treated because the risk of recurrence then rises to 80%. Patients presenting with a new seizure, a history of brain injury or lesion, and an abnormal EEG have a 65% chance of recurrence in 2 years; therefore, these patients receive treatment. Most patients can be adequately managed with one drug. The principles that guide therapy are (1) the slow titration of medications to attain satisfactory seizure control, or (2) increased doses of medication until, in the absence of any appreciable effect on seizures, unacceptable side effects occur. If one medication fails, the physician should try a drug with a different mechanism of action rather than one with the same mechanism. If several trials of monotherapy are ineffective, polydrug therapy is a reasonable option. The risk of congenital anomalies is apparently increased in offspring of epileptic women, but extant studies contain a number of methodologic flaws. The presumption that antiepileptic drugs cause such anomalies is based on the observations that (1) a dose-response relationship seems to exist, and (2) multidrug therapy seems to increase the frequency of seizures owing to decreased serum levels of

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anticonvulsant drugs caused by the physiologic changes of pregnancy. Therefore, it is prudent to monitor serum drug concentrations in pregnant women. Also, pregnant women taking antiepileptic medications appear to be at 1.5- to 3-fold greater risk for hemorrhage, preterm labor, toxemia, placental abruption, and stillbirth than normal parturients.

No data exist regarding the incidence of epilepsy that first presents in the perioperative period. It is likely that the vast majority of patients with seizure disorders (aside from those associated with local anesthetic systemic toxicity; see Chapter 56) have been diagnosed and placed on antiseizure medications before they present for elective surgery. The history should suffice for recognizing the presence of epilepsy and assessing the patient’s compliance with the prescribed therapy. However, it is useful to query these patients about seizure frequency, known triggers, compliance with medications and dosing, and side effects of antiseizure medications.

Risk Assessment Patients with epilepsy have a mortality rate about 20 times that of the general population. Causes of death include accidents, arrhythmias, pulmonary edema, and myocardial infarction. Perioperative risk of morbidity and mortality has not been quantified with rigorous methodology. Likely, the most important consideration is to maintain the best possible control of seizure activity by maintaining appropriate antiepileptic therapy during the perioperative period. Antiepileptic medications typically have sedative effects, which could affect the speed of the patient’s recovery from general anesthesia, opiates, or sedative-hypnotics. Many of the anticonvulsants interfere with the hepatic metabolism of other drugs, and anesthesiologists must be aware of this issue. The drugs gabapentin, levetiracetam, tiagabine, and topiramate are less likely to affect hepatic metabolism. Finally, anesthesiologists may be called on to assist with the management of patients in status epilepticus (especially those with airway and cardiovascular issues). Patients in status epilepticus can have a very high mortality (10% to 30%) when not properly managed.

Implications Because of the prevalence of epilepsy and the increased use of anticonvulsants to manage various pain syndromes, anesthesiologists are likely to care for patients receiving anticonvulsants. Though unquantified, the risk of adverse outcomes in these patients is likely low. Awareness of the potential problems and use of the measures outlined in the next section are probably sufficient. There are no data to support the notion that one anesthetic technique is preferable to another.

MANAGEMENT AND PREVENTION Anesthesiologists should evaluate patients’ compliance with antiepileptic therapy and its effectiveness with a careful history.

Patients with Seizure Disorders

201

A patient’s report of the success of therapy is more meaningful than serum concentrations of the drugs used; the latter are used to evaluate compliance with therapy. Patients should take their usual medications with a sip of water before surgery and resume their regimens as soon as possible after surgery. If patients are unable to take oral medications, tablets can be crushed and given via a gastric tube. Consultation with a pharmacist may be necessary. If the enteric route is inappropriate, consider administering a parenteral form or substituting a comparable parenteral agent. Consultation with a neurologist may be needed. Because pain and sleep deprivation may provoke seizures, adequate pain management, combined with sedatives and anxiolytics, may be beneficial during the perioperative period. Anesthesiologists may be called on to assist with the management of status epilepticus. They have the necessary expertise in airway management, ventilation, intravascular line placement, cardiopulmonary monitoring, assessment and management of acid-base derangements, and use of neuromuscular blockade. It is important to keep in mind that untreated electrical brain activity can be associated with morbidity, even without seizure-related motor activity. When standard anticonvulsants fail to control status epilepticus, the anesthesiologist may have to administer general anesthesia with either midazolam or propofol. Effective general anesthesia for status epilepticus is induced with intravenous midazolam in a dose of 0.2 mg/kg and an intravenous maintenance dose of 0.75 to 10 μg/kg per minute. If propofol is used, it is induced with 1 to 2 mg/kg intravenously and maintained at 10 mg/kg per hour intravenously. The EEG is used to monitor the therapeutic effectiveness of either drug. If midazolam and propofol are ineffective, continuous intravenous thiopental or pentobarbital may be necessary. Patients under general anesthesia may require aggressive intravenous fluid therapy and hemodynamic support with dopamine or dobutamine to maintain adequate vital organ perfusion.

Further Reading Brodie MJ, Dichter MA: Antiepileptic drugs. N Engl J Med 334:168-175, 1996. Broune TR, Holmes GR: Epilepsy. N Engl J Med 344:1145-1151, 2001. Chang BS, Lowenstein DH: Epilepsy. N Engl J Med 349:1257-1266, 2003. Dichter MA, Brodie MJ: New antiepileptic drugs. N Engl J Med 334: 1583-1590, 1996. Lowenstein DH, Alldredge BK: Status epilepticus. N Engl J Med 338: 970-976, 1998. McNamara JC: Drugs effective in the therapy of the epilepsies. In Hardman JG, Limbird LE (eds): Goodman and Gilman’s The Pharmacological Basis of Therapeutics, 10th ed. New York, McGraw-Hill, 2001, pp 521-547. Pedley TA: The epilepsies. In Goldman L, Bennett JC (eds): Cecil Textbook of Medicine, 21st ed. Philadelphia, WB Saunders, 2000, pp 2151-2163. Rowbotham MC, Petersen KL: Anticonvulsants and local anesthetic drugs. In Loeser JD, Butler SH, Chapman CR, Turk DC (eds): Bonica’s Management of Pain, 3rd ed. Philadelphia, JB Lippincott–Williams & Wilkins, 2001, pp 1727-1735.

GENERAL ANESTHESIA

Recognition

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ANCILLARY TOPICS

Blood and Blood Products: Transfusion Reaction

49

Lester T. Proctor Case Synopsis A 40-year-old woman undergoing an abdominal hysterectomy receives a unit of blood for a hematocrit of 24. Shortly after the transfusion begins, the patient’s blood pressure decreases by 20 mm Hg. The urine is noted to be bloody.

PROBLEM ANALYSIS Definition Transfusion reactions are broadly defined as any unfavorable consequence of blood transfusion. This chapter addresses primarily transfusion reactions that are immune mediated (Table 49-1).

Recognition When the transfusion of blood or a blood product is associated with fever, chills, flank pain, hemodynamic instability, wheals, nausea, and symptoms of anaphylaxis, this suggests the occurrence of a transfusion reaction. Certain symptoms (fever, chills, dyspnea, urticaria) can be helpful in delineating the type of reaction involved (Table 49-2). The identification of a transfusion reaction may be more challenging in anesthetized patients, when the only obvious symptoms may be hypotension, hemoglobinuria, or a bleeding diathesis. The features of the major immune-mediated transfusion reactions are noted in Table 49-3 and discussed individually in the paragraphs that follow.

the fixing of complement to red cell membranes, resulting in hemolysis and the release of cellular debris, which may trigger the development of disseminated intravascular hemolysis. Immune complexes also induce the formation of cytokines, which results in hypotension, fever, and the mobilization and activation of leukocytes. The elaboration of sympathetic amines in response to hypotension contributes to renal failure by renal vasoconstriction. AHTRs usually involve antibodies to antigens from the ABO blood group. Because these antibodies are readily identifiable, most AHTRs are the result of clerical errors. Symptoms of an AHTR, especially those occurring while a patient is anesthetized, are limited to hemoglobinuria, hemodynamic instability, bleeding diathesis, and failure to achieve the expected rise in hematocrit. A positive direct antiglobulin (Coombs’) test confirms the diagnosis. In contrast, evidence of hemolysis (e.g., hemoglobinuria, high free serum hemoglobin, low serum haptoglobin) with a negative direct Coombs’ test suggests hemolysis from a nonimmune cause (Table 49-4). FEBRILE NONHEMOLYTIC TRANSFUSION REACTION Febrile nonhemolytic transfusion reactions (FNTRs) present as a temperature increase of at least 1°C associated with

ACUTE HEMOLYTIC TRANSFUSION REACTION Acute hemolytic transfusion reactions (AHTRs) result from the binding of donor red blood cell antigens with recipient antibodies to form immune complexes. Complexes trigger

Table 49–1

■

Immune-Mediated Transfusion Reactions

Acute Hemolytic Nonhemolytic Febrile Allergic: anaphylactoid (immediate generalized reaction) or anaphylactic Transfusion-related acute lung injury

Delayed Hemolytic

202

Table 49–2

■

Determination of Transfusion Reaction Type by Presenting Symptom

Fever or chills Hemolytic transfusion reaction: acute or delayed Bacterial contamination of blood product Febrile nonhemolytic reaction Hemolysis (may present as hemoglobinuria) Acute hemolytic transfusion reaction Bacterial contamination of blood product Dyspnea Anaphylactic reaction Transfusion-related acute lung injury Congestive heart failure or volume overload Urticaria Urticarial transfusion reaction Adapted from Welborn JL, Hersch J: Blood transfusion reactions: Which are lifethreatening and which are not? Postgrad Med 90:125-138, 1991.

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Table 49–3

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Blood and Blood Products: Transfusion Reaction

■

203

Nonimmune-Mediated Causes of Hemolysis Cause

Characteristics

Incidence per Unit

Mortality

Acute hemolytic transfusion reaction

Recipient Ab vs donor RBC Ag

1 in 25,000

10%

Febrile nonhemolytic transfusion reaction Allergic reaction

Recipient Ab vs donor granulocyte Ag Recipient Ab vs donor Ag

Hemolysis, hypotension, DIC, hypoperfusion, renal failure, fever Fever

1 in 200

None reported

Urticaria: 1 in 200 Anaphylaxis: 1 in 150,000

Rare

Transfusion-related acute lung injury

Donor Ab vs recipient leukocyte Ag

1 in 2400

5%

Delayed hemolytic transfusion reaction

Recipient Ab vs donor RBC Ag

1 in 2500

Rare

IGR: hives only Anaphylactic: potentially severe hypotension and bronchospasm Respiratory distress with noncardiogenic pulmonary edema Fever, jaundice, decreasing hemoglobin

Ab, antibody; Ag, antigen; DIC, disseminated intravascular coagulation; IGR, immediate generalized reaction; RBC, red blood cell.

a transfusion and without any other explanation. FNTRs are usually caused by binding of the recipient’s antibodies to antigens on donor granulocytes, lymphocytes, or platelets. An FNTR often presents with chills and rigor and is a diagnosis of exclusion once AHTR and bacterial contamination of transfused blood are ruled out. ALLERGIC REACTION Allergic reactions are either immunoglobulin E (IgE) mediated (anaphylactic) or not IgE mediated (anaphylactoid or immediate generalized reaction; see Chapter 27). Immediate generalized reactions are typically mild, involving reactions to transfused serum proteins, medications taken by

Table 49–4

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Nonimmune-Mediated Causes of Hemolysis

Mechanical trauma to red blood cells Thermal injury Overheating (>40°C) Freezing or partial freezing Osmotic injury Sterile water for bladder irrigation during cystoscopy Reconstitution of red blood cells with nonisotonic solutions Shearing injury High-pressure infusion or small catheter size Mechanical valves, vascular grafts, hematomas Extracorporeal circulation Bacterial contamination (gram-negative bacteremia) Drug-induced hemolysis: penicillin, quinidine, methyldopa Disease-mediated hemolysis Hemolytic anemias: glucose-6-phosphate dehydrogenase deficiency, autoimmune anemias Paroxysmal nocturnal hemoglobinuria; hemolytic uremic syndrome Thrombotic thrombocytopenic purpura; malaria; mononucleosis Sepsis with disseminated intravascular coagulation Modified from Cooper CL: Complications of transfusion therapy. In Lake CL, Moore RA (eds): Blood: Hemostasis, Transfusion, and Alternatives in the Perioperative Period. New York, Raven Press, 1995, p 320.

the donor (e.g., penicillin), or additives from blood product preparation. Diagnosis is based on the presence of only mild allergic symptoms that respond to an antihistamine. Anaphylactic reactions are typically more severe in presentation and usually manifest within minutes after the transfusion begins. Symptoms include shock, respiratory distress, dermatologic findings, and generalized enteritis, usually in the absence of fever. Although most such reactions commence immediately after the transfusion begins, the presentation may be delayed for up to an hour after the transfusion has been completed. Anaphylactic reactions are most commonly mounted by patients who lack immunoglobulin A (IgA) but have an anti-IgA antibody. IgA deficiency occurs in 1 in 700 patients in the general population, although only 20% of IgA-deficient patients develop antibodies to IgA. Of these, only 20% have clinically significant reactions. The diagnosis is usually based on the striking presentation and confirmed by finding anti-IgA antibody in the patient’s serum. TRANSFUSION-RELATED ACUTE LUNG INJURY Transfusion-related acute lung injury (TRALI) presents as a syndrome of respiratory distress, fever, hypoxia, hypotension, and noncardiogenic pulmonary edema that occurs 1 to 6 hours after the transfusion of plasma containing blood products. The proposed mechanism involves the reaction between the donor’s antibodies and the recipient’s leukocytes. Cytokines present in the donated unit may also augment this response. An aggressive search for cardiogenic or other noncardiogenic sources of pulmonary edema must be undertaken, because TRALI is relatively rare. The diagnosis may be confirmed by identifying an antileukocyte antibody in the donor blood unit that corresponds to the patient’s human leukocyte antigen type. DELAYED HEMOLYTIC TRANSFUSION REACTION Delayed hemolytic transfusion reactions (DHTRs) present with red blood cell hemolysis from 2 days to several months after a transfusion. Symptoms and signs include fever,

GENERAL ANESTHESIA

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mild jaundice, and an inexplicable decline in hemoglobin concentration. Other serious symptoms, more typical of an AHTR (e.g., renal failure, hemoglobinuria), are uncommon. DHTRs commonly result in postoperative jaundice and may significantly lower the patient’s hemoglobin level. The cause of DHTRs is the delayed generation of an antibody to a donor antigen to which the recipient has been previously exposed. The culprit antibody binds a non-ABO group such as the Rh, Kidd, Kell, or Duffy groups. The diagnosis of a DHTR may be difficult. A direct antiglobulin test is not positive until several days after the transfusion and then remains positive only while there are active symptoms.

Risk Assessment The risk of developing a transfusion reaction varies, depending on the type of reaction. An AHTR typically results from an antibody against an antigen of the ABO blood group. Because antibodies to the ABO group are readily identifiable, an AHTR is usually the result of a clerical error, typically involving the administration of a unit of blood to a patient without confirming the patient’s identification. Careful attention to paperwork, especially during multiple-unit transfusions, should reduce the incidence of AHTRs. FNTRs occur more frequently in multiparous women and in patients who have received multiple transfusions, because antibody production is induced by prior exposure to foreign antigens. It has been estimated that up to 55% of women develop leukoagglutinins after three pregnancies. Allergic reactions can occur in any patient, although certain groups of patients are at higher risk than others. The most severe reactions are noted in IgA-deficient patients. Most of these persons are genetically deficient in IgA, although some with common variable immune deficiency who receive multiple gamma globulin injections may also develop antiIgA antibodies. Less severe reactions are typical of non-IgAdeficient patients. Renal dialysis patients are particularly prone to allergic reactions because they may develop a sensitivity to sterilizers or plasticizers found in dialysis equipment and react to these substances in transfusion equipment. Atopic patients are more sensitive to vasoactive substances released during reactions, and they manifest more clinically significant reactions than do nonatopic individuals. TRALI does not appear to be any more common in one patient population than another. Screening of donor serum is discussed under the section on prevention. DHTRs occur almost exclusively in patients who have undergone multiple transfusions in the past or in multiparous women. In most cases, these individuals have become sensitized to non-ABO blood groups that are undetectable in the serum until after the patient has been re-exposed to the antigen via transfusion.

20 deaths per year due to AHTRs in the United States. TRALI is a rare complication but results in an estimated 5% mortality. FNTRs and allergic reactions rarely result in death.

MANAGEMENT Management of transfusion reactions varies with the type of reaction involved. Often the clinician must base therapy on only one or two symptoms. The management of any reaction begins by stopping the transfusion while maintaining intravenous access. Next, the type of reaction must be identified. This section outlines an appropriate diagnostic plan based on the presenting symptom. Once the type of transfusion reaction has been identified, more specific therapy can be applied. Therapies for immune-mediated transfusion reactions are given in Table 49-5.

Fever and Chills Fever and chills, the most common presenting symptoms of a transfusion reaction, are usually due to an FNTR, AHTR, or sepsis from bacterial contamination. The primary goal is to rule out an AHTR by (1) confirming that the patient is receiving the intended unit of blood and (2) drawing a sample of the patient’s blood for a free hemoglobin and direct antiglobulin (Coombs’) test. Ruling out septic contamination requires (1) examination of the unit for discoloration or gas and (2) stain and culture for bacteria in the transfused blood and the patient’s blood. In the absence of positive results, the diagnosis of exclusion is FNTR. The occurrence of hemoglobinuria, hypotension, or bleeding diathesis should prompt a second look for AHTR or septic contamination, because these findings are not characteristic of FNTR.

Hemoglobinuria Hemoglobinuria may be the sole indicator of a transfusion reaction, and its presence should prompt a search for evidence of hemolysis, which may be caused by an AHTR, bacterial contamination, or a nonimmune-mediated source (see Table 49-4). Hemolysis in the absence of other symptoms is characteristic of a nonimmune-mediated hemolytic cause.

Dyspnea Dyspnea may be caused by an anaphylactic reaction, cardiogenic pulmonary edema from fluid overload, or (more rarely) TRALI. The management of dyspnea relies less on making the diagnosis than on supportive care for the patient’s condition, which may require mechanical ventilation. Invasive monitoring or transesophageal echocardiography to determine whether the cause of the pulmonary edema is cardiogenic or noncardiogenic is often helpful.

Implications The risk of death associated with the major immunemediated transfusion reactions is given in Table 49-3. The majority of transfusion-related deaths are related to AHTRs. It is estimated that 1 out of 33,000 transfused units of blood are incompatible. This estimate predicts a mortality of

Urticaria Urticaria in the absence of other symptoms is characteristic of an immediate generalized reaction, although the patient should be reevaluated periodically for progression to a fullblown anaphylactic reaction.

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Table 49–5

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Blood and Blood Products: Transfusion Reaction

205

Treatment of Immune-Mediated Transfusion Reactions Treatment

Acute hemolytic transfusion reaction (AHTR) with positive direct antiglobulin test

1. 2. 3. 4. 5. 1. 2.

Febrile reaction secondary to bacterial contamination Febrile nonhemolytic transfusion reaction

1. 2. 3. 4.

Allergic: urticarial reaction

1. 2. 3. 4. 1. 2. 3. 4. 1. 2.

Allergic: anaphylaxis

Transfusion-related acute lung injury

Delayed hemolytic transfusion reaction

3. 1. 2. 3.

Stop the transfusion Maintain systolic blood pressure >100 mm Hg Maintain urine output (diuretics; fluids ≥100 mL/hr) Support blood pressure with pressors as needed Maintain vigilance for DIC and treat as needed Treat as for AHTR (above) After Gram stain and cultures, cover with broad-spectrum antibiotic for gram-positive and -negative organisms Stop the transfusion Rule out AHTR and bacterial contamination Administer an antipyretic Consider a leukocyte filter (blood products) or antipyretics before the next transfusion Stop the transfusion Administer diphenhydramine 20-50 mg IV Restart blood slowly after 30 min Consider giving an antihistamine before the next transfusion Stop the transfusion Administer epinephrine 400 μg SC Support ventilation; use bronchodilators or intubation if needed Support circulation; administer vasopressors if needed Stop the transfusion Rule out cardiogenic pulmonary edema and other sources of noncardiogenic pulmonary edema Support ventilation as needed Usually, no acute treatment required Maintain urine output with evidence of renal failure Maintain hemoglobin level with additional transfusions after identifying responsible antibody

DIC, disseminated intravascular coagulation. Data from Jenner PW, Holland PV: Diagnosis and management of transfusion reactions. In Petz LD, Swisher SN, Kleinman S, et al (eds): Clinical Practice of Transfusion Medicine. New York, Churchill Livingstone, 1996, p 908; and Welborn JL, Hersch J: Blood transfusion reactions: Which are life-threatening and which are not? Postgrad Med 90:125-138, 1991.

PREVENTION ●

Vigilance and a high index of suspicion lead to early recognition of transfusion reactions and may limit their severity. In addition, specific measures can be taken to reduce the risk of certain immune-mediated transfusion reactions: ●

●

●

●

●

AHTRs are usually the result of misidentification of the patient or the unit of blood. Because one third of all transfusion reactions occur in the operating room, the anesthesiologist should carefully match the patient with the blood unit to limit the risk of AHTR. FNTRs may be limited by the use of leukocyte filters to reduce the number of leukocytes in transfused blood. Prophylactic antipyretics may help limit the symptoms. Antihistamines can be used before transfusion to pretreat patients with a history of mild allergic reactions. The use of washed blood products is generally reserved for patients who do not benefit from antihistamines. Patients with known IgA deficiency should receive blood products from IgA-deficient donors. In an emergency situation, washing of red blood cells or platelets should limit the risk of a fatal reaction. TRALI can be prevented if the antibody responsible for the antileukocyte reaction can be determined. If so, the

administration of blood products containing this antibody can be avoided. DHTRs usually cannot be prevented before the first episode, because the antibody responsible for the reaction is present in undetectable titers. Once a DHTR has occurred, however, and the culprit antibody has been identified, blood with the corresponding antigen should be avoided.

Further Reading Brand A: Immunological aspects of blood transfusions. Transpl Immunol 10:183-190, 2002. Cooper CL: Complications of transfusion therapy. In Lake CL, Moore RA (eds): Blood: Hemostasis, Transfusion, and Alternatives in the Perioperative Period. New York, Raven Press, 1995, pp 319-334. Gilstad CW: Anaphylactic transfusion reactions. Curr Opin Hematol 10:419-423, 2003. Heddle NM: Universal leukoreduction and acute transfusion reactions: Putting the puzzle together. Transfusion 44:1-4, 2004. Janatpour K, Holland PV: Noninfectious serious hazards of transfusion. Curr Hematol Rpt 1:149-155, 2002. Jenner PW, Holland PV: Diagnosis and management of transfusion reactions. In Petz LD, Swisher SN, Kleinman S, et al (eds): Clinical Practice of Transfusion Medicine. New York, Churchill Livingstone, 1996, pp 905-929. Lozano M, Cid J: The clinical implications of platelet transfusions associated with ABO or Rh(D) incompatibility. Transfus Med Rev 17:57-68, 2003.

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Reaction Type

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Noninfectious Complications of Blood Transfusion. In Technical Manual of the American Association of Blood Banks. Bethesda, Md., American Association of Blood Banks, 543-562, 1996. Sharma AD, Grocott HP: Platelet transfusion reactions: febrile nonhemolytic reaction or bacterial contamination? Diagnosis, detection, and current preventive modalities. J Cardiothorac Vasc Anes 14:460-466, 2000.

Telen MJ: Principles and problems of transfusion in sickle cell disease. Sem Hematol 38:315-323, 2001. Welborn JL, Hersch J: Blood transfusion reactions: Which are life-threatening and which are not? Postgrad Med 90:125-138, 1991.

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Blood and Blood Products: Hepatitis and HIV

50

Jonathan M. Anagnostou GENERAL ANESTHESIA

Case Synopsis An otherwise healthy 40-year-old woman experiences 2000 mL blood loss while undergoing abdominal hysterectomy. She receives 2 units of packed red blood cells during the course of her resuscitation. Following surgery, the patient’s husband is very upset that his wife “probably caught something from the blood she received.”

PROBLEM ANALYSIS Definition Blood-borne infections are a concern of patients, family members, and health care providers alike. Individuals may be exposed to these infections through the transfusion of banked blood products or through blood-contaminated injuries (e.g., needle sticks). Although blood products (especially platelets) can transmit bacterial infections, viral infections are more common. Despite the modern screening of blood products, hepatitis C is a major cause of post-transfusion hepatitis, although hepatitis B remains a clinical concern. Hepatitis D is a blood-borne viral infection that affects only patients infected with hepatitis B, because it requires the hepatitis B virus for replication. Although the parenteral spread of hepatitis A has been reported, it is normally spread through the oral-fecal route. Human immunodeficiency virus (HIV) has become an increasing concern since its recognition in the early 1980s.

of suspicion and the development of viral symptoms weeks to months after exposure. Initial HIV infection is often asymptomatic, although roughly half of infected patients develop a viral syndrome (e.g., fever, pharyngitis, myalgia, lymphadenopathy) within 6 weeks of exposure. Similarly, initial infection with hepatitis B or C may be asymptomatic or may involve a flulike syndrome weeks or even months after exposure. Clinical jaundice develops in less than one third of patients. A chronic infection may result in 10% of those infected with hepatitis B and in up to 80% to 90% of patients with hepatitis C. The development of symptoms consistent with hepatitis (e.g., malaise, jaundice) several weeks after exposure to blood should prompt referral for appropriate hematologic studies, such as hepatic enzyme levels and antigen-antibody testing. Antibody testing for hepatitis B has been available for many years, and similar testing for hepatitis C is now available. Serologic evidence of anti-HIV antibodies by enzyme-linked immunosorbent assay (ELISA) testing confirms HIV infection.

Risk Assessment Recognition Given the emotional impact associated with the risk of bloodborne infections, this issue must be put in its proper perspective during the patient’s preoperative visit. In the case of any procedure that might involve significant blood loss, a discussion of the potential risks of transfusion should take place. Many hospitals include a separate consent form for blood products in their admission paperwork. Blood-contaminated injuries to health care providers are another important issue. Each health care facility should have defined infection-control procedures to deal with such events. Although painful needle-stick or scalpel injuries are obvious, practitioners should also recognize that blood seepage under torn or defective gloves onto a preexisting hand wound also constitutes a blood-contaminated injury. Clearly, risks from patient blood contact are significant. In the United States, approximately 0.2% to 0.4% of the population are carriers of the hepatitis B virus, and 0.5% carry hepatitis C. The incidence of HIV infection varies widely from near zero in some areas to well over 5% in certain urban populations. Following transfusion or other blood exposure, the diagnosis of hepatitis or HIV infection depends on an index

The risk of transfusion-related infection is estimated as follows (per unit of blood): ● ●

Hepatitis: 1 in 180,000 to 220,000 HIV: 1 in 900,000 to 1.4 million

The risk of needle-stick infection is estimated as follows (per incident): ● ●

HIV-positive: 1 in 250 to 300 Hepatitis C-positive: 1 in 20

Improved blood screening has reduced but not eliminated the risk of transfusion-associated infections. False-negative test results can occur, and in the case of antibody testing (e.g., for HIV), there is an interval between infection with the virus and the appearance of detectable antibodies in blood. It was estimated in 1996 that the risk of transfusionrelated hepatitis in the United States was approximately 0.3 per 10,000 units transfused, and the risk of HIV infection from a single transfused blood unit was roughly 1 in 493,000 transfusions. Blood-contaminated injuries are a significant occupational hazard for health care workers. The risk of infection 207

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via a hepatitis C–contaminated needle stick is estimated to be 0.5%, and that for anti-HIV antibody seroconversion after an HIV-contaminated needle stick is approximately 0.004%. The risk of infection may be greater under certain circumstances (e.g., hollow-core needles, large virus inoculum).

Implications Infections from blood-borne viruses can be benign or lethal, and the emotional impact of blood transfusion can represent a distinct psychological complication. The manifestations of hepatitis range from an asymptomatic infection to fulminant hepatic dysfunction and death. Chronic infection with hepatitis B or C can result in cirrhosis, hepatic failure, or hepatocellular carcinoma. Although HIV infection commonly leads to acquired immunodeficiency syndrome (AIDS), many otherwise healthy individuals remain asymptomatic for years after documented HIV seroconversion.

MANAGEMENT Management of transfusion-related hepatitis or AIDS is clearly beyond the typical anesthesia provider’s scope of practice. Recognition and appropriate referral are of the utmost importance, although transmission of these illnesses is only retrospectively linked with a patient’s history of blood product transfusion or a provider’s history of occupational exposure.

PREVENTION Avoiding contact with blood and blood products is the obvious key to prevention. Blood or banked blood products should not be administered as generic volume expanders but should be given only for specific indications, such as to increase oxygen carrying capacity or increase clotting factor levels. The predonation of autologous blood, the use of isovolumic hemodilution, or both may be useful in avoiding exposure to homologous blood products. For practitioners, strict

Table 50–1

■

adherence to universal precautions (Table 50-1) should minimize the risk of contact with potentially infectious blood and body fluids. Needle-stick injuries can be minimized by careful operating technique and by the use of alternative equipment when possible (e.g., needleless intravenous injection systems, “blunt” suture needles). Vaccination is an important preventive measure for many infectious diseases. Although no vaccines are currently available for HIV or hepatitis C, hepatitis B vaccination is strongly advised for high-risk health care providers, including anesthesia personnel. For those who have received the vaccination, no set schedule for booster doses has been established. With the recent recommendation of the U.S. Public Health Service for childhood hepatitis B vaccination, the overall incidence of hepatitis in the United States (including hepatitis D) should continue to decline. When a blood-contaminated injury occurs, the affected area should be washed immediately with soap and water. Involved mucous membranes are flushed with water or an appropriate salt solution. Injuries contaminated with blood should be reported to the institution’s infection-control office for documentation, counseling, and management. There is no accepted postexposure prophylaxis available for hepatitis C, but if the source patient is infected with hepatitis B and the provider has not been immunized, passive immunization with hepatitis immune globulin (0.06 mL/kg intramuscularly), followed by hepatitis B vaccination, is advised. If the source patient is HIV infected, the initiation of postexposure chemoprophylaxis within 24 to 36 hours may be appropriate to reduce the risk of HIV infection. Although data regarding efficacy are limited, chemoprophylaxis after percutaneous exposure normally includes the use of two or even three antiretroviral drugs (e.g., zidovudine, lamivudine, stavudine, didanosine). In practice, the timely institution of chemoprophylaxis may be complicated if the source patient’s HIV status is unknown and by the legal difficulties involved in obtaining informed consent for HIV testing. The National HIV/AIDS Clinician’s Consultation Center offers a 24-hour postexposure prophylaxis hotline (1-888-HIV-4911). The Centers for Disease Control and Prevention has current information on its Web site (http://www.cdc.gov/niosh/topics/bbp).

Highlights of Universal Precautions

Barrier precautions with all patients to prevent blood and body fluid contact Gloves when contacting blood or body fluids or nonintact skin (do not wash or disinfect gloves, because disinfectants can cause deterioration) Gown, mask, eyewear if splash or spray is likely Avoid sharps injuries Prompt disposal in appropriate container Avoid recapping needles Hand washing after glove removal or any blood or body fluid contact Artificial mouthpieces and airways for cardiopulmonary resuscitation Providers with exudative or weeping cutaneous lesions should refrain from direct patient contact until condition resolves From Centers for Disease Control and Prevention: Recommendations for prevention of HIV transmission in the health-care setting. MMWR Morb Mortal Wkly Rep 36:3-18, 1987; updated MMWR Morb Mortal Wkly Rep 37:377-388, 1988.

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209

Perillo RG, Regenstein FG: Viral and immune hepatitis. In Kelly WN (ed): Textbook of Internal Medicine. Philadelphia, Lippincott-Raven, 1997, pp 822-833. Petrovitch CT: Hemostasis and hemotherapy. In Barash PG, Cullen BF, Stoelting RK (eds): Clinical Anesthesia, 3rd ed. Philadelphia, Lippincott-Raven, 1997, pp 189-217. Rehm SJ: Approach to the patient with human immunodeficiency virus exposure. In Kelly WN (ed): Textbook of Internal Medicine. Philadelphia, Lippincott-Raven, 1997, pp 1867-1868. Schreiber GB, Busch MP, Kleinman SH, et al: The risk of transfusiontransmitted viral infections. N Engl J Med 334:1685-1690, 1996.

GENERAL ANESTHESIA

Centers for Disease Control and Prevention: Updated US Public Health Service guidelines for the management of occupational exposures to HBV, HCV, and HIV and recommendations for postexposure prophylaxis. MMWR Morb Mortal Wkly Rep 50:1-54, 2001. Goodnough LT: Risks of blood transfusion. Crit Care Med 31:S678-S686, 2003. Murray DJ: Blood component therapy: Indications and risks. In Rogers MC, Tinker JH, Covino BG, et al (eds): Principles and Practice of Anesthesiology. St. Louis, Mosby–Year Book, 1993, pp 2482-2498. Ockner RK: Acute viral hepatitis. In Wyngaarden JB, Smith LH Jr, Bennett JC (eds): Cecil Textbook of Medicine. Philadelphia, WB Saunders, 1992, pp 763-771.

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Nosocomial Infections: Bacterial Pneumonia

51

Charles E. Edmiston, Jr. Case Synopsis A 78-year-old man is diagnosed with pneumonia 4 days after exploratory abdominal laparotomy. While the patient was mechanically ventilated, a fever and purulent tracheal secretions developed. Radiographic evidence was consistent with pneumonia involving both lower lobes.

PROBLEM ANALYSIS Definition Nosocomial, or hospital-acquired, pneumonia is defined as pneumonia occurring more than 48 hours after hospital admission. However, this definition excludes any infection that is incubating at the time of hospital admission. Pneumonia is the second most common nosocomial infection. The proportion of patients who acquire pneumonia in the intensive care unit (ICU) ranges from 10% to 65%. This is associated with significant morbidity and mortality. Data from the National Nosocomial Infection Surveillance program indicate that 75% of all cases of nosocomial bacterial pneumonia occur postoperatively. Patients having a thoracoabdominal procedure have a 38-fold higher risk than other patients do. Those with mechanically assisted ventilation constitute the population at highest risk for the development of nosocomial pneumonia. Ventilator-associated pneumonia occurs in 8% to 28% of mechanically ventilated patients. Rates of ventilator-associated pneumonia are dependent on the duration of mechanical ventilation; the incremental risk is 1% to 3% per day (5% at 5 days, and >68% for patients ventilated for ≥30 days). Along with causing significant morbidity and mortality, ventilator-associated pneumonia is an important determinant of excessive hospital length of stay and inpatient resource utilization. The most probable cause of nosocomial pneumonia is colonization of the aerodigestive tract by pathogenic microorganisms. Subsequently, these contaminated secretions are aspirated into the lower airways. Aerobic microorganisms are the predominant isolates recovered, including gram-negative bacilli such as Escherichia coli, Klebsiella species, Enterobacter species, and Pseudomonas aeruginosa. Staphylococcus aureus and Streptococcus pneumoniae are other important isolates and may express drug resistance (e.g., methicillin-resistant S. aureus [MRSA], penicillinresistant pneumococci). Late-onset infections (occurring >72 hours after admission) are most often associated with multidrug-resistant microorganisms such as Acinetobacter, Pseudomonas, and MRSA. Yeasts such as Candida albicans or other Candida species are an infrequent cause of nosocomial pneumonia (<4%). 210

Pneumonia-associated morbidity prolongs hospitalizations by 4 to 9 days and is associated with significant institutional costs. Death from nosocomial pneumonia accounts for 60% of all nosocomial-associated fatalities.

Recognition Nosocomial bacterial pneumonia is extremely difficult to diagnose, especially in intubated ICU patients with mechanically assisted ventilation. Generally accepted criteria include the following: fever, cough with productive or purulent sputum, and radiographic evidence of a pulmonary infiltrate. The diagnosis of pneumonia in these patients is especially difficult because traditional culture methods may be highly nonspecific or have low sensitivity. Endotracheal aspiration is the most common sampling technique used in mechanically ventilated patients. The accuracy of the method, however, is compromised by contamination with upper respiratory flora. A consensus recommendation proposed a standardized method for diagnosing pneumonia in this patient population. It is based on direct—rather than clinical—evidence and includes one of the following: ●

● ●

Bronchoscopically acquired protective specimen brush (PSB) with quantitative culture Bronchoalveolar lavage (BAL) Protected BAL

The sensitivity of these procedures is reported to vary from 70% to 100%, and their specificity varies from 60% to 100%. PSB is widely accepted as the reference method for pneumonia diagnosis in ventilator patients. False-positive findings have been reported, however, and may be related to prior antibiotic therapy.

Risk Assessment Tracheal intubation and mechanical ventilation alter the patient’s first-line barrier defenses and greatly enhance the risk of nosocomial pneumonia. This risk is 6 to 21 times greater than that for patients who do not receive ventilator support. In addition to a thoracoabdominal procedure or intubation, other risk factors include the following: ● ●

Mean age older than 70 years Reintubation or self-extubation

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● ● ● ● ● ●

●

In addition, manipulation of the ventilator circuit or endotracheal tube increases the potential for cross-contamination. Recent studies have shown that interdisciplinary educational initiatives coupled with appropriate infection-control practices can reduce the risk of cross-contamination.

Implications The high morbidity and mortality associated with pneumonia in ventilator-dependent patients encourage a more aggressive approach to diagnosis and treatment. Yet invasive bronchoscopic techniques (e.g., PSB, protected BAL) may be associated with complications, including hypoxemia, bleeding, or arrhythmia.

MANAGEMENT Once the diagnosis of nosocomial pneumonia has been made, the choice of therapeutic agent is based on which organisms are associated with hospital-acquired pneumonia in the specific ICU environment, as well as the sensitivity and resistance patterns of those organisms. Recent studies suggest that selecting an inappropriate antibiotic for the treatment of nosocomial pneumonia is an independent risk factor for mortality, especially with highly resistant gram-negative bacilli (e.g., Pseudomonas, Acinetobacter, MRSA). In addition, if the patient received prior antibiotic therapy, it is likely that an extended-spectrum agent will be needed. Selected empirical antimicrobial agents for the treatment of nosocomial pneumonia include the following: ●

●

Early-onset infections: third- or fourth-generation cephalosporin (ceftriaxone, ceftizoxime, cefepime), βlactam inhibitor combination (ampicillin-sulbactam or piperacillin-tazobactam), new extended-spectrum fluoroquinolone (moxifloxacin), or aztreonam plus clindamycin Late-onset infections: aminoglycoside or fluoroquinolone (ciprofloxacin) plus one of the following: imipenem, antipseudomonal broad-spectrum β-lactam, or aztreonam

A glycopeptide (vancomycin) or oxazolidinone (linezolid) should be added for the treatment of MRSA infection. Recent studies suggest that linezolid for documented MRSA nosocomial pneumonia reduces patient mortality compared with traditional glycopeptide therapy. Resistant gram-negative pathogens such as Enterobacter species have been successfully treated with either imipenem or ciprofloxacin. If P. aeruginosa is recovered or suspected, ceftazidime or ciprofloxacin is included. If anaerobic species involvement is suspected, especially in an aspirationprone patient, the addition of clindamycin is appropriate.

Nosocomial Infections: Bacterial Pneumonia

211

However, the emerging resistance among some anaerobic gram-negative bacteria suggests that a β-lactam inhibitor combination or fourth-generation fluoroquinolone (e.g., moxifloxacin) should be considered. The rate of MRSA infections in the ICU population continues to increase, and resistance among gram-negative microbial pathogens (e.g., Klebsiella, E. coli) to extendedspectrum third-generation cephalosporins is being reported with greater frequency. Therefore, prior knowledge of existing patterns of gram-positive and gram-negative resistance within the ICU is crucial for the development of an appropriate therapeutic strategy for nosocomial pneumonia. Once microbiologic results are available, broad-spectrum antimicrobial therapy should be de-escalated to a specific antimicrobial agent in an effort to minimize the emergence of resistance.

PREVENTION Prevention of nosocomial pneumonia is complex and requires attention to patient-, device-, and personnel-related factors. The use of antimicrobial prophylaxis to prevent nosocomial pneumonia is highly questionable and may lead to superinfection. An attempt should be made to prevent microbial colonization of the oropharynx, trachea, and stomach by gramnegative pathogens. For instance, the use of sucralfate rather than antacids or H2-blockers to prevent stress bleeding in critically ill, postoperative, or mechanically ventilated patients may prevent gastric bacterial overgrowth by preserving gastric acidity. Other interventions aimed at reducing the risk of postoperative pneumonia include earlier ambulation, deepbreathing exercises, chest physiotherapy, use of incentive spirometry, intermittent positive-pressure breathing, and continuous positive airway pressure by facemask. Simply placing a patient in a semirecumbent position may reduce the aspiration of oropharyngeal secretions with potential nosocomial pathogens. Studies have shown that the longer a patient remains supine, the greater the volume of secretions aspirated. Control of pain in the immediate postoperative period with intravenous or regional analgesia has also been shown to be beneficial in decreasing the incidence of pulmonary complications after surgery. Bacteria rapidly adhere to biomaterial surfaces. Over time, they can produce a biofilm that is effective at protecting them from antibiotic and host defense mechanisms. These organisms can be dislodged by mechanical ventilatory flow, tube manipulations, or suctioning. Therefore, gentle suctioning and barrier precautions by the caregiver can decrease the incidence of cross-contamination to patients from either contaminated respiratory therapy devices or the hands of health care professionals. Appropriate hand hygiene should be emphasized among health care workers. For intubated patients, chlorhexidine-based oral hygiene can reduce the risk of endotracheal tube colonization. It is difficult to prevent the pooling of secretions around the endotracheal cuff, but this situation can provide bacteria with direct access to the lower respiratory tract. The internal machinery of mechanical ventilators is rarely associated with bacterial contamination of inhaled gases.

GENERAL ANESTHESIA

●

Depressed level of consciousness (e.g., closed head trauma) Underlying chronic lung disease Supine head position Conditions favoring aspiration or reflux 24-hour ventilator circuit changes Stress-bleeding prophylaxis with cimetidine (with or without antacid) Antimicrobial administration Exposure to contaminated respiratory equipment

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However, bacterial contamination from the patient’s oropharynx or condensate in the inspiratory-limb tubing of the ventilator circuit may occur rapidly after the initiation of mechanical ventilation (33% at 2 hours, and 80% after 24 hours). Tracheobronchial tree spillage may occur when the endotracheal tube is manipulated. Therefore, less frequent ventilator circuit tube changing (every 24 to 48 hours versus 6 to 8 hours) has been suggested as a way to reduce such contamination.

Further Reading American Thoracic Society: Hospital-acquired pneumonia in adults: Diagnosis, assessment of severity, initial antimicrobial therapy, and preventive strategies: A consensus statement, American Thoracic Society, November 1995. Am J Respir Crit Care 153:1711-1725, 1996. Babcock HM, Zack JE, Garrison T, et al: An educational intervention to reduce ventilator-associated pneumonia in an integrated health system. Chest 125:224-231, 2004.

Croce MA, Fabian TC, Stewart RM, et al: Empiric monotherapy versus combination therapy of nosocomial pneumonia in trauma patients. J Trauma 35:303-309, 1993. Eggimann P, Hugonnet S, Sax H, et al: Ventilator-associated pneumonia: Caveats for benchmarking. Intensive Care Med 29:2086-2089, 2003. Guidelines for prevention of nosocomial pneumonia. MMWR Morb Mortal Wkly Rep RR-I:1-79, 1997. Hoffken G, Niedermann MS: Nosocomial pneumonia: The importance of a de-escalating strategy for antibiotic treatment of pneumonia in the ICU. Chest 122:2183-2196, 2002. Leroy O, Soubrier S: Hospital-acquired pneumonia: Risk factors, clinical features, management and antibiotic resistance. Curr Opin Pulm Med 10:171-175, 2004. Pringleton SK, Fagon J-Y, Leeper KV: Patient selection for the clinical investigation of ventilator-associated pneumonia: Criteria for evaluating diagnostic technique. Chest 102(Suppl 5):553S-556S, 1992. Pugin J, Auckenthaler R, Lew DP, et al: Oropharyngeal decontamination decreases incidence of ventilator-associated pneumonia. JAMA 265:2704-2710, 2001. Sanford JP, Gilbert DN, Sande M: The Sanford Guide to Antimicrobial Therapy, 25th ed. Dallas, Antimicrobial Therapy Inc, 1996, pp 26-28.

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52

Postobstruction Pulmonary Edema Kenneth W. Travis and John L. Atlee

GENERAL ANESTHESIA

Case Synopsis Progressive Respiratory Distress After 3 days of malaise and fever, a 5-year-old, 16-kg girl develops a barking cough, stridor, and progressive respiratory distress. Her respiratory rate is 32 breaths per minute. Lung auscultation reveals reduced breath sounds and coarse rales. Her room air oxygen (O2) saturation is 82%, and the chest radiograph shows bilateral infiltrates. Postextubation Stridor A 22-year-old, 90-kg triathlete has marked inspiratory stridor lasting about 1 minute after tracheal extubation in the operating room, after an otherwise uneventful general anesthetic for septorhinoplasty. Within 15 minutes, he has tachycardia and tachypnea, with forced exhalations. His O2 saturation is 88% while breathing O2 via facemask at 6 L/minute.

PROBLEM ANALYSIS Definition Acute pulmonary edema that develops during or shortly after relief of severe upper airway obstruction is called postobstruction or negative-pressure pulmonary edema. The precipitating event is the generation of extreme negative intrapleural pressure, which increases the pulmonary transvascular hydrostatic pressure gradient (Table 52-1). In addition, associated hypoxia, catecholamine excess, exaggerated hemodynamic changes, and increased pulmonary vascular permeability disrupt the dynamic fluid equilibrium in the lung (Figs. 52-1 and 52-2). The accelerated movement of fluid from the pulmonary vasculature to the interstitium eventually exceeds the clearing capacity of the pulmonary lymphatic system, and the alveolar epithelial barrier becomes compromised; alveolar flooding is the end result. Owing to the rapidity and the severe pathophysiology associated with postobstruction pulmonary edema (POPE), prompt recognition and management of the condition are mandatory.

Recognition PRESENTATION POPE is suspected in the following situations: ●

●

●

A child (see also Chapter 157) or adult has hypoxemia, prolonged expiration, wheezing, and rales, with or without signs of bilateral pulmonary infiltrates. Pink, frothy tracheal secretions accumulate suddenly after tracheal intubation for acute or chronic upper airway obstruction. Oxygenation deteriorates after resolution of acute laryngospsam or removal of a foreign body (see Table 52-1).

Usually, POPE develops immediately or within minutes after intubation or extubation of the trachea. Sometimes, however, symptoms and signs of POPE do not appear for several hours, prompting some physicians to advise up to 18 hours of close surveillance for patients who have had significant perioperative or out-of-hospital obstructive events. NOTABLE FINDINGS In the most severe cases, the voluminous pulmonary edema fluid is pink and frothy and high in protein content. The chest radiograph frequently reveals bilateral, perihilar, patchy infiltrates and edema around the major pulmonary arteries. These arteries are believed to have endothelial damage as a result of high intravascular volumes and pressures. TIME COURSE In general, the more rapid the onset of the obstruction, the more severe the associated acute pulmonary edema. It has been postulated that patients with fixed upper airway obstruction, in whom the negative inspiratory forces are largely compensated for by forced expiration (Valsalva’s maneuver) or the development of air trapping (which causes increased positive end-expiratory pressure—auto-PEEP), are more likely to develop pulmonary edema following relief of the obstruction. Patients with variable upper airway obstruction that is more severe during inspiration are more prone to develop pulmonary edema during the obstruction. DIFFERENTIAL DIAGNOSIS With prompt treatment, POPE usually resolves within 12 to 24 hours, but recovery may take as long as 96 hours. Many mild cases probably go undetected. Common differential diagnoses include aspiration pneumonitis and other causes of increased capillary permeability edema (e.g., fat or amniotic 213

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Mechanisms, Recognition, and Management of Postobstruction Pulmonary Edema

Mechanism

Recognition

Management

Severe upper airway obstruction: Airway-related causes: Ensure and maintain patent airway: Partial or complete laryngospasm Inspiratory stridor Insert naso- or oropharyngeal airway Upper airway tumor or foreign body Wheezing Insert laryngeal mask airway Relaxed tongue or other Barking cough Suction or remove upper airway secretions, blood, oropharyngeal soft tissue structure Emesis (aspiration pneumonitis) vomit, particulate matter, foreign body Hypertrophy of tonsils or adenoids Perform endotracheal intubation or reintubation Croup or epiglottitis Perform cricothyrotomy or tracheostomy Extremely negative intrapleural Pulmonary edema with airway Respiratory management: pressures: obstruction: Ensure adequate oxygenation and ventilation Increased pulmonary transvascular Variable obstruction (most severe Increase FiO2 hydrostatic pressure gradient with inspiration) Facial, endotracheal or tracheal CPAP Hypoxia, hypercarbia, acidosis: Hypoxia, rales, prolonged expiration, Mechanical ventilation with pressure support or PEEP associated vasoconstriction of wheezing the pulmonary bed leads to Chest radiograph—perihilar, myocardial depression and fluffy (patchy) infiltrates increased capillary permeability Hyperadrenergic state: peripheral arterial or venous constriction leads to increased preload or afterload, “forward heart failure,” increased capillary permeability Associated hemodynamic changes: Pulmonary edema after relief of Additional measures: Marked increase in venous return upper airway obstruction: IV sedation and muscle relaxants to RV Fixed obstruction compensated Diuretics; vasoactive medications Ventricular interdependence by Valsalva’s maneuver or Invasive cardiovascular monitoring Reduced LV compliance auto-PEEP Specific therapy directed at cause Increased RV and LV Florid, pink, frothy, proteinaceous Indicated therapy for complications preload and afterload (“cotton candy”) airway fluids Admission to an appropriate facility for postevent Reduced LV stroke volume Onset can be immediate, within observation and treatment Increased pulmonary vascular minutes after relief of obstruction, volume and pressure or delayed (hours) Increased alveolar interstitial fluid Progressive respiratory distress Chest radiograph—often shows bilateral infiltrates Other pathophysiologic mechanisms: Common differential diagnoses: Pulmonary lymphatic system Aspiration pneumonitis overwhelmed Iatrogenic fluid overload Alveolar epithelial barrier breached Cardiogenic fulminant heart failure Alveolar flooding CPAP, continuous positive airway pressure; FiO2, fraction of inspired oxygen; LV, left ventricle; PEEP, positive end-expiratory pressure; RV, right ventricle.

Figure 52–1 ■ The Starling equation describes fluid flux in pulmonary capillaries: Q = K [(Pmv – Ppmv) – ∑(πmv – πpmv)], where K is the hydraulic conductance, Pmv is the hydrostatic pressure in the microvasculature, Ppmv is the hydrostatic pressure in perivascular tissue (interstitium), ∑ is the reflection coefficient for albumin, πmv is the osmotic pressure within the microvasculature, and πpmv is the osmotic pressure in the perimicrovascular tissue. Extremely negative intrapleural pressure increases the pulmonary transvascular hydrostatic gradient. (Modified from Nunn JF: Nunn’s Applied Respiratory Physiology, 4th ed. Oxford, Butterworth-Heinemann, 1993, p 487.)

P = Hydrostatic pressure (kPa or cm H2O) – relative to atmosphere π = Protein osmotic pressure (kPa or cm H2O) Lumen of alveolus P = zero

Route for alveolar flooding Lymphatic π = 1.5 (15) P= –0.7 (–7)

P= –0.6 (–6)

Interstitium P = – 0.4 (–4) π = 1.5 (15) P = 1.7 (17)

Arterial end

P = 1.2 (12) π = 3 (30) Microcirculation

Venous end

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Right Heart

II) Hyperadrenergic response leads to central redistribution of blood volume due to • Anxiety • Hypoxia • Hypercarbia • Cerebral ischemia

Postobstruction Pulmonary Edema

Lungs

Left Heart

I) Factors promoting pulmonary edema 1) Negative interstitial pressure 2) Increased pulmonary blood volume 3) HPV and hyperadrenergic environment 4) Increased pulmonary venous pressure (LV dysfunction) 5) Increased pulmonary capillary permeability

I) LV dysfunction leading to decreased LVSV 1) ↑Afterload 2) Acidosis 3) Hypoxemia

II) Factors opposing pulmonary edema 1) Auto-PEEP 2) Lymphatics 3) Valsalva maneuver 4) Fixed vs. variable extrathoracic airway obstruction

215

II) Elevated left-sided pressures secondary to decreased compliance 1) Ventricular interdependence 2) Hypoxia 3) Acidosis

BLOOD FLOW OUT

BLOOD FLOW IN

Figure 52–2 ■ Hypoxia causes pulmonary vasoconstriction, increased capillary permeability, and myocardial depression. The hyperadrenergic state, which results from hypoxia, anxiety, hypercarbia, acidosis, and cerebral ischemia, favors a central redistribution of blood volume. This, combined with the markedly negative intrapleural pressure during inspiration, dramatically increases venous return to the right ventricle (RV) and afterload stress to both the RV and the left ventricle (LV). Increased right ventricular volumes and pressures also cause a leftward shift of the interventricular septum. This reduces left ventricular compliance (ventricular interdependence) and raises end-diastolic and pulmonary microvascular pressures. Hypoxia, hypercarbia, and acidosis contribute to left ventricular dysfunction. Reduced left ventricular stroke volume causes a further rise in pulmonary blood volume and vascular pressure, which mechanically increases the transudation of fluid into the alveolar interstitium. When the rate of interstitial fluid flux exceeds the capacity of lymphatic clearance mechanisms, discontinuities appear in the alveolar epithelial cells, accompanied by crescentic alveolar fluid filling, flooding, and atelectasis. (Modified from Lang SA, Duncan PG, Shephard DAE, et al: Pulmonary oedema associated with airway obstruction. Can J Anaesth 37:213, 1990.)

fluid embolism, sepsis, cardiogenic causes, iatrogenic fluid overload). Acute pulmonary edema has also been reported in patients with head injury, heroin or other narcotic overdose, overly abrupt reversal of intraoperative narcotics (e.g., using 400 μg of naloxone as opposed to 20- to 40-μg increments), venous air embolism, pulmonary embolectomy, and high-altitude exposure. Usually, careful review of the patient’s past medical history and temporal events points to a cause. However, if it is still unclear, echocardiography, invasive hemodynamic monitoring, or both may be needed to rule out other causes. Patients with POPE have shown normal hemodynamic measurements after relief of upper airway obstruction. Other causes of extremely negative pulmonary interstitial pressures and pulmonary edema are rapid expansion of a collapsed lung and overly aggressive pleural suctioning during chest tube thoracentesis.

Risk Assessment Anyone strong enough to generate significant sustained negative intrapleural pressure against a closed glottis (Müller’s maneuver) or severely restricted upper airway is at risk for the development of POPE. This condition more commonly occurs in younger, healthy patients. Although the exact incidence is unknown, it is estimated that 11% to 12% of adult or pediatric patients who require urgent tracheal intubation or tracheostomy due to upper airway obstruction of various causes have associated POPE. Laryngospasm during emergence from general anesthesia accounts for 50% of reported cases in adults. In children younger than 10 years old,

croup and epiglottitis are associated with more than half the reported cases of POPE.

Implications In most instances, establishment of a patent airway improves the clinical condition of patients with significant upper airway obstruction. The dramatic appearance of pulmonary edema before, during, or after the relief of upper airway obstruction in a previously healthy individual is, to say the least, disconcerting. Further, without prompt recognition and treatment, it can lead to severe morbidity. However, it is important to remember that when POPE occurs in such patients and is appropriately managed, it is usually self-limited. If so, staff, family, and friends can be reassured that there is likely to be a favorable outcome and that the problem is unlikely to recur.

MANAGEMENT After recognition, management includes maintenance of a patent airway and the provision of adequate arterial oxygenation. Supplemental O2 is required, with or without continuous positive airway pressure (CPAP) or mechanical ventilation with PEEP (see Table 52-1). Tracheal intubation or reintubation is necessary to sustain the airway in 85% of adults and children. Slightly more than 50% of adults and just under 50% of children require mechanical ventilation. It therefore seems prudent, after ensuring upper airway patency, to first administer 100% O2 and CPAP in some

GENERAL ANESTHESIA

I) Negative intrapleural pressure → ↑ venous return

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form (e.g., spontaneous breathing with CPAP, tracheal intubation and CPAP, mechanical ventilation with pressure support and PEEP) while assessing the severity of the POPE and ruling out other causes of acute pulmonary edema. Along with appropriate sedation, treatment includes titrating the fraction of inspired O2 (FiO2) into the range of 0.4 as the alveolar-arterial O2 difference improves and the patient no longer demonstrates respiratory distress. The ventilatory and airway pressure supports can then be reduced. If fluid overload or coexisting cardiogenic dysfunction compounds the problem, diuretics or vasoactive agents may be indicated. Often, however, no additional medication is needed. Patients with a mild case may require only supplemental O2. The decision of where to manage patients with POPE depends on local capabilities and the availability of experienced caregivers. The most severely affected patients and those in whom the diagnosis is less certain benefit from admission to a designated critical care facility. Well-staffed freestanding ambulatory surgery centers might retain less severe cases of POPE in the postanesthesia care unit, but others might choose to transfer patients to an affiliated institution with critical care facilities. Office-based practitioners are best advised to transfer such patients to an acute care facility.

PREVENTION Vaccination against invasive Haemophilus influenzae type B has effectively reduced the number of cases of severe epiglottitis and, by inference, the number of cases of severe POPE from that cause in children. Other measures to protect against POPE include the following: ●

Use of bite blocks to prevent patients from biting and obstructing the endotracheal tube while attempting to inhale at the same time

●

●

Avoidance of factors that cause laryngospsam: (1) repeated failed attempts at endotracheal intubation (“Woody Woodpecker” syndrome), (2) inadequate anesthetic depth or skeletal muscle relaxation for tracheal intubation, and (3) excessive oropharyngeal secretions Careful timing of tracheal extubation after general anesthesia to avoid stimulation during the excitement phase

The immediate, judicious use of CPAP after tracheal intubation or extubation in patients at high risk for POPE might mitigate the severity of the syndrome and minimize the need for reintubation and mechanical ventilation.

Further Reading Benumof JL: Anesthesia for Thoracic Surgery, 2nd ed. Philadelphia, WB Saunders, 1995, pp 43-56. Capatanio MK, Kirkpatrick JA: Obstruction of the upper airway in children as reflected by the chest radiograph. Pediatr Radiol 107:159-161, 1973. Lang SA, Duncan PG, Shephard DAE, et al.: Pulmonary oedema associated with airway obstruction. Can J Anaesth 37:210-218, 1990. Meissner HH, Robinson L, Dubinett SM, et al: Pulmonary edema as a result of chronic upper airway obstruction. Respir Med 92:1174-1176, 1998. Nunn JF: Nunn’s Applied Respiratory Physiology, 4th ed. Oxford, Butterworth-Heinemann, 1993, pp 484-493. Oswalt CE, Gates GA, Holmstrom FMG: Pulmonary edema as a complication of upper airway obstruction. JAMA 238:1833-1835, 1977. Ringold S, Klein EJ, Del Beccaro MA: Postobstructive pulmonary edema in children. Pediatr Emerg Care 20:391-395, 2004. Staub NA: Pathophysiology of pulmonary edema. In Staub NA, Taylor AE (eds): Edema. New York, Raven Press, 1984, pp 719-741. Travis KW, Todres ID, Shannon DC: Pulmonary edema associated with croup and epiglottitis. Pediatrics 59:695-698, 1977. Van Kooy MA, Gargiulo RF. Postobstructive pulmonary edema. Am Fam Physician 62:401-404, 2000. Wilson WC, Benumof JL: Respiratory physiology and respiratory function during anesthesia. In Miller RD (ed): Miller’s Anesthesia, 6th ed. Philadelphia, Churchill Livingstone, 2005, pp 679-722.

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53

Latex Reactions in Health Care Personnel Kevin J. Kelly and Robert E. Kettler

GENERAL ANESTHESIA

Case Synopsis A 44-year-old anesthesiologist notes a rash on his right middle finger that has recently progressed to urticaria. He has been in good general health all his life; however, he is allergic to fish and ragweed pollen, and he was treated for eczema as a child. The rash has been intermittently present for several years and is exacerbated by wearing gloves to perform medical procedures. In the past 2 weeks, he has experienced chest tightness and rhinoconjunctivitis on entering the operating room. His only medication is an antihistamine taken during autumn for hay fever.

PROBLEM ANALYSIS Definition Natural rubber latex allergy (see also Chapter 161) is an issue of clinical importance for health care workers in terms of both patient management and occupational health. Use of rubber gloves dates to the late 1800s, when Halsted apparently produced them to protect the hands of his scrub nurse from the disinfectant solution she used to wash her hands. Skin lesions on the hands caused by the wearing of rubber gloves were first described in the medical literature in the 1930s. The increasing prevalence of latex-induced reactions is due to a confluence in the late 1980s of a number of factors: the increasing prevalence of hepatitis and acquired immunodeficiency syndrome (AIDS) led to the need for universal precautions; this led to increased demand for and use of barrier devices, including gloves made from natural rubber latex. The rubber industry responded to meet this demand, but final product quality may have been compromised by new entrants into the field, new geographic locations for rubber production, political turmoil in rubber-producing countries, and changes in the manufacturing process to increase output while complying with environmental and occupational health concerns. This increase in demand was associated with a greater number of medical gloves imported into the United States. As the use of latex gloves increased, allergic reactions in patients and health care providers were reported, leading to greater awareness of the problem, which in turn led to efforts to recognize and report it. This growing medical awareness was reflected by an increase in MEDLINE citations of journal articles published with latex as a key word, as shown in Table 53-1. There was an increase in both the absolute number of these citations and the number of these citations relative to the entire database. By mid-2004, the number of latex citations had increased to 0.1% of the MEDLINE database. Natural latex contains several polypeptides that bind immunoglobulin E (IgE) and that may be altered during

denaturation, polymerization, or breakdown during the manufacturing process. Most latex gloves have a cornstarch powder to facilitate donning. This powder binds various latex antigens and can be dispersed in the atmosphere, readily facilitating exposure through the respiratory system.

Recognition Three types of untoward latex reactions are recognized (Table 53-2): irritant dermatitis, type I IgE-mediated reactions, and type IV delayed contact hypersensitivity reactions. IRRITANT DERMATITIS Irritant reactions occur because the glove creates a local environment that can cause physical or chemical irritation to the skin. Risk factors for irritant reactions include increased age, cold weather, and excessive sweating. The skin breaks down over several days, and erythema and fissures are noted on inspection of the affected area. These reactions are not immunologically mediated. However, by disrupting the cutaneous barrier to allergens, they may be risk factors for the development of immunologically mediated reactions.

Table 53–1

Year 1966-1974 1975-1979 1980-1984 1985-1989 1990-1993 1994-1997 1966-1997

■

Latex Citations in MEDLINE Database Number (%) of Latex Citations 445 241 286 348 472 679 2471

(0.02) (0.02) (0.02) (0.02) (0.03) (0.07) (0.03)

Total Literature Citations (Millions)* 2.0 1.3 1.4 1.7 1.5 1.0 8.8

*All entries are rounded to nearest 100,000. In August 2004 the MEDLINE database contained 14 million citations, of which 14,372 (10%) were about latex.

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Manifestations of Irritant, Immediate, and Delayed Reactions to Latex

Reaction Type

Time of Onset

Clinical Signs

Immune Mechanism

Irritant dermatitis

Often gradual (days)

None

IgE-mediated reaction (type I)

Within minutes; rarely >2 hr

Erythema; scalded or parched appearance; chapped, cracked, fissured, or scaling skin; possibly vesicles or blisters Swelling, pruritus, urticaria, rhinoconjunctivitis, asthma, hypotension, anaphylaxis

Delayed contact hypersensitivity reaction (type IV)

6-48 hr after contact

Acute: erythema, pruritus, vesicles, blisters, cracking, crusting, desquamation Chronic: dryness, scaling, fissures, thickening or darkening of skin

IgE release of mast cell mediators; antigens are natural latex proteins Delayed or cell-mediated immunity; T-cell response to small rubber chemicals acting as haptens

From Ownby DR: Manifestations of latex allergy. Immunol Allergy Clin North Am 15:34, 1995.

TYPE I IGE-MEDIATED REACTION Type I reactions are mediated by IgE and usually occur within minutes of contact with latex proteins. The allergen binds to IgE, resulting in the release of vasoactive substances from mast cells (i.e., histamine, bradykinin, leukotrienes, prostanoids). There are several potential manifestations of IgE-mediated reactions, including urticaria, pruritus, bronchospasm, rhinoconjunctivitis, flushing, hypotension, angioedema, and anaphylaxis. TYPE IV DELAYED HYPERSENSITIVITY REACTION Type IV reactions to latex gloves are cell-mediated reactions to chemicals retained in the glove. The symptoms are apparent within several days and include erythema, pruritus, vesicles, fissuring, scaling, and thickening. The rash usually extends beyond the site of contact. Natural rubber latex is usually not the cause of type IV reactions; additives from the manufacturing process, such as thiuram and mercaptobenzathiazole, are more likely causes.

Risk Assessment There are few studies on the natural history and clinical course of natural rubber latex reactions; in addition, owing

Table 53–3

■

to differences in their methodology, there is variation in the reported prevalence. Even so, the prevalence of latex allergy in the general population has been consistently reported as less than 1%. Although a study of blood donors revealed detectable antibody in 6.5% of subjects, this does not indicate the presence of clinical allergy. The pediatric spina bifida population has been estimated to have a prevalence of 28% to 67%. The prevalence of latex allergy in health care workers is 5% to 17%, but its prevalence in health care workers with a history of atopy is 24% to 36%. Latex reaction risk factors include a history of environmental allergy, food allergy (especially to banana, kiwi, or avocado), hay fever, eczema, asthma, and chronic latex exposure (either occupational or as a result of repeated therapeutic procedures, with both frequency and exposure intensity being factors). The skin is relatively impermeable to latex proteins. However, disruption of the skin by irritant or contact reactions may predispose subjects to the development of IgE-mediated disease and subsequent systemic reactions. Cornstarch powder lubricant, which binds latex protein, and any activity that disperses these particles in the atmosphere can increase the quantity of respiratory exposure. If a patient’s history indicates a risk of latex allergy, a serum level of IgE reactive to latex allergens or skin testing from an allergist may be obtained. Further workup can be performed as outlined in Table 53-3.

Manifestations of Irritant, Immediate, and Delayed Reactions to Latex

Negative

Positive

Patient at Risk of Latex Allergy* No symptoms; no latex allergy; no testing needed

Symptomatic; possible latex allergy; perform diagnostic tests

Serum Test Negative; do further testing

Positive; no further testing needed (latex allergy confirmed)

Latex Use Test Negative; do further testing

Positive; no further testing needed (latex allergy confirmed)

Skin Test Negative; no latex allergy

Positive; no further testing needed (latex allergy confirmed)

*Some investigators have advocated latex testing in all patients with spina bifida. This approach would identify asymptomatic patients who have positive serum test results. Until further studies are performed, this patient group should be considered to be allergic to latex. From Kelly KJ, Kurup VP, Reijula KE, et al: The diagnosis of natural rubber latex allergy. J Allergy Clin Immunol 93:814, 1994.

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Implications

MANAGEMENT The mainstays of management are as follows: ● ● ●

Avoidance of allergens Topical therapy Systemic therapy (see Chapter 27)

Antigen avoidance can be difficult because of the ubiquitous presence of natural rubber products, especially in the health care environment. However, steps can be taken, such as wearing nonlatex gloves or using some type of barrier between the latex gloves and the skin (e.g., vinyl gloves). Using gloves only when necessary can also reduce exposure. Individuals who suffer severe reactions and cannot avoid allergens may have to change their specialty or profession. Airborne exposure can be eliminated or reduced to levels that are clinically insignificant by the exclusive use of powder-free, low-allergen latex gloves or synthetic gloves. Topical therapy with steroids and moisturizers can relieve the symptoms of irritant and type IV reactions. Therapy for systemic IgEmediated reactions includes airway management, ventilatory and circulatory support if necessary (including the use of epinephrine), antihistamines, and bronchodilators.

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PREVENTION Susceptible individuals should be advised to avoid latex products, but as already noted, this can be difficult. They should wear allergy-alert identification and carry an autoinjectable device for the emergency administration of epinephrine. Institutions should consider managing prevention through a multidisciplinary committee that develops guidelines for patients, health care workers, and other employees. This committee should provide guidelines for the identification of latex-containing medical products, the identification and purchase of latex-free substitutes, the establishment of latex-free treatment areas for susceptible individuals, and the use of powder-free gloves.

Further Reading Garabrant DH, Schweitzer S: Epidemiology of latex sensitization and allergies in health care workers. J Allergy Clin Immunol 110:S82-S95, 2002. Kelly KJ: Management of the latex-allergic patient. Immunol Allergy Clin North Am 15:139-157, 1995. Kelly KJ, Kurup VP, Reijula KE, et al: The diagnosis of natural rubber latex allergy. J Allergy Clin Immunol 93:813-816, 1994. Landwehr LP, Boguniewicz M: Current perspectives on latex allergy. J Pediatr 128:305-312, 1996. Ownby DR: Manifestations of latex allergy. Immunol Allergy Clin North Am 15:31-43, 1995. Ranta PM, Owenby DR: A review of natural-rubber latex allergy in health care workers. Clin Infect Dis 38:252-256, 2004. Sussman GL, Beezhold DH: Allergy to latex rubber. Ann Intern Med 122: 43-46, 1995. Truscott W: The industry perspective on latex. Immunol Allergy Clin North Am 15:89-121, 1995.

GENERAL ANESTHESIA

The severity of a latex reaction can range from a minor annoyance to life-threatening anaphylaxis and can include disabling symptoms (e.g., asthma). In addition to these medical complications, there are social implications, such as the need to change responsibilities or careers and the cost of disability payments. Institutions and individuals may have to change aspects of their medical practice to reduce the risk of latex reactions in others.

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Spinal Anesthesia: Post–Dural Puncture Headache

54

Matthew P. Feuer and Spencer S. Liu REGIONAL ANESTHESIA & PAIN MANAGEMENT

Case Synopsis A 25-year-old woman undergoes spinal anesthesia with a 25-gauge Quincke needle for outpatient knee arthroscopy. The following day, she complains of a severe frontaloccipital headache in the upright position that resolves when she is supine.

PROBLEM ANALYSIS Definition

●

●

Presence of less common associated symptoms: shoulder pain, cranial nerve dysfunction, auditory complaints Spontaneous resolution between 1 and 6 weeks after dural puncture

Post–dural puncture headache (PDPH) is a well-known complication of spinal anesthesia. It commonly occurs 24 to 48 hr after dural puncture (in 92% of affected patients), but the presentation can be delayed for as long as 5 days. Current evidence from laboratory and clinical imaging studies strongly supports the theory that loss of cerebrospinal fluid (CSF) from the puncture site is the key initiating factor (Fig. 54-1). Reduction in CSF fluid and pressure allows sagging of the brain and supporting structures when the patient assumes the upright position. Sagging of the brain places direct traction on pain-sensitive structures and can also cause painful reflex vasodilatation of cerebral blood vessels. This theory is also supported by PDPH’s pathognomonic feature of occurrence or exacerbation in the upright position and resolution in the supine position. Typically, 70% of PDPHs resolve spontaneously by 1 week after dural puncture, and 95% resolve by 6 weeks.

Recognition PDPH should be considered a diagnosis of exclusion. Medical conditions that have been misdiagnosed as PDPH include hypothalamic tumors, eclampsia, spinal meningitis, and superior sagittal sinus thrombosis. Clinical features of PDPH include the following: ● ●

●

● ●

History of dural puncture Delayed presentation of headache (usually 24 to 48 hours after dural puncture) Positional nature of headache (exacerbated when upright and resolved when supine) Headache that is typically frontal or occipital in nature Presence of common associated symptoms: neck ache (57%), backache (35%), nausea (22%)

Figure 54–1 ■ Lumbar spine magnetic resonance image in a patient with post–dural puncture headache before the administration of an epidural blood patch. The static collection of fluid at L2-L3 (arrows) corresponds to leakage of cerebrospinal fluid from the dural puncture site. (From Vakharia SB, et al: Magnetic resonance imaging of cerebrospinal fluid leak and tamponade effect of blood patch in postdural puncture headache. Anesth Analg 84:585, 1997.)

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Risk Assessment With current anesthetic practice, the incidence of PDPH typically ranges from 1% to 7% after spinal anesthesia. Both patient characteristics and anesthetic technique have been implicated as risk factors for the subsequent development of PDPH. Patient factors that increase the risk include the following: ●

● ●

Younger age, probably owing to changes in the elastic properties of the dura with aging Female gender Previous history of PDPH

Anesthetic factors that reduce the risk of PDPH are the following: ●

●

●

Smaller-diameter spinal needles, probably owing to smaller dural punctures (Figs. 54-2 and 54-3) Use of pencil-point rather than cutting-tip spinal needles— the former result in less CSF leakage in vitro (see Figs. 54-2 and 54-3) Orientation of the bevel of cutting-tip needles parallel to the long axis of the dura, which may produce a smaller rent in the dura because of the longitudinal splitting of fibers, as opposed to direct transection (cutting)

Figure 54–2 ■ From the left: Atraucan, Quincke, Gertie Marx, Sprotte, and Whitacre needles. Note the cutting points on the Atraucan and Quincke needles. Also, note the differences in the configuration of the lateral eyes of the pencil-point needles. The eye of the Gertie Marx needle is the smallest and situated closest to the needle tip. The left horizontal markings are in 2-mm increments. (From Vallejo MC, et al: Postdural puncture headache: A randomized comparison of five spinal needles in obstetric patients. Anesth Analg 91:916, 2000.)

MANAGEMENT Implications PDPH can result in significant discomfort and limitation of activity owing to its positional nature. Approximately 60% of affected patients can be treated with mild analgesics until spontaneous resolution occurs. Of these patients, approximately 18% will have slight restriction of physical activity, 31% will be partially bedridden with restricted physical activity, and 51% will be entirely bedridden.

Both systemic and invasive therapies have been advocated for the treatment of PDPH. It is reasonable to try systemic treatments before instituting more invasive therapies (Fig. 54-4).

Systemic Therapy Because the proposed pathophysiology of PDPH includes reflex vasodilatation of cerebral blood vessels, systemic

mL/5 hr 140

120 116 100

80

60 54.6 40 40.3 31.2 25.5

20

22.5 17.2

16.2

11.8

9.4

27 W

26 A

0 22 Q

25 Q

24 S

27 Q

25 W

25 S

26 W

29 Q

Needle type

Figure 54–3 Relationship between needle size and bevel type and leakage of cerebrospinal fluid after dural puncture in a laboratory model. (From Holst D, et al: In vitro investigation of cerebrospinal fluid leakage after dural puncture with various spinal needles. Anesth Analg 87:1331, 1998.) ■

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Signs and symptoms of PDPH

12–24 hr PO fluids Mild analgesics Caffeine 300 mg PO Caffeine 500 mg IV 12–24 hr

Figure 54–4 headache.

■

12–24 hr

Epidural blood patch 20 mL blood

Suggested treatment algorithm for post–dural puncture

therapies generally focus on the administration of vasoconstrictive agents or adrenocorticotropic hormone (ACTH). Caffeine. The intravenous administration of caffeine (500 mg) has been observed to decrease cerebral blood flow by 22% in patients suffering from PDPH. Success rates with intravenous caffeine therapy range from 40% to 80%, with mild side effects (dizziness, flushing). Oral caffeine can also be an effective therapy, with an approximately 50% success rate after 300 mg of oral caffeine.

Spinal Anesthesia: Post–Dural Puncture Headache

225

after “bloody” dural punctures. Epidural blood patch (EBP) is currently the gold standard for PDPH treatment, with a success rate ranging from 90% to 99%. Its mechanisms of action are thought to involve increased intracranial CSF pressure due to mass effect and sealing of the dural puncture site with fibrin clot (Fig. 54-5). Injection of blood into the epidural space results in an immediate mass effect persisting for at least 3 hours. Mature clot formation and sealing of the dural rent occurs by 7 hours after injection. Initial reports of EBP used small volumes of blood (2 to 3 mL), but recent recommendations are for larger volumes (15 to 20 mL). These larger volumes provide greater spread of clot (five to nine spinal segments), greater mass effect, and a higher incidence of successful treatment. Although safe and effective, the use of EBP is not risk free. Contraindications to EBP include systemic infection, localized infection of the back, and active neurologic disease. Reported complications of EBP include transient backache (35% to 100% incidence), mild temperature elevation (5%), sudden bradycardia, and radicular pain. Prolonged sequelae from EBP may also occur. Less successful epidural analgesia after prior EBP has been reported. Epidural Injection of Other Solutions. Both saline and dextran have been injected into the epidural space for the treatment of PDPH. Highly variable success rates have been reported, ranging from no effect to 90% success. The variable and often temporary nature of relief from saline or dextran,

Sumatriptan. This serotonin type 1d receptor agonist is a potent cerebral vasoconstrictor that is an effective treatment for migraine and cluster headaches. Sumatriptan can be administered intranasally, orally, or by subcutaneous injection. Case reports on the use of sumatriptan to treat PDPH are conflicting, and the sole available small randomized trial showed no benefit. Adrenocorticotropic Hormone. ACTH and its synthetic analogues have been administered intravenously for the treatment of PDPH. Proposed mechanisms of action include increased CSF production, dural edema secondary to aldosterone production, and increased β-endorphin production. Anecdotal evidence suggests a success rate of 70% to 95%, but the sole randomized controlled trial to date showed no benefit. There have been case reports of seizures in obstetric patients treated with ACTH analogues.

Invasive Therapy Loss of CSF pressure due to leakage of CSF from the dural puncture site has prompted investigators to inject substances into the epidural space to try to return CSF pressure to normal: Epidural Blood Patch. Epidural injection of autologous blood was first proposed as a treatment for PDPH in 1960, after anecdotal observations of a reduced incidence of PDPH

Figure 54–5 ■ Magnetic resonance image of 20-mL epidural blood patch demonstrating sealing of the dural leak and spread from L4 to T12 (arrowheads). (From Vakharia SB, et al: Magnetic resonance imaging of cerebrospinal fluid leak and tamponade effect of blood patch in postdural puncture headache. Anesth Analg 84:585, 1997.)

REGIONAL ANESTHESIA & PAIN MANAGEMENT

Sumatriptan 6 mg SQ? Cosyntropin 0.5 mg IV?

12–24 hr

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coupled with the inherent risk of an epidural injection, makes their use questionable. A recent case report documented the successful use of 3 mL of fibrin glue to treat a PDPH resistant to three EPBs.

PREVENTION The cornerstone of preventing PDPH is the selection of small, non-cutting-tipped needles for dural puncture. The prophylactic administration of systemic therapies has not been well studied, and results are disappointing. The prophylactic administration of EBP is controversial. Because not all patients undergoing dural puncture will develop PDPH, many experts recommend EBP only after the development of symptoms. Another argument against the prophylactic use of EBP is its questionable efficacy when administered early (<24 hours after dural puncture). Several studies of the early administration of relatively small volumes of blood (7 to 10 mL) via an epidural catheter after dural puncture with a large-gauge Tuohy needle reported virtually no effects on the subsequent development of PDPH. However, these studies have been criticized for using small volumes of blood. A recent study administering a larger volume of blood (15 mL) via an epidural catheter after dural puncture with a large-gauge Tuohy needle reported

a marked reduction in the incidence of PDPH in obstetric patients (5% in treated versus 88% in untreated patients). Another recent controlled trial demonstrated the efficacy of the immediate injection of 10 mL of saline after inadvertent dural puncture (32% of treated patients developed PDPH, versus 62% of those untreated). Thus, if patient and anesthetic risk factors are considered great enough to warrant prophylactic therapy, a large-volume EBP or immediate saline injection may be a reasonable and effective therapy.

Further Reading Canovas L, Barros C, Gomez A, et al: Use of intravenous tetracosactin in the treatment of postdural puncture headache: Our experience in forty cases. Anesth Analg 94:1369, 2002. Connelly NR, Parker RK, Rahimi A, Gibson CS: Sumatriptan in patients with postdural puncture headache. Headache 40:316-319, 2000. Halpern S, Preston R: Postdural puncture headache and spinal needle design: Metaanalyses. Anesthesiology 81:1376-1383, 1994. Harrington BE: Postdural puncture headache and the development of the epidural blood patch. Reg Anesth Pain Med 29:136-163, 2004. Kroin JS, Nagalla SK, Buvanendran A, et al: The mechanisms of intracranial pressure modulation by epidural blood and other injectates in a postdural puncture rat model. Anesth Analg 95:423-429, 2002. Lybecker H, Djernes M, Schmidt J: Postdural puncture headache (PDPH): Onset, duration, severity, and associated symptoms. Acta Anaesthesiol Scand 39:605-612, 1995.

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Local Anesthetic Neurotoxicity: Cauda Equina Syndrome

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Kenneth Drasner Case Synopsis

PROBLEM ANALYSIS Definition As the term cauda equina syndrome (CES) implies, clinical manifestations are related to injury to the nerve roots below the conus medullaris. Consequently, CES results in varying degrees of bowel and bladder dysfunction, perineal sensory loss, and lower extremity motor weakness. Although there are multiple potential causes, two are of most concern to anesthesiologists: (1) compressive injuries (e.g., epidural hematoma or epidural abscess), and (2) direct toxicity of substances administered into the intrathecal space. Recent clinical experience and experimental data suggest that, under certain circumstances, local anesthetics in current clinical use have the potential to induce neurotoxic damage. That is the focus of this chapter.

Recognition Throughout the last century of clinical use, sporadic reports of neurologic injury associated with spinal and epidural anesthesia raised the concern that local anesthetics might be neurotoxic. Clinical and experimental evidence accumulated over the last decade, beginning with reports of CES associated with continuous spinal anesthesia (CSA), has substantiated this concern. All the CSA-related cases shared certain common elements: there was evidence of a restricted sacral block that required repetitive doses of local anesthetic to achieve adequate surgical anesthesia, and the cumulative dose far exceeded that commonly used with single-injection spinal anesthesia. It was suggested that the combination of maldistribution and high dose of anesthetic led to neurotoxic concentrations

REGIONAL ANESTHESIA & PAIN MANAGEMENT

A 48-year-old man underwent right inguinal hernia repair under spinal anesthesia. With the patient in a sitting position, a 24-gauge pencil-point needle was inserted at the L4-L5 level, and 75 mg of 5% lidocaine hydrochloride with 7.5% glucose, 0.1 mg of epinephrine, and 25 μg of fentanyl was administered, resulting in an L3 block after 5 minutes. The patient was then placed in the right lateral decubitus position, and an additional 50 mg of 5% lidocaine with glucose was administered intrathecally. A T10 block was achieved, and surgery proceeded uneventfully. Twelve hours postoperatively, perineal numbness persisted, and the patient was unable to void. Anal sphincter tone was diminished, and anal reflexes were absent. Lumbosacral spine films and lumbosacral magnetic resonance imaging results were within normal limits. Six months postoperatively, the patient had to strain to urinate, was unable to have a spontaneous bowel movement, and continued to have diminished sensation in the S3-S5 region bilaterally.

in a restricted area of the subarachnoid space, a mechanism supported by subsequent in vitro and in vivo experimental data. Although most of the injuries involved the administration of 5% lidocaine through small-bore microcatheters, not all were associated with lidocaine, and some involved intrathecal delivery of anesthetic through an epidural catheter. Therefore, withdrawal of microcatheters from clinical practice has not eliminated the risk of injury, as practitioners remain at liberty to use epidural equipment for CSA. Further, some clinicians routinely convert to a continuous spinal technique if dural puncture accidentally occurs during attempted epidural placement. Factors that lead to neurotoxic injury with CSA are not unique to this technique; they also apply to single-injection spinal anesthesia. Specifically, inadequate sensory block with single-injection spinal anesthesia is often the result of maldistribution. Under such circumstances, there is the potential for repeat injections to distribute in the same pattern, resulting in neurotoxic concentrations of local anesthetic within a restricted area of the subarachnoid space. Case reports and review of the closed claims database appear to support this concern. There is a third mechanism by which high doses of anesthetic may be administered into the subarachnoid space. If a practitioner is administering an epidural anesthetic and fails to appreciate that the needle or catheter has traversed the dura or arachnoid, the doses administered may achieve neurotoxic concentrations in the subarachnoid space. Such doses may be sufficient to induce injury even in the absence of maldistribution, as evidenced by case reports. Reports of neurologic injury with CSA, repetitive injection after failed spinal anesthesia, and inadvertent intrathecal injection of anesthetic intended for the epidural space established the potential toxicity of anesthetics administered at a dose 227

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exceeding the usual clinical range for spinal anesthesia. More surprising, two fairly recent reports raised the suspicion that neurologic deficits might occur with the administration of lidocaine at doses recommended for single-injection spinal anesthesia. One was a case report of CES following the intrathecal injection of 100 mg of lidocaine with epinephrine. The second was a prospective study of regional anesthesia from France. In both reports there were persistent deficits following single injections of lidocaine that could not be otherwise explained. In all cases, relatively high doses (≥75 mg) were used, and cases of permanent injury occurred only after injection of the maximum recommended clinical dose (100 mg).

Risk Assessment In prospective studies, retrospective reviews, and epidemiologic studies, the incidence of CES resulting from neurotoxic reactions to local anesthetic varies. Such information is potentially misleading, however, because the incidence depends on practice patterns. For example, the very high incidence associated with the repetitive administration of high doses of anesthetic through continuous spinal catheters has little relevance to current anesthetic practice. Similarly, the roughly 1 in 5000 incidence of permanent deficits with single-injection lidocaine spinal anesthesia in the aforementioned report from France may overestimate the risk, because modifications have been made to reduce the risk of injury (see “Prevention”). Nonetheless, when assessing the likelihood that postoperative CES is the result of a neurotoxic reaction, one should consider the circumstances of the case relative to factors known to be associated with clinical toxicity (e.g., inadvertent intrathecal injection of an intended epidural dose of anesthetic). In addition to the rare occurrence of CES following spinal or epidural anesthesia, transient neurologic symptoms— defined as pain or dysesthesia in the buttocks and lower extremities—may occur in up to a third of individuals receiving lidocaine for spinal anesthesia. Known risk factors include outpatient status and surgical positioning (e.g., patients undergoing knee arthroscopy or placed in the lithotomy position). However, transient neurologic symptoms can be readily distinguished from CES because the former is not associated with sensory or motor deficits or disturbance of bladder and bowel function. Although there has been considerable speculation that these transient symptoms and CES may represent opposite ends of a spectrum of toxicity, recent evidence suggests that these two entities are not mediated by the same mechanism.

Implications CES is a rare but disastrous complication that may result from neurotoxic injury to the nerve roots below the conus medullaris. Because of its seriousness and lack of effective treatment, attention must be focused on the adoption of clinical strategies that minimize risk (see “Prevention”).

MANAGEMENT Although some advocate the use of high-dose steroids, these agents have no proven benefit for nerve root injuries resulting

from local anesthetic toxicity. As mentioned earlier, there are many potential causes of CES. It is critical to consider the possibility that clinical manifestations may be due to a compressive lesion (e.g., hematoma, abscess). Unlike neurotoxic damage, injury from compression is readily reversible, and the extent of recovery is related to the degree of functional loss and the time from the onset of deficits to surgical decompression. The clinical circumstances, such as coagulation status, may provide guidance as to the likelihood of this alternative. Also, local anesthetic neurotoxicity presents with a block that does not recede, whereas a period of normal postoperative function followed by progressive loss in the absence of ongoing administration of local anesthetic is strongly suggestive of a compressive lesion. Because time is of the essence, any suspicion should be investigated by emergent magnetic resonance imaging.

PREVENTION Analysis of the clinical reports of CES occurring with spinal and epidural anesthesia and data generated in experimental studies of neurotoxicity has led to the identification of factors that appear to potentiate risk. This information forms the basis of practice modifications.

Continuous Spinal Anesthesia Injuries occurred with CSA because high doses of anesthetic were administered intrathecally to compensate for a restricted sensory block. Guidelines have been proposed that emphasize reliance on a test dose, adjustment of technique, and abandonment of the technique if adequate block is not achieved within the normal clinical dose range for singleinjection spinal anesthesia (Table 55-1).

Repeat Injection after Failed Spinal Anesthesia Similar to CSA, guidelines for the management of failed spinal anesthesia have been proposed. These include an assessment of the likelihood of technical error (e.g., failure to inject the drug intrathecally) and appropriate adjustment of the dosage for the repeat injection. However, a more efficient

Table 55–1

■

Continuous Spinal Anesthesia: Guidelines for Administration

Insert the catheter just far enough to confirm and maintain placement. Use the lowest effective anesthetic concentration. Place a limit on the amount of anesthetic to be used. Administer a test dose, and assess the extent of block. If maldistribution is suspected, use maneuvers to increase the spread of local anesthetic (e.g., change the patient’s position, alter the lumbosacral curvature, switch to a solution with a different baricity). If well-distributed sensory anesthesia is not achieved before the dose limit is reached, abandon the technique. Adapted from Rigler ML, Drasner K, Krejcie TC, et al: Cauda equina syndrome after continuous spinal anesthesia. Anesth Analg 72:275-281, 1991.

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Local Anesthetic Neurotoxicity: Cauda Equina Syndrome

(and perhaps safer) strategy is to simply limit the combined anesthetic dosage to the maximum amount a clinician would consider reasonable to administer as a single intrathecal injection.

Epidural Anesthesia

Lidocaine Spinal Anesthesia Most of the recent injuries associated with spinal and epidural anesthesia have been associated with the use of lidocaine. Experimental investigations have reinforced concerns about this anesthetic, suggesting that its inherent toxicity exceeds that of bupivacaine. Modified guidelines for the use of this agent are summarized in Table 55-2 and detailed in the following paragraphs (although lidocaine is the focus, most of these considerations apply to any intrathecal anesthetic agent). Dose. Most studies indicate that the potency ratio of lidocaine to bupivacaine is approximately 1:4. Yet the maximum recommended doses of 100 mg and 20 mg, respectively, or the administration of whole ampules of these agents (100 mg and 15 mg), result in ratios of 5:1 or 6.7:1. The issue of relative toxicity aside, 100 mg exceeds the dose of lidocaine required for reliable spinal anesthesia. This, combined with case reports of probable neurotoxicity at the upper end of the dose range, leaves little justification for the continued use of a 100-mg ceiling. The data are inadequate to make a firm recommendation regarding the maximum safe dose, but it is my personal practice not to exceed 60 mg. Concentration. Abundant data suggest that anesthetic neurotoxicity is, to some extent, concentration dependent. It is therefore hard to justify the continued use of concentrations that far exceed that required for adequate blockade.

Table 55–2

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Lidocaine Spinal Anesthesia: General Guidelines

Dosage should be limited to 60 mg. Concentration should not exceed 2%. Epinephrine should not be used to enhance anesthesia or prolong the duration of block. Modified from Drasner K: Lidocaine spinal anesthesia: A vanishing therapeutic index? Anesthesiology 87:469-472, 1995.

With respect to lidocaine, the injected concentration should not exceed 2% lidocaine because it will produce sensory anesthesia that is clinically equivalent to a 5% solution. Glucose. A feature common to most recent cases of clinical injury is the use of an anesthetic solution with a high concentration of glucose and a tonicity far exceeding the normal physiologic range. Despite this association, 7.5% glucose does not affect the compound action potential in vitro or potentiate anesthetic-induced conduction failure. Moreover, dose-dependent loss of sensory function produced by intrathecal lidocaine in vivo is unaffected by the presence of 7.5% glucose, and the administration of 10% glucose does not induce impairment or morphologic damage. These findings suggest that it is appropriate to continue to use glucose to increase baricity. Vasoconstrictors. Vasoconstrictors might contribute to toxicity by promoting ischemia, decreasing anesthetic uptake, or directly affecting neural elements. Recent data indicate that epinephrine potentiates sensory impairment induced by intrathecal lidocaine. Combined with the clinical report of a deficit following the intrathecal injection of 100 mg lidocaine with epinephrine, these data argue against using a vasoconstrictor with lidocaine for spinal anesthesia. Moreover, if the goal is to provide a longer duration of surgical anesthesia, this can be readily achieved with bupivacaine. Thus, there is no cogent argument for the continued use of epinephrine with lidocaine.

Further Reading Auroy Y, Narchi P, Messiah A, et al: Serious complications related to regional anesthesia: Results of a prospective survey in France. Anesthesiology 87:479-486, 1997. Drasner K: Lidocaine spinal anesthesia: A vanishing therapeutic index? Anesthesiology 87:469-472, 1997. Drasner K, Rigler M: Repeat injection after a “failed spinal”—at times, a potentially unsafe practice. Anesthesiology 75:713-714, 1991. Drasner K, Rigler M, Sessler D, Stoller M: Cauda equina syndrome following intended epidural anesthesia. Anesthesiology 77:582-585, 1992. Freedman J, Li D, Drasner K, et al: Transient neurologic symptoms after spinal anesthesia: An epidemiologic study of 1863 patients. Anesthesiology 89:633-694, 1998. Hampl KF, Schneider MC, Ummenhofer W, Drewe J: Transient neurologic symptoms after spinal anesthesia. Anesth Analg 81:1148-1153, 1995. Hashimoto K, Bollen A, Ciriales R, Drasner R: Comparative toxicity of glucose and lidocaine administered intrathecally in the rat. Reg Anesth Pain Med 23:444-450, 1998. Hashimoto K, Hampl K, Nakamura Y, et al: Epinephrine increases the neurotoxic potential of intrathecally administered local anesthetic in the rat. Anesthesiology 94:876-883, 2001. Lambert L, Lambert D, Strichartz G: Irreversible conduction block in isolated nerve by high concentrations of local anesthetics. Anesthesiology 80:1082-1093, 1994. Pollock JE, Neal JM, Stephenson CA, Wiley CE: Prospective study of the incidence of transient radicular irritation in patients undergoing spinal anesthesia. Anesthesiology 84:1361-1367, 1996. Rigler M, Drasner K: Distribution of catheter-injected local anesthetic in a model of the subarachnoid space. Anesthesiology 75:684-692, 1991. Rigler M, Drasner K, Krejcie T, et al: Cauda equina syndrome after continuous spinal anesthesia. Anesth Analg 72:275-281, 1991.

REGIONAL ANESTHESIA & PAIN MANAGEMENT

The potential for toxicity with inadvertent intrathecal injection of an epidural dose of anesthetic underscores the importance of a test dose and the fractional administration of anesthetic. Additionally, should high doses of anesthetic be administered through a misplaced catheter, repetitive withdrawal of small volumes of cerebrospinal fluid and replacement with saline should be considered, regardless of the anesthetic agent.

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Francis V. Salinas Case Synopsis A 65-year-old man (183 cm, 87 kg, American Society of Anesthesiologists [ASA] status 1) was scheduled for a left total knee arthroplasty revision. His only medical problem was hypertension that was well controlled with atenolol 50 mg/day. After resolution of an uneventful 15-mg isobaric bupivacaine subarachnoid block, a continuous femoral nerve block was planned for postoperative analgesia. The patient was positioned supine for the femoral nerve block, and a brisk quadriceps response was obtained at a minimal current of 0.4 mA. A perineural catheter was advanced 10 cm beyond the needle tip, and the stimulating needle was removed. After a negative catheter aspiration test, ropivacaine 0.5% with epinephrine 2.5 μg/mL (30 mL) was injected slowly over 60 seconds. Near the end of the injection, the patient complained of unfocused vision and suddenly developed a generalized tonic-clonic seizure.

PROBLEM ANALYSIS Definition Local anesthetics are used to block the generation and propagation of electrical impulses (action potentials) in electrically excitable tissues. They bind to voltage-gated sodium channels and prevent conformational changes within those channels that allow the movement of ions for the propagation of action potentials. Clinically, local anesthetics are usually injected directly into perineural tissues (central neuraxis, major plexus, or peripheral nerves), joint spaces, and subcutaneous tissues. Additionally, they can be applied topically to mucosal surfaces to provide anesthesia of the airway or interpleural and intraperitoneal spaces. They may also be administered intravenously to provide regional anesthesia or treat arrhythmias. Adverse reactions to local anesthetics are either systemic or localized (e.g., direct neurotoxicity; see Chapter 55). Systemic toxicity involves primarily the central nervous system (CNS) and the cardiovascular system (CVS). In practice, systemic toxicity occurs as a result of the inadvertent intravascular injection or systemic absorption of excessive doses of local anesthetics from the injection site. Less commonly, systemic toxic reactions are due to methemoglobinemia, allergic reactions, or direct myo- or neurotoxicity. For example, ortho-toluidine (a metabolite of benzocaine and prilocaine) may oxidize deoxyhemoglobin to methemoglobin; deoxyhemoglobin does not bind oxygen or carbon dioxide.

Recognition CENTRAL NERVOUS SYSTEM TOXICITY Based on studies of unsedated human volunteers receiving intravenous infusions of local anesthetics, the early symptoms of local anesthetic-induced CNS toxicity include perioral numbness, lightheadedness or dizziness, tinnitus, difficulty 230

focusing visually, paresthesia, disorientation, and drowsiness. As the local anesthetic’s plasma concentration increases, common signs include dysarthria, skeletal muscle twitching, and tremors; these can progress to generalized tonic-clonic seizures. With still higher plasma concentrations, CNS toxicity may cause unconsciousness, respiratory arrest, and coma. Symptoms of CNS excitation are thought to be related to an initial blockade of inhibitory neurons in the cerebral cortex, thereby allowing facilitative neurons to function in an unopposed manner. This may ultimately lead to generalized seizures. With further increases in plasma and CNS concentrations of local anesthetics, both inhibitory and facilitative neurons are blocked, leading to more global CNS depression. This stereotypical pattern of initial CNS excitation relates primarily to slow intravenous injection or absorption of local anesthetics. Because the most common cause of clinical systemic toxicity is inadvertent intravenous injection of large amounts of local anesthetics, symptoms and signs of toxicity may progress much more rapidly, and generalized seizures may be the initial presentation of CNS toxicity. Also, the use of intravenous sedatives during the performance of an epidural or peripheral nerve block can attenuate early signs and symptoms of CNS toxicity. If so, skeletal muscle twitching and tremors or loss of consciousness may be the initial presentation. CARDIOVASCULAR SYSTEM TOXICITY Local anesthetics’ inhibition of cardiac sodium channels reduces the action potential duration, the effective refractory period, and the maximal depolarization rate of Purkinje fibers and ventricular muscle. Electrophysiologic studies in animal models have shown that local anesthetics produce dosedependent depression of cardiac conduction, leading to a prolonged P-R interval and QRS duration and depression of sinoatrial and atrioventricular activity. Local anesthetics also exert direct dose-dependent negative inotropic effects

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on the ventricular myocardium, which may be related to the blockage of calcium channels and mitochondrial energy metabolism. Further, local anesthetics are peripheral vasodilators and exert potent inhibitory effects on sympathetic smooth muscle vasoconstriction. CVS toxicity from local anesthetics’ direct actions on both myocardium and the peripheral vasculature may present as arrhythmias (refractory ventricular arrhythmias, sinus bradycardia or arrest), profound hypotension (due to negative inotropic effects or vasodilatation), or cardiovascular collapse.

Risk Assessment Multiple factors determine the risk of developing local anesthetic–induced systemic toxicity and its severity: ● ● ●

●

Regional anesthetic technique Pharmacokinetic factors Physiochemical and stereoselective properties of individual local anesthetics Individual patient characteristics

Based on several large series from the mid-1980s to the late 1990s, the reported overall incidence of seizures and cardiac arrest is relatively low (Table 56-1). Because premonitory signs precede the vast majority of seizures, they are most likely the result of acutely increased plasma levels of local anesthetic secondary to inadvertent intravascular injection. Seizures are five times more frequent after peripheral nerve block than after epidural anesthesia; this difference may be explained by the fact that the former usually requires larger

Table 56–1

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Reported Incidence of Seizures and Cardiac Arrest after Regional Anesthesia

Technique

Seizures

Cardiac Arrest

Peripheral nerve block

36/72,746 (4.9/10,000) 9/52,844 (1.3/10,000) 3/11,229 2.6/10,000

4/72,746 (0.54/10,000) 3/52,844 (0.57/10,00) 0/11,229 0

Epidural Intravenous regional

231

●

● ●

●

Amount of administered drug Physiochemical properties (e.g., lipid solubility, protein binding) of the individual local anesthetic Regional blood flow Presence of perineural tissue and fat that can bind local anesthetics Concomitant use of vasoconstrictors with local anesthetics

In general, perineural tissue with greater regional blood flow has a more rapid and complete uptake of local anesthetic, regardless of its type. Based on technique, the rates of systemic absorption generally decrease, in the following order: interpleural, intercostal, epidural, brachial plexus, sciatic-femoral (Table 56-2). The greater the total dose administered, the greater the systemic absorption and peak plasma levels. Within clinically recommended doses, and with the exception of speed of injection, this relationship is nearly linear. The addition of epinephrine causes a 20% to 30% reduction in peak plasma levels during epidural anesthesia and peripheral nerve blocks. After systemic absorption, local anesthetics are rapidly distributed throughout different tissues in the body, based on organ perfusion. Because the CNS and CVS are highly perfused, initial tissue levels of local anesthetics may not correlate with systemic blood levels. Thus, regional pharmacokinetics play an important role in the subsequent systemic pharmacodynamic effects of these anesthetics. The severity of local anesthetic–induced toxicity can also be influenced by the patient’s acid-base status. With increased arterial carbon dioxide tension or decreased pH, the seizure threshold is reduced. Increased hydrogen ion concentrations enhance cerebral blood flow, so that more local anesthetic is delivered to the CNS. Also, hypercapnia or acidosis reduces plasma protein binding of local anesthetics, which increases the amount of free drug available to diffuse across cell membranes. Patients with advanced liver disease may be particularly susceptible to local anesthetic–induced toxicity with the amide class of drugs, owing to the combination of reduced protein synthesis and hepatic degradation.

Implications In general, more potent local anesthetics produce seizures at lower plasma concentrations and doses than do less potent local anesthetics. The relative CNS toxicity of bupivacaine and lidocaine is approximately 4:1, which mirrors their relative anesthetic potency. The cardiovascular manifestations during the excitatory phase of CNS toxicity can include increased heart rate, blood pressure, and cardiac output. The CVS is much more resistant to the toxic effects of local anesthetics than the CNS is. Severe CVS toxicity is rare with the less potent amide local anesthetics, and severe direct myocardial

REGIONAL ANESTHESIA & PAIN MANAGEMENT

Methemoglobinemia is characterized by central cyanosis that is refractory to supplemental oxygen. Central cyanosis usually develops with methemoglobin levels greater than 15%. Higher concentrations may result in anxiety, dyspnea, headache, weakness, nausea, and vomiting. Severe methemoglobinemia (>50% to 60% methemoglobin) may cause confusion, seizures, arrhythmias, hemodynamic instability, and death. The diagnosis is suggested by the presence of “chocolate-colored” blood that does not change color when exposed to air and an arterial percentage of oxygen saturation gap when analyzed by pulse oximetry and arterial blood gases. The diagnosis is confirmed by qualitative measures of methemoglobin concentrations by co-oximetry.

Local Anesthetic Systemic Toxicity

doses of local anesthetics than the latter does. In contrast, the frequency of cardiac arrest is low with either technique. Although the systemic toxic effects of local anesthetics are dose dependent, the rate of change in plasma levels is also an important factor. In the absence of intravascular injection, local anesthetics are absorbed into the systemic circulation by uptake and distribution from the surrounding perineural tissue. Subsequent plasma levels are governed by the following factors: ●

METHEMOGLOBINEMIA

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Table 56–2

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Lidocaine

Mepivacaine

Ropivacaine

Levobupivacaine

Regional Anesthesia and Pain Management

Typical Maximal Plasma Concentrations of Common Local Anesthetics, by Regional Technique

Local Anesthetic Bupivacaine

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Technique Brachial plexus Epidural Intercostal Sciatic/femoral Brachial plexus Epidural Intercostal Sciatic/femoral* Brachial plexus Epidural Intercostal Sciatic/femoral Brachial plexus Epidural Intercostal Femoral† Psoas compartment† Brachial plexus‡ Epidural

Dose (mg) 150 50 140 400 400 400 400 650 500 500 500 500 190 150 140 150 150 250 150

Cmax (μg/mL) 1.00 1.50 1.26 1.89 4.00 4.27 6.80 2.39 3.68 4.95 8.06 3.59 1.30 1.07 1.10 0.65 1.19 1.20 1.02

Tmax (min) 20 1.7 20 15 25 20 15 30 24 16 9 31 53 40 21 30 15 55 2

Toxic Plasma Concentration (μg/mL) 3 3 3 3 5 5 5 5 5 5 5 5 4 4 4 4 4 >4 >4

*Data from Elmas C, Atanassoff PG: Combined inguinal paravascular (3-in-1) and sciatic nerve blocks for lower limb surgery. Reg Anesth 18:88-92, 1993. † Data from Kaloul I, Guay J, Cote C, et al: Ropivacaine plasma concentrations are similar during continuous lumbar plexus block using the anterior three-in-one and the posterior psoas compartment techniques. Can J Anaesth 51:52-56, 2004. ‡ Data from Crews JC, Weller RS, Moss J, James RL: Levobupivacaine for axillary brachial plexus block: A pharmacokinetic and clinical comparison in patients with normal renal function or renal disease. Anesth Analg 95:219-223, 2002. Cmax, maximal plasma concentration; Tmax, maximal time. From Salinas FV: Ion channel ligands/sodium channel blockers/local anesthetics. In Evers AS, Maze M (eds): Anesthetic Pharmacology: Physiologic Principles and Clinical Practice, 1st edition. Philadelphia, Churchill Livingstone, 2004, pp 507-537.

depression and peripheral vasodilatation occur only with extremely high levels of either lidocaine or mepivacaine. Conversely, more potent amide local anesthetics, such as bupivacaine, have a significantly narrower margin of CVS safety, expressed as the ratio of the dosage or plasma concentration required to produce irreversible cardiovascular collapse (CC) to that required to produce CNS toxicity (generalized seizures). In contrast to lidocaine, the CC/CNS ratio for bupivacaine can result in nearly simultaneous progression from CNS toxicity to cardiovascular collapse, in large part owing to bupivacaine’s ability to cause malignant ventricular arrhythmias. Bupivacaine’s enhanced ability to precipitate ventricular arrhythmias is thought to be related primarily to differences in the recovery of sodium channel block between bupivacaine and lidocaine. Both drugs rapidly block sodium channels during systole; however, bupivacaine dissociates from the sodium channel receptor much more slowly than lidocaine during diastole. Thus, within the physiologic range of heart rate, lidocaine dissociates rapidly (fast on–fast off) from the sodium channel, whereas bupivacaine remains avidly bound to it during diastole (fast on–slow off). The net electrophysiologic effect is slowed ventricular conduction and prolonged refractoriness, both of which are conducive to reentry ventricular arrhythmias. Although bupivacaine has the advantage of prolonged duration of block, with enhanced sensory-motor dissociation, concerns about its potent cardiotoxicity led to the development of alternative long-acting amide local anesthetics with the same beneficial properties but an enhanced margin of safety.

Ropivacaine is the propyl homologue of mepivacaine and bupivacaine. In contrast to older amide local anesthetics, which exist as racemic mixtures, ropivacaine is an enantiomerically pure (levorotatory isomer) local anesthetic. In general, the levorotatory isomer has less potential for systemic toxicity than the dextrorotatory isomer of the same local anesthetic. Animal and human volunteer studies have confirmed that ropivacaine is approximately 30% to 40% less cardiotoxic than racemic bupivacaine. Ropivacaine causes less prolongation of cardiac conduction and less direct negative inotropic effects than equivalent doses of bupivacaine. During cardiac resuscitation after incremental overdosage in anesthetized dogs, free plasma concentrations of ropivacaine causing cardiac arrest were more than twice those of bupivacaine. Further, the inability to resuscitate dogs with bupivacaine was higher than with ropivacaine (50% versus 10%). Recent case reports attest to ropivacaine’s lower cardiotoxicity, even after the injection of large doses sufficient to cause cardiac arrest. Although the incidence of severe systemic toxicity from local anesthetics appears to be decreasing, the potential catastrophic outcomes from cardiotoxicity cannot be underestimated. In the most recent ASA closed claims analysis of injuries associated with regional anesthesia, unintentional intravascular injections were the second largest category of neuraxial anesthesia claims that were block related and resulted in high-severity outcome (death or brain damage). Of 12 such cases, 11 occurred in the 1980s and only 1 in the 1990s; 75% of these were associated with cardiac arrest. Clinically significant methemoglobinemia can occur when large doses of prilocaine (>600 mg) are administered.

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MANAGEMENT Management of systemic toxicity depends on the severity of the event. Because plasma levels of local anesthetics associated with minor reactions fall rapidly, as long as normal metabolic processes are functional, such events can be allowed to terminate spontaneously, provided attention is paid to maintaining airway patency and providing supplemental oxygen and hemodynamic support. Seizures can be terminated with small doses of intravenous midazolam (0.05 to 0.1 mg/kg), sodium thiopental (1 to 2 mg/kg), or propofol (0.5 to 1.5 mg/kg). If generalized tonic-clonic seizures are not aborted with these doses of intravenous anesthetics, administration of succinylcholine followed by endotracheal intubation is indicated. Prompt termination of seizure activity is important to prevent the rapid development of severe metabolic acidosis associated with tonic-clonic muscular contractions.

Table 56–3

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Local Anesthetic Systemic Toxicity

233

Cardiovascular depression should be treated by fluid resuscitation and vasopressors, if required. Because hypotension is usually due to a combination of direct myocardial depression and peripheral vasodilatation, agents with both β1 and α1 activity are recommended: ephedrine or phenylephrine or both (even epinephrine or norepinephrine) in incremental doses until the desired response is obtained. With cardiovascular collapse refractory to these drugs, vasopressin should be considered. Malignant ventricular arrhythmias should be managed with direct-current cardioversion and amiodarone if needed to prevent recurrences. If CVS toxicity is not responsive to any of these measures, intravenous lipid infusion or cardiopulmonary bypass should be considered. Recent animal models have demonstrated that intravenous lipid emulsion can facilitate resuscitation from acute bupivacaine overdose.

PREVENTION Because the vast majority of systemic toxic reactions to local anesthetics are the result of either inadvertent intravascular injection or systemic absorption of excessive doses, efforts should be made to minimize that potential. The anesthesiologist must be aware of the risk factors associated with both the regional technique and physiologic status of the patient that predispose to clinically significant systemic toxic reactions. Proper patient preparation includes appropriate monitoring of heart rate, blood pressure, and oxygenation; recent data indicate the added value of continuous electrocardiography. Resuscitative drugs and equipment should be immediately available. Sedatives may increase the seizure threshold but also attenuate the patient’s ability to report subjective symptoms of CNS toxicity, as well as reducing the heart rate’s response to the traditional 15-μg epinephrine “test dose.” Techniques that reduce the likelihood of direct intravascular injection should be used. Although no single measure is 100% reliable in preventing severe systemic toxicity, the following measures are recommended: ●

●

●

Inject local anesthetics in small, fractionated doses, with frequent aspiration of the syringe to assess for intravascular placement of either the needle or catheter. In the absence of contraindications, add epinephrine to local anesthetic solutions to aid in the identification of intravascular injections (“test dose”) and to decrease systemic absorption from the injection site. Be aware of the different criteria for a positive epinephrine test dose during different clinical scenarios (Table 56-3).

Criteria for Positive Epinephrine (15 μg) Test Dose in Adults

Clinical Scenario

Heart Rate Increase (bpm)

Systolic Blood Pressure Increase (mm Hg)

>20

>15

Decrease ≥25%

NA >9 >8

>15 >15 >15

NA Decrease ≥25% Decrease ≥25%

Age <60 yr (not on β-blockers) β-blockers Age >60 yr General anesthesia bpm, beats per minute; NA, not applicable.

T-Wave Amplitude

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After several cases reports of methemoglobinemia after intravenous prilocaine was used for regional anesthesia, it was withdrawn for such use. However, it is still available as a eutectic mixture of prilocaine 2.5% and lidocaine 2.5% (EMLA cream), commonly used as a topical anesthetic. Neonatal patients have immature reductase enzyme pathways that may predispose them to methemoglobinemia with the application of EMLA cream. Benzocaine is an ester-type local anesthetic commonly used for topical anesthesia before fiberoptic intubation, bronchoscopy, transesophageal echocardiography, and upper gastrointestinal endoscopy procedures. The Food and Drug Administration’s adverse event reporting system described 132 cases of methemoglobinemia secondary to benzocaine between 1997 and 2002. These resulted in two deaths (1.5%) and 55 (42%) life-threatening complications. Potential risk factors include concomitant use of other oxidizing agents and excessive absorption from either breaks in the mucosal barrier or delivery of excessive dosages. Clinically significant toxicity is effectively treated with intravenous methylene blue (1 mg/kg). Immunologic-mediated (allergic) reactions to preservative-free amide local anesthetics are extremely rare. However, ester local anesthetics may produce allergic reactions due to their metabolism to para-aminobenzoic acid (PABA), a known allergen. Amide local anesthetics are not metabolized to PABA unless preservatives (e.g., methylparaben) are used in their formulation; methylparaben is metabolized to PABA. Patients with true allergic reactions to ester local anesthetics should be treated with preservative-free local anesthetics.

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Although the scientific basis for maximum recommended doses is tenuous, and actual plasma levels vary with the site of injection, always administer the minimum effective dose. For blocks with a higher risk of intravascular injection or systemic absorption, consider using ropivacaine. During the administration of the local anesthetics, be vigilant for symptoms and signs of toxicity. Early intervention can reduce the complications of local anesthetic–induced toxicity.

Further Reading Albright GA: Cardiac arrest following regional anesthesia with etidocaine or bupivacaine [editorial]. Anesthesiology 51:285-287, 1979. Auroy Y, Benhamou D, Barguues L, et al: Major complications of regional anesthesia in France: The SOS regional anesthesia hotline service. Anesthesiology 97:1274-1280, 2002. Auroy Y, Narchi P, Messiah A, et al: Serious complications related to regional anesthesia: Results of a prospective survey in France. Anesthesiology 87:479-486, 1997. Berkum Y, Ben-Zvi A, Levy Y, et al: Evaluation of adverse reactions to local anesthetics: Experience with 236 patients. Ann Allergy Asthma Immunol 91:342-345, 2003. Bernards CM, Carpenter RL, Rupp SM, et al: Effects of midazolam and diazepam premedication on the central nervous system and cardiovascular toxicity of bupivacaine in pigs. Anesthesiology 70:318-323, 1989. Braid DP, Scott DB: The effect of adrenaline on the systemic absorption of local anaesthetic drugs. Acta Anaesthesiol Scand Suppl 23:334-346, 1996. Brown DL, Ransom DM, Hall JA, et al: Regional anesthesia and local anesthetic-induced systemic toxicity: Seizure frequency and accompanying cardiovascular changes. Anesth Analg 81:321-328, 1995. Butterworth JF, Brownlow RC, Leith JP, et al: Bupivacaine inhibits cyclic-3′, 5′-adenosine monophosphate production: A possible contributing factor to cardiovascular toxicity. Anesthesiology 79:88-95, 1993. Butterworth JF, Strichartz GR: Molecular mechanisms of local anesthesia: A review. Anesthesiology 72:711-734, 1990. Chazalon P, Tourtier JP, Villevielle T, et al: Ropivacaine-induced cardiac arrest after peripheral nerve block: Successful resuscitation. Anesthesiology 99:1449-1451, 2003. Clarkson CW, Hondeghem LM: Mechanism for bupivacaine depression of cardiac conduction: Fast block sodium channels during the action potential with slow recovery during diastole. Anesthesiology 62: 396-405, 1985. Dernedde M, Furlan D, Verbesselt R, et al: Grand mal convulsions after accidental intravenous injection of ropivacaine. Anesth Analg 98:521-523, 2004. Gall H, Kaufmann R, Kalveram CM: Adverse reactions to local anesthetics: Analysis of 197 cases. J Allergy Clin Immunol 97:933-937, 1996. Groban L: Central nervous system and cardiac effects from long-acting amide local anesthetic toxicity in the intact animal model. Reg Anesth Pain Med 28:3-11, 2003. Groban L, Butterworth J: Lipid reversal of bupivacaine toxicity: Has the silver bullet been identified? [editorial] Reg Anesth Pain Med 28:167-169, 2003.

Groban L, Deal DD, Vernon JC, et al: Cardiac resuscitation after incremental overdosage with lidocaine, bupivacaine, levobupivacaine, and ropivacaine in anesthetized dogs. Anesth Analg 92:37-43, 2001. Heavner JE: Cardiac toxicity of local anesthetics in the intact isolated heart model: A review. Reg Anesth Pain Med 27:545-555, 2002. Huet O, Eyrolle LJ, Mazoit JX, Ozier YM: Cardiac arrest after injection of ropivacaine for posterior lumbar plexus blockade. Anesthesiology 99:1451-1453, 2003. Knudsen K, Suurkula MB, Blomberg S, et al: Central nervous and cardiovascular effects of IV infusions of ropivacaine, bupivacaine, and placebo in volunteers. Br J Anaesth 78:507-514, 1997. Lee LA, Posner KL, Domino KB, et al: Injuries associated with regional anesthesia in the 1980s and 1990s: A closed claims analysis. Anesthesiology 101:143-152, 2004. Liu PL, Feldman HS, Giasi R, et al: Comparative CNS toxicity of lidocaine, etidocaine, bupivacaine, and tetracaine in awake dogs following rapid intravenous administration. Anesth Analg 62:375-379, 1983. Lofstrom JB: 1991 Labat lecture: The effects of local anesthetics on the peripheral vasculature. Reg Anesth 17:1-11, 1992. Moore JM, Liu SS, Neal JM: Premedication with fentanyl and midazolam decreases the reliability of intravenous lidocaine test dose. Anesth Analg 86:1015-1017, 1998. Moore TJ, Walsh CS, Cohen MR: Reported adverse event cases of methemoglobinemia associated with benzocaine products. Arch Intern Med 164:1192-1196, 2004. Mulroy MF: Systemic toxicity and cardiotoxicity from local anesthetics: Incidence and preventative measures. Reg Anesth Pain Med 27:556-561, 2002. Orringer CE, Eustace JC, Wunsch CD, Gardner LB: Natural history of lactic acidosis after grand-mal seizures. N Engl J Med 297:796-799, 1977. Salinas FV: Ion channel ligands/sodium channel blockers/local anesthetics. In Evers AS, Maze M (eds): Anesthetic Pharmacology: Physiologic Principles and Clinical Practice, 1st ed. Philadelphia, Churchill Livingstone, 2004, pp 507-537. Scott DB: Evaluation of the toxicity of local anesthetic agents in man. Br J Anaesth 47:56-59, 1975. Soltesz EG, van Pelt F, Byrne JG: Emergent cardiopulmonary bypass for bupivacaine cardiotoxicity. J Cardiothorac Vasc Anesth 17:357-358, 2003. Stewart J, Kellett N, Castro D: The central nervous system and cardiovascular effects of levobupivacaine and ropivacaine in healthy volunteers. Anesth Analg 97:412-416, 2003. Szocik JF, Gardener CA, Webb RC: Inhibitory effects of bupivacaine and lidocaine on adrenergic neuroeffector junctions in rat-tail artery. Anesthesiology 78:911-917, 1993. Tanaka M, Nishikawa T: T-wave amplitude as in indicator for detecting intravascular injection of epinephrine test dose in awake and anesthetized elderly patients. Anesth Analg 93:1332-1337, 2001. Tanaka M, Sato M, Nishikawa T: The efficacy of simulated intravascular test dose in sedated patients. Anesth Analg 93:1612-1617, 2001. Weinberg GL: Current concepts in resuscitation of patients with local anesthetic cardiac toxicity. Reg Anesth Pain Med 27:568-575, 2002. Weinberg GL, Ripper R, Feinstein DL, Hoffman W: Lipid emulsion infusion rescues dogs from bupivacaine-induced cardiac toxicity. Reg Anesth Pain Med 28:198-202, 2003. Xuecheng J, Xiaobin W, Bo G, et al: The plasma concentration of lidocaine after slow versus rapid administration of an initial dose of epidural anesthesia. Anesth Analg 84:570-573, 1997.

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Spinal Hematoma Terese T. Horlocker Case Synopsis A 75-year-old man undergoes total knee replacement under continuous epidural anesthesia. The epidural catheter is left indwelling to provide postoperative analgesia with 0.125% bupivacaine. Thromboprophylaxis with low-molecular-weight heparin (LMWH), 30 mg twice daily, is initiated 24 hours after surgery. Forty-eight hours later, the epidural catheter is removed 1 hour after a dose of LMWH. The patient’s sensory and motor block progresses, however, despite discontinuation of the local anesthetic infusion. A magnetic resonance image reveals an epidural hematoma at T12. Immediate surgical decompression results in complete neurologic recovery.

Definition The actual incidence of neurologic dysfunction resulting from hemorrhagic complications associated with neuraxial blockade is unknown; however, estimates in the literature are less than 1 in 150,000 for epidural anesthesia and less than 1 in 220,000 for spinal anesthesia. In a review of the literature between 1906 and 1994, Vandermeulen and colleagues reported 61 cases of spinal hematoma associated with epidural or spinal anesthesia. In 42 of the 61 patients (69%) with spinal hematomas associated with central neural blockade, there was evidence of hemostatic abnormality. Twenty-five of the patients had received intravenous or subcutaneous (unfractionated or low-molecular-weight) heparin, and an additional five patients were presumably administered heparin during vascular surgical procedures. In addition, 12 patients had evidence of coagulopathy or thrombocytopenia or were treated with antiplatelet drugs (aspirin, indomethacin, ticlopidine), oral anticoagulants (phenprocoumon), thrombolytics (urokinase), or dextran 70 immediately before or after the spinal or epidural anesthetic. Needle and catheter placement

Table 57–1

■

was difficult in 15 patients (25%) and bloody in 15 patients (25%). Overall, in 53 of 61 cases (87%), either a clotting abnormality or difficult needle placement was noted. A spinal anesthetic was administered in 15 patients. The remaining 46 patients received an epidural anesthetic, including 32 patients with indwelling catheters. In 15 of the latter, spinal hematoma occurred immediately after removal of the epidural catheter. These results suggest that catheter removal is not entirely atraumatic and that the patient’s coagulation status should be optimized at the time of both catheter placement and removal.

Recognition In Vandermeulen’s series, neurologic compromise presented as progression of sensory or motor block (68% of patients) or bowel or bladder dysfunction (8% of patients), rather than severe radicular back pain. Spinal hematoma should be ruled out in patients exhibiting early signs of cord compression in the postoperative period. The differential diagnosis includes cauda equina syndrome, epidural abscess, and anterior spinal artery syndrome (Table 57-1). If spinal hematoma is suspected, radiographic confirmation must be sought immediately,

Differential Diagnosis of Epidural Abscess, Epidural Hemorrhage, and Anterior Spinal Artery Syndrome

Finding

Epidural Abscess

Epidural Hemorrhage

Anterior Spinal Artery Syndrome

Age of patient Previous history Onset Generalized symptoms

Any age Infection* 1-3 days Fever, malaise, back pain

Elderly Arteriosclerosis, hypotension Sudden None

Sensory involvement Motor involvement Segmental reflexes Myelogram/CT scan Cerebrospinal fluid Blood data

None or paresthesias Flaccid paralysis, later spastic Exacerbated*; later obtunded Signs of extradural compression Increased cell count Rise in sedimentation rate

50% >50 yr Anticoagulants Sudden Sharp, transient back and leg pain Variable, late Flaccid paralysis Abolished Signs of extradural compression Normal Prolonged coagulation time*

Minor, patchy Flaccid paralysis Abolished Normal Normal Normal

*Infrequent findings. CT, computed tomography. From Wedel DJ, Horlocker TT: Risks of regional anesthesia—infectious, septic. Reg Anesth 21:57-61, 1996.

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PROBLEM ANALYSIS

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because delay can lead to irreversible cord ischemia. Although spontaneous recovery has been reported, the treatment of choice is decompressive laminectomy. Complete neurologic recovery is unlikely if surgery is postponed for more than 8 hours.

Risk Assessment The risk of spinal hematoma depends on the timing of needle or catheter placement and removal and the degree of anticoagulation with the following drugs: ● ● ● ●

Standard heparin (intravenous and subcutaneous) Low-molecular-weight heparin (LMWH) Oral anticoagulants Antiplatelet medications

STANDARD HEPARIN Ruff and Dougherty reported spinal hematomas in 7 of 342 patients (2%) who underwent diagnostic lumbar puncture with subsequent heparinization. Three factors were associated with increased risk: less than 60 minutes between the administration of heparin and the lumbar puncture, traumatic needle placement, and concomitant use of other anticoagulants (aspirin). These findings have been used to define safe practice protocols for patients undergoing neuraxial blockade during systemic heparinization, particularly in the case of vascular surgery. Intrathecal and epidural anesthesia and analgesia, along with complete heparinization and cardiopulmonary bypass, have been reported without neurologic sequelae. However, at this time, there are insufficient data and experience to quantify the risk of spinal hematoma among this patient population. Low-dose subcutaneous, unfractionated heparin is administered for thromboprophylaxis in patients undergoing major thoracoabdominal surgery and in those at increased risk for hemorrhage with oral anticoagulant or LMWH therapy. A review by Schwander and Bachmann noted no spinal hematomas in more than 5000 patients who received subcutaneous heparin with spinal or epidural anesthesia. There were five cases of spinal hematoma associated with neuraxial blockade in patients receiving low-dose heparin. This confirms the limited risk associated with the use of epidural and spinal anesthesia in the presence of subcutaneous heparin treatment. LOW-MOLECULAR-WEIGHT HEPARIN Despite a notable safety record in Europe, in the first 5 years after the release of LMWH in North America, there were 40 cases of spinal hematoma associated with LMWH and neuraxial anesthesia. The risk of spinal hematoma, based on LMWH sales, prevalence of neuraxial techniques, and reported cases, was estimated to be approximately 1 in 3000 continuous epidural anesthetics, compared with 1 in 40,000 spinal anesthetics. However, this risk was later found to be much higher. Similar to the Vandermeulen series, severe radicular back pain was not the presenting symptom. Most patients complained of new-onset numbness, weakness, or bowel and

bladder dysfunction. About half of patients undergoing a continuous technique reported neurologic deficits 12 hours or more after catheter removal. The median interval between initiation of LMWH therapy and neurologic dysfunction was 3 days, and the median time to onset of symptoms and laminectomy was more than 24 hours. Less than one third of patients reported fair or good neurologic recovery. Over the past 5 years, the number of reported cases of spinal hematoma associated with LMWH therapy has declined markedly. This may be a result of decreased reporting, improved management, or simple avoidance of all neuraxial techniques in patients receiving LMWH. Continued monitoring is necessary. Indications and labeled uses for LMWH continue to evolve, including for thromboprophylaxis and the treatment of deep venous thrombosis. In addition, several off-label applications of LMWH are of special interest to the anesthesiologist and warrant discussion. LMWH has been shown to be efficacious as “bridge therapy” for patients chronically anticoagulated with warfarin, including parturients and patients with prosthetic cardiac valves, a history of atrial fibrillation, or preexisting hypercoagulable conditions. The patient is therapeutically anticoagulated with LMWH while the warfarin effect is allowed to resolve before surgery. Doses of LMWH are two- to threefold higher than those used for thromboprophylaxis. At least 24 hours is required for normal hemostais following this level of LMWH anticoagulation. ORAL ANTICOAGULANTS Few data exist regarding the risk of spinal hematoma in patients with indwelling epidural catheters who are anticoagulated with warfarin. The optimal duration of an indwelling catheter and the timing of its removal in an anticoagulated patient are also controversial. A combined series of 651 patients reported no spinal hematomas in those receiving neuraxial block in conjunction with low-dose warfarin therapy. The mean international normalized ratio (INR) at the time of catheter removal was 1.4. However, marked variability in patient response to warfarin was noted. ANTIPLATELET MEDICATIONS Several large studies have demonstrated the relative safety of neuraxial blockade in obstetric, surgical, and ambulatory pain clinic patients receiving antiplatelet medications. In a prospective study involving 1000 patients, Horlocker and colleagues reported that preoperative antiplatelet therapy did not increase the incidence of blood present at the time of needle or catheter placement or removal, suggesting that trauma during needle or catheter placement is neither increased nor sustained by these medications. The paucity of case reports among these patients is notable, given the prevalence of aspirin and other nonsteroidal anti-inflammatory drug (NSAID) use among patients with acute, chronic, or cancer pain who receive interventional therapy. No series involving the performance of neuraxial blockade in the presence of thienopyridine derivatives (clopidogrel and ticlopidine) or platelet glycoprotein IIb/IIIa receptor antagonists has been reported. Although case reports are inconsistent, increased perioperative bleeding has been noted in patients undergoing cardiac and vascular surgery after

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receiving ticlopidine, clopidogrel, and glycoprotein IIb/IIIa antagonists. This suggests that these medications may increase the risk of regional anesthesia–related hemorrhagic complications.

●

Low-molecular-weight heparin ● Proceed cautiously. ● For preoperative LMWH, administer spinal anesthesia 12 to 24 hours after the administration of LMWH, depending on dose (i.e., treatment versus thromboprophylaxis). ● Epidural catheters may remain indwelling with oncedaily dosing of LMWH. Place or remove catheters in the morning; administer LMWH in the evening. ● Epidural catheters should not remain indwelling with twice-daily dosing of LMWH. Remove the epidural catheter 2 hours before the initiation of twice-daily LMWH therapy.

●

Oral anticoagulants ● Preoperative administration does not preclude regional technique. ● Monitor the prothrombin time postoperatively; there is marked variability in patient response. ● Remove the catheter when the INR is less than 1.5.

●

Antiplatelet agents ● NSAIDs do not represent significant risk. ● Allow the antiplatelet effects of clopidogrel, ticlopidine, and glycoprotein IIb/IIIa inhibitors to resolve before neuraxial block.

Intravenous heparin ● Administer heparin 60 minutes after needle placement. ● Monitor the effect of the heparin. ● Remove the catheter when heparin activity is low or completely reversed.

Table 57–2

■

PREVENTION The patient’s coagulation status should be optimized at the time of spinal or epidural needle or catheter placement, and

Pharmacologic Activities of Anticoagulants, Antiplatelet Agents, and Thrombolytics Effect on Coagulation Variables

Time to Normal Hemostasis after Discontinuation

Agent

PT

aPTT

Time to Peak Effect

Intravenous heparin Subcutaneous heparin Low-molecular-weight heparin Warfarin

↑ — — ↑↑↑

↑↑↑ ↑ — ↑

Minutes 40-50 min 3-5 hr 4-6 days (less with loading dose)

4-6 hr 4-6 hr 12-24 hr 4-6 days

Antiplatelet agents Aspirin Other NSAIDs Ticlopidine, clopidogrel Platelet glycoprotein IIb/IIIa receptor inhibitors Fibrinolytics

—

— Hours Hours Hours Minutes

5-8 days 1-3 days 1-2 wk 8-48 hr

Minutes

24-36 hr

↑

↑↑

aPTT, activated partial thromboplastin time; NSAID, nonsteroidal anti-inflammatory drug; PT, prothrombin time; —, no effect; ↑, clinically insignificant increase; ↑↑, possibly clinically significant increase; ↑↑↑, clinically significant increase.

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Subcutaneous heparin ● Consider delaying administration until after needle or catheter placement in patients with anticipated technical difficulties. ● Monitor platelet count in patients receiving heparin for more than 4 days.

MANAGEMENT Before surgery, the patient’s history should be reviewed for medical conditions associated with bleeding tendencies, and the patient should be questioned about previous episodes of sustained bleeding after trauma or surgery. Because patients respond to anticoagulants with varying sensitivities, it may be helpful to verify the reversal of heparin’s or warfarin’s effects before the performance of epidural or spinal blockade (Table 57-2). The following guidelines will assist in the management of patients with altered hemostasis undergoing regional anesthetic techniques. Except in the most extraordinary circumstances, spinal and epidural blockade should be avoided in fully anticoagulated patients or those who have received thrombolytic therapy.

Spinal Hematoma

●

Implications Whether to perform spinal or epidural anesthesia or analgesia and the timing of catheter removal in a patient receiving thromboprophylaxis should be decided on an individual basis, weighing the small but definite risk of spinal hematoma against the benefits of regional anesthesia for the particular patient. Alternative anesthetic and analgesic techniques exist for patients considered to be at an unacceptably high risk.

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the level of anticoagulation must be carefully monitored during the period of epidural catheterization. It is important to note that patients respond with variable sensitivities to anticoagulant medications. Indwelling catheters should not be removed in the presence of therapeutic anticoagulation, because this appears to significantly increase the risk of spinal hematoma. In addition, communication among clinicians involved in the perioperative management of patients receiving anticoagulants for thromboprophylaxis is essential to decrease the risk of serious hemorrhagic complications.

Further Reading Bergqvist D, Lindblad B, Matzsch T: Low molecular weight heparin for thromboprophylaxis and epidural/spinal anaesthesia: Is there a risk? Acta Anaesthesiol Scand 36:605-609, 1992. Chaney MA: Intrathecal and epidural anesthesia and analgesia for cardiac surgery. Anesth Analg 84:1211-1221, 1997. CLASP (Collaborative Low-Dose Aspirin Study in Pregnancy): A randomized trial of low-dose aspirin for the prevention and treatment of preeclampsia among 9364 pregnant women. Lancet 343:619-629, 1994. Ho AM, Chung DC, Joynt GM: Neuraxial blockade and hematoma in cardiac surgery: Estimating the risk of a rare adverse event that has not (yet) occurred. Chest 117:551-555, 2000. Horlocker TT, Bajwa ZH, Ashraft Z, et al: Risk assessment of hemorrhagic complications associated with nonsteroidal antiiflammatory

medications in ambulatory pain clinic patients undergoing epidural steroid injection. Anesth Analg 95:1691-1697, 2002. Horlocker TT, Wedel DJ, Benzon H, et al: Regional anesthesia and anticoagulation—defining the risk. The Second ASRA consensus conference on neuraxial anesthesia and anticoagulation. Reg Anesth Pain Med 28:172-197, 2003. Horlocker TT, Wedel DJ, Offord KP, et al: Preoperative antiplatelet therapy does not increase the risk of spinal hematoma associated with regional anesthesia. Anesth Analg 80:303-309, 1995. Odoom JA, Sih IL: Epidural analgesia and anticoagulant therapy. Anaesthesia 38:254-259, 1983. Rao TLK, El-Etr AA: Anticoagulation following placement of epidural and subarachnoid catheters: An evaluation of neurologic sequelae. Anesthesiology 55:618-620, 1981. Ruff RL, Dougherty JH: Complications of lumbar puncture followed by anticoagulation. Stroke 12:879-881, 1981. Schroeder DR: Statistics: Detecting a rare adverse drug reaction using spontaneous reports. Reg Anesth Pain Med 23:183-189, 1998. Schwander D, Bachmann F: Heparin and spinal or epidural anesthesia: Decision analysis [review]. Ann Fr Anesth Reanim 10:284-296, 1991. Tryba M: Epidural regional anesthesia and low molecular heparin: Pro [German]. Anasth Intensivmed Notfallmed Schmerzther 28:179-181, 1993. Vandermeulen EP, Van Aken H, Vermylen J: Anticoagulants and spinalepidural anesthesia. Anesth Analg 79:1165-1177, 1994. Wu CL, Perkins FM: Oral anticoagulant prophylaxis and epidural catheter removal. Reg Anesth 21:517-524, 1996.

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James C. Crews Case Synopsis

PROBLEM ANALYSIS Definition Infectious complications of central neuraxial anesthetic and analgesic procedures occur rarely but may be associated with significant patient morbidity, including sepsis, epidural or paravertebral abscess formation, meningitis, and paraplegia. A high index of suspicion, early diagnosis, and prompt intervention with appropriate therapy are important for achieving optimal outcomes. Infectious complications of central neuraxial block techniques may range from superficial infection at the percutaneous puncture site to more consequential infections, such as epidural abscess or meningitis. Most consequential infectious complications are associated with percutaneous catheter techniques, although epidural abscess and meningitis have been reported after single-injection epidural anesthesia or corticosteroid injections. Potential mechanisms for infection associated with central neuraxial block include (1) direct inoculation during needle or catheter placement; (2) infection at the catheter exit site, with spread along the catheter track; (3) contamination of the injectate; and (4) hematogenous spread (“bacteremic seeding”) from a distant site of infection. Progressive neurologic impairment of bowel and bladder function or lower extremity sensory and motor function may result from epidural or paravertebral abscess with spinal cord or nerve root compression. The specific pathogenesis underlying spinal cord dysfunction with spinal epidural abscess is thought to be related to direct mechanical

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A 63-year-old woman with a history of diabetes mellitus, hypertension, and chronic low back pain underwent a small bowel resection for obstruction secondary to metastatic colon cancer. A thoracic epidural catheter was placed for perioperative analgesia, and the patient received an epidural infusion of bupivacaine and morphine for 3 days postoperatively. At the time of epidural catheter removal, the insertion site was surrounded by a small area of erythema, with a scant amount of serosanguineous drainage. The patient was followed by the Acute Pain Service for an additional 2 days, at which time she reported severe thoracolumbar back pain, low-grade fever, and heaviness in her legs. Examination of the back revealed a small erythematous area at the previous epidural catheter insertion site with a small amount of purulent drainage. The neurologic examination was unremarkable. Laboratory studies demonstrated leukocytosis. Owing to the patient’s history and complaints, a magnetic resonance imaging (MRI) scan with and without gadolinium contrast was obtained of the thoracic, lumbar, and sacral spine. MRI demonstrated an extensive posterior spinal epidural abscess from T10 to L2. The patient underwent a laminotomy drainage procedure and culture-directed antibiotic therapy for Staphylococcus aureus. The remainder of her hospital recovery was uneventful, and she was discharged home without neurologic sequelae.

compression or vascular damage, with resultant spinal cord hypoxia.

Recognition Superficial infectious complications usually present with localized erythema and drainage at the needle or catheter insertion site. Deep infections may present with local symptoms at the needle or catheter insertion site in addition to the following: ● ● ● ●

Back pain Fever Localized tenderness Leukocytosis

Neurologic impairment due to deep tissue abscess and spinal cord or nerve root compression may present with the following: ● ● ●

Radicular irritation Progressive sensory or motor neurologic deficit Bowel and bladder incontinence The clinical features of meningitis include the following:

● ● ● ●

Nuchal rigidity Headache Leukocytosis and fever Photophobia

Patients with evidence of superficial infection should be evaluated and monitored for the development of symptoms associated with deep infection. Culture of purulent drainage at the site of infection or epidural catheter tip may 239

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be important to direct appropriate antibiotic therapy. Before hospital discharge, patients must be instructed to notify appropriate health care personnel or to seek emergency medical evaluation in the event of any of the following: ● ● ● ●

New onset of back pain Fever Redness or soreness at the needle or catheter insertion site Subtle signs or symptoms of neurologic impairment

Patients with signs or symptoms suggestive of spinal or epidural abscess should be urgently evaluated for fever and leukocytosis and have a thorough neurologic evaluation. Radiographic diagnosis of spinal epidural abscess is best made by gadolinium-enhanced MRI scan of the spine (Figs. 58-1 and 58-2). Diagnosis and treatment of epidural abscess should not be delayed until neurologic deficits become apparent.

Risk Assessment In a meta-analysis of 915 patients with spinal epidural abscess reported in the world literature between 1954 and 1997, neuraxial anesthesia or analgesia had been performed in 5.5% of them; other invasive procedures as diverse as vascular access and spinal surgery accounted for 16.5%. Estimates of the incidence of spinal epidural abscess after central neuraxial block range from 1 in1930 for continuous epidural catheter techniques to 1 in 100,000 for single-injection and short-term techniques. For patients with chronically implanted epidural catheter systems, infectious risk has been reported as 1 per 1702 catheter-days. Although the specific incidence is unclear, the presence of any of the following factors suggests a higher risk for infection following central neuraxial block: ●

● ●

Immunocompromised state (e.g., acquired immunodeficiency syndrome [AIDS], cancer chemotherapy, organ transplantation, chronic dialysis, intravenous drug abuse, chronic alcoholism) Diabetes mellitus Concomitant steroid treatment

Figure 58–2 ■ Sagittal T1-weighted magnetic resonance image of the spine following intravenous administration of gadolinium. There is a large gadolinium-enhanced mass (arrow) in the posterior epidural space extending from T9 to L3. The area of low signal density within the abscess represents a poorly perfused area of liquefaction. (From Rathmell JP, Garahan MB, Alsofrom GF: Epidural abscess following epidural analgesia. Reg Anesth Pain Med 25:79-82, 2000.)

● ● ● ●

Localized infection at insertion site Sepsis Long-term catheter use Bacteremia

Implications Both meningitis and epidural abscess can be life threatening or result in permanent neurologic sequelae if not treated immediately. A high index of clinical suspicion, early diagnosis, and prompt treatment before massive neurologic symptoms occur are key to optimizing patient outcomes.

MANAGEMENT

Figure 58–1 ■ Axial T2-weighted magnetic resonance image of the spine at the level of L1. There is a large, high-signal fluid collection in the posterior epidural space. The abscess is causing anterior displacement of the dural sac (arrowheads), producing approximately 30% reduction in the anteroposterior diameter of the spinal canal. (From Rathmell JP, Garahan MB, Alsofrom GF: Epidural abscess following epidural analgesia. Reg Anesth Pain Med 25:79-82, 2000.)

Patients with superficial infectious complications can be managed by local drainage and antibiotic therapy. However, even these patients, especially those at increased risk for more serious infectious complications, should be carefully instructed and monitored for the development of any signs or symptoms of epidural or spinal abscess or meningitis. They should also be advised to seek immediate medical attention for progressive back pain, fever, or the development of subtle neurologic changes. This will facilitate timely detection, diagnosis, and therapy. Patients with a history of central neuraxial block who present with back pain and fever should undergo a thorough evaluation for serious infectious complications as part of the differential diagnosis. Epidural abscess following

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PREVENTION As with any invasive procedure, the risks associated with a planned central neuraxial block must be weighed against its potential benefits. Although infectious complications are rare, patients who might benefit most from such blocks are often those with associated morbidities or other factors that increase the risk for serious infectious complications. If central neuraxial blocks are used in patients at increased risk for complications, especially if the extended use of indwelling catheters is anticipated for postoperative or post-traumatic injury pain relief, a higher index of suspicion is required when evaluating these patients for potential infectious complications. Meticulous attention to sterile technique is vital for reducing infectious complications associated with central neuraxial blocks or catheters. Thorough hand washing, sterile gloves, surgical caps or hoods and masks, and sterile block techniques are all important considerations. A wide area of skin should be prepared with povidone-iodine, iodophor-inisopropyl alcohol, or chlorhexidine. Adequate time must be given for the solution to dry before the central neuraxial block is performed. Also, use of a “no-touch” technique (i.e., landmarks identified and marked, if necessary, before skin preparation) helps reduce the risk of central neuraxial infectious complications. Chlorhexidine and iodophor-in-isopropyl alcohol reportedly provide better antimicrobial skin disinfection and prevention of bacterial regrowth compared with povidone-iodine. Use of clear plastic surgical drapes offers the advantage of being able to visualize landmarks during the block procedure. Further, covering epidural catheters with clear sterile dressings allows daily assessment of the insertion site. Sterile technique should be maintained for dosing catheters and when changing infusion connections for continuous epidural infusions. Maintaining a tightly closed infusion system throughout therapy should help reduce catheter contamination during line or infusate changes. Infusion solutions should be prepared by pharmacy personnel with sterile technique and under a laminar flow hood. Central neuraxial block in patients with bacteremia remains controversial. If such blocks are deemed necessary or appropriate in patients with bacteremia, one should consider performing the block only after appropriate antibiotic

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coverage has been provided. For patients with indwelling epidural catheters who become bacteremic, it is my practice to remove the catheter, provide indicated antibiotic therapy, and then replace the catheter at a different level if continuous epidural therapy is still desired. Both for cost considerations and because of its low predictive value in identifying contamination and infection, routine culture of epidural catheter tips is not advised. However, if the epidural catheter insertion site is surrounded by an area of localized inflammation or drainage, bacteriologic examination of the epidural catheter tip may suggest appropriate antibiotic therapy. Although preventive measures are important, they cannot entirely eliminate the risk of infectious complications of central neuraxial block. A high index of suspicion for the development of infectious complications, prompt diagnosis, and immediate therapy are paramount for reducing patient morbidity and permanent neurologic injury.

Further Reading Aota Y, Onari K, Suga Y: Iliopsoas abscess and persistent radiculopathy: A rare complication of continuous infusion techniques of epidural anesthesia. Anesthesiology 96:1023-1025, 2002. Birnbach DJ, Meadows W, Stein DJ, et al: Comparison of povidone iodine and DuraPrep, an iodophor-in-isopropyl alcohol solution, for skin disinfection prior to epidural catheter insertion in parturients. Anesthesiology 98:164-169, 2003. Dawson S: Epidural catheter infections. J Hosp Infect 47:3-8, 2001. Du Pen SL, Peterson DG, Williams A, Bogosian AJ: Infection during chronic epidural catheterization: Diagnosis and treatment. Anesthesiology 73:905-909, 1990. Hooten WM, Kinney MO, Huntoon MA: Epidural abscess and meningitis after epidural corticosteroid injection. Mayo Clin Proc 79:682-686, 2004. Huang RC, Shapiro GS, Lim M, et al: Cervical epidural abscess after epidural steroid injection. Spine 29:E7-E9, 2004. Kindler CH, Seeberger MD, Staender SE: Epidural abscess complicating epidural anesthesia and analgesia: An analysis of the literature. Acta Anaesthesiol Scand 42:614-620, 1998. Kinirons B, Mimoz O, Lafendi L, et al: Chlorhexidine versus povidone iodine in preventing colonization of continuous epidural catheters in children: A randomized, controlled trial. Anesthesiology 94:239-244, 2001. Koka VK, Potti A: Spinal epidural abscess after corticosteroid injections. South Med J 95:772-774, 2002. Lee BB, Kee WD, Griffith JF: Vertebral osteomyelitis and psoas abscess occurring after obstetric epidural anesthesia. Reg Anesth Pain Med 27: 220-224, 2002. Leys D, Lesoin F, Viaud C, et al: Decreased morbidity from acute bacterial spinal epidural abscesses using computed tomography and nonsurgical treatment in selected patients. Ann Neurol 17:350-355, 1985. Rathmell JP, Garahan MB, Alsofrom GF: Epidural abscess following epidural analgesia. Reg Anesth Pain Med 25:79-82, 2000. Reihsaus E, Waldbaur H, Seeling W: Spinal epidural abscess: A meta-analysis of 915 patients. Neurosurg Rev 23:175-204, 2000. Sorensen P: Spinal epidural abscesses: Conservative treatment for selected subgroups of patients. Br J Neurosurg 17:513-518, 2003. Steffen P, Seeling W, Essig A, et al: Bacterial contamination of epidural catheters: Microbiological examination of 502 epidural catheters used for postoperative analgesia. J Clin Anesth 16:92-97, 2004. Trautmann M, Lepper PM, Schmitz FJ: Three cases of bacterial meningitis after spinal and epidural anesthesia. Eur J Clin Microbiol Infect Dis 21:43-45, 2002. Wang LP, Hauerberg J, Schmidt JF: Incidence of spinal epidural abscess after epidural analgesia: A national 1-year survey. Anesthesiology 91: 1928-1936, 1999. Wittum S, Hofer CK, Rolli U, et al: Sacral osteomyelitis after single-shot epidural anesthesia via the caudal approach in a child. Anesthesiology 99:503-505, 2003.

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central neuraxial block has been diagnosed days, weeks, and even months after the intervention. Although more conservative treatment approaches have been reported, surgical drainage and antibiotic therapy for epidural abscess are still the definitive treatment of choice. Epidural abscess with neurologic signs or symptoms requires urgent surgical intervention to prevent progressive and possibly permanent neurologic injury. Antibiotic therapy should be initiated promptly. The initial agent used should be effective against Staphylococcus aureus and able to penetrate bone. Ultimately, antibiotic therapy should be directed by specific culture and sensitivity determinations, as well as by clinical or institutional considerations. Depending on the nature and severity of the infection, antibiotic therapy may be required for 4 to 6 weeks or longer.

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Thomas McCutchen and J. C. Gerancher Case Synopsis A frail, 55-kg, 79-year-old woman is admitted for elective hip replacement as the first surgery of the day in a busy ambulatory surgery center. An epidural catheter is placed for surgical anesthesia and postoperative analgesia. With the patient sitting on the operating room table, catheter placement is uneventful. Fifteen milliliters of a slightly hypobaric solution (2% lidocaine with 5 μg/mL of both fentanyl and epinephrine) is administered via the catheter in three 5-mL doses over 3 minutes. Pain in the arthritic hip is immediately relieved, and the patient’s lower extremities become insensate. Five minutes later, she complains of weakness and experiences difficulty breathing. She then becomes apneic and unconscious, with subsequent oxygen desaturation and hypotension. She is ventilated with a mask and then intubated. Blood pressure is maintained with ephedrine and intravenous fluid.

PROBLEM ANALYSIS Definition When local anesthetic in volumes typically used for epidural analgesia or anesthesia is unintentionally administered into the subarachnoid (intrathecal) space, morbidity and mortality may result due to high spinal anesthesia. Such injection may occur if local anesthetic is delivered through a needle or catheter that has fully or partially penetrated the dura and arachnoid membranes.

Recognition The clinical consequences of unintended intrathecal injection depend on the amount of local anesthetic introduced into the cerebrospinal fluid (CSF). Small amounts result in numbness of the lower extremities; larger amounts result in extensive spread and possibly unconsciousness and respiratory arrest secondary to brainstem anesthesia.

Risk Assessment: Anatomic Considerations The epidural space lies outside the dura mater. This tough outer layer of the meninges fuses with periosteum at the foramen magnum. The epidural space extends laterally to the spinal nerve roots, where it fuses with epineurium in the intervertebral foramina, caudad to the sacrococcygeal ligament and anterior to the posterior longitudinal ligament, ligamentum flavum, and laminae. It communicates with the paravertebral space via intervertebral foramina. The contents of the epidural space consist of fat, which is found predominantly posteriorly and laterally. Valveless veins are found predominantly in the lateral and anterior epidural space. 242

The arachnoid membrane is a delicate membrane that abuts the inner surface of the dura mater. It consists of layers of flattened cells with connective tissue fibers running between these layers. The cells are interconnected by tight junctions, which likely accounts for the fact that the arachnoid is the principal physiologic barrier for drugs diffusing from the epidural space to the intrathecal space. In the region of the foramina, where spinal nerve roots traverse both the arachnoid and the dura mater, the arachnoid membrane herniates through the dura to form granulations. Both spinal and intracranial arachnoid granulations serve as portals for CSF and its constituents to exit the central nervous system. The pia mater is an even more delicate layer of the meninges that is adherent to the spinal cord. The intrathecal space lies between the arachnoid membrane and the pia mater and contains CSF. Spinal CSF directly communicates with intracranial CSF.

Implications The epidural space is a potential space, as the majority of the dura is in contact with the walls of the vertebral canal. It is also a discontinuous series of compartments that become continuous only when liquid or air is injected. Thus, a larger dose of local anesthetic is required for epidural anesthesia or analgesia compared with spinal anesthesia. This anatomy also explains the bandlike block that develops in dermatomes just above and below the level of epidural local anesthetic injection, with further spread directly related to the volume of local anesthetic injected. In contrast, when local anesthetic is introduced into and diffuses throughout CSF within the intrathecal space to produce spinal anesthesia, it can produce block well above and below the level of injection. In addition to the volume of drug delivered and its concentration, spread

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MANAGEMENT Early recognition of unintentional spinal injection is paramount to prevent further injections and limit the potential for morbidity. If the patient is in pain as the epidural is being dosed (e.g., an obstetric patient in active labor), the first sign of an unintended intrathecal injection may be almost immediate, total cessation of all pain after injection of a small test dose. This may be followed by motor and sensory block that develops more rapidly and extensively than expected with epidural injection. Treatment for unintended spinal injection is supportive and consists of ensuring a patent airway, oxygenating and ventilating the patient, and supporting blood pressure with fluids (volume) and vasopressors (if needed) until the high block resolves. In any setting where neuraxial anesthesia is used, basic airway equipment must be readily available, along with a wellthought-out plan for managing unconscious and apneic patients with possible complete cardiovascular collapse.

PREVENTION Prevention requires a high index of suspicion during epidural needle and catheter placement, with careful aspiration and appropriate test dosing of the needle and catheter before the administration of the planned epidural volume of local anesthetic. With obvious free flow of CSF via the epidural needle or catheter during attempts to locate the epidural space, epidural-strength doses and volumes of local anesthetic should not be administered. Often, inadvertent intrathecal needle or catheter placement is not obvious. For example, a dural rent or small tear may be made by the tip of the needle intended for epidural placement. This rent or tear may be large enough to admit an epidural catheter, but there would be no CSF return from the needle because its tip resides mostly in the epidural space. In this case, slow, deliberate aspiration of the catheter before injection might identify CSF.

If saline is used for the loss-of-resistance technique or an epidural catheter is being replaced after recent dosing via a previously placed epidural catheter, it may be difficult to determine whether the clear fluid aspirated from the supposed epidural space is previously injected saline or local anesthetic or CSF. Several maneuvers have been suggested to distinguish CSF from other fluids, including measurement of pH, temperature, glucose, and turbidity when mixed with thiopental. Unfortunately, none of these methods has broad clinical utility. If bubbles are aspirated along with the clear fluid and the total amount of clear fluid that can be aspirated is less than 3 to 5 mL, the catheter is not likely to be in the intrathecal space. However, the catheter should not be used until it has been adequately tested. Epidural test doses consist of a small amount of local anesthetic. The rationale is that such small amounts injected into the intrathecal space would produce an easily recognizable motor and sensory spinal block without producing unacceptably high spinal anesthesia; if the same test dose were injected epidurally, it should produce minimal or no obvious effects. A typical test dose might be 40 to 60 mg of lidocaine, which would quickly produce signs and symptoms of relatively low-level spinal block if injected intrathecally. One must also keep in mind that if combined spinal-epidural anesthesia is performed and the patient has received sufficient spinal local anesthetic for high- or low-level surgical anesthesia, any subsequent epidural test dose might result in an unacceptably high level of spinal anesthesia. In all instances, repeat dosing of an in situ epidural catheter should be incremental. Case reports have noted catheter migration into the intrathecal space. Providing an appropriate time interval between incremental dosing to assess for intrathecal injection should allow for the detection of migrated catheters. Finally, intrathecal catheters left in place intentionally should be clearly labeled as such, to prevent accidental dosing with epidural volumes of local anesthetic.

Further Reading Bernards CM: Epidural and spinal anesthesia. In Barash PG, Cullen BF, Stoelting RK (eds): Clinical Anesthesia, 4th ed. Philadelphia, Lippincott Williams & Wilkins, 2001, pp 689-713. Bernards CM, Hill H: The spinal nerve root sleeve is not a preferred route for redistribution of drugs from the epidural space to the spinal cord. Anesthesiology 75:827, 1991. Calimaran AL, Strauss-Hoder TP, Wang WY, et al: The effect of epidural test dose on motor function after a combined spinal-epidural technique for labor analgesia. Anesth Analg 96:167-172, 1996. Hogan Q: Epidural catheter tip position and distribution of injectate evaluated by computed tomography. Anesthesiology 90:964-970, 1994. Poblete B, Van Gessel EF, Gaggero G, Gamulin Z: Efficacy of three test doses to detect epidural catheter misplacement. Can J Anaesth 46:34-39, 1999. Reisner LS: Epidural test solution or spinal fluid? Anesthesiology 44:451, 1976. Tessler MJ, Wiesel S, Wahba RM, Quance DR: A comparison of simple identification tests to distinguish cerebrospinal fluid from local anaesthetic solution. Anaesthesia 49:821-822, 1994. Visser WA: Delayed subarachnoid migration of an epidural catheter. Anesthesiology 88:1414-1415, 1998. Waters JH, Rizzo VL, Ramanathan S: A re-evaluation of the ability of thiopental to identify cerebrospinal fluid in epidural catheter aspirate. J Clin Anesth 7:224-227, 1995.

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of an intrathecally administered local anesthetic is related to the patient’s position, depending on whether a hypotonic or hypertonic local anesthetic solution is injected. If the solution is isotonic, spread of the block is more dependent on the volume and concentration of the local anesthetic injected intrathecally, regardless of whether vasoconstrictors are used to prolong the block. The C3-C5 spinal nerve roots, which contribute to the phrenic nerves, may be anesthetized with “high” epidural blocks. Thus, phrenic nerve paralysis may result from high epidural anesthesia. This can lead to respiratory paralysis with complete awareness. However, because intracranial and vertebral spinal fluid are continuous, spinal anesthetics can reach and anesthetize the brainstem. Finally, direct communication between the epidural and paravertebral spaces may result in a one-sided epidural block, especially if the epidural catheter is placed near, or the majority of local anesthetic is deposited into, a nerve root foramen laterally or the posterior longitudinal ligament anteriorly.

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Thomas McCutchen and J. C. Gerancher Case Synopsis A healthy, 80-kg primigravida (38 weeks’ gestation) is admitted in active labor, with a cesarean section (C-section) planned for breech presentation. Because of an anticipated 1-hour delay before the C-section can begin, a lumbar epidural block is requested for analgesia and anesthesia. This is placed without incident. The patient experiences a significant amount of pain with injection of the 3-mL test dose (1.5% lidocaine with 1:200,000 epinephrine). There are no signs of intrathecal or intravenous administration. The catheter is pulled back 1 cm, and 10 mL of 2% lidocaine is injected in 5-mL increments, with less pain. Her contraction pain resolves completely, and she develops a T6-level block to temperature. Fifteen minutes before the C-section, an additional 15 mL of 2% lidocaine is administered through the epidural catheter, with total loss of sensation below T6 5 minutes after arrival in the operating room. Fifteen minutes later, the patient complains of difficulty breathing; her hand grip and biceps strength are weak. The patient becomes lethargic, followed by a loss of consciousness and finally apnea. She is successfully intubated, and the case proceeds under general anesthesia. She is mechanically ventilated in the operating room and postanesthesia care unit for 3 hours after the initial epidural dosing. She then begins to awaken, gains strength, and is successfully extubated. Later that day, radiopaque contrast material is injected through the epidural catheter and reveals cephalad, parallel, “train-tracking” of the contrast medium.

PROBLEM ANALYSIS Definition If local anesthetic in volumes typically used for epidural analgesia or anesthesia are unintentionally administered into the subdural space, considerable morbidity and mortality may result. Also, such injections may result in inadequate blockade.

Recognition Classically, subdural injection has been described as an unexpectedly high block 15 to 35 minutes after intended lumbar epidural injection. When investigated with radiographic contrast material, a stereotypical cephalad “railroad tracking” of contrast material (outlining the subdural space circumferentially around the thecal sac) has been seen (Figs. 60-1 to 60-3). Since 1975, there have been 30 reports of unusually extensive blocks with subdural injection that were confirmed by radiocontrast radiography. Because the subdural space extends above the foramen magnum, some cases presented as unconsciousness with centrally mediated apnea. Recent work, mainly by Collier, suggests that cases with the latter presentation are merely one subset of the possible clinical manifestations of subdural injection. Other presentations, including low block, unilateral block, and dermatomal block, are usually not investigated with radiographic contrast 244

material and thus are not recognized as attributable to local anesthetic subdural injection. The myriad possible presentations of subdural injection have not been identified owing to the dearth of investigation. Collier recently used radiography to investigate 35 cases of atypical or inadequate epidural blocks for cesarean delivery and found four instances (11.4%) of subdural radiocontrast injection. Each patient had severe pain with injection of less than 5 mL of “epidural” local anesthetic. Three had low blocks, and one had a one-sided block. With time (25 to 50 minutes), and after the injection of 10 to 20 mL of additional local anesthetic, all patients eventually achieved surgical anesthesia. Depending on the volume injected and the force and direction of injection, local anesthetic may track cephalad, caudad, or laterally toward a nerve root or form a well-localized “pocket” of local anesthetic. Further, use of multiple orifice catheters may facilitate multicompartment (e.g., subduralepidural or subdural-intrathecal) injections. Collier further speculates that several potential tissue planes exist within the arachnoid membrane and the arachnoid-dura interface,“with each plane having its own radiographic findings and clinical significance.”

Risk Assessment Subdural injections are not injections into a potential space, as epidural injections are. Rather, the injectate produces

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A

B

Figure 60–1 ■ Anteroposterior (A) and lateral (B) views of the lumbar spine after radiocontrast injection through a lumbar catheter (dotted line) reveal a focal collection of contrast material in the subdural space anterior to the thecal sac. (From Collier CB: Accidental subdural injection during attempted lumbar epidural block may present as failed or inadequate block: Radiographic evidence. Reg Anesth Pain Med 29:45-51, 2004.)

A

B

Figure 60–2 ■ Anteroposterior (A) and lateral (B) views of the lumbar spine after contrast injection through a lumbar catheter (dotted line) reveal multicompartment spread of radiocontrast around the thecal sac in the subdural space of L3-L5 (S), and anterior-caudad spread of radiocontrast into the sacral canal (E). (From Collier CB: Accidental subdural injection during attempted lumbar epidural block may present as failed or inadequate block: Radiographic evidence. Reg Anesth Pain Med 29:45-51, 2004.)

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A

B

Figure 60–3 ■ Anteroposterior (A) and lateral (B) views of the lumbar spine after radiocontrast injection through a lumbar catheter reveal multicompartment subdural spread of radiocontrast (S), including localized extension along the L4 nerve root (visible in A) and into the epidural space (E) of L3. (From Collier CB: Accidental subdural injection during attempted lumbar epidural block may present as failed or inadequate block: Radiographic evidence. Reg Anesth Pain Med 29:45-51, 2004.)

a disruptive dissection between two tissue planes. Both Collier and Reina and colleagues describe the subdural space as the dura-arachnoid interface formed by a cellular junction between the two membranes. This junction is composed of neuroepithelial cells surrounded by an amorphous substance. There is no subdural space in nontraumatized tissues. Both groups hypothesize that a subdural space may appear if the neuroepithelial cells break up as a result of pressure exerted by mechanical shear forces, air, or injected fluids. Any of these have the potential to create fissures within the amorphous substance of the dura-arachnoid interface. Such fissures could readily expand toward weaker areas, especially laterally, where the amorphous substance is more prolific. Unintended subdural injection occurs when local anesthetic is injected through a needle or catheter that has created a disruption in the subdural space large enough to accommodate local anesthetic. Subdural injections are unpredictable. Given the flimsy nature of the arachnoid and its intimate relationship with the dura, it is remarkable that subdural injections are even possible. Indeed, the most skilled neurosurgeons have difficulty incising the dura under direct vision without disrupting the arachnoid membrane. The reported rate of unintended subdural injection during epidural anesthesia is about 0.8%. However, it is now believed that subdural injections are more common than previously thought. Indeed, the radiology literature reports a 10% rate of subdural injection during attempted spinal myelography. A likely explanation for this discrepancy is that radiologists have readily available radiocontrast materials for detecting subdural injections. Thus, unusual blocks following

epidural injection that are not investigated radiographically may be the result of subdural injection.

Implications Patients may have transient pain with the injection of small volumes of local anesthetic. This is uncommon with epidural or intrathecal injection of similar volumes. This pain is thought to be caused by either cleaving of meningeal tissues or nerve root compression due to the mass effect of subdural injectates. Pain is short-lived and without sequelae. Additional doses cause little if any pain. Subdural local anesthetic injection can present in multiple ways, depending on the spread and direction of the dissecting injectate and the amount that enters the epidural, subdural, or intrathecal compartment. Subdural and multicompartment injections may present as a high block, low block, radicular block, “patchy” block, or one-sided block. High blocks caused by subdural injections have a clinical presentation similar to that of high spinal blockade (unconsciousness, centrally mediated apnea, hypotension). High subdurals may be difficult to distinguish from high epidurals, because both blocks mature over a relatively long period (15 to 30 minutes). With additional local anesthetic and time, inadequate blocks may eventually resemble a normal epidural block, or they may require catheter manipulation and replacement. Attempted intrathecal block after subdural injection may be difficult, because the needle and injectate tend to reenter the newly created subdural space. This may occur even several months after suspected subdural injection, suggesting

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that a permanent defect may be formed that predisposes the patient to subsequent subdural injections. Indeed, two of Collier’s most recent cases involved one patient who experienced subdural injection during what appeared to be uncomplicated epidural catheter placements for two cesarean deliveries.

MANAGEMENT Treatment of extensive blockade is supportive, as for unintended high intrathecal injection. Inadequate subdural blockade may be overcome with additional doses of local anesthetic, but there is the associated risk of more extensive block.

Unlike the situation with intrathecal needle or catheter placement, aspiration and incremental dosing do not prevent

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subdural injection. However, removing a needle or catheter through which small injections of local anesthetic produced pain may prevent subdural blockade.

Further Reading Bernards CM: Epidural and spinal anesthesia. In Barash PG, Cullen BF, Stoelting RK (eds):Clinical Anesthesia, 4th ed. Philadelphia, Lippincott Williams & Wilkins, 2001, pp 689-713. Collier CB: Accidental subdural block: Four more cases and a radiographic review. Anesth Intensive Care 20:215-232, 1992. Collier CB: Accidental subdural injection during attempted lumbar epidural block may present as a failed or inadequate block: Radiographic evidence. Reg Anesth Pain Med 29:45-51, 2004. Jones M, Newton T: Inadvertent extra-arachnoid injections in myelography. Radiology 80:818, 1963. Lubenow T, Keh-Wong E, Kristof K, et al: Inadvertent subdural injection: A complication of epidural block. Anesth Analg 67:175, 1988. Reina MA, De Leon Casasola O, Lopez A, et al: The origin of the spinal subdural space: Ultrastructure findings. Anesth Analg 94:991-995, 2002. Schultz GH, Brogden BG: The problem of subdural placement in myelography. Radiology 79:91-95, 1962.

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PREVENTION

Epidural Anesthesia: Unintended Subdural Injection

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Alain Borgeat and Steffan Blumenthal Case Synopsis A 25-year-old man presents for rotator cuff repair and has an interscalene block and catheter placed. The block is performed using Winnie’s landmarks and with the aid of a nerve stimulator. A triceps response is obtained at a depth of 2.5 cm. The catheter is threaded 6 cm past the tip of the stimulating needle. The procedure is uneventful, except for transient resistance encountered during catheter placement. After negative aspiration for blood and cerebrospinal fluid, 0.5% bupivacaine is slowly injected through the catheter. After 10 mL is injected, the patient becomes drowsy, then unresponsive and apneic, with loss of muscle tone in all extremities; his pupils are widely dilated. The patient is given oxygen with manual assisted ventilation, followed by tracheal intubation.

PROBLEM ANALYSIS Definition Total spinal anesthesia is one of the most severe complications that can occur during the performance of an interscalene block. Other severe complications include injection of the local anesthetic into the vertebral artery, high epidural anesthesia, subdural injection, pneumothorax, and neuropathy.

Recognition The signs and symptoms of total spinal anesthesia result from blockade of the cervicothoracic segments of the central neuraxis. Symptoms of central nervous system involvement are virtually always present and range from the inability to phonate to unconsciousness and the rapid development of bilateral flaccid paralysis. Bilateral dilated, nonreactive pupils are frequently observed, consistent with a block of parasympathetic efferent activity from the Edinger-Westphal nucleus. The latter sign demonstrates that some amount of local anesthetic entered the cranium. Apnea is usually (but not always) present, due to the close proximity of the phrenic nerve roots (C3-C5) to the site of interscalene injection (C6-C7). The development of bradycardia and hypotension is explained by either cervicothoracic spinal block of the cardiac accelerator fiber (T1-T4) or penetration of local anesthetic into the medullary region of the central nervous system. The application of local anesthetic in this structure results in hypotension, bradycardia, and ventricular arrhythmias. The differential diagnosis includes injection of local anesthetic into the vertebral artery. When this occurs, seizures and unconsciousness are almost immediate. Hypotension and bradycardia may also be due to the cardiotoxic effects of local anesthetics. After epidural injection, such signs and symptoms develop more slowly. Moreover, the epidural 248

space does not extend intracranially. Therefore, signs and symptoms related to intracranial spread of local anesthetic are unlikely. Subdural injection is also part of the differential diagnosis. In this case, the development of clinical block is even slower and usually asymmetrical and incomplete. Intravascular injection or rapid reabsorption of the local anesthetic should always be considered with both central nervous system toxicity and hemodynamic instability. However, the presence of bilateral flaccid paralysis makes this diagnosis very unlikely. Different mechanisms may be implicated in the occurrence of total spinal anesthesia following interscalene block (Table 61-1). Direct injection into the subdural or epidural space may be the consequence of incorrect needle placement through an intervertebral foramen. A perineural or intraneural injection may lead to secondary migration of the drug into the subdural space. Finally, long dural sleeves have been shown in autopsy studies, extending as far as 3 to 5 cm beyond the intervertebral foramen. Placement of a needle into an abnormally long dural root sleeve may explain the spread of local anesthetic into the intrathecal space.

Risk Assessment Total spinal anesthesia following interscalene block, either with or without a perineural catheter, is a rare but serious complication. Such events are often documented as case

Table 61–1

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Proposed Mechanisms of Intrathecal Migration of Local Anesthetics

Injection through intervertebral foramen Direct intraneural injection Injection into dural root sleeve

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Advantages/ Disadvantages Spinal injection Epidural injection Vertebral artery injection Intravenous injection Pneumothorax Discomfort Ease of catheter placement

Winnie ++ ++ + + + +/− −

Posterior ++ ++ +/– + + ++ +

Modified Lateral – – − + + +/− ++

reports. Thus, there is no way to estimate the specific risk for this complication. The only identifiable factor that increases risk is the approach used to perform the block. Three main techniques are used: the Winnie approach, the posterior approach, and the modified lateral approach. The relative advantages and disadvantages of each technique are given in Table 61-2.

Implications Total spinal anesthesia is a rare complication following interscalene block. However, its diagnosis should be prompt. The differential diagnoses of vertebral artery or intravenous injection should be rapidly ruled out so that the appropriate remedial measures can be instituted. Spontaneous breathing often ceases promptly, so assisted manual or mechanical ventilation will be necessary. Bradycardia and hypotension may occur as a result of vasodilatation and block of the cardiac accelerator fibers, which may lead to cardiac arrest if not treated urgently.

Figure 61–1 ■ Winnie’s technique. The needle is directed medially, caudad, and slightly posteriorly toward the transverse process of C6. The needle is close to the spinal structures. C, clavicle; MC, cricothyroid membrane; MS, clavicular head of sternocleidomastoid muscle; dotted line, interscalene groove.

intra-arterial, or intrathecal drug administration is still possible. The choice of approach for performing the interscalene block has implications in the occurrence of complications. Winnie’s approach (Fig. 61-1) directs the needle more toward the spine and therefore increases the risk of injection through an intervertebral foramen, especially if the needle is directed too horizontally. The posterior approach is a paravertebral block. All paravertebral blocks carry at least some risk of puncturing the dural cuff (whether abnormally long or not) that accompanies spinal nerves distal to the intervertebral foramina. The modified lateral approach (Fig. 61-2) directs the needle away from spinal structures and is likely the safest technique for avoiding intervertebral or inadvertent dural puncture Advancing the catheter more than 2 to 3 cm past the tip of the stimulating needle carries no advantage. In fact, by threading it

MANAGEMENT The first step is to immediately cease the local anesthetic injection. Further management includes the following: ●

●

●

●

●

Provide assisted manual or mechanical ventilation with 100% oxygen. Tracheal intubation is often necessary but not always mandatory. Consider the patient’s mental status, drugs administered, and surgical procedure. Volume expansion may be required to treat or prevent hemodynamic instability. Vasopressors, positive chronotropic drugs, or temporary pacing may be required to treat bradycardia or hypotension. Monitor the patient in the intensive care unit or recovery room until the block wears off.

PREVENTION The most important precaution is to administer the drug slowly, with repeated aspiration; however, intravenous,

Figure 61–2 ■ Modified lateral approach. The needle is inserted toward the plane of the interscalene space at an angle of between 45 and 60 degrees. The needle avoids the spinal structures. C, clavicle; MC, cricothyroid membrane; MS, clavicular head of sternocleidomastoid muscle; dotted line, interscalene groove.

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++, most likely/easiest; +, less likely/easy; +/−, possible; − unlikely/difficult.

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farther, the anesthesiologist loses control over its position (e.g., interscalene catheters have been placed within the pleura). Last, an important precaution is to perform the interscalene block only in awake or lightly sedated patients. This allows the patient to report paresthesia (needle encounters a nerve root) or pain due to intraneural injection, and it allows the operator to more promptly recognize early signs of central nervous system toxicity.

Further Reading Borgeat A, Dullenkopf A, Ekatodramis G, Nagy L: Evaluation of the lateral modified approach for continuous interscalene block after shoulder surgery. Anesthesiology 99:436-442, 2003.

Borgeat A, Ekatodramis G, Kalberer F, Benz C: Acute and nonacute complications associated with interscalene block and shoulder surgery: A prospective study. Anesthesiology 95:875-880, 2001. Brown AR: Regional anesthesia for shoulder surgery. Tech Reg Anesth Pain Manage 3:64-78, 1999. Iocolano CF: Total spinal anesthesia after an interscalene block. J Perianesth Nurs 12:163-170, 1997. Long TR, Wass CT, Burkle CM: Perioperative interscalene blockade: An overview of its history and current clinical use. J Clin Anesth 14:546-556, 2002. Norris D, Klahsen A, Milne B: Delayed bilateral spinal anaesthesia following interscalene brachial plexus block. Can J Anaesth 43:303-305, 1996.

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Supraclavicular and Infraclavicular Block: Pneumothorax Sandra L. Kopp Case Synopsis

PROBLEM ANALYSIS Definition Pneumothorax is an accumulation of air or gas in the space between the lung and the chest wall (pleural space). With the supraclavicular approach, the brachial plexus is blocked at the level of its three trunks, where it is most compactly arranged (Fig. 62-1). There are several advantages to the supraclavicular brachial plexus technique, including neutral position of the arm, quick onset of blockade, and a very homogeneous block. Limitations of this approach include difficulty describing or teaching the technique and the risk of pneumothorax. This block is best avoided in uncooperative patients or those with unclear landmarks. Special consideration must be given to patients who could not tolerate the respiratory distress that may accompany a pneumothorax or phrenic nerve block, such as those with severe respiratory disease. The infraclavicular approach to brachial plexus block allows local anesthetic injection above the level where the musculocutaneous and axillary nerves branch off the plexus. This approach is more proximal than the axillary technique and more distal than the supraclavicular approach, thus leading to blockade of all the nerves derived from the plexus, but with a lower incidence of pneumothorax (Fig. 62-2). As with the supraclavicular approach, the arm can remain in a neutral position. This approach has recently gained favor for use in patients requiring a continuous catheter technique, because maintaining an aseptic dressing at this site is much more practical than in the axilla.

Recognition Recognition of a pneumothorax is based largely on the clinical presentation. A pneumothorax may occur immediately during block placement, or it may present hours later. The diagnosis of pneumothorax should be suspected if air is aspirated through the needle during performance of the block, or if a patient becomes acutely dyspneic after block placement.

Unilateral phrenic nerve paralysis and concomitant elevation of the hemidiaphragm must be ruled out, as this is very common after proximal brachial plexus blocks (e.g., interscalene blocks). Although the incidence of hemidiaphragmatic paresis is significantly lower in patients having supraclavicular block compared with interscalene block, it is still estimated to occur in approximately 50% of all patients. Infraclavicular block is rarely associated with changes in pulmonary function. If a patient’s clinical condition suddenly deteriorates during mechanical ventilation, pneumothorax must be considered.

Middle and anterior scalene muscles

Brachial plexus

A

First rib

Brachial plexus

B

Subclavian artery

Figure 62–1 ■ A, Supraclavicular block. The needle is systematically walked anteriorly and posteriorly along the rib until the brachial plexus is located. B, Trunks of the brachial plexus are compactly arranged at the level of the first rib. (From Miller RD [ed]: Anesthesia, 5th ed. Philadelphia, Churchill Livingstone, 2000, p 1524.)

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A 42-year-old man complains of shortness of breath and mild right-sided chest pain in the outpatient recovery area, shortly after a right wrist fusion. A preoperative brachial plexus block was placed using the supraclavicular approach. Upon examination, the patient’s respiratory rate is 20 breaths per minute, and his room-air saturation is 94%. His blood pressure and heart rate are normal. A chest radiograph is positive for a small, right-sided pneumothorax.

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Chassaignac's tubercle C6

B 2.5 cm Insertion site

A Figure 62–2 ■ A, Surface markings for the infraclavicular approach to brachial plexus block. B, Cephalocaudad arc of needle redirection. (From Brown DL: Atlas of Regional Anesthesia, 2nd ed. Philadelphia, WB Saunders, 1999, p 47.)

Patients who are being ventilated with volume-controlled ventilators present with increased peak and plateau pressures; those ventilated with pressure-controlled ventilators have reduced tidal volumes with a new pneumothorax. The chest may have a hyperresonant or tympanitic sound during percussion. There may also be absent breath sounds on the affected side. These signs are most notable when there is at least a 25% reduction in lung volume. Although a computed tomography (CT) scan is the most sensitive study, a chest radiograph is usually diagnostic. Radiographs obtained at the end of expiration allow easier visualization because the pneumothorax takes up a greater proportion of the hemithorax during this part of the respiratory cycle. The main radiographic feature of a pneumothorax is a white visceral pleural line, separated from the parietal pleura by an avascular collection of gas. In most cases, no pulmonary vessels are visible beyond the visceral pleural edge (Fig. 62-3).

Implications Normally, the pressure in the pleural space is negative with respect to the alveolar pressure during the entire respiratory cycle. If the needle punctures the chest wall during block placement, it creates a communication between the atmosphere and the pleural space. Air begins to enter the pleural space until

Risk Assessment The incidence of pneumothorax during supraclavicular block ranges from 0.5% to 6.1%. There is an inverse relationship between the incidence of pneumothorax and the experience of the anesthesiologist performing the block. Relatively new techniques, such as the “plumb-bob” approach, have been used to reduce the risk of pneumothorax. Routine chest radiography following a supraclavicular block is not justified because of the low incidence of pneumothorax and the fact that the onset of symptoms may take up to 24 hours.

Figure 62–3 ■ Right-sided 40% pneumothorax. Arrows mark the visceral pleural line.

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MANAGEMENT If the patient has minimal symptoms and the pneumothorax is less than 15% of the lung volume, simple observation is advised. It is also necessary to provide the patient with supplemental oxygen, which will increase the rate of absorption of the pneumothorax. Because nitrogen is the primary gas in the pleural space, the gradient for nitrogen absorption into the blood is the main factor in determining the rate of reabsorption of a pneumothorax. Reabsorption can be accelerated by breathing 100% oxygen, which lowers the partial pressure of nitrogen in the blood, thereby increasing the gradient for nitrogen absorption from the pleural space. If the patient has more than minimal symptoms or if the pneumothorax occupies more than 15% of the hemithorax, aspiration with a plastic catheter is the treatment of choice. If aspiration does not prevent expansion of the pneumothorax, tube thoracostomy should be performed. Treatment of patients who are undergoing positivepressure mechanical ventilation should include tube thoracostomy to prevent the development of a tension pneumothorax.

Most often, the chest tube is inserted via an incision at the fourth or fifth intercostal space in the anterior axillary or midaxillary line and directed apically. A tension pneumothorax is a medical emergency. When it is suspected, the patient should immediately receive 100% oxygen to alleviate hypoxia. A large-bore angiocatheter should be inserted into the pleural space through the second intercostal space, along the midclavicular line. If the diagnosis is confirmed by the aspiration of air through the catheter, the patient should undergo immediate tube thoracostomy.

PREVENTION Many modifications have been made to supraclavicular and infraclavicular blocks to decrease the complication rate. In 1949 Bonica and colleagues first recommended a careful, gentle technique; thorough familiarity with anatomic relationships; use of the first rib as a protective shield over the lung; and use of a short, fine needle to help prevent complications, including pneumothorax. Although many years have passed, and several reviews have been published since then, this careful approach is still the best advice for any anesthesiologist planning to perform these techniques.

Further Reading Bonica JJ, Moore DC, Orlov M: Brachial plexus block anesthesia. Am J Surg 65, 1949. Brown DL, Bridenbaugh LD: The upper extremity: Somatic block. In Cousins MJ, Bridenbaugh PO (eds): Neural Blockade in Clinical Anesthesia and Management of Pain, 3rd ed. Philadelphia, Lippincott-Raven, 1998, pp 345-371. Brown DL, Cahill DR, Bridenbaugh LD: Supraclavicular nerve block: Anatomic analysis of a method to prevent pneumothorax. Anesth Analg 76:530-534, 1993. Light RW, Broaddus VC: Pneumothorax, chylothorax, hemothorax, and fibrothorax. In Murray JF, Nadel JA (eds): Textbook of Respiratory Medicine, 3rd ed. Philadelphia, WB Saunders, 2000, pp 2043-2066. Neal JM, Moore JM, Kopacz DJ, et al: Quantitative analysis of respiratory, motor, and sensory function after supraclavicular block. Anesth Analg 86:1239-1244, 1998. Rodriquez J, Barcena M, Rodriguez V, et al: Infraclavicular brachial plexus block effects on respiratory function and extent of the block. Reg Anesth Pain Med 23:564-568, 1998.

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the pressure gradient is eliminated or the communication is repaired. The main physiologic changes associated with a pneumothorax are decreased arterial partial pressure of oxygen (PO2) and decreased vital capacity. The consequences are much more pronounced in patients with poor lung function, because a decrease in vital capacity can lead to respiratory insufficiency, which manifests as hypoventilation and ultimately respiratory acidosis. Although a tension pneumothorax is unlikely in a spontaneously breathing patient, those who have positive-pressure mechanical ventilation are at significantly increased risk. A tension pneumothorax occurs when the positive pressure of inspiration forces more air into the pleural space than exits during expiration. A sudden decline in the patient’s cardiopulmonary status should raise suspicions of the presence of a tension pneumothorax. The deterioration in cardiopulmonary status is likely due to the combination of decreased cardiac output secondary to decreased venous return and extreme hypoxia due to ventilation-perfusion mismatching.

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Gilbert Y. Wong and David L. Brown Case Synopsis A 55-year-old woman presents with epigastric abdominal pain of several months’ duration and a recent diagnosis of pancreatic cancer. To manage her pain, a neurolytic celiac plexus block is performed using the classic posterior percutaneous approach. Soon after injection of the neurolytic solution, she notices sensory loss and impaired motor control of her lower extremities.

PROBLEM ANALYSIS Definition Neurolytic celiac plexus block (CPB) is an effective analgesic technique used primarily for pain management in patients with intra-abdominal malignancies, especially pancreatic cancer. Neurolytic solutions are injected in the area of the celiac plexus or splanchnic nerves, which are the neural structures transmitting the majority of visceral pain from the abdomen. Because the targeted area of neurolysis is in close proximity to vascular and other neurologic structures (Fig. 63-1), neurologic side effects and complications are the primary concerns associated with CPB. Neurologic side effects such as orthostatic hypotension or bowel hypermotility often occur after an effective neurolytic CPB. The celiac plexus and splanchnic nerves are primarily sympathetic nervous system structures. Neurolysis of these structures results in sympatholysis and a relative increase in parasympathetic tone in the splanchnic region. As a result, vasodilatation of the splanchnic vasculature, especially the venous capacitance bed (which effectively reduces venous return and cardiac preload), can result in orthostatic hypotension. In addition, the relative increase in parasympathetic outflow to the viscera can result in increased peristalsis and bowel hypermotility. Neurologic complications are the most serious concerns associated with neurolytic CPB. Although they are rare, these complications can include sensory and motor deficits of the lower trunk and lower extremities, loss of bladder or bowel control or both, and impotence in males. Neurolysis of sensory or motor nerves can occur from direct contact of the neurolytic solution, such as alcohol or phenol, spreading to the intrathecal or epidural space or thoracic or lumbar nerve roots (see Fig. 63-1). In a separate mechanism, alcohol has been shown to cause arterial spasm of feeding arteries to the spinal cord, which can result in ischemia and permanent neurologic deficits (Fig. 63-2).

Recognition Neurologic side effects, such as orthostatic hypotension and bowel hypermotility, are not appreciated until after the 254

neurolytic procedure is completed. Patients with intraabdominal malignancies often have decreased oral intake owing to pain or nausea. Decreased intravascular volume can potentiate the hypotensive effects of neurolytic CPB. Symptoms associated with orthostatic hypotension include syncope or dizziness in the upright position, which may be exacerbated during a rapid shift from the supine position. These symptoms may occur immediately after the CPB. Orthostatic hypotension can be diagnosed based on blood pressure measurements performed before and after the neurolytic CPB with the patient in the supine and upright positions. Bowel hypermotility effects may not be noticed until hours after the neurolytic CPB. Because patients experiencing pain associated with intra-abdominal malignancies are frequently treated with opioid medications, and because constipation is a common side effect of opioid medications, such patients often consider increased bowel motility to be beneficial. Neurologic complications, such as sensory and motor changes of the lower trunk and extremities, must be carefully evaluated both during and after the CPB procedure. Although not completely reliable, needle aspiration for cerebrospinal fluid or blood should occur both before and during the incremental injections of neurolytic solution. If cerebrospinal fluid or blood is aspirated, no additional injections should occur until the needle position is reevaluated. Before the injection of a neurolytic agent, a functional test consisting of local anesthetic injection is important to rule out incorrect needle placement. Neurologic deficits occurring as a result of local anesthetic injection into the intrathecal or epidural space or in contact with the thoracolumbar nerve roots confirm incorrect needle positioning. Radiographic guidance, such as fluoroscopy or CT, can also be used to recognize grossly inaccurate needle placement.

Risk Assessment The risks of neurologic side effects and complications must be carefully considered and weighed against the benefits of neurolytic CPB in patients with intra-abdominal malignancies and limited life expectancy. Meta-analysis of the literature regarding patients undergoing neurolytic CPB found that hypotension occurred in

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Aorta Retrocrural spread

L1

Splanchnic nerves Celiac plexus

REGIONAL ANESTHESIA AND PAIN MANAGEMENT

Ao

Anterocrural spread

Diaphragmatic crura Figure 63–1 ■ The spread of neurolytic solution in a celiac plexus block occurs in anterocrural or retrocrural regions. The neurolytic solution is in close proximity to vital structures associated with the spine, including the intrathecal and epidural spaces, thoracic and lumbar nerve roots, and major feeding arteries of the spinal cord.

Ant. sulcal a.

Ant. radicular a. A. of Adamkiewicz Ant. spinal a. T – 12

L–1

L–2

Lumbar a. Aorta

Figure 63–2 ■ Arterial supply of the spinal cord at low thoracic and high lumbar vertebral levels. The largest feeding artery to the spinal cord is the artery of Adamkiewicz (anterior radicular artery), which branches from the lumbar artery (in this case).

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38% of cases and bowel hypermotility occurred in 31% to 44% of cases. A case series of 136 patients who had neurolytic CPB reported that 8 patients (6%) with symptomatic orthostatic hypotension required treatment. Another study (61 patients) that prospectively compared different CPB techniques reported a 38% incidence of transient decreases in systolic blood pressure greater than 33% compared with baseline measurements. Bowel hypermotility also occurred in 31% of these patients. In the largest series (2730 patients) evaluating neurologic complications associated with neurolytic CPB, four cases (0.15%) of permanent paraplegia were identified. In three of these cases, there was also loss of anal and bladder sphincter function. Radiographic guidance with radiocontrast dye was used for CPB in all four cases. In a case series by Brown and coworkers, there were no cases of permanent paraplegia in 136 patients undergoing neurolytic CPB. Meta-analysis of the literature revealed a 1% incidence of neurologic complications, including lower extremity weakness, paresthesia, epidural anesthesia, and lumbar puncture, after neurolytic CPB.

Implications Benign neurologic side effects can occur in patients receiving neurolytic CPB. These side effects can usually be treated in a symptomatic manner with no significant impact on the patient. Orthostatic hypotension typically improves shortly after equilibration of the intravascular volume. Bowel hypermotility is usually transient and may actually be desirable in many patients. The potential for neurologic side effects should be discussed with the patient and family before the procedure. Neurologic complications are very uncommon but can have a significant impact. In patients with intra-abdominal malignancies, these neurologic deficits are likely to continue for the remainder of their lives.

MANAGEMENT The management of neurologic side effects is directed toward symptomatic relief. Orthostatic hypotension, if symptomatic, can be treated by increasing oral fluid intake or intravenous fluids. Leg wrappings with elastic bandages or support stockings can also decrease venous capacitance and improve hypotension. Antihypertensive medications, if any, should be discontinued until equilibration of intravascular volume is reached. If symptoms are sustained and not responsive to conservative therapy, pharmacologic treatment with an α1-agonist, such as midodrine, can be considered. Bowel hypermotility can be treated symptomatically with antihypermotility medications such as diphenoxylate with atropine.

The management of neurologic complications is more complicated. If neurologic deficits occur during neurolytic CPB, the procedure should be terminated immediately. Aspiration of the injectate can be attempted but is unlikely to be effective. Emergency consultation with a neurologist is recommended. If ischemia of the spinal cord is suspected as a result of spasm of a lumbar radicular artery, the immediate involvement of an interventional radiologist for arterial vasodilatation should be considered.

PREVENTION The neurologic side effects of orthostatic hypotension and bowel hypermotility are not preventable; they are merely the result of a successful CPB. The ability to prevent neurologic complications with the use of radiographic guidance is controversial. Traditionally, the CPB procedure relies on anatomic landmarks rather than radiographic guidance. Needle position is confirmed with a functional test of injected local anesthetic. If the patient notes an appropriate improvement in preexisting pain with no neurologic deficits, the needle position is considered to be correct. This approach requires that the patient not be oversedated, so that he or she can provide reliable responses. The large case series of 2730 patients undergoing neurolytic CPB revealed four cases of permanent paraplegia, all of which involved the use of radiography and radiocontrast dye to confirm final needle placement. Thus, radiographic guidance cannot ensure the prevention of neurologic complications. Despite these observations, the use of radiographic guidance provides the advantage of confirming needle position and the spread of injectate, as traced by the radiocontrast dye, before the injection of neurolytic solution.

Further Reading Brown DL, Bulley CK, Quiel EL: Neurolytic celiac plexus block for pancreatic cancer pain. Anesth Analg 66:869-873, 1987. Davies DD: Incidence of major complications of neurolytic coeliac plexus block. J R Soc Med 86:264-266, 1993. Eisenberg E, Carr DB, Chalmers TC: Neurolytic celiac plexus block for treatment of cancer pain: A meta-analysis. Anesth Analg 80:290-295, 1995. Goudas L, Carr DB, Bloch R, et al: Management of Cancer Pain: Evidence Report/Technology Assessment No. 35 (AHCPR Publication No. 02E002). Rockville, Md, Agency for Healthcare Research and Quality, 2001. (Prepared by the New England Medical Center Evidence-Based Practice Center under Contract No. 290-97-0019.) Ischia S, Ischia A, Polati E, et al: Three posterior percutaneous celiac plexus block techniques. Anesthesiology 76:534-540, 1992. Wong GY, Brown DL: Transient paraplegia following celiac plexus block. Reg Anesth 20:352-355, 1995. Wong GY, Schroeder DR, Carns PE, et al: Effect of neurolytic celiac plexus block on pain relief, quality of life, and survival in patients with unresectable pancreatic cancer—a randomized controlled trial. JAMA 291:1092-1099, 2004.

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Robert S. Weller Case Synopsis

PROBLEM ANALYSIS Definition Retroperitoneal hemorrhage after psoas compartment block (PCB) results from arterial bleeding into the retroperitoneal space. Signs and symptoms of PCB depend on the rate and extent of bleeding and whether the hematoma compresses adjacent structures. The most rapid and dramatic bleeding occurs with aortic rupture, which is often fatal. However, bleeding from smaller arteries after PCB can also cause morbidity or mortality. Numerous cases of retroperitoneal hemorrhage have been reported following interventional radiology procedures requiring femoral artery cannulation, especially if the artery is injured proximal to the inguinal ligament. The incidence following cardiac catheterization is reportedly 0.12%. Only a few cases of retroperitoneal hemorrhage have been reported after PCB or lumbar sympathetic block; anticoagulant therapy at the time of or after the block was involved in each of those cases. Spontaneous retroperitoneal hematoma may also occur in patients on chronic anticoagulant therapy. The risk of this complication increases as the degree of anticoagulation increases. Finally, spontaneous iliopsoas hemorrhage with femoral nerve palsy is the most common nerve palsy caused by spontaneous bleeding in hemophiliacs.

Recognition Retroperitoneal bleeding is deep, concealed, and rarely obvious until significant blood loss has occurred. The most common signs of retroperitoneal hemorrhage are hypotension and tachycardia due to intravascular volume depletion, and

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A 76-year-old man with a mechanical aortic valve was scheduled for left above-knee amputation. Chronic warfarin (Coumadin) was stopped, and a heparin infusion was begun on admission but stopped 4 hours before surgery. On arrival in the preoperative area, his prothrombin time, international normalized ratio, and activated partial thromboplastin time were normal; hemoglobin was 13 g/dL. A posterior approach to the lumbar plexus block (psoas compartment block) was performed, in combination with a subgluteal sciatic block. His vital signs remained stable, and the surgery and recovery room stay were uneventful. The estimated blood loss was 300 mL. The patient was returned to the floor, and heparin was restarted 8 hours postoperatively at 1200 units/hour. His blood pressure gradually declined overnight from his usual 140/90 to 95/55 mm Hg, and he became confused and oliguric. He received several 500-mL normal saline fluid challenges. The blood pressure improved, but urine output remained low. The next morning, his hemoglobin was 7.3 g/dL. Two units of packed red blood cells were given. Hemoglobin was 7.7 g/dL. He was moved to the intensive care unit, heparin was discontinued, and a computed tomography (CT) scan of the abdomen showed a large left retroperitoneal hematoma.

anemia (Table 64-1). In one series, 64% of patients had hypotension (systolic blood pressure <90 mm Hg), and 73% showed progressive anemia. Ultimately, there is hemorrhagic shock, with oliguria and mental status changes. Oliguria can also result from ureteral obstruction, although retroperitoneal hematoma usually does not extend across the midline. Therefore, oliguria is more commonly due to hypovolemia. Symptoms of retroperitoneal hematoma include abdominal, flank, groin, or leg pain, as well as lumbar plexus irritation or dysfunction. In the series noted earlier, 45% of patients complained of pain in the lower extremity, and 55% had femoral nerve palsy. Over time, patients may also develop flank ecchymoses (Grey Turner’s sign; Fig. 64-1). In addition to the complications of PCB itself, the differential diagnosis for hypotension and anemia hours after PCB includes inadequate surgical blood replacement or continued surgical bleeding, which is usually obvious after lower extremity surgery. Perioperative hypotension may also be due to sepsis, with anemia absent and fever usually present. Abdominal CT should be performed if retroperitoneal bleeding is suspected; it readily demonstrates retroperitoneal hematoma (Fig. 64-2).

Table 64–1

■

Signs and Symptoms of Retroperitoneal Hemorrhage

Hypotension Anemia Shock Abdominal, flank, groin, or leg pain Femoral neuropathy Flank ecchymoses (Grey Turner’s sign)

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Figure 64–1 ■ Patient in the left lateral decubitus position showing widespread flank ecchymoses (Grey Turner’s sign) due to retroperitoneal hematoma after psoas compartment block.

Risk Assessment The translumbar, posterior approach to lumbar plexus block or PCB was described in 1974. The approach and landmarks have since been modified. The most popular contemporary approach for PCB requires the use of a nerve stimulator to identify the femoral nerve component of the lumbar plexus. Local anesthetic injection through a PCB needle or catheter has a much higher rate of success in blocking the femoral, lateral femoral cutaneous, and obturator branches (especially the last) of the lumbar plexus, compared with about a 25% success rate with the inguinal perivascular (three-inone) block of these branches. PCB has also been used to provide analgesia following hip replacement. Some have found that PCB provides equivalent analgesia to epidural local anesthetic, with fewer side effects; others have found it inferior to intrathecal morphine. Continuous PCB has been used for patients with femoral neck fracture, and although it is inadequate for surgical anesthesia, PCB produces analgesia that is superior to systemic

meperidine analgesia. When used alone for analgesia following knee replacement surgery, continuous PCB is equivalent to a continuous femoral block; both blocks are superior to intravenous patient-controlled morphine. The incidence of epidural spread of local anesthetic after PCB ranges from 2% to 25% and must be considered a side effect of this approach. Epidural and even intrathecal catheter placement has occurred during attempted continuous PCB. This is not unexpected, given the anatomic proximity of the intervertebral foramen to the intended site of needle or catheter placement. Although PCB is usually safe and successful, a number of serious complications have been reported in addition to retroperitoneal hematoma (Table 64-2). In a survey of major complications associated with regional anesthesia, Auroy and colleagues cautioned that PCB may be associated with a higher rate of life-threatening complications (8:1000) than other peripheral nerve block procedures. However, this survey included only 394 PCBs, a small percentage of the total number of peripheral nerve blocks performed. The retroperitoneal space contains a rich network of arteries and veins. Segmental lumbar arteries arise from the aorta, run along the vertebral bodies, and then course behind the psoas major and lumbar plexus between the lumbar transverse processes. The iliolumbar arteries ascend from their origin at the hypogastric arteries and anastomose with the fourth lumbar artery at the medial border of the psoas major. Segmental lumbar veins connect to each other by the ascending lumbar vein (Fig. 64-3), which feeds into the inferior vena cava. With this abundant vascular supply in the vicinity of the lumbar plexus, it is not surprising that needles or catheters may occasionally enter or injure these vessels during PCB, producing hemorrhage or systemic local anesthetic toxicity. The potential for concealed, significant hemorrhage must be taken into account when calculating the risk-benefit ratio of PCB for each patient. Alternative techniques, the use of anticoagulant or antiplatelet drugs, and the degree of anticoagulation must be included in this analysis. The American Society of Regional Anesthesia and Pain Medicine (ASRAPM) has developed consensus guidelines for the performance of central neuraxial blocks in the setting of anticoagulant therapy (see Chapter 67), but no such guidelines exist for the performance of peripheral nerve and plexus blocks. The incidence of clinically significant retroperitoneal bleeding following single-injection or continuous PCB with the typical dose of drugs used for perioperative thromboprophylaxis or anticoagulation therapy is not known.

Table 64–2

Figure 64–2 ■ Abdominal computed tomography scan showing a large retroperitoneal hematoma after psoas compartment block.

■

Complications following Psoas Block

Retroperitoneal hematoma Renal injury and hematoma Intrathecal, epidural, and intra-abdominal catheter placement Development of severe phantom limb pain Femoral neuropathy Total spinal anesthesia with cardiac arrest Systemic toxicity with cardiac arrest Death

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In contrast to retroperitoneal hematoma following PCB, epidural hematoma with spinal cord compression after epidural block requires urgent diagnosis and surgical decompression to reduce the risk of catastrophic injury to the patient (i.e., paraplegia). However, retroperitoneal bleeding after PCB, if diagnosed early and treated with transfusion and supportive care, typically results in complete recovery and usually does not require surgical intervention. For this reason, some believe that it is not necessary to apply the ASRAPM guidelines to PCB. Others argue that, at a minimum, significant retroperitoneal hemorrhage requires substantial transfusion, an extended hospital stay, and the reversal of anticoagulation, with its attendant risks. Even worse, retroperitoneal hemorrhage after PCB can cause persistent femoral neuropathy, life-threatening hemorrhagic complications, and even death. Therefore, the more conservative approach is to avoid PCB in patients with coagulation abnormalities that preclude epidural or spinal anesthesia.

Implications Consideration of PCB as a component of surgical anesthesia or postoperative analgesia must take into account its success rate and benefits compared with those of alternative techniques, as well as the potential for severe complications, including life-threatening bleeding. This is especially true for patients with significant bleeding abnormalities, including those who are fully anticoagulated or on high-dose antithrombolytic therapy. The risk is less well established for those receiving antiplatelet drugs or perioperative thromboprophylaxis. Because the signs and symptoms of retroperitoneal hemorrhage are well known, one must maintain a strong index of suspicion for bleeding-related complications in any patient receiving PCB, especially those with seemingly less consequential acquired or intrinsic coagulation abnormalities (e.g., patients taking nonsteroidal anti-inflammatory drugs).

MANAGEMENT The most common presentation of retroperitoneal hematoma is hypovolemia and anemia. In this case, intravascular volume repletion is the first priority (Table 64-3). Hemoglobin concentration, platelet count, and coagulation parameters should be measured to guide transfusion and other therapy. Discontinuation or reversal of anticoagulation may be necessary, although this must be weighed against the risk of venous thrombosis and embolism that such therapy was intended to prevent. It might be necessary to transfer the patient to a high-observation unit until cardiovascular stability has been achieved. Once the patient has stabilized, a CT scan can confirm the diagnosis and demonstrate the extent of bleeding. If active bleeding continues, technetium 99 scanning can help identify its source and guide embolization of the bleeding vessel. Many authorities believe that patients with continued or progressive nerve dysfunction from compression of branches

Table 64–3

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Management of Retroperitoneal Hemorrhage following Psoas Block

Restore intravascular volume Measure blood count and coagulation activity Transfuse blood and coagulation factors as indicated Reverse anticoagulation pharmacologically Transfer to high-acuity unit until cardiovascular stability achieved Perform abdominal computed tomography scan to confirm diagnosis when stable Consider interventional radiology for continued hemorrhage Consider surgical exploration for continued hemorrhage or femoral palsy

REGIONAL ANESTHESIA & PAIN MANAGEMENT

Figure 64–3 ■ Anatomic cross section through the L4 vertebral body. The enlarged image shows the lumbar artery and much larger ascending lumbar vein close to the lumbar plexus.

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of the lumbar plexus should undergo urgent decompressive surgery. Others believe that surgical intervention is a last resort and recommend that evolving femoral neuropathies be managed more expectantly, especially in patients with congenital coagulopathies.

PREVENTION The vascularity of the tissues through which the needle passes for PCB makes it impossible to completely avoid arterial or venous trauma. Because the larger needles and catheters used for continuous epidural anesthesia carry a higher risk for epidural hematoma than does single-injection spinal anesthesia, it seems logical that this would also be true for peripheral nerve blocks, including PCB. If an insulated needle and nerve stimulator are used to locate the lumbar plexus for PCB, vascular puncture might go unrecognized. Even with hollow-core needles, vascular injury might not be obvious. Regardless of the type of needle used, retroperitoneal hematoma following PCB has been reported. Thus, the following precautions are prudent: ●

●

●

●

●

Avoid PCB in fully anticoagulated patients or if thrombolytic therapy is likely. Maintain an index of suspicion for concealed bleeding in patients who have undergone PCB and are anticoagulated postoperatively. If known vascular puncture has occurred during PCB, communicate this to the surgical team and delay potent thromboprophylactic therapy postoperatively. Also, careful patient follow-up and monitoring of serial hematocrits are advised. Avoid PCB catheter removal during therapeutic anticoagulation, and maintain a high index of suspicion for bleeding after catheter removal in patients on more modest prophylactic anticoagulation postoperatively. Communicate the potential for concealed bleeding with members of the primary surgical service so that they too have the appropriate index of suspicion for bleeding complications after PCB, especially when unanticipated anemia or hypovolemia occurs in the postoperative period.

Further Reading Auroy Y, Benhamou D, Bargues L, et al: Major complications of regional anesthesia in France: The SOS Regional Anesthesia Hotline Service. Anesthesiology 97:1274-1280, 2002.

Capdevila X, Biboulet P, Morau D, et al: Continuous three-in-one block for postoperative pain after lower limb orthopedic surgery: Where do the catheters go? Anesth Analg 94:1001-1006, 2002. Capdevila X, Marcaire P, Dadure C, et al: Continuous psoas compartment block for postoperative analgesia after total hip arthroplasty: New landmarks, technical guidelines, and clinical evaluation. Anesth Analg 94:1606-1613, 2002. Chudinov A, Berkenstadt H, Salai M, et al: Continuous psoas compartment block for anesthesia and perioperative analgesia in patients with hip fractures. Reg Anesth Pain Med 24:563-568, 1999. Kaloul I, Guay J, Cote C, Fallaha M: The posterior lumbar plexus (psoas compartment) block and the three-in-one femoral nerve block provide similar postoperative analgesia after total knee replacement. Can J Anaesth 51:45-51, 2004. Klein SM, D’Ercole F, Greengrass RA, Warner DS: Enoxaparin associated with psoas hematoma and lumbar plexopathy after lumbar plexus block. Anesthesiology 87:1576-1579, 1997. Levine MN, Raskob G, Landefeld S, Kearon C: Hemorrhagic complications of anticoagulant treatment. Chest 119(1 Suppl):109S-121S, 2001. Maier C, Gleim M, Weiss T, et al: Severe bleeding following lumbar sympathetic blockade in two patients under medication with irreversible platelet aggregation inhibitors. Anesthesiology 97:740-743, 2002. Souron V, Delaunay L, Schifrine P: Intrathecal morphine provides better postoperative analgesia than psoas compartment block after primary hip arthroplasty. Can J Anaesth 50:574-579, 2003. Sreeram S, Lumsden AB, Miller JS, et al: Retroperitoneal hematoma following femoral artery catheterization: A serious and often fatal complication. Am Surg 59:94-98, 1993. Tokarz VA, McGrory JE, Stewart JD, Croslin AR: Femoral neuropathy and iliopsoas hematoma as a result of postpartum factor-VIII inhibitor syndrome. J Bone Joint Surg Am 85:1812-1815, 2003. Turker G, Uckunkaya N, Yavascaoglu B: Comparison of the cathetertechnique psoas compartment block and the epidural block for analgesia in partial hip replacement surgery. Acta Anaesthesiol Scand 47:30-36, 2003. Weller R, Gerancher JC, Crews JC, Wade KL: Extensive retroperitoneal hematoma without neurologic deficit in two patients who underwent lumbar plexus block and were later anticoagulated. Anesthesiology 98:581-585, 2003. Williams P: Gray’s Anatomy: The Anatomical Basis of Medicine and Surgery, 38th ed. New York, Churchill Livingstone, 1995, pp 1562, 1558, 1600. Wilson MW, Fidelman N, Lull RJ, et al: Evaluation of active bleeding into hematomas by technetium-99m red blood cell scintigraphy before angiography. Clin Nucl Med 27:763-766, 2002. Winnie A, Ramamurthy S, Durrani Z, Radonjic R: Plexus blocks for lower extremity surgery: New answers to old problems. Anesthesiol Rev 1:11-16, 1974. Witz M, Cohen Y, Lehmann JM: Retroperitoneal haematoma—a serious vascular complication of cardiac catheterisation. Eur J Vasc Endovasc Surg 18:364-365, 1999.

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ACUTE AND CHRONIC PAIN MANAGEMENT

Side Effects of Neuraxial Opioids

65

Susan B. McDonald Case Synopsis

PROBLEM ANALYSIS

Risk Assessment RESPIRATORY DEPRESSION

Definition Epidural and intrathecal administration of opioids in humans was first described in 1979. It was termed “selective spinal analgesia” because it offered profound segmental analgesia without the motor, sensory, and autonomic blockade of local anesthetics. Since then, neuraxial opioids have been widely accepted as a means of providing prolonged analgesia in acute postoperative, obstetric, and chronic pain scenarios. There is evidence that patients may have better postoperative outcomes with neuraxial opioid analgesia than with conventional opioid use. The addition of intrathecal fentanyl to spinal anesthesia prolongs the duration of sensory blockade without increasing the time to discharge, making it a popular choice in the ambulatory surgery setting. Intrathecal narcotics for labor analgesia, or “walking epidurals,” are a desirable option for parturients.

Recognition The most common side effects associated with neuraxial opioids are the following: ● ● ● ● ●

Respiratory depression Sedation Pruritus Nausea and vomiting Urinary retention

In general, the adverse effects associated with neuraxial opioids are similar to those seen with intravenous, intramuscular, or oral opioids. However, the severity, incidence, and timing differ owing to the interaction of receptors in the spinal cord and the brain. The most serious complication is respiratory depression, which can be early or delayed.

The degree and rate of the opioid’s rostral spread in the cerebrospinal fluid (CSF) determine the side effect profile for respiratory depression. The natural circulation of CSF brings residual drug into direct contact with the brain’s respiratory center, which lies on the floor of the fourth ventricle. Typically, lumbar CSF reaches the brain in about 4 to 6 hours. Thus, factors that determine the amount of drug reaching the rostral CSF include where the drug was placed (intrathecally versus epidurally; thoracic versus lumbar area), its dose, and its lipid solubility. When a highly lipophilic drug such as fentanyl or sufentanil is placed intrathecally, it rapidly penetrates the spinal cord tissues to directly act on the dorsal horn neurons. Low residual concentrations of the drug remain in the CSF; therefore, such drugs have a more segmental analgesic effect. In contrast, morphine is not highly lipophilic and has a slower uptake into the spinal cord and efflux from the CSF (via arachnoid granulations). Therefore, higher concentrations of drug remain in the CSF for longer periods. As a result, morphine is much more likely to reach the brain’s respiratory center and cause delayed respiratory depression than is fentanyl or sufentanil. If an opioid is placed epidurally, it can have spinal or supraspinal (systemic) effects, imparting a biphasic nature to respiratory depression. This may manifest early (<2 hours) due to vascular uptake and redistribution, similar to what occurs after intramuscular dosing, or late (6 to 12 hours) due to rostral migration of the drug in the CSF. The ratio of spinal to supraspinal effects depends on how much of the drug is absorbed into the epidural venous plexus, how much is deposited in epidural fat, and how much penetrates the meninges and passes into the CSF. The drug’s lipid solubility and molecular weight and shape in large part determine dural penetration and the amount that remains in the CSF long enough to spread rostrally. This explains why hydrophilic morphine or hydromorphone has more dural 261

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A 55-year-old obese woman undergoes a total vaginal hysterectomy under spinal anesthesia comprising local anesthetic and 100 μg of morphine. Later that evening, her oxygen saturation is normal with oxygen supplementation by nasal cannula, but she appears excessively somnolent.

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penetration (and therefore spinal activity) than highly lipophilic drugs such as fentanyl or sufentanil. For the same reason, there is a much greater risk of respiratory depression when morphine or hydromorphone is placed in the high thoracic or cervical epidural space. Patients considered at increased risk for respiratory depression include the elderly and debilitated, those with significant pulmonary disease (including sleep apnea), and those receiving concomitant opioids or central nervous system depressants. Patients receiving chronic opioid therapy are drug tolerant and thus much less likely to experience centrally mediated, neuraxial opioid respiratory depression. Postpartum patients also demonstrate less respiratory depression, possibly because of their younger age and increased ventilatory drive due to pregnancy. Finally, the overall reported incidence of significant respiratory depression (i.e., that requiring treatment) from neuraxial opioids is 0.2% to 2%, which is not much different from that associated with more conventional use (about 1%). Table 65-1 lists risk factors for respiratory depression. SEDATION Sedation correlates with respiratory depression for two reasons. First, the opioid may have a direct effect on the thalamus, limbic system, or cerebral cortex from rostral spread in the CSF. Second, if significant respiratory depression does occur, resultant hypercapnia may create carbon dioxide narcosis. Therefore, when a patient becomes increasingly somnolent after neuraxial opioids, episodic hypoventilation and respiratory depression should be carefully considered, even when respiratory rate and oxygenation are within acceptable limits. PRURITUS The incidence of pruritus with neuraxial opioids ranges from 30% to 100%, but it is severe in only about 1% of patients. Larger doses and intrathecal administration carry a higher risk for pruritus, as does pregnancy (possibly owing to high plasma estrogen). Fentanyl and morphine are more likely to cause itching, but all opioids have been implicated. The exact mechanism is unclear. Neuraxial opioids appear to interact with medullary inhibitory pathways in the spinal cord. The time course for itching correlates with the analgesic effect. Opioids may also

Table 65–1

■

Factors That Increase the Risk of Respiratory Depression

Opioid Characteristics Larger doses Intrathecal administration Hydrophilic morphine or hydromorphone Repeated boluses versus continuous infusion

Patient Characteristics Elderly Debilitated Significant pulmonary disease Sleep apnea Opioid naïve Concomitant opioids or central nervous system depressants

act on an “itch center” in the medulla, which is associated with the trigeminal nucleus; this may explain why facial itching is most common. Histamine release is not a cause of neuraxial opioid-induced pruritus. NAUSEA

AND

VOMITING

Nausea is less likely with neuraxial administration than with more conventional dosing. The incidence is about 30%. The risk is higher in female patients and with morphine and intrathecal use, probably due to the drug’s direct interaction with the vomiting center and chemoreceptor trigger zone located in the fourth ventricle. URINARY RETENTION The incidence of urinary retention with neuraxial opioids varies widely but is higher than that seen after parenteral or oral administration. The opioid’s effect on the sacral spinal cord receptors likely interferes with parasympathetic outflow and causes detrusor muscle relaxation and decreased sensation of the urge to void. It occurs more often in males and is dose dependent in duration. Time to complete recovery can be more than 5 hours after intrathecal sufentanil and more than 15 hours after intrathecal morphine.

Implications Proper patient selection and careful vigilance can reduce serious adverse effects from neuraxial opioid use, especially central respiratory depression. Appropriate postoperative care requires the recognition that hydrophilic drugs (morphine, hydromorphone) can lead to a delayed onset and longer duration of respiratory depression. Monitoring is necessary for at least 24 hours after the administration of neuraxial morphine or hydromorphone. Excessive somnolence may be the first sign, which is why mental status checks should be performed during postoperative observation. Most hospitals provide thorough nurse education and have precise written protocols for monitoring and treatment in the case of significant respiratory depression. An example is given in Table 65-2. Also, concomitant administration of other narcotics or central nervous system depressants should be avoided, especially in opioid-naïve patients. Small doses of lipophilic drugs such as fentanyl can be safely used in ambulatory surgery settings. Studies have shown that the risk of respiratory depression is minimal with intrathecal doses of less than 25 μg of fentanyl, even in elderly patients. For patients receiving postoperative epidural analgesia, no special monitoring is necessary if fentanyl is used in reasonable doses, even with thoracic epidural catheters. Side effects such as pruritus, nausea and vomiting, and urinary retention may be viewed as nuisance or minor complications, but even so, there can be undesirable consequences. If they are severe enough, there may be an unanticipated hospital admission or a delay in discharge, unpleasant side effects from the treatment medications, or unwanted procedures such as an indwelling bladder catheter for inability to void. Use of intrathecal narcotics for labor and delivery has become increasingly popular. Complications such as prolonged early labor and severe fetal bradycardia have been reported,

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Table 65–2

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Example of Postoperative Orders for Patients Receiving Neuraxial Morphine

Table 65–3

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Side Effects of Neuraxial Opioids

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263

Common Treatment Modalities for Neuraxial Opioid Side Effects

Respiratory Depression Postoperative Orders for Intrathecal or Epidural Morphine

but a causal relationship is still debated in the obstetric literature. The incidence of fetal heart rate abnormalities, especially bradycardia, may be dose dependent. The presumed cause is uterine hyperactivity due to an imbalance in circulating catecholamines after the rapid onset of analgesia. It should be emphasized that such heart rate abnormalities respond to conservative measures and are not associated with poor neonatal outcomes.

MANAGEMENT For serious adverse effects, including respiratory depression, the best reversal agent is a pure opioid antagonist such as naloxone. Although intravenous naloxone has a rapid onset, the duration of a single bolus may be insufficient, and infusions are often warranted. For less critical side effects (e.g., pruritus), naloxone may be hard to titrate to effect without the reversal of at least some analgesia. If so, a mixed agonistantagonist such as nalbuphine may be more suitable. Studies have shown that nalbuphine can effectively treat pruritus, nausea, or vomiting without altering the level of pain control. Other agents have been used to treat the side effects of neuraxial opioids (Table 65-3). Serotonin 5-HT3 antagonists (e.g., ondansetron) are effective for the treatment of both pruritus and nausea. Droperidol, with its weak serotonin antagonist activity, may help treat pruritus but is more useful against nausea and vomiting, whether administered intravenously or epidurally. Propofol inhibits dorsal horn signal transmission and can effectively treat nausea and pruritus; however, the management and cost of a propofol infusion

Pruritus Nalbuphine Diphenhydramine Propofol Ondansetron

Nausea or Vomiting Droperidol Ondansetron Propofol Nalbuphine

Urinary Retention Naloxone Bladder catheterization

for this purpose probably outweigh the benefits. Although histamine release is not the mechanism for opioid-induced pruritus, the sedating effect of antihistamines such as diphenhydramine may be beneficial by breaking the itchscratch cycle, but they do not directly reduce the itch. Future directions include the development of peripheral opioid antagonists. These may reduce side effects such as pruritus and postoperative nausea and vomiting without affecting analgesia. Respiratory depression, however, is less likely to be treated with such agents, as it is a centrally mediated effect.

PREVENTION Limiting the dose of a neuraxial opioid can reduce the incidence of side effects. Thus, a multimodal approach to postoperative analgesia may be the best prophylactic regimen. Nonsteroidal anti-inflammatory drugs, for example, reduce opioid requirements, provide analgesia, and perhaps even prevent pruritus by inhibiting prostaglandin synthesis. Dexamethasone is also an effective prophylaxis against nausea and vomiting and, in higher doses, may enhance analgesia. Droperidol may help reduce postoperative nausea and vomiting. Prophylactic ondansetron has been shown to reduce nausea, vomiting, and pruritus. Nalbuphine, however, may be a better drug for treatment than for prophylaxis. Intraoperative propofol infusions do not prevent either pruritus or nausea in the postoperative period. For continuous epidural analgesia, adding a low concentration of local anesthetic to the infusion reduces the opioid dose via a synergistic effect.

Further Reading Bates JJ, Foss JF, Murphy DB: Are peripheral opioid antagonists the solution to opioid side effects? Anesth Analg 98:116-122, 2004. Chaney MA: Side effects of intrathecal and epidural opioids. Can J Anaesth 42:891-903, 1995.

REGIONAL ANESTHESIA & PAIN MANAGEMENT

Pain Service beeper no: _______________ Patient received morphine ____________mg (dose) Intrathecal Epidural (circle correct route) at ___________(time) Epidural morphine __________mg bolus every ___________hours DO NOT administer any narcotic until patient reports discomfort No other opioids or sedative-hypnotics are to be given without notifying the Pain Service  Vitals: check respiratory rate and level of sedation q1hr × 12 hr, q2hr × 12 hr, and q4hr thereafter NOTIFY the Pain Service in case of the following: • Respiratory depression: respiratory rate <8 and patient unarousable • Inadequate analgesia  Activity: assisted ambulation only  IV fluids: maintain IV access for 12 hours following intrathecal or epidural morphine dose Medications (medication management of side effects to be discontinued 12 hours after epidural discontinued): Naloxone 0.1mg IV STAT (may repeat ×3) for respiratory rate <8 and patient unarousable Droperidol 0.5 mg IV q4hr PRN for nausea or vomiting Diphenhydramine 25 to 50 mg IV or PO q4hr PRN for itching Nalbuphine 2.5 mg IV q4hr PRN for itching Other: ____________________________

Naloxone Close observation and frequent monitoring Supplemental oxygen Avoid concomitant opioids and central nervous system depressants

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Cousins MJ, Mather LE: Intrathecal and epidural administration of opioids. Anesthesiology 61:276-310, 1984. de Leon-Casasola OA, Lema MJ: Postoperative epidural opioid analgesia: What are the choices? Anesth Analg 83:867-875, 1996. Etches RC, Sandler AN, Daley MD: Respiratory depression and spinal opioids. Can J Anaesth 36:165-185, 1989. Kuipers PW, Kamphuis ET, van Venrooij GE, et al: Intrathecal opioids and lower urinary tract function: A urodynamic evaluation. Anesthesiology 100:1497-1503, 2004.

Szarvas S, Harmon D, Murphy D: Neuraxial opioid-induced pruritus: A review. J Clin Anesth 15:234-239, 2003. Van de Velde M, Teunkens A, Hanssens M, et al: Intrathecal sufentanil and fetal heart rate abnormalities: A double-blind, double placebocontrolled trial comparing two forms of combined spinal epidural analgesia with epidural analgesia in labor. Anesth Analg 98:1153-1159, 2004.

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Brian A. Williams and Tetsuro Sakai REGIONAL ANESTHESIA & PAIN MANAGEMENT

Case Synopsis An otherwise healthy 30-year-old man underwent outpatient high tibial osteotomy. The uncomplicated procedure was performed with the patient under general anesthesia with endotracheal intubation. After emergence, the patient experienced severe, uncontrolled pain and then postoperative nausea and vomiting (PONV) after opioids were used in the postanesthesia care unit for pain control. He later required unplanned hospital admission for intractable pain, PONV, and somnolence. The patient was discharged after 2 days, when he was finally able to tolerate oral intake. However, he was readmitted to the emergency room 5 days later with constipation, episodic nausea, and wound dehiscence. The wound cultured positive for methicillin-resistant Staphylococcus aureus and vancomycin-resistant Enterococcus faecalis.

PROBLEM ANALYSIS Definition The development of anesthesia techniques for outpatient surgery has led to great improvements in the management of PONV and postoperative pain. A growing demand for ambulatory surgery and anesthesia has resulted, because these adverse sequelae are the most common causes of unplanned hospital admissions. Multimodal analgesic techniques are especially recommended in ambulatory surgery patients to reduce many of the complications associated with high-dose opioid analgesia. Successful same-day discharge also protects patients from nosocomial and iatrogenic complications inherent to hospitalization. Currently, many complex procedures are performed on an outpatient basis. This trend will continue in order to meet patients’ desire for a more rapid return of cognitive and social function, as well as the public desire to reduce health care expenditures. The evolving subspecialties of outpatient orthopedic anesthesia and acute postoperative pain management are increasingly recognized for their positive effect on reducing hospital length of stay and improving functional recovery and patient satisfaction. Complications in the setting of outpatient orthopedic anesthesia and surgery require a multidisciplinary approach by anesthesiologists, nursing staff, surgeons, and hospital administrators. The goals of ambulatory surgery are as follows: ● ●

To maintain or improve quality and safety of care To schedule cases efficiently

●

● ●

To minimize complications, such as poorly controlled pain and PONV To avoid unplanned postoperative hospital admissions To minimize readmissions after initial hospital discharge

The choice of anesthetic technique has paramount importance in achieving these goals, particularly in orthopedic surgery.

Recognition Traditional belief in the safety and efficacy of general endotracheal anesthesia (GETA) in the inpatient setting should be reexamined in the context of outpatient surgery. In the setting of same-day surgery, a postoperative in-hospital care “buffer” is not necessarily available to manage such common problems as uncontrolled pain and PONV. For orthopedic outpatients, problems associated with GETA include the following: ● ● ●

●

●

Dental or oral mucosal injury from airway instrumentation Respiratory complications from mechanical ventilation Complications from volatile anesthetics (e.g., PONV, malignant hyperthermia) Prolonged or adverse effects from induction agents and systemic muscle relaxants Side effects from opioids (e.g., PONV, somnolence, delayed awakening, pruritus, respiratory depression, urinary retention, constipation)

Prolonged recovery from GETA often requires laborintensive admission to a postanesthesia care unit for prolonged surveillance with physican-directed/interpreted monitoring and intervention. Significant cardiopulmonary 265

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changes caused by GETA are to be expected among elderly patients or those with predisposing medical risk factors. Unplanned admissions to an intensive care unit may also be necessary if prolonged mechanical ventilation or other patient support measures are required for cardiorespiratory or other complications. Regional anesthesia, including peripheral nerve block (PNB), has traditionally been reserved for patients with contraindications to GETA. In outpatient orthopedic surgery, however, there is a shift toward the preferential use of PNB among progressive practitioners, whereas GETA (with volatile agents and no PNB) is reserved for outpatients in whom PNB is contraindicated. PNB for orthopedic outpatients can help avoid the risks associated with GETA mentioned earlier. Williams and colleagues recently reviewed 1200 consecutive cases of outpatient knee surgery and reported that general anesthesia with a volatile agent was associated with a 200% increase in nursing interventions for pain control in the same-day recovery unit and a 300% increase in unplanned hospital admissions compared with anesthesia consisting of sedation and femoralsciatic nerve block techniques. In addition, continuous PNB using indwelling catheters and portable infusion pumps can offer excellent postoperative pain control for 2 to 3 days at home.

Risk Assessment Absolute contraindications to PNB for outpatient surgery include the following: ●

●

● ●

Patient refusal (with appropriate patient education by the anesthesiologist, which may take 10 to 15 minutes, many patients who initially refuse PNB ultimately will accept it) Coagulopathies (systemic anticoagulants such as warfarin should be converted to intravenous heparin preoperatively, if PNB is indicated) Infection at the site of needle placement Systemic bacteremia or sepsis

In practice, these contraindications are highly unlikely in outpatients presenting for same-day orthopedic surgery. Preexisting neurologic conditions are relative contraindications to PNB. Careful documentation of any preexisting neurologic deficit is mandatory if PNB will be performed in such patients. To perform successful ambulatory surgery with PNB, the environment and resources must be coordinated. Good communication between the anesthesiologist and the surgical team is mandatory. To select the appropriate PNB modality, the anesthesiologist must be familiar with the surgical procedure, its invasiveness, and the dermatomes that must be covered. Also, the anesthesiologist must be comfortable performing the indicated PNB. All precautions for conversion to general anesthesia must be immediately available. This includes proper preoperative airway assessment and preparation of the required airway equipment before any regional procedure is performed. Ideally, an induction room or separate facility where PNB can be performed is preferable, to reduce time in the operating room. Anesthesiologists and nursing staff need to be aware of PNB-associated risks. These include central nervous system

and cardiovascular toxicity of local anesthetics and potential peripheral nerve damage with the PNB procedure; the incidence of the latter ranges from 4 in 1000 to 2 in 10,000. The centerpiece of anesthesia care in outpatient orthopedic surgery is multimodal analgesia, including the use of PNB, the prevention of PONV with routine multimodal antiemetic prophylaxis, and the avoidance of general anesthesia with volatile agents whenever possible. A propofol-based intravenous anesthesia technique should be considered as an adjunct to PNB if sedation is required.

Implications Preferential (but careful) use of PNB in orthopedic outpatients is beneficial in terms of reducing hospital costs and improving patient satisfaction. The use of PNB for anesthesia has been associated with earlier discharge (fewer nursing interventions for pain or PONV and fewer unplanned hospital admissions) when compared with GETA in patients undergoing ambulatory orthopedic surgery.

MANAGEMENT There are two methods of PNB: single-injection PNB and continuous PNB with an indwelling catheter. Although single-injection techniques are effective, they offer postoperative analgesia for only a few hours—certainly no more than 12 to 24 hours—depending on the local anesthetic and adjuncts used. Consequently, the duration of the block may be too brief to provide adequate postoperative analgesia or sufficient analgesia to initiate physical therapy. Early physical therapy is essential to optimize functional recovery after orthopedic surgery. Continuous PNB catheter techniques have the following advantages over single-injection or neuraxial techniques: ● ● ●

●

Longer duration of postoperative analgesia Titratable dosage Preferential sensory block, when active physical therapy is required Avoidance of the neuraxis and associated complications (especially in the context of systemic anticoagulation)

Once it is established that PNB is indicated, one must select the correct PNB modality according to the invasiveness of the planned orthopedic procedure. An example of a PNB algorithm for the care of outpatients undergoing knee surgery is given in Table 66-1. Use of a peripheral nerve stimulator facilitates PNB and catheter placement (Fig. 66-1). The patient can later be discharged with the PNB catheter in place and a portable infusion pump. Written instructions for catheter and pump management should be provided and explained to the patient at the time of discharge. Further, the anesthesia care team should make daily contact with the patient by telephone and be available by pager if the patient has questions. PNB can be used safely in patients who require postoperative anticoagulation with intravenous unfractionated heparin or subcutaneous low-molecular-weight heparin to prevent deep venous thrombosis and pulmonary embolism. Systemic anticoagulation is seldom used in surgical outpatients.

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Table 66–1

■

■

Complications in Orthopedic Outpatients Not Receiving Peripheral Nerve Blocks

267

Recommended Peripheral Nerve Blocks for Outpatient Knee Surgery

Category I (Mild) No blocks unless unanticipated postoperative pain occurs

Category II (Moderate) Single-injection femoral nerve block recommended: arthrotomy, deep hardware removal, microfracture, mosaicplasty or chondroplasty, ACL allograft Femoral bolus: 30 mL of preferred long-duration local anesthetic No sciatic block unless unanticipated pain refractory to femoral block Continuous catheter recommended: ACL patellar tendon autograft, femoral osteotomy Femoral catheter initial bolus: 20 to 30 mL of preferred long-duration local anesthetic Femoral catheter infusion: 5 mL/hr of low-concentration, long-duration local anesthetic No sciatic block unless unanticipated pain refractory to femoral block

Category III (Severe) Femoral Nerve Block

Sciatic Nerve Block

Continuous femoral catheter−initial bolus: 20-30 mL of intermediate-concentration, long-duration local anesthetic Catheter dose: 5 mL/hr of low-concentration, long-duration local anesthetic

Continuous sciatic catheter−initial bolus: 5-10 mL of low-concentration, longduration local anesthetic Catheter dose (postoperatively): 5-20 mL bolus as needed, followed by 3 mL/hr of low-concentration, long-duration local anesthetic

Continuous femoral catheter−initial bolus: 20 mL of low- concentration, long-duration local anesthetic Catheter dose: 5 mL/hr of low-concentration, long-duration local anesthetic

Single-injection sciatic: 20 mL of intermediate-concentration, long-duration local anesthetic

Most Invasive Category III* Total knee replacement High tibial osteotomy Multiligament reconstruction (including PCL, LCL, MCL, POL) Posterolateral corner reconstruction

Moderately Invasive Category III ACL hamstring autograft Meniscal reconstruction Unicompartmental knee arthroplasty

Less Invasive Category III Distal patella realignment

Single-injection femoral: 30 mL of Single-injection sciatic: 20 mL of intermediate-concentration, long-duration low- to intermediate-concentration, local anesthetic long-duration local anesthetic Algorithm for the use of nerve block additives: −If a catheter is used, clonidine is not routinely added. −If no catheter is used, clonidine is routinely recommended if ropivacaine is the local anesthetic used. −Regardless of catheter status, buprenorphine may be a useful analgesic adjunct (as part of the catheter bolus dose or single-injection dose). The buprenorphine dose should be restricted to a total of 150 μg for an adult patient to prevent nausea, vomiting, and pruritus associated with higher doses. *Test for dorsiflexion postoperatively before ablating sciatic nerve motor response. ACL, anterior cruciate ligament; LCL, lateral collateral ligament; MCL, medial collateral ligament; PCL, posterior cruciate ligament; POL, posterior oblique ligament.

Figure 66–1 ■ Patient receiving a continuous sciatic nerve block catheter after already having received a femoral nerve block catheter (not shown). Note that the catheter is a stimulating catheter (StimCath, Arrow International, Reading, Pa) and that its proper placement can be confirmed with nerve stimulation before the nerve block catheter is dosed with local anesthetic. The operator’s hand is highlighting the attachment of a nerve stimulator adapter clip to the catheter’s Luer-Lok connection device. This catheter can later be attached to an infusion pump containing low-dose local anesthetic that can be infused for up to 72 hours after surgery.

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Procedure

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Finally, use of a continuous propofol infusion as an adjunct to PNB is beneficial for ambulatory surgery patients to reduce the risk of PONV, especially if intraoperative sedation or total intravenous anesthesia is indicated.

PREVENTION One should avoid the underutilization of PNB techniques in outpatient orthopedic surgery, assuming the availability of anesthesiologists who are skilled in such techniques. Anesthesiologists must be proactive and educate patients and surgeons about the benefits of PNB techniques. Using PNB, either as the main anesthetic or as an adjunct to total intravenous anesthesia with propofol, facilitates rapid emergence and perioperative analgesia. Finally, to prevent nosocomial wound infections and unplanned hospital admissions, it is important to discharge patients home the same day. This requires a comprehensive plan for symptom management as part of the total anesthesia and analgesia care plan.

Further Reading Chelly JE, Ben-David B, Williams BA, Kentor ML: Anesthesia and postoperative analgesia: Outcomes following orthopedic surgery. Orthopedics 26(8 Suppl):S865-S871, 2003.

Gupta A, Wu CL, Elkassabany N, et al: Does the routine prophylactic use of antiemetics affect the incidence of postdischarge nausea and vomiting following ambulatory surgery? A systematic review of randomized controlled trials. Anesthesiology 99:488-495, 2003. Ilfeld BM, Morey TE, Enneking FK: Continuous infraclavicular brachial plexus block for postoperative pain control at home: A randomized, double-blinded, placebo-controlled study. Anesthesiology 96:1297-1304, 2002. Ilfeld BM, Morey TE, Wright TW, et al: Continuous interscalene brachial plexus block for postoperative pain control at home: A randomized, double-blinded, placebo-controlled study. Anesth Analg 96:1089-1095, 2003. Klein SM, Nielsen KC, Greengrass RA, et al: Ambulatory discharge after long-acting peripheral nerve blockade: 2382 blocks with ropivacaine. Anesth Analg 94:65-70, 2001. Williams BA, Kentor ML, Vogt MT, et al: Femoral-sciatic nerve blocks for complex outpatient knee surgery are associated with less postoperative pain before same-day discharge: A review of 1200 consecutive cases from the period 1996-1999. Anesthesiology 98:1206-1213, 2003. Williams BA, Kentor ML, Vogt MT, et al: The economics of nerve block pain management after anterior cruciate ligament reconstruction: Significant hospital cost savings via associated PACU bypass and same-day discharge. Anesthesiology 100:697-706, 2004. Williams BA, Vogt MT, Kentor ML, et al: Nausea and vomiting after outpatient ACL reconstruction with regional anesthesia: Are lumbar plexus blocks a risk factor? J Clin Anesth 16:276-281, 2004.

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67

James R. Hebl Case Synopsis

PROBLEM ANALYSIS Definition The use of peripheral nerve blocks (PNBs) for perioperative anesthesia and analgesia has increased dramatically over the past several years. Importantly, this shift in practice does not appear to be a transient phenomenon. For example, more than 40% of clinicians surveyed in 1998 in the United States estimated that their use of PNB techniques would increase over the next several years. Further, use of PNB in France increased approximately 18-fold between 1980 and 1996. Reasons for the increased use of PNB include not only its potential benefits (Table 67-1) but also the avoidance of complications that may accompany central neuraxial techniques, including concerns about perioperative anticoagulation, hemodynamic instability due to sympathetic block, and delayed discharge after outpatient surgery. However, the use of PNB is associated with its own unique set of concerns and complications. In particular, hemorrhagic complications have been reported with greater frequency as changes in clinical practice occur (e.g., more aggressive perioperative anticoagulation, new regional techniques, continuous perineural catheters) and the popularity of PNB continues to increase. Although hemorrhagic complications are quite rare, they can be among the most devastating complications

Table 67–1

■

Potential Benefits of Peripheral Nerve Block

Superior postoperative analgesia Improved rehabilitative efforts (owing to analgesia) Decreased perioperative nausea and vomiting Faster emergence and recovery Earlier mobilization (unilateral blockade) Faster outpatient discharge Improved blood flow to affected extremity Benefits extended with continuous catheter techniques

of PNB. Such injury has been reported with a variety of PNBs, including interscalene, axillary, intercostal, paravertebral, femoral, ilioinguinal, posterior lumbar plexus, and lumbar sympathetic blocks. Patients at greatest risk include those receiving unfractionated heparin, LMWH, warfarin, antiplatelet aggregation medications, or antithrombolytic therapy.

Recognition In general, localized bruising and tenderness are very common following PNB, with reported frequencies ranging from 8% to 23%. True hemorrhagic complications appear to be much less common. For example, the reported frequency of hematoma formation after brachial plexus block ranges from 0.2% to 3%. Most hematomas are small, unrecognized, and clinically inconsequential. However, there have been reports of more severe hemorrhagic complications, as well as significant neurologic impairment after hematoma formation. Recognition of bleeding complications relies on astute clinical vigilance throughout the perioperative period; this is especially important in patients receiving perioperative anticoagulation with intravenous heparin, warfarin, LMWH, or antiplatelet drugs. Significant hypotension, localized pain or tenderness, severe ecchymosis, unexplained anemia, or the development of neurologic deficits may signal underlying hemorrhage or a compressive hematoma. Computed tomography (CT), magnetic resonance imaging, or ultrasonography may be required for confirmation and to determine the location and extent of injury.

Risk Assessment There are no reports on the frequency or severity of hemorrhagic complications with PNB in patients receiving anticoagulants. However, there are reports of serious complications following neurovascular sheath cannulation for central vascular access. Although this intervention is not the same as PNB, it may predict what can occur after PNB 269

REGIONAL ANESTHESIA & PAIN MANAGMENT

A 73-year-old man with a history of ischemic heart disease and diabetes mellitus is scheduled to undergo an elective total hip arthroplasty. The patient has been receiving daily anticoagulation with warfarin since his aortic valve replacement 3 years ago. Five days before surgery, the patient’s warfarin was discontinued by his primary care physician, at which time he began therapeutic anticoagulation bridging therapy with low-molecularweight heparin (LMWH). The patient’s last injection of LMWH was about 24 hours ago. The orthopedic surgeon intends to reinitiate anticoagulation with LMWH 12 hours after surgery. During the preanesthetic interview, the patient requests spinal anesthesia and a peripheral nerve catheter for extended postoperative analgesia.

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needle- or catheter-caused vascular injury in patients receiving anticoagulants or antiplatelet drugs. Fransson and Nylander reported vascular complications in 0.26% of 4879 patients having cardiac catheterization, coronary angiography, or angioplasty at one university hospital. These included pseudoaneurysm (12 cases), thromboembolism (4 cases), and excessive bleeding (3 cases). There was no neurologic impairment in any patient. Among those with vascular complications, 58% were receiving anticoagulation, compared with 10% of those with no complications. Reports of vascular injury after PNB are limited to case reports. Such complications have occurred in patients with normal hemostasis and in those receiving anticoagulation therapy. Complications include anemia with profound hypotension and the need for transfusion, myocardial ischemia, acute renal insufficiency, localized pain and tenderness, neurologic injury, and even death. Of note, all reported adverse neurologic sequelae were transient and self-limited, with full recovery by 12 months. Thus, in contrast to central neuraxial bleeding, bleeding into a more compliant peripheral nerve site seems unlikely to be associated with irreversible, permanent nerve injury. The majority of severe hemorrhagic complications after PNB have been associated with either posterior lumbar plexus (i.e., psoas compartment; see Chapter 64) or lumbar sympathetic blocks. In all instances, patients received anticoagulants before, during, or after PNB. Klein and associates reported one case of psoas compartment hematoma with transient neuropathy after lumbar plexus block for belowknee amputation. That patient received 30 mg of enoxaparin 20 hours before the attempted PNB and also 4 hours afterward. After several attempts at posterior lumbar plexus block, an anterior three-in-one block (lumbar plexus and sciatic nerves) was performed. On postoperative day 1, the patient had right hip pain, which progressed to complete paralysis by day 9. A CT scan revealed a large retroperitoneal hematoma in the psoas compartment, displacing the kidney anteriorly. Her coagulation profile and platelet count were normal. She was treated conservatively, enoxaparin was stopped, and motor function gradually returned over the next 5 days, with complete return by 4 months. Also, Weller and coworkers reported extensive retroperitoneal hemorrhage in two patients, both of whom were anticoagulated after three-inone blocks. Neither had new neurologic deficits, and both had normal coagulation profiles at the time of the block. One received enoxaparin (30 mg) 90 minutes after removal of a catheter within the neurovascular sheath (postoperative day 2) and later developed severe right paravertebral low back pain, hypotension (hemoglobin 7.1 g/dL), and transient renal insufficiency. A CT scan revealed a large retroperitoneal hematoma with renal displacement. The other patient had previously undergone aortic valve replacement and was taking warfarin (Coumadin); this drug was stopped, and the coagulation profile was normal before single-injection three-inone block for knee arthroscopy. Heparin was started 8 hours after the block, and Coumadin was restarted the evening of postoperative day 1. On day 3, the patient had back pain at the block site, with a slow decline in hemoglobin from 12.8 to 8.5 g/dL. The CT scan revealed moderate retroperitoneal hematoma, which was treated conservatively, without residual neurologic impairment.

Irreversible platelet aggregation inhibitors (e.g., ticlopidine, clopidogrel) are implicated as contributing to hemorrhagic complications in patients with PNB. Maier and colleagues reported two cases of severe bleeding after lumbar sympathetic block (LSB). The first patient had peripheral vascular disease, and his medications included ticlopidine (500 mg/day) for stroke prevention. After his first LSB, hemoglobin decreased from 13.5 to 10.3 g/dL, and he complained of groin pain and medial thigh numbness. Inadvertent vascular puncture occurred during a second LSB performed 6 days later. The next night, the patient experienced severe groin pain, with a simultaneous drop in blood pressure and hemoglobin to 8.9 g/dL. A large retroperitoneal hematoma was diagnosed. He was transfused and discharged 5 days later, with no permanent neurologic deficits. The second patient was referred for diagnostic LSB and was receiving clopidogrel (75 mg/day). This drug was discontinued 3 days before the LSB, which was uneventful. Nine hours later, the patient complained of burning groin and medial thigh pain, which was treated with intravenous opioids. Twelve hours after LSB, she was found pulseless. Attempted resuscitation was unsuccessful. At autopsy, there was a massive, congealed retroperitoneal hematoma. As these cases show, severe hemorrhage, but not permanent neurologic injury, may be the most serious complication of PNB in anticoagulated patients. It appears to be most likely if PNB is performed at concealed, noncompliant sites (e.g., psoas compartment). Further, such occult bleeding may go unrecognized for several hours to days.

Implications Perioperative anticoagulation for the prevention of venous thromboembolism can result in significant morbidity, mortality, and resource allocation. Knowledge of specific clinical risk factors for thromboembolism (Table 67-2) is the basis for the proper use of perioperative anticoagulation treatment or prophylaxis. These risk factors are present alone or in combination

Table 67–2

■

Clinical Risk Factors for Venous Thromboembolism

Increased age Prolonged immobility Prior stroke or paralysis Previous venous thromboembolism Cancer Major surgery Abdominal surgery Pelvic surgery Lower extremity surgery Trauma Obesity Varicose veins Cardiac dysfunction Indwelling central venous catheter Inflammatory bowel disease Nephrotic syndrome Pregnancy or estrogen use From American College of Chest Physicians: Sixth ACCP Consensus Conference on Antithrombotic Therapy. Chest 119(Suppl), 2001.

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in a high proportion of hospitalized patients. Consequently, many patients who present for elective or emergency surgery are, or will be, receiving medications that alter normal hemostasis. All clinicians should be aware of this, especially when performing regional anesthesia.

MANAGEMENT Patients receiving anticoagulants may be at the greatest risk of hemorrhagic complications after PNB. Therefore, astute clinical vigilance is mandatory. If such a complication is suspected, immediate clinical evaluation should occur, including the following:

●

Focused review of the patient’s perioperative history ● Past medical history ● Preoperative coagulation status ● Pre- and perioperative medications (e.g., hemostasisaltering drugs, herbals) ● Surgical course, including intra- and postoperative blood loss ● Immediate postoperative course Consideration of the patient’s chief complaint ● Pain (location, duration, nature) ● Neurologic deficits (sensory or motor, onset, duration, fluctuation) ● Orthostatic symptoms ● Fatigue, syncope, lightheadedness, postural hypotension

Table 67–3

■

●

●

Anticoagulants and Peripheral Nerve Block

Physical examination (including a detailed neurologic assessment) Laboratory investigation (complete blood count, coagulation profile, electrolytes) Radiographic imaging for definitive diagnosis (CT, magnetic resonance imaging, ultrasonography)

Surgical decompression with hematoma evacuation may be necessary if (1) the hematoma continues to expand, (2) there is progressive neurologic deterioration, (3) neural dysfunction does not improve despite hematoma resolution, or (4) there is evidence of airway, vascular, or lymphatic obstruction. In select cases, when these criteria are not satisfied, observation and conservative management may be appropriate. However, prompt assessment and appropriate intervention are critical in all patients to prevent hemorrhagic catastrophes and irreversible neurologic impairment.

PREVENTION Development of a central neuraxial hematoma due to bleeding into a fixed and noncompressible site is clearly the most significant and potentially devastating hemorrhagic complication of regional anesthesia. In an effort to reduce this risk, the American Society of Regional Anesthesia and Pain Medicine (ASRAPM) developed consensus guidelines for central neuraxial anesthesia and analgesia in anticoagulated patients (Table 67-3). Because the risk of such complications

American Society of Regional Anesthesia and Pain Medicine Guidelines for Central Neuraxial Anesthesia in Patients Receiving Thromboprophylaxis

Anticoagulant

Recommendation

Antiplatelet medications

No contraindication with NSAIDs Discontinue ticlopidine for 14 days Discontinue clopidogrel for 7 days Discontinue glycoprotein IIb/IIIa inhibitors 8-48 hr in advance

Unfractionated heparin Subcutaneous Intravenous Low-molecular-weight heparin (LMWH)

Warfarin Thrombolytics Herbal therapy

271

No contraindication; consider delaying heparin until after block if technical difficulty is anticipated Heparinize 1 hr after neuraxial technique Remove catheter(s) 2-4 hr after last heparin dose No mandatory delay if traumatic needle placement Preoperative dosing: Needle placement should occur at least 10-12 hr after last LMWH dose (prophylactic dosages) or at least 24 hr after higher doses (treatment dosages) Postoperative twice-daily dosing: LMWH 24 hr after surgery, regardless of technique Remove neuraxial catheter(s) 2 hr before first LMWH dose Postoperative once-daily dosing: LMWH 6-8 hr after surgery Give second postoperative dose no sooner than 24 hr after first dose Indwelling catheter(s) can be safely maintained Remove catheter(s) 10-12 hr after last dose of LMWH and 2 hr before subsequent dosing Document normal INR after discontinuation (before neuraxial technique) Remove catheter(s) when INR ≤1.5 (within initiation of therapy) No data on safe performance of neuraxial techniques or catheter removal No evidence of mandatory discontinuation before neuraxial techniques Be mindful of potential drug interactions (see Chapter 39)

INR, international normalized ratio; NSAID, nonsteroidal anti-inflammatory drug. Adapted from Horlocker TT, Wedel DJ, Benzon H, et al: Regional anesthesia in the anticoagulated patient: Defining the risks (the Second ASRA Consensus Conference on Neuraxial Anesthesia and Anticoagulation). Reg Anesth Pain Med 28:172-197, 2003.

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●

●

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in anticoagulated patients undergoing PNB is not clearly defined, one approach might be to apply these guidelines to all patients receiving regional anesthesia, including PNB. However, this might be overly cautious. Instead, it might be more prudent to consider the compressibility of the PNB needle insertion site and the vascular structures at risk. Also, it is strongly advised that, in patients with inherent or drug-induced coagulopathies, PNB be used only after a careful risk-benefit analysis, and that it be performed with extra caution. This is especially true if the PNB will be performed in a region where an expanding hematoma could compress the airway (e.g., deep cervical plexus, interscalene, or “plumb-bob” supraclavicular block) or might not become apparent for several hours to days in a noncompressible site (e.g., psoas compartment with a lumbar plexus block). Regardless, good communication among all clinicians involved in the perioperative care of any patient receiving drugs that affect hemostasis is critical to provide optimal patient care and to reduce the risk of serious hemorrhagic complications.

Further Reading Aida S, Takahashi H, Shimoji K: Renal subcapsular hematoma after lumbar plexus block. Anesthesiology 84:452-455, 1996. American College of Chest Physicians: Sixth ACCP Consensus Conference on Antithrombotic Therapy. Chest 119(Suppl), 2001. Ben-David B, Stahl S: Axillary block complicated by hematoma and radial nerve injury. Reg Anesth Pain Med 24:264-266, 1999. Bergman BD, Hebl JR, Kent J, Horlocker TT: Neurologic complications of 405 consecutive continuous axillary catheters. Anesth Analg 96: 247-252, 2003. Clergue F, Auroy Y, Perquignot F, et al: French survey of anesthesia in 1996. Anesthesiology 91:1509-1520, 1999.

Ekatodramis G, Macaire P, Borgeat A: Prolonged Horner syndrome due to neck hematoma after continuous interscalene block. Anesthesiology 95:801-803, 2001. Fransson SG, Nylander E: Vascular injury following cardiac catheterization, coronary angiography, and coronary angioplasty. Eur Heart J 15: 232-235, 1994. Hadzic A, Vloka JD, Kuroda MM, et al: The practice of peripheral nerve blocks in the United States: A national survey. Reg Anesth Pain Med 23:241-246, 1998. Horlocker TT: Peripheral nerve blocks: Regional anesthesia for the new millennium. Reg Anesth Pain Med 23:237-240, 1998. Horlocker TT, Wedel DJ, Benzon H, et al: Regional anesthesia in the anticoagulated patient: Defining the risks (the Second ASRA Consensus Conference on Neuraxial Anesthesia and Anticoagulation). Reg Anesth Pain Med 28:172-197, 2003. Johr M: A complication of continuous blockade of the femoral nerve [German]. Reg Anaesthesie 10:37-38, 1987. Klein SM, D’Ercole F, Greengrass RA, Warner DS: Enoxaparin associated with psoas hematoma and lumbar plexopathy after lumbar plexus block. Anesthesiology 87:1576-1579, 1997. Maier C, Gleim M, Weiss T, et al: Severe bleeding following lumbar sympathetic blockade in two patients under medication with irreversible platelet aggregation inhibitors. Anesthesiology 97:740-743, 2002. Neal JM, Hebl JR, Gerancher JC, Hogan QH: Brachial plexus anesthesia: Essentials of our current understanding. Reg Anesth Pain Med 27: 402-428, 2002. Nielsen CH: Bleeding after intercostal nerve block in a patient anticoagulated with heparin. Anesthesiology 71:162-164, 1989. Sada T, Kobayashi T, Murakami S: Continuous axillary brachial plexus block. Can Anaesth Soc J 30:201-205, 1983. Thomas PW, Sanders DJ, Berrisford RG: Pulmonary haemorrhage after percutaneous paravertebral block. Br J Anaesth 83:668-669, 1999. Vaisman J: Pelvic hematoma after an ilioinguinal nerve block for orchialgia. Anesth Analg 92:1048-1049, 2001. Weller RS, Gerancher JC, Crews JC, Wade KL: Extensive retroperitoneal hematoma without neurologic deficit in two patients who underwent lumbar plexus block and were later anticoagulated. Anesthesiology 98:581-585, 2003.

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Chronic Nonsteroidal Anti-inflammatory Drug Use Celeste M. Lombardi Case Synopsis

REGIONAL ANESTHESIA & PAIN MANAGMENT

A 60-year-old man with a history of osteoarthritis has been taking naproxen for the past 3 years without complications or side effects. He experienced sudden severe nausea and vomited frank blood. He was taken to the emergency room and underwent an urgent upper gastrointestinal (GI) endoscopy, which revealed a bleeding gastric ulcer.

PROBLEM ANALYSIS Definition Nonsteroidal anti-inflammatory drugs (NSAIDs) are widely used drugs that act by inhibiting cyclooxygenase and the formation of prostaglandins. Prostaglandins are derived from arachidonic acid, formed by phospholipase A2 acting on cell membrane phospholipids (Fig. 68-1). NSAIDs are among the most commonly used drugs worldwide and are usually well tolerated. However, like all medications, NSAIDs are not without side effects. They are known to cause the following: ● ●

●

●

●

GI toxicity, leading to the formation of peptic ulcers Unwanted antiplatelet effects (nonselective inhibitors of cyclooxygenase) Potential for increased thrombogenicity (selective cyclooxygenase-2 [COX-2] inhibitors) Renal toxicity, with potential alterations of potassium and fluid balance, decreased renal function, nephrotic syndrome with interstitial nephritis, papillary necrosis, and rhabdomyolysis Anaphylactic and anaphylactoid reactions in select patients

Recognition GASTROINTESTINAL EFFECTS NSAID use is the second most important cause of peptic ulcers after Helicobacter pylori infection. The primary mechanism of ulcer formation is from suppression of gastric prostaglandins, although decreases in nitric oxide and calcitonin gene-related peptide may also be involved. This leads to decreases in epithelial mucus, bicarbonate secretion, and mucosal resistance to injury. NSAIDs also reduce gastric mucosal blood flow, with subsequent damage to the vascular endothelium (an early effect of NSAID administration) in conjunction with an enhanced adherence of neutrophils to the vascular endothelium. The neutrophil adherence causes endothelial injury by release of oxygen-derived free radicals.

Arachidonic acid

COX-1 +

Lipoxygenase

COX-2 + Prostaglandins

Thromboxane

Gastric PGE Pain, inflammation, fever

Platelet aggregation

Mucosal blood flow Mucus secretion HCO3 secretion Cell restitution Scavenging of free radicals

+

Gastric mucosal protection

Figure 68–1 ■ Biosynthesis of prostaglandins from arachidonic acid via the cyclooxygenase (COX-1 and COX-2) pathways. Arachidonic acid, the immediate precursor of prostaglandins, is derived from membrane phospholipids in reactions catalyzed by the two COX isoenzymes. The gene for COX-1 (the “housekeeping” enzyme) is expressed constitutively and maintains organ homeostasis, including integrity of the gastric mucosa. The gene for COX-2 (the “inflammatory” enzyme) is inducible. Thromboxane derived via COX-1 causes platelet aggregation or the listed gastric mucosal protective effects. In contrast, prostaglandins such as prostacyclin (PGI2) derived via COX-2 are mediators of pain, inflammation, and fever. PGE, prostaglandin E. (Adapted from Wolfe MM: Therapy and prevention of NSAID-related gastrointestinal disorders. In Wolfe MM [ed]: Therapy of Digestive Disorders: A Companion to Sleisenger and Fordtran Gastrointestinal Diseases. Philadelphia, WB Saunders, 2000, pp 96-112.)

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THROMBOGENIC EFFECTS Thromboxane A2 is a major product of COX-1 metabolism in platelets (see Fig. 68-1). It causes platelet aggregration, vasoconstriction, and smooth muscle proliferation. In patients with peripheral vascular disease, increased thromboxane production is associated with increased risk of major vascular events. Aspirin is a potent inhibitor of platelet cyclooxygenase (COX-1), which blocks thromboxane production for the life of the platelet. With other NSAIDs, this process lasts 24 hours or less. This effect underlies aspirin’s ability to reduce the incidence of cardiovascular death, myocardial infarction, and stroke in high-risk patients. However, high doses or toxic doses of aspirin can inhibit vitamin K–dependent coagulation factors, leading to an increase in prothrombin time and international normalized ratio. In contrast, prostacyclin is a product of COX-2 metabolism in vascular endothelium. This is postulated from the finding that pharmacologic inhibition of COX-2 leads to the inhibition of prostacyclin formation. Prostacyclin inhibits platelet aggregation and smooth muscle proliferation and causes vasodilatation. Nabumetone, etodolac, and nonacetylated salicylates (relatively COX-2–selective NSAIDs) inhibit COX-2–mediated prostacyclin biosynthesis and seem to have little or no effect on platelet aggregation. Other NSAIDs block COX-1 thromboxane biosynthesis and COX-2 prostacyclin production with less selectivity (Table 68-1; Fig. 68-2).

Aspirin

3.12

Naproxen

1.79

Indomethacin

1.78

Ibuprofen

1.69

Nabumetone

0.64

Etodolac

0.11

Celecoxib

0.11

Meloxicam

0.09

Rofecoxib

0.05

0.00

0.50

1.00

1.50

2.00

2.50

3.00

3.50

IC50 for COX-2/IC50 for COX-1

Figure 68–2 ■ Selectivity of COX-2 inhibitors. Comparison of in vivo inhibitory concentration (IC50) ratios (COX-2/COX-1) of selective and nonselective nonsteroidal anti-inflammatory drugs. A lower ratio indicates an increased degree of selectivity for COX-2. (Adapted from Feldman M, McMahon AT: Do cyclooxygenase-2 inhibitors provide benefits similar to those of traditional anti-inflammatory drugs, with less gastrointestinal toxicity? Ann Intern Med 132:134-143, 2000.)

RENAL EFFECTS Up to 5% of patients on regular NSAID therapy develop one or more nephrotoxic side effects, including fluid and electrolyte abnormalities, acute renal failure, and nephrotic syndrome (Table 68-2). The mechanism of action of these side effects is inhibition of the production of prostaglandins I2, E2, and D2 by blocking of the COX-1 isoenzyme. This reduces renal perfusion by causing acute renal artery vasoconstriction, medullary ischemia, and, in some cases, acute renal failure. NSAIDs also decrease the efficacy of antihypertensive medications because they require intact renal prostaglandin function. The exceptions are calcium channel blockers and angiotensin II receptor antagonists, which are not influenced by renal prostaglandins. Various NSAIDs have different effects on blood pressure, depending on their capacity to inhibit renal

vasodilatory prostaglandins. Sulindac, for instance, may be a weaker inhibitor of renal prostaglandins and thus exert less effect on blood pressure in hypertensive individuals. Blood pressure needs to be closely monitored in patients who are started on NSAID therapy and take antihypertensive medication, especially those 55 years and older. Fluid and electrolyte disturbances are common NSAIDassociated renal side effects. They occur as a result of inhibition of prostaglandin formation in the thick ascending limb of the loop of Henle and the distal renal tubule, leading to hypotonic sodium and water retention. With the inhibition

Table 68–2

Table 68–1

■

Inhibition of Prostacyclin and Thromboxane Biosynthesis and Risk of Thrombosis

Drug Low-dose aspirin Conventional COX-2 specific inhibitors

Prostacyclin

Thromboxane

Thrombosis Risk

+/− ⇓ ⇓

⇓⇓ ⇓ +/–

⇓ Unclear Unclear

COX, cyclooxygenase; NSAID, nonsteroidal anti-inflammatory drug. From Catella-Lawson F, Crofford LJ: Cyclooxygenase inhibition and thrombogenicity. Am J Med 110:28-32, 2001.

■

Renal Syndromes Related to Therapy with Conventional Nonsteroidal Anti-inflammatory Drugs

Fluid and electrolyte abnormalities Acute renal failure Hemodynamic compromise Nephrotic syndrome (minimal-change glomerulopathy, interstitial nephritis) Acute papillary necrosis (typically, single drug cause) Other systemic interactions Hypernatremia Water retention Hyperkalemia Membranous glomerulopathy Chronic papillary necrosis (typically, multidrug causes) Chronic heart failure Hypertension (treated)

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ANAPHYLACTIC

AND

ANAPHYLACTOID REACTIONS

A small number of patient experience allergic and pseudoallergic reactions to aspirin and NSAIDs. Some reactions are caused by the similar pharmacologic properties of traditional NSAIDs, which inhibit both COX-1 and COX-2. Prostaglandin E2 formation is blocked by the inhibition of COX-1, leading to a relative increase in leukotriene formation and histamine release from mast cells. Such a pseudoallergic reaction occurs after the first exposure to the NSAID, which makes prior sensitization impossible. Aspirin and other NSAIDs that are more specific for COX-1 than COX-2 (see Fig. 68-2) can induce rhinorrhea, bronchospasm, and laryngospasm in patients with a prior history of sinusitis and asthma. Cross-sensitivity of aspirin and other relatively COX-1–specific NSAIDs with newer COX-2–selective antagonists does not occur. This is further evidence that COX-1 inhibition is the inciting event in aspirin-induced respiratory symptoms. Some patients display a true allergy to a specific NSAID, with prior exposure leading to the formation of immunoglobulin E (IgE) antibodies. On subsequent exposure, they experience symptoms, including urticaria, angioedema, and anaphylaxis. Assays for specific drug haptens have not been developed, and IgE antibodies are rarely found in the blood of these patients. Therefore, the term anaphylactoid has been used to describe such reactions. These reactions are caused by a specific NSAID, and patients are able to take other NSAIDs without difficulty.

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age (older than 65 years), renal or hepatic impairment, prior history of ulcers, smoking, alcohol use, concomitant use of oral corticosteroids or anticoagulants, high doses of NSAIDs, and prolonged duration of therapy. Since recognition of the two isoforms of cyclooxygenase, the COX-1 enzyme has been identified as the one responsible for the formation of gastric prostaglandin E1, and nonselective NSAIDs have been implicated in a higher risk of GI complications. It is important to understand the relative selectivity of the NSAIDs for COX isoforms, because this may influence the decision of which drug to choose for a patient. For example, etodolac, meloxicam, and nabumetone have a relatively higher affinity for COX-2 than for COX-1 (see Fig. 68-2) and have a safer profile with respect to GI toxicity. The Celecoxib Long-Term Arthritis Safety Study (CLASS) was a 6-month randomized, double-blind, controlled trial comparing the GI toxicity of celecoxib (400 mg twice a day) with that of more traditional NSAIDs (diclofenac 75 mg twice a day; ibuprofen 800 mg three times a day). The primary end point was ulcer-related complications (gastric perforation, gastric outlet syndrome, GI bleeding), and the secondary end point was symptomatic ulcers. Although there appeared to be a difference in symptomatic and complicated ulcers, this was not statistically significant. Two confounding factors in the study were the supratherapeutic doses of celecoxib used and the inclusion of 21% of patients on low-dose aspirin for cardiovascular prophylaxis. Aspirin is known to increase the risk of upper GI hemorrhage. The ulcer complication rate among the nonaspirin users who took celecoxib was similar to that of the general population, but because there was no placebo group, it was difficult to assess the risk of ulcers with celecoxib. However, we were able to ascertain that patients tolerate celecoxib better than diclofenac and ibuprofen, with less decline in hematocrit, a reduced incidence of dyspepsia, and fewer required endoscopies. The Vioxx Gastrointestinal Outcomes Research (VIGOR) was a 12-month trial performed to compare the GI toxicity of rofecoxib (Vioxx)1 50 mg daily to the more traditional NSAID naproxen 500 mg twice a day. The primary end point was confirmed clinical upper GI events, including symptomatic gastroduodenal ulcers, perforation, or obstruction or upper GI bleeding. The secondary end point was complicated GI events causing severe patient compromise. Results showed a statistically significant reduction in GI events with rofecoxib compared with naproxen. The reduced incidence of GI toxicity with rofecoxib was even present in patients with risk factors for GI events, including advanced age, corticosteroid use, prior history of GI perforation or obstruction, and H. pylori infection. This was the first study to demonstrate a definitive benefit with the use of a selective COX-2 inhibitor.

Risk Assessment and Implications

THROMBOGENICITY

GASTROINTESTINAL INJURY

COX-2–selective antagonists preferentially block the formation of prostacyclin, with little effect on thromboxane production. Thus, there is a theoretical concern about an increased risk

Dyspepsia is not a reliable means of assessing GI mucosal damage. Ten percent to 20% of patients on NSAID therapy complain of dyspepsia, yet 50% of endoscopic findings show normal GI mucosa. Most patients do not complain of GI symptoms until they develop a life-threatening upper GI bleed. Risk factors for the development of ulcers include advanced

1 Rofecoxib (Vioxx) was voluntarily withdrawn from the market by its manufacturer (Merck) on September 30, 2004, owing to an increased risk of coronary events.

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of the cyclooxygenase pathway, there is a theoretical increase in leukotriene formation via the 5-lipoxygenase pathway, leading to increased capillary permeability and edema formation. This is often seen in patients who develop congestive heart failure. Hyperkalemia is a rare but serious complication of chronic NSAID therapy. This can occur as a result of inhibition of prostaglandin-mediated renin release. This, in turn, leads to decreased aldosterone formation and decreased secretion of potassium in the distal renal tubules. The development of nephrotic syndrome with interstitial nephritis is rare and is not clearly understood. It is theorized that the preferential formation of leukotrienes and inhibition of prostaglandins increase vascular permeability, leading to nephrotic-range proteinuria and interstitial nephritis. Renal papillary necrosis is also rare and is thought to occur in cases of NSAID overdose in severely dehydrated patients. The combination of prostaglandin inhibition and high intrapapillary doses of NSAIDs, which may be cytotoxic themselves, leads to papillary necrosis. This is unlikely to occur with conventional doses of NSAIDs.

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of thrombosis.2 This may be especially true among elderly patients, who are at higher risk of atherosclerotic disease. In the CLASS study, there was no notable difference in cardiovascular events among patients taking celecoxib compared with diclofenac or ibuprofen. In the VIGOR study, there was a statistically significant increase in major cardiovascular events among patients taking rofecoxib versus naproxen. However, in my view, this is not necessarily indicative of a higher cardiovascular risk for patients taking rofecoxib: 27% of patients from the celecoxib study group and 100% of patients from the rofecoxib study group had rheumatoid arthritis, which increases the risk of cardiovascular events. Further, 21% of patients in the celecoxib study were on lowdose aspirin for cardiovascular prophylaxis; low-dose aspirin was an exclusion criterion in the rofecoxib study. RENAL INJURY Patients with the greatest risk of developing renal insufficiency due to the inhibition of renal prostaglandins are the elderly and those with renal or liver disease, hypertension, some degree of cardiovascular compromise, congestive heart failure, or hypovolemia. It has been noted that COX-2 is also produced in the kidney, so both nonselective and selective inhibition of COX-2 can lead to edema formation. Celecoxib has been evaluated for its ability to impair renal function—specifically, nephrotic syndrome, interstitial nephritis, increased serum creatinine levels, and papillary necrosis. Celecoxib seems to cause less renal impairment compared with nonselective COX inhibitors, but this has not been tested rigorously. Therefore, at least for now, selective COX-2 inhibitors must be used with caution in patients with preexisting renal disease, just as with traditional NSAIDs. ALLERGIC REACTIONS There have been rare reported cases of aseptic meningitis in patients with arthritis who were treated for months with specific NSAIDs. In these cases, the aseptic meningitis is thought to be an immune reaction to the NSAID. IgG and immune complexes have been found in the cerebrospinal fluid of patients with aseptic meningitis. This has not been reported with aspirin. There have also been rare reports of cough, fever, pulmonary infiltrates, and eosinophilia after exposure to multiple NSAIDs, except aspirin. Such allergic alveolitis or hypersensitivity pneumonitis is also thought to be mediated by an immune reaction, because interstitial lymphocytes and eosinophils were found in lung biopsies taken from these patients. This could be either an IgE-mediated reaction or delayed hypersensitivity.

MANAGEMENT Gastrointestinal Toxicity About 15,000 people die each year as a result of major GI complications from NSAIDs, including hemorrhage, perforation, 2 See footnote 1 and Topol EJ: Failing the public health—rofecoxib, Merck, and the FDA. N Engl J Med 351:1707-1709, 2004; and Fitzgerald GA: Coxibs and cardiovascular disease. N Engl J Med 351:1709-1711, 2004.

and obstruction. NSAID-induced ulcers heal spontaneously, but slowly, once the NSAID is discontinued; antisecretory therapy accelerates ulcer healing. Althoughe H2-antagonists are inexpensive, proton pump inhibitors are generally preferred. They cause more rapid ulcer healing and early symptomatic relief. If patients continue to take NSAIDs while on ulcer therapy with an H2-antagonist (e.g., ranitidine 150 mg twice a day) or proton pump inhibitor (e.g., omeprazole 20 mg daily), there is a high rate of ulcer recurrence. Surgery is reserved for patients who present with severe GI hemorrhage or perforation.

Allergic Reactions Aspirin desensitization has been successfully undertaken, with patients receiving aspirin 650 mg twice a day for up to 2 weeks. Urine leukotrienes have been followed, with a significant decrease noted after desensitization. Such desensitization may be especially beneficial for older patients with cardiovascular disease who need to be on long-term aspirin therapy.

PREVENTION Peptic Ulcers Misoprostol, a prostaglandin E1 analogue, decreases the risk of gastric and duodenal ulcers. H2-antagonists and proton pump inhibitors are used to reduce the incidence of duodenal ulcers and gastric ulcers, respectively. For patients at high risk of developing GI complications, a selective COX-2 antagonist is preferred.

Thrombogenicity If patients are taking traditional NSAIDs and COX-2–selective antagonists, those at risk for cardiovascular events should be on low-dose aspirin. Because the traditional NSAIDs and aspirin inhibit COX-1, there may be competitive antagonism. There is also the added risk of upper GI bleeding. Thus, for patients taking aspirin, an H2-antagonist may be the better choice for GI prophylaxis. Omeprazole increases aspirin’s rate of absorption. It may rapidly increase salicylate levels, with potential toxic effects.

Renal Toxicity In general, patients with a serum creatinine level of 2.5 mg/dL or higher should not be started on conventional NSAID therapy. Those on antihypertensive therapy need to have their blood pressure closely monitored during the initiation of NSAID therapy. Patients at risk of developing congestive heart failure should also be closely monitored while on NSAID therapy.

Further Reading Boyce EG, Takiya L: Nonsteroidal anti-inflammatory drugs: Review of factors guiding formulary selection. Formulary 35:142-168, 2000. Buttgereit F, Burmester GR, Lee LS: Gastrointestinal toxic side effects of nonsteroidal anti-inflammatory drugs and cyclooxygenase-2-specific inhibitors. Am J Med 110(Suppl 3A):13S-19S, 2001.

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Catella-Lawson F, Crofford LJ: Cyclooxgenase inhibition and thrombogenicity. Am J Med 110(Suppl 3A):28S-32S, 2001. Frishman WH: Effects of nonsteroidal anti-inflammatory drug therapy on blood pressure and peripheral edema. Am J Card 89:18D-25D, 2002. Oviedo JA, Wolfe MM: Gastroprotection by coxibs: What do the Celecoxib Long-Term Arthritis Safety Study and the Vioxx Gastrointestinal Outcomes Research Trial tell us? Rheum Dis Clin North Am 29: 769-788, 2003. Shiotani A, Graham DY: Pathogenesis and therapy of gastric and duodenal ulcer disease. Med Clin North Am 86:1447-1466, 2002.

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Stevenson DD: Anaphylactic and anaphylactoid reactions to aspirin and other nonsteroidal anti-inflammatory drugs. Immunol Allergy Clin North Am 21:745-768, 2001. Stevenson DD: Aspirin and NSAID sensitivity. Immunol Allergy Clin North Am 24:491-503, 2004. Whelton A: Renal aspects of treatment with conventional nonsteroidal anti-inflammatory drugs versus cyclooxygenase-2-specific inhibitors. Am J Med 110(Suppl 3A):33S-42S, 2001.

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Opioid Tolerance William S. Blau Case Synopsis A 32-year-old woman with ovarian carcinoma, chronic cancer-related pain, and a previous history of intravenous drug abuse presents with small bowel obstruction and is posted for an emergency laparotomy. Her current medications include continuousrelease morphine and an oxycodone-acetaminophen preparation that she takes for breakthrough pain (8 to 12 pills daily).

PROBLEM ANALYSIS Definition Tolerance occurs when increasing doses of a substance are required to sustain a given effect. It may develop within 1 to 2 weeks after initiating opioid therapy, although recent evidence suggests that its onset may be faster, especially with potent, ultra-short-acting opioids such as remifentanil. The degree of tolerance depends on the magnitude and duration of exposure. Variable degrees of cross-tolerance occur between different opioids and different routes of administration (e.g., systemic versus epidural). It is important to distinguish tolerance (a predictable, involuntary physiologic response to drug exposure) from the related phenomena of physical dependence, addiction, and pseudoaddiction (Table 69-1).

Recognition Tolerance should be suspected when a patient requires greater than the usual dose of analgesic or fails to obtain appropriate relief at the usual dose. Any patient receiving opioid medications for 2 weeks or more can be presumed to have some degree of tolerance, related to the dose of opioid medication. Some patients who present for surgery may have developed opioid tolerance from prolonged therapy for chronic or cancer-related pain or from prior substance abuse. Tolerance is often not readily detectable from the preoperative history in drug abusers. Suspicion should be raised in patients who report multiple “allergies” to opioid medications, express a

Table 69–1

■

preference for specific medications, or are known to abuse alcohol or other substances. Prior medical records or history from family members may provide further evidence. In some cases, an unexpectedly high intraoperative or postoperative opioid requirement may be the first indication of prior exposure; however, it is important to recognize that there is a wide range of interindividual variability in opioid requirements, even among patients who are opioid naïve.

Risk Assessment Any patient with prolonged hospitalization, multiple surgeries, or history of chronic or cancer pain is at risk and should be carefully assessed for the possibility of tolerance. The lifetime prevalence of nonalcohol drug addiction ranges from 5% to 6%. There is probably a higher prevalence of chemical dependency among hospitalized individuals with acute pain problems caused by medical illnesses, trauma, or surgical procedures than among the general population. As many as half of acute trauma victims use drugs or alcohol before injury and may be habitual users. Patients receiving daily methadone or buprenorphine for chemical dependency should be assumed to have significant tolerance and crosstolerance to other opioids as well.

Implications Patients with opioid tolerance are difficult to assess and are at risk for inadequate postoperative pain control. These patients require higher than customary doses of opioids,

Definition of Terms

Term

Definition

Tolerance

Phenomenon whereby exposure to a drug results in diminution of effect or the need for a higher dose to maintain that effect Physiologic phenomenon characterized by the development of an abstinence syndrome following abrupt discontinuation of therapy, substantial dose reduction, or administration of an antagonist drug Psychological and behavioral syndrome characterized by (1) intense desire for a drug and overwhelming concern about its continued availability; (2) evidence of compulsive drug use; or (3) evidence of one or more associated behaviors, including manipulation of the treating physician or medical system for the purpose of obtaining additional drugs, acquisition of drugs from other medical or nonmedical sources, drug hoarding or sale, or unapproved use of other drugs during opioid therapy Iatrogenic syndrome of abnormal behavioral symptoms, mimicking those of addiction, that is a direct consequence of inadequate pain management

Physical dependence Addiction

Pseudoaddiction

278

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yet many physicians are inclined to undermedicate. As patients become more vocal about their needs, hospital staff may react negatively or even punitively, ultimately leading to the syndrome of pseudoaddiction. The risk of side effects from pain therapy, such as oversedation or respiratory depression, is also increased in patients with opioid tolerance. Many opioid-tolerant patients also exhibit physical dependence and are at risk of experiencing withdrawal during the postoperative period, especially when surgery eliminates the source of chronic pain and opioids are rapidly tapered or discontinued. Symptoms generally begin 8 to 12 hours after the last dose of an intermediate-acting opioid and may be difficult to distinguish from those of undertreated pain (e.g., hypertension, tachycardia, abdominal pain).

General Considerations Effective management of a patient with opioid tolerance begins with the preoperative assessment. The possibility of tolerance should be identified and anticipated, based on the patient’s history. Particular attention should be paid to preexisting sites and intensity of pain, baseline functional limitations, and the success of previous pain therapies. It is essential to establish a good therapeutic relationship with the patient as early as possible. Make the patient a partner in developing the analgesic plan, provide reassurance that every effort will be made to provide adequate pain control, but be direct and honest about the limitations of therapy. Patients can help establish realistic goals for pain and activity; for example, obtaining a score of 3 out of 10 after surgery may be unrealistic if the baseline score at home is 7 out of 10. Reassure the patient that his or her reporting of postoperative pain will be taken seriously but will also be corroborated by objective data whenever possible (e.g., quality of sleep; ability to cough, move, and participate in therapy). Involvement of family members may be helpful. Seek preoperative consultation from a pain specialist, as necessary. The patient’s preferences and requests for particular analgesics should be honored to the extent allowable by institutional policy and principles of safe pharmacologic practice. Plans and goals should be clearly communicated to the anesthesia team, postanesthesia care unit staff, and postoperative ward. The overriding principle of acute pain management for patients with opioid tolerance is to titrate analgesic therapy to effect, while anticipating the need for higher than usual doses. Frequent assessment, intervention, and reassessment are required. These patients are at increased risk for anxiety or sedation, and special arrangements may be necessary for postoperative monitoring of respiration and level of consciousness. Whenever possible, the cause or mechanism of pain should be identified and treated primarily. A multimodal approach should be taken, and the pain management plan should be initiated as early as possible. In some cases, preoperative intervention may have preemptive effects. Pharmacologic therapy for symptom control should be based on sound pharmacologic principles. Trials of alternative opioids or routes of delivery should be considered, owing to the possibility of incomplete cross-tolerance. Additional alternative

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therapies include nonopioid analgesics or adjuncts, regional analgesia, and nonpharmacologic interventions (e.g., transcutaneous electrical nerve stimulation, relaxation, heat or cold, massage, distraction). Every effort should be made to avoid the discontinuation of routine daily psychotropic medications that may promote psychological coping mechanisms.

Medications For patients receiving chronic opioids preoperatively, the daily baseline medication dose or analgesic equivalent should be continued throughout the perioperative period. In many cases, this may need to be administered parenterally and can often be incorporated into a basal infusion as part of a patient-controlled analgesia (PCA) prescription. For patients in substance abuse maintenance programs, continuation of the baseline methadone or buprenorphine dose is equally important. Also, avoid substituting medications if at all possible. On the day of surgery, the usual oral dose can be administered in the morning, with the remainder of the daily requirement titrated intravenously intraoperatively and after surgery. Additional intraoperative dosing above baseline requirements should be expected; double doses or greater of morphine, methadone, hydromorphone, or fentanyl may be required. It may be helpful to allow muscle relaxation to wear off near the end of general anesthesia and titrate additional opioid to a mild slowing of the spontaneous respiratory rate. Postoperatively, avoid administering analgesic medications solely on an as-needed basis. Intravenous PCA therapy is often appropriate and effective, even in a patient with a history of drug abuse. A loading dose should be provided and titrated to the level of pain so that the patient starts from a position of adequate pain control. If the patient is able to continue oral medications, PCA bolus dosing can be added, in combination with the baseline oral opioid dose. Otherwise, the total daily opioid dose can be converted to the intravenous morphine, hydromorphone, or fentanyl equivalent using standard conversion tables (Table 69-2) and provided as a basal infusion over 24 hours. Bolus dosing requirements

Table 69–2

■

Equianalgesic Opioid Conversion*

Drug

Oral Equivalent (mg)

Parenteral Equivalent (mg)

Morphine

60 (acute) 30 (chronic)

10 10

Methadone (Dolophine) Fentanyl (Duragesic) Hydromorphone (Dilaudid) Codeine Hydrocodone (Lorcet, Vicodin) Oxycodone (Percocet, Tylox)

†

†

— 7.5

0.125 1.5

180-200 15

130 —

15

—

*Based on single-dose studies only. † Conversions to and from methadone are unpredictable; they vary among patients and with the overall magnitude of opioid dose. However, acutely, the parenteral equivalent for methadone is the same as morphine (10 mg).

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MANAGEMENT

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1.5 to 3 times greater than those of opioid-naïve patients should be anticipated, correlating with the magnitude of the preoperative dose, intraoperative opioid requirements, and titrated loading dose. It should also be anticipated that the duration of therapy for acute or postoperative pain will be longer than for opioid-naïve patients. Most opioids have no specific toxicity, so there is no upper limit to dose titration. However, the agonist-antagonists and partial agonists, such as butorphanol and buprenorphine, exhibit an analgesic ceiling that limits dose titration and may precipitate withdrawal in patients with physical dependence. Meperidine and propoxyphene have active metabolites that may cause central nervous system toxicity, especially in the setting of impaired renal function. Combination drugs (e.g., oxycodone with acetaminophen) are relatively contraindicated because of the risk of acetaminophen or aspirin toxicity. Morphine alone and at extremely high doses, especially when delivered intrathecally, can rarely produce a state of paradoxical pain, which may be related to metabolite accumulation. Morphine and other opioid agonists are more or less equivalent in terms of clinical efficacy. Nevertheless, converting to an alternative opioid can improve analgesia in some cases, owing to incomplete cross-tolerance. In particular, methadone sometimes provides effective analgesia even at modest doses in the setting of inadequate pain control with high and rapidly escalating doses of morphine. Methadone can be administered at a dose of 20 to 40 mg orally (or half as much parenterally) over 24 hours, with additional breakthrough doses of 1 to 2.5 mg intravenously as often as every 5 to 10 minutes. However, care must be taken to avoid rapid dose escalation with methadone because of its prolonged half-life and variable pharmacokinetics. In addition to opioids, adjunctive medications should be used for pain. These include nonsteroidal anti-inflammatory drugs, tricyclic antidepressants and anticonvulsants for neuropathic sources of pain, muscle relaxants, and anxiolytics. There is accumulating evidence that some other medications, when administered perioperatively, may have novel analgesic applications that enhance the chance of successful pain modulation. These include gabapentin, clonidine, adenosine, lidocaine, and ketamine. Of these, ketamine has the most evidence supporting an analgesic benefit. It is my practice to infuse ketamine at 0.1 mg/kg per hour intraoperatively, along with the administration of 1 to 2 g magnesium intravenously, to suppress NMDA receptor activation in patients with opioid tolerance. The pain management plan continues through the hospital discharge process. The 24-hour parenteral opioid dose should be converted to an oral equivalent, with two thirds as the standing dose and one third administered on an as-needed basis. Depending on the severity and persistence of postoperative pain, the patient may be discharged on his or her baseline preoperative analgesic with a provision for breakthrough pain; often, however, upward adjustment of the baseline dose is required, at least temporarily. It is essential to have a clear postdischarge plan, with a responsible physician willing to manage and taper pain medications on an outpatient basis.

Regional Anesthesia Continuous regional anesthesia techniques can be invaluable in enhancing pain control and avoiding the escalation

of opioid doses, but they do not eliminate the need for ongoing administration of baseline analgesic medications in tolerant or dependent patients. Epidural analgesia is an acceptable and useful adjunct. For drug abusers or patients at high risk for opioid withdrawal, it may be advantageous to infuse only local anesthetic through the epidural catheter (e.g., bupivacaine 0.1% to 0.25%) and give the patient systemic analgesics to cover baseline needs.

Drug Abusers In patients with opioid tolerance due to active drug abuse or addiction, all the previously discussed principles of pain management apply; however, there are some special considerations. The first and foremost goal is satisfactory control of pain. This is not an appropriate time to attempt detoxification or assume a punitive role. It is essential to engage in a frank discussion with the patient preoperatively to (1) reassure him or her that all reasonable efforts will be made to provide satisfactory pain control and (2) set reasonable expectations and clear limits to avoid excessive negotiation about drug choices or doses. Avoid multiple pain managers, and aim for consistency of response rather than negotiation. Drug abuse–related behaviors should not be tolerated; ignore negative behaviors and reward cooperation with therapy. Consider the use of urine toxicologic screens, especially with the occurrence of oversedation or respiratory depression or the suspicion of unsanctioned drug use. Intravenous PCA is an acceptable technique for pain management. Offering the patient some degree of control, within specified limits, helps reduce negotiation and confrontation with hospital staff. Care must be taken, however, to monitor closely for evidence of tampering with the PCA device. Tapering and discontinuation of pain therapy should proceed according to a predetermined schedule, usually over 3 to 4 weeks. At discharge, clear instructions should be provided, along with a limited supply of pain medication, and only one physician should be responsible for any refills. Aberrant drug-related behaviors should not be tolerated. Some patients may require transfer to a detoxification center rather than discharge to home. Patients with a remote history of substance abuse do not necessarily require special treatment and can be managed with standard techniques. If the risk of relapse is deemed high, however, efforts should be made to rely minimally on systemic opioid analgesics in favor of other modalities, including single or continuous peripheral nerve blocks or epidural analgesia. Consultation with an addiction specialist should be obtained, and intensification of a formal relapse prevention program should be considered.

PREVENTION Tolerance is a predictable neurophysiologic response to continued opioid exposure. The possibility of tolerance is not a reason to avoid analgesic therapy if it is indicated. Propensity toward addiction is more a characteristic of the person using the drug than of the drug itself. The risk of creating a drug addiction problem when opioids are part of an analgesia plan for acute pain control is extremely low and is no reason to withhold therapy or to underdose.

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Care must be taken to prevent withdrawal after the transition to epidural therapy or during the tapering of therapy as pain resolves. A daily 10% to 50% dose reduction is usually well tolerated. Conversion to methadone before weaning can be helpful because of methadone’s longer half-life. The addition of clonidine 6 μg/kg per day, divided in four to six doses, can help prevent many autonomic features of withdrawal; this dose can be increased to 17 μg/kg per day as necessary and tolerated. Once symptoms are suppressed, clonidine can be weaned over several days.

Further Reading

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Fukunaga AF, Alexander GE, Stark CW: Characterization of the analgesia actions of adenosine: Comparison of adenosine and remifentanil infusions in patients undergoing major surgical procedures. Pain 101:129-138, 2003. Goyagi T, Tanaka M, Nishikawa T: Oral clonidine premedication enhances postoperative analgesia by epidural morphine. Anesth Analg 89: 1487-1497, 1999. Groudine SB, Fisher HAG, Kaufman RP Jr, et al: Intravenous lidocaine speeds the return of bowel function, decreases postoperative pain, and shortens hospital stay in patients undergoing radical retropubic prostatectomy. Anesth Analg 86:235-259, 1998. Guignard B, Bossard AE, Coste C, et al: Acute opioid tolerance: Intraoperative remifentanil increases postoperative pain and morphine requirement. Anesthesiology 93:409-417, 2000. Mitra S, Sinatra RS: Perioperative management of acute pain in the opioiddependent patient. Anesthesiology 101:212-227, 2004. Rapp SE, Ready LB, Nessly ML: Acute pain management in patients with prior opioid consumption: A case-controlled retrospective review. Pain 61:195-201, 1995. Steindler EM: ASAM addiction terminology. In Graham AW, Schultz TK (eds): Principles of Addiction Medicine, 2nd ed. Chevy Chase, Md, American Society of Addiction Medicine, 1998, pp 1301-1304. Weissman DE, Haddox JD: Opioid pseudoaddiction: An iatrogenic syndrome. Pain 36:363-366, 1989.

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De Kock M, Lavand’homme P, Waterloos H: “Balanced analgesia” in the perioperative period: Is there a place for ketamine? Pain 92:373-380, 2001. Dirks J, Fredensborg BB, Christensen D, et al: A randomized study of the effects of single-dose gabapentin versus placebo on postoperative pain and morphine consumption after mastectomy. Anesthesiology 97:560-564, 2002. Doverty M, Somogyii AA, White JM, et al: Methadone maintenance patients are cross-tolerant to the antinociceptive effects of morphine. Pain 93:155-163, 2001.

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Stuart Grant Case Synopsis A 62-year-old man undergoing unilateral total knee arthroplasty has lumbar plexus and sciatic nerve perineural catheters placed for surgical anesthesia and postoperative analgesia. He receives ropivacaine 0.2% by patient-controlled infusion through the lumbar plexus catheter and ropivacaine 0.2% as a continuous infusion via the sciatic nerve catheter. In the recovery room he is pain free, but during the first postoperative night he complains of pain. This is managed using bolus 0.5% ropivacaine, but the next day, the physical therapist and surgeon complain because of the profound motor block.

PROBLEM ANALYSIS Definition Numerous studies have shown that perineural local anesthetic infusions provide profound analgesia. These techniques have been used to provide both intraoperative anesthesia and postoperative analgesia. Certain complications are block specific, such as a pneumothorax with classic (non-“plumbbob”) supraclavicular or infraclavicular blocks or epidural spread with a lumbar plexus block. This chapter does not discuss block-specific complications; rather, the focus is on those complications that can occur using continuous perineural local anesthetic infusions at any insertion site. A variety of complications have been reported, including the following: ●

● ● ● ● ● ● ●

Insertion difficulty or inability to insert a catheter, leading to block failure Local anesthetic toxicity Catheter migration into a vessel Retained catheter fragments Infectious complications Neurologic complications Prolonged motor block Pain during injection or infusion via the perineural catheter

Recognition The clinical features of local anesthetic toxicity are discussed in Chapter 56. The clinical features of infectious complications include the following: ●

● ● ●

Late onset of symptoms, 2 to 3 days after peripheral nerve catheter placement Tissue erythema and swelling at catheter insertion site Leukocytosis and fever Pain and tenderness at catheter insertion site

282

The clinical features of neurologic complications include the following: ●

●

●

Prolonged motor block long after cessation of local anesthetic infusion Reduced touch or paresthesias that persist or worsen after cessation of infusion Pain that is neuropathic in nature

The clinical features of motor block and inadequate analgesia include the following: ● ● ● ●

Numbness and perception of a heavy or weak extremity Loss of proprioception Increasing or high patient-reported pain score Increased opioid-related side effects

Risk Assessment The incidence of complications following peripheral nerve block is low and must be balanced against the risks of general anesthesia and central neuraxial techniques. Auroy and coworkers reported the incidence of serious complications related to regional anesthesia in a prospective study using data from 103,730 cases. The incidence of cardiac arrest and neurologic injury related to regional anesthesia was low, but both complications were more than three standard deviations greater after spinal anesthesia than after other regional procedures. These data did not discriminate between singleinjection and continuous peripheral nerve block techniques, but peripheral nerve blocks in general were associated with fewer neurologic injuries and cardiac arrests than were central neuraxial techniques. Bergman and coworkers retrospectively examined the neurologic complications after 405 consecutive continuous axillary nerve block catheter procedures. They found no greater incidence of neurologic complications using continuous catheter techniques than using single injections for axillary nerve block. Borgeat and colleagues prospectively examined complications associated with interscalene block

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Continuous Nerve Blocks: Perineural Local Anesthetic Infusion

Implications Infection can result in discomfort and limitation of activity. Neurologic complications can result in weakness and chronic pain, with reduced functional capacity after surgery. Careful technique and patient selection are important factors in reducing these complications. Prolonged motor block produced by high local anesthetic concentrations may delay early ambulation but has not been shown to affect long-term functional outcomes following arthroplasty. In fact, patients given either epidural or peripheral nerve catheters after knee arthroplasty have increased rates of recovery for the first 6 weeks after surgery compared with those on opioid analgesia regimens. Failed blocks result in pain and reduced patient satisfaction. This can lead to increased use of opioid analgesics and opioid-related side effects such as respiratory depression, pruritus, nausea, vomiting, and constipation.

MANAGEMENT Infection ● ● ● ●

Remove the infected catheter. Culture the catheter tip and obtain antibiotic sensitivities. Commence treatment with a broad-spectrum antibiotic. Convert to an appropriate multimodal analgesic regimen.

Neurologic Complications ●

Obtain a careful history and complete neurologic examination.

● ●

●

●

Refer the patient to a neurologist. Consider computed tomography to exclude hematoma (e.g., in the psoas compartment around the lumbar plexus; see Chapter 64). Perform early electromyography (EMG) to document any preexisting neurologic deficit, followed by late EMG to identify any perioperative nerve injury. Consider commencing gabapentin (Neurontin), especially in patients with symptoms of neuropathic pain.

Pain Pain should be assessed using the patient-reported analog scale. Peripheral nerve catheter techniques should be part of any balanced analgesic regimen. Use of nonsteroidal antiinflammatory agents and COX-2 enzyme inhibitors should be considered in all cases, unless contraindicated. The postoperative management of peripheral nerve catheters for pain control includes the following: ● Postoperative pain assessment ● Clinical examination for evidence of nerve block

PREVENTION Infectious complications can be reduced by the use of appropriate skin preparations. Chlorhexidine is more effective than iodine-based preparations in this regard. Care must be taken to ensure that the chlorhexidine has dried before needle insertion, because of the potential for neurotoxicity. Additionally, the choice of catheter insertion site is important. For example, a femoral nerve catheter placed in an obese patient with a large pannus is more likely to become infected. Surgeons fully appreciate that best medical practice supports the use of prophylactic antibiotics whenever foreign material is being inserted. The perineural nerve catheter is a foreign material, and if the surgical team prescribes prophylactic antibiotics, it makes sense to start these before peripheral nerve catheter insertion. If the surgeon does not prescribe antibiotics for the patient, the anesthesiologist may want to consider prescribing them for prophylaxis of perineural catheter infection. Evidence regarding the prevention of neurologic perineural catheter complications is scant, but by performing blocks in lightly sedated patients, minimizing pressure when injecting local anesthetics, and stopping injections immediately when pain is experienced, a practitioner may be able to reduce the likelihood of nerve injury. The use of blunt versus sharp needles is often debated in the literature, as is the technique of eliciting paresthesia versus the use of a nerve stimulator. The likelihood of motor block can be reduced by using lower concentrations of drug in perineural local anesthetic infusions. There is also evidence of better sensory versus differential motor blockade with ropivacaine than bupivacaine. Careful attention to the details of catheter fixation at the time of insertion, use of bolus local anesthetic via the catheter for breakthrough pain, and use of a patient-controlled regional anesthesia catheter can help reduce the likelihood of postoperative pain.

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and shoulder surgery and found no differences between catheter techniques and single-injection blocks. Leaving a catheter in situ entails the potential risk of infection and catheter migration into a vessel. This risk must be balanced against the improved analgesia. Although Cuvillon and coworkers were able to isolate bacterial colonization in 57% of 208 femoral nerve catheters, no clinically relevant infectious complications occurred. There was one case (0.1% incidence) of a serious infection (abscess), and superficial erythema was observed in 0.7% of the patients in Borgeat’s series (cited earlier). Only superficial skin infections (5% incidence) were reported in the recent series by Boezaart and associates. Only one case report of migration into a vessel has been reported in the literature, so the incidence of that complication is unknown. After resolution of the primary block with long-acting amide local anesthetics, inadvertent catheter dislodgment or incorrect initial catheter positioning is the most common cause of pain 12 hours or more after the initial block. This can occur in up to 10% to 20% of patients and is by far the most common complication of continuous perinural nerve blocks. Some patients with infusions of low concentrations of local anesthetics in a functional perineural catheter suffer breakthrough pain. Use of a patient-controlled bolus, in addition to the background basal infusion, can reduce the severity of breakthrough pain. As the case synopsis illustrates, the challenge for the clinician is to balance the risk of motor block or even local anesthetic toxicity against the patient’s discomfort from inadequately controlled pain.

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Further Reading Auroy Y, Narchi P, Messiah A, et al: Serious complications related to regional anesthesia: Results of a prospective survey in France. Anesthesiology 87:479-486, 1997. Bergman BD, Hebl JR, Kent J, Horlocker TT: Neurologic complications of 405 consecutive continuous axillary catheters. Anesth Analg 96: 247-252, 2003. Boezaart AP, De Beer JF, Nell ML: Early experience with continuous cervical paravertebral block using a stimulating catheter. Reg Anesth Pain Med 28:406-413, 2003. Borgeat A, Dullenkopf A, Ekatodramis G, Nagy L: Evaluation of the lateral modified approach for continuous interscalene block after shoulder surgery. Anesthesiology 99:436-442, 2003. Borgeat A, Kalberer F, Jacob H, et al: Patient-controlled interscalene analgesia with ropivacaine 0.2% versus bupivacaine 0.15% after major open shoulder surgery: The effects on hand motor function. Anesth Analg 92:218-223, 2001.

Capdevila X, Barthelet Y, Biboulet P, et al: Effects of perioperative analgesic technique on the surgical outcome and duration of rehabilitation after major knee surgery. Anesthesiology 91:8-15, 1999. Cuvillon P, Ripart J, Lalourcey L, et al: The continuous femoral nerve block catheter for postoperative analgesia: Bacterial colonization, infectious rate and adverse effects. Anesth Analg 93:1045-1049, 2001. Gillespie WJ, Walenkamp G: Antibiotic prophylaxis for surgery for proximal femoral and other closed long bone fractures. Cochrane Database Syst Rev 2000(2):CD000244, 2000. Grant SA, Nielsen KC, Greengrass RA, et al: Continuous peripheral nerve block for ambulatory surgery. Reg Anesth Pain Med 26:209-214, 2001. Tuominen MK, Pere P, Rosenberg PH: Unintentional arterial catheterization and bupivacaine toxicity associated with continuous interscalene brachial plexus block. Anesthesiology 75:356-358, 1991. Yentur EA, Luleci N, Topcu I, et al: Is skin disinfection with 10% povidone iodine sufficient to prevent epidural needle and catheter contamination? Reg Anesth Pain Med 28:389-393, 2003.

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Persistent Paresthesia Terese T. Horlocker

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Case Synopsis A 58-year-old woman with insulin-dependent diabetes mellitus is scheduled to undergo total wrist arthroplasty. An axillary block is performed with the transaxillary technique using 45 mL of 1.5% mepivacaine containing 5 μg/mL of epinephrine. Total tourniquet time is 130 minutes. After surgery, the patient has residual numbness in her fourth and fifth fingers. Electromyography performed at 8 weeks demonstrates a diffuse sensorimotor neuropathy and an ulnar neuropathy at the level of the axilla. The symptoms slowly and completely resolve over a period of 10 weeks.

Definition Perioperative nerve injuries have long been recognized as a complication of regional anesthesia. Fortunately, severe or disabling neurologic complications rarely occur. Cheney and coworkers examined the American Society of Anesthesiologists’ closed claims database to determine the role of nerve damage in malpractice claims filed against anesthesia care providers. Of the 4183 claims reviewed, 670 (16%) were for anesthesiarelated nerve injury. The most frequent sites of injury were the ulnar nerve (190 claims), brachial plexus (137 claims), lumbosacral roots (105 claims), and spinal cord (84 claims). Upper extremity nerve injuries were more often associated with general anesthesia. However, spinal cord and lumbosacral nerve root injuries having identifiable causes were associated predominantly with regional anesthetic techniques and were related to paresthesias during needle or catheter placement or pain during injection of local anesthetic. It is also notable that despite intensive medicolegal investigation, a definite mechanism of injury is rarely determined. The lack of an apparent mechanism often leads the patient (and consulting specialists) to assume that something must have been done incorrectly during the perioperative period to cause the nerve injury. This review demonstrates that although perioperative nerve injury is a significant source of anesthesia-related claims, the exact mechanism of injury is often unclear. The potential risk of nerve injury due to needle trauma, local anesthetic toxicity, or neural ischemia during regional anesthetic techniques increases the probability that neurologic deficits will be attributed to anesthetic agents. However, several series have demonstrated that neurologic deficits are more likely to be associated with a cause that is unrelated to regional anesthesia. For example, Horlocker and colleagues reported 61 nerve injuries after 1614 upper extremity surgical procedures performed under axillary block, for a 3.8% overall frequency of neural dysfunction. Only 7 of the 61 injuries (11%) were the result of the anesthetic; the remaining 54 (89%) were related to surgical factors. The anesthesiologist must therefore be aware of the surgical, medical, and anesthetic risk factors associated with perioperative nerve injuries to reduce the incidence of neurologic complications.

Recognition Neurologic complications associated with regional anesthesia can be divided into two broad categories: those that are unrelated to the regional anesthetic but coincide temporally, and those that are the direct result of the regional anesthetic agent or technique. Causes of nerve injury unrelated to the regional anesthetic agent or technique include the following: ● ● ● ● ● ●

Surgical trauma Surgical retractor Patient positioning Tourniquet ischemia Improperly placed dressings or casts Preexisting neurologic diseases

Causes of nerve injury directly related to the regional anesthetic agent or technique include the following: ● ● ● ●

Direct or indirect needle or catheter trauma Neural ischemia Local anesthetic neurotoxicity Infection

Risk Assessment Trauma, ischemia, infection, and local anesthetic neurotoxicity contribute to the development of neurologic complications after peripheral neural block. Patient and anesthetic factors that may be associated with an increased risk of neurologic complications after regional anesthetic agents or techniques include the following: ● ● ● ●

Preexisting neurologic disorder or diagnosis Needle bevel and configuration Local anesthetic (drug and concentration) Use of vasoconstrictors

The elicitation of a paresthesia while performing an axillary block may represent direct needle-induced trauma and increased risk of persistent paresthesia associated with regional anesthesia. Selander and coworkers reported a 2.8% incidence of postoperative nerve injury in patients in whom paresthesia was sought during axillary block, compared with a 0.8% incidence in those undergoing a perivascular technique (the difference was not statistically significant, however). 285

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The neurologic deficits ranged from slight hypersensitivity to severe paresis and persisted from 2 weeks to more than 1 year. Theoretically, using a nerve stimulator to localize neural structures should allow a high success rate without increasing the risk of neurologic complications, but this hypothesis has not been formally tested. Fanelli and colleagues prospectively evaluated 3996 patients undergoing sciatic-femoral, axillary, and interscalene blocks using multiple-injection and nerve stimulator techniques. During the first month after surgery, 69 patients (1.7%) developed neurologic dysfunction; recovery was complete in all but 1 patient by 4 to 12 weeks. (This frequency and outcome are similar to those reported using a paresthesia technique.) Direct needle trauma also may cause disturbances in nerve conduction without clinical evidence of a neuropathy. After sciatic nerve impalement with an axillary block needle in rats, histologic changes consistent with axonal injury persisted for 28 days. However, clinical evidence of hind leg hyposensitivity was present for only 2 weeks. Similar findings have been reported after sciatic nerve penetration with a microneurographic electrode in rats. These data suggest that a subclinical neuropathy may occur with greater frequency and longer duration than anticipated. Needle gauge, type (short versus long bevel), and bevel configuration may also influence the degree of nerve injury, although evidence from animal models is unclear, and there are no relevant human studies. The passage into and presence of an indwelling catheter in a peripheral nerve sheath represent an additional source of direct trauma. Although difficulty during catheter insertion may lead to vessel puncture, tissue trauma, and bleeding, significant complications are uncommon, and permanent sequelae are rare. The largest series of continuous brachial plexus blocks with indwelling catheters included only 405 patients. Bergman and coworkers reported nine complications in eight patients, for an overall frequency of 2.2%, including one each of the following: localized infection (treated with catheter removal and antibiotics), axillary hematoma, and retained catheter fragment requiring surgical excision. Two patients reported signs and symptoms of systemic local anesthetic toxicity manifesting as preseizure activity. Four patients (1%) reported new neurologic deficits postoperatively, only two of which were anesthesia related. Peripheral nerves have a dual blood supply consisting of intrinsic endoneural vessels and extrinsic epineural vessels. A reduction in or disruption of nerve blood flow may result in neural ischemia. Intraneuronal injection of volumes as small as 50 to 100 μL may generate intraneuronal pressures that exceed capillary perfusion pressure for as long as 10 minutes, thus causing neural ischemia. Endoneural hematomas have also been reported after intraneuronal injection. Epineural blood flow is responsive to adrenergic stimuli. Theoretically, the use of local anesthetic solutions containing epinephrine can produce local nerve ischemia, especially in patients with microvascular disease; however, the actual risk of significant neurologic ischemia in patients given local anesthetic solutions containing vasoconstrictors is unknown. Neurologic complications after regional block may be a direct result of local anesthetic toxicity. There is both laboratory and clinical evidence that local anesthetic solutions are potentially neurotoxic. Differences in neurotoxicity are dependent on pKa, lipid solubility, protein binding, and potency.

In histopathologic, electrophysiologic, and neuronal cell models, lidocaine and tetracaine appear to have a greater potential for neurotoxicity than does bupivacaine at clinically relevant concentrations. Additives such as epinephrine and bicarbonate may also affect neurotoxicity. Patients with microangiopathic processes, such as diabetes, demonstrate a reduction in neural blood flow and local anesthetic uptake. Concurrently, the presence of a peripheral neuropathy reduces the amount of local anesthetic required to produce neural block and toxicity. Therefore, these patients are more sensitive to the clinical effects of local anesthetic solutions. The concentration of local anesthetic selected, as well as the use of vasoconstrictors, must be carefully evaluated in patients with peripheral neuropathies, because prolonged exposure to or high concentrations of local anesthetic solutions within the neurovascular compartment may result in permanent neurologic deficits. The presence of a preexisting neurologic condition may predispose a nerve to injury by the neurotoxic effects of local anesthetics. The presumed mechanism is a “double crush” of the nerve at two locations, resulting in a nerve injury of clinical significance. The double-crush concept suggests that nerve damage caused by traumatic needle placement, local anesthetic toxicity, or neural ischemia during the performance of regional anesthesia may worsen neurologic outcome in the presence of an additional patient factor or surgical injury.

Implications Neurologic deficits that arise within the first 24 hours most likely represent extraneural or intraneural hematoma, intraneural edema, or a lesion involving a sufficient number of nerve fibers to permit immediate diagnosis. However, in many cases of persistent paresthesias after regional anesthesia, the symptoms of nerve injury do not develop until days to weeks later. The presentation of late disturbances in nerve function suggests an alternative cause, such as tissue reaction or scar formation, although it is unknown whether this reaction is due to mechanical trauma, chemical toxicity, or both.

MANAGEMENT Major complications after regional anesthetic techniques are rare but can be devastating to the patient and the anesthesiologist. Prevention and management begin during the preoperative visit with a careful evaluation of the patient’s medical history and a discussion of the risks and benefits of the available anesthetic techniques. Patients with preexisting neurologic disorders such as multiple sclerosis, poliomyelitis, or amyotrophic lateral sclerosis may develop new neurologic deficits perioperatively, and it is often difficult to differentiate between surgical and anesthetic causes. In these patients, if a regional anesthetic is indicated (or requested), the patient’s preoperative neurologic examination should be formally documented, and the patient must be made aware of the possible progression of the underlying disease process. Stable preexisting neurologic conditions (e.g., documented peripheral neuropathy, inactive lumbosacral radiculopathy, hemiparesis due to an old cerebrovascular accident) are not contraindications to the use of regional anesthesia. However, the

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timely evaluation with a multidisciplinary approach involving neurology, radiology, internal medicine, and surgery will allow appropriate treatment.

PREVENTION Further Reading Preventive measure include all of the following: ● ● ●

● ● ●

Appropriate patient selection Meticulous regional anesthetic technique Avoidance of direct needle trauma and intraneuronal injection Weighing of the risks and benefits of vasoconstrictors Use of appropriate local anesthetic concentrations Prompt evaluation of perioperative neuropathies

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Meticulous technique must be used during any central neuraxial or peripheral nerve block. Paresthesias elicited during needle or catheter placement or injection of local anesthetic should be documented. Painful paresthesias are associated with nerve injury and should be avoided. The total local anesthetic dose and concentration, as well as the addition of vasoconstrictors, must be carefully considered. Hadzic and associates recently evaluated the use of peripheral nerve stimulators to identify the nerves to be blocked to achieve regional anesthesia. They found that the nerve stimulators in common use in the United States vary greatly in terms of accuracy of current output and manufacturer-selected electrical characteristics (e.g., current duration, stimulating frequency, maximum voltage output). They also noted that most authors recommend obtaining a motor response with a current of 0.5 mA or less before injecting a local anesthetic, and they suggested that stimulation at currents higher than 0.5 mA may result in failure of the block; this was attributed to the needle being too far from the nerve to be blocked. In contrast, injection after nerve stimulation thresholds of 0.1 mA or less may increase the risk of nerve injury because of the possibility of intraneuronal local anesthetic injection. Finally, although postoperative neurologic complications may present immediately after surgery, some require days to weeks to emerge. Should such neurologic dysfunction occur,

Auroy Y, Narchi P, Messiah A, et al: Serious complications related to regional anesthesia: Results of a prospective survey in France. Anesthesiology 87:479-486, 1997. Bergman BD, Hebl JR, Kent J, Horlocker TT: Neurologic complications of 405 consecutive continuous axillary catheters. Anesth Analg 96: 247-252, 2003. Cheney FW, Domino KB, Caplan RA, Posner K: Nerve injury associated with anesthesia: A closed claims analysis. Anesthesiology 90: 1062-1069, 1999. Fanelli G, Casati A, Garancini P, et al: Nerve stimulator and multiple injection technique for upper and lower limb blockade: Failure rate, patient acceptance, and neurologic complications. Anesth Analg 88:847-852, 1999. Hadzic A, Vloka J, Hadzic N, et al: Nerve stimulators used for peripheral nerve blocks vary in their electrical characteristics. Anesthesiology 98:969-974, 2003. Horlocker TT, Kufner RP, Bishop AT, et al: The risk of persistent paresthesia is not increased with repeated axillary block. Anesth Analg 88:382-387, 1999. Kalichman MW, Calcutt NA: Local anesthetic-induced conduction block and nerve fiber injury in streptozotocin-diabetic rats. Anesthesiology 77:941-947, 1992. Neal JM: Effects of epinephrine in local anesthetics on the central and peripheral nervous systems: Neurotoxicity and neural blood flow. Reg Anesth Pain Med 28:124-134, 2003. Neal JM, Hebl JR, Gerancher JC, Hogan QH: Brachial plexus anesthesia: Essentials of our current understanding. Reg Anesth Pain Med 27: 402-428, 2002. Rice ASC, McMahon SB: Peripheral nerve injury caused by injection needles used in regional anaesthesia: Influence of bevel configuration, studied in a rat model. Br J Anaesth 69:433-438, 1992. Selander D, Dhuner KG, Lundborg G: Peripheral nerve injury due to injection needles used for regional anesthesia. Acta Anaesthesiol Scand 21: 182-188, 1977. Selander D, Edshage S, Wolff T: Paresthesiae or no paresthesiae? Acta Anaesthesiol Scand 23:27-33, 1979. Selander D, Sjostrang J: Longitudinal spread of intraneurally injected local anesthetics. Acta Anaesthesiol Scand 22:622-634, 1978. Stan TC, Krantz MA, Solomon DL, et al: The incidence of neurovascular complications following axillary brachial plexus block using a transarterial approach: A prospective study of 1000 consecutive patients. Reg Anesth 20:486-492, 1995.

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Anticoagulation Initiation and Reversal for Cardiac Surgery

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Peter Tassani-Prell Case Synopsis

PROBLEM ANALYSIS Definition Unfractionated heparin is a heterogeneous mixture of sulfated oligosaccharides with molecular weights ranging from 5000 to 50,000 daltons. The anticoagulant activity of heparin is initiated via binding to AT-III, which results in a conformational change that increases its inactivation of thrombin and factors Xa and IXa. Thus, in the setting of low AT-III activity, the clinical effect of heparin is reduced.

Recognition, Risk Assessment, and Implications There is wide individual variability in the clinical anticoagulant response to a single dose of heparin. This necessitates evaluation with on-site or laboratory coagulation testing. Owing to the extreme importance of ensuring sufficient anticoagulation before initiating CPB, on-site testing is preferred. A number of options are available to clinically assess heparininduced anticoagulation. The activated partial thromboplastin time is sensitive to low plasma heparin concentrations (0.1 to 1.0 units/mL). However, with the high doses of heparin required for the initiation of CPB, values exceed this method’s detection limit. The ACT assesses the clinical anticoagulation effect of the large doses of heparin (200 to 400 units/kg) required for the initiation of CPB. Though somewhat controversial, ACT values between 400 and 600 seconds are generally considered safe for anticoagulation during routine CPB, based on the observation of a lack of fibrin deposits on extracorporeal circuits. Even so, ACT values may be misleading because they

can be prolonged by factors other than heparin, such as hypothermia, hemodilution, and thrombocytopenia. Further, clinical investigations have shown that ACT values correlate poorly with plasma heparin concentrations in patients during mild hypothermic CPB. Commercially available ACT measurement devices use two different activators. Celiteactivated clotting time is prolonged by aprotinin, which may lead to inadequate heparinization during CPB. Kaolinactivated clotting time is unaffected by aprotinin. If aprotinin is used and only celite ACT testing is available, most clinicians prefer to maintain the ACT at greater than 800 seconds during CPB to ensure adequate heparinization. Heparin-protamine titration has been proposed as an alternative and more specific method for ensuring adequate heparin levels or protamine reversal in patients during CPB. However, the advantages of heparin-protamine titration (if any) over traditional methods have yet to be proved. Heparin resistance results in an unanticipated small increase in ACT values after initial and subsequent heparin dosing. Approximately 1 in 2000 patients has a heterozygotic deficiency (40% to 70% activity) of AT-III and is thus predisposed to developing deep vein thrombosis and pulmonary embolism. Significant reductions in AT-III levels may also occur secondary to AT-III consumption during heparin therapy. Other causes of heparin resistance include left ventricular clot, use of oral contraceptives, and thrombocytosis. These entities may be due to reduced plasma concentrations of heparin caused by its increased binding to plasma proteins and endothelium. Heparin may cause thrombocytopenia via immune- and nonimmune-mediated mechanisms. There are two types of heparin-induced thrombocytopenia (HIT) that can result from heparin use. Type I is nonimmune mediated, and 291

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An 81-year-old woman with dyspnea at rest due to aortic stenosis (valve area 0.4 cm2, mean gradient 50 mm Hg) presents for aortic valve replacement. Past medical history is significant for a recent pulmonary embolism, for which she received intravenous heparin therapy. At the time of operation, antithrombin III (AT-III) levels are low, and the activated partial thromboplastin time is elevated. After heparinization (375 units/kg), the activated clotting time (ACT) increases to 325 seconds. An additional 125 units/kg heparin and 2000 units of AT-III concentrate are given. Thereafter, the ACT increases to 866 seconds, and cardiopulmonary bypass (CPB) is commenced without further complications.

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type II is immune mediated. For standardization, the term non-heparin immune-associated thrombocytopenia is recommended for type I HIT. This is a benign condition, with no heparin-dependent antibodies present. The term heparininduced thrombocytopenia is recommended for type II HIT, in which heparin-dependent antibodies are detectable and produce thrombocytopenia.

MANAGEMENT Three different aspects of anticoagulation during cardiac surgery with CPB are discussed: routine management using anticoagulation with heparin and neutralization with protamine, management of AT-III deficiency (as in the case synopsis), and HIT. For the initiation of CPB, the heparin dose is based on body weight (300 to 400 units/kg, or 3 mg/kg). It is essential to obtain an ACT of about 480 seconds before initiating CPB. Determining the ACT before initiating CPB allows one to detect inadequate heparin dosing or AT-III deficiency. It is also recommended that the heparin injection be given via a central venous line after aspirating blood to ensure central vascular delivery. Patient-specific heparin dosing can be automatically extrapolated by several commercially available heparin monitoring systems. Subsequent heparin can be dosed empirically during CPB (e.g., 5000 to 10,000 units/hour, one third the initial dose every hour) if the ACT is less than 400 to 480 seconds or if plasma heparin concentration values are appropriate. Some commercial systems also calculate a heparin concentration corresponding to an ACT greater than 480 seconds. Hypothermia and hemodilution prolong ACT values independent of heparin concentration. Thus, basing subsequent heparin doses on ACT values may lead to inadequate inhibition of thrombin activity and subclinical thrombosis, fibrinolysis, and depletion of coagulation factors and platelets. Maintenance of patient-specific heparin concentrations during CPB may result in more accurate heparin dosing, more complete thrombin inhibition, and reduced postoperative bleeding and blood product use. With suspected heparin resistance, one must first confirm that the heparin was indeed given intravenously, followed by the administration of additional heparin from another vial or lot to exclude lot-specific reduced heparin activity. If the ACT values still remain below those expected, despite large doses of heparin, AT-III concentrates should be given, with an initial dose of at least 2000 units. Because of the danger of AT-III deficiency (thrombosis during CPB), the routine clinical practice in some centers is to confirm adequate AT-III levels in patients before any operation is performed requiring extracorporeal circulation. Non-heparin immune-associated thrombocytopenia (type I HIT) implies absent heparin-dependent antibodies. This entity is probably caused by direct nonimmune platelet activation by heparin. Type I HIT is usually associated with larger doses of heparin. In contrast, type II HIT can occur with any heparin dose. Further, type I HIT occurs earlier in the clinical treatment course (usually within 4 days) in 30% of patients receiving intravenous heparin therapy. The induced platelet abnormality is usually mild and reversible, even with

continued heparin administration. Type I HIT is self-limited and usually causes no important complications (e.g., thrombosis). Heparin therapy is continued despite low platelet counts. The clinical importance of type I HIT lies in the necessity to differentiate it from the more serious type II HIT. Type II HIT (or heparin-induced thrombocytopenia with thrombosis [HITT] syndrome) is an immune-mediated reaction to heparin that is often underdiagnosed and may lead to venous and arterial thrombosis. Type II HIT exists as three distinct entities: (1) latent (antibodies without thrombocytopenia), (2) HIT (antibodies with thrombocytopenia), and (3) HITT (antibodies with thrombocytopenia and thrombosis). Type II HIT is potentially more dangerous than type I HIT because it can be associated with thromboembolic complications (absent in type I). About 0.5% to 3% of patients given heparin develop type II HIT and moderate thrombocytopenia. In some, this leads to venous or arterial thrombosis. Thrombosis frequently leads to disastrous clinical sequelae, including loss of limbs and even death. The basis for this severe adverse drug reaction is production of an immunoglobulin G antibody that reacts with heparin and platelet factor 4 antigenic complexes. The diagnosis of type II HIT is made with the heparin-induced platelet aggregation (HIPA) assay. Alternatively, an enzyme-linked immunosorbent assay (ELISA) can detect the binding of antibodies to immobilized heparin–platelet factor 4 antigenic complexes. For patients with type II HIT who will be exposed to CPB, treatment generally includes either the use of alternative anticoagulants or combined treatment with platelet function inhibitors and heparin. Examples include the following: ●

●

●

●

●

Danaproid sodium. This is a low-molecular-weight heparinoid (i.e., a mixture of dermatan, glycosaminoglycans, and chondroitin sulfates) that does not contain heparin. Ancrod. This is an inhibitor of fibrin derived from Malayan pit viper venom. It provides a treatment option for patients with type II HIT who require anticoagulation. Hirudin and lepirudin. This combination is also used for anticoagulation in type II HIT patients. Hirudin is a direct inhibitor of thrombin, acting independently of cofactors such as antithrombin. Lepirudin (a form of recombinant hirudin derived from yeast cells) is a highly specific, direct, irreversible inhibitor of thrombin (one molecule of lepirudin binds with one of thrombin). Typically, patients given hirudin have more perioperative bleeding, require multiple allogeneic blood product transfusions, and have higher rates of mediastinal re-exploration for bleeding after CPB. Bivalirudin. This is a direct thrombin inhibitor and an analogue of the peptide fragment hirugen derived from hirudin. Bivalirudin is approved by the U.S. Food and Drug Administration for patients with unstable angina undergoing coronary angioplasty who are also receiving aspirin. Randomized clinical trials in cardiac surgery are currently in progress. Argatroban. This is a synthetic, competitive thrombin inhibitor derived from L-arginine. It reversibly binds to thrombin’s catalytic site. One recent case report described the successful use of argatroban as an alternative to heparin during CPB in a patient with type II HIT, end-stage renal failure, and ischemic cardiomyopathy with ventricular fibrillation.

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●

Type I is the most common, consisting of hypotension from too rapid administration of protamine. It is likely related to the release of histamine, and hypotension can be associated with a marked decrease in systemic vascular resistance. Type II is anaphylaxis and can be mediated by immunoglobulins. It occurs more frequently in patients with a history

●

of fish allergy. Subsequent release of histamine and leukotrienes results in systemic and pulmonary capillary leakage. Type III is associated with the formation of heparinprotamine complexes. Pulmonary macrophages activate complement and leukocyte aggregation, causing the release of free radicals and activation of the arachidonic acid pathway, which leads to the formation of thromboxane. This causes intense pulmonary vasoconstriction, pulmonary hypertension, and reduced left atrial pressure. The net result is right heart chamber dilatation and heart failure. Fortunately, type III responses are very uncommon.

PREVENTION The appearance of heparin resistance can delay surgery and disrupt the operating room schedule. Consequently, some clinicians advise preoperative AT-III level screening for all patients having cardiac surgery requiring CPB. Determination of the heparin dose-response curve can also alert clinicians to heparin resistance before CPB. This allows advance planning for subsequent heparin dosing. If possible, surgery is delayed in patients with type II HIT until antibody titers are absent. New drugs, such as bivalirudin, may be useful alternatives to heparin in such patients. To eliminate protamine reactions, antihistamines can be used. Also, protamine should be given slowly, preferably via a peripheral vein after substantial dilution. Some surgeons inject it into the aortic root to bypass the lungs during its initial distribution. Although heparin-bonded CPB circuitry may allow lower doses of intravenous heparin, this technology remains unproved.

Further Reading Anderson EF: Heparin resistance prior to cardiopulmonary bypass. Anesthesiology 64:504-507, 1986. Bull BS, Huse WM, Brauer FS, et al: Heparin therapy during extracorporeal circulation. II. The use of a dose-response curve to individualize heparin and protamine dosage. J Thorac Cardiovasc Surg 69:685-689, 1975. DeBois WJ, Liu J, Lee LY, Girardi LN: Diagnosis and treatment of heparininduced thrombocytopenia. Perfusion 18:47-53, 2003. Despotis GJ, Joist JH, Hogue CW Jr, et al: The impact of heparin concentration and activated clotting time monitoring on blood conservation. J Thorac Cardiovasc Surg 110:46-54, 1995. Despotis GJ, Joist JH, Hogue CW Jr, et al: More effective suppression of hemostatic system activation in patients undergoing cardiac surgery by heparin dosing based on heparin blood concentrations rather than ACT. Thromb Haemost 76:902-908, 1996. Despotis GJ, Levine V, Joist JH, et al: Antithrombin III during cardiac surgery: Effect on response of activated clotting time to heparin and relationship to markers of hemostatic activation. Anesth Analg 85:498-506, 1997. Edwards JT, Hamby JK, Worrall NK: Successful use of argatroban as a heparin substitute during cardiopulmonary bypass: Heparin-induced thrombocytopenia in a high-risk cardiac surgical patient. Ann Thorac Surg 75:1622-1624, 2003. Greinacher A: The use of direct thrombin inhibitors in cardiovascular surgery in patients with heparin-induced thrombocytopenia. Semin Thromb Hemost 30:315-327, 2004. Koster A, Spiess B, Chew DP: Effectiveness of bivalirudin as a replacement for heparin during cardiopulmonary bypass in patients undergoing coronary artery bypass grafting. Am J Cardiol 93:356-359, 2004.

CARDIOTHORACIC & VASCULAR SURGERY

The management of patients with HIT antibodies who require heart surgery is challenging, because heparin anticoagulation is an integral part of cardiac operations, with or without extracorporeal circulation. A standard approach to patients with HIT has not been established, although several options have been proposed for using the previously listed nonheparinoid anticoagulants. However, there is little experience with approved alternative anticoagulants, specific antidotes are not available, and special tests (which are not readily available) are needed to ascertain their effectiveness. In patients with a history of HIT but no detectable antibodies, heparin is currently the safest approach to the highdose anticoagulation required for CPB. However, before and after surgery, alternative anticoagulants should be used. The risk of clinical HIT after cardiac surgery may be reduced by substituting low-molecular-weight heparin for postoperative anticoagulation in patients with type II HIT antibodies found immediately before surgery. Alternatively, hirudin can be used as the anticoagulant for CPB in these patients. If hirudin is used, the ecarin clotting time (instead of ACT) can be used to guide anticoagulation therapy during CPB. A more recent approach in patients with a history of HIT is to selectively block platelet aggregation using monoclonal antibodies directed toward glycoprotein IIb/IIIa (GP IIb/IIIa) or to use a specific GP IIb/IIIa inhibitor (e.g., tirofiban). An 80% block of GP IIb/IIIa receptors and suppressed platelet aggregation (<20%) permit the use of unfractionated heparin and CPB in the usual way. After CPB, as usual, unfractionated heparin is neutralized with protamine. After approximately 2 to 12 months, most patients with a history of type II HIT no longer have laboratory evidence of heparin-induced platelet aggregation. If so, heparin use is likely acceptable. However, caution is advised with regard to further heparin exposure during the postoperative period (e.g., heparin flushes, cardiac catheterization). Use of aspirin or dipyridamole for anticoagulation in patients with type II HIT has been successful. Heparin reversal after CPB is usually accomplished with protamine, a protein derived from salmon sperm. The appropriate dosage is controversial. Most cardiac anesthesiologists use 1.0 to 1.3 mg/100 units of previously administered heparin. Commercial systems for whole blood, circulating heparin assays may allow exact titration of the required amount of protamine; however, despite their theoretical advantage, a fixed dose based on the amount of heparin used is more conventional. Additional protamine may be given about 30 minutes after heparin reversal. Protamine has a high number of positively charged arginine residues that form stable complexes with negatively charged heparin and are eliminated via the reticuloendothelial system. Protamine has been associated with significant clinical complications, consisting of three major types of adverse responses:

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Levy JH: New concepts in anticoagulation and reversal. In Stanley TH, Bailey PL (eds): Anesthesiology and the Cardiovascular Patient. Norwell, Mass, Kluwer Academic Publishers, 1996. Makhoul RG, McCann RL, Austin EH, et al: Management of patients with heparin-associated thrombocytopenia and thrombosis requiring cardiac surgery. Ann Thorac Surg 43:617-621, 1987. Messerli FH (ed): Cardiovascular Drug Therapy, 2nd ed. Philadelphia, WB Saunders, 1996. Nuttall GA, Oliver WC Jr, Santrach PJ: Patients with a history of type II heparin-induced thrombocytopenia with thrombosis requiring cardiac surgery with cardiopulmonary bypass: A prospective observational case series. Anesth Analg 96:344-350, 2003. Pravinkumar E, Webster NR: HIT/HITT and alternative anticoagulation: Current concepts. Br J Anaesth 90:676-685, 2003.

Sabbagh AH, Chung GKT, Shuttleworth P, et al: Fresh frozen plasma: A solution to heparin resistance during cardiopulmonary bypass. Ann Thorac Surg 37:466-468, 1984. Sane DC, Califf RM, Topol EJ, et al: Bleeding during thrombolytic therapy for acute myocardial infarction: Mechanisms and management. Ann Intern Med 111:1010-1022, 1989. Visentin GP, Ford SE, Scott JP, et al: Antibodies from patients with heparininduced thrombocytopenia/thrombosis are specific for platelet factor 4 complexed with heparin or bound to endothelial cells. J Clin Invest 93:81-88, 1994. Walenga JM, Jeske WP, Prechel MM: Newer insights on the mechanism of heparin-induced thrombocytopenia. Semin Thromb Hemost 30(Suppl 1):57-67, 2004.

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73

Hemodilution and Blood Conservation Glenn P. Gravlee Case Synopsis A 61-year-old, 80-kg man is scheduled for removal and replacement of a total hip prosthesis. He is concerned about blood transfusion and the transmission of infectious diseases, particularly human immunodeficiency virus (HIV). He requests that transfusion of homologous blood be avoided, if possible. He predonated 2 units of autologous blood. During surgery, blood loss is more than 2000 mL, and the hemoglobin level is 7.5 g/dL after both units of autologous blood are given. Vital signs and urine output remain within normal limits. An additional 500 mL of intraoperative blood loss is expected.

PROBLEM ANALYSIS

Complications arising from the transfusion of homologous (also called allogeneic) blood products have been recognized since the beginning of modern transfusion therapy. Bacterial blood contamination was fairly common before the introduction of refrigerated storage and sterile plastic bags. Subsequently, contamination with viruses (e.g., cytomegalovirus, hepatitis B and C, HIV, and human T-cell lymphotropic virus) became a source of greater morbidity. Now, West Nile virus and possibly variant Creutzfeldt-Jakob disease have been added to the list of viral diseases transmissible by blood transfusion. Fortunately, improvements in donor screening and blood component testing have reduced the risk of both HIV and hepatitis C transmission to less than 1 per 1 million units, and that for hepatitis B to about 1 per 137,000 units. Cytomegalovirus remains prevalent in the blood pool, but its transmission is generally not a problem in the absence of clinical immunosuppression. Nevertheless, many blood banks now routinely apply leukoreduction techniques to all cellular blood components before dispensing them, which has greatly reduced the risk of cytomegalovirus transmission. Thus, viral transmission by blood transfusion is now so rare that bacterial contamination once again poses the highest risk for infectious complications, which is 1 in 30,000 red blood cell (RBC) units and 1 in 2000 to 3000 platelet units. Blood group incompatibility and anaphylactic reactions remain rare.

Implications Considerable evidence supports immunosuppression as a significant consequence of blood transfusion. This increases the risk of cancer recurrence and of bacterial infection among transfusion recipients. Large blood loss and hemodilution also raise the question of what constitutes a reasonable minimum hemoglobin level in an anesthetized patient with acceptable intravascular

MANAGEMENT This section focuses on available techniques (Table 73-1) and a cost-benefit analysis of autotransfusion techniques that may reduce or avoid the need for homologous RBC or blood component therapy.

Autologous Predonation Patients can donate blood up to 42 days before operation, which constitutes the maximum storage period for modern

Table 73–1

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Autotransfusion Techniques

Technique

Cost

Risk

Advisability*

Autologous predonation Acute normovolemic hemodilution Intraoperative salvage Postoperative salvage, unwashed Postoperative salvage, washed

Moderate Low

Low Low

Yes No

High Low

Low Moderate

Yes No

Moderate

Low

Yes

*For the patient described in the case synopsis.

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Definition, Recognition, and Risk Assessment

volume and vital signs. This is a surprisingly complex issue, but in general, healthy patients safely tolerate hemoglobin concentrations as low as 6 g/dL. Sicker patients may require hemoglobin concentrations as high as 10 g/dL. Assuming that the hypothetical patient described in the case synopsis is otherwise healthy, the limiting factor may be the rate and predictability of blood loss, because some margin of safety is desirable if sudden additional blood loss should occur. Also, one must consider the possibility of significant postoperative bleeding. Consequently, the patient’s hemoglobin concentration of 7.5 g/dL signals the possible need for homologous transfusion, unless shed blood is being effectively salvaged.

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anticoagulant and storage solutions. The frequency and amount of donation depend on the patient’s ability to tolerate serial phlebotomy while maintaining an adequate hemoglobin level. Typically, a patient donates 2 units of blood per week starting 2 to 4 weeks before surgery. The minimum recommended hemoglobin level for donation is 11 g/dL. To maintain this level, patients are routinely given iron supplementation. Erythropoietin can be used to increase hemoglobin levels during predonation, which enables patients to donate more units; this is quite expensive, however, costing approximately $800 per unit of erythropoietin “manufactured.” Erythropoietin augmentation of autologous predonation may be justified if some combination of the following factors exists: ● ●

● ●

The preoperative timeline is short (e.g., cancer resection). Homologous transfusion is not possible (e.g., Jehovah’s Witness). The patient is anemic. The anticipated surgical blood loss is large (>2000 mL).

Autologous predonation is most effective at avoiding homologous transfusion when used in combination with other autotransfusion techniques, such as intraoperative blood salvage. The cost-effectiveness of autologous donation varies widely, but it often fails to meet the usual standards of efficacy. For this reason, its popularity has dropped substantially over the past several years. The donation itself carries a hospitalization risk of approximately 1 in 17,000, which is 12 times that for community donations by healthy individuals. Even though the blood is autologous, its use still incurs some of the usual homologous transfusion risks, including bacterial contamination or clerical errors leading to incompatible blood transfusions. Compared with allogeneic blood units, autologous units typically require the same testing procedures but more complex storage and identification procedures, so the cost for each unit is higher.

drop in hemoglobin concentration could induce unanticipated end-organ ischemia if there is an undiagnosed condition such as critical stenosis of a coronary artery or carotid artery. Mathematical analyses strongly suggests that the blood loss savings are fairly minor unless this technique is used quite aggressively—for example, hemodilution from a starting hematocrit of 40% to one of 20% or lower. Typically, this would require withdrawing 6 to 10 500-mL bags of blood. One study found no difference in allogeneic transfusion exposure when 3 units of acute normovolemic hemodilution were compared with a similar volume of autologous predonation in patients undergoing total hip arthroplasty.

Postoperative Blood Salvage This technique involves the collection and reinfusion of blood shed postoperatively. The blood is collected through a relatively large filter and reinfused through a small-pore filter. This blood can be reinfused unmodified (“unwashed”), or it can be washed and concentrated in the same way as for intraoperative blood salvage. Reinfused blood typically contains very low concentrations of plasma coagulation factors and platelets. It also contains elevated levels of fibrin degradation products, free hemoglobin, and inflammatory products such as cytokines. With total hip arthroplasty, it might also contain fat and bone spicules. As a result, many clinicians elect to administer salvaged blood only after it has been washed. This somewhat controversial technique reduces the need for allogeneic blood only when postoperative blood losses are large (e.g., >1000 mL), because the hematocrit of blood shed postoperatively is typically in the 15% to 20% range.

Intraoperative Blood Salvage Acute Normovolemic Hemodilution Acute normovolemic hemodilution involves the removal of blood just before or after the induction of anesthesia, combined with volume replacement using crystalloid or colloid. The technique requires standard anesthesia monitors (electrocardiogram, blood pressure, pulse oximetry, and temperature) and large-bore intravenous access with a 14- or 16-gauge peripheral or central venous catheter. Blood is collected into standard citrate-phosphate-dextrose bags. Removed blood is then stored in anticoagulated sterile bags and returned to the patient intraoperatively or postoperatively. The rationale is that the patient will be losing fewer RBCs into the surgical field because shed blood has a lower hematocrit due to hemodilution. Assuming that the lowest hematocrit remains acceptable (>20%) and that intravascular volume also remains intact, tissue perfusion will be maintained (and perhaps enhanced). Also, oxygen delivery will be sufficient owing to reduced blood viscosity. Additional clinical advantages include low cost, simple storage, and ease of transportation and record keeping. Acute normovolemic hemodilution risks hypovolemia if volume replacement is inadequate. Further, the obligatory

This method involves using a suction apparatus to collect the patient’s blood as it is shed intraoperatively into the surgical field. An anticoagulant solution is added to the shed blood, and it is then stored in a filtered reservoir. Once an adequate amount of blood has been collected (typically >700 mL), it is washed and concentrated so that the final product usually has a hematocrit between 55% and 70%. Because intraoperative blood salvage conserves RBCs but not plasma or platelets, a dilutional coagulopathy should be anticipated if blood losses approach or exceed one blood volume. Otherwise, the risks of this technique are low if appropriate procedures and standards are followed and the blood is not contaminated with bacteria. The ability to conserve RBCs with this technique depends largely on the surgeon’s ability to capture shed blood using suction. In this regard, total hip arthroplasty is in an intermediate category between laparotomy for aortic aneurysm repair, where blood pools in a body cavity and is easily captured, and a more superficial procedure such as reduction mammaplasty, where blood typically runs off the surgical field onto the drapes or is absorbed by sponges.

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Table 73–2

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Other Potential Blood-Conservation Techniques

Technique

Cost

Risk

Advisability*

Induced hypotension Prophylactic aprotinin Spinal or epidural anesthesia

Varies Expensive Low

Varies Low Low

Questionable; patient’s age is cause for some concern Unclear; reduces blood loss, but expensive Facilitates blood pressure control; reduces deep vein thrombosis

*For the patient described in the case synopsis.

PREVENTION Often, clinicians fail to appreciate how much blood loss can be safely tolerated by patients before the need for transfusion. This can be estimated using the following formula: ABL = V × (Hi – Hd)/Hm,

Autologous Predonation In retrospect, if one could have predicted the amount of blood loss experienced by the patient in the case synopsis based on the surgeon’s track record with reoperative hip arthroplasties, the patient should have been given supplemental iron therapy and predonated 3 or 4 units of autologous blood over 3 to 4 weeks before surgery. If the patient’s original hematocrit was less than 40%, supplementation with erythropoietin would have been reasonable, although health insurance policies often do not cover the cost of erythropoietin used for this purpose.

Acute Normovolemic Hemodilution Arguably, the most common application of this procedure is to withdraw 2 units in smaller patients (e.g., those <70 kg) and 3 units in larger ones. This saves 1 to 2 units of allogeneic packed RBCs if the intraoperative blood loss is between 3000 and 6000 mL, which crudely approximates one half to one normal blood volume. As blood losses exceed 6000 mL, the number of units saved gradually diminishes (to 0.5 to 1 unit) with this technique. Initially, one bag containing approximately 450 mL of blood is collected. As this is occurring, either 500 mL of colloid solution or about 1500 mL of crystalloid solution is infused into the patient to maintain intravascular volume. Hypotension or tachycardia suggests inadequate volume replacement. The exchange continues to the desired end point, as long as the patient tolerates the procedure. Checking the hematocrit or hemoglobin concentration periodically is

Intraoperative Blood Salvage In the case presented here, intraoperative blood salvage may offer the best chance of respecting the patient’s wish to avoid homologous blood. Further, effective use of this technique tends to override any theoretical benefits of acute normovolemic hemodilution. Alternatively, if the patient is otherwise completely healthy, one might “tough it out” to a hematocrit as low as 20%. Considering this patient’s age, however, reducing the hematocrit below that level is probably ill advised.

Postoperative Blood Salvage Because the cost of this technique is low and the likelihood of substantial postoperative bleeding is high in the patient described in the case synopsis, postoperative salvage is appropriate. Wound drainage contains various undesirable elements, however, so washing the product before reinfusion is advisable. Bacterial contamination can also occur, so this strategy should be avoided unless the drainage exceeds 500 mL over an 8-hour period. After this time, the collection device should be replaced if reinfusion is planned.

Alternative Blood Conservation Techniques Other potential blood-conserving options are listed in Table 73-2. Moderate deliberate hypotension is reasonable if the patient is otherwise healthy; for a patient in his 60s, however, setting a relatively conservative lower mean arterial pressure limit, in the range of 70 mm Hg for 1 to 2 hours, might be prudent.1 Another reasonable approach for deliberate hypotension might be to reduce the mean arterial pressure

1 Because our hypothetical patient is male and older than 60 years, and assuming no coronary artery disease or risk factors for it (hyperlipidemia, hypertension, or smoking history; see Chapter 38), another way to estimate the minimal acceptable pressure for deliberate hypotension (i.e., that required to maintain coronary perfusion pressure) is diastolic blood pressure – left ventricular end-diastolic pressure = 50 mm Hg. The value for adequate coronary perfusion pressure may be higher in patients with advanced age, diastolic heart failure, or a strong family history of coronary artery disease, hypertension, or other heart disease (all associated with some amount of elevated left ventricular end-diastolic pressure).

CARDIOTHORACIC & VASCULAR SURGERY

where ABL is allowable blood loss; V is blood volume; Hi and Hd are the initial and lowest desired hematocrit values, respectively; and Hm is the hematocrit average of Hi and Hd. Assuming a blood volume of 5600 mL (80 kg × 70 mL/kg), an Hi of 40%, and an Hd of 25%, the patient in the case synopsis can tolerate a blood loss of almost 2600 mL without transfusion therapy. Intraoperative RBC salvage increases this figure in direct proportion to the efficacy of salvage.

advisable to reassess the appropriateness of the calculated end point. The blood is then stored at room temperature if it will be used within 8 hours; otherwise, refrigerated storage is required.

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by about 20% below the patient’s preoperative baseline level, which could probably be safely sustained for several hours if necessary. Aprotinin and its lysine analogues (e.g., tranexamic acid) can also reduce blood loss in hip replacement surgery with a low risk of complications, but the high cost of aprotinin must be considered.

Further Reading American Association of Blood Banks: All about blood (2004). Available at www.aabb.org/All_About_Blood. American Society of Anesthesiologists Task Force on Blood Component Therapy: Practice guidelines for blood component therapy. Anesthesiology 84:732-747, 1996. Birkmeyer JD, Goodnough LT, AuBuchon JP, et al: The cost effectiveness of preoperative autologous blood donation for total hip and knee replacement. Transfusion 33:544-551, 1993.

Goodnough LT: Red blood cell support in the perioperative setting. In Simon TL, Dzik WH, Snyder EL, et al (eds): Rossi’s Principles of Transfusion Medicine, 3rd ed. Philadelphia, JB Lippincott–Williams & Wilkins, 2002, pp 590-601. Goodnough LT, Despotis GJ, Merkel K, Monk TG: A randomized trial comparing acute normovolemic hemodilution and preoperative autologous blood donation in total hip arthroplasty. Transfusion 40:1054-1057, 2000. Goodnough LT, Monk TG, Brecher ME: Autologous blood procurement in the surgical setting: Lessons learned in the last 10 years. Vox Sang 71:133-141, 1996. Jacobs MR, Palavecino E, Yomtovian R: Don’t bug me: The problem of bacterial contamination of blood components—challenges and solutions. Transfusion 41:1331-1334, 2001. Wu W-C, Rathore SS, Wang Y, et al: Blood transfusion in elderly patients with acute myocardial infarction. N Engl J Med 345:1230-1236, 2001.

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74

Prashant Lotlikar and John R. Cooper, Jr.

COMPLICATIONS OF AORTIC ROOT CANNULATION: ACUTE AORTIC ROOT DISSECTION Case Synopsis

PROBLEM ANALYSIS Definition Acute aortic dissection following aortic cannulation is an infrequent but serious complication of cardiac surgery. The diagnosis must be made early and thus requires a high index of suspicion. Dissection may also occur during CPB or after decannulation. In this case, the cannula orifice was situated within the media of the arterial wall rather than the true lumen, owing to a dissection created during cannulation. For aortic dissection to occur, blood under pressure must gain access to the media of the aortic wall. In this case, access was obtained via cannula insertion and initiation of perfusion. Additional manipulation of the ascending aorta (e.g., aortic cross-clamp, antegrade cardioplegia line, proximal bypass grafts) may increase the risk of dissection. Predisposing factors that increase the risk for acute aortic dissection include conditions that weaken the aortic wall, such as the following: ● ● ● ●

elevation in arterial line pressure and bluish discoloration and enlargement of the aortic root. Myocardial ischemia, aortic insufficiency, or both may develop, and signs of organ hypoperfusion (including oliguria and pupil asymmetry) may be present if the dissection extends to other major arterial vessels. If transesophageal echocardiography is used, dissection may be evident on examination of the thoracic aorta (Fig. 74-1).

Cystic medial necrosis Elastic or medial degeneration associated with aging Poststenotic dilatation (aortic stenosis) Atheromatous disease

Dissection may occur spontaneously in the operating room or during the postoperative period in the intensive care unit.

Recognition A sudden, unexplained decrease in mean arterial pressure and venous return is usually seen, associated with an acute

Figure 74–1 ■ Transesophageal echocardiography of the ascending aorta just distal to the aortic valve, with an intraoperative aortic dissection evident showing true and false lumens. This dissection propagated from the antegrade cardioplegia administration site.

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A 75-year-old man with a history of calcific aortic stenosis was scheduled for valve replacement. Induction of anesthesia, sternotomy, and placement of cannulas were uneventful. The aortic tissue, however, appeared thin and calcified. The aortic purse strings and cannula appeared well placed, but on beginning cardiopulmonary bypass (CPB), the pump arterial line pressure increased, and systemic blood pressure (radial artery) decreased. The aorta appeared acutely dilated.

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MANAGEMENT

●

CPB must be discontinued immediately. The surgeon must then either reposition or replace the arterial cannula into the true lumen at a more distal site on the aortic arch or initiate femoral artery cannulation. Surgical repair of the aortic dissection is almost always necessary, including coronary artery reimplantation if patency of the coronary arteries is threatened.

●

●

●

●

PREVENTION

Blood pressure control (to avoid hypertension) at the time of cannulation Insertion of the cannula at a right angle to the aorta to prevent dissection into tissue planes Special care in locating the tip in the true lumen of the aorta Blood pressure reduction when the aortic cross-clamp is applied or removed Use of atraumatic clamps, with as few applications to the aorta as possible Continuous monitoring of arterial cannula pressure by the perfusionist

Measures that may be effective in reducing the incidence of aortic dissection during cannulation include the following:

CAROTID OR INNOMINATE ARTERY HYPERPERFUSION Case Synopsis A 58-year-old woman underwent CPB for coronary artery bypass grafting. After successful aortic and venous cannulation by the surgeon, the anesthesiologist noted right-sided facial blanching. Further examination showed the presence of a right carotid thrill.

Cannula too long

A

Cannula misdirected

B

Cannula too small Jet effect

D

Correct

C Figure 74–2 ■ Carotid or innominate artery hyperperfusion. A, The cannula is too long, causing it to enter the left carotid artery. B, The cannula angulation is incorrect, directing the majority of flow to the innominate artery. C, Correct position. D, The cannula is too small, resulting in a high-velocity jet. See Definition (next page) for further discussion. (From Moores WY: Cardiopulmonary bypass strategies in patients with severe aortic disease. In Utley JR [ed]: Pathophysiology and Techniques of Cardiopulmonary Bypass, vol 2. Baltimore, Williams & Wilkins, 1983, p 190.)

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PROBLEM ANALYSIS

MANAGEMENT

Definition

Repositioning of the cannula is necessary. Measures to reduce cerebral edema, including diuretics or head-up position, may be indicated.

Pump flow can be directed primarily into the carotid or innominate artery instead of the aorta. This can result in cerebral edema or arterial rupture due to high perfusion pressure or the creation of an intimal flap that obstructs arterial flow (Fig. 74-2).

Recognition Signs of innominate artery cannulation include ipsilateral facial blanching, pupillary dilatation, and conjunctival chemosis. Hypotension measured via a left radial or femoral artery catheter may be observed, but a right radial artery catheter may show hypertension.

PREVENTION Use of a short aortic cannula with a flange to prevent insertion too far into the aorta is usually effective. The anesthesiologist can check for bilateral carotid pulses without thrills after cannulation and initiation of CPB, but this may not reliably detect problems caused by carotid or innominate artery hyperperfusion.

OBSTRUCTION TO VENOUS RETURN Case Synopsis

PROBLEM ANALYSIS Definition Obstruction of venous return to the pump-oxygenator may have several causes: ●

● ● ● ● ●

An “air lock” created by the presence of large air bubbles within the venous cannula or tubing Failure to remove a venous line clamp Lifting of the heart within the chest by the surgeon Use of venous cannulas too small for the patient Presence of thrombus or tumor Kinked or malpositioned cannula (most common)

When two cannulas are used, the superior vena cava cannula may be placed into the azygos vein or, if advanced too far cephalad, into the innominate vein. The inferior vena cava cannula may be placed into the hepatic vein. In this case synopsis, the single cannula was placed so far into the inferior vena cava that there could be no venous return from the superior vena cava.

Recognition Decreasing venous reservoir volume in the pump-oxygenator is the first sign. Failure to reduce pump flow immediately can result in emptying of the venous reservoir, with a risk of massive arterial air embolism. Increased central venous

pressure occurs, along with obvious venous engorgement in the face and neck and later conjunctival chemosis. Also, lack of drainage from the right side of the heart may result in compression of the left ventricle, detected by direct visualization or by an increase in pulmonary artery or left atrial pressure.

MANAGEMENT Pump flow should be reduced until the cause of obstruction to venous return is found. The surgeon can propel an air lock through the venous tubing by progressively raising and tapping the tubing downstream from the bubble. Venous cannulas will probably have to be repositioned. Only after adequate venous return is established, with recovery of volume in the venous reservoir, should full-flow CPB be continued.

PREVENTION The surgeon should inspect the venous cannula for large bubbles and ensure proper venous cannula position. The anesthesiologist should routinely check the patient’s face, neck, and conjunctiva for signs of high venous pressures. Monitoring central venous pressures may not detect a superior vena cava obstruction because the catheter tip may be below the obstruction point.

CARDIOTHORACIC & VASCULAR SURGERY

A 60-year-old man was placed on CPB after uneventful aortic cannulation and use of a single venous cannula in the right atrium. There was an immediate decrease in both arterial pressure and pump-oxygenator venous reservoir volume. Obvious venous engorgement in the patient’s face and neck was noted immediately.

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MASSIVE GAS EMBOLISM Case Synopsis A 65-year-old woman undergoing mitral valve replacement was placed on CPB after uneventful insertion of aortic and venous cannulas. Before application of the aortic cross-clamp, the surgeon inserted a vent cannula into the left atrium via the left superior pulmonary vein. Blood initially began to drain normally toward the venous reservoir but then reversed direction, and a large quantity of air entered the heart and was ejected systemically.

●

PROBLEM ANALYSIS ●

Definition Systemic gas embolism is the most common serious adverse event associated with CPB and is largely preventable. Principal causes include the following: ●

Vortexing—air being pumped out of an empty or near empty oxygenator reservoir

●

●

●

Reversed roller-pump tubing in the vent line or arterial cannula Disconnection, leak, oxygenator disruption, or line occlusion proximal to the arterial pump, with air entrainment or cavitation Development of positive pressure in the cardiotomy reservoir, producing retrograde airflow into the heart or aorta Injection of air into the aortic root from the cardioplegia delivery system Clotted oxygenator or runaway pump head

Retrograde SVC pumping

A

B

Figure 74–3 ■ A, Massive air embolus through the aortic cannula. (circles represent the aortic root) B, The aortic cannula is removed, purged of air (circles), and inserted into the divided superior vena cava (SVC) cannula. Retrograde perfusion at 1200 mL/minute at 20∞C is carried out for 1 to 2 minutes. Air exits the aortic cannulation site. (From Mills NL, Ochsner JL: Massive air embolism during CPB: Causes, prevention and management. J Thorac Cardiovasc Surg 80:713, 1980.)

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Ejection of blood before the removal of air from the heart, or opening a beating heart Disconnection or rupture of the oxygenator or lines during CPB Failure to clamp the aortic line at the end of CPB, resulting in air infusion if the pump head is accidentally restarted

Recognition Air in the arterial cannula is usually visually apparent, but signs of myocardial or other organ ischemia may also occur. Rarely, withdrawal of air from an arterial pressure monitoring line indicates air embolism.

MANAGEMENT After recognition, if the embolus is massive, CPB must be discontinued. The patient is then placed in a steep Trendelenburg position, the aortic cannula is removed, and the CPB circuit is reprimed. Retrograde perfusion of the superior vena cava is initiated (Fig. 74-3). CPB is then restarted with hypothermia, increasing perfusion pressure, and

303

100% oxygen. Consideration can then be given to pharmacologic interventions to reduce cerebral injury, including mannitol, steroids, and barbiturates. Postoperative interventions may include initiation of hyperbaric oxygen treatment, reverse Trendelenburg position, initiation of slight hyperventilation, and avoidance of hyperglycemia and hyponatremia.

PREVENTION Special attention must be paid to maintaining a safe volume of blood in the oxygenator reservoir. Low-level alarms and bubble detectors should be used. The surgical team must protect the venous lines and communicate with the perfusionist when venous return is likely to be compromised. Other measures include the use of the following: ● ● ●

● ●

Centrifugal pumps Arterial line filters Bubble traps with an open air purge line guarded by a one-way valve Collapsible reservoirs One-way valves placed in the left heart vent line

Case Synopsis A 68-year-old man underwent CPB for combined mitral valve replacement and coronary bypass grafting. Five minutes after initiation of CPB, dark blood was observed by the anesthesiologist in the aortic cannula. An immediate blood gas sampling revealed a low arterial oxygen tension (PaO2).

PROBLEM ANALYSIS

MANAGEMENT

Definition

If oxygenator failure is suspected, a blood gas measurement from the arterial inflow line should be obtained, and the perfusionist should increase oxygen gas flows and determine the adequacy of mechanical pump flow. Additionally, the following actions should be taken:

This situation can be caused by oxygenator failure, with three possible causes of arterial inflow desaturation: (1) the gas supply system, (2) the oxygenator itself, or (3) specific patient characteristics or pathophysiology. Low PaO2 can also be caused by pump failure. This can occur by means of electrical or mechanical failure, tubing rupture or disconnection, or automatic shutoff by the bubble or reservoir level detector. A runaway pump head may inappropriately raise the pump flow rate to maximum. If the occlusion of a roller pump is improperly set, excessive regurgitation can cause reduced forward blood flow, hypotension, and metabolic acidosis.

Recognition Oxygenator failure results in dark blood in the arterial cannula and severe vasodilatation. Blood leaking into the heater-cooler water may also be seen with oxygenator rupture. With pump failure and low PaO2, one observes hypotension, metabolic acidosis, and perhaps hemolysis.

●

●

●

●

Careful inspection of the gas circuit, including gas sources, all connections, tubing, gas line filter, and vaporizer Inspection of the oxygenator for appropriate blood levels and adequacy of foaming (bubble oxygenator), and examination of the shell for leaks or cracks Inspection of the venous and arterial cannulas for appropriate patient connections Assurance of adequate muscle relaxation, appropriate patient temperature, and depth of anesthesia

If the heart is still beating, one should consider allowing it to eject blood into the pulmonary circulation for additional oxygenation and continue ventilation of the lungs until apparent arterialization of blood is observed in the aortic cannula. If there is pump failure, a hand crank can be used until a replacement is obtained or tubing is replaced. In the case

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PUMP OR OXYGENATOR FAILURE

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of a runaway pump head, the machine must be unplugged, and the tubing must be switched to a different roller head. If flow will be low or absent for more than a few minutes, and if the patient cannot be weaned immediately from CPB, hypothermia should be induced. One should then consider packing the head and heart in ice for additional protection.

PREVENTION Vigilance is paramount. Use of a pump arterial line oxygen saturation monitor and/or a partial pressure of oxygen analyzer may be beneficial. Backup equipment should always be available.

CLOTTED OXYGENATOR OR CIRCUIT Case Synopsis A 60-year-old man underwent aortocoronary bypass and concurrent abdominal aortic aneurysm repair. After weaning from CPB, while the aneurysm was being repaired, the CPB circuit was used for blood salvage and reinfusion. After 1 hour, as blood was given through the aortic cannula, a large clot was discovered in the oxygenator. The activated clotting time was greater than 400 seconds.

PROBLEM ANALYSIS

PREVENTION

Definition

The surgical team should ensure adequate heparin administration and monitoring in prolonged cases, plus visual inspection of the circuit and arterial line filter for clots. Heparinizing any blood products added to the circuit should be considered, and stagnant blood pooling in the CPB circuit should be avoided, even if heparinization is “adequate” by laboratory measurements.

This adverse event can prevent CPB flow, cause massive gas embolus, and interfere with gas exchange. Causes include inadequate heparinization, stagnation in the bypass circuit (no flow in the circuit during circulatory arrest), and, occasionally, addition of unheparinized blood products during CPB.

Recognition Visual inspection of the circuit for clots is most reliable, but the observation of air exiting from a bubble oxygenator or high arterial cannula pressure may also indicate a large clot.

MANAGEMENT Stop CPB and reheparinize the patient using a different lot of heparin, if possible. Hypothermia should be initiated, and open cardiac massage should be performed if the patient cannot be acutely weaned from CPB. The oxygenator may need to be replaced. The protocol for massive air embolism should be followed, if appropriate.

Further Reading Gravlee GP, Davis RF, Krusz M, Utley JR: Cardiopulmonary Bypass: Principles and Practice. Philadelphia, JB Lippincott–Williams & Wilkins, 2000, pp 69-97, 578-612. Hensley FA Jr, Martin DE, Gravlee GP: A Practical Approach to Cardiac Anesthesia, 3rd ed. Philadelphia, JB Lippincott–Williams & Wilkins 2003, pp 513-556. Mills NL, Ochsner JL: Massive air embolism during cardiopulmonary bypass: Causes, prevention, and management. J Thorac Cardiovasc Surg 80:708-717, 1980. Mora CT: Cardiopulmonary Bypass: Principles and Techniques of Extracorporeal Circulation. New York, Springer-Verlag, 1995, pp 302-307. Reed CC, Kurusz M, Lawrence AE Jr: Safety and Techniques in Perfusion. Stafford, Tex, Qualimed, 1988, pp 123-133.

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Bleeding after Cardiac Surgery Peter Tassani-Prell Case Synopsis A 73-year-old man presents with a history of aortic stenosis, coronary artery disease, peripheral vascular disease, dyspnea at rest, and chronic renal failure (creatinine level 1.6 mg/dL). Myocardial function is reduced (left ventricular ejection fraction is 35%). Combined aortic valve replacement and coronary artery bypass graft surgery is performed. Total cardiopulmonary bypass (CPB) time is 142 minutes. Increased bleeding is noted via the mediastinal tubes after surgery. Blood loss via these tubes is 2200 mL in the first 24 hours postoperatively.

PROBLEM ANALYSIS Definition

Risk Assessment Risk factors for postoperative bleeding include the following: ● ● ●

● ● ● ● ● ●

Recognition Surgical exploration for bleeding begins in the operating room (OR) following heparin neutralization with protamine after separation from CPB or completion of “off-pump” cardiac surgery. There are great individual differences in the amount of bleeding that can be detected by direct observation of the operative field. The multifactorial nature of coagulation disorders often makes the distinction between surgical and nonsurgical bleeding difficult. The typical delay in obtaining laboratory test results further complicates the decision as to what therapeutic treatment is needed (e.g., platelets, fresh frozen plasma, cryoprecipitate). Postoperatively, mediastinal chest tube drainage is monitored hourly. As a rule, drainage should not exceed 100 to 125 mL/hour for the first 4 postoperative hours, 250 mL for any hour during this period, or 50 to 75 mL/hour for the subsequent 24 hours. Life-threatening hypotension from postoperative bleeding can result from cardiac tamponade or hypovolemia. It is essential to initiate diagnostic efforts long before the patient’s arrival in the postoperative intensive care unit. Nonsurgical bleeding may be detected in the OR by the surgical team. Appropriate laboratory analysis should be initiated early to obtain results in the OR. Early detection of specific hemostatic deficiencies leads to specific therapy instead of nonspecific

● ●

Prolonged duration of CPB Repeat cardiac procedures Combined procedures (e.g., bypass grafting and valve surgery) Low body temperature after surgery Increased cell salvage usage Advanced age Chronic steroid use Intra-aortic balloon counterpulsation Internal mammary artery harvesting Female sex Preoperative use of anticoagulant drugs

Individual screening in the preoperative period is essential to identify patients at increased risk for postoperative bleeding. Clinical observation and the patient’s medical history are extremely important. Drugs that alter the coagulation system or platelet function are commonly used in patients scheduled for cardiac surgery. Glycoprotein IIb/IIIa inhibitors, including abciximab, eptifibatide, and tirofiban, are used extensively as short-term adjuncts to heparin or aspirin therapy in patients with acute coronary syndromes or in those having preoperative percutaneous coronary interventions. It is also likely that many patients requiring emergency cardiac surgery will have received anticoagulation therapy before arriving in the OR. When in doubt, additional laboratory analysis for specific coagulation disorders may be indicated.

Implications Use of CPB during cardiac surgery disrupts the normal hemostatic system in several ways. Combined effects of hypothermia, hemodilution, blood loss, and transient activation of platelets are often seen. Activated platelets following exposure to CPB are “exhausted” and have lost their function. 305

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Excessive bleeding after cardiac surgery is broadly categorized as surgical or nonsurgical. Surgical bleeding can originate from multiple locations, including bypass graft anastomoses, cannulation sites, mammary beds, sternal wires, or wherever blood vessel integrity has been interrupted. Nonsurgical or microvascular bleeding can result from hemostatic abnormalities involving the endothelium, platelets, coagulation factors, or fibrinolysis. The combined effects of large heparin and protamine doses required for cardiac surgery, CPB circuitry, blood scavenging systems, hypothermia, and, occasionally, massive transfusion can contribute to postoperative bleeding.

transfusion (“shotgun therapy”) of multiple types of blood products and coagulation therapies.

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However, with normal CPB duration, detrimental quantitative and qualitative platelet defects are usually short-lived. Hemodilution. Crystalloid CPB priming and cardioplegia solutions dilute platelets and coagulation factors. The significance of this depends on their baseline concentrations, as well as the volume used relative to the patient’s circulating blood volume. Recent efforts to reduce the volume of CPB priming solutions by using different CPB circuits for adults with lower body weight or using blood versus crystalloid cardioplegia may significantly reduce the amount of clinical hemodilution. Even so, hemodilution is rarely the sole cause of postoperative bleeding, because coagulation factor concentrations of 25% to 30% and platelet counts of 50,000 to 100,000/mm3 can be tolerated without excessive bleeding if platelet function is normal. Cardiopulmonary Bypass Circuitry. The exposure of blood to nonendothelial surfaces of the CPB circuit activates platelets and the coagulation and fibrinolytic pathways. Platelet dysfunction is the single most important cause of bleeding after cardiac surgery. Use of pericardial suction devices during surgery traumatizes blood cells and returns activated coagulation factors to the circulation via the venous reservoir. The use of closed reservoirs, coated CPB circuits, and retransfusion of the suctioned blood after preparation in an autotransfusion device have all been proposed to reduce the detrimental effects of CPB on coagulation. Hypothermia. Hypothermia may result in impaired platelet function and reduced function of temperature-dependent coagulation factors. Also, laboratory coagulation system assessment is uniformly done at 37°C. Therefore, misleading results might be obtained when analyzing cold blood samples obtained during hypothermic CPB. Cooling to more tepid temperatures (mild hypothermia) has been proposed by some to reduce the activation of inflammatory cascades and lessen coagulation abnormalities. Cell Salvage Systems. Because coagulation factors and platelets are removed during routine red cell salvage, reinfused products from cell salvage devices are deficient in these components. Thus, red cell salvage may contribute to abnormalities of coagulation. Heparin. Despite initial neutralization with protamine, heparin rebound can occur 2 to 6 hours afterward, leading to inhibition of platelet function. Antibody-mediated, heparininduced thrombocytopenia and thrombosis (type II HIT; see Chapter 72) is a distinct, severe, and rare entity that involves accelerated clearance or activation of platelets. The target antigen is generated in the presence of platelet factor 4 and heparin at a concentration that allows the formation of heparin–platelet factor 4 complexes. Such interaction then exposes neoepitopes, which bind to the heparin-dependent antibodies. These antibodies are generated in a minority of heparin-treated patients, and occasionally one subgroup develops thrombocytopenia associated with thrombosis.

MANAGEMENT Treatment of postoperative bleeding can be challenging because of its complex and multifactorial causes. Excessive mediastinal

tube drainage, especially when accompanied by hemodynamic instability, indicates a probable surgical source of bleeding and requires surgical re-exploration in the OR. However, the amount of mediastinal drainage does not allow one to differentiate between surgical and nonsurgical causes of bleeding—a distinction that is of the utmost importance. Therefore, a scientifically based algorithm (based on laboratory values) should be used for the precise diagnosis of specific hemostatic abnormalities. When the activated clotting time (ACT) returns to baseline values, this is often interpreted as meaning that heparin neutralization is complete. However, the ACT is insensitive to low circulating heparin concentrations. Even when the ACT has returned to baseline, heparin plasma concentrations can be as high as 0.2 unit/mL, which corresponds to an activated partial thromboplastin time (aPTT) of 1.5 times control. More sensitive tests for residual heparin following surgery include whole blood or plasma aPTT, thrombin time, whole blood heparin concentration measurements, or heparinase ACT values. Continued bleeding in the absence of detectable heparin concentrations warrants further evaluation of the coagulation system. Results of laboratory-based coagulation studies (e.g., prothrombin time, aPTT, platelet count) may take an hour or more to obtain. Commercially available onsite or point-of-care testing methods can provide clinically relevant coagulation test results in about 5 minutes. Such testing can provide a whole blood determination of prothrombin time and aPTT (i.e., plasma separation is not required). Because of the relative importance of quantitative and qualitative platelet defects following CPB, it is important to evaluate and correct such defects as soon as possible. It is difficult to obtain adequate surgical hemostasis without at least 50,000 to 100,000/mm3 of fully functional platelets. Therefore, use of an OR-based hemocytometer can provide rapid information about platelet concentrations. Normal counts, however, do not guarantee adequate platelet function. Modified computerized thromboelastography provides more rapid results than conventional thromboelastography and may be useful. This system allows rapid whole blood coagulation testing with different activators and additives, typically reaching the maximal amplitude after about 15 minutes. It is also possible to see this process in the OR while the test is still running in the laboratory. It is important to initiate diagnostic evaluation early, when microvascular bleeding (“oozing”) in the surgical field is first observed. Timely point-of-care, laboratory-assisted assessment of coagulation leads to reduced and more appropriate use of blood products in the OR.

Platelet Dysfunction Once the determination of thrombocytopenia or qualitative platelet dysfunction has been made, treatment includes the administration of desmopressin acetate (DDAVP), platelet transfusions, or both. DDAVP, a synthetic analogue of antidiuretic hormone, is thought to augment platelet function by the release of factor VIII and von Willebrand’s factor from endothelial cells. Other studies, however, indicate that DDAVP may have direct beneficial effects on platelets, such as increased expression of the adhesive receptor (glycoprotein Ib). The usual dose of DDAVP is 0.3 μg/kg, given intravenously over

Broad-spectrum serine protease inhibitor Interacts with trypsin, kallikrein, chymotrypsin Blood-sparing effects likely related to plasmin inhibition, with platelet function preserved Reduced activation of the hemostatic system via inhibition of contact (kallikrein inhibitor) and tissue factor (binding of VIIa-TF) pathways, with resultant reductions in thrombin and anti-inflammatory properties See above

Aprotinin (full-dose regimen)

Binds to plasmin, inhibiting fibrinolysis

Tranexamic acid

Comments

Loading dose: 10 mg/kg Maintenance dose: 1 mg/kg/hr

Test dose: 1 mL (10,000 units) to test for anaphylaxis Loading dose: 100 mL (1 million units) over 30 min before starting CPB Maintenance dose: 25 mL/hr (0.25 million units/hr); 100 mL in CPB prime solution Loading dose: 100-150 mg/kg or 5-10 g (adults) over 30 min Maintenance dose: 10-20 mg/kg/hr or 1 g/hr (adults)

Renal excretion; dose must be reduced in patients with renal failure Contraindicated with DIC or in presence of hematuria, because ureteral obstruction may result Risks include thrombotic complications Not approved by FDA for prophylaxis of cardiac surgical bleeding Renal excretion; dose must be reduced in patients with renal failure Contraindicated with DIC or in presence of hematuria, because ureteral obstruction may result Risks include thrombotic complications Not approved by FDA for prophylaxis of cardiac surgical bleeding

Half-dose regimen is effective for reducing blood loss for complex or repeat CABG surgery Anti-inflammatory effects with the full-dose regimen may affect other outcomes

Test dose: 1 mL (10,000 units) to test for Aprotinin prolongs the celite ACT, which may lead to anaphylaxis inadequate heparinization during CPB; kaolin ACT Loading dose: 200 mL (2 million units) is unaffected by aprotinin over 30 min before starting CPB Whole blood heparin concentrations (>3 units/mL) Maintenance dose: 50 mL/hr (0.5 million units/hr); can also be maintained with the heparin-protamine 200 mL in CPB prime solution titration method If only celite ACT is available, ACT should be kept >800 sec during CPB, or fixed heparin dosing should be used

Dose

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ACT, activated clotting time; CABG, coronary artery bypass graft; CPB, cardiopulmonary bypass; DIC, disseminated intravascular coagulation; FDA, Food and Drug Administration; TF, tissue factor.

Binds to plasmin, inhibiting fibrinolysis

∈-aminocaproic acid (EACA)

Aprotinin (half-dose regimen)

Mechanism of Action

Antifibrinolytic Drugs to Reduce Blood Loss and Requirements for Blood Transfusion after Cardiac Surgery

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30 minutes. The principal adverse side effect is hypotension. A similar beneficial effect, but without hypotension, can be achieved by giving 4 μg/kg of DDAVP intranasally. Platelet transfusion should consist of an appropriate number of units, preferably obtained by apheresis from a single donor. During cardiac transplantation, blood from the organ donor can be acquired during cardiac explantation, from which platelet-rich plasma is derived by separation plasmapheresis. Such platelet-rich plasma is then transfused into the organ recipient. This can substantially reduce the need for perioperative blood transfusion in cardiac transplant recipients.

Coagulation Factor Deficiencies When the prothrombin time is greater than 16 seconds or the aPTT is greater than 57 seconds, coagulation factor deficiencies are treated with fresh frozen plasma. Although the amount needed varies, depending on initial factor concentrations and circulating blood volume, 1 mL/kg of fresh frozen plasma usually increases coagulation factor concentrations by 1% to 2%. Cryoprecipitate provides a concentrated source of fibrinogen, which is beneficial when deficiencies of this coagulation factor are documented. A prothrombin complex concentrate may be useful when liver function is compromised or liver-generated coagulation factors have been chemically reduced by warfarin. Substitution or supplementation of native antithrombin III leads to higher ACT values and reduced concentrations of fibrin monomer and D-dimer. Substitution of antithrombin III is essential when its activity is less than 60%, because the heparin effect is dependent on it. Several case reports have described using recombinant activated factor VII in cases of life-threatening hemorrhage after cardiac surgery. Randomized, controlled trials to assess the efficacy and safety of such therapy are under way.

PREVENTION Measures to prevent bleeding after cardiac surgery include the following: ● ●

● ●

Minimal CPB duration Autologous blood procurement before CPB to provide a source of fresh whole blood with functioning platelets and coagulation factors for use after heparin neutralization Maintenance of normothermia Judicious postoperative blood pressure control

The fibrinolytic system is known to be up-regulated during CPB owing to the activation of multiple physiologic systems. This results in clot dissolution, coagulation factor

consumption, and platelet dysfunction. Multiple clinical studies indicate that the prophylactic administration of antifibrinolytic drugs reduces blood loss and the number of transfusions in patients after cardiac surgery, particularly reoperations (Table 75-1).

Further Reading Cammerer U, Dietrich W, Rampf T, et al: The predictive value of modified computerized thromboelastography and platelet function analysis for postoperative blood loss in routine cardiac surgery. Anesth Analg 96:51-57, 2003. Caputo M, Bryan AJ, Calafiore AM, et al: Intermittent antegrade hyperkalaemic warm blood cardioplegia supplemented with magnesium prevents myocardial substrate derangement in patients undergoing coronary artery bypass surgery. Eur J Cardiothorac Surg 14:596-601, 1998. Despotis GJ, Filos KS, Zoys TN, et al: Factors associated with excessive postoperative blood loss and hemostatic transfusion requirements: A multivariate analysis in cardiac surgical patients. Anesth Analg 82:13-21, 1996. Hekmat K, Zimmermann T, Kampe S, et al: Impact of tranexamic acid vs aprotinin on blood loss and transfusion requirements after cardiopulmonary bypass: A prospective, randomized, double-blind trial. Curr Med Res Opin 20:121-126, 2004. Herbertson M: Recombinant activated factor VII in cardiac surgery. Blood Coagul Fibrinolysis 15(Suppl 1):S31-S32. 2004. Levi M, Cromheecke ME, de Jonge E: Pharmacological strategies to decrease excessive blood loss in cardiac surgery: A meta-analysis of clinically relevant endpoints. Lancet 354:1940-1947, 1999. Levy JH, Despotis GJ, Szlam F, et al: Recombinant human transgenic antithrombin in cardiac surgery: A dose-finding study. Anesthesiology 96:1095-1102, 2002. Mongan PD, Hosking MP: The role of desmopressin acetate in patients undergoing coronary artery bypass surgery: A controlled clinical trial with thromboelastographic risk stratification. Anesthesiology 77:38-46, 1992. Nuttall GA, Fass DN, Oyen LJ, et al: A study of a weight-adjusted aprotinin schedule during cardiac surgery. Anesth Analg 94:283-289, 2002. Nuttall GA, Oliver WC, Santrach PJ, et al: Efficacy of a simple intraoperative transfusion algorithm for nonerythrocyte component utilization after cardiopulmonary bypass. Anesthesiology 94:773-781, 2001. Ohata T, Sawa Y, Kadoba K, et al: Effect of cardiopulmonary bypass under tepid temperature on inflammatory reactions. Ann Thorac Surg 64:124-128, 1997. Remadi JP, Marticho P, Butoi I, et al: Clinical experience with the miniextracorporeal circulation system: An evolution or a revolution? Ann Thorac Surg 77:2172-2175, 2004. Richter JA, Meisner H, Tassani P, et al: Drew-Anderson technique attenuates systemic inflammatory response syndrome and improves respiratory function after coronary artery bypass grafting. Ann Thorac Surg 69:77-83, 2000. Spiess BD, Gillies BS, Chandler W, et al: Changes in transfusion therapy and reexploration after institution of a blood management program in cardiac surgical patients. J Cardiothorac Vasc Anesth 9:168-173, 1995. Tassani P, Otto D, Szekely A, et al: Transfusion of platelet-rich plasma from the organ donor during cardiac transplantation. J Clin Anesth 9:409-414, 1997. Woodman RC, Harker LA: Bleeding complications associated with cardiopulmonary bypass. Blood 76:1680-1697, 1990.

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Mark A. Chaney Case Synopsis A 62-year-old man is scheduled for elective coronary artery bypass grafting. Immediately after uneventful induction of general anesthesia and tracheal intubation, new ST segment depression is observed on the electrocardiogram (ECG) tracing.

PROBLEM ANALYSIS Definition

Recognition Ischemia Anginal symptoms and hemodynamic alterations are not necessarily reliable indicators of myocardial ischemia. Reliance on increased pulmonary artery wedge pressure for the detection of ischemia is controversial at best. In fact, acutely increased pulmonary artery wedge pressure probably signifies only global ischemia. Detection of regional wall motion abnormalities with transesophageal echocardiography is the most sensitive of the currently available, clinically useful techniques for detecting myocardial ischemia. In addition to wall motion abnormalities, decreased systolic wall thickening or abnormal diastolic filling patterns, detected by Doppler interrogation across the left ventricular

INFARCTION The ECG is the most commonly used modality to detect myocardial ischemia and acute MI. Transmural MI presents initially with prominent T waves, hyperacute ST segment elevation, or both. This evolves over minutes, hours, or even days to a pattern of significant Q waves (i.e., >40 msec duration, >30% of QRS amplitude) or persistent ST-T wave changes. Subendocardial (non-Q-wave) MI is less clearly defined because it may present only as subtle ST-wave or T-wave changes. Detection of non-Q-wave MI often relies on other modalities (e.g., CK, cardiac-specific troponins, transesophageal echocardiographic radionuclide imaging) to confirm the diagnosis. Most perioperative MIs are subendocardial in nature. Serum CK exceeds the normal range within 4 to 8 hours following acute MI and declines to normal by 2 to 3 days. Three isoenzymes of CK (BB, MM, MB) have been identified. Brain and kidney contain predominantly BB, skeletal muscle MM (with 1% to 3% MB), and myocardium both MM and MB (isoforms MB1 and MB2). One study found 59% and 92% sensitivity for the diagnosis of acute MI at 2 to 4 and 4 to 6 hours, respectively, for CKMB2 greater than 1 unit/L or CKMB2/CKMB1 ratio greater than 1.5. Cardiac troponins are highly sensitive and specific chemical markers for myocardial necrosis and predict increased risk of mortality and reinfarction in patients presenting with acute coronary syndrome. The troponin (Tn) complex consists of three subunits (TnC, TnI, TnT) that regulate calciummediated contraction in striated muscle. TnC binds to calcium, TnI binds to actin, and TnT binds to tropomyosin. Both TnI and TnT are present in skeletal and cardiac muscle, but they are encoded by different genes and have different amino acid sequences. This permits the production of specific antibodies for cardiac Tn (cTn) and the development of 309

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Myocardial ischemia results from an imbalance between myocardial oxygen supply and demand. If this persists, ischemia eventually leads to myocardial infarction (MI). Patients in whom perioperative ischemia develops are at increased risk for subsequent cardiac morbidity and mortality. Postoperative MI and major cardiac complications occur in more than 4% of patients who have either an established diagnosis of coronary artery disease or risk factors for it and who undergo major noncardiac surgery. In the United States alone, 1.5 to 2 million patients are at such risk for postoperative MI each year. There is marked variability in the reported short-term mortality (<10% to 70%), but few data exist for long-term prognosis after postoperative MI. Well over 50,000 patients a year sustain perioperative MI, adding substantial cost to postoperative care. Unlike nonsurgical MI, the clinical diagnosis of perioperative MI is often difficult or impossible, especially if it is based on the classic triad of (1) cardiac symptoms, (2) typical ECG findings, and (3) biochemical markers. The silent nature of perioperative MI, the subtle and transient ST depression changes on ECG (resulting in non-Q-wave MI), and the low specificity of the creatine kinase (CK) MB isoenzyme all lead to inconsistencies in the diagnosis of MI and uncertainty about the longterm significance of perioperative markers of MI.

inflow region at the tips of the mitral valve, may also contribute to the recognition of myocardial ischemia. However, transient systolic wall motion abnormalities without accompanying hemodynamic or ECG changes indicative of ischemia are not always related to ischemia. Nevertehless, patients who demonstrate new, persistent wall motion abnormalities perioperatively are more likely to experience a postoperative adverse cardiac outcome than are those with normal wall motion.

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quantitative assays for cTnI and cTnT. In patients with acute MI, cTnT and cTnI levels first begin to rise above their normal reference limits by 3 hours after the onset of chest pain. Elevations of cTnI may persist for 7 to 10 days, and cTnT for 10 to 14 days, following acute MI. The kinetics of release are similar in those with Q-wave or non-Q-wave acute MI. The assay for cTnI is currently the most sensitive and specific marker of myocardial injury. In surgical patients, cardiac troponins have been shown to identify postoperative MI better than CKMB isoenzymes. Finally, the cTnT assay is probably capable of detecting episodes of myocardial necrosis below the detection limit of current CKMB assays. Hence the terms minor myocardial damage and microinfarction have been coined to describe myocardial changes in patients with chest pain and elevated TnT but normal CKMB levels. Regardless, it is well established that such patients are at increased risk for an adverse clinical outcome (e.g., recurrent MI, need for revascularization, death).

Risk Assessment Most studies have focused on historical predictors of cardiac risk discovered during preoperative assessment. Of these, only recent MI (<6 months) and congestive heart failure are significant predictors of perioperative cardiac morbidity. New data show that postoperative ischemia is also a significant predictor of subsequent cardiac morbidity. All cardiac surgical patients are considered at risk for the development of perioperative ischemia, which may occur preoperatively (up to 20% of patients), intraoperatively (up to 50% of patients), and postoperatively (up to 30% of patients). A smaller proportion of noncardiac surgical patients are at risk for perioperative ischemia, depending on their underlying disease. In such patients, most ischemic episodes occur postoperatively. Contributing factors to perioperative myocardial ischemia are listed in Table 76-1. Traditionally, increases in myocardial oxygen demand were thought to be the most important causes of perioperative ischemia; however, recent data reveal that decreases in supply may also be a significant cause.

Table 76–1

■

Factors that Contribute to Myocardial Ischemia

Coronary artery vasoconstriction or vasospasm and thrombosis likely account for a large percentage of episodes of perioperative ischemia that occur without hemodynamic aberrations. Also, because oxygen extraction is near maximum in working myocardium, maintenance of normal blood oxygen content is critical in the presence of restrictions to coronary flow.

Implications Myocardial ischemia may initiate both systolic and diastolic myocardial dysfunction, lead to arrhythmias, or progress to MI. There is a proven association between the occurrence of perioperative ischemia and increased cardiac morbidity and mortality. Moreover, studies suggest a causal relationship between perioperative ischemia and MI. In cardiac surgical patients, intraoperative ischemia exhibits the strongest correlation with perioperative MI. In noncardiac surgical patients, postoperative ischemia exhibits the strongest correlation with perioperative MI. Perioperative MI increases mortality in both cardiac and noncardiac surgical patients. Development of acute MI is often preceded by a period of myocardial ischemia. Thus, early detection of perioperative myocardial ischemia should prompt therapeutic measures to relieve the ischemia, thereby reducing the incidence or size of any subsequent MI.

MANAGEMENT Management of perioperative myocardial ischemia is based on interventions that decrease myocardial oxygen demand or increase its oxygen supply (Table 76-2). Nitroglycerin. Nitroglycerin reduces myocardial oxygen demand by lowering left ventricular end-diastolic volume and afterload. It increases oxygen delivery by coronary artery vasodilatation and a reduction in left ventricular enddiastolic volume. Nitroglycerin is often the initial drug of choice for the management of perioperative myocardial ischemia. However, if such ischemia is associated with tachycardia, β-blockers are also indicated.

Table 76–2

■

Management of Myocardial Ischemia

Increased Myocardial Oxygen Demand

Reduce Myocardial Oxygen Demand

Increased Increased Increased Increased

Decrease heart rate Decrease contractility Decrease left ventricular end-diastolic volume Reduce afterload

heart rate contractility left ventricular end-diastolic volume wall tension (afterload)

Decreased Myocardial Oxygen Supply

Increase Myocardial Oxygen Supply

Decreased coronary blood flow Vasoconstriction Thrombosis Decreased diastolic time Decreased aortic diastolic pressure Increased ventricular end-diastolic pressure Decreased blood oxygen content Decreased hematocrit Decreased oxygen saturation

Increase coronary blood flow Decrease vasoconstriction Decrease thrombosis Increase diastolic time Increase aortic diastolic pressure Reduce ventricular end-diastolic pressure Increase blood oxygen content Optimize hematocrit Increase oxygen saturation

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β-Blockers. β-Blockers decrease myocardial oxygen demand by reducing heart rate and contractility. They increase oxygen supply by increasing diastolic time and reducing ventricular wall stress, especially in patients with left ventricular hypertrophy. Recent data indicate that β-adrenergic antagonists may decrease morbidity and mortality associated with myocardial ischemia and MI. Calcium Channel Blockers. The calcium channel blockers diltiazem and verapamil, but not the dihydropyridine calcium channel blockers (e.g., nicardipine), decrease myocardial oxygen demand by reducing heart rate and contractility and may increase oxygen supply via coronary artery vasodilatation,1 an increase in diastolic time, or a reduction in wall stress. Although still somewhat controversial, dihydropyridines such as sublingual nifedipine or intravenous nicardipine may be specifically indicated when coronary artery vasospasm is suspected.

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In summary, if myocardial ischemia occurs in association with tachycardia or hypertension, initially one must ensure adequate anesthesia, oxygenation, and ventilation. If all of these are present, nitroglycerin or β-blockers (or both) should be used. If myocardial ischemia is associated with tachycardia and hypotension, judicious volume expansion or careful use of α1-receptor agonists is instituted. If ischemia is associated with a normal heart rate and hypotension, therapy should be directed toward the suspected cause of hypotension (e.g., left ventricular pump failure, hypovolemia, reduced systemic vascular resistance). Intra-aortic balloon counterpulsation, via afterload reduction and diastolic augmentation, may also be beneficial and should be considered. When ischemia is not associated with hemodynamic aberrations, coronary vasodilator drugs (e.g., nitroglycerin) or those that both dilate coronary arteries and relieve coronary vasospasm (e.g., nifedipine,4 nicardipine) are used.

PREVENTION

Phosphodiesterase Inhibitors. The physiologic benefits are similar to those of β-adrenergic agonists. However, systemic and pulmonary vasodilatation, along with little effect on heart rate, makes these drugs more appealing than the traditional β-adrenergic agonists.

Perioperative myocardial ischemia and infarction result from a complex interaction among hemodynamic parameters, vascular tone, neural influences, and the coagulation system. Most attempts to prevent perioperative ischemia and infarction (especially with a single drug) have failed. Patients receiving cardiac medications should continue taking them until the time of operation. Preoperative antiischemic therapy should be directed at optimizing the cause of ischemia (myocardial oxygen supply and demand imbalance) and treating its consequences (e.g., congestive heart failure, arrhythmias). Anesthesia should be administered to maintain stable perioperative hemodynamic parameters. No evidence exists that the type of anesthesia (general versus regional, inhalation versus intravenous) affects the incidence of perioperative ischemia or MI in patients at risk. However, prophylactic use of β-blockers may significantly decrease the incidence of perioperative ischemia and subsequent cardiac morbidity. Prophylactic perioperative nitroglycerin is controversial, and the role of drugs that reduce the risk of coronary thrombosis remains to be determined. Aggressive control of postoperative pain with regional anesthesia and analgesia to attenuate associated stress may decrease cardiac morbidity and mortality in both cardiac and noncardiac surgical patients. Perioperative use of thoracic epidural anesthesia with local anesthetics may benefit all patients by blocking cardiac sympathetic efferent activity and improving the balance between myocardial oxygen demand and supply. Finally, studies have revealed that maintenance of normothermia may decrease perioperative myocardial ischemia and subsequent cardiac morbidity.

1 It is likely that diltiazem and verapamil also relieve coronary vasospasm. 2 Many believe that α1-mediated venoconstriction of the splanchnic venous capacitance bed (increasing venous return and preload) is mechanistically more important for any noted blood pressure increase than increased systemic vascular resistance per se. 3 Sodium nitroprusside also dilates the venous capacitance bed to reduce venous return and left ventricular preload. This enhances the effect of systemic arterial vasodilatation to reduce blood pressure.

4 Caution: Nifedipine is not available in intravenous form. It is available in capsule form for oral or sublingual use. However, owing to variable absorption after sublingual dosing and potentially adverse hemodynamic actions due to the drug’s polysorbate vehicle (direct depression of myocardial contractility, systemic venous and arterial dilatation), in 1985 the Food and Drug Administration advised against using nifedipine in hypertensive emergencies. Among the adverse effects reported with sublingual nifedipine in this setting were fatalities due to acute MI.

Sodium Nitroprusside. The physiologic benefits of sodium nitroprusside are similar to those of nitroglycerin, with the added benefit of afterload reduction. However, the precise role of sodium nitroprusside in the management of myocardial ischemia is controversial because of the possibility of coronary artery steal (from vasodilatation of coronary artery resistance vessels).3 β-Receptor Agonists. The physiologic effects of β-agonists may be beneficial (decreased left ventricular diastolic volume, increased aortic diastolic pressure) or detrimental (increased heart rate, reduced diastolic time, increased contractility). Their precise role, if any, in the management of myocardial ischemia is determined by the specific clinical hemodynamic aberration present.

CARDIOTHORACIC & VASCULAR SURGERY

α-Adrenergic Agonists. α1-Receptor agonists can increase myocardial oxygen supply by increasing aortic diastolic blood pressure, but they may also increase myocardial oxygen demand by increasing left ventricular end-diastolic volume and wall stress. α1-Agonists also have the potential to cause coronary artery vasoconstriction or vasospasm. These drugs should be used cautiously, and only in patients who would clearly benefit from systemic vasoconstriction and increased aortic diastolic pressure.2 α2-Receptor agonists reduce central nervous system sympathetic efferent tone. This leads to decreased myocardial oxygen demand secondary to reduced heart rate, blood pressure, and left ventricular end-diastolic volume and wall stress (i.e., dilatation of splanchnic venous capacitance bed).

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Further Reading Antman EM, Braunwald E: Acute myocardial infarction. In Braunwald E (ed): Heart Disease, 5th ed. Philadelphia, WB Saunders, 1997, pp 1184-1188. Apple FS, Wu AHB: Myocardial infarction redefined: Role of cardiac troponin testing. Clin Chem 47:337-339, 2001. Badner NH, Knill RL, Brown JE, et al: Myocardial infarction after noncardiac surgery. Anesthesiology 88:572-578, 1998. Beattie C, Fleisher LA: Perioperative myocardial ischemia and infarction: Preface. Int Anesthesiol Clin 30:xix-xxii, 1992. Brown CS, Bertolet BD: Cardiac troponin: See ya later, CK! Chest 111:2-4, 1997. Carrier M, Pellerin M, Perrault LP, et al: Troponin levels in patients with myocardial infarction after coronary artery bypass grafting. Ann Thorac Surg 69:435-440, 2000.

Chaney MA: Intrathecal and epidural anesthesia and analgesia for cardiac surgery. Anesth Analg 84:1211-1221, 1997. Duke PC (ed): Myocardial ischemia and performance. Anesthesiol Clin North Am 9:455-730, 1991. Fleisher LA, Barash PG: Preoperative cardiac evaluation for noncardiac surgery: A functional approach. Anesth Analg 74:586-598, 1992. Keats AS: Adventures in perioperative myocardial ischemia. Texas Heart Inst J 20:5-11, 1993. Leslie JB: Prevention and treatment of intraoperative myocardial ischemia Anesth Analg 84(Suppl):79-89, 1997. Mangano DT: Perioperative cardiac morbidity. Anesthesiology 72:153-184, 1990. Mangano DT, Goldman L: Preoperative assessment of patients with known or suspected coronary disease. N Engl J Med 333:1750-1756, 1995. Perez-Carceles MD, Osuna E, Vieira DN, et al: Biochemical assessment of acute myocardial ischaemia. J Clin Pathol 48:124-128, 1995.

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Perioperative Hypertension Jerrold H. Levy and Kenichi A. Tanaka

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Case Synopsis A 58-year-old man has just had abdominal aortic aneurysm repair. He is noted to be hypertensive, with a blood pressure of 160/110 mm Hg. His heart rate is 72 beats per minute in sinus rhythm, pulmonary artery pressure is 45/25 mm Hg, pulmonary artery occlusion pressure is 6 mm Hg, and central venous pressure is 5 mm Hg. The patient also has ST segment depression in the anterior precordial electrocardiogram (ECG) leads. Preoperative evaluation revealed no prior history of hypertension, but a history of peripheral vascular disease.

PROBLEM ANALYSIS Definition

Recognition Because BP monitoring is an essential part of perioperative management, either invasive or noninvasive methods may be acceptable for diagnosis and institution of therapy. In cardiac surgical patients, BP is usually kept at lower levels to avoid graft or suture line disruption. Based on data collected from an international survey, hypertension following cardiac surgery is defined as a sustained BP greater than 140/90 mm Hg. When pressures exceed this, most anesthesiologists institute therapy. Recently, new BP guidelines in medical patients were formulated following the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure.

Implications When to treat perioperative hypertension and how rapidly to decrease the BP are not well-resolved issues. Management goals to maintain hemodynamic stability depend on many factors, especially preoperative BP—that is, the patient’s “normal” pressure. There are few data to guide management, and in selected patients (e.g., neurosurgical and cardiac surgical patients), BP may be kept at even lower values immediately following surgery to avoid complications such as hemorrhage, rupture of suture lines, cerebrovascular accidents, myocardial ischemia, and arrhythmias.

MANAGEMENT Therapeutic approaches to perioperative hypertension include the following: ●

● ●

Intravenous vasodilators, dihydropyridine (DHP) calcium channel blockers such as nicardipine,1 dopamine receptor agonists (fenoldopam), hydralazine, or, potentially, angiotensin-converting enzyme (ACE) inhibitors (enalaprilat) Intravenous β-adrenergic blockers Deepening anesthesia

Risk Assessment

Vasodilators

Reported risk factors for hypertension in the postanesthesia care unit include increasing age, smoking, and renal disease. Patients with a preoperative history of angina and those with inadequate ventilation during the postoperative period are also at increased risk for hypertension. Hypertension and tachycardia are associated with increased long-term morbidity and mortality. Preexisting hypertension is also a risk factor.

Nitroprusside and nitroglycerin release nitric oxide to produce arterial vasodilatation and venodilatation, which

1 Clevidepine, another rapid-acting DHP calcium channel blocker, is similar to nicardipine and has a similar hemodynamic profile. It, too, is suitable for intravenous administration and was set to enter phase III clinical trials in 2005.

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The definition of perioperative hypertension differs from that of chronic hypertension. Perioperatively, patients may have acute changes in blood pressure (BP) because of multiple factors, including rapid intravenous volume shifts and changes in sympathetic tone secondary to surgical stimulation, stress responses, or pain. Patients with otherwise normal BP may develop hypertension perioperatively because of these factors. Also, because oral antihypertensive therapy is not possible at this time, patients require parenteral treatment. Hypertension is a major problem after both cardiac and noncardiac surgery. The incidence of postoperative hypertension ranges from 6% to 20% in various noncardiac surgical studies, occurring more commonly in patients with preoperative hypertension, irrespective of anesthetic regimen.

Hypertension following surgery for coronary artery bypass grafting has been reported in 30% to 80% of patients. Augmentation of the stress response because of cardiopulmonary bypass has been suggested as the pathophysiologic basis of increased vascular resistance. Other factors to consider are rapid weaning from mechanical ventilation following cardiac surgery and coronary graft spasm. Ventricular dysfunction is common even in patients with normal preoperative function.

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contribute significantly to the labile hemodynamic state. In a hypertensive patient, intravenous volume administration is often used to allow nitroprusside to be infused when the patient is hypovolemic.2 Although nitroprusside is often used to control postoperative hypertension in other surgical interventions, it may contribute to myocardial ischemia by producing nonspecific coronary vasodilatation and coronary steal. Hydralazine, a more arterioselective vasodilator, is also used in obstetric patients and in perioperative settings, often concomitantly with a β-blocker.

Calcium Channel Blockers There are three types of calcium channel blockers: verapamil, diltiazem, and the DHPs (e.g., nicardipine). Vasodilatation can be produced by any of these drugs, which reduce calcium entry into vascular smooth muscle. DHP calcium channel blockers act by binding with high affinity to the L-type calcium channels, which modulates their voltage-dependent calcium conductivity. DHPs are mainly dilators of the peripheral resistance arteries. In doses that effectively reduce BP, the DHPs have little or no direct negative effect on cardiac contractility or conduction. Their lack of negative chronotropic effect allows an initial reflex increase in heart rate, which decreases during prolonged antihypertensive treatment. Calcium channel blockers do not affect venous smooth muscle; therefore, unlike nitrodilators, they are not venodilators and have little influence on filling pressure and preload. As a result, cardiac output is well maintained or increased when calcium channel blockers are given to reduce arterial pressure. Nicardipine also is a potent coronary and cerebral vasodilator, with important applications in neurosurgical and cardiac surgical patients.

Other Agents Although ACE inhibitors are widely used to treat heart failure, the only intravenous form available is enalaprilat, an indirect-acting agent that is used on occasion to treat perioperative hypertension. ACE inhibitors are complex drugs that interfere with angiotensin II synthesis and may increase nitric oxide release from blood vessels by increasing bradykinin levels. Specific dopamine (DA) receptor agonists are a new class of agents that are under clinical investigation. Fenoldopam, a selective agonist to peripheral DA1-receptors, produces vasodilatation, increases renal perfusion, and enhances natriuresis but may have variable effects on BP and heart rate.

2 Nitroprusside has prominent vasodilatory effects on the venous capacitance bed (i.e., is a potent venodilator) in addition to its arteriodilator effect. Venodilatation reduces venous return and cardiac preload. Because patients with chronic hypertension are often preload restricted—an adaptive response to chronic increased systemic vascular resistance and ventricular wall stress (i.e., afterload)—they may become relatively hypovolemic when given antihypertensive drugs with prominent venodilator effects.

β-Adrenergic Blockers β-Adrenergic blockers reduce heart rate and myocardial contractility, decreasing cardiac output and thus reducing both diastolic and systolic BP. Therefore, β-blockers should be considered in treating perioperative hypertension in patients with tachycardia. Because heart rate is a major determinant of myocardial blood supply, tachycardia must be treated aggressively in patients with ischemic heart disease, and β-blockers should be used as first-line therapeutic agents. Several β-blockers can be administered intravenously and are used as antihypertensive agents in the perioperative period: propranolol, metoprolol, atenolol, esmolol, and labetalol. Distinct advantages of esmolol are its short elimination half-life (<10 minutes) and β1-selectivity.

Deepening Anesthesia Increasing anesthetic depth is always a potential means of treating increased BP during surgery, but it may not always be possible or effective. Regional anesthetic techniques may also be effective at preventing perioperative hypertension. Not to be overlooked is the effect of positive-pressure ventilation or continuous positive airway pressure to impede venous return, effectively reducing preload and systemic BP.

PREVENTION Perioperative hypertension commonly occurs as part of the normal response to induction, surgery, emergence, and pain. Continuing treatment for chronic hypertension is important in the perioperative management of hemodynamic stability. Increasing use of regional anesthetic techniques to better control perioperative pain may also have important effects in preventing perioperative hypertension. Although increasing anesthetic depth can be effective in maintaining hemodynamic control, this technique may not always be feasible; thus, use of the specific antihypertensive agents reviewed here may be required.

Further Reading Aronson S, Boisvert D, Lapp W: Isolated systolic hypertension is associated with adverse outcomes from coronary artery bypass grafting surgery. Anesth Analg 94:1079-1084, 2002. Bailey JM, Tanaka KA, Levy JH: Cardiac surgical pharmacology. In Cohn LH, Edmunds H (eds): Adult Cardiac Surgery, 2nd ed. New York, McGraw-Hill, 2003, pp 85-118. Rose DK, Cohen MM, DeBoer, et al: Cardiovascular events in the postanesthesia care unit: Contribution of risk factors. Anesthesiology 84: 772-781, 1996. Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7). Available at www.nhlbi.nih.gov/guidelines/hypertension/. Tanaka KA, Tsuda A, Yamaguchi K, et al: In vitro effects of antihypertensive drugs on thromboxane agonist (U46619)-induced vasoconstriction in human internal mammary artery. Br J Anaesth 93:257-262, 2004. Vuylsteke A, Feneck RO, Jolin-Mellgard A, et al: Perioperative blood pressure control: A prospective survey of patient management in cardiac surgery. J Cardiothorac Vasc Anesth 14:269-273, 2000.

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Isobel Muhiudeen-Russell and James E. Baker Case Synopsis A 46-year-old woman with primary pulmonary hypertension requires assessment in the postanesthesia care unit. She underwent laparoscopy for acute cholecystitis but required conversion to an open procedure (via a right subcostal incision) to remove the gallbladder. She was mechanically ventilated for 2 hours postoperatively but has since been extubated. Her blood pressure is 78/50 mm Hg, with a heart rate of 110 beats per minute (sinus rhythm). Oxygen saturation is 93% despite receiving oxygen via a facemask with a reservoir bag. A pulmonary artery catheter was placed in the operating room, and her pulmonary artery pressure is 75/45 mm Hg. Temperature is 35.5∞C. The patient is dyspneic, complains of moderate abdominal pain, and appears to be splinting, with rapid, shallow tidal volumes. Her blood pressure has not improved despite a volume challenge with 250 mL of intravenous colloid solution.

Definition Pulmonary artery pressure (PAP) is normally substantially lower than systemic arterial blood pressure. Mean PAP greater than 25 mm Hg, or peak pressure greater than 40 mm Hg, is usually interpreted as pulmonary hypertension. Degrees of pulmonary hypertension are inconsistently defined and may be classified as mild (systolic PAP 40 to 49 mm Hg), moderate (systolic PAP 50 to 59 mm Hg), or severe (systolic PAP 60 mm Hg or above). In keeping with its low-pressure workload, the right ventricle (RV) is a low-pressure, thin-walled structure, but it is able to transmit all its blood to the left atrium owing to the large cross-sectional area and high compliance of the pulmonary vascular bed. Indeed, whereas systemic vascular resistance (SVR) is normally 900 to 1500 dynes •sec•cm–5, pulmonary vascular resistance (PVR) is usually 90 to 120 dynes•sec•cm–5 (1.1 to 1.5 Wood’s units).

Table 78–1

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Thus, pulmonary hypertension is due to either increased PVR, which requires a commensurate increase in the pressure generated by the RV, or a hyperdynamic cardiac state that increases PAP despite a normal PVR. Many disease entities that elevate PVR are chronic processes that, in addition to damaging pulmonary parenchyma, damage or destroy pulmonary blood vessels at both the arteriolar and capillary levels. Notable causes of pulmonary hypertension are listed in Table 78-1 and include chronic obstructive pulmonary disease and interstitial lung disease. Less commonly, pulmonary hypertension due to increased PVR may be congenital (persistent pulmonary hypertension of the newborn) or acquired as an idiopathic entity (primary pulmonary hypertension), as exemplified by the case synopsis. Also, systemic or extrathoracic disease processes may act on previously normal lungs to increase PVR (see Table 78-1). Abnormal cardiac physiology may cause secondary pulmonary hypertension in the absence of elevated PVR.

Causes of and Risk Factors for Pulmonary Hypertension

Idiopathic (primary pulmonary hypertension) Congenital heart disease with increased pulmonary artery blood flow or pressure Cardiac disease with elevated left atrial pressure (e.g., left-sided valvular disease or left ventricular failure) Respiratory system disorders with pulmonary parenchymal or vascular damage Chronic obstructive pulmonary disease Interstitial lung disease (idiopathic or secondary to rheumatoid arthritis, systemic lupus erythematosus, sarcoidosis) Alveolar hypoxemia (e.g., obstructive sleep apnea, chronic high-altitude exposure) Chronic pulmonary thrombosis or thromboembolism (also, sickle cell disease) Congenital (e.g., persistent pulmonary hypertension of the newborn) Portal hypertension Compression of pulmonary veins (e.g., by tumor, lymphadenopathy, anastomotic stricture after lung transplantation) Miscellaneous causes Drugs or toxins Infections, including schistosomiasis and opportunistic infections with human immunodeficiency virus

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PROBLEM ANALYSIS

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Congenital heart disease with left-to-right intracardiac shunting may cause pulmonary hypertension by subjecting the lungs to increased blood flow (e.g., atrial septal defect) or backpressure from the left ventricle (LV; e.g., ventricular septal defect). Also, any cardiac disease that leads to increased left atrial pressure (e.g., dilated cardiomyopathy, ischemic heart disease, mitral stenosis) can also result in pulmonary hypertension, because mean PAP must be sufficiently higher than left atrial pressure to allow blood to flow through the pulmonary vasculature. Unfortunately, many sustained processes that begin as pulmonary hypertension with a normal PVR eventually lead to pulmonary arterial and arteriolar remodeling. This compounds the problem by causing a secondary increase in PVR. Such pulmonary remodeling includes increased muscularity of the medial layer, thickening of the connective tissue within the adventitial layer, and abnormal pulmonary endothelial regulatory function. These changes are usually at least partially irreversible and may perpetuate pulmonary hypertension, even when the underlying hemodynamic problem is corrected.

Recognition and Risk Assessment The ability to recognize pulmonary hypertension has important perioperative implications. It begins with being able to recognize which patients are at risk. When reviewing the patient’s preoperative history, special note should be made of congenital heart disease (whether corrected or not) and chronic pulmonary disease. Such patients constitute the majority of those at risk for significant perioperative pulmonary hypertension, but the other predisposing factors (see Table 78-1) should also be kept in mind. In some of these patients, pulmonary hypertension may have been diagnosed already, and they may have undergone an evaluation to define or quantify the problem. Cardiac catheterization is the gold standard for diagnosing pulmonary hypertension, although noninvasive echocardiography can also be used. In the absence of preoperative information that specifically confirms the diagnosis of pulmonary hypertension, a chest radiograph may show evidence of right-sided cardiac enlargement, and the electrocardiogram may show right axis deviation, right atrial enlargement, or an RV strain pattern. In the case synopsis, a pulmonary artery catheter was inserted preoperatively, prompted by the prior diagnosis of primary pulmonary hypertension. In such instances, the pulmonary artery catheter can confirm any significant elevation in PAP. Generally, mean PAP greater than 40 mm Hg or greater than two thirds of systemic arterial pressure can be interpreted as severe pulmonary hypertension. Although no degree of pulmonary hypertension is necessarily associated with adverse consequences, no degree is necessarily safe either. Indeed, many patients with pulmonary hypertension may tolerate PAP levels that appear quite alarming. Others may suffer adverse consequences even with relatively minor elevations, especially when the increase is acute. The difference is probably related to the RV’s ability to adapt to chronically elevated afterload by concentric hypertrophy, as does the LV in patients with systemic hypertension. Finally, many stresses related to surgery or the conduct of anesthesia influence the degree of perioperative pulmonary hypertension and patient tolerance.

Implications It must be remembered that the real significance of perioperative pulmonary hypertension is not its presence or any particular degree of hypertension but rather the RV’s ability to tolerate any increased afterload. Although pulmonary hypertension is an important cause of hemodynamic instability, the pattern depends on the RV’s inability to eject against increased afterload and to provide adequate LV filling to maintain cardiac output. As the RV fails, both its diastolic and systolic dimensions increase, displacing the ventricular septum to the left. LV function is subsequently impaired due to inadequate diastolic filling and its inability to adequately contract during systole. RV coronary perfusion is also reduced due to RV wall stretching and intracavitary hypertension (recall that unlike the LV, the RV normally receives significant coronary perfusion during systole and is therefore vulnerable to increased systolic and diastolic intracavitary pressures). If systemic hypotension develops from reduced LV stroke volume, RV coronary perfusion pressure is further reduced, and the problem becomes selfpropagating. Severe shock and cardiovascular collapse may be the ultimate expression of postoperative pulmonary hypertension.

MANAGEMENT Although pulmonary hypertension can be difficult to manage, especially when it is chronic and associated with pulmonary vascular remodeling, treatment is based on evidence that elevated PVR may be at least partly reversible. In any event, some factors may actually aggravate PVR, and care must be taken to avoid them to the extent possible. Table 78-2 summarizes the current approach to management.

Ventilatory Management Ventilation has an important impact on PVR and may worsen or improve pulmonary hypertension. Either a very high fraction of inspired oxygen (FiO2 1.0) or severely reduced arterial carbon dioxide tension (PaCO2 <30 mm Hg; significant respiratory alkalosis) may appreciably improve PVR. To reduce PVR, especially with respiratory acidosis, one can increase minute ventilation to lower PaCO2 (keeping it >20 mm Hg) or increase pH (keeping it <7.6). It is likely that pH mediates changes in pulmonary arteriolar tone, not PaCO2 itself. Therefore, if pulmonary parenchymal disease precludes this degree of hyperventilation, systemic alkalinization (sodium bicarbonate) might be considered. Ventilatory management must be conducted to avoid significant increases in lung volume and airway pressure. As lung volumes increase above functional residual capacity, the alveolar capillaries are stretched. This can lead to progressive collapse and reduction in the total cross-sectional area of the pulmonary capillary bed. Conversely, low lung volumes may contribute to the collapse of extra-alveolar vessels and alveolar atelectasis. The former directly increases PVR, whereas the latter increases it through hypoxic pulmonary vasoconstriction.

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Table 78–2

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Management of Severe Pulmonary Hypertension with Right Ventricular Heart Failure

Type of Treatment

Features of Therapy

Conservative and remedial measures to lower PVR Pharmacologic therapy to lower PVR Inotropic support for right ventricle Maintenance of coronary perfusion

High FiO2; avoid hypercarbia and acidosis; correct respiratory alkalosis (pH <7.6); avoid hypothermia or shivering; prevent both alveolar collapse and overdistention; optimize pain control Nitrates; PGE1; inhaled NO; prostacyclin

Optimization of RV preload Mechanical support

Milrinone, dobutamine, or isoproterenol for adequate SAP; norepinephrine or epinephrine if SAP is marginal or inadequate Add α-adrenergic agonist (e.g., phenylephrine) to a combined inotrope-vasodilator (e.g., milrinone); consider norepinephrine for combined inotropic support and elevation of SAP; avoid RV distention Avoid RV distention and underfilling; consider invasive (RAP or PAP) monitoring or transesophageal echocardiography where appropriate RV assist device; intra-aortic balloon pump

FiO2, fraction of inspired oxygen; NO, nitric oxide; PAP, pulmonary artery pressure; PGE1, prostaglandin E1; PVR, pulmonary vascular resistance; RAP, right atrial pressure; RV, right ventricular; SAP, systemic systolic arterial blood pressure.

Other Nonpharmacologic Management

Pharmacologic Management Pharmacologic management of pulmonary hypertension is undertaken to (1) lower PVR directly, (2) support RV inotropic function, and (3) maintain sufficient systemic arterial blood pressure for adequate RV coronary perfusion. Many drugs reduce PVR and have been used in patients with pulmonary hypertension. Nitroglycerin, nitroprusside, calcium channel antagonists, and especially prostaglandin E1 may be effective in reducing PVR and PAP. However, all these drugs have the same limitation: lack of specificity for the pulmonary vasculature. To whatever extent PVR is lowered by these agents, SVR may be similarly decreased. Given the importance of maintaining adequate RV coronary perfusion pressure, any significant reduction in SVR may be poorly tolerated and precipitate acute RV failure. Similarly, some inotropes, such as dobutamine, isoproterenol, and milrinone, are well known for their ability to lower PVR while also increasing inotropy, but use of these drugs is limited by their potential to reduce SVR and cause systemic hypotension when coronary perfusion pressure must be maintained. Use of α-agonists (e.g., phenylephrine) to reduce systemic hypotension may negate any salutary effects of other drugs given to reduce PVR. Thus, inotropes or systemic vasodilators that are also pulmonary vasodilators may be used with caution in patients with preserved systemic blood pressure, but the possibility of an overall deleterious effect

CARDIOTHORACIC & VASCULAR SURGERY

Other factors that may promote acutely elevated PVR and PAP include hypothermia, excess circulating catecholamines due to light anesthesia or uncontrolled postoperative pain, and sepsis. Patients having cardiac surgery are vulnerable to increased PVR due to an increase in circulating inflammatory mediators associated with cardiopulmonary bypass. Although not all of these factors can be controlled, it is important to maintain or reestablish normothermia postoperatively and to treat or prevent postoperative pain as effectively as possible.

and the need to support systemic blood pressure should be kept in mind. Although intravenous drugs that selectively reduce PVR are lacking, inhaled nitric oxide (NO) directly dilates the pulmonary vasculature. By virtue of its rapid degradation by circulating hemoglobin, its vasodilating action is effectively confined to the pulmonary vasculature; SVR is not significantly altered. NO dosages range from 10 parts per million (ppm) to a maximum of 80 ppm. These doses reduce RV afterload without compromising systemic blood pressure or coronary perfusion. Beneficial effects are achieved with NO in many perioperative and critical care settings, including lung or heart transplantation and surgery for congenital heart disease. Improved ventilation-perfusion matching and arterial oxygen tension (PaO2) may also be achieved because inhaled NO increases blood flow to those lung units that are best ventilated. Inhaled prostacyclin also selectively lowers PVR in patients with pulmonary hypertension. Although norepinephrine has the potential to increase PVR, it has been used successfully in many patients with critical pulmonary hypertension. In fact, it is preferred when systemic blood pressure is low or marginal. Owing to wellbalanced α- and β-adrenergic effects, coronary perfusion pressure is well maintained or improved, while RV contractility is enhanced. To the extent that high left-sided heart pressures contribute to pulmonary hypertension (e.g., severe mitral valve disease, ischemic LV failure), inotropic support for the LV may also reduce RV afterload by lowering left atrial pressure. Judicious volume therapy is important in patients with impaired RV function. An excessively low RV preload reduces cardiac output. However, RV overload increases RV wall stress, reduces coronary perfusion (via increased RV intracavitary pressure), and worsens tricuspid insufficiency. Most patients with severely elevated PAP, especially with RV failure or tricuspid insufficiency, do not require more RV preload unless volume or blood loss is significant. If so, any volume loading should be done with caution. For example, patients without improved hemodynamics after a 250-mL colloid or blood product challenge are unlikely to benefit from more volume.

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Also, invasive monitoring may be of some help. A central venous or right atrial pressure greater than 15 mm Hg suggests that more volume is unlikely to be beneficial. If available, transesophageal echocardiography provides the best assessment of left- or right-sided intracardiac volume status.

PREVENTION Unfortunately, pulmonary hypertension severe enough to cause perioperative RV failure is likely the result of a chronic or preexisting condition. Although it cannot be prevented, it may be mitigated or optimized by careful anesthetic management. An exception is new-onset or aggravated pulmonary hypertension caused by intraoperative protamine. This can be prevented by giving the drug more slowly or not giving it at all in patients with a history of protamineassociated pulmonary hypertension. Most other pulmonary hypertension cases, and any attendant cardiac dysfunction, should be diagnosed and quantified during preoperative assessment. Then perioperative management can be adjusted to prevent the development of further PAP increases in at-risk patients. This may require PAP monitoring, transesophageal echocardiography, or both to assess the effects of surgical stress and anesthetic drugs and techniques on PVR, cardiac output, and RV function.

Most nonpharmacologic strategies for treating pulmonary hypertension are also used in preventive intraoperative management for high-risk patients. Ventilator and overall blood gas management should aim to promote appropriate alveolar expansion, oxygenation, and respiratory alkalosis. If possible, agents that might increase PVR (e.g., histamine-releasing muscle relaxants, opioids) should be avoided. If necessary, systemic arterial blood pressure should be supported to maintain RV coronary perfusion. Also, as the case synopsis illustrates, the anesthetic plan must address the need for optimal postoperative pain control, especially when pain impairs ventilatory mechanics. Consider the use of regional analgesia when appropriate, use patient warming devices, and provide an appropriate duration of postoperative mechanical ventilation. Tracheal extubation should be attempted only when the patient is likely to have adequate respiratory mechanics and gas exchange without mechanical assistance.

Further Reading Fischer LG, Van Aken H, Burkle H: Management of pulmonary hypertension: Physiological and pharmacological considerations for anesthesiologists. Anesth Analg 96:1603-1616, 2003. Meyer KC, Love RB, Zimmerman JJ: The therapeutic potential of nitric oxide in lung transplantation. Chest 113:1360-1371, 1998. Stobierska-Dzierzek B, Awad H, Michler RE: The evolving management of acute right-sided heart failure in cardiac transplant recipients. J Am Coll Cardiol 38:923-931, 2001.

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Perioperative Tachyarrhythmias John L. Atlee Case Synopsis A 62-year-old man sustains sudden-onset monomorphic ventricular tachycardia (Fig. 79-1) after separation from cardiopulmonary bypass (CPB) for aortic valve replacement and coronary artery bypass grafting. The tachycardia terminates with internal cardioversion. The patient is returned to CPB for revision of a vein graft. Subsequent separation from CPB and the early postoperative course are uneventful. However, 16 hours after arrival in the intensive care unit, the patient has atrial fibrillation (Fig. 79-2), which is terminated by cardioversion. Antiarrhythmic drug therapy with intravenous amiodarone is begun. However, atrial fibrillation recurs two times over the next 12 hours. On each occasion, it is terminated by cardioversion. After this, the patient stabilizes. He is continued on intravenous amiodarone, with transition to the oral form during his hospitalization and after discharge home. At 1-year follow-up, there has been no recurrence of atrial fibrillation.

Definition Ventricular tachycardia, ventricular flutter or fibrillation, and atrial flutter or fibrillation commonly complicate cardiovascular and thoracic surgery in the early postoperative course. Indeed, without prophylaxis, the incidence of postoperative atrial flutter or fibrillation approaches 50%, especially after valve repair or replacement. Other tachyarrhythmias that may complicate the perioperative course of patients undergoing cardiothoracic or vascular surgery (or other high-risk surgery in high-risk patients) include paroxysmal supraventricular tachycardia, ectopic (uniform or multiform) atrial tachycardia, and junctional or idioventricular tachycardia. Tachyarrhythmias with ventricular preexcitation (i.e., WolffParkinson-White syndrome) or long QT syndromes are discussed in Chapters 80 and 81, respectively.

electrocardiogram (ECG) rhythm strip and place a copy in the patient’s chart. Other attributes that aid in arrhythmia diagnosis are (1) the presence or absence of cannon a waves (indicative of atrioventricualr dissociation), (2) the suddenness of onset and termination (paroxysmal tachycardias), and (3) a gradual rate increase at onset (“warm-up”) and slowing at termination (“fade”), which are characteristic of automatic or ectopic, in contrast to reentrant, tachycardias. The latter usually have a more abrupt onset (often following a supraventricular or ventricular extrasystole) and termination. Also, the onset of tachyarrhythmias can often be recognized by a sudden change in the patient’s hemodynamic status, which should prompt a look at the ECG monitor.

Risk Assessment Predisposing factors for perioperative tachyarrhythmias include (1) advanced age; (2) a history of tachyarrhythmias,

Recognition Electrocardiographic and other features of tachyarrhythmias are provided in Table 79-1. When confronted with a sustained tachyarrhythmia, it is useful (time permitting), for purposes of diagnosis and patient follow-up, to record an

Figure 79–1

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Onset of monomorphic ventricular tachycardia.

Figure 79–2

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Atrial fibrillation.

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Characteristic Electrocardiographic Rates and Rhythms of Perioperative Tachyarrhythmias

Arrhythmia

Rate (bpm)

Rhythm

Comments

Accelerated idioventricular rhythm Atrial fibrillation

A: 50-100* V: 50-110

A: regular V: fairly regular; may be irregular A: highly irregular V: highly irregular A: regular V: regular (with fixed AVHB) or “regularly” irregular (with varying AVHB) A: regular or irregular (with AVHB) V: fairly regular

Hemodynamic insufficiency; intermittent cannon a waves; not amenable to cardioversion

Atrial flutter

AV junctional tachycardia†

A: 400-600 V: 100-160 A: 250-360 V: 75-180 A: 70-130* V: 70-130

Ectopic atrial tachycardia

A: 100-250 V: ≥100‡

Paroxysmal supraventricular tachycardia

A: 150-250§ V: 150-250

Sinus tachycardia

A: 100-180 V: 100-180

Ventricular fibrillation

A: 60-100 V: 400-600

Ventricular flutter

A: 60-100*

Ventricular tachycardia

V: 150-300 A: 60-100*

V: 110-250

No a waves; ventricular rate slows with CSM but remains highly irregular Flutter waves; ventricular rate slows with CSM but remains “regularly” irregular; type 1 flutter (atrial rate ≤340 bpm) may be converted by rapid atrial pacing Hemodynamic insufficiency; intermittent cannon a waves; may slow slightly with vagal maneuvers or β-blocker; not amenable to cardioversion; can be overdriven by atrial pacing More a waves than c- -v waves; possible slowing with vagal maneuvers or CSM, followed by return to usual rate; not amenable to cardioversion

A: abnormal P waves (uniform or multiform); may be irregular V: normal appearance; may be irregular with AVHB A: very regular (if apparent), Constant cannon a waves; CSM or vagal maneuvers may except at onset and cause abrupt slowing and termination of tachycardia or termination have no effect V: very regular, except at onset and termination; normal QRS contour A: regular Rate may gradually slow with CSM or vagal maneuvers, then V: regular unless patient has gradually return to former rate ≥ second degree AVHB A: normal, but difficult Cannon a waves; imminently lethal unless early termination by to see on surface leads DC defibrillation V: grossly irregular and multiform appearance A: normal, but difficult Cannon a waves; imminently lethal unless terminated by DC to see on surface leads cardioversion V: regular, sine waves A: normal, but often not Intermittent cannon a waves; “slow” VT may be tolerated seen on surface leads hemodynamically; prompt DC cardioversion recommended unless capture beats are for most VT present (confirming VT) V: regular (R-R interval may vary by ≥20 msec in 20% of patients, unless interrupted by capture beats from higher pacemakers

*Constant and same as ventricular rate (AV junctional tachycardia, accelerated idioventricular rhythm, or ventricular flutter or tachycardia with retrograde atrial activation). † Also known as accelerated AV junctional rhythm or nonparoxysmal AV junctional tachycardia. ‡ Usually <250 bpm or limited by AV block. § P waves often nonapparent or may be inverted, depending on mechanism for reentry, which could be the AV node or the AV node with retrograde atrial activation via an electrically silent accessory pathway (i.e., the accessory pathway does not conduct from atria to ventricles during sinus rhythm to produce a δ wave associated with ventricular preexcitation). A, atrial; AV, atrioventricular; AVHB, AV heart block; bpm, beats per minute; CSM, carotid sinus massage; DC, direct current; V, ventricular; VT, ventricular tachycardia.

even if the patient is receiving adequate treatment and is now asymptomatic; (3) cardiovascular or chronic pulmonary disease; (4) the presence of an implanted cardiac rhythm management device (e.g., pacemaker, defibrillator, cardiac resynchronization device); (5) hepatic or renal insufficiency; (6) central nervous system disease or space-occupying lesion; (7) dysautonomias; and (8) metabolic or physiologic imbalance (e.g., circulatory or hemorrhagic shock, sepsis, hypercarbia, hypoxia, acid-base imbalance, adverse drug effects or interactions, stress, pain, anxiety, hyperthyroidism, other hyperadrenergic states). Also, some surgical procedures are more likely to be associated with tachyarrhythmias. Aside from cardiothoracic and vascular surgery, neurosurgery for

aneurysms and posterior fossa tumors is not uncommonly associated with bradycardia or tachyarrhythmias. Among the causes of perioperative tachyarrhythmias are ischemia-reperfusion injury, CPB, high circulating catecholamines secondary to physiologic stress (pain, anxiety), and physiologic or metabolic imbalance. Generally, it is uncommon for a patient with a structurally normal heart to develop sustained ventricular tachyarrhythmias. The most common cardiac disorder associated with sustained ventricular tachycardia is coronary artery disease with an acute coronary syndrome (e.g., myocardial ischemia or infarction) or healed myocardial infarction with scar (the substrate) and a superimposed trigger (e.g., ischemia, proarrhythmia, stress).

Ischemia; myocardial reperfusion injury; acute MI; digitalis toxicity Clinical or subclinical cardiovascular disease; cardiac surgery, especially valve surgery; history of treated hypertension, left atrial enlargement, stroke, valvular heart disease, or CHF; COPD; occult or manifest thyrotoxicosis See AFB; also, may occur after congenital heart disease surgery

Inferior wall MI; open heart surgery; acute rheumatic fever; myocarditis; digitalis toxicity*

EAT: possibly digitalis toxicity; more likely, significant structural heart disease

Accelerated idioventricular rhythm

Atrial fibrillation (AFB)

Atrial flutter (AFT)

AV junctional tachycardia (AVJT)

Ectopic atrial tachycardia: uniform (EAT) or multiform (MAT) MAT: commonly COPD or CHF; digitalis is an unlikely cause; theophylline has been implicated

Cause

Arrhythmia

Optimize treatment for COPD or CHF; stop digitalis and give potassium if not elevated; consider magnesium if hypomagnesemia is present

Possibly β-blockers; indicated treatment for predisposing factors; possibly magnesium supplementation in pediatric congenital heart surgery

Amiodarone; left or biatrial pacing or β-blockers for primary prevention in cardiac surgery; sotolol (class II and III activity) may also be effective; in thoracic surgery, primary prophylaxis with a β-blocker; indicated therapy for predisposing disease or conditions to facilitate more specific measures See AFB

Measures to correct cause; usually transient (seconds to minutes), so little or no effect on outcome

Prevention

Causes, Prevention, and Treatment of Tachyarrhythmias

Table continued on following page

MAT: possibly a β-blocker (nonasthmatics); give potassium or magnesium if low; antiarrhythmics include verapamil, diltiazem, or amiodarone; does not respond to DC cardioversion

DC cardioversion is preferred initial therapy (promptly restores sinus rhythm in most cases); IV ibutilide converts 60%-90% of episodes (but 8%-10% risk of proarrhythmia); rapid atrial pacing (AFT ≤340 bpm) converts some AFT (also, see AFB) If digitalis is the cause, stop it; potassium, β- blockers, lidocaine, or phenytoin may also be used; atrial or AV overdrive pacing (slowly reduce rate to wean from pacing); DC cardioversion should not be used if digitalis could be the cause; otherwise, it might be effective if AVJT is not caused by enhanced automaticity (e.g., if AVJT occurs with myocardial reperfusion injury) EAT: digitalis; consider β-blocker or CCB to slow ventricular rate; possibly add class IA, IC, or III antiarrhythmic; does not respond to DC cardioversion

Often transient (after establishing coronary reperfusion); overdrive atrial pacing preferred to drugs (atropine or other positive chronotropes) to increase atrial rate; easily overdriven by atrial pacing If hemodynamically destabilizing and acute, DC cardioversion; drugs for chemical conversion of acute AFB include class IA, IC, and III antiarrhythmics, but consider proarrhythmia risk (up to 8%-10% with ibutilide and dofetilide)

Treatment

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322 Stress, anxiety, or pain; sepsis; hypovolemia, hypercarbia, or hypoxia; light anesthesia; MH; sympathomimetic, anticholinergic, and some illicit drugs Myocardial ischemia, MI, reperfusion injury; cardiomyopathy (end stage) due to any cause; idiopathic Myocardial ischemia, MI, reperfusion injury; cardiomyopathy (end stage) due to any cause; specific types of VT†; severe imbalance due to physiologic or metabolic imbalance or drug related (e.g., proarrhythmia)

Sinus tachycardia

Indicated treatment for primary heart disease; removal of offending drugs(s); correction of physiologic or metabolic imbalance

Indicated treatment for primary heart disease

Treat, remove, or avoid the underlying cause

Rest, reassurance, or sedation may abort attacks; provide adequate pain control and avoid triggers; RF ablation of APs or AVN pathways is definitive for prevention

Immediate DF followed by IV amiodarone or procainamide to prevent recurrences; search for and correct causative conditions If destabilizing (some slow VT is not), immediate DC followed by IV amiodarone or procainamide to prevent recurrences; search for and correct identifiable causative or contributing conditions

After vagal maneuvers, adenosine, edrophonium, or CCB; if patient is unstable, immediate DC cardioversion; class IA antiarrhythmics increase AP conduction time and refractory periods; class II antiarrhythmics, adenosine, and digitalis increase AVN conduction time and refractory periods; class IC and III antiarrhythmics increase conduction time and refractory periods in both APs and AVN None unless symptomatic or causes myocardial ischemia; β-blockers

Treatment

*Recognized by regularization of rate in patients with AFB receiving digitalis, and signs of digitalis toxicity. † Idiopathic VT or that associated with arrhythmogenic right ventricular dysplasia, a surgical scar involving the right ventricular outflow tract (e.g., after correction of tetralogy of Fallot), bundle branch reentry, or mitral valve prolapse. AP, accessory pathway; AV, atrioventricular; AVN, AV node; bpm, beats per minute; CCB, calcium channel blocker; CHF, congestive heart failure; COPD, chronic obstructive pulmonary disease; DC, direct current; DF, defibrillation; IV, intravenous; MH, malignant hyperthermia; MI, myocardial infarction; RF, radiofrequency; WPW, Wolff-Parkinson-White syndrome.

Ventricular tachycardia

Ventricular flutter or fibrillation

Anxiety; panic attacks; caffeine; theophylline; catecholamines; WPW

Paroxysmal supraventricular tachycardia

Prevention

Causes, Prevention, and Treatment of Tachyarrhythmias—cont’d

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Idiopathic left ventricular tachycardia and right ventricular outflow tract tachycardia are two uncommon but specific types of ventricular tachycardia that occur in patients without demonstrable heart disease. In addition, idiopathic ventricular fibrillation is a potentially lethal tachyarrhythmia that occurs in otherwise healthy individuals and requires aggressive management.

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of inducing a proarrhythmic event (ventricular tachycardia or fibrillation); this risk is greatest for patients with structural heart disease. Among the antiarrhythmic drugs approved for intravenous use, amiodarone carries the least risk of proarrhythmia (1% to 2%). The risk of proarrhythmia can be as high as 8% to 10% with some class IA or IC drugs and with ibutilide or dofetilide, especially in patients with structural heart disease.

Implications

MANAGEMENT Prompt direct-current cardioversion or defibrillation is the preferred initial treatment for all hemodynamically disadvantageous tachyarrhythmias that can be terminated by such shocks. Those that cannot be terminated by these methods are ectopic atrial tachycardias (uniform or multiform), accelerated atrioventricular junctional rhythm or idioventricular tachycardia, and tachyarrhythmias due to digitalis toxicity. For all tachyarrhythmias with distinct QRS complexes, synchronized shocks (direct current) are used. This applies to most non-sinus-origin supraventricular tachycardia and ventricular tachycardia. Defibrillation is used for ventricular fibrillation and polymorphic ventricular tachycardia if QRS complexes and T waves are indistinguishable. Antiarrhythmic drugs can be used for cardioversion if the arrhythmia does not pose an imminent threat to life. Examples are intravenous ibutilide or amiodarone for “chemical” conversion of atrial flutter or fibrillation. However, the use of drugs for cardioversion carries the risk

PREVENTION The old adage “an ounce of prevention is worth a pound of cure” is especially applicable to perioperative tachyarrhythmias. Meticulous attention to the preservation of optimal physiologic and metabolic balance is fundamental to the prevention of adverse arrhythmic events. Also, multiple antiarrhythmic drug therapy may have an adverse impact on cardiac arrhythmia “substrates” (any diseased myocardium). Further, one must be mindful of drug interactions that might promote arrhythmias or have other untoward circulatory or neuroregulatory consequences. Causes, prevention, and treatment of specific tachyarrhythmias (aside from those associated with ventricular preexcitation or long QT syndromes) are outlined in Table 79-2.

Further Reading Atlee J: Perioperative cardiac dysrhythmias. Anesthesiology 86:1397-1424, 1997. Crystal E, Connolly SJ, Sleik K, et al: Interventions on prevention of postoperative atrial fibrillation in patients undergoing heart surgery. Circulation 106:75-80, 2002. Dorman BH, Sade RM, Burnette JS, et al: Magnesium supplementation in the prevention of arrhythmias in pediatric patients undergoing surgery for congenital heart defects. Am Heart J 139:522-528, 2000. Ho RT, Cullans DJ: Malignant ventricular arrhythmias. In Antman EM (ed): Cardiovascular Therapeutics. Philadelphia, WB Saunders, 2002, pp 477-501. Hollenberg SM, Dellinger RP: Noncardiac surgery: Postoperative arrhythmias. Crit Care Med 28:145-150, 2000. Mangrum JM, DiMarco JP: Acute and chronic pharmacologic management of supraventricular tachyarrhythmias. In Antman EM (ed): Cardiovascular Therapeutics. Philadelphia, WB Saunders, 2002, pp 423-444. Olgin JE, Zipes DP: Specific arrhythmias: Diagnosis and management. In Braunwald E, Zipes DP, Libby P (eds): Heart Disease, 6th ed. Philadelphia, WB Saunders, 2001, pp 815-889. Thomas RG: Supraventricular tachycardia: Implications for the intensivist. Crit Care Med 28:129-135, 2000. Waktare JEP, Camm AJ: Atrial fibrillation: A comprehensive approach. In Antman EM (ed): Cardiovascular Therapeutics. Philadelphia, WB Saunders, 2002, pp 458-476.

CARDIOTHORACIC & VASCULAR SURGERY

Hemodynamic tolerance of tachycardia depends on the inherent stability of the rhythm, its rate and duration, and the status of atrial transport function, ventricular compliance, and ventricular function. Ventricular fibrillation, polymorphic ventricular tachycardia, and fast ventricular tachycardia are inherently unstable and pose an immediate threat to life. Tachyarrhythmias with sustained high ventricular rates impair ventricular filling, reduce diastolic time and coronary perfusion, and increase myocardial oxygen demand. Atrial transport function loss (which occurs with atrial fibrillation, junctional tachycardia, and all ventricular tachyarrhythmias) reduces ventricular filling and is especially disadvantageous for patients with reduced ventricular compliance. Finally, patients with marginally compensated heart failure may rely on sinus rhythm or a paced equivalent to meet their basic metabolic needs. Otherwise, they may develop overt heart failure.

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80

John L. Atlee Case Synopsis A 61-year-old woman has paroxysmal, irregular, wide QRS tachycardia in the recovery room following general anesthesia for left thoracotomy and upper lobe lung resection (Fig. 80-1). The ventricular rate exceeds 220 beats per minute for some beats, and the rhythm disturbance is poorly tolerated. Her preoperative electrocardiogram (ECG) during sinus rhythm revealed δ waves consistent with ventricular preexcitation.

PROBLEM ANALYSIS Definition The association of paroxysmal tachycardia with ECG evidence of ventricular preexcitation during sinus rhythm (δ waves) is known as Wolff-Parkinson-White (WPW) syndrome. Ventricular preexcitation requires functional accessory atrioventricular (AV) pathways that bypass normal AV conduction via the AV node during sinus rhythm to cause ventricular preexcitation. The fast conduction and refractory periods of accessory pathways (APs) are similar to those of atrial muscle. APs may also conduct from the ventricles to the atria (retrograde or ventriculoatrial conduction) to participate in AV reciprocating tachycardia (AVRT) (Fig. 80-2). Further, they may conduct atrial impulses more rapidly during atrial flutter or fibrillation than would otherwise be the case with conduction via the

Figure 80–1 ■ Electrocardiogram from the recovery room (leads V1-V3). Note the highly irregular, wide QRS tachycardia, with ventricular rates ranging from 150 to 300 beats per minute.

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AV node. Usually, the ventricular rate during atrial flutter or fibrillation is limited by the AV node refractory period (300 msec) to less than 200 beats per minute. In contrast, the AP refractory period is shorter (240 msec), which allows ventricular rates greater than 250 beats per minute. If such rates are sustained, rapid deterioration to ventricular fibrillation is possible.

Figure 80–2 ■ Atrioventricular reciprocating tachycardia (AVRT) in a patient with ventricular preexcitation (δ waves) during sinus rhythm. During AVRT, conduction to the ventricles (i.e., orthodromic conduction) is via the AV node, giving rise to a narrow QRS complex tachycardia. The propagating impulse returns to the atria via the accessory pathway (i.e., antidromic conduction) to complete the reentry circuit. The rate of tachycardia is about 210 beats per minute and is associated with evidence of myocardial ischemia (elevated or depressed ST segments, depending on which lead is viewed). Although retrograde P waves often accompany antidromic AVRT, in this example, the P waves are not apparent, possibly due to the ST segment changes related to ischemia.

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Recognition Features of WPW syndrome and ventricular preexcitation include the following: ● ●

● ●

Short P-R interval (<0.12 second) Wide QRS complex (>0.12 second) with slurred initial QRS (δ wave) in some leads Usually, normal terminal QRS ST-T changes commonly directed opposite to the major δ wave and QRS vectors

●

●

●

During orthodromic AVRT, inverted P waves (leads II, III, aVF) usually follow a narrow QRS complex. This contrasts with AV nodal reentry PSVT (the other >40% of all PSVTs), where P waves are usually nonapparent. With antidromic AVRT (<5% of PSVTs), retrograde P waves (if apparent) are upright in the inferior leads, and the QRS complex is widened (i.e., maximal preexcitation). Antidromic AVRT may be difficult to distinguish from monomorphic or polymorphic ventricular tachycardia. The appearance depends on whether single or multiple APs participate in ventricular activation during tachycardia. During atrial flutter or fibrillation in patients with WPW syndrome, antegrade conduction may occur via the AV node or APs. In this case, there might be no, incomplete, or maximal preexcitation. With maximal preexcitation, atrial flutter or fibrillation may be difficult to distinguish from polymorphic ventricular tachycardia; however, it may be better tolerated, and the R-R intervals are more irregular. Irregular R-R intervals with wide QRS tachycardia, with minimally or maximally preexcited beats (see Fig. 80-1), suggest atrial flutter or fibrillation as the mechanism for tachycardia.

Tachyarrhythmias with Ventricular Preexcitation

●

325

Primary ventricular tachycardia or fibrillation is rare in WPW syndrome (<1% of tachycardias).

The incidence of WPW syndrome is 1 to 3 per 1000 persons (60% to 70% male preponderance). However, the incidence is difficult to estimate, because the presence of ventricular preexcitation can be highly variable on the same day in the same individual. Indeed, APs may manifest (i.e., antegrade conduction over the AP during sinus rhythm) only at certain times in one’s lifetime. For example, the incidence of orthodromic AVRT in patients with WPW syndrome increases from 10% in adults younger than 40 years to 35% or more in those older than 60 years. The most common paroxysmal tachycardia with WPW syndrome is AVRT (70% to 80%), with orthodromic AVRT accounting for 90% to 95% of AVRT. Atrial fibrillation accounts for 15% to 30%, and atrial flutter for 5% of paroxysmal tachycardias in WPW syndrome. In the absence of coronary artery disease, heart failure, or other causes for arrhythmias, primary ventricular tachycardia is uncommon (<1% of tachyarrhythmias in patients with WPW syndrome). This is important to remember when confronted with a paroxysmal wide QRS tachycardia in a patient with WPW syndrome. For example, lidocaine to treat "presumed" ventricular tachycardia (see Fig. 80-1) might further reduce AP refractoriness and accelerate AP conduction, thereby increasing the rate of preexited tachycardia and possibly causing ventricular fibrillation. Any event that temporarily dissociates conduction via the AV node and APs can initiate paroxysmal AVRT. This could be an atrial, junctional, or ventricular extrasystole, asynchronous atrial or ventricular pacing, sinus tachycardia with rate-dependent AV block, or the use of certain drugs (e.g., theophylline, catecholamines, caffeine, illicit stimulants). Also, the risk of tachyarrhythmia is increased by stress, anxiety, fatigue, exercise, and alcohol abuse. No studies have shown that anesthetic drugs (except ketamine) facilitate the induction of tachyarrhythmias in patients with WPW syndrome. Indeed, many anesthetic drugs act directly or indirectly to increase AV node and AP refractoriness, so that AVRT is uncommon during anesthesia and surgery. However, orthodromic AVRT or preexcited tachyarrhythmias may occur in preoperative holding areas or postanesthesia care units in patients with WPW syndrome in response to stress, pain, anxiety, or some imbalance. Except for patients at increased risk for postoperative atrial tachyarrhythmias (e.g., cardiac surgery), anesthesia and surgery should have little effect on the incidence of perioperative atrial flutter or fibrillation in patients with WPW syndrome.

Implications Risk Assessment ●

●

●

●

Preexcitation can be highly variable (present or absent) over one’s lifetime. The most common paroxysmal tachycardia in WPW syndrome is orthodromic AVRT (70% to 80%); this is a narrow QRS tachycardia. Atrial flutter or fibrillation accounts for most other (20% to 25%) tachycardias in WPW syndrome. Ninety percent to 95% of AVRT in WPW syndrome is orthodromic tachycardia (narrow QRS), and 5% to 10% is antidromic tachycardia (wide QRS, preexcited tachycardia).

Due to the fast rates with orthodromic or antidromic AVRT (180 to 250 beats per minute—faster than AV node reentry PSVT) and the fact that the rate of atrial flutter or fibrillation may exceed 300 beats per minute, ischemia with early hemodynamic collapse and rapid deterioration to ventricular fibrillation is possible. Prompt intervention is thus required for most paroxysmal tachycardias in patients with WPW syndrome. Patients with WPW syndrome require a different approach to management, because AV conduction may occur exclusively or preferentially over the APs rather than over the AV node. A paradoxical acceleration of rate after the administration of

CARDIOTHORACIC & VASCULAR SURGERY

The QRS appearance with ventricular preexcitation may be confused with bundle branch block, ventricular hypertrophy, or even myocardial infarction. It varies, depending on the location of APs (left or right anterior, posterior septal, or free walls) and coexisting ECG abnormalities. APs may conduct antegradely (atria to ventricles) to cause δ waves or preexcited tachycardia, or retrogradely (ventricles to atria) to cause orthodromic AVRT, the mechanism for more than 40% of paroxysmal supraventricular tachycardias (PSVTs) in all patients, with or without WPW syndrome. Preexcited tachycardias include wide QRS antidromic AVRT and preexcited atrial flutter or fibrillation (see Fig. 80-1). Finally, APs may “manifest” (cause δ waves or preexcited tachycardia) at any time during one’s lifetime, but not at others. The ECG appearance with supraventricular tachyarrhythmias in WPW syndrome is as follows:

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cardiac glycosides, calcium channel blockers, or adenosine is due to both direct and indirect effects of these drugs, and they should generally be avoided in patients known to have WPW syndrome.

MANAGEMENT ●

●

Narrow QRS AVRT ● Vagal maneuvers ● Drugs that increase AV node or AP refractoriness, such as β-blockers, amiodarone, class IA or IC antiarrhythmics, or sotalol (a β-blocker possessing class III activity) ● Cardioversion, if hemodynamically unstable Wide QRS tachycardias: antidromic AVRT and preexcited atrial flutter or fibrillation ● Cardioversion with hemodynamic instability (equipment should be available at bedside when treating any wide QRS tachycardia with drugs in a patient with WPW syndrome) ● Intravenous amiodarone to terminate and prevent recurrences if not hemodynamically unstable ● A drug that increases AV node refractoriness (β-blocker) along with one that increases AP refractoriness (class IA or IC antiarrhythmic, amiodarone, sotalol)

For narrow QRS (orthodromic) AVRT, vagal maneuvers (e.g., carotid sinus massage) are attempted first, followed by drugs that increase AV node refractoriness (e.g., β-blockers, adenosine, and possibly verapamil if adenosine is ineffective). Verapamil will compound any hypotension that may ensue if AVRT fails to terminate, mandating immediate cardioversion. Early cardioversion is required for any AVRT that causes hemodynamic compromise (angina, heart failure, or hypotension). β-Blockers, diltiazem, or verapamil may help prevent recurrences. As a rule, however, patients with recurrent AVRT are best treated with catheter or surgical AP ablation. Although digitalis prolongs conduction time and refractoriness in the AV node, it has been reported to shorten refractoriness in the APs and speed the ventricular response in some patients with WPW syndrome and atrial fibrillation. Therefore, digitalis should not be used as a single drug in patients with WPW syndrome who are prone to or have atrial flutter or fibrillation. Further, because atrial fibrillation can develop during AVRT in many patients with WPW syndrome, this caveat probably applies to all patients with tachycardia and WPW syndrome. Instead, drugs that prolong refractoriness in the APs should be used, such as class IA and IC drugs. For preexcited (wide QRS) tachycardia with hemodynamic compromise, early cardioversion is required. Procainamide or flecainide (both increase AP refractoriness and reduce conduction over the APs) can be used if supine systolic blood pressure is >90 mm Hg. Either may reduce the ventricular rate and terminate preexcited tachycardia. Amiodarone increases AP and AV node refractoriness and may be effective. After direct-current cardioversion for hemodynamically unstable preexcited tachycardia, the previously mentioned drugs that increase AP refractoriness are used to prevent recurrences. Amiodarone increases AV node, atrial, and AP refractoriness and can be used when other drugs fail to prevent recurrences. However, AP ablation is definitive therapy.

With atrial flutter or fibrillation in a WPW patient, dangerous ventricular rates and rapid deterioration into ventricular fibrillation are of paramount concern. If cardioversion is not readily available, the immediate goal is to slow the ventricular rate. Drugs that increase refractoriness and conduction time in the AV node (β-blockers, verapamil, diltiazem), along with those that increase AP refractoriness (sotalol, procainamide, amiodarone), may temporarily reduce the ventricular rate while awaiting direct-current cardioversion.

PREVENTION ●

● ●

●

Provide stress-free circumstances (e.g., reassurance, sedation). Regional or general anesthesia (except ketamine) is safe. Risk of paroxysmal tachycardia is greatest during emergence from anesthesia and during the first few days following major or stressful surgery. Continue any antiarrhythmic drugs the patient may be taking.

For WPW patients with a history of tachyarrhythmias and facing surgery with a high risk of postoperative atrial fibrillation or flutter (e.g., cardiac surgery), consideration should be given to AP ablation before elective surgery. For all other surgery, the circumstances should be as stress free as possible. Reassurance, adequate preoperative sedation and analgesia, and local anesthesia for vascular access will help prevent attacks of paroxysmal tachycardia before surgery. Except for ketamine, it makes little difference which anesthetic agents or techniques are chosen, provided that the patient is adequately anesthetized for periods of maximal stress (e.g., airway or surgical manipulation). There is no literature suggesting that regional or general anesthesia is preferable for procedures that can be performed with either. The risk of paroxysmal tachyarrhythmias is likely highest during emergence and recovery from anesthesia due to sudden awareness and pain, and possibly during the first few postoperative days due to physiologic imbalance and increased stress (e.g., uncontrolled pain). Attention to minimizing these factors should help reduce the risk of paroxysmal tachycardias. Finally, as for any systemic condition requiring chronic medication, it is important that patients receiving antiarrhythmic drugs to prevent recurrences be given these medications up to and throughout the perioperative period. When there is any doubt, a cardiologist should be consulted.

Further Reading Atlee J: Perioperative cardiac dysrhythmias. Anesthesiology 86:1397-1424, 1997. Kastor J: Arrhythmias. Philadelphia, WB Saunders, 2000. Mangrum JM, DiMarco JP: Acute and chronic pharmacologic management of supraventricular tachyarrhythmias. In, Antman EM (ed): Cardiovascular Therapeutics. Philadelphia, WB Saunders, 2002, pp 423-444. Olgin JE, Zipes D: Specific arrhythmias: Diagnosis and treatment. In Braunwald E, Zipes DP, Libby P (eds): Heart Disease, 7th ed. Philadelphia, WB Saunders, 2005, pp 803-863. Thomas RG: Supraventricular tachycardia: Implications for the intensivist. Crit Care Med 28:129-135, 2000.

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John L. Atlee Case Synopsis A 48-year-old woman takes amitriptyline for depression and combined hydrochlorothiazide and triamterene for hypertension. In the recovery room following general anesthesia for abdominal hysterectomy, she has sudden-onset polymorphic ventricular tachycardia. This is poorly tolerated, does not respond to intravenous bolus lidocaine, and recurs following direct-current cardioversion. The corrected Q-T interval on her preoperative electrocardiogram (ECG) was 0.48 second, and her serum potassium concentration was 3.2 mEq/L.

PROBLEM ANALYSIS Definition and Causes

Recognition Figure 81–1 ■ Wide QRS, polymorphic tachycardia (PMVT) in lead II (contiguous tracings). The rate of tachycardia is about 250 beats per minute. Note that normal sinus beats preceding tachycardia in the upper tracing are associated with prolonged Q-T intervals. Therefore, this PMVT qualifies as torsades de pointes, which begins with an extrasystole during inscription of the T wave.

The upper limit of normal for the Q-Tc interval (Q-T interval corrected for heart rate using Bazett’s formula: Q-Tc = Q-T/[R - R1/2]) is 0.46 second for men and 0.47 second for women. In patients with either form of LQTS, there may be U-wave or T-wave abnormalities, such as notched or biphasic T waves or T-wave alternans. These reflect the heterogeneity 327

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The long QT syndrome (LQTS) is the association of polymorphic ventricular tachycardia (PMVT) with Q-T interval prolongation on the ECG (Fig. 81-1). Such PMVT is known as torsades de pointes (TdP). Without Q-T interval prolongation, often in association with an acute coronary syndrome, it is just termed PMVT. This distinction is important, because causes, management, and prevention differ. PMVT is discussed in Chapter 79, along with other perioperative tachyarrhythmias. LQTS has two forms: congenital and acquired. Although congenital LQTS was once thought to be caused by left-sided sympathetic imbalance, it is now known that LQTS is due to intrinsic (congenital) or acquired abnormalities of ionic currents that underlie cardiac repolarization. Prolongation of cardiac repolarization is critical to the generation of early afterdepolarizations (EADs), which in turn can generate spontaneous or triggered action potential upstrokes. If these propagate throughout the heart, ventricular extrasystoles preceded by normal sinus beats with long Q-T intervals are recorded on the surface ECG (see Fig. 81-1). Available evidence implicates EADs and triggered activity in the genesis of TdP. Notably, conditions that elicit EADs experimentally

(e.g., slow heart rate, hypokalemia, drugs that prolong the Q-T interval) are known to be associated with clinical TdP. Also, certain populations of cells within the ventricles (Purkinje fibers, midmyocardium or M cells) are more likely to develop EADs on drug challenge. EADs with heterogeneity in the development of prolonged cardiac action potentials result in a myocardial substrate vulnerable to reentry of excitation, the probable proximate cause for TdP. Genetic studies have now identified at least six separate genes that, if mutated, may cause congenital LQTS. Study of one of these genes (HERG), which encodes a potassium channel protein that regulates a major repolarizing current in cardiac fibers (IKr), has been especially informative with regard to drug-associated TdP. Mutations in HERG reduce IKr and thus prolong action potentials in individual cells, causing congenital LQTS. Further, virtually all drugs that prolong the Q-T interval and cause TdP also block IKr. Unfortunately, this finding is nonspecific, because many drugs that do not cause TdP also block IKr. It is also known that congenital LQTS can show incomplete penetrance; that is, family members with near-normal Q-T intervals may carry the same genetic mutations associated with LQTS that increase the risk of sudden death in their relatives. Available evidence also suggests that 5% to 10% of persons in whom TdP develops on exposure to drugs or other factors that prolong the Q-T interval harbor mutations associated with congenital LQTS and therefore can be viewed as having a subclinical form of the syndrome. This observation is consistent with the clinical concept of reduced repolarization reserve arising from an ion channel gene mutation that predisposes the carrier to drug or other forms of stress-induced TdP.

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of ventricular repolarization. ECG features of TdP with either form of LQTS are as follows (see Fig. 81-1): ●

●

●

QRS complexes that vary in amplitude and appear to twist around the isoelectric baseline Rate of tachycardia usually between 200 and 250 beats per minute Often associated with bradycardia or heart block (especially acquired LQTS)

Risk Assessment There are two forms of congenital LQTS. One (Jervell and Lange-Nielsen syndrome) is accompanied by deafness, and the other (Romano-Ward syndrome) is not. With either, there may be a history of syncope or sudden death due to TdP. With congenital LQTS, TdP is often precipitated by stress, sudden noise, or adrenergic stimulation. Adrenergic dependence may be explained as follows: (1) Mutant cardiac ion channels respond abnormally to adrenergic stimulation in a manner conducive to prolongation of repolarization; and (2) prolonged repolarization increases intracellular Ca2+ accumulation and the likelihood of EAD-triggered activity and TdP. In contrast, TdP with acquired LQTS is facilitated by bradycardia or sinus pauses (i.e., bradycardia- or pausedependent TdP). Syncope with congenital LQTS may initially be misdiagnosed as a seizure disorder, and ECGs may not be obtained. About 30% of patients are diagnosed during clinical evaluation for unexplained syncope or aborted sudden death. Another 60% are identified when family members of an individual with syncope or cardiac arrest (the proband) undergo ECG screening. The remaining 10% are identified by Q-T prolongation on routine ECG testing. What is the risk for syncope or cardiac arrest in individuals with congenital LQTS? Among 328 families with at least one affected family member, 50% of probands, 8% of affected family members, and 2% of unaffected family members experienced one or more cardiac events by 12 years of age. During 10 years of follow-up, 37% of probands, 5% of affected family members, and less than 1% of unaffected family members experienced a cardiac event. Among probands, event rates for syncope and sudden death were 5% and 0.9% per year, respectively. Risk factors for these included length of Q-T interval, history of cardiac event, and heart rate.

Implications Factors that predispose to Q-T interval prolongation and increase risk for TdP include baseline Q-T interval prolongation, high concentrations or rapid infusions of Q-T intervalprolonging drugs, older age, female sex, low left ventricular ejection fraction, congestive heart failure, left ventricular hypertrophy, digitalis, ischemia, bradycardia, hypokalemia or hypomagnesemia, and recent conversion from atrial flutter or fibrillation, especially with drugs that prolong the Q-T interval (e.g., dofetilide, ibutilide). Drugs that may prolong the Q-T interval and cause TdP are listed in Table 81-1. A more extensive list of such drugs can be found at http.//www.torsades.org.

Table 81–1

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Drugs that May Prolong the Q-T Interval and Cause Torsades de Pointes*

Antiarrhythmics

Anti-infectives

Amiodarone† Bepridil Disopyramide Dofetilide Ibutilide Procainamide Quinidine Sotalol

Azithromycin Ciprofloxacin Clarithromycin Clindamycin Erythromycin Fluconazole Gatifloxacin Halofantrine Levofloxacin Pentamidine Sparfloxacin Trimethoprim-sulfamethoxazole

Antidepressants Amitriptyline Desipramine Fluoxetine Imipramine Paroxetine Sertraline Venlafaxine

Antipsychotics Chlorpromazine Haloperidol Mesoridazine Olanzapine Pimozide Risperidone Thioridazine Ziprasidone

Antiemetics Domperidone Droperidol

Migraine Drugs Sumatriptan Zolmitriptan

Miscellaneous Arsenic trioxide Cisapride Isradipine Lidoflazine‡ Methadone Nicardipine

*For relative risk, consult http.//www.torsades.org. † Least likely of listed antiarrhythmic drugs to cause acquired long QT syndrome and torsades de pointes (<2%). ‡ Calcium channel blocker not marketed in the United States.

When an antiarrhythmic drug promotes arrhythmias, these are termed proarrhythmic events. For example, in patients with structural heart disease (especially ischemic cardiomyopathy), the class IC drugs flecainide or propafenone may cause proarrhythmia but not TdP; the proarrhythmia in this setting is incessant monomorphic ventricular tachycardia. Potent inhalational anesthetics also prolong the Q-T interval, but this prolongation is small and is not known to be associated with TdP. Bupivacaine and etidocaine, both of which avidly bind to cardiac sodium channels and have very slow offset kinetics, may be associated with malignant ventricular arrhythmias and severe myocardial depression (cardiotoxicity), but they are not listed as associated with Q-T interval prolongation or TdP (see http.//www. torsades.org). However, in an older study in pentobarbitalanesthetized dogs, both bupivacaine and etidocaine were associated with PMVT resembling TdP following ventricular burst pacing.1 In my view, it is prudent to avoid either local anesthetic in patients with congenital LQTS.

1 Burst pacing is a series of rapidly paced beats (often 10 to 15) intended to initiate or reproduce clinical atrial or ventricular tachyarrhythmias.

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MANAGEMENT Torsades de Pointes with Congenital Long QT Syndrome ●

●

●

●

Torsades de Pointes with Acquired Long QT Syndrome ●

●

●

●

If known, correct or remove the cause of Q-T interval prolongation. Intravenous magnesium sulfate is the initial drug of choice for TdP from an acquired cause. Also, consider administering intravenous potassium if the serum potassium concentration is low. Institute prophylactic atrial, dual-chamber, or ventricular pacing at 75 to 100 beats per minute for bradycardia or pause-dependent TdP. If pacing is not feasible or practical, cautious use of isoproterenol can achieve the same rates. If antiarrhythmic drugs are used to suppress TdP, they must be ones that do not prolong the Q-T interval (see Table 81-1).

2 A task force was commissioned by the American Society of Anesthesiologists (ASA) in 2003 to prepare a practice advisory for the management of patients with CRMD. This was approved by the ASA House of Delegates during the 2004 annual ASA meeting. See Further Reading.

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Polymorphic Ventricular Tachycardia Resembling Torsades de Pointes With PMVT resembling TdP and a normal Q-T interval, antiarrhythmic drugs used for ventricular tachycardia in the absence of Q-T interval prolongation (see Chapter 79) are used for treatment and to prevent recurrences. These include antiarrhythmic drugs that prolong the Q-T interval. With instability or tachycardia intolerance, immediate direct-current cardioversion is advised.

PREVENTION ●

●

●

●

●

With any Q-T interval prolongation, avoid drugs that might further prolong it. Provide stress-free perioperative circumstances, to the extent possible. Continue effective antiarrhythmic drugs (i.e., ones that do not cause Q-T interval prolongation). Consider prophylactic temporary pacing for bradycardia or pause-dependent tachycardia. If the patient is not receiving β-blockers (congenital LQTS), perioperative β-blockade is advised.

For patients with congenital LQTS facing anesthesia and surgery, it is important to provide circumstances that are as stress free as possible. Reassurance, adequate preoperative sedation and analgesia, and local anesthesia for vascular access can help prevent attacks of paroxysmal tachycardia before surgery. Except for ketamine and “sensitizing” inhalational anesthetics (halothane or enflurane, especially if preceded by thiopental induction), it makes little difference which anesthetic agents or techniques are used, provided the patient is adequately anesthetized during periods of maximal stress. There is no literature suggesting that either regional or general anesthesia is preferable for procedures that can be performed with either type. Risk for TdP may be increased during emergence and recovery from anesthesia and possibly for the first few days after major or stressful surgery. If a patient with congenital LQTS is receiving β-blockers, these should be continued throughout the perioperative period. Finally, consideration should be given to temporary perioperative pacing if the patient does not already have a functioning CRMD, and an external cardioverter-defibrillator should be available on site. For patients having elective surgery with ECG evidence of acquired LQTS (i.e., receiving drugs known to cause Q-T interval prolongation) and with a history of syncope, it is prudent to postpone surgery until the cause of syncope is explored thoroughly, and TdP should be high on the list of suspects. If TdP is identified as the cause of syncope, elective surgery should be delayed until the Q-T interval is normalized by withdrawal of the offending drugs. It is almost always possible to substitute another drug (or drugs) less likely to cause Q-T interval prolongation and TdP. Similar precautions apply when physiologic or nutritional imbalance causes acquired LQTS and TdP.

CARDIOTHORACIC & VASCULAR SURGERY

●

Patients with congenital LQTS and a history of syncope or aborted sudden death will likely have an implanted cardiac rhythm management device (CRMD2; see Chapter 97). The CRMD provides rate support (pacing) for bradycardia and internal cardioversion or defibrillation for TdP or ventricular fibrillation. For patients without CRMDs, institute maximally tolerated doses of β-blockers in those with a history of syncope, aborted sudden death, or complex ventricular tachyarrhythmias. If, despite maximally tolerated doses of β-blockers, the patient continues to experience complex ventricular arrhythmias or syncope and does not have a CRMD, consider left stellate ganglion block for patients requiring urgent or emergent surgery. If surgery is elective or can be postponed until after CRMD implantation, consider doing so. Treat TdP with class IB antiarrhythmics (e.g., lidocaine, mexiletine, diphenylhydantoin) and magnesium sulfate. Temporary pacing is advised for patients with bradycardia or pause-dependent TdP to reduce heterogeneity of repolarization with slow rates. Even in patients without profound bradycardia, temporary pacing at 75 to 100 beats per minute may provide rhythm stabilization. If temporary pacing is not feasible or practical, cautious use of isoproterenol to increase heart rate to 75 to 100 beats per minute may prevent recurrences of TdP.

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Further Reading Al-Khatib SM, LaPointe NMA, Califf RM: What clinicians should know about the QT interval. JAMA 289:2120-2127, 2003. American Society of Anesthesiologists Task Force on Perioperative Management of Patients with Cardiac Rhythm Management Devices: Practice advisory for the perioperative management of patients with cardiac rhythm management devices: pacemakers and implantable cardioverter-defibrillators: A report by the American Society of Anesthesiologists Task Force on Perioperative Management of Patients with Cardiac Rhythm Management Devices. Anesthesiology 103:186-198, 2005. Atlee JL: Management of perioperative dysrhythmias. Anesthesiology 86:1397-1424, 1997. Chaudhry G, Muqtada G, Haffagee CI: Antiarrhythmic agents and proarrhythmia. Crit Care Med 28:158-164, 2000.

El-Sherif N, Turitto G: The long QT syndrome and torsade de pointes. Pacing Clin Electrophysiol 22:91-110, 1999. Ho RT, Cullans DJ: Malignant ventricular arrhythmias. In Antman EM (ed): Cardiovascular Therapeutics. Philadelphia, WB Saunders, 2002, pp 477-501. Kasten GW: Amide local anesthetic alterations of effective refractory period temporal dispersion: Relationship to ventricular arrhythmias. Anesthesiology 65:61-66, 1986. Keating MT, Sanguinetti MC: Molecular and cellular mechanisms of cardiac arrhythmias. Cell 104:569-580, 2001. Olgin JE, Zipes DP: Specific arrhythmias: Diagnosis and treatment. In Braunwald E, Zipes DP, Libby P (eds): Heart Disease, 7th ed. Philadelphia, WB Saunders, 2001, pp 815-889. Roden DM: Drug-induced prolongation of the QT interval. N Engl J Med 350:1013-1022, 2004.

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Bradyarrhythmias Paul B. Zanaboni and Charles B. Hantler Case Synopsis During an open abdominal aortic aneurysm repair, a 71-year-old man suddenly becomes profoundly hypotensive following acute blood loss. The mean arterial blood pressure is 40 mm Hg, and the electrocardiogram (ECG) shows a wide complex rhythm of 35 beats per minute. The patient’s preoperative ECG showed a first degree heart block with a bifascicular bundle branch block pattern.

PROBLEM ANALYSIS Definition

Table 82–1

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Causes of Bradyarrhythmias

Failure of Impulse Formation Sinus bradycardia Slow sinus node automatic rate Sinoatrial conduction block Carotid sinus hypersensitivity Neurocardiogenic syncope (with decrease in sympathetic outflow)

Subsidiary Atrial Pacemakers. These pacemakers are found along the sulcus (crista) terminalis and around the coronary sinus orifice. Subsidiary atrial pacemaker rhythms are identified by flattened, biphasic, or negative P waves (e.g., wandering atrial pacemaker) in leads with normally upright P waves (leads II, III, and aVF). Both lower and upper rate cutoffs for subsidiary atrial pacemakers appear to be similar to those for the SA node. The P-R interval may be the same or slightly less than that of the SA node (<0.10 second).

Failure of Impulse Conduction Atrioventricular node heart block First degree Second degree Type I Type II Third degree

1 Fast-response fibers have higher action potential maximum amplitudes and overshoots and faster rates of conduction than do SA or AV node cells. They also have more prominent early rapid (phase 1) repolarization. 2 Advanced second degree AV heart block is defined as two or more successive, blocked P waves, but with some that are conducted. With third degree (complete) AV heart block, no P waves are conducted to the ventricles.

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Bradyarrhythmias include cardiac rhythm abnormalities associated with a slow ventricular depolarization rate (<60 beats per minute). Such rhythm disturbances are clinically significant when associated with abnormalities of vital organ function, such as central nervous system impairment (syncope, altered mental status), postural hypotension, heart failure, or other major organ system dysfunction (especially renal, hepatic, or gastrointestinal). Bradyarrhythmias are caused by failure of impulse formation, failure of impulse conduction, or both (Table 82-1). Anatomic structures involved in the generation and propagation of electrical impulses within the heart (i.e., its specialized conduction system) are depicted in Figure 82-1. The maximum diastolic potential of the sinoatrial (SA) node is between −50 and −60 mV. When maximum diastolic potential is reached, SA node cells immediately begin to depolarize. Spontaneous phase 4 depolarization is due to an imbalance between slowly decaying delayed rectifier (an outward potassium current) and slowly recovering inward calcium currents. The latter cause the cell interior to become progressively less negative with respect to the exterior. A pacemaker current is involved only when the cell interior is less negative than –50 mV. In SA node cells, this current is probably subserved by L-type calcium channels. However, T-type current may be activated during the latter half of spontaneous

phase 4 depolarization (i.e., normal automaticity). Cells of the SA node depolarize to +10 mV, their maximum action potential overshoot. Thus, maximum amplitudes are 60 to 70 mV. Once these are reached, SA node cells repolarize. During early repolarization, especially in atrial or ventricular muscle or Purkinje fibers (i.e.,“fast-response” fibers),1 sodium “window” and calcium currents contribute, along with several different potassium repolarizing (outward) currents. Regardless, in all fiber types, net ionic movements during repolarization favor net outward movement of positive charges (mainly potassium), in addition to a variable contribution of reduced inward calcium and sodium current. During the action potential upstroke (depolarization), net ionic movements favor the net inward movement of positive charges. These are carried mainly by sodium and calcium, but there is also reduced outward movement of potassium. The normal SA firing rate is 60 to 100 beats per minute. Drugs, neural input (both sympathetic and parasympathetic), temperature, and hormones influence the rate of sinus node depolarization by affecting either the rate of spontaneous (phase 4) depolarization or the threshold for a regenerative (self-sufficient) action potential upstroke. In addition to sinus bradycardia (sinus rhythm with a rate <60 beats per minute; Fig. 82-2), there may be bradycardic (slow) escape rhythms arising in lower pacemakers. Such escape pacemaker rhythms (i.e., originating below the atrioventricular [AV] junction) are often associated with advanced second and third degree AV heart block.2

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LA

Sinoatrial (SA) node Subsidiary atrial pacemakers AV junction

Figure 82–1 ■ Anatomic structures involved in the generation and propagation of electrical impulses within the heart (i.e., its specialized conduction system). LA, left atrium, LV, left ventricle; RA, right atrium; RV, right ventricle.

RA

Atrioventricular (AV) node His bundle

Interventricular septum RV

LV

Purkinje fibers

Right bundle branch

Left bundle branch

Atrioventricular Junctional Pacemakers. With AV junctional bradycardia, there may be no apparent P waves, or they may be inverted in ECG leads with normally upright P waves during sinus rhythm. Associated, inverted P (retrograde) waves may occur just before the QRS complex (P-R interval <0.10 second) or, less commonly, after the QRS complex. Purkinje Fibers. Typically (e.g., during escape rhythms associated with advanced second degree or complete [third degree] AV heart block), escape rates are less than 50 beats per minute (may be lower in adults). Commonly, there are no associated P waves; however, there may be dissociated, upright P waves. These originate in the SA node or subsidiary atrial pacemakers but are blocked and bear no relationship to QRS complexes. However, even with advanced second or third degree AV heart block, retrograde (ventriculoatrial) conduction may be intact, so that associated P waves may be possible. If so, these will be inverted in leads with normally positive P waves.3 Ventricular Muscle Fibers. Rarely, ventricular fibers exhibit automaticity. When this occurs, it is due to loss of resting membrane potential. The partial depolarization of these fibers may be the result of disease, usually in association with myocardial ischemia or infarction. Ventricular rates are generally less than 40 beats per minute, and retrograde

3 During advanced second or third degree AV heart block, the sinus node beats independently of the ventricles, and its rate is faster than that of the pacemaker controlling the ventricles. This is because sinus nodes are under autonomic control, blood pressure is lower with ventricular escape rhythm, and there is a baroreflex-mediated increase in sympathetic efferent activity.

P waves are uncommon. Not uncommonly, the atria beat independently of the ventricles (AV dissociation). Following SA node depolarization, the impulse is conducted via specialized atrial conducting tissue. SA conduction block is failure of conduction within the atrial tissue; it is characterized by the absence of P waves on the ECG. When this occurs (or the SA node fails to depolarize), lower pacemaker fibers must assume control of the ventricles. Finally, as alluded to earlier, the SA node is most influenced by altered parasympathetic or sympathetic (autonomic) control. Often, this is mediated by baroreceptors and cardiac mechanoreceptors.

Recognition ECG features of sinus bradycardia and lower pacemaker escape rhythms were already discussed. In addition, bradycardia may also be due to AV conduction delay or block. First degree AV block is simply delayed AV impulse transmission (P-R interval >0.12 second), with no dropped ventricular beats (QRS complexes). Second degree AV block is block of

Figure 82–2 ■ In sinus bradycardia, there is a regular relationship between the P waves and QRS complexes. The rate is less than 60 beats per minute.

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Figure 82–3 ■ With Mobitz type I (Wenckebach) second degree atrioventricular (AV) block, there is progressive P-R interval prolongation before blocked P waves (i.e., the fourth P wave). As with first degree AV block, the P-R interval is greater than 0.12 second, but there are no dropped ventricular beats. In this example, block would be variable (not shown) if the ratio of conducted to nonconducted atrial beats varied (e.g., 3:2, 4:3), as commonly occurs with Mobitz type I second degree AV block. Block usually occurs within the AV node or at its margins.

Risk Assessment Bradyarrhythmias can arise from either intrinsic myocardial causes or external influences, such as increased vagal tone or electrolyte imbalance. Implanted artificial pacemakers (see Chapter 97) are indicated for patients with symptomatic bradyarrhythmias (e.g., easy fatigability, near or true syncope) without reversible causes. GENERAL ANESTHESIA

AND

SURGERY

Bradyarrhythmias that occur during general anesthesia can have many causes. Deep inhalation anesthesia (especially with older volatile agents) and opiates are well-known

Figure 82–4 ■ With Mobitz type II second degree atrioventricular (AV) block, there may be no P-R interval variability (fixed block), or block may be variable (as shown) or intermittent. If fixed, block is constant at some fixed ratio of atrial to conducted beats (e.g., 2:1, 3:1, 4:1). If variable, block varies on a recurring basis (e.g., 2:1 and 3:1). If block is intermittent, periods of normal AV conduction are interrupted by occasional dropped beats, but not on a recurring basis. Type II second degree AV block most commonly occurs at or below the bundle of His.

Bradyarrhythmias

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Figure 82–5 ■ With third degree atrioventricular (AV) heart block (almost always at or below the bundle of His), P waves are independent of the QRS complexes (i.e., complete AV dissociation, as with ventricularorigin brady- or tachyarrhythmias). With third degree AV heart block, the QRS complexes can be narrow (as shown) if the pacemaker that controls the ventricles is within or above the bifurcation of the bundle of His, or widened if the pacemaker controlling the ventricles is more distal.

causes of significant bradycardia during anesthesia. Surgical stimulation may be associated with a relative increase in vagal tone, leading to slowing of SA node automaticity, AV node conduction, or both. Well-known examples are the oculocardiac reflex, peritoneal stimulation, and stimulation of the carotid body; such responses terminate when the stimulation is discontinued. Although both drug- and surgery-induced bradyarrhythmias usually respond to drugs—either anticholinergics (atropine, glycopyrrolate) or sympathomimetics (epinephrine, isoproterenol)—if temporary transvenous or pacing wires are available (e.g., during cardiac surgery), pacing is always preferable to drugs. Drugs have the potential to cause excessive tachycardia, are not easily reversed, and may cause arrhythmias. If AV conduction is intact and transesophageal pacing is available, it is preferred over drugs as treatment for sinus bradycardia and AV junctional rhythms. Drug-resistant, clinically significant bradyarrhythmias should always be treated with external (transesophageal or transcutaneous) or internal (transvenous or epicardial) pacing to improve hemodynamics. NEURAXIAL BLOCKADE Neuraxial blockade, involving the high thoracic level, may lead to vagal dominance (bradycardia) by blocking sympathetic outflow from the cardiac accelerator fibers that originate in the upper thoracic spinal cord. This bradycardia usually responds well to treatment with anticholinergic agents. DRUG-INDUCED BRADYCARDIA Many patients undergoing surgery are taking medications that slow the sinus heart rate or AV node conduction (e.g., β-blockers, nondihydropyridine calcium channel blockers). The combination of these medications, anesthesia, and surgery may result in significant bradyarrhythmias. Again, bradycardia is usually reversed with either anticholinergic or sympathomimetic agents. However, caution is advised, because excess tachycardia can put patients with ischemic heart disease or arrhythmias at further risk. In the case of elective surgery, one should consider a preoperative dose reduction of any drugs that may cause untoward bradycardia due to reduced heart rate or AV conduction block. METABOLIC CAUSES Metabolic conditions may cause significant preoperative or intraoperative bradyarrhythmias. These include hypothermia (now rare with the widespread use of forced air warming blankets), endocrine disorders, and electrolyte abnormalities.

CARDIOTHORACIC & VASCULAR SURGERY

some impulses between the atria and ventricles. It is further subdivided into Mobitz type I, Mobitz type II, and advanced second degree AV block. With Mobitz type I (Wenckebach) AV block (Fig. 82-3), some but not all atrial beats are blocked in a recurring pattern, with progressively prolonged P-R intervals before dropped beats. The ratio of conducted to dropped beats may be fixed (e.g., 3:2, 4:3) or variable (e.g., 4:3 and 3:2). With Mobitz type II block, there are no progressively prolonged P-R intervals before dropped beats, but the block may also be variable (Fig. 82-4). With advanced second degree AV block, there are two or more dropped beats between conducted beats; again, the ratio between the two can vary. Finally, with third degree (complete) AV block, there are no conducted atrial beats (Fig. 82-5). The atria and ventricles are controlled by different pacemakers, and the QRS complexes may be narrow (if the pacemaker that controls the ventricles is above the bifurcation of the bundle of His) or widened (if below the bifurcation). Thus, in third degree AV heart block, there is complete AV dissociation (independent beating of the atria and ventricles).

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With severe hypothermia, there may be sinus bradycardia or escape rhythms, with or without associated Osborne or J waves.4 Patients with hypothyroidism and Addison’s disease often have preoperative bradycardia that may become more clinically significant during surgery and anesthesia due to effects of anesthetic drugs. Hyperkalemia (which hyperpolarizes cells of the SA and AV nodes) can also cause significant sinus bradycardia or slow AV node conduction. The ECG may show a slow, wide-complex rhythm. Severe hyperkalemia can result in AV heart block or asystole. Hypermagnesemia may also cause sinus bradycardia by reducing the slow, inward, depolarizing calcium current. Both hyperkalemia and hypermagnesemia should be corrected before elective surgery to prevent bradyarrhythmias.

Implications Because cardiac output is often reduced with bradyarrhythmias, especially with impaired or loss of atrial transport function (e.g., slow atrial fibrillation or escape rhythms), bradyarrhythmias may be poorly tolerated during anesthesia. Moreover, any vasodilatation, hypovolemia, or myocardial depression is even more poorly tolerated with significant bradycardia. For example, the normal physiologic response to acute hypotension is impaired if there can be no increase in heart rate or cardiac output to maintain tissue perfusion. It is important to remember that cardiac output is the product of both heart rate and stroke volume. Whereas stroke volume is altered by contractility and preload, in addition to the effects of increased heart rate,5 cardiac output is reduced by bradycardia and bradyarrhythmias, especially if the latter are associated with loss of atrial transport function. Properly timed atrial contractions are critical for left ventricular filling in patients with impaired ventricular relaxation (diastolic dysfunction). These include aged patients and those with chronic hypertension, aortic stenosis, or hypertrophic cardiomyopathy. Patients with impaired ventricular systolic function may also tolerate slow heart rates poorly. In this case, stroke volume is reduced by increased end-systolic volume; forward flow must be increased by higher heart rates. Valvular regurgitation, such as mitral regurgitation, is more severe at slower heart rates, possibly due to an increase in mitral annular size.

(e.g., ephedrine, epinephrine, isoproterenol) is considered. If this is ineffective, or if sinus bradycardia results in severe hemodynamic compromise or collapse, artificial pacing (transcutaneous, transvenous, or transesophageal) should be instituted. ATRIOVENTRICULAR JUNCTIONAL ESCAPE RHYTHM AV junctional rhythms, whether bradycardia or tachycardia (rate >100 beats per minute), abolish any atrial transport function and may also be associated with tricuspid or mitral regurgitation. In patients dependent on atrial transport function (those with severe diastolic dysfunction), restoration of sinus rhythm is highly desirable. Anticholinergic or sympathomimetics are often ineffective or only increase the rate of AV junctional rhythm. Use of a β-adrenergic blocker (e.g., esmolol) may restore dominance of the SA node during general anesthesia. However, use of a drug that may exacerbate bradycardia is risky and should be attempted only when the AV junctional rhythm is greater than 60 beats per minute. Other measures include changing to an intravenous anesthetic that may have less impact on the SA node compared with volatile anesthetics. Transesophageal atrial pacing restores atrial transport function and improve preload. SICK SINUS SYNDROME Sick sinus syndrome includes sinus bradycardia, sinus arrest, and chronotropic incompetence; it also may be associated with supraventricular tachyarrhythmias (bradycardiatachycardia, or “brady-tachy” syndrome), the most common of which is atrial flutter or fibrillation. Regardless, treatment for bradycardia is as described earlier for sinus bradycardia. Management of associated tachycardia is discussed in Chapter 79. Always keep in mind, especially in patients with sick sinus syndrome and a history of tachyarrhythmias, that excessive tachycardia or tachyarrhythmias are a distinct possibility with any positive chronotropic treatment. Often, patients with symptomatic sick sinus syndrome have had dual-chamber pacemakers implanted, as well as drug treatment to prevent tachyarrhythmias and to slow AV node conduction.

Failure of Impulse Propagation FIRST DEGREE ATRIOVENTRICULAR BLOCK

MANAGEMENT Failure of Impulse Formation SINUS BRADYCARDIA Clinically significant sinus bradycardia is treated according to the severity of any physiologic impairment. Conservative management includes removing or reducing the dose of drugs known to inhibit the SA node or removing the surgical stimulus (e.g., oculocardiac reflex). If this is not effective or possible, use of anticholinergics (e.g., atropine) or sympathomimetics 4 Osborne or J waves consist of prominent notching of the terminal QRS complex with ST segment elevation. 5 Except for the treppe or Bowditch effect, whereby an increase in heart rate increases cardiac contractile force.

No treatment is indicated for first degree AV block, unless it is associated with symptomatic or hemodynamically significant bradycardia or escape rhythms. There are, however, rare exceptions. For example, after cardiac surgery, shorter P-R intervals may improve diastolic filling (preload), especially after hypertrophic cardiomyopathy repair. Thus, dual-chamber sequential (AV) pacing with surgically placed temporary pacing wires to shorten the P-R interval may result in improved ventricular filling. Also, if hemodynamic insufficiency is due to P-R interval prolongation, both perioperative and long-term (if symptomatic) dual-chamber pacing should be considered. SECOND DEGREE ATRIOVENTRICULAR BLOCK Mobitz type I AV block is usually due to impaired AV node conduction. It rarely progresses to complete heart block.

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have published guidelines for the implantation of permanent pacemakers (see “Further Reading”). Indications for temporary perioperative pacing are less well established. However, temporary pacing should be strongly considered for patients without an implanted cardiac rhythm management device and with debilitating symptoms or documented disadvantageous bradycardia, escape rhythms, or AV heart block and facing intermediate- or high-risk surgery.

THIRD DEGREE ATRIOVENTRICULAR BLOCK

Further Reading

Some children with congenital complete AV heart block are asymptomatic, and permanent pacemaker implantation can be postponed until adolescence. However, pacing is indicated for all adult patients with third degree block unless it has a reversible cause (e.g., digoxin intoxication, β-blocker overdose).

Atlee JL: Perioperative cardiac arrhythmias: Diagnosis and management. Anesthesiology 86:1397-1423, 1997. Atlee JL, Pattison CZ, Mathews EL, et al: Transesophageal atrial pacing for intraoperative sinus bradycardia or AV junctional rhythm: Feasibility as prophylaxis in 200 anesthetized adults and hemodynamic effects of treatment. J Cardiothorac Vasc Anesth 7:436-441, 1993. De Costa D, Brady WJ, Edhouse J: Bradycardias and atrioventricular conduction block. BMJ 324:535-538, 2002. Goodacre S, McLeod K: ABC of clinical electrocardiography. BMJ 324: 1382-1385, 2002. Gregoratos G, Abrams J, Epstein AE, et al: ACC/AHA/NASPE 2002 guideline update for implantation of cardiac pacemakers and antiarrhythmia devices: A report of the American College of Cardiology/ American Heart Association Task Force on Practice Guidelines (ACC/AHA/NASPE Committee on Pacemaker Implantation). Circulation 106:2145-2161, 2002. Zimetbaum PJ, Josephson ME: Use of the electrocardiogram in acute myocardial infarction. N Engl J Med 348:933-940, 2003.

PREVENTION Patients undergoing surgery have similar indications for permanent pacemaker placement as the general population. The American Heart Association, American College of Cardiology, and North American Society for Pacing and Cardiac Electrophysiology (now the Heart Rhythm Society)

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Pacing (temporary or permanent) is indicated only when any associated bradycardia is hemodynamically significant or severely symptomatic. Mobitz type II AV block can be treated conservatively in the absence of preoperative symptoms. It is likely due to intra- or infra-Hisian disease and frequently progresses to advanced second or third degree heart block. Symptomatic, hemodynamically disadvantageous bradycardia is an indication for temporary pacing (surgery) and, if persistent, permanent pacing.

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Mohammed Minhaj Case Synopsis A 62-year-old man underwent coronary artery bypass graft surgery via a median sternotomy, with harvesting of the internal mammary artery. During a routine postoperative visit, the patient complains of a “tingling” sensation in the fourth and fifth fingers of his left hand. On physical examination, he has decreased sensation over those fingers, with minimally reduced muscular function in the ulnar distribution. A neurologic consultation is obtained, and the patient is diagnosed with a brachial plexus injury.

PROBLEM ANALYSIS Definition Nerve injuries are a well-recognized complication of anesthesia, causing substantial morbidity for patients and liability for anesthesiologists. Despite their prominence in closed claims analyses (16% of injuries in the most recent American Society of Anesthesiologists [ASA] Closed Claims Project database), no single cause has been clearly delineated. Although the proportion of nerve injuries has remained relatively constant over the last two closed claims surveys, there has been a relative decrease in the proportion of ulnar nerve-related injuries. The reason for this decrease is probably more stringent attention to proper positioning, but given the multifactorial nature of this complication, it is unlikely that simple improvements in positioning can entirely eradicate this problem in the future. The ASA closed claims study found that anesthesia care was appropriate in 66% of all nerve injury claims, reinforcing the notion that multiple factors likely contribute to such complications. These factors include the following: ● ●

●

Ischemia to the brachial plexus Direct trauma (e.g., during central venous cannulation of the internal jugular vein via the needle or postprocedural hematoma) Needle injury, metabolic insults, and idiopathic injuries

The clinical syndrome of idiopathic brachial neuritis has been reported in a wide range of patient populations, including obstetric, arthritic, and noncardiac surgical patients. However, injuries to the ulnar nerve and brachial plexus occur more frequently during cardiac than noncardiac surgery. For example, the incidence of nerve injury in noncardiac surgery ranged from 0.02% to 0.06%, whereas that in cardiac surgery ranged from 2% to 38%. 336

Recognition Most often, nerve injuries that occur during cardiac surgery are identified postoperatively. Intraoperative identification of injury is limited, given that most patients are under general anesthesia (85% of all ulnar nerve injuries in ASA closed claims analyses were associated with general anesthesia). Further, there is no intraoperative monitoring that reliably detects nerve injury. Although some investigators have attempted to identify intraoperative signs that may predict postoperative dysfunction, these have not proved very reliable. Somatosensory evoked potentials (SEPs) reportedly allow the early identification of nerve injury, especially when harvesting of the internal mammary artery is involved. Such harvesting is typically associated with greater chest retraction, potentially producing excessive stretch on the brachial plexus. Transient intraoperative changes in SEPs obtained during venous cannulation have not reliably predicted postoperative sequelae, although SEPs obtained at the conclusion of surgery may do so. In general, nerve injury in cardiac surgical patients differs from that in noncardiac patients. As mentioned earlier, such injuries are more common in the former. Cardiac patients also typically demonstrate sensory deficits in the lower roots of the brachial plexus (C8-T1), compared with more upper and middle nerve root distributions in noncardiac surgical patients. Further, sensory deficits are typically more prominent than motor deficits in cardiac surgical patients; the opposite is true in noncardiac patients. Finally, symptoms are usually present in the early postoperative period in both groups of patients.

Risk Assessment Most peripheral nerve injuries are attributed to ischemia of the intraneural vasculature. The interruption of adequate oxygen and nutrient delivery leads to injury and postoperative deficits. Such ischemia is generally thought to be a result

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Table 83–1

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Risk Factors for Perioperative Nerve Injury during Cardiac Surgery

Sternal retraction Positioning of sternal retractors Asymmetrical sternal retraction Internal mammary artery harvesting Duration of surgery Duration of cardiopulmonary bypass Hypothermia Penetration injury due to first rib fracture during sternotomy Injury during cannulation of internal jugular vein Direct, needle-related injury Hematoma formation resulting in compression of brachial plexus

Table 83–2

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Preexisting Anatomic and Pathophysiologic Risk Factors for Perioperative Nerve Injury

Diabetes Neuropathy Alcoholism Herpes zoster Polyarteritis nodosa Peripheral vascular disease Coagulopathies Hypertension Hypothyroidism Cervical rib Deformities in shoulder or derivation of brachial plexus

Implications Most cardiac patients with postoperative brachial plexus injury recover quickly. It has been estimated that more than 90% of such patients recover substantially within 1 month of surgery. In one study, 94% of patients were asymptomatic by the time of hospital discharge. Subsequent referral to a hand clinic for continued symptoms has been reported in only 0.2% of all cardiac surgical patients. Even when recovery is prolonged, most patients recover fully within a year, and it is rare to have a patient with incomplete recovery. Coexisting diseases such as diabetes have been implicated in more prolonged or incomplete recoveries.

MANAGEMENT Because most cases resolve quickly and spontaneously, supportive management is often sufficient. Splints and physical therapy have been reported to be beneficial, even immediately postoperatively. These measures help prevent muscle atrophy and provide support until symptoms resolve. Only if symptoms are prolonged (>3 months) should more comprehensive interventions be considered. Electrophysiologic studies are usually performed only if symptoms persist and spontaneous recovery is prolonged. Electromyography may be performed to evaluate signs and symptoms of denervation during rest, reinnervation of motor units during weak effort, and loss of motor units during maximal effort. In one clinical study in which bilateral nerve conduction studies were performed in patients who experienced perioperative ulnar neuropathy, 12 of 14 patients with unilateral symptoms had abnormal nerve conduction studies on the contralateral side. These findings suggest that preexisting neuropathies may manifest during the perioperative period. Surgical intervention is usually limited to conditions that involve anatomic abnormalities, such as thoracic outlet syndrome, fracture of the first rib resulting in penetration of the brachial plexus, or compression by bony prominences.

PREVENTION Prevention of perioperative nerve injuries is difficult, given that the mechanisms of injury are incompletely understood.

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of stretching or compression of the plexus caused by patient malpositioning. There is, however, some debate regarding “appropriate” positioning during cardiac surgery. One study reported a higher rate of nerve injury in patients whose arms were at their sides compared with those whose arms were abducted (23.5% versus 14.5%), although this difference was not statistically significant. Some authorities advocate a “hands-up” position, with the arms abducted 90 degrees but flexed at the shoulder by 15 to 20 degrees, and the forearm flexed at the elbow by 90 to 110 degrees to reduce stretch on the brachial plexus and the associated risk of nerve injury. However, no data exist to show that this significantly reduces brachial plexus injuries when compared with the more traditional practice of tucking patients’ arms at their sides and padding the elbows. Because patient positioning is a concern in all surgeries, there has been considerable debate about ideal positioning. Also, because the incidence of postoperative nerve injury is higher with cardiac surgery than noncardiac surgery, investigators have searched for mechanisms (other than ischemia) specific to cardiac surgery. Multiple mechanisms have been postulated by various authors (Table 83-1); however, excessive sternal retraction is the most commonly accepted risk factor for brachial plexus injury. Understanding the anatomy of the brachial plexus and the effects of sternal retraction on it may help determine causative factors for perioperative injury. The nerve roots of the brachial plexus are fixed at their points of exit from the vertebral canal and are distally anchored to the axillary fascia. Moreover, the plexus lies close to many bony structures, such as the head of the humerus, first rib, clavicle, and coracoid process, making it vulnerable to compression at these sites. Autopsy studies have shown that excessive spread of the sternal retractor pushes the clavicles into the retroclavicular space and rotates the first rib upward. These movements may result in stretch of the brachial plexus. Finally, some investigators have postulated that fracture of the first rib during sternal retraction may cause direct penetration injury to the plexus. In addition, preexisting anatomic and pathophysiologic disease processes have been reported as risk factors not only for brachial plexus injury but also for delayed postoperative recovery (Table 83-2).

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Although proper patient positioning, along with adequate padding of pressure points and avoidance of brachial plexus stretch, may not prevent all nerve injuries, the importance of such measures cannot be overemphasized. A thorough understanding of the anatomy involved and the potential mechanisms of injury enables anesthesiologists to reduce such postoperative complications. In addition to awareness of the specific risk factors postulated to contribute to postoperative nerve injury in cardiac surgery, most clinicians advocate the following: ●

●

●

●

Proper vigilance with regard to patient positioning and position changes Minimal sternal retraction, especially during harvesting of the internal mammary artery, and placement of sternal retractors as caudally as possible Maintenance of a neutral (midline) head position to minimize tension on the brachial plexus produced by head rotation Avoidance of asymmetrical retraction when possible (perform true median sternotomy)

Further Reading Alvine FG, Schurrer ME: Postoperative ulnar-nerve palsy: Are there predisposing factors? J Bone Joint Surg Am 69:255-259, 1987. Ben-David B, Stahl S: Prognosis of intraoperative brachial plexus injury: A review of 22 cases. Br J Anaesth 79:440-445, 1997.

Cheney FW, Domino KB, Caplan RA, Posner KL: Nerve injury associated with anesthesia: A closed claims analysis. Anesthesiology 90:1062-1069, 1999. Dumitru D, Liles RA: Postpartum idiopathic brachial neuritis. Obstet Gynecol 73:473-475, 1989. Eggers KA, Asai T: Postoperative brachial plexus neuropathy after total knee replacement under spinal anaesthesia. Br J Anaesth 75:642-644, 1995. Hanson MR, Breuer AC, Furlan AJ, et al: Mechanism and frequency of brachial plexus injury in open-heart surgery: A prospective analysis. Ann Thorac Surg 36:675-679, 1983. Hickey C, Gugino LD, Aglio LS, et al: Intraoperative somatosensory evoked potential monitoring predicts peripheral nerve injury during cardiac surgery. Anesthesiology 78:29-35, 1993. Jellish WS, Martucci J, Blakeman B, Hudson E: Somatosensory evoked potential monitoring of the brachial plexus to predict nerve injury during internal mammary artery harvest: Intraoperative comparisons of the Rultract and Pittman sternal retractors. J Cardiothorac Vasc Anesth 8:398-403, 1994. Kroll DA, Caplan RA, Posner K, et al: Nerve injury associated with anesthesia. Anesthesiology 73:202-207, 1990. Lederman RJ, Breuer AC, Hanson MR, et al: Peripheral nervous system complications of coronary artery bypass graft surgery. Ann Neurol 12:297-301, 1982. Tomlinson DL, Hirsch IA, Kodali SV, Slogoff S: Protecting the brachial plexus during median sternotomy. J Thorac Cardiovasc Surg 94: 297-301, 1987. Vahl CF, Carl I, Muller-Vahl H, Struck E: Brachial plexus injury after cardiac surgery: The role of internal mammary artery preparation: A prospective study on 1000 consecutive patients. J Thorac Cardiovasc Surg 102:724-729, 1991. Vander Salm TJ, Cereda JM, Cutler BS: Brachial plexus injury following median sternotomy. J Thorac Cardiovasc Surg 80:447-452, 1980. Vander Salm TJ, Cutler BS, Okike ON: Brachial plexus injury following median sternotomy. Part II. J Thorac Cardiovasc Surg 83:914-917, 1982.

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David Muzic and Mark A. Chaney Case Synopsis A 68-year-old man with a history of non-insulin-dependent diabetes mellitus, hypertension, alcohol abuse, and heavy smoking is scheduled for four-vessel off-pump coronary artery bypass grafting (CABG). After uneventful induction of anesthesia, severe aortic atheromatous disease is observed via transesophageal echocardiography (TEE) in the descending aorta, and the aortic root is not well visualized. Epiaortic ultrasound scanning is performed to ascertain the best location for a planned radial artery graft anastomosis. The patient’s biventricular function is adequate, and the CABG is performed successfully. The postoperative course is complicated, however, by significant short-term memory loss, and the patient is discharged first to a skilled nursing facility and eventually to an assisted-living home.

Definition Central neurologic injury following CABG is much more common than was previously recognized. Such impairment was formerly observed primarily as stroke, which currently has a perioperative incidence of 1% to 5% for CABG surgery. However, studies of postoperative neuropsychological function using rigorous testing strategies have shown neurocognitive dysfunction in 50% to 90% of patients at discharge and in 20% to 40% throughout the first year after CABG. Accordingly, postoperative central nervous system (CNS) impairment is often divided into two types of adverse outcomes, along these same lines: ●

●

Type I outcomes due to macroembolic focal injury, associated with stupor and coma Type II outcomes due to macroembolic global injury, associated with deterioration of intellectual function or memory

The focal neurologic deficits representing overt stroke (type I outcomes) are caused mainly by macroemboli of atheroma debris, thrombus, and air. Current data suggest that microemboli of similar materials and debris such as bone wax, marrow, and lipid particles from retransfused cardiotomy suction blood are major contributors to the more diffuse (and much more common) injuries associated with type II outcomes. The systemic inflammatory response of surgical stress and blood contact with the cardiopulmonary bypass (CPB) circuit are believed to contribute importantly to type II injury. Other causes of both type I and type II CNS injury include cerebral hyperthermia during rewarming, arterial hypotension, and neurohormonal derangements.

A recent randomized, controlled trial comparing type II neurocognitive outcomes in patients undergoing conventional CABG with and without CPB showed a nonsignificant trend toward a benefit of off-pump CABG at 3 and 12 months postoperatively. The incidence of type II outcomes was 29% versus 21% at 3 months (P = 0.15) and 33% versus 31% at 12 months (P = 0.69) for conventional CABG versus off-pump CABG, respectively. Importantly, these findings suggest that type II neurologic outcomes are more common than previously thought and that rigorous neurocognitive testing is necessary for detection. For example, an earlier multicenter study demonstrated only a 3% incidence of type II outcomes at discharge for patients undergoing conventional CABG, whereas a more recent study with more thorough neurocognitive testing revealed incidences of 53%, 36%, 24%, and 42% at discharge, 6 weeks, 6 months, and 5 years after discharge following CABG, respectively.

Recognition The presence of type I CNS injury is often apparent in the immediate postoperative recovery period. This type of injury commonly presents with failure to awaken from anesthesia, obtundation, generalized or localized hypertonicity, aphasia, visual field deficits, hemineglect, or seizures and is thought to be caused by intraoperative embolic phenomena or global or regional cerebral hypoperfusion. Progressive deficits or signs of elevated intracranial pressure, especially in the presence of anticoagulation, suggest intracranial hemorrhage and require immediate evaluation. Computed tomography (CT) is often used in the first 24 hours to evaluate for hemorrhage and then again after 48 hours to detect evidence of infarction (infarcted brain tissue often appears normal on CT imaging before 48 hours). Magnetic resonance imaging is sometimes used in the first 24 hours owing to its higher 339

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sensitivity for diagnosing hemorrhage and brain ischemia; however, it cannot be used in the presence of implanted cardiac rhythm management devices. Worsened or new deficits postoperatively also warrant echocardiography for detection of a cardiac embolic source. Recognition of type II CNS injury is much more difficult. The first sign is often the patient’s report of “not feeling right” or the patient’s family members noting that their loved one has “slowed down” or become more forgetful. Studies to measure intellectual deterioration and memory deficits related to type II injury rely on changes in neurocognitive test scores compared with a preoperative baseline; in practice, however, such a baseline test is almost never performed. Therefore, any neurocognitive decline noted after CABG is rarely quantifiable.

Risk Assessment Perioperative neurologic risk can be divided into patientrelated preoperative risk factors and intraoperative procedurerelated factors. Recognized independent patient-related risk factors for type I injury include the following: ● ● ● ● ● ● ● ● ●

Advanced age Proximal aortic atherosclerosis Previous CABG Peripheral vascular disease Preexisting neurologic disease Diabetes mellitus Hypertension Pulmonary disease Unstable angina

Patient-related risk factors for type II injury include the following: ● ● ● ● ● ●

Advanced age Systolic hypertension greater than 180 mm Hg on admission Excessive alcohol consumption Previous CABG Arrhythmia on day of surgery Antihypertensive therapy

Whether the presence of the apoE ε-4 allele, which is associated with late-onset Alzheimer’s disease and poorer outcome after stroke or subarachnoid hemorrhage, is a risk factor for type I or type II injury remains controversial. Intraoperative procedure-related factors also play a major role in type I and type II injury after cardiac surgery, perhaps owing to increased microembolic and macroembolic load to the brain, cerebral hypoperfusion, or normal or increased cerebral metabolic rate. Manipulation of the aorta by CPB cannulation, cross-clamping, side-clamping, unclamping, or lifting of the heart and the use of an intraaortic balloon pump are also believed to increase the risk of CNS injury. Microembolic load to the brain, as measured by transcranial Doppler, has been shown to correlate with the severity of neurocognitive decline, and an association between microembolization and such aortic manipulations has been demonstrated. Similarly, manipulation of the CPB circuit itself and prolonged CPB time have been implicated as risk factors for CNS injury by increasing the embolic load of air and microthrombi. Open-heart procedures, such as

valve surgery or septal defect repair, also appear to be associated with a greater risk of CNS injury. Possibly the most important intraoperative risk factor is the surgeon’s choice of aortic cannulation site for CPB. Approximately 20% of patients undergoing CABG have moderate to severe ascending aortic atherosclerotic disease. If so, it is critical that the anesthesiologist be involved in the decision making to determine the optimal cannulation site. It has been shown that TEE is more accurate than direct palpation for locating aortic plaques. Therefore, TEE-guided aortic cannulation has become standard in most centers. More recent data show that detecting these plaques is best accomplished with direct epiaortic scanning using a sterilesheathed surface ultrasound probe applied directly to the aorta. Additionally, TEE is helpful in diagnosing other procedure-related risk factors for type I and II adverse neurologic outcomes, including intracardiac thrombi and air, septal defects, and iatrogenic aortic dissection. Maintaining a somewhat depressed cerebral metabolic rate intraoperatively is thought to help prevent CNS injury. Procedures performed under normothermic conditions, or those allowing rapid rewarming after CPB, increase the risk of type I and II injury. Rapid rewarming has been shown to cause a desaturation of jugular venous hemoglobin and is believed to correlate with poorer CNS outcomes. Similarly, avoiding glucose-containing CPB priming fluids and maintaining normoglycemia are believed to reduce risk. One might think that avoiding CPB altogether, by performing off-pump CABG whenever possible, would greatly reduce the risk of CNS injury. However, as mentioned earlier, a recent randomized, controlled trial failed to show any significant difference in type I or II CNS injuries for off-pump versus conventional CABG. Whether off-pump CABG involving bilateral internal mammary artery grafting and the avoidance of aortic manipulation could reduce CNS injury has yet to be shown.

Implications Perioperative CNS injury, whether overt type I or more subtle type II, can be devastating in terms of quality of life and resource utilization. In-hospital mortality is about 10-fold and 5-fold higher for type I and type II injuries, respectively. The need for skilled nursing facilities on hospital discharge also increases approximately 6-fold for type I and 4-fold for type II injury. The economic burden for CNS injury after cardiac surgery reaches well above the billion dollar mark annually.

MANAGEMENT AND PREVENTION Preventing or reducing the risk of neurologic injury during cardiac surgery is of the utmost importance. Even more subtle and common type II injuries have a great impact on postoperative autonomy and patient lifestyle and undermine the primary goal of surgery, which is to improve longevity and quality of life. Therefore, all patients should be considered at risk, and certain steps should be taken to identify and reduce specific risks for neurologic injury. Aortic Imaging. Intraoperative TEE or direct epiaortic scanning allows informed aortic cannulation. Without such

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imaging, an unacceptably large fraction of patients is unnecessarily exposed to large cerebral embolic loads from cannulation and clamping through or near aortic atheromas. Moderate Hypothermia. Cooling during CPB to approximately 32°C reduces the cerebral metabolic rate and provides cerebral protection. Careful rewarming is equally important in preventing unnecessary increases in cerebral metabolism. Avoidance of Arterial Hypotension. Some data suggest that higher mean arterial pressure during CPB is associated with better neurologic outcomes in higher-risk patients as identified by TEE evaluation or direct epiaortic scanning, but this is controversial. It is hypothesized that in these patients, optimizing collateral cerebral flow minimizes the risk of embolic neurologic injury. However, there is little evidence that maintaining a specific mean or cerebral perfusion pressure range improves outcome.

Avoidance of Retransfusion of Unprocessed Blood. Retransfusion of unprocessed cardiotomy suction blood delivers particulate microemboli consisting of cell aggregates, bone wax, lipids, and surgical debris to the circulation. This has been implicated in neurologic injury. Antifibrinolytic Therapy. Aprotinin, a serine protease inhibitor, reduces the inflammatory response to CPB and has the potential to reduce the incidence of stroke in CABG patients. Pharmacotherapy. Many drugs have been evaluated for their ability to reduce neurologic injury after cardiac surgery, but with conflicting results. Thiopental, propofol, etomidate, glucocorticoids, nimodipine, inhalational anesthetics, and others have been studied for their ability to reduce cerebral

metabolic rate, inhibit inflammation and brain edema, and limit the embolic load through cerebral vasoconstriction. However, none has yet been shown to improve neurologic outcome. Devices. Newly developed sutureless and clampless grafting devices allow surgeons to perform aortic proximal anastomoses without the need for aortic side-clamping. This may reduce the embolic load and improve neurologic outcome. Other Surgical Techniques. Minimizing CPB time or performing off-pump CABG may improve neurologic outcomes, but so far, the data have been inconsistent. Also, left and right internal mammary artery grafts (which avoid aortic manipulation), nontraditional aortic cannulation sites, and deep hypothermia have been advocated. However, further study is required to determine whether any of these techniques is truly effective.

Further Reading Arrowsmith JE, Grocott HP, Newman MF: Neurologic risk assessment, monitoring, and outcome in cardiac surgery. J Cardiothorac Vasc Anesth 13:736-743, 1999. Gringore AM, Grocott HP, Mathew JP, et al: The rewarming rate and increased peak temperature alter neurocognitive outcome after cardiac surgery. Anesth Analg 94:4-10, 2002. Mackensen GB, Ti LK, Phillips-Bute BG, et al: Cerebral embolization during cardiac surgery: Impact of aortic atheroma burden. Br J Anaesth 91:656-661, 2003. Mark DB, Newman MF: Protecting the brain in coronary artery bypass graft surgery. JAMA 287:1448-1450, 2002. Mora CT, Henson MB, Weintraub WS, et al: The effect of temperature management during cardiopulmonary bypass on neurologic and neuropsychologic outcomes in patients undergoing coronary revascularization. J Thorac Cardiovasc Surg 112:514-522, 1996. Murkin JM: Attenuation of neurologic injury during cardiac surgery. Ann Thorac Surg 72:S1838-S1844, 2001. Newman MF, Wolman R, Kanchuger M, et al: Multicenter preoperative stroke risk index for patients undergoing coronary artery bypass graft surgery. Circulation 94:II74-II80, 1996. Roach GW, Kanchuger M, Mangano CM, et al: Adverse central nervous system outcomes following coronary artery bypass graft surgery in a multicenter study: Incidence, predictors and resource utilization. N Engl J Med 335:1857-1863, 1996. Scarborough JE, White W, Derilus FE, et al: Combined use of off-pump techniques and a sutureless proximal aortic anastomotic device reduces cerebral microemboli generation during coronary artery bypass grafting. J Thorac Cardiovasc Surg 126:1561-1567, 2003. Van Dijk D, Jansen EW, Hijman R, et al: Cognitive outcome after off-pump and on-pump coronary artery bypass graft surgery: A randomized trial. JAMA 287:1405-1412, 2002.

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Alpha-Stat pH Management. During cooling, targeting a pH of 7.4 corrected to 37°C (i.e., alpha-stat pH management) and maintaining cerebral autoregulation may provide improved neurologic outcomes when compared with pH-stat management. The latter requires the addition of carbon dioxide to the CPB circuit in order to maintain the pH at 7.4 measured at the hypothermic patient’s actual body temperature. However, pH-stat may be beneficial during procedures requiring deep hypothermia, because it may provide better cerebral protection by decoupling cerebral autoregulation and enhancing cerebral blood flow. Even so, the relative importance of these techniques remains unclear.

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Mark Nunnally and Robert N. Sladen Case Synopsis A 75-year-old man with long-standing hypertension and type 2 diabetes mellitus underwent open repair of an infrarenal aortic aneurysm. His baseline creatinine was 1.6 mg/dL and rose to 2.0 mg/dL on the second postoperative day. On the fifth postoperative day, he developed progressive hypoxemia, fever, and hypotension. A contrastenhanced scan of the pulmonary vessels was not suggestive of pulmonary embolism. He was started on a β-lactam and an aminoglycoside for probable pneumonia. Over the next 12 hours, he became hypotensive and anuric. Renal replacement therapy was started, and antibiotic therapy was shifted to a quinolone. The patient’s renal function returned after several weeks, and he was eventually discharged.

PROBLEM ANALYSIS Definition Postoperative acute renal failure (ARF) describes a spectrum of renal dysfunction that occurs after surgery. Unfortunately, multiple definitions of this complication exist, including those based on intervention (dialysis required or not), relative or absolute decline in glomerular filtration rate (GFR), or relative or absolute increase in serum creatinine (SCr) level. It can include new-onset renal failure as well as acute worsening of chronic renal failure. The fractional change in SCr has emerged as a practical and consistent index of the severity of perioperative renal injury; however, the need for dialysis is a potent predictor of outcome. In one study of patients undergoing coronary artery bypass grafting (CABG), mortality associated with ARF was 14%, but this doubled to 28% when dialysis was required. The cause of ARF has traditionally been classified as prerenal (decreased perfusion), renal (parenchymal injury), or postrenal (urinary obstruction). Although these distinctions remain useful for directing diagnostic strategy, they frequently overlap. In about 90% of cases, postoperative ARF is a consequence of sustained prerenal injury that culminates in ischemic acute tubular necrosis (ATN). ATN can also be caused by nephrotoxic insults, which may themselves exacerbate ischemic injury. In animal models, transient low perfusion creates a prerenal state characterized by oliguria and low urine sodium, with salt and water retention. This is the normal renal tubular response to hypovolemia. With increased perfusion, urine flow returns to normal. This is a hemodynamically mediated event with preserved tubular function; it is reversed by restoration of normal hemodynamic function. More prolonged perfusion deficits result in oliguria (with high urine sodium) that does not reverse when perfusion increases. In this scenario, ATN occurs, characterized by tubular obstruction and “backleak.” The latter is a hemodynamically mediated event with loss of tubular function; it is not 342

reversed by restoration of normal hemodynamic function. Even so, intrinsic renal architecture is preserved, and the kidney may ultimately recover. The pathogenesis of ARF reflects the kidney’s unique sensitivity to insult. Figure 85-1 demonstrates several sensitive areas of the nephron. The medulla and inner cortex have marginal blood flow and are therefore at risk for ischemic ATN from alterations in renal oxygen delivery. This could result from intravascular volume depletion, hypotension, diminished cardiac output, or anemia. In nephrotoxic ATN, damage to the tubules is the result of inflammatory signaling, free radical damage, disturbances in cellular metabolism, and disruption of intrinsic renal vasodilators such as prostaglandins and nitric oxide. Tubular cell necrosis and apoptosis lead to loss of function, disruption of architecture, and nephron obstruction by cellular debris. Once this has occurred, restoration of renal blood flow can no longer reestablish GFR.

Recognition Perioperative oliguria is an unreliable index of renal function because it is almost inevitably prerenal in nature. It reflects absolute or relative hypovolemia, with vasoconstriction and sodium retention as a consequence of activation of the sympathoadrenal, renin-angiotensin-aldosterone, and antidiuretic hormone systems. With two very important exceptions (sepsis and liver failure), it is reversed by restoration of normal renal hemodynamics. In contrast, when postoperative ATN occurs, it is often a culmination of multiple lesser insults in a protected milieu, resulting in nonoliguric renal failure, defined as ARF with urine flow 15 to 80 mL/hour. In summary, oliguria is common but seldom implies ARF, but the presence of a normal urine flow rate does not exclude it. When ARF does ensue, loss of renal solute clearance begins to result in the buildup of serum concentrations of electrolytes, urea, water, and other osmotic elements (azotemia). Blood urea nitrogen and SCr are the most commonly used indicators of renal function. Urea depends on

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High levels of catecholamines and angiotensin II constrict the afferent arteriole and worsen GFR. Endothelin is involved in pathologic vasoconstriction. Afferent arteriole Glomerulus Efferent arteriole

Catecholamines Angiotensin II Vasopressin

Low levels of catecholamines and angiotensin II constrict the efferent arteriole and maintain GFR. Vasopressin constricts the efferent arteriole only.

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NO, PGE2, urodilatin

Distal proximal convoluted tubule: High risk for ischemic injury. Alpha receptor predominance makes blood flow sensitive to catecholamines in the setting of hypovolemia. Necrotic tubular cells slough and obstruct the pars recta and sustain low GFR despite restoration of RBF.

Medullary thick ascending loop of Henle: Receives <10% of RBF and is at constant risk of ischemia. Blood flow is maintained by endogenous vasodilators (prostaglandins, nitric oxide). Impaired vasodilation induces ischemicnephrotoxic injury (e.g., NSAIDs, intravenous contrast).

Figure 85–1 ■ The proximal tubule and medullary thick ascending loop of Henle are potential sites of ischemic and nephrotoxic tubular injury. Both segments have high oxygen consumption and are at risk owing to supply-demand imbalance. GFR, glomerular filtration rate; NO, nitric oxide; NSAIDs, nonsteroidal anti-inflammatory drugs; PGE2, prostaglandin E2; RBF, renal blood flow.

tubular excretion but may be a misleading surrogate for tubular function because its blood level is affected by nonrenal pathology, such as gastrointestinal hemorrhage and protein catabolism (abnormally increased) or malnutrition and end-stage liver disease (abnormally decreased). SCr reflects the balance between creatinine production and excretion. These come into equilibrium when renal function is in a steady state. Therefore, SCr is a reliable surrogate for GFR.

However, the relationship between SCr and GFR is not direct; it is exponentially inverse. That is, a doubling of SCr implies a halving of GFR. Thus, a “trivial” increase in SCr from 0.6 to 1.2 mg/dL implies a 50% decrease in GFR. Moreover, SCr does not increase above normal limits until GFR has decreased below 50 mL/minute. In cachectic patients with low creatinine production, SCr may be “normal” with a GFR as low as 30 mL/minute.

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Creatinine clearance provides a real-time estimate of GFR because its calculation (UV/SCr, where U is urine creatinine and V is urine flow rate) incorporates the creatinine excretion rate (UV), which is directly proportional to GFR. If a patient has a urinary catheter and the urine flow rate is carefully measured, reliable estimates of GFR can be obtained with urine collection times of 2 hours or less. A shortcut that is often used in perioperative studies of renal function is to forgo the necessity of urine collection by calculating creatinine clearance from a nomogram—the Cockroft-Gault formula: Creatinine clearance = [(140 – Age [years]) × Weight [kg] × 1.73 m2 × 0.85∗] 72 × SCr [mg/dL] × Body surface area [m2] In the presence of oliguria, evaluation of tubular function may help distinguish a prerenal syndrome from established ARF. The prerenal state is characterized by avid tubular sodium and water retention, leading to small quantities of concentrated urine with low urinary sodium (<10 mEq/L) and a fractional excretion of sodium (FENa) less than 1%. Prerenal states leading to elevated sodium excretion with intact tubular function (e.g., metabolic alkalosis, diuretic use) may spuriously elevate the FENa to greater than 3%. In this setting, a high FENa is unreliable, but persistence of FENa less than 1% is highly suggestive of a prerenal state. Fractional excretion of urea nitrogen has recently been proposed as a more sensitive and specific method to differentiate prerenal azotemia from ATN, especially when diuretics are used. In established ARF, tubular function is lost. The kidney is unable to concentrate urine and retain sodium, leading to small quantities of dilute urine with high urinary sodium (>80 mEq/L) and high FENa (>3%). Additional objective data may be derived from electrolyte disturbances and hemodynamic monitoring. Ultrasonography of the renal vasculature, kidneys, and urinary drainage system can help rule out obstructive uropathy and confirm the diagnosis of ATN (normal renal blood flow) or ischemic injury (regional or global deficits). Risk assessment serves to clarify suspicion and evaluate for treatable risk factors.

Risk Assessment Identification of patients at risk permits more accurate prediction of postoperative ARF and offers the opportunity for intervention. Risk assessment is achieved by integrating patient factors, the surgical procedure, and the perioperative milieu. The potential for acute renal injury increases exponentially as risk factors accumulate. For example, exposure to a single nephrotoxin (e.g., ketorolac) seldom causes a problem, but if combined with other nephrotoxins (e.g., gentamicin) and decreased perfusion (hypovolemia), the risk for ARF becomes extremely high. Of all preoperative risk factors, the most predictive is preexisting renal dysfunction. Renal risk increases exponentially when the preoperative SCr exceeds 2.0 mg/dL. Other important risk factors include advancing age and markers ∗0.85 conversion factor is used for females only.

for vascular disease and end-organ damage, such as diabetes, abnormal cholesterol metabolism, and hypertension. Severe obstructive jaundice and the hepatorenal syndrome are associated with abnormal portal absorption of endotoxin, which induces renal vasoconstriction and a refractory prerenal state characterized by low urine sodium. Sepsis induces a similar milieu, along with the insults of hypotension and sympathetic renal vasoconstriction. Finally, there may be a genetic predisposition to renal injury, as suggested by the finding of a decreased risk associated with a specific apolipoprotein genotype. Intraoperative risk factors are related to the type of surgery (potential for complications such as bleeding, hypotension, or low cardiac output states) and specific interventions that may cause renal injury (e.g., aortic cross-clamping, cardiopulmonary bypass). Suprarenal aortic cross-clamping leads to a complete cessation of GFR, and full recovery may take 24 to 48 hours. Infrarenal cross-clamping also induces a decrease in GFR through reflex vasoconstriction. In either event, the duration of cross-clamping correlates with the risk for ARF. The risk of postoperative renal dysfunction and ARF requiring dialysis is 12% to 25% and 3% to 8%, respectively, for thoracoabdominal aneurysm repair; the risk is 2% to 30% and 0.6% to 1%, respectively, for abdominal aortic aneurysm repair. Cardiopulmonary bypass also increases the risk of ARF, but this is remarkably well tolerated by patients with normal preexisting renal function who have an uncomplicated course. Despite early optimism, off-pump CABG does not consistently decrease the incidence of perioperative renal injury. The most important risk factors in cardiac surgery remain preoperative renal insufficiency, the complexity of the procedure, and postoperative cardiac dysfunction. For all types of surgery, the most important postoperative risk factor is circulatory instability. Sepsis alone may induce renal injury through local vasoconstriction and nephrotoxicity without substantial hemodynamic perturbations. The risk is markedly exacerbated by the concomitant occurrence of nephrotoxic insults. These include pigment nephropathy due to rhabdomyolysis, intravascular hemolysis, severe obstructive jaundice, contrast nephropathy, and drugs. In the case synopsis, the patient had preoperative renal dysfunction (i.e., high SCr), underwent a high-risk procedure (aortic aneurysm repair, even though infrarenal), and was later exposed to several other renal insults (sepsis, contrast exposure, and an aminoglycoside antibiotic).

Implications Overall outcome is substantially determined by the severity of renal injury, but it is adversely affected even when renal dysfunction is moderate. For example, ARF requiring dialysis is uncommon after CABG but is associated with high mortality. Renal dysfunction (SCr increased >1 mg/dL above baseline) is considerably more common and is associated with significantly greater mortality compared with patients with no renal dysfunction. This may be explained by concomitant cardiac dysfunction, or it may be related to an independent adverse effect of renal failure on global organ function. For high-risk surgeries, in-hospital mortality can exceed 60% with ARF; this also leads to a substantial increase in resource utilization.

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This forbidding mortality rate has been little altered despite the development of improved renal replacement therapies (RRTs), including continuous venovenous hemodialysis. Although RRT consistently controls electrolyte and acid-base abnormalities, circulatory overload, and acute uremia, it does not eliminate the risk of sepsis, multiorgan system dysfunction, or impaired wound healing, which also contribute substantially to postoperative morbidity and mortality. Isolated ATN is inherently reversible, but additional ischemic or nephrotoxic insults may convert it into protracted ARF or even established chronic renal failure. In particular, there is compelling evidence that autoregulation is lost in ARF, so when dialysis causes hypotension, it injures the tubular cells and paradoxically delays renal recovery.

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PREVENTION The simplest approach to preventing ARF is the maintenance of hemodynamic stability. This is predicated on the fact that 25% of the cardiac output normally goes to the kidneys. Ultimately, it is wiser to err on the side of hypervolemia rather than to restrict fluids and precipitate ARF. Hemodynamic stability implies the maintenance of both renal blood flow and renal perfusion pressure, especially in states in which autoregulation is lost (ARF) or impaired (vasodilatory shock). Nephrotoxic insults should be minimized or avoided, keeping in mind that the risk of nephrotoxic ATN is exponentially related to the number of insults, which are far more damaging in the presence of shock or sepsis. There are no pharmacologic “magic bullets” for the prevention of ARF. Osmotic diuresis with mannitol can prevent or even reverse tubular obstruction by cellular debris. This is of particular benefit in pigment nephropathy and is routinely used for renal protection during suprarenal aortic cross-clamping. However, although mannitol increases urine flow in infrarenal cross-clamping, it is no better than saline hydration in preserving GFR. Furosemide may decrease oxygen consumption in the thick ascending loop of Henle by diminished ion transport. To obtain its protective effects, however, furosemide must be administered before the insult occurs, and adequate intravascular volume must be maintained. “Renal dose” dopamine has become an increasingly controversial intervention because a number of studies have shown either no effect or possibly harm associated with prophylactic low-dose dopamine. In part, this may be due to the almost 30-fold variability in intersubject plasma dopamine levels, such that patients on low-dose dopamine may have plasma dopamine levels akin to high-level infusions, and vice versa. Nevertheless, we should not discount dopamine’s potential therapeutic role as an inotropic agent to restore normal renal perfusion in patients who are putatively normovolemic but have impaired cardiac function. Fenoldopam is a selective DA-1 receptor agonist and pure vasodilator that increases renal blood flow and blocks tubular sodium reabsorption. Unlike dopamine, it has predictable dose-related effects and is not arrhythmogenic. However, it may cause reflex tachycardia. It may prove to be useful for the prevention of ARF, but human outcome data are lacking, and a recent prospective study failed to show any benefit for reducing radiocontrast nephropathy. Human recombinant B-type natriuretic peptide (nesiritide) is approved by the Food and Drug Administration for the management of decompensated cardiac failure. It is a balanced venous and arterial vasodilator with natriuretic properties that can relieve pulmonary congestion and promote diuresis. Its role in perioperative renal protection is currently being investigated. Early results showing a decrease in radiocontrast renal injury with the prophylactic administration of oral N-acetylcysteine, a free radical scavenger, prompted considerable interest. However, subsequent studies were more equivocal and suggested that the benefit is no greater than that offered by hydration with saline. Most recently,

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A coherent strategic approach is predicated on vigilance for worsening renal function and its associated complications, judicious diuresis, and timely institution of RRT. Hyponatremia, acidosis, azotemia, and elevations in serum potassium, magnesium, and phosphate should be anticipated and treated promptly. Above all, maintenance of adequate renal blood flow and perfusion pressure helps avoid further damage. Diuretics may be helpful for the management of pulmonary congestion and electrolyte disorders, thereby delaying or even avoiding the need for RRT. With aggressive hydration, diuretics form an essential component of “tubular washout” therapy for pigment nephropathy (intravascular hemolysis, rhabdomyolysis). However, tubular delivery of loop diuretics is impaired because of the accumulation of organic acids that compete for active transport in the proximal tubule. Double or triple the normal doses may be required. Continuous infusion of furosemide (1 to 10 mg/hour) is a pharmacokinetically rational means of enhancing the drug’s tubular concentration at lower doses and is effective even in states of low GFR. Another effective strategy is dual segment blockade of sodium reabsorption, at the medullary thick ascending loop of Henle and the distal tubule, by combined administration of a loop diuretic (furosemide, ethacrynic acid, torsemide) and a thiazide diuretic (metolazone, hydrochlorothiazide). Initiation of RRT is required when pulmonary edema, acidosis, or hyperkalemia threaten life or when manifestations of acute uremia (encephalopathy, enteropathy, serositis, thrombocytopathy) are profound. There is limited evidence that early elective RRT may be favorable in ARF, but there is no established threshold for intervention on the basis of blood urea nitrogen or SCr values. Continuous venovenous hemodialysis provides both hemodialysis and ultrafiltration with minimal hemodynamic perturbation, allowing its use in much sicker patients. Nonetheless, because autoregulation is impaired, it is imperative to avoid episodic hypotension. Animal data suggest that intrarenal vascular responsiveness to norepinephrine is markedly decreased in ARF. If this applies to human patients, the use of this drug for the treatment of hypotension is unlikely to compromise renal blood flow.

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sodium bicarbonate appeared to prevent contrast nephropathy in a small randomized, controlled trial, but corroboration by larger clinical trials is needed. The low acquisition costs of these interventions make them particularly appealing. Other novel agents being investigated are prostaglandin analogues, human growth factors, and selective adenosine agonists and antagonists. All have theoretical advantages in ARF, but outcome data are preliminary.

Further Reading Bellomo R, Champman M, Finfer S, et al: Low-dose dopamine in patients with early renal dysfunction: A placebo-controlled randomised trial. Australian and New Zealand Intensive Care Society (ANZICS) Clinical Trials Group. Lancet 356:2139-2143, 2000. Birck R, Krzossok S, Markowetz F, et al: Acetylcysteine for prevention of contrast nephropathy: Meta-analysis. Lancet 362:598-603, 2003. Braams R, Vossen V, Lisman BAM, et al: Outcome in patients requiring renal replacement therapy after surgery for ruptured and nonruptured aneurysm of the abdominal aorta. Eur J Vasc Endovasc Surg 18:323-327, 1999. Brezis M, Rosen S: Hypoxia of the renal medulla—its implications for disease. N Engl J Med 332:647-655, 1995. Carvounis CP, Nisar S, Guro-Razuman S: Significance of the fractional excretion of urea in the differential diagnosis of acute renal failure. Kidney Int 62:2223-2229, 2002. Chen G, Paka L, Kako Y, et al: A protective role for kidney apolipoprotein E: Regulation of mesangial cell proliferation and matrix expansion. J Biol Chem 276:49142-49147, 2001. Chertow GM, Lazarus JM, Christiansen CL, et al: Preoperative renal risk stratification. Circulation 95:878-884, 1997. Cockcroft DW, Gault MH: Prediction of creatinine clearance from serum creatinine. Nephron 16:31-41, 1976. Conlon PJ, Stafford-Smith M, White WD, et al: Acute renal failure following cardiac surgery. Nephrol Dial Transplant 14:1158-1162, 1999.

Forni LG, Hilton PJ: Continuous hemofiltration in the treatment of acute renal failure. N Engl J Med 336:1303-1309, 1997. Gines P, Guevara M, Arroyo V, et al: Hepatorenal syndrome. Lancet 362:1819-1827, 2003. Huynh TTT, Miller CC III, Estrera AL, et al: Determinants of hospital length of stay after thoracoabdominal aortic aneurysm repair. J Vasc Surg 35:648-653, 2002. Kelleher S, Robinette J, Miller F, et al: Effect of hemorrhagic reduction in blood pressure on recovery from acute renal failure. Kidney Int 31:725-730, 1987. MacGregor DA, Smith TE, Prielipp RC, et al: Pharmacokinetics of dopamine in healthy male subjects. Anesthesiology 92:338-346, 2000. Marik PE: Low-dose dopamine: A systematic review. Intensive Care Med 28:877-883, 2002. Merten GJ, Burgess WP, Gray LV, et al: Prevention of contrast-induced nephropathy with sodium bicarbonate. JAMA 291:2328-2334, 2004. Modi KS, Rao VK: Atheroembolic renal disease. J Am Soc Nephrol 12: 1781-1787, 2001. Novis BK, Roizen MF, Aronson S, et al: Association of preoperative risk factors with postoperative acute renal failure. Anesth Analg 78: 143-149, 1994. Ryckwaert F, Boccara G, Frappier J-M, et al: Incidence, risk factors, and prognosis of a moderate increase in plasma creatinine early after cardiac surgery. Crit Care Med 30:1495-1498, 2002. Singri N, Ahya SN, Levin ML: Acute renal failure. JAMA 289:747-751, 2003. Stone GW, McCullough PA, Tumlin JA, et al: Fenoldopam mesylate for the prevention of contrast-induced nephropathy. JAMA 290:2284-2291, 2003. Tang ATM, El-Gamel A, Keevil B, et al: The effect of “renal-dose” dopamine on renal tubular function following cardiac surgery: Assessed by measuring retinol binding protein (RBP). Eur J Cardiothorac Surg 15:717-722, 1999. Wahlberg E, DiMuzio PJ, Stoney RJ: Aortic clamping during elective operations for infrarenal disease: The influence of clamping time on renal function. J Vasc Surg 36:13-18, 2002.

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Postoperative Respiratory Failure David Porembka Case Synopsis

PROBLEM ANALYSIS Definition Numerous issues are involved in the trauma situation described in the case synopsis. The patient arrived at the hospital in hypovolemic shock with end-organ ischemia due to several life-threatening injuries (splenic rupture, liver injury, severe pelvic injury). Significant occult blood loss can occur with pelvic fractures alone, especially those involving vertical shear injury. Often, severe lactic acidosis accompanies such traumatic injuries and the associated hypovolemia and hypotension. Because the patient also sustained chest wall trauma with multiple rib fractures and pulmonary contusion, hypoxemia is inevitable. Indeed, with multiple trauma and associated lung injury, the potential for significant acute respiratory failure is high. In this case, aggressive blood and fluid resuscitation and immediate corrective surgery are required. However, these may compound the risk for acute respiratory failure. Fortunately, after surgery, the need for blood products and fluid replacement will be reduced. In the case described, however, the patient’s oxygenation worsened, suggesting associated severe lung injury or early acute respiratory distress syndrome (ARDS) and associated cellular, humoral, and oxidative pathophysiologic processes (Table 86-1).

Recognition Diagnostic criteria for ARDS are listed in Table 86-2. Early diagnosis and corrective measures are key to a successful

outcome. Initially, the work of breathing is greatly increased. Therefore, patients become tachypneic, tachycardic, and agitated. Typically, arterial blood gas measurement reveals respiratory alkalosis with hypoxemia or relative hypoxemia with supplemental oxygen. Subsequently, this progresses to an increase in the alveolar-arterial oxygen gradient. Without intervention (i.e., airway control and mechanical ventilatory support with positive end-expiratory pressure [PEEP]), the

Table 86–1

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Cellular

Oxidative

Endothelial cells Eosinophils Epithelial cells Fibroblasts Neutrophils Monocytes and macrophages

Antioxidant depletion Hypoxia-reoxygenation phenomena Oxygen toxicity Reactive oxygen species Superoxide radical Hydrogen peroxide Singlet oxygen Hypochlorous acid Reactive nitrogen species Nitric oxide Peroxynitrite Transition metal ion catalysts Xanthine oxidase

Humoral Arachidonic acid metabolites Thromboxane A2 Leukotrienes Complement C5a, C3a Cytokines TNF-α, IL-1β, IL-6, IL-8 Endotoxin Platelet-activating factor Prostaglandins

IL, interleukin, TNF, tumor necrosis factor.

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A 25-year-old person involved in a high-speed motor vehicle accident required prolonged extrication and underwent an emergency laparotomy for a positive diagnostic abdominal ultrasonogram. Injuries included a ruptured spleen, a grade III liver laceration, multiple right-sided rib fractures with an ipsilateral pulmonary contusion, and a vertical shear pelvic fracture. The initial vital signs were heart rate 120 beats per minute, respiratory rate 35, and systolic arterial blood pressure 80 mm Hg. Resuscitation required multiple transfusions (approximately 5 L). Following corrective surgery, the patient underwent embolization for the pelvic fracture. In the surgical intensive care unit, a continuous right ventricular ejection catheter with mixed venous saturation capabilities was placed. Also, transesophageal echocardiography (TEE) was used for initial diagnostic interrogation (ventricular function and volume, ventricular interaction, aortic interrogation) and for continuous postoperative hemodynamic assessment. During subsequent aggressive hemodynamic resuscitation, the patient’s hemodynamic instability improved, but oxygenation saturation status deteriorated (arterial oxygen tension [PaO2] 60 mm Hg with fraction of inspired oxygen [FiO2] of 1.0). After sedation and an appropriate level of analgesia (with continuous infusions of lorazepam and fentanyl) to a modified Ramsey score of 3 to 4, initial ventilator adjustments to improve static compliance did not improve PaO2.

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Diagnostic Criteria for Acute Respiratory Distress Syndrome

Clinical Criteria Appropriate risk factors or precipitating causes Respiratory distress with severe hypoxemia Radiographic evidence of noncardiac pulmonary edema Loss of lung compliance No obvious cardiac failure

NHLBI Criteria Widespread, bilateral infiltrates on chest radiograph <7 days duration Hypoxemia with PaO2/FiO2 <150 off PEEP or <200 on PEEP Pulmonary artery occlusion pressure <18 mm Hg *0, no lung injury; 0.1 to 2.5, mild to moderate lung injury; >2.5, severe lung injury (acute respiratory distress syndrome). FiO2, fraction of inspired oxygen; NHLBI, National Heart, Lung, and Blood Institute; PaO2, arterial oxygen tension; PEEP, positive end-expiratory pressure.

Figure 86–2 ■ Chest radiograph with bilateral fluffy infiltrates (panacinar pattern), consistent with severe acute respiratory distress syndrome.

work of breathing is so great that severe hypoxemia occurs. This is compounded by increased alveolar fluid, a significant decrease in the functional residual capacity, atelectasis, and loss of lung compliance. Metabolic acidosis may ensue if the hypoxemia is not reversed or becomes refractory, leading to end-organ and cellular damage. In addition to hypoxemia, the chest radiograph may reveal a pattern consistent with early ARDS, including bilateral patchy interstitial infiltrates (Fig. 86-1). Later, with severe ARDS, this pattern progresses to bilateral, fluffy infiltrates with a panacinar pattern (Fig. 86-2). These findings may worsen or even appear to dissipate with positive-pressure ventilation, especially if plateau pressures and PEEP are significantly elevated. Although patients were once considered to have ARDS if the pulmonary artery occlusion (wedge) pressure was

less than 18 mm Hg, today, with the greater use of echocardiography, this criterion may not apply to acidotic, underresuscitated patients. Because the left ventricle may be noncompliant, even if relatively empty, the pulmonary artery occlusion pressure may be falsely elevated. Even in the static phase of resuscitation, ongoing cellular injury occurs, and the phenomena of reperfusion injury proceed and continue to impair left ventricular function, which is inadequately measured by information derived from a pulmonary artery catheter. Even with correction of the medical or surgical pathology associated with ARDS, the pathophysiologic processes initiated by severe acute lung injury are unabated, leading to pulmonary microcirculation compromise.

Risk Assessment

Figure 86–1 ■ Chest radiograph consistent with the pattern of early acute respiratory distress syndrome following right-sided pulmonary contusion with multiple rib fractures. In addition to diffuse patchy infiltrates, note diffuse subcutaneous emphysema from either the traumatic insult or pulmonary barotrauma.

Conceptually, there are several categories of pulmonary edema, depending on cause and associated factors. Hydrostatic pulmonary edema results from volume overload, left ventricular failure, valvular heart disease, and lymphatic insufficiency. Permeability pulmonary edema (alveolar capillary leak) is associated with the systemic inflammatory response syndrome (SIRS; see Chapter 119) due to shock (e.g., traumatic, septic, cardiogenic, anaphylactic), pulmonary contusion, thermal injury, fat embolism, closed head injury, infectious agents, near-drowning, inhaled toxins, pancreatitis, drug ingestion, multiple transfusions, and so forth. Mixed pulmonary edema combines elements of both and often occurs in patients with subtle heart failure (due to systolic or diastolic dysfunction) with superimposed SIRS. The presence of mixed pulmonary edema in the intensive care unit is not well documented. However, it is a definite entity in gravely ill surgical and trauma patients, and it perplexes physicians with regard to the modulation of intravascular volume. Again, echocardiography (especially TEE) can help clinicians diagnose pathologic entities that might be involved and assess the patient’s hemodynamic

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apoptosis in pulmonary vascular endothelial cells. Also, the impaired coagulation observed in patients with septic shock may improve with activated protein C. It is unknown whether the use of such pharmacotherapy may benefit ARDS patients with impaired fibrinolysis and enhance platelet-fibrin thrombus formation. Although intensive glucose control is considered standard in critically ill patients, there are no prospective randomized trials of this practice in patients with severe ARDS. However, conventional wisdom dictates that such a course may be prudent. Ventilation-induced lung injury is a well-known entity, but it has only recently gained attention because of the unexpected results from the ARDS Network multicenter study. Patient enrollment was halted in that study because patients who received standard ventilatory support (12 mL/kg tidal volume) with a maximal plateau pressure of 50 cm H2O had a mortality rate of 39.8%, compared with 31.0% for those with 6 mL/kg and a maximal plateau pressure of 30 cm H2O (P =.007). However, in clinical practice, there is varying compliance with the lowered ventilatory settings promulgated by the ARDS Network. This is disconcerting, and clinicians must be encouraged to use more protective ventilatory strategies. What is also clear from the ARDS Network study is that ARDS is not a homogeneous process. Some alveoli will be overdistended by high pressure and volumes; others will never be opened, even with higher pressures and volumes. The latter include dependent regions of the lung. More recent studies show that simple alterations in mechanical ventilation can have deleterious effects. It is now known that systemic cytokine up-regulation is possible with high-pressure, high-volume ventilation. Another benefit of protective lung strategies is that systemic cytokine levels are significantly lower with lower-pressure, lower-volume ventilation. These levels decrease significantly over time owing to reduced lung injury (overdistention), while lung recruitment is maintained throughout the ventilatory cycle by more modest maximal plateau pressure. Other investigators have examined plasma chemokines (MCP-1, IL-8, and GRO) in patients with conventional (high volume, high plateau pressure) and protective (lower volume, lower plateau pressure) ventilation strategies. Plasma cytokines were increased in patients with conventional ventilation. Thus, there may be an associated risk of end-organ damage and the development of multiple organ failure. Circulating pro-apoptotic soluble factors (e.g., soluble Fas ligand) may contribute. Finally, studies in a rat model of ischemic gut suggest that patients with acute lung injury and ischemic gut may be at even higher risk for ARDS. This might be due to more pronounced release of inflammatory cytokines from ischemic gut.

Implications In the past, mortality from ARDS was significant, ranging from 53% to 69%. Recently, mortality from isolated ARDS has declined to 26% to 47%. This has been attributed to the following factors: ● Better ventilator management: pressure-controlled ventilation, reduced tidal volumes, permissive hypercapnia, and measures to recruit alveoli and avoid derecruitment

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status, particularly biventricular performance and interactions. Until clinicians have the capability to construct rightleft heart pressure-volume loops, clinical interventions are optimized with the appropriate use of pulmonary artery catheters and TEE. The pathogenesis of ARDS is complex. Our understanding of initiating factors in ARDS, as well as disease progression, resolution, and healing, is ever-changing. Recent strides in both basic and clinical research have increased our understanding of ARDS. Also, since the establishment of the ARDS Network, we have finally reduced earlier stagnant mortality rates (40% to 60%) by such simple interventions as reducing mechanical ventilatory tidal volumes and plateau pressures. The incidence of ARDS in the United States approaches 150,000 patients per year (75 per 100,000 population per year). The incidence depends on the primary cause of ARDS and associated pathophysiology: SIRS (41%), multiple transfusions (36%), near-drowning (33%), pulmonary aspiration (21%), multiple fractures (11%), drug overdose (8.5%). In patients with two risk factors, the incidence increases to 42%; in those with three risk factors, it is 85%. The 1-year outcome for ARDS survivors is not necessarily benign. Rapid resolution of lung injury, even without associated multiorgan system dysfunction, is more often observed in previously healthy patients. Even so, muscle wasting and weakness may occur, possibly related to critical myopathic illness that may accompany prolonged stays in the intensive care unit. By 6 months, pulmonary function generally improves in ARDS patients. However, most have a persistent reduction in carbon monoxide diffusing capacity. Only about half of ARDS survivors return to work in their prior capacity. There are many pathogenic processes involved in ARDS. However, because ARDS is a continuum, these are not easily subdivided. Nonetheless, in the acute phase of lung injury, there is an influx of protein-enriched fluid into the alveolar spaces. Transmigration of gases across the alveolar membrane is impaired owing to a breakdown of the alveolar-capillary barrier. This sets the stage for problematic management of ARDS patients. The alveolar epithelium (90% type I cells; 10% type II [cuboidal] cells) is also injured in early ARDS, and the extent of such injury is a predictor of ARDS mortality. Type I cells produce surfactant and are involved in ion transport. They also proliferate and differentiate into type II cells following lung injury. The loss of vital type I cell functions reduces the integrity of the barrier, leading to (1) pneumonia, sepsis, and septic shock and (2) cellular disorganization that interferes with epithelial repair and fibrosis. Neutrophil transmigration and consequent injury are well known in ARDS and contribute to continued injury and interference with healing. Extrapulmonary and pulmonary proinflammatory substances and cytokines are also implicated in the aggressive pathophysiology of ARDS involving alveolar epithelial cells, neutrophils, and fibroblasts. With such overwhelming inflammation and the production of interleukin-8 (IL-8) and tumor necrosis factor-α, any glucocorticoid-mediated inhibition is ineffective. Thus, the balance between pro- and anti-inflammatory cytokines and mediators is altered, but this is not yet well understood. ARDS also increases alveolar epithelial cell apoptosis and dysfunction. This process is enhanced by a kinase-1 signaling pathway that regulates hydrogen peroxide-induced

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Altering the patient’s position to improve ventilationperfusion mismatch, such as the use of special beds that can be tilted horizontally or vertically (“posturing”) to improve ventilation-perfusion matching by increasing hydrostatic pressure in the dependent lung1 Better control of circulatory dynamics, early and more aggressive management of nosocomial pneumonia, therapy with corticosteroids in late-phase ARDS, and anti-inflammatory modalities More timely, aggressive hemodynamic assessment and therapy; increased understanding of underlying pathophysiology; use of echocardiography, computed tomography, and electrical impedance tomography

Despite the apparent decline in mortality associated with isolated ARDS, mortality for multiorgan system failure has not declined. No matter what severity scoring system is used, mortality for ARDS with the failure of one, two, three, or four additional organs is 54%, 72%, 84%, and 99%, respectively. Reducing mortality from multiorgan system failure involves early intervention and aggressive treatment of the underlying causes, with meticulous attention to ventilatory management.

MANAGEMENT Understanding the pathogenesis of ARDS is critical to minimizing the numerous potential adverse consequences. If possible, underlying causes that may have precipitated ARDS must be identified and treated, and associated pathophysiology must be ameliorated or reversed (see Table 86-1). Maintaining adequate (not necessarily optimal) oxygenation and delivery can be challenging. Aggressive interventional strategies should be used to inhibit the activation of inflammatory responses. Especially in patients with sepsis, early treatment may prevent or minimize associated ARDS. An important caveat is that ARDS is a heterogeneous disease in terms of both cause and pathophysiology. Not all alveolar lung units are equally affected, and this can change during acute and resolving ARDS. Early identification of the extent and distribution of the disease process (collapsed lung areas) by computed tomography can guide clinicians in use of PEEP and posturing to improve regional distribution of gas flow and ventilatory pressures. With hypoxia due to ARDS, supplemental oxygenation is required, usually with an artificial airway. With mild acute lung injury, high-flow continuous positive airway pressure (CPAP) mask ventilation may be sufficient. With more severe injury, tracheal intubation and ventilator support may be required to deliver adequate oxygen and reduce the work of breathing. Assisted modes include proportional assist ventilation and synchronized intermittent mandatory ventilation with pressure support. Proportional assist ventilation proportionally amplifies instantaneous patient ventilatory efforts. With very severe injury, PEEP with increased mean airway pressure and lower tidal volumes (matched to the patient’s 1 The editor (JLA) benefited from such posturing therapy when he was treated in 2003 for ARDS secondary to pneumonia and empyema (due to Streptococcus pneumoniae). His condition was compounded by septic shock and multiorgan system failure.

ideal body weight) is used to recruit alveoli and improve ventilation-perfusion matching. Mean airway pressure depends on the degree of lung injury and hemodynamic tolerance, with caution required to avoid barotrauma or volume trauma. “Best” PEEP is difficult to define. Generally, pressure between 5 and 15 cm H2O is sufficient, with mean airway pressures initially maintained at less than 35 cm H2O. PEEP greater than 15 cm H2O may open collapsed alveoli but could expose normal alveoli to injury. PEEP greater than 20 cm H2O may be required on occasion, but this should be critically evaluated on a case-by-case basis. Recruitment of collapsed airways is crucial, especially during mechanical or assisted ventilation, so that derecruitment does not occur. The latter has been observed in dynamic studies in both animal models and humans. Thus, there is still uncertainty about the best level of PEEP for a given patient—one that will avoid untoward pulmonary volume trauma or barotrauma. Prone and, in some centers, postural positioning is used to manage patients with severe acute lung injury. This method is more prevalent in Europe and Canada than in the United States and may be more efficacious early in ARDS. In my opinion, once the clinician has identified the extent of injury to all pulmonary segments, increased PEEP and prone positioning may benefit some patients. However, with a predominant parenchymal component of ARDS (e.g., pulmonary contusion), increasing PEEP may actually worsen oxygenation, even in the prone position or with posturing. Surfactant instillation is used to replenish endogenous surfactant lost due to injury to type I alveolar epithelium. Although surfactant is useful in infants, only anecdotal reports show any benefit in adults. A multicenter study in progress, with direct administration of surfactant into 15 distal lung segments, has shown no encouraging results to date. Although inhaled nitric oxide initially showed some promise in severely ill patients, it has not withstood the test of time or well-designed prospective clinical trials. However, in an animal model of the effects of L-NAME (a nitric oxide synthetase inhibitor) and inhaled nitric oxide on ventilatorinduced lung injury (perfused rabbit lung), L-NAME attenuated the resultant microvascular leak, while nitric oxide appeared to further the induced lung injury. Of note in this study, measuring nitric oxide metabolites in bronchoalveolar lavage fluid may provide a method of measuring lung injury induced by mechanical stress. Prolonged exposure to high inspired oxygen concentrations can produce lung injury similar to ARDS. Thus, FiO2 should be adjusted to the lowest level possible to ensure adequate oxygenation (arterial blood oxygen saturation >90%). Today, lower tidal volumes (6 mL/kg of ideal body weight) are used in patients with ARDS. The idea is to avoid barotrauma while providing satisfactory oxygenation and alveolar ventilation. However, because alveolar ventilation may be decreased by up to 50% with these lower tidal volumes, arterial carbon dioxide tension (PaCO2) invariably rises (“permissive hypercapnia”) to greater than 80 mm Hg. Such high PaCO2 levels are not always benign and may have detrimental hemodynamic effects. Although increasing ventilator rates may reduce such high PaCO2 levels, ventilator rates greater than 30 are often ineffective. Judicious sedation

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PREVENTION At present, there are no clinically proven interventions to prevent ARDS in patients at risk. However, prompt recognition and treatment or removal of mitigating factors (e.g., heart failure, source of sepsis), along with the institution of supportive therapy, may favorably modify the course of ARDS and reduce associated morbidity and mortality. New measures and criteria for ventilatory management, as promulgated by the ARDS Network (www.ardsnet.org) have changed the standards of practice. The goal of maintaining optimal recruitment of alveoli without triggering airway collapse is critical. Thus, it may be necessary for clinicians to

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obtain dynamic computed tomography scans early in ARDS to characterize lung involvement and then use such scans to determine the appropriate management strategy (e.g., higher PEEP levels, prone or postural positioning). There is no proven method (evidence-based practice standard) of preventing all lung injury during ARDS treatment. However, the use of newer protective management strategies discussed in this chapter may help minimize such injury.

Further Reading Acute Respiratory Distress Syndrome Network: Ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome. N Engl J Med 342:1301-1308, 2000. Bouadma L, Schortgen F, Ricard J-D, et al: Ventilation strategy affects cytokine release after mesenteric ischemia-reperfusion in rats. Crit Care Med 32:1563-1569, 2004. Brower RG, Lanken PN, MacIntyre N, et al: Higher versus lower positive end-expiratory pressures in patients with the acute respiratory distress syndrome. N Engl J Med 351:327-336, 2004. Gainnier M, Michelet P, Thirion X, et al: Prone position and positive end-expiratory pressure in acute respiratory distress syndrome. Crit Care Med 31:2719-2726, 2003. Galic O, Dara SI, Mendez JL, et al: Ventilator-associated lung injury in patients without acute lung injury at the onset of mechanical ventilation. Crit Care Med 32:1817-1824, 2004. Goss CH, Brower RG, Hudson LD, et al: ARDS Network: Incidence of acute lung injury in the United States. Crit Care Med 31:1607-1611, 2003. Gunther A, Mosavi P, Heinemann S, et al: Alveolar fibrin formation caused by enhanced procoagulant and depressed fibrinolytic capacities in severe pneumonia: Comparison with the acute respiratory distress syndrome. Am J Respir Crit Care 161:454-462, 2000. Herridge MS, Cheung AM, Tansey CM, et al: One-year outcomes in survivors of the acute respiratory distress syndromes. N Engl J Med 348:683-693, 2003. Hickling KG: Low tidal volume ventilation: A PEEP at the mechanism of derecruitment. Crit Care Med 31:318-320, 2003. Hotchkiss RS: The pathophysiology and treatment of sepsis. N Engl J Med 348:138-150, 2005. Ince C: Microcirculation in distress: A new resuscitation end point? Crit Care Med 32:1963-1964, 2004. Lew TWK, Kwek TK, Tai D, et al: Acute respiratory distress syndrome in critically ill patients with severe acute respiratory syndrome. JAMA 290:374-380, 2003. Lim C-M, Jung H, Koh Y, et al: Effect of alveolar recruitment maneuver in early acute respiratory distress syndrome according to antiderecruitment strategy, etiological category of diffuse lung injury, and body position of the patient. Crit Care Med 31:411-418, 2003. Machino T, Hashimoto S, Maruoka S, et al: Apoptosis signal-regulating kinase 1-mediated signaling pathway regulates hydrogen peroxideinduced apoptosis in human pulmonary vascular endothelial cells. Crit Care Med 31:2776-2781, 2003. Oczenski W, Hormann C, Keller C, et al: Recruitment maneuvers after a positive end-expiratory pressure trial do not induce sustained effects in early adult respiratory distress syndrome. Anesthesiology 101: 620-625, 2004. van Genderingen HR, van Vught AJ, Jansen JRC: Regional lung volume during high-frequency oscillatory ventilation by electrical impedance tomography. Crit Care Med 32:787-794, 2004. van Kaam AH, Haitsma JJ, Dik WA, et al: Response to exogenous surfactant is different during open lung and conventional ventilation. Crit Care Med 32:774-780, 2004. Victorino JA, Borges JB, Okamoto VN, et al: Imbalances in regional lung ventilation: A validation study on electrical impedance tomography. Am J Respir Crit Care Med 169:791-800, 2004. Young MP, Manning HL, Wilson DL, et al: Ventilation of patients with acute lung injury and acute respiratory distress syndrome: Has new evidence changed clinical practice? Crit Care Med 32:1260-1265, 2004.

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and neuromuscular relaxation (rarely) may help reduce agitation, carbon dioxide production, and high spontaneous respiratory rates with permissive hypercapnia. Also, coordinating spontaneous respiratory efforts with any mechanical ventilation is key to avoiding lack of synchrony, diaphragmatic wasting, or the triggering of mechanical ventilator responses to spontaneous respirations. The strategy for selecting the best inspiration/expiration (I/E) ratio is based on a consideration of internal or external PEEP. Internal PEEP may be increased with higher tidal volumes, shorter expiratory time, or higher ventilatory constants (e.g., inverse I/E ratio). External PEEP is applied from the ventilator. It must be remembered that respiration is dynamic, and distended alveoli can collapse during expiration if the pressure applied is too low. Fast alveolar compartments expire easily and may collapse prematurely; external PEEP may be helpful in this situation. Conversely, increased internal PEEP may be required to match slower alveolar compartments and to make ventilation and perfusion more homogeneous. This can be accomplished by shortening expiratory time (inverse I/E ratio ventilation). In general, patients with ARDS have more fast compartments, so PEEP is ideal to prevent alveolar collapse. Yet with inverse I/E ratio ventilation, both external and internal PEEP should be monitored to limit internal PEEP. In summary, management of postoperative ARDS should be problem oriented and aggressive. Causes and contributing factors should be identified and corrected or treated. Aggressive monitoring (pulmonary artery catheter, TEE) is indicated to assess volume status, pulmonary and peripheral hemodynamics, oxygen supply and demand, and right and left heart function. For optimal ventilatory management, a strategy should be implemented to ensure adequate arterial oxygen saturation (>90%) with the lowest possible FiO2. Protective lung strategies, including a tidal volume of 6 mL/kg of predicted body weight, a plateau pressure of 30 to 35 cm H2O, optimal PEEP to avoid derecruitment and overdistention of a significant proportion of compliant alveoli, permissive hypercapnia (in patients without increased intracranial pressure), sedation, and neuromuscular blockers, are required. However, treatment must always be individualized in an effort to optimize outcome. The approach to these patients may be quite diverse, considering the pathologic differences between pulmonary ARDS and extrapulmonary ARDS.

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Avery Tung Case Synopsis A 78-year-old man with chronic ischemic cardiomyopathy and renal insufficiency underwent redo coronary artery bypass grafting and mitral valve repair. Cardiopulmonary bypass time was 200 minutes. Upon weaning from bypass, persistent hypoxemia (PaO2/FiO2 ratio <100) and a low systemic vascular resistance (500 dyne•sec•cm–5) were noted. Intravenous norepinephrine was begun, an intra-aortic balloon pump was placed, and the patient was transferred to the intensive care unit. Over the next 48 hours, the patient continued to require intravenous norepinephrine for reduced systemic vascular resistance. His creatinine levels increased, and there were radiographic changes consistent with acute respiratory deficiency syndrome, with continued hypoxemia despite 15 cm H2O positive end-expiratory airway pressure. He was intermittently agitated and had nonfocal neurologic changes. On the morning of the third postoperative day, he developed atrial fibrillation.

PROBLEM ANALYSIS Definition Complications specific to cardiopulmonary bypass (CPB) range from minor to severe and include mechanical issues, introduction of air and other debris, damage to blood elements, metabolic and electrolyte derangements, and alterations in vital organ perfusion. Mechanical complications of CPB involve abnormalities of blood flow between the CPB machine and the patient and include obstruction, embolization, and damage to the native vasculature. In addition, CPB triggers a systemic inflammatory response that can have significant effects on end-organ function during the immediate postbypass period. Organs commonly affected by the inflammatory response to CPB include the lungs, heart, gastrointestinal tract, brain, and kidneys. Although surgical trauma, blood loss, and hypothermia can all induce an inflammatory response, the physiologic response to CPB is unusual in its complexity. Three distinct mechanisms likely participate in the post-CPB inflammatory state: 1. Direct activation of the cellular and humoral immune system by artificial surfaces of the CPB circuit. This process involves complement and cytokines, leading to activation of both leukocytes and the vascular endothelium. 2. Aortic cross-clamping leads to ischemia-reperfusion injury and the resultant activation of the inflammatory mediator cascade. 3. Damage to mucosal barriers due to hypoperfusion induces endotoxin translocation and immune system activation. This leads to a systemic inflammatory response that alters 352

microvascular perfusion, systemic pressure, endothelial integrity, and end-organ perfusion postoperatively. Figure 87-1 depicts pathways of inflammatory activation during CPB.

Recognition A number of mechanical complications of CPB have been described. Obstruction to either arterial flow or venous drainage, embolization of air or debris, aortic dissection, dislodgment of aortic debris, and malposition of inflow and outflow cannulas can all cause catastrophic injury. Table 87-1 lists mechanical complications of bypass and their detection. Clinical signs and symptoms of the inflammatory response mediated by CPB are more subtle and involve primarily end-organ dysfunction and systemic hypotension. Renal function may decline slowly after CPB and progress to acute renal failure of sufficient severity to require temporary dialysis. Increased capillary endothelial leak may lead to pulmonary edema, with altered lung compliance and worsened gas exchange. Microvascular occlusion from leukocyte aggregates may produce an altered mental status, commonly without focal neurologic findings. Depressed myocardial contractility and arrhythmias can result, leading to increased fluid or vasopressor requirements and worsened perfusion. Finally, systemic activation of complement and cytokines can induce vasodilatation and consequent hypotension. Because of the protean manifestations of the CPBmediated inflammatory response, related signs and symptoms are similar to those resulting from any inflammatory insult and may not be universally present. For example, white blood cell counts may not be elevated, and fever may or may not be present. Urine volumes are typically low,

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Figure 87–1 ■ Pathways of inflammatory activation during cardiopulmonary bypass.

↑ Bradykinin SURGICAL TRAUMA ↑ Kallikrein Factor XII Neutrophil activation Foreign body contact

Complement

Endotoxin translocation

Cytokines

Inflammatory response

Ischemia/reperfusion Monocyte activation Cardiopulmonary bypass

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Detection of Mechanical Complications of Cardiopulmonary Bypass

Complication

Detection

Aortic dissection

Visual inspection of cannula or aorta Abnormal inflow pressure Alterations in peripheral arterial waveform Chest radiography Aortography Transesophageal or epivascular echocardiography Direct palpation Inspection of head and jugular veins Sudden or unexpected changes in CVP while on CPB Transesophageal echocardiography Transcranial Doppler Bubble detectors in CPB circuit Arterial line filters Arterial pressure and flow monitoring during CPB Hypothermia Mixed venous oxygen saturation monitoring Electroencephalography

Dislodgment of aortic debris

Obstruction to venous drainage Embolization

Cerebral hypoperfusion

CPB, cardiopulmonary bypass; CVP, central venous pressure.

Risk Assessment Almost any exposure to CPB induces some degree of systemic inflammation. Nonetheless, several pre-, intra-, and post-CPB factors are known to predispose patients to a clinically relevant, increased inflammatory response. Preoperative Factors. Although the amount and degree of cytokine release does not vary with age, both ischemic heart disease and perioperative left ventricular dysfunction appear to increase the intensity of the cytokine response to CPB. This increased response has been correlated with impaired postoperative hemodynamics and an increase in perioperative complications. Diabetes, particularly when poorly controlled, also appears to increase the inflammatory response. Renal failure, perhaps by impairing the kidneys’ ability to clear pro- and anti-inflammatory mediators, intensifies the inflammatory response as well. In general, a greater perioperative severity of illness predicts a greater inflammatory response. Intraoperative Factors. Both splanchnic hypoperfusion and increased gastrointestinal mucosal permeability occur during CPB. Consequent ischemia-reperfusion injury leads to free radical production, sequestration of pulmonary neutrophils, and possible bacterial translocation and endotoxin formation. Cytokine levels appear to be higher in heart or heart-lung transplant patients, possibly owing to their more severe illness. However, the cytokine levels in patients undergoing valve surgery are similar to the levels in those having coronary artery bypass grafting. Anesthetic Agents. Although most anesthetic agents have some immunomodulatory activity, the clinical impact of their use in patients undergoing CPB is unknown. Both propofol and thiopental (Pentothal) inhibit neutrophil activation, and propofol may enhance anti-inflammatory cytokine production. Morphine down-regulates immune cell function and suppresses the antibody response. Sevoflurane and isoflurane reduce inflammatory cytokine activity.

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and urine sediment frequently demonstrates only acute tubular necrosis. Altered pulmonary mechanics and gas exchange are nonspecific, resemble those of acute respiratory distress syndrome, and can be severe. Neurologic dysfunction may not be focal, manifesting instead as agitation, delirium, or delayed emergence from anesthesia. Hypotension may result from decreased cardiac output or vascular resistance. Systemic vasodilatation responds to α-adrenergic agonists such as norepinephrine, phenylephrine, or vasopressin.

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Although thoracic epidural anesthesia decreases the perioperative stress response, it does not significantly alter the cytokine response due to CPB. Cardiopulmonary Bypass Factors. The data are unclear regarding what effect the type of oxygenator, pump, or extracorporeal circuit and the temperature during CPB have on the duration and extent of the inflammatory response. The duration of CPB has been correlated with interleukin (IL)-8 concentrations and measures of neutrophil adhesion and may alter clinical outcomes for several reasons. Although warm CPB increases the inflammatory response when compared with cold CPB, warm cardioplegia appears to reduce consequent inflammation. Membrane oxygenators produce less inflammation than bubble oxygenators do, but the effects are not sustained and do not alter clinical pulmonary function. No clear effect on outcome has been observed based on CPB prime, type of pump, or pulsatility, although pulsatile flow is associated with less endotoxin release and lower cytokine levels. Transfusion Factors. Allogeneic blood transfusion clearly increases the intensity of the CPB inflammatory response. Autotransfusion of mediastinal blood may not be any better, because such blood contains high levels of tumor necrosis factor-α and IL-6. CPB reservoir blood processed through washing devices typically has higher neutrophil counts than blood in the circulation but significantly lower levels of inflammatory mediators (e.g., IL-1, IL-6, tumor necrosis factor-α). However, cell-saver or similar techniques have no significant effects on bleeding or other CPB-related morbidity and mortality.

Implications The effects of CPB-mediated systemic inflammation can be severe. Global immunosuppression can predispose to sepsis, potentially altering outcomes in susceptible individuals. CPB results in neutrophil sequestration into the lung, with damage to pulmonary epithelial and endothelial surfaces. The consequent increase in pulmonary vascular permeability produces interstitial and alveolar edema, reducing oxygenation and lung compliance. Detectable changes in lung function are present in up to 12% of CPB patients, with severe acute lung injury in as many as 3%. Increased duration of CPB increases both the likelihood and the severity of lung injury. Postoperative neurologic dysfunction is also linked to the CPB inflammatory response. Mechanisms include neutrophilmediated vascular endothelial damage and loss of vasomotor control from inappropriate production of nitric oxide. Mild cognitive dysfunction has been documented in up to 69% of patients, seizures in 5% to 10%, and focal cerebral deficits in 1% to 3%. Perioperative renal dysfunction occurs in 7% to 13% of patients and may increase mortality 20- to 30-fold. The need for dialysis is associated with even greater mortality. Although specific mechanisms linking progression of the CPB inflammatory response to renal dysfunction are incompletely understood, ischemia-reperfusion injury has been shown in animal models. Impaired vascular regulation may play a role in altering glomerular perfusion along with elevated cytokine levels.

Coagulation disorders are an especially relevant sign of the CPB inflammatory response. CPB-induced platelet dysfunction, complement and fibrinolytic cascade activation, and elevated cytokine levels have all been implicated in the hemostatic defects following CPB. Evidence that a reduction in cytokine levels during bypass correlates with less postoperative blood loss supports an inflammatory cause for some of the coagulation deficits that occur after CPB.

MANAGEMENT Management of the inflammatory state following CPB centers primarily on prevention and secondarily on supportive care for end-organ dysfunction. Although no specific agent has been identified that directly modulates the inflammatory response, a number of potentially useful strategies have been studied. Avoidance of Cardiopulmonary Bypass and Aortic Crossclamping. Current evidence suggests that although offpump cardiac surgery does not prevent CPB-induced inflammation, it does diminish the intensity of the response. It is unclear whether this actually improves clinical outcomes. Heparin-Coated Bypass Circuits. The goal of using heparin-coated bypass circuits is to reduce contact-mediated complement activation by decreasing factor XII activation. Use of such circuits does reduce neutrophil and complement activation. When combined with leukocyte filtration, there is a synergistic effect. Trials have shown a benefit only in high-risk groups, with no improvement in outcome in lowrisk patients. It may be that the benefits of heparin-coated circuits are maximal only with prolonged bypass and crossclamp times. Selective Digestive Decontamination. By reducing the endotoxin burden contained in the gut, adverse consequences of gut translocation due to poor perfusion during CPB may be reduced. Early trials of preoperative administration of oral nonabsorbable antibiotics showed decreased endotoxin and cytokine levels after CPB and fewer postoperative infections. However, no decrease in mortality has been observed to date. Hemofiltration and Leukocyte Depletion. By removing inflammatory mediators from the circulation, the CPB inflammatory response may be reduced in scope. In high-risk patients, hemofiltration improves post-CPB renal function and reduces the magnitude of pulmonary complications but has no significant effect on overall outcome. Aprotinin and Other Modulators of the Immune Response. Aprotinin is the best known of the class of agents known as serine protease inhibitors. These drugs reduce systemic inflammation by blocking hydrolysis and activation of inflammatory cascade mediators. Aprotinin is known to reduce blood loss during cardiac surgery, but it also has several anti-inflammatory actions, including limiting platelet activation and decreasing complement and leukocyte activation as well as cytokine levels. Clinical studies have not shown a definite improvement in mortality but have demonstrated reduced blood loss, decreased reoperation rates, fewer perioperative strokes, and less lung reperfusion injury.

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Steroids. Although steroids would seem to have utility in blunting the consequences of uncontrolled inflammation, little outcome benefit has been demonstrated with peri-CPB steroid use. In small studies, steroids have been shown to decrease endotoxin and proinflammatory cytokine levels after CPB. Animal studies have shown that steroids reduce the indicators of pulmonary inflammation and may reduce inflammatory effects on pulmonary, cardiac, renal, and hematologic function. However, no outcome studies clearly show a benefit from perioperative steroid use.

Finally, it should be remembered that systemic infection can mimic the clinical presentation of CPB-related systemic inflammation. The postoperative presence of vasodilatation, pulmonary capillary leak, renal dysfunction, and cardiac dysfunction should thus prompt not only supportive care but also a careful search for infection as a potential treatable cause. Catheter sepsis, mediastinitis, endocarditis, and preexisting pulmonary or urinary tract infections all represent possible sources of systemic infection in postoperative cardiac surgery patients. These causes must be excluded in the presence of systemic inflammation.

PREVENTION

Further Reading Anselmi A, Abbate A, Girola F, et al: Myocardial ischemia, stunning, inflammation, and apoptosis during cardiac surgery: A review of evidence. Eur J Cardiothorac Surg 25:304-311, 2004. Asimakopoulos G, Gourlay T: A review of anti-inflammatory strategies in cardiac surgery. Perfusion 18:7-12, 2003. Chaney MA: Corticosteroids and cardiopulmonary bypass: A review of clinical investigations. Chest 121:921-931, 2002. Laffey JG, Boylan JF, Cheng DCH: The systemic inflammatory response to cardiac surgery: Implications for the anesthesiologist. Anesthesiology 97:215-252, 2002. Mojcik CF, Levy JH: Aprotinin and the systemic inflammatory response after cardiopulmonary bypass. Ann Thorac Surg 71:745-754, 2001. Paparella D, Yau TM, Young E: Cardiopulmonary bypass induced inflammation: Pathophysiology and treatment. An update. Eur J Cardiothorac Surg 21:232-244, 2002. Rady MY, Ryan T, Starr NJ: Early onset of acute pulmonary dysfunction after cardiovascular surgery: Risk factors and clinical outcome. Crit Care Med 25:1831-1839, 1997.

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All the previously described measures are mainly preventive. Once the inflammatory reaction is initiated, treatment is primarily supportive. Maintenance of hemodynamic stability can reduce the extent of subsequent ischemia-reperfusion injury and is obviously mandatory. Mechanical ventilation should be adjusted to avoid overdistention of alveoli and consequent lung injury. Postoperative renal failure may require dialysis; in hemodynamically unstable patients, continuous venovenous hemodialysis may be better tolerated. Hyperglycemia worsens outcomes in cardiac surgery patients, and postoperative blood glucose levels should be kept below 150 mg/dL. Although no truly effective prophylaxis exists for postoperative atrial fibrillation, maintenance of normal electrolytes, perioperative β-blockade, and possibly temporary left or biatrial pacing may reduce its incidence and should be considered in high-risk patients.

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Fast-Track Cardiac Surgery David C. H. Cheng Case Synopsis An 80-year-old man presents with crescendo angina and is scheduled for urgent coronary bypass surgery. Significant medical history includes prior tobacco use, non-insulindependent diabetes mellitus, and prior transient ischemic attacks with occasional slurred speech. Heart catheterization reveals significant coronary artery disease with subtotal occlusion of the left anterior descending coronary artery, complete occlusion of the right coronary artery, and 90% stenosis of the circumflex and acute obtuse marginal branch. Left ventricular ejection fraction is 45%, and the electrocardiogram shows right bundle branch block and an old inferior myocardial infarction. Off-pump coronary artery bypass grafting (CABG) is attempted but is electively converted to on-pump CABG during revascularization, owing to an intramural left anterior descending coronary artery. The aortic cross-clamp is positioned after epiaortic scanning, and all four coronary vessels are revascularized under cardiopulmonary bypass (CPB). A low-dose narcotic and inhalation anesthesia are used for the operation. The patient is separated from CPB with low-dose epinephrine for heart rate control and is transferred to the intensive care unit (ICU) with a sedative dose of propofol. His recovery is uneventful. He is extubated after about 6 hours in the ICU and discharged from the hospital 5.5 days after surgery.

PROBLEM ANALYSIS

between the step-down unit and the ICU, and good communication among cardiac patient management team members.

Definition and Recognition The costs related to the morbidity and mortality associated with cardiac surgery are increasing by about $1.2 billion per year owing to more severe disease, older patients, more extensive medical therapy, and often prior angioplasty or revascularization. Moreover, the number of CABG surgeries doubles every 5 years in the elderly population. With the escalating number of patients requiring cardiac surgery, more efficient use of limited facilities and resources is vital for cost containment in health care delivery. Fast-track cardiac anesthesia (FTCA) is a perioperative anesthetic management regimen designed to facilitate the early tracheal extubation of patients, within 8 hours after cardiac surgery. Although it is feasible to extubate some post-CPB patients in the operating room, the risks (e.g., cardiorespiratory instability, bleeding) outweigh the potential cost-saving benefits, and it is not recommended at most centers. However, it has been demonstrated that early extubation anesthesia is safe and cost-effective and can improve resource use in some cardiac patients. It is important to realize, however, that early tracheal extubation does not necessarily mean early discharge from the ICU or hospital. To achieve maximal cost benefit, a team approach to a FTCA and surgery program must be implemented. This process includes preoperative patient education, same-day admission surgery, an anesthetic protocol conducive to early extubation, expeditious and meticulous surgery, flexibility in ICU nursing shifts, early postoperative extubation, avoidance of complications, horizontal integration 356

Risk Assessment Key considerations for the patient described in the case synopsis are the following: (1) elderly patient with high comorbidity risks (prior myocardial infarction, diabetes, transient ischemic attacks) and critical coronary artery disease; (2) planned off-pump CABG surgery, with unanticipated need for conversion to CPB; and (3) perioperative anesthetic agents and techniques, monitoring, and preventive measures for perioperative anesthetic complications.

Implications MEDICAL Early extubation anesthetic management provides more stable perioperative hemodynamics and adequately suppresses the perioperative stress response without increasing the requirement for vasoactive medications. There is no significant laboratory evidence of greater myocardial injury during the first 48 hours with early versus conventional late extubation (Fig. 88-1). Respiratory mechanics after extubation are comparable between early- and late-extubation patients. The first hour after extubation is most crucial for respiratory care (Table 88-1). Tidal volume and central respiratory drive progressively improve over the first hour after extubation. There is no increased risk for respiratory acidosis, hypoxemia, or atelectasis with early extubation.

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CK:MB enzyme levels (IU/L)

24

Trial

Early Conv

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Favors FTCA

Favors TCA

22 Slogoff 1989

20 18

Bell 1994

16

Cheng 1996

14

Myles 1997

12

Silbert 1998

10

Berry 1998

8 0

6

12

18 24 30 Postoperative hours

36

42

48

Figure 88–1 ■ Comparison of postoperative creatine kinase MB (CK-MB) enzyme levels between early and conventional (Conv) extubation groups over 48 hours. (From Cheng DCH, Karski J, Peniston C, et al: Morbidity outcome in early versus conventional tracheal extubation after coronary artery bypass grafting: A prospective randomized controlled trial. J Thorac Cardiovasc Surg 112:755-764, 1996.)

Table 88–1

■

Apnea* in Early- and Late-Extubated Patients after Coronary Artery Bypass Grafting

Incidence of apnea episodes Duration of apnea (sec) Index (apnea episodes/hr) 1 hr 2 hr 3 hr 4 hr

Early

Late

27.5% (14/51) 17.7 ± 23.0

33.3% (17/51) 15.7 ± 28.6

13 4 2 2

15 8 9 8

*Apnea is defined as expiratory pause of more than 10 seconds or tidal volume of less than 100 mL as measured with inductive plethysmography. From Cheng DCH, Karski J, Peniston C, et al: Morbidity outcome in early versus conventional tracheal extubation after coronary artery bypass grafting: A prospective randomized controlled trial. J Thorac Cardiovasc Surg 112:755-764, 1996.

1.00

10.00

Relative risk

Figure 88–2 ■ Relative risk of mortality with a low-dose opioid regimen (fast-track cardiac anesthesia [FTCA]) and the more traditional high-dose opioid regimen (traditional cardiac anesthesia [TCA]). (From Myles PS, Daly DJ, Djaiani G, et al: A systematic review of the safety and effectiveness of fast track cardiac anesthesia. Anesthesiology 99:982-987, 2003.)

37 randomized trials revealed that off-pump bypass does not significantly reduce mortality, stroke, myocardial infarction, or renal dysfunction compared with conventional CABG with CPB. Further, off-pump CABG may improve selected 30-day clinical outcomes (e.g., reduced postoperative atrial fibrillation, respiratory infections, and need for inotropic support or blood transfusions) without measurable increased risk to the patient. At the same time, off-pump CABG reduces resource utilization, including ventilation time and ICU and total hospital length of stay, leading to potential reductions in hospitalization costs. However, there is an increased risk for significant mortality and morbidity in patients emergently converted from off-pump to conventional CABG with CPB. Economic The strongest predictors of cost for cardiac surgical patients are patient age, operating room time, ICU and hospital length of stay, and postoperative complications. Differences in CABG costs are primarily a reflection of accounting methods (e.g., charges, actual patient costs, reimbursed costs). Additional important factors are the following: ●

●

● ●

Are costs reimbursed by a health maintenance organization or managed care provider? Is CABG performed in a teaching hospital or a community cardiac center? Are physician fees or cardiac catheterization costs included? What is the impact of patient-specific factors (e.g., number of coronary vessels grafted, extent and severity of postoperative complications)?

Early extubation protocols significantly lower CABG costs compared with more traditional management methods. They also reduce the intensity of nursing care by reducing ICU and hospital length of stay and by allowing more timely patient mobilization and hospital discharge. Early extubation

CARDIOTHORACIC & VASCULAR SURGERY

Also, early extubation improves the intrapulmonary shunt fraction by 30% to 40% after CABG. Cognitive function has also been shown to return to baseline earlier in patients given early extubation versus conventional anesthetic management. This allows earlier mobilization and oral intake of food in the early postoperative period, resulting in shorter ICU and hospital length of stay. Importantly, early extubation does not increase ICU readmission or mortality rates. A systematic review and meta-analysis of 10 randomized trials in adult cardiac surgical patients undergoing CABG or valve surgery with CPB showed a nonsignificant reduction in mortality in patients undergoing FTCA versus traditional care based on high-dose opioids, as well as no significant difference between groups with respect to major morbidity (Fig. 88-2). Currently, approximately 25% of all CABG surgery in the United States is off-pump CABG. A meta-analysis of

0.10

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Preoperative Care

Total Costs for Early- and Late-Extubation Anesthesia, Including Complications Costs (Canadian $)

Preoperative Operating room Cardiovascular ICU Postoperative ward CABG: mean CABG: median

Early (n = 50)

Late (n = 50)

P

1347 ± 7619 ± 6463 ± 4169 ± 19,596 17,269

1353 ± 7755 ± 12,046 4963 ± 26,116 19,372

.76 .24 .026 .25 .019 .019

104 499 4943 1426 ± 5766

92 653 ± 16,573 3068 ± 18,175

CABG, coronary artery bypass grafting; ICU, intensive care unit. From Cheng DCH, Karski J, Peniston C, et al: Early tracheal extubation after coronary artery bypass graft surgery reduces costs and improves resource use: A prospective randomized controlled trial. Anesthesiology 85:1300-1310, 1996.

also improves ICU use and allows for increased caseloads with significantly fewer surgery cancellations (0.3% versus 2.0%). Finally, it results in up to a 28% lower rate of ICU readmission. Importantly, to reduce perioperative costs, in addition to improving efficiency, perioperative morbidity rates must be minimized. This is because postoperative complications are far more costly than uncomplicated recoveries. Postoperative myocardial infarction or stroke can increase the cost of CABG three- to fivefold, infection two- to fourfold, and repeat surgery for postoperative bleeding or atrial arrhythmia control by 30% to 40%. Early extubation anesthesia can be performed without increasing CABG complication rates while reducing ICU costs by 53% and overall costs by 25% (Table 88-2). In a 1-year follow-up study of FTCA patients after surgery, there was also evidence of reduced resource utilization after their index hospital discharge. Fifteen patients (25%) from both groups were readmitted to acute care hospitals during the follow-up period. The mean length of stay for acute care readmission was 0.3 day in the FTCA group and 1.6 days in the conventional group at 3 months (95% confidence interval [CI], 0.1 to 5.7; P = .01); it was 0.8 and 2.9 days, respectively, at 12 months (95% CI, 0.2 to 7.5; P = .01). The cost reduction associated with FTCA was 68% at 3 months and 50% at 1 year.

MANAGEMENT An effective FTCA program requires appropriate patient selection, a balanced anesthetic technique (i.e., low-dose opioids and inhalational agents), early tracheal extubation, a short stay in a postoperative unit, and coordinated perioperative care. It is also necessary to avoid postoperative complications such as excessive bleeding, myocardial ischemia, low cardiac output states, stroke, arrhythmias, and renal failure. Finally, it is important for anesthesiologists to participate in the development and implementation of an FTCA and surgery program, based on their knowledge of perioperative medicine and skills with perioperative management.

Preoperative patient education is important to reduce anxiety and to establish realistic patient expectations. A preadmission clinic and same-day surgery program can reduce hospital length of stay by 1 to 2 days. Further, it reduces surgery cancellation or delays due to abnormal test results or patients’ suboptimal clinical condition.

Intraoperative Care The anesthetic regimen consists of balanced anesthesia with a low-dose narcotic, propofol, and inhalational agents: ●

●

●

●

● ●

●

Sedation: intravenous midazolam (1 to 3 mg) for line instrumentation Prophylactic antifibrinolytic treatment: intravenous tranexamic acid (50 to 100 mg/kg over 15 minutes) or aprotinin (6 million units total for induction, CPB, and post-CPB) Induction: propofol (0.5 mg/kg) or thiopental (1 mg/kg), low-dose narcotic (up to 10 μg/kg fentanyl, or 1 to 2 μg/kg sufentanil, or 1 μg/kg per minute remifentanil), rocuronium (0.10 mg/kg), and midazolam (1 to 3 mg) Before CPB: inhalational agent (isoflurane, sevoflurane, or desflurane) During CPB: inhalational agents After CPB: postoperative analgesia (indomethacin 50 to 100 mg as needed, if not contraindicated) is essential, and sedation (propofol) is titrated to allow tracheal extubation within 1 to 6 hours Fluids and arrhythmia: tight fluid balance and aggressive arrhythmia control

Trials of remifentanil in cardiac surgery suggest that it provides excellent hemodynamic stability, minimal elevation of catecholamines, and reliable awakening, with most patients being eligible for early extubation. A remifentanil infusion and a low-dose fentanyl-based anesthetic regimen appear to be equivalent in the following respects: time to tracheal extubation, need for less intense monitoring, ICU and hospital length of stay, and resource utilization after CABG surgery. However, remifentanil’s short duration of action necessitates the use of one or more supplementary methods for postoperative analgesia. These must be started before cessation of the remifentanil infusion. Inhalational anesthetic agents have been recommended to provide cardioprotective effects via preconditioning and the reduction of reperfusion injury. The cardioprotective effects of sevoflurane appear to be most efficacious when the agent is administrated throughout the operation. Shorter-acting neuromuscular blocking drugs should be used in FTCA; at a minimum, reversal of pancuronium neuromuscular blockade should be done before commencing weaning from mechanical ventilation. Hemofiltration, but not steroids, results in earlier tracheal extubation following CPB. Intrathecal morphine doses as low as 250 μg are effective for reducing pain scores and postoperative parenteral opiate requirements, but their effect on time to tracheal extubation is not clear. Also, numerous well-conducted clinical trials have demonstrated a reduced time to tracheal extubation with thoracic epidural anesthesia in patients undergoing

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cardiac surgery. However, when compared with general anesthesia designed to facilitate early tracheal extubation, the differences are arguably of little clinical significance, because the majority of patients receiving thoracic epidural anesthesia still require ICU admission for a brief period of ventilation. Also, the majority of patients having general anesthesia can be extubated within 8 hours, so either technique appears to be consistent with FTCA. Transesophageal echocardiography (TEE) during CABG surgery remains a class II indication and is valuable or informative in 15% to 50% of cases and essential in 5% to 20%. Epiaortic echocardiography is the current gold standard for diagnosing and evaluating patients for ascending aortic atherosclerosis during heart surgery. Results of urgent TEE in hemodynamically unstable patients or those with thromboembolic phenomena in the post-cardiac surgery ICU are unpredictable in more than half of cases. Clinical management is often modified based on TEE findings, and TEE is essential for the management of hemodynamically unstable patients after cardiac surgery.

Postoperative Care

Table 88–3

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Independent Predictors of Delayed Extubation by Multiple Logistic Regression Analysis

Independent Predictors

No. of Patients (%)

Odds Ratio

P

Age (versus <60 yr) 60-69 yr 70-79 yr ≥80 yr Intraoperative inotropes Intraoperative IABP Postoperative atrial arrhythmias

338 (38.1) 193 (21.8) 18 (2.0) 61 (6.9) 57 (6.4) 109 (12.3)

1.67 2.22 1.86 1.86 3.58 1.85

.0004 .0004 .0004 .004 .0001 .003

IABP, intra-aortic balloon pump. From Wong DT, Cheng DCH, Kustra R, et al: Risk factors of delayed extubation, prolonged length of stay in the intensive care unit, and mortality in patients undergoing CABG with fast track cardiac anesthesia: A new cardiac risk score. Anesthesiology 91:936-944, 1999.

■

Fast-Track Cardiac Surgery

359

Tracheal Extubation Guidelines

Central nervous system: Responsive and cooperative Cardiovascular system: CI >2.0; absence of uncontrolled arrhythmia Respiratory system: VC >10 mL/kg, NIF >–20 mm Hg; pH >7.30, PaO2 >80 on FiO2 < 0.5 Bleeding: Chest tube drainage <100 mL/hr Renal: Urine output >0.5 mL/kg/hr Temperature: >36.5°C CI, cardiac index; FiO2, fraction of inspired oxygen; NIF, negative inspiratory force; PaO2, arterial oxygen tension; VC, vital capacity.

extubation protocols. Early extubation may allow for chest tube removal, mobilization, and food intake on postoperative day 1, facilitating early ICU discharge and hospital discharge by days 4 to 5. Finally, health care providers should be cognizant of the need for continuous improvement in quality of care and for cost savings, which can be facilitated by following appropriate weaning and extubation guidelines, arrhythmia management regimens, post-valvular anticoagulation protocols, and ICU and hospital discharge guidelines (Table 88-5).

PREVENTION Bleeding and Chest Re-exploration. The incidence of postoperative bleeding necessitating chest re-exploration ranges from 1% to 5%. The common use of the potent antiplatelet medications (glycoprotein IIb/IIIa receptor antagonists) abciximab, eptifibatide, and tirofiban necessitates the delay of elective cardiac surgery for 1 to 2 days, 2 to 4 hours, or 3 to 4 hours, respectively, after discontinuing these medications. Aprotinin is more effective in preventing postoperative bleeding than either tranexamic acid or ε-aminocaproic acid, and it may provide additional antiinflammatory protection. Because of its high cost, aprotinin is usually reserved for cases with a high likelihood of allogeneic blood transfusion (e.g., reoperations, combined CABG-valve procedures, aortic surgery). Atrial Arrhythmia. Atrial fibrillation is common after cardiac surgery, occurring in up to 35% of patients. Drugs with β-blocking properties are effective at reducing the frequency of postoperative atrial fibrillation. The added benefit versus

Table 88–5

■

Intensive Care Unit Discharge Guidelines

Central nervous system: Alert and cooperative Cardiovascular system: No uncontrolled arrhythmia; stable hemodynamics Respiratory system: PaO2 > 80, PaCO2 < 60, SaO2 > 90% at ≤60% facemask Bleeding: Chest tube drainage <50 mL/hr × 2 hr Renal: Urine output >0.5 mL/kg/hr PaCO2, arterial carbon dioxide tension; PaO2, arterial oxygen tension; SaO2, arterial oxygen saturation.

CARDIOTHORACIC & VASCULAR SURGERY

Although high-risk patients are more likely to incur postoperative complications, both intraoperative and postoperative complications ultimately determine whether early extubation and reduced ICU length of stay are possible (Table 88-3). All patients should be assessed for the feasibility of tracheal extubation once certain criteria are met (Table 88-4). Nonsteroidal anti-inflammatory drugs have been used widely in cardiac surgery patients who lack contraindications such as peptic ulcer, renal impairment, or coagulopathies. Diclofenac appears to be more effective than indomethacin and ketoprofen. Enteric-coated aspirin is routinely given postoperatively and is associated with a reduced risk of death and major complications after CABG surgery. Nursing support is needed to achieve 1-day ICU stays and transfer to the floor or a step-down unit. There must be appropriate changes in analgesia and sedation practices and adherence to accelerated weaning and tracheal

Table 88–4

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the safety of combining class III antiarrhythmic activity (e.g., amiodarone) with β-blocking activity is not clearly defined. Therefore, the use of amiodarone to prevent or manage postoperative atrial fibrillation should be considered on a case-by-case basis (assessing risk versus benefit). The role of magnesium for the prevention of atrial fibrillation is not clearly defined, but it is usually well tolerated. Biatrial pacing is likely to reduce the incidence of postoperative atrial fibrillation, but the ideal pacing strategy (i.e., left, right, or biatrial pacing) remains to be defined. Stroke. Stroke occurs in 2% to 4% of patients after cardiac surgery and carries a high 1-year mortality of 15% to 30%. Steps to reduce the perioperative stroke rate have been suggested and include routine epiaortic scanning for cannulation and cross-clamping, higher CPB perfusion pressure, avoidance of unprocessed cardiotomy blood, and preservation of cerebral oximetry. Renal Failure. Approximately 8% to 15% of cardiac surgery patients sustain moderate renal injury (>1.0 mg/dL peak creatinine rise), with 1% to 5% requiring dialysis. Patients with preexisting renal dysfunction are at greater risk for needing dialysis. However, patients with preexisting renal dysfunction are not at greater risk for additional renal injury relative to baseline. Steps to minimize postoperative acute renal injury include higher CPB flow rates and avoidance of excessive hemodilution during CPB (e.g., hematocrit <20%).

Further Reading Chaney MA: Intrathecal and epidural anesthesia and analgesia for cardiac surgery. Anesth Analg 84:1211-1221, 1997. Cheng DCH: Fast track cardiac surgery pathways: Early extubation, process of care, and cost containment. Anesthesiology 88:1429-1433, 1998. Cheng DC, Bainbridge D, Martin JE, et al: Does off-pump coronary artery bypass reduce mortality, morbidity and resource utilization when compared to conventional coronary artery bypass? A meta-analysis of randomized trials. Anesthesiology 102:188-203, 2005. Cheng DCH, Byrick RJ, Knobel E: Structural models for intermediate care areas. Crit Care Med 27:2266-2271, 1999. Cheng DCH, Karski J, Peniston C, et al: Early tracheal extubation after coronary artery bypass graft surgery reduces costs and improves resource use: A prospective randomized controlled trial. Anesthesiology 85:1300-1310, 1996.

Cheng DCH, Karski J, Peniston C, et al: Morbidity outcome in early versus conventional tracheal extubation after coronary artery bypass grafting: A prospective randomized controlled trial. J Thorac Cardiovasc Surg 112:755-764, 1996. Cheng DCH, Newman M, Duke P, et al: Efficacy and resource utilization of remifentanil and fentanyl in fast track CABG surgery: A prospective randomized double blind controlled multicenter trial. Anesth Analg 92:1094-1102, 2001. Cheng DCH, Wall C, Djaiani G, et al: A randomized assessment of resource utilization in fast-track cardiac surgery one-year after hospital discharge. Anesthesiology 98:651-657, 2003. Cohen DJ, Breall JA, Ho KKL, et al: Economics of elective coronary revascularization: Comparison of costs and charges for conventional angioplasty, directional arthrectomy, stenting and bypass surgery. J Am Coll Cardiol 22:1052-1059, 1993. De Hert SG, Van der Linden PJ, Cromheecke S, et al: Cardioprotective properties of sevoflurane in patients undergoing coronary surgery with cardiopulmonary bypass are related to the modalities of its administration. Anesthesiology 101:299-310, 2004. Dowd N, Cheng DCH, Karski J, et al: Intraoperative awareness in fast track cardiac anesthesia. Anesthesiology 89:1068-1073, 1998. Dowd NP, Karski JM, Cheng DCH, et al: Cognitive recovery and resource utilization following fast track cardiac anesthesia for CABG surgery in the elderly: Propofol versus benzodiazepines. Br J Anaesth 86:68-76, 2001. Edgerton JR, Dewey TM, Magee MJ, et al: Conversion in off-pump coronary artery bypass grafting: An analysis of predictors and outcomes. Ann Thorac Surg 76:1138-1143, 2003. Engelman RM, Rousou JA, Flack JE, et al: Fast-track recovery of the coronary bypass patient. Ann Thorac Surg 58:1742-1746, 1994. Hynninen MS, Cheng DC, Hossain I, et al: Non-steroidal anti-inflammatory drugs in treatment of postoperative pain after cardiac surgery. Can J Anaesth 47:1182-1187, 2000. Kogan A, Cohen J, Raanani E, et al: Readmission to the intensive care unit after “fast-track” cardiac surgery: Risk factors and outcomes. Ann Thorac Surg 76:503-507, 2003. Mangano D: Aspirin and mortality from coronary bypass surgery. N Engl J Med 347:1309-1317, 2002. Myles PS, Daly DJ, Djaiani G, et al: A systematic review of the safety and effectiveness of fast track cardiac anesthesia. Anesthesiology 99:982-987, 2003. Wake PJ, Ali M, Carroll J, et al: Clinical and echocardiographic diagnoses disagree in patients with unexplained hemodynamic instability after cardiac surgery. Can J Anaesth 48:778-783, 2001. Westaby S, Pillai R, Parry A, et al: Does modern cardiac surgery require conventional intensive care? Eur J Cardiothorac Surg 7:313-318, 1993. Wong DT, Cheng DCH, Kustra R, et al: Risk factors of delayed extubation, prolonged length of stay in the intensive care unit, and mortality in patients undergoing CABG with fast track cardiac anesthesia: A new cardiac risk score. Anesthesiology 91:936-944, 1999.

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89

Komal Patel and Mark A. Chaney Case Synopsis An obese 53-year-old woman with right-sided heart failure and ovarian cancer has an exploratory laparotomy under general anesthesia for tumor debulking. On postoperative day 1, she experiences sudden-onset shortness of breath.

PROBLEM ANALYSIS Definition and Recognition

● ●

●

●

●

●

●

Coagulation factors circulate in inactive form. Normal blood flow dilutes the concentration of activated factors and removes them from the site of injury. These are subsequently removed from the circulation by the liver and reticuloendothelial system. Some coagulation factors (e.g., factor Xa) require a phospholipid surface (tissue factor, platelet phospholipid) for proper interaction. Antithrombin (AT; formerly known as antithrombin III) complexes with and inactivates thrombin as well as other circulating coagulation factors (with the exception of factor VII). AT molecules have two critical domains: one binds to thrombin and other activated clotting factors, and the other binds heparin. In the presence of heparin, the rate of AT binding to thrombin and other activated clotting factors is markedly accelerated. Thrombin binds to thrombomodulin (a protein located on the vascular endothelial surface), which activates protein C, thereby inactivating factors Va and VIIIa. Protein S is a cofactor (along with protein C) in the inactivation of factors Va and VIIIa. Tissue factor pathway inhibitor is synthesized by vascular endothelium and inhibits factor X in two ways: it directly inhibits factor Xa, and it complexes with factor Xa to inhibit tissue factor VIIIa, thereby inhibiting the extrinsic pathway.

Hypercoagulable states represent a spectrum of processes that increase the activation of coagulation, decrease endogenous anticoagulation, or decrease the activity of thrombolytic systems. These disorders may be qualitative or quantitative, and their clinical manifestations depend on the severity of the disorder. Hypercoagulable disorders are classified as inherited disorders (conditions for which specific defects of the endogenous anticoagulation system have been identified; Table 89-1) or acquired disorders (disease or states associated with increased risk of thrombotic complications compared with that in general population; Table 89-2). 361

CARDIOTHORACIC & VASCULAR SURGERY

More than 150 years ago, Virchow suggested a triad that leads to intravascular coagulation: injury to blood vessels, venous stasis, and hypercoagulability. Injury to blood vessels, as might occur with direct trauma, major burns, surgical manipulation, or central venous access, causes endothelial damage, leading to the formation of local clot (thrombus) and subsequent propagation (thromboembolism). Venous stasis, as might occur in anesthetized surgical or immobilized patients, results in sluggish venous flow and a propensity for thrombus formation. An understanding of hypercoagulability requires a basic knowledge of the coagulation process. Thrombus formation is triggered by endothelial injury, exposing subendothelial collagen to circulating platelets. These adhere and form a platelet plug. As this is forming, the clotting cascade is activated via one of two pathways. In the intrinsic pathway, subendothelial collagen is activated through activation of factor XII (which requires factors VIII, IX, and XI). In the extrinsic pathway, tissue thromboplastin (tissue factor) is released by injured tissue to activate factor VII. The final (common) pathway begins with activated factor X (Xa). Once factor X is activated, it binds with its cofactor, factor V, and platelet phospholipid, and this complex activates prothrombin (factor II) to form thrombin (factor IIa). Thrombin, bound to platelet phospholipid, cleaves fibrinogen to fibrin monomers. These aggregate to form a fibrin polymer that is loosely held together by hydrogen bonds (soluble fibrin, or fibrin S). Subsequently, factor XIII (fibrin stabilizing factor), which is activated by thrombin and calcium ions, mediates the formation of covalent peptide bonds between the fibrin monomers to yield a stable fibrin clot (insoluble fibrin, or fibrin I). Normally, the clotting process is balanced by an endogenous anticoagulant and thrombolytic system that limits clot formation and eventually dissolves the clot. Thrombolysis is initiated by tissue-type plasminogen activator (t-PA) from injured cells near the fibrin clot. As t-PA cleaves circulating plasminogen to plasmin, this dissolves fibrin within the clot matrix.

Several physiologic mechanisms regulate the coagulation process, thus limiting clot formation to the injured area and preventing excessive clotting (i.e., disseminated intravascular coagulation [DIC]):

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Table 89–1

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Inherited Disorders Causing Hypercoagulable States

Affected Component

Expression

Factor V gene mutation

Resistance to activated protein C by factor V Increased prothrombin production Deficiency and dysfunction Deficiency and dysfunction Deficiency Dysfunctional protein Deficiency Deficiency Deficiency or dysfunctional protein Deficiency Elevation

Prothrombin gene mutation Antithrombin Protein C Protein S Fibrinogenemia Heparin cofactor II Procoagulant factor Plasminogen Plasminogen activator Plasminogen activator inhibitor-1

INHERITED HYPERCOAGULABLE DISORDERS Factor V Leiden Mutation and Resistance to Activated Protein C. Activated factor V serves as a cofactor in the conversion of prothrombin to thrombin. Factor Va is inactivated by activated protein C. A single point mutation in the factor V gene (R506Q [factor V Leiden]) makes the molecule resistant to degradation by activated protein C and thus leads to a hypercoagulable state by increasing the generation of thrombin. About 3% of the general population is heterozygous for this mutation. It accounts for 21% to 25% of patients with recurrent deep venous thrombosis (DVT). Prothrombin Gene Mutation. A specific point mutation in the prothrombin gene (G20210A) results in a 30% increase in the plasma prothrombin levels. Heterozygotes account for about 6% to 18% of patients with recurrent DVT.

Table 89–2

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Acquired Disorders Predisposing to Thrombosis

Venous Stasis Immobilization Pregnancy Congestive heart failure Varicosities Obesity

Coagulation Activation Trauma Surgery Malignancies Factor IX concentrates Lupus inhibitor Myocardial infarction Myeloproliferative disorders Nephrotic syndrome Oral contraceptives

Abnormal Vascular Surface Atherosclerosis, hyperlipidemia

Diabetes Homocysteinemia Cigarette smoking Estrogen therapy Prosthetic cardiovascular device Indwelling vascular catheters

Vascular Occlusive Disorders Hyperviscosity, polycythemia Sickle cell disease Plasma cell dyscrasias

Increased Platelet Reactivity Thrombocytosis Surgery

Antithrombin Deficiency. AT is an α2-globulin synthesized in the liver that inactivates thrombin; factors XIIa, XIa, Xa, and IXa; and kallikrein. AT deficiency was the first identified cause of hereditary hypercoagulable disorders. It is inherited in an autosomal dominant fashion and accounts for approximately 0.5% to 1% of patients with recurrent DVT. Protein C and Protein S Deficiency. Proteins C and S are vitamin K–dependent plasma proteins that inactivate factors Va and VIIIa. Their deficiency is transmitted in an autosomal dominant fashion and accounts for 5% to 10% of patients with recurrent DVT. ACQUIRED HYPERCOAGULABLE DISORDERS Acquired Protein C Deficiency. Acquired protein C deficiency has been observed in patients with DIC, acute leukemia, hepatic disease, and nephrotic syndrome; renal transplant patients; and patients taking warfarin or oral contraceptives. Malignancy. The incidence of clinical thromboembolic disease in patients with cancer has been estimated to be as high as 11%. Thrombotic episodes may precede the diagnosis of malignancy by months to years. It may present as migratory superficial thrombophlebitis (Trousseau’s syndrome), DVT, DIC, nonbacterial thrombotic endocarditis, or, rarely, arterial thrombosis. Tumors may secrete procoagulants (cysteine protease, tissue factor–like procoagulant). Tumors can also lead to venous thrombosis by external compression, vascular invasion (renal tumor), or hepatic involvement and dysfunction. Pregnancy. Pregnancy and the postpartum period are associated with the presence of all three components of Virchow’s triad: venous stasis within the lower extremity veins (the gravid uterus impedes venous return), endothelial injury to the pelvic veins produced during delivery, and hypercoagulability. Pregnancy is also associated with increases in factors I, II, VII, VIII, IX, and X, along with decreases in protein S and AT activity. In addition, the activity of fibrinolytic inhibitors PAI-1 and PAI-2 is increased during pregnancy. Surgery. DVT and pulmonary emboli may occur postoperatively. Thrombosis in surgical patients appears to be related to surgical tissue trauma and the liberation of tissue factor, leading to thrombin formation. In addition, inflammation (leukocyte reactivity) and surgery-induced hemostatic changes may contribute to thromboembolism (Table 89-3). Hemostatic changes appear to correlate with the type of surgery and magnitude of surgical intervention and are maximal during the first 48 hours after surgery. Immobilization. It is postulated that venous stasis contributes to thrombosis by causing local hypoxia (with resulting endothelial injury) and inadequate clearance of activated procoagulant proteins. Myeloproliferative Disease. Patients with myeloproliferative disorders (e.g., polycythemia rubra vera, essential thrombocythemia, myelofibrosis with myeloid metaplasia, agnogenic myeloid metaplasia, megakaryocytic myelosis, chronic myelocytic leukemia) have an increased incidence of

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Table 89–3

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Surgery-Induced Hemostatic Changes

Increased Platelet Reactivity

↑ Von Willebrand’s factor ↑ Thrombin formation

↑ Aggregation ↑ Dense granule release

Decreased Endogenous Anticoagulants

Increased Leukocyte Reactivity

↓ Antithrombin III ↓ Heparin cofactor II ↓ Tissue factor pathway inhibitor ↓ Protein C, protein S

↑ Free radical release ↑ Surface adhesion molecules

Increased Coagulation Cascade Activation ↑ Fibrinogen ↑ Factor VIII

■

Decreased Fibrinolysis ↑ Plasminogen activator inhibitor-1

Hypercoagulable States: Thrombosis and Embolism

mutations affecting the cystathion β-synthase (CBS) gene or the methylenetetrahydrofolate reductase (MTHFR) gene. Other Factors. Other factors that may be associated with hypercoagulable states are nephrotic syndrome, oral contraceptive use, hormone replacement therapy, prolonged travel, heavy smoking, hypertension, paroxysmal nocturnal hemoglobinuria, heparin-induced thrombocytopenia, thrombocytosis, and inflammatory bowel disease. THROMBOEMBOLISM Arterial thromboembolism may lead to cerebral or other vital end-organ infarction. For all intents and purposes, venous thromboembolism is pulmonary embolism, which has the following pathophysiologic effects: ●

thrombotic events. Both arterial and venous thrombosis may occur at unusual anatomic sites, including the mesenteric, renal, splenic, portal, and hepatic (Budd-Chiari syndrome) circulations.

●

● ●

● ●

Increased pulmonary vascular resistance secondary to vascular obstruction, neurohumoral mediators, cytokines, and reflex vasoconstriction Impaired gas exchange secondary to increased alveolar dead space, ventilation-perfusion mismatch, and rightto-left shunt Compensatory alveolar hyperventilation Right heart dysfunction and dilatation secondary to increased pulmonary artery pressure, wall tension, oxygen consumption, and ischemia Bronchoconstriction and increased airway resistance Reduced lung compliance secondary to edema, hemorrhage, and surfactant loss

Risk Assessment

Lupus Anticoagulant. Lupus anticoagulants are antiphospholipid antibodies (usually immunoglobulin [Ig] G and, rarely, IgM) directed against plasma proteins (e.g., β2glycoprotein I, prothrombin, annexin V) bound to anionic phospholipids. Lupus anticoagulants occur in about 5% to 10% of patients with systemic lupus erythematosus. They block the in vitro assembly of the prothrombinase complex, resulting in a prolongation of protein assays such as activated partial thromboplastin time, dilute Russell viper venom time, kaolin plasma clotting time, and, rarely, prothrombin time. Although these changes suggest impaired coagulation, patients with lupus anticoagulants have a paradoxical increase in the frequency of arterial and venous thrombotic events. The mechanism for thrombosis is incompletely understood but may involve IgG binding to phospholipids that are essential for the normal activating and degrading effects of protein C and protein S, thus shifting the balance in favor of thrombus formation.

INHERITED HYPERCOAGULABLE STATES

Hyperhomocysteinemia. High levels of homocysteine are associated with both venous and arterial thrombosis. The mechanism by which hyperhomocysteinemia predisposes to thrombosis is unclear; however, potential mechanisms include endothelial activation, proliferation of smooth muscle cells, changes in endothelial nitric oxide production, or changes in endothelial sterol metabolism. The disorder can be congenital or acquired. Acquired forms are found in patients with dietary deficiencies of folate, vitamin B12, or vitamin B6. Congenital hyperhomocysteinemia is most commonly due to

Malignancy. Intravascular thrombus formation can occur with any malignancy but is more common with neoplasms of the mucin-secreting organs (gastrointestinal and pulmonary). Migratory superficial thrombophlebitis occurs in up to 10% of patients with pancreatic carcinoma. Patients with malignancy also have other predisposing factors for venous thrombosis (e.g., surgery, immobilization).

The prevalence of factor V Leiden mutation and prothrombin gene mutation in patients with DVT is about 21% to 25% and 6% to 18%, respectively. However, patients with these mutations have a relatively low risk for thrombosis. By age 65 years, only about 6% of carriers of these mutations have experienced venous thrombosis, with most thrombotic events occurring during high-risk periods such as surgery. The frequency of factor V Leiden varies by ethnicity; it is common in people of European descent but rare in those of African or Asian descent. AT deficiency accounts for only 0.5% to 1% of patients with DVT, but more than 50% of affected patients experience venous thrombotic events by age 60 years. Protein C and protein S deficiency accounts for 0.5% to 4% and 1% to 7% of patients with DVT, respectively. ACQUIRED HYPERCOAGULABLE STATES

Pregnancy. Pregnancy is associated with an approximate sixfold increased risk of venous thromboembolism compared

CARDIOTHORACIC & VASCULAR SURGERY

Hyperviscosity Syndrome. Blood viscosity is increased when there is an elevated red cell mass (polycythemia), increased immature adherent leukocytes (aplastic anemia), deformed red cell membrane (sickle cell anemia), and increased globulin concentrations (plasma cell disorders). Sluggish flow associated with these conditions can result in vascular occlusion in any vascular bed. It is believed that immature white cells cause leukostasis; this in turn releases proteases, which promote thrombus formation.

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with nonpregnant patients (see also Chapter 196). Risk is greatest in the third trimester and first month post partum. The incidence of DVT and pulmonary embolism has been estimated to be as high as 0.05% to 0.1%. Pulmonary embolism is estimated to account for 12% of fatalities during pregnancy. Risk factors for thrombosis in pregnancy include increasing age, cesarean delivery, prolonged immobilization, obesity, prior thromboembolism, and coexistent thrombophilia. Surgery. Orthopedic procedures on the hip and lower extremities are among the most thrombogenic surgical procedures. In the absence of prophylaxis, the risk of DVT after total knee replacement ranges from 45% to 70%, and fatal pulmonary embolism has been reported to occur in 1% to 3% of patients undergoing hip surgery. Coronary artery bypass grafting surgery is associated with up to a 20% risk of DVT and a 4% risk of pulmonary embolism. Although the risk of thromboembolism is greatest during the first 2 postoperative days, embolic events may occur weeks to months after knee or hip surgery. Immobilization. Conditions leading to prolonged immobility (e.g., heart failure, stroke, spinal cord injury, old age, obesity, major trauma, surgery) increase the risk for hypercoagulability. DVT incidence rates of 58% in patients after major trauma and 33% in immobilized patients requiring medical intensive care have been reported. Myeloproliferative Disease. There is a correlation between elevated hematocrit, blood viscosity, and occlusive vascular events. Indwelling Vascular Catheters. Thrombotic complications are common with central venous catheters and are often associated with catheter sepsis. Thrombosis can be due to fibrin deposition or vascular occlusion.

Implications Because the heparin effect (anticoagulation) depends on adequate AT levels, patients with AT deficiency may not respond appropriately to heparin. The use of warfarin may produce a deficiency in protein C and protein S before anticoagulation, which is responsible for warfarin-induced skin necrosis. For patients with hypercoagulable states, heparin therapy may be indicated for conditions that significantly increase the risk of venous thrombosis and pulmonary embolism (e.g., surgery, major trauma, immobilization).

MANAGEMENT Except for AT deficiency (see Prevention), there is no specific therapy for hypercoagulable states other than anticoagulation with heparin (standard unfractionated or low molecular weight) or warfarin to prevent pulmonary embolism and thrombolysis (streptokinase, urokinase, recombinant t-PA) to dissolve clots. Nonspecific measures include hemodilution and avoidance of factors that might increase blood viscosity or facilitate coagulation (e.g., packed red blood cells, plasma, calcium).

Treatment of pulmonary embolism may be primary or secondary. Primary treatment to remove clot includes thrombolysis, catheter embolectomy, clot fragmentation, or surgical embolectomy. Secondary treatment for the prevention of recurrences includes systemic anticoagulation (heparin, warfarin) and inferior vena cava filters (e.g., bird’s nest or Greenfield filters).

PREVENTION Preventive measures for venous thrombosis and pulmonary embolism in high-risk patients include subcutaneous lowmolecular-weight or unfractionated heparin, graduated compression stockings, and pneumatic compression devices. Fondaparinux (a synthetic heparin pentasaccharide) has been approved by the Food and Drug Administration for the prophylaxis of DVT in patients undergoing surgery for hip fracture or hip or knee replacement. Recombinant hirudin preparations have been used as prophylactic agents for DVT in European countries. In the United States, they are currently approved only for the treatment of heparin-induced thrombocytopenia. The following preventive measures should be considered for patients with acquired or inherited hypercoagulable states. Antithrombin Deficiency. AT concentrations routinely decrease after surgery but can be increased with the administration of plasma. Recombinant human AT is also available, and its use should be considered perioperatively in patients with AT deficiency, keeping in mind that heparin can decrease AT concentrations. Protein C and Protein S Deficiency. Concentrations of protein C and protein S can be increased by the administration of plasma. Specific protein C concentrate is also available. Myeloproliferative Disease. Because there is a correlation between occlusive vascular events and elevated hematocrit, blood viscosity, and leukocytosis, these three parameters should be returned to a more normal range with the appropriate use of phlebotomy, chemotherapy, or crystalloid solutions.

Further Reading Bucur SZ, Levy JH, Despotis GJ, et al: Uses of antithrombin III concentrate in congenital and acquired deficiency states. Transfusion 38:481-498, 1998. Loscalzo J, Schafer A: Thrombosis and Hemorrhage, 3rd ed. Philadelphia, JB Lippincott–Williams & Wilkins, 2003. Martinelli I, Mannucci PM, De Stefano VD, et al: Different risk of thrombosis in four coagulation defects associated with inherited thrombophilia: A study of 150 families. Blood 92:2353-2358, 1998. Mateo J, Oliver A, Borrell M, et al: Laboratory evaluation and clinical characteristics of 2132 consecutive unselected patients with venous thromboembolism: Results of the Spanish Multicentric Study on Thromboembophilia (EMET-Study). Thromb Haemost 77:444-451, 1997. Santoro SA: Antiphospholipid antibodies and thrombotic predisposition: Underlying pathologic mechanisms. Blood 83:2389-2391, 1994. Sixth ACCP guidelines for antithrombotic therapy for prevention and treatment of thrombosis. American College of Chest Physicians. Chest 119(1 Suppl):1S-370S, 2001. Van Guldener C, Stehouwer CD: Hyperhomocysteinemia, vascular pathology and endothelial dysfunction. Semin Thromb Hemost 26:281-289, 2000.

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One-Lung Ventilation Peter D. Slinger

90

Case Synopsis A 70-year-old woman with recurrent carcinoma of the right lung is scheduled for a right thoracotomy and possible pneumonectomy (Fig. 90-1). After induction of general anesthesia, a 37 French left-sided double-lumen endotracheal tube is placed, and satisfactory positioning is confirmed through auscultation (Figs. 90-2 and 90-3). After the patient is turned to the left lateral decubitus position, the tracheal (right) lumen of the double-lumen tube is clamped, and the bronchial cuff is inflated with 3 cm3 of air. On thoracotomy, the right lung remains inflated, and the patient’s pulse oximetric saturation falls below 85%.

PROBLEM ANALYSIS Definition

Recognition Management of arterial desaturation takes precedence over the diagnosis of tube malposition. Once adequate oxygenation has been ensured, fiberoptic bronchoscopy is performed to confirm double-lumen tube position or assist with repositioning of the bronchial blocker. If a bronchoscope is not immediately available, palpation of the lung hilum and carina by the surgeon may be useful to determine the position of the double-lumen tube. Surgical exploration also helps rule out pneumomediastinum, the most common presenting sign of tracheal or bronchial laceration by the double-lumen tube. There are many other methods that can aid in the intraoperative diagnosis of double-lumen tube malposition, including the following: ●

Figure 90–1 ■ Preoperative chest radiograph of a 70-year-old woman with recurrent carcinoma of the right lung who is scheduled for right thoracotomy and possible completion pneumonectomy. Tracheal deviation is a warning that double-lumen tube placement may be difficult.

●

Chest auscultation. This is difficult to perform after the patient has been prepped and draped for surgery, and it may fail to diagnose lobar obstruction from distal migration of a double-lumen tube. Changes in lung mechanics. These may be revealed by airway pressure changes or changes in flow-volume or pressure-volume loops. Although any of these is a fairly sensitive indicator of changes in lung mechanics, they are 365

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This case synopsis demonstrates two of the major complications of one-lung ventilation: inadequate lung isolation and hypoxemia (Table 90-1). Persistent inflation of the operative lung results from one of three potential causes: (1) doublelumen tube or bronchial blocker malposition or migration due to surgical manipulation or patient positioning;

(2) delayed lung deflation in a patient with obstructive airway disease, bullae or both; or (3) iatrogenic tracheal or bronchial rupture, or both, from the tube. Although there are many potential causes of intraoperative hypoxemia during one-lung ventilation, it usually results from pulmonary shunting through the nonventilated lung. Hypoxemia due to shunting usually becomes clinically evident 10 to 20 minutes after the start of one-lung ventilation. Arterial desaturation very early in the course of one-lung ventilation is often due to inadequate gas exchange in the dependent lung due to malposition of the double-lumen tube. The concurrence of inadequate lung isolation and early desaturation in the patient described in the case synopsis suggests intraoperative migration of the double-lumen tube as the most likely cause.

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1 2

3

Figure 90–2 ■ Three-step method of auscultation to confirm double-lumen endobronchial tube positioning. Step 1: Inflate the tracheal cuff. Auscultate to confirm bilateral ventilation. Step 2: Clamp the tracheal lumen proximally (clamp the short side short) and inflate the bronchial cuff. Open the tracheal port and ventilate. Auscultate to confirm correct unilateral ventilation. Step 3: Release the tracheal lumen clamp, and close the tracheal port. Auscultate to confirm resumption of bilateral ventilation.

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367

2a

3

3

Figure 90–3 ■ Common initial malpositions of double-lumen endobronchial tubes can be detected sequentially during the three-step method of auscultation. Step 1: Overly distal placement in either main bronchus is revealed by unequal breath sounds. Step 2a: Overly proximal placement results in inability to achieve unilateral ventilation during ventilation by the bronchial lumen. Step 2b: Incorrect side of bronchial intubation is revealed by unilateral breath sounds in the incorrect hemithorax. Step 3: Slightly too proximal placement results in appropriate isolation but unequal auscultation with resumption of bilateral ventilation.

●

all relatively nonspecific and can be due to surgical manipulation, pulmonary air leaks, airway blockage due to secretions or tube malposition, inadequate muscle relaxation, and many other causes. Changes in end-tidal carbon dioxide (CO2) tension. The onset of one-lung ventilation is usually associated with

a small (≤5 mm Hg) and transient (≤5 minutes) drop in end-tidal CO2. Sudden, severe, or prolonged declines in end-tidal CO2 suggest inadequate gas exchange in the dependent lung. Because similar changes in end-tidal CO2 can be caused by alterations in cardiac output, this is also a fairly nonspecific indicator.

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2b

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Complications of One-Lung Ventilation and Double-Lumen Endobronchial Tubes

Hypoxemia Malpositioning (primary or delayed) Soiling of healthy lung regions Inadequate ventilation Interference with surgery Airway trauma Laryngeal Tracheal Bronchial Difficulty managing secretions Surgical damage to distal bronchial lumen

Risk Assessment Difficult Lung Isolation. Although techniques to predict difficult endotracheal intubation are well described, the methods of assessment for difficult endobronchial intubation are not widely appreciated. Problems with double-lumen tube or bronchial blocker placement can occasionally be anticipated on the basis of the preoperative history, the physical examination, or a bronchoscopy report that suggests abnormal tracheobronchial anatomy. The majority of potentially difficult endobronchial intubations can be anticipated by examining the preoperative chest radiograph and computed tomography (CT) scan. Hypoxemia during One-Lung Ventilation. Factors associated with increased risk of oxygen desaturation during one-lung ventilation include (1) a larger proportion of preoperative ventilation or blood perfusion to the operative lung, (2) an increased alveolar-arterial oxygen gradient during two-lung ventilation, (3) right-sided thoracotomy, and (4) predictive preoperative spirometry.

Implications Although lung isolation is usually performed to facilitate surgery, in certain circumstances (e.g., bronchopleural fistula, pulmonary hemorrhage, lung abscess), the inability to adequately isolate the lungs can be life-threatening. Iatrogenic tracheal or bronchial rupture due to double-lumen tubes or bronchial blockers is estimated to occur in 0.5 to 2 in 1000 cases.

MANAGEMENT Inadequate Lung Isolation Immediate treatment for inadequate lung isolation is deflation of the bronchial cuff (or blocker, if one is used) and manual ventilation of both lungs to assess compliance. Ventilation of the dependent lung can be confirmed by observing mediastinal movement with lung inflation in the open chest. Ventilation of the nondependent lung can be observed directly. If ventilation of both lungs is not quickly confirmed, the double-lumen tube should be withdrawn

until the distal end of the bronchial lumen is above the carina (<25 cm by the tube markings from the inferior alveolar ridge for most adults) and ventilation is resumed. Once ventilation of both lungs is ensured by the return of satisfactory pulse oximetric oxygen saturations and end-tidal CO2 concentrations, definitive repositioning of the doublelumen tube can be undertaken. The fiberoptic bronchoscope should be passed via the bronchial lumen, and the carina should be identified. During repositioning, if the tube persistently tends to enter the right main-stem bronchus, tube rotation or right flexion or rotation of the patient’s head often facilitates left mainstem bronchial intubation. If this fails, the bronchoscope should be advanced into the left main-stem bronchus and used as a guide to advance the bronchial lumen. This is easier to perform with fiberoptic bronchoscopes, which are specifically designed for anesthesia (e.g., Olympus LF-1 or LF-2) and are more rigid than pediatric bronchoscopes of similar diameter (<4 mm). If bronchoscopy does not help achieve tube repositioning, an attempt can be made to advance a partially withdrawn tube into the left main-stem bronchus while the surgeon compresses the right main-stem bronchus. If this fails, an attempt can be made to ventilate the left lung via the tracheal (incorrect) lumen of the left double-lumen tube with the bronchial lumen malpositioned in the right main-stem bronchus. If it is not possible to position the left-sided doublelumen tube satisfactorily, there are two major options (Fig. 90-4): 1. Continue the surgery with the double-lumen tube positioned above the carina and two-lung ventilation. 2. Replace the airway catheter or choose another technique for lung isolation (e.g., right-sided double-lumen tube, single-lumen endotracheal tube plus a bronchial blocker or single-lumen left endobronchial tube). The left double-lumen tube can be changed to a singlelumen tube or a right-sided tube without repositioning the patient with the use of a specifically designed, commercially available tube exchanger or with the fiberoptic bronchoscope. The problem of obstruction of the right upper lobe, which is seen commonly with right double-lumen tubes, is not a concern during left lung ventilation. If a single-lumen tube is used, a bronchial blocker (e.g., Arndt Blocker, Cook Critical Care, Bloomington, Ind.) can be passed intraluminally and positioned in the right main-stem bronchus under direct fiberoptic bronchoscopic vision. Alternatively, some bronchial blockers can be passed through the vocal cords extraluminally to a single-lumen tube. Another method for bronchial blockade is the use of a Univent tube (Fugi Corp., Tokyo), which is a single-lumen tube with an enclosed bronchial blocker. However, all forms of bronchial blockers are more likely than double-lumen tubes to migrate intraoperatively, causing loss of lung isolation, particularly when placed in the shorter right main-stem bronchus. A final option is to advance a small (<7 mm internal diameter) single-lumen tube as an endobronchial tube under fiberoptic guidance. However, this may be difficult in a patient with distorted carinal anatomy.

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Figure 90–4 ■ Management options for failure to achieve lung isolation with a left-sided double-lumen tube.

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Hypoxemia Hypoxemia should resolve with reinstitution of two-lung ventilation. During one-lung ventilation with an appropriately placed double-lumen tube or blocker and a fraction of inspired oxygen (FiO2) of 1.0, hypoxemia occurs in less than 5% of cases. Airway suctioning should be performed to ensure that thick bronchial secretions are not obstructing ventilation. When hypoxemia occurs during one-lung ventilation despite correct double-lumen tube positioning, continuous positive airway pressure (CPAP) with 2 to 5 cm H2O to the reinflated, nonventilated lung is the only therapy required in most cases. Positive endexpiratory pressure (PEEP) to the ventilated lung is not useful in patients with obstructive lung disease who develop auto-PEEP during one-lung ventilation. However, low levels of PEEP (<5 cm H2O) are useful in children or patients with normal lungs.

PREVENTION Inadequate lung isolation can be prevented by following the “ABCs”: ●

●

Anatomy: A thorough knowledge of the lobar bronchial anatomy is necessary to achieve successful lung isolation (Fig. 90-5). Understanding the lengths and diameters of the bronchi and their variations with age and sex enables the anesthesiologist to plan the appropriate technique for lung isolation. Bronchoscope: The anesthesiologist should always use a fiberoptic bronchoscope to assess double-lumen tube or bronchial blocker position and to gain familiarity with bronchial anatomy. This familiarity will be useful when there is distorted anatomy or blood or pus in the airway. Because double-lumen tubes or bronchial blockers commonly

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RIGHT LUNG

LEFT LUNG 19 Apical posterior

Apical 22

Posterior

UPPER LOBE

Anterior

50 16

10

13

Anterior

UPPER LOBE

Superior Superior

9

Inferior

LINGULA

Superior

Lateral MIDDLE LOBE Medial

Anterior basal Lateral basal

Anterior basal Medial basal Posterior basal Posterior basal

Lateral basal

LOWER LOBE

LOWER LOBE Figure 90–5 ■ Diagram of the tracheobronchial tree. Mean lengths and diameters are given in millimeters. Note that the right middle lobe bronchus exits directly anteriorly, whereas the superior (also called apical) segments of both lower lobes exit posteriorly. If the superior segment of the right lower lobe is called the apical, the segments from top to bottom on the right spell the mnemonic APALM.

●

migrate during patient positioning, the most important time to perform bronchoscopy is after final positioning of the patient for surgery and just before the start of onelung ventilation. Chest radiography and CT scanning: Examining the preoperative chest radiographs and CT scans can provide information about anatomic problems and airway size (see Fig. 90-1). This information is useful when selecting lung isolation methods and tube sizes.

Prevention of hypoxemia is most reliably performed with the use of an FiO2 of 100% and prophylactic application of CPAP to the nonventilated lung in selected high-risk patients (e.g., those with large alveolar-arterial oxygen gradients during two-lung ventilation, right-sided thoracotomies, and good preoperative spirometry). CPAP must be applied to a reinflated lung for optimal effect. To reduce the risk of tracheobronchial trauma during endobronchial tube or blocker insertion, use the appropriate size tube; avoid nitrous oxide, which can cause bronchial cuff overinflation; always manipulate the tube or blocker gently; and position the double-lumen tube under direct bronchoscopic guidance when problems are anticipated

or encountered. The suggested double-lumen tube sizes based on gender and height are as follows: females less than 160 cm tall, 35 French; females greater than 160 cm tall, 37 French; males less than 170 cm tall, 39 French; and males greater than 170 cm tall, 41 French. Smaller double-lumen tubes (26 to 28 French) are available for children and small adults. The bronchial cuff volume required to seal the airway is usually less than 3 mL. The bronchial cuff should be slowly inflated to the minimal volume required to achieve isolation. It is important to be aware that airway trauma is always a risk whenever a double-lumen tube or blocker is used.

Further Reading Arndt GA, Kranner PW, Rusy DA, Love R: Single-lung ventilation in a critically ill patient using a fiberoptically directed wire-guided endobronchial blocker. Anesthesiology 90:184-186, 1999. Bardoczky G, Szegedi L, d’Hollander A: Two-lung and one-lung ventilation in COPD patients: The effects of position and FiO2. Anesth Analg 90:35-41, 2000. Bauer C, Winter C, Hentz JG, et al: Bronchial blocker compared to doublelumen tube for one-lung ventilation during thoracoscopy. Acta Anaesth Scand 45:250-254, 2001.

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Fujiwara M, Abe K, Mashimo T: The effect of positive end-expiratory pressure and continuous positive airway pressure on the oxygenation and shunt fraction during one-lung ventilation with propofol anesthesia. J Clin Anesth 13:473-477, 2001. Licker M, de Perrot M, Spiliopoulos A: Risk factors for acute lung injury after thoracic surgery for lung cancer. Anesth Analg 97:1558-1565, 2003.

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Russell WJ, James MF: The effects of increasing cardiac output with adrenalin or isopenaline on arterial haemoglobin oxygen saturation and shunt during one-lung ventilation. Anaesth Intensive Care 28:636-641, 2000. Slinger P, Kruger M, McRae K, Winton T: The relation of the static compliance curve and positive end-expiratory pressure to oxygenation during one-lung ventilation. Anesthesiology 95:1096-1102, 2002.

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Mediastinal Masses Jerome M. Klafta Case Synopsis A 23-year-old previously healthy man presents with a 3-month history of cough (worse when he is lying flat). He says he has “head fullness.” His chest radiograph demonstrates mediastinal lymphadenopathy with no other abnormalities. He is scheduled for parasternal mediastinotomy. After induction with propofol and succinylcholine, the patient is easily intubated, but manual ventilation is extremely difficult.

●

PROBLEM ANALYSIS

● ●

Definition Patients with anterior mediastinal masses are prone to develop certain potentially life-threatening complications because of the influence of these masses on neighboring structures (superior vena cava, tracheal bifurcation or main-stem bronchi, main pulmonary artery, aortic arch, and heart). Principal anesthetic considerations for patients with anterior mediastinal masses involve the following three potential complications: ● ● ●

Tracheobronchial tree compression or obstruction Superior vena cava syndrome Compression of the heart and pulmonary vessels

Also, patients may present for anesthesia or monitored anesthesia care for a variety of reasons, including: ● ●

Excision of intrathoracic tumor (primary or metastatic) Lymph node biopsy (for tissue diagnosis)

Suprasternal notch

●

Central line placement (for chemotherapy) Biopsy of intrathoracic mass (open or thoracoscopic) Any other procedure, either related to the disease (e.g., open reduction and internal fixation of pathologic fracture) or not (cesarean section) Imaging studies (children)

Although these masses are referred to as “anterior,” they are often at the confluence of the anterior, superior, and middle mediastinum (Fig. 91-1).

Recognition TRACHEOBRONCHIAL TREE COMPRESSION

Angle of Louis

Posterior mediastinum

Xiphoid Middle mediastinum

372

OBSTRUCTION

Tracheobronchial tree compression or obstruction is the most common of the three potential complications arising from anterior mediastinal masses. There can be both static and dynamic components to such compression or obstruction. The dynamic components may not be unmasked until

Superior mediastinum

Anterior mediastinum

OR

Figure 91–1 ■ The mediastinum is divided into superior and inferior portions. The inferior mediastinum is divided into anterior, middle, and posterior portions. (From Benumof JL: Anesthesia for Thoracic Surgery, 2nd ed. Philadelphia, WB Saunders, 1995, p 39.)

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Figure 91–2 ■ Fiberoptic bronchoscopic appearance of the lower trachea in an anesthetized patient in the supine position (A) with a large anterior mediastinal mass that almost totally obstructs the trachea in the anteroposterior plane. With the patient in the sitting position (B), the lumen appears normal. (From Prakash UBS, Abel MD, Hubmayr RD: Mediastinal mass and tracheal obstruction during general anesthesia. Mayo Clin Proc 63:1004-1011, 1988.)

A

● ● ●

●

History of orthopnea, positional dyspnea Chest radiograph showing large mass, airway compression Chest computed tomography (CT) scan showing compression of airway or other structures (Fig. 91-3) Flow-volume loops with truncation of expiratory and possibly inspiratory limbs (Fig. 91-4)

Table 91–1

■

SUPERIOR VENA CAVA SYNDROME Superior vena cava syndrome occurs as a result of tumor compression or direct invasion of the superior vena cava and has the following features: ● ● ● ●

●

Facial or upper extremity edema Dilated facial or upper extremity veins with collateralization Respiratory symptoms (nasal congestion, cough, orthopnea) Central nervous system effects (mental status changes, headache) Collateralization evident on chest CT with contrast enhancement

Possible Contributory Causes of Tracheobronchial Tree Compression or Cardiovascular Obstruction after the Induction of General Anesthesia and Tracheal Intubation in Patients with Mediastinal Masses

Cause

Result

Loss of lung volume

The mass remains constant in size, but pressure on the lung increases with applied positive airway pressure The mass remains constant in size, but an increased transmural pressure gradient* created by the mass interferes with cardiac filling, thereby increasing central blood volume The mass remains constant in size, but pressure on more compliant superior, middle, or posterior mediastinal cardiovascular structures (superior or inferior vena cava, left or right atria, or even right ventricle) impairs venous filling and cardiac preload, effectively reducing cardiac output The mass increases the transmural pressure gradient and increases intrapleural pressure and (potentially) vital organ perfusion The mass compresses the wall of the tracheobronchial tree, resulting in tracheobronchial distortion (e.g., bending, unusual curves), and can produce mechanical obstruction at the endotracheal tube tip Airway collapse, atelectasis, increased intrapulmonary shunt, and arterial O2 desaturation can occur Tumor size can increase intraoperatively as a result of surgical manipulation, leading to edema or bleeding into the tumor mass (hematoma) Turbulence created by extrinsic airway compression by the tumor mass may be aggravated by overly vigorous positive-pressure ventilation Especially when the tumor mass involves the RLN, surgical dissection to remove the tumor may damage the nerve, leading to partial or complete vocal cord paralysis

Increase in central blood volume Reduction in cardiac output

Loss of negative pleural pressure Tracheobronchial obstruction at the endotracheal tube tip Associated tracheobronchial tree malacia Intraoperative increase in tumor size Creation of turbulent airway flow Injury to the recurrent laryngeal nerve (RLN)

*Transmural pressure gradient is the difference between a cardiac chamber pressure and the juxtacardiac or pericardial pressure. Modified from Benumof JL: Anesthesia for Thoracic Surgery, 2nd ed. Philadelphia, WB Saunders, 1995, p 569.

CARDIOTHORACIC & VASCULAR SURGERY

after supine positioning (Fig. 91-2), induction of general anesthesia, or administration of paralytic agents (Table 91-1). Difficulty in mask ventilation or difficulty ventilating despite successful endotracheal intubation is a classic scenario. Preoperative features include the following:

B

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Normal Intrathoracic mass

TLC

RV

Figure 91–4 ■ Flow-volume loop for a patient with a normal airway and for a patient with an intrathoracic mass. TLC, total lung capacity; RV, residual volume. (From Pullerits J, Holzman R: Anaesthesia for patients with mediastinal masses. Can J Anaesth 36:681-688, 1989.)

Figure 91–3 ■ Chest computed tomography scan showing extrinsic compression at the level of the trachea (top) and main-stem bronchi (bottom).

COMPRESSION

OF

HEART

AND

PULMONARY ARTERY

Compression of the heart or pulmonary artery is a rare but life-threatening complication. A history of syncope or with Valsalva’s maneuver is suggestive and merits at least a focused preoperative two-dimensional echocardiographic examination (look for extrinsic compression of cardiac chambers or of the pulmonary artery).

Risk Assessment Generally, the larger the mass, the greater physiologic embarrassment it is likely to cause. However, the ability to prospectively identify which patients with mediastinal masses are at high risk for perioperative cardiorespiratory complications with general anesthesia is limited. The incidence of these complications may be significantly higher in pediatric patients. This can be explained by the fact that infants and

small children are more susceptible than adults to extrinsic airway obstruction because their airways are more compressible and because small decreases in airway diameter result in proportionally greater effects on airway crosssectional area and resistance. In children, tracheal cross-sectional area (as measured by CT) less than 50% to 66% of predicted has been suggested as a cutoff below which general anesthesia should be avoided if possible. The only symptom that has been shown to strongly correlate with the degree of tracheal narrowing is orthopnea; however, its value in predicting intraoperative airway collapse is questionable. In another report, pulmonary function testing performed in both sitting and supine positions revealed peak expiratory flow rates below 50% of predicted in 5 of 31 children in whom the tracheal cross-sectional area was more than 50% of predicted. Therefore, peak expiratory flow rate may be more sensitive than cross-sectional area alone in detecting airflow compromise due to the compressive effects of a mediastinal mass. In adults, the presence of a pericardial effusion or mixed pattern of obstructive and restrictive pulmonary disease is associated with a high rate of postoperative respiratory complications. However, in all these studies (both children and adults), patients in the highest risk groups were anesthetized with a local anesthetic and sedation, thus limiting any conclusions regarding the safety of a general anesthetic technique.

Implications ●

●

Tracheobronchial tree compression ● Inability to ventilate or oxygenate, with hypercarbia or hypoxia ● Possible cardiorespiratory arrest Superior vena cava syndrome ● Excessive bleeding if the surgical site involves the head, neck, or upper extremities ● Unreliable drug or fluid delivery via upper extremity intravenous (IV) lines

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Relative contraindication for jugular or subclavian central IV access ● Potential for airway edema Compression of heart and pulmonary vessels ● Hypotension; cardiovascular collapse ●

●

●

Tracheobronchial Tree Compression

●

● ●

●

●

●

●

Superior Vena Cava Syndrome ●

● ●

●

Recognize the effect of associated airway edema on intubation. Elevate the head of the bed to reduce venous pressure. Use lower extremity IV access as a more reliable route to the central circulation. Consider the use of diuretics and steroids.

Compression of Heart and Pulmonary Artery ●

●

●

● ●

Perform intraoperative echocardiography to assess the degree of impairment. Position the patient to minimize compression (lateral or even prone). Maintain venous return, pulmonary artery pressure, and cardiac output as needed with fluids, pressors, and inotropic agents. Spontaneous ventilation may help. Have cardiopulmonary bypass available on a standby basis (have the groins prepped and draped).

PREVENTION In patients with significant vascular, cardiac, or airway compromise, preoperative radiation therapy to shrink the tumor or local anesthesia for the procedure (if feasible) should be strongly considered. A potential disadvantage of preoperative radiation therapy is that it may obscure the histologic diagnosis and jeopardize treatment. CT-guided transsternal core biopsy is an alternative diagnostic technique at some centers. A multidisciplinary approach (oncology, radiation oncology, surgery, and anesthesiology) is required to make an intelligent decision regarding the risk-benefit ratio for proceeding with therapy.

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●

●

Have a low threshold for placing a preinduction arterial line in patients undergoing general anesthesia who have any symptoms or other evidence (e.g., CT scans) of airway compression. This will provide beat-to-beat blood pressure monitoring in the event of respiratory or hemodynamic compromise. A rigid bronchoscope should be available with the attending surgeon in the operating room for induction if there is particular concern about airway collapse. In the absence of contraindications (e.g., aspiration risk, difficult mask airway), slow induction of general anesthesia is preferred (IV or inhalation). Maintain spontaneous ventilation until effective positive-pressure ventilation is confirmed. If needed, perform tracheal intubation with succinylcholine (unless contraindicated); its short duration of action is advantageous in the event that muscle relaxation has a deleterious effect on the ability to ventilate the patient. Also, use the smallest dose of succinylcholine possible (≤1.0 mg/kg ideal or lean body weight). If feasible, perform fiberoptic intubation in an awake, spontaneously breathing patient. The fiberoptic bronchoscope can also be used to assess positional or dynamic airway collapse. Aim for a very smooth emergence and extubation sequence, because excessive coughing and straining can exacerbate both airway obstruction and the symptoms of superior vena cava syndrome. If central venous access or monitoring is required (indications are related to coexisting disease), access should be obtained via the femoral route.

Further Reading Bechard P, Letourneau L, Lacasse Y, et al: Perioperative cardiorespiratory complications in adults with mediastinal mass. Anesthesiology 100:826-834, 2004. Hnatiuk OW, Corcoran PC, Sierra A: Spirometry in surgery for anterior mediastinal masses. Chest 120:1152-1156, 2001. Hoerbelt R, Keunecke L, Grimm H, et al: The value of a noninvasive diagnostic approach to mediastinal masses. Ann Thorac Surg 75: 1086-1090, 2003. Johnson D, Hurst T, Cujec B, et al: Cardiopulmonary effects of an anterior mediastinal mass in dogs anesthetized with halothane. Anesthesiology 74:725-736, 1991. Neuman GG, Weingarten AE, Abramowitz RM, et al: The anesthetic management of the patient with an anterior mediastinal mass. Anesthesiology 60:144-147, 1984. Pullerits J, Holzman R: Anaesthesia for patients with mediastinal masses. Can J Anaesth 36:681-688, 1989. Shamberger RC, Holzman RS, Griscome NT, et al: CT quantitation of tracheal cross-sectional area as a guide to the surgical and anesthetic management of children with anterior mediastinal masses. J Pediatr Surg 26:138-142, 1991. Shamberger RC, Holzman RS, Griscome NT, et al: Prospective evaluation by computed tomography and pulmonary function tests of children with mediastinal masses. Surgery 118:468-471, 1995. Tempe DK, Arya R, Dubey S, et al: Mediastinal mass resection: Femorofemoral cardiopulmonary bypass before induction of anesthesia in the management of airway obstruction. J Cardiothorac Vasc Anesth 15:233-236, 2001.

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●

Change the patient’s position to a lateral or semi-Fowler’s position. Resume spontaneous ventilation. Attempt to advance the endotracheal tube past the obstruction (however, this could cause severe hemorrhage). ● Consider using fiberoptic bronchoscopic guidance or an endotracheal tube changer. ● Consider a smaller endotracheal tube. Attempt to bypass the obstruction and ventilate with a rigid bronchoscope. Oxygenate via femorofemoral cardiopulmonary bypass.

Mediastinal Masses

The anesthetic plan and required setup vary, depending on the proposed operation (and surgical approach), the severity of the patient’s symptoms, and other coexisting conditions and diseases. However, the following guidelines can be used:

MANAGEMENT

The best approach is prevention. However, if tracheobronchial tree compression does occur, the following maneuvers should be attempted:

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Gordon Lee Collins and Eric Jacobsohn Case Synopsis A 74-year-old man is scheduled for a right-sided pneumonectomy for lung cancer. He has a past medical history of hypertension and coronary artery disease, with a coronary artery stent placed in his left anterior descending artery. He has mild chronic obstructive pulmonary disease, with no reversible airway obstruction. He does moderate (>4 METS) daily physical activity without any difficulty. A nuclear medicine stress test performed 1 year previously was negative for myocardial ischemia. Medications include aspirin, simvastatin, and atenolol. Aspirin therapy was discontinued 7 days before surgery. His anesthetic and surgical course is uncomplicated and includes a combined general anesthetic-thoracic epidural technique. There is minimal blood loss, and he receives limited intra- and postoperative fluid. The chest tube is removed on postoperative day 1. Aspirin therapy is restarted on postoperative day 2. On postoperative day 3, the patient has increasing dyspnea, and a chest radiograph shows that the left lung has diffuse bilateral pulmonary infiltrates, in keeping with pulmonary edema. Because of progressive respiratory distress, he is intubated, and mechanical ventilation is commenced. The patient’s oxygen saturation remains between 90% and 94% on 100% oxygen, 10 cm H2O positive end-expiratory pressure, and optimal ventilator settings. A pulmonary artery catheter is judiciously inserted, and appropriate placement is confirmed by chest radiograph. The cardiac output and wedge pressure are low, there is moderate pulmonary artery hypertension and a transpulmonary gradient, and the right atrial pressure is elevated. A transesophageal echocardiogram shows mild right ventricular and right atrial dilatation, with no demonstrable intracardiac shunt. A diagnostic bronchoalveolar lavage is performed and is negative for inflammatory cells or organisms (subsequent cultures are negative). A diagnosis of postpneumonectomy pulmonary edema, complicated by right ventricular dysfunction, is made. Supportive therapy includes diuresis, lung-protective ventilatory support, low-dose dobutamine, and inhaled prostacyclin (for increased pulmonary artery pressure and refractory hypoxemia). On postoperative day 5, hemodynamically unstable atrial fibrillation develops, and the patient is cardioverted. An amiodarone infusion is commenced. The patient’s troponin level increases to 1.1 ng/mL. He is fully heparinized, and β-blockade is intensified. After 14 days of supportive therapy, including an early tracheostomy, he is successfully weaned from mechanical ventilation. After discharge from the intensive care unit, an angiogram shows stable coronary artery disease.

PROBLEM ANALYSIS Definition and Recognition Pneumonectomy is most frequently performed for bronchogenic carcinoma involving the hilum. Occasionally it is performed for inflammatory lung disease, traumatic lung injury, congenital lung disease, and irreversible atelectatic conditions. It is a major operation that results in changes in anatomy and cardiopulmonary physiology. Potentially serious and sometimes life-threatening postpneumonectomy pulmonary, cardiovascular, or other complications are relatively frequent. These are summarized in Table 92-1.

Risk Assessment Many postoperative complications can be minimized by appropriate patient selection. This involves an assessment of 376

pulmonary function, as well as the evaluation of and optimal therapy for any coexisting diseases or conditions, including obesity, cigarette smoking, reversible lung disease, coronary artery disease, and physical nonconditioning. Although baseline pulmonary function testing may have limited predictive value, the results of lung spirometry, lung diffusing capacity, maximal oxygen uptake, and arterial blood gas analysis are the cornerstones of most clinical decisions (Fig. 92-1). There may be less adverse physiologic impact from lung resection in some situations (e.g., resection of an obstructed, nonperfused lobe; concomitant resection of emphysematous bullae).

Implications Right-sided pneumonectomy is associated with greater mortality compared with left-sided pneumonectomy (10% to 12% versus 1% to 3.5%). The indication for pneumonectomy

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Table 92–1

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Complications after Pneumonectomy

Pulmonary Hypoxemia Postoperative respiratory failure Chronic pulmonary debility or deficiency Postpneumonectomy pulmonary edema Postpneumonectomy syndrome Bronchopleural fistula Pulmonary embolism Empyema Esophagopleural fistula Hemothorax Chylothorax Contralateral pneumothorax Pneumomediastinum Mediastinal infection (mediastinitis) Vocal cord paralysis

Postoperative Respiratory Failure. Proper patient selection and the identification and treatment of reversible disorders involving the heart and lungs have greatly reduced postoperative respiratory failure. The following factors may also reduce the incidence of perioperative respiratory complications associated with pneumonectomy: ●

●

●

●

Miscellaneous

Chronic Pulmonary Insufficiency. This condition is largely preventable by appropriate patient selection and preoperative assessment of lung function. Postpneumonectomy Pulmonary Edema. This syndrome develops in up to 5% of patients undergoing pneumonectomy. Mortality exceeds 50%. Postpneumonectomy pulmonary edema results in hypoxemic respiratory failure, with chest radiograph findings of diffuse infiltrates resembling those of acute respiratory distress syndrome. It usually occurs on about the third postoperative day. Its pathogenesis is multifactorial, including the following: ● ● ● ●

●

MANAGEMENT AND PREVENTION Complications occurring after pneumonectomy may be pulmonary, cardiac, or unrelated to either of these systems.

Figure 92–1 ■ Algorithm for the preoperative pulmonary assessment of pneumonectomy patients. DLCO, diffusing capacity of the lung for carbon monoxide; FEV1, forced expiratory volume over 1 second; PFT, pulmonary function test; PPO, predicted postoperative; VO2 max, maximum oxygen uptake.

Surgery performed by a certified thoracic surgeon in a medical center that does a large volume of pulmonary surgeries Appropriate perioperative use of pulmonary rehabilitation, bronchodilators, steroids, and antibiotics Smoking cessation before surgery Effective postoperative physical therapy and incentive spirometry Good postoperative pain control (e.g., thoracic epidural analgesia)

Excessive fluid administration or use of fresh frozen plasma Hyperinflation injury during one-lung ventilation Coexisting pulmonary hypertension Impaired lymphatic drainage due to surgical dissection of hilar lymph nodes Occult pulmonary aspiration

There are no specific methods for managing or preventing postpneumonectomy pulmonary edema. Likely beneficial measures include avoidance of hypervolemia and excessive diuresis, lung-protective ventilatory support, and

Routine PFTs ⇒ FEV1 >60% and DLCO >60% ⇒ Proceed to surgery ⇓ FEV1 <60% and DLCO <60% ⇒ Proceed to lung scan ⇓ PPO FEV1 >40% and PPO DLCO >40% ⇒ Proceed to surgery ⇓ PPO FEV1 <40% and PPO DLCO <40% ⇓ Exercise testing with VO2 max >15 mL/kg/min ⇒ Proceed to surgery ⇓ VO2 max <15 mL/kg/min ⇒ Consider other options before surgery

CARDIOTHORACIC & VASCULAR SURGERY

may affect outcome; for example, pneumonectomy for lung cancer has a mortality of 3% to 4%, whereas that performed for benign disease may be as high as 26%. Emergent pneumonectomy in cases of trauma or massive hemoptysis is associated with mortality rates greater than 30%. Also, pneumonectomy performed by thoracic surgeons has a lower mortality than that performed by general surgeons. Associated lung disease, history of coronary artery disease, history of congestive heart failure, hypertension, atrial fibrillation, cerebrovascular accident, cigarette smoking, and a 10% or greater weight loss over the 6-month period before surgery all contribute to higher mortality.

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Intraoperative Hypoxemia. The differential diagnosis and approach to the prevention and management of hypoxemia during one-lung ventilation are discussed in Chapter 90.

●

Postpneumonectomy paralysis Postpneumonectomy scoliosis Difficulty interpreting pulmonary artery catheter data

Complications after Pneumonectomy

Pulmonary Complications

Cardiovascular Arrhythmias Myocardial infarction Intracardiac shunt Cardiac tamponade or herniation Pneumopericardium

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inhaled pulmonary artery vasodilators if pneumonectomy is associated with refractory hypoxemia or elevated pulmonary artery pressures. Patients with this condition may also benefit from early tracheostomy. Postpneumonectomy Syndrome. This syndrome is the result of extrinsic compression of the distal trachea and mainstem bronchus, caused by a mediastinal shift toward the side of pneumonectomy and hyperinflation of the remaining lung. It occurs about 6 months after surgery, is more common in patients having pneumonectomy during childhood, and is usually a complication of right pneumonectomy. Treatment involves repositioning the mediastinum and filling the empty thorax with a nonabsorbable material. Bronchopleural Fistula. The incidence of bronchopleural fistula ranges from 1.5% to 4.5%; it is associated with 30% to 80% mortality and is more common after right pneumonectomy. It often presents 1 to 2 weeks after pneumonectomy as fever, productive cough, hemoptysis, and subcutaneous emphysema. Other associations include large bronchial stump size, incomplete tumor resection, concurrent radiation or chemotherapy, and poor wound healing (e.g., debilitated patients, steroid therapy). Treatment includes antibiotics, longer-term drainage of the pleural space, and repair of any air leaks with muscle flap procedures when appropriate. Pulmonary Embolism. Most pulmonary emboli arise from the deep veins of the legs. Rarely, they can arise from the pulmonary artery stump or the tumor itself. This complication can be devastating for patients with an already reduced pulmonary vascular reserve. Proper prophylaxis for perioperative deep venous thrombosis is critical. Management includes anticoagulation, but emergent embolectomy may be required immediately postoperatively. In patients further removed from surgery, intravenous thrombolytics should be considered. In those presenting with significant deep venous thrombosis and no pulmonary embolism, retrievable inferior vena cava filter placement may be indicated. Other Pulmonary Complications. Other complications include empyema, chylothorax and acute hemithorax, esophagopleural fistula, contralateral pneumothorax, and vocal cord paralysis. Management may require surgery (incision and drainage, fistula closure, mediastinal repositioning and filling of the empty thorax with nonabsorbable material). For partial or complete vocal cord paralysis, consultation with an otolaryngologist is recommended.

Cardiac Complications Arrhythmia. Atrial tachyarrhythmias (see Chapter 79), especially atrial flutter or fibrillation, are common after thoracic surgical procedures and occur in about 20% of cases. Eighty percent occur within the first 72 hours after surgery. Risk factors for such arrhythmias include age older than 60 years, right pneumonectomy, intrapericardial pneumonectomy, preexisting coronary artery disease, and chronic hypertension. Primary prophylaxis for atrial tachyarrhythmias after pneumonectomy is a β-blocker—either a primary β-blocker or sotalol, which is a β-blocker but also has class III antiarrhythmic activity (see Chapters 11, 12, and 79).

Amiodarone1 may also be effective, but its role in the prophylaxis of postpneumonectomy or thoracotomy atrial tachyarrhythmias has not been established. In addition, pulmonary toxicity with chronic amiodarone administration is known to occur. It is possible that intravenous amiodarone for the prophylaxis or treatment of postpneumonectomy or thoracotomy atrial tachyarrhythmias might aggravate acute lung injury. Hemodynamically unstable atrial flutter or fibrillation requires immediate direct-current cardioversion, with further management and prevention according to established (advanced cardiovascular life support) guidelines (see Chapter 79). Myocardial Infarction. Perioperative myocardial infarction (MI) occurs in 1% to 5% of patients after thoracic surgery. Prophylactic perioperative β-blockers should reduce the incidence of acute MI and other cardiac events after thoracic surgery. Preoperative risk stratification for patients having pneumonectomy should follow existing American Heart Association–American College of Cardiology guidelines, which classify pneumonectomy as an intermediaterisk surgical procedure (see Chapter 38). The patient described in the case synopsis had only one intermediate-risk predictor (remote history of non-Q-wave MI), but he had been revascularized and was physically active. He also had a negative stress test a year before the planned pneumonectomy, making further preoperative testing unnecessary. All patients receiving chronic β-blocker therapy should continue these drugs. Patients with known coronary artery disease or peripheral vascular disease, and those with two or more risk factors for coronary disease (age older than 65 years, treated or untreated hypertension, diabetes mellitus, hypercholesterolemia, current or recent mI [≤ 6 months]), should receive perioperative β-blockers. Routine withdrawal of aspirin therapy before major surgery in patients with coronary artery disease or peripheral vascular disease is probably contraindicated. However, the decision whether to cease such therapy must be individualized. Patients with coronary artery disease on chronic aspirin therapy may develop an aspirin withdrawal syndrome leading to acute MI. Factors such as the severity of cardiovascular and cerebrovascular disease and the presence and age of any stents must also be considered. The risk of withdrawing aspirin must be weighed against the risk of possible increased bleeding. There is accumulating evidence that statin therapy may be protective in the perioperative period in patients with cardiovascular disease. This is likely related to the drugs’ pleiotropic effects. Patients taking statins should not have their therapy interrupted in the perioperative period. Intracardiac Shunting. A patent foramen ovale may be present in 30% of the population. This can cause significant right-to-left shunting and severe hypoxemia if right heart pressure becomes elevated. This could occur due to poor patient selection, increased preoperative pulmonary artery pressures, pulmonary embolism, pneumonia, pneumothorax, postpneumonectomy pulmonary edema, or pulmonary aspiration. 1 Amiodarone is listed as a class III drug, but it has all four VaughanWilliams antiarrhythmic class actions.

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Treatment for the underlying cause of increased right atrial pressure is critical. This includes optimizing right ventricular function and reducing pulmonary artery pressures, if elevated. Measures include inhaled pulmonary artery vasodilators, such as prostacyclin or nitric oxide. Percutaneous closure of the shunt may have to be done in some patients. Cardiac Herniation. Herniation of the heart through a defect in the pericardium can occur at any time after the surgical procedure. In addition to herniation through a pericardial defect, the heart or mediastinal contents may herniate into the pleural space if a chest tube is inadvertently placed on suction. Hence, many surgeons believe that routine chest tubes, even for short periods, are contraindicated after pneumonectomy. Cardiac herniation presents as sudden-onset hypotension and shock, cyanosis, chest pain, and symptoms of the superior vena cava syndrome. Emergent reopening of the thoracotomy is required to immediately reposition the heart. Suturing the edges of the pericardium to the myocardium or placing a prosthetic patch over the pericardial defect during surgery can prevent this complication. If it is caused by inadvertent chest tube suctioning, this must be stopped immediately. Repositioning the patient with the pneumonectomy side up may also be helpful.

Only a few of the more common and difficult to manage complications unrelated to the heart and lungs are discussed here. Postpneumonectomy Spinal Cord Ischemia and Paralysis. This is a rare complication caused by intraoperative injury of the intercostal arteries to the thoracolumbar region of the spinal cord, leading to an anterior spinal artery syndrome. Treatment options are limited and largely unproved. They include maintaining a high spinal cord perfusion pressure and use of cerebrospinal fluid drainage. Postpneumonectomy Scoliosis. Scoliosis is estimated to affect 90% of patients undergoing pneumonectomy. This complication is due to shrinkage of the thoracic cage after surgery. Associated symptoms are usually mild and mostly inconsequential. Difficulty Interpreting Pulmonary Artery Catheter Data. A pulmonary artery catheter or central venous access is not routinely required for pneumonectomy. However, if a pulmonary artery catheter is used during thoracic surgery, it is important to note that data derived from the catheter may vary, depending on which lung or segment it floats to (e.g., dependent or nondependent zone), whether one-lung ventilation is used, and when the readings are made. Depending on the clinical circumstances, a pulmonary artery catheter has the potential to provide misleading data. If placed in the postoperative period, caution must be exercised when floating and inflating the balloon in the newly sutured or stapled pulmonary artery. Further, one should consider floating the pulmonary artery catheter under fluoroscopy or echocardiographic guidance.

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Other Complications. Other complications after pneumonectomy involve primarily the gastrointestinal system and include motility disorders and gastric volvulus. Optimal management may be medical or surgical; if necessary, appropriate consultation should be sought as soon as these complications become apparent.

Further Reading Attar S, Hankins JR, Turney SZ, et al: Paraplegia after thoracotomy: Report of five cases and review of the literature. Ann Thorac Surg 59: 1410-1415, 1995. Bachamn DS: Discontinuing chronic aspirin therapy: Another risk factor for stroke? Ann Neurol 51:137-138, 2002. Cerfolio RJ, Bryant AS, Thurber JS, et al: Intraoperative Solu-Medrol helps prevent postpneumonectomy pulmonary edema. Ann Thorac Surg 76:1029-1033, 2003. Datta D, Lahiri B: Preoperative evaluation of patients undergoing lung resection surgery. Chest 123:2096-2103. 2003. De Wet CJ, Affleck DJ, Jacobsohn E, et al: Inhaled prostacyclin is safe, effective, and affordable in patients with pulmonary hypertension, right heart dysfunction, and refractory hypoxemia after cardiothoracic surgery. J Thorac Cardiovasc Surg 127:1058-1067, 2004. De Wet CJ, McConnell K, Jacobsohn E: Progress in postoperative ICU management. Thorac Surg Clin 15:159-180, 2005. Eagle KA, Berger PB, Calkins H, et al: ACC/AHA update for perioperative cardiovascular evaluation for noncardiac surgery. Circulation 105:1257-1267, 2002. Guggino G, Doddoli C, Barlesi F, et al: Completion pneumonectomy in cancer patients: Experience with 55 cases. Eur J Cardiothorac Surg 25:449-455, 2004. Handschin AE, Lardinois D, Schneiter D, et al: Acute amiodarone-induced pulmonary toxicity following lung resection. Respiration 70:310-312, 2003. Hoff WS, Hoey BA, Wainwright GA, et al: Early experience with retrievable inferior vena cava filters in high-risk trauma patients. J Am Coll Surg 199:869-874, 2004. Kertai MD, Boersma E, Westerhout CM, et al: A combination of statins and beta-blockers is independently associated with a reduction in the incidence of perioperative mortality and nonfatal myocardial infarction in patients undergoing abdominal aortic aneurysm surgery. Eur J Vasc Endovasc Surg 28:343-352, 2004. Khan SN, Stansby G: Cerebrospinal fluid drainage for thoracic and thoracoabdominal aortic aneurysm surgery. The Cochrane Database of Systematic Reviews 2003, Issue 4. Art. No.: CD003635. DOI: 10.1002/ 14651858. CD003635.pub2. Miller DL, Deschamps C, Jenkins GD, et al: Completion pneumonectomy: Factors affecting operative mortality and cardiopulmonary morbidity. Ann Thorac Surg 74:876-883, 2002. Poldermans D, Boersma E, Bax JJ, et al: The effect of bisoprolol on perioperative mortality and myocardial infarction in high-risk patients undergoing vascular surgery. Dutch Echocardiographic Cardiac Risk Evaluation Applying Stress Echocardiography Study Group. N Engl J Med 341:1789-1794, 1999. Rahimtoola A, Bergin JD: Acute pulmonary embolism: An update on diagnosis and management. Curr Probl Cardiol 30:61-114, 2005. Senior K: Aspirin withdrawal increases risk of heart problems. Lancet 362:1558, 2003. Sugarbaker DJ, Jaklitsch MT, Bueno R, et al: Prevention, early detection, and management of complications after 328 consecutive extrapleural pneumonectomies. J Thorac Cardiovasc Surg 128:138-146, 2004. Van Mieghem W, Coolen L, Malysse I, et al: Amiodarone and the development of ARDS after lung surgery. Chest 105:1642-1645, 1994. Vaporciyan AA, Correa AM, Rice DC, et al: Risk factors associated with atrial fibrillation after noncardiac thoracic surgery: Analysis of 2588 patients. J Thorac Cardiovasc Surg 127:779-786, 2004.

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Complications Unrelated to the Cardiopulmonary System

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Carotid Endarterectomy Vivek Moitra and John Ellis

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Case Synopsis A 72-year-old woman with a significant past medical history of hypertension and coronary artery disease undergoes carotid endarterectomy under general anesthesia. Electroencephalogram (EEG) monitoring is used. Her intraoperative course includes placement of a carotid artery shunt. On the following day, the patient experiences right upper extremity weakness.

PROBLEM ANALYSIS Definition Stroke is the third leading cause of death in the United States. Little can be done after a cerebrovascular accident (stroke) to reverse any permanent vascular brain injury. Stroke may result from aneurysm rupture with intracerebral bleeding, occlusion of intracerebral arteries, or carotid artery occlusion or thromboembolism. For the last, the focus is on prevention. Carotid endarterectomy and stenting are the most commonly performed procedures to minimize the risk of further stroke in patients with carotid atherosclerosis, a systemic and progressive disease. Both symptomatic and asymptomatic patients with carotid lesions (i.e., atheromatous plaques) may benefit from carotid endarterectomy. Frequently, such plaques involve the proximal internal carotid artery and the carotid bifurcation. This may result in luminal narrowing and compromised blood supply to the brain, especially with contralateral atheromatous disease or disease involving the circle of Willis. In addition to luminal narrowing, atheromatous plaques may rupture, leading to thrombus formation and thromboembolism. Transient ischemic attacks and reversible ischemic neurologic deficits are believed to be the result of embolism or hypoperfusion. In many patients, however, carotid disease may manifest only as an asymptomatic carotid bruit. The anesthetic management of candidates for carotid endarterectomy or stenting requires a clear understanding of cerebral circulation and physiology, appropriate monitoring techniques, and the potential for cardiovascular compromise.

thromboembolism, shunt kinking, or air embolism may occur. Methods used to assess the need for a shunt include neurologic assessment of awake patients (if carotid endarterectomy is performed under local or regional anesthesia, such as deep and superficial cervical plexus block), transcranial Doppler, EEG, somatosensory evoked potentials (SEPs), measurement of distal cerebral artery stump pressures (i.e., pressure created by backflow from the contralateral carotid artery across the circle of Willis), or direct measurement of cerebral blood flow with xenon (Table 93-1). The purpose of these measures is to avoid routine shunting, which can cause air embolism or thromboembolism. Different techniques or combinations of these methods may be preferred by different centers. However, the sensitivity of any technique for detecting perioperative ischemia or strokes is limited, because most strokes occur after surgery and are likely caused by thromboembolic phenomena. The gold standard for cerebral monitoring is neurologic assessment of an awake patient. Awake patients having carotid endarterectomy have fewer EEG changes, and many practitioners advocate the use of regional anesthesia to allow the detection of cerebral ischemia, which manifests as acute changes in mental status or motor response to verbal commands. A successful regional anesthetic requires that the patient be comfortable and cooperative throughout the surgery. If combined with general anesthesia, regional blocks may reduce general anesthetic requirements, hasten awakening, and reduce the need for opiate analgesia after surgery.

Table 93–1

Recognition During carotid endarterectomy, the carotid artery is surgically occluded. Early recognition of cerebral ischemia is essential to guide subsequent surgical and anesthetic management. Many surgeons elect to place a shunt to maintain ipsilateral carotid flow, and the use of intraoperative monitors of cerebral perfusion and ischemia can aid the surgeon in making that decision. Placement of a surgical shunt may be routine, or the need for one may be determined by various methods (discussed later). Surgical shunting is not without risk; vessel wall disruption, dislodgment of atheromatous plaque with 380

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Monitors of Cerebral Ischemia during Carotid Endarterectomy

Regional Anesthesia Repeated neurologic examination of the awake patient

General Anesthesia Electroencephalogram Somatosensory evoked potentials Internal carotid artery stump pressure Xenon 133 washout Transcranial Doppler ultrasonography Jugular venous oxygen saturation Transconjunctival oxygen saturation

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Risk Assessment Important risk factors for carotid disease include advanced age, hypertension, tobacco abuse, and a history of diabetes mellitus. Patients with left main coronary artery disease or other peripheral vascular disease are also more likely to have carotid disease. Conversely, patients with carotid disease often have concomitant coronary artery disease. Because these patients are at high risk for stroke but are more likely to die from myocardial infarction, the preoperative risk assessment, workup, and timing of surgery can be challenging and controversial. Cardiac risk assessment may include exercise or dobutamine stress testing to determine the need for preoperative coronary revascularization (e.g., coronary artery bypass grafting or percutaneous coronary transluminal angioplasty, with or without stenting). The appropriate amount of preoperative risk assessment and subsequent preventive intervention is debatable for several reasons. Both the surgeon and the anesthesiologist must consider the risk of neurologic insult if carotid surgery is delayed in favor of a coronary intervention that may prevent the cardiac morbidity associated with

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carotid endarterectomy. Also, both the anesthesiologist and the surgeon must assess the possibility of stroke in patients with carotid stenosis who undergo coronary artery bypass grafting. There are no clear guidelines for anesthesiologists who are managing patients with both carotid and coronary artery disease, and the decision to pursue an invasive intervention is often based on the patient’s clinical history, stability of symptoms, and institutional preference.

Implications A number of trials have demonstrated the benefit of carotid endarterectomy for the prevention of stroke in both symptomatic and asymptomatic patients. This procedure is not without risk, however. In the postoperative period, patients may develop a second neurologic insult, respiratory insufficiency, hemodynamic instability, carotid body damage, hyperperfusion syndrome, or wound hematoma (Table 93-2). Because most perioperative strokes are a result of postoperative thrombus, many vascular surgeons are asking their patients to continue taking antiplatelet agents (e.g., clopidogrel) up until the time of surgery. The use of aggressive antiplatelet therapy in patients with postoperative hypertension may predispose to wound hematoma, which may compromise the airway through laryngeal edema or extrinsic compression. A number of randomized trials have compared carotid endarterectomy to carotid angioplasty and stenting. The challenge during angioplasty is to limit stroke from distal embolization of plaque. Transcranial Doppler has demonstrated that embolic events are far more common with carotid angioplasty than with endarterectomy. Even so, such events are not necessarily associated with increased rates of cognitive dysfunction. “Umbrella” devices that capture embolic particles may improve the results of angioplasty. The ischemic time for angioplasty and stenting is much shorter than for carotid endarterectomy, which may have benefits. Large randomized trials are currently under way, but it will be several years before definitive results are available. Several studies have sought to elucidate predictors of outcome after carotid endarterectomy. Risk factors such as age older than 70 years, history of angina, coronary artery disease, congestive heart failure, severity of preoperative neurologic symptoms, occlusion of the contralateral internal

Table 93–2

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Common Postoperative Problems

Hemodynamic instability Hypertension Hypotension Myocardial infarction Wound hematoma Glossopharyngeal edema with loss of airway Cranial nerve damage Respiratory insufficiency through loss of carotid body function Neurologic dysfunction Acute graft thrombosis (may require re-exploration) Minor focal deficits Hyperperfusion syndrome

CARDIOTHORACIC & VASCULAR SURGERY

Use of superficial or deep cervical plexus block may also minimize the hemodynamic changes associated with general anesthesia. Even so, the vast majority of patients undergo carotid surgery under general anesthesia, and several monitors are available to evaluate the adequacy of collateral circulation and cerebral perfusion. Carotid stump pressure can be measured manually or invasively. The presence of a palpable pulse or a mean stump pressure greater than 60 mm Hg suggests sufficient backflow to prevent ischemia. However, ischemia may occur despite adequate carotid stump pressures if there is middle cerebral artery stenosis on the operative side and distal to the circle of Willis. The EEG represents cortical electrical activity, which decreases with cerebral ischemia. Disadvantages of EEG monitoring include the inability to monitor deep brain structures, the presence of false-negative findings due to preexisting or fluctuating neurologic deficits, and the influence of general anesthesia on EEG patterns. Unlike EEG monitoring, SEPs can monitor deeper brain structures. SEPs are a result of electrical impulses that originate peripherally and travel through first- and second-order neurons to synapse in the brainstem. Subsequently, these impulses are transmitted to the somatosensory cortex. As with EEG monitoring, false-negatives may result if anesthetics produce SEP changes that mimic cerebral hypoxia. Transcranial Doppler measures the velocity of blood flow in the middle cerebral artery. It can be used to detect acute thrombotic occlusion or embolization during or after carotid surgery, or to identify patients at risk for developing a postoperative hyperperfusion syndrome. However, the need for temporal ultrasound probe placement limits surgical and anesthetic access to the head. Cerebral blood flow can also be measured by the intravenous or intracarotid administration of radioactive xenon or krypton. This method requires considerable expertise for the interpretation of data, and it is highly specialized and expensive.

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carotid artery, and so-called siphon stenosis1 have been both supported and refuted, leading many to question their prognostic significance. Perioperative risk may also be affected by the surgeon’s experience.

MANAGEMENT AND PREVENTION The two main goals of intraoperative management are protecting the brain and protecting the heart, but these two goals are often in conflict. For example, increasing blood pressure to augment cerebral blood flow can increase afterload or myocardial contractility, thereby increasing the oxygen demand of the heart. Also, although hypothermia may provide effective cerebral protection, it poses a severe challenge to cardiac homeostasis if the patient is awake and shivering. Thus, the anesthetic plan involves trade-offs if both organs are to be protected.

Cerebral Protection Several strategies have been proposed to protect the brain during carotid endarterectomy. A stable high-normal blood pressure is maintained throughout surgery on the assumption that because blood vessels in ischemic or hypoperfused areas of the brain have lost their normal autoregulation, flow is directly proportional to pressure. Manipulation of arterial carbon dioxide tension (PaCO2) also affects cerebral blood flow. Although permissive hypercapnia dilates cerebral vessels in nonischemic areas of the brain, it may be detrimental if blood flow is diverted from already maximally dilated cerebral arteries perfusing ischemic areas. Conversely, hypocapnia may constrict vessels in adequately perfused, nonischemic areas of the brain to reroute blood to ischemic areas, thereby causing inverse steal. Because neither of these responses is predictable, most experts recommend normocarbia. Hyperglycemia may worsen ischemic brain injury. Elevated blood sugar is associated with elevated glucose levels in the brain and cerebral lactic acidosis from anaerobic glycolysis. Many candidates for carotid endarterectomy are diabetic, and the administration of dextrose-containing intravenous solutions may adversely affect cerebral injury. Although the exact mechanism of hyperglycemia’s adverse effect on ischemic brain injury is unknown, maintaining normoglycemia may be protective. However, isovolemic hemodilution with dextran or hetastarch may be beneficial in cases of cerebral ischemia. Blood viscosity may be reduced, with attendant microcirculatory disturbances thereby ameliorated. Some volatile anesthetic agents (e.g., isoflurane) may offer cerebral protection by reducing cerebral metabolism and decreasing the brain’s requirement for oxygen. Under these circumstances, the brain’s tolerance for temporary ischemia may be enhanced. Barbiturates also offer a degree of brain protection during periods of regional ischemia by

1 Flow to the brain at risk for ischemia or stroke is siphoned from the ipsilateral diseased internal carotid artery by the more normal contralateral internal carotid artery to increase ischemia or stroke risk.

decreasing cerebral metabolic oxygen requirements to about 50% of baseline. Maximal reductions in oxygen requirements correspond to an electrically silent or isoelectric EEG. Hypothermia can depress neuronal activity and reduce reperfusion injury sufficiently to put cellular oxygen requirements below the minimal levels normally required for viability. In theory, hypothermia represents the most effective method of cerebral protection. Even a mild decrease in temperature by about 2°C to 3°C during cerebral arterial hypoxemia has the potential to reduce ischemic damage to the brain.

Cardiac Protection Adequate preoperative preparation and intraoperative monitoring to protect the myocardium can prevent perioperative myocardial infarction. Maintaining the patient’s hemodynamic stability begins before surgery. Patient reassurance during the preoperative evaluation may prevent anxietyinduced myocardial ischemia. If sedatives are necessary, a short-acting premedication facilitates early preoperative neurologic assessment. Blood pressure and heart rate values obtained from the preoperative visit or previous hospital admissions determine the acceptable hemodynamic range for the patient. Chronic antianginal, antihypertensive, and aspirin therapy is generally continued on the day of surgery. β-Blockade has been shown to be cardioprotective in vascular patients with a positive stress test. The American Heart Association and American College of Cardiology 2002 guidelines recommend β-blockers in vascular patients with evidence of stress test–induced ischemia or symptomatic angina, arrhythmias, or hypertension (class I), as well as for patients with untreated hypertension, coronary artery disease, or risk factors for coronary artery disease (class IIa). However, β-blockade may make efforts to increase blood pressure during carotid clamping more difficult, and it may be associated with exaggerated bradycardia if the carotid sinus is stimulated during surgery. Monitoring during carotid endarterectomy includes the usual measures for general or regional anesthesia: temperature probe, blood pressure cuff, pulse oximeter, and end-tidal carbon dioxide. Often, an intra-arterial catheter is placed for beat-to-beat blood pressure monitoring for earlier detection and treatment of changes in blood pressure. Leads II and V4 or V5 of the electrocardiogram should be monitored for ST-T segment changes due to the high incidence of myocardial ischemia after carotid reperfusion. In high-risk patients, monitoring with transesophageal echocardiography may be added.

Further Reading Crawley F, Stygall J, Lunn S, et al: Comparison of microembolism detected by transcranial Doppler and neuropsychological sequelae of carotid surgery and percutaneous transluminal angioplasty. Stroke 31: 1329-1334, 2000. Endarterectomy for asymptomatic carotid artery stenosis. Executive Committee for the Asymptomatic Carotid Atherosclerosis Study. JAMA 273:1421-1428, 1995. Jordan WD Jr, Voellinger DC, Doblar DD, et al: Microemboli detected by transcranial Doppler monitoring in patients during carotid angioplasty versus carotid endarterectomy. Cardiovasc Surg 7:33-38, 1999.

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Munro FJ, Makin AP, Reid J: Airway problems after carotid endarterectomy. Br J Anaesth 76:156-159, 1996. Naylor AR, Rothwell PM, Bell PR: Overview of the principal results and secondary analyses from the European and North American randomised trials of endarterectomy for symptomatic carotid stenosis. Eur J Vasc Endovasc Surg 26:115-129, 2003. Riles TS, Imparato AM, Jacobowitz GR, et al: The cause of perioperative stroke after carotid endarterectomy. J Vasc Surg 19:206-214, 1994.

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Tangkanakul C, Counsell CE, Warlow CP: Local versus general anaesthesia in carotid endarterectomy: A systematic review of the evidence. Eur J Vasc Endovasc Surg 13:491-499, 1997. Wilke HJ II, Ellis JE, McKinsey JF: Carotid endarterectomy: Perioperative and anesthetic considerations. J Cardiothorac Vasc Anesth 10:928-949, 1996. Zvara DA: Pro: Regional anesthesia is the best technique for carotid endarterectomy. J Cardiothorac Vasc Anesth 12:111-114, 1998.

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Thoracic Aortic Aneurysm Annette Schure and John Ellis Case Synopsis A 67-year-old man underwent repair of a thoracoabdominal aortic aneurysm. The aortic occlusion time was 37 minutes, and left atriofemoral bypass was used during crossclamping for distal perfusion. Blood pressure and heart rate were maintained within 20% of the patient’s preoperative values. Urine output exceeded 0.5 mL/kg per hour in the postrepair period. On emergence from anesthesia, the patient was paraplegic.

PROBLEM ANALYSIS Definition Diseases of the thoracic aorta fall into four categories: 1. Aortic aneurysm: an atheromatous dilatation of the entire vessel wall 2. Aortic dissection (often incorrectly referred to as “dissecting aneurysm”): an expanding hematoma within the aortic wall, caused by either an intimal tear or degeneration of the media 3. Aortic rupture: secondary to trauma involving major shear forces 4. Coarctation: congenital stenosis of the aorta. Exact information about type, location, and extent of the lesion is extremely important, both for surgical approach and for anesthetic management.

Aortic dissections are commonly described according to the Stanford classification (types A and B) or the DeBakey classification (types I, II, IIIA, and IIIB) (Fig. 94-1); for aortic aneurysms, the Crawford classification (types I to IV) is used (Fig. 94-2). Both aneurysms and dissections involving the ascending aorta and the aortic arch are usually approached via a median sternotomy and require cardiopulmonary bypass, often with deep hypothermic circulatory arrest or retrograde or anterograde cerebral perfusion. The perioperative complications and anesthetic management of these aneurysms and dissections are beyond the scope of this chapter. The following discussion focuses on the management of patients with descending thoracic aneurysms.

Recognition Patients with lesions of the descending thoracic aorta may be completely asymptomatic, and the aneurysm may be

Stanford Classification

DeBakey Classification Type I

Type II

Type A

Type III

A

Type B

B

Figure 94–1 ■ DeBakey (types I, II, IIIA, and IIIB) and Stanford (types A and B) classifications of aortic dissection. (From Kouchoukos NT, Dougenis D: Surgery of the thoracic aorta. N Engl J Med 336:1876-1888, 1997.)

384

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II

III

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IV

Figure 94–2 Crawford classification of aortic aneurysms. (From Norris EJ, Frank SF: Anesthesia for vascular surgery. In Miller RD [ed]: Anesthesia, 5th ed. Philadelphia, Churchill Livingstone, 2000, p 1870.) ■

discovered incidentally on a chest radiograph or computed tomography (CT) scan. Alternatively, these aneurysms can present with a wide range of symptoms, depending on type, location, and extent of the lesion (Table 94-1). Imaging studies include a chest radiograph (revealing the classic widened mediastinum and aortic knob), spiral CT, and magnetic resonance imaging to assess the exact location and size of the aneurysm or dissection. Transesophageal echocardiography is useful for the diagnosis of dissections, especially in unstable patients. Angiography is still considered

Table 94–1

■

the gold standard; however, it is invasive, is associated with a high rate of complications (e.g., hemorrhage, nephropathy), and should be reserved for selected cases. Electrocardiogram and laboratory tests provide useful but nonspecific information.

Risk Assessment Patients with aortic disease have a high incidence of comorbidities: coronary artery disease (66%), hypertension (42%), chronic obstructive pulmonary disease (23%), peripheral

Presenting Clinical Signs and Symptoms of Thoracic Aortic Aneurysm and Dissection Aneurysm

Dissection

General presentation Location of pain Cardiovascular

Chronic or acute with leak or rupture Chronic back pain Normal or elevated blood pressure

Respiratory

Dyspnea if associated with left main-stem bronchial obstruction; hoarseness with laryngeal nerve compression; hemoptysis due to erosion Usually normal Possible renal insufficiency with aortic occlusive disease Commonly no associated neurologic symptoms or signs

Dramatic onset and fulminant course Acute-onset back or midscapular pain Elevated blood pressure due to pain; hypotension (possibly shock) if ruptured Dyspnea if associated with left main-stem bronchial obstruction; hemorrhagic pleural effusion

Gastrointestinal (GI) Renal Neurologic

Acute abdomen or GI bleeding Renal insufficiency with involvement of renal arteries Paraplegia if blood supply to spinal cord is impaired

Modified from Skeehan TM, Cooper R Jr: Anesthetic management for thoracic aneurysms and dissections. In Hensley FA, Martin DE, Gravlee GP (eds): A Practical Approach to Cardiac Anesthesia, 3rd ed. Philadelphia, Lippincott Williams & Wilkins, 2003, pp 624-625.

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I

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vascular disease (22%), cerebrovascular disease (14%), diabetes mellitus (8%), and chronic renal disease (3%). The preoperative evaluation should assess the extent, severity, and therapy for any of these comorbidities. Further assessment should focus on the following: ● ●

●

● ●

●

Risk of aspiration (i.e., recent oral intake) Airway evaluation and evidence of tracheal or left mainstem compression on chest radiograph or CT Cardiac evaluation (left ventricular function, regional wall motion abnormalities) Vascular access Preexisting renal insufficiency (diabetic nephropathy, contrast dye load) Preexisting neurologic impairment (possibly associated with dissection or diabetes)

A wide variety of severe perioperative complications can be associated with the surgical repair: ● ●

●

● ● ● ●

Difficult airway management Acute heart failure, myocardial infarction or disadvantageous tachy- or bradyarrhythmias Pulmonary hemorrhage and postoperative respiratory failure Hemorrhage and coagulopathy Hepatic and intestinal ischemia Renal failure Paraplegia

Implications SURGICAL APPROACH

especially in the case of difficult airways, are Univent tubes and Arndt endobronchial blockers. Additionally, extensive postoperative airway edema and facial swelling can complicate extubation or the change of a double-lumen tube to a single-lumen tube, even with a tube exchanger. Sometimes, it is safer to refrain from any such attempt, pull the doublelumen tube tip back into the trachea, and reassess the patient in 24 to 36 hours. HEMODYNAMIC CHANGES AND UNCLAMPING

WITH

CLAMPING

Cross-clamping of the thoracic aorta is often associated with severe hemodynamic and neuroendocrine responses. In contrast to infrarenal clamping, exclusion of the splanchnic circulation significantly reduces the available venous capacitance vasculature, so the sudden increase in impedance to aortic outflow, as well as the proximal shift of blood volume, results in drastic increases in afterload and preload, with the potential for cardiac decompensation or cerebral hemorrhage. Injudicious use of vasodilators (nitroprusside, nitroglycerine, milrinone, inhalational agents) can interfere with hypoxic pulmonary vasoconstriction, which is essential for adequate gas exchange; it can also decrease distal blood flow via the collateral circulation. The goal is careful titration of vasodilators to balance “permissive hypertension” for the maintenance of distal perfusion against the risk of cardiac decompensation. Finally, unclamping of the thoracic aorta can result in severe hypotension. Causes include reactive hyperemia, acidosis, hypercarbia, release of humoral factors such as cytokines and thromboxane, cardiac depression, and blood loss from the anastomosis.

The thoracic aorta is usually approached via a left-sided thoracotomy, with the patient in the right lateral decubitus position. Single-lung ventilation and, depending on the surgeon’s preference and experience, either a simple crossclamping technique (“clamp and sew”) or various forms of distal circulatory support are used. These include heparinbonded shunts (Gott shunts, 7 or 9 mm) that connect the proximal aorta with the femoral artery and provide adequate proximal decompression and maintenance of distal perfusion. Unfortunately, they can be difficult to place and tend to kink. Extracorporeal circulation via an atriofemoral or axillofemoral bypass (partial bypass without oxygenator) and full femorofemoral bypass are alternatives, but they require some degree of heparinization, with the associated risk of increased bleeding.

HEMORRHAGE

AIRWAY MANAGEMENT

The incidence of perioperative acute renal failure ranges from 3% to 14%. Aortic cross-clamping decreases renal blood flow from 80% to 90%, resulting in an ischemic insult. The risk is higher in older patients with coronary artery disease, diabetes, or preexisting renal dysfunction. Acute renal failure is a major predictor of increased morbidity and mortality. Intraoperative urine output is not predictive of postoperative renal function. Acute renal failure may occur despite apparently adequate perfusion (using distal circulatory support) or infrarenal clamping. Various methods of renal protection have been tried, including mannitol, furosemide,

Single-lung ventilation is critical for optimal surgical exposure and prevention of tissue trauma. Preoperative evaluation of the chest radiograph, CT scan, or magnetic resonance image is important, because large thoracic aneurysms can distort or compress the left main-stem bronchus, impairing proper positioning of a left-sided double-lumen tube. If in doubt, the double-lumen tube should be advanced only after fiberoptic examination of the left main bronchus. Right-sided double-lumen tubes, in contrast, easily dislodge and tend to obstruct the right upper lobe. Appropriate alternatives,

Patients undergoing thoracic aneurysm or dissection repair are at increased risk for intra- and postoperative bleeding. Along with renal and cardiac dysfunction, intraoperative blood loss correlates directly with perioperative mortality. In addition to bleeding from the aorta, intrapulmonary hemorrhage may occur due to adhesions and lung manipulations. Heparin use and hypothermia and coagulopathy associated with massive transfusions and liver ischemia are other contributing factors. Liver and bowel ischemia can lead to severe hypocalcemia and endotoxin-induced disseminated intravascular coagulation. RENAL PROTECTION

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fenoldopam, dopexamine, and cold perfusion, all without good scientific evidence. It seems that maintenance of intravascular volume and myocardial function are the most important determinants. SPINAL CORD PROTECTION Paraplegia occurs in about 1% to 11% of surgeries involving the thoracic aorta and is probably the most devastating complication. It usually presents as an anterior spinal artery syndrome with loss of motor function (anterior horn) and partially intact sensation (posterior columns), either immediately on emergence or within the first 24 hours. Interruption of spinal cord blood flow or prolonged hypoperfusion (>30 minutes) results in spinal cord ischemia. The blood supply for the spinal cord is provided by a single anterior spinal artery (75%) and two posterior spinal arteries (25%). In the upper cervical area, the anterior spinal artery is formed by branches of the vertebral arteries, with multiple collaterals from deep cervical and costovertebral arteries. In the middle portion, only a few intercostal arteries provide additional blood supply; the lower part of the spinal cord is

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almost entirely supplied by one intercostal artery branch (artery of Adamkiewicz). This artery is quite variable in origin, arising somewhere between T5 and T8 in 15%, T9 and T12 in 75%, and L1 and L2 in 10% of patients (Fig. 94-3). In addition to an unpredictable blood supply for vulnerable areas, increased cerebrospinal fluid (CSF) pressure can contribute to spinal cord ischemia. Spinal cord perfusion pressure is the mean arterial pressure minus CSF pressure. During aortic cross-clamping, hypertension and increased preload lead to increased intracranial pressure, followed by redistribution of CSF toward the spine and increased CSF pressure. Spinal cord edema after prolonged clamping or with reperfusion can further decrease spinal cord perfusion and contribute to neurologic dysfunction. Somatosensory evoked potentials (SEPs) and motor evoked potentials (MEPs) are used to monitor spinal cord ischemia. However, SEPs monitor only posterior column function, not the more vulnerable anterior part of the spinal cord, which likely explains the number of case reports of patients with paraplegia despite normal SEPs during clamping. MEPs appear to be more promising in this respect. Also, there can be a substantial delay between the onset of ischemia

Basilar artery Anterior spinal artery

Vertebral artery

1 2 3 4 5

Subclavian artery Cervical segmental arteries

Radicular arteries C3-C4 Radiculomedullary arteries C5-C6

6 7

Radiculomedullary arteries C7-C8 1 2 3 4 5

Radiculomedullary arteries T3-T4 Posterior spinal arteries

6

10 11 12

7 8 9 Great anterior radiculomedullary artery of Adamkiewicz T11-T12

1 2 3 4 5

Lumbosacral radicular arteries

CARDIOTHORACIC & VASCULAR SURGERY

Figure 94-3 Blood supply of the spinal cord. (From Marijic J, El-Magharbel I, Weiss L, Mahajan A: Anesthesia for patients with thoracic aortic disease. In Leung J [ed]: Cardiac and Vascular Anesthesia: The Requisites in Anesthesiology. Philadelphia, Mosby, 2004, p 180.)

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and the appearance of SEP changes. Finally, SEP and MEP monitoring in the operating room is technically cumbersome and influenced by many factors, including anesthetic agents, hypercarbia, temperature, and electrical interference.

MANAGEMENT Monitoring and Intravascular Access Blood pressure should be monitored proximal and distal to the aortic cross-clamp, usually via a right radial artery line (because blood flow to the left subclavian artery might be compromised by the cross-clamp) and a right femoral line. A pulmonary artery catheter and transesophageal echocardiography are useful monitors to assess ventricular function and volume status during clamping and unclamping. In preparation for massive blood loss, one or two 9 French introducers, possibly a dialysis-type catheter in a femoral vein, and one or two large-bore peripheral intravenous lines are advised. Blood warmer and rapid infusion devices should be set up and ready, and an adequate number of blood products should be typed and crossmatched. Also, one or two lumbar CSF drains can be placed and monitored for CSF pressure.

Clamping and Unclamping Anesthetic management depends on the surgical technique and the use of distal circulatory support or electrophysiologic monitoring. An important goal is the prevention of hemodynamic instability (hypertension or hypotension) and myocardial ischemia. Usually, “balanced anesthesia” is used: a combination of potent opioids, benzodiazepines, and lowdose inhalational agents, with or without muscle relaxants. Inotropes or vasodilators are used as required. Some centers advocate the use of combined general-epidural or general-spinal anesthesia, despite the risk of hematoma and medicolegal concerns. In preparation for simple aortic cross-clamping (without bypass), the patient should be allowed to become slightly hypovolemic (pulmonary capillary wedge pressure

Table 94–2

■

5 to 15 mm Hg). Mannitol is often given as a free radical scavenger for renal and spinal cord protection. During clamping, as discussed earlier, vasodilators and inhalational agents should be carefully titrated to balance distal perfusion via permissive hypertension with cardiac function. Before aortic cross-clamp removal, vasodilators and anesthetics are reduced, preload is optimized, and blood products, bicarbonate, and calcium are prepared. A temporary lowdose norepinephrine drip, epinephrine, and occasionally sequential release of the clamp by the surgeon are other useful measures of providing hemodynamic support after aortic cross-clamp release. Adverse hemodynamic changes are usually much less of a concern when extracorporeal circulation systems are used. Flow rates and volume status can be adjusted according to pre- and postclamp pressures, trying to achieve distal aortic pressures greater than 50 to 60 mm Hg.

PREVENTION Many techniques and methods have been described to reduce the risk of spinal cord ischemia (Table 94-2). Unfortunately, the scientific evidence supporting these modalities is inadequate or controversial. Some recent studies support the use of CSF drainage, but only as a component of a multimodal approach to spinal cord protection. Others suggest preoperative identification and selective or serial reimplantation of critical intercostal arteries under SEP or MEP guidance. At present, a combined strategy involving short crossclamp time, some form of distal circulatory support, CSF drainage, adjunctive pharmacotherapy, hypothermia, and avoidance of hyperglycemia is recommended. Finally, the current trend toward endovascular repair has provided a new perspective. So far, the results are promising, but paraplegia can still occur. Further experience and larger case series are necessary before a final recommendation can be made. For the time being, this minimally invasive technique presents anesthesiologists with new challenges.

Methods of Spinal Cord Protection during Descending Thoracic Aortic Surgery

Limitation of cross-clamp duration (<30 min) Distal circulatory support: shunt, atriofemoral or femorofemoral bypass Reattachment of critical intercostal arteries Cerebrospinal fluid drainage Moderate systemic hypothermia (32°C-34°C), epidural cooling, or circulatory arrest Maintenance of proximal blood pressure to improve collateral blood flow Neuroprotective pharmacotherapy Systemic: corticosteroids, barbiturates, naloxone, calcium channel blockers, free radical scavengers, NMDA receptor antagonists, mannitol, magnesium, vasodilators (adenosine, papaverine, prostacyclin), perfluorocarbons, colchicine Intrathecal: papaverine, magnesium, tetracaine, perfluorocarbons Avoidance of postoperative hypotension Sequential aortic clamping Neurologic monitoring for spinal cord ischemia Somatosensory evoked potentials Motor evoked potentials Avoidance of hyperglycemia From Ellis JE, Roizen MF, Mantha S, et al: Anesthesia for vascular surgery. In Barash PG, Cullen BF, Stoelting RK (eds): Clinical Anesthesia, 4th ed. Philadelphia, JB Lippincott–Williams & Wilkins, 2001, p 952.

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Further Reading Coselli JS, LeMaire SA, K¨oksey C, et al: Cerebrospinal fluid drainage reduces paraplegia after thoracoabdominal aortic aneurysm repair: Results of a randomized clinical trial. J Vasc Surg 35:631-639, 2002. Ellis JE, Roizen MF, Mantha S, et al: Anesthesia for vascular surgery. In Barash PG, Cullen BF, Stoelting RK (eds): Clinical Anesthesia, 4th ed. Philadelphia, JB Lippincott–Williams & Wilkins, 2001, pp 929-967. Gelman S: The pathophysiology of aortic cross-clamping. Anesthesiology 82:1026-1060, 1995. Greenberg R, Resch T, Nyman U, et al: Endovascular repair of descending thoracic aortic aneurysms: An early experience with intermediateterm follow up. J Vasc Surg 31:147, 2000. Khan RA, Moskowitz DM, Marin M, Hollier L: Anesthetic considerations for endovascular aortic repair. Mt Sinai J Med 69:57-67, 2002. Khan SN, Stansby G: Cerebrospinal fluid drainage for thoracic and thoracoabdominal aortic aneurysm surgery. Cochrane Library, vol 2, 2004. Ling E, Arellano R: Systematic overview of the evidence supporting the use of cerebrospinal fluid drainage in thoracoabdominal aneurysm surgery for prevention of paraplegia. Anesthesiology 93:1115-1122, 2000. Lippman M, Lingham K, Rubin S, et al: Anesthesia for endovascular repair of abdominal and thoracic aortic aneurysms: A review article. J Cardiovasc Surg 44:443-451, 2003.

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Marijic J, El-Magharbel I, Weiss L, Mahajan A: Anesthesia for patients with thoracic aortic disease. In Leung J (ed): Cardiac and Vascular Anesthesia: The Requisites in Anesthesiology. Philadelphia, Mosby, 2004, pp 169-185. O’Connor CJ, Rothenberg DM: Anesthetic considerations for descending thoracic aortic surgery: Part I. J Cardiothorac Vasc Anesth 9:581-588, 1995. O’Connor CJ, Rothenberg DM: Anesthetic considerations for descending thoracic aortic surgery: Part II. J Cardiothorac Vasc Anesth 9:734-747, 1995. Oliver WC Jr, Nuttall G, Murray MJ: Thoracic aortic disease. In Kaplan JA (ed): Cardiac Anesthesia, 4th ed. Philadelphia, WB Saunders, 1999, pp 821-859. Skeehan TM, Cooper R Jr: Anesthetic management for thoracic aneurysms and dissections. In Hensley FA, Martin DE, Gravlee GP (eds): A Practical Approach to Cardiac Anesthesia, 3rd ed. Philadelphia, JB Lippincott–Williams & Wilkins, 2003, pp 617-647. Svensson LG, Patel V, Robinson MF, et al: Influence of preservation or perfusion of intraoperatively identified spinal cord blood supply on spinal motor evoked potentials and paraplegia after aortic surgery. J Vasc Surg 13:355-365, 1991.

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Abdominal Aortic Aneurysm Repair Christopher J. O’Connor Case Synopsis A 74-year-old man with chronic stable angina, hypertension, and a previous myocardial infarction undergoes repair of an infrarenal abdominal aortic aneurysm (AAA) with the use of combined epidural and general anesthesia. Preoperative dipyridamole thallium testing revealed a large, fixed myocardial defect with no evidence of reversible disease. Transient hypotension during aneurysm exposure responds promptly to phenylephrine. After placement of the aortic cross-clamp, there is 1-mm ST segment depression and an increase in the pulmonary capillary wedge pressure. Both resolve with intravenous nitroglycerin therapy. However, moderate hypotension occurs after release of the aortic cross-clamp. Aggressive fluid and cell-saver blood replacement and the administration of phenylephrine restore blood pressure to normal. The patient is successfully extubated at the completion of the procedure and transported to the intensive care unit with an epidural infusion of bupivacaine-fentanyl for perioperative analgesia.

Definition Hypotension is relatively common during infrarenal AAA repair, although it is usually transient and well tolerated. The cause is multifactorial, and treatment depends on the specific cause. Myocardial ischemia, although less frequent, is often encountered in patients with known or previously undiagnosed coronary artery disease (CAD) and may be accompanied by increased pulmonary capillary wedge pressure, reduced cardiac output (Fig. 95-1), and transesophageal echocardiogram (TEE) evidence of regional wall motion abnormalities. In addition to hypotension and myocardial ischemia, other important intraoperative complications include hypertension and left ventricular (LV) dysfunction after aortic occlusion; hypothermia; hypoxemia due to abdominal retraction and underlying obstructive pulmonary disease; severe hemorrhage; and coagulopathy as a result of dilutional changes, hypocalcemia, and acidosis. Mild hypertension is typically encountered after placement of the aortic cross-clamp, although the magnitude of the blood pressure rise is substantially less than that with occlusion at the level of the thoracic aorta. Hypertension during aortic clamping may be absent, however, if blood and third-space fluid losses have not been adequately replaced. Table 95-1 compares the hemodynamic changes with supraceliac and suprarenal versus infrarenal aortic occlusion.

Recognition Recognition of these hemodynamic events is facilitated by the use of direct arterial and central venous pressure monitoring. A pulmonary artery catheter and TEE are monitors for the assessment of preload and LV function and are also used to detect myocardial ischemia. Pulmonary artery 390

catheter and TEE are likely indicated in patients with severe CAD or LV dysfunction. Hypovolemia is diagnosed on the basis of a significant decline in pulmonary capillary wedge pressure, pulmonary artery end-diastolic pressure, or central venous pressure and diminished LV end-diastolic area on TEE. Myocardial ischemia typically manifests as ST segment changes and new regional wall motion abnormalities on TEE. Alterations in pulmonary artery pressure, which also may be observed, are less sensitive indicators of myocardial ischemia. The cause of intraoperative hypotension depends, in part, on the stage of the procedure in relation to the application of

Coronary artery disease

No heart disease

12 Change in pressure after aortic clamping (mm Hg)

PROBLEM ANALYSIS

8 4

* *

*

* *

*

* *

* 0 −4 −8 −12

CVP, P < .01 PA, P < .01 PCW, P < .05

Figure 95–1 ■ Comparison of changes in central venous pressure (CVP), pulmonary artery (PA) pressure, and pulmonary capillary wedge (PCW) pressure in patients with and without coronary artery disease (CAD). Values with asterisks refer to patients developing myocardial ischemia during infrarenal aortic occlusion. Significance values refer to the comparison between patients with and without heart disease. (From Attia RR, Murphy JD, Snider M, et al: Myocardial ischemia due to infrarenal aortic cross-clamping during aortic surgery in patients with severe coronary artery disease. Circulation 53:961-965, 1976.)

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Table 95–1

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Percentage Change in Cardiovascular Variables on Initiation of Aortic Occlusion during Supraceliac versus Infrarenal Aortic Aneurysm Surgery Level of Aortic Occlusion

Variable

Supraceliac

SuprarenalInfraceliac

Infrarenal

+54

+5*

+2*

+38

+10*

0*

+28 +69 −38 +92

+2* +10* −10* +33

+9* +11* −8* 0

Mean arterial blood pressure Pulmonary capillary wedge pressure End-diastolic area End-systolic area Ejection fraction Patients with wall motion abnormalities New myocardial infarction

+8

0

0

*Statistically different (P <.05) from group undergoing supraceliac aortic occlusion. From Roizen MF, Beaupre PN, Alpert RA, et al: Monitoring with two-dimensional transesophageal echocardiography: Comparison of myocardial function in patients undergoing supraceliac, suprarenal-infraceliac, or infrarenal aortic occlusion. J Vasc Surg 1:300-305, 1984.

Figure 95–2 unclamping.

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preparation, may substantially reduce preload, cardiac output, and blood pressure. Also, if myocardial ischemia develops, LV dysfunction may further diminish cardiac output, thereby augmenting the effects of hypovolemia and vasodilatation. It is critical to recognize that hypotension during this stage of the procedure suggests profound hypovolemia, because aortic occlusion usually results in mild hypertension. A thorough assessment of cardiac filling pressures, surgical blood loss, and current fluid replacement is indicated in this situation. Hypotension after release of the aortic cross-clamp is a common and expected event. It is attributed to a decrease in vascular resistance and central hypovolemia. Ischemic vasodilatation develops in the lower extremities during the period of occlusion. With reperfusion of these vascular beds, ischemic metabolites and humoral factors released into the systemic circulation cause a fall in systemic vascular resistance. In addition, pooling of blood in these dilated venous and arterial vessels contributes to reduced venous return. The degree of hypotension encountered depends on the level and duration of occlusion, speed of clamp removal, intravascular volume status before aortic clamp release, and persistent effects of anesthetics and pharmacologic vasodilators. Severe hypotension can be largely avoided with appropriate fluid loading and replacement of blood losses before unclamping the aorta, as well as gradual release of the occlusion. The pathophysiology of hypotension resulting from cross-clamp release is depicted in Figure 95-2.

Risk Assessment Patients with underlying CAD are at the highest risk for myocardial ischemia and ventricular dysfunction during abdominal aortic surgery. Up to two thirds of patients with AAAs have angiographic evidence of significant CAD, and 30% of these will sustain a perioperative cardiac complication, such as myocardial infarction with or without associated heart failure. Although there is ongoing controversy regarding the appropriate preoperative cardiac evaluation of vascular surgical patients, a careful clinical and functional assessment is essential, along with noninvasive tests of

Cause of hypotension after aortic

AORTIC CROSS-CLAMPING Distal ischemia

Local mediator release

Distal venous/arterial dilation

AORTIC UNCLAMPING Mediator washout Systemic vasodilation

Blood pooling in dilated vessels ↓ Venous return

HYPOTENSION

CARDIOTHORACIC & VASCULAR SURGERY

the aortic cross-clamp. Hypotension before placement of the cross-clamp may be secondary to prostacyclin release from bowel eventration and mesenteric traction, causing profound vasodilatation, tachycardia, and facial flushing–the so-called mesenteric traction syndrome. Although this is a transient event, it usually requires treatment with a vasopressor such as phenylephrine. Further, the concomitant use of regional anesthesia may contribute to arterial hypotension by means of reduced vascular resistance and venous return (preload). Hypotension during the period of aortic occlusion is typically due to hypovolemia from ongoing blood loss, evaporative fluid loss from exposure of the abdominal cavity and its contents, and third-space loss. These operative fluid losses, when superimposed on the potential effects of preoperative diuretics, contrast dye administration, and bowel

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coronary vascular reserve, when appropriate. Individuals with LV dysfunction may be more susceptible to intraoperative hemodynamic instability. In addition, blood pressure changes are less pronounced in patients with aorto-occlusive disease compared with those undergoing simple aneurysm repair. Chronic occlusive disease results in the formation of extensive periaortic collateral vessels that continue to perfuse the lower extremities during the period of aortic occlusion; thus, changes in vascular resistance with both aortic clamping and release are considerably attenuated. In addition to these preoperative factors, the degree of preexisting volume depletion and the rate of intraoperative blood loss determine the response to aortic cross-clamping and release. Although blood loss typically ranges from 800 to 1500 mL, hemorrhage may be severe enough to require fresh frozen plasma or platelet transfusions if a dilutional coagulopathy develops.

Implications Hypotension and myocardial ischemia are poorly tolerated in patients with CAD. Mortality rates for elective AAA repair are 2% to 7%. The majority of deaths are due to myocardial infarction and other fatal cardiac events (e.g., acute heart failure, ventricular tachyarrhythmias). Mortality rates may be as much as fivefold higher in patients with clinically evident CAD. In addition, owing to coexisting renal disease, sustained and prolonged intraoperative hypotension and renal artery embolization may contribute to postoperative renal failure. The incidence rates of postoperative complications and a comparison of the causes of early mortality after elective and ruptured AAA repair are given in Tables 95-2 and 95-3, respectively. Endovascular stent-graft repair has become an important alternative to the open treatment of AAA, and it is associated with less morbidity. Even though endovascular repair is typically recommended for high-risk patients, it is still associated with lower complication rates. These devices are typically placed in the operating room by a team of vascular

Table 95–3

■

Incidence of Immediate Postoperative Complications after Elective Abdominal Aortic Aneurysm Repair

Complication Cardiac Myocardial infarction Pulmonary Pneumonia Renal insufficiency Renal failure requiring dialysis Hemorrhage Lower extremity ischemia Ischemic colitis Stroke Ureteral injury

Incidence (%) 15 2-8 8-12 5 5-12 1-6 2-5 1-4 1 1 <1

From Cronenwett JL, Sampson LN: Aneurysms of the abdominal aorta and iliac arteries. In Dean RH, Yao JS, Brewster D (eds): Diagnosis and Treatment in Vascular Surgery. Norwalk, Conn., Appleton & Lange, 1995, pp 230-233.

Causes of Early Mortality after Elective and Ruptured Abdominal Aortic Aneurysm Repair Mortality Rate (%)

Cause Cardiac Pulmonary Renal Colon infarction Hemorrhage Multisystem organ failure Other

Elective

Ruptured

58 6 4 1 0 1 24

20 3 9 9 18 35 6

From Cronenwett JL, Sampson LN: Aneurysms of the abdominal aorta and iliac arteries. In Dean RH, Yao JS, Brewster D (eds): Diagnosis and Treatment in Vascular Surgery. Norwalk, Conn., Appleton & Lange, 1995, pp 230-233.

surgeons and interventional radiologists. Anesthesia is easily provided with either spinal or combined spinal-epidural anesthesia, although some institutions prefer general anesthesia. Comparisons of open versus endovascular repair have demonstrated reduced 30-day mortality rates, bleeding, duration of time in the intensive care unit, and incidence of cardiac and pulmonary complications in patients treated with endovascular devices (Table 95-4). The long-term durability and rupture-free periods following placement of these devices are not yet well established, and largescale, prospective, randomized comparisons of these two approaches are still under way.

MANAGEMENT When hypotension develops, aggressive evaluation of the intravascular volume and degree of blood loss is the first diagnostic maneuver, because hypovolemia is the most

Table 95–4 Table 95–2

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■

Perioperative Complications: Open versus Endovascular Repair of Abdominal Aortic Aneurysms

Complication

Open Repair

Endovascular Repair

30-day mortality (%) Cardiac complications (%) Pulmonary complications (%) Neurologic complications (%) Renal complications (%) ICU stay (days) Transfusion (% transfused) Blood loss (mL) Graft-related complications

1-4 4-22 13-16 3 4-8 2 51 1200 3.8

0-3* 3-11* 3-4* 1* 4.3-5† 0.5-1* 26* 450* 13.8*

*P <.05; endovascular versus open repair. † Not significant; endovascular versus open repair. ICU, intensive care unit. From Miraude A, Bosch JL, Halpern EF, et al: Elective endovascular versus open surgical repair of abdominal aortic aneurysms: Systematic review of short-term results. Radiology 224:739-747, 2002; Elkouri S, Gloviezki P, McKusick MA, et al: Perioperative complications and early outcome after endovascular and open surgical repair of abdominal aortic aneurysms. J Vasc Surg 39:497-505, 2004.

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likely cause. Evidence of myocardial ischemia should be assessed with ST segment analysis, TEE, or both. It is treated by providing adequate coronary perfusion pressure, possibly intravenous nitroglycerin, and β-blockers when there is associated tachycardia. Maintenance of β-blockade throughout the perioperative period is essential for patients at risk for postoperative cardiac morbidity due to CAD. Management of hypotension depends on its relation to aortic occlusion: ●

●

●

PREVENTION Prevention of intraoperative hypotension requires an understanding and anticipation of the specific surgical events that precipitate vasodilatation and blood loss. A fastidious approach to monitoring cardiac filling pressures, along with frequent assessment of ongoing blood and fluid losses, is essential to maintaining a stable blood pressure. Discontinuation of anesthetics and vasodilators, along with appropriate volume loading before the release of aortic occlusion, attenuates accompanying vasodilatation. The incidence of myocardial ischemia may be reduced by recognizing and controlling the determinants of myocardial oxygen supply and demand in high-risk patients. Prophylactic intravenous nitroglycerin is not consistently effective for preventing myocardial ischemia or myocardial infarction in high-risk patients. Although it may be reasonable therapy in patients receiving preoperative nitrates, careful monitoring of preload is essential to avoid possibly deleterious reduced coronary

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perfusion pressure. Finally, substantial data suggest that prophylactic perioperative oral β-blockers and α2-agonists can reduce the incidence of postoperative cardiac events in patients undergoing major noncardiac surgery.

Further Reading ACC/AHA guidelines for perioperative cardiovascular evaluation for noncardiac surgery. Circulation 93:1280-1317, 1996. Attia RR, Murphy JD, Snider M: Myocardial ischemia due to infrarenal aortic cross-clamping during aortic surgery in patients with severe coronary artery disease. Circulation 53:961-965, 1976. Cronenwett JL, Sampson LN: Aneurysms of the abdominal aorta and iliac arteries. In Dean RH, Yao JS, Brewster D (eds): Diagnosis and Treatment in Vascular Surgery. Norwalk, Conn., Appleton & Lange, 1995, pp 230-233. Elkouri S, Gloviezki P, McKusick MA, et al: Perioperative complications and early outcome after endovascular and open surgical repair of abdominal aortic aneurysms. J Vasc Surg 39:497-505, 2004. Ellis JE, Roizen M, Mantha S, et al: Anesthesia for vascular surgery. In Barash PG, et al (eds): Clinical Anesthesia. Philadelphia, Lippincott-Raven, 1997, pp 871-910. Gelman S: The pathophysiology of aortic cross-clamping and unclamping. Anesthesiology 82:1026-1060, 1995. Gewertz BL, Kremser PC, Zarins CK, et al: Transesophageal echocardiographic monitoring of myocardial ischemia during vascular surgery. J Vasc Surg 5:607-613, 1987. Johnston WE, Balestrieri FJ, Plonk G, et al: The influence of periaortic collateral vessels on the intraoperative hemodynamic effects of acute aortic occlusion in patients with aorto-occlusive disease or abdominal aortic aneurysm. Anesthesiology 66:386-389, 1987. Mangano DT, Layug E, Wallace A, et al: Effect of atenolol on mortality and cardiovascular morbidity after noncardiac surgery. Multicenter Study of Perioperative Ischemia Research Group. N Engl J Med 335:1713-1720, 1996. Miraude A, Bosch JL, Halpern EF, et al: Elective endovascular versus open surgical repair of abdominal aortic aneurysms: Systematic review of short-term results. Radiology 224:739-747, 2002. Pevec WC: Morbidity associated with vascular surgery. In Callow A, Ernst C (eds): Vascular Surgery. Stamford, Conn., Appleton & Lange, 1995, pp 1373-1395. Poldermans D, Boersma E, Bax JJ, et al: The effect of bisoprolol on perioperative morbidity and myocardial infarction in high-risk patients undergoing vascular surgery. Dutch Echocardiographic Cardiac Risk Evaluation Applying Stress Echocardiography Study Group. N Engl J Med 341:1789-1794, 1999. Roizen MF, Beaupre PN, Alpert RA, et al: Monitoring two-dimensional transesophageal echocardiography: Comparison of myocardial function in patients undergoing supraceliac, suprarenal-infraceliac, or infrarenal aortic occlusion. J Vasc Surg 1:300-305, 1984. Wallace A, Galindez D, Salahieh A, et al: Effect of clonidine on cardiovascular morbidity and mortality after noncardiac surgery. Anesthesiology 101:284-293, 2004. Wallace A, Layug E, Tateo I, et al: Prophylactic atenolol reduces postoperative myocardial ischemia. McSPI Research Group. Anesthesiology 88:7-17, 1998.

CARDIOTHORACIC & VASCULAR SURGERY

Hypotension before aortic occlusion: Consider the effects of epidural anesthesia, mesenteric traction, or preoperative hypovolemia. Hypotension during occlusion: Consider severe hypovolemia. Aggressive volume resuscitation with blood and crystalloid solutions is indicated before release of the aortic cross-clamp, to increase central venous pressure or pulmonary capillary wedge pressure by 10% to 20% above baseline levels. Hypotension after release of the aortic cross-clamp: Administration of all anesthetic agents and vasodilators should be temporarily discontinued. Vasopressors such as dopamine or phenylephrine should be available to counteract the accompanying vasodilatation and preload reduction. Blood must be available in case hemorrhage is severe, and cell-saver systems for intraoperative blood salvage are strongly recommended.

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Peripheral Vascular Surgery Ronak Desai Case Synopsis A 74-year-old woman with insulin-dependent diabetes, hypertension, and a long-standing history of smoking requires a redo right lower limb revascularization on a semiurgent basis. There is a possibility of using upper extremity vessels as graft material. A general orotracheal anesthetic is planned. An hour after uneventful surgery, while the patient is in the recovery unit, the surgeon recognizes impending graft thrombosis after the loss of Doppler signals. The graft must be re-explored in the operating room. The surgeon also mentions the possible intraoperative use of urokinase, a thrombolytic agent.

PROBLEM ANALYSIS Definition Lower limb atherosclerotic peripheral vascular disease (PVD) is common in the elderly but is asymptomatic in more than 90% of cases. When it is symptomatic, intermittent claudication is by far the most common complaint. Indications for elective peripheral vascular surgery (PVS) include claudication, ischemic pain at rest, ulceration, and gangrene. Goals of revascularization are to improve the natural course of PVD and ultimately to avoid amputation. However, bypass grafts may fail acutely or long term, with 25% to 60% of grafts occluded after 5 years. Critical leg ischemia occurs in less than 10% of patients and is defined as pain at rest or the presence of gangrene or ulcers. Because such patients are at risk for imminent limb loss, surgery is semiurgent or urgent. During revascularization, aortoiliac (inflow) or distal (outflow) obstructions are bypassed with axillofemoral or femoropopliteal distal bypass grafts, respectively.

Recognition The prevalence of cardiac risk factors is usually greater in patients undergoing PVS than in those having nonvascular surgery. Therefore, careful attention to metabolic and cardiac status is critical. Also, successful surgery and long-term survival of the graft depend on blood flow through the graft, blood coagulability, and the future development of atherosclerotic changes in the graft. Anesthesia care can have an important impact on immediate and longer-term outcomes.

Risk Assessment Primary concerns are the impact of the planned anesthetic technique on the surgical revascularization procedure, the patient’s tolerance of the anesthetic and surgery (which often takes many hours), and preoperative cardiopulmonary risk factors. Another important concern is the effect of anesthetic technique—regional anesthesia (RA) versus general 394

anesthesia (GA)—on the success of revascularization and perioperative outcomes. The following factors should be considered: ●

●

●

●

Sympathectomy. This procedure dilates the venous capacitance bed to reduce cardiac preload, thus increasing fluid requirements to maintain cardiac output. It also reduces systemic vascular resistance. If this decreases cardiac afterload and work, it may improve global and regional left ventricular function for the duration of the sympathetic block. Analgesia. Successful RA provides analgesia and reduces or eliminates the need for systemic narcotics. This benefit is extended with continuous RA techniques. Surgical stress. RA attenuates the surgical stress response, including renin-angiotensin-aldosterone system activation and the associated increased release of vasopressin and catecholamines. Postoperative hypercoagulability. Sympathetic block may reduce stress-related hypercoagulability.

Although it is difficult to compare studies of anesthetic techniques, medications, and surgical factors related to PVD, recent prospective randomized trials have found no difference in mortality between spinal or epidural RA and GA (Table 96-1). The lack of reported differences in outcome may be attributed to improved cardiovascular management in these trials compared with earlier ones. RA continued as postoperative analgesia may improve graft patency, as indicated by a reduced need for regrafting, thrombectomy, or amputation. Two studies in Table 96-1 (Tuman and Christopherson) showed marked differences in graft failure rates between GA alone and RA with or without GA; the other studies found no such difference. Conflicting outcomes may be ascribed to differences in methodology, type of graft material, extent of distal vessel disease, and adjunct anesthetic drugs. Thus, RA for PVD surgery may benefit patients at highest risk for early graft failure or those who require reoperation for whatever reason. For limb salvage surgery, hypercoagulable states and prosthetic conduits are independent risk factors for graft failure. RA may have beneficial effects on some procoagulant parameters (e.g., platelet function, fibrinogen and plasminogen

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Table 96–1

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395

Summary of Studies Comparing Regional Anesthesia and General Anesthesia for Peripheral Vascular Surgery Perioperative Mortality (%)

Study

GA

RA

GA

RA

GA

RA

GA

RA

Remarks

Cook et al 1986

51

50

5.9

2.0

7.8

4.0

—

—

Tuman et al 1991

40

40

0

0

27

10

—

—

Christopherson et al 1993

51

49

3.9

4.1

7.8

8.2

21*

4*

Bode et al 1996

138

285

2.9

3.1

19

23

—

—

Pierce et al 1997

96

86/82

—

—

—

—

2.1

2.3/2.4

145

5.0

3.4

—

—

9.4

14

Spinal anesthesia; higher incidence of hypotension (RA) and HTN (GA); blood loss less with spinal anesthesia; risk of postoperative MI similar GA with postoperative epidural analgesia vs GA with postoperative PCA Controls (N = 40) were randomly selected GA patients (non-CV surgery), but no PVD EA for surgery followed by epidural analgesia, or GA for surgery and IV PCA 11 (GA) vs 2 (RA) patients had regrafting or embolectomy EA (N = 149); spinal anesthesia (N = 136); GA (N = 138) Overall, the patient population included 86% with DM, 69% with HTN, 36% with prior MI, and 41% with a history of smoking Of 423 patients randomized to GA, spinal anesthesia, or EA, 76 did not meet protocol standards, 32 had inadequate anesthesia, 51 were lost to follow-up There were no differences among groups for 30-day graft patency, reoperation rates, 30-day graft occlusion, death, amputation, or length of hospital stay EA vs GA; retrospective analysis of femoralpopliteal-tibial bypass graft patients with similar demographic profiles Conclusion was that EA vs GA choice should be based on preanesthesia findings

Schunn et al 1998 158

Cardiovascular Complications (%)

PVS Graft Thrombosis (%)

*P ≤.05. CV, cardiovascular; DM, diabetes mellitus; EA, epidural anesthesia; GA, general anesthesia; HTN, hypertension; IV, intravenous; MI, myocardial infarction; PCA, patientcontrolled analgesia; PVD, peripheral vascular disease; PVS, peripheral vascular surgery; RA, regional anesthesia.

CARDIOTHORACIC & VASCULAR SURGERY

Number of Patients

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activator inhibitor levels). Furthermore, serologically proven hypercoagulability is known to be associated with inferior long-term graft patency and lower rates of limb salvage and survival after infrainguinal bypass grafts. However, whether RA protects against graft thrombosis remains controversial. As for preoperative cardiopulmonary risk assessment, 20% to 60% of patients with PVD have manifest or silent coronary artery disease. The preoperative history and physical examination should focus on identifying cardiac functional status and associated risk factors (see Chapter 38). In a post hoc review of 10 studies on outcomes after femoropopliteal bypass graft surgery, combined perioperative mortality was 0.8% for patients at low risk versus 4.7% for those at high risk. The cause of death was similar for both groups (multiorgan failure, stroke, or cardiac complications). Cardiac risk factors for those having PVS are similar to those for patients having other major noncardiac surgery (see Chapter 38). They include the following: ● ● ●

● ● ● ●

History of ischemic heart disease History of congestive heart failure Uncontrolled stage 2 hypertension, especially if associated with evidence of end-organ damage1 Associated cerebrovascular disease Preoperative treatment with insulin Preoperative serum creatinine greater than 2 mg/dL High-risk surgery

Implications Although multiple anesthetic techniques have been evaluated to date, the ideal technique for lower limb revascularization surgery, especially femoral-popliteal-tibial (distal) bypass grafting, remains unclear. Nonetheless, a number of medical and surgical factors may help determine the best technique for a particular patient. The duration of surgery is one important consideration. Surgeons may expend considerable time harvesting the patient’s own veins because acute and chronic patency is significantly enhanced with these grafts compared with frozen veins or prosthetic materials. Repeat revascularization procedures are typically longer and more complex. Certainly RA may still be possible, because continuous epidural infusions and spinal catheters are available and routinely employed. However, patients may have difficulty tolerating intravenous sedation for long periods. Another consideration is whether arm veins will be harvested, particularly for reoperations. Reconstructions of this type may preclude the use of RA alone, but combined RA and GA may be appropriate. Patients with severe pulmonary disease may also benefit from RA, but lengthy surgeries that require them to lie flat for prolonged periods may be difficult to tolerate. Further, sudden

1 Stage 2 hypertension is systemic blood pressure of 160/100 mm Hg or higher (sequential measurements on separate days). If stage 2 hypertension is associated with evidence of end-organ damage (e.g., aortic dissection, renal failure, cerebral symptoms, heart failure, retinopathy), this constitutes a true hypertensive emergency; if not, it is a hypertensive crisis. The former requires more urgent therapy (intravenous drugs) than the latter (oral drugs). See Chapter 77.

patient movement due to spasmodic coughing secondary to bronchitis, chronic pulmonary disease, smoking, or reactive airway disease may make creating delicate vascular anastomoses nearly impossible. Similarly, patients with cardiovascular disease may experience orthopnea, especially those with low cardiac ejection fractions (≤0.35) or a past history of congestive heart failure, and they may be unable to remain supine for long periods. Use of modified semi-Fowler positioning2 and back supports may help reduce discomfort or reduce or eliminate orthopnea. If it is determined that RA is optimal for a patient, the use of perioperative anticoagulation must be given consideration. Guidelines of the American Society of Regional Anesthesia address the implications of anticoagulation and offer advice for the prevention and management of bleeding complications with RA (see Chapter 67).

MANAGEMENT In general, all prescribed cardiac medications should be given preoperatively to optimize the cardiovascular dynamics (see Chapter 38). If RA is used, perioperative anticoagulation status must be determined, and appropriate precautions exercised (see Chapter 67).

Monitoring Indicated monitoring includes at least a two-lead electrocardiogram with precise placement of V4 or V5 leads, surface pulse oximetry, end-tidal carbon dioxide and inhalational anesthetic monitoring, and noninvasive blood pressure monitoring. Invasive monitoring is indicated for some patients, especially those with symptomatic or severe cardiovascular disease (e.g., stage III or IV heart failure, chronic atrial fibrillation, symptomatic arrhythmias, stage 2 hypertension). Such monitoring includes an arterial line, central venous pressure, and possibly a pulmonary artery catheter. These are placed before or after anesthesia induction. With severe hypertension,3 poor left ventricular function (ejection fraction ≤0.35), or symptomatic coronary artery disease, preinduction invasive monitoring allows tighter control of hemodynamic changes during induction and tracheal intubation and during periods of increased cardiovascular stress. The anesthetic technique (RA versus GA) should not affect the decision to institute central venous pressure or pulmonary artery catheter monitoring. Central lines may be required for patients with poor peripheral access or when arm veins will be used. Transesophageal echocardiography is useful for monitoring cardiac function and volume status when GA is used, especially for hemodynamically unstable patients or if a cardiac (atrial fibrillation) or aortic (unstable plaque) source for thromboembolism is present.

2 Namely, 15- to 30-degree versus 30- to 45-degree head-up tilt, without compromising surgical groin access. 3 Stage 1 (blood pressure >140/90 but <160/100 mm Hg) or stage 2 hypertension (see footnote 1).

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Hemodynamic Changes

Fluid Management Most patients having PVS require careful attention to fluid status, because there is a fine line between fluid overload with pulmonary edema and hypovolemia with impaired flow to the graft and vital organs. Maintenance crystalloid is used to replace preoperative insensible deficits (e.g., caused by lack or oral intake or by bowel preparation). Inpatients are often dehydrated or may have received dye loads during preoperative angiograms and require volume repletion. Thirdspace fluid loss is moderate for typical lower extremity PVS. The starting point is often 5 mL/kg per hour. Blood replacement is accomplished with colloids or red blood cells as needed. However, vascular surgeons are especially cognizant of the fact that reduced blood viscosity increases blood flow through the bypass graft.4 Thus, some degree of anemia may be beneficial for high-risk grafts; however, it is also associated with reduced vital organ and tissue oxygen delivery. A reasonable trade-off for intraoperative hemoglobin concentration is maintaining a hematocrit of 28 in high-risk patients.

Temperature Temperature homeostasis is important owing to the detrimental cardiovascular effects associated with hypothermia. 4

From Poiseuille’s formula.

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Hypothermia increases the risk for myocardial ischemia, promotes instability in heart rate and blood pressure, and may cause postoperative confusion. Thus, forced air warming blankets, a warm operating room, warmed intravenous fluids, a humidifier on the ventilator circuit, or low fresh gas flows are appropriate for maintaining normothermia.

PREVENTION Any patient having lower extremity PVS is presumed to have generalized atherosclerotic disease and coronary artery disease. Therefore, preoperative considerations are similar to those for patients with known cardiac disease having major noncardiac surgery (see Chapter 38). Aggressive preventive strategies such as risk factor modification and drug therapy (e.g., β-blockers, lipid-lowering agents, antiplatelet drugs) are needed. Antiplatelet drugs and RA may reduce the rate of postoperative graft thrombosis. β-Blockers reduce the risk for myocardial ischemia and myocardial infarction, which are responsible for most of the morbidity associated with PVS. The superiority of RA or GA for preventing adverse cardiovascular outcomes, graft thrombosis, or mortality has not been established. As discussed earlier, a number of proposed mechanisms may explain the trend toward improved outcomes with RA, but these have not been firmly established. Thus, the choice of anesthetic management should be made on a case-by-case basis after discussions with both the surgeon and the patient. Medical and surgical factors, as well as patient preferences, can help determine the best strategy for each patient.

Further Reading Bode RH, Lewis KP, Zarich SW, et al: Cardiac outcome after peripheral vascular surgery: Comparison of general and regional anesthesia. Anesthesiology 84:3-13, 1996. Breslow MJ, Parker SD, Frank SM, et al: Determinants of catecholamine and cortisol responses to lower extremity revascularization. The PIRAT study group. Anesthesiology 79:1202-1209, 1993. Caldicott L, Lumb A, McCoy D: Lower limb revascularization. In Caldicott L, Lumb A, McCoy D (eds): Vascular Anaesthesia: A Practical Handbook. Oxford, Butterworth-Heinemann, 1999, pp 198-224. Christopherson R, Beattie C, Frank SM, et al: Perioperative morbidity in patients randomized to epidural or general anesthesia for lower extremity vascular surgery. Anesthesiology 79:422-434, 1993. Collins CC, Peterson NJ, Suarez-Almazor M, et al: The prevalence of peripheral arterial disease in a racially diverse population. Arch Intern Med 163:1469-1474, 2003. Cook PT, Davies MJ, Cronin KD, et al: A prospective randomized trial comparing spinal anaesthesia using hyperbaric cinchocaine with general anaesthesia for lower limb vascular surgery. Anaesth Intensive Care 14:373-380, 1986. Criqui MH, Denenberg JO: The generalized nature of atherosclerosis: How peripheral arterial disease may predict adverse events from coronary artery disease. Vasc Med 3:241-245, 1998. Curi MA, Skelly CL, Baldwin ZK, et al: Long-term outcome of infrainguinal bypass grafting in patients with serologically proven hypercoagulability. J Vasc Surg 37:301-306, 2003. Dormandy J, Heeck L, Vig S: The fate of patients with critical leg ischemia. Semin Vasc Surg 12:142-147, 1999. Frank SM, Beattie C, Christopherson R, et al: Unintentional hypothermia is associated with postoperative myocardial ischemia. Anesthesiology 78:468-476, 1993. Hertzer NR, Beven EG, Young JR, et al: Coronary artery disease in peripheral vascular patients: A classification of 1000 coronary angiograms and results of surgical management. Ann Surg 199:223-233, 1984.

CARDIOTHORACIC & VASCULAR SURGERY

Careful assessment of hemodynamic parameters and myocardial ischemia during a stress test is invaluable. The purpose of serially recording the patient’s blood pressure during stress (e.g., admission to hospital, invasive procedures) is to gain knowledge of its range and lability. Notation of the range of blood pressure at night provides an idea of how well low blood pressure values will be tolerated. Also, during RA, vasopressor support (e.g., phenylephrine) for hypotension may be better (safer) than increased fluid infusion. Sustained tachycardia is one of the least tolerated hemodynamic alterations. It is important to determine and correct the cause, such as surgical stimulation or excessive or rapid blood loss; the latter often occurs during thrombectomy. Changing anesthetic depth or administering β-blockers is first-line therapy. Patients at high risk for cardiovascular complications (see Chapter 38) benefit from perioperative β-blockade, especially when GA is used. However, it is unclear whether this advice applies to similar patients having the same surgical procedures performed under RA. In large part, this will depend on whether RA produces cardiac sympathetic blockade (which, in itself, blocks against heart rate increases). Emergence from GA is a common time for perioperative myocardial ischemia to occur. It may be associated with hypertension and tachycardia due to subconscious or conscious pain awareness. Labetalol or esmolol can attenuate elevated heart rate responses. These drugs as well as nitroglycerin, hydralazine, or nicardipine can be used to reduce blood pressure or treat ischemia if it persists after a favorable heart rate has been restored.

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Hickey NC, Wilkes MP, Howes D, et al: The effect of epidural anaesthesia on peripheral resistance and graft flow following femoro-distal reconstruction. Eur J Endovasc Surg 9:93-96, 1995. Horlocker TT, Wedel DJ, Benzon H, et al: Regional anesthesia in the anticoagulated patient: Defining the risks (the Second ASRA Consensus Conference on Neuraxial Anesthesia and Anticoagulation). Reg Anesth Pain Med 28:172-197, 2003. Hunink MGM, Wong JB, Donaldson MC, et al: Revascularization for femoropopliteal disease: A decision and cost-effectiveness analysis. JAMA 274:165-171, 1995. Johnson WC, Lee KK: A comparative evaluation of polytetrafluoroethylene, umbilical vein, and saphenous vein bypass grafts for femoral-popliteal above-knee revascularization: A prospective randomized Department of Veterans Affairs cooperative study. J Vasc Surg 32:268-277, 2000. Lee TH, Marcantonio ER, Mangione CM, et al: Derivation and prospective validation of a simple index for prediction of cardiac risk of major noncardiac surgery. Circulation 100:1043-1049, 1999. Mangano DT, Layug EL, Wallace A, et al: Effect of atenolol on mortality and cardiovascular morbidity after non-cardiac surgery. N Engl J Med 335:1713-1720, 1996. Modig J, Borg T, Bagge L, et al: Role of extradural and of general anesthesia in fibrinolysis and coagulation after total hip replacement. Br J Anaesth 55:625-629, 1983. Nelson AH, Fleisher LA, Rosenbaum SH: Relationship between postoperative anemia and cardiac morbidity in high-risk vascular patients in the intensive care unit. Crit Care Med 21:860-866, 1993. Pierce ET, Pomposelli FB, Stanley GD, et al: Anesthesia type does not influence early graft patency or limb salvage rates of lower extremity bypass. J Vasc Surg 25:226-233, 1997. Poldermans D, Boersma E, Bax JJ, et al: The effect of bisoprolol on perioperative mortality and myocardial infarction in high-risk patients undergoing vascular surgery. Dutch Echocardiographic Cardiac Risk Evaluation Applying Stress Echocardiography Study Group. N Engl J Med 341:1789-1794, 1999.

Raby KE, Brull SJ, Timimi F, et al: The effect of heart rate control on myocardial ischemia among high-risk patients after vascular surgery. Anesth Analg 88:477-482, 1999. Roizen MF: Anesthesia for vascular surgery. In Barash PG, Cullen BF, Stoelting RK (eds): Clinical Anesthesia. Philadelphia, JB Lippincott, 1989, pp 1041-1043. Rosenfeld BA, Beattie C, Christopherson R, et al: The effects of different anesthetic regimens on fibrinolysis and the development of postoperative arterial thrombosis. Anesthesiology 79:435-443, 1993. Schunn CD, Hertzer NR, O’Hara PJ, et al: Epidural versus general anesthesia: Does anesthetic management influence early infrainguinal graft thrombosis? Ann Vasc Surg 12:65-69, 1998. Sixth report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. Arch Intern Med 157:2413-2446, 1997; erratum, Arch Intern Med 158:573, 1998. Stone JG, Foex P, Sear JW, et al: Myocardial ischemia in untreated hypertensive patients: Effect of a single small oral dose of a beta-adrenergic blocking agent. Anesthesiology 68:495-500, 1988. Summary of the second report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel II). JAMA 269:3015-3023, 1993. Tuman KJ, McCarthy RJ, March RJ, et al: Effects of epidural anesthesia and analgesia on coagulation and outcome after major vascular surgery. Anesth Analg 73:696-704, 1991. Vandermeulen EP, Van Aken H, Vermylen J: Anticoagulants and spinalepidural anesthesia. Can J Anaesth 43:R129-R141, 1996. Wildsmith JA, McClure JH: Anticoagulant drugs and central nerve blockade [editorial]. Anaesthesia 46:613-614, 1991. Wulf H: Epidural anaesthesia and spinal haematoma. Can J Anaesth 43:1260-1271, 1996.

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John L. Atlee Case Synopsis

PROBLEM ANALYSIS Definition Pacemakers (PMs) and internal cardioverter-defibrillators (ICDs) have evolved rapidly since the first asynchronous single-chamber PM and ICD implantations in 1958 and 1980, respectively. Today, more than 500,000 persons in the United States have PMs, and more than 115,000 new devices are implanted each year. Also, more than 50,000 ICDs are implanted worldwide each year. Contemporary single- and dual-chamber PMs and ICDs are sophisticated devices. Both types of cardiac rhythm management devices (CRMDs) incorporate some or all of the following features or capabilities: ●

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AV universal pacing: single- or dual-chamber sequential sensing and pacing. Adaptive-rate pacing: activity or metabolic sensors1 increase pacing rates in response to exercise-related increases in metabolic demand. Multisite pacing: two or more pacing electrodes are used to synchronize left ventricular (LV) or right ventricular (RV) contractions (or both) in patients with ventricular conduction delay. Cardiac resynchronization therapy (CRT): biventricular or LV pacing to synchronize RV and LV contractions (Fig. 97-1). With LV pacing alone, LV contraction must be timed with

1 Piezoelectric crystals or accelerometers that detect changes in motion, acceleration, vibration, or pressure with exercise. However, minute ventilation or stimulus or Q-T interval sensors may provide a rate response that is more proportional to increased metabolic demand with exercise.

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respect to atrial and RV contractions (i.e., RV conduction cannot be delayed). Programmable lead configuration: this can be unipolar or bipolar. Tachycardia sensing and discrimination: detects and diagnoses tachyarrhythmias as atrial or ventricular in origin and decides on the sequence of therapy (pacing or shocks). Antitachycardia pacing (ATP): ATP terminates reentry atrial or ventricular arrhythmias. Biphasic shock waveforms: such shocks are delivered when ATP fails to terminate a tachyarrhythmia or the disturbance is not amenable to termination by a programmed pacing sequence (e.g., atrial or ventricular fibrillation). Such shocks are more efficient (require less energy) than their monophasic counterparts used in earlier ICDs.

Recognition Pacing may be temporary or permanent. If temporary, an external pulse generator (PG) transmits pulses either indirectly to the heart via leads on the body’s surface or within the esophagus or directly to the heart via endocardial or epicardial electrodes within or on the heart’s surface. For permanent pacing, an implantable PG (or “can”) transmits pulses directly to the heart via endocardial or epicardial leads to electrodes within the heart or on its surface, respectively. Pacing leads can have a unipolar or bipolar configuration. With the former, the PG serves as an anode (+) and the cardiac electrode as a cathode (−). With the latter, both electrodes are within the heart (endocardial), on its surface (epicardial), immediately behind the heart (transesophageal), or on the body’s surface (transcutaneous). With implanted CRMDs, the PG is often located in the left or right pectoral region. However, it may be subcostal, 399

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A 32-year-old man with congenital complete heart block has been pacemaker dependent since early childhood. He has an adaptive-rate atrioventricular (AV) universal pacemaker (DDDR) and presents for elective orthognathic surgery. His preoperative electrocardiogram (ECG) reveals sinus rhythm with AV synchronous (atrial-triggered) pacing artifacts. The electrocautery grounding pad is placed on the patient’s left thigh before surgery. Intermittently, with electrocautery, the anesthesiologist notices no pulse pressure in the radial artery pressure tracings. Several hours into the procedure, the patient suffers cardiac arrest. Despite aggressive attempts at resuscitation, including external pacing, the resuscitation is unsuccessful and the patient dies.

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DCM baseline

A

DCM—abnormal LV contraction pattern; early septal movement

DCM-CRT

B

CRT—better LV contraction pattern with decreased systolic dimension

especially in infants or small children. Knowledge of the PG’s location and leads is important for predicting the CRMD’s susceptibility to malfunction in the hospital or other environments where electromagnetic interference (EMI), or “noise,” is present (see “Implications”). Aside from pacing in cases of acute myocardial infarction, there are no consensus indications for temporary pacing (see later). Temporary pacing is often used for rate support with transient, hemodynamically disadvantageous bradycardia or escape rhythms or for slow atrial fibrillation, bradyasystole, or high-degree AV heart block in acute myocardial infarction. It is widely used in cardiac surgery; in fact, epicardial pacing wires are routinely placed as a precautionary measure in many centers. In other settings, atrial or ventricular transvenous pacing leads (or both) are widely used (especially in cardiac intensive care units and in high-risk patients before cardiac surgery). Noninvasive pacing includes transcutaneous pacing (causes global myocardial depolarization) and transesophageal pacing (primarily for atrial pacing, but feasibility for ventricular pacing has been shown). Indications for temporary pacing are summarized in Table 97-1.

Table 97–1

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Figure 97–1 ■ Cardiac resynchronization therapy (CRT) in a patient with dilated cardiomyopathy (DCM) and left ventricular (LV) conduction delay. A, Before CRT, the echocardiogram (EC) shows early septal movement, with the lower interventricular septum moving toward the LV cavity. Note that the lateral wall of the left ventricle has not yet begun to contract (due to conduction delay), and on the electrocardiogram (ECG), the QRS complex beneath the EC is widened. B, After CRT (biventricular pacing to synchronize contraction of both ventricles), the LV septum and lateral wall contract nearly simultaneously, and the ECG QRS complexes beneath the EC are now narrowed.

Indications for permanent PMs and ICDs are summarized in Tables 97-2 and 97-3. These indications are based on the 1998 American College of Cardiology (ACC)–American Heart Association (AHA) guidelines and the most recent (2002) update by a task force comprising ACC and AHA members and a committee appointed by the North American Society of Pacing and Electrophysiology (NASPE; now the Heart Rhythm Society). Only class I and III indications are listed. Class I indications are conditions for which there is evidence or general agreement that a procedure or treatment is useful and effective. Class III indications are those for which there is evidence or general agreement that the procedure or treatment is not useful or effective and in some cases may be harmful. Class II indications are conditions for which there is conflicting evidence or a divergence of opinion about the usefulness or efficacy of a procedure or treatment. Class II indications are subdivided into IIa if the weight of evidence favors usefulness or efficacy and IIb if usefulness or efficacy is less well established by evidence or opinion (hereafter, class IIa and IIb indications are collectively considered as “possible” indications).

Indications for Temporary Pacing in Children or Adults

Common Indications

Less Common Indications

Sinus bradycardia or escape rhythms due to reversible causes, with symptoms or signs of disadvantageous hemodynamics As a bridge to insertion of an implanted CRMD for any class I or IIa indication (see text and Tables 97-2 and 97-3) With acute MI: asystole; new bifascicular block with first degree AVHB; alternating BBB; bradycardia with symptoms of hemodynamic compromise not responsive to drugs*; type II second degree† or advanced second degree AVHB‡ Bradycardia-dependent tachyarrhythmias (e.g., torsades de pointes with long QT syndromes)

During acute MI: new or age-indeterminate right BBB with LAFB, LPFB, or first degree AVHB, or with left BBB; recurring sinus pauses refractory to atropine; overdrive pacing for incessant VT; new or age-indeterminate bifascicular block or isolated right BBB During heart surgery: during overdrive disadvantageous lower pacemaker escape rhythms; to pace or terminate reentry SVT or VT; to prevent pause- or bradycardia-dependent tachyarrhythmias; during PAC insertion with left BBB

*Especially in cardiac surgery or if atrioventricular conduction is intact and transesophageal atrial pacing is available, pacing is preferable to drugs because they may have unpredictable and deleterious effects on cardiac rate and rhythm. † No progressive P-R prolongation before nonconducted atrial beats, as with type I second degree AVHB. ‡ Two or more nonconducted atrial beats before conducted atrial beats. AVHB, atrioventricular heart block; BBB, bundle branch block; CRMD, cardiac rhythm management device; LAFB, left anterior fascicular block; LPFB, left posterior fascicular block; MI, myocardial infarction; PAC, pulmonary artery catheter; SVT, supraventricular tachycardia; VT, ventricular tachycardia.

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Class I and III indications for Permanent Pacing in Adults

Class I (Useful and Effective)

Class III (Not Useful or Effective)

Acquired Atrioventricular Heart Block

Acquired Atrioventricular Heart Block

Third degree and advanced second degree AVHB at any anatomic level, with any of the following: AVHB and bradycardia with symptoms Arrhythmias or conditions that require drugs leading to bradycardia with symptoms Proven asystole ≥3.0 sec or escape rate <40 bpm (awake patient without symptoms) After catheter ablation or modification of AV junction Postoperative AVHB not expected to resolve after cardiac surgery Neuromuscular diseases with AVHB (with or without symptoms owing to unpredictable disease progression) Second degree AVHB, regardless of type or site, with bradycardia and symptoms

Asymptomatic first degree AVHB Type I* second degree AVHB above the His bundle without symptoms AVHB expected to resolve or unlikely to recur (e.g., drug toxicity, Lyme disease, sleep apnea without symptoms)

Atrioventricular Heart Block after Acute Myocardial Infarction

Atrioventricular Heart Block after Acute Myocardial Infarction

Persistent second degree AVHB in His-Purkinje system with bilateral BBB or third degree AVHB within or below the His-Purkinje after acute MI Transient advanced (second or third degree) infranodal AVHB with BBB; if site is uncertain, EPS may be necessary Persistent second or third degree AVHB with symptoms

Transient AVHB in absence of intraventricular conduction defects Transient AVHB with isolated LAFB without AVHB Acquired LAFB in absence of AVHB Persistent first degree AVHB with old or age-indeterminate BBB

Sinus Node Dysfunction

SND with documented bradycardia and symptoms, including frequent sinus pauses (possibly the result of essential long-term drug therapy for which there are no acceptable alternatives) Symptomatic chronotropic incompetence

SND in asymptomatic patients, including those with substantial sinus bradycardia (heart rate <40 bpm) caused by long-term drug treatment SND in patients with symptoms suggesting bradycardia that is clearly documented as not being associated with slow heart rate SND with bradycardia and symptoms due to nonessential drug therapy

Hypersensitive Carotid Sinus and Neurally Mediated Syndromes

Hypersensitive Carotid Sinus and Neurally Mediated Syndromes

Recurrent syncope with CSS; minimal carotid sinus pressure induces ventricular asystole >3 sec in absence of drug that depresses sinus node or AV conduction

Hyperactive cardioinhibitory response to CSS with no symptoms or vague ones (e.g., dizziness, lightheadedness) Recurrent syncope, lightheadedness, or dizziness in absence of hyperactive cardioinhibitory response Situational vasovagal syncope in which avoidance behavior is effective

AV, atrioventricular; AVHB, AV heart block; BBB, bundle branch block; bpm, beats per minute; CSS, carotid sinus stimulation; EPS, electrophysiologic study (cardiac); LAFB, left anterior fascicular block; MI, myocardial infarction; SND, sinus node dysfunction.

Table 97–3

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Class I and III Indications for an Internal Cardioverter-Defibrillator for Primary* or Secondary Prevention†

Class I (Always Indicated)

Class III (Never Indicated)

Cardiac arrest due to VT or VF not due to transient or reversible cause Spontaneous sustained VT (lasting >30 sec) in patients with SHD Syncope of undetermined origin with clinically relevant, hemodynamically significant sustained VT or VF induced at EPS when AD therapy is ineffective, not tolerated, or not preferred NSVT in patients with CAD, prior MI, LV dysfunction, and inducible VF or sustained VT at EPS not suppressed by class I AD Spontaneous sustained VT in patients without SHD amenable to other treatments

Syncope of undetermined cause in patients without inducible tachyarrhythmias or SHD Incessant VT or VF VT or VF due to arrhythmias amenable to surgical or catheter ablation (e.g., atrial tachyarrhythmias in WPW, RV outflow tract VT, idiopathic LV VT, fascicular VT) VT or VF due to transient or reversible cause (e.g., acute MI, electrolyte imbalance, drugs, trauma) when correction is feasible and will likely reduce risk for further VT or VF Significant psychiatric illness that may be aggravated by ICD implantation or may preclude systematic follow-up Terminal illness and life expectancy <6 mo CAD patients with LV dysfunction and QRS >130 msec, and without spontaneous or inducible sustained or NSVT having CABG NYHA class IV drug-refractory congestive heart failure in patients not candidates for cardiac transplantation

*ICDs are used for primary prevention in patients with class I or II indications but without a history of cardiac arrest due to VT or VF or without inducible sustained VT or VF at EPS. † ICDs are used for secondary prevention in patients with a history of sudden cardiac death or who have documented or inducible (at EPS) sustained VT or VF. AD, antiarrhythmic drug; CABG, coronary artery bypass grafting; CAD, coronary artery disease; EPS, electrophysiologic study (cardiac); ICD, internal cardioverterdefibrillator; LV, left ventricular; MI, myocardial infarction; NSVT, nonsustained VT; NYHA, New York Heart Association; RV, right ventricular; SHD, structural heart disease; VF, ventricular fibrillation; VT, ventricular tachycardia; WPW, Wolff-Parkinson-White syndrome.

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Permanent pacing is indicated for any patient with symptomatic bradycardia or slow escape rhythms due to sinus node dysfunction or AV heart block. Also, pacing is indicated for syncope due to neurally mediated syndromes (e.g., hypersensitive carotid sinus syndrome) with a more prominent cardioinhibitory component in response to carotid sinus stimulation (i.e., bradycardia or escape rhythm) than a vasodepressor response (i.e., vasodilatation with hypotension). Further, the syncope must not be due to a reversible condition or a medication for which there is no suitable alternative therapy. In the 1998 and 2002 guidelines, the indications for pacing in infants, children, or adolescents with congenital heart disease are similar to those in adults, except that they are based on the correlation of symptoms with bradycardia rather than on arbitrary rate criteria per se. Also, pacing is indicated for bradycardia only after the exclusion of other causes (e.g., seizures, breath holding, apnea, neurally mediated mechanisms). Revisions in the 2002 guidelines include the following: (1) substituting “ventricular dysfunction” for “congestive heart failure” in pacing for advanced second or third degree AV heart block, (2) specifying greater than 7 days for advanced second or third degree AV heart block after cardiac surgery, and (3) adding the qualifier “with complex ventricular ectopy” to class I indications for congenital third degree AV heart block. New qualifiers for class IIa indications in children with congenital heart disease are the following: (1) congenital third degree AV heart block “associated with symptoms,” (2) increasing the resting heart rate from 35 to 40 beats per minute in children with complex congenital heart disease, and (3) adding the phrases “and impaired hemodynamics due to sinus bradycardia” or “loss of AV synchrony” to the indication for pacing in children with complex congenital heart disease. For updates to Class IIb indications for pacing in patients with congenital heart disease, see the 2002 ACC-AHA-NASPE guidelines. The indications for pacing in other conditions (e.g., chronic bifascicular and trifascicular block, hypertrophic or obstructive cardiomyopathy, idiopathic dilated cardiomyopathy, cardiac transplantation, detection and pacing to terminate tachycardias) are beyond the scope of this chapter (see the 1998 and 2002 ACC-AHA-NASPE guidelines). Class II indications are constantly evolving. For example, what constitutes a class II indication in AV heart block revolves around whether second or third degree block at any anatomic site is expected to persist, and certainly not any arbitrary rate if the block is associated with cardiomegaly or LV dysfunction. Even asymptomatic first degree AV heart block is a class IIa indication if associated symptoms are similar to those of the pacemaker syndrome.2 However, the patient must have LV dysfunction and symptoms of heart failure, especially when first degree AV heart block is associated with neuromuscular disease. This is due to the unpredictable progression of associated AV conduction system disease.

2 This syndrome was originally reported with ventricular-inhibited pacing but can occur with any pacing mode if there is associated AV dissociation. The most common symptoms are shortness of breath, dizziness, fatigue, pulsations in the back or abdomen, apprehension, and cough.

For sinus node dysfunction, the important element is whether there is a clear association between bradycardia (<40 beats per minute) and symptoms. A clear association constitutes a class I indication, and the 2002 guidelines specify that even in the absence of a clear, documented association between significant symptoms and the actual presence of bradycardia, this constitutes a class IIa indication. The 1998 guidelines specified chronic heart rates less than 30 beats per minute with minimal symptoms as class IIb. For hypersensitive carotid sinus syncope, there must be recurrent syncope, no clear provocative events, and a hypersensitive cardioinhibitory response. For neurocardiogenic syncope, the patient must be significantly symptomatic. Also, syncope must be associated with bradycardia documented spontaneously or during tilt-table testing (class IIa). Finally, biventricular pacing (simultaneous LV and RV pacing) in medically refractory and symptomatic New York Heart Association class III or IV heart failure or dilated ischemic cardiomyopathy, with a QRS duration of ≥130 msec, LV end-diastolic diameter of ≥55 mm, or ejection fraction of 0.35, is listed as a class IIa indication for CRT in the 2002 ACC-AHA-NASPE Guidelines. However, given recent additional evidence (e.g., COMPANION trial, CARE-HF study) and similar findings from other large trials of biventricular pacing in comparable patients, it is possible that it might soon become a class I indication. Finally, ICDs are prescribed for the primary or secondary prevention of destabilizing atrial or ventricular tachyarrhythmias (see Table 97-3). For primary prevention, ICDs have been used in patients with asymptomatic coronary artery disease and nonsustained ventricular tachyarrhythmias. Other settings include after coronary artery bypass surgery or percutaneous coronary intervention in patients with ejection fractions less than 35%. Also, they have been used in patients with abnormal signal-averaged ECGs or those awaiting heart transplantation. For secondary prevention, the patient must have survived an incident of sudden death, usually due to coronary artery disease, but possibly due to other causes, such as the following: ● ● ● ●

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Congenital or acquired long QT syndromes Brugada syndrome Idiopathic ventricular fibrillation Ventricular tachycardia with infiltrative, dilated, or hypertrophic cardiomyopathy Bundle branch reentry ventricular tachycardia Idiopathic monomorphic ventricular tachycardia (subdivided into RV outflow tract obstruction or arrhythmogenic RV dysplasia) Idiopathic LV tachycardia

Tachycardia discrimination algorithms used with ICDs have evolved and can now distinguish between atrial fibrillation with ventricular aberration and polymorphic ventricular tachycardia or fibrillation. Thus, ICDs are prescribed that provide lower-energy atrial shocks for atrial fibrillation (i.e., indicated for “atrioversion”).

Risk Assessment Both PMs and ICDs are subject to primary or secondary malfunction. The former is due to device failure. The latter

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may be caused by electromagnetic or mechanical interference. Because all ICDs incorporate at least single- or dual-chamber and adaptive-rate pacing, they are also subject to any PM malfunction. Malfunctions unique to devices for CRT have not yet been adequately defined.3 PACEMAKER MALFUNCTION

thereby significantly reducing the need for painful shocks. Actual ICD malfunctions include the following: ●

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Primary PM malfunction is rare (<2% of all device-related problems in one large center over a 6-year period). Some devices have programmed functions (e.g., rate hysteresis), whereby the pacing cycle duration lengthens after sensed versus paced events. Although this simulates true CRMD malfunction, it is actually a pseudomalfunction. True PM malfunction includes the following: ●

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INTERNAL CARDIOVERTER-DEFIBRILLATOR MALFUNCTION Specific ICD malfunctions include inappropriate delivery of ATP therapy, failure to deliver or ineffective pacing or shock therapies, and interactions with drugs or other devices that affect the efficacy of such therapies. Because any unsuccessful ATP is sequenced to shock delivery, such ATP “malfunction” is not really a true ICD malfunction. In fact, in studies cited by Atlee and Bernstein, ATP effectively converted 89% to 96% of episodes of ventricular tachycardia,

3 A MEDLINE OVID database search (April 6, 2005) failed to identify any case reports or other literature pertaining to primary or secondary malfunction unique to CRT devices. 4 The PM must be programmed to an atrial tracking mode (VAT, VDD, DDD; see ASA practice advisory for code designations), and the patient must have intact retrograde (ventriculoatrial) conduction; PM reentrant tachycardia is often initiated by a premature ventricular beat.

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Inappropriate delivery of shocks: electrical artifact due to lead malfunction or caused by surgical electrocautery artifact may be misinterpreted as tachycardia, leading to shocks. Failure to deliver or ineffective pacing or shock therapies: magnet application may disable sensing and therefore the ability to deliver therapy for tachyarrhythmias. Lead-related problems may also cause such failure. Acute myocardial infarction, drugs, and other imbalances may also affect sensing or increase shock thresholds, influencing the efficacy of ICD therapies. Imbalances may also affect the rate or morphology of ventricular tachycardia, leading to misdiagnosis or unnecessary pacing or shock therapies. Interactions with drugs or other implanted devices: antiarrhythmic drugs are prescribed with ICDs to suppress the need for frequent shocks and for other reasons (e.g., to suppress atrial fibrillation). Possible adverse effects of such interactions are (1) proarrhythmia (see Chapters 12 and 81); (2) slowing of the heart rate below the detection threshold (e.g., with the use of amiodarone); (3) increased defibrillation thresholds; (4) altered P or T waves or QRS intervals, leading to overcounting and spurious shocks; or (5) morphologic alterations, leading to failure to detect or discriminate ventricular tachycardia or fibrillation. Device-device interactions: in the past, it was not uncommon for patients to have both a PM and an ICD, with the potential for adverse interactions between the two. This is rare today.

Implications PMs and ICDs are subject to EMI from nonphysiologic sources. Most devices implanted today are effectively shielded or protected from EMI. The use of bipolar lead configurations (electrodes on PM or ICD leads) reduces the sensing “antenna” and has greatly reduced EMI-related CRMD malfunction (Fig. 97-2). With unipolar leads, the PG is the anode, and electrodes on the lead are the cathode, greatly increasing the antenna and the susceptibility to EMI (Fig. 97-3). Importantly, EMI signal frequencies between 5 and 100 Hz are not filtered by CRMDs because they overlap the frequency range of intracardiac signals. Therefore, EMI entering the CRMD in this frequency range has the potential to cause abnormal behavior, including the following: ● ●

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Inhibition or triggering of pacing stimulation. Asynchronous pacing (asynchronous interference mode) when continuous EMI is sensed throughout the lower rate interval (e.g., surgical electrocautery). The device appears to have reverted to asynchronous pacing (VOO), but in fact, it senses EMI as noise after the ventricular refractory period and restarts the ventricular refractory period. This continues until the programmed lower rate interval times out with the delivery of stimulation—in effect, VOO pacing. EMI may cause a change to another mode that persists after the noise stops (backup or reset mode). The rate may be similar to the battery end-of-life indicator. Random or “phantom” reprogramming, reported in the early 1980s,

CARDIOTHORACIC & VASCULAR SURGERY

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Failure to pace: no pacing artifacts in one or both chambers (atrium and ventricle). Failure to capture: visible (12-lead ECG) pacing artifacts are present for one or both chambers, but there are no or only intermittent atrial or ventricular depolarizations. Pacing at an abnormal rate: this can occur in a singleor dual-chamber device and may be normal (elective battery replacement indicator or response to an adaptiverate sensor) or abnormal behavior (e.g., pacemaker runaway due to more than two system component failures, with the upper rate limited by contemporary devices to 200 beats per minute). Dual-chamber PMs may show such behavior as PM reentrant tachycardia4 or 1:1 tracking of supraventricular tachycardia by the ventricular chamber. Undersensing (failure to sense): the intracardiac electrogram must have a sufficient amplitude and frequency to be sensed properly, and there are many potential causes of failure (e.g., progression of cardiac disease, effect of drugs; component malfunction). Oversensing: any electrical signal of sufficient amplitude occurring during the PM alert period (i.e., sensing in one or both chambers) can reset the device’s timing. For example, if the atrial chamber senses ventricular depolarization, this may inhibit atrial stimulus delivery.

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Figure 97–2 ■ Illustration of a cardiac rhythm management device with a bipolar lead configuration. With bipolar leads, both the anode (+) and the cathode (−) are on the lead and near the site of stimulation (apex of the right ventricle [RV]). Such proximity reduces interelectrode distance and the “antenna” (as shown by the TV antenna). PG, pulse generator.

is considered virtually impossible with today’s CRMDs, because unique radiofrequency sequences (code) are required to reprogram a CRMD. Damage to the CRMD’s PG or circuitry, causing output failure, PM runaway (see earlier), or other malfunction that necessitates PG replacement. Triggering of unnecessary (spurious) ICD shocks and ATP therapies.

Although unipolar surgical electrocautery (bovie)5 is the most widely recognized source of EMI in hospitals, other sources also exist: external defibrillator-cardioverter shocks, magnetic resonance imaging (MRI), radiation therapy (but not diagnostic radiographs or computed tomography scans), electroconvulsive therapy, extracorporeal shock wave lithotripsy, radiofrequency catheter ablation, and transcutaneous nerve stimulation units. (For a more complete discussion of the risks associated with specific EMI, see part II of the review by Atlee and Bernstein and the American Society of Anesthesiologists [ASA] practice advisory under “Further Reading.”) Less risky alternatives to surgical electrocautery include bipolar cautery and the harmonic scalpel, neither of which appears to pose a risk of EMI-related malfunction of implanted CRMDs. With bipolar cautery, the current pathway is between the two tips (electrodes) of the cautery tool, which are usually less than 1 cm apart during the application of bipolar cautery. Unless the CRMD leads are actually between these electrodes (in the current pathway) or in the immediate vicinity (within 1 cm of the PG or leads) when bipolar cautery is used, there is virtually no risk of CRMD malfunction, because the “antenna” (i.e., the ability to sense EMI) is very small.

MANAGEMENT Patients with CRMDs have significant heart disease and often significant coexisting medical conditions as well. They may be taking medications with implications for perioperative CRMD management. Preoperative and preprocedural evaluation is indicated before any planned intervention, regardless of where it will be performed (e.g., operating room, radiology suite, critical care unit, ambulatory facility), that might put a CRMD patient at risk for adverse events related to EMI or other device malfunction. It is important to determine what risk the planned intervention poses to the patient or the CRMD. This may require consultation with the hospital’s CRMD follow-up service or a cardiologist. Most patients with implanted CRMDs carry cards that identify the device and manufacturer, the date of implantation, serial numbers of the CRMD and lead systems, and a 24-hour toll-free hotline; thus, relevant information can be obtained, even in emergencies, from the manufacturer. Based on the advice given, it may be Figure 97–3 ■ With unipolar leads, the cardiac rhythm management device’s pulse generator serves as the anode (+), and the most distal electrode on the pacing lead serves as the cathode (−). Compared with the bipolar configuration (see Fig. 97-2), this greatly increases the “antenna” and susceptibility to electromagnetic interference.

5 With unipolar cautery, the cautery tool (cathode) is variably removed from the grounding plate (anode), which creates a small or large current pathway between the two, depending on the distance between them.

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PREVENTION Precautions for some specific EMI are listed here. However, these cannot guarantee that there will be no CRMD-related malfunction due to EMI during surgical or other interventions. ●

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Evaluate the patient before the procedure to determine whether a CRMD is present, the type of device, and whether the patient is PM dependent and the device is functioning. For a patient undergoing a procedural or surgical intervention: ● ● ●

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Determine whether EMI is likely to occur. Program the PM adaptive-rate therapy off. Program the PM to an asynchronous mode, especially if the patient is PM dependent. Program all antitachycardia therapies off. Use bipolar electrocautery or a harmonic scalpel if possible. Ensure the availability of external temporary pacing and a cardioverter-defibrillator. Consider possible untoward effects of any drugs or interventions on CRMD function.

Use appropriate monitoring: ● Continuous ECG and arterial oxygen saturation monitoring by pulse oximetry.

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End-tidal carbon dioxide monitoring when general anesthesia is used.

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For procedures that require surgical electrocautery: ● Use bipolar cautery or harmonic scalpel if possible. ● Position the electrocautery grounding (receiving) plate so that the current pathway does not pass through or near the PG or leads. ● Avoid proximity or contact of the cautery tool with the PG or leads. ● Use short, intermittent, irregular bursts of cautery and the lowest possible energy.

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For radiofrequency ablation (e.g., for arrhythmogenic foci or reentry pathways): ● Avoid direct contact between the radiofrequency catheter and CRMD or leads. ● Keep the current path (electrode to return plate) as far away from the PG or leads as possible.

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For MRI and radiation therapy: ● MRI is generally contraindicated for CRMD patients, but exceptions have been reported (consult the device manufacturer before proceeding with MRI). ● CRMD malfunction or damage to PG circuitry or components is related to the cumulative dose of radiation; thus, device function should be checked after each session. Alternatively, the device may have to be explanted and reimplanted away from the ionizing beam of radiation; shielding can also be used.

Further Reading American Society of Anesthesiologists Task Force on Perioperative Management of Patients with Cardiac Rhythm Management Devices: Practice advisory for the perioperative management of patients with cardiac rhythm management devices: Pacemakers and implantable cardioverter-defibrillators. Anesthesiology 103:186-198, 2005 (additional material available at http://www.anesthesiology.org). Atlee JL, Bernstein AD: Cardiac rhythm management devices (part I). Anesthesiology 95:1265-1280, 2001. Atlee JL, Bernstein AD: Cardiac rhythm management devices (part II). Anesthesiology 95:1492-1506, 2001. Baller MR, Kirsner KM: Anesthetic implications of implanted pacemakers: A case study. AANA J 63:209-216, 1995. Bristow M, Saxon LA, Boehmer J, et al: Comparison of medical therapy, pacing, and defibrillation in heart failure (COMPANION) investigators: Cardiac-resynchronization therapy with or without an implantable defibrillator in advanced chronic heart failure. N Engl J Med 350:2140-2150, 2004. Cleland JGF, Daubert J-C, Erdmann E, et al: The effect of cardiac resynchronization therapy on morbidity and mortality in heart failure. N Engl J Med 352:1539-1549, 2005. Epstein MR, Mayer JE Jr, Duncan BW: Use of an ultrasonic scalpel as an alternative to electrocautery in patients with pacemakers. Ann Thorac Surg 65:1802-1804, 1998. Furman S, Robinson G: The use of an intracardiac pacemaker in the correction of total heart block. Surg Forum 9:245-248, 1958. Gregoratos G, Abrams J, Epstein AAE, et al: ACC/AHA/NASPE 2002 guideline update for implantation of cardiac pacemakers and antiarrhythmia devices. Summary article: A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (ACC/AHA/NASPE Committee to Update the 1998 Pacemaker Guidelines). Circulation 106:2145-2161, 2002. Gregoratos G, Cheitlin M, Conill A, et al: ACC/AHA guidelines for implantation of cardiac pacemakers and antiarrhythmia devices: A report of the ACC/AHA Task Force on Practice Guidelines (Committee on Pacemaker Implantation). Circulation 97:1325-1335, 1998.

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necessary to have the device reprogrammed to an asynchronous mode (i.e., if the patient is PM dependent) or to have ATP or shock therapies programmed off. This can be done by a manufacturer’s representative, a cardiologist, or the hospital CRMD service. For any elective intervention, all the necessary information for optimal CRMD perioperative or peri-interventional management must be obtained. If the risk to the patient is high (e.g., MRI scans, therapeutic radiation, unipolar cautery in the vicinity of the PG, leads in the current pathway) or even moderate, the PM is programmed to sense (e.g., AAI, VVI, VAT, VDD, DDI, DDD; see ASA practice advisory for code designations), and the patient is mostly PM dependent, then it may be necessary to interrogate and reprogram the CRMD to an asynchronous mode (AOO, VOO, DOO). Generally, it is ill advised to place a magnet over the PG of a CRMD without knowing what the magnet response is. Again, this information can be obtained from the manufacturer or CRMD service. In some devices, the magnet response may be programmed off; in others, it may not confer immunity to sensing and potential malfunction during the planned intervention or after the patient has been discharged. However, for emergent intervention or surgery, when one cannot take the previously mentioned precautions (or have someone else obtain the needed information), it is reasonable to place a magnet over the PG if unusual pacing behavior is observed or spurious shocks or ATP therapies are initiated in response to sensed EMI. Finally, the CRMD should be interrogated after the procedure for any alteration in programmed settings. For patients with CRMDs who are receiving sequential radiation therapy for the treatment of cancer, the CRMD should be checked after each session.

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Kleinman B, Hamilton J, Heriman R, et al: Apparent failure of a precordial magnet and pacemaker programmer to convert a DDD pacemaker to VOO mode during use of the electrosurgical unit. Anesthesiology 86:247-250, 1997. Mirowski M, Reid PR, Mower MM, et al: Termination of malignant ventricular arrhythmias with an implanted automatic defibrillator in human beings. N Engl J Med 303:322-324, 1980. Nichol G, Kaul P, Huszti E, et al: Cost-effectiveness of cardiac resynchronization therapy in patients with symptomatic heart failure. Ann Intern Med 141:343-351, 2004.

Ozeren M, Dogan OV, Duzgun C, et al: Use of an ultrasonic scalpel in the open-heart reoperation of a patient with a pacemaker. Eur Cardiothorac Surg 21:761-762, 2002. Smith CL, Frawley G, Hamar A: Diathermy and the telectronics “META” pacemaker. Anaesth Intensive Care 21:452-454, 1993.

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Mechanical Assist Devices Sheela S. Pai and Avery Tung

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Case Synopsis A 78-year-old man with New York Heart Association class III heart failure, hypertension, type 2 diabetes mellitus, and chronic renal insufficiency had coronary artery bypass grafting with mitral valve repair. A prebypass transesophageal echocardiogram (TEE) revealed an ejection fraction of 20%, septal akinesis, severe mitral regurgitation with annular dilatation, and a patent foramen ovale. Owing to the low prebypass ejection fraction, an intra-aortic balloon pump (IABP) was placed before initiation of cardiopulmonary bypass (CPB). Total CPB time was 210 minutes. Despite the use of IABP support and dobutamine and epinephrine infusions, repeated attempts to separate the patient from CPB failed. Therefore, a left ventricular assist device (LVAD) was placed. On postoperative day 2, the patient developed acute right-sided weakness and facial palsy. A computed tomography scan revealed a large translucent defect in the territory supplied by the left middle cerebral artery.

PROBLEM ANALYSIS

Mechanical circulatory assist devices are artificial devices that perform some or all of the functions of the heart. They vary significantly in design and indication but are typically used to provide either partial or full support for a heart that is unable to function adequately. Those used for temporary support include the IABP, extracorporeal membrane oxygenation (ECMO), LVAD, and right ventricular assist device (RVAD). Those used for full support include biventricular assist device (BiVAD) and total artificial heart (TAH). Indications for mechanical assist devices are evolving but fall into three broad categories: 1. Temporary support for a heart that is expected to recover 2. Bridge therapy to cardiac transplantation 3. Destination therapy for a patient whose heart is unlikely to regain adequate function Also, as shown in Table 98-1, devices are classified according to (1) the indication for the device (emergent versus urgent), (2) the expected duration of therapy (short versus long term), or (3) the degree of support provided (augmentation of intrinsic cardiac function versus full cardiac support). The modern era of mechanical cardiac assist devices began in 1957, with the first successful use of CPB. Although it was first intended to provide intraoperative circulatory support, CPB’s success led physicians to consider mechanical circulatory support for other indications as well. In 1966 DeBakey first used a pneumatic ventricular assist device (VAD) for a patient with left ventricular failure. In 1967 the IABP was first used to treat patients with acute heart failure, but it subsequently became a mainstay of therapy for severe, decompensated heart failure and unstable angina. In 1994 pneumatically driven VADs for partial (LVAD or RVAD) or complete (BiVAD) support of the heart were approved by the Food and Drug Administration. Today, single-chamber assist devices (e.g., IABP, LVAD, RVAD) are used to treat

Table 98–1

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Classification of Mechanical Assist Devices

By Indication Urgent (unstable angina or uncontrolled congestive heart failure with worsening symptoms) IABP VAD Emergent (hypotension incompatible with life or inability to separate from cardiopulmonary bypass) IABP VAD ECMO

By Duration of Therapy Short term IABP Abiomed VAD ECMO Long term Thoratec VAD Implantable VAD

By Degree of Support Provided Augmentation (IABP) LVAD or RVAD alone Total support (BiVAD, ECMO) BiVAD, biventricular assist device; ECMO, extracorporeal membrane oxygenation; IABP, intra-aortic balloon pump; LVAD, left ventricular assist device; RVAD, right ventricular assist device; VAD, ventricular assist device.

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Definition

failure due to a wide variety of causes; dual-chamber assist devices (BiVAD, TAH) allow patients without any native heart function to survive. Unlike an IABP or VAD, ECMO is similar to CPB because it provides both oxygenation and circulatory support, bypassing the heart and lungs altogether. Although experience with ECMO in adults is limited, venoarterial ECMO is a therapeutic option if intractable cardiovascular instability and inadequate pulmonary gas exchange are encountered after cardiac surgery. ECMO drains blood from either the arterial or venous circulation and delivers it to the arterial circulation.

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Institution of ECMO can be quick (i.e., CPB tubing can be used), but an experienced CPB perfusionist must be present to monitor and adjust anticoagulation and to troubleshoot. Although ECMO has been used successfully in children, good outcomes in adults are mostly anecdotal. Because the management of patients on ECMO is by CPB perfusionists under the supervision of cardiovascular surgeons and is confined to intensive care settings, ECMO is not discussed further here.

Recognition INTRA-AORTIC BALLOON PUMP The IABP is the most commonly used assist device in cardiac surgery. IABPs are inserted percutaneously or via surgical cutdown from the femoral artery. A Seldinger introducer is used for placement of the large-diameter IABP introducer sheath. The IABP catheter is passed via the introducer and positioned with its tip at the junction of the descending aorta and the aortic arch, just distal to the subclavian artery. This position minimizes the risk of subclavian or renal artery injury or occlusion. If the IABP is placed intraoperatively, TEE can determine proper balloon tip location before pump initiation. Patients with femoral atherosclerotic vascular disease may require IABP insertion into a subclavian artery or directly into the aorta with transthoracic access. Patient suitability for IABP depends on the presence of appropriate access, the stability of the proximal descending aorta, the absence of aortic dissection, and the absence of aortic insufficiency. Perioperative indications for IABP include the following: ●

●

Preoperative placement for patients undergoing emergent coronary artery bypass grafting or with low ejection fractions Intraoperative placement for left ventricular failure despite maximal inotropic support or unabated regional myocardial ischemia not amenable to surgical revascularization

The definitions used for low ejection fraction, left ventricular failure, maximal inotropic support, and ongoing regional myocardial ischemia can vary widely among institutions performing coronary artery bypass graft surgery. Contraindications to placement of an IABP are aortic insufficiency, sepsis, and severe vascular disease. Because the IABP inflates in the descending thoracic aorta during diastole to promote retrograde flow into the ascending aorta, this has the potential to increase aortic regurgitation and further distend the left ventricle at the expense of coronary perfusion. As with any prosthetic intravascular device, infectious bacteremia is difficult to treat if surfaces of the prosthesis become seeded with bacteria. In addition to technical difficulties with placing an IABP in patients with severe vascular disease, such patients are prone to aortic rupture and thromboembolic complications (see “Risk Assessment” and “Implications”). Although use of an IABP was once considered primarily after one or more failed attempts at separation from CPB in the operating room, today the number of IABPs placed in the cardiac catheterization laboratory approaches or exceeds the number placed in the operating room in some centers.

VENTRICULAR ASSIST DEVICE VADs are designed to completely replace the function of the native heart. They can be left-sided (LVAD), right-sided (RVAD), or biventricular (BiVAD). VADs bypass the left or right ventricle by withdrawing blood from the circulation as it enters the failing ventricle and pumping it back into the circulation immediately downstream from the failing ventricle. Flow from the patient into the VAD is from systemic (RVAD inflow) or pulmonary (LVAD inflow) venous drainage. Venous cannulas are placed in the ventricle (series cannulation) or the atria (parallel cannulation). Outflow is via pulmonary (RVAD) or systemic (LVAD) arterial cannulas. Arterial cannulas are usually placed in the aorta (LVAD), pulmonary artery (RVAD), or both (BiVAD or TAH). The two primary types of VADs are displacement and rotary pumps. The former are used mostly in adults, and the latter are used in both children and adults. Displacement pumps can be intracorporeal or extracorporeal, designating the pumping chamber’s location within or outside the body, respectively. Displacement pumps provide pulsatile flow, and rotary pumps do not. Rotary pumps are smaller in size and weight, operate more quietly, and have relatively low power consumption. However, they are more prone than displacement pumps to thrombus formation and bearing failure, which limits their longevity to several weeks. Indications for VADs are as follows: ●

●

●

●

Post-CPB: Patients with post-CPB ventricular failure that persists despite maximal pharmacologic support (often in combination with IABP support) require placement of a pneumatic VAD if they are to survive the immediate postoperative period. Post–myocardial infarction: Formerly, mortality rates associated with early VAD placement for severe left ventricular failure after acute myocardial infarction were dismal (>75%). However, more recent rates are closer to 15%. This is encouraging, given the high mortality rate reported for this patient population without such therapy. Bridge to cardiac transplantation: Technologic advances have allowed VADs to become mostly intracorporeal, with increasingly smaller extracorporeal components. Also, as the incidence of adverse side effects has declined, the acceptable duration of VAD circulatory support has increased to longer than 3 months. Destination therapy: Improved VAD portability and reduced associated morbidity have enabled more patients to survive many months with intracorporeal VADs. As a result, and because of the limited availability of human hearts, VADs are now being given serious consideration as “destination therapy” (i.e., TAH as an alternative to cardiac transplantation).

Accepted hemodynamic criteria for long-term VAD placement include the following: ● ● ●

Cardiac index less than 2 L/minute per square meter Pulmonary capillary wedge pressure greater than 20 mm Hg Systolic blood pressure less than 80 mm Hg

Other considerations can also affect the decision to implant a VAD. For example, for LVADs, the status of right ventricular function is an important concern. Associated right

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ventricular disease (e.g., high preoperative central venous pressure, TEE evidence of right ventricular free wall hypokinesis) may be aggravated by the sudden increase in cardiac output and right ventricular preload following LVAD placement.

Risk Assessment INTRA-AORTIC BALLOON PUMP The incidence of IABP complications has decreased significantly since its first use, but significant associated morbidity still exists. The most frequent complications are vascular in nature, with a reported morbidity of 6% to 33%: ● ● ● ● ●

Limb ischemia Compartment syndrome Mesenteric infarction Aortic perforation Aortic dissection

VENTRICULAR ASSIST DEVICE Patients who require a VAD are severely ill, and the necessary surgery is extensive. Thus, the decision to place a VAD should involve a careful, individualized evaluation of benefit, risk, and likelihood of an acceptable outcome. In addition, careful attention should be paid to patient status at the time of device placement. Although VADs are typically reserved for acute, lifesaving indications, placement during a more stable period may be better tolerated. Ideal candidates for VAD placement are patients with preserved end-organ function. Further, post-VAD survival appears to be better in patients who are hemodynamically stable and have lower APACHE scores than in those in shock or with higher APACHE scores. Although altered mental status and pulmonary or hepatic dysfunction do not predict outcome after VAD placement, preplacement confirmation of adequate renal function plays a critical role. For example, preplacement dependence on dialysis has been associated with 50% or more mortality after VAD placement. Additional predictors of adverse outcomes after VAD placement include age older than 65 years and the presence of multiple medical comorbidities. Technical aspects of placement should also play a significant role in the decision to implant a VAD. Increased bleeding and poor myocardial function often accompany repeat sternotomy and CPB. Further, there may be injury to myocardial structures that adhere to the sternum or to previously placed bypass grafts. Finally, VAD cannulas have the potential to limit intrathoracic volume, prevent complete ventricular filling, and possibly decrease coronary blood flow by compressing bypass grafts.

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Implications INTRA-AORTIC BALLOON PUMP IABP inflation exerts mechanical stress forces on the aortic wall. Therefore, known aortic dissection or a proximal aortic graft is a contraindication to IABP placement. Also, in patients with aortic insufficiency, the IABP will exacerbate regurgitant blood flow into the left ventricle during diastole, leading to ventricular dilatation and compromised coronary perfusion. There are few restrictions to IABP use. However, it is important to remember that the IABP provides support to the left ventricle only and is unlikely to improve primary right ventricular systolic dysfunction. Further, the IABP’s ability to augment cardiac output and unload the left ventricle is limited because it does not directly alter left ventricular function. With severe left ventricular failure, an IABP will not provide enough flow to sustain the circulation, and a VAD will have to be considered. The risk of air embolism to the brain from the IABP pressure monitoring line is greater than that from a radial or femoral arterial line. This is because the IABP monitoring port is at the tip of the balloon catheter, which resides close to the origin of the carotid arteries. Samples for blood gas determinations should be drawn from the IABP monitoring line only if there is no other suitable site. Also, one must be sure that no air bubbles or other debris is flushed through the IABP line. Inappropriate timing of IABP inflation and deflation can worsen myocardial oxygen supply and increase myocardial oxygen balance. Early inflation (before closure of the aortic valve) can be detected by an arterial waveform demonstrating IABP inflation before the dicrotic notch and results in dramatically increased afterload, end-diastolic wall stress, and myocardial oxygen consumption. Delayed IABP inflation (after aortic valve closure) is detected by balloon inflation after the dicrotic notch and results in suboptimal coronary perfusion. Similarly, early deflation during diastole results in suboptimal coronary perfusion and afterload reduction, as well as increased myocardial oxygen consumption. Also, late deflation may lead to ineffective afterload reduction and excessive impedance of left ventricular ejection. IABPs are foreign bodies and may promote clot formation. Although anticoagulation is not routine with IABP placement, a low degree of anticoagulation may be required to prevent thromboembolic phenomena. As with any large-bore femoral arterial access catheter, the IABP introducer sheath poses a significant infectious risk. It must be placed under strictly sterile conditions and removed as soon as possible. VENTRICULAR ASSIST DEVICE The venous cannula may be placed in either the ventricle (series cannulation) or the atria (parallel cannulation). Often, series cannulation allows more effective ventricular emptying, but it requires that the cannula be placed through ventricular myocardium. Although the associated myocardial trauma is less important to a transplant candidate, even a small amount of direct myocardial injury in a post-CPB patient with cardiogenic shock may significantly impede myocardial recovery.

CARDIOTHORACIC & VASCULAR SURGERY

Risk factors for these complications include a history of peripheral vascular disease, female gender, tobacco smoking, diabetes mellitus, and postoperative IABP placement. Other complications of IABP include infection (primarily at the groin site of the IABP introducer sheath), coagulopathies, and balloon rupture with gas embolism. The last may be related to aortic arteriosclerotic severity and associated aortic calcifications, which become increasingly severe in elderly patients.

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MANAGEMENT AND PREVENTION Intra-aortic Balloon Pump In the United States, IABP balloon catheters are available in four lengths: 25, 34, 40, and 50 inches. The patient’s height determines the appropriate length; 34 inches (for patients 64 inches tall or less) and 40 inches (for taller patients) are the most commonly used sizes. Placement of an IABP may be technically difficult in patients with extensive atherosclerosis, and these patients are more prone to arterial thrombosis during use of an IABP. Therefore, for patients with severe aortoiliac or femoral artery disease, another option is to place the balloon directly into the descending thoracic aorta. Proper balloon tip placement is 2 inches below the origin of the left subclavian artery. This is necessary to prevent occlusion of the artery during balloon inflation. Correct placement can be confirmed radiographically or by TEE. The balloon is timed to inflate immediately after aortic valve closure (dicrotic notch, which signals aortic valve closure and the start of diastole). Inflation too early will impede left ventricular ejection. If inflation is too late, its effectiveness for increasing coronary perfusion pressure and reducing afterload will be less than optimal. Also, balloon deflation must be timed so that arterial pressure has reached its minimal level at the onset of the next ventricular systole. If it deflates too soon, the aorta will not be maximally evacuated before the next ventricular systole, and coronary perfusion will be suboptimal. If the balloon deflates too late, it will impede left ventricular ejection systole. Appropriate timing of balloon inflation and deflation is depicted in Figure 98-1. Two methods are used to synchronize the IABP inflations with the cardiac rhythm: (1) the largest detectable

Ventricular Assist Device Patients with valvular dysfunction or artificial heart valves are challenges to VAD placement. The cannulas should be

A = cardiac cycle

R

B = unassisted aortic end-diastolic pressure (EDP)

T

P

Q

ventricular electrocardiographic (ECG) signal (e.g., QRS complex) or (2) the arterial pressure waveform. If intrinsic arterial pulse pressure is greater than 40 mm Hg, the arterial waveform is preferred in the operating room because electrocautery artifact can inhibit some ECG-triggered IABP consoles. However, this has become less of a problem with the incorporation of electronic artifact suppression circuitry that makes IABPs less susceptible to electrocautery inference. Further, contemporary IABP consoles can differentiate pacing artifacts, thereby allowing proper balloon inflation timing, even if atrial or ventricular pacing is used. Balloon inflation is often initiated at a ratio of 1:2 (one IABP beat for every two cardiac beats). Thus, natural and augmented ventricular beats can be compared to determine IABP timing and efficacy. Depending on the patient’s condition, the ratio may be increased to 1:1 to produce maximal augmentation, or it may be decreased to 1:3, 1:4, or less during weaning. Typically, the volume of balloon inflation is set at 50% to 60% of the patient’s ideal stroke volume. Overinflation risks balloon rupture and arterial gas embolization. During extended use of IABP, anticoagulation is generally indicated. However, in the early postoperative period, anticoagulation may not be instituted until the chest tube drainage is acceptable (<100 to 150 mL/hour). Some surgeons prefer low-molecular-weight dextran to heparin because its antithrombogenic effects are fairly mild, even though no specific reversal agent exists.

S

C = unassisted systole

D

C

F B E A

Inflation occurs at the onset of diastole (aortic valve closure— i.e., dicrotic notch), giving rise to the sharp V wave on the arterial waveform. This leads to increased coronary perfusion.

D = diastolic augmentation E = reduced aortic EDP F = reduced systolic pressure

Deflation occurs at the end of diastole prior to systole, resulting in reduced aortic end-diastolic and systolic pressures. This leads to decreased afterload, myocardial oxygen consumption (MVO2), and increased cardiac output.

Figure 98–1 ■ Appropriate timing of IABP balloon inflation and deflation. (Adapted from Rao V, Slater JP, Edwards NM, et al: Surgical management of valvular heart disease in patients requiring left ventricular assist device support. Ann Thorac Surg 71:1448-1453, 2001.)

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medications (steroids), mechanical ventilation, and intravascular catheters. It is imperative to correct as many of these factors as possible before device implantation. Further, all vascular access lines and drains should be removed as soon as possible, drive-line sites should be inspected routinely, and aseptic conditions should be aggressively maintained during dressing changes. Treatment depends on the type of infection. Pocket infections may require surgical drainage. VADrelated endocarditis is extremely challenging. Often, the VAD must be explanted and replaced, with all the attendant complications of reoperation. Many patients requiring VAD implantation for left ventricular failure have coexistent pulmonary disease and pulmonary hypertension. For such patients, placement of an LVAD may result in inadequate VAD flow rates due to right ventricular failure and reduced blood flow to the left ventricle, where the inflow cannula is located. In these patients, careful attention to factors influencing pulmonary vascular resistance (e.g., hypoxemia, hypercarbia, acidosis, bronchospasm, vasopressors) is important to reduce the likelihood of right ventricular failure. In extreme cases, an RVAD may be necessary to ensure adequate blood return to the LVAD.

Further Reading Baskett RJF, Ghali WA, Maitland A, et al: The intraaortic balloon pump in cardiac surgery. Ann Thorac Surg 74:1276-1287, 2002. Datascope Cardiac Assist CS100. Datascope Corporation, Cardiac Assist Division, Fairfield, NJ. Available at http://www.datascope.com/ca/ caeducmaterials.html. Frazier OH, Delgado RM: Mechanical circulatory support for advanced heart failure: Where does it stand in 2003? Circulation 108:3064-3068, 2003. Harter RL, Michler RE: Circulatory assist devices. In Hensley FA Jr, Martin DE, Gravlee GP (eds): Practical Approach to Cardiac Anesthesia, 3rd ed. Philadelphia, JB Lippincott–Williams & Wilkins, 2003, pp 557-573. Holman WL, Rayburn BK, McGiffin DC, et al: Infection in ventricular assist devices: Prevention and treatment. Ann Thorac Surg 75:S48-S57, 2003. Ko W, Jin C, Chen RJ, et al: Extracorporeal membrane oxygenation support for adult postcardiotomy shock. Ann Thorac Surg 73:538-545, 2002. Loebe M, Koerner MM, Lafuente JA, et al: Patient selection for assist devices: Bridge to transplant. Curr Opin Cardiol 18:141-146, 2003. Melhorn U, Kroner A, deVivie ER: 30 Years of clinical intra-aortic balloon pumping: Facts and figures. Thorac Cardiovasc Surg 47(Suppl 2): 298-303, 1999. Rao V, Slater JP, Edwards NM, et al: Surgical management of valvular heart disease in patients requiring left ventricular assist device support. Ann Thorac Surg 71:1448-1453, 2001. Rose EA, Gelijns AC, Moskowitz AJ, et al: Randomized Evaluation of Mechanical Assistance for the Treatment of Congestive Heart Failure (REMATCH) study group: Long-term mechanical left ventricular assistance for end-stage heart failure. N Engl J Med 345:1435-1443, 2001. Smedira NG, Blackstone EH: Postcardiotomy mechanical support: Risk factors and outcomes. Ann Thorac Surg 71:S60-S66, 2001. Smith C, Bellomo R, Raman JS, et al: An extracorporeal membrane oxygenation-based approach to cardiogenic shock in an older population. Ann Thorac Surg 71:1421-1427, 2001. Thoratec TLC-II VAD Portable Driver and System Operator’s Manual, rev ed. Pleasanton, Calif, Thoratec Corporation, 2004. Available at www.thoratec.com. Tisol WB, Mueller DK, Hoy FB, et al: Ventricular assist device use with mechanical heart valves: An outcome series and literature review. Ann Thorac Surg 72:2051-2055, 2001.

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aligned such that there is maximal flow across the mechanical valve. There is also some evidence that maximizing flow across the valves (valve washing) by adjusting VAD flow rates (depending on myocardial recovery) may decrease the incidence of thrombus formation. If aortic valve insufficiency is present, regurgitant flow may prevent a VAD from effectively decompressing the left ventricle to reduce myocardial oxygen consumption. Inadequate decompression is particularly problematic when aortic insufficiency is severe and with apical versus left atrial LVAD placement. Because VAD placement can (and is expected to) reduce left atrial and left ventricular pressures, atrial and ventricular septal defects should be identified and repaired before VAD placement to prevent potentially dangerous right-to-left shunting. The presence of native or prosthetic valvular heart disease can complicate VAD placement. Severe mitral stenosis limits VAD filling during serial cannulation and may result in restricted VAD flow. In contrast, VAD placement in patients with mitral regurgitation results in complete unloading of the left ventricle and improved valve function. Aortic stenosis alone is not a contraindication to placement of an LVAD. However, aortic insufficiency will allow regurgitant blood flow from the VAD outflow cannula across the incompetent aortic valve to distend the left ventricle and compromise end-organ perfusion. Even mild to moderate aortic insufficiency may become more severe with institution of LVAD support. Because inflow and outflow VAD cannulas must be placed in the thoracic cavity, they may compromise cardiac filling in the early postoperative period. Therefore, most VADs are approved for use in patients with a body surface area greater than 1.5 m2 or weighing more than 42 kg. Often, left ventricular preload improves over 12 to 24 hours as intrathoracic contents shift to accommodate the VAD cannulas. Anticoagulation is usually required with most VAD devices except the HeartMate LVAS (for left ventricular assist system; Thoratec Laboratories, Pleasanton, Calif.). The goal for anticoagulation is the same as for patients with prosthetic valves. The usual practice is to start heparin after postoperative bleeding from the chest tubes is less than 50 mL/hour and then to switch to warfarin after adequate anticoagulation has been obtained. With the HeartMate LVAS, only aspirin (80 mg/day) is required after the initial postoperative bleeding has subsided. Infectious complications of VAD placement are classified into two types: device related and non–device related. Non-device-related infections include pneumonia, urinary tract infection and sepsis. Device-related infections tend to involve the blood-contacting surface of the VAD, the outer surface of an implanted VAD, or the VAD inflow or outflow cannulas. Because the VAD cannot be removed, all infections with the potential for VAD colonization are potentially life threatening. Usually, Staphylococcus, Pseudomonas, Enterococcus, or Candida species are the offending agents, but other infectious causes have been described. Patient risk factors for infectious complications include preoperative infection, malnutrition, immunosuppressive

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99

Hyperglycemia and Diabetic Ketoacidosis Martin L. De Ruyter and Barry A. Harrison Case Synopsis A 75-year-old woman with type 2 diabetes mellitus, controlled by glyburide 5 mg twice a day, presents for scheduled coronary artery bypass grafting. She has diabetic nephropathy with a serum creatinine of 1.8 mg/dL. The patient did not take her oral antidiabetic medication before surgery, and her fasting plasma glucose was 130 mg/dL. After cardiopulmonary bypass, the intraoperative plasma glucose was 236 mg/dL. There was a brisk diuresis. The serum potassium was 5.8 mEq/L with a base deficit of –4.0 mEq/dL. The patient received furosemide and mannitol while on cardiopulmonary bypass and repeated doses of cardioplegia. Cardiopulmonary bypass took 130 minutes.

PROBLEM ANALYSIS Definition

Recognition Preoperatively, clinical symptoms and signs of hyperglycemia may be absent or vary widely. One third of patients with DM are unaware that they have the condition. Symptoms and signs include the following: ● ●

Polyphagia Polydipsia Table 99–1

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Normal Values for Plasma Glucose

Fasting plasma glucose: <100 mg/dL Peak plasma glucose*: <200 mg/dL 2-hr postprandial glucose: <140 mg/dL *After glucose tolerance testing.

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Hyperglycemia in adults is defined as a random plasma glucose level greater than 200 mg/dL, but this definition does not reflect today’s target for glucose control. Perioperative plasma glucose levels are determined by many factors, including preoperative glucose and nutritional status, metabolic activity, catecholamines, cortisol, glucagon, and insulin levels. At times of illness or acute severe stress, hyperglycemia may be present; this is referred to as hyperglycemic stress syndrome. In some patients this may reflect the unmasking of an abnormality of glucose tolerance, which should be treated to reduce the risk of increased morbidity and mortality. The patient should subsequently be reevaluated and reclassified after recovering from surgery or acute illness. A similar approach is used in the management of gestational diabetes. Diabetes mellitus (DM) is a chronic, multisystem disease heralded by signs and symptoms of persistent hyperglycemia and confirmed by a random plasma glucose level greater than 200 mg/dL, a fasting plasma glucose level greater than 126 mg/dL, or a plasma glucose level of 200 mg/dL or greater based on 2-hour postprandial testing or 2 hours following an oral glucose tolerance test. In the absence of acute metabolic decompensation or severe hyperglycemia, these criteria should be reconfirmed at least 24 hours apart. Type 1 DM is due to a failure to produce endogenous insulin. Type 2 DM is a metabolic syndrome characterized by relative degrees of reduced insulin secretion, increased insulin receptor resistance, and increased glucose availability. Impaired glucose tolerance is defined as a 2-hour postprandial or glucose tolerance test plasma glucose level between 140 and 200 mg/dL. Normal values for plasma glucose are given in Table 99-1.

Diabetic ketoacidosis is usually associated with type 1 DM. It generally occurs in the setting of absent insulin, poor glucose utilization, and often some pathologic stressor (e.g., illness, infection, trauma). The body attempts to preserve energy stores via gluconeogenesis, which is the mobilization of fats and amino acids into glucose-producing pathways, resulting in hyperglycemia and ketosis (Fig. 99-1). Nonketotic hyperosmolar syndrome occurs in type 2 diabetics with insufficient production of insulin or altered receptor sensitivity to insulin. Endogenous insulin is present in sufficient quantities to prevent these patients from developing ketoacidosis; however, they present with an anion gap metabolic acidosis secondary to lactic acidosis. This acid-base derangement occurs as a result of cellular hypoxia, likely due to hypovolemia, inadequate organ perfusion, or a shock state. Nonketotic hyperosmolar syndrome is characterized by severe hyperosmolarity (>320 mOsm/L), hyperglycemia (>600 mg/dL), and marked dehydration.

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Figure 99–1 ketoacidosis.

Insulin deficiency / Glucagon excess

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Pathogenesis of diabetic

Activation of lipolysis

Hepatic ketogenesis

Increased glycogenolysis/ gluconeogenesis

Ketoacidosis

● ● ●

Impaired glucose utilization

Hyperglycemia

Polyuria Confusion Coma Intraoperative signs are as follows:

● ● ● ●

Unexplained diuresis Tachycardia and hypotension Anion gap metabolic acidosis Hyponatremia and hyperkalemia

Frequently hyperglycemia is first recognized by an increased plasma blood glucose level.

Risk Assessment Causes of perioperative hyperglycemia are listed in Table 99-2. Emergency surgery increases the risk of type 1 diabetics developing diabetic ketoacidosis and type 2 diabetics developing nonketotic hyperosmolar syndrome. In emergency situations (e.g., trauma), patients may miss their usual insulin dose, interrupt their usual caloric intake, or encounter excessive pathologic stresses, which alter the normal counterregulatory hormone balance. The patient’s inability to increase insulin production results in hyperglycemia. DM is associated with significant complications, including retinopathy, neuropathy, gastropathy, and nephropathy. DM also accelerates atherosclerosis, leading to increased coronary artery disease, cerebrovascular disease, and peripheral vascular disease.

Implications The effects of hyperglycemia are related to the severity and duration of increased plasma glucose levels. Cellular. Hyperglycemia leads to nonenzymatic glycosylation of immunoglobulins, granulocyte dysfunction, and reduction

of both CD4 and CD8 lymphocyte populations. It also exaggerates ischemia-reperfusion cellular injury, induces cardiac cell death, and reduces coronary collateral blood flow. Hyperglycemia induces platelet hyperreactivity, which increases thrombosis, and it increases levels of interleukin-6, interleukin-8, and tumor necrosis factor-α, reflecting

Table 99–2

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Causes of Perioperative Hyperglycemia

Diabetes mellitus (types 1 and 2) Dextrose-containing intravenous fluids Maintenance solutions or parenteral nutrition Medications Catecholamine-induced stress response Burns Trauma Surgery Sepsis Stroke Pain Cardiopulmonary bypass Excess counterregulatory hormones Cushing’s disease or syndrome Pheochromocytoma Acromegaly Glucagonoma Drugs Thiazide diuretics Glucocorticosteroids Phenytoin Pentamidine β-Adrenergic receptor blockers Oral contraceptives Pancreatic disease Pancreatitis or pancreatic trauma Hemochromatosis Pregnancy

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a proinflammatory action. Hyperglycemia and insulin resistance lead to endothelial cell dysfunction, inactivation of nitric oxide, decreased synthesis of prostacyclin, and increased synthesis of endothelin-1, which all lead to decreased local blood flow.

Cardiovascular. A meta-analysis of patients admitted for acute myocardial infarction, with or without a prior diagnosis of DM, found that hyperglycemia (>110 mg/dL) was associated with increased hospital mortality and congestive heart failure. Inpatients. Newly noted hyperglycemia in medical and surgical inpatients resulted in an 18-fold increase in hospital mortality and longer hospital stays. Major Surgery. Thirty percent to 40% of cardiac surgical patients have DM. Hyperglycemia is associated with increased mortality and deep-seated infections in cardiac surgical patients.

Intraoperative Hyperglycemia In December 2003 the American Association of Clinical Endocrinologists published a position statement on inpatient diabetes and metabolic control. For intensive care unit patients (including cardiac, vascular, thoracic, and major surgical patients), the consensus as to the tolerable upper limit for glucose is 110 mg/dL. For non–critically ill patients, the consensus is 110 mg/dL for preprandial plasma glucose levels and 180 mg/dL for maximal glucose levels. During the perioperative period, intravenous (IV) infusion of insulin is advocated. In hospitalized patients, high IV doses of insulin may be necessary to achieve acceptable plasma glucose levels. Studies have demonstrated that the use of standardized protocols, developed by multidisciplinary teams, can successfully control hyperglycemia, decrease hypoglycemia, decrease length of stay, and improve outcome in diabetic patients. A continuous IV insulin infusion algorithm is presented in Table 99-3. Subcutaneous regular insulin is not advocated in the critically ill and those undergoing major surgery but may find applications in less severe cases. Table 99-4 illustrates a regimen of regular insulin dosing via the subcutaneous route.

Algorithm for Continuous Intravenous Infusion of Insulin*

Blood Glucose (mg/dL) >400 351-400 301-350 250-300 200-249 150-199 120-149 100-119 70-99 <70

Insulin Infusion Rate (U/hr) 8 6 4 3 2.5 2 1.5 1 0 0

*Algorithm is designed for the average 70-kg patient. Adjustments should be based on hourly glucose determinations.

Diabetic Ketoacidosis Diabetic ketoacidosis is a medical emergency. Initial assessment includes the following: ●

●

● ● ● ●

●

●

MANAGEMENT

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Identification of the precipitating event—infection, ischemia, missed insulin administration Volume status ● Tachycardia, hypotension ● Increased urea and creatinine Mental status—cerebral edema Hyperglycemia—increased plasma glucose and urine glucose Ketosis—increased serum ketones and β-hydoxybutyrate Increased anion gap acidosis ● Increased respiratory rate (Kussmaul’s respiration) ● Serum bicarbonate <15 mEq/dL; pH <7.3 Potassium—initially increased secondary to metabolic acidosis, but decreased total potassium stores Sodium—laboratory measurement secondary to hyperglycemia

Fluid resuscitation, IV insulin administration, and correction of electrolytes are crucial. Fluid Resuscitation. The fluid deficit is often between 4 and 8 L of sodium and free water. Initial resuscitation includes infusion of normal saline (0.9% NaCl). Within the first 2 hours, patients should receive enough fluid to stabilize their hemodynamic parameters (usually 2 to 3 L of nonglucose-containing crystalloid solution). After initial rehydration with isotonic saline, subsequent administration of

Table 99–4

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Subcutaneous Supplementation of Regular Insulin

Blood Glucose (mg/dL) 200-250 251-300 301-350 >350

Regular Insulin Dose (U)* 2 4 6 8

*Subcutaneous insulin dosing is approximately every 4 to 6 hr.

PHYSIOLOGIC IMBALANCE & COEXISTING DISEASE

Critical Illness. In 1826 critically ill patients, there was a direct and proportional correlation between increasing blood glucose levels and mortality.

Hyperglycemia and Diabetic Ketoacidosis

Table 99–3

Renal. Blood glucose levels in excess of 250 mg/dL overwhelm renal tubular absorption capabilities, which leads to hypovolemia secondary to an osmotic diuresis. A profound diuresis may result in prerenal azotemia, altered organ perfusion, cellular hypoxia, and lactic acidosis. Cerebral. Patients with DM or newly recognized hyperglycemia are at increased risk for severe strokes and increased mortality. A meta-analysis of studies of stroke patients found increased mortality in patients with blood glucose levels of 110 to 126 mg/dL. Serum osmolarity greater than 330 mOsm/L is associated with central neurologic dysfunction and coma.

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0.45% normal saline should be started, because free water loss typically exceeds the natriuresis. Once blood glucose levels have declined to less than 250 mg/dL, 5% dextrose is added to the IV fluids to maintain acceptable glucose levels and reduce the risk of cerebral edema. Infusions with hypotonic fluid may cause cerebral edema secondary to reverse osmotic shifts. Hypertonic solutions have no role because they may worsen the acidosis, dehydration, and hyperosmolar state. Insulin Therapy. Regular insulin is administered as a bolus (0.1 to 0.2 unit/kg), followed by a continuous IV insulin infusion (0.1 unit/kg per hour) and hourly determinations of blood glucose levels. Additional glucose supplementation may be necessary, but care must be taken to avoid hypoglycemia. Blood glucose levels of 200 to 250 mg/dL are a reasonable initial goal. As the patient improves, titration to 150 to 200 mg/dL should be the goal. A continuous IV infusion algorithm is presented in Table 99-3. Metabolic Acidosis. The administration of bicarbonate is controversial. A paradoxical rebound central nervous system acidosis can be observed with excessive bicarbonate therapy. IV bicarbonate replacement should be reserved for patients with an arterial pH less than 7.0 after initial rehydration, and it should be discontinued once the pH rises above this value. Electrolytes. Serum potassium may be elevated despite a depletion in total body stores. Hyperglycemic osmotic diuresis causes systemic potassium wasting (up to 10 mEq/kg), whereas an extracellular shift in potassium secondary to metabolic acidosis results in an elevated serum concentration. Provided the patient’s urine output is adequate, acute renal failure is not evident, and a normal serum potassium level is documented, potassium should be repleted promptly. In general, replacement with potassium chloride at a rate of 20 to 30 mEq/hour should be sufficient. Electrocardiographic monitoring is recommended during repletion of potassium. Measured hyponatremia is a laboratory phenomenon secondary to the dilutional effect of hyperglycemia. In general, for each 100 mg/dL increase in glucose above normal levels, serum sodium levels decrease by 1.6 to 2.0 mEq/L. No specific therapy is required other than correction of the hyperosmolar state. Phosphate levels may be depleted because this anion is excreted with osmotic diuresis. Routine replacement is controversial because rapid replacement can cause hypocalcemia. Phosphate replacement should be guided by periodic surveillance of magnesium, calcium, and phosphate levels.

PREVENTION Diabetes affects 18.2 million Americans and is the seventh leading cause of death in the United States. Preoperatively, random plasma glucose testing is advised for patients older

than 60 years and those with symptoms or with DM. Diabetic patients need a complete medical evaluation to detect diabetic complications and comorbidities. Oral agents need to be stopped before surgery. Long-acting sulfonylureas or chlorpropamide are stopped for at least 72 hours, whereas shorter-acting sulfonylureas and metformin are stopped the night before surgery. For type 1 DM patients and patients with uncontrolled type 2 DM, it is essential to administer insulin. The aim of any regimen is to maintain good control without hypoglycemia. It also must be practical and easy to use as the patient is transferred from the ward to the operating room, to the recovery room, and back to the ward. It is important to monitor plasma glucose at frequent intervals. One regimen that fulfills all these criteria is the continuous IV administration of regular insulin. With an increasing number of type 1 DM patients on continuous subcutaneous insulin maintenance, the use of a continuous IV infusion perioperatively is advised. For stable type 2 DM patients having minor or moderately stressful surgery, oral therapy can resume postoperatively. Unless insulin is part of a type 2 diabetic patient’s usual regimen, it can be reserved for glucose levels exceeding 180 mg/dL.

Further Reading American College of Endocrinology position statement on inpatient diabetes and metabolic control. Endocr Pract 10:77-82, 2004. Clement S, Braithwaite SS, Mangee MF, et al: Management of diabetes and hyperglycemia in hospitals. Diabetes Care 27:553-591, 2004. Coursin DB, Connery LE, Ketzler JT: Perioperative diabetic and hyperglycemic management issues. Crit Care Med 32:S116-S125, 2004. Expert Committee on the Diagnosis and Classification of Diabetes Mellitus: Report of the Expert Committee on the Diagnosis and Classification of Diabetes Mellitus. Diabetes Care 20:1183-1197, 1997. Furnary AP, Gao G, Grunkemeier GL, et al: Continuous insulin infusion reduces mortality in patients with diabetes undergoing coronary artery bypass grafting. J Thorac Cardiovasc Surg 125:1007-1021, 2003. Malmberg K, Norhammar A, Wedel H, Ryde´n L: Glycometabolic state at admission: Important risk marker of mortality in conventionally treated patients with diabetes mellitus and acute myocardial infarction: Long-term results from the Diabetes and Insulin-Glucose Infusion in Acute Myocardial Infarction (DIGAMI) study. Circulation 99:2626-2632, 1999. Pittas AG, Siegel RD, Lau J: Insulin therapy for critically ill hospitalized patients: A meta-analysis of randomized controlled trials. Arch Intern Med 164:2005-2011, 2004. Savage MW, Mah PM, Weetman AP, Newell-Price J: Endocrine emergencies Postgrad Med J 80:506-515, 2004. Van den Berghe G, Wouters P, Weekers F, et al: Intensive insulin therapy in critically ill patients. N Engl J Med 345:1359-1367, 2001. Wass T, Lanier W: Glucose modulation of ischemic brain injury: Review and clinical recommendations. Mayo Clin Proc 71:801-812, 1996.

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Hypothermia Christopher C. Young and Robert N. Sladen Case Synopsis A 74-year-old woman with insulin-dependent diabetes mellitus is found several hours after a fall. She is admitted for emergency surgery with epidural and general anesthesia for repair of a fractured hip. She receives 4 units of packed red blood cells. In the postanesthesia care unit, she is confused and disoriented after tracheal extubation. Her heart rate is 110 beats per minute; blood pressure, 160/90 mm Hg; temperature, 33.8°C (oral); arterial oxygen tension (PaO2), 63 mm Hg; and arterial carbon dioxide tension (PaCO2), 54 mm Hg (on nasal oxygen at a rate of 6 L/minute).

PROBLEM ANALYSIS Definition Normal body temperature is 37°C (98.6°F). Hypothermia is classified as mild to moderate (33°C to 36°C), severe (23°C to 33°C), or profound (< 23°C). Accidental (Table 100-1) or iatrogenic (Table 100-2) causes may contribute to hypothermia. The patient in the case synopsis is at increased risk for hypothermia owing to the following factors: ● ● ●

Age-impaired thermoregulatory responses Anesthesia-impaired thermoregulatory responses Ambient factors (e.g., cold environment, air conditioning)

Table 100–1

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Accidental Causes of Hypothermia

Environmental Wind chill Cold water immersion

Impaired Thermoregulation Extremes of age (neonates, elderly) Prolonged immobilization Drugs Alcohol Central nervous system depressants Drug overdose

●

Radiation (heat exchange from one surface to another), such as from the skin or mucosa to the colder environment of the operating room

1 Before air conditioning was introduced, inadvertent hyperthermia was not uncommon.

Medical Conditions Hypothyroidism Large body surface area burns Infection or sepsis Malnutrition Hypoglycemia Hypothalamic stroke or tumor Unconsciousness

Table 100–2

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Iatrogenic Causes of Hypothermia

Prolonged anesthesia and surgery Prolonged cardiopulmonary resuscitation Blood or blood product transfusions* Large-volume fluid resuscitation* *Without adequate warming.

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Age-related impairment involves decreased perception of cold, decreased ability to prevent heat loss (blunted vasoconstrictor response), and diminished ability to increase heat production (reduced muscle mass). Microvascular atheroma and diabetic autonomic neuropathy also impair thermoregulatory vasoconstriction in response to cold. General and regional anesthesia disrupts physiologic thermoregulatory responses (Fig. 100-1). For example, the hypothermic vasoconstriction threshold (about 37°C) is

suppressed 2°C to 4°C in a dose-dependent manner by volatile or opioid anesthesia, with significantly greater suppression occurring in the elderly. Regional anesthesia induces a sympathetic blockade that prevents vasoconstriction in the affected dermatomes, and heat generation from muscle activity is reduced in proportion to the extent of segmental motor blockade. Spinal thermoregulatory centers may be depressed by central neuraxial anesthesia or analgesia. Shivering is abolished by anesthetic agents and neuromuscular blocking agents. Conversely, physiologic thermoregulatory responses to warmth (i.e., vasodilatation and sweating) are also suppressed by anesthetic agents, such that their thresholds are elevated about 1°C above normal. The interthreshold range is the range of core temperatures within which no physiologic responses are evoked. Normally, this is very narrow (about 0.5°C). However, from Figure 100-1, it is apparent that anesthesia widens the interthreshold range to as much as 4°C. This implies, for example, that the central temperature could vary from 34°C to 38°C without any physiologic responses to conserve or eliminate heat. Within this range, the patient is poikilothermic (i.e., the central temperature varies directly with ambient temperature). This and the widespread use of air conditioning in operating rooms put anesthetized patients at high risk for inadvertent hypothermia.1 Also, heat balance is the sum of heat production and loss, with heat production (via exercise or metabolism) negligible during anesthesia. In fact, heat loss dominates due to the following physical factors, in decreasing order of importance:

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Risk Assessment and Implications

Figure 100–1 ■ Schematic illustration of thermoregulatory thresholds in nonanesthetized (normal) and anesthetized humans. The intersection of each regulatory response (e.g., shivering, sweating) with the temperature scale (core body temperature) is the threshold. The interthreshold range is shown as the distance between the first cold response (vasoconstriction) and the first warm response (sweating); temperatures within this range do not elicit autonomic thermoregulatory compensation. Because each thermoregulatory response has its own threshold and gain, there is an orderly progression of responses, and response intensities, in proportion to need. During general anesthesia (bottom), the thresholds for vasoconstriction and nonshivering thermogenesis are shifted down to about 34.5°C (depending on anesthetic type and dose). Similarly, thresholds for active precapillary vasodilatation and sweating are increased about 1°C. Interthreshold range thus increases from 0.2°C to about 4°C. (From Sessler DI: Temperature monitoring. In Miller RD [ed]: Anesthesia, 4th ed. New York, Churchill Livingstone, 1994, pp 1363-1382.)

●

●

●

Evaporation (heat lost by the movement of molecules from liquid to gas phase), such as from cold skin preparation and irrigation solutions, and evaporative loss from exposed body serosal surfaces Convection (heat lost by eddy currents), such as from drafts and the infusion of cold blood and fluids Conduction (heat exchanged by direct molecular contact), such as from the skin to the cold operating table

Recognition During general and regional anesthesia, intraoperative hypothermia has three distinct stages: 1. Internal redistribution: abrupt decline of about 0.5°C to 1.0°C in central temperature caused by redistribution of heat from the warm central core to the cold periphery due to anesthetic-induced peripheral vasodilatation. The colder the skin at anesthetic induction, the greater the central temperature decline. 2. Environmental heat loss: passive heat loss by radiation, evaporation, convection, and conduction continues to the extent that physiologic responses are depressed, usually to about a central temperature of 34°C to 35°C. Advanced age and diabetes can contribute to depression of the vasoconstrictor threshold to less than 34°C, as in the patient described in the case synopsis. 3. Plateau phase: once thermoregulatory vasoconstriction is evoked, heat loss becomes constrained, and the central temperature reaches a plateau. However, further declines can be caused by massive blood loss and transfusion, for example.

Hypothermia may benefit the patient by providing organ protection against ischemia. Oxygen utilization is halved for each 10°C decrease in normal body temperature. Mild hypothermia (33°C to 36°C) provides important central nervous system protection. There is increasing evidence that it may play a protective role after stroke and cardiac arrest due to ventricular fibrillation. Even mild hypothermia induces platelet dysfunction and may increase intraoperative bleeding. Platelet thromboxane generation, required for platelet aggregation and local hemostatic vasoconstriction, is impaired by cold. Quantitative laboratory assessment is misleading because blood samples are warmed to 37°C. Massive transfusion of cold blood can induce severe hypothermic coagulopathy with irreversible bleeding. There is now evidence that even mild intraoperative hypothermia may increase the risk for postoperative wound infection, possibly due to vasoconstriction with low tissue oxygen tension. This impairs chemotaxis and facilitates bacterial growth. Severe hypothermia (<33°C) has adverse effects on almost every organ system (Table 100-3; Fig. 100-2). Emergence from anesthesia may be delayed by a number of cold-induced factors, including impairment of central nervous system function (e.g., obtundation, confusion, somnolence), slowed hepatic or renal clearance of anesthetic drugs and neuromuscular blocking agents, and impaired ventilatory response to hypoxemia and hypercarbia. Cold-induced vasoconstriction and increased systemic vascular resistance may exacerbate postoperative hypertension (blood pressure of 160/90 mm Hg in the patient in the case synopsis is characteristic). Together with high norepinephrine concentrations, both may produce myocardial ischemia in susceptible patients. The consequences of rewarming from hypothermia may outweigh the implications of hypothermia itself. Postoperative shivering greatly increases oxygen demand and carbon dioxide production, leading to increased minute ventilation, work of breathing, and oxygen consumption. If minute ventilation is fixed (mechanical ventilation) or suppressed (by anesthetic agents or opioids), hypercarbia and acute respiratory acidosis may result. When oxygen consumption is increased but cardiac output cannot compensate, oxygen extraction increases, setting the stage for hypoxemia and its sequelae. Shivering can also cause patient discomfort and other adverse sequelae, such as wound disruption and increased bleeding or intracranial and intraocular pressures. Subsequently, rewarming vasodilatation may unmask hypovolemia, resulting in even more dangerous hypotension and tachycardia.

MANAGEMENT AND PREVENTION The management and prevention of hypothermia are inseparable and include the following. ● ● ●

Preoperative skin warming Adjusted ambient temperature in the operating room Intraoperative temperature monitoring

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Table 100–3

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Hypothermia

421

Adverse Effects of Hypothermia on Organ System Function

Cardiovascular Early: tachycardia, hypertension, increased cardiac output, vasoconstriction (catecholamine release) Late: bradycardia, decreased cardiac output, hypotension ECG: Generalized slow conduction, sinus bradycardia, T-wave inversion, Q-T prolongation, ventricular ectopy (32°C, Osborne waves; 30°C, ventricular fibrillation; see Fig. 100–2)

Respiratory Early: increased respiratory rate Late: reduced respiratory rate and tidal volume, diminished hypoxic pulmonary vasoconstriction and responsiveness to hypoxemia and hypercarbia, diminished mucociliary activity

Renal Early: initial “cold” diuresis (increased central blood volume with peripheral vasoconstriction); diuresis continues due to impaired renal tubular sodium reabsorption Late: oliguria and azotemia

Hematologic Early: hemoconcentration, increased viscosity (sludging, poor tissue perfusion, ischemia), decreased oxygen availability (left shift of oxyhemoglobin dissociation curve) Late: disseminated intravascular coagulation, thrombocytopenia

Metabolic Early: hyponatremia, hyperkalemia, hyperglycemia (inhibition of insulin release and block of its cellular uptake) Late: metabolic acidosis

Neurologic Cerebral blood flow decreases 6% to 7% per 1°C decrease in temperature: 34°C: amnesia 30°C: obtundation 26°C: loss of pupillary and deep tendon reflexes 18°C: loss of brain activity (isoelectric electroencephalogram)

Gastrointestinal Early: decreased intestinal motility (full stomach), diminished hepatic clearance Late: ulceration of stomach, ileum, and colon; hemorrhagic pancreatitis ECG, electrocardiogram.

● ● ● ● ●

Heated and humidified anesthesia circuits Forced-air warming blankets and other devices Warmed intravenous fluids and blood products Postoperative mechanical ventilation Prevention and treatment of postoperative shivering Anticipation and treatment of rewarming vasodilatation

A simple way to prevent redistribution hypothermia is to warm the patient’s skin before anesthetic induction. In many cases, warming with a forced-air blanket can be initiated in the preoperative holding area or preinduction room. Before anesthetic induction, the ambient temperature in the

operating room should be increased to 23°C to 26°C to maintain normothermia. Once the patient is fully draped and protected, the temperature can be decreased so that it does not impair the performance of the surgeon or assistants. Ambient room temperature should be increased again at the end of the operation. Temperature monitoring is mandatory for all procedures lasting 30 minutes or longer. However, “normal” temperature (like blood pressure) depends on where it is measured. Monitors for core body temperature include the tympanic membrane (susceptible to injury), nasopharynx (influenced by anesthetic gas temperature), esophagus

Figure 100–2 ■ Two electrocardiographic leads obtained during cooling with cardiopulmonary bypass. Sinus bradycardia (about 30 beats per minute) and prominent J (Osborne) waves (arrows) distinguish the first three complexes. Ventricular ectopy increases in frequency and progresses to fibrillation as the patient rapidly becomes hypothermic. Bladder and nasopharyngeal temperatures were 35.8°C and 31.4°C, respectively. (From Mark JB: Atlas of Cardiovascular Monitoring. New York, Churchill Livingstone, 1997, p 331.)

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(dependent on depth of insertion),2 and pulmonary artery (if a thermistor-equipped pulmonary artery catheter is used). The rectum and bladder may reflect central core body temperature if the patient is warm and vasodilated, or peripheral body temperature if the patient is cold and vasoconstricted. Skin temperature may be useful to evaluate gradients but may have little or no relationship to core temperature changes. Routine use of heated and humidified anesthesia circuits is not warranted in adult patients except to reduce further heat loss in an already hypothermic patient or for extended, major surgical procedures. Such circuits do little to increase core temperature. After the induction of anesthesia, reduction of the total fresh gas flow to less than 2 L/minute will help reduce heat and moisture loss from the airway, as will an “artificial nose” (i.e., a heat- and moistureexchanging filter or hygroscopic condenser humidifier). A forced-air warming blanket should be placed to prevent intraoperative hypothermia and even induce rewarming. Full-body or half-body blankets are available, and this convection-based device is by far the most effective system for perioperative warming. One caveat is that it should not be placed over the lower body3 during aortic cross-clamping, because this will exacerbate the tissue oxygen demandsupply imbalance. Passive insulation (blankets, drapes) and circulating water mattresses are not nearly as effective, and there is a risk of thermal injury with the latter if water temperature exceeds 40°C. Although an overhead radiant heater is frequently used for infants and small children, the patient’s skin must be left exposed for heat transfer to occur. Heat transfer is blocked by interposed surgical or nursing personnel. Also, overhead heaters restrict access to the patient. Whenever large volumes of crystalloid, colloid, or blood products are infused, a fluid warming device should be used. Four units of refrigerated blood at 4°C or 1 L of roomtemperature crystalloid can decrease mean body temperature by about 1°C. During massive blood transfusion, the use of a rapid infusion device (which can deliver up to 1000 mL/minute at 37°C) is essential to prevent potentially life-threatening hypothermia and irreversible hypothermic coagulopathy. When patients are hypothermic to less than 35°C following anesthesia and surgery, it is prudent to consider deferring tracheal extubation and providing mechanical ventilation until the core temperature has normalized. Capnometry is useful to detect early increases in carbon dioxide production and facilitate appropriate adjustments in minute ventilation. The most effective means of preventing postoperative shivering is to warm the skin (e.g., with a forced-air warming blanket). Impulses from skin thermoreceptors govern the

2 If the thermistor is behind the trachea, core temperature will be <0.2°C below its true value. 3 Or, if a lower body warming blanket is in place, it must not be used at this time.

hypothalamic response to cold; the warmer the skin, the lower the central temperature threshold for the onset of shivering. There is considerable evidence that premedication with α2-adrenergic receptor agonists (clonidine, dexmedetomidine) suppress postoperative shivering. Active shivering can be treated with intravenous meperidine (12.5 to 25 mg), which likely has a specific hypothalamic effect. However, it is effective only about 50% to 60% of the time. Intravenous dexmedetomidine is also an effective treatment for postoperative shivering and has an additive effect when used with meperidine. Rewarming vasodilatation begins variably after the patient’s arrival in the postanesthesia care unit and depends on hypothermia severity. Increased muscle tone (i.e., subclinical shivering) initially generates heat during persistent peripheral vasoconstriction. As a result, core temperature climbs and may even “overshoot” to 38°C to 40°C, especially after hypothermic cardiopulmonary bypass. When peripheral vasodilatation finally occurs, heat generation is balanced by heat loss, so that the central temperature reaches a plateau before returning to normal. If patients are hypovolemic, rewarming vasodilatation can produce acute hypotension, reflex tachycardia, and myocardial ischemia. Thus, in the early postoperative period, patients who are hypothermic, vasoconstricted, and hypertensive may benefit from vigorous fluid replacement, along with judicious use of vasodilator therapy (e.g., nitroprusside, nitroglycerin). Once rewarming vasodilatation occurs, fluid replacement is essential, together with a vasopressor if needed.

Further Reading Doufas AG, Lin CM, Suleman MI, et al: Dexmedetomidine and meperidine additively reduce the shivering threshold in humans. Stroke 34: 1218-1223, 2003. Frank SM, Higgins MS, Breslow MJ, et al: The catecholamine, cortisol, and hemodynamic responses to mild perioperative hypothermia: A randomized clinical trial. Anesthesiology 82:83-93, 1995. Giesbrecht GG, Ducharme MB, McGuire JP: Comparison of forced-air patient warming systems for perioperative use. Anesthesiology 80:806-810, 1994. Kurz A, Sessler DI, Lenhardt R: Perioperative normothermia to reduce the incidence of surgical-wound infection and shorten hospitalization. N Engl J Med 334:1209-1215, 1996. Nesher N, Zisman E, Wolf T, et al: Strict thermoregulation attenuates myocardial injury during coronary artery bypass graft surgery as reflected by reduced levels of cardiac-specific troponin I. Anesth Analg 96:328-335, 2003. Sessler DI: Temperature monitoring. In: Miller RD (ed): Miller’s Anesthesia, 6th ed. Philadelphia, Churchill Livingstone, 2005, pp 1571-1598. Young CC, Sladen RN: Temperature monitoring. Int Anesth Clin 34: 149-174, 1996.

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Hyperthermia Melissa M. Vu Case Synopsis A 24-year-old, 62-kg, gravida I para 0 woman presents at 39 + 5 weeks for elective induction of labor under combined spinal-epidural analgesia. After approximately 5 hours of labor, the patient’s oral temperature is noted to be 38°C (100.4°F). The fetal heart rate is 120 to 130 beats per minute, with normal variability.

PROBLEM ANALYSIS Definition

Recognition Optimal detection of temperature disturbances during anesthesia is achieved by monitoring core body temperature. Core temperature can be assessed from a variety of locations, including the pulmonary artery (the gold standard, but even this may be misleading in some surgeries), nasopharynx, tympanic membrane (a reflection of brain temperature), and distal esophagus.1 Sites outside the core compartment include the bladder, rectum, axilla, and skin, with the last being the least reliable. These sites can be used when clinical circumstances preclude the use of core temperature monitoring, such as surgery under regional anesthesia. Peripheral temperature (skin, extremity) may show a large discrepancy with core temperature as a result of the

1 The thermistor element should be 2 to 3 cm beyond the tracheal bifurcation or point of best breath sounds. Exposure to cooler inspired gases will reduce core temperature by about 0.3°C, depending on inspired gas flow, respiratory rate, and tidal volume.

Risk Assessment Hyperthermia itself has a variety of physiologic implications. Of greatest significance is that hyperthermia or fever may be a sign of a more serious underlying pathologic process (Table 101-1). As previously mentioned, hyperthermia occurs far less often than hypothermia during general anesthesia. The incidence of hyperthermia depends largely on its cause. Malignant hyperthermia is reported to occur in 1 in 5000 to 65,000 cases of general anesthesia in which triggering agents such as inhalational agents or succinycholine are used. Approximately 50% of patients in whom malignant hyperthermia is triggered (see also Chapter 162) have undergone prior uneventful general anesthesia. Ninety percent of all transfusion reactions are associated with increased temperature. Temperature elevation occurs in about 1% to 2% of all transfusions. The incidence of other causes of hyperthermia (e.g., infection, thyrotoxicosis, neuroleptic malignant syndrome, other hypermetabolic conditions) is variable. Passive hyperthermia is common in pediatric patients brought to a heated operating room and placed on the operating table under warming lights. Nonetheless, hyperthermia should alert the anesthesiologist to search for a cause rather than to simply treat the elevated temperature elevation itself.

Implications Hyperthermia has physiologic effects on multiple organ systems. First, elevated temperature results in increased metabolic rates, with consequent increased oxygen consumption. To meet this increase in oxygen demand, cardiac output and heart rate are increased. Acidosis may develop if cellular metabolic demand exceeds oxygen delivery. Myocardial ischemia will occur if the oxygen supply is insufficient. Also, compensatory thermoregulation (perspiration, vasodilatation) may lead to decreased intravascular volume and preload, with possible worsening of oxygen delivery. Perspiration may also cause electrolyte abnormalities due to loss of electrolytes or free water. Hypothermia is known to provide some measure of cerebral protection during periods of ischemia, whereas 423

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Normal core body temperature is 36.7°C to 37.0°C ± 0.2°C to 0.4°C and is maintained via a complex system of neuroregulatory sensors and responses. A person’s age and level of activity, the time of day, medications, the hormonal milieu, and other factors determine the hypothalamic “setpoint” to which core body temperature is compared. Consequently, whether the core temperature is below or above this setpoint determines whether the body will generate, conserve, or lose heat. Hyperthermia exists if body temperature during homeostatic conditions rises above the normal range. This may be due either to heat production exceeding heat loss or to heat storage. The opposite is true for hypothermia. During general and regional anesthesia, thermoregulation is impaired via pharmacologic and central mechanisms. Mild hypothermia commonly occurs in a characteristic pattern during anesthesia and surgery due to this impairment, as well as exposure to the cooler operating room environment. Thus, a less common but more functional definition of hyperthermia is a rise in core temperature more than 2°C per hour or more than 0.5°C over 15 minutes. Such a rise typically warrants further investigation.

physiologic thermal gradient between the two sites. A reasonable alternative is axillary temperature, which may be closer to core temperature values. Transitional zone temperatures (rectal, bladder) fall between core and peripheral temperatures.

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Causes of Hyperthermia during General Anesthesia

Iatrogenic Increased room temperature Warming devices Airway humidifiers or warmers Excessive rewarming after cardiopulmonary bypass

or even death. Transfusion reactions may be fatal. Pheochromocytoma and thyrotoxicosis are associated with severe hemodynamic disturbances as well as endocrine complications. Neuroleptic malignant syndrome may behave very similarly to malignant hyperthermia. Although elevated temperature is typically not the only sign of these conditions, it may serve as an early indicator of underlying pathology and assist in the diagnosis.

Infectious Preoperative fever associated with upper respiratory tract infection or condition related to surgical indication Sepsis Bacteremia or sepsis associated with surgical manipulation (e.g., oral surgery)

Pulmonary Aspiration pneumonia Atelectasis Deep venous thrombosis or pulmonary embolus

Metabolic Pheochromocytoma Thyrotoxicosis or thyroid storm Adrenal insufficiency

Central Nervous System Status epilepticus Hypothalamic pathology Parkinson’s disease

Drug Induced Malignant hyperthermia Neuroleptic malignant syndrome Anticholinergic effect Cocaine, tricyclic antidepressants Antibiotic-induced drug fever Monoamine oxidase inhibitors interacting with opioids, especially meperidine

Miscellaneous Monitoring error Connective tissue diseases Hematoma Transfusion reactions Infusion of blood components with infectious contamination

hyperthermia has been shown to worsen neurologic injury following ischemic events or status epilepticus. Numerous central nervous system effects may occur, including the following: ●

●

● ●

●

Cerebral blood flow increases 5% to 7% for each degree change in temperature. Release of excitatory neurotransmitters, such as glutamate, is increased with temperatures greater than 39°C during ischemia. Hyperthermia can result in seizure activity in children. Permanent central nervous system damage can occur with temperatures above 42°C. Increased temperature affects somatosensory evoked potentials by reducing latency.

Hyperthermia causes a rightward shift of the oxygenhemoglobin dissociation curve. This rightward shift means that hemoglobin has a lower affinity for oxygen and is less saturated at a given arterial oxygen tension. Further, the cause of hyperthermia may have a variety of untoward effects. Malignant hyperthermia may lead to acidosis, renal dysfunction, hematologic disturbances,

MANAGEMENT Management for hyperthermia is directed primarily at the underlying cause (i.e., fever from infection versus other conditions). One should review the patient’s history and examine the patient for clues to possible causes of hyperthermia. The perioperative course, including drugs administered, the nature of the surgical procedure, and any other perioperative complications, should also be examined. Patients with sepsis require antibiotics and possibly hemodynamic support as well. Patients with malignant hyperthermia should be treated with dantrolene and supportive therapy. Those in whom fever develops during a transfusion need to be evaluated to rule out a possibly severe transfusion reaction. Active patient cooling should be considered when the temperature exceeds 39°C. Treatment of hyperthermia itself may be as simple as lowering the room temperature, removing drapes or coverings, turning off warming devices, and blowing cool air over the patient. In more severe cases, one may consider the following: ● ● ●

●

Apply ice to the groin, axilla, or neck. Use cooled intravenous solutions. Undertake ice-water lavage into the surgical wound, bladder, stomach, or rectum (ice-water peritoneal lavage has also been used in extreme cases). In desperate situations, use cardiopulmonary bypass to provide rapid cooling.

PREVENTION Prevention of intraoperative hyperthermia begins with a preoperative history and physical examination. Does the patient have a history of malignant hyperthermia? Does the patient have known sepsis, pheochromocytoma, thyroid dysfunction, or other possible preoperative causes of hyperthermia? What was the patient’s temperature preoperatively? Iatrogenic hyperthermia or hypothermia is prevented by monitoring the patient’s core body temperature after the establishment of a baseline temperature and using a blanket cooling or warming device as necessary. If hyperthermia occurs, one should review recent intraoperative events: ● ● ● ●

Has a transfusion just begun? Were malignant hyperthermia–triggering agents used? Where is the site of surgery? What drugs have been given recently?

Although some mild hyperthermia or fever may be beneficial with infection, the potential physiologic effects on the heart and brain can be detrimental, especially in the elderly. If so, the condition must be treated aggressively.

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Further Reading Baughman V: Brain protection during neurosurgery. Anesthesiol Clin North Am 20:315-327, 2002. Cereda M, Maccioli GA: Intraoperative temperature monitoring. Int Anesthesiol Clin 42:41-54, 2004. Chiharu N, Lenhardt R: Fever during anaesthesia. Best Pract Res Clin Anesthesiol 17:499-517, 2003. Oku G, Rosenberg H: Thermoregulation in the postoperative patient. In Brown M, Brown EM (eds): Comprehensive Postanesthesia Care. Baltimore, Williams & Wilkins, 1997, pp 283-301.

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Rosenberg H, Frank S: Causes and consequences of hypothermia and hyperthermia. In Benumof JL, Saidman U (eds): Anesthesia and Perioperative Complications. St. Louis, Mosby–Year Book, 1999, pp 338-356. Sessler DI: Temperature monitoring. In Miller RD (ed): Anesthesia, 6th ed. Philadelphia, Churchill Livingstone, 2004, pp 1571-1597.

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Angioedema and Urticaria Saeed Habibi and Catherine Drexler

102

Case Synopsis A 24-year-old woman with a vague history of swelling of the lips and tongue and wheezing associated with exercise, anxiety, and cold temperature receives general anesthesia for shoulder arthroscopy. After induction of general anesthesia and tracheal intubation, severe bronchospasm develops, followed by generalized angioedema and cardiovascular collapse.

PROBLEM ANALYSIS Definition Angioedema and urticaria are clinical signs that may result from a vast array of causes, including immune-mediated and non-immune-mediated mechanisms. They often occur together and represent a clinical spectrum ranging from a minor irritating reaction to life-threatening laryngeal edema or anaphylaxis. Urticaria is characterized by erythematous, pruritic wheals of cutaneous edema. These blanch with pressure but remain surrounded by a “flare” of erythema. Although angioedema is a similar process, it occurs in the deeper subcutaneous tissues and produces more diffuse swelling. Sites of involvement may include the face, tongue, larynx, and gastrointestinal tract, as well as the extremities. Involvement of the upper respiratory tract has potential to cause life-threatening airway obstruction. Most episodes of urticaria and angioedema are acute but may recur during a period of 6 weeks or less. Periodic episodes lasting longer than 6 weeks are viewed as chronic, and most are idiopathic in origin. Hereditary angioneurotic edema (HAE), or complement 1 esterase inhibitor (C1-INH) deficiency, is a rare form of angioedema. HAE is an autosomal dominant inherited disease characterized by absolute (type 1) or relative (type 2) deficiency of C1-INH activity. The deficiency of C1-INH allows C1 esterase to cleave C1 and subsequently to activate the complement cascade, resulting in vasodilatation and angioedema. The diagnosis of HAE is crucial, because the treatment for an acute episode of C1-INH deficiency differs dramatically from that for other types of angioedema. Further, HAE has a significant mortality rate due to associated laryngeal edema. Acquired C1-INH deficiency is associated with systemic diseases such as autoimmune disorders, B-cell lymphomas (type I), and carcinomas. It can also be secondary to immunoglobulin (Ig) G anti–C1-INH autoantibodies (type II). Acute urticaria or angioedema results from activation and degranulation or degradation of mast cells and basophils due to IgE-mediated or non-IgE-mediated mechanisms (e.g., complement-mediated or direct mast cell– releasing agents). These cells release or generate several mediators that cause vasodilatation and increased vascular permeability. These include histamine, histamine-releasing 426

factors, prostaglandin D2, leukotrienes C4 and D4, plateletactivating factor, anaphylatoxins (C3a, C4a, C5a), bradykinin, kallikrein, cytokines such as interleukin (IL)-4 and IL-5, and interferon γ. The clinical features of mast cell degradation are similar, regardless of the classification and underlying cause (Table 102-1).

Recognition Perioperative urticaria or angioedema warrants immediate recognition and careful evaluation for laryngeal edema, which may be life threatening, particularly in pediatric patients with small airways. Intraoperative diagnosis of urticaria or angioedema may be difficult for several reasons. Surgical drapes, warming blankets, and surgical preparation solutions may obscure and limit patient exposure, thereby delaying recognition of

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Classification of Angioedema

Idiopathic Immune-mediated angioedema Immunoglobulin E mediated Physical urticaria Contact reactions

Complement Mediated C1 esterase inhibitor (C1-INH) deficiency Hereditary angioneurotic edema Acquired C1-INH deficiency Serum sickness Urticarial vasculitis Systemic lupus erythematosus Transfusion reactions

Non–Immune Mediated Direct mast cell or histamine release Angiotensin-converting enzyme inhibitor related

Other Rare Syndromes Systemic mastocytosis C3b inactivator deficiency Infection Helminthic Fungal Viral Systemic diseases Hyperthyroidism Collagen vascular diseases Malignancies

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any cutaneous manifestations. Further, bronchospasm secondary to histamine release may be incorrectly attributed to airway manipulation or asthma. Also, hypotension consequent to vasodilatation from more generalized reactions may wrongly be assumed to be secondary to myocardial depression, anesthetic effects, or blood loss. Finally, multiple drugs capable of immunologic or nonimmunologic mast cell activation and degranulation may be administered over a brief period; these include antibiotics, induction and neuromuscular blocking agents, and opioids. Therefore, even when a reaction is recognized, it is often difficult to identify the cause or to determine whether a true “allergic” reaction has occurred. Once urticaria or angioedema is recognized, it is crucial to document the temporal relation between the administration of drugs and the onset of the reaction. The reaction may be significantly delayed from the presumed time of contact with the causal agent.

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the magnitude of reaction is related to both the dose and the rate of administration).

Implications Acute intraoperative urticaria or angioedema can progress to laryngeal edema or anaphylaxis with respiratory failure or hemodynamic collapse. In an immune-mediated reaction, repeated exposure may increase the risk of a reaction. In a patient with a past history of intraoperative urticaria or angioedema reactions, the options for anesthetic drugs are limited, depending on the mechanism and cause of such reactions. Preoperative prophylaxis with anabolic steroids (danazol, stanozolol) or glucocorticoids may be useful in certain patients with a history of perioperative angioedema.

MANAGEMENT AND PREVENTION Risk Assessment

It is essential to avoid known causative agents and those with the potential for cross-reactivity. Although prophylactic use of antihistamines or corticosteroids is common, and although leukotriene antagonists have been used with some success, their efficacy in preventing and modulating perioperative allergic or nonimmunologic reactions is unknown. With suspected acute urticaria or angioedema, the causative agent should be removed when possible. Because laryngeal edema may develop rapidly, the adequacy of ventilation must be assessed immediately. If indicated, the airway should be secured by tracheal intubation. Difficult intubation should be anticipated, and the airway must be evaluated for residual edema before extubation. Urticaria or angioedema may be associated with significant intravascular volume depletion. Consequently, fluid resuscitation is mandatory. Epinephrine is used if cardiovascular collapse, anaphylaxis, or severe respiratory compromise occurs. Other β-agonists (e.g., terbutaline, albuterol) may replace epinephrine for the treatment of isolated bronchospasm. Antihistamines may be used alone or in conjunction with epinephrine when clinical features do not warrant the sole use of epinephrine. Although H2-blockers alone have minimal effects, they may be effective when used in combination with H1-blockers. Corticosteroids are used for the management of acute, recurrent, or persistent angioedema or urticaria. However, long-term use of these drugs is associated with frequent complications. In HAE, the goal is to increase C1-INH activity to at least 50% of its normal level. This can be achieved by transfusion of fresh frozen plasma, which contains C1-INH, antifibrinolytics, attenuated androgens, and C1-INH concentrate. ε-Aminocaproic acid and tranexamic acid have been used for perioperative prophylaxis. Anabolic steroids (danazol, stanozolol) can induce hepatic synthesis of C1INH and provide effective preoperative prophylaxis for HAE. For short-term prophylaxis, these agents are administered for several days before and after the scheduled surgery (e.g., danazol 10 mg/kg per day, to a maximum of 600 mg/day; stanozolol 6 mg/day). C1-INH concentrate has been used as preoperative prophylaxis in a dose of 500 or 1000 units;

PHYSIOLOGIC IMBALANCE & COEXISTING DISEASE

Approximately 15% to 20% of the population will experience an episode of angioedema or urticaria during their lifetime, and it is more prevalent in middle-aged women. However, it is extremely difficult to identify patients at risk for angioedema or urticaria because of the multitude of potential initiators. Patients with a history of past reactions, HAE, collagen vascular diseases, B-cell lymphoma or other malignancies, occult infections, or thyroid disorders may be at increased risk. The mainstays of the evaluation of acute or chronic urticaria and angioedema are a thorough history, physical examination, and identification of all medication administered. The appropriate initial laboratory evaluation of chronic urticaria is controversial. In general, it may include a complete blood cell count with (manual) differential cell count, erythrocyte sedimentation rate, and thyroid gland studies (thyroid-stimulating hormone, antithyroglobulin, and antithyroid peroxisomal antibody titers). In atypical cases, or if urticarial vasculitis is suspected, complement studies, hepatocellular enzyme tests, and skin biopsies are advised. Further testing depends on the individual circumstances. It may include blood chemistries, serologic studies, skin testing for IgE-mediated reactions, and radioallergosorbent testing (RAST) for specific IgE antibodies. In the evaluation of patients with suspected intraoperative urticaria or angioedema reactions, meticulous documentation of the time course of events in relation to drug administration is of paramount importance. Unfortunately, even when a specific drug is suspected, proving a causal relationship is often difficult. Specific IgE antibodies may be demonstrated in immunologically mediated reactions (e.g., to thiopental, latex, succinylcholine, blood products, protamine, plasma expanders, antibiotics). A positive skin test or RAST indicates sensitization and a potential risk of generalized reaction with re-exposure to the agent. Although rechallenge with the drug may confirm the diagnosis, it is potentially dangerous and not usually recommended. Although a past history of anaphylaxis to a specific drug contraindicates its future use, a nonimmunologic reaction is more difficult to interpret and may not be a contraindication to such use (e.g., for drugs causing histamine release,

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however, C1-INH is expensive and is currently not available in the United States. It has been used mainly in Europe. Antihistamines, corticosteroids, and epinephrine are usually ineffective in treating acute episodes of HAE, but they are often administered when the specific mechanism of the reaction is unclear.

Further Reading Abraham D, Grammer L: Idiopathic anaphylaxis. Immunol Allergy Clin North Am 21:783-794, 2001. Agostoni A, Aygoren-Pursun E, Binkley KE, et al: Hereditary and acquired angioedema: Problems and progress. Proceeding of the third C1 esterase inhibitor deficiency workshop and beyond. J Allergy Clin Immunol 114(Suppl):S51-S131, 2004.

Dibbern DA Jr, Dreskin SC: Urticaria and angioedema: An overview. Immunol Allergy Clin North Am 24:141-162, 2004. Hepner DL, Castells MC: Anaphylaxis during the peioperative period. Anesth Analg 97:1381-1395, 2003. Ledford DK: Allergy, anaphylaxis, and general anesthesia. Immunol Allergy Clin North Am 21:795-812, 2001. Lieberman P: Anaphylactic reactions during surgical and medical procedures. J Allergy Clin Immunol 110(Suppl):S64-S69, 2002. Mertes PM, Laxenaire MC, Alla F: Anaphylactic and anaphylactoid reactions occurring during anesthesia in France in 1999-2000. Anesthesiology 99:536-545, 2003. Muller BA: Urticaria and angioedema: A practical approach. Am Fam Physician 69:1123-1128, 2004.

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103

Disorders of Water Homeostasis: Hyponatremia and Hypernatremia Brenda G. Fahy, J. Thomas Murphy, and John L. Atlee

HYPONATREMIA Case Synopsis A 55-year-old man with small cell lung carcinoma presents for preanesthetic evaluation for right upper lobectomy. His past medical history includes emphysema, hypertension, and insulin-dependent diabetes mellitus. On physical examination, his blood pressure is 140/80 mm Hg, and his pulse is 86 beats per minute, with good skin turgor. His laboratory values are as follows: serum sodium, 126 mEq/L; serum osmolality, 390 mOsm/kg; serum uric acid, 3.7 mg/dL; urine sodium, 30 mEq/L; and normal glucose, blood urea nitrogen (BUN), and thyroid and adrenal function tests. The patient denies nausea, lethargy, or weakness.

Definition Serum sodium concentration and osmolality are closely regulated by water homeostasis. This is mediated by thirst, arginine vasopressin, and the kidneys. A disruption in water homeostasis is manifested by an abnormal serum sodium concentration—either hyponatremia or hypernatremia. The former is defined as a serum sodium concentration less than 135 mEq/L, with severe hyponatremia occurring at values less than 120 mEq/L. The patient described in the case synopsis had hypo-osmotic hyponatremia and was euvolemic with normal thyroid and adrenal function. Causes of true hyponatremia are listed in Table 103-1; causes of pseudohyponatremia are listed in Table 103-2. The case presented is due to the syndrome of inappropriate secretion of antidiuretic hormone (SIADH) related to small cell lung carcinoma (Table 103-3).

Recognition Symptoms of hyponatremia are related to the serum sodium concentration and how rapidly it decreases. The blood-brain barrier is virtually impermeable to sodium. Thus, rapid decreases in serum sodium cause water entry into the cells of the brain and other tissues. This can lead to cerebral edema, with progression to intracranial hypertension. Both the magnitude and the rapidity of water entry into brain cells explain the central nervous system (CNS)

symptoms associated with hyponatremia. These also correlate with symptom severity (Fig. 103-1). Early symptoms of hyponatremia-related CNS water entry are lethargy, weakness, and somnolence. Unabated, there may be progression to seizures, coma, and death. Therefore, hyponatremia must always be considered in the differential diagnosis of any mental status deterioration. The diagnosis of hyponatremia is based on laboratory testing, specifically, serum sodium concentration (Fig. 103-2). The next step is to measure plasma osmolality. This may help establish the diagnosis of pseudohyponatremia (see Table 103-2). Pseudohyponatremia occurs when the extracellular fluid compartment contains an impermeable solute (e.g., lipids) or there has been translocation or extravasation of large volumes of non-salt-containing fluids (e.g., transurethral resection of prostate or bladder tumor, hysteroscopy). This causes a shift of water from the intracellular to extracellular fluid compartment, causing dilutional hyponatremia. With more laboratories using ion-selective electrodes to measure serum sodium concentrations, dilutional hyponatremia has become less of a problem. Normal values for plasma osmolality range from 274 to 290 mOsm/kg. Calculated plasma osmolality (Posm) is determined by the following formula: Posm = (2.0 × [Na+]) + Glucose (mg/dL)/18 + BUN (mg/dL)/2.8 Patients with disorders such as hyperproteinemia or hyperlipidemia, which cause increased osmolality and pseudohyponatremia, have an abnormal osmolality gap (measured Posm – calculated Posm >10 mOsm/L). These disorders highlight 429

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Causes of True Hypo-osmotic Hyponatremia

Table 103–3

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Causes of Syndrome of Inappropriate Secretion of Antidiuretic Hormone

Hypovolemia

Hypervolemia Renal causes (urinary sodium >20 mEq/L) Renal failure Other causes (urinary sodium <20 mEq/L) Congestive heart failure Hepatic cirrhosis Nephrotic syndrome Pregnancy

Euvolemia (Urinary Sodium >20 mEq/L) Glucocorticoid deficiency Hypothyroidism Syndrome of inappropriate antidiuretic hormone (SIADH) Reset osmostat—psychosis, malnutrition

the importance of measuring plasma osmolality in hyponatremic patents. Other important laboratory tests are urine osmolality and sodium and a complete chemistry panel, including uric acid concentrations. Other electrolyte abnormalities (e.g., hypokalemia, hypomagnesemia) are often associated with hyponatremia. Once pseudohyponatremia has been excluded, the next diagnostic step is to determine the volume status, because true hypo-osmotic hyponatremia may be hypovolemic, hypervolemic, or euvolemic (see Table 103-1). This is assessed by clinical signs and symptoms in conjunction with hemodynamic and laboratory data. The serum uric acid level may be helpful in determining the patient’s volume status. A low serum uric acid level (<4 mg/dL) likely indicates euvolemia, whereas an elevated uric acid level may be present with hypovolemia or hypervolemia.

Malignancy Lung (especially small cell carcinoma) Central nervous system Pancreas

Pulmonary Pneumonia Tuberculosis Fungal Abscess

Neurologic Infection Trauma Cerebrovascular accident

Drugs (Most Common) Amitriptyline Chlorpropamide Cyclophosphamide Desmopressin Morphine Nicotine Nonsteroidal anti-inflammatory drugs Oxytocin Selective serotonin reuptake inhibitors Vincristine

500

normal Brain water, g/100g dry weight

Renal losses (urinary sodium >20 mEq/L) Diuretic therapy Mineralocorticoid deficiency Cerebral salt wasting syndrome (e.g., subarachnoid hemorrhage) Renal disease Renal tubular acidosis (bicarbonaturia with renal tubular acidosis and metabolic alkalosis) Renal tubular defect (salt wasting nephropathy) Extrarenal losses (urinary sodium <20 mEq/L) Gastrointestinal diseases—vomiting, diarrhea, and gastric suctioning Skin—burns, sweating, cystic fibrosis Pancreatitis Trauma

died

asymptomatic

lethargic

450

400

350

300

Table 103–2

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Causes of Pseudohyponatremia

Normal Plasma Osmolarity Hyperlipidemia Hyperproteinemia Transurethral resection of prostate or bladder tumor; hysteroscopy

Increased Plasma Osmolarity Hyperglycemia Mannitol administration From Rose BD: Hypoosmolal states: Hyponatremia. In Jeffers JD, Navrozov M (eds): Clinical Physiology of Acid-Base and Electrolyte Disorders. New York, McGraw-Hill, 1994, pp 651-694.

Plasma Na 139 mEq/L

Plasma Na Plasma Na Plasma Na 139-119 mEq/L 140-122 mEq/L 139-99 mEq/L in 2h in 3.5 days in 16 days

Figure 103–1 ■ Brain water content in control and hyponatremic rabbits. When plasma sodium was acutely lowered to 119 mEq/L over 2 hours, brain water content increased to 17% above normal. This was associated with severe symptoms and death. In contrast, slowly lowering plasma sodium to the same level over 3.5 days resulted in a smaller increase in brain water (7%) and no symptoms. Finally, gradually reducing plasma sodium to extremely low levels (99 mEq/L) produced a small increase in brain water and only mild neurologic symptoms. (From Arieff AI, Llach F, Massry SG: Neurological manifestations and morbidity of hyponatremia: Correlation with brain water and electrolytes. Medicine 55:121-129, 1976.)

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Hyponatremia

Figure 103–2 ■ Major steps in the initial evaluation of hyponatremia and the syndrome of inappropriate antidiuretic hormone secretion (SIADH).

Exclude pseudohyponatremia History and physical examination Exclude thiazide diuretics

History of fluid loss Postural hypotension Prerenal azotemia

Hyponatremia resolves when thiazides stopped

Equivocal volume status by history and physical examinaion

Edematous conditions

Exclude advanced renal failure Congestive Cirrhosis heart with failure ascites

Urinary sodium

Matches sodium intake

<20 mEq/L

Hypovolemic hyponatremia

Nephrotic syndrome

Isovolemic hyponatremia

Hypervolemic hyponatremia

Pursue differential diagnosis of SIADH

Pharmacologic agents

Hyponatremia is a common clinical electrolyte disorder. Fifteen percent to 22% of hospitalized patients have serum sodium values less than 135 mEq/L, and 1% to 4% have values less than 130 mEq/L. Hyponatremia can occur preoperatively, intraoperatively, or postoperatively. It can be diagnosed during the preoperative assessment as being caused by SIADH (as was the case in the patient presented earlier) or as a known side effect of medical management (e.g., thiazide diuretics, carbamazepine). Hyponatremia often presents perioperatively as hypovolemic hyponatremia. Intraoperative hypervolemic hyponatremia occurs with transurethral resection of prostate (TURP), transurethral resection of bladder tumor (TURBT), or hysteroscopy with intravascular translocation of irrigating solutions (e.g., glycine, sorbitol). The manifestations of such absorption are due to combined hyponatremia and hypoosmolality. Severe hyponatremia can cause problems in the absence of hypo-osmolality, however. Most other causes of hyponatremia also result in hypo-osmolality, and the manifestations attributed to low serum sodium concentrations cannot be separated from those occurring as a consequence of concomitant hypo-osmolality. During procedures utilizing irrigating solutions, hyponatremia can develop quickly, presenting with CNS manifestations. Prompt recognition and therapy are key. One cause of postoperative hyponatremia is the increased effect of antidiuretic hormone (ADH). This occurs if the sodium in perioperative intravenous fluids is excreted while

Endocrine disorders

Neurologic disorders

Tumorassociated

some of the infused water is retained. If extreme, postoperative hyponatremia may cause death. Hyponatremia is often accompanied by other electrolyte abnormalities (see also Chapters 14 to 16). For example, hypokalemia may be associated with hypovolemic hyponatremia due to gastrointestinal losses (vomiting, diarrhea), use of loop diuretics, or renal tubular acidosis. Metabolic alkalosis may accompany vomiting or diuretic use, and metabolic acidosis may accompany diarrhea or mineralocorticoid deficiency. With euvolemic hyponatremia, there may be associated hypokalemia due to SIADH and polydipsia (psychogenic water drinking). In contrast, hyperkalemia accompanies glucocorticoid deficiency. Azotemia is common with hypervolemic hyponatremia. Serum sodium serves as a marker for disease severity with hypervolemic hyponatremia.

Implications The risk for hyponatremia is related to the absolute level of serum sodium. However, more critical is how rapidly the serum sodium falls due to accompanying fluid shifts. Upon exclusion of pseudohyponatremia, it is necessary to determine the type of hyponatremia, because therapy differs. Whether correction of hyponatremia is required and how fast it should be accomplished depend on the severity of symptoms. With acute CNS symptoms, the risk of cerebral edema outweighs the risk of rapid correction; thus, correction is undertaken quickly, while realizing that too rapid correction may cause excess morbidity or even mortality.

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Risk Assessment

Pulmonary conditions

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MANAGEMENT Major steps in the initial evaluation of hyponatremia are outlined in Figure 103-2. Treatment involves two basic principles: identifying and treating the underlying cause, and increasing serum sodium safely when indicated. With serious CNS symptoms or serum sodium less than 110 mEq/L, rapid sodium replacement with hypertonic saline (3%) may be required to prevent death. Under these circumstances, the goal of hypertonic saline replacement should be to increase serum sodium 1 to 2 mEq/L per hour over a maximum of 3 hours. Careful monitoring is required throughout this process. Sodium replacement should not exceed 12 mEq/L over 24 hours, or 25 mEq/L over 48 hours. Despite the risks associated with acute, severe hyponatremia, too rapid correction may cause demyelinating lesions in the pons, which can develop over several days. This disorder, termed central pontine myelinolysis or the osmotic demyelination syndrome, can lead to quadriparesis, coma, and death. Diagnostic confirmation is by computed tomography or magnetic resonance imaging; however, changes may not be detectable for up to 4 weeks. Risk factors for central pontine myelinolysis include (1) sodium correction rate greater than 12 mEq/L in 24 hours or 25 mEq/L in 48 hours, (2) overcorrection of serum sodium greater than 140 mEq/L within 2 days, (3) hypoxic or anoxic episodes before therapy, (4) hypercatabolic states (e.g., burns) or malnutrition (e.g., chronic alcoholism), and (5) chronic rather than acute hyponatremia. Unfortunately, determining the duration of hyponatremia may be difficult. Chronic hyponatremia is less likely to be accompanied by CNS manifestations because it develops more slowly. If rapid correction of serum sodium is not required, a hypovolemic hyponatremic patient may receive isotonic saline with any required electrolyte supplementation to correct the fluid deficit and hyponatremia. If diuretics are the cause, these should be stopped, and appropriate fluids and electrolytes administered. Mineralocorticoids should be replaced if indicated. Euvolemic hyponatremia therapy requires free water restriction. Steroid or thyroid hormone replacement may be required. If SIADH is determined to be the cause, treatment includes strict fluid restriction, especially free water. Isotonic saline should not be used to treat SIADH hyponatremia

because it can result in urinary sodium excretion, exacerbate water retention, and worsen hyponatremia. Reversible causes of SIADH should be sought and treated (see Table 103-3). If SIADH is caused by medications that inhibit ADH (e.g., demeclocycline, phenytoin, loop diuretics, lithium), these may need to be discontinued. Hypervolemic hyponatremia is due to excessive secretion of ADH. This occurs when a disease process (e.g., cirrhosis, nephritic syndrome, congestive heart failure) results in increased total body fluids (i.e., hypervolemia), but there is an associated decrease in effective circulating intravascular volume and glomerular filtration rate. This triggers ADH secretion. Therapy focuses on the underlying disease process and fluid restriction, especially free water. The patient in the case synopsis had SIADH from small cell carcinoma of the lung, with euvolemic hypo-osmotic hyponatremia. His hyponatremia was likely chronic, based on absent CNS symptoms. Free water should be restricted, with serial serum sodium monitoring. Aggressive intraoperative hydration with isotonic saline could potentially worsen this patient’s hyponatremia.

PREVENTION Identifying high-risk patients and having a high index of suspicion for hyponatremia can help prevent hyponatremic complications. Because of the high frequency of hyponatremia in hospitalized patients, serum sodium should be monitored. Hyponatremia can occur throughout the perioperative period, and vigilance for its development during procedures that use irrigating solutions (TURP, TURBT, hysteroscopy) is required. Once hyponatremia is diagnosed, and pseudohyponatremia has been excluded, it is important to evaluate the patient’s volume status to seek treatable causes of hypo-osmotic hyponatremia. Careful monitoring of serum sodium can help prevent the development of hyponatremia during high-risk procedures, as well as in high-risk patients. If slower correction of serum sodium is indicated for hypo-osmotic hyponatremia, the volume status determines treatment. With euvolemia, free water is restricted; with hypervolemia, free water and salt are restricted; with hypovolemia, isotonic saline is administered.

HYPERNATREMIA Case Synopses Case 1 A 62-year-old woman with postoperative ileus had a nasogastric suctioning tube placed. Within 3 days, she had reduced skin turgor and mild orthostatic hypotension. Her serum sodium was 155 mEq/L, serum potassium was 3.8 mEq/L, and body weight was 62 kg. Case 2 A 7-year-old boy with severe colitis had a diverting colostomy placed. Subsequently, he received intravenous and nasogastric nutrition for several years. Over that period,

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he presented two times with confusion, hypernatremia, and weight gain. However, on both occasions, there was no fever, diarrhea, or vomiting. Plasma and urine samples collected on the second visit revealed plasma and urine sodium concentrations of 155 and 172 mEq/L, respectively.

PROBLEM ANALYSIS Definition

Recognition The signs and symptoms of hypernatremia mostly reflect CNS dysfunction. They are more prominent when the increase in serum sodium concentration is large or occurs rapidly (i.e., over a few hours). Most outpatients with hypernatremia are either very young or very old. Common presenting symptoms in the young include hyperpnea, agitation, irritability, insomnia, and a typical high-pitched cry. These can progress to muscle weakness, confusion, listlessness, lethargy, and coma. Neurologic examination often reveals increased tone, nuchal rigidity, and brisk reflexes. Myoclonus, asterixis, and chorea can be present. Tonic-clonic and absence seizures have been described. Hyperglycemia is an especially common consequence of hypernatremia in children. Severe hypernatremia also can result in rhabdomyolysis. Finally, although hypocalcemia was once believed to be associated with hypernatremia, this has not been a common finding in more recent reports. Unlike infants, elderly patients generally have few symptoms until the serum sodium concentration exceeds 160 mEq/L. Intense thirst may be present early, but it dissipates as the disorder progresses, and it is absent in those with hypodipsia. Convulsions in either age group are typically absent, except with inadvertent sodium loading or overly aggressive rehydration. The level of consciousness correlates with the severity of hypernatremia. Muscle weakness,

Risk Assessment Hypernatremia represents a deficit of water relative to whole body sodium stores. This can result from a net water loss or a gain in hypertonic sodium Table 103-4. Net water loss accounts for the majority of cases. Because sustained hypernatremia can occur only when the thirst sensation is impaired or access to water is limited, persons at highest risk are those with impaired mental status, those on mechanical ventilators, infants, and the elderly. Hypernatremia in infants usually results from gastroenteritis (vomiting and diarrhea); in the elderly it is usually associated with thirst impairment, febrile illness, or infirmity. Also, frail nursing home residents and hospitalized patients are prone to hypernatremia because they depend on others for their water requirements.

Implications Hypernatremia results in the efflux of fluid from the intracellular space to the extracellular space to maintain osmotic equilibrium. This leads to transient cerebral dehydration and brain shrinkage. Brain cell volume can decrease by as much as 10% to 15% acutely, but it adapts quickly. Within 1 hour, the brain significantly increases its intracellular content of sodium and potassium, amino acids, and unmeasured organic substances or idiogenic osmoles (i.e., rapid adaptation). Normalization of brain volume is completed by 1 week (slow adaptation), as the brain regains approximately 98% of its water content. When severe hypernatremia develops acutely, the brain may not be able to increase its intracellular solute sufficiently to preserve its volume. If so, resulting cellular shrinkage can lead to structural changes. Cerebral dehydration from hypernatremia can result in physical separation of the brain from the meninges, leading to rupture of delicate bridging veins and subarachnoid or intracerebral hemorrhage, with permanent neurologic damage or death. Venous sinus thrombosis progressing to cerebral infarction can also develop. Acute hypernatremia has also been shown to cause cerebral demyelinating lesions in both animal models and humans. Patients with hepatic encephalopathy appear to be at higher risk for developing such lesions.

PHYSIOLOGIC IMBALANCE & COEXISTING DISEASE

Hypernatremia is defined as a serum sodium concentration greater than 145 mEq/L. In both children and adults, hypernatremia is seen primarily in persons with restricted access to water for a variety of reasons (e.g., patients in hospitals, convalescence facilities, or homes for the elderly; those who are debilitated or mentally impaired). Hypernatremia can also be iatrogenic, resulting from inappropriate fluid therapy or excessive administration of sodium bicarbonate during cardiopulmonary resuscitation. The body has two defense mechanisms to protect against hypernatremia: the ability to produce concentrated urine, and a powerful thirst mechanism. Release of ADH occurs when plasma osmolality exceeds 275 to 280 mOsm/kg, and the urine becomes maximally concentrated when plasma osmolality exceeds 290 to 295 mOsm/kg. Thirst provides the ultimate protection against hypernatremia, however. If the thirst mechanism is intact and there is unrestricted access to free water, it is rare for an individual to develop sustained hypernatremia from either excess sodium ingestion or a renal concentrating effect.

confusion, and coma may be manifestations of coexisting disorders rather than of hypernatremia itself. Finally, unlike outpatient hypernatremia, that acquired in hospital settings affects patients of all ages. In addition, the clinical symptoms are even more elusive, because these patients often have preexisting neurologic dysfunction. As in children, rapid sodium loading can result in convulsions and coma. In patients of all ages, orthostatic hypotension and tachycardia reflect marked hypovolemia.

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Table 103–4

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Causes of Water Deficit Relative to Whole Body Sodium Stores

Net Free Water Deficit Pure Water Unreplaced insensible loss Hypodipsia Neurogenic diabetes insipidus Post-traumatic Due to brain tumor, cyst, histiocytosis, tuberculosis, sarcoidosis Idiopathic Due to aneurysm, meningitis, Guillain-Barre´ syndrome Due to ethanol ingestion (transient) Congenital or acquired nephrogenic diabetes insipidus Renal disease (e.g., medullary cystic disease) Hypercalemia or hypokalemia Drugs (lithium, demeclocycline, foscarnet, methoxyflurane, amphotericin B, vasopressin V2-receptor antagonists)

Hypertonic Fluids Renal causes Loop diuretics Osmotic diuresis (glucose, mannitol, urea) Postobstructive diuresis Polyuric phase of acute tubular necrosis Intrinsic renal disease Gastrointestinal causes Vomiting Nasogastric drainage Enterocutaneous fistula Diarrhea Osmotic cathartics (e.g., lactulose) Cutaneous causes Burns Excessive sweating

Hypertonic Sodium Gain Hypertonic sodium bicarbonate Hypertonic feeding preparations Ingestion of sodium chloride Ingestion of sea water Sodium chloride–rich emetics Hypertonic saline enemas Intrauterine injection of hypertonic saline Hypertonic sodium chloride infusion Hypertonic dialysis Primary hyperaldosteronism Cushing’s syndrome

The amount of fluid required depends on the fluid composition. For example, to correct a 3-L free water deficit, approximately 4 L of 0.2% saline or 6 L of 0.45% saline would be needed, because these solutions contain approximately 75% and 50% free water, respectively. The calculated deficit does not account for insensible or ongoing urinary or gastrointestinal losses. Maintenance fluids, which include replacement of urine volume with hypotonic fluids, are given in addition to the deficit. If there are signs of severe hypovolemia or circulatory collapse, fluid resuscitation with normal saline, lactated Ringer’s solution, or colloid should be instituted before correcting the free water deficit. The type of therapy depends largely on the cause of hypernatremia and should be tailored to the pathophysiologic events involved in each patient (Table 103-5). Oral hydration should be started as soon as it can be safely tolerated. Plasma electrolytes should be measured every 2 to 3 hours until the patient is neurologically stable. In patients with hypernatremia that has developed over hours (e.g., accidental sodium overloading), rapid correction improves the prognosis without increasing the risk of cerebral edema. This is because accumulated electrolytes are rapidly extruded from brain cells. In such patients, reducing the serum sodium concentration by 1 mEq/L per hour is appropriate. A slower pace of correction is advised for patients with hypernatremia of longer or unknown duration, because full dissipation of brain solutes occurs over a period of days. In such patients, reducing the serum sodium concentration at a maximal rate of 0.5 mEq/L per hour prevents cerebral edema and convulsions. Consequently, some authorities (e.g., Adrogué and Madias) advise a target reduction in serum sodium concentration of 10 mEq/L per day for all patients with hypernatremia, except those in whom the disorder has developed over a period of hours. The goal of treatment is to reduce serum sodium concentration to 145 mEq/L. The preferred route for administering fluids is orally or via a feeding tube. If neither is feasible, fluids are given intravenously. The more hypotonic the fluid is (see Table 103-5), the lower the infusion rate should be. This reduces the risk for cerebral edema formation. Finally, except in cases of

From Adrogue´ HJ, Madias NE: Hypernatremia. N Engl J Med 342:1493-1499, 2000.

MANAGEMENT AND PREVENTION

Table 103–5

Treatment for hypernatremia must correct the underlying cause, normalize the serum sodium concentration, and restore the normal circulatory volume. The therapeutic cornerstone is the provision of adequate free water to correct the serum sodium concentration. The free water deficit cannot be easily assessed by physical examination in patients with hypernatremic dehydration, because most of the free water losses are intracellular. Accordingly, the signs of volume depletion are less apparent owing to better preservation of extracellular volume. A simple method for estimating the minimum amount of fluid necessary to correct the serum sodium concentration is the following equation:

Cause

Treatment

Sodium and water loss* Gastroenteritis Primary water loss* Ineffective breast feeding Hypodipsia Nephrogenic diabetes insipidus*

0.45% NaCl in 5% dextrose and water 0.2% NaCl in 5% dextrose and water

Free water deficit (mL) = 4 mL × Lean body weight (kg) × [Desired Δserum Na+ (mEq/L)]

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Management of Hypernatremia

Central diabetes insipidus* Sodium overload*

0.1% NaCl in 2.5% dextrose and water† Desmopressin acetate 5% dextrose and water‡

*See also Table 103-4. † Acute management. ‡ Diuretics may be needed. Adapted from Moritz ML, Ayus JC: Disorders of water metabolism in children. Pediatr Rev 23:371-380, 2002; and Adrogué HJ, Madias NE: Hypernatremia. N Engl J Med 342:1493-1499, 2000.

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frank circulatory compromise, 0.9% normal saline or lactated Ringer’s solution is unsuitable therapy for hypernatremia.

Further Reading Adrogué HJ, Madias NE: Hypernatremia. N Engl J Med 342:1493-1499, 2000. Adrogué HJ, Madias NE: Hyponatremia. N Engl J Med 342:1581-1589, 2000. Arieff AI, Llach F, Massry SG: Neurological manifestations and morbidity of hyponatremia: Correlation with brain water and electrolytes. Medicine 55:121-129, 1976. Berl T: Treating hyponatremia: Damned if we do and damned if we don’t. Kidney Int 37:1006-1018, 1990. Brunner JE, Redmond JM, Haggar AM, et al: Central pontine myelinolysis and pontine lesions after rapid correction of hyponatremia: A prospective magnetic resonance imaging study. Ann Neurol 27:61-66, 1990. Coulthard MG, Haycock GB: Distinguishing between salt poisoning and hypernatraemic dehydration in children. BMJ 326:157-160, 2003. Estes CM, Maye JP: Severe intraoperative hyponatremia in a patient scheduled for elective hysteroscopy: A case report. AANA J 71:203-205, 2003. Issa MM, Young MR, Bullock AR, et al: Dilutional hyponatremia of TURP syndrome: A historical event in the 21st century. Urology 64:298-301, 2004.

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Janicic N: Evaluation and management of hypo-osmolality in hospitalized patients. Endocrinol Metab Clin North Am 32:459-481, 2003. Moritz ML, Ayus JC: Disorders of water metabolism in children. Pediatr Rev 23:371-380, 2002. Nguyen MK, Kurtz I: New insights into the pathophysiology of the dysnatremias: A quantitative analysis. Am J Physiol Renal Physiol 287: F172-F180, 2004. Norenberg MD, Papendick RE: Chronicity of hyponatremia as a factor in experimental myelinolysis. Ann Neurol 15:544-547, 1984. Ofran Y, Lavi D, Opher T, et al: Fatal voluntary salt intake resulting in the highest ever documented sodium plasma level in adults (255 mmol L-1): A disorder linked to female gender and psychiatric disorders. J Intern Med 256:525-528, 2004. Oster JR, Singer I: Hyponatremia, hypoosmolalilty and hypotonicity: Tables and fables. Arch Intern Med 159:333-336, 1999. Rose BD: Hypoosmolal states: Hyponatremia. In Jeffers JD, Navrozov M (eds): Clinical Physiology of Acid-Base and Electrolyte Disorders. New York, McGraw-Hill, 1994, pp 651-694. Steele A, Gowrishankar M, Abrahamson S, et al: Postoperative hyponatremia despite near-isotonic saline infusion: A phenomenon of desalination. Ann Intern Med 126:20-25, 1997. Weisberg LS: Pseudohyponatremia: A reappraisal. Am J Med 86:315-318, 1989.

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Mark Nunnally and Patrick Neligan Case Synopsis A 56-year-old man is chronically critically ill. Serum chemistries and blood gas analysis are performed. The data are as follows: sodium (Na+) 130 mEq/L, potassium (K+) 4 mEq/L, chloride (Cl–) 100 mEq/L, total carbon dioxide (CO2) 24 mEq/L, urea 10 mg/dL, creatinine 1.0 mg/dL, albumin 1.0 g/dL, lactate 6.0 mEq/dL, pH 7.42, CO2 tension (PCO2) 40 mm Hg, bicarbonate (HCO3) 24 mEq/L, and base excess (BE)+1 mEq/L.

PROBLEM ANALYSIS Definition Acid-base analysis is a method of identifying abnormalities of ventilation or electrolyte balance that relies on the chemical properties of water. Water is a highly ionizing solvent and exists in high concentration (55 M), but there is little dissociation into its components: hydrogen and hydroxyl ions. The potential for such dissociation is determined by electrical charge and temperature. Electrical neutrality is always constant. Clinical quantification of water dissociation relies on measurement of the hydrogen ion concentration in arterial blood, which averages 0.00004 mEq/L. For convenience, this is expressed in negative logarithmic form as pH. The physiologic pH of serum is meticulously maintained by the body and is 7.4 at 37°C. If serum pH is less than 7.35, a state of acidemia exists. If it is greater than 7.45, a state of alkalemia exists. The extracellular fluid is a cellular and ionic mix of chemicals and organic proteins whose charges influence the dissociation of water. An acid substance may increase the hydrogen ion concentration of extracellular fluid (lower the pH), whereas a base substance may decrease the hydrogen ion concentration of extracellular fluid (raise the pH). Acids either dissociate in solution to yield an anion or associate with a hydroxyl ion to form water. Bases either dissociate to form a cation plus a hydroxyl ion or associate with a hydrogen ion to form water. Thus, anions are acids, and cations bases. This process is governed by three principles: 1. Electrical neutrality: The number of positive charges must equal the number of negative charges. 2. Mass conservation: The quantity of a substance remains constant unless added, generated, or destroyed. 3. Dissociation equilibria: The dissociation equilibria for all partially dissociated substances must be satisfied. In all cases, the water dissociation equilibrium readjusts to the ionic milieu. Although a variety of complicated approaches have been used to explain acid-base chemistry, the approach proposed by Stewart is most applicable to perioperative medicine. 436

Using a complex mathematical model, Stewart determined that only three independent variables govern water dissociation and thus acid-base balance (Table 104-1): 1. Arterial partial pressure of carbon dioxide (PaCO2): CO2 hydrates to form carbonic acid, which is transported in blood bound to hemoglobin and as bicarbonate. 2. Strong ion difference (SID): Strong ions are fully dissociated in solution. One example is lactate, whose pKa is 3.4. The SID is the electrical difference between the positively charged strong cations (sodium, potassium, magnesium, calcium) and the negatively charged strong anions (chloride, lactate, ketones, sulfate, formate). The SID is always positive and is determined mainly by the relative concentrations of sodium and chloride. Removal of strong cations or anions, or a change in their volume of distribution (e.g., the extracellular fluid volume of free water), alters the SID. Normally, the SID is 44 mEq/L. If it increases, the net effect is alkalinizing; if it decreases, the net effect is acidifying. 3. Total concentration of partially dissociated weak anions (ATOT): The major weak acids are albumin and phosphate. Both quantity and dissociation equilibria determine the effect of ATOT on water dissociation. There are two reasons why acid-base disorders are important. First, tissue dysfunction occurs at extremes of acidosis and alkalosis. Second, and perhaps more important, acidosis and alkalosis may be indicators of serious underlying pathology, such as tissue hypoperfusion, dehydration, and renal failure. As such, acid-base abnormalities are critical manifestations of underlying pathologies.

Recognition Four primary disturbances of acid-base balance exist: respiratory acidosis, respiratory alkalosis, metabolic acidosis, and metabolic alkalosis. Mixed respiratory acidosis and metabolic acidosis is common in severely injured or infected patients, while mixed respiratory acidosis and metabolic alkalosis is seen in chronic respiratory failure. Respiratory acid-base disorders arise from the partial pressure of CO2 in the blood and are related to ventilation. Respiratory acidosis results from hypoventilation due to loss

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Classification of Primary Acid-Base Abnormalities Acidosis

Alkalosis

At-a-Glance Pearls

Respiratory Metabolic Abnormal SID

Increased PCO2

Decreased PCO2

↓pH 0.08 for each 10 mm Hg in PCO2

Due to water

Water excess, dilutional ↓ SID, ↓ [Na+]

Water deficit, contraction ↑ SID,↑ [Na+]

Dilutional acidosis is usually present when NaCl <136 mEq/L, contraction alkalosis when >148 mEq/L

Chloride excess – ↓ SID, ↑ [Cl ]

Chloride deficit – ↑ SID, ↓ [Cl ]

Hyperchloremic acidosis is usually present if – corrected serum Cl >112 mEq/L, hypochloremic alkalosis if <100 mEq/L – – [Cl CORRECTED] = [Cl MEASURED] × ([Na+ NORMAL] / [Na+ MEASURED]) – Most, but not all, [A ] behave as strong anions; – in renal failure, [A ] consist of formate and sulfate (hyperphosphatemia is also a common acidosis) Hypoalbuminemic alkalosis is usually present when the serum albumin is >35 g/dL Hyperphosphatemic acidosis is usually present when the serum phosphate is >2.0 mmol/L

Due to electrolytes Chloride

Unmeasured anions [A–], e.g., lactate, keto acids

↓ SID, ↑ [A–]

Abnormal ATOT Albumin [Alb]

↑ [Alb] (rare)

↓ [Alb]

Phosphate [Pi]

↑ [Pi]

↓ [Pi]

ATOT, total concentration of partially dissociated weak anions; SID, strong ion difference. From Fencl V, Jabor A, Kazda A, et al: Diagnosis of metabolic acid-base disturbances in critically ill patients. Am J Respir Crit Care Med 162:2246-2251, 2000.

1. Lactic acidosis: This is caused by increased glycolysis and lactate production. It may be due to hypoxemia, hypoperfusion, congenital errors of metabolism, or exposure to biguanide or toxins. 2. Ketoacidosis: Ketones include acetate, acetoacetate, and β-hydroxybutyrate. All act as strong anions. Ketoacidosis results from starvation or insulin deficiency. Diabetic ketoacidosis is characterized by ketosis and hyperglycemia. 3. Acute renal failure: Renal acidosis is caused by the accumulation of ions excreted exclusively by the kidney— sulfate, formate, and the weak acid phosphate. A variety of other processes can also cause metabolic acidosis. Low serum sodium (<135 mEq/L) should alert the clinician to the possibility of a dilutional acidosis.

Alcohol toxicity is suspected with an osmolar gap. A difference between measured and calculated serum osmolality greater than 12 mOsm indicates the presence of unmeasured osmoles. Following infusion of large volumes of 0.9% saline, 5% albumin, or 6% hetastarch, hyperchloremic acidosis is common. All of these contain 154 mEq of both Na+ and Cl– (SID = 0) and thus reduce serum SID. Metabolic alkalosis can be caused by chloride loss, an increase in sodium relative to chloride, or loss of weak acid. Renal chloride loss is a compensatory response to chronic respiratory acidosis. Chloride may also be lost via the gastrointestinal tract with vomiting or nasogastric suctioning. The sodium concentration increases due to a loss of free water (contraction alkalosis) or after administration of sodium with a weak anion (e.g., bicarbonate, citrate, acetate). Finally, albumin is the most contributory weak acid, and hypoalbuminemia is a common cause of metabolic alkalosis in critically ill or malnourished patients.

Risk Assessment Historically, the gradual introduction of serum assays directly influenced the evaluation of acid-base abnormalities. Early assays for pH resulted in quantification of serum or blood by titration to a pH of 7.4. The base deficit-excess (BDE) is the amount (in mEq/L) of strong cation or anion required to return pH to 7.4, with PaCO2 adjusted to 40 mm Hg. Current algorithms for computing BDE are derived from the Van Slyke equation. Modern analyzers sample PCO2, electrolytes, and lactate and make more comprehensive analysis possible. However, BDE is still a useful tool for quantitative comparison. Figure 104-1 demonstrates a stepwise approach to acid-base disorders that includes BDE.

PHYSIOLOGIC IMBALANCE & COEXISTING DISEASE

of respiratory drive, neuromuscular or chest wall disorders, rapid or shallow breathing, ventilation-perfusion mismatching, or an increase in the fraction of dead space ventilation. Respiratory alkalosis arises from increased alveolar minute ventilation (e.g., with pain, anxiety, sepsis, or hepatic insufficiency). Acute respiratory alkalosis usually accompanies acute metabolic acidosis. Metabolic acidosis is caused by a decrease in SID or an increase in ATOT. A change in SID can be caused by anion gain (as occurs with lactic, renal, keto-, and hyperchloremic acidosis) or cation loss (severe diarrhea, renal tubular acidosis). Acidosis can also be caused by strong ion dilution in a larger extracellular volume (dilutional acidosis), excessive hypotonic fluid intake, certain poisons (methanol, ethylene glycol, isopropyl alcohol), hyperglycemia, mannitol administration, or reduced ability to excrete free water. In acute metabolic acidosis, three possible diagnoses should be investigated immediately:

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<7.35 = Acidosis

7.35–7.5 = Normal or compensated

>7.5 = Alkalosis

Pure respiratory acidosis? Rule of thumb: pH ↓ 0.08 for every 10 mm Hg ↑ in PCO2

Compensated chronic respiratory acidosis or respiratory compensation for metabolic alkalosis

Metabolic alkalosis with inadequate compensation

Metabolic acidosis without compensation (suspect respiratory failure)

Normal physiologic value, may be balanced metabolic acidosis and alkalosis

Metabolic alkalosis with inadequate compensation

Metabolic acidosis with inadequate compensation (suspect respiratory failure)

Compensated metabolic acidosis

Pure respiratory alkalosis? Rule of thumb: pH ↑ 0.08 for every 10 mm Hg ↓ in PCO2

BD < −5 = metabolic acidosis

BDE +5 to −5 = normal range

BE >5 = alkalosis

Acidosis, PCO2 < 35 mm Hg, ± BD < −5 = metabolic acidosis

Normal range pH, PCO2 > 45, BE > +5 = prolonged respiratory acidosis

Alkalosis, PCO2 >45, BE > +5 = metabolic alkalosis

OR

OR

OR

Acidosis, PCO2 > 45 mm Hg, BDE normal range = respiratory acidosis, possibly acute

Normal-range pH PCO2 < 35 mm Hg, BD < −5 = metabolic acidosis + compensation

Alkalosis, PCO2 < 35 mm Hg, BDE normal range = respiratory alkalosis

Figure 104–1 ■ Stepwise approach to blood gas analysis. Analysis of measured variables and base deficitexcess (BDE). If the acid-base picture does not conform to any of these, a mixed picture is present, and the Stewart-Fencl-Gilfix method should be used to tease out coexisting acidifying and alkalinizing processes. BD, base deficit; BE, base excess.

Step 2. Evaluate respiratory component (volatile acid = CO2)

PCO2 > 45 mm Hg = respiratory acidosis PCO2 = 35–45 mm Hg = normal range PCO2 < 35 mm Hg = respiratory alkalosis

Step 3. Analyze the metabolic component (e.g., buffer base utilization) Step 4. Synthesize

Implications The anion gap theory was developed by Emmett and Narins in 1977 as a method to evaluate simple metabolic acidosis. The system is based on the contribution of weak acids (i.e., phosphate and albumin) and unmeasured anions to electrical neutrality. The sum of the difference in charge of common extracellular ions reveals an unaccounted for “gap” of 10 to 12 mEq/L—the anion gap: Na+ + K+ – (Cl– + HCO3–). If a patient develops a metabolic acidosis and the gap widens to, for example, 16 mEq/L, the acidosis is caused by unmeasured anions, such as lactate or ketones. If the gap does not widen, then the anions are measured and the acidosis is hyperchloremic. Figure 104-2 depicts an approach to the diagnosis of metabolic acidosis using the anion gap. Although this is a useful tool, it is weakened by the assumption of what is or is not a “normal” gap and should be corrected in critically ill patients for hypoalbuminemia using the following formula: Anion gap = Calculated anion gap + 2.5 × (4.5 g/dL – Observed albumin [g/dL]).

The most comprehensive approach to acid-base physiology is Stewart’s quantitative approach. This technique permits quantitative comparison of the relative contributions of the different components of acid-base balance. It is the most complete assessment of the variables influencing acid-base chemistry, but it is too cumbersome for rapid application. A simpler, more workable approach is to use a modification of this approach, the BDE gap. This allows recalculation of BDE using strong ions, free water, and albumin. The resulting BDE gap should mirror the SID and reveal the true anion gap: BDE = Standard base deficit-excess Modern blood gas analyzers calculate the BDE by the following equation: –

BDE = 0.9287 × [HCO3 – 24.4 + 14.83 × (pH – 7.4)] BEfw = Changes in free water = 0.3 × (Na – 140) BECl = Changes in chloride = 102 – ([Cl] × 140 [Na])

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Figure 104–2 ■ Evaluation of metabolic acidosis using the anion gap. BUN, blood urea nitrogen.

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Is the acidosis caused by measured (chloride) or unmeasured anions? Review the blood chemistry. Calculate the anion gap: Na+ + K+– (Cl− + HCO3−)

If the gap is normal, there is too much chloride due to excessive administration, excess loss of sodium (diarrhea, ileostomy), or renal tubular acidosis.

If the gap is wide (>12), there are other unmeasured anions present, causing the acidosis.

Is the gap acid lactate? Check a serum lactate: if >2, probably lactic acidosis.

Yes

For previously healthy patients, [lactate] = [base deficit].

No Is there renal failure? Evaluate the creatinine and urine output.

Yes

If the patient is in renal failure, renal acids are invariably present.

No Is there ketoacidosis? Send blood and urine for ketone levels.

Yes

If all of these tests are negative, less common causes must be sought. Send toxicology labs (particularly salicylates) and serum osmolality, and calculate osmolality using the following formula: 2(Na+ + K+) + Glucose/18 + BUN/2.8. Measured osmolality/calculated osmolality?

BEalb = Changes in albumin = 3.4 × (4.5 – Albumin [g/dL]) CBE = Calculated BDE = BEfw + BECl + BEalb BEG = Base excess caused by unmeasured anions = BDE – CBE This useful approach separates multiple simultaneous acid-base disturbances, such as those that occur in critically ill patients. A further simplification of this approach has been proposed and validated by Story and colleagues: Sodium-chloride effect (mEq/L) = [Na+] – [Cl—] – 38 Albumin effect (mEq/L) = 0.25 × (42 – [Albumin (g/L)]) Thus, the sodium-chloride effect on the BDE plus the albumin effect minus the calculated BDE equals the BDE gap.

MANAGEMENT Therapy is directed at the cause of the acid-base abnormality. Respiratory alkalosis is corrected by reducing iatrogenic

Yes

Consider alcohol ingestion.

hyperventilation or removing the causes of an increased respiratory drive (e.g., hypoxemia, pain, anxiety). Respiratory acidosis may require reversal of hypnotics or opioids or an increase in minute ventilation, but in isolation it is probably a minor abnormality. Hypercapnia is often well tolerated (e.g., patients with acute respiratory distress syndrome and multiorgan system dysfunction). Lactic acidosis due to circulatory failure is treated with resuscitation and hemodynamic optimization. Electrolyte abnormalities are corrected by replacement of specific deficiencies, correction of free water disturbances, and hemodialysis, if necessary. Toxic ingestions may require specific therapies (e.g., ethanol infusion in methanol poisoning, methemoglobin induction in cyanide toxicity), purging, adsorption, or hemodialysis. Ketoacidosis compels a search for a cause (starvation, diabetes, excessive alcohol consumption) and appropriate therapy. Figure 104-2 outlines an approach to the management of metabolic acidosis. Metabolic alkalosis (Fig. 104-3) is generally well tolerated but may be treated with chloride replacement if it is the result of hypochloremia. This is accomplished by the administration of 0.9% saline solution.

PHYSIOLOGIC IMBALANCE & COEXISTING DISEASE

No

If the patient is hyperglycemic and ketotic, this is diabetic ketoacidosis. If the patient is ketotic and normoglycemic, this is either alcoholic or starvation ketosis.

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Is this due to hypernatremia/free water deficit?

Yes

No

Is this due to excessive chloride loss?

Yes

Hypernatremia. Correct free water deficit

The component of the base excess contributed by hypernatremia can be calculated as 0.3 × (Na − 140)

Chloride replacement. Evaluate urine chloride if renal loss (mineralocorticoid effect, Bartter’s syndrome) suspected

The component of the base excess due to hyperchloremia is calculated as 102 – ([Cl] ×140/[Na])

No

Yes

Is this due to excessive sodium solution administration (sodium acetate, bicarbonate, citrate, massive transfusion)? No Yes Is this due to hypoalbuminemia?

Figure 104–3 ■ Evaluation of metabolic alkalosis.

Check the serum albumin; the component of the base excess due to hypoalbuminemia is calculated as 3.4 × (4.5 −[albumin]). Albumin is in g/dL.

Chloride replacement

Nutrition

No Is this due to hypophosphatemia?

Check the serum phosphate.

Hypoalbuminemia is a marker of severe illness and resolves with treatment of the underlying cause.

PREVENTION Significant perioperative acid-base derangements are better avoided rather than managed after the fact. Adequate prevention requires vigilance for common sources of acid-base abnormalities. Serum lactate is used to follow the quality of resuscitation for patients in shock, particularly hemorrhagic shock. The magnitude of the base deficit and speed of resolution have prognostic implications. Type 1 diabetics should be treated with insulin perioperatively, and patients with acute or chronic renal failure may have to undergo dialysis. Care should be taken to avoid hyperventilation, especially in the setting of chronic respiratory acidosis. Hyperventilation reduces the central respiratory drive, making it more difficult to subsequently wean the patient from the ventilator. Appropriate fluid selection avoids SID disturbances due to

Table 104–2

■

Phosphate replacement

dilution or excess chloride administration. Hypotonic and dextrose-containing fluids are best avoided. Fluid choice makes little difference in patients having small-volume resuscitation. If larger-volume resuscitation is expected, then solutions that more closely match the electrolyte content of extracellular fluid (lactated Ringer’s, Normosol, Plasma-Lyte) are advised. Many commercially available colloids also contain high concentrations of chloride. Human albumin solution, some hetastarches, and gelatins are formulated in sodium chloride; large volumes of these can cause hyperchloremic acidosis. In the setting of chloride loss from nasogastric suctioning, normal saline can be administered until the base excess returns to zero. Normal saline is also therapeutic with excess sodium citrate administration (e.g., large-volume blood or fresh frozen plasma transfusions). Proactive management strategies minimize the risk of patients developing multiple complex acid-base disturbances in the postoperative setting. Using the approach advocated by Fencl and colleagues and Gilfix and associates, correcting the BDE for acidifying and alkalinizing processes for the patient presented in the

Correction of Base Deficit-Excess

Acidifying Process

Magnitude

BDC

Alkalinizing Process

Magnitude

BEC

Hyponatremia Hyperchloremia Lactate Total

130 mEq/L 100 mEq/L 6 mEq/L

–3 –3 –6 –12

Hypoalbuminemia

1.0 g/dL

+11.9

BDC, base deficit corrected; BEC, base excess corrected. BDC − BEC = 0.9

Total

+11.9

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case synopsis is complex (Table 104-2). In this example, the patient has three significant acidifying processes. The presence of lactic acidosis is ominous. However, by using traditional approaches to acid-base analysis (bicarbonate or BDE), the presence of this abnormality would not be apparent.

Further Reading Alfaro V, Torras R, Ibanez J, et al: A physical-chemical analysis of the acidbase response to chronic obstructive pulmonary disease. Can J Physiol Pharmacol 11:1229-1235, 1996. Balasubramanyan N, Havens PL, Hoffman GM: Unmeasured anions identified by the Fencl-Stewart method predict mortality better than base excess, anion gap, and lactate in patients in the pediatric intensive care unit. Crit Care Med 27:1577-1581, 1999. Emmett M, Narins RG: Clinical use of the anion gap. Medicine 56:38-54, 1977. Fencl V, Jabor A, Kazda A, et al: Diagnosis of metabolic acid-base disturbances in critically ill patients. Am J Respir Crit Care Med 162: 2246-2251, 2000. Figge J, Jabor A, Kazda A, et al: Anion gap and hypoalbuminemia. Crit Care Med 26:1807-1810, 1998. Figge J, Rossing TH, Fencl V: The role of serum proteins in acid-base equilibria. J Lab Clin Med 117: 453-467, 1991.

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Gilfix BM, Bique M, Magder S: A physical chemical approach to the analysis of acid-base balance in the clinical setting. J Crit Care 8:187-197, 1993. Hickling KG: Permissive hypercapnia. Respir Care Clin N Am 8:155-169, 2002. Morgan TJ, Clark C, Endre ZH: Accuracy of base excess—an in vitro evaluation of the Van Slyke equation. Crit Care Med 28:2932-2936, 2003. Morgan TJ, Venkatesh B, Hall J: Crystalloid strong ion difference determines metabolic acid-base change during in vitro hemodilution. Crit Care Med 30:157-160, 2002. Rutherford EJ, Morris JA Jr, Reed GW, et al: Base deficit stratifies mortality and determines therapy. J Trauma 33:417-423, 1992. Salem MM, Mujais SK: Gaps in the anion gap. Arch Intern Med 152: 1625-1629, 1992. Schlichtig R, Grogono AW, Severinghaus JW: Human PaCO2 and standard base excess compensation for acid-base imbalance. Crit Care Med 26:1173-1179, 1998. Siggaard-Andersen O: The Van Slyke equation. Scand J Clin Lab Invest 37:S15-S20, 1977. Stewart PA: Modern quantitative acid-base chemistry. Can J Physiol Pharmacol 61:1444-1461, 1983. Story DA, Morimatsu H, Bellomo R: Strong ions, weak acids and base excess: A simplified Fencl-Stewart approach to clinical acid-base disorders. Br J Anaesth 92:54-60, 2004.

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COEXISTING DISEASE AND ALTERED STATES

Adrenal Insufficiency Jonathan T. Ketzler and Douglas B. Coursin

105

Case Synopsis A 68-year-old, 5-foot 10-inch tall, 100-kg man develops refractory hypotension toward the end of a laparotomy to remove the left colon because of recurrent diverticulitis and suspected peridiverticular abscess. The patient remains intubated at the end of the procedure and is taken to the intensive care unit (ICU), where a pulmonary artery catheter is placed. The pulmonary artery occlusion pressure is 6 mm Hg, the systemic vascular resistance is 475 dynes/cm5, cardiac output is 10 L/minute and cardiac index is 6 L/minute/m2. The patient is being mechanically ventilated; he has a heart rate of 128 beats per minute in sinus rhythm and blood pressure of 88/42 mm Hg on norepinephrine at 0.1 μg/kg per minute and dobutamine at 5 μg/kg per minute. The patient’s medical history is remarkable for hypertension and type 2 diabetes chronically treated with lisinopril and metformin (Glucophage), respectively. Both were withheld on the day of surgery. Shortly after his admission to the ICU, a diagnostic test is performed and a new medication is added to the therapeutic regimen. After several hours, the patient is hemodynamically stable, and vasopressors have been discontinued.

PROBLEM ANALYSIS Definition Adrenal insufficiency (AI) is a relatively rare but potentially life-threatening condition that can be quiescent until unmasked by medical stressors such as sepsis, traumatic insults, or surgical procedures. Sir Thomas Addison described primary AI in 1855. Approximately a century later Harvey Cushing developed the concept of secondary AI. Causes for primary and secondary AI are listed in Table 105-1. The hypothalamic-pituitary-adrenocortical (HPA) axis (Fig. 105-1) regulates the amount of cortisol released by the adrenals. The cycle begins with the release of corticotropinreleasing factor from the hypothalamus, which stimulates the release of adrenocorticotropic hormone (ACTH) from the anterior pituitary. ACTH then stimulates the release of cortisol from the adrenal cortex at a rate of about 20 mg/day. Cortisol (or a synthetic analogue) acts on the hypothalamus to inhibit the release of corticotropin-releasing factor and on the anterior pituitary to inhibit the release of ACTH. The associated diurnal variation in cortisol release peaks in the morning and midafternoon and then tapers off to a nadir in the evening. Although normal adults secrete about 5 to 10 mg/m2 of cortisol (or hydrocortisone) each day, during periods of acute stress the adrenal cortex can secrete as much as 100 mg/m2 per 24 hours. Primary adrenal failure is rare and may be caused by trauma, hemorrhage, infection, or infiltrative disease. Secondary adrenal failure may be brought about by adrenal atrophy due to acute or chronic glucocorticoid therapy. Patients with adrenal atrophy may show no symptoms of AI. 442

However, when subjected to the stress of even modest surgery or acute illness, these patients may develop life-threatening symptoms of AI. Along with the classification of AI as a primary or secondary process, there is now recognition of absolute or relative AI. Classic Addison’s disease due to autoimmune destruction of the adrenals is an example of primary, absolute AI. In contrast, the normal stress-induced increase in cortisol production may be blunted during life-threatening illnesses (e.g., sepsis) in some patients owing to relative AI. Alternatively, there may be down-regulation of cortisol binding and adrenergic receptors despite the normal stress-induced increase in steroid genesis, another explanation for relative AI. It is still uncertain whether etomidate blunts normal adrenal steroid genesis (see Table 105-1) to cause relative AI in critically ill patients. Finally, as illustrated in the case synopsis, relative AI may underlie life-threatening hemodynamic instability. However, if it is recognized as such and treated with stress doses of glucocorticoids, this process may be reversed.

Recognition The presentation of acute AI varies from a gradual onset over many days in a patient who is not stressed to a sudden fall in blood pressure associated with major stress such as an operation, trauma, or infection. Hypotension associated with AI can be severe and refractory to treatment. Chronic AI can be insidious and nonspecific in onset and remain undiagnosed for months. The prevalence of signs and symptoms associated with AI are detailed in Table 105-2. The most specific sign of primary AI is hyperpigmentation of the skin and mucosal surfaces caused by the high levels of corticotropin resulting from decreased cortisol feedback.

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Table 105–1

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Adrenal Insufficiency

Causes of Adrenal Insufficiency

443

HYPOTHALAMUS

Primary Adrenal Insufficiency

Secondary Adrenal Insufficiency Exogenous steroid administration Pituitary or hypothalamic diseases Infiltrative tumor (adenoma) Sarcoid Hemorrhage Autoimmune Isolated ACTH deficiency Surgical Pituitary surgery Removal of a functioning adrenal adenoma *Still unproven and therefore speculative. ACTH, adrenocorticotropic hormone.

Because primary AI (Addison’s disease) develops from failure of the adrenal gland itself, there is evidence of both glucocorticoid and mineralocorticoid deficiencies. Because secondary AI is an interruption of the pituitary-hypophysial axis that stimulates the adrenal glands to secrete cortisol, but spares the gland itself, it presents as pure glucocorticoid deficiency. In this case, the patient may also have hyponatremia;

inhibition Corticotropin-releasing factor (CRF)

ANTERIOR PITUITARY inhibition Adrenocorticotropin (ACTH)

ADRENAL CORTEX

Cortisol Figure 105–1

■

Hypothalamic-pituitary-adrenocortical axis.

this is not related to sodium excretion but rather to water intoxication secondary to an elevated level of antidiuretic hormone (ADH), as well as a primary defect in free water excretion related to glucocorticoid deficiency. Hypotension can be a common finding in both chronic and acute AI. Hypotension associated with acute AI has been reported as high-output circulatory failure with hallmarks of elevated cardiac output and index, normal pulmonary artery occlusion pressure, and decreased systemic vascular resistance. The pathogenesis of such hypotension is unknown but may include a combination of three possible mechanisms: (1) impairment of the direct effect of glucocorticoids on vascular smooth muscle, (2) loss of the “permissive” glucocorticoid effect on catecholamine synthesis and action, and (3) a decrease in the effects of glucocorticoids on vasoactive peptides. Dehydration can also be a factor in the hypotension associated with acute and chronic AI.

Table 105–2

■

Prevalence of Signs and Symptoms of Chronic Adrenal Insufficiency

Signs and Symptoms Weakness and fatigue Weight loss Hyperpigmentation Hypertension Hyponatremia Hyperkalemia Gastrointestinal symptoms Postural dizziness Adrenal calcification Hypercalcemia Muscle and joint pain Vitiligo

Prevalence (%) 74-100 56-100 92-96 59-88 88-96 52-64 56 12 9-33 6-41 6 4

Data from De Rosa G, Corsello SM, Cecchin L, et al: Clinical study of Addison’s disease. Exp Clin Endocrinol 90:232-242, 1987.

PHYSIOLOGIC IMBALANCE & COEXISTING DISEASE

Autoimmune Polyglandular autoimmune syndrome types I and II Infectious Tuberculosis Histoplasmosis Blastomycosis Coccidiomycosis Cryptococcosis Human immunodeficiency virus Cytomegalovirus Mycobacterium avium-intracellulare Cryptococcus Toxoplasmosis Kaposi’s sarcoma Fibrosis Infarction Adrenal hemorrhage Waterhouse-Friderichsen syndrome Lupus anticoagulant Antiphospholipid antibodies Immune thrombocytopenic purpura Heparin-induced Thrombocytopenia Anticoagulants Metastatic disease Lung Gastric Breast Malignant melanoma Lymphoma Drugs Decreased steroid synthesis Metyrapone Aminoglutethimide Mitotane Etomidate* Ketoconazole Increased steroid catabolism Rifampin Dilantin Phenobarbital Familial Familial glucocorticoid deficiency Adrenoleukodystrophy Adrenomyeloneuropathy

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Risk Assessment Using clinical indicators, there is no way to predict consistently which patients are at risk for developing AI during the stress of a surgical procedure or severe illness. Patients with certain comorbid diseases such as asthma, inflammatory bowel disease, collagen vascular disease, and rheumatoid arthritis may have received corticosteroids within 1 year, and the HPA axis can be suppressed by a relatively modest dose of exogenous steroids administered for as short a period as 7 to 10 days. Except for low-dose (prednisone ≤5 to 7.5 mg/day) and alternate-day regimens, chronic administration of corticosteroids suppresses the HPA axis, and recovery of its function can take up to 12 months. Normalization of pituitary function comes first; adrenocortical function returns more gradually. The reported incidence of perioperative AI is between 0.01% and 0.7%. A report by Rivers and colleagues suggested that older patients may have a greater risk of relative AI. The incidence during septic shock also appears to be significant, and steroid replacement therapy has been reported to significantly improve outcome in a selected subpopulation of such patients. Even though there are ample case reports of hypotension and even death secondary to AI, there are also many reports of glucocorticoid-treated patients undergoing major surgery without any perioperative glucocorticoid coverage. Most of these patients had uneventful perioperative courses, probably because they had normal perioperative biochemical indices of HPA function. This suggests that a historical assessment of glucocorticoid administration alone is unreliable. Endocrine evaluation is necessary in patients with suspected adrenal failure. A random screening cortisol level less than 25 μg/dL is abnormal when measured during the stress of an acute illness. A higher level does not preclude a subsequent abnormal cosyntropin stimulation test. A low cortisol level (<25 μg/dL) during a stressful illness or following stressful surgery mandates further evaluation. Major trauma and surgical stress usually result in a two- to threefold increase in plasma cortisol levels, with levels returning to normal 4 to 5 days after the stress. Levels may remain increased if there are complications. The cosyntropin stimulation test is still the best test for evaluating adrenal function in critically ill patients. After injection of 250 μg of cosyntropin, cortisol levels are compared with baseline levels at 30 and 60 minutes. The exact interpretation of test results remains controversial, but the best outcomes in septic patients occur in those with baseline values greater than 36 μg/dL and with at least a 9 μg/dL difference between baseline and peak values. Finally, if life-threatening AI is strongly suspected, treatment need not be delayed for diagnostic testing. Dexamethasone provides glucocorticoid coverage without interfering with cosyntropin studies.

During such times of stress, the patient is unable to secrete adequate amounts of cortisol to maintain hemodynamic stability.

MANAGEMENT Because AI can progress rapidly, early recognition and intervention are essential to improve outcome. Adrenal crisis is a medical emergency, and treatment cannot be delayed for extensive diagnostic studies. Therapy is directed toward rapidly increasing the circulating levels of cortisol. Without such treatment, even symptomatic treatment for volume depletion and electrolyte imbalance is inadequate. If AI is suspected, baseline plasma cortisol levels can be obtained just before treatment. Serum electrolytes, complete blood count, glucose, blood urea nitrogen, and creatinine are analyzed to assess for sodium depletion, potassium retention, and hypoglycemia. During adrenal crisis, patients can lose up to 20% of their circulating intravascular blood volume. This can result in hypovolemic shock and tissue hypoperfussion, both of which can lead to lactic acidemia. Therefore, rapid infusion of intravenous fluid is started to correct dehydration and hypovolemia. Normal saline is the initial fluid of choice. Subsequent treatment of electrolyte abnormalities, volume deficits, and hypoglycemia can be guided by laboratory measurements and the patient’s response to treatment. If a patient is known to have AI, replacement therapy should be individualized, depending on the degree of surgical or medical stress. For patients at high risk who undergo major procedures or have life-threatening injuries or illnesses, hydrocortisone 100 mg can be given, with additional intravenous doses of 50 to 100 mg every 6 to 8 hours (see also Chapter 34). Such doses can usually be rapidly tapered as the patient’s clinical condition improves. If the patient has no known history of AI, dexamethasone 4 to 10 mg can be given as an intravenous bolus. Dexamethasone does not interfere with the measurement of serum cortisol levels, so diagnostic tests can still be performed. However, because dexamethasone has no aldosterone activity, fludrocortisone, a mineralocorticoid, may also be needed. Patients usually respond quickly to initial therapies, and improvement is usually seen within several hours. Adrenal dysfunction has been shown to be present in as many as 70% of patients with septic shock, and the outcome can be significantly improved with replacement therapy in 20% of such patients. Finally, because 40% to 65% of critically ill patients have high plasma renin activity, previous recommendations did not include the administration of a mineralocorticoid. Based on more recent data, some experts now advise the addition of fludrocortisone 50 μg/day or greater by mouth in patients with sepsis-induced relative AI.

Implications

PREVENTION

An acute adrenal crisis can occur spontaneously or in response to significant emotional or physiologic stress. Stressors may include extreme psychological stress, trauma, withdrawal from alcohol or opioids, infection, general anesthesia, or surgery.

There are many ways to approach the administration of steroids in stressed patients with likely adrenal suppression. Some studies suggest tailoring the dose of hydrocortisone to the magnitude of the stress. Others advocate testing the HPA

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axis in patients at risk for AI. This is done using the cosyntropin stimulation test, which is easy and safe. However, there is controversy over how to interpret the test and even over what dose of cosyntropin to use. Some advocate the use of a more physiologic dose (e.g., 1 μg) instead of the currently recommended 250 μg for stimulation. Because the risk of steroids is so small in most stressed patients, most authorities suggest the use of stress doses in any patient at risk for AI. Because cortisol production under extreme stress is as much as 300 mg/day, hydrocortisone can be administered in 100-mg intravenous doses every 8 hours for 2 days or as a continuous infusion of 300 mg/day for 2 days (see also Chapter 34). In the absence of continued stress, these doses can be tapered to 50 mg every 8 hours for 1 to 2 days and then stopped, or continued at 25 mg every 8 hours for 1 to 2 days and then stopped. How steroids are tapered must be determined on a case-by-case basis, depending on the amount and duration of stress in patients with likely adrenal suppression. Finally, some have reported better outcomes with weight-related dosing for the treatment of chronic AI.

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Coursin DB, Wood KE: Corticosteroid supplementation in adrenal insufficiency. JAMA 287:236-240, 2002. Eichacker PQ, Parent C, Kalil A, et al: Risk and the efficacy of anti-inflammatory agents: Retrospective and confirmatory studies of sepsis. Am J Respir Crit Care Med 9:1197-1205, 2002. Goldberg PA, Inzucchi SE: Critical issues in endocrinology. Clin Chest Med 24:583-606, 2003. Holmes CL, Walley KK: The evaluation and management of shock. Clin Chest Med 24:775-789, 2003. Mah PM, Jenkins RC, Rostami-Hodjegan A: Weight-related dosing, timing and monitoring hydrocortisone replacement therapy in patients with adrenal insufficiency. Clin Endocrinol 61:367-375, 2004. Marik PE, Zaloga GP: Adrenal insufficiency in the critically ill: A new look at an old problem. Chest 122:1784-1796, 2002. Minneci PC, Deans KJ, Banks SM, et al: Meta-analysis: The effect of steroids on survival and shock during sepsis depends on the dose. Ann Intern Med 1:47-56, 2004. O’Brien JM Jr, Abraham E: New approaches to the treatment of sepsis. Clin Chest Med 24:521-548, 2003. Oelkers W: Adrenal insufficiency. N Engl J Med 335:1206-1211, 1996. Rivers EP, Gaspari M, Saad GA, et al: Adrenal insufficiency in high-risk surgical ICU patients. Chest 119:889-896, 2001. Salem M, Tainsh RE, Bromberg J, et al: Perioperative glucocorticoid coverage: A reassessment 42 years after emergence of a problem. Ann Surg 219:416-425, 1994.

Further Reading Connery LE, Coursin DB: Assessment and therapy of selected endocrine disorders. Anesthesiol Clin North Am 22:93-123, 2004. Cook DM: Safe use of glucocorticoids: How to monitor patients taking these potent agents. Postgrad Med 93:145-154, 1992.

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HIV Infection and AIDS Michael S. Avidan and Nicola Jones

106

Case Synopsis A 34-year-old woman with known human immunodeficiency virus (HIV) infection and a recent diagnosis of acquired immunodeficiency syndrome (AIDS) with Pneumocystis jirovecii (previously carinii) pneumonia presents for elective cesarean section at 38 weeks’ gestation. She has been taking antiretroviral therapy throughout her pregnancy. She is very short of breath and has a dry cough, and her peripheral arterial oxygen saturation is 84% on room air. She weighs 62 kg, and her height is 164 cm. Her tympanic temperature is 37.2°C. She is alert and oriented, with no localizing neurologic signs. Her blood pressure is 90/50 mm Hg; her heart rate is 115 beats per minute, with no respiratory variation; and her respiratory rate is 26 breaths per minute. Recent laboratory tests show a CD4 T-cell count of 186 cells/mL and an HIV viral load of 240,000 copies/mL.

PROBLEM ANALYSIS Definition AIDS was first described in 1981 in the United States. HIV and the AIDS pandemic pose a major threat to global health. It is estimated that more than 40 million people worldwide are infected with HIV, which is thought to have caused more than 20 million deaths to date. The infection continues to spread apace, with the most rapid increases observed in southern and central Africa and in South Asia. The predominant mode of HIV transmission is heterosexual sex, and women represent a high proportion of new infections, including in developed countries. Increasing numbers of patients presenting for surgery are HIV-seropositive or have AIDS. Anesthesiologists should be familiar with this disease and be aware of the impact of HIV on anesthesia. An understanding of the pathogenesis of HIV and an awareness of the possible drug interactions occurring with HIV therapy may help guide the choice of anesthetic technique. The possibility of nosocomial transmission of HIV highlights the need for anesthesiologists to enforce rigorous infection control policies to protect themselves, other health care workers, and their patients. Antiretroviral therapy decreases the rate of disease progression, but there is no cure available, nor is a vaccine likely in the foreseeable future.

Recognition HIV belongs to the family Retroviridae and the genus Lentivirus. Members of this genus are cytopathic (cell damaging), have long latent periods, and run a chronic course. When cases of AIDS first appeared, its pathogenesis was frustratingly elusive because the disease does not appear immediately on infection with HIV. There is a variable period during which the patient remains healthy but is viremic. Acute seroconversion illness occurs with a high viral load soon after infection. After several months, there is a gradual decrease in the viremia as the immune response occurs. The viral load is often at a steady state as the rate of viral 446

production equals the rate of destruction. Up to 98% of T-helper lymphocytes (CD4 T cells) are located in lymph nodes, which are the major site of viral replication and T-cell destruction. There is a gradual involution of the lymph nodes, with a concomitant decrease in CD4 T cells and an increase in viral load as the inexorable onset of AIDS occurs (Fig. 106-1). Before 1995, prospects for the treatment of HIV were gloomy. Subsequently, the situation changed dramatically as a result of four factors: 1. Improved understanding of the pathogenesis of HIV infection 2. Availability of surrogate markers of immune function and plasma viral burden 3. Development of new and more powerful drugs, such as the protease inhibitors and non-nucleoside reverse transcriptase inhibitors 4. Completion of several large clinical end-point trials that conclusively demonstrated that antiretroviral combinations significantly delayed the progression of HIV disease to AIDS and improved survival

Risk Assessment HIV is a virus found mainly in CD4 T cells, macrophages, and monocytes, and it requires a large infecting dose for transmission. HIV has been isolated from blood, cerebrospinal fluid, tears, saliva, semen, synovial fluid, pleural fluid, peritoneal fluid, pericardial fluid, amniotic fluid, vaginal secretions, and breast milk. Modes of transmission are through oral, rectal, and vaginal sexual intercourse, blood product transfusion, shared intravenous needles, occupational acquisition, and vertical transmission from mother to child. The screening of blood products for HIV antibodies has reduced the risk of transfusion-associated infection (<1 per 750,000 donor units); the exact risk is difficult to quantify, however, and it may increase as the HIV infection rate increases in the general population. Antibody screening fails to detect the virus in the so-called window period before antibody formation, which lasts about 3 months. Nuclear amplification is an alternative technique that may allow for early virus detection.

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HIV Infection and AIDS

Infection

447

Death Seroconversion Symptomless

Symptomatic

AIDS

10,000,000 1,000,000

1000

CD4 T cell count (cells/mL)

100,000 10,000

500

1000

Plasma viral load (copies/mL)

100 10 copies/mL

CD4 T cells/mL

Viral Load 4-8 weeks

~10 years (off HAART) to decades (on HAART)

2-3 Years

Figure 106–1 ■ Progression to acquired immunodeficiency syndrome (AIDS) of those infected with human immunodeficiency virus (HIV). Note that highly active antiretroviral therapy (HAART) greatly delays development of clinical AIDS.

Implications UNIVERSAL PRECAUTIONS Universal precautions for the prevention of transmission of blood-borne viruses were recommended in 1987 by the Centers for Disease Control. These precautions advise that every patient be regarded as potentially infected with a blood-borne virus.

Following accidental exposure to a high-risk body fluid, such as a (hollow) needle-stick injury, postexposure prophylaxis is recommended for health care workers. This should commence as soon as possible after the injury, ideally within 1 to 2 hours, but it can be considered up to 1 to 2 weeks after the injury. Very-high-risk exposures may be treated beyond this time with a view to modifying rather than preventing infection. A recommended postexposure prophylaxis regimen of 4 weeks’ duration is the following: ● ● ●

Zidovudine 300 mg every 12 hours Lamivudine 150 mg every 12 hours Indinavir 800 mg every 8 hours

However, the high rate of toxicity and noncompliance may necessitate other regimens.

MANAGEMENT Antiretroviral Drug Therapy Three major classes of antiretroviral agents are currently in use (Table 106-1): 1. Nucleoside analogue reverse transcriptase inhibitors (NRTIs) bind to the evolving viral DNA and prevent the completion of reverse transcription. 2. Non-nucleoside reverse transcriptase inhibitors (NNRTIs) interfere with the transcriptional activity of reverse

Table 106-1 lists examples of these major classes of antiretroviral agents currently in use, as well as routes of administration and common side effects. A typical antiretroviral regimen consists of three agents: a PI or NNRTI combined with two NRTIs. Such combined therapy has been termed highly active antiretroviral therapy (HAART). In some circumstances, combinations of four or more drugs are used. The aim of therapy in treatment-naïve patients is to achieve an undetectable viral load by 24 weeks of therapy and to improve and extend the length and quality of life. However, there is a downside to HAART. The AIDS pandemic, one of the most devastating to ever affect humankind, has now entered its third decade, and there is still no cure in sight. The initial enthusiasm that greeted HAART has been tempered by the recent discovery of multidrug-resistant viral strains. Also, there is the issue of important adverse side effects. SIDE EFFECTS

OF

HAART REGIMENS

Numerous side effects and drug interactions complicate HAART regimens and decrease compliance. Patients may experience drug hypersensitivity reactions, causing fever, hypotension, and acute interstitial pneumonitis with respiratory failure. Concurrent use of zidovudine and corticosteroids may result in severe myopathy and respiratory muscle dysfunction. In addition, reports have documented several cases of respiratory failure related to HAART initiation and immune reconstitution resulting in a paradoxical worsening of Pneumocystis pneumonia; distinguishing this event from a superimposed respiratory infection is often clinically challenging. Of particular importance to anesthesiologists is that patients receiving HAART are subject to

PHYSIOLOGIC IMBALANCE & COEXISTING DISEASE

POSTEXPOSURE PROPHYLAXIS

transcriptase by binding to it directly, downstream of the active catalytic site. 3. Protease inhibitors (PIs) inhibit the HIV protease, which cleaves the polyprotein precursors that ultimately make up the core proteins of the mature virions. PIs bind specifically to the active cleavage site.

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Major Classes of Antiretroviral Agents Currently in Use

Drug Name

Dosing

Common Side Effects

Nucleoside Analogue Reverse Transcriptase Inhibitors Zidovudine (AZT/ZDV) Didanosine (DDI) Zalcitabine (DDC) Stavudine (D4T) Lamivudine (3TC) Abacavir

Oral/IV Oral Oral Oral Oral Oral

Bone marrow suppression (neutropenia), GI upset, headache Peripheral neuropathy, pancreatitis, diarrhea Peripheral neuropathy, pancreatitis, oral ulcers Peripheral neuropathy Anemia, GI upset GI upset, potentially fatal acute hypersensitivity

Non-nucleoside Analogue Reverse Transcriptase Inhibitors Nevirapine Delavirdine Efavirenz

Oral Oral Oral

Rash, hepatitis, increased liver enzymes Rash, increased liver enzymes Dizziness, rash, dysphoria, increased liver enzymes

Ritonavir

Oral Oral + ≥1.5 L H2O/24 hr Oral

Nelfinavir

Oral

Diarrhea, raised transaminases, hyperlipidemia, cytochrome P-450 inhibition Nephrolithiasis, hyperbilirubinemia, hyperlipidemia, lipodystrophy, cytochrome P-450 inhibition GI upset, circumoral paresthesia, hyperlipidemia, lipodystrophy, cytochrome P-450 inhibition Diarrhea, hyperlipidemia, lipodystrophy, cytochrome P-450 inhibition

Protease Inhibitors Saquinavir Indinavir

GI, gastrointestinal.

long-term metabolic complications, including lipid abnormalities and glucose intolerance, which may result in the development of diabetes, coronary artery disease, and cerebrovascular disease. A syndrome resembling acute gram-negative sepsis has been reported in patients taking NRTIs. Lactic acidosis and hepatic steatosis are usually found. Patients develop high fever and can rapidly become confused and comatose. Nucleoside analogue drugs may cause inhibition of DNA polymerase gamma, the sole DNA polymerase required for the replication of mitochondrial DNA. This in turn causes mitochondrial dysfunction and impaired aerobic cellular respiration. Inhibition of oxidative phosphorylation and derangement of respiratory chain enzymes have been implicated. Riboflavin has been suggested as a potential treatment. Unfortunately, most patients die despite intensive care unit (ICU) support. HAART DRUG INTERACTIONS PIs, particularly ritonavir, are inhibitors of cytochrome P450 (see Table 106-1). In contrast, drugs such as nevirapine are inducers of hepatic microsomal enzymes. These variable effects on liver enzymes complicate the dosing of drugs, including anesthetic and analgesic agents, many of which undergo hepatic metabolism.

Respiratory Complications Pneumocystis jirovecii pneumonia (PJP) does not usually occur until the CD4 T-cell count is less than 200 cells/mL. Breathlessness, night sweats, and weight loss are frequent complaints. The chest examination of may be unremarkable, and the chest radiograph is normal in many instances. Complications include respiratory failure, pneumothorax. and chronic pulmonary disease. The chest radiograph typically shows bilateral “groundglass” shadowing. Pneumothoraces may be evident, and there

may be multiple pneumatoceles. High-resolution computed tomography scanning reveals a ground-glass appearance even when the radiograph is normal. Lung function tests show reduced lung volumes with decreased compliance and diminished diffusing capacity for carbon monoxide. Oxygen saturation measurements during exercise may be more helpful than lung function tests. If PJP is suspected, fiberoptic bronchoscopy and bronchoalveolar lavage should be performed. The advantage of an early diagnosis compensates for the high frequency of negative examinations. Combined high-dose sulfamethoxazole (100 mg/kg per day) with trimethoprim (20 mg/kg per day) remains the treatment of choice. Systemic steroid therapy, such as prednisolone 1 mg/kg per day, is advised for patients with low oxygen saturation values. Respiratory support and supplementary oxygen are invariably required. Use of continuous positive airway pressure can, in some instances, obviate the need for positive-pressure mechanical ventilation. The prognosis for patients who require mechanical ventilation despite adjunct corticosteroid therapy is poor. Further, the use of positive end-expiratory pressure may cause pneumothorax. Cavitary lung disease can be due to a pyogenic bacterial lung abscess, pulmonary tuberculosis (TB), fungal infection, and Nocardia species. Kaposi’s sarcoma (KS) and lymphoma can also affect the lung. Adenopathy can lead to tracheobronchial obstruction or compression of the great vessels. Endobronchial KS may cause massive hemoptysis. HIV also directly affects the lungs, causing a destructive pulmonary syndrome similar to emphysema. Disseminated TB is a potential cause of severe respiratory failure, and respiratory secretions should be examined routinely for acid-fast bacilli in AIDS patients with pulmonary infiltrates. Bacterial pneumonia (Streptococcus pneumoniae, Moraxella catarrhalis, Haemophilus influenzae, Staphylococcus aureus, Pseudomonas aeruginosa) can also cause severe acute respiratory failure. Empirical antibacterial treatment to cover

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these microorganisms should be given when a bacterial agent is suspected. Outbreaks of multidrug-resistant TB have occurred in patients with HIV infection and in health care workers. Airborne transmission by inhalation of infective aerosols justifies appropriate isolation measures to protect medical staff and other patients from TB transmission.

Central Nervous System Complications Neurologic disease ranging from AIDS dementia to infectious or neoplastic involvement may complicate AIDS. Three entities constitute mostly focal cerebral processes: cerebral toxoplasmosis, primary central nervous system (CNS) lymphoma, and progressive multifocal leukoencephalopathy. Focal lesions may increase intracerebral pressure, thereby precluding neuraxial anesthesia. Spinal cord involvement, peripheral neuropathy, and myopathy may occur with cytomegalovirus or HIV infection itself. Giving succinylcholine may be hazardous in this setting. Cryptococcus neoformans, HIV, and TB can cause meningitis. HIV infection is associated with autonomic neuropathy, and this can manifest as hemodynamic instability during anesthesia or in the ICU.

Cardiovascular Disease

HIV Infection and AIDS

449

Obstetric Patients HIV and AIDS are increasing in women of childbearing age. In one study, zidovudine monotherapy was shown to dramatically reduce the incidence of vertical transmission of HIV from 25.5% to 8.3%. However, zidovudine monotherapy has limited long-term benefits because HIV resistance develops rapidly. Therefore, in pregnancy, combination therapy is now believed to be preferable. There are limited data on the use of PIs in pregnancy. A recent meta-analysis strongly suggested that cesarean section independently reduces the incidence of vertical transmission. Combined antiretroviral therapy and elective cesarean section reduce the rate of vertical transmission to 2%. However, cesarean section is a major surgical intervention with wellknown complications (see Section 9). There is a higher incidence of morbidity following cesarean compared with vaginal delivery, even in healthy women, including more prolonged and intense pain, longer duration of bed rest, increased blood loss, and more frequent venous thrombosis and wound infection. Many practitioners today do not recommend elective cesarean section to HIV-infected women who are compliant with antiretroviral therapy and have undetectable HIV viral loads. Unfortunately, HIV-positive women with low CD4 lymphocyte counts, whose infants would theoretically benefit most from cesarean delivery, are also those who are most likely to experience significant postoperative complications. In a study of HIV-seropositive parturients receiving regional anesthesia, there were no infectious or neurologic complications related to the anesthetic or obstetric courses. In the immediate postpartum period, immune function measurements remained essentially unchanged, as did the severity of the disease. There have been concerns that epidural and lumbar puncture in HIV-seropositive patients may allow entry of the virus into the CNS. However, the natural history of HIV includes CNS involvement early in the clinical course, and expression of CNS infection varies widely. Finally, epidural blood patches for the treatment of post–dural puncture headache have been reported as safe and effective in HIV-seropositive patients. Nevertheless, given the very small theoretical risk of introducing virus to the CNS, other analgesic strategies should be tried first.

Surgery and Anesthesia HIV infection does not increase the risk for postprocedural complications, including death, up to 30 days after the procedure. Thus, surgical intervention should not be limited because of HIV status and concern for subsequent complications. However, during anesthesia, tachycardia is more frequently seen in HIV-seropositive patients. Also, high fever, anemia, and tachycardia are more frequent postoperatively. Several studies indicate that general anesthesia and opiates may impair immune function. Although this is likely of little clinical importance in healthy individuals, the implications for HIV-infected patients are not known. Immunosuppression due to general anesthesia occurs within 15 minutes of induction and may persist for as long as 3 to 11 days. Postoperative immunosuppression may last longer in inherently immunosuppressed patients and may predispose to the development of postoperative infections or facilitate tumor growth or metastasis.

Intensive Care Unit Complications APACHE II scoring significantly underestimates mortality risk for HIV-seropositive patients admitted to a medical ICU with a total lymphocyte count less than 200 cells/mL. This is particularly true for those admitted with pneumonia or sepsis. There is a diverse range of indications for critical care in patients with HIV infection. Historically, respiratory failure due to PCP has been the most common reason for admission to an ICU, accounting for 34% of cases. Mechanical ventilation for PCP and other pulmonary disorders is associated with a mortality rate greater than 50%. In contrast, ICU admission and mechanical ventilation for nonpulmonary disorders are associated with a mortality rate less than 25%. In patients with septic shock, HIV infection is an independent predictor of poor outcome. In the era of HAART, fewer patients with HIV infection are admitted to ICUs with AIDS-defining illnesses such as PJP. In fact, many

PHYSIOLOGIC IMBALANCE & COEXISTING DISEASE

Cardiac involvement in the course of HIV is common but is often clinically silent. Up to 50% of patients with HIV have abnormal echocardiographic findings at some point in their disease. Approximately 25% have pericardial effusions. Myocarditis is more common in advanced HIV and may be caused by toxoplasmosis, disseminated cryptococci, coxsackievirus B, cytomegalovirus, lymphoma, Aspergillus species, and HIV itself. Ventricular dilatation and cardiac dysfunction may result. With PIs, glucose intolerance and disorders of lipid metabolism are common. Aggressive generalized vascular disease, including cardiac and cerebral, may occur as a complication of antiretroviral therapy. If patients exhibit unexplained hypotension, adrenal insufficiency should be considered, because this may occur with advanced HIV infection.

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patients are now admitted with unrelated critical illnesses and are coincidentally found to be infected with HIV. Nonetheless, initiation of HAART in patients with PCP is known to improve outcome. However, this benefit must be weighed against problems associated with immune reconstitution, which may occur in septic patients when HAART is initiated.

PREVENTION There is little specific information concerning the overall risk of anesthesia and surgery in HIV-seropositive patients. The American Society of Anesthesiologists’ physical status assessment and the inherent surgical risk probably provide a measure of global risk. This information, when combined with the Centers for Disease Control and Prevention stage of HIV infection, the degree of immunosuppression, and the presence and severity of opportunistic infection or neoplasm, may offer the best predictor of global preoperative risk for HIV-seropositive patients. With regard to choice of anesthetic technique to minimize complications, regional anesthesia is the technique of choice, except in certain cases of neuropathies. Finally, anesthesiologists and intensivists have contact with a broad range of patients, many of whom may be HIVseropositive. Therefore, rigorous adherence to infection control practices is imperative. Further, all clinicians should

keep abreast of current knowledge about HIV therapy to ensure that their patients are receiving optimal treatment.

Further Reading Afessa B, Green B: Bacterial pneumonia in hospitalized patients with HIV infection: The Pulmonary Complications, ICU Support, and Prognostic Factors of Hospitalized Patients with HIV (PIP) Study. Chest 117:1017-1022, 2000. Avidan MS, Groves P, Blott M, et al: Low complication rate associated with cesarean section under spinal anesthesia for HIV-1-infected women on antiretroviral therapy. Anesthesiology 97:320-324, 2002. Avidan MS, Jones N, Pozniak AL: The implications of HIV for the anaesthetist and the intensivist. Anaesthesia. 55:344-354, 2000. Casalino E, Mendoza-Sassi G, Wolff M, et al: Predictors of short- and longterm survival in HIV-infected patients admitted to the ICU. Chest 113:421-429, 1998. Casalino E, Wolff M, Ravaud P, et al: Impact of HAART advent on admission patterns and survival in HIV-infected patients admitted to an intensive care unit. AIDS 18:1429-1433, 2004. Evron S, Glezerman M, Harow E, et al: Human immunodeficiency virus: Anesthetic and obstetric considerations. Anesth Analg 98:503-511, 2004. Hughes SC, Dailey PA, Landers D, et al: Parturients infected with human immunodeficiency virus and regional anesthesia: Clinical and immunologic response. Anesthesiology 82:32-37, 1995. Morris A, Wachter RM, Luce J, et al: Improved survival with highly active antiretroviral therapy in HIV-infected patients with severe Pneumocystis carinii pneumonia. AIDS 17:73-80, 2003. Vincent B, Timsit JF, Auburtin M, et al: Characteristics and outcomes of HIV-infected patients in the ICU: impact of the highly active antiretroviral treatment era. Intensive Care Med 2004;30:859-866.

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Hypothyroidism: Myxedema Coma Pamela R. Roberts and Richard C. Prielipp Case Synopsis A 59-year-old man with history of a previous myocardial infarction with preserved left ventricular function underwent three-vessel coronary artery bypass grafting. He remained intubated and was taken to the intensive care unit (ICU) for postoperative care. On arrival in the ICU, he was receiving continuous infusions of propofol, phenylephrine, and fenoldopam. After several hours, he was awake and following commands and showed evidence of good perfusion and cardiac function, but he had a mild respiratory acidosis (PaCO2 49 mm Hg). Subsequently he was extubated and had persistent respiratory acidosis over the next few hours. His vital signs were remarkable overnight for a temperature that remained below 36°C (measured via a pulmonary artery catheter), heart rate paced at 90 beats per minute, blood pressure 95/62 to 105/68 mm Hg, respiratory rate 10 to 18 breaths per minute, and cardiac index greater than 2.4 L/minute/m2. About 8 hours after extubation, his oxygenation, ventilation, cardiac index, and mental status deteriorated, and he was reintubated. A chest radiograph showed mild pulmonary edema. Thyroid function studies revealed very elevated thyrotropin and very low thyroxine levels; the cortisol level was appropriate for a stress response. Therapy with thyroid hormone was initiated, after which the patient improved; he was extubated the following day. Later discussions with the patient revealed a previous diagnosis of hypothyroidism and noncompliance with medical therapy.

Definition Hypothyroidism is thyroid gland hypoactivity with decreased synthesis and secretion of thyroxine (T4). Normal regulation and activity of thyroid hormone can be summarized as follows: ●

●

●

●

●

●

●

● ●

Thyrotropin-releasing hormone (TRH) is released from the hypothalamus. TRH stimulates the synthesis and release of thyrotropin (also called thyroid-stimulating hormone [TSH]) from the pituitary gland. Circulating TSH stimulates the thyroid gland to produce and secrete thyroid hormone (about 80% as T4 and about 20% as triiodothyronine [T3]). The remainder of T3 (the physiologically active form of thyroid hormone) is produced in extrathyroidal tissues (mainly the liver and kidneys) by monodeiodination of circulating T4. T3 and T4 circulate bound to serum proteins, but free T3 and T4 are metabolically active. T3 feeds back on the pituitary gland to inhibit the production of TSH. Some of the circulating T4 is metabolized to the inactive product “reverse T3.” Both T3 and reverse T3 are rapidly cleared from the serum. Thyroid hormone activity begins with the binding of T3 to receptors on cell nuclei, which is needed for normal cellular function.

Recognition HISTORY Patients may present with previously undiagnosed hypothyroidism or may have been noncompliant with thyroid hormone replacement therapy. They may manifest decreased mental acuity, hoarseness, somnolence, cold intolerance, dry skin, brittle hair, and weight gain. Myxedema is usually precipitated by a stressful event such as an acute infection, trauma, myocardial infarction, or surgery or following anesthesia. PHYSICAL EXAMINATION The following findings may be evident on physical examination: ● ● ●

● ● ● ● ●

Hypothermia (core temperature typically <35°C) Dry skin, with a thickened and doughy appearance Facial and generalized puffiness (periorbital edema, large tongue) Depressed mental status (lethargy, coma) Hypoventilation (slow respiratory rate, shallow breaths) Sinus bradycardia Hypotension Low-output cardiac failure and cardiomyopathy (possibly pericardial effusion with muffled heart sounds) 451

PHYSIOLOGIC IMBALANCE & COEXISTING DISEASE

PROBLEM ANALYSIS

Myxedema or myxedema coma is a life-threatening complication of hypothyroidism characterized by a decreased level of consciousness or even coma.

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Disorders of muscle function (paralytic ileus, urinary retention, atonic bowel)

Thyroid hormone is essential for the normal metabolism of all cells, and deficiency presents with widespread symptoms. For example, thyroid hormone is required for the synthesis of many proteins (e.g., β-receptors), and deficiency contributes to a lack of responsiveness to vasoactive drugs. In myxedema, decreased circulating levels of thyroid hormones contribute to decreased mental responsiveness, bradycardia, and reduced stroke volume. This leads to low cardiac output and decreased cerebral perfusion. Hypothermia results from a decreased metabolic rate and an inability to shiver. Decreased plasma volume and intense peripheral vasoconstriction are common. Alveolar hypoventilation is secondary to (1) respiratory center depression (exacerbated by use of analgesics, sedatives, and anesthesia); (2) defective respiratory muscle function; and (3) occasionally, airway obstruction due to tongue enlargement. The actual mechanism whereby hypothyroidism deteriorates into severe illness and coma is poorly understood, but it most often occurs after a stressful event, as illustrated in the case synopsis. Regardless of the cause, the resulting syndrome consists of a severe hypometabolic state. The reported mortality rate for untreated myxedema coma is over 80%. However, with treatment, the mortality rate is decreased to less than 10%. Hypothyroidism occurs secondary to autoimmune thyroid disease (Hashimoto’s thyroiditis), previous chronic treatment with lithium or amiodarone, iodine excess or deficiency (extremely rare in the United States, but an important cause of goitrous hypothyroidism in many countries), radioactive thyroid ablation, surgical resection, and pituitary or hypothalamic disease. The last two can be secondary or tertiary causes of hypothyroidism. Occasionally a patient may have thyroid hormone resistance or congenital thyroid agenesis. The incidence of hypothyroidism is three times higher in females than in males, and elderly women seem to be most susceptible to myxedema coma.

Risk Assessment and Implications The diagnosis of myxedema is based on clinical suspicion, and confirmation relies on thyroid studies with the following results (Table 107-1): ● ● ●

Decreased T4 Decreased T3 Elevated TSH (but not in secondary or tertiary hypothyroidism)

Other routine studies include complete blood count, electrolytes, urinalysis, arterial blood gases, chest radiograph, electrocardiogram, and blood and urine cultures. Serum cortisol levels should be drawn initially to evaluate for concomitant adrenal insufficiency. Additional studies should evaluate for infection as indicated by the history and physical examination. Associated laboratory abnormalities that may be present include hyponatremia, hypoglycemia, hypercholesterolemia, and normochromic normocytic anemia. The chest radiograph may reveal signs of pleural or pericardial effusion or infection. The electrocardiogram may reveal many associated or potential abnormalities, including sinus bradycardia, small-voltage

Table 107–1

■

Thyroid Function Studies in Thyroid Disorders Disorder

Test

Hyperthyroid

Hypothyroid

TSH

Low

High

Total T4 Total T3 Reverse T3 Free T4 T3 resin uptake*

High High High High High

Low Low Low to normal Low Low

Euthyroid Sick Syndrome Low to slightly high Low to normal Low High Normal Normal to high

*Approximates serum hormone binding by thyroxine-binding globulin (normal range is 33-48%). T3, triiodothyronine; T4, thyroxine; TSH, thyroid-stimulating hormone.

QRS complexes, prolonged Q-T intervals, isoelectric T-wave changes, or supraventricular tachycardia. Arterial blood gases may reveal hypoxemia, hypercarbia, and respiratory acidosis. Sepsis should be considered in the differential diagnosis. Other causes for depressed mental status, such as stroke, electrolyte disturbances (e.g., hyponatremia), hypoglycemia, or renal failure with uremia, should also be considered. Hypopituitarism causing both hypothyroidism and adrenal insufficiency should be ruled out. Finally, the differential diagnosis should include hypothermia and drug overdose with β-receptor or calcium channel antagonists, encephalitis, and hypothalamic strokes.

MANAGEMENT AND PREVENTION Do not wait for laboratory values to begin treatment if there is sufficient clinical suspicion of myxedema. Appropriate treatment includes the following: ●

Thyroid hormone replacement ● Intravenous (IV) administration is necessary owing to unreliable gastrointestinal absorption. ● The best therapeutic regimen remains controversial, and clinical trials are unlikely because the disease is so rare. We prefer a combination of T3 and T4: T3 20 μg IV bolus followed by 10 μg every 8 hours and T4 200 μg IV followed by 100 μg IV every 24 hours for 1 to 2 days, followed by T4 alone. ● If IV T is not immediately available, IV T (in the pre3 4 ceding dosage) can be given with oral T3 (25 μg every 12 hours) until the patient can be treated with oral T4 alone. ● Previously, T alone was frequently used (200 to 500 μg 4 IV bolus followed by 50 to 100 μg IV every 24 hours). ● Peripheral conversion of T to T requires the presence 4 3 of some T3 for enzyme activity. ● An advantage of IV T includes a more rapid onset of 3 action than T4; also, peripheral conversion of T4 is not required for activity. ● T is more arrhythmogenic than T , so careful monitor3 4 ing is essential.

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●

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453

of myxedema coma because of potential cardiac complications. In addition, definitive treatment may require diagnosis and treatment of the underlying cause (e.g., infection, stroke, myocardial infarction, narcotics, gastrointestinal bleeding). Mortality in myxedema coma may approach 80%, and improved survival depends on early, aggressive therapy. One retrospective study suggested that delaying surgery did not improve the outcome in patients with severe hypothyroidism. However, optimizing a patient’s chance for the best outcome may be achieved by preoperative therapy when the need for surgery is not urgent.

Further Reading Cone AM: Anaesthesia in a patient with untreated myxoedema coma. Anaesth Intensive Care 22:295-298, 1994. Hellman DE: The thyroid gland. Contemp Anesth Pract 3:109-145, 1980. James ML: Endocrine disease and anaesthesia: A review of anaesthetic management in pituitary, adrenal, and thyroid diseases. Anaesthesia 25:232-252, 1970. Marcaine JM: Anesthesia and hypothyroidism: A review of thyroxine physiology, pharmacology, and anesthetic implications. Anesth Analg 61:371-383, 1982. Myers L, Hays J: Myxedema coma. In Zaloga GP (ed): Critical Care Clinics—Endocrine Crises. Philadelphia, WB Saunders, 1991, pp 43-56. O’Connor CJ, March R, Tuman K: Severe myxedema after cardiopulmonary bypass. Anesth Analg 96:62-64, 2003. Rodriguez I, Fluiters E, Perez-Mendez LF, et al: Factors associated with mortality of patients with myxoedema coma: Prospective study in 11 cases treated in a single institution. J Endocrinol 180:347-350, 2004. Smallridge RC: Metabolic and anatomic thyroid emergencies: A review. Crit Care Med 20:276-291, 1992. Weinberg AD, Brennan MD, Gorman CA, et al: Outcome of anesthesia and surgery in hypothyroid patients. Arch Intern Med 143:893-897, 1983.

PHYSIOLOGIC IMBALANCE & COEXISTING DISEASE

Monitor T3 and T4 levels after 5 days, and adjust doses accordingly if the patient remains unconscious. General supportive measures ● Give IV fluids to restore intravascular volume. ● Use passive warming (active warming can cause peripheral vasodilatation and worsen shock). ● Mechanical ventilation may be required. ● Seizures can be treated with standard anticonvulsant drugs. ● Use sedatives judiciously. ● Hydrocortisone (100 mg IV every 8 hours) should be given until initial evaluation of hypothalamic-pituitaryadrenal axis function is performed; this therapy may be lifesaving in patients with secondary or tertiary hypothyroidism. Cardiovascular supportive measures ● After restoring intravascular volume, inotropic or vasopressor therapy may be required for cardiovascular support. ● Hypotension is poorly responsive to vasopressors until thyroid hormone replacement is initiated. ● Monitor for the presence of arrhythmias (the dosage of thyroid hormone replacement may have to be decreased). ● Hypothyroidism is associated with a high incidence of coronary artery disease, and patients should be monitored for evidence of myocardial ischemia, which is exacerbated by increased myocardial oxygen consumption during T3 and T4 treatment. Special considerations ● Euthyroid patients tolerate short-term administration of thyroid hormone well. ● Delay of treatment in a myxedematous patient can make the difference between survival and death. ● This treatment regimen should not be routinely instituted in hypothyroid patients without clinical evidence ●

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108

Hyperthyroidism: Thyroid Storm Richard C. Prielipp and Pamela R. Roberts Case Synopsis A 32-year-old woman undergoes general anesthesia with 1% isoflurane in a mixture of 60-40 nitrous oxide and oxygen for open fixation of a humeral fracture. Preoperative history is significant for anxiety and intolerance to heat. Physical examination is noteworthy for periorbital swelling; warm, moist skin with sweaty palms; and a midline lower neck mass consistent with an enlarged thyroid. Thirty minutes after induction, sinus tachycardia (128 beats per minute), arterial hypertension (190/100 mm Hg), and hyperpyrexia (core temperature 38.1°C despite a cool operating room environment) are noted. Increasing the depth of anesthesia with 2% isoflurane results in occasional ventricular premature beats. Muscle rigidity is absent.

PHYSICAL EXAMINATION FINDINGS

PROBLEM ANALYSIS Definition Normal regulation and activity of thyroid hormone are summarized in Chapter 107. The following definitions apply to the discussion of hyperthyroidism: ●

●

●

●

True hyperthyroidism is thyroid gland hyperactivity with increased synthesis and secretion of thyroid hormone. Thyrotoxicosis refers to the clinical and biochemical manifestations of excess thyroid hormone. It affects 2% of women and 0.2% of men in the general population. Thyrotoxic crisis or thyroid storm is a life-threatening complication of hyperthyroidism characterized by a severe, sudden exacerbation of thyrotoxicosis. Patients with uncontrolled hyperthyroidism presenting for surgical or trauma care are at considerable risk of developing thyrotoxicosis. Therefore, anesthesiologists should ensure that patients are euthyroid before proceeding with elective surgery. Thyrotoxicosis factitia refers to thyrotoxicosis without true hyperthyroidism (e.g., ingestion of thyroid hormone, ectopic thyroid hormone production) and is associated with decreased synthesis of thyroid hormone.

Findings on physical examination that support the diagnosis of hyperthyroidism include the following symptoms (in decreasing order of frequency): ●

● ● ●

● ●

Signs of hyperthyroidism include the following (in decreasing order of frequency): ●

●

● ● ● ● ●

●

Recognition, Risk Assessment, and Implications

Altered mental status (nervousness, agitation, anxiety, confusion, possible psychosis or even coma) Sweating, heat intolerance Weight loss, fatigue, muscle weakness Increased appetite, diarrhea, other gastrointestinal symptoms Prominent, dry eyes Leg swelling

●

Sinus tachycardia (virtually 100% incidence) and tachyarrhythmias Goiter—neck mass with potential airway compromise (Fig. 108-1) Warm, moist skin Muscle tremor Systolic hypertension; widened pulse pressure Enlarged thyroid with thyroid bruit Ophthalmic signs, including exophthalmos, lid lag, lid retraction, periorbital swelling, and conjunctival injection Pretibial edema Atrial fibrillation, classically in the elderly (about 10% incidence)

HISTORY Patients with undiagnosed hyperthyroidism often have a history of anxiety (occasionally progressing to psychosis or even coma), significant recent weight loss, heat intolerance, gastrointestinal disturbances (diarrhea, nausea, vomiting, abdominal pain), unexplained fever, muscle weakness, and tremor. Thyroid storm is usually precipitated by a stressful event such as surgery, childbirth, infection, myocardial infarction, diabetic ketoacidosis, or trauma. 454

PATHOPHYSIOLOGY The actual mechanism whereby thyrotoxicosis decompensates into thyroid crisis is poorly understood, but it most often develops after a stressful precipitating event. Whatever the cause, the resulting syndrome resembles prolonged, severe β-adrenergic agonist overdose. Catecholamine concentrations appear to be normal, despite the apparent hypermetabolic state.

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Table 108–2

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455

Results of Thyroid Function Studies in Patients with Thyroid Disorders Disorder

Test

Hyperthyroid

Hypothyroid

TSH Total T4 Total T3 Reverse T3 Free T4 T3 resin uptake*

Low High High High High High

High Low Low Low to normal Low Low

*Approximates serum hormone binding by thyroxine-binding globulin (normal range is 33-48%). T3, triiodothyronine; T4, thyroxine; TSH, thyroid-stimulating hormone.

Figure 108–1 ■ Computed tomography scan (with intravenous contrast) of lower neck–upper thorax region reveals an enlarged thyroid gland (goiter) compressing the trachea and esophagus. Anesthetists must recognize the potential for significant airway compromise during induction of anesthesia in patients with large goiters in the neck and anticipate possible extension of the goiter to the retrosternal space. Up to 6% of tracheal intubations in patients anesthetized for thyroid surgery are difficult.

CAUSE

DIAGNOSIS The diagnosis of thyroid storm is clinical. Corroboration and confirmation rely on thyroid studies with the following findings (Table 108-2): ● ● ●

Elevated thyroxine (T4) Elevated triiodothyronine (T3) Decreased thyroid-stimulating hormone (TSH)

Table 108–1

■

Disorders Associated with Thyrotoxicosis

Graves’ disease (may account for 85% of cases) Toxic multinodular goiter Toxic adenoma Subacute thyroiditis Neonatal thyrotoxicosis (consequent to maternal Graves’ disease) TSH-secreting pituitary tumor Labor and childbirth Hydatidiform mole Metastatic (hyperfunctioning) thyroid carcinoma Thyrotoxicosis factitia TSH, thyroid-stimulating hormone.

DIFFERENTIAL DIAGNOSIS Malignant hyperthermia must be investigated simultaneously and treatment initiated if triggering anesthetic agents are used. This is especially true in children or when severe hypercarbia, acidosis, hyperkalemia, and increased creatine phosphokinase are present. Other hypermetabolic states such as sepsis, pheochromocytoma, or thyrotoxicosis without crisis should be considered. Last, the differential diagnosis should include severe drug intoxication with either cocaine or amphetamines.

MANAGEMENT Do not wait for laboratory results to begin treatment if there is sufficient clinical suspicion. Appropriate treatment includes general supportive measures; inhibition of thyroid hormone synthesis, thyroid hormone release, peripheral β-adrenergic activity, and peripheral conversion of T4 to T3; and regulation of intracellular calcium.

General Supportive Measures ● ●

● ●

Intravenous (IV) fluids to restore intravascular volume Acetaminophen for hyperthermia (avoid aspirin, because it displaces T4 from thyroid-binding globulin, thereby increasing free T4) Cooling blankets Magnesium salts to reduce the severity and incidence of cardiac arrhythmias

PHYSIOLOGIC IMBALANCE & COEXISTING DISEASE

Undiagnosed hyperthyroidism (usually Graves’ disease or toxic multinodular goiter) in a patient with major stress is the most common cause of thyroid storm. Another cause may be inadequate treatment in a known hyperthyroid patient. Disorders associated with thyrotoxicosis are listed in Table 108-1. The many causes of thyrotoxicosis can be distinguished by a 24-hour radioactive iodine uptake study performed when the patient’s condition is stable.

However, T4 and T3 concentrations may correlate poorly with the severity of clinical signs. Other routine studies include complete blood cell count, electrolyte levels, urinalysis, chest radiograph, and electrocardiogram. Additional studies looking for infectious processes should be performed. Associated laboratory abnormalities (present 5% to 20% of the time) include hypercalcemia, hypokalemia, hyperglycemia, hypocholesterolemia, microcytic anemia, lymphocytosis, granulocytopenia, hyperbilirubinemia, and increased alkaline phosphatase level.

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Inhibition of Thyroid Hormone Synthesis ●

●

Propylthiouracil (PTU)—up to 1000 mg initially as a loading dose, then 200 to 300 mg orally or via nasogastric tube every 4 to 6 hours. It may take 6 to 8 weeks to achieve a full euthyroid state; PTU also inhibits peripheral conversion of T4 to T3. Methimazole—20 to 30 mg orally or via nasogastric tube every 4 to 6 hours. Achieves a euthyroid state more quickly than PTU and has a lower incidence of agranulocytosis, hepatitis, and vasculitis.

●

Dexamethasone 2 mg intravenously or orally every 6 hours, or hydrocortisone 50 mg intravenously every 6 hours

Intracellular Calcium Regulation Dantrolene in doses of 1 mg/kg (equivalent to that used for malignant hyperthermia) has been reported in anecdotal cases; however, its utility and efficacy in the setting of thyroid storm are not well defined.

PREVENTION Iodide Therapy Iodide inhibits thyroid hormone synthesis (Wolff-Chaikoff effect). Delay iodide therapy at least 4 hours after beginning PTU therapy. ● ●

●

Sodium iodide—1 g intravenously every 8 hours Potassium iodide (SSKI, a saturated solution of potassium iodide), such as Lugol solution—10 drops orally every 6 hours. Lugol solution was once widely administered for 7 to 10 days before elective thyroidectomy in an effort to reduce vascularity of the gland. Iopanoic acid—0.5 to 1.0 g/day (also blocks peripheral conversion of T4 to T3)

Inhibition of Peripheral β-Adrenergic Activity ●

β-blockers, which also block peripheral conversion of T4 to T3 ● Propranolol—0.5 to 1.0 mg/minute intravenously, up to a total dose of 2 to 10 mg; repeat every 3 to 4 hours. After initial control with IV drug, treat with 20 to 40 mg orally every 6 hours; occasionally, a patient may require up to 2 g/day orally owing to the variability of hepatic metabolism in thyrotoxic individuals. ● Esmolol—IV bolus with 0.5 to 0.75 mg/kg, followed by IV infusion with 50 μg/kg per minute. If effect is inadequate after 5 minutes, repeat IV bolus and increase IV infusion to 100 μg/kg per minute; it may even be necessary to increase the infusion to 300 μg/kg per minute. ● Titrate β-blockade to achieve a heart rate of 80 to 90 beats per minute. ● If the patient has a history of reactive airway disease, use caution and a short-acting cardioselective agent such as esmolol, atenolol, or metoprolol. ● If β-blockers are contraindicated, other sympatholytic drugs (e.g., reserpine, a depleter of catecholamines, or guanethidine, an inhibitor of catecholamine release) may be useful as second-line agents.

Inhibition of Peripheral Conversion of T4 to T3 ● ●

PTU (see dosages given earlier) β-blockade (see dosages given earlier)

Prevention of complications in patients with hyperthyroidism (especially thyroid storm) relies on recognition of the stigmata of undiagnosed hyperthyroidism during the preoperative evaluation. In addition, anesthesiologists must anticipate potential airway difficulties during tracheal intubation, which occurs in 6% of patients anesthetized for thyroid surgery (see Fig. 108-1). Mortality with thyroid storm may be as high as 20%. Improved survival relies on early, aggressive therapy. In addition, definitive therapy requires treatment of any associated disorders, such as infection or diabetic ketoacidosis.

Further Reading Ambus T, Evans S, Smith NT: Thyrotoxicosis factitia in the anesthetized patient. Anesthesiology 81:254-256, 1994. Bennett MH, Wainwright AP: Acute thyroid crisis on induction of anaesthesia. Anaesthesia 44:28-30, 1989. Benua RS, Becker DV: Thyroid storm. In Bardin CW (ed): Current Therapy in Endocrinology and Metabolism, 4th ed. Philadelphia, BC Decker, 1991, pp 68-70. Burch HB, Wartofsky L: Life-threatening thyrotoxicosis. Endocrinol Metab Clin North Am 22:263-277, 1993. Connery LE, Coursin DB: Assessment and therapy of selected endocrine disorders. Anesthesiol Clin North Am 22:93-123, 2004. Farling PA: Thyroid disease. Br J Anaesth 85:15-28, 2000. Gavin LA: Thyroid crises. Med Clin North Am 75:179-193, 1991. Knighton JD, Crosse MM: Anaesthetic management of childhood thyrotoxicosis and the use of esmolol. Anaesthesia 52:62-76, 1997. Lacoste L, Gineste D, Karayan J, et al: Airway complications in thyroid surgery. Ann Otol Rhinol Laryngol 102:441-446, 1993. Nishiyama K, Kitahara A, Natsume H, et al: Malignant hyperthermia in a patient with Graves’ disease during subtotal thyroidectomy. Endocr J 48:227-232, 2001. Pandey CK, Raza M, Dhiraaj S, et al: Rapid preparation of severe uncontrolled thyrotoxicosis due to Graves’ disease with iopanoic acid. Can J Anaesth 51:38-40, 2004. Peters KR, Nance P, Wingard DW: Malignant hyperthyroidism or malignant hyperthermia? Anesth Analg 60:613-615, 1991. Pugh S, Lalwani K, Awal A: Thyroid storm as a cause of loss of consciousness following anaesthesia for emergency caesarean section. Anaesthesia 49:35-37, 1994.

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Sarcoidosis Barry A. Harrison and Martin L. De Ruyter Case Synopsis A 50-year-old African American woman with stage III pulmonary sarcoidosis is scheduled to undergo a thoracotomy for resection of a right upper lobe aspergilloma. Chronically, she has a hoarse voice, dyspnea at rest, and swollen ankles. She is receiving corticosteroids and ambulatory oxygen therapy at a rate of 2 L/minute. She complains of palpitations and fainting spells.

PROBLEM ANALYSIS Definition Sarcoidosis is a systemic granulomatous disease of unknown cause. A complex interaction of genetic, environmental, and infectious agents triggers a type 1 T-lymphocyte response that is characterized by chronic inflammation, monocyte recruitment, and granuloma formation. Characteristic pathohistologic findings include noncaseating granulomas that are both discrete and compact. These granulomas are composed of mononuclear phagocytes, including epithelioid cells, multinucleated central giant cells, and lymphocytes. The multinucleated central giant cells are surrounded by fibroblasts and mast cells (Fig. 109-1).

CLINICAL FEATURES Sarcoidosis occurs mainly in individuals between the ages of 20 and 40 years, with a prevalence in the United States of approximately 20 in 100,000. It is slightly more common in females than in males and has a black-white ratio of 15:1. Sarcoidosis may present acutely, subacutely, or insidiously. Between 30% and 60% of cases are asymptomatic, detected incidentally by an abnormal chest radiograph. Constitutional symptoms may occur and consist of fever, fatigue, anorexia,

PULMONARY PRESENTATION Upper Airway. Although laryngeal sarcoid involvement may be an isolated finding, it is usually associated with systemic manifestations. It occurs in <5% of patients with sarcoidosis. Symptoms and signs of laryngeal sarcoidosis include dysphagia, hoarseness, throat pain, dyspnea, and stridor. Granulomas or nodules involving the supraglottic larynx or the entire larynx are often found (Fig. 109-2). Airway obstruction can occur, and a tracheostomy may be necessary in some cases. Recurrent laryngeal nerve involvement can result in unilateral vocal cord paralysis. Lower Airway. Enlarged intrathoracic lymph nodes can compress large airways, potentially causing tracheal and bronchial stenosis, airflow obstruction, and pulmonary atelectasis. Pulmonary Parenchyma. The lung and intrathoracic lymph nodes are involved in >90% of cases. Approximately 50% of patients develop permanent pulmonary abnormalities, with 5% to 15% developing pulmonary fibrosis. Chronic hypoxemic respiratory failure and cor pulmonale may result from pulmonary sarcoidosis.

Figure 109–1 ■ Sarcoid granulomas in lung tissue. (Photomicrograph courtesy of Dr. Thomas A. Gaffey, Department of Pathology, Mayo Clinic and Foundation, Rochester, Minn.)

Chest Radiographic and Laboratory Findings. Ninety percent of patients with sarcoidosis have an abnormal chest radiograph at some time. Three classic chest radiographic patterns have been described, with higher stages correlating with an increased frequency of dyspnea (Table 109-1). An increase in the serum concentration of angiotensin-converting enzyme (ACE), which is secreted by sarcoid granulomas, can assist in making the diagnosis. Unfortunately, other chronic inflammatory conditions are also associated with increased 457

PHYSIOLOGIC IMBALANCE & COEXISTING DISEASE

Recognition

cough, dyspnea, and vague retrosternal discomfort. Syndromes such as erythema nodosum, anterior uveitis, arthritis, parotid enlargement, and facial nerve palsy occur in acute sarcoidosis. In patients with an insidious presentation, respiratory symptoms usually predominate. Diagnosis requires relevant clinical features and a tissue biopsy showing characteristic noncaseating granulomas. The degree and variability of disease activity together with the organ involved determine the clinical presentation. These factors contribute to the delay in diagnosis observed in sarcoid patients. Death from sarcoidosis usually results from progressive pulmonary, cardiac, or neurologic involvement.

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disease elsewhere. Cardiac involvement may manifest as cardiac arrhythmias (ventricular more often than supraventricular), conduction disorders, cardiomyopathy, pericarditis, wall motion abnormalities, or cardiac arrest. Electrocardiography, echocardiography, and, in select patients, cardiac catheterization with myocardial biopsy may be helpful in evaluating patients with cardiac findings. Myocardial sarcoidosis may be difficult to diagnose in the absence of systemic manifestations. Myocardial biopsy may be falsely negative owing to sampling bias. Cor pulmonale may result from pulmonary parenchymal disease. Sudden death is associated with cardiac sarcoidosis; however, with progress in the development of antiarrhythmic drugs, cardiac pacemakers, and implantable defibrillators, congestive heart failure associated with myocardial sarcoidosis is now a more frequent cause of death. MULTISYSTEM PRESENTATION Sarcoidosis is a systemic disease; multiple organ systems can be involved and have implications for the anesthesiologist (Table 109-2). Figure 109–2 ■ Granulomas involving the supraglottic region. (From Neel HB, McDonald TJ: Laryngeal sarcoidosis. Ann Otol Rhinol Laryngol 91:361, 1982.)

Risk Assessment Risk assessment is dependent on the extent and severity of sarcoidosis and the organ system affected.

serum ACE. Recent findings demonstrate that serum ACE is not consistently correlated with disease activity or treatment response. Computed Tomography. High-resolution computed tomography (CT) is helpful if the chest radiograph is equivocal; a diagnosis can be made in up to 75% of cases. Highresolution CT can be used to diagnose small, well-defined nodes and peribronchial interstitial thickening, whereas conventional CT is better for the evaluation of diffuse parenchymal sarcoidosis (Fig. 109-3). Transbronchial Biopsy. Transbronchial biopsy is diagnostic in 90% of cases. The yield is excellent even if interstitial infiltrates are not detectable on chest radiography. Bronchoalveolar Lavage. Lavage may be helpful, especially if the lymphocyte population is analyzed. A CD4/CD8 ratio greater than 3.5 is 94% specific for sarcoidosis. CARDIAC PRESENTATION Clinically overt cardiac involvement occurs in about 5% of patients with sarcoidosis, usually without evidence of

Table 109–1

■

PULMONARY ASSESSMENT As elastic resistance of the lungs is increased, patients with sarcoidosis adapt to reduce the work of breathing by taking rapid, shallow breaths. Most commonly there are reductions in lung volume and the diffusing capacity for carbon monoxide (Fig. 109-4). Expiratory flow rates may also be decreased, suggesting airflow obstruction. Arterial hypoxemia with exercise occurs frequently; arterial hypoxemia at rest indicates severe disease. Although sarcoid lung pathology is caused by granuloma and fibrosis, pulmonary function testing may reflect disease extent but not necessarily disease activity. However, such testing may provide objective data when following a patient’s response to therapy. CARDIAC ASSESSMENT Electrocardiography and 24-hour electrocardiographic monitoring, echocardiography, and cardiac catheterization with myocardial biopsy may be helpful in the evaluation of cardiac sarcoidosis. Thallium 201 myocardial imaging may demonstrate segmental defects consistent with sarcoid granulomas or fibrous scars. Magnetic resonance imaging has

Three Classic Chest Radiograph Patterns in Sarcoidosis

Chest Radiograph Pattern

Radiographic Findings

Stage I Stage II Stage III

Hilar and mediastinal abnormality without pulmonary parenchymal abnormality Hilar and mediastinal abnormality associated with pulmonary parenchymal abnormality Diffuse pulmonary disease without node enlargement

ACE, angiotensin-converting enzyme.

Incidence of ACE Elevation (%) 67 88 95

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Figure 109–3 ■ Left, Bilateral hilar lymphadenopathy (stage I). Middle, Bilateral hilar lymphadenopathy and interstitial infiltrates (stage II). Right, Highresolution chest computed tomography scan showing extensive nodular interstitial process. (Radiographs courtesy of Department of Radiology, Mayo Clinic and Foundation, Rochester, Minn.)

also been used to identify areas of myocardium affected by sarcoidosis and to guide myocardial biopsy.

Self-Limited Disease

Implications

■

Over a 3-year period following diagnosis, approximately 30% to 50% of cases remit spontaneously. Of the remaining approximately 50% of cases that do not show remission, over the next 5 to 10 years, 30% of those patients show disease progression, while the remaining 20% remain stable. Thus, not all patients with sarcoidosis require specific therapy, especially those with a stage I radiographic pattern.

Corticosteroids, Cytotoxics, and Immunosuppressive Therapy Treatment for sarcoidosis is indicated for progressive symptomatic disease. Clear-cut examples include cardiac and neurologic sarcoidosis and hypocalcemia secondary to sarcoidosis. Pulmonary sarcoidosis with respiratory symptoms

Multisystem Involvement in Sarcoidosis

Organ System (Incidence of Involvement) Nervous (5%)

Manifestations

Hepatic (12%) Hematopoietic (26%)

Peripheral neuropathies, central nervous system symptoms: meningitis, encephalitis, epilepsy, cranial nerve disturbances Arthritis of peripheral joints: ankles, knees, wrists, hands; ankylosis of temporomandibular joints Hypercalciuria with or without hypercalcemia, nephrocalcinosis, nephrolithiasis Hepatomegaly, abnormal liver function tests Anemia, thrombocytopenia, neutropenia, eosinophilia, splenomegaly

Eye (12%) Skin (15%)

Uveitis, conjunctival nodules, keratoconjunctivitis sicca Erythema nodosum, plaques, subcutaneous nodules

Endocrine (4%)

Posterior pituitary: diabetes insipidus, hypercalcemia

Musculoskeletal (1%) Renal (1%)

Anesthetic Implications Use caution with muscle relaxants Examine the airway Altered drug excretion Altered drug metabolism Check complete blood count Standard eye precautions Lesions may be tender and painful Monitor serum Ca2+, Na+, and urine output

From Baughman RP, Teirstein AS, Judson MA, et al: Clinical characteristics of patients in a case control study of sarcoidosis. Am J Respir Crit Care Med 164:1885–1889, 2001.

PHYSIOLOGIC IMBALANCE & COEXISTING DISEASE

Patients with sarcoidosis undergo procedures for biopsy and diagnosis that may require anesthesia. These include fiberoptic bronchoscopy with transbronchial biopsy, scalene node biopsy, and mediastinoscopy for hilar lymph node biopsy and lung biopsy, either by video-assisted thoracoscopy or thoracotomy. Many patients with sarcoidosis require anesthesia owing to a complication of therapy (e.g., perforated duodenal ulcer secondary to corticosteroid therapy). Sarcoid patients routinely require anesthesia for comorbid conditions. In the case synopsis, the patient had developed an aspergilloma fungus ball in a lung cavity due to cystic destruction of lung tissue by sarcoidosis. Progressive pulmonary sarcoidosis with chronic hypoxemic respiratory failure and right heart failure or progressive cardiac sarcoidosis can cause problems with anesthesia and increase risk.

Table 109–2

MANAGEMENT

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Maximal expiratory flow (L/sec)

12 Spirometry FVC FEV1 FEV1/FVC FEF 25-75 Lung volumes TLC (Pleth) VC RV RV/TLC Diffusing capacity DLCO(SB) Alveolar volume

10 8 6 4

Found

Predicted(%)

1.19 1.14 95.8 2.6

37 42

2.02 1.19 0.83 41.1

47 37 77 164

4 1.80

18 42

94

2 0

0

1

2

3 4 5 Expired volume (L)

6

7

8

Figure 109–4 ■ Expiratory flow volume loop. Solid line is the patient with sarcoid; dashed line is the normal predicted loop. The insert contains the values of spirometry, lung volumes, and diffusing capacity of a patient with pulmonary sarcoidosis. DLCO(SB), diffusing capacity of carbon monoxide, single breath; FEF25-75, forced expiratory flow rate between 25% and 75% of a forced vital capacity; FEV1, forced expiratory volume in 1 second; FVC, forced vital capacity; RV, residual volume; TLC, total lung capacity; VC, vital capacity. (Data from Pulmonary Function Laboratory, Mayo Clinic and Foundation, Rochester, Minn.)

Chronic Hypoxemic Respiratory Failure and Cor Pulmonale Long-standing progressive pulmonary sarcoidosis may give rise to chronic hypoxemic respiratory failure and cor pulmonale. The latter is pulmonary arterial hypertension resulting from diseases affecting lung structure or function. Pulmonary arterial hypertension results in right ventricular enlargement (hypertrophy or dilatation) and may progress over time to right heart failure. The treatment of both conditions is first and foremost the titration of continuous oxygen to increase arterial oxygen saturation to above 90%. If right-sided heart failure is present, diuresis, initially with bed rest and then, if necessary, with diuretics (often furosemide), should be initiated. Excessive fluid loss is dangerous, however, because it may decrease right ventricular preload. Digitalis use is controversial because the potential for digitalis toxicity is high, even with low serum concentrations, when hypoxemia, alkalosis-induced hypokalemia, and cor pulmonale are present. The use of pulmonary vasodilators is undergoing investigation.

PREVENTION associated with progressive loss of lung function also requires treatment. A systemic evidence-based review of corticosteroids in sarcoidosis found that they improved radiographic assessment (stage II and III radiographic patterns) and pulmonary function. However, no data exist demonstrating that corticosteroids have a significant effect on long-term disease progression. A 3-month trial of corticosteroids is required before reevaluating the patient. Although inhaled corticosteroids have been tried, insufficient clinical trials have been conducted to determine their efficacy. Cytotoxics and antimalarials are used in sarcoidosis to control disease progression, especially if cortocosteroids have failed or in an effort to decrease the corticosteroid dosage. Methotrexate, azathioprine, and chloroquine have all been used. However, such use has usually been reported anecdotally or in small case series. There have been only four studies evaluating these drugs in a prospective, controlled manner. Results were inconclusive, and all the drugs were associated with severe side effects. Activated T lymphocytes secreting interleukin-2 may play a role in sarcoidosis, which has led to trials of cyclosporine for the treatment of sarcoidosis. Unfortunately, these trials have also failed to show any benefit. Thalidomide and antagonists to tumor necrosis factor-α are currently undergoing therapeutic trials.

Lung Transplantation Single or bilateral lung transplantation has been tried in patients with end-stage lung disease who are refractory to aggressive medical therapy. Recurrence of sarcoid granulomas within the lung allografts occurs in a majority of patients but rarely causes clinical symptoms. The survival rate for single- or double-lung transplantation is 70% at 2 years.

Preoperative Because sarcoidosis is a multisystem disease, all systems must be evaluated for possible sarcoid involvement during the preoperative assessment. Symptoms and signs of upper airway involvement with sarcoidosis must be specifically addressed before tracheal intubation. Chronic corticosteroid use and the associated potential for adrenal insufficiency must be evaluated, and preoperative corticosteroids should be administered if necessary.

Operative If chronic hypoxemic respiratory failure and right-sided heart failure are present, hypoxia, hypercapnia, and acidosis must all be avoided because they act to increase pulmonary artery pressure, further exacerbating right heart failure. Central venous pressure monitoring to guide intravascular fluid administration and the use of a pulmonary artery catheter to determine pulmonary artery pressure and cardiac output may also be necessary. Regional anesthesia may be advantageous if the surgical site is below the level of the umbilicus. In patients with ventilatory compromise, the usual accessory function of the intercostal muscles may make a larger contribution to overall ventilation. If so, high central neuraxial blockade may interfere with intercostal muscle function and exacerbate the tenuous oxygen supplydemand balance. Large-volume intravenous fluid administration to treat hypotension associated with sympathetic blockade may exacerbate right-sided heart failure. Therefore, blood pressure is maintained with intravenous vasopressors (e.g., phenylephrine) to ensure adequate venous return to the right heart. During general anesthesia, mechanical ventilation may be necessary. If so, titration of positive endexpiratory pressure and oxygen to maintain an oxygen saturation of at least 90% is necessary. Limit the plateau airway

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pressure to less than 35 cm H2O by adjusting the tidal volume and inspiratory flow rates. Careful titration of all these parameters may help prevent further lung injury.

Postoperative With sarcoidosis-induced chronic hypoxemic respiratory failure and right-sided heart failure, careful consideration must be given to postoperative analgesia. Systemic opioid administration may depress ventilation and precipitate hypoxia. Thus, a central neuraxial technique may be preferable, with the use of local anesthetic agents, opioids, or both. Also, use of local anesthetics via continuous peripheral nerve blockade optimizes analgesia and limits respiratory side effects. Titration of inspired oxygen is advised to maintain oxygen saturation greater than 92%.

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Further Reading Baughman RP, Lower EE, Du Bois R: Sarcoidosis. Lancet 361:1111-1118, 2003. Clark D, Mitchell AW, Dick R, et al: The radiology of sarcoidosis [review]. Sarcoidosis 11:90-99, 1994. Karl TK: Sarcoidosis. JAMA 289:3300-3303, 2003. Paramothayan S, Jones PW: Corticosteroid therapy in pulmonary sarcoidosis: A systematic review. JAMA 287:1301-1307, 2002. Paramothayan S, Lasserson T, Walters EH: Immunosuppressive and cytotoxic therapy for pulmonary sarcoidosis. Cochrane Database of Syst Rev 2:2004. Weitzenblum E: Chronic cor pulmonale. Heart 89:225-230, 2003. Wills MH, Harris MM: An unusual airway complication with sarcoidosis. Anesthesiology 66:554-555, 1987.

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Klaus D. Torp Case Synopsis A 43-year-old gas station attendant is scheduled for emergency exploratory laparotomy after sustaining an abdominal stab wound during an attempted robbery. He is dialysis dependent and awaiting renal transplantation. His last hemodialysis was 52 hours earlier. He is awake and alert. His blood pressure is 102/90 mm Hg; heart rate, 114 beats per minute; and respiratory rate, 24 breaths per minute. His hemoglobin level is 8.2 g/dL after receiving 3 units of packed red blood cells; the serum potassium level before the transfusion was 6.0 mEq/L. While cricoid pressure is applied, anesthesia is induced with etomidate, fentanyl, and rocuronium. Soon after the operation begins, the surgeon complains of difficulty achieving hemostasis. T waves on the electrocardiogram are tall and peaked.

PROBLEM ANALYSIS Definition Approximately 500,000 patients are affected by end-stage renal disease (ESRD) in the United States, with an estimated incidence of about 333 per 1 million persons (quadrupled from 1980) and a prevalence of 1435 per 1 million (quintupled from 1980). Prevalence rates are 1.4 times higher for males than for females and 4 times higher for African Americans than for whites. Those aged 45 to 64 years account for the largest number of patients. About 45% of all ESRD patients have a primary diagnosis of diabetes, another 30% are hypertensive, and less than 20% have glomerulonephritis; the remainder have rarer diseases, such as the following: ● ● ● ● ● ● ● ●

Polycystic kidney disease Immunoglobulin (Ig) A and IgM nephropathies Systemic lupus erythematosus Wegener’s granulomatosis Multiple myeloma Amyloidosis Acquired immunodeficiency syndrome (AIDS) nephropathy Miscellaneous causes or conditions

Patients with these rarer causes tend to be younger and are less likely to present with the typical comorbidities of dialysis patients. In 2002 about 100,000 patients began treatment for ESRD with hemodialysis, peritoneal dialysis, or renal transplantation. Dialysis is usually required when the glomerular filtration rate falls below 20 mL/minute. Dialysis may also be indicated for hospitalized patients with volume overload refractory to diuretics, severe metabolic acidosis, hyperkalemia, seizures or other neurologic symptoms, or pericarditis. It is usually started when the blood urea nitrogen is 462

greater than 100 mg/mL or the creatinine level approaches 10 mg/dL. Regardless of cause, ESRD affects virtually all organ systems (Table 110-1) and has implications for anesthesiologists, intensivists, and surgeons. These abnormalities result from the failure to excrete urea and other waste products of metabolism or the loss of metabolic and endocrine functions normally performed by the kidney.

Recognition Perioperative complications of ESRD are listed in Table 110-2. The most frequent life-threatening perioperative complication is hyperkalemia. It is frequently associated with acidosis and with trauma due to the release of potassium from damaged tissue and hematomas. Hyperkalemia can cause progressive cardiac conduction defects, ending in ventricular fibrillation or, less commonly, asystole (Table 110-3). Electrocardiographic changes are critically dependent on the rate of rise in serum potassium levels (i.e., acute versus chronic hyperkalemia). An increased propensity for bleeding often occurs in the presence of uremia because of an acquired defect in primary hemostasis. Tests of coagulation are typically normal, although a slight reduction in platelet counts may be seen. The pathogenesis is multifactorial, and the major defects involve decreased platelet–vessel wall adhesion and plateletplatelet interactions manifesting as impaired aggregation in response to epinephrine, adenosine diphosphate, collagen, and fibrinogen. Platelets from uremic patients release less adenosine triphosphate and serotonin and also display reduced cyclooxygenase activity. The activation-dependent receptor function of the glycoprotein IIb/IIIa complex is defective in uremia, as shown by decreased binding of both von Willebrand’s factor (vWF) and fibrinogen to stimulated platelets. Cutaneous bleeding time remains the most readily

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Table 110–1

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Perioperative Management of Dialysis-Dependent Patients

Clinical Abnormalities in End-Stage Renal Disease

Nervous System Sleep disorders Motor weakness Polyneuritis Asterixis Seizures Coma

Hematologic System Anemia Increased fragility of red blood cells Platelet dysfunction with bleeding Thrombosis

Metabolic and Endocrine Systems Glucose intolerance Hyperparathyroidism Hypogonadism

Immunologic System Increased susceptibility to infection

Integumentary System Pruritus

Cardiovascular System Hypertension Hypotension Cardiomyopathy Diastolic dysfunction Left ventricular hypertrophy Congestive cardiac failure Pericarditis

Gastrointestinal System

Acid-Base and Electrolytes Anion gap metabolic acidosis Hyperkalemia Hyponatremia Hypermagnesemia or hypomagnesemia Hyperphosphatemia

■

Electrocardiographic Changes with Progressive Hyperkalemia

K+ (mEq/L)

Electrocardiographic Abnormality

5.0 6.0 7.0

Usually none or tenting of T waves Tall and peaked T waves Prolonged P-R interval with depressed ST segments Sinoatrial arrest with “sine wave” QRS complex Ventricular fibrillation

8.0 9.0

frequently noted. In fact, some patients receive antiplatelet agents to prevent thrombosis of arteriovenous grafts, as well as for cardiovascular disease, which in turn may contribute to the bleeding tendency. Cardiovascular dysfunction is common in patients with ESRD. This is not surprising, given the high prevalence of hypertension, left ventricular hypertrophy, and coronary artery disease in patients on chronic dialysis. Further, diminished responsiveness of cardiac α- and β-adrenergic receptors due to dysautonomia results in poor compensatory responses to acute hemodynamic changes. Hypoxemia and dysequilibrium syndrome are two complications of which anesthesiologists should be aware. They can occur either during or soon after dialysis. Hypoxemia is more common when acetate rather than bicarbonate is used in the dialysate, and it is due to both alveolar hypercapnia and complement-induced pulmonary inflammation. Any associated hypoxemia is usually transient. Dysequilibrium is caused by rapid removal of urea and other osmotically active agents while the blood-brain barrier prevents their rapid removal from brain cells. These become relatively hypertonic. Fluid diffuses into brain cells along an osmotic gradient. Therefore, cerebral edema may result.

Musculoskeletal System

Risk Assessment

Renal osteoporosis or osteomalcia

Patients who are dialysis dependent and undergo major surgical procedures have a higher perioperative mortality rate than patients with normal renal function. It is particularly high for patients undergoing open-heart surgery (approximately 12%, versus 2.9% in nondialysis patients). The risk of major surgery is related to abnormalities directly attributable to ESRD, as well as to the underlying disease process (e.g., hypertension). In dialysis patients, diastolic dysfunction is as common a cause of congestive heart failure as dilated cardiomyopathy is. Therefore, in patients with ESRD, a relatively small excess of ingested sodium chloride and water can lead to a large increase in left ventricular enddiastolic pressure, resulting in pulmonary edema. The probability of having angina or a myocardial infarction requiring hospitalization is 10% per year, and cardiac disease accounts for 45% of deaths in patients on dialysis. Anemia and hypertension are independent predictors of mortality. The 5-year survival rate after the initiation of dialysis is around 33%, and the life expectancy is only about one fourth that of the general population. Anesthetic drugs such as succinylcholine (which causes an increase in serum potassium levels after intubating doses)

available test of platelet function, although its accuracy is often questioned. A markedly prolonged bleeding time with a relatively normal platelet count should trigger efforts to correct this abnormality. Despite the bleeding tendency in patients with ESRD, hypercoagulability markers (e.g., elevated vWF activity and thromboelastographic amplitudes) are

Table 110–2

■

Perioperative Complications of End-Stage Renal Disease

Hyperkalemia Bleeding Cardiovascular dysfunction Hypertension or hypotension Congestive heart failure Ischemia Sepsis Graft thrombosis

PHYSIOLOGIC IMBALANCE & COEXISTING DISEASE

Gastrointestinal bleeding Pancreatitis

Table 110–3

463

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can contribute to the risk of death. The need for multiple blood transfusions also increases serum potassium levels, as does acidosis resulting from long periods of hypoperfusion or the failure to adequately compensate for increasing metabolic acidosis with an increase in minute ventilation. Drug overdoses can occur owing to reduced renal clearance of the drug itself or its active metabolites, which is more of a concern with repeat dosing. However, increased unbound fractions of a drug caused by decreased plasma proteins may lead to relative overdose with initial intravenous dosing of some drugs (e.g., thiopental, methohexital, diazepam). All anesthetic techniques have the potential to reduce renal perfusion and adversely affect any residual renal function, with important implications for the patient’s health.

Implications The potential for serious life-threatening problems relating to electrolyte, coagulation, and acid-base problems is always present. This is compounded by any underlying or coexistent diseases, especially serious cardiovascular abnormalities.

MANAGEMENT General principles for the management of all ESRD patients undergoing surgery, regardless of the cause of ESRD, are listed in Table 110-4.

Hyperkalemia The management of acute hyperkalemia can be divided into three steps (Table 110-5). First, treatment is directed toward antagonizing the adverse effects of increased potassium by administering intravenous calcium. Second, potassium is shifted intracellularly by stimulating Na+,K+-ATPase or using its electrochemical gradient. Third, potassium is removed from the body with dialysis or exchange resins.

Bleeding in Uremic Patients Treatment with erythropoietin or infusion of washed red blood cells has been shown to significantly reduce bleeding times in uremic patients with a hematocrit above 30%. Erythrocytes enhance platelet function by releasing adenosine

Table 110–5

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Table 110–4

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General Management Principles for Patients with End-Stage Renal Disease Undergoing Surgery

Dialysis within 24 hr of surgical procedure Serum potassium in normal range Serum bicarbonate ≥20 mEq/L desirable Euvolemic or minimally hypovolemic before surgical procedure Hematocrit around 30% Use potassium-free fluid; wash red blood cells to minimize transfused potassium load Use caution with succinylcholine Choose drugs that do not depend on renal elimination; adjust (decrease) dosages of drugs that depend on renal metabolism or that are highly protein bound Use strict aseptic techniques when placing intravascular devices Identify and adequately protect functioning shunts during surgical procedures Pay attention to padding of pressure points

diphosphate, inactivating prostacyclin, and increasing platelet–vessel wall contact (i.e., directing platelets toward the vessel wall instead of the usual axial flow). Infusion of desmopressin (DDAVP), which has less pressor effect than vasopressin, stimulates the release of vWF from endothelial cells. This may explain its therapeutic effect in uremia. DDAVP is given intravenously at a dose of 0.3 μg/kg in 50 mL of normal saline over 15 to 30 minutes. It shortens bleeding times in 50% to 75% of uremic patients. This correction occurs in 30 to 60 minutes and lasts for about 4 hours, correlating with increased plasma concentrations of vWF, as well as an increase in the proportion of high-molecularweight multimers of vWF. Tachyphylaxis typically occurs after the second DDAVP dose, possibly owing to depletion of endothelial multimer stores. Cryoprecipitate, which is rich in factor VIII and vWF, can also be used at an initial dose of 10 to 20 units. Its onset of action is similar to that of desmopressin, but the beneficial effects persist for 24 to 36 hours. Conjugated estrogen (Premarin 0.6 mg/kg per day intravenously for 5 days) is effective before elective major operations, and its beneficial effects persist for 3 to 4 weeks. Hemodialysis significantly ameliorates platelet dysfunction and should be used, if required, within 24 hours of the planned operation.

Treatment Modalities for Acute Hyperkalemia

Mechanism

Intervention

Antagonism of K+ effects Shift K+ intracellularly (effective within 30 min)

Calcium chloride or calcium gluconate 1-2 g (slow IV push) Moderate hyperventilation Insulin 20 units/dextrose 50 g IV infusion over 20-30 min Sodium bicarbonate 50-100 mEq IV Albuterol 10 mg (nebulized) Epinephrine 0.01 μg/kg/min IV Sodium polystyrene sulfonate (Kayexalate: 30 g sodium polystyrene sulfonate in 100 mL 20% sorbitol) administered via nasogastric tube (100 mL = 30 g) or rectally (100-200 mL = 30-60 g) Caution: This exchanges potassium for sodium and may lead to pulmonary edema Emergency hemodialysis (even intraoperatively, if required) Caution: Increases risk for hypotension and bleeding

Remove K+ from the body

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PREVENTION Complications of ESRD in the perioperative period are best prevented by consulting a nephrologist to perform dialysis the day before surgery and to arrange for dialysis in the immediate postoperative period or intraoperatively if necessary. There is accumulating evidence that more aggressive treatment of predialysis hypertension is a potent intervention for reducing subsequent perioperative cardiovascular mortality. Also, early treatment of anemia is recommended because it may delay or prevent left ventricular hypertrophy and reduce bleeding problems. Prevention and treatment of acidosis (serum bicarbonate >20 mEq/L) to establish an acid buffer can help reduce the risk of hyperkalemia. After major surgery, any of these methods has the potential to reduce the high morbidity and mortality rates formerly associated with ESRD and improve patient outcomes.

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Janson PA, Jubelirer SJ, Weinstein MJ, et al: Treatment of bleeding tendency in uremia with cryoprecipitate. N Engl J Med 303:1318-1322, 1980. Kasiske BL: Dialysis in special clinical situations: Anesthesia. In Jacobs C, et al (eds): Replacement of Renal Function by Dialysis. Dordrecht, The Netherlands, Kluwer Academic Publishers, 1996, pp 954-957. Kentro TB, Lottenberg R, Kitchens CS: Clinical efficacy of desmopressin acetate for hematocrit control in patients with primary platelet disorder undergoing surgery. Am J Hematol 24:215-219, 1987. Morbidity and mortality of renal dialysis: An NIH consensus conference statement. Ann Intern Med 121:62-70, 1994. Remuzzi G, et al: Effect of renal failure on hemostasis. In Brenner & Rector’s The Kidney, 7th ed. Philadelphia, WB Saunders, 2004, pp 2173-2178. Sladen R: Anesthetic considerations for the patient with renal failure. Anesthesiol Clin North Am 18:863-882, 2000. United States Renal Data System 2004 Annual Data Report. Bethesda, Md, National Institute of Diabetes and Digestive and Kidney Diseases, 2004. Available at www.usrds.org.

Further Reading Boccardo P: Platelet dysfunction in renal failure. Semin Thromb Hemost 30:579-589, 2004. Foley RN, Parfrey PS, Harnett JD, et al: Clinical and echocardiographic cardiovascular disease in patients starting end stage renal disease therapy: Prevalence, association and progress. Kidney Int 47:186-192, 1995.

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Perioperative Care for Patients with Hepatic Insufficiency (Cirrhosis) Laurence C. Torsher Case Synopsis A 67-year-old man is scheduled for a right total hip arthroplasty. He has consumed more than 80 g/day of alcohol for the past 15 years. The physical examination is remarkable for numerous spider angiomas, hepatosplenomegaly, and moderate ascites. Laboratory results (with range of normal values) are as follows: hemoglobin, 11.2 g/dL (13.6 to 17.2 g/dL); platelet count, 87 × 109/L (150 to 300 × 109/L); total bilirubin, 2.4 mg/dL (0.3 to 1.0 mg/dL); aspartate aminotransferase, 117 units/L (0 to 35 units/L); alanine aminotransferase, 52 units/L (0 to 35 units/L); and prothrombin time, prolonged by 5 to 15 seconds, with an international normalized ratio (INR) of 1.5.

PROBLEM ANALYSIS Definition As the prevalence of liver disease, as well as the survival of those affected, increases, patients with hepatic insufficiency presenting for elective surgery will become more common. Cirrhosis is a disease characterized by irreversible fibrous scarring of the liver in response to hepatocyte injury and death, with regenerative parenchymal nodule formation that disrupts the normal hepatic architecture. Cirrhosis results in loss of functioning hepatocyte mass, and associated scarring and hepatocellular regeneration disorganize the usual hepatic vasculature, leading to portal hypertension. Cirrhosis impairs the liver’s normal function, which includes filtration of portal blood; metabolism of protein, carbohydrates, fat, hormones, and exogenous chemicals, including drugs; synthesis and excretion of bile; and synthesis of coagulation factors. The most common cause of cirrhosis in the United States is excessive and prolonged consumption of alcohol, but it can result from other chronic diseases as well (Table 111-1). Complications of cirrhosis are listed in Table 111-2.

Recognition As many as 10% of men and 5% of women are alcoholic at some time in their lives; however, only 10% to 15% of alcoholics develop cirrhosis. Up to 50% of all hospitalized patients have abused alcohol at one time or another. Ten percent of patients with liver disease undergo operative procedures during the final 2 years of their lives. Cirrhosis has numerous signs and symptoms that may involve many organ systems. Cardiovascular. Cirrhosis is usually associated with a hyperdynamic circulatory state and an increased cardiac output. 466

The increase in cardiac output may be secondary to arteriovenous malformations, especially in the lungs; hypoviscosity secondary to anemia; and increased intravascular volume. Chronic alcohol ingestion can also lead to an alcoholinduced cardiomyopathy that manifests with arrhythmias, low cardiac output, and congestive heart failure.

Table 111–1

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Causes of Cirrhosis

Alcohol Biliary cirrhosis Primary Secondary Sclerosing cholangitis Biliary atresia Bile duct stricture or tumor Infection Viral (hepatitis A, B, C; cytomegalovirus; Epstein-Barr; herpes) Bacterial (brucellosis) Parasitic (capillariasis, echinococcosis, schistosomiasis, toxoplasmosis) Autoimmune chronic active hepatitis Drugs and toxins Methotrexate Methyldopa Amiodarone Isoniazid Steroids Oral contraceptives Arsenic Inherited and metabolic disorders Hemochromatosis Wilson’s disease α1-Antitrypsin deficiency Galactosemia Cystic fibrosis Cryptogenic Graft-versus-host disease Nonalcoholic steatohepatitis

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Perioperative Care for Patients with Hepatic Insufficiency (Cirrhosis)

Complications of Cirrhosis

Portal hypertension Varix formation and variceal bleeding Splenomegaly with hypersplenism and platelet sequestration Ascites formation Spontaneous bacterial peritonitis Decreased gastric emptying Decreased appetite Hydrothorax Hepatorenal syndrome Hepatic encephalopathy Portopulmonary hypertension Coagulopathy Thrombocytopenia Decreased coagulation factor production Low-grade disseminated intravascular coagulation Anemia Hepatocellular carcinoma Malnutrition Osteoporosis Altered immune defenses

Hematologic. Patients with liver disease have multiple hemostatic defects due to reduced synthesis of clotting and fibrinolytic factors. Vitamin K–dependent factors (II, VII, IX, and X) are decreased, as are plasminogen and fibrinogen levels. Owing to splenomegaly caused by portal hypertension, thrombocytopenia and leukopenia are common. Abnormal platelet function has also been observed in patients with cirrhosis. Anemia is due to acute and chronic gastrointestinal blood loss, nutritional deficiency, and bone marrow depression. Gastrointestinal. Portal hypertension may lead to collateral circulation, causing large varices of the stomach, esophagus, anus (hemorrhoids), and umbilicus. These are susceptible to bleeding. Portal venous blood flow is reduced. Ascites and splanchnic congestion can lead to decreased bowel motility and gastric emptying. Renal. Fluid and electrolyte disorders can present as ascites, edema, hyponatremia, hypokalemia, or the hepatorenal syndrome. There is also the potential for hypoalbuminemia and hypoglycemia. Patients with cirrhosis have decreased glomerular filtration rate, avid sodium and water retention, and impaired free water clearance. Secondary hyperaldosteronism and diuretic-induced hypovolemia may lead to

increased water retention, hyponatremia, and other electrolyte abnormalities. Multiple factors may lead to abnormalities in functional circulating fluid volume. Thus, prerenal renal failure is common. Measurement of creatinine levels may underestimate the degree of renal impairment. Central Nervous System. The symptoms of hepatic encephalopathy can range from apathy and restlessness to coma. It is believed to be secondary to inadequate removal of toxins or nitrogenous compounds. Asterixis is a common finding in hepatic encephalopathy. Also, patients who are still actively consuming alcohol are at risk for alcohol withdrawal during hospitalization.

Risk Assessment The history should focus on (1) risk factors for liver disease (e.g., alcohol, drug, or chemical exposure), (2) family history, and (3) symptoms suggestive of liver disease (e.g., jaundice, easy bleeding, expanding abdominal girth). The physical examination focuses on identifying findings compatible with liver disease (e.g., hepatosplenomegaly, right upper quadrant tenderness, ascites, encephalopathy, asterixis, palmar erythema, gynecomastia in men). If the history and physical examination suggest liver disease, blood should be tested for prothrombin time, aspartate aminotransferase and alanine aminotransferase concentrations, total and direct bilirubin, alkaline phosphatase, albumin, complete blood count, creatinine, electrolytes, glucose, and hepatitis viral serology. Other laboratory tests based on comorbid conditions should be carried out as indicated. Table 111-3 lists other perioperative risk factors.

Implications The modified Child-Pugh score (Table 111-4) identifies patients as class A, B, or C, based on prothrombin time, albumin and bilirubin concentrations, and the presence of ascites or encephalopathy. Although originally developed for the risk stratification of patients undergoing esophageal surgery, the Child-Pugh score has also been validated for patients undergoing other abdominal surgeries. Mortality rates for abdominal surgery in one study were 10%, 30%, and 80% for Child-Pugh class A, B, and C patients, respectively. Although patients with mild chronic liver disease tolerate surgery well, for those with higher Child-Pugh scores, an honest discussion of nonsurgical options is warranted.

Table 111–3

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Factors Associated with Poor Perioperative Outcomes in Patients with Cirrhosis

Elevated creatinine American Society of Anesthesiologists risk classification ≥3 History of gastrointestinal bleeding Perioperative infection Need for intraoperative blood transfusion Intraoperative hypotension Hepatic encephalopathy Emergency operation

PHYSIOLOGIC IMBALANCE & COEXISTING DISEASE

Pulmonary. Hepatopulmonary syndrome, which results in an increased alveolar-arterial gradient due to the reduced transit time of blood through the lungs (caused by the hyperdynamic circulatory state and the presence of rightto-left intrapulmonary and intrahepatic shunts), occurs to some degree in 47% of patients. Resultant hypoxia may be worsened by ventilation-perfusion mismatching from altered respiratory mechanics, impairment of diaphragmatic function by ascites, presence of hydrothorax, or generalized weakness from malnutrition. Hyperventilation with primary respiratory alkalosis is common. Two percent of patients may exhibit portopulmonary hypertension—the presence of pulmonary hypertension in conjunction with portal hypertension.

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Modified Child-Pugh Score Points*

Presentation Albumin (g/dL) Prothrombin time Prolonged (sec) INR Bilirubin (mg/dL)† Ascites Encephalopathy

1

2

3

>3.5

2.8-3.5

<2.8

<4.0 <1.7 <2 Absent None

4-6 1.7-2.3 2.0-3.0 Slight-moderate Grade I-II

6.0 >2.3 >3.0 Tense Grade III-IV

*Class A, 5-6 points; class B, 7-9 points; class C, 10-15 points. † For cholestatic diseases (e.g., primary biliary cirrhosis), the bilirubin level is disproportionate to the impairment of hepatic function. For these conditions, assign 1 point for bilirubin level <4 mg/dL, 2 points for bilirubin 4-10 mg/dL, and 3 points for bilirubin >10 mg/dL. INR, international normalized ratio.

Usual causes of perioperative mortality include hemorrhage, sepsis, and acute hepatic function decompensation with or without associated hepatorenal syndrome. Abnormalities in protein concentration, drug clearance, and volume of distribution may have unexpected effects on the onset and duration of medications. Reduced platelet numbers and function and coagulation factor deficiencies associated with low-grade disseminated intravascular coagulation can lead to significant hemorrhage. Moreover, reduced intravascular volume, surgical traction, poor patient positioning, hypocapnia, and impairment of autoregulatory mechanisms may lead to decreased hepatic blood flow, with possible further liver damage. Finally, untreated alcohol withdrawal in the perioperative period with delirium tremens has a mortality rate of 20%. However, with appropriate treatment, mortality rates from withdrawal can be reduced to 1%.

MANAGEMENT AND PREVENTION Preoperatively, if diaphragmatic movement is impaired by tense ascites, respiratory function may be improved by paracentesis. Coagulopathy should be corrected with platelet transfusion (for severe thrombocytopenia), administration of vitamin K, and transfusion of fresh frozen plasma (for prolonged prothrombin time). Cryoprecipitate and desmopressin (DDAVP) may also be helpful. If hemoglobin is less than 10 g/dL, transfusion of red blood cells should be considered to maintain oxygen carrying capability, particularly to the liver. Careful assessment of volume status (with normalization, if necessary) is important, especially for patients receiving diuretics to control ascites or who have undergone recent paracentesis. Evaluation of the patient’s preoperative mental status and function is helpful if there are concerns about worsening encephalopathy perioperatively. Preoperative nutrition consultation may be helpful. Premedication with sedative drugs is usually unnecessary and may have unpredictable effects. In addition to routine intraoperative monitors, an arterial cannula is useful for beat-to-beat monitoring of blood pressure and frequent blood sampling. Use of a peripheral

nerve stimulator to monitor the response to neuromuscular blocking agents is necessary. A pulmonary artery catheter may help with fluid management for patients with significant ascites or for procedures in which large fluid shifts are anticipated. Transesophageal echocardiography may also be helpful for assessing volume status and cardiac function. However, one must be cautious when placing the probe in patients at risk for or with known esophageal varices. Rapid volume administration may be necessary. If so, one should consider at least two large-bore cannulas for venous access. Medication doses may need to be individually tailored owing to altered drug metabolism and volume of distribution in cirrhotic patients. The influence of cirrhosis on a specific drug’s pharmacokinetics depends on its first-pass hepatic extraction. Most sedatives and opioids have prolonged effects and may exacerbate encephalopathy. Neuromuscular blocking agents that depend on hepatic elimination may have prolonged effects. Because atracurium and cisatracurium are eliminated by Hoffman degradation, they offer the advantage of increased predictability of duration of action. The effects of succinylcholine may be prolonged owing to reduced pseudocholinesterase concentrations, but this is rarely clinically significant. Titration to effect, rather than using precalculated doses, is the safest approach for various anesthetic drugs. One must be cautious of medications with potential hepato- and nephrotoxicity (e.g., halothane, nonsteroidal anti-inflammatory drugs, aminoglycoside antibiotics). Patients with cirrhosis may undergo a regional anesthetic technique if no coagulopathy exists and blood pressure is well maintained. With a general anesthetic, rapidsequence induction is necessary. Decreased arterial blood pressure or cardiac output, positive-pressure ventilation, and elevated central venous pressure impair hepatic blood flow, as does surgical trauma to the liver or splanchnic bed. Isoflurane and desflurane appear to increase hepatic blood flow, and sevoflurane maintains it, provided that blood pressure and cardiac output are maintained. Fluid management to correct hypovolemia due to bleeding or reaccumulation of ascites is required to maintain cardiac output and hepatic blood flow. Colloid-containing solutions have theoretical benefits as replacement fluids, especially for patients with hypoalbuminemia. However, this has not been conclusively shown in clinical trials. Postoperatively, observation in a closely monitored setting facilitates the management of fluids, electrolytes, coagulation, respiratory function, and alcohol withdrawal. Finally, if the patient is cirrhotic because of viral hepatitis, the risk of transmission to caregivers is an important concern. All health care workers should be vaccinated against hepatitis B. Universal precautions are recommended for all patients, not just those with a diagnosis of viral hepatitis. In the event of high-risk exposure of a health care worker to contaminated body fluids or tissues from a patient with viral hepatitis, the hospital employee health service should be notified immediately.

Further Reading Gatecel C, Losser M, Payen D: The postoperative effects of halothane versus isoflurane on hepatic artery and portal vein blood flow in humans. Anesth Analg 96:740-745, 2003.

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Ginès R, Càrdenas A, Arroyo V, et al: Management of cirrhosis and ascites. N Engl J Med 350:1646-1654, 2004. Mansour A, Watson W, Shayani V, et al: Abdominal operations in patients with cirrhosis: Still a major surgical challenge. Surgery 122:730-735, 1997. O’Riordan J, O’Beirne HA, et al: Effects of desflurane and isoflurane on splanchnic microcirculation during major surgery. Br J Anaesth 78:95-96, 1997.

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Patel T: Surgery in the patient with liver disease. Mayo Clin Proc 74: 593-599, 1999. Schuckit MA: Alcohol and alcoholism. In Braunwald E, Fauci AS, Kaper DL, et al (eds): Harrison’s Principles of Internal Medicine. New York, McGraw-Hill, 2001, p 2561. Ziser A, Plevak DJ, Wiesner RH, et al: Morbidity and mortality in cirrhotic patients undergoing anesthesia and surgery. Anesthesiology 90:42-53, 1999.

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Porphyrias Bradly J. Narr Case Synopsis A 56-year-old woman with a 23-year history of intermittent abdominal pain was admitted to the hospital. For 24 hours before admission, she had nausea, vomiting, and palpitations, and on admission, she was “out of her head.” She retched during the evaluation, so rapid-sequence induction was performed with thiopental (350 mg) and succinylcholine (100 mg); maintenance was with nitrous oxide and fentanyl (700 μg). Following abdominal computed tomography (the scan was normal), she was lethargic and had increased pulse (125 beats per minute) and blood pressure (196/110 mm Hg). Because the bladder appeared distended, catheterization was performed, which produced 400 mL of dark red urine.

PROBLEM ANALYSIS Definition The porphyrias are rare, inherited disorders of one of the steps in the biosynthesis of heme (Fig. 112-1). Each porphyria has a characteristic set of symptoms and a specific pattern of heme precursor (porphyrin) overproduction that distinguish it from the others. Carriers of abnormal genes encoding porphyrias often do not have clinical symptoms. Porphyrins that accumulate as a result of individual enzyme defects may be deposited into a variety of tissues, based on the lipid solubility and size of the porphyrin

Succinyl CoA

Glycine

δ-Aminolevulinic acid (ALA)

Porphobilinogen (PBG)

Hydroxmethylbiline

Acute intermittent porphyria

Uroporphyrinogen

Coproporphyrinogen

Hereditary coproporphyria

molecule. The porphyrins that occur in the first half of the heme synthetic pathway (see Fig. 112-1) are water soluble and are excreted in urine. Those that accumulate in the nervous system cause neuroporphyrias, and those that accumulate in skin cause cutaneous porphyrias. Those that accumulate in both cause neurocutaneous porphyrias. The disorders of most interest to anesthesiologists fall into the class called acute porphyrias (Table 112-1). Enzymeinducing drugs are the most important triggering factor during anesthesia.

Recognition The neuroporphyrias and neurocutaneous porphyrias are characterized by acute attacks that can be precipitated by infection, fasting, alcohol intoxication, or administration of some drugs (Tables 112-2 and 112-3). These events stimulate heme synthesis, but because of the enzyme defects, heme is not produced. Therefore, negative feedback to the rate-limiting step (glycine + succinyl coenzyme A → δ-aminolevulinic acid catalyzed by the enzyme δ-aminolevulinic acid synthetase) does not occur. The resulting buildup of porphyrins is believed to cause acute symptoms and signs. The disease is hereditary and is transmitted most often by an autosomal dominant path. Everyone inherits two copies of each of the heme synthetic enzyme genes. Mutation of one allelle, which results in a 50% reduction in enzyme activity, may be completely asymptomatic until the stresses on the heme synthetic system noted earlier provoke an acute problem. More than 90 mutations that cause acute intermittent porphyria have been identified. There is no evidence that any specific genotype determines the severity of an acute attack.

Protoporphyrinogen Variegate porphyria Protoporphyrin ⫹Fe2⫹ Heme Figure 112–1 ■ Simplified diagram of the metabolic pathways for heme synthesis. As shown, the porphyrias are inherited disorders of one of the steps in the biosynthesis of heme.

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Table 112–1

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Disorders of Heme Biosynthesis of Most Importance to Anesthesiologists

Acute intermittent porphyria Variegate porphyria Hereditary coproporphyria δ-Aminolevulinic acid dehydratase deficiency

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Table 112–2

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Conditions That May Precipitate Acute Porphyrias

Fasting Hormones Alcohol (excessive use) Drugs (barbiturates and sulfonamides)

Risk Assessment

471

the use of drugs with no or low risk (see Table 112-3)—has made the risk of inducing acute porphyria during administration of anesthesia a remote possibility.

Data comparing drugs of different classes are incomplete in that there are no prospective, randomized studies. Lists have been published categorizing drugs as safe, probably safe, and unsafe (see Table 112-3), based on personal experience, case reports, and the screening of different drugs in animal (chemically primed rats) or tissue (chick embryo) models. Recent reviews have recommended a more permissive attitude toward precipitating factors, especially during the quiescent phase of the disease, which accounts for a great majority of patients with porphyria. Triggering events vary among patients. Those who are very sensitive may require strict avoidance of all potentially porphyrinogenic events.

MANAGEMENT Appropriate therapy is difficult without an accurate diagnosis, which is hindered by other variables. These include lack of specific symptoms, latent disease that may recur in only 10% of susceptible individuals, and the high response rate of acute porphyria to supportive therapy. Supportive therapy includes dextrose-containing intravenous fluids because fasting, dehydration, or alcohol intoxication1 may induce acute porphyria. Additional measures include analgesics and anxiety relief (anxiolytics)2 and treatment of any associated hypertension and tachycardia. The use of intravenous heme preparations (hematin and its analogues) to provide exogenous negative feedback to the rate-limiting steps in heme synthesis may be lifesaving when employed early in severe attacks. 1 Alcohol (ethanol) inhibits the release of antidiuretic hormone, resulting in enhanced diuresis. 2 Droperidol and phenothiazines, but possibly not all benzodiazepines, appear to be safe (see Lambrecht, Gildemeister, Pepe, et al under “Further Reading”).

Drugs Relevant to Anesthesia that May Produce Acute Porphyrias

Use/Safety*

Induction

Maintenance

Other

Do not use (unsafe)

Barbiturates

Enflurane

Use carefully (probably safe)

Ketamine Etomidate

Use (safe)

Propofol

Isoflurane Sevoflurane Desflurane Nitrous oxide Halothane

Pentazocine, hydralazine, calcium channel blockers†, chlordiazepoxide, ketorolac, sulfonamides Atracurium, mivacurium, vecuronium, rocuronium, mepivacaine, benzodiazepines, cimetidine, ranitidine, ondansetron, sodium nitroprusside, metoclopramide, clonidine, ACE inhibitors, β-blockers‡ Analgesics or antagonists: narcotics, aspirin, acetaminophen, naloxone Muscle relaxants or reversal agents: pancuronium, succinylcholine, glycopyrrolate, neostigmine Local anesthetics: procaine, bupivacaine, tetracaine, prilocaine Supportive: droperidol, phenothiazines, atropine, corticosteroids, α-agonists

*The evidence against the use of drugs in the “do not use” category is robust. There is much less evidence, conflicting evidence, or only educated guesses based on chemical structure–activity relationships (CSAR) in the “use carefully” category. For drugs in the “use” category, there is no hard or CSAR evidence against their use. † Based on animal studies, dihydropyridine calcium channel blockers are more likely than diltiazem or verapamil to cause acute porphyria. ‡ Based on a single report (Moore et al; see “Further Reading”), β-blockers appear to be safe for treating tachycardia associated with acute porphyria. ACE, angiotensin-converting enzyme.

PHYSIOLOGIC IMBALANCE & COEXISTING DISEASE

In the past, anesthesia posed a real risk for patients with unrecognized porphyria. In South Africa, which had the highest world incidence of variegate porphyria, a study was conducted at Groote Schur Hospital in Cape Town between 1950 and 1971. It showed that 31 of 145 hospital admissions for acute attacks of porphyria were likely precipitated by thiopental induction of anesthesia. Since that time, this incidence has been markedly reduced by better clinical and historical assessment, improved biochemical testing, and an awareness of the potential for drug interactions in patients with porphyria. Historically, acute porphyria was always considered in the differential diagnosis of patients presenting with an acute abdomen. However, the proliferation of modern imaging techniques has made exploratory surgery a thing of the past in most medical centers. This evolution in patient care, in concert with modern, balanced anesthetic techniques—including

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Porphyrias

Implications

The clinical presentation includes recurrent unexplained abdominal pain, sensory or motor neuropathy, autonomic dysfunction (e.g., hypertension, tachycardia), nausea, vomiting, and a history of red or dark urine. Acute porphyria attacks are always associated with elevated levels of δ-aminolevulinic acid, porphobilinogen, or both. Diagnosis is based on biochemical investigation. Only a doubling of the upper normal limits for δ-aminolevulinic acid and porphobilinogen justifies further workup. Also, symptoms should not be attributed to porphyria without a marked increase (several times normal) in urinary porphyrin excretion.

Table 112–3

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PREVENTION Many drugs considered unsafe for patients who have been diagnosed with porphyria have been implicated on theoretical grounds. Such drugs either induce heme synthesis or stimulate the cytochrome P-450 system. There is sufficient evidence to recommend complete avoidance of barbiturates, sulfonamides, and excessive alcohol use. Enzyme-inducing drugs remain the most important triggering factor related to porphyria and anesthesia. Use of drugs based on the recommendations in Table 112-3 should provide a good outcome for patients with documented porphyria. Blood loss with a resultant increase in heme demand does not stimulate the heme synthetic pathway enough to result in acute porphyria.

Further Reading Elder GH, Hift RJ, Meissner PN: The acute porphyrias. Lancet 349: 1613-1617, 1997. Harper P, Hybinette T, Thunell S: Large phlebotomy in variegate porphyria. J Intern Med 242:255-259, 1997. Harrison GG, Meissner PN, Hift RJ: Anaesthesia for the porphyric patient. Anaesthesia 48:417-421, 1993.

James MFM, Hift RJ: Porphyrias. Br J Anaesth 85:143-153, 2000. Kauppinen R, Mustajoki P: Prognosis of acute porphyria: Occurrence of acute attacks, precipitating factors, and associated disease. Medicine 71:1-13, 1992. Lambrecht RW, Gildemeister OS, Pepe JA, et al. Effects of antidepressants and benzodiazepine-type anxiolytic agents on hepatic porphyrin accumulation in primary cultures of chick embryo liver cells. J Pharmacol Exp Ther 291:1150-1155, 1999. Lambrecht RW, Gildemeister OS, Williams A, et al: Effects of selected antihypertensives and analgesics on hepatic porphyrin accumulation: Implications for clinical porphyria. Biochem Pharmacol 58:887-896, 1999. Marks GS, Goldman DR, McCluskey SA, et al: The effects of dihydropyridine calcium antagonists on heme biosynthesis in chick embryo liver cell culture. Can J Physiol Pharmacol 64:438-443, 1986 Meissner PN, Meissner DM, Sturrock ED, et al: Porphyria: The University of Cape Town experience. S Afr Med J 72:755-761, 1987. Moore MR, McColl KE, Goldberg A: The porphyrias. Diabete Metab 5: 323-336, 1979. Mustajoki P, Nordmann Y: Early administration of heme arginate for acute porphyric attacks. Arch Intern Med 153:2004-2008, 1993. Pierach CA: Did Ulysses have porphyria? J Lab Clin Med 144:7-10, 2004. Tefferi A, Colgan JP, Solberg LA Jr: Acute porphyrias: Diagnosis and management. Mayo Clin Proc 69:991-995, 1994. Tefferi A, Solberg LA Jr, Ellefson RD: Porphyrias: Clinical evaluation and interpretation of laboratory tests. Mayo Clin Proc 69:289-290, 1994.

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Acute Pancreatitis David M. Rothenberg Case Synopsis A 56-year-old woman is admitted to the intensive care unit (ICU) following 5 days of increasing abdominal pain, nausea, and vomiting. The patient describes repeated episodes of right upper quadrant pain after certain meals for the past 2 years, but she has not sought medical attention. On physical examination she is noted to have tachypnea, tachycardia, and hypotension. Her sclerae are mildly icteric. Breath sounds are diminished in the lower left lung field, and abdominal palpation reveals diffuse rebound tenderness. Arterial blood gas analysis reveals a mixed respiratory and metabolic alkalosis with an arterial oxygen tension (PaO2)of 70 mm Hg (fraction of inspired oxygen [FiO2], 0.5). The white blood cell count is 8000/mm3. The serum amylase level is normal, although lipase, bilirubin, and alanine aminotransferase levels are elevated. Computed tomography (CT) of the abdomen shows an enlarged pancreas with two peripancreatic fluid collections.

PROBLEM ANALYSIS Definition

Recognition Signs and symptoms of acute pancreatitis include the following: ●

● ●

Diffuse, constant abdominal pain, typically radiating to the back and flank areas, in association with nausea and vomiting Tachycardia and tachypnea (common findings) Hypotension relative to the degree of hypovolemia, hemorrhage, or systemic vasodilatation

Table 113–1

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Causes of Acute Pancreatitis

Biliary tract disease (e.g., choledocholithiasis, ampullary tumor, pancreas divisum) Ethanol abuse Hypertriglyceridemia Hypercalcemia Trauma Postsurgical (e.g., cardiopulmonary bypass, endoscopic retrograde cholangiopancreatography) Vascular insufficiency (e.g., hypoperfusion, shock, vasculitis) Drugs (e.g., azathioprine, furosemide, pentamidine) Infection (e.g., mumps, ascariasis, Mycobacterium tuberculosis, AIDS) Other toxins (e.g., methanol, scorpion bites) Idiopathic AIDS, acquired immunodeficiency syndrome.

473

PHYSIOLOGIC IMBALANCE & COEXISTING AND COEXISTINGDISEASE DISEASE

Acute pancreatitis commonly presents as a mild, self-limited disorder, but severe systemic manifestations may develop in 20% to 25% of patients, resulting in sepsis, shock, and multiorgan dysfunction syndrome. The majority of cases of acute pancreatitis are associated with gallstones and alcohol abuse, but the link between cause and pathogenesis remains poorly understood. It appears that dysfunction of the acinar cell, the most active protein-synthesizing cell in the body, is responsible for initiating a host response that may lead to local edema, hemorrhage, or necrosis, with subsequent release of inflammatory mediators into the peritoneal space and circulation. The acinar cell normally secretes and packages digestive and lysosomal enzymes into vacuoles; these enzymes eventually mature into zymogen granules and lysosomes, respectively. Fusion occurs at the luminal surface, allowing the release of enzyme precursors in a process known as exocytosis. Experimental studies have noted that luminal enzyme secretion is decreased in acute pancreatitis, whereas synthesis remains normal. It is speculated that the clinical process is the result of reflux of bile into or septal compression of the pancreatic ductal tree. Intra-acinar activation of the proteolytic enzyme trypsin, from its precursor trypsinogen, is instrumental in precipitating acute pancreatitis. Intracellular activation of trypsin leads to the conversion of other proteolytic enzymes, such as elastase and phospholipase A2, to their active forms, causing autodigestive damage of the pancreas. In mild cases of acute pancreatitis it is presumed that trypsin combines with intracellular α1-antitrypsin to inactive trypsin. The complex is transferred to α2-macroglobulin for eventual consumption by circulating monocytes and macrophages. In severe forms of acute pancreatitis this process is overwhelmed, resulting in a more systemic inflammatory response. The release of elastase into the peripancreatic space may cause degradation

of blood vessels and produce local hemorrhage; the release of phospholipase A2 may degrade surfactant and be the factor by which acute lung injury occurs. Mediators such as kallikreins, complement, thrombin, and chymotrypsin are also released and modulate the degree of local or systemic injury, most likely through a complex interplay of cytokines and reactive oxygen metabolites. The more common causes of acute pancreatitis are listed in Table 113-1.

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Tenderness, guarding, and diminished bowel sounds on abdominal examination Periumbilical and flank ecchymosis (Cullen’s and Grey Turner’s signs, respectively; these occur less commonly and represent pancreatic hemorrhage and dissection of blood into the retroperitoneal space) Jaundice (seen in 15% of cases, usually in association with biliary tract obstruction from gallstones)

Elevation of the serum amylase level is a characteristic, albeit somewhat nonsensitive, marker of acute pancreatitis. Amylase is released early in the course of the disease and tends to peak within 5 days of the onset of symptoms, yet it may be undetectable in 20% to 30% of cases. Hyperamylasemia is also nonspecific, as it may exist in other disease states (e.g., perforated peptic ulcer, small bowel obstruction, mesenteric infarction, pelvic inflammatory disease, diabetic ketoacidosis, all of which are characterized by acute abdominal pain). Fractionated serum amylase levels, urine amylase levels, and amylase-creatinine clearance ratios do not appear to contribute to diagnostic accuracy in acute pancreatitis. The serum lipase level is a more accurate test for acute pancreatitis (90% sensitive and specific), and it tends to remain elevated long after the onset of symptoms. Elevation in alanine aminotransferase, alkaline phosphatase, and bilirubin levels points toward a diagnosis of gallstone-induced pancreatitis. Additional serum markers that may be useful in predicting the severity of acute pancreatitis include C-reactive protein (a nonspecific acute-phase reactant), polymorphonuclear elastase, and trypsinogen-activating peptide. Elevated trypsinogen-activating peptide levels in either urine or peritoneal fluid have been shown to be highly indicative of pancreatic necrosis. Imaging techniques are invaluable in diagnosing acute pancreatitis. Chest radiographs may show basilar atelectasis or pleural effusions (these effusions are exudative in nature and characterized by high levels of amylase and lipase). Plain abdominal films may be useful if only to rule out a perforation or to reveal a “sentinel loop,” signifying a localized ileus due to acute pancreatitis. Ultrasonography, though important in detecting gallstones or complications of acute pancreatitis (e.g., pseudocysts, abscesses), has a limited role in the detection of acute pancreatitis, because findings may be obscured by obesity or the presence of overlying bowel gas. Contrast-enhanced CT of the abdomen is the most accurate method of diagnosing acute pancreatitis and its local complications. Pancreatic abnormalities are discovered in more than 90% of patients with acute pancreatitis, the severity of which can be graded by CT to correlate with pancreatic abscess or necrosis. Table 113-2 presents a useful grading system for acute pancreatitis. Patients with grades A through D have a less than 2% incidence of abscess formation, whereas those classified as grade E have a 57% incidence of abscess formation. In addition to contrast-enhanced CT, dynamic CT pancreatography offers the possibility of detecting pancreatic perfusion abnormalities that correlate with the location and extent of pancreatic and retroperitoneal fat necrosis. Finally, magnetic resonance imaging may be beneficial in distinguishing between uncomplicated pseudocysts and those associated with necrosis. Identifying these patients early in the course of the disease is critical for the prevention

Table 113–2

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Grading System for Pancreatitis

Grade A: Normal pancreas Grade B: Pancreatic enlargement, focal or diffuse Grade C: Pancreatic enlargement with mild peripancreatic inflammation Grade D: Enlarged pancreas associated with fluid in anterior pararenal space Grade E: Enlarged pancreas with fluid collections in at least two areas

of subsequent infection and in the timing of surgical debridement.

Risk Assessment A number of prognostic grading systems have been used to gauge the severity of acute pancreatitis and determine optimal treatment. Despite their inability to predict late morbidity or mortality, Ranson’s criteria (Table 113-3) are the most frequently used method of predicting early complications of acute pancreatitis. Mortality rates are 1% for patients with fewer than three signs, 15% for those with three to four signs, 40% for those with five to six signs, and up to 100% for patients with seven or more signs. The addition of CT data may improve the accuracy of this scoring system. The acute physiologic assessment and chronic health evaluation (APACHE) II scoring system (Table 113-4) is a specific and sensitive method of assessing the severity of acute pancreatitis. Unlike Ranson’s criteria, it is applicable throughout the course of the illness. One study in young patients with gallstone pancreatitis identified heart rate greater than 110 beats per minute, white blood cell count greater than 14.5/mm3, blood urea nitrogen greater than 12 mmol/L, serum glucose greater than 150 mg/dL, and APACHE II score greater than 5 as predictive of the development of serious complications, such as necrotizing pancreatitis. Finally, obesity is thought to be a major risk factor for increased mortality from acute pancreatitis (36% in obese patients versus 6.9% in nonobese patients). The higher mortality is thought to be due to increased peripancreatic fat and greater necrosis.

Table 113–3

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Causes of Acute Pancreatitis

At Admission Age >55 yr White blood cell count >16,000/mm3 Blood glucose level >200 mg/dL Serum lactate dehydrogenase level >350 IU/L Serum glutamic-oxaloacetic transaminase level >250 units/dL

During Initial 48 Hours Hematocrit decline >10% Blood urea nitrogen level rise >5 mg/dL Serum calcium level <8 mg/dL Arterial PO2 <60 mm Hg Base deficit >4 mEq/L Estimated fluid sequestration >6 L From Ranson JHC: Etiological and prognostic factors in human acute pancreatitis: A review. Am J Gastroenterol 77:633-638, 1982.

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Table 113–4

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■

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Acute Pancreatitis

APACHE II Severity of Disease Classification System High Abnormal Range

Physiologic Variable

+4

+3

+2

Low Abnormal Range +1

0

+1

+2

+3

+4

APS, APACHE score. From Knaus WA, Draper EA, Wagner DP, et al: APACHE II: A severity of disease classification system. Crit Care Med 13:818-829, 1985.

Implications Although the majority of patients with acute pancreatitis have an uncomplicated course, 20% to 25% develop sequelae that may be life threatening, requiring either ICU support or surgical intervention. Local complications include sterile or infected tissue necrosis, pseudocysts, abscesses, colonic fistulas, gastrointestinal hemorrhage, and splenic rupture. Systemic complications include shock, acute renal failure, acute lung injury, coagulopathy, hyperglycemia, hypocalcemia, retinopathy, and psychosis.

MANAGEMENT The treatment of uncomplicated acute pancreatitis is primarily supportive, with the judicious use of intravenous fluids and parenteral analgesia. Nasogastric suctioning is beneficial only in patients with documented ileus. Recent randomized, controlled trials have confirmed the benefits of early enteral feedings in patients with severe acute pancreatitis, noting

less end-organ failure, a diminished systemic inflammatory response, and shorter length of hospital stay compared with parenteral feedings. The use of prophylactic antibiotics for severe acute pancreatitis remains controversial. A 1998 metaanalysis of eight prospective, randomized, controlled trials found that reduced mortality was limited to patients who were administered broad-spectrum antibiotics that could penetrate pancreatic tissue. However, a more recent study cited an increase in the incidence of fungal infections and higher perioperative mortality. Also, controlled trials investigating the use of H2-antagonists, protease inhibitors, and peritoneal lavage were unable to document improved outcomes. Early use of endoscopic retrograde cholangiopancreatography (ERCP) and papillotomy for biliary pancreatitis is also controversial. One prospective multicenter study in the late 1990s failed to show a benefit from ERCP. In more severe forms of acute pancreatitis, ICU support with mechanical ventilation for respiratory failure, dialysis for acute renal failure, and infusions of vasoactive drugs may be required. Urgent surgery is indicated only in cases of deteriorating condition or evidence of pancreatic sepsis. The diagnosis of

PHYSIOLOGIC IMBALANCE & COEXISTING DISEASE

Temperature, rectal (°C) ≥41 39-40.9 38.5-38.9 36-38.4 34-35.9 32-33.9 30-31.9 ≤29.9 Mean arterial pressure (mm Hg) ≥180 130-179 110-129 70-109 50-69 ≤49 Heart rate (ventricular response) ≥180 140-179 110-139 70-109 55-69 40-54 ≤39 Respiratory rate (nonventilated or ≥50 35-49 25-34 12-24 10-11 6-9 ≤5 ventilated) Oxygenation: PAO2 – PaO2, or PaO2 (mm Hg) a. FiO2 ≥0.5: 500 350-499 200-349 <200 record PAO2 – PaO2 b. FiO2 <0.5: PO2 >70 PO2 61-70 PO2 55-60 PO2 <55 record only PaO2 Arterial pH ≥7.7 7.6-7.69 7.5-7.59 7.33-7.49 7.25-7.32 7.15-7.24 <7.15 Serum sodium (mmol/L) ≥180 160-179 155-159 150-154 130-149 120-129 111-119 <110 Serum potassium (mmol/L) ≥7 6-6.9 5.5-5.9 3.5-5.4 3-3.4 2.5-2.9 <2.5 Serum creatinine (mg/100 mL) ≥3.5 2-3.4 1.5-1.9 0.6-1.4 <0.6 (double point score for acute renal failure) Hematocrit (%) ≥60 50-59.9 46-49.9 30-45.9 20-29.9 <20 White blood cell count ≥40 20-39.9 15-19.9 3-14.9 1-2.9 <1 (total/mm3, in 1000s) Glasgow coma score (GCS): Score = 15 minus actual GCS A Total APS: Sum of the 12 individual variable points Serum HCO3 (venous, mmol/L) ≥52 41-51.9 32-40.9 22-31.9 18-21.9 15-17.9 <15 (not preferred; use if no arterial blood gases) B Age points: C Chronic health points: APACHE II Score Assign points as follows: If the patiet has a history of severe organ system insufficiency Sum of A + B + C Age (yr) Points or is immunocompromised, assign points as follows: A APS points _____________ ≥44 0 a. For nonoperative or emergency postoperative patients— B Age points _____________ 45-54 2 5 points 55-64 3 or C Chronic health points _________ 65-74 5 b. For elective postoperative patients—2 points ≥75 6 Total APACHE II ___________

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infected necrotizing pancreatitis is often made by CT-guided fine-needle aspiration and signals the need for urgent surgical debridement. The role of surgical intervention for sterile necrotizing pancreatitis remains controversial. Intraoperative management relies on the maintenance of intravascular volume, monitoring of serum electrolytes and glucose levels, and recognition of sepsis and acute lung injury. In this regard, pulmonary artery catheterization may be useful in directing vasopressor or other supportive therapies.

PREVENTION Episodes of acute pancreatitis are prevented by avoiding exposure to precipitating factors such as alcohol and by early surgical therapy for choledocholithiasis. Use of biochemical and radiographic markers to facilitate the early recognition of necrotizing pancreatitis may further reduce the morbidity and mortality from acute pancreatitis.

Further Reading Arnell TD, de Virgilio C, Chang L, et al: Admission factors can predict the need for ICU monitoring in gallstone pancreatitis. Am Surg 62: 815-819, 1996.

Balthazar EJ: Acute pancreatitis: Assessment of severity with clinical and CT evaluation. Radiology 223:603-613, 2002. Folsch UR, Nitsche R, Ludtke R, et al: Early ERCP and papillotomy compared with conservative treatment for acute biliary pancreatitis: The German Study Group on Acute Biliary Pancreatitis. N Engl J Med 336:237-242, 1997. Funnell IC, Bornman PC, Weakley SP, et al: Obesity: An important prognostic factor in acute pancreatitis. Br J Surg 80:484-486, 1993. Golub R, Siddiqi F, Pohl D: Role of antibiotics in acute pancreatitis. J Gastrointest Surg 2:496-503, 1998 Gudgeon AM, Heath DI, Hurley P, et al: Trypsinogen activation peptides assay in the early prediction of severity of acute pancreatitis. Lancet 335:4-8, 1990. Gumaste V, Dave P, Sereny G: Serum lipase: A better test to diagnose acute alcoholic pancreatitis. Am J Med 92:239-242, 1992. Isenmann R, Runzi M, Kron M, et al: Prophylactic antibiotic treatment in patients with predicted severe acute pancreatitis: A placebocontrolled, double-blind trial. Gastroenterology 126:997-1004, 2004. Ranson JHC: Etiological and prognostic factors in human acute pancreatitis: A review. Am J Gastroenterol 77:633-638, 1982. Swaroop VS, Chari ST, Clain JE: Severe acute pancreatitis. JAMA 291: 2865-2868, 2004. Wilson C, Heath DI, Imrie CW: Prediction of outcome in acute pancreatitis: A comparative study of APACHE II, clinical assessment and multiple factor scoring systems. Br J Surg 77:1260-1264, 1990. Yousaf M, McCallion K, Diamond T: Management of severe acute pancreatitis. Br J Surg 90:402-420, 2003.

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Autonomic Hyperreflexia C. Lee Parmley and Steven J. Allen

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Case Synopsis A 25-year-old woman develops headache and severe hypertension following a urologic procedure performed with topical anesthesia. She has C6 quadriplegia resulting from a motor vehicle accident 5 years ago. Examination reveals blood pressure 240/130 mm Hg, pulse 45 beats per minute, facial flushing, and cool lower extremities.

PROBLEM ANALYSIS Definition

Table 114–1

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Autonomic Hyperreflexia Triggers

Bladder or large or small bowel distention Cutaneous stimulation Uterine contractions Lower or upper extremity surgery Sexual pathology Urogenital pathology Cystoscopy and other genitourinary instrumentation Extracorporeal lithotripsy

Autonomic hyperreflexia should be suspected when headache or hypertension develops in any patient with paraparesis of greater than 2 weeks’ duration. Autonomic hyperreflexia’s onset is variable among patients, and some may exhibit signs as early as the fourth postinjury day. Clinical findings are related to the level of intact innervation. Evidence of sympathetic stimulation below the level of the lesion may include skin pallor, pilomotor erection, spastic muscle contraction, and increased muscle tone. Above the lesion, one may find flushing of the face and neck, diaphoresis, mydriasis, and lid retraction. Awake patients frequently complain of headache, dyspnea, blurred vision, chest pain, nausea, and a sense of ill ease.

Risk Assessment The severity of autonomic hyperreflexia is dependent on the amount of cord below the lesion that is involved with sympathetic outflow. Thus, lesions below T10 generally are not associated with autonomic hyperreflexia, because there are few sympathetic spinal synapses to disinhibit. Conversely, lesions above T5 tend to be associated with the worst autonomic hyperreflexia–related problems, because the majority of spinal sympathetic efferents arise below this level. The site and nature of the planned procedure may also play a role. The majority of patients come to the operating room for urologic procedures, all of which are likely to produce autonomic hyperreflexia. One group of at-risk patients that has been the subject of increased interest in recent years is spinal cord–injured parturients. Because uterine contractions may result in strong sympathetic outflow, these patients pose a unique challenge during labor. The literature suggests that the incidence of autonomic hyperreflexia is as high as 75% in this population. In addition, it may be difficult to distinguish autonomic hyperreflexia from preeclampsia. Accordingly, some clinicians advise epidural anesthesia for all spinal cord–injured women in labor to prevent autonomic hyperreflexia.

Implications If untreated, autonomic hyperreflexia can lead to serious complications and even death. Cardiovascular complications include left ventricular failure, myocardial ischemia, and possibly arrhythmias, all related to increased demands related to severe hypertension or central nervous system complications. 477

PHYSIOLOGIC IMBALANCE & COEXISTING DISEASE

Autonomic hyperreflexia is a disturbance arising in patients with chronic spinal cord injury. It is also termed autonomic dysreflexia, hypertensive autonomic crisis, and mass reflex. Autonomic hyperreflexia is characterized by massive sympathetic activity set off by reflex stimulation from a variety of triggers (Table 114-1). It has been reported in 85% of patients within 2 to 3 weeks of spinal cord injury. Because it requires viable spinal cord below the level of injury or transaction, the disturbance does not occur in patients with paraplegia due to spinal cord infarction. Autonomic hyperreflexia occurs when the hypothalamus and brainstem can no longer modulate segmental spinal sympathetic nerves and thereby inhibit their output. In the acute phase following spinal cord injury, there is low sympathetic activity. However, sympathetic activity returning to viable cord below the lesion is isolated from upper inhibitory control. This can result in an uncontrolled sympathetic response to a stimulus. The sympathetic activity causes vasoconstriction in the vasculature below the spinal cord lesion, leading to systemic hypertension. The hypertension stimulates the baroreceptors in the aortic arch and carotid sinus, inducing bradycardia and vasodilatation above the spinal cord defect. The vasodilatation is thought to be the cause of headaches and flushing. The severity of autonomic hyperreflexia is dependent on the amount of cord below the lesion that is involved with sympathetic outflow. Thus, higher cord lesions have a more profound response than do lower lesions.

Recognition

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Central nervous system complications are typically those associated with hypertensive encephalopathy, such as confusion, seizures, and stroke. Autonomic hyperreflexia may also increase surgical blood loss.

MANAGEMENT The onset of hypertension requires immediate intervention, because systemic blood pressure can quickly escalate to dangerous levels. The first maneuver should be to remove the offending stimulus (e.g., relieving a distended bladder). If hypertension develops during a general anesthetic, the concentration of volatile agent should be increased. If an epidural catheter is being used, raising the level of the block may help. Pharmacologic intervention can consist of any agent that interrupts the sympathetic reflex and has the characteristics of rapid onset, short duration, and low toxicity. The most frequently recommended drugs are sodium nitroprusside and nifedipine. Sodium nitroprusside has the advantages of reliability, rapid onset, and titratability. However, continuous use may require monitoring for cyanide toxicity. Also, nitroprusside may be harder to titrate to the desired effect (requiring more dosing changes), and it may be associated with untoward hypotension.1 Nifedipine has an acceptable degree of effectiveness in treating autonomic hyperreflexia. Its advantages are oral (sublingual) administration, relatively short duration, and minimal toxicity in this patient population. Disadvantages are unreliable or delayed absorption, possibly leading to excessive dosing and hypotension. Nicardipine’s actions are similar to those of nifedipine; it has a short half-life of elimination (minutes) after intravenous bolus administration and no specific organ toxicity during prolonged infusion.2 For these reasons, nicardipine might be preferred over nifedipine or sodium nitroprusside for hypertensive emergencies in patients with autonomic hyperreflexia, but there is little precedent for such use. There are also anecdotal reports of excellent results with magnesium sulfate.

PREVENTION The main goal in patients at risk for autonomic hyperreflexia is to prevent hypertension. The purpose of anesthetic management is not to prevent pain in an insensate area but rather to prevent enhanced sympathetic activity due to visceral organ stimulation. Although topical and general anesthesia may be used, regional anesthesia is associated with the lowest incidence of perioperative hypertension.

1 Nicardipine is a primary arterial dilator, whereas sodium nitroprusside has both venodilator (reduces preload) and arterial dilator properties that are about equal. 2 Nicardipine differs from nifedpine in two important respects, however. First, it has no vehicle (polysorbate). Polysorbate has direct myocardial depressant and vasodilatory properties on both venous capacitance and arterial beds. Second, nicardipine is approved for intravenous dosing.

This is because regional techniques most directly block conduction of the afferent nerves in the spinal cord. For urologic procedures, most of the stimulation is via the sacral nerves, suggesting that a subarachnoid block is an appropriate technique. Lumbar epidural anesthesia is less reliable, because the sacral nerve roots may not be completely blocked. Regional anesthesia also has the advantage of providing muscle relaxation and preventing sudden leg flexion during visceral organ manipulation. Some clinicians are reluctant to perform a regional technique in the presence of a neurologic deficit. One reason is that the level of the block is difficult to determine owing to the lack of sensation. As an alternative, some clinicians employ nifedipine or nicardipine for hypertension prophylaxis. General anesthesia can be problematic in patients with autonomic hyperreflexia. Inadequate anesthesia (especially for tracheal intubation, electroconvulsive therapy, aortic cross-clamping, and the like) may trigger dangerous hypertension, whereas anesthetic overdose may result in profound hypotension. Typically, anesthesia must be deep to prevent autonomic hyperreflexia. For that reason, a technique based solely on nitrous oxide and opioids may not be satisfactory. Isoflurane and sevoflurane have been used successfully, likely owing to their salutary vasodilatory effects (i.e., reducing both preload and afterload). Emergence must be carefully managed, because patients with high spinal cord injury have some degree of respiratory compromise. The adequacy of ventilation must be ensured before and after extubation.

Further Reading Amzallag M: Autonomic hyperreflexia. Int Anesthesiol Clin 31:87-102, 1993. Baker ER, Cardenas DD, Benedetti TJ: Risks associated with pregnancy in spinal cord-injured women. Obstet Gynecol 80:425-428, 1992. Bernstein A, Richlin D, Sotolongo JR Jr: Nifedipine pretreatment for prevention of autonomic hyperreflexia during anesthesia-free extracorporeal shock wave lithotripsy. J Urol 147:676-677, 1992. Jones NA, Jones SD: Management of life-threatening autonomic hyperreflexia using magnesium sulphate in a patient with a high spinal cord injury in the intensive care unit. Br J Anaesth 88:434-438, 2002. Kobayashi A, Mizobe T, Tojo H, et al: Autonomic hyperreflexia during labour. Can J Anaesth 42:1134-1136, 1995. Krassioukov AV, Furlan JC, Fehlings MG: Autonomic dysreflexia in acute spinal cord injury: An underrecognized clinical entity. J Neurotrauma 20:707-716, 2003. Lambert DH, Deane RS, Mazuzan JE Jr: Anesthesia and the control of blood pressure in patients with spinal cord injury. Anesth Analg 61:344-348, 1982. Maehama T, Izena H, Kanazawa K: Management of autonomic hyperreflexia with magnesium sulfate during labor in a woman with spinal cord injury. Am J Obstet Gynecol. 813:492-493, 2000. Pereiara L: Obstetric management of the patient with spinal cord injury. Obstet Gynecol Surg 58:678-687, 2003.

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Perioperative Management of Patients with Muscular Dystrophy

115

Katarzyna Luba

Case Synopsis

PROBLEM ANALYSIS Definition Muscular dystrophies are a clinically and genetically diverse group of hereditary disorders of the structure of striated muscle, characterized by progressive muscle weakness and wasting. The diagnosis of a muscular dystrophy is based on elevated serum CK, myopathic electromyogram features, and muscle biopsy. The morphologic changes common to all forms of muscular dystrophy present a random pattern of normal or hypertrophic muscle fibers, necrotic and necrotizing fibers, and interstitial accumulation of fatty and fibrous tissue. The latter changes result in the characteristic pseudohypertrophy of the calf muscles seen in Duchenne’s muscular dystrophy. The previous classification of muscular dystrophies was based on patterns of inheritance and clinical features. A more recently proposed classification takes into account the type, localization, and function of defective proteins involved in the pathogenesis of different muscular dystrophies.

PHYSIOLOGIC IMBALANCE & COEXISTING DISEASE

An 8-month-old boy undergoes myringotomy tube removal. His previous general anesthesia for tube placement was uneventful. Anesthesia is induced with intravenous thiopental and atropine and is maintained with nitrous oxide, halothane, and oxygen via a facemask. After removal of the myringotomy tube, the surgeon performs a digital examination and decides to perform an adenoidectomy. Airway obstruction at this time necessitates emergency intubation. After succinylcholine 2 mg/kg intravenously, an increase in masseter muscle tone is noted. The electrocardiogram (ECG) monitor shows a wide complex tachycardia progressing to bradycardia. End-tidal carbon dioxide (CO2) of 40 to 50 mm Hg gradually decreases to 25 mm Hg. Arterial saturation decreases from 100% to 80%, then cannot be detected. Halothane is discontinued. Calcium chloride, epinephrine, and sodium bicarbonate are given intravenously. The ECG becomes increasingly dysmorphic, and pulses cannot be palpated. Chest compressions start. Venous blood analysis shows that pH is 7.13, CO2 tension (PCO2) is 73 mm Hg, and potassium level is more than 10 mmol/L. Calcium, epinephrine, and bicarbonate are repeated. After 13 minutes of cardiopulmonary resuscitation, the ECG shows the return of a narrow complex tachycardia, and systolic blood pressure increases to 100 mm Hg. Twenty minutes after succinylcholine administration, a venous blood sample shows pH 7.30, PCO2 49 mm Hg, and potassium 7.1 mmol/L. A urinary catheter reveals red urine. The patient is transported to a pediatric intensive care unit. The creatine kinase (CK) level is 285,760 units/L. The patient is treated with vigorous intravenous hydration. He is discharged home in good condition. DNA studies before discharge show a deletion of the dystrophin gene, consistent with a diagnosis of Duchenne’s muscular dystrophy.

PLASMA MEMBRANE–ASSOCIATED PROTEINS Defective plasma membrane–associated proteins or the lack of such proteins causes the most common muscular dystrophies, including Duchenne’s muscular dystrophy (DMD), Becker’s muscular dystrophy (BMD), the sarcoglycanopathies, and other forms of limb-girdle muscular dystrophy (LGMD). Dystrophinopathies. The most common muscular dystrophies are X-linked recessive disorders caused by mutations of the dystrophin gene. Dystrophin is a sarcolemmal protein that plays a role in maintaining the integrity of the sarcolemma. The severe DMD form results from deficiency of dystrophin. The milder allelic form (BMD) is associated with a reduced amount of the truncated protein. The incidence of DMD is 1 in 3500 live male births. Affected males have delayed motor development, and when they start walking, they present with gait abnormalities. By age 5 years, muscle weakness is evident. Calf enlargement is due to replacement of necrotic muscle by fat and fibrous tissue. Lumbar hyperlordosis and toe-walking result from progressive loss of muscle strength and tendon contractures. By age 479

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12 years, most patients are confined to a wheelchair. Scoliosis, chest deformity, and diaphragmatic weakness lead to restrictive pulmonary disease by age16 to 18 years. Respiratory failure, the most common cause of death, occurs in the third decade of life. Almost all patients have cardiomyopathy, but this rarely causes death. Intellectual impairment is common. Compared with DMD, BMD has a later onset and a milder clinical course. Symptoms of proximal muscle weakness commonly start between ages 5 and 15 years, although the onset may be delayed until the third or fourth decade of life. Patients generally ambulate beyond age 15 years. Calf hypertrophy occurs early and is prominent. Patients have a short life expectancy, but many live to their 30s or 40s. Mental retardation is milder than in DMD. In patients with mild or subclinical BMD, cardiomyopathy may be the presenting feature of the disease. Most BMD patients die of complications of cardiomyopathy. Sarcoglycanopathies. These disorders are caused by mutations of genes encoding four transmembrane glycoproteins of the sarcoglycan complex. Mutations of any of the four sarcoglycan genes (alpha, beta, gamma, and delta) result in LGMD 2D, 2E, 2C, and 2F. Both males and females are affected. Proximal leg muscle weakness generally appears in the second or third decade but may be delayed. Upper limb involvement with scapular winging develops. Diaphragmatic weakness with respiratory insufficiency, cardiomyopathy, congestive heart failure (CHF), and arrhythmias may develop. Intellectual function is normal. Caveolin Deficiency. This is a rare form of autosomal dominant muscular dystrophy. LGMD 1C is caused by deficient caveolin, a ubiquitous plasma membrane protein. EXTRACELLULAR MATRIX PROTEINS Deficiencies in extracellular matrix proteins result in congenital muscular dystrophies (CMDs), a group of autosomal recessive disorders that become symptomatic at birth or in infancy. They are diagnosed by hypotonia and a dystrophic muscle biopsy. The most severe form is merosin-deficient CMD. The maximal functional ability of a child with CMD is sitting unsupported. Further, cardiomyopathy may be present. PROTEINS WITH ENZYMATIC ACTIVITY Mutations in Genes Encoding Glycosyltransferases. These mutations are a recently identified mechanism for CMDs. The gene encoding the fukutin-related protein (FKRP—a glycosyltransferase) is mutated in a severe form of muscular dystrophy, CMD type 1C, as well as a mild form, LGMD 2I. Central nervous system involvement is present in the severe form, with cerebellar cysts, seizures, and developmental delay. Mild cardiomyopathy may also be present. Protein Kinases. Heterozygosity for a trinucleotide repeat ([CTG]n) expansion mutation in the 3′ untranslated region of a protein kinase gene on chromosome 19 is the cause of myotonic dystrophy, the most common adult form of muscular dystrophy. This has a prevalence of 1 in 8000. Myotonic dystrophy is an autosomal dominant disorder characterized by myotonia, slowly progressive muscle weakness and wasting,

frontal baldness, cataracts, and insulin resistance secondary to aberrant insulin receptor expression. Type 2 diabetes may develop. OTHER MUSCLE PROTEINS Sarcomeric Proteins. Mutations in the titin gene, encoding a giant sarcomeric protein, underlie an autosomal dominant form of congenital dilated cardiomyopathy. Recently, mutations of the same gene have been found in patients with isolated tibial muscular dystrophy. Nuclear Proteins. Defects in two nuclear proteins are responsible for two distinct forms of Emery-Dreifuss muscular dystrophy (EDMD). X-linked EDMD is due to mutations in the gene encoding the nuclear protein emerin. Autosomal dominant EDMD results from mutations in the lamin A/C gene, encoding a protein of the nuclear lamina. Mutations in this gene also lead to a form of dominant proximal LGMD 1B and dilated cardiomyopathy. Skeletal muscle involvement in EDMD is usually mild and slowly progressive. Cardiac involvement is the predominant feature of the disease. CARDIOMYOPATHY

IN

MUSCULAR DYSTROPHIES

Cardiac involvement is a universal feature of muscular dystrophies. The severity of cardiac involvement may determine the long-term prognosis for persons with any type of muscular dystrophy. In DMD and BMD, lacking or faulty dystrophin has been demonstrated in both cardiac and skeletal muscle. Heart failure is often the proximate cause of death, alone or in association with respiratory failure. Myocardial damage is initially subclinical but can be recognized through minor ECG and echocardiographic changes. Myocardial involvement progresses to a clinically evident stage of hypertrophy; arrhythmias, characterized by conduction defects (atrioventricular block, bundle branch block) or severe supraventricular or ventricular arrhythmias; and, finally, dilated cardiomyopathy due to widespread myocardial fibrosis. Heart failure is the most common cause of death in patients with BMD. Female carriers of DMD and BMD have a 10% incidence of cardiomyopathy that is age-progressive. Sarcoglycanopathies (LGMD 2C, 2D, 2E, 2F) may have associated dilated cardiomyopathy. This results from disrupted sarcoglycan complexes in both skeletal and cardiac muscle. LGMD due to mutations in the FKRP gene (LGMD 2I) may be associated with myocardial fibrosis, leading to dilated cardiomyopathy and repolarization abnormalities. In myotonic dystrophies, cardiac conduction defects are a major cause of sudden death. The incidence of complete atrioventricular block among these patients is higher than in the general population. A prolonged His-ventricular conduction interval puts these patients at risk of paroxysmal atrioventricular block and justifies early pacemaker implantation. In congenital (neonatal) myotonic dystrophy, abnormal myocardial relaxation results in left ventricular diastolic dysfunction. Severe cardiac involvement is common in EDMD. Both X-linked and autosomal dominant forms involve the risk of

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bradyarrhythmias (often requiring pacemaker implantation) and atrial fibrillation or flutter. Atrial fibrillation often precedes atrial standstill and may be the cause of embolic stroke at a young age. Prophylactic anticoagulation is recommended in EDMD patients with atrial arrhythmias or standstill. Finally, left ventricular failure is rare but may be severe enough to require a heart transplant.

Recognition

Risk Assessment All patients with muscular dystrophy are at risk for cardiomyopathy or conduction disorders. Signs and symptoms of myocardial dysfunction at the time of preoperative evaluation may be overt or masked by confinement to a wheelchair. Therefore, all patients with muscular dystrophy should have their cardiac function evaluated preoperatively. ECG abnormalities (sinus tachycardia or bradycardia, short P-R interval, signs of left ventricular hypertrophy, conduction defects) are very common. However, the best correlation between severe

cardiac involvement and mortality is the degree of left ventricular echocardiographic dysfunction. Guidelines for the assessment of cardiac involvement in patients with DMD and BMD advise that those with DMD have an echocardiogram and ECG at the time of diagnosis, every 2 years up to the age of 10, and annually thereafter. BMD patients should have an echocardiogram and ECG at the time of diagnosis and then every 5 years. The same recommendations apply to patients with other forms of muscular dystrophy. Additional echocardiograms or ECGs should be obtained before surgery or if clinically indicated. Patients with EDMD should have an ECG and echocardiogram at the time of diagnosis and annually thereafter. They should also be monitored annually for arrhythmias with a Holter monitor. An implanted pacemaker is justified for symptomatic patients or for asymptomatic patients whose ECG shows sinus node or atrioventricular node dysfunction. In autosomal dominant EDMD, sudden death is a possibility, even in patients with pacemakers. Therefore, a pacemaker with the full range of internal cardioverter-defibrillator capabilities should be considered whenever antibradycardia pacing is indicated. When atrial fibrillation or atrial standstill is diagnosed, antithromboembolic prophylaxis with warfarin is indicated. Intracardiac conduction should be evaluated in all adult myotonic dystrophy patients. Patients are selected to undergo cardiac electrophysiologic investigation based on the results of signal-averaged ECGs. In patients with DMD, a steady decrease in vital capacity (VC) follows progressive muscle weakness and the development of scoliosis. Once VC falls below 20% of predicted values, ventilatory failure is inevitable, and 73% of patients die of respiratory failure. Obstructive sleep apnea is common, leading to chronic hypoxemia and right ventricle failure. Preoperative pulmonary function tests and sleep studies are indicated to assess the severity of restrictive pulmonary disease and obstructive sleep apnea.

Implications Patients with muscular dystrophies are at increased risk of perioperative CHF, arrhythmias, and respiratory failure. If the VC is less than 30% of predicted, the patient will likely require prolonged postoperative ventilatory support. Obstructive sleep apnea and weak pharyngeal muscles increase the risk for early postoperative airway obstruction and hypoxia. Outpatient general anesthesia is not advised owing to the risk of delayed respiratory depression. Also, delayed gastric emptying increases the risk of aspiration. Succinylcholine can trigger MH or cause hyperkalemic cardiac arrest; therefore, its use is not advised. Nondepolarizing muscle relaxants (NDMRs) may have prolonged effects. Also, neostigmine reversal is unpredictable. Volatile anesthetics may trigger MH in DMD patients. In patients with myotonic dystrophy, hypothermia, shivering, succinylcholine, neostigmine, and direct muscle stimulation may precipitate a myotonic crisis, characterized by prolonged contracture of the skeletal muscles. For these reasons, regional or local anesthesia, when suitable, is preferred for all patients with muscular dystrophy.

PHYSIOLOGIC IMBALANCE & COEXISTING DISEASE

Patients with muscular dystrophy usually present for muscle biopsy, tendon contracture release, correction of kyphoscoliosis, or pacemaker implantation. Pediatric patients with undiagnosed muscular dystrophy may present for procedures unrelated to the disease. All patients with muscular dystrophy should be suspected of having respiratory and cardiac dysfunction. Pulmonary function tests should be performed in all patients with muscle weakness because of the high incidence of restrictive lung disease secondary to diaphragmatic weakness and scoliosis. In asymptomatic patients with the diagnosis of muscular dystrophy, the specific type of dystrophy and the risk of cardiac involvement determine the need for further cardiac workup. Intraoperative CHF may present as tachycardia and hypotension unresponsive to intravenous fluids. Physical signs of CHF include jugular vein distention, pulmonary rales, and dyspnea in a spontaneously breathing patient. Severe CHF results in acute pulmonary edema, with hypoxia and pink, frothy respiratory secretions. Diagnosis may be confirmed by hemodynamic parameters measured with a pulmonary artery catheter. Typically, pulmonary artery occlusion pressure is elevated (>18 mm Hg), cardiac index is low (<2.2 L/minute/m2 body surface area), and systemic vascular resistance is high (>1200 dynes•sec•cm–5). In children with undiagnosed DMD, succinylcholine has been reported to induce hyperkalemic cardiac arrest. On the basis of these reports, the Food and Drug Administration recommended against the use of succinylcholine for nonemergent intubation in children. Malignant hyperthermia (MH), a rare inherited disorder of sarcolemmal calcium flux, may be triggered by volatile anesthetics and succinylcholine in genetically susceptible individuals. Patients with DMD may be susceptible to MH. Signs of MH include muscle rigidity; an unanticipated, rapid rise in temperature and end-tidal CO2; hypertension; metabolic acidosis; tachyarrhythmias; myoglobinuria; and elevated serum CK.

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Finally, patients with DMD previously treated with glucocorticoid steroids require supplemental perioperative steroids.

MANAGEMENT The need to minimize the use of myocardial depressant and MH-triggering agents favors the use of regional anesthesia or total intravenous general anesthesia. Agents used for the latter include propofol, ketamine, dexmedetomidine, and opioids. Short-acting opioids (remifentanil, sufentanil) may be preferable to reduce the risk of postoperative respiratory depression. Premedication with benzodiazepines and opioids may cause respiratory depression, airway obstruction, and delayed emergence from anesthesia and should be avoided. Airway management should take into account the increased risk of aspiration. Premedication with an H2-blocker and metoclopramide is advised. Modified rapid-sequence endotracheal intubation with the use of an NDMR is the method of choice. The choice of agent is limited by contraindications to succinylcholine and increased sensitivity to NDMRs. Shortacting NDMRs (mivacurium, cisatracurium) should be used, and their dose should be titrated to the train-of-four response. Even with the use of short-acting NDMRs, prolonged recovery has been reported in children with DMD. Reversal of NDMRs with neostigmine has been reported without adverse events. However, as mentioned earlier, reversal with neostigmine may be unpredictable. The management of intraoperative CHF depends on hemodynamic stability. Diuresis and positive end-expiratory pressure may be sufficient. If hypotension develops, an inotrope (dobutamine or dopamine) should be used, and an arterial line placed. An arterial line is advised for all major surgery in patients with muscular dystrophy. Further management is guided by transesophageal echocardiography or pulmonary artery catheter measurements. If preload is adequate, inotropy and afterload reduction may help increase cardiac output and tissue perfusion. In patients with myotonic dystrophy, anesthetic goals should include avoidance of the triggers of myotonic contractures. Severe contractures may result in jaw and chest rigidity, impeding efforts to intubate and ventilate. Contractures do not respond to NDMRs; they may respond to intravenous quinidine, infiltration of the muscle with local anesthetic, and rewarming the patient. MH management requires immediate discontinuation of inhalational anesthetics, administration of dantrolene, 100% oxygen, active cooling, and treatment of associated arrhythmias, hyperkalemia, and acidosis. To prevent acute renal failure secondary to rhabdomyolysis, patients should be treated with intravenous hydration, alkalinization of urine with intravenous sodium bicarbonate, and mannitol. Patients with impaired respiratory function require admission to the intensive care unit for prolonged ventilatory support after extensive surgical procedures under general anesthesia.

PREVENTION Prevention of perioperative complications in patients with muscular dystrophy requires thorough evaluation of the surgical risk. Surgery for the correction of scoliosis in patients with DMD should be performed before pulmonary function declines and precludes a safe anesthetic and postoperative course. Knowledge of the severity of myocardial involvement is necessary to prevent perioprative exacerbation of CHF or life-threatening arrhythmias. The preoperative evaluation should include a recent ECG, echocardiogram, and electrophysiologic testing if indicated by the results of signal-averaged ECGs. In the presence of severe cardiomyopathy and respiratory dysfunction, invasive hemodynamic monitoring and postoperative critical care management should be anticipated for major surgical procedures. Outpatient surgery in this patient population is discouraged, because overnight monitoring for delayed respiratory complications after general anesthesia of any duration is warranted. Aspiration risk should be minimized by premedication with H2-blockers and metoclopramide and by the use of an appropriate intubation technique. Succinylcholine should never be used. Also, inhalational anesthetics should be avoided because of their MH-triggering potential. The use of regional or local anesthesia, whenever feasible, may help avoid respiratory, cardiac, and metabolic complications of general anesthesia in patients with muscular dystrophy.

Further Reading Abraham RB, Cahana A, Krivosic-Horber RM, Perel A: Malignant hyperthermia susceptibility: Anesthetic implications and risk stratification. QJM 90:13-18, 1997. Baraka A, Jalbout MI: Anesthesia and myopathy. Curr Opin Anaesthesiol 15:371-376, 2002. Barresi R, Di Blasi C, Negri T: Disruption of heart sarcoglycan complex and severe cardiomyopathy caused by β-sarcoglycan mutations. J Med Genet 37:102-107, 2000. Boriani G, Gallina M, Merlini L, et al: Clinical relevance of atrial fibrillation/flutter, stroke, pacemaker implant, and heart failure in EmeryDreifuss muscular dystrophy: A long-term longitudinal study. Stroke 34:901-908, 2003. Buckley AE, Dean J: Cardiac involvement in Emery Dreifuss muscular dystrophy: A case series. Heart 82:105-108, 1999. Corrado G, Lissoni A, Beretta S, et al: Prognostic value of electrocardiograms, ventricular late potentials, ventricular arrhythmias, and left ventricular systolic dysfunction in patients with Duchenne muscular dystrophy. Am J Cardiol 89:838-841, 2002. Do T: Orthopedic management of the muscular dystrophies. Curr Opin Pediatr 14:50-53, 2002. Dubowitz V: What is muscular dystrophy? Forty years of progressive ignorance. J R Coll Physicians Lond 34:464-468, 2000. Frankowski GA, Johnson J, Tobias J: Rapacuronium administration to two children with Duchenne’s muscular dystrophy. Anesth Analg 91: 27-28, 2000. Le Corre F, Plaud B: Neuromuscular disorders. Curr Opin Anaesthesiol 11:333-337, 1998. Mathieu J, Allard P, Gobeil G, et al: Anesthetic and surgical complications in 219 cases of myotonic dystrophy. Neurology 49:1646-1650, 1997. Melacini P, Fanin M, Danielli GA, et al: Myocardial disease: Myocardial involvement is very frequent among patients affected with subclinical Becker’s muscular dystrophy. Circulation 94:3168-3175, 1996.

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Muntoni F: Cardiomyopathy in muscular dystrophies. Curr Opin Neurol 16:577-583, 2003. Parker SF, Bailey A, Drake AF: Infant hyperkalemic arrest after succinylcholine. Anesth Analg 80:206-207, 1995. Politano L, Nigro V, Nigro G, et al: Development of cardiomyopathy in female carriers of Duchenne and Becker muscular dystrophies. JAMA 275:1335-1338, 1996. Ririe DG, Shapiro F, Sethna NF: The response of patients with Duchenne’s muscular dystrophy to neuromuscular blockade with vecuronium. Anesthesiology 88:351-354, 1998.

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Rosenberg H, Gronert GA: Intractable cardiac arrest in children given succinylcholine [letter]. Anesthesiology 77:1054, 1992. Schramm CM: Current concepts of respiratory complications of neuromuscular disease in children. Curr Opin Pediatr 12:203-207, 2000. Stevens R: Neuromuscular disorders and anesthesia. Curr Opin Anaesthesiol 14:693-698, 2001. Uslu M, Mellinghoff H, Diefenbach C: Mivacurium for muscle relaxation in a child with Duchenne’s muscular dystrophy. Anesth Analg 89: 340-341, 1999.

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Case Synopsis A 22-year-old woman, 154 cm tall and weighing 44.2 kg, presents with a 4-month history of myasthenia gravis and mild generalized weakness (Osserman’s class II). The diagnosis is confirmed by the patient’s rapid improvement after the administration of intravenous edrophonium chloride and by the presence of antibodies to acetylcholine receptors (12.3 nmol/L; reference value <0.25 nmol/L). The patient is scheduled for transcervical-sternal thymectomy. Preoperatively, she took pyridostigmine 60 mg orally three times a day and had plasmapheresis. Results of her preoperative pulmonary function tests were as follows: forced vital capacity (FVC), 2.79 L/second (79% of predicted); maximum expiratory flow at 50% of FVC, 3.2 L/second (68% of predicted); and forced midexpiratory flow between 25% and 75% of FVC, 3.03 L/second (77% of predicted). Anesthesia was induced with fentanyl and propofol and maintained with a thoracic epidural block supplemented with propofol and 70% nitrous oxide in oxygen. Tracheal intubation was performed under topical laryngotracheal anesthesia (4 mL 4% lidocaine). No neuromuscular blockers were used. She required mechanical ventilation for 12 hours postoperatively.

PROBLEM ANALYSIS Definition Neuromuscular transmission is dependent on a coordinated mechanism involving (1) synthesis, storage, and release of acetylcholine from the presynaptic motor nerve endings at the neuromuscular junction; (2) binding of acetylcholine to nicotinic receptors on the postsynaptic region of the muscle membrane, with consequent generation of the action potential; and (3) rapid hydrolysis of acetylcholine by acetylcholinesterase enzyme present in the synaptic cleft. Autoimmune or genetic defects at the presynaptic region, synaptic basal lamina, or postsynaptic structure of the neuromuscular junction can compromise the safety margin of neuromuscular transmission. This can result in a diverse array of myasthenic disorders (Fig. 116-1). Fluctuating muscle weakness and fatigability are the main characteristics of myasthenic disorders (mys, meaning “muscle”; aesthenia, meaning “weakness”). Myasthenic disorders affect the motor system only. Sensory and autonomic functions are not impaired. The exception is Lambert-Eaton syndrome, a myasthenic syndrome in which a significant minority of patients have autonomic dysfunction. Myasthenic disorders can be classified into three main categories: myasthenia gravis, congenital myasthenic syndromes, and LambertEaton myasthenic syndrome (Tables 116-1 and 116-2).

Recognition, Risk Assessment, and Implications MYASTHENIA GRAVIS Myasthenia gravis (MG) is the most common myasthenic disorder. MG is an antibody-mediated autoimmune disease with a prevalence of 0.25 to 2 per 100,000. Antibodies against 484

the α-subunit of nicotinic acetylcholine receptors are present in approximately 80% to 85% of patients with MG. In the remaining 15% to 20% of patients (called seronegative patients), nicotinic acetylcholine receptor antibodies are not detectable. The majority of these seronegative patients have antibodies against the muscle-specific receptor tyrosine kinase; these antibodies are not present in seropositive patients. Muscle-specific kinase mediates the agrin-induced clustering of nicotinic acetylcholine receptors during synapse formation and is also expressed at the mature neuromuscular junction. Triggers for the immune response in MG are not known. Thymic lymphoid follicular hyperplasia with germinal centers that produce antibodies to nicotinic acetylcholine receptors is present in approximately 70% of MG patients. A small percentage of MG patients develops autoantibodies as part of a paraneoplastic syndrome (12% of MG patients have thymoma). It is believed that antibodies to nicotinic acetylcholine receptors are produced in other locations, because thymectomy does not cure MG and does not protect against the occurrence of MG. There is also some evidence that antibodies generated in response to microbial antigens may constitute a trigger for MG in some patients. The antirheumatic drug D-penicillamine can induce a reversible form of MG. MG can occur at any age. Extraocular and bulbar muscles are initially affected in a large majority of patients, resulting in ptosis, diplopia, dysphagia, and respiratory failure. As the disease progresses, neck and limb-girdle muscle weakness becomes apparent. In the rat model of MG, there is also evidence that diaphragmatic function is impaired. The clinical features of seropositive and seronegative patients are very similar. Osserman and Genkins proposed the following clinical classification of MG: class I (ocular signs and symptoms only), class II (mild generalized weakness), class III (moderate generalized weakness with or without bulbar involvement), and

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Presynaptic

Defective resynthesis or vesicular packing of ACh → CMS (genetic)

SV Nerve terminal

SV LEMS (autoimmune)

Postsynaptic Synaptic

Myasthenic disorders

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Figure 116–1 ■ Myasthenic disorders. AChE, acetylcholinesterase; CMS, congenital myasthenic syndrome; LEMS, Lambert-Eaton myasthenic syndrome; MG, myasthenia gravis; MuSK, musclespecific kinase; nAChR, nicotinic acetylcholine receptor; SV, synaptic vesicle; VGCC (P/Q), voltage-gated calcium channel (P/Q type).

VGCC (P/Q)

AChE deficiency CMS (genetic)

Synaptic cleft

Seropositive MG (autoimmune) Slow- and fast-channel CMS (genetic)

■

nAChR MuSK

Seronegative MG (autoimmune) Rapsyn-deficiency CMS (genetic)

Rapsyn

CONGENITAL MYASTHENIC SYNDROMES Congenital myasthenic syndromes (CMSs) are a rare group of heterogeneous disorders that are caused not by autoantibodies but by inherited mutations in the synaptic vesicles, acetylcholinesterase, or nicotinic acetylcholine receptors. This results in either an increase (gain of function) or decrease (loss of function) in the magnitude of response to acetylcholine. The most frequent type of postsynaptic CMS is the slow-channel syndrome. The inheritance of CMS is either autosomal dominant or recessive. In contrast to neonatal MG, caused by passive transfer of antibodies to the fetus from a myasthenic mother, the mothers of infants with CMS do not have myasthenia. The onset of CMS usually occurs before 2 years of age. In contrast to autoimmune MG, immunosuppression and plasmapheresis are not effective in the management of CMS because antibodies play no role in its pathogenesis. In patients with MG and CMS, electromyography is characterized by decremental responses on repetitive stimulation and block with single-fiber recordings. However, patients

with a slow-channel CMS can also show characteristic repetitive discharges in response to a single supramaximal stimulus, the so-called double response. LAMBERT-EATON MYASTHENIC SYNDROME Lambert-Eaton myasthenic syndrome (LEMS) is an acquired disorder resulting from autoantibodies targeting the presynaptic P/Q voltage-gated calcium channels and possibly another presynaptic component (synaptotagmin), leading to a reduction in acetylcholine release. Synaptotagmin is an exocytotic calcium sensor and plays an important role in synaptic vesicle fusion and the fast release of acetylcholine. Anti-P/Q-type voltage-gated calcium channel antibodies are detected in 85% of patients with LEMS (seropositive). A fraction of seronegative LEMS patients have antisynaptotagmin antibodies in their sera. In approximately 60% of LEMS patients, the syndrome is a paraneoplastic disorder, most often associated with small cell carcinoma of the lung. In patients without malignancy, LEMS is an autoimmune disorder. LEMS is characterized by proximal muscle weakness in the lower and upper extremities, fatigability, and autonomic dysfunction. Involvement of bulbar or respiratory muscles is uncommon in LEMS patients. In patients with LEMS, electromyography typically shows low-amplitude compound muscle action potentials, associated with fade at slow rates of stimulation (2 Hz). Facilitation of response is seen after brief exercise or at high rates of repetitive stimulation (30 to 50 Hz).

MANAGEMENT AND PREVENTION Thymectomy is an elective procedure and should be performed after optimization of the patient’s condition. Preoperative assessment and preparation of MG patients should include

PHYSIOLOGIC IMBALANCE & COEXISTING DISEASE

class IV (severe generalized weakness with or without bulbar involvement). Improvement in strength after intravenous injection of edrophonium (Tensilon) helps confirm the diagnosis of MG. After a test dose of 1 to 2 mg, a total dose of 10 mg is administered intravenously. A positive response is expected within 5 minutes. There is no specific immunotherapy for MG. Nonspecific immunosuppression with steroids and immunosuppressants (e.g., azathioprine) and plasmapheresis are often combined with thymectomy. Anticholinesterases are used to treat symptoms. Thymectomy is the standard treatment for young patients and for those with thymoma. Plasmapheresis and intravenous immunoglobulin are effective in myasthenic crisis and for the preoperative optimization of the patient’s condition.

Muscle

486 Genetic

Postsynaptic Myasthenia Autoimmune gravis: Seropositive or seronegative

AChE deficiency

Antibodies to MuSK

Antibodies to nAChRs

Mutations in the gene encoding the collagenic tail subunit of the enzyme anchoring AChE in the synaptic cleft decrease the expression or the catalytic efficacy of the enzyme

Choline acetyltransferase mutations cause insufficient ACh resynthesis

Choline Genetic acetyltransferase deficiency

Synaptic

Antibodies target voltage-gated calcium (Ca2+) channels at motor nerve terminal and possibly another presynaptic component (synaptotagmin), leading to reduction in ACh release

LambertAutoimmune Eaton myasthenic syndrome

Cause

Presynaptic

Type

Myasthenic Disorders Clinical Features

Management

Normal ACh contents and NMJ architecture

≈ 60% of patients With malignancy, successful treatment can lead to have paraneoplastic marked improvement in symptoms response, often 3,4-Diaminopyridine blocks prejunctional in association with potassium (K) channels to (1) prevent K efflux, small cell lung (2) increase action potential duration, (3) prolong carcinoma activation of voltage-gated Ca2+ channels, and Weakness and (4) increase intracellular Ca2+ stores and ACh release fatigability Pyridostigmine potentiates response to 3, 4-diaminopyridine Often, plasmapheresis or IV immunoglobulin provides transient improvement Number of Characteristic AChE inhibitors nAChRs apneic attacks and end-plate along with structure myasthenic are normal symptoms Absent or Autosomal recessive Due to deficiency of AChE enzyme, patients do not reduced AChE disease with benefit from anticholinesterase therapy activity (by variable phenotypic histochemical expression staining) Moderately severe, Secondary loss generalized of nAChR and weakness and postsynaptic scoliosis with region restrictive lung degeneration disease are common End-plate regions Age at onset of Preoperative optimization by plasmapheresis and have simplified myasthenic continued pyridostigmine therapy architecture symptoms is earlier Patients are extremely sensitive to NDMRs with smaller in MuSK antibody- Response to SCh and mivacurium depends on folds and positive patients butyrylcholinesterase activity, which is expected marked Neck muscles are to decrease after plasmapheresis or pyridostigmine reduction commonly involved in nAChR— in MuSK antibody≈30% of that positive patients, in normal and limb muscles NMJ in MuSK antibodynegative patients

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Kinetic defects and/or gain-of-function mutations in nAChR cause lengthy nAChR opening and excessive Ca2+ influx with postsynaptic degeneration

Mutations in nAChR markedly reduce binding affinities, resulting in rapid ACh dissociation from binding sites, reducing the rate of channel opening, and increasing its closure rate

Slow-channel Genetic congenital myasthenic syndromes

Fast-channel Genetic congenital myasthenic syndromes

Patients exhibit myasthenic symptoms from birth or infancy Facial malformations are common in rapsyn deficiency

Usual dominant inheritance Selective weakness in cervical, scapular, and finger extensor muscles; variable weakness in other muscles NMJ structure Dominant or recessive normal; density inheritance of nAChRs Moderate symptoms normal or from birth to decreased infancy Partial response to AChE inhibitors

Changes in end-plate regions are similar to those seen with autoimmune MG Postsynaptic degeneration with loss of nAChRs; AChE is normal

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Combination treatment with 3,4-diaminopyridine and AchE

Open channel blockers (quinidine, fluoxetine) normalize slow-channel mutant opening durations No response to AChE medications Avoid SCh because it can worsen excitotoxicity

Response to anticholinesterase is incomplete Combined therapy with 3,4-diaminopyridine (which increases ACh release) is beneficial

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ACh, acetylcholine; AChE, acetylcholinesterase; MG, myasthenia gravis; MuSK, muscle-specific kinase; nAChR, nicotinic acetylcholine receptor; NDMR, nondepolarizing muscle relaxant; NMJ, neuromuscular junction; SCh, succinylcholine.

Mutations in nAChR or in rapsyn decrease expression of nAChRs

Reduced Genetic expression of nAChR or rapsyn deficiency

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488 Facilitation Transient Minimal therapeutic value

Absent After rest From myasthenic mother to fetus, causing neonatal MG Injecting healthy animals with MG IgG causes signs of MG Fade Transient Effective in managing symptoms No effect

Dysautonomias

Improvement in muscle strength Antibody transfer

Electromyography (response to 30-50 Hz stimulation) Effect of plasmapheresis Anticholinesterases

Response to 3,4-diaminopyridine

Significant improvement in symptoms

Present in ≈30% of patients (dry mouth, impotence) After exercise IgG from LEMS patients can block Ca2+ channels, inhibiting muscle contraction

Presynaptic

Effective in fast-channel congenital myasthenic syndromes

No effect Minimal therapeutic value

Fade

After rest Antibodies are not present

Presynaptic, synaptic, or postsynaptic component of NMJ Absent

Genetic mutations of presynaptic, synaptic, or postsynaptic proteins Dominant or recessive inheritance (no antibodies against nAChRs, MuSK, or P/Q type Ca2+ channels)

Congenital Myasthenic Syndromes

ACh, acetylcholine; IgG, immunoglobulin G; LEMS, Lambert-Eaton myasthenic syndrome; MG, myasthenia gravis; MuSK, muscle-specific kinase; nAChR, nicotinic acetylcholine receptor; NMJ, neuromuscular junction.

Target location

60% of LEMS patients have paraneoplastic autoimmune response Small cell lung carcinomas express voltagesensitive Ca2+ channels; antitumor antibodies to these channels cross-react with prejunctional voltage-gated Ca2+ channels at the NMJ to impair ACh release

Thymic lymphoid follicular hyperplasia present in 70% of MG patients Thymoma present in 12% of MG patients (paraneoplastic autoimmune response) Associated autoimmune conditions include thyrotoxicosis, systemic lupus erythematosus, rheumatoid arthritis, and pernicious anemia Postsynaptic

Autoantibodies targeting presynaptic voltagegated (P/Q) calcium (Ca2+) channels or synaptotagmin

Lambert-Eaton Myasthenic Syndrome

Associated conditions

Myasthenia Gravis

Differential Diagnosis of Myasthenic Disorders

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Table 116–2

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anesthetics on neuromuscular transmission. Therefore, it may be safer to use a small dose of an intermediate nondepolarizing neuromuscular blocker to facilitate tracheal intubation than to use deep inhalation anesthesia. Total intravenous anesthesia with a propofol-opioid infusion is a suitable alternative to a volatile anesthetic technique. A thoracic epidural anesthetic in combination with balanced general anesthesia provides excellent analgesia both intraoperatively and following transsternal thymectomy. Regional anesthesia has also been used successfully to provide labor analgesia in parturients with MG. However, local anesthetics are known to potentiate neuromuscular blocking drugs, and the metabolism of ester local anesthetics may be impaired if butyrylcholinesterase activity is reduced due to pyridostigmine therapy. Patients with LEMS are sensitive to depolarizing and nondepolarizing neuromuscular blockers. In patients with LEMS, neostigmine is an ineffective antagonist for residual neuromuscular block. Oral 3,4-diaminopyridine should be continued after surgery. All myasthenic patients should be closely monitored for neuromuscular weakness postoperatively in the surgical intensive care unit. The differential diagnosis of postoperative weakness in myasthenic patients should include the residual effects of neuromuscular blockers or anesthetic drugs, drugs that interfere with neuromuscular transmission (e.g., aminoglycoside antibiotics, antiarrhythmics, psychotropics), and myasthenic or cholinergic crisis.

Further Reading Abel M, Eisenkraft JB: Anesthetic implications of myasthenia gravis. Mt Sinai J Med 69:31-37, 2002. Baraka A: Onset of neuromuscular block in myasthenic patients. Br J Anaesth 69:227-228, 1992. Drachman DB: Myasthenia gravis. N Engl J Med 330:1797-1810, 1994. Engel AG, Ohno K, Sine SM: Congenital myasthenic syndromes: Progress over the past decade. Muscle Nerve 27:4-25, 2003. Leveque C, Hoshino T, David P, et al: The synaptic vesicle protein synaptotagmin associates with calcium channels and is a putative LambertEaton myasthenic syndrome antigen. Proc Natl Acad Sci U S A 89:3625-3629, 1992. Lindstrom JM: Acetylcholine receptors and myasthenia. Muscle Nerve 23:453-477, 2000. Naguib M, el Dawlatly AA, Ashour M, Bamgboye EA: Multivariate determinants of the need for postoperative ventilation in myasthenia gravis. Can J Anaesth 43:1006-1013, 1996. Naguib M, Flood P, McArdle JJ, Brenner HR: Advances in neurobiology of the neuromuscular junction: Implications for the anesthesiologist. Anesthesiology 96:202-231, 2002. Takamori M, Maruta T, Komai K: Lambert-Eaton myasthenic syndrome as an autoimmune calcium-channelopathy. Neurosci Res 36:183-191, 2000. Vincent A: Unravelling the pathogenesis of myasthenia gravis. Nat Rev Immunol 2:797-804, 2002. Vincent A, Palace J, Hilton-Jones D: Myasthenia gravis. Lancet 357: 2122-2128, 2001. Whitney KD, McNamara JO: Autoimmunity and neurological disease: Antibody modulation of synaptic transmission. Annu Rev Neurosci 22:175-195, 1999.

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(1) review of the patient’s neurologic history and a neurologic examination; (2) preoperative drug therapy (e.g., pyridostigmine and immunosuppressant drugs); (3) evaluation of bulbar symptoms or signs, such as dysphagia, dysarthria, or oropharyngeal weakness (because patients with bulbar involvement are at increased risk for postoperative respiratory complications); (4) search for the presence of other autoimmune diseases, such as diabetes mellitus, thyroid disease, systemic lupus erythematosus, or rheumatoid arthritis; (5) evaluation of pulmonary function tests, which should include flow-volume loops to help predict the need for postoperative mechanical ventilation; and (6) optimization of the patient’s condition by preoperative plasmapheresis or highdose intravenous immunoglobulin. Pyridostigmine therapy should be continued preoperatively. Myasthenic patients are generally resistant to succinylcholine owing to the decreased number of nicotinic acetylcholine receptors. However, butyrylcholinesterase (plasma cholinesterase) activity may be decreased in myasthenic patients by preoperative plasmapheresis or the administration of pyridostigmine, and this may result in the potentiation of succinylcholine. In the final analysis, the interplay between these factors (resistance to succinylcholine versus reduction in butyrylcholinesterase activity) should be considered when administering succinylcholine (or mivacurium) to patients with MG. Succinylcholine should be avoided in patients with slow-channel CMS because it can worsen excitotoxicity. Patients with MG are extremely sensitive to nondepolarizing neuromuscular blockers due to the significant loss of postsynaptic nicotinic acetylcholine receptors. Nevertheless, nondepolarizing neuromuscular blockers are not contraindicated in these patients. With careful titration and with adequate monitoring of neuromuscular function, nondepolarizing agents have been safely used in myasthenic patients undergoing thymectomy. Long-acting neuromuscular blocking drugs should be avoided in these patients. Intermediate-acting drugs are better alternatives. Approximately one fifth the ED95 of an intermediate-acting neuromuscular blocker should be given as a test dose. This helps estimate the patient’s drug requirement as guided by a quantitative neuromuscular monitoring device. Myasthenic patients typically exhibit marked variations in their sensitivities to nondepolarizing neuromuscular blockers. In myasthenic patients, reversal of residual block after surgery may be ineffective because acetylcholinesterase inhibition already exists as a result of chronic pyridostigmine therapy. Therefore, it is advisable to allow spontaneous recovery from relaxation postoperatively, while continuing supportive mechanical ventilation. Different anesthetic techniques have been used in myasthenic patients. Although surgical relaxation can be provided using only a potent inhaled anesthetic without neuromuscular blockers, this technique may be associated with a prolonged recovery from anesthesia due to the effects of inhalational

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Case Synopsis A 74-year-old man is seen in the preoperative holding area for repair of a fractured hip. For the past 10 years, he has been treated for Parkinson’s disease with carbidopalevodopa (Sinemet); pramipexole (Mirapex) was added 4 years ago. On examination, facial masking and bradykinesia are apparent. He also has a tremor, muscle rigidity, and pain. He has been taking his medications as directed, but because of off-period symptoms, he has recently begun using apomorphine (Apokyn) and domperidone for related nausea.

PROBLEM ANALYSIS Definition and Recognition James Parkinson described the disease that bears his name in 1817. He highlighted the characteristic stooped posture, as well as the triad of tremor, muscle rigidity, and bradykinesia. The most common initial symptom, exhibited by 70% of people with Parkinson’s disease (PD), is a resting tremor of the hand. Although the precise cause of PD is unknown, the symptoms are the result of increased depletion of dopamineproducing cells in the substantia nigra. The subsequent imbalance between acetylcholine and dopamine leads to the aforementioned motor symptoms and often causes dysautonomia as well. Posited factors related to the decrement in nigral cells include age, genetics, exposure to environmental toxins, and a combination thereof.

Risk Assessment As life expectancy has increased, so too has the likelihood that anesthesiologists will encounter patients with PD in their practices. The primary risk factor for PD is advanced age. Improvements in the pharmacotherapy of PD, particularly the development of levodopa, have also increased the life expectancy of the estimated 1 million people in the United States with PD (as well as 3% of the population of Europe older than 65 years), leading to an increased prevalence of this movement disorder. Because current treatments provide relief from most symptoms but not the associated postural instability of PD, the possibility of patients’ falling and requiring surgical repair of hip or long bone fractures has also increased. Patients also commonly require anesthesia for the surgical treatment of PD itself, such as deep brain thalamic or globus pallidus stimulation, and for urologic, ophthalmic, gastrointestinal, orthopedic, or vascular surgery.

Implications Correction of the imbalance in the neurotransmitters in the basal ganglia includes increasing dopamine levels, decreasing acetylcholine levels, or both (Table 117-1). Levodopa has been the principal therapy for PD since its introduction in 490

the 1960s; however, the use of dopamine receptor agonists has increasingly become first-line therapy in patients with early PD or as add-on therapy in later disease. Levodopa is converted to dopamine after crossing the blood-brain barrier and is administered with a decarboxylase inhibitor (carbidopa) to reduce the peripheral breakdown of levodopa, thereby increasing its availability in the brain and reducing peripheral side effects such as hypotension, nausea, and vomiting. The catechol-O-methyltransferase (COMT) inhibitors tolcapone and entacapone may be given with levodopa-carbidopa to further prevent the peripheral conversion of levodopa to dopamine. The short half-life of levodopa (30 to 60 minutes) may be implicated in the development of dyskinesias associated with its use. A rapidly dissolving tablet form of levodopa (Parcopa) has recently been approved by the Food and Drug Administration for the treatment of PD and has an onset of action of 10 minutes. However, other forms of levodopa must be discontinued 12 hours or more before introduction of the short-acting form. Dopamine receptor agonists, which enhance dopamine levels by mimicking the effects of dopamine in the brain, typically have a half-life of 3 to 69 hours: bromocriptine, 3 to 8 hours; pergolide, 27 hours; pramipexole, 7 to 17 hours; ropinirole, 6 hours; and cabergoline, 63 to 69 hours. All of these dopaminergic drugs are available only in parenteral form. However, a continuous duodenal infusion of a gel form of levodopa-carbidopa (Duodopa) and a transdermal patch containing a newly developed dopamine receptor agonist (rotigotine) are currently under investigation. Apomorphine, which is injected or infused subcutaneously, has recently been approved as rescue therapy for the “off ” periods of late-stage PD—a wearing-off or end-ofdose phenomenon during which motor and nonmotor symptoms are most severe. The onset of action is generally 5 to 15 minutes, with effects lasting from 45 to 90 minutes. Because apomorphine is highly emetogenic, patients are typically started on domperidone by mouth at a dose of 20 mg three times a day 3 days before starting apomorphine therapy. Domperidone is a dopamine receptor blocking agent that does not cross the blood-brain barrier and is therefore one of the few antiemetic agents that can be used in patients with PD; however, it is not approved for sale in the United States. Patients usually import this medication from Canada.

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Drugs Used in the Treatment of Parkinson’s Disease

Category Dopaminergic agents Dopamine enhancers Dopamine receptor agonists

MAO-B inhibitor Anticholinergic agents

Antiviral agent COMT inhibitors

Drug

Administration

Levodopa-carbidopa (Sinemet) Levodopa-carbidopa (Parcopa) Levodopa-carbidopa-entacapone (Stalevo) Apomorphine (Apokyn) Bromocriptine (Parlodel) Cabergoline (Dostinex) Pergolide (Permax) Pramipexole (Mirapex) Ropinirole (Requip) Selegiline (Eldepryl) Trihexyphenidyl (Artane, Trihexane, Trihexy) Procyclidine (Kernadrin) Benztropine (Cogentin) Ethopropazine (Parsidol) Amantadine (Symmetrel) Entacapone (Comtan) Tolcapone (Tasmar)

Oral Oral* Oral Subcutaneous† or intravenous injection Oral Oral Oral Oral Oral Oral Oral Oral Oral Oral Oral Oral Oral

*Rapidly dissolving oral agent that is metabolized in the gut, not sublingually. † Subcutaneous injection or infusion. COMT, catechol-O-methyltransferase; MAO-B, monoamine oxidase B.

MANAGEMENT AND PREVENTION The perioperative care of patients with PD is complicated by (1) potential anesthetic interactions with pharmacotherapy for PD, (2) the effects of anesthetic drugs on the dopamine

Table 117–2

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system and the patient’s symptoms, and (3) the fact that many patients with PD have decreased pulmonary function and gastrointestinal motility and autonomic nervous system derangements. The use of levodopa predisposes individuals to develop cardiac arrhythmias, as well as hypotension related to dopamine’s effects on renal blood flow. Therefore, ketamine and epinephrine-containing local anesthetics and inhalational agents that sensitize the heart to the effects of catecholamines (i.e., produce ventricular arrhythmias) should be avoided, and vasopressors such as phenylephrine may be required for hemodynamic support. A variety of other drugs used in the perioperative period may have deleterious effects on the symptoms of PD (Table 117-2). These include the typical antipsychotic drugs and most antiemetic agents—in particular, droperidol, prochlorperazine, metoclopramide, and thiethylperazine. Analgesic agents that may have an adverse effect on patients with PD include meperidine (particularly in patients receiving monoamine oxidase B

Drugs Contraindicated in Patients with Parkinson’s Disease

Category

Drug

Comments

Butyrophenones Inhalational agents

Haloperidol, droperidol Halothane, enflurane

Antiemetic Phenothiazines Analgesics

Metoclopramide Chlorpromazine, fluphenazine, prochlorperazine Fentanyl, sufentanil, morphine Meperidine

Block dopamine receptors Increase myocardial sensitivity to catecholamines (ventricular arrhythmias) Blocks dopamine receptors Block dopamine receptors May increase muscle rigidity Causes severe reaction in patients taking monoamine oxidase B inhibitors May cause acute dysautonomia May increase dyskinesias; may obliterate tremor during stereotactic procedures

Intravenous induction agent

Alfentanil Propofol

PHYSIOLOGIC IMBALANCE & COEXISTING DISEASE

Other drugs used to treat PD include the monoamine oxidase B inhibitor selegiline (rasagiline is currently undergoing clinical trials); the anticholinergic agents trihexyphenidyl and benztropine, which are effective primarily in treating tremor and rigidity but have potentially severe side effects in the elderly; and amantadine. Surgical treatment includes pallidotomy, thalamotomy, and deep brain stimulation of the subthalamic nucleus, globus pallidus internus, or thalamus. Ablative procedures have increasingly been abandoned in favor of deep brain stimulation.

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inhibitors), fentanyl, sufentanil, and alfentanil. Antihypertensive drugs to avoid include clonidine, propranolol, rauwolfia serpentina, and reserpine. Maintaining the required levels of dopaminergic agents is of the utmost importance in optimizing the perioperative care of patients with PD. Patients should continue their medications as long as possible before coming to the operating room. If a regional or local anesthetic is used, patients may be able to receive their medications during surgery, either by mouth or via a nasogastric tube. The use of apomorphine may be continued, but not initiated, throughout the perioperative period and delivered as a subcutaneous bolus or an intermittent infusion, if necessary. Patients who do not take their medications are at risk of developing increased muscle rigidity and laryngospasm, which could interfere with airway management, including ventilation and tracheal intubation or extubation. Other abnormalities in the control and function of the upper airway, which may lead to an obstructive airway pattern in as many as one third of patients with PD, also have an impact on the perioperative management of ventilation. Because of associated dysautonomia, many patients with PD are at risk for problems with temperature regulation throughout the perioperative period. Patients who experience increased symptoms in the preoperative holding area are treated with an anticholinergic (e.g., atropine, glycopyrrolate) or antihistamine (e.g., diphenhydramine). The latter can be especially helpful for managing exacerbations of tremor and for sedation, and the former for decreasing secretions. Regional and local techniques should be used to the extent possible in patients with PD to avoid the cognitive and emetogenic effects of general anesthesia. These techniques also allow for continued communication with the patient and the oral administration of dopaminergic agents, as needed. When general anesthesia is required, there is no agent of choice for induction, but halothane and, to a lesser extent, enflurane are best avoided because of their arrhythmogenic properties (i.e., sensitization of the heart to the effects of catecholamines). In particular, caution is warranted in patients on long-term levodopa therapy who are at risk of developing hemodynamic flux due to autonomic instability, catecholamine depletion, sensitization to catecholamines, and relative hypovolemia. Significant hypotension is treated with directacting α-adrenergic receptor agonists (e.g., phenylephrine). In general, there are no concerns about the use of neuromuscular blocking agents. A review of the literature indicates that although hyperkalemia and profound bradykinesia

occurred in one patient who received intravenous succinylcholine, there is little additional evidence of such a link. Support for the use of propofol is equivocal, as this drug may increase the severity of dyskinesias. However, it is also known to have antiparkinsonian effects. Propofol may be contraindicated in patients undergoing stereotactic procedures because this drug has been shown to abolish tremor. During emergence from anesthesia and before extubation, ventilation, airway reflexes, and the ability to follow commands should be assessed. Particular care should be exercised in optimizing respiratory function, owing to increased secretions and the propensity to develop aspiration pneumonia and compromised ventilatory function. If the patient develops confusion, as is common in patients with PD, the use of a benzodiazepine in the postoperative period rather than a typical antipsychotic agent may be preferred. However, care should be taken not to depress the respiratory drive. Morbidity and mortality rates during the perioperative period are increased in patients with PD compared with patients of similar age without PD. However, careful assessment and reduction of risk, optimization of cardiac and respiratory systems, and maintenance of dopaminergic therapy to the extent possible go a long way toward leveling the playing field.

Further Reading Anderson BJ, Marks PV, Futter ME: Propofol-contrasting effects in movement disorders. Br J Neurosurg 8:387-388, 1994. Bowron A: Practical considerations in the use of apomorphine injectable. Neurology 62(Suppl 4):S32-S36, 2004. Brindle GF: Anesthesia in the patient with parkinsonism. Primary Care 4:513-528, 1977. Eventou I, Moreno M, Geller E, et al: Hip fractures in patients with Parkinson’s syndrome. J Trauma 33:98-101, 1983. Furuya R, Hirai A, Andoh T, et al: Successful perioperative management of a patient with Parkinson’s disease by enteral levodopa administration under propofol anesthesia. Anesthesiology 89:261-263, 1998. Lozano AM, Mahant N: Deep brain stimulation surgery for Parkinson’s disease: Mechanisms and consequences. Parkinsonism Relat Disord 10(Suppl 1):S49-S57, 2004. Mason LJ, Cojocaru TT, Cole DJ: Surgical intervention and anesthetic management of the patient with Parkinson’s disease. Int Anesthesiol Clin 34:133-150, 1996. Nicholson G, Pereira AC, Hall GM: Parkinson’s disease and anaesthesia. Br J Anaesth 89:904-916, 2002. Schramm BM, Orser BA: Dystonic reaction to propofol attenuated by benztropine (Cogentin). Anesth Analg 94:1237-1240, 2002 Shults CW: Treatments of Parkinson disease. Arch Neurol 60:1680-1684, 2003.

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Alzheimer’s Disease Michael J. Murray and Catherine Friederich Murray Case Synopsis A 72-year-old woman with anemia is found to have adenocarcinoma of the colon, for which she is scheduled to have a laparotomy and resection of the lesion. The patient is anxious. A woman at the bedside in the preoperative holding area tells you that the patient, her mother, has Alzheimer’s disease and that she, the daughter, has a durable power of attorney for her mother’s health care.

PROBLEM ANALYSIS Definition

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Mini–Mental Status Examination

PHYSIOLOGIC IMBALANCE & COEXISTING DISEASE

Alzheimer’s disease (AD) is the most common neurodegenerative disease, accounting for approximately two thirds of all cases of dementia and affecting up to 20% of individuals older than 80 years. AD is progressive, leading to irreversible loss of neurons in the cerebral cortex and hippocampus. The pathologic hallmarks of the disease are neurofibrillary tangles, which contain the hyperphosphorylated form of the microtubular protein tau and extracellular plaques, which contain the peptide β-amyloid. β-Amyloid is cleaved from a larger protein, β-amyloid precursor protein, by the α, β, and γ secretases. The γ secretases cleave to Aβ42, a 42–amino acid sequence amyloid protein, which forms insoluble fibrils that accumulate in senile plaques isolated at autopsy from patients with AD. In some patients with familial disease, a genetic defect accounts for the increased activity of γ secretases. In the majority of patients, however, there is no identified defect that explains the presence of the neurofibrillary tangles and senile plaques.

during the perioperative period are goals in patients with AD. Much has been written about informed consent for surgical procedures and anesthesia. Patients with AD, by definition, have cognitive impairment, but in many states, depending on the degree of impairment, they may drive, vote, and give informed consent. The anesthesiologist must be able to assure himself or herself that the patient understands the procedure, the options, and the risks. If not, then

Recognition There is a broad spectrum of disease, but progressive impairment in memory, judgment, decision making, awareness of surroundings, and ability to care for oneself are the hallmarks of AD. Some patients who are seen preoperatively for unrelated problems may appear lucid and able to give informed consent. An accompanying family member, a person with a durable power of attorney for health care, or a review of the medical record may bring to the anesthesiologist’s attention the fact that the patient has AD. Other patients with more advanced disease or uncommon presentations may be belligerent or may have aphasia or spastic paraparesis. There is no clinical test to diagnose AD, although neurocognitive testing confirms the presence of dementia (Table 118-1). Anesthesiologists may use simpler tests to assess whether a patient is oriented and able to understand and provide informed consent.

Risk Assessment Obtaining informed consent, minimizing the chance of postoperative confusion, and optimizing management

From http://www.emedicine.com/neuro/topic13.htm.

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consent should be obtained from the next of kin. Obviously, if the patient has a representative with a durable power of attorney for health care, the process is easier. In either case, as with adolescents, it is best to have the patient sign the consent form to “assent” to the procedure and have a legal representative give “legal consent.” Agitation in patients with AD is not uncommon. Therefore, patients with AD may receive a benzodiazepine to reduce preoperative agitation. However, because postoperative cognitive impairment is often associated with anesthesia, benzodiazepines should not be part of the routine anesthetic plan for these patients. If they are used at all, benzodiazepines should be administered only after a risk-benefit analysis has been performed.

Implications There are no specific recommendations for managing anesthesia in patients with AD. Consent, as mentioned, is often an issue. However, regardless of who provides consent, the anesthesiologist must be patient when educating and calming a patient with AD. Many such patients have advanced directives. Discussion of the implications of the directive must occur preoperatively with the patient, the patient’s legal surrogate, or both. Regional anesthesia may seem preferable because there is less risk of worsening the patient’s cognitive impairment compared with general anesthesia. However, because many patients with AD are disoriented, agitated, and uncooperative, regional anesthesia can present quite a challenge. There is no single best type of anesthesia or anesthetic agent for patients with AD. They often have reduced reserves in vital organ function—pulmonary, cardiac, neurologic—and these factors must be taken into account.

MANAGEMENT There is no known cure for AD. As the disease progresses, patients are often institutionalized in nursing homes or their equivalent. Behavioral therapies include patient-centered approaches to try to minimize the effects of memory loss (e.g., established daily routines); caregiver training enables aides and therapists to recognize and deal with the common behavioral manifestations of AD. Psychotropic medications such as risperidone, olanzapine, and quetiapine are recommended at low doses to treat common manifestations of the disease such as anxiety, agitation, and depression. Decreased levels of acetylcholine in the cerebral cortex of AD patients are thought to account for many of the symptoms and signs of the disease. Therefore, drugs targeted at inhibiting the degradation of acetylcholine by cholinesterases in the cerebral cortex have been developed and are used to treat AD (e.g., tacrine, donepezil, rivastigmine, galantamine). Cholinesterase inhibition has been associated with improvement in cognitive function. Patients taking cholinesterase inhibitors should take their medication with a small sip of water the morning of surgery, because acute, severe cognitive and behavioral decline has been reported in patients who abruptly discontinue their medication.

In addition, an N-methyl-D-aspartate antagonist (memantine) has been approved in the United States to treat AD patients and is of some benefit in other patients with dementia. Patients with AD should have a responsible family member present with them whenever possible—someone they recognize and who can reassure and calm them during the perioperative period. This individual should also have the capacity to give informed consent for the anesthetic. Although these patients may be anxious, sedating drugs are avoided because they contribute to the postoperative confusion and delirium that often occur. Regional anesthesia, if indicated, should be attempted only if the patient is cooperative. Inhalational agents are used if general anesthesia is indicated, mainly owing to their rapid elimination. Glycopyrrolate does not cross the blood-brain barrier and is therefore preferred if an anticholinergic agent is required.

PREVENTION There are no known agents to prevent AD. Even drugs such as donepezil are effective in less than half of AD patients, and in those who do show a benefit, it lasts for only a few years at best. Although cognitive impairment is associated with general anesthesia, there is no evidence that general anesthesia increases the severity of AD. Caregivers may think so, because borderline cognitive impairment may worsen after an anesthetic. However, such worsening is transient, and patients should return to baseline within days to weeks following anesthesia. As discussed earlier, there is no ideal anesthetic type, technique, or agent. In developing an anesthetic plan, the anesthesiologist must consider the degree of cognitive impairment, the amount of agitation, the degree of cooperation, comorbid conditions, and possible drug interactions. With careful planning and management, the patient’s caregiver should notice only mild, if any, worsening of neurologic function postoperatively.

Further Reading Bohnen N, Warner MA, Kokmen E, et al: Early and midlife exposure to anesthesia and age of onset of Alzheimer’s disease. Int J Neurosci 77:181-185, 1994. Clark CM, Ewbank D, Lee VM-Y, et al: Molecular pathology of Alzheimer’s disease: Neuronal cytoskeletal abnormalities. In Growdon JH, Rosser MN (eds): The Dementias, vol 19 of Blue Books of Practical Neurology. Boston, Butterworth-Heinemann, 1998, pp 285-304. Dickson DW: Apoptotic mechanisms in Alzheimer neurofibrillary degeneration: Cause or effect? J Clin Invest 114:23-27, 2004. Esler WP, Wolfe MS: A portrait of Alzheimer secretases—new features and familiar faces. Science 293:1449-1454, 2001. Fernandez CR, Fields A, Richards T, et al: Anesthetic considerations in patients with Alzheimer’s disease. J Clin Anesth 15:52-58, 2003. Gasparini M, Vanacore N, Schiaffini C, et al: A case-control study on Alzheimer’s disease and exposure to anesthesia. Neurol Sci 23:11-14, 2002. Hutton M, Perez-Tur J, Hardy J: Genetics of Alzheimer’s disease. Essays Biochem 33:117-131, 1998. Iwatsubo T, Odaka A, Suzuki N, et al: Visualization of A beta 42(43) and A beta 40 in senile plaques with end-specific A beta monoclonals: Evidence that an initially deposited species is A beta 42(43). Neuron 13:45-53, 1994.

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Langa KM, Foster NL, Larson EB: Mixed dementia: Emerging concepts and therapeutic implications. JAMA 292:2901-2908, 2004. Larson EB, Kukull WA, Buchner D, et al: Adverse drug reactions associated with global cognitive impairment in elderly persons. Ann Intern Med 107:169-173, 1987.

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Nussbaum RL, Ellis CE: Alzheimer’s disease and Parkinson’s disease. N Engl J Med 348:1356-1364, 2003. Selkoe DJ: Alzheimer disease: Mechanistic understanding predicts novel therapies. Ann Intern Med 140:627-638, 2004.

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Jacob Gutsche and Clifford S. Deutschman Case Synopsis A 22-year-old man presents with fever and abdominal pain. A computed tomography scan indicates that he has appendicitis. Laparoscopic exploration reveals a perforated appendix with pus and stool in the abdomen. The patient undergoes laparotomy and appendectomy. The open abdomen is irrigated extensively with antibiotic-containing saline. During the procedure the patient develops hypotension and oliguria, requiring the administration of significant volumes of intravenous fluid. The anesthesiologist inserts an arterial line and pulmonary artery catheter to monitor the resuscitation. Peritoneal fluid and blood cultures are obtained, and broad-spectrum antibiotics are started.

PROBLEM ANALYSIS Definition and Recognition The systemic inflammatory response syndrome (SIRS) and multiple organ dysfunction syndrome (MODS) were first described in the 1970s. Early reports of MODS heralded our ability to support patients through such major medical or surgical catastrophes as ruptured aortic aneurysms, severe trauma, pancreatitis, multiple transfusions, and major systemic infections. Unfortunately, surviving patients subsequently developed dysfunction in organs that were unaffected by the initial injury. Multiple terms were applied to these syndromes, which led to confusion and limited the ability to stratify risk and compare therapeutic options. In 1991 the American College of Chest Physicians and Society of Critical Care Medicine convened a consensus conference to formalize definitions, allowing the comparison of patient populations from different institutions or geographic regions. These deliberations generated the new term SIRS, which was necessary because there were patients who developed signs and symptoms of systemic inflammation but without identifiable infection. The presence of any two of four criteria is sufficient to establish the diagnosis of SIRS (Table 119-1). In addition, the consensus conference provided formal definitions for sepsis (Table 119-2), and the syndrome of organ failure following SIRS or sepsis was renamed MODS. Although these definitions greatly improved our ability to compare patient populations and conduct more meaningful clinical trials, several problems remained. Key was the 496

excessive sensitivity and lack of specificity inherent in the definition of SIRS. Namely, many events or interventions provoke a stress response in patients sufficient to meet the criteria for SIRS. For example, virtually every postoperative patient meets the SIRS criteria, but it is clear that most should not be included in studies of the pathogenesis of MODS. Primarily for this reason, North American and European critical care societies convened an International Sepsis Definitions Conference in 2001 to revisit and modify the definitions established in 1991. Conference participants chose to de-emphasize the use of the term SIRS and to lengthen the list of signs and symptoms characterizing sepsis (Table 119-3). In addition, more specific criteria for organ dysfunction were adopted (Table 119-4).

Risk Assessment and Implications Humans respond to physiologic stress such as trauma, stroke, pneumonia, ischemia, pancreatitis, bowel perforation,

Table 119–1

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Criteria for Systemic Inflammatory Response Syndrome

Fever (core temperature >38.3°C) or hypothermia (core temperature <36°C) White blood cell count >12,000 or < 4000 Heart rate >90 beats/min or >2 standard deviations above normal for age Tachypnea

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Consensus Definitions of Sepsis and Septic Shock

Severe sepsis: sepsis with the presence of dysfunction in at least one organ Septic shock: sepsis with persistent hypotension Mean arterial pressure <60 mm Hg Systolic blood pressure (SBP) <90 mm Hg Decrease in SBP >40 mm Hg from patient’s normal baseline, despite adequate volume resuscitation

large-volume blood loss, and infection in a specific manner. This characteristic physiologic response is referred to as the stress response, and it may have evolved as a way to promote recovery from localized trauma or infection. The initial phase of the response is commonly called shock. In most cases, shock is rapidly reversible. The second phase includes hypermetabolism and can be thought of as occurring to facilitate the repair of damaged tissue. This second phase also includes leukocytosis, which features (1) mobilization of leukocytes to the area of damage, (2) enhanced hepatic gluconeogenesis to provide fuel for these leukocytes, (3) increased oxygen extraction at the tissue level, and (4) breakdown of endogenous proteins, primarily by catabolism of skeletal muscle. This process provides the necessary substrates for gluconeogenesis, increased hepatic protein synthesis, and repair of damaged tissue. Further, the process is driven by catecholamines, cortisol, glucagon, and cytokines

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Criteria for Suspected or Documented Sepsis

General Variables Fever (core temperature >38.3°C) Hypothermia (core temperature <36°C) Heart rate >90 beats/min or >2 SD above normal for age Tachypnea Altered mental status Significant edema or positive fluid balance (>20 mL/kg over 24 hr) Hyperglycemia (plasma glucose >120 mg/dL) in patients without diabetes

Inflammatory Variables Leukocytosis (WBC count >12,000) Leukopenia (WBC count < 4000) Normal WBCs with >10% immature forms C-reactive protein >2 SD above normal value Plasma procalcitonin >2 SD above normal value

Hemodynamic Variables Arterial hypotension (SBP <90 mm Hg, MAP <70 mm Hg, or SBP decrease ≥40 mm Hg or to <2 SD below normal for age) SvO2 >70% (this level can be normal in children, so this is not a criterion for pediatric patients) Cardiac index >3.5 (this level can be normal in children, so this is not a criterion for pediatric patients)

Tissue Perfusion Variables Hyperlactatemia (>1 mmol/L) Decreased capillary refill or mottling MAP, mean arterial pressure; SBP, systolic blood pressure; SD, standard deviations; SvO2, venous oxygen saturation; WBC, white blood cell. Adapted from Levy MM, Fink MP, Marshall JC, et al: 2001 SCCM/ESICM/ ACCP/ATS/SIS International Sepsis Definitions Conference. Intensive Care Med 29:530-538, 2003.

released by leukocytes. The resultant hyperglycemia is associated with an increased release of insulin. Finally, substrate delivery is facilitated by vasodilatation, fluid retention, increased cardiac output, and capillary leak, all of which appear to be essential, because damaged tissue is avascular. The hypermetabolic phase of the stress response can evolve via two possible pathways; one is normal, and the other is pathologic. In the normal pathway, completion of angiogenesis by postinjury day 4 leads to the resolution of inflammation, hypermetabolism, and the hyperendocrine state. This is the more common scenario and is normal. Although it meets all the criteria for SIRS, it is clearly not what the 1991 consensus conference participants had in mind when they coined the term “systemic inflammatory response syndrome.” In some patients, however, inflammation becomes pathologic. The mechanism of such transformation is unknown. These patients have SIRS or, with infection, sepsis. Either of these is characterized by important changes in metabolism and regulation: ●

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In contrast to simple stress, the ability to extract and use oxygen is diminished, despite increased cellular demand. The increased demand for energy by white blood cells, coupled with an inability to use molecular oxygen, leads to aerobic glycolysis. That is, oxygen delivery is adequate, but the inability to use oxygen increases lactate production. This causes persistent hyperglycemia, impaired glucose utilization, and a state of relative glucose intolerance. Endocrine abnormalities become prominent. The production and release of some hormones, notably vasopressin, are reduced, resulting in relative deficiency. Also, tissues become resistant to the effects of other hormones. This is exemplified by the development of insulin resistance or the diminished ability of catecholamines to modulate vascular tone.

Cellular dysfunction leads to biochemical abnormalities without overt organ failure. For example, hepatic dysfunction impairs gluconeogenesis, which prevents the conversion of lactate to pyruvate. Also, oxidation of long-chain triglycerides and the expression of key β-oxidative enzymes are decreased. As a result, amino acids become an increasingly important fuel source, despite the fact that hepatic dysfunction compromises ureagenesis. Importantly, contractile dysfunction is often observed in patients with MODS. In each case, compensatory mechanisms (increased substrate delivery to the liver, vasodilatation, and increased diastolic volume in the heart) may mask organ dysfunction.

MANAGEMENT AND PREVENTION There is no “magic bullet” to cure SIRS, sepsis, or MODS. It is not known what causes a controlled inflammatory response to become pathologic. In the absence of a specific target for therapy, management is based on source control, supportive care, and prevention of further complications.

Source Control The patient history, physical examination, and laboratory or diagnostic studies are used to identify infectious causes of continuing inflammation.

PHYSIOLOGIC IMBALANCE & COEXISTING DISEASE

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Physiologic Imbalance and Coexisting Disease

Criteria for Organ Dysfunction Severity of Dysfunction

Body System

Mild