Anesthesiology

ANESTHESIOLOGY NOTICE Medicine is an ever-changing science. As new research and clinical experience broaden our knowl...

Author: David Longnecker | David Brown | Mark Newman | Warren Zapol

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ANESTHESIOLOGY

NOTICE Medicine is an ever-changing science. As new research and clinical experience broaden our knowledge, changes in treatment and drug therapy are required. The authors and the publisher of this work have checked with sources believed to be reliable in their efforts to provide information that is complete and generally in accord with the standards accepted at the time of publication. However, in view of the possibility of human error or changes in medical sciences, neither the authors nor the publisher nor any other party who has been involved in the preparation or publication of this work warrants that the information contained herein is in every respect accurate or complete, and they disclaim all responsibility for any errors or omissions or for the results obtained from use of the information contained in this work. Readers are encouraged to confirm the information contained herein with other sources. For example and in particular, readers are advised to check the product information sheet included in the package of each drug they plan to administer to be certain that the information contained in this work is accurate and that changes have not been made in the recommended dose or in the contraindications for administration. This recommendation is of particular importance in connection with new or infrequently used drugs.

ANESTHESIOLOGY Edited By: David E. Longnecker, MD, FRCA Robert D. Dripps Professor Emeritus Department of Anesthesiology and Critical Care University of Pennsylvania Philadelphia, Pennsylvania

David L. Brown, MD Edward Rotan Distinguished Professor and Chairman Department of Anesthesiology and Pain Medicine University of Texas, MD Anderson Cancer Center Houston, Texas

Mark F. Newman, MD Merel H. Harmel Professor and Chairman Department of Anesthesiology Duke University Medical Center Durham, North Carolina

Warren M. Zapol, MD Anesthetist-in-Chief Department of Anesthesia and Critical Care Massachusetts General Hospital Reginald Jenney Professor of Anaesthesia Harvard Medical School Boston, Massachusetts

Medical New York Chicago San Francisco Lisbon London Madrid Mexico City New Delhi San Juan Seoul Singapore Sydney Toronto

Copyright © 2008 by The McGraw-Hill Companies, Inc. All rights reserved. Manufactured in the United States of America. Except as permitted under the United States Copyright Act of 1976, no part of this publication may be reproduced or distributed in any form or by any means, or stored in a database or retrieval system, without the prior written permission of the publisher. 0-07-159333-0 The material in this eBook also appears in the print version of this title: 0-07-145984-7. All trademarks are trademarks of their respective owners. Rather than put a trademark symbol after every occurrence of a trademarked name, we use names in an editorial fashion only, and to the benefit of the trademark owner, with no intention of infringement of the trademark. Where such designations appear in this book, they have been printed with initial caps. McGraw-Hill eBooks are available at special quantity discounts to use as premiums and sales promotions, or for use in corporate training programs. For more information, please contact George Hoare, Special Sales, at [email protected] or (212) 904-4069. TERMS OF USE This is a copyrighted work and The McGraw-Hill Companies, Inc. (“McGraw-Hill”) and its licensors reserve all rights in and to the work. Use of this work is subject to these terms. Except as permitted under the Copyright Act of 1976 and the right to store and retrieve one copy of the work, you may not decompile, disassemble, reverse engineer, reproduce, modify, create derivative works based upon, transmit, distribute, disseminate, sell, publish or sublicense the work or any part of it without McGraw-Hill’s prior consent. You may use the work for your own noncommercial and personal use; any other use of the work is strictly prohibited. Your right to use the work may be terminated if you fail to comply with these terms. THE WORK IS PROVIDED “AS IS.” McGRAW-HILL AND ITS LICENSORS MAKE NO GUARANTEES OR WARRANTIES AS TO THE ACCURACY, ADEQUACY OR COMPLETENESS OF OR RESULTS TO BE OBTAINED FROM USING THE WORK, INCLUDING ANY INFORMATION THAT CAN BE ACCESSED THROUGH THE WORK VIA HYPERLINK OR OTHERWISE, AND EXPRESSLY DISCLAIM ANY WARRANTY, EXPRESS OR IMPLIED, INCLUDING BUT NOT LIMITED TO IMPLIED WARRANTIES OF MERCHANTABILITY OR FITNESS FOR A PARTICULAR PURPOSE. McGraw-Hill and its licensors do not warrant or guarantee that the functions contained in the work will meet your requirements or that its operation will be uninterrupted or error free. Neither McGraw-Hill nor its licensors shall be liable to you or anyone else for any inaccuracy, error or omission, regardless of cause, in the work or for any damages resulting therefrom. McGraw-Hill has no responsibility for the content of any information accessed through the work. Under no circumstances shall McGraw-Hill and/or its licensors be liable for any indirect, incidental, special, punitive, consequential or similar damages that result from the use of or inability to use the work, even if any of them has been advised of the possibility of such damages. This limitation of liability shall apply to any claim or cause whatsoever whether such claim or cause arises in contract, tort or otherwise. DOI: 10.1036/0071459847

Dedication “Life is no brief candle to me; it is a sort of splendid torch which I've got a hold of for the moment and I want to make it burn as brightly as possible before handing it on to future generations.” George Bernard Shaw Irish playwright (1856–1950)

The editors were fortunate indeed to have outstanding mentors who dedicated their professional lives to the development of our generation in the specialty. Through their guidance, wisdom and actions, they truly handed the torch to us. As their progeny, we are ever grateful for both their professional guidance and their personal friendship. In recognition of their influence on us individually, and the specialty overall, we dedicate this book to: Robert M. Epstein, Harold Carron Professor and Chair Emeritus of Anesthesiology, University of Virginia, on behalf of David E. Longnecker Richard J. Kitz, Henry Isaiah Dorr Distinguished Professor of Research and Teaching in Anaesthetics and Anaesthesia, Harvard Medical School and Massachusetts General Hospital, on behalf of Warren M. Zapol Edward Lowenstein, Henry Isaiah Dorr Professor of Research and Teaching in Anaesthetics and Anaesthesia, Harvard Medical School and Massachusetts General Hospital, on behalf of Warren M. Zapol Daniel C. Moore, Chair Emeritus of Anesthesiology, Virginia Mason Medical Center, Seattle, Washington, on behalf of David L. Brown Jerry Reves, Vice-President for Medical Affairs and Dean, College of Medicine, Medical University of South Carolina, Professor of Anesthesiology and Pharmacology (former Chair, Duke University Department of Anesthesiology), on behalf of Mark F. Newman

Copyright © 2008 by The McGraw-Hill Companies, Inc. Click here for terms of use.

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Contents

CONTRIBUTORS FOREWORD

xiii

SECTION B: Preoperative Evaluation of the Anesthesia Patient

xxiii CHAPTER 6

PREFACE

xxv

89

Appropriate and Effective Use of Consultants Lee Goldman, MD, and Thomas H. Lee, MD

PART 1

CHAPTER 7

THE SPECIALTY OF ANESTHESIOLOGY CHAPTER 1

Evaluation of the Patient with Cardiovascular Disease 2

The Evolution of Anesthesiology as a Clinical Discipline—A Lesson in Developing Professionalism

Ronald P. Olson, MD

CHAPTER 8

Douglas R. Bacon, MD, MA

Evaluation of the Patient with a Difficult Airway

CHAPTER 2

James C. Phero, DMD, Andranik Ovassapian, MD, and William E. Hurford, MD

12

The Scope and Future of Anesthesia Practice

CHAPTER 9

Michael S. Avidan, MBBCh, DA, FCA and Alex S. Evers, MD

CHAPTER 3

95

122

134

Evaluation of the Patient with Pulmonary Disease 20

Philip G. Boysen, MD, MBA

Safety and Quality: The Guiding Principles of Patient-Centered Care

CHAPTER 10

Jeffrey B. Cooper, PhD, and David E. Longnecker, MD, FRCA

Evaluation of the Patient with Neuropsychiatric Disease

145

John Morris, MD, and Dell Burkey, MD

PART 2

CHAPTER 11

PREPARING FOR ANESTHESIA

Evaluation of the Patient with Neuromuscular or Skeletal Disease Philip D. Bailey, Jr., DO, and Joseph R. Tobin, MD

SECTION A: Approach to the Anesthesia Patient CHAPTER 4

40

CHAPTER 12

Overview of Preoperative Assessment and Management

Evaluation of the Patient with Endocrine Disease or Diabetes Mellitus

Bobbie Jean Sweitzer, MD

A.D. John, MD, and F.E. Sieber, MD

CHAPTER 5

156

68

CHAPTER 13

173

194

The Anesthetic Plan for Healthy Patients

Evaluation of the Patient with Renal Disease

Patrick E. Benedict, MD, and Kevin K. Tremper, PhD, MD

Mark Stafford-Smith, MD, CM, FRCPC, George Lappas, MD, and Andrew D. Shaw, MB, BS, FRCA

viii

CONTENTS

CHAPTER 14

216

Evaluation of Patients with Hepatic Disease

SAFETY AND RISK REDUCTION IN ANESTHESIA PRACTICE

Richard A. Wiklund, MD

CHAPTER 15

239

Anesthetic Considerations for the Patient with Anemia or Coagulation Disorders

267

CHAPTER 25

David S. Smith, MD, PhD, and Lee A. Fleisher, MD

279

CHAPTER 26

Principles of Antimicrobial Therapy

Positioning of Patients for Operation

Richard Teplick, MD, and Robert H. Rubin, MD, FACP, FCCP

Vijaya Gottumukkala, MB, BS, MD (Anes), FRCA, DipABA

300

Myron Yaster, MD, and Richard A. Elliott, MD

476

Robert H. Stiefel, MS, CCE, and Julian M. Goldman, MD

310

Evaluation of Children

PART 4

Randall C. Wetzel, MBBS, MRCP, LRCS, MBA, FAAP, FCCM

CHAPTER 20

CHAPTER 27

465

Electricity, Electrical Safety, and Instrumentation in the Operating Room

Preoperative Assessment of the Newborn

CHAPTER 19

452

Approaches to Quality Improvement in Anesthesia Care

Jacob T. Gutsche, MD, and Clifford S. Deutschman, MS, MD, FCCM

CHAPTER 18

424

Anesthesia Risk

Evaluation of the Patient with Perioperative Malnutrition

CHAPTER 17

CHAPTER 24 Fredrick K. Orkin, MD, MBA, MSc, and David E. Longnecker, MD, FRCA

Edwin G. Avery, IV, MD

CHAPTER 16

PART 3

MANAGING ANESTHESIA CARE 341

SECTION A: Monitoring the Anesthesia Patient

Evaluation of the Geriatric Patient CHAPTER 28

Stanley Muravchick, MD, PhD, and Katherine Grichnik, MD

CHAPTER 21

498

Perioperative Information Management Systems 358

J.P. Abenstein, MSEE, MD

Evaluation of the Pregnant Patient CHAPTER 29

Robert Gaiser, MD

519

Hemodynamic Monitoring CHAPTER 22

374

Evaluation of the Obese Patient

Shahar Bar-Yosef, MD, Rebecca A. Schroeder, MD, and Jonathan B. Mark, MD

Babatunde O. Ogunnaike, MD, and Charles W. Whitten, MD

CHAPTER 30

CHAPTER 23

Intraoperative Transesophageal Echocardiography: A Systematic Approach

Evaluation of the Patient with Alcohol or Drug Addiction Paul S. Pagel, MD, PhD, Judith A. May, MD, and David C. Warltier, MD, PhD

396

552

Larry Field, MD, George Lappas, MD, Angus Christie, MD, Andrew Green, MD, Steven Morozowich, MD, Tamas Szabo, MD, PhD, Qin Zhang, MD, Stephen Murphy, MD, Ravi Bissessar, MD, and Solomon Aronson, MD

CHAPTER 31 Monitoring Respiratory Function Dean R. Hess, PhD, RRT, and Robert M. Kacmarek, PhD, RRT

579

CONTENTS

CHAPTER 32 Intraoperative Neurologic Monitoring

598

CHAPTER 42 Total Intravenous Anesthesia

897

John C. Keifer, MD, and Cecil O. Borel, MD

John Sear, MA, PhD, MBBS, FFARCS, FANZCA

CHAPTER 33 619 Monitoring and Managing Neuromuscular Blockade

CHAPTER 43 Cardiovascular Drugs

Richard M. Pino, MD, PhD, and Hassan H. Ali, MD

Alina Nicoara, MD, Mark Abel, MD, David Bronheim, MD, and Daniel Thys, MD

CHAPTER 34 639 Monitoring and Managing Perioperative Electrolyte Abnormalities, Acid-Base Disorders, and Fluid Replacement

CHAPTER 44 Pharmacology of Local Anesthetics

918

954

James E. Heavner, DVM, PhD

Patrick J. Neligan, MD, and Jiri Horak, MD

SECTION D: Regional Anesthesia SECTION B: Managing the Airway CHAPTER 35 Airway Management

685

CHAPTER 45 Incorporating Regional Anesthesia into Anesthetic Practice

P. Allan Klock Jr., MD, and Andranik Ovassapian, MD

Richard W. Rosenquist, MD, and David L. Brown, MD

SECTION C: Anesthesia Drugs and Drug Delivery Systems

CHAPTER 46 Neuraxial Anesthesia

974

978

Daniel T. Warren, MD, and Spencer S. Liu, MD

CHAPTER 36 Mechanisms of General Anesthetic Action

718

Max B. Kelz, MD, PhD, Jay Yang, MD, PhD, and Roderic G. Eckenhoff, MD

CHAPTER 47 Paravertebral Anesthesia

1009

Holly Evans, MD, FRCPC, and Stephen M. Klein, MD

CHAPTER 37 Pharmacology of Inhalational Anesthetics

739

CHAPTER 48 Peripheral Nerve Blocks

1025

Denise J. Wedel, MD, and Terese T. Horlocker, MD

Stuart A. Forman, MD, PhD, and George A. Mashour, MD, PhD

CHAPTER 38 Anesthesia Delivery System

767

CHAPTER 49 Managing Adverse Outcomes during Regional Anesthesia

1053

James B. Eisenkraft, MD

Ban CH Tsui, MSc, MD, FRCPC, and Brendan T. Finucane, MBBCh, FRCPC

CHAPTER 39 821 Principles of Pharmacokinetics and Pharmacodynamics: Applied Clinical Pharmacology for the Practitioner

SECTION E: Specialty Areas of Anesthetic Practice

Ken B. Johnson, MD, and Talmage D. Egan, MD

CHAPTER 40 Pharmacology of Intravenous Anesthetics

849

Mark Dershwitz, MD, PhD, and Carl E. Rosow, MD, PhD

CHAPTER 41 Pharmacology of Opioid Analgesics

869

Carl E. Rosow, MD, PhD, and Mark Dershwitz, MD, PhD

CHAPTER 50 Neuroanesthesia

1081

Michael M. Todd, MD, David S. Warner, MD, PhD, Mazen A. Maktabi, MD, and Kamila Vagnerova, MD

CHAPTER 51 Cardiac Anesthesia Mark A. Chaney, MD, Albert T. Cheung, MD, Christopher A. Troianos, MD, Jessica L. Willert, MD, David A. Zvara, MD, and Stanton K. Shernan, MD

1140

ix

x

CONTENTS

CHAPTER 52 1174 Anesthesia for Surgical Treatment of Congenital Heart Disease: A Problem-Oriented Approach James S. Harrington, MD, Avinash C. Shukla, MBBS, and Paul R. Hickey, MD

CHAPTER 53 Thoracic Anesthesia

1213

Stuart J. Weiss, MD, PhD, and E. Andrew Ochroch, MD, MSCE

CHAPTER 54 Anesthesia for Major Vascular Surgery

1284

Alina Nicoara, MD, and Madhav Swaminathan, MD

CHAPTER 55 Anesthesia for Gastrointestinal Surgery

1314

CHAPTER 56 1338 Anesthesia for Liver Surgery and Transplantation Warren S. Sandberg, MD, PhD, and Douglas E. Raines, MD

1378

Lucinda L. Everett, MD

CHAPTER 64 Anesthesia for Orthopedic Surgery

1541

Gavin Martin, MB, Dara Breslin, MB, and Todd Stevens, MD

CHAPTER 65 Anesthesia for Ophthalmic Surgery

1558

Salvatore J. Basta, MD

CHAPTER 66 1582 Anesthesia for Otorhinolaryngolic (Ear, Nose, and Throat) Surgery

CHAPTER 67

1608

Outpatient Anesthesia J. Lance Lichtor, MD, and Suhas V. Kalghatgi, MBBS, MD, FFARCSI

CHAPTER 68 1625 Monitored Anesthetic Care and Conscious Sedation Robert S. Harris, MD, and Peter S. Sebel, MB, BS, PhD, MBA

Benjamin A. Kohl, MD, and Joseph S. Savino, MD

CHAPTER 58 Anesthesia for Kidney, Pancreas, or Other Organ Transplantation

1520

Bil Ragan, MD

Martin Slodzinski, MD, PhD, and William T. Merritt, MD, MBA

CHAPTER 57 Anesthesia for Heart or Lung Transplantation

CHAPTER 63 Anesthesia for Children

1396

CHAPTER 69 Anesthesia Care for Diagnostic or Therapeutic Procedures Outside of the Operating Room

1649

Monica Davis, MD

David S. Beebe, MD, and Kumar G. Belani, MBBS, MS

CHAPTER 59 1420 Endocrine Surgery and Intraoperative Management of Endocrine Conditions Robert A. Peterfreund, MD, PhD, and Stephanie L. Lee, MD, PhD

CHAPTER 60 Anesthetic Considerations for Genitourinary and Renal Surgery

CHAPTER 70 Anesthesia for Trauma Patients John K. Stene, MD, PhD, and Christopher M. Grande, MD, MPH

CHAPTER 71 Anesthetic Management of the Burned Patient 1450

1660

1674

Edward A. Bittner, MD, PhD, Loreta Grecu, MD, and J.A. Jeevendra Martyn, MD

Maurizio Cereda, MD, and Sean Kennedy, MD

PART 5 CHAPTER 61 1471 Anesthesia for Obstetric Care and Gynecologic Surgery

POSTOPERATIVE CARE OF THE ANESTHESIA PATIENT

Lawrence C. Tsen, MD

CHAPTER 62 Anesthesia for Newborn Surgical Emergencies Myron Yaster, MD, and Mark I. Rossberg, MD

1502

CHAPTER 72 Recovery of the Healthy Patient Loreta Grecu, MD, Edward A. Bittner, MD, PhD, and Edward George, MD, PhD

1688

CONTENTS

CHAPTER 73 Postoperative Complications

1700

CHAPTER 83 Mechanical Ventilation for the Surgical Patient

1852

Robert M. Kacmarek, PhD, RRT, and Dean R. Hess, PhD, RRT

Edward A. Bittner, MD, PhD, Loreta Grecu, MD, and Edward George, MD, PhD

CHAPTER 74 Management of Acute Postoperative Pain

1716

CHAPTER 84 Cardiopulmonary Resuscitation

1873

Charles W. Otto, MD, FCCM

Jane C. Ballantyne, MD, FRCA

PART 7

PART 6

SPECIAL CONSIDERATIONS IN ANESTHESIA CARE

THE CRITICALLY ILL PATIENT CHAPTER 75 The Pathophysiology of Critical Illness

1738

Luca M. Bigatello, MD, Judith Hellman, MD, David Liu, MD, PhD, and Warren M. Zapol, MD

CHAPTER 76 Evaluation of the Patient with Multiple Organ Dysfunction Syndrome

1754

CHAPTER 85 Blood and Blood Component Therapy

1892

Ian J. Welsby, BSc, MBBS, FRCA, and Steven J. Bredehoeft, MD

CHAPTER 86 1912 Cognitive Dysfunction after Anesthesia and Surgery Mark F. Newman, MD, and Joseph P. Matthews, MD

Jean Kwo, MD, and Judith Hellman, MD

CHAPTER 77 Evaluation of the Burned Patient

1772

Edward A. Bittner, MD, PhD, Loreta Grecu, MD, and J. A. Jeevendra Martyn, MD

CHAPTER 78 Evaluation of the Trauma Patient

1784

CHAPTER 87 Protection of the Central Nervous System in Surgical Patients

1925

W. Andrew Kofke, MD, MBA, FCCM

CHAPTER 88 Anaphylactic Reactions and Anesthesia

1947

Robert S. Holzman, MD, FAAP

Edward George, MD, PhD

CHAPTER 79 Developing the Anesthetic Plan for the Critically Ill Patient

1797

CHAPTER 89 Malignant Hyperthermia, Thermoregulation, and Perioperative Hypothermia

1964

Sheila Muldoon, MD, Nyamkhishig Sambuughin, PhD, Maria Voelkel, BA, Rolf Bunger, MD, PhD, Hilary P. Grocott, MD, FRCPC, and Christopher Sulzer, MD

Jean Kwo, MD

CHAPTER 80 Monitoring and Transport of the Critically Ill Patient

1811

PART 8

Michael G. Fitzsimons, MD, FCCP, and Nathaniel Sims, MD

CARE OF THE CHRONIC PAIN PATIENT CHAPTER 81 Postoperative Care of the Noncardiac Surgical ICU Patient

1828 CHAPTER 90 Mechanisms of Chronic Pain

Gary J. Brenner, MD, PhD, and Clifford J. Woolf, MD, PhD

Michael C. Banks, MD, and C. William Hanson, III, MD

CHAPTER 82 Hemodynamic Support of the Critically Ill Patient Jean-Louis Vincent MD, PhD

2000

1841

CHAPTER 91 Common Pain Syndromes Basem Hamid, MD

2020

xi

xii

CONTENTS

CHAPTER 92 Medical Management of Chronic Pain

2042

Marc A. Huntoon, MD

CHAPTER 96 Substance Dependence and Abuse in Anesthesia Care Providers

2135

Raymond C. Roy, PhD, MD

CHAPTER 93 Interventional Management of Chronic Pain

2072 CHAPTER 97 The Economics of Health Care and Anesthesia Practice

Carlos A. Pino, MD, and James P. Rathmell, MD

CHAPTER 94 Palliative and Cancer Pain Care

2106

Franklin Dexter, MD, PhD, and Amr E. Abouleish, MD, MBA

CHAPTER 98 Practice Management

Phillip C. Phan, MD, and Allen W. Burton, MD

2155

2172

Philip J. Mesisca, MBA, CMPE, and Susan Chapman Moss, MPH

PART 9 PRACTICE RELATED ISSUES

APPENDIX A CHAPTER 95 Legal Issues in Anesthesiology C. Lee Parmley, MD, JD

2126

2183

Mark Dershwitz, MD, PhD, and Carl E. Rosow, MD, PhD

INDEX

2197

Contributors

Mark Abel, MD

Douglas R. Bacon, MD, MA

David S. Beebe, MD

Associate Professor of Clinical Anesthesiology Department of Anesthesiology Montefiore Medical Center Bronx New York

Professor of Anesthesiology and History of Medicine Mayo Clinic College of Medicine Rochester Minnesota

Department of Anesthesiology University of Minnesota Minneapolis Minnesota

Philip D. Bailey, Jr., DO

Departments of Anesthesiology, Medicine, Pediatrics and Environmental Health University of Minnesota Minneapolis Minnesota

J. P. Abenstein, MSEE, MD Associate Professor of Anesthesiology Department of Anesthesiology Mayo Clinic College of Medicine Rochester Minnesota

Amr E. Abouleish, MD, MBA Professor of Department of Anesthesiology University of Texas Medical Branch Galveston Texas

Hassan H. Ali, MD Professor Emeritus Harvard Medical School Boston Massachusetts

Solomon Aronson, MD Professor of Anesthesiology Executive Vice Chairman Department of Anesthesiology Duke University Medical Center Durham North Carolina

Edwin G. Avery, IV, MD Chief Division of Cardiac Anesthesia Instructor of Anesthesia Department of Anesthesia and Critical Care Massachusetts General Hospital Harvard Medical School Boston Massachusetts

Michael S. Avidan, MBBCh., DA, FCA Associate Professor of Anesthesiology and Surgery Division Chief, CT Anesthesiology and CT Intensive Care Washington University School of Medicine St. Louis Missouri

Assistant Professor Department of Anesthesiology and Critical Care Medicine Uniformed Services University of the Health Sciences Bethesda Maryland

Jane C. Ballantyne, MD, FRCA Chief Division of Pain Medicine Massachusetts General Hospital Department of Anesthesia and Critical Care Associate Professor in Anesthesia Harvard Medical School Boston Massachusetts

Michael C. Banks, MD Assistant Professor of Clinical Anesthesiology and Critical Care Department of Anesthesiology and Critical Care University of Pennsylvania School of Medicine Philadelphia Pennsylvania

Kumar G. Belani, MBBS, MS

Patrick E. Benedict, MD Assistant Professor of Anesthesiology Director, Preoperative Assessment Clinic Department of Anesthesiology University of Michigan Health System Ann Arbor Michigan

Luca M. Bigatello, MD Associate Professor of Anesthesia Harvard Medical School Director, Critical Care Division Department of Anesthesia Massachusetts General Hospital Boston Massachusetts

Ravi Bissessar, MD University of North Carolina Hospital Chapel Hill North Carolina

Shahar Bar-Yosef, MD

Edward A. Bittner, MD, PhD

Assistant Professor Department of Anesthesiology and Critical Care Duke University Medical Center Veterans Affairs Medical Center Durham North Carolina

Instructor of Anaesthesia Harvard Medical School Assistant in Anesthesia Massachusetts General Hospital Boston Massachusetts

Salvatore J. Basta, MD

Associate Professor of Anesthesiology and Surgery Duke University Division Chief Neuroanesthesia Duke University Medical Center Durham North Carolina

Chief Anesthesiology Massachusetts Eye and Ear Infirmary Assistant Professor Harvard Medical School Boston Massachusetts


Cecil O. Borel, MD

xiv

CONTRIBUTORS

Philip G. Boysen, MD, MBA

Allen W. Burton, MD

Professor of Anesthesiology and Medicine Executive Associate Dean for Graduate Medical Education University of North Carolina at Chapel Hill Chapel Hill North Carolina

Professor and Section Chief UT MD Anderson Cancer Center Section of Cancer Pain Management, Department of Anesthesiology and Pain Medicine Houston Texas

Steven J. Bredehoeft, MD Director Transfusion Services Duke University Medical Center Durham North Carolina

Department of Anesthesiology and Critical Care University of Pennsylvania Philadelphia VA Medical Center Philadelphia Pennsylvania

Gary J. Brenner, MD, PhD

Mark A. Chaney, MD

Assistant Professor of Anesthesia Harvard Medical School Program Director Massachusetts General Hospital Pain Medicine Fellowship Boston Massachusetts

Associate Professor Director of Cardiac Anesthesia Department of Anesthesia and Critical Care University of Chicago Chicago Illinois

Dara Breslin, MB

Albert T. Cheung, MD

Assistant Clinical Professor Duke University Medical Center Durham North Carolina

Professor Department of Anesthesiology and Critical Care Medicine University of Pennsylvania Pennsylvania

David Bronheim, MD Associate Professor Department of Anesthesiology Mount Sinai School of Medicine New York New York

David L. Brown, MD Edward Rotan Distinguished Professor and Chairman Department of Anesthesiology and Pain Medicine University of Texas, MD Anderson Cancer Center Houston, Texas

Rolf Bunger, MD, PhD Professor Department of Anatomy, Physiology and Genetics Uniformed Services University of the Health Sciences Bethesda Maryland

Professor of Anesthesiology and Critical Care and Surgery University of Pennsylvania School of Medicine Philadelphia Pennsylvania

Maurizio Cereda, MD

Angus Christie, MD University of North Carolina Hospital Chapel Hill North Carolina

Jeffrey B. Cooper, PhD Director, Biomedical Engineering Partners HealthCare System, Inc. Associate Professor of Anesthesia Harvard Medical School Department of Anesthesia and Critical Care Massachusetts General Hospital Director, Center for Medical Simulation Boston Massachusetts

Monica Davis, MD Assistant Professor Department of Anesthesiology MD Anderson Cancer Center Houston Texas

Dell Burkey, MD Clinical Associate Professor Anesthesiology and Pain Medicine Director of Acute Pain Service Hospital of the University of Pennsylvania Department of Anesthesiology and Critical Care Philadelphia Pennsylvania

Clifford S. Deutschman, MS, MD, FCCM

Mark Dershwitz, MD, PhD Professor and Vice Chair of Anesthesiology Professor of Biochemistry and Molecular Pharmacology University of Massachusetts Worcester Massachusetts

Franklin Dexter, MD, PhD Director Division of Management Consulting Professor Departments of Anesthesia and Health Management and Policy University of Iowa Iowa City Iowa

Roderic G. Eckenhoff, MD Austin Lamont Professor Department of Anesthesiology and Critical Care University of Pennsylvania Philadelphia Pennsylvania

Talmage D. Egan, MD Professor of Anesthesiology KC Wong Presidential Chair University of Utah Department of Anesthesiology Salt Lake City Utah

James B. Eisenkraft, MD Professor, Department of Anesthesiology Mount Sinai School of Medicine New York University Attending Anesthesiologist Mount Sinai Hospital New York New York

Richard A. Elliott, MD Assistant Professor Department of Anesthesiology/Critical Care Medicine The Johns Hopkins Medical Institutions Baltimore Maryland

Holly Evans, MD, FRCPC Assistant Professor Department of Anesthesiology University of Ottawa Ontario Canada

CONTRIBUTORS

Lucinda L. Everett, MD

Stuart A. Forman, MD, PhD

Christopher M. Grande, MD, MPH

Associate Professor of Anaesthesia Harvard Medical School Chief of Pediatric Anesthesiology Department of Anesthesia and Critical Care Massachusetts General Hospital Boston Massachusetts

Associate Professor of Anaesthesia Harvard Medical School Associate Anesthetist Department of Anesthesia and Critical Care Massachusetts General Hospital Boston Massachusetts

Clinical Professor of Anesthesiology and CCM University of Pittsburgh School of Medicine Executive Director TraumaCare International (ITACCS) World Headquarters Baltimore Maryland

Alex S. Evers, MD

Robert Gaiser, MD

Henry Mallinkrodt Professor and Chairman Department of Anesthesiology Professor of Internal Medicine and Molecular Biology and Pharmacology Washington University School of Medicine Anesthesiologist-in-Chief Barnes-Jewish Hospital St. Louis Missouri

Associate Professor of Anesthesia, Pharmacology, Obstetrics and Gynecology Department of Anesthesiology and Critical Care University of Pennsylvania Philadelphia Pennsylvania

Larry Field, MD Assistant Professor Departments of Anesthesia and Perioperative Medicine Medical University of South Carolina Charleston South Carolina

Edward George, MD, PhD Instructor Harvard Medical School Assistant Anesthetist Department of Anesthesia and Critical Care Massachusetts General Hospital Boston Massachusetts

Julian M. Goldman, MD Brendan T. Finucane, MBBCh, FRCPC Professor Department of Anesthesiology and Pain Medicine University of Alberta Adult Anesthesiologist University of Alberta Hospital Edmonton Alberta Canada

Assistant in Anesthesia Massachusetts General Hospital Instructor Harvard Medical School Physician Advisor to Partners HealthCare Biomedical Engineering at Massachusetts General Hospital Boston Massachusetts

Lee Goldman, MD Michael G. Fitzsimons, MD, FCCP Instructor in Anesthesia Division of Cardiac Anesthesia Division of Critical Care Department of Anesthesia and Critical Care Massachusetts General Hospital Boston Massachusetts

Lee A. Fleisher, MD Robert Dunning Dripps Professor and Chair Department of Anesthesiology and Critical Care University of Pennsylvania Philadelphia Pennsylvania

Executive Vice President Health and Biomedical Sciences Columbia University Dean of the Faculties Health Sciences and Medicine Columbia's College of Physicians and Surgeons New York New York

Vijaya Gottumukkala, MB, BS, MD (Anes), FRCA Associate Professor Clinical Director University of Texas MD Anderson Cancer Center Houston Texas

Loreta Grecu, MD Instructor in Anesthesia Department of Anesthesia and Critical Care Harvard Medical School Department of Anesthesia and Critical Care Massachusetts General Hospital Boston Massachusetts

Andrew Green, MD University of North Carolina Hospital Chapel Hill North Carolina

Katherine Grichnik, MD Associate Professor Duke University Department of Anesthesia Duke University Medical Center Durham North Carolina

Hilary P. Grocott, MD, FRCPC Professor Department of Anesthesiology Division of Cardiothoracic Anesthesiology and Critical Care Medicine Duke University Medical Center Durham North Carolina

Jacob T. Gutsche, MD Instructor of Anesthesiology and Critical Care University of Pennsylvania School of Medicine Philadelphia Pennsylvania

Basem Hamid, MD Assistant professor Department of Anesthesiology and Pain Medicine University of Texas M.D. Anderson Cancer Center Houston Texas

XV

xvi

CONTRIBUTORS

C. William Hanson, III, MD

Jiri Horak, MD

John C. Keifer, MD

Professor of Anesthesiology and Critical Care, Surgery and Internal Medicine Department of Anesthesiology and Critical Care University of Pennsylvania School of Medicine Philadelphia Pennsylvania

Assistant Professor Department of Anesthesiology and Critical Care Hospital of the University of Pennsylvania Philadelphia Pennsylvania

Associate Clinical Professor of Anesthesiology Duke University Medical Center Durham North Carolina

Terese T. Horlocker, MD

Assistant Professor Department of Anesthesiology and Critical Care University of Pennsylvania Philadelphia Pennsylvania

James S. Harrington, MD Instructor in Anesthesia Harvard Medical School Assistant in Cardiac Anesthesia Children's Hospital Boston Boston Massachusetts

Robert S. Harris, MD Assistant Professor Department of Anesthesiology Emory University School of Medicine Atlanta Georgia

James E. Heavner, DVM, PhD Professor Anesthesiology and Physiology Director of Research Department of Anesthesiology Tech University Health Sciences Center Lubbock Texas

Judith Hellman, MD Department of Anesthesia and Critical Care Massachusetts General Hospital Harvard Medical School Boston Massachusetts

Dean R. Hess, PhD, RRT

Department of Anesthesiology Mayo Clinic College of Medicine Rochester Minnesota

Marc A. Huntoon, MD Chair Division of Pain Medicine Department of Anesthesiology Mayo Clinic Rochester Minnesota

William E. Hurford, MD Professor and Chair Department of Anesthesiology University of Cincinnati College of Medicine Cincinnati Ohio

A. D. John, MD Assistant Professor Department of Anesthesiology and Critical Care Medicine Johns Hopkins Bayview Medical Center Johns Hopkins Medical Institutions Baltimore Maryland

Ken B. Johnson, MD

Associate Professor of Anesthesiology Harvard Medical School Assistant Director Respiratory Care Massachusetts General Hospital Boston Massachusetts

Associate Professor of Anesthesiology Learned Family Associate Professorship University of Utah Department of Anesthesiology Salt Lake City Utah

Paul R. Hickey, MD

Robert M. Kacmarek, PhD, RRT

Professor of Anesthesia Harvard Medical School Anesthesiologist-in-Chief Children's Hospital Boston Boston Massachusetts

Director, Respiratory Care Massachusetts General Hospital Professor of Anesthesiology Harvard Medical School Boston Massachusetts

Robert S. Holzman, MD, FAAP

Suhas V. Kalghatgi, MBBS, MD, FFARCSI

Department of Anesthesiology Perioperative and Pain Medicine Children's Hospital Boston Boston Massachusetts

Max B. Kelz, MD, PhD

Anesthesiologist Trinity Medical Center Moline Illinois

Sean Kennedy, MD Associate Professor of Anesthesia Department of Anesthesiology and Critical Care University of Pennsylvania Chief of Anesthesia Philadelphia Veterans Affairs Medical Center Philadelphia Pennsylvania

Stephen M. Klein, MD Assistant Professor Department of Anesthesiology Duke University Medical Center Durham North Carolina

P. Allan Klock, Jr., MD Associate Professor Vice Chair for Clinical Affairs Department of Anesthesia and Critical Care University of Chicago Chicago Illinois

W. Andrew Kofke, MD, MBA, FCCM Director of Neuroanesthesia Professor of Anesthesiology and Critical Care Department of Anesthesiology and Critical Care University of Pennsylvania Philadelphia Pennsylvania

Benjamin A. Kohl, MD Assistant Professor Department of Anesthesiology and Critical Care Section of Cardiothoracic Anesthesia and Critical Care University of Pennsylvania School of Medicine Philadelphia Pennsylvania

CONTRIBUTORS

Jean Kwo, MD

Spencer S. Liu, MD

William T. Merritt, MD, MBA

Instructor in Anaesthesia Harvard Medical School Assistant in Anesthesia Department of Anesthesia and Critical Care Massachusetts General Hospital Boston Massachusetts

Staff Anesthesiologist Virginia Mason Medical Center Clinical Professor of Anesthesiology University of Washington School of Medicine Department of Anesthesiology Virginia Mason Medical Center Seattle Washington

Department of Anesthesia and Critical Care Medicine Johns Hopkins University Baltimore Maryland

George Lappas, MD

David E. Longnecker, MD, FRCA

Fellow Cardiothoracic Anesthesia Department of Anesthesiology Duke University Medical Center Durham North Carolina

Robert D. Dripps Professor Emeritus Department of Anesthesiology and Critical Care University of Pennsylvania Philadelphia Pennsylvania

Stephanie L. Lee, MD, PhD Associate Professor of Medicine Boston University School of Medicine Director of Endocrine Clinics Section of Endocrinology, Diabetes and Nutrition Department of Medicine Boston Medical Center Boston Massachusetts

Thomas H. Lee, MD Professor of Medicine Harvard Medical School and the Harvard School of Public Health CEO of the Partners Community HealthCare, Inc Brigham and Women's Hospital Massachusetts General Hospital Boston Massachusetts

J. Lance Lichtor, MD Professor Department of Anesthesia University of Iowa Iowa City Iowa

David Liu, MD, PhD Instructor Department of Anesthesia and Critical Care Harvard University Clinical Instructor Staff Anesthesiologist Department of Anesthesia and Critical Care Massachusetts General Hospital Boston Massachusetts

Mazen A. Maktabi, MD Associate Professor University of Iowa Department of Anesthesia Iowa City Iowa

Jonathan B. Mark, MD Department of Anesthesiology and Critical Care Duke University Medical Center Veterans Affairs Medical Center Durham North Carolina

Gavin Martin, MB Associate Professor Duke University Medical Center Durham North Carolina

J. A. Jeevendra Martyn, MD Professor Harvard Medical School Professor and Director Clinical and Biochemical Pharmacology Laboratory Massachusetts General Hospital Boston Massachusetts

George A. Mashour, MD, PhD Instructor in Anaesthesia Harvard Medical School Department of Anesthesia and Critical Care Massachusetts General Hospital Boston Massachusetts

Judith A. May, MD Assistant Professor Department of Anesthesiology Medical College of Wisconsin Milwaukee Wisconsin

Philip J. Mesisca, MBA, CMPE Chief Operating Officer Department of Anesthesiology and Critical Care Department of Otorhinolaryngology University of Pennsylvania Health System Philadelphia Pennsylvania

Steven Morozowich, MD Clinical Associate Division of Cardiothoracic Anesthesia and Critical Care Medicine Department of Anesthesiology Duke University Medical Center Durham North Carolina

John Morris, MD Department of Anesthesiology and Critical Care Hospital of the University of Pennsylvania Philadelphia Pennsylvania

Susan Chapman Moss, MPH Senior Administrative Director Department of Anesthesia and Critical Care Massachusetts General Hospital Boston Massachusetts

Sheila Muldoon, MD Professor Department of Anesthesiology Director of Malignant Hyperthermia Biopsy Center Uniformed Services University of the Health Sciences Bethesda Maryland

Stanley Muravchick, MD, PhD Professor of Anesthesia University of Pennsylvania Department of Anesthesia Hospital of the University of Pennsylvania Philadelphia Pennsylvania

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CONTRIBUTORS

Stephen Murphy, MD

Fredrick K. Orkin, MD, MBA, MSc

James C. Phero, DMD

University of North Carolina Hospital Chapel Hill North Carolina

Adjunct Professor of Anesthesiology Yale University School of Medicine New Haven Connecticut

Professor of Clinical Anesthesia Clinical Surgery and Clinical Pediatrics Department of Anesthesiology University of Cincinnati College of Medicine Cincinnati Ohio

Patrick J. Neligan, MD Assistant Professor Department of Anesthesiology and Critical Care Hospital of University of Pennsylvania Philadelphia Pennsylvania

Mark F. Newman, MD Merel H. Harmel Professor and Chairman Department of Anesthesiology Duke University Medical Center Durham North Carolina

Alina Nicoara, MD Assistant Professor Department of Anesthesiology Yale University School of Medicine Attending Anesthesiologist West Haven Veterans Affairs Medical Center West Haven Connecticut

E. Andrew Ochroch, MD, MSCE Department of Anesthesiology and Critical Care University of Pennsylvania School of Medicine Philadelphia Pennsylvania

Babatunde O. Ogunnaike, MD Associate Professor Director of Anesthesia Parkland Surgical Services Department of Anesthesiology and Pain Management University of Texas Southwestern Medical Center Dallas Texas

Ronald P. Olson, MD Assistant Clinical Professor Department of Community and Family Medicine Department of Anesthesiology Duke University Director Preoperative Screening Duke University Health System Durham North Carolina

Charles W. Otto, MD, FCCM Professor of Anesthesiology Associate Professor of Medicine University of Arizona College of Medicine Director Critical Care Medicine University Medical Center Tucson Arizona

Andranik Ovassapian, MD Professor of Clinical Anesthesia Department of Anesthesia and Critical Care University of Chicago Chicago Illinois

Paul S. Pagel, MD, PhD Professor Department of Anesthesiology Medical College of Wisconsin Milwaukee Wisconsin

C. Lee Parmley, MD, JD Professor of Anesthesiology Vanderbilt University Medical Center Department of Anesthesiology Division of Critical Care Nashville Tennessee

Robert A. Peterfreund, MD, PhD Associate Professor of Anesthesia Harvard Medical School Anesthetist Department of Anesthesia and Critical Care Massachusetts General Hospital Boston Massachusetts

Carlos A. Pino, MD Instructor Department of Anesthesiology University of Vermont College of Medicine Burlington Vermont

Richard M. Pino, MD, PhD Associate Professor Harvard Medical School Associate Anesthetist Massachusetts General Hospital Boston Massachusetts

Bil Ragan, MD Assistant Anesthesiologist Massachusetts Eye and Ear Infirmary Clinical Instructor of Anaesthesia Harvard Medical School Boston Massachusetts

Douglas E. Raines, MD Associate Professor of Anesthesia Harvard Medical School Associate Anesthetist Department of Anesthesia and Critical Care Massachusetts General Hospital Boston Massachusetts

James P. Rathmell, MD Professor of Anesthesiology, University of Vermont College of Medicine Burlington Vermont

Richard W. Rosenquist, MD Phillip C. Phan, MD Assistant Professor University of Texas MD Anderson Cancer Center Section of Cancer Pain Management, Department of Anesthesiology and Pain Medicine Houston Texas

Professor of Anesthesia Director Pain Medicine Division University of Iowa University of Iowa Hospitals and Clinics Department of Anesthesia Iowa City Iowa

CONTRIBUTORS

Carl E. Rosow, MD, PhD

Rebecca A. Schroeder, MD

Martin Slodzinski, MD, PhD

Professor of Anaesthesia Harvard Medical School Anesthetist Department of Anesthesia and Critical Care Massachusetts General Hospital Boston Massachusetts

Department of Anesthesiology and Critical Care Duke University Medical Center Veterans Affairs Medical Center Durham North Carolina

Department of Anesthesiology and Critical Care Medicine Johns Hopkins Bayview Medical Center Johns Hopkins Medical Institutions Baltimore Maryland

Mark I. Rossberg, MD

Professor of Anaesthetics Hon. Consultant Anaesthetist Nuffield Department of Anaesthetics University of Oxford John Radcliffe Hospital Headington Oxford United Kingdom

Assistant Professor, Department of Anesthesiology and Critical Care Medicine The Johns Hopkins Medical Institutions Baltimore Maryland

Raymond C. Roy, PhD, MD Professor and Chair of Anesthesiology Wake Forest University School of Medicine Winston-Salem North Carolina

Robert H. Rubin, MD, FACP, FCCP Gordan and Marjorie Osborne Professor of Health Sciences and Technology Professor of Medicine Harvard Medical School Co-director Division of Infectious Disease Brigham and Women's Hospital Boston Massachusetts

Nyamkhishig Sambuughin, PhD Assistant Professor Department of Anesthesiology Uniformed Services University of the Health Sciences Bethesda Maryland

Warren S. Sandberg, MD, PhD Assistant Professor of Anaesthesia Harvard Medical School Department of Anesthesia and Critical Care Massachusetts General Hospital Boston Massachusetts

Joseph S. Savino, MD Associate Professor Vice Chairman, Strategic Planning and Clinical Operations Department of Anesthesiology and Critical Care Section of Cardiothoracic Anesthesia and Critical Care University of Pennsylvania School of Medicine Philadelphia Pennsylvania

John Sear, MA, PhD, MBBS, FFARCS, FANZCA

Peter S. Sebel, MB, BS, PhD, MBA Professor and Vice Chair Department of Anesthesiology Emory University School of Medicine Atlanta Georgia

Andrew D. Shaw, MB, BS, FRCA Associate Professor of Anesthesiology Department of Anesthesiology Duke University Medical Center Durham North Carolina

Stanton K. Shernan, MD Assistant Professor of Anesthesia Harvard Medical School Division Chief Cardiac Anesthesia Brigham and Women's Hospital Boston Massachusetts

Avinash C. Shukla, MBBS Instructor in Anaesthesia Harvard Medical School Associate in Cardiac Anesthesia Children's Hospital Boston Boston Massachusetts

F.E. Sieber, MD Associate Professor Department of Anesthesiology and Critical Care Medicine Johns Hopkins Bayview Medical Center Johns Hopkins Medical Institutions Baltimore Maryland

Nathaniel Sims, MD Assistant Professor of Anesthesia Department of Anesthesia and Critical Care Massachusetts General Hospital Boston Massachusetts

David S. Smith, MD, PhD Associate Professor Department of Anesthesiology and Critical Care University of Pennsylvania Philadelphia Pennsylvania

Mark Stafford-Smith, MD, CM, FRCPC Associate Professor of Anesthesiology Director Duke Cardiothoracic Anesthesia Fellowship Duke University Medical Center Durham North Carolina

John K. Stene, MD, PhD Professor Department of Anesthesiology Penn State University College of Medicine Director Perioperative Anesthesia Trauma Services Penn State Milton S. Hershey Medical Center Hershey Pennsylvania

Todd Stevens, MD Faculty Fellow Duke University Medical Center Durham North Carolina

Robert H. Stiefel, MS, CCE Director Clinical Engineering Department University of Maryland Medical Center Baltimore Maryland

Christopher Sulzer, MD Assistant Professor Department of Anesthesiology Division of Cardiothoracic Anesthesiology and Critical Care Medicine Duke University Medical Center Durham North Carolina

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CONTRIBUTORS

Madhav Swaminathan, MD

Christopher A. Troianos, MD

Denise J. Wedel, MD

Associate Professor Division of Cardiothoracic Anesthesia Department of Anesthesiology Duke University Medical Center Durham North Carolina

Chairman and Program Director Department of Anesthesiology Western Pennsylvania Hospital Pittsburgh Pennsylvania

Professor of Anesthesiology Department of Anesthesiology Mayo Clinic College of Medicine Rochester Minnesota

Lawrence C. Tsen, MD

Stuart J. Weiss, MD, PhD

Bobbie Jean Sweitzer, MD

Associate Professor in Anaesthesia Harvard Medical School Brigham and Women's Hospital Boston Massachusetts

Associate Professor of Anesthesiology and Critical Care University of Pennsylvania Philadelphia Pennsylvania

Ban CH Tsui, MSc, MD, FRCPC

Ian J. Welsby, BSc, MBBS, FRCA

Assistant Professor Director of Clinical Research Department of Anesthesiology and Pain Medicine University of Alberta Alberta Canada

Assistant Professor Department of Anesthesiology and Critical Care Duke University Medical Center Durham North Carolina

Associate Professor Department of Anesthesia and Critical Care University of Chicago Director Anesthesia Perioperative Medicine Clinic Chicago Illinois

Tamas Szabo, MD, PhD Department of Anesthesiology SUNY Upstate Medical University Syracuse New York

Richard Teplick, MD Chief of Staff University of South Alabama Hospitals Associate Dean for Clinical Affairs University of South Alabama College of Medicine University of South Alabama Mobile Alabama

Daniel Thys, MD Professor Department of Anesthesiology St. Luke's-Roosevelt Hospital Center College of Physicians and Surgeons Columbia University New York New York

Joseph R. Tobin, MD Professor and Section Head Pediatric Anesthesiology and Pediatric Critical Care Wake Forest University School of Medicine Medical Center Boulevard Winston-Salem North Carolina

Michael M. Todd, MD Professor and Chair University of Iowa Department of Anesthesia Iowa City Iowa

Kevin K. Tremper, PhD, MD Robert B. Sweet Professor and Chairman Department of Anesthesiology University of Michigan Health System Ann Arbor Michigan

Kamila Vagnerova, MD Visiting Assistant Professor Oregon Health and Sciences University Department of Anesthesiology Portland Oregon

Jean-Louis Vincent, MD, PhD Head Department of Intensive Care Erasme Hospital Free University of Brussels Belgium

Maria Voelkel, BA Research Assistant Department of Anesthesiology Uniformed Services University of the Health Sciences Bethesda Maryland

David C. Warltier, MD, PhD Professor and Chairman Department of Anesthesiology Medical College of Wisconsin Milwaukee Wisconsin

David S. Warner, MD, PhD Professor Duke University Department of Anesthesiology Medical Center Durham North Carolina

Daniel T. Warren, MD Staff Anesthesiologist Virginia Mason Medical Center Department of Anesthesiology Virginia Mason Medical Center Seattle Washington

Randall C. Wetzel, MBBS, MRCP, LRCS, MBA, FAAP, FCCM Chairman of Anesthesiology Critical Care Medicine The Anne O'M Wilson Professor of Critical Care Medicine Director of Critical Care Medicine Childrens Hospital Los Angeles Professor of Pediatrics and Anesthesiology USC Keck School of Medicine Director of the Laura P. and Leland K. Whittier Virtual PICU Los Angeles California

Charles W. Whitten, MD Professor Vice Chairman for Resident Affairs M.T. “Pepper” Jenkins Professor in Anesthesiology Department of Anesthesiology and Pain Management University of Texas Southwestern Medical Center Dallas Texas

Richard A. Wiklund, MD Associate Clinical Professor of Anesthesia Harvard Medical School Anesthetist Massachusetts General Hospital Boston Massachusetts

Jessica L. Willert, MD Instructor Department of Anesthesiology Harvard Medical School Staff Cardiac Anesthesiologist Department of Anesthesiology Brigham & Women's Hospital Boston Massachusetts

CONTRIBUTORS

Clifford J. Woolf, MD, PhD

Myron Yaster, MD

Qin Zhang, MD

Richard J. Kitz Professor of Anesthesia Research Harvard Medical School Director Neural Plasticity Research Group Boston Massachusetts

Richard J. Traystman Professor, Departments of Anesthesiology, Critical Care Medicine and Pediatrics The Johns Hopkins Medical Institutions Baltimore Maryland

Fellow Duke University Durham North Carolina

Jay Yang, MD, PhD

Warren M. Zapol, MD

Professor Department of Anesthesiology Columbia University College of Physicians and Surgeons New York New York

Anesthetist-in-Chief Department of Anesthesia and Critical Care Massachusetts General Hospital Boston, Massachusetts Reginald Jenney Professor of Anaesthesia Harvard Medical School Boston Massachusetts

David A. Zvara, MD Associate Professor Head, Section on Cardiothoracic Anesthesiology and Perioperative Echocardiography Wake Forest University School of Medicine Medical Center Winstom-Salem North Carolina

XXI


Foreword

Fifteen years ago, Dr. Mark C. Rogers, then Chair of Anesthesiology at Johns Hopkins, “conned” the late Benjamin Covino, MD, then Chair at the Brigham and Women's Hospital and Professor at Harvard, and me, then Chair at Iowa, into joining him at a small hotel near Washington, D.C., where he spent the better part of a day “selling” us on his idea to create a more “user friendly” general text of anesthesiology. (The term “user friendly” was quite new and in vogue in those days.) His vision was to approach the subject in a way that would benefit the brand new trainee, while at the same time creating a definitive reference work for the “veteran” anesthesiologist. Up to then, major texts had started with dry history, then jumped into complex theories of anesthesia, then physiology and pharmacology. Rogers' idea was to start with the preoperative evaluation of the patient and delineate anesthesiology in the manner that trainees actually approach patients. As Dr. Covino and I neared our saturation point with Rogers' “hard sell,” the two of us adjourned outside to talk it over. We agreed that Rogers had an exciting concept. That was never the issue. We simply wanted to try to figure out whether or not we had it in us to do that much work, at that stage in our careers! We decided to tackle the task. Ben Covino's tragic death, before the first edition was completed, was devastating to us. Without the addition of David Longnecker, MD, Chair of Anesthesiology at the University of Pennsylvania, the submitted manuscripts would probably still be causing my office shelves to sag. Longnecker brought an organizational ability, and a “toughness” that spurred us on to finish the job. A subsequent edition, which came out in 1998, was much improved; cleaner, leaner, and simply all-around better, but it followed the same philosophy. With that effort, I determined to “hang up my spikes” and not participate in another major editing effort, for the work is daunting. Fortunately for the specialty of anesthesiology, Longnecker was persuaded by an outstanding medical publisher, McGrawHill, to carry this concept forward into an

entirely new work which you have here. This new text builds on the tradition of former efforts but is expanded considerably to include the increased breadth of the specialty in areas such as regional anesthesia, pain medicine and critical care medicine, yet all with the same philosophy of approaching the specialty as a medical discipline that encompasses the full range of patient care, not simply the technical aspects of anesthesia practice. With his legendary “arm twisting” ability, Longnecker even managed to persuade me to tackle writing a preface. This is much more than a new cover on an old work. Dr. Longnecker and his colleagues have recognized that anesthesiology has moved dramatically forward. They have made a major effort to capture new concepts and have succeeded in encompassing the full spectrum of stateof-the-art anesthesiology. Section 1 sets the stage by discussing where we came from, where we are, and where we might go. The emphasis is on quality care and safety principles. Just as “user-friendly” was in vogue fifteen years ago, now a key principle is “evidence-based medicine.” The chapter authors and editors have worked diligently to apply this modern principle wherever possible throughout the work. There is a new emphasis on the “operations” aspects of anesthesia care, which has been termed “OR management,” but which really emphasizes that we do need to learn how to run our OR suites more efficiently for the benefit of the patients and their surgeons. Notably, the emphasis on preoperative evaluation and preparation of the patient is extensive and rooted in the concept that anesthesiologists must think of themselves as perioperative physicians. There has clearly been a resurgence of interest in and emphasis on regional anesthesia care, both intraoperatively and for postoperative pain management. Similarly, a separate and thorough section on chronic pain underscores the importance of this area in modern anesthetic practice. Critical Care Medicine (CCM) has been an important part of anesthesiology training and practice for many years, but


recently emphasis on this aspect of our specialty has grown dramatically, and soon will result in a doubling of the required time in CCM in training programs. This new work has recognized this with an expanded ten chapter section dealing with the critically ill patient. I would like to thank David Longnecker, MD, for several major contributions: first, for stepping in after Ben Covino's untimely death and helping us complete our prior book, next for spearheading a second edition of that work, and now for giving our specialty a wonderfully useful new general text. From my early primitive attempts to blindly find the internal jugular vein so as to be able to pass a Swan Ganz catheter, to today's transesophageal echocardiography; from my primitive attempts to “find” a paresthesia to today's sophisticated nerve blocks using stimulators; from the monitors I began with in 1969, where the “bouncing ball” EKG signal disappeared, sometimes for minutes, whenever the surgeon fired the “spark gap Bovie;” from early volatile anesthetics which were associated with frightening hypotension and dysrhythmias, not to mention wakeups that had surgeons pacing and muttering, we have made strides in anesthesiology that are truly amazing. If anyone had told me in my training that patients would go home directly after a general or major regional anesthetic, I'd have told them...never mind what I'd have told them! The famous Baltimore Oriole third baseman Cal Ripken, as he ended his career, said, “it’s been a good run.” For me, that’s just as true. It is just as exciting for me, nearing the end of my “good run,” to see the vitality, and feel the excitement, of my colleagues and trainees who are continuing to move forward with our wonderful specialty of anesthesiology. This new text and reference will make us proud. With respect and admiration, John H. Tinker, MD Professor and Chair Department of Anesthesiology University of Nebraska Medical Center Editor Emeritus, Anesthesiology


Preface

The specialty of anesthesiology continues to evolve from an earlier era when it was often viewed as a technically oriented procedural discipline, to its present status as a medical discipline whose practitioners focus their expertise in the areas of perioperative and intraoperative care, critical care medicine and pain medicine. Anesthesiologists are now viewed as physicians who use combined medical and interventional approaches to achieve desired endpoints and enhanced outcomes across a broad spectrum of medical practice. Further, the specialty is recognized as the pioneering leader in the growing movement for patient safety. That movement is perhaps the most important new initiative to emerge in health care in the last century. The patient safety movement will likely be viewed in the future as akin to the “sea change” that Abraham Flexner pioneered in medical education some 100 years ago. We believe that positioning our specialty at the continued forefront of this movement is a key strategy for both the current and future success of anesthesiology and its practitioners. In 2000, the Institute of Medicine published its landmark analysis of American health care, “To Err is Human,” a treatise that emphasized the fallibility of humans, even those with the greatest dedication to their profession and their patients, and emphasized that systems of safe care must be constructed to protect patients from potential harm. That report specifically cited anesthesiology as a leader in the patient safety movement and urged others to follow the lead of our discipline, which many throughout health care have done subsequently. A subsequent IOM publication, “Crossing the Quality Chasm; A New Health System for the 21st Century” (2001), went beyond patient safety alone; it described the attributes of a model health care system as one that is safe, timely, efficient, effective, patient centered and equitable to all. We agree with these principles and have worked diligently to adopt them in our own practic-

es and departments, for they are guideposts to the professional and ethical practice of medicine and anesthesiology. In particular, we have designed this text around the concepts of safe, effective and patient-centered care, and we urge others to approach their practice with the same enthusiasm that we share for these principles. There are multiple sources of information about the clinical practice of anesthesiology, or about the research that forms the basis for that practice. Further, there are numerous subspecialty books that delve into the subdisciplines in great detail—often more detail than the advanced trainee or practitioner desires or needs. In this text, we have focused on what is truly important for the clinical practice of anesthesiology in all its dimensions, while being efficient in the presentation of this essential material. Throughout, we have asked “What is important?” “Why is it important?” “When should it be applied?” and “How should it be applied?” Our overarching goal was to write for the practitioner, not for the small cadre of physician scientists who may be exploring a narrow subdiscipline in great detail— such work is essential for the future scientific basis and direction of the specialty, but it often leads to extensive discussions of minutiae that distract rather than enlighten the clinical practitioner; it simply becomes too difficult to glean the key clinical principles from the blizzard of scientific detail. That said, this is not a users manual of anesthesia care, but rather a text that constantly builds on the concepts of safe, effective (i.e., evidence-based) and patient centered care, hopefully distilled in a manner that facilitates easy access to the key concepts that underpin the rationale for that practice. We have taken a comprehensive approach to the full range of anesthesiology practice, and to the role of anesthesia care within the overall care process. Thus, we have emphasized the trends in


both the specialty and the health care system in general, to assure that the reader is not required to go elsewhere for additional information to support the mainstream of their practice. Those trends in the specialty include the expanded use of regional anesthesia, the remarkable explosion in pain medicine practice and the expanded need for the skills and experience that anesthesiologists bring to the practice of critical care medicine. No careful observer of the specialty could miss these trends, and no text could be considered “comprehensive” if it did not address each of them in a way that embraces them as full components of the modern practice of anesthesiology. We view the key trends in health care overall as those involving patient safety, quality, patient centered care and a systems approach to care that encompasses the entire care process, rather than individual components that function independently. Here again, we have woven these concepts into the text by emphasizing that anesthesia care is a system of care within a larger system of care that focuses on overall patient outcomes, not isolated events by individual practitioners working in isolated clinical disciplines. We have approached these and other key “drivers” of contemporary and future anesthesia practice with care, commitment and enthusiasm for the future of the specialty. We trust that you share this enthusiasm and hope our efforts will serve you well as you continue to translate your knowledge and skills into safe, effective, efficient and patient-centered care; our patients want nothing less and our surgical and medical colleagues are looking to anesthesiology to continue to set the example for implementation of these principles. We are honored to serve you through our efforts here. David E. Longnecker, MD, FRCA David L. Brown, MD Mark F. Newman, MD Warren M. Zapol, MD


PART 1 THE SPECIALT Y OF ANESTHESIOLOGY


PART 1: The Specialty of Anesthesiology

CHAPTER 1 2

The Evolution of Anesthesiology as a Clinical Discipline: A Lesson in Developing Professionalism Douglas R. Bacon, MD, MA

The quest for insensibility to the surgeon’s knife is a primordial one. Stretching back to antiquity, physicians have sought ways to render a patient pain free while an operation was being performed. Many different regimens were tried, with varying success, until October 16, 1846, when surgical anesthesia was publicly demonstrated at the Massachusetts General Hospital by William Thomas Green Morton. Yet, there remained a long road from that fall day in Boston to the current operating room full of electronic machines whose sole purpose is to measure the anesthetic state, or physiologic parameters of the anesthetized patient. How did anesthesiology evolve from a simple glass globe inhaler to the vast array of machines that makes the modern operating room? In many ways, the history of anesthesiology is the history of the men and women who have devoted their career to the administration of anesthetics. Without physicians interested in the anesthetic state and the ability to adapt to new conditions demanded of anesthetists by surgeons, there would be neither modern surgery nor the specialty of anesthesiology. Yet each individual was a real human, many displaying professionalism beyond what was required or expected; others seem reprehensible by “modern” standards. Although many of the individuals in this story would not consider themselves specialists in anesthesia, their contributions were critical in moving this area of the practice of medicine forward. The development of anesthesiology can be told as the history of involved physicians who

dedicated themselves to providing safer, focused care of the patient, first in the operating room, and later in the critical care unit and pain clinic. The story begins in ancient Egypt, and ends in the sterile environment of the modern operating room.

PREHISTORY: THE QUEST FOR SURGICAL ANESTHESIA Imagine, for a moment that there is no surgical anesthesia. The Edwin Smith Papyrus describes 48 surgical cases done between 3000 and 2500 B.C. Al-

KEY POINTS 1. The history of anesthesiology is an interesting and complicated story of professionals seeking to understand the anesthetic state and to safely anesthetize patients. 2. Shortly after the first public demonstration of ether anesthesia on October 16, 1846, the news spread across the world. At first anesthetics were given based on written accounts, often in the lay press. 3. John Snow, a London physician, worked out the physics of vaporization of volatile agents using ether and chloroform and used this information to design vaporizers and anesthetic techniques that were safer for the patient. 4. The first professional organization devoted to anesthesia was the London Society of Anaesthetists founded on May 30, 1893. The first similar group in the United States was the Long Island Society organized by Adolph Frederick Erdmann in 1905. The Long Island Society eventually became the American Society of Anesthesiologists. 5. Francis Hoffer McMechan, crippled by rheumatoid arthritis and unable to work clinically after 1911, organized professional anesthesia. He helped create the first national organization, the Associated Anesthetists of America in 1912, and went on to found several national and international organizations, of which the International Anesthesia Research Society (IARS) remains active. He was the founding editor of the first journal in the world devoted to the specialty, Current Researches in Anesthesia and Analgesia, which is currently published as Anesthesia and Analgesia, giving the specialty a way to communicate the most recent advances in science, technique, and technology. 6. Ralph Water is credited with the first department of anesthesia within an academic setting at the University of


Wisconsin in 1927. Much of the current residency structure comes from this seminal department. This helped establish the specialty on an equal footing with other medical specialties—and created a method to train physicians in the art and science of anesthesia. 7. John Lundy, working at the Mayo Clinic, organized the Anaesthetists Travel Club, whose members were the leading young anesthetists of the United States and Canada. These individuals helped create, by 1938, the American Board of Anesthesiology, which defined what it meant to be an anesthesiologist in the United States. 8. The need for physician specialists in World War II exposed a large number of young men to anesthesiology who would not have otherwise considered the specialty. After the hostilities ceased, these physicians returned and helped create the tremendous growth in the 1950s and 1960s that the specialty enjoyed. 9. In the mid-1950s, the World Federation of Societies of Anesthesiologists (WFSA) was formed. It was the culmination of a dream that dated to the late 1930s. The WFSA made it possible for nations with a long tradition of physician specialization in anesthesia to help train and create the specialty in countries that were either recovering from the effects of the war or were beginning their national infrastructure in healthcare. 10. In the 1980s, the Anesthesia Patient Safety Foundation (APSF) and the Foundation for Anesthesia Education and Research (FAER) were created. They are additional examples of the professionalism demonstrated throughout the history of anesthesiology. These two organizations work to create a safe anesthetic environment. In addition, they support educational and research efforts in the specialty.

CHAPTER 1: The Evolution of Anesthesiology as a Clinical Discipline: A Lesson in Developing Professionalism

though there is no specific mentioning of anesthesia, within the papyrus there is evidence of compression anesthesia. In one instance, a surgeon is compressing the antecubital fossa while operating on the hand; in another instance, the patient is compressing his brachial plexus while the surgeon operates on his palm.1 The ancient Chinese reported the use of an anesthetic for surgery in the 2nd century B.C.2 The use of hemp smoke as an anesthetic was noted in India3 long before Western medicine developed crude forms of anesthesia. During the Middle Ages and early Renaissance, a mixture of herbs purported to induce anesthesia was created. Boiled into a sponge, at the time of surgery the sponge was placed in water and the vapors inhaled. Although the vinca alkaloids were a major component of the drugs used in the spongia somnifera, the resultant anesthetic was less than satisfactory. Another Renaissance solution was the use of parallel lines of ice, with the incision placed between them. This was effective for simple operations, and found use in the Russo–Finnish War of 1939–1940. Compression anesthesia, whereby a large clamp-like device was used to put pressure on a nerve, succeeded in short, peripheral operations.4 Yet, the nerve compression itself caused pain. Alcohol, when drunk in sufficient quantities, was noted to render individuals insensible. Thus, the age-old intoxicant was used as a standard against which all anesthetics could be measured.3 In the early 1840s, the effects of nitrous oxide and diethyl ether were well known. Humphry Davy had described the intoxicating effects well in his book, Researches Chemical and Philosophical: Chiefly Concerning Nitrous Oxide, published in 1800. Ether, which had been first synthesized in the 1500s, had been observed to lessen the “air hunger” of asthmatics.5 Both drugs were well known to medical students as intoxicants. In January 1842, in Rochester, New York, a medical student, William E. Clark, anesthetized the sister of a classmate, for the extraction of a molar using ether. Instructed not to pursue this observation, as it most likely was a “hysterical reaction of women,” Clarke continued his training and became a respected Chicago, Illinois area physician.6 Two months later, in rural Georgia, a country doctor, Crawford Long, who

had hosted parties where ether was used as an intoxicant, used the drug to render James Venable insensitive for the removal of tumors from the back of his neck. He charged Venable $2 for the anesthetic, thus delineating anesthesia as part of a professional service. Two years later, in 1844, Horace Wells, a Hartford Connecticut dentist, would gain the insight that, during a nitrous oxide (N2O) show, when an individual was intoxicated by N2O, pain was abolished. Wells then tried this idea on himself for the removal of one of his teeth by his partner, and was successful. Soon he was using “painless dentistry” as part of his professional advertisement. Wells even attempted to demonstrate a painless tooth extraction at the Massachusetts General Hospital in 1844, but the patient groaned, and the demonstration was considered a failure.7 Clearly, by the middle of the 19th century, there were sufficient observations about chemical agents that could potentially abolish the pain of surgery. On a limited scale in rural Jefferson, Georgia, surgery with ether anesthesia was happening. Yet, Long lacked sufficient cases to study the effects of this new agent because of the rural nature of his practice.8 Wells’ use of nitrous oxide was groundbreaking, yet he lacked the emotional stability to overcome his failed demonstration.9 Thus, the stage was set for another dentist to demonstrate reproducible surgical anesthesia, and give birth to what would grow and develop into the specialty of anesthesiology.

DISCOVERY On October 16, 1846, William Thomas Green Morton, a dentist and medical student, provided surgical anesthesia for Gilbert Abbott for the removal of a tumor of the jaw at the Massachusetts General Hospital. The events of that day are well known.10 Upon completing the operation, the surgeon, John Collins Warren, remarked, “Gentlemen, this is no humbug.” The miracle of pain-free surgery so impressed the Boston medical establishment that letters were sent to colleagues across the world. Considerable scholarship has been spent discerning when these letters arrived, and where they arrived, and who provided anesthesia first in the new location. For example, the

generally accepted view of the spread of anesthesia to the United Kingdom is a letter from Jacob Bigelow to Francis Boot. However, by careful study of the ships sailing between Boston and Liverpool, another letter, written almost 2 weeks before Bigelow’s and only 12 days after the public demonstration of ether, arrived in England on November 1, 1846. Interestingly, this letter was to a patent attorney.11 Morton wanted to patent the process by which ether was administered, so writing to the foremost patent attorney in England to secure rights to the administration of ether in the United States and the United Kingdom,9 and perhaps the world, is not surprising. He also tried to patent ether itself, calling his anesthetizing mixture “Letheon.” However, the distinctive odor of ether gave away the true nature of the concoction. The Boston medical establishment had convinced Morton to allow the Massachusetts General Hospital to use Letheon without charge. With ether a well-known and easy-to-synthesize compound, and its effects reproducible without the “Morton’s Inhaler,” the patent was quickly broken. Morton would spend the rest of his life attempting to be compensated for patent infringement, fighting with the medical establishment and into the halls of Congress.8 Morton clearly was not the embodiment of medical professionalism as we currently understand it. Despite the patent, news of Morton’s achievement did travel, and quickly, given the nature of communication in the 1840s. On December 16, 1846, the news, in the form of a letter, arrived in London. On December 19, the first ether anesthetic was given in the United Kingdom for the removal of a tooth. On December 21, Robert Liston, the famous surgeon, amputated the leg of a butler and uttered the famous words, “This Yankee dodge beats mesmerism hollow.” By early 1847, anesthetics were being given in Europe. By June of that year, the news had spread to Australia.12 Peter Parker, minister and physician missionary in China, gave the first anesthetics there on October 4, 1847.13 How the news traveled, and when it arrived are matters of historical fact. Yet, for the profession of anesthesia, and the specialty of anesthesiology, what is almost more important is how willing physicians and dentists were to

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use ether in this new way. Consider for a moment that outside of Boston, none of the recipients of the news that ether produced insensibility to the surgeon’s knife had actually witnessed the event. Many accounts, especially those reaching South Africa and Australia, were newspaper articles or letters to the editor, often signed by a pseudonym. The hope that these medical professionals had, their desperation at their inability to alleviate pain, and their desire to help patients may well have motivated them to try this new technique. Yet, when viewed from the perspective of current early 21st century medical practice, this willingness to go on purely written accounts, often in the lay press, without the collaborating voices of the medical profession, seems to be dangerous, and without regard for the basic principle of medicine: first do no harm. And what of the surgeons? Tolerance of the pain of surgery limited operations to those that could be performed quickly. Anesthesia obviated the need for speed, presenting the possibility of operating within the visceral cavities for hours rather than seconds. But as the physician responsible for the patient, long before the specialty of anesthesiology would be defined, why were these professionals willing to risk lives to find an anesthetic? What does this behavior say to the modern student of medical professionalism?

JOHN SNOW, SPECIALIZATION, AND EARLY PROFESSIONALISM As reprehensible as Morton’s actions appear in patenting his “discovery,” Morton was acting within the ethics of his time. The American Medical Association (AMA) was only just beginning to be formed. Meeting for the first time in May 1846, 5 months before the public demonstration, the National Medical Convention adopted a resolution to write a code of medical ethics. A year later, the code was adopted. Morton’s actions were covered under section 4: Equally derogatory to professional character is it, for a physician to hold a patent for any surgical instrument, or medicine, or to dispense a secret nostrum, whether it be the composition or exclusive property of himself or others. For, if such nostrum be of real efficacy, any concealment regarding it is inconsistent

FIGURE 1–1. John Snow. (Photograph courtesy of the Wood Library-Museum of Anesthesiology.)

with beneficence and professional liberality;…14 Thus, at the time when Morton was trying to patent either ether or the apparatus for its vaporization, medicine was starting to organize and promulgate statements against such behavior. In contrast, John Snow (Fig. 1–1), a London physician, became very interested in this new state of anesthesia. He began to study the chemical and physical properties of ether, and by 1847 had developed a vaporizer. “Snow never patented any apparatus he designed. On the contrary, he published clear descriptions, including engraved

figures, so that others could copy them if they chose.”15 Snow, by careful observation worked out the vaporization characteristics of ether. His vaporizer (Fig. 1–2) was temperature compensated, being made of coiled copper (Fig. 1–3), an excellent heat-conducting metal, housed in a water bath to ensure constant temperature of the ether. Thus, Snow was able to calculate the amount of ether a patient required for anesthesia within a decade of the discovery of anesthesia.13 Following the introduction of chloroform as an anesthetic in 1847 by Edinburgh obstetrician James Young Simpson, Snow began to investigate this second anesthetic agent. Snow used his experience with ether as a guide for investigating the properties of chloroform. He concluded that it was far safer to give this new anesthetic in measured quantities through an inhaler. He did not favor the handkerchief method, whereby chloroform was applied to a cloth and held close to the nose and mouth, as being too difficult to adequately control the anesthetic depth of the patient. His deliberate nature and strong powers of observation allowed Snow to create a calibrated, temperature-compensated vaporizer for this agent as well.13 Snow is unique among his colleagues in the 1850s in London. A physician with many interests, it was the giving of anesthetics that accounted for the vast majority of Snow’s clinical income throughout the decade. In a day when operations were still rarely performed, Snow specialized in anesthetics. In some ways, his expert knowledge al-

FIGURE 1–2. Snow’s vaporizer. (Image courtesy of the Wood Library-Museum of Anesthesiology.)


FIGURE 1–3. Coil from Snow’s vaporizer. (Image courtesy of the Wood Library-Museum of Anesthesiology.)

lowed him entrée into the upper echelons of both social and physician circles, a status he could not have obtained had he not limited his practice. Perhaps this is best illustrated by his attendance upon Queen Victoria for the birth of her last two children. While Snow did not use his inhaler, he also did not induce the full anesthetic state in the Queen. Rather, he strove for analgesia with chloroform, and in so doing, created a form of obstetrical analgesia, chloroform a la reine, which would persist in various forms over the next century.13 Aside from working out the physics of vaporization, Snow was intensely interested in outcome data. He studied every report concerning a death under anesthesia, and often times had data in advance of the published reports of death. He commented extensively on the death of Hannah Greener, thought to be the first death under anesthesia in the world.16 In his posthumous book, On Chloroform and other Anesthetics,17 published in 1858, Snow compiled the first 50 deaths under chloroform, with comments about the pathophysiology present. Snow’s spirit of inquiry, which went from the bench top to the pathologic findings at death, helped him to understand the nature of the anesthetic process and the agents that produced insensibility. In following his inquiring mind, Snow created the scientific underpinnings for a specialty.18

A PROFESSION EMERGES After Snow’s untimely death, anesthesia faded into the medical background again. In larger cities, there were those

who made a majority of their clinical income from providing anesthesia, yet it would not be until the advent of Listerism and the “taming” of infection that operations would become more frequent. As the number of operations increased, so did the need for anesthesia and, unfortunately, mortality became an issue. Chloroform was responsible for deaths that seemed unexplainable. Ether appeared to be safer, yet the side effects of nausea and vomiting, and the prolonged induction when compared to chloroform, made ether a less-than-ideal agent. Surgeons began to search for alternative methods for the administration of anesthetics. In 1884, Carl Koller, a resident in ophthalmology in Vienna, was introduced by Sigmund Freud to a new crystalline substance called cocaine. Koller sought a local anesthetic to replace ether anesthesia for operations on the eye; because fine suture material to close the eye wound did not exist, any postoperative retching potentially could cause the loss of vision. Thus, when Koller’s tongue became numb from droplets of a solution containing cocaine, he made the conceptual leap that this same solution could be applied to the cornea with similar anesthetic effects on the eye. Using the facilitates of the laboratory in which he worked, Koller soon numbed the eyes of several animals, a fellow investigator, and himself. He took this new topical anesthetic to the clinic and used it with great success. On September 15, 1884, Koller had a paper on the subject on the program at the German Ophthalmological Society meeting in Heidelberg. Because Koller was too poor to travel, his colleague, Dr. Josef Brettauer presented the paper for him.19 While Koller continued his career in ophthalmology, eventually immigrating to the United States, other physicians modified this new form of anesthesia into an alternative to general narcosis. One of the early practitioners was William Halstead, future chair of surgery at Johns Hopkins University, who was in Vienna at the time of Koller’s discovery. Using cocaine topically, Halstead eventually learned to dissect down to a nerve, and to anesthetize it directly. Much of the work he did on himself, becoming addicted to cocaine in the process.20 Another of the pioneers of regional anesthesia was the German surgeon Carl Ludwig Schleich, who developed

the technique of infiltration anesthesia.21 Combining infiltration techniques with the newly discovered lumbar puncture, August Bier, another academic German surgeon, initiated spinal anesthesia in the late 1890s. Working with his fellow August Hildebrandt, Bier successfully cannulated the subarachnoid space of Hildebrandt and produced a satisfactory anesthetic state. Hildebrandt was unsuccessful in cannulating Bier’s subarachnoid space; however, both men suffered postduralpuncture headaches.22 Ten years later, Bier described his intravenous regional anesthetic technique, which is still referred to as the Bier block.23 At the same time that regional anesthesia was being developed in Germany, concern over the safety of chloroform, especially when compared to ether, was developing. In India, then a colony of England, a Chloroform Commission was seated in Hyderabad to attempt to determine which anesthetic agent was safest. Funded by the Nizam of Hyderabad, the 1888 study of anesthetic agents was an effort to find out if there was an intrinsic mortality associated with chloroform. The findings were tainted by the British medical officer in charge, Dr. Edward Lawrie, who was a strong chloroform proponent, having trained in Edinburgh, chloroform’s birthplace. The findings of the Hyderabad Chloroform Commission were not conclusive, and a second was ordered, which also was inconclusive. But what was important in these commissions, like the drive to discover regional anesthetic techniques, was that physicians were studying anesthesia and trying to increase patient safety. For many physicians, it was slowly becoming apparent that there was a need for a specialty practice of anesthesia.24 Early in the 20th century, the American Medical Association set up a commission to study anesthetics. A preliminary report was issued in 1908.25 All forms of anesthesia were accounted for, including spinal anesthesia, and various combinations of inhalational agents. The conclusions of the report are interesting, for they foreshadow the development of a separate specialty: …[A]ll the newer methods demand expertness, experience, and special apparatus. They appeal especially to the surgeons who are equipped with the paraphernalia of expensive and

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highly specialized clinics. They are little suited to physicians in general practice. For the latter great class of practitioners, the old general anesthetics, chloroform and ether, will probably hold their own until increasing experience has enabled us to simplify and to make safe the newer and more novel methods.25 The commission had three very interesting recommendations: 1. That for the general practitioner, and for all anesthetists not specially skilled, ether must be the anesthetic of choice—ether administered by the open-drop method. 2. That the use of chloroform, particularly for the minor operations, be discouraged, unless it is given by an expert. 3. That the training of skilled anesthetists be encouraged and that undergraduate students be more generally instructed in the use of anesthetics.25 The third suggestion of the commission would take almost the entire 20th century to implement.

THE RISE OF THE SPECIALIST In 1905, in Brooklyn, New York, a group of 8 physicians and a medical student, led by Adolph Frederick Erdmann (Fig. 1–4), gathered to discuss

FIGURE 1–4. Adolph Frederick Erdmann. (Photograph courtesy of the Wood Library-Museum of Anesthesiology.)

the problem of anesthetics. These young physicians thought, like the AMA commission, that there was more to the giving of an anesthetic than simply dropping ether on a cloth held near the patient’s face, and that there needed to be discussions and a free exchange of scientific and practical information about anesthesia.26 This was the second specialty group in the world that was created, the first being the London Society of Anesthetists in 1893, and it would become the catalyst for the development and recognition of physicians who were specialists in anesthesia.27 Thus, the Long Island Society of Anesthetists was born. The society met quarterly, in the evening, with a short business meeting followed by the presentation of 2 or 3 papers, or a couple of papers and a demonstration of a new anesthetic technique or apparatus. Science aside, the society provided a “support” group for those seeking to improve their anesthetic skills, and a forum at which to exchange ideas and deal with problems beyond the science of anesthesia.26 The group flourished and, in 1912, moved across the river to New York City, changed the organization’s name, and became the New York Society of Anesthetists. Over the next 24 years, the society would grow, both in membership and in scope. Starting out as a New York City group, by the mid 1920s, the group encompassed all of the state. By 1936, it had become a national organization.28 The transformation focused on the recognition of physicians who primarily anesthetized patients as specialists. The first significant political move of the New York Society was a motion put before the House of Delegates of the American Medical Association asking for a Section on Anesthetics in 1912. The members of the society were concerned about nonphysicians giving anesthetics, and echoed some of the findings of the AMA’s Commission on Anesthetics some 6 years earlier.28 James Gwathmey (Fig. 1–5), the society’s president, was developing a new method of anesthesia—rectal ether. Like chloroform, rectal ether could be unpredictable and needed to be administered by someone very familiar with its use and with the effects of anesthesia in general.29 The quest for a section within the AMA was, in some ways, the beginning of a quest for patient safety in anesthesia, a

FIGURE 1–5. James Tayloe Gwathmey. (Photograph courtesy of the Wood Library-Museum of Anesthesiology.)

movement that would take the specialty by storm in the latter half of the 20th century. The motion was denied by the AMA House of Delegates. However, Gwathmey and Francis Hoeffer McMechan (Fig. 1–6) gathered the defeated physician anesthetists and created the American Association of Anesthetists (AAA). This was the first national group of physician anesthetists in the United States. The following year, 1913, the group met for a day of papers, mostly clinical in origin, and a dinner, with spouses (Fig. 1–7). The

FIGURE 1–6. Francis Hoeffer McMechan. (Photograph courtesy of the Wood Library-Museum of Anesthesiology.)


FIGURE 1–7. Program of the first meeting of the American Association of Anesthetists, June 18, 1913, Minneapolis, Minnesota. (Image courtesy of the Wood Library-Museum of Anesthesiology.)

science presented at the meeting is memorable in that the day was devoted to anesthesia; the evening meal signified a group, however small, that was willing to be recognized as specialists in anesthetics and by uniting, to move the field forward.28 The AAA, and its successor, the Associated Anesthetists of the United States and Canada, were run by Francis Hoeffer McMechan. A third-generation physician who entered anesthesia against the advice of his father, McMechan had crippling rheumatoid arthritis, and was out of clinical practice by 1911. McMechan was a visionary who desired to see, on a worldwide scale, the elevation of anesthesia to “stand shoulder to shoulder” with surgery and internal medicine. He realized that without a place to publish papers on the specialty, and without a place to gather the news of the various societies and names of physicians practicing anesthesia, the specialty would be doomed. Convincing his friend Joseph McDonald, the editor of the American Journal of Surgery to publish a supplement on anesthesia gave the specialty its first U.S. quarterly. McMechan also edited the Yearbook of Anesthesia between 1914–1919, compiling all the papers published in the

specialty in the preceding year into a single volume.30 McMechan also understood that the specialty would never develop as a discipline within medicine without a strong scientific underpinning. To that end, first nationally, and internationally in the mid 1920s, McMechan organized a society devoted to research in anesthesia. The International Anesthesia Research Society brought together basic science researchers and the physicians most in need of their talents. Most importantly, the IARS sponsored the first journal in the world devoted to anesthesiology, Current Researches in Anesthesia and Analgesia.31 The education of physician specialists, especially in the postgraduate period, was another of McMechan’s concerns. Partnering with Ralph Waters, an opportunity emerged at the University of Wisconsin in 1926, as the medical school transformed itself from a 2-year institution offering only basic science education into a 4-year curriculum with all the clinical sciences. One addition was a section on anesthesia, headed by Waters, in the department of surgery. Waters immediately began to teach anesthesia to medical students and interns. He collaborated with the basic science researchers, at first on problems of carbon dioxide absorbance, and later, through various members of his department, on all aspects of anesthesiology. Perhaps most importantly, Waters established the first residency training program in an academic center. The training was 3 years beyond the intern experience. Years 1 and 3 were clinical in nature, with year 2 devoted to laboratory research. Two weekly conferences were established, one discussing the week’s cases in a format similar to current morbidity and mortality conferences, and another devoted to the current literature in anesthesia. By 1933, the teaching program was the envy of the world, and Waters understood that the final step had to be taken. He sent one of his faculty members, and an early graduate of the program, Emery Rovenstine, to Bellevue Hospital and New York University to try to replicate the University of Wisconsin department. Rovenstine was successful beyond any expectation and, in some ways, his graduates would eclipse the contributions of Waters’ graduates in the development of academic anesthesiology across the country.32

In 1929, the year of the stock market crash and the beginnings of the Great Depression, another pivotal event occurred in anesthesiology. The Anaesthetists Travel Club was organized by John Lundy at the Mayo Clinic. The group was organized along the lines of the Society of Clinical Surgery, with members going to other members’ institutions to see their anesthetic practice in action. It was a young man’s group, with the oldest member being Lahey Clinic anesthesiologist Lincoln Sise at 55 years of age, and the youngest being Philadelphian and future first editor of Anesthesiology Henry Ruth at 30 years of age, and Mayo resident Ralph Tovell at 28 years of age. The average age was just 40 years. These young, influential anesthesiologists were those “standing in line” in the McMechan organization, or those who believed that McMechan’s international vision of the specialty, while important, would not solve domestic issues. The Travel Club would come to dominate the New York Society, and become the nidus of leadership for the effort to create the American Board of Anesthesiology.33

THE CREATION OF THE AMERICAN BOARD OF ANESTHESIOLOGY Once there was an organization in place to address national issues, regular meetings of a society devoted to the specialty, a university presence, ongoing research into clinical problems, and a residency training program to continue to retain and transmit the knowledge already gained, some recognition of a physician practicing the specialty was important. The gains in clinical practice in the 1920s and 1930s are best summed up by Harold Griffith, a leading Canadian physician-anesthetist of the time when he wrote, in 1939, the following: Seventeen years ago when I began to give anesthetics, the anesthesia equipment in the small hospital which has ever since been my hospital home, consisted of bottles of ether and chloroform and a few face masks. This was typical of the fairly wellequipped hospitals of that time. Today in that hospital there are eight gas machines of various models, suction equipment in every room, oxy-

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gen- and helium-therapy equipment, at least fifteen different anesthetic agents, and much technical equipment for their administration. This transformation has been taking place everywhere in anesthesia.34 Economic reasons played a role in the need to define a specialist in anesthesia, for physician anesthetists were not well compensated and faced competition from a number of groups. Surgeons, for example, could hire a nurse to help in the office and give anesthetics. The surgeon could then charge each patient a fee for anesthesia in addition to the fee for surgery. The income generated from the anesthetic fee was in excess of what he paid the nurse, and thus profitable. Likewise, hospitals could hire nurses to give anesthetics, charge a fee that cumulatively was in excess of the salaries, and make a profit. Finally, general practitioners would refer cases to surgeons with the caveat that they could give the anesthetic and collect the anesthetic fee.35 McMechan proposed an International College of Anesthetists and certified the first fellows in 1935. There were two serious problems with his certification process. First, and foremost, the clinical criteria were weak. The applicant only had to document 10 anesthetic cases, with lessons learned, to be eligible. In one instance, an intern on the anesthesia service for 1 month wrote up the necessary cases and was certified. In another, a surgeon who occasionally gave an anesthetic, completed the necessary paperwork and was certified. With certificate in hand, he attempted to become the head of a hospital division of anesthesia. Second, the college had no standing with the AMA, and the certificate meant nothing “official” in the United States.36 Members of the Anaesthetists Travel Club, especially Paul Wood, John Lundy, and Ralph Waters, believed that certification was essential if anesthesiology was going to be recognized as an equal with all other specialty practices. Using AMA criteria, which included documentation of either postgraduate training in the specialty, or 2500 cases where the applicant had administered the anesthetic, Wood and his colleagues at the New York Society created a special classification of members called “fellows.” This new form of membership was extremely popular, and the membership of the New York Society skyrocketed. Now

FIGURE 1–8. Erwin Schmidt. (Photograph courtesy of the Wood Library-Museum of Anesthesiology.)

national in membership, the society changed its name to the American Society of Anesthetists in February of 1936.37 In 1945, the American Society of Anesthetists became the American Society of Anesthesiologists. The AMA took note largely through Lundy’s efforts, and Waters, working closely with Erwin Schmidt (Fig. 1–8), the chair of surgery at the University of Wisconsin, was able to secure an agreement for the American Board of Anesthesiology (ABA) to be created as a subboard of the American Board of Surgery. Using AMA criteria, which included, in addition to the heavy clinical training, the stipulation that the physician had to be in full-time practice of the specialty the ABA was created in 1938. The first written examination of the ABA was held in March 1939. It was an essay format, with 5 subject subheadings: pharmacology, anatomy, physics and chemistry, pathology, and physiology. There was an oral examination and a practical one at the candidate’s place of practice.38 Thus, there was a heavy emphasis on the clinical practice of anesthesiology.

WORLD WAR II AND BEYOND The New York World’s Fair opened on April 30, 1939, the eve of World War II. In the Hall of Man, an anesthesiology exhibit (Fig. 1–9) allowed the general public to learn more about the special-

ty. The exhibit was paid for by the Winthrope Chemical Company at a cost equivalent to several million dollars today. This is important for two reasons; first, it demonstrated that anesthesia had enough of a market impact that industry was willing to spend lavishly to support such a display. Second, the clinical practice of anesthesiology had become both complex and commonplace enough that the lay public needed to learn about it.39 At the same time, Lewis Wright was hired by Squibb Pharmaceuticals to investigate new anesthesia drugs, among them, curare. Wright was a self-taught anesthesiologist who, in midcareer, took a leave of absence from his job at Squibb and did a residency with Emery Rovenstine at Bellevue Hospital.40 It was to Rovenstine and Emmanuel Papper that he gave some of the first commercially prepared curare. Papper felt that the agent was a poor anesthetic, as all the test animals stopped breathing when it was administered to them.41 It was Harold Griffith and Enid Johnson, of Montreal, who discovered the true value of curare in anesthesia.42 As the United Sates plunged into World War II, the anesthesia community was determined not to repeat the mistakes of World War I. Physician anesthetists had been in short supply and often ran from unit to unit training corpsmen in the administration of ether by open drop.43 By the early 1940s, anesthesia had become too complex for this to be successful. The leaders of the American Society of Anesthetists worked with the advisors to the armed forces and developed short courses, 90 days in length, to train medical officers in the basics of anesthesia. These young physicians managed many horrific clinical situations and, applying what they learned, were able to decrease mortality.44 The case of Samuel Lieberman, who won the Legion of Merit for his work in the South Pacific, is illustrative. By using continuous spinal anesthesia he decreased the mortality from abdominal wounds from 46–12.5%.45 Returning from the war, these physicians had tremendous clinical experience, especially with regional anesthesia. Nerve blocks were invaluable, because corpsmen could take vital signs and talk to the soldier while the operation was ongoing, freeing the anesthesiologist to treat others. Likewise, these military anesthesiologists had


FIGURE 1–9. Postcard image of the anesthesia exhibit at the 1939 World’s Fair. (Image courtesy of the Wood Library-Museum of Anesthesiology.)

extensive experience with transfusion and fluid therapy. Returning to the United States, approximately 40% sought additional formal training as anesthesiologists. Thus, the specialty expanded tremendously after the end of the war, not only because of the returning physicians, but because surgeons exposed to the field work of the anesthesiologists demanded physician involvement in the anesthesia.44

THE SECOND HALF OF THE 20TH CENTURY McMechan’s vision of an international community of anesthesiologists came to fruition in the 1950s. The first world meeting of anesthesiologists had been scheduled for Paris in the spring of 1940, but was canceled as the German army took the city. By the early 1950s, Europe was starting to recover from the effects of the war and the original French organizers were still interested in seeing the meeting become a reality. Working within the European community and Canada, and with help from the World Heath Organization, preliminary meetings were organized and the structure of the WFSA was created. The first World Congress, held at The Hague in the Netherlands in 1955, was a success despite the absence of the Americans. The WFSA wanted to bring the best clinical practice of the specialty to the fore; the World Congress was a way to bring first-, second-, and third-world anes-

thesiologists together to discuss problems and to seek solutions. The WFSA set up programs to share information with those in need of it.46 However, it would not be until the end of the decade of the 1950s that the American Society of Anesthesiologists would join the WFSA. The reluctance on the part of the Americans was multifactorial. First, because dues to the WFSA were on a per capita basis, the American Society of Anesthetists felt that they would be providing the majority of the finances of the organization without an equal voice in its government. There was also reluctance on the part of some American anesthesiologists to join an organization that contained communists. Time, dialogue, and the performance of the WFSA eliminated those fears.47 Along with the international concerns, the specialty faced a challenge in the United States as well. There was a significant part of the anesthesiology community that felt that no physicians should accept a contract for services and allow a third party, such as a hospital or other employer, to bill in the physician’s name. Enforcement of this edict was done by the component societies of the American Society of Anesthetists. An anesthesiologist could not be a member of the American Society of Anesthetists if the anesthesiologist wasn’t a component society member. If the anesthesiologist was not an American Society of Anesthetists member, the anesthesiologist was ineligible to take

the American Board of Anesthesiology examination.48 In response to this, the Association of University Anesthesiologists (AUA) was formed. The majority of academic anesthesiologists were employed by the university for a salary, in violation of the American Society of Anesthetists rules. The establishment of the organization is important not only as a protest, but because it underscores how important academics had become to the fledgling field in the 30 years between the creation of the Waters department to the first AUA meeting.49 It was a rapid expansion and one that continued to delineate the scientific underpinnings of the specialty. In the 1960s, the U.S. federal government sought to support medical research and created the National Institutes of Health (NIH). Emmanuel Papper (Fig. 1–10) was invited to Washington, DC to help organize the new agency. Dr. Papper worked tirelessly to see that anesthesiologists were treated fairly by the NIH and were eligible for funding. However, he was unable to secure an independent study section for anesthesia, and the battle to obtain this for the specialty remains a leading agenda item for many.41 The 1970s were a decade of crisis for anesthesiology. To assure billing that was commensurate with services, the American Society of Anesthesiologists had endorsed a relative value guide that

FIGURE 1–10. Emmanuel Papper. (Photograph courtesy of the Wood Library-Museum of Anesthesiology.)

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helped place a unit value on work done by the physician. Other specialties, including orthopedics and radiology, had adopted similar guides, but the Federal Trade Commission (FTC) thought this was a monopolistic practice. All of the specialties but anesthesiology agreed to cease and desist; the American Society of Anesthetists went to court. After a 2-week trial, the judge ruled that the relative value guide did not represent a monopolistic practice; rather, it was simply a tool that applied monetary value differently in different parts of the country. In one of history’s little ironies, 30 years after the verdict, the federal government now states the relative value guides are the preferred billing methodology. The 1970s also saw another federal government suit against the American Society of Anesthetists for the fee-for-service rule. Here there was little chance of a successful suit, yet the federal government, cautious after its defeat, agreed to a cease-anddesist order.50 The 1980s, by contrast, witnessed the development of two organizations that have served anesthesiology well. The Foundation for Anesthesia Education and Research (FAER) is devoted to the promotion of research within the specialty. The group has a special interest in those just beginning their careers, and has supported a successful starter grant program. Indeed many of the leaders of academic anesthesiology in the early 21st century began their careers with a FAER grant. At the same time FAER was being established, the Anesthesia Patient Safety Foundation (APSF) was created. Its mission is simple: no patient should ever be harmed by an anesthetic. APSF has partnered the academic, private practice, and industrial communities to work toward decreasing anesthetic risk. The establishment of the Harvard standards of monitoring, at the beginning of the APSF, was an important step in this direction. APSF and its work is the model for the patient safety movement across the country, and is used by the AMA as a model for its patient safety foundation.51

CONCLUSIONS By comparison with most other medical specialties, the history of clinical anesthesia is short. Perhaps Francis

Hoeffer McMechan summed it best when he wrote, in 1935, the following: Anesthesia was the gift of pioneer doctors and dentists to suffering humanity, and every significant advance in its science and practice has been contributed by doctors, dentists, and research workers of similar standing. In contrast, technicians have added nothing of any consequence. Anesthetics are among the most potent and dangerous drugs used in the practice of medicine; they penetrate to every cell and organ of the body and may cause almost instant or delayed death by their toxic effects. The dosage of general inhalation anesthetics cannot be prescribed in advance but must be determined from moment to moment during administration. The dosage of local and other anesthetics must be determined by the risk of the patient, the nature and duration of the operation to be done—certainly a challenge to the knowledge and experience of the keenest doctor. No patient should ever be given an anesthetic whose condition and risk has not been diagnosed in advance of the operation, so that every resource of medical science can be used to lessen the risk and make the recovery more assuring. Certainly in this preoperative evaluation and the selection of the safest anesthetic and best method of administration, the medical anesthetist is more in a position to act as a consultant than a technician…. The safety of the patient demands that the anesthetist be able to treat every complication that may arise from the anesthetic itself by the use of methods of treatment that may be indicated. The medical anesthetist can do this, the technician cannot. More recent developments have extended the field of medical anesthesia to include resuscitation, oxygen therapy, and therapeutic nerve block for intractable pain, and treatment of various conditions of disease, and the rehabilitation of the disabled—all fields of practice quite beyond the capacity of the technician.52 McMechan’s vision of professionalism, and its 21st century equivalents, needs to continue to guide the specialty. The history of anesthesia is interesting, filled with fascinating events and people, and it is replete with the highest examples of professionalism.

KEY REFERENCES 1. Smith HM, Bacon DR. The history of anesthesia. In: Barash P, Cullen B, Stoelting R, eds. Clinical anesthesia. 5th ed. Philadelphia: Lippincott Williams & Wilkins, 2005:3–26. 2. Fenster J. Ether Day. New York: HarperCollins, 2001. 3. Johansen PV, Paneth N, Rachman S, Rip M. Cholera, Chloroform, and the Science of Medicine: A Life of John Snow. New York: Oxford University Press, 2003. 4. Goerig M, Agarwal K, Schulte am Esch J. The versatile August Bier (1861–1949), father of spinal anesthesia. J Clin Anesth 2000;12:561– 569. 5. Bacon DR, Lema MJ, McGoldrick KE, eds. The American Society of Anesthesiologists: A Century of Challenges and Progress. Park Ridge, IL: Wood Library-Museum of Anesthesiology Press, 2005. 6. Wells CJ. Francis Hoeffer McMechan. Curr Res Anesth Analg 1948;27:S. 7. Bacon DR, Lema MJ. To define a specialty: a brief history of the American Board of Anesthesiology’s first written examination. J Clin Anesth 1992;4:489–497. 8. Waisel DB. The role of World War II and the European theater of operations in the development of anesthesiology as a physician specialty in the USA. Anesthesiology 2001; 94(5):907–14. 9. Bacon DR. The World Federation of Societies of Anesthesiologists (WFSA): McMechan’s final legacy. Anesth Analg 1997;84:1130–1135. 10. Griffith HR, Johnson GE. The use of curare in general anesthesia. Anesthesiology 1942;3:418–420.

REFERENCES 1. Smith HM, Bacon DR. The history of anesthesia. In: Barash P, Cullen B, Stoelting R, eds. Clinical Anesthesia. 5th ed. Philadelphia: Lippincott Williams & Wilkins, 2005:3–26. 2. Madigan SR, Raj PP. History and Current Status of Pain Management. In: Raj PP, ed.


Practicle Management of Pain, 2nd ed. St. Louis, Mosby Yearbook, 1992:5. 3. Raper HR. Man Against Pain. New York: Prentice-Hall, 1945. 4. Robinson V. Victory Over Pain: A History of Anesthesia. New York: Henry Schuman, 1945. 5. Bergman NA. The Genesis of Surgical Anesthesia. Park Ridge, IL: Wood LibraryMuseum of Anesthesiology, 1998. 6. Stetson JB. William E. Clark and His 1842 Use of Ether. In: Fink BR, Morris LE, Stephen CR, eds. The History of Anesthesia: Third International Symposium Proceedings. Park Ridge, IL: 1992:400–406. 7. Lyman HM. Artificial Anaesthesia and Anaesthetics. New York: William Wood & Company, 1881. 8. Long CW. An account of the first use of sulphuric ether by inhalation as an anaesthetic in surgical operations. South Med Surg J 1849;5:12. 9. Wolfe RJ. “I sleep to awaken:” an appreciation of Elizabeth Wales Wells. In: Wolfe RJ, Menczer LF, eds. I Awaken to Glory. Boston: Boston Medical Library, 1994:229–231. 10. Fenster J. Ether Day. New York: HarperCollins, 2001. 11. Ellis RH. Early ether anaesthesia: the news of anaesthesia spreads to the United Kingdom. In: Atkinson RS, Boulton TB, eds. The History of Anaesthesia. New York: Parthenon, 1989:69–76. 12. Wilson G. One Grand Chain. Melbourne, Australia: The Australian and New Zealand College of Anaesthetists, 1995:41–43. 13. Sim P, Du B, Bacon DR. Pioneer Chinese Anesthesiologists. Anesthesiology 2000;93: 256–264. 14. Anonymous. Code of Medical Ethics of the American Medical Association. Chicago, American Medical Association Press, 1847: 98. Available at: http://www.ama-assn.org/ ama/pub/category/1930.html. Last accessed November 16, 2005. 15. Johansen PV, Paneth N, Rachman S, Rip M. Cholera, Chloroform, and the Science of Medicine: A Life of John Snow. New York: Oxford University Press, 2003:113. 16. Knight PR, Bacon DR. An unexplained death: Hannah Greener and chloroform. Anesthesiology 2002;96(5):1250–1253. 17. Snow J. On Chloroform and Other Anesthetics. London, John Churchill 1858, reprinted by The Wood Library-Museum of Anesthesiology, Park Ridge, Illinois. 18. Shepard DAE. John Snow. Cornwall, PA: York Point Publishing, 1995. 19. Koller C. Personal reminiscences of the first use of cocaine as a local anesthetic in eye surgery. Curr Res Anesth Analg 1928;7: 9–11. 20. Olch PD. William S. Halstead and local anesthesia: contributions and complications. Anesthesiology 1975;42:479–486. 21. Goerig M. Carl Ludwig Schleich and the introduction of infiltration anesthesia into clinical practice. Reg Anesth Pain Med 1998; 23(6):538–539.

22. Bacon DR. Regional anesthesia and chronic pain therapy: a history. In: Brown DL, ed. Regional Anesthesia and Analgesia. Philadelphia: WB Saunders, 1996:10–22. 23. Goerig M, Agarwal K, Schulte am Esch J. The versatile August Bier (1861–1949), father of spinal anesthesia. J Clin Anesth 2000;12: 561–569. 24. Ramachari A, Patwari A. Edward Lawrie and the Hyderabad Chloroform Commissions. In: Atkinson RS, Boulton TB, eds. The History of Anaesthesia. Park Ridge, NJ: Parthenon Publishing, 1989:236–242. 25. Mumford JG, Binnie JF, Powers CA, Haggard WD, Rodman WL. Preliminary report of the anaesthesia commission of the American Medical Association. JAMA 1908; 19:1572–1574. 26. Erickson JC III. In the beginning: Adolph Frederick Erdmann and the Long Island Society of Anesthetists. In: Bacon DR, Lema MJ, McGoldrick KE, eds. The American Society of Anesthesiologists: A Century of Challenges and Progress. Park Ridge, IL: Wood LibraryMuseum of Anesthesiology Press, 2005:1–8. 27. Young TM. A Short History of the Section on Anaesthetics of the Royal Society of Medicine and the Society of Anaesthetists. London: The Royal Society of Medicine, 1998. 28. Bacon DR. The New York Society of Anesthetists: building the foundation. In: Bacon DR, Lema MJ, McGoldrick KE, eds. The American Society of Anesthesiologists: A Century of Challenges and Progress. Park Ridge, IL: Wood Library-Museum of Anesthesiology Press, 2005:9–18. 29. Cope DK. James Tayloe Gwathmey: seeds of a developing specialty. Anesth Analg 1993;76:642–647. 30. Wells CJ. Francis Hoeffer McMechan. Curr Res Anesth Analg 1948;27:S. 31. Ranney O. Francis Hoeffer McMechan A.B., A.M., M.D., F.I.C.A. His life and work. Curr Res Anesth Analg 1939;18:(S). 32. Bacon DR, Ament R. Ralph Waters and the beginnings of academic anesthesiology in the United States: The Wisconsin template. J Clin Anesth 1995;7:534–543. 33. MacKenzie RA, Bacon DR, Martin DP. The Anaesthetists’ Travel Club: A transformation of the Society of Clinical Surgery? Bull Anesth Hist 2004;22(3):7–10. 34. Griffith HR. The recent revolution in anesthesia. J Conn State Med Soc 1939;1:509–514. 35. Haines FE. Economic problems in anesthesia. Curr Res Anesth Analg 6:25–28 1927. 36. Letter from Paul M. Wood, MD, to Wallace W. Dill, MD, May 27, 1937. The Collected Papers of Paul M. Wood, MD. Park Ridge, IL: Wood Library-Museum of Anesthesiology Collection. 37. Bacon DR. The creation of the American Society of Anesthesiologists: an intriguing decade. In: Bacon DR, Lema MJ, McGoldrick KE, eds. The American Society of Anesthesiologists: A Century of Challenges and Progress. Park Ridge, IL: Wood Library-Museum of Anesthesiology Press, 2005:19–34.

38. Bacon DR, Lema MJ. To define a specialty: a brief history of the American Board of Anesthesiology’s first written examination. J Clin Anesth 1992;4:489–497. 39. Bacon DR, Lema MJ, Yearley CK. For all the world to see: anesthesia at the 1939 New York World’s Fair. J Clin Anesth 1993;5:252– 258. 40. Foldes FF. The impact of muscle relaxants on the development of anesthesia and surgery: the role of Lewis H. Wright. Anesth Hist Assoc News 1993;11(4):1, 4–6. 41. Papper EM. The palate of my mind. In: Fink BR, ed. Careers in Anesthesiology. Vol I. Park Ridge, IL: The Wood Library-Museum of Anesthesiology, 1997:66–217. 42. Griffith HR, Johnson GE. The use of curare in general anesthesia. Anesthesiology 1942;3:418–420. 43. Courington FW, Calverley RK. Anesthesia on the western front: the Anglo-American experience of World War I. Anesthesiology 1986;65(6):642–653. 44. Waisel DB. The role of World War II and the European theater of operations in the development of anesthesiology as a physician specialty in the USA. Anesthesiology 2001;94(5):907–914. 45. Bacon DR, Lema MJ. Standing on the promises. Sphere 1989;42:20–24. 46. Bacon DR. The World Federation of Societies of Anesthesiologists (WFSA): McMechan’s final legacy. Anesth Analg 1997;84: 1130–1135. 47. Papper EM, Bacon DR. With great reluctance: the American perspective on joining the World Federation of Societies of Anesthesiologists 1935–1963. In: Rupreht J, ed. The History of the World Federation of Societies of Anesthesiologists. Springer, Paris: 2004:35–54. 48. Curry TB, Tandy CC. The 1950s: a decade of turmoil. In: Bacon DR, Lema MJ, McGoldrick KE, eds. The American Society of Anesthesiologists: A Century of Challenges and Progress. Park Ridge, IL: Wood Library-Museum of Anesthesiology, 2005: 75–84. 49. Papper EM. The origins of the Association of University Anesthesiologists. Anesth Analg 1992;74:436–53. 50. Gotta AW. The 1970s: a decade of crisis. In: Bacon DR, Lema MJ, McGoldrick KE, eds. The American Society of Anesthesiologists: A Century of Challenges and Progress. Park Ridge, IL: Wood LibraryMuseum of Anesthesiology, 2005:147–157. 51. Smith BE. The 1980s: a decade of change. In: Bacon DR, Lema MJ, McGoldrick KE, eds. The American Society of Anesthesiologists: A Century of Challenges and Progress. Park Ridge, IL: Wood Library-Museum of Anesthesiology, 2005:173–191. 52. McMechan FH. Should the radiologist, pathologist and the anesthetist be licensed to practice medicine? Point of view of the anesthetist. Proceedings of the Annual Congress on Medical Education, Medical Licensure and Hospitals, 1935.

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PART 1: The Specialty of Anesthesia

CHAPTER 2 12

The Scope and Future of Anesthesia Practice Michael S. Avidan, MBBCh, DA, FCA, and Alex S. Evers, MD Anesthesiology arose as a medical specialty because the dangers associated with anesthetic drugs and techniques demanded that they be administered by skilled and knowledgeable physicians. As safer drugs were developed and physiologic monitoring improved, the need for anesthesiologists was propelled by increasing surgical complexity and severity of patient illness, as well as by increasing expectations for patient safety. Whereas the original raison d’être for the specialty remains today, a variety of professional and economic factors have challenged anesthesiology and produced large “swings of fortune” during the past few decades. During the 1970s and 1980s the emergence of critical care attracted many talented medical students to American anesthesiology training programs. However, these were halcyon days for anesthesiologists practicing in the operating room, where professional income was high, job opportunities were ample and increasing surgical complexity demanded an increasing level of medical knowledge and skills. Thus there was little incentive for anesthesiologists to expand their roles beyond the confines of the operating suites and most of the trainees who were initially attracted by critical care subsequently practiced operating room anesthesia only. In contrast, during this same period, anesthesiologists in Europe and Canada were consolidating their positions in the burgeoning subspecialties of pain, intensive care, and resuscitation. In the mid 1990s, gloom beset anesthesiology in the United States as predictions, widely reported in lay press such as the Wall Street Journal, suggested that the need for anesthesiologists would decrease dramatically in an anticipated managed care environ-

ment. Medical graduates were discouraged from pursuing careers in anesthesiology, and residency programs contracted dramatically. Anesthesiologists in other parts of the world have also experienced fluctuating fortunes. Currently there is a shortage of doctors in general, and of anesthesiologists in particular, in many countries. The future of anesthesiology depends on several factors, including changes in surgery and interventional medical practice, technological advances in anesthesiology, the evolving scope of anesthesia practice, and the role of nonphysicians (e.g., nurse anesthetists and anesthesia physician assistants) and physicians trained in other specialties in the provision of anesthesia care; healthcare financing will also influence trends in anesthesia practice. This chapter briefly reviews the current scope of anesthetic practice and offers some possible scenarios for future directions of the specialty.

OPERATING ROOM ANESTHESIA The operating room remains the primary focus for the vast majority of anesthesiologists. The anesthesiologist’s primary responsibility in this

arena is to ensure the patients’ comfort and safety when they are exposed to the trespass of surgery; this includes protecting the patient from pain, undesired awareness and organ system injury, and fostering full recovery from the surgical and anesthetic interventions. Over the past decades it has become increasingly clear that the intraoperative conduct of anesthesia has a profound effect on patient safety and comfort in the postoperative period. For example, modest intraoperative hypothermia can either decrease the incidence of wound infection1 or provide neuroprotection,2 depending on the clinical situation. Anesthesiologists are increasingly sophisticated in their understanding of patient safety and they are focusing on such issues as appropriate perioperative medications, antibiotic prophylaxis and infection control, multimodal analgesia, maintenance of normothermia and normoglycemia, and appropriate fluid and electrolyte therapy. Recent findings raise the intriguing possibility that anesthetic management may contribute to postoperative cognitive decline and to long-term outcomes.3 This growing responsibility for overall postoperative outcomes raises new expectations for knowledge and skills of the practicing anesthesiologist and challenges our

KEY POINTS 1. The operating room remains the primary focus for the vast majority of anesthesiologists.

overcoming the political infighting between organized anesthesiology and nurse anesthesia.

2. The anesthesiologist’s primary responsibility is to ensure patients’ comfort and safety when they are exposed to the trespass of surgery.

7. It is important for the future of the specialty that anesthesiologists increase their commitment to critical care medicine.

3. The intraoperative conduct of anesthesia has effects on patient safety and comfort in the postoperative period.

8. Recent advances in knowledge and technology create an enormous opportunity for anesthesiologists to address the scientific questions at the core of the specialty as well as a variety of important clinical problems.

4. The provision of safe anesthetic care across geographically dispersed sites and encompassing wide ranges of patient health, in an economically responsible manner, is a challenge that anesthesiologists need to address proactively. 5. It is arithmetically impossible to provide a fully trained anesthesiologist for every anesthetic procedure. 6. Meeting the manpower, safety, and cost demands of the future requires


9. Apart from traditional areas of involvement, such as operating room anesthesia, critical care, pain medicine, teaching, research, and resuscitation, there will be future opportunities for anesthesiologists in pharmacogenomics, healthcare systems management and new technologies.

CHAPTER 2: The Scope and Future of Anesthesia Practice

previously narrower definitions of anesthetic outcome. Despite the demands imposed by increasing severity of illness in surgical patients, growing surgical complexity and more comprehensive postoperative considerations, anesthesiology is often viewed as a victim of its own perceived success. One widely cited study from the United Kingdom, the Confidential Enquiry into Perioperative Deaths (CEPOD) study, reports that patients undergoing general anesthesia have a 1 in 185,000 chance of dying as a consequence of anesthetic misadventure.4–6 This finding was highlighted in the Institute of Medicine report on medical errors7 and anesthesiology was cited as the specialty that had best addressed safety issues (see Chap. 3 for a more comprehensive review of quality and safety in anesthesia practice). Unfortunately, this widely publicized perception that anesthesia is “safe” has encouraged nonphysician anesthesia providers to advocate for independent practice and has suggested to insurers that anesthetic care by an anesthesiologist is needlessly expensive. However, studies from other countries have reported much higher rates of death attributable to anesthesia than those reported in the CEPOD study.8 In a large French study, the perioperative mortality directly attributable to anesthesia was found to be 1 in 13,000.9 In studies reported from Australia,10 Denmark,11 Finland,12 and the Netherlands,13 perioperative death attributable to anesthesia ranged from 1 in 250011 to 1 in 67,000.12 The mortality attributable to anesthesia is probably much greater in developing countries. For example, a 1992 study from a Zimbabwean teaching hospital reported an alarming incidence of death or coma— 1 in 388—attributable to anesthesia.14 Whereas the bulk of evidence suggests that anesthesia is not nearly as safe as publicized,15 it is undoubtedly true that advances in anesthetic practice in developed countries have rendered the care of healthy patients undergoing low- or intermediate-risk surgery much safer than in the past (see Chap. 24 for a more detailed review of anesthesia risk). The challenges to anesthesiology are exacerbated by the massive expansion in demand for anesthesia services for a variety of nonoperative procedures, ranging from cerebral aneurysm coiling to general anesthesia for

screening colonoscopy, and by the introduction of freestanding ambulatory surgery centers and office-based surgical suites where anesthesia is administered. The demands for safe anesthesia care provided in numerous remote locations, present significant challenges to the workforce, and to the financing and practice of anesthesiology. Current practice models vary widely both in the United States and worldwide. In the United States, some anesthesiologists (or practice groups) personally provide all anesthetic care regardless of complexity, an approach that is also common in the United Kingdom, Canada, and Australia. In other practices, anesthesiologists supervise ancillary providers (e.g., nurse anesthetists, residents, or anesthesia assistants) in more than one operating room; a practice model that is also common in the Netherlands. The provision of safe anesthetic care across geographically dispersed practice sites and encompassing wide ranges of severity of patient illness, in an economically responsible manner, is a major challenge that anesthesiologists need to address proactively. The expectations for operating room anesthesia can be simply stated: we need to provide an ever-increasing quality of perioperative care for a lower cost. In turn, these expectations and predictions require that the anesthesiologist community consider who will, or should, provide each component of anesthesia care, what levels of knowledge and skill will be required of each provider, and how the responsibility for care will be organized, managed, and rewarded. Currently, at least 50% of anesthesia care in the United States involves nurse anesthetists; in several states, physician supervision is not mandatory. Worldwide, anesthesia practice often includes some form of nonphysician provider, or a physician provider who is not a fully trained anesthesiologist. For example, staff-grade noncertified anesthetists provide a significant proportion of anesthesia care in the United Kingdom. One report asserts that nonanesthesiologists can safely provide anesthesia for selected procedures (e.g., colonoscopy) and patients.16 It is also clear that patients with minimal physiologic reserve, those undergoing major interventions, and those with complex medical problems require the direct involvement of a skilled anesthesiologist

to enhance patient safety.17,18 Unfortunately, practitioner skill and experience are often not matched to these factors, but determined by availability of providers, or a fixed model of care delivery, rather than one that is tailored to the specific clinical situation. This is a fruitful area for further work by anesthesiologists to assure proper matching of resources to the clinical needs. It is arithmetically impossible to provide a fully trained anesthesiologist for every anesthetic procedure. Furthermore, the increasing demands for anesthesia services (aging population, proliferation of ambulatory surgery centers, escalating demand for nonsurgical anesthesia and sedation) will outstrip even the most aggressive output of anesthesiologists. Medical schools simply do not have the capacity to train sufficient numbers of doctors to feed exponentially increasing anesthesia programs. For reasons of both anesthesiologist availability and cost, it is apparent that the future of anesthesia practice will involve an increasing role for nonphysician providers. How can this be made compatible with the demands for increasing safety and quality? By involving skilled anesthesiologists in the cognitive aspects of every anesthetic. This will require coordination and cooperation with nonphysician providers, allowing them to perform at the highest levels their training allows, while ensuring that a fully trained specialist is involved in planning and managing care for highrisk cases and is readily available for complex diagnostic and therapeutic decision making. Technologic developments in monitoring and information systems should facilitate these changes. The development of telemedicine could make this model of care feasible even in communities where an anesthesiologist is not physically present.19 Meeting the manpower, safety and cost demands of the future will require that we overcome the political infighting between organized anesthesiology and nurse anesthesia. Furthermore, the training of anesthesiologists will increasingly need to encompass the development of skills in supervising other anesthesia providers. It is in the interests of public safety and healthcare delivery that unity be forged among anesthesia providers under the leadership of specialist anesthesiologists, whose medical training and education is required for

13


complex medical decision making, supplemented by the skills and abilities of nonphysician providers who enhance this team approach. 14

OUTSIDE THE OPERATING ROOM Preoperative Care Perioperative morbidity is frequently attributable to poor preoperative patient assessment and optimization. These roles have always been integral to the anesthesiologist’s practice. However, as patients increasingly present to the hospital on the day of surgery, it has become necessary to ensure that patients are properly evaluated well before the immediate preoperative interval. Recognizing this need has led to burgeoning preoperative assessment clinics, where problems such as ischemic heart disease, pulmonary disease or sleep apnea may be evaluated and appropriate perioperative interventions may be planned. (See Chap. 4 for a more detailed discussion of the benefits and operation of preoperative clinics.) In some practice settings, preoperative assessment of complicated patients has been largely relegated to nonanesthesiology trained physicians or physician extenders. In other settings, the challenge of same-day surgery admission has left preoperative assessment as a day-of-surgery activity; neither of these approaches is optimal. From the standpoint of continuity of care and so that anesthesiologists can implement best practices that contribute to the continuum of care and long-term outcomes, it is essential that anesthesiologists continue to play an integral role in preoperative assessment clinics. This should also be a key component of anesthesia resident training programs, for it represents an important aspect of future anesthesia practice.

Pain Medicine Doctors cannot always cure disease but they should always try to alleviate suffering. Physical pain is among the most unpleasant of human experiences. Anesthesiologists are often involved in the management of severe pain associated with surgery and the perioperative use of analgesics constitutes an important component of anesthetic care. Anesthesiologists are more comfortable with opiate administration than many other

physicians, because of their knowledge of pharmacology (especially opioid pharmacology), as well as their skill and experience in managing side effects such as respiratory depression. Anesthesiologists pioneered regional anesthetic techniques, many of which are applicable to the treatment of chronic intractable pain. Increasing numbers of anesthesiologists are specializing in pain management and the effective relief of pain will remain an important component of the anesthesiologist’s role even for those who do not subspecialize specifically in pain medicine.

Critical Care Medicine Anesthesiologists pioneered the development of critical care medicine.20 In many countries, anesthesiologists constitute the bulk of the physician workforce in critical care. In most of Europe, full training in critical care is an integral component of an anesthesia residency and critical care anesthesiologists are responsible for organizing and staffing most hospital critical care units. In contrast, U.S. anesthesia residents receive only a few months of critical care training and anesthesiologists constitute a minority of the nation’s critical care physicians. Many believe it is important for the future of the specialty that anesthesiologists increase their commitment to critical care medicine. Consistent with this view, there is impetus in the United States to increase the minimum duration of critical care training to 6 months during the anesthesia residency. The intent is to broaden the scope of expertise of anesthesiologists, thus partially addressing the marked shortage of critical care physicians in the United States.21 Clearly, this would enhance the perception of anesthesiologists as broad-based physicians who can contribute additionally to the general healthcare needs of the United States, but the feasibility of this proposal requires both redesign of the residency programs (including either modifying the duration of the residency or altering the duration of specific rotations in the current residency continuum) and the commitment of future trainees to embrace the practice of critical care medicine.

Clinical Services Administration The operating suite is a complex environment that is inefficiently managed.

Anesthesiologists are an integral component of this important but unwieldy organization. The need for effective management and administration is being increasingly recognized and anesthesiologists are often sought for this management function. In many countries, including in Europe and North America, anesthesiologists are acquiring formal training in management and business administration. Today’s doctors, even in academic institutions and national health services, cannot afford to isolate themselves from the realities of reimbursement, cost, efficiency, patient satisfaction, and overall system performance. There appears to be a bright future for physician leaders in healthcare organizations; anesthesiologists are, and will continue to be, an important part of this management evolution.

Patient Safety Anesthesiologists are at the forefront of pioneering patient safety. So dramatic have been the improvements implemented by anesthesiologists that liability insurance for anesthesia practice has decreased, while that for most other specialties has steadily increased (some dramatically). The Anesthesia Patient Safety Foundation (APSF) was founded in the United States in 1984 with the expressed purpose of assuring “that no patient shall be harmed by the effects of anesthesia.” Since 1985, the American Society of Anesthesiologists’ (ASA) Committee on Professional Liability has been studying records of closed malpractice claims files for anesthesia-related patient injuries.22 More than 5000 claims have been studied. In 1987, the Australian Patient Safety Foundation was established and the Australian Incident Monitoring Study initiated.23 More than 4000 critical incidents have been reported through 2000. Analysis of these incidents has reinforced the value of technological advances, such as capnography and oximetry, in improving patient safety. The results also confirm the value of structured algorithms in anesthesia care, by documenting favorable outcomes in a range of life-threatening crises during anesthesia. CEPOD was started in the United Kingdom in 1989. Changes in consultant practice, an increase in the number of medical audits, improvements in physiologic monitoring, appropriate matching of specialist expe-


rience to patient’s medical conditions, and increasing awareness of the need for critical care services are believed to have been influenced by this inquiry.24 Critical events occur within the context of complex system failures, and anesthesiologists have been developing safeguards to decrease the likelihood that human error may result in patient harm. Examples include written “check lists,” audible alarm settings, and automated anesthesia machine checks. This expertise in patient safety should be developed and translated into the broader medical context, including application in areas not historically viewed as the purview of anesthesia practice (such as diagnostic and treatment suites, obstetrical suites, intensive care units and intermediate care units).

Research Anesthesiology has a vibrant history of research and intellectual contributions to clinical medicine. Historically anesthesia research has focused on laboratory investigations in physiology and pharmacology and their application to patient care. These contributions have improved the safety of anesthesia and surgery, and constituted pioneering efforts in the initial application of scientific principles to individual patient care. Until recently many of the scientific questions at the core of anesthesiology have been relatively inaccessible to investigation; this stems from the absence of tools to study the mechanisms of the complex behaviors (e.g., consciousness, memory, pain) that anesthesiologists manipulate. Recent advances in cellular physiology (e.g., patch clamp recording), molecular biology, genetics, functional imaging, and behavioral sciences have enabled serious investigation of these complex behaviors. It is thus now possible that the fundamental mysteries of anesthesia (including the molecular mechanism of the hypnotic, amnestic, and analgesic effects of anesthetics agents) will be solved. These same new scientific tools also make it feasible to define the mechanisms of hyperalgesia and chronic pain and to design effective treatments. Finally, advances in the understanding and manipulation of inflammation and the immune response provide a new opportunity to delineate how organ system injury occurs in the perioperative period and to identify strategies for

protection of the brain, heart, kidneys and other organs. Collectively, recent advances in knowledge and technology create an enormous opportunity for anesthesiology to address the scientific questions at the core of the specialty, as well as a variety of important clinical problems. The application of information technology and epidemiologic techniques (often referred to as outcomes research) to the perioperative period has also created new research opportunities for anesthesiology. These approaches quantify and describe perioperative morbidity and mortality, facilitating recognition of patterns and causes of adverse patient outcomes. Outcomes research has already identified a variety of problems with the process and substance of anesthetic care; it has also led to identification of previously unrecognized adverse patient outcomes (e.g. postoperative cognitive decline). The broad application of information technology coupled to epidemiologic analysis will provide the opportunity to define and monitor “best practices” and to systematically evaluate the efficacy of new technologies, techniques and approaches. Academic anesthesia has been challenged in recent years, with decreased academic funding of some departments, a decreasing share of extramural grant funds,25 and a contraction in the number of young anesthesiologists embarking on rigorous research training and careers. One reason put forward for reducing funding for anesthesia research is that the current safety of anesthesia implies that anesthesia research is not a pressing public health concern. As noted earlier, this may be a misconception; although intraoperative mortality is rare, postoperative mortality and major morbidity still occur commonly, and anesthesia care has been shown to contribute to this process, both positively and negatively. There is much room for improvement before any field can conclude that we have overcome the hurdles in surgical care that challenge the extremes of age, those with significant comorbidities or those undergoing extensive surgical procedures. Many of the advances in these areas will come from improved perioperative care, built on evidence-based techniques that are confirmed by careful clinical investigation and innovation. One of the priorities for research, as

identified by the National Institutes of Health, is for investigators to embark on more multidisciplinary and multicenter research initiatives. It is also crucial to foster translational research where advances in the basic sciences, including genetics, can lead to progress in the clinical arena. A strong commitment to research will be necessary to ensure the continued advance of the specialty, and to insure that anesthesiology remains a mainstream medical discipline that contributes to the overall good of society.

EDUCATION AND TRAINING Clearly, the future of the specialty requires a robust commitment to education and training at all levels, from undergraduate medical education through the most advanced subspecialty levels. Strong training programs depend on an excellent teaching faculty, ample and diverse clinical cases, a well-organized teaching program and an emphasis on the knowledge required for future as well as current practice. One challenge facing academic anesthesia in the United States is that reimbursement is halved when a resident provides anesthesia supervised by a teaching anesthesiologist. This reduces the funds available to the academic department for support of nonclinical teaching time, educational resources such as simulators, libraries, or administrative support staff, and compensation for the teaching faculty. The American Society of Anesthesiologists has engaged in a major legislative effort to remedy this funding problem, but resolution of this issue is far from assured because of overall funding limitations and political maneuvering among medical and surgical specialties. Adequate funding for anesthesiology education by the federal government, by teaching hospitals and by our specialty societies is an imperative if the specialty is to flourish in future decades. The current shortfall in anesthesiologists (particularly in teaching hospitals) creates a temptation to increase training numbers and churn out many more anesthesiologists; this may be particularly true in training programs that need to use residents primarily as work force. The danger is that this approach will decrease the selectivity of training programs and downgrade the quality of anesthesiolo-

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gists. Training must be broadened as well; if the next generation of anesthesiologists is to be prepared for the future, anesthesiology training programs must emphasize preoperative assessment, critical care, pain management, supervision of nonphysician providers and operating room administration, among others. Also important will be an increased emphasis on fellowship programs, with formal recognition of fellowships in areas such as regional anesthesia, transplant anesthesia, and obstetric anesthesia. To attract high-caliber applicants to anesthesiology, it is important that medical students continue to receive adequate exposure to the specialty. In addition to perioperative medicine and pain medicine, anesthesiologists are well placed to teach medical students applied respiratory and cardiovascular physiology, several aspects of neuroscience and numerous aspects of pharmacology, in addition to their more traditional educational roles in resuscitation and emergency airway management. The model of academic anesthesia care facilitates excellent learning, with medical students able to spend high quality one-on-one time with experienced anesthesiologists.

SIMULATION The aerospace industry has long appreciated the value of simulation in increasing safety and decreasing errors. Within the medical profession, anesthesiologists were among the first to recognize the potential role of simulation in improving both education and patient safety. Anesthesiologists established simulation facilities to train anesthesiologists in the management of infrequent but life-threatening problems that arise in the operating room. It rapidly became apparent that simulation might be useful for teaching other topics that are not unique to anesthesia practice (e.g., diagnosis and management of pneumothorax, hemorrhagic shock, myocardial infarction, insertion of central vascular catheters). Computer modeling also can be employed in research. Speculation is rife about a role for simulation in credentialing and recredentialing in various medical specialties. Increasingly, physician and nursing professionals, including those in critical care and emergency medicine,

are seeking time in simulation facilities for purposes of training and honing their skills in crisis management. Simulation centers are mushrooming internationally and are also being embraced by medical schools. Anesthesiologists have led this initiative, and it is important that we continue to lead innovation in this field of evolving technology.

Public Perception of Anesthesiologists Anesthesiology is one of the largest physician based specialties, but few mainstream medical specialties are as poorly understood by members of the public and by other health professionals.26 Many patients do not realize that anesthesiologists are doctors or that they have responsibilities outside the operating room.26 In Swiss and Austrian studies 93–99% of patients knew that anesthesiologists are qualified physicians. In addition, many of the patients were aware that the anesthesiologists are engaged in activities outside the operating room. However, many patients also thought that the anesthesiologists played a subservient role to the surgical team.27,28 In studies from Singapore, Pakistan, and the West Indies, only 56–66% of patients were aware that anesthesiologists are physicians, and most patients had a limited knowledge of the anesthesiologists’ roles.29–31 In contrast to these findings, a Finnish study reported that anesthesiologists were generally recognized as specialist physicians and were held in high esteem.32 In the United Kingdom, the bodies representing anesthesiologists initiated National Anaesthesia Day in an attempt to increase the profile of anesthesiologists. Clearly, there is variation among countries in the way anesthesiologists are perceived. Heightening public awareness and improving public perception about anesthesiologists and their many essential functions may be important to the future of the specialty in several respects, including allocation of research funding, quality of applicants to residencies and the future role of anesthesiologists within healthcare in general. A recent Scandinavian study explored perceptions of the anesthesiologist’s role. The study was titled: “Professional artist, good Samaritan, servant and co-coordinator: four ways of understanding the anesthetist’s

work.”33 According to these authors, the current scope of anesthesia practice encompasses: 1. The provision of safe anesthesia while controlling patients’ vital functions. 2. Helping patients including the alleviation of pain and anxiety. 3. Providing service to the whole hospital, including support to other doctors and nurses who are caring for severely ill patients. 4. Participation in the organization and direction of the operating suites to ensure that lists run smoothly. Whereas these are essential and important components of the specialty, even collectively they do not encompass the spectrum of anesthesiology as we view it currently, or as we look to the future, which seems particularly attractive if we maintain a comprehensive view of the opportunities for our discipline.

THE FUTURE OF ANESTHESIA PRACTICE The future of the specialty depends on several key drivers: (a) the vision and actions of organized anesthesiology; ( b) technological changes in surgery and anesthesiology and; (c) the directions chosen by academic institutions, the trainers of future practitioners. These drivers will influence the attractiveness of anesthesiology as a specialty choice for medical students, the career paths of young anesthesiologists, and the scope and organization of anesthetic practice. There will be tough choices faced by future anesthesiologists. New drugs and increasingly sophisticated monitoring will facilitate safer anesthesia. Such technological advances will allow more effective remote supervision of anesthesia providers. There is likely to be a steady growth in the demand for anesthesia. Anesthesiologists will have to decide whether to try to expand their ranks at all costs and to defend their turf, or refine their training according to future conditions. It is highly unlikely that anesthesiologists alone will be able to meet all the demands for anesthesia. Anesthesiology faces many challenges in the years ahead. To meet these challenges, perioperative medi-


cine, which includes the spectrum of care from preoperative assessment to postoperative care, may offer the best chance for the specialty to survive and prosper.34 While there is a vision that future anesthesiologists will practice as much outside as inside operating rooms,35 the expansion of anesthesiologists’ activities could lead to dilution of the specialty’s identity, endangering the vitality of anesthesiology in an era of sweeping changes in healthcaredelivery systems.36 An expansion of anesthesiology practice into nonoperative domains of perioperative medicine may also be challenged by other specialties. The role of perioperative physician may fall to hospitalists, the role of critical care physicians to intensivists and the role of pain management to pain specialists. Anesthesia may grow and acquire new tentacles or it may have its subspecialties amputated, leaving it as a restricted operating room bound specialty (Fig. 2–1). In the United Kingdom, there was a recent struggle in which the Royal College of Anaesthetists opposed efforts to establish a fully autonomous College of Intensive Care Medicine; it is likely that this will be revisited in the United Kingdom and other countries in future. As an academic specialty, anesthesiology evolved out of fundamental contributions to healthcare, including the prevention of pain from surgery and the development of critical care medicine, cardiopulmonary resuscitation, and pain medicine.37 In recent years, many advances have occurred in the basic science of anesthesiology, including mechanisms of pain, receptor physiology, modes of action of anesthetic agents, and cellular responses to sepsis. If anesthesiology is to flourish as an academic specialty, it is crucial that research is pursued and encouraged. Without intellectual advances, anesthesiology is in danger of becoming a sterile technical discipline.37 University departments of anesthesiology are increasingly experiencing pressure to emphasize clinical delivery at the expense of academic pursuits. Succumbing to these pressures will threaten undergraduate perioperative medicine teaching, development of critical appraisal skills among anesthesiologists, and the future of research programs.38 The irony would be that by immersing themselves entirely in the clinical arena, anesthesiologists would neglect the

A

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B

FIGURE 2–1. The future of anesthesiology—two possible outcomes. A. The specialty may come to resemble a bloated octopus, based only in the operating room with all its tentacles amputated. B. Anesthesiology may retain its integral role in the operating room (lean body), but expand its tentacles in other areas, such as critical care, pain medicine, medical education, health system management, simulation, resuscitation, and research.

education of medical students and trainees, thus jeopardizing the future of clinical anesthesiology practice. Although it is easy to teach others as we were taught, or as we practice today, focus on the future is an essential element of education. Long-term success for the specialty will depend on our efforts in undergraduate and graduate medical education, whereas shortterm success will depend on our efforts in the continuing medical education of current practitioners.39 A different approach may be required to redefine the scope of the practice with broadened training to provide increased expertise in the evolving medical marketplace. This approach could include solid training in business, informatics, data man-

agement, and critical thinking on outcomes. This paradigm shift may be challenging, and requires redirection, reallocation of assets, reeducation, and a new mindset. If successfully applied, however, it presents a means to strengthen the respected position of the specialty and to promote the medical care and practice of perioperative specialists in the rapidly changing landscape of modern medicine.40

VISIONS OF THE FUTURE Scenario 1: To Each Patient a Dedicated Anesthesiologist This is the current model of anesthesia care in much of the developed world


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and many in the United States are adherents of this model. Most American residency programs are structured to train anesthesiologists to practice in this model. As discussed earlier, it is unlikely that this model of anesthesia care will be sustainable given the mismatch between surgical demand and anesthesiology manpower and the inevitable pressure to reduce the cost of anesthesia.

Meeting the Challenge of Change

Scenario 2: Physicians for the Perioperative Period

1. Commitment to the care of critically ill patients as well as those experiencing acute and chronic pain.

Many advocate that anesthesiologists should play a greater role in perioperative care. This is an appealing option, but is fraught with difficulties. An expansion of anesthesiologists’ roles will mean that even more anesthesiologists must be trained. There is simply a limited capacity to achieve this. It also is not clear whether anesthesiologists are prepared to financially compete in many perioperative roles. Anesthesiologists are accustomed to high remuneration for their procedure-driven roles, whereas hospitalists are willing to accept lower compensation. Thus far anesthesiologists have not shown enthusiasm in adopting the mantle of perioperative physicians. Tremendous inertia will have to be overcome for this to become a possibility.

Scenario 3: Process Managers and Perioperative Care Directors To achieve this, anesthesiologists will require formal training in business, management and finance. They will also need to broaden their medical knowledge and experience. Perhaps, most importantly, anesthesiologists would have to be trained to supervise others effectively and to utilize physician extenders throughout the perioperative period. Certified registered nurse anesthetists (CRNAs) are also expensive, and other physician extender roles should be explored. This model runs counter to the current training process. There are anesthesia programs that are offering novel fellowships, such as operating room management. The philosophy behind this model is that anesthesiologists would receive broader training, where operating room anesthesia would be only a component. Fellowships and academic tracks would also increase. If this model is to succeed, residencies will have to undergo major paradigm shifts.

At the ASA’s 2005 Rovenstein Lecture, Mark Warner opined that as long as anesthesiologists remain steadfast in their commitment to the specialty’s core values, the specialty would continue to develop as a vibrant academic medical specialty.41 Dr Warner identified two quintessential values of anesthesiology41:

2. Promoting and improving patient safety in the operating room and in the perioperative period. Change will be driven by several imperatives, including shifting demographics, technological advances, patterns of surgery, and economic realities. There will be an increasing number of elderly people, high-risk obstetric patients, and children with complex medical problems requiring surgery. It is important to further increase the safety of surgical, anesthetic, and perioperative care to minimize both short-term morbidity and long-term deterioration when vulnerable patients undergo surgery and anesthesia. Improved monitoring, safer drugs, less-invasive surgery, and sophisticated communication networks may allow anesthesiologists and other anesthesia providers to extend their roles without compromising patient safety. Intensive care units may serve as a useful model. Typically, one nurse attends to 1 or 2 critically ill patients. Usually a small number of physicians, with 1 experienced intensivist, regularly assess all the patients and modify treatment plans over the course of the day. A derivative of this model could be conceptualized for future operating room anesthesia care. As individual patients present with their genetic profiles, it may become possible to tailor anesthetic and analgesic therapy with increased efficacy and decreased side effects. This pharmacogenomic model would represent a major advance in patient safety.

able and irreplaceable members of the healthcare team. Anesthesiologists must extend their physician skills and increasingly pursue subspecialty fellowships. Anesthesiologists should have a meaningful presence in all areas of medicine. Apart from traditional areas of involvement, such as operating room anesthesia, critical care, pain medicine, teaching, research and resuscitation, there will be future opportunities for anesthesiologists in pharmacogenomics, healthcare systems management, and new technologies.

KEY REFERENCES 1. Lagasse RS. Anesthesia safety: model or myth? A review of the published literature and analysis of current original data. Anesthesiology 2002;97:1609–1617. 2. Ewart GW, Marcus L, Gaba MM, Bradner RH, Medina JL, Chandler EB. The critical care medicine crisis: a call for federal action. A white paper from the critical care professional societies. Chest 2004;125: 1518–1521. 3. Schwinn DA, Balser JR. Anesthesiology physician scientists in academic medicine: a wake-up call. Anesthesiology 2006;104:170–178. 4. Larsson J, Holmstrom I, Rosenqvist U. Professional artist, good samaritan, servant and co-ordinator: four ways of understanding the anaesthetist’s work. Acta Anaesthesiol Scand 2003;47:787–793. 5. Warner MA. Who better than anesthesiologists? The 44th Rovenstine lecture. Anesthesiology 2006; 104:1094–1101.

REFERENCES 1. Kurz A, Sessler DI, Lenhardt R. Perioperative normothermia to reduce the incidence of surgical-wound infection and shorten hospitalization. Study of Wound Infection and Temperature Group. N Engl J Med 1996;334(19):1209–1215.

CONCLUSION

2. Mild therapeutic hypothermia to improve the neurologic outcome after cardiac arrest. N Engl J Med 2002;346(8):549–556.

Healthcare systems are evolving at a rapid rate. Anesthesiology as a specialty must adapt to the changes so that anesthesiologists remain invalu-

3. Monk TG, Saini V, Weldon BC, Sigl JC. Anesthetic management and one-year mortality after noncardiac surgery. Anesth Analg 2005;100(1):4–10.


4. Buck N DH, Lunn JN. Report on the Confidential Enquiry into Perioperative Deaths. London: Nuffield Provincial Hospitals Trust, The Kings Fund Publishing House; 1987. 5. Devlin HB, Lunn JN. Confidential inquiry into perioperative deaths. Br Med J 1986; 292(6536):1622–1623. 6. Lunn JN, Devlin HB. Lessons from the confidential enquiry into perioperative deaths in three NHS regions. Lancet 1987; 2(8572):1384–1386. 7. Kohn LT CJ, Donaldson MS, eds. To Err Is Human: Building a Safer Health System. Washington, DC: National Academy Press, 2000. 8. Aitkenhead AR. Injuries associated with anaesthesia. A global perspective. Br J Anaesth 2005;95:95–109. 9. Tiret L, Desmonts JM, Hatton F, Vourc’h G. Complications associated with anaesthesia—a prospective survey in France. Can Anaesth Soc J 1986;33:336–344. 10. Holland R. Anaesthetic mortality in New South Wales. Br J Anaesth 1987;59:834–841. 11. Pedersen T. Complications and death following anaesthesia. A prospective study with special reference to the influence of patient-, anaesthesia-, and surgery-related risk factors. Dan Med Bull 1994;41:319–331. 12. Tikkanen J, Hovi-Viander M. Death associated with anaesthesia and surgery in Finland in 1986 compared to 1975. Acta Anaesthesiol Scand 1995;39:262–267. 13. Chopra V, Bovill JG, Spierdijk J. Accidents, near accidents and complications during anaesthesia. A retrospective analysis of a 10-year period in a teaching hospital. Anaesthesia 1990;45:3–6. 14. McKenzie AG. Mortality associated with anaesthesia at Zimbabwean teaching hospitals. S Afr Med J 1996;86:338–342. 15. Lagasse RS. Anesthesia safety: model or myth? A review of the published literature and analysis of current original data. Anesthesiology 2002;97:1609–1617. 16. Kulling D, Rothenbuhler R, Inauen W. Safety of nonanesthetist sedation with propofol for outpatient colonoscopy and esophagogastroduodenoscopy. Endoscopy 2003;35:679–682.

17. Silber JH, Kennedy SK, Even-Shoshan O, et al. Anesthesiologist direction and patient outcomes. Anesthesiology 2000;93:152–163. 18. Silber JH, Kennedy SK, Even-Shoshan O, et al. Anesthesiologist board certification and patient outcomes. Anesthesiology 2002;96:1044–1052. 19. Breslow MJ, Rosenfeld BA, Doerfler M, et al. Effect of a multiple-site intensive care unit telemedicine program on clinical and economic outcomes: an alternative paradigm for intensivist staffing. Crit Care Med 2004;32:31–38. 20. Ibsen B. The anaesthetist’s viewpoint on the treatment of respiratory complications in poliomyelitis during the epidemic in Copenhagen, 1952. Proc R Soc Med 1954; 47:72–74. 21. Ewart GW, Marcus L, Gaba MM, Bradner RH, Medina JL, Chandler EB. The critical care medicine crisis: a call for federal action. A white paper from the critical care professional societies. Chest 2004;125:1518–1521. 22. Cheney FW, Posner K, Caplan RA, Ward RJ. Standard of care and anesthesia liability. JAMA 1989;261:1599–1603. 23. Webb RK, Currie M, Morgan CA, et al. The Australian Incident Monitoring Study: an analysis of 2000 incident reports. Anaesth Intensive Care 1993;21:520–528. 24. Lunn JN. The history and achievements of the National Confidential Enquiry into Perioperative Deaths. J Qual Clin Pract 1998;18:29–35. 25. Schwinn DA, Balser JR. Anesthesiology physician scientists in academic medicine: a wake-up call. Anesthesiology 2006;104: 170–178. 26. Smith A. Audit commission tackles anaesthetic services. BMJ 1998;316:3–4. 27. Deusch E, Weber T, Libal G, Christian L, Ofner C. Patient knowledge concerning anesthesia general practice and the responsibilities of the anesthetist. Anasthesiol Intensivmed Notfallmed Schmerzther 1996; 31:409–413. 28. Kindler CH, Harms C, Alber C. The patients’ perception of the anaesthetist in a Swiss university hospital. Anaesthesist 2002;51:890–896.

29. Chew ST, Tan T, Tan SS, Ip-Yam PC. A survey of patients’ knowledge of anaesthesia and perioperative care. Singapore Med J 1998;39:399–402. 30. Khan FA, Hassan S, Zaidi A. Patients view of the anaesthetist in a developing country. J Pak Med Assoc 1999;49:4–7. 31. McGaw CD, Hanna WJ. Knowledge and fears of anaesthesia and surgery. The Jamaican perspective. West Indian Med J 1998;47:64–67. 32. Tohmo H, Palve H, Illman H. The work, duties and prestige of Finnish anesthesiologists: patients’ view. Acta Anaesthesiol Scand 2003;47:664–666. 33. Larsson J, Holmstrom I, Rosenqvist U. Professional artist, good Samaritan, servant and co-ordinator: four ways of understanding the anaesthetist’s work. Acta Anaesthesiol Scand 2003;47:787– 793. 34. Rock P. The future of anesthesiology is perioperative medicine. Anesthesiol Clin North America 2000;18:495–513. 35. Lindahl SG. Future anesthesiologists will be as much outside as inside operating theaters. Acta Anaesthesiol Scand 2000;44: 906–909. 36. Greene NM. The 31st Rovenstine Lecture. The changing horizons in anesthesiology. Anesthesiology 1993;79:164–170. 37. Miller RD. The place of research and the role of academic anaesthetists in anaesthetic departments. Best Pract Res Clin Anaesthesiol 2002;16:353–370. 38. Menon DK, Wheeler DW, Wilkins IA, et al. Integrated approaches to academic anaesthesia—the Cambridge experience. Anaesthesia 2004;59:785–792. 39. Longnecker DE. Education in anesthesiology for the twenty-first century. J Anesth 2002;16:65–69. 40. Coursin DB, Maccioli GA, Murray MJ. Critical care and perioperative medicine. How goes the flow? Anesthesiol Clin North America 2000;18:527–538. 41. Warner MA. Who better than anesthesiologists? The 44th Rovenstine lecture. Anesthesiology 2006;104:1094–1101.

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CHAPTER 3 20

Safety and Quality: The Guiding Principles of Patient-Centered Care Jeffrey B. Cooper, PhD, and David Longnecker, MD, FRCA Anesthesia providers develop a comfort with their craft, despite its inherent dangers. Over time, the administration of potentially lethal drugs, the management of apnea, and the control of altered physiologic systems become almost routine. As experience grows, they may even take for granted the inherently hazardous art and science of rendering patients insensible to pain, unconscious, and paralyzed. Yet, patients do not take anesthesia for granted. To the contrary, many fear it. They fear the possibility of experiencing pain or awareness, as well as the potential for death or other serious complications.1,2 They also fear what professionals might consider “minor complications.” Anesthesia providers may view postoperative nausea and vomiting as minor side effects that pale when compared with the potential life-threatening complications that can occur during complex surgical and medical procedures, but patients often view postoperative nausea and vomiting as dreaded and prominent complications associated with the procedure. Although this chapter focuses on patient safety and quality, it is firmly based on the concept that the patient is the center of care. The person or team performing the procedure has requirements that must be accommodated in the anesthetic plan. But the patient’s concerns, fears, values, and expectations also must be addressed. Although that may seem obvious, historically, the design of healthcare systems, including anesthesia care, has been centered on the needs and convenience of the providers and the facility. The underlying concept was that quality of care alone was enough,

whereas quality of service (i.e., “patient centeredness”) was relatively insignificant in the process. That concept is changing, but it is not yet fully addressed in many approaches to teaching, education, and practice in anesthesia. Thus, to establish the foundation for talking about patient safety and quality, this chapter begins by emphasizing that patient perceptions must be considered in the design of a safe, high-quality anesthetic experience. The patient’s most fundamental needs are for high quality and complete safety. Meeting these expectations demands knowledge, skills, and continuous vigilance. Equally important is a system that ensures safe practitioners; provides the appropriate drugs, technologies, policies, and procedures to foster safe practice; monitors performance of the entire process (including both outcomes and patient satisfaction); identifies safety and quality problems; and implements corrections. All of these demand a culture of safety and quality at all levels of the system, a culture that supports these needs not just in word, but in deeds and actions. In 2001, an Institute of Medicine (IOM) committee identified patient safety, quality of care, and patientcentered care (i.e., individualized care) as progressively increasing levels of excellence in the overall healthcare process.3 This view is consistent with the tenants of other organizations that serve the public while dealing with potentially lethal outcomes (e.g., the commercial aviation industry). In

short, safety is the foundation upon which quality (e.g., the application of evidence-based approaches) and then patient-centeredness are built, but all are required to meet the goal of highest-quality care. The demands for quality and safety start with the patient’s needs guided by the needs of the physicians performing the procedure (medical, surgical, or diagnostic) that requires anesthesia care. Quality and safety goals must be met before, during, and after application of the anesthetic, including the various transport processes. Within this framework, constraints are introduced by the needs of all parties in the care process, including the expectations of other clinicians (e.g., surgeon or other operator, medical consultants), facilities (e.g., hospital or ambulatory care site), and the patient (or family or guardian, for example). Sometimes these are competing expectations, requiring thoughtful tradeoffs based on essential priorities. When balancing these tradeoffs, involvement of the patient is a key to positive patient satisfaction with the overall process. Every subsequent chapter in this text has the delivery of safe and highquality care as its primary objectives. This chapter defines a strategy and generic principles for achieving these objectives, centering on the patient while also meeting the other demands of modern perioperative care. Subsequent sections in this book provide specific elements of evidence-based anesthesia care that are required to meet these strategic objectives.

KEY POINTS 1. The patient should be the center focus of anesthesia care. 2. The goal of anesthesia care must be to ensure that no patient is harmed. 3. Preventing harm is challenging because care is complex, serious adverse events are relatively rare and almost always the result of many causes rather than a single one. 4. Serious adverse events are usually the result of weaknesses in the “system” of anesthesia care, not the fault of incompetent clinicians. 5. To prevent adverse events, a strategy is needed, not simply vigilance.


6. Organizations, departments, and groups must employ a top-down approach and a commitment to creating a safe environment and system for safety. 7. Safety must be the number 1 organizational priority to create an organization that operates at the highest level of reliability. 8. Anesthesia professionals must employ a broad array of safety tactics. 9. Teamwork and communication among the perioperative caregivers are critical components of patient safety.

CHAPTER 3: Safety and Quality: The Guiding Principles of Patient-Centered Care

DEFINING QUALITY AND SAFETY The key terms commonly used to discuss quality and patient safety are as follows: • Patient-centered care encompasses the qualities of compassion, empathy, open and complete communication, and responsiveness to the needs and preferences of each patient.3 • Quality of care is the extent to which health services for individuals and populations increase the likelihood of desired health outcomes and are consistent with current professional knowledge.4 • Patient safety is the avoidance, prevention, and amelioration of adverse outcomes or injuries stemming from the processes of healthcare. These events include “errors,” “deviations,” and “accidents.” Safety emerges from the interactions among the components of the system; it does not reside in a single person, device, or department. Improving safety depends on learning how safety emerges from the interactions of the components through analysis of “near misses” and adverse outcomes or injuries. Patient safety is a subset of healthcare quality.5 • Quality assurance is the formal and systematic monitoring and reviewing of medical care delivery and outcome; designing activities to improve healthcare and to overcome identified deficiencies in providers, facilities, or support systems; and the carrying out of followup steps or procedures to ensure that actions have been effective and no new problems have been introduced.6 • Adverse event is an injury that was caused by medical management that results in measurable disability.7 • Accident is an unplanned, unexpected, and undesired event, usually with an adverse consequence.8 • Error is when a planned sequence of mental or physical activities fails to achieve its intended outcome and these failures cannot be attributed to the intervention of some chance agency.9 • Human factors refers to the scientific discipline concerned with understanding interactions among humans and other elements of a sys-

tem, and to the profession that applies theory, principles, data, and methods to design so as to optimize human well-being and overall system performance.10 • Risk management is the clinical and administrative activities undertaken to identify, evaluate, and reduce the risk of injury to patients, staff, and visitors, and to identify, evaluate, and reduce the risk of loss to the organization itself.11 The concepts of quality and safety are a continuum. There is no uniform agreement on their differences in the larger healthcare community. Some view safety as a subset of quality; most agree that quality care must be founded on safe care. There is perhaps more of an argument for that in the larger world of healthcare and less in anesthesia. One important difference is that quality is generally measured in terms of success in achieving desired outcomes, whereas safety is measured in failures, particularly catastrophic failures. Success in achieving the desired outcomes includes not only a safe experience, but also one that incorporates the elements of evidence-based medicine, especially because personal provider experience is almost never adequate to evaluate either the overall positive or negative consequences of a specific drug, technique, or procedure. Because anesthesia is generally not therapeutic, complete safety must be the most important goal of every anesthetic. Simply stated, this means a goal that no patient is caused any injury or complication from the effects of the overall anesthesia encounter. This may seem unattainable. But, as described below, adopting such lofty goals and committing to achieve them leads to greater safety and better care. The concept of healthcare quality has broader implications than safety alone. In the context of anesthesia, quality can be thought of as a balance between providing the patient a healing experience with the least possible pain and discomfort, optimal conditions for surgery, smooth flow of patient care for the organization, and absolutely no injury or unwanted complication caused by the anesthetic. Because safety focuses on preventing rare events, it is much harder to develop an evidence base for actions that create safety. Randomized con-

trolled trials, while possible for testing many types of quality improvement measures, are almost unheard of for trials of safety measures. Many safety measures arise from investigation of serious adverse events. More intuitive arguments and judgments guide the implementation of safety principles. To the benefit of all, quality and safety have attained increasing importance in modern healthcare. There is a rich history of attention to quality assurance; that is, attention to the processes of improving care. Those activities can be traced to the work of Donebedian, who developed principles by which quality can be measured and improved for healthcare in general, but with specific applications to hospital care.12 It was only in the late 1990s that the concept of patient safety was raised to prominence in the broad healthcare environment, a result of a landmark study of medical error.13 Yet, in anesthesia, patient safety has a much richer history. Indeed, the specialty of anesthesiology is often identified as the earliest adopter of patient safety principles, and lauded for achieving dramatic improvements in outcomes (see Anesthesia Risk and Accidents below for the history of patient safety in anesthesia). The concepts of patient safety, quality assurance, and risk management are related but have important distinctions. Patient safety is focused on prevention of injury. Quality assurance generally deals with the broader spectrum of quality, including the success of treatments. Risk management historically was directed at managing the aftermath of adverse outcomes, especially to manage legal issues, malpractice, and avoidance of financial loss for insurers. But modern risk management is focused on proactive patient safety, based on the principle that prevention of injuries via error reduction and system improvements reduces the adverse events from which malpractice awards arise.

ANESTHESIA RISK AND ACCIDENTS The roots of safety run deep in anesthesiology. Dating to the first survey of anesthetic deaths,14,15 there has been a regular and continuous self-examination within the anesthesia profession

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22

to understand the causes of harm and how to prevent them. In the modern era of healthcare, anesthesia was the specialty that coined the term “patient safety,” which is now in the lexicon of healthcare and broadly applied to all medical disciplines.

History of Patient Safety in Anesthesia The history of safety in anesthesiology may have begun with the first description of an anesthetic death— that of Hannah Greener, who died during administration of chloroform for amputation of her large toe in 1848.16 This examination of cause illustrates the early focus of anesthesia providers on understanding mechanisms of adverse outcomes and their prevention. Although outcome studies were reported over the years, it was not until the landmark study of Beecher and Todd that a large population was sampled and specific causality suggested.17 Although that study drew the wrong conclusion from the data, ascribing inherent toxicity to curare, the stage was strongly set to document and enhance the safety of anesthesia care through frequent reviews of outcome and revisions in practice based on these reviews. Other studies followed during the 1950s and 1960s, with a focus generally on the morbidity and mortality associated with general or regional anesthesia, and the cause of death or serious injury in surgical patients.18,19 One of the earliest safety interventions of relatively modern times was the development of safety features of anesthesia equipment. Safety features incorporated into anesthesia machines in the 1950s and 1960s are still in use today, including the fail-safe system for protecting against loss of oxygen supply pressure and pin-indexing of gas cylinders to prevent their being interchanged. The concept of “patient” safety arose in the early 1980s, in response to several factors. The first study of the contribution of human error in anesthesia was reported in 1978, and was followed by later studies of a larger cohort and specific issues of how errors occur and strategies for their prevention.20,21 In these studies, Cooper et al. studied “critical incidents” gathered in interviews with anesthesiologists, residents and nurse anesthetists from four hospitals. The

findings elucidated the mechanisms of what were then called anesthesia “mishaps” as being multidimensional in that a number of errors and other factors contributed to each event. Other reports described attributes of a specific event, disconnection in the breathing circuit, and a generic contributor to critical events, the relief of one anesthesia provider by another. Several studies replicated the methods and general findings in other settings and countries.22,23 A “crisis” of increasing costs for malpractice insurance for many medical specialists, especially anesthesiologists, prompted intense interest in reducing settlements for claims through tort reform. More importantly, leadership among the anesthesia community took a then unique approach of concentrated efforts to reduce the number of adverse events that led to claims. The American Society of Anesthesiologists (ASA), under its then president, Ellison C. Pierce, Jr., MD, created a committee on Patient Safety and Risk Management, which likely was the first use of the term “patient safety.”24 In 1984, an International Symposium on Preventable Anesthesia Mortality and Morbidity was held in Boston, and the concept of a directed effort toward anesthesia patient safety was conceived. The Anesthesia Patient Safety Foundation (APSF) was formed in 1985. Its newsletter, research program, and other activities represented the first organized efforts in healthcare to address patient safety as a single topic. The ASA later sponsored studies of closed malpractice claims, which led to numerous reports about causes of the most severe adverse events and their trends.25 Many efforts contributed to what appears to be a substantial reduction in catastrophic adverse anesthesia outcomes among relatively healthy patients.26 Among these were improvements in educational programs, safer drugs and equipment, more intense patient monitoring (especially oxygen analyzers, pulse oximetry, and capnography), and new technologies for managing difficult airways (a specific contributor to numerous severe adverse outcomes). Standards and guidelines for anesthesia care also played a role in reducing adverse events. The Harvard Medical School Department of Anaesthesia promulgated the first standards for care in 1986;27 these were later adopted by the ASA as national stan-

BOX 3–1. Key Influences Leading to Increasing Patient Safety in Anesthesia Research in human error, human factors, and closed claims. Development and routine use of pulse oximetry. Development and routine use of capnometry. Enhanced alarms and safety features in anesthesia machines/workstations. Development of safer anesthetic drugs. Anesthesia Patient Safety Foundation focus on patient safety. ASA adoption of standards and guidelines for safe practice. Development of new airway-management tools such as fiberoptic bronchoscopy. Data from American Society of Anesthesiologists: Standards, Guidelines and Procedures. http://www.asahq.org/publications AndServices/sgstoc.htm. Accessed May 23, 2006.

dards. It is claimed that these standards are associated with a reduction in serious outcomes among ASA physical status (ASA-PS) 1 and 2 patients in the ensuing years.30 Many other standards and guidelines followed. Box 3–1 summarizes key milestones in the path to safer anesthesia care. A national movement in patient safety was catalyzed by the 1999 publication of the IOM report To Err is Human: Building a Safer Healthcare System.13 This landmark study identified failures in the healthcare system to be an important public health issue and the eighth leading cause of death in the United States. It and subsequent reports recommended fundamental changes in the healthcare system to combat a problem with deep roots in the way patient care is organized (or disorganized), particularly the culture of healthcare that did not place a high priority on the overall safety of patients relative to the delivery of specific services. A federal agency was later assigned to direct U.S. government initiatives to improve safety. Patient safety became a higher priority in the mission of numerous health-related organizations, and the sole mission of others. Anesthesiology was singled out in the IOM’s report, and in other writings, as the one specialty that addressed patient safety early and with positive results.


Current State of Knowledge of Anesthesia Risk and Relationship to Error There is a general belief that the risk of preventable death or injury from anesthesia is relatively low compared to many other medical and nonmedical risks. Yet, there are no accurate estimates of the rate of adverse outcomes in general or for an individual patient presenting with specific risk factors. One reason is that there are no standard methods for assigning causality appropriately among numerous factors that include anesthesia, surgery, the facility (and its systems), and the patient’s disease. Particularly in the United States, the fear of malpractice claims hinders reporting and open, candid discussion of errors. Federal legislation, similar to that enacted in Australia in the late 1980s, now protects voluntary reporting, although the process for doing that has not been implemented as of this writing.28 Despite the absence of strong evidence, estimates of the risk of untoward outcome to a relatively healthy patient are believed to be on the order of 1:100,000 patients.29,30 However, for patients presenting at greater risk, the risk may be on the order of 1:10,000, which is not different from early estimates for all patients.29,31 Thus, there remains substantial room for improvement in overall safety of anesthesia. Chapter 24 has a comprehensive discussion of risk, mortality, and morbidity.

ACCIDENT MODELS Most people, both in and out of healthcare, seek to assign blame to specific individuals for specific lapses in performance associated with an adverse event. Yet, the evidence demonstrates that most injurious accidents are typically complex events for which there is no single cause.32–34 Although it would be possible to envision a scenario wherein a specific act by one individual led to an accident, assigning such pinpoint causality is not a useful approach to accident prevention. Substantial research is targeted at learning how accidents occur and how humans are involved in that process. The science emerging from that research supports the concept that there are few simple solutions for

prevention of accidents. However, it offers possible strategies and tactics for lowering the potential for accidents, by preventing human error and its precursors (i.e., the factors that promote and propagate errors), and by creating resilience in systems to respond to those errors that will inevitably occur despite the best of intentions and preventive actions. When moving toward a goal of zero failures in patient care, we must consider models for both organizational and individual failure. The goal of adverse event-free anesthesia care can be achieved only by applying a broad spectrum of prevention strategies and building resilience throughout the entire system of anesthesia care, for the overall system is no stronger than its weakest links. This section examines several models and issues at the organizational and human levels to inform our thinking about designing for failure.

The “System” of Anesthesia Care Before examining models for failure, we need a model for anesthesia practice. Whereas anesthesia could be viewed simply as a single provider administering drugs to a single patient, that narrow perspective does not represent the much more intricate and multidimensional processes that characterize care delivery. Rather, the anesthesia encounter consists of several components that comprise the “system of anesthesia care.” The anesthesia processes can be thought of broadly in three phases: preanesthetic planning and preparation, provision of anesthesia for the procedure, and postanesthesia care. Within each of these phases, the anesthesia provider (or providers) performs a set of tasks that are intended to provide quality care for the patient, surgeon, or other operator, and the healthcare organization. Achieving patient care quality and safety requires that these anesthesia activities not be independent from the needs of other providers, allied health professionals, technical staff, support staff, hospital or organization programs, and, especially, not independent of the patient’s needs and expectations. The interactions between all of these components comprise a “system” of care that has yet to be fully modeled for the perioperative experience. Furthermore, this “anes-

thesia system” takes place within a system of systems that comprise the overall course of care, and numerous elements of this larger system may interact with anesthesia care at multiple points in the delivery process; such interactions often contribute to a less-than-optimal experience for the patient. The Accreditation Council for Graduate Medical Education (ACGME) has established a set of 8 competencies that must be met for all medical trainees.35 One competency is to understand and know how to practice within a system of healthcare. That requirement arose in recognition of the interdependencies among all the members of the care team and the larger system in which they all operate. In the case of anesthesia, that implies having an understanding of the requirements and needs of all other participants in the perioperative system and implementing an anesthesia plan that appropriately meets these various needs, rather than acting individually in an introverted fashion.

Models of Organizational Failure Several models offer generic explanations of how accidents occur. James T. Reason is perhaps the most widely cited author for overall conceptual thinking about the mechanisms of human error and system failures, although his work is founded on the basic work of Rasmussen. Their thinking derives from research in highhazard industries, such as nuclear power, aviation, and chemical manufacture. Gaba has offered insightful interpretations of this work and other research as it applies specifically to anesthesia practice.34 The basic concepts are relatively simple: Accidents are not one-dimensional; rather, they are the result of the interaction of several elements. There are generic, individual elements that influence the evolution of accidents, but each accident is somewhat unique in the way that elements combine to result in injury. (Note that in the context of “safety,” we are addressing only those adverse outcomes that could be prevented given the application of current knowledge; death or injury that appears to be caused primarily by the patient’s disease process or the unpredictable influences of drugs or operation, likely cannot be altered by safety

23


Triggering events and precursors

Cost cutting

Fear of litigation

Production pressure Poor communication

24 Excessive regulation

Device failure Conflict Distraction

Government Organization (latent failures) Team Poor design Technology

Accident!

Complexity Anesthesia provider

Unsafe acts Fatigue

FIGURE 3–1. “Swiss cheese” model of accidents in anesthesia. Reason J. Managing the Risk of Organizational Accidents. Aldershot, Hants, UK: Ashgate Publishing; 1997.

interventions.) Reason depicted the process of accident evolution in what is widely referred to as the “Swiss cheese” model (Fig. 3–1).9 The “Swiss cheese” model illustrates that accidents are typically the result of a series of events that include precursors, which trigger or allow the chain of events that result in the final (active) adverse event. Reason termed these precursors latent errors. This concept is now widely accepted in understanding healthcare system failures. Latent factors are situations that exist on a regular basis within any work environment. They have the potential for influencing the initiation or propagation of an evolving accident. Examples are failure to maintain equipment or replace obsolete equipment; selection of low-quality supply items; poor scheduling practices that promote haste or fatigue; and case scheduling and staffing models that allow assignment of relatively inexperienced clinicians to unfamiliar cases or high-risk patients. Cultural influences are an important source of latent failures. Examples include the pressure to proceed with cases in remote locations where the resources are insufficient to meet minimal anesthesia safety requirements; pressures to move rapidly to avoid “turnover delays;” pressures to assign an experienced provider to a case in order to “keep the schedule moving;” a hostile

atmosphere within an operating room that limits preemptive communication of care concerns; and failure to heed a patient’s warnings or concerns. Latent errors rarely lead to an immediate accident. Rather, they can be seen as a lurking enemy, or, as Reason called them, “resident pathogens,” awaiting the circumstances that will combine to produce a catastrophic outcome, often in ways that are unusual and what may be called “unpredictable.” Avoiding the consequences of latent errors requires a broad set of defenses and resilience throughout the system, to mitigate evolving failure that results from alignment of the “holes in the cheese.” Reason’s model highlights the need for broad and varying mechanisms to trap errors and failures during the patient’s healthcare encounter and thus mitigate or prevent the full cascade from unfolding. His work on managing risk begins at the organizational level and offers a spectrum of strategies and tactics for accident prevention. Both the attitude and actions of the organization and each individual in the chain of care can either bolster or undermine those defense mechanisms. There is a competing theory that postulates that prevention is not always possible or even probable. The normal accident theory (NAT), as described by Perrow,32 characterizes

some industrial systems as being particularly resistant to strategies for prevention of catastrophic accidents if the systems are both complex and “tightly coupled”; that is, the connections between processes are such that one quickly affects the other in ways that can evolve into an accident that is not predictable by deterministic analysis. NAT does not offer much hope for prevention of accidents in many highrisk industries. Fortunately, although human physiology and all of the processes involved in anesthesia administration may together create a “complex” system, there is not usually the extent of “tight coupling” that is necessary in Perrow’s model, although it may occur in certain high-risk patients whose disease processes present a less-stable condition. Still, the NAT view of accidents and how they evolve provides many lessons for anesthesia practice, and for constructing resilient systems to minimize the potential for accidents. Of special concern is that some protections and safety features can actually make systems more complex, mask impending problems, and impart a false sense of security. This concept is an example of how certain prevention or mitigation strategies may affect other parts of the system in unanticipated ways and thus lead to new, unexpected risks. Anesthesia has many examples: Pulse oximetry can lead to practicing closer to the edge of acceptable levels of oxygenation or inappropriate assumptions that a functioning pulse oximeter implies adequate blood flow as well; automated noninvasive blood pressure monitors can fail to cycle and thus continue to present falsely high readings even in the presence of blood loss; or alarms on anesthesia monitors may be turned off to avoid “distraction” during the procedure. Moreover, the relative safety of anesthesia itself has been called an “insidious hazard,” for some become complacent about anesthesia care and vigilance and assume that nothing will go wrong, based on prior experience.21 The development of complacency about safety, based on prior experiences, has led to major disasters in a variety of organizations; a prime example is the loss of the orbiter (“shuttle”) Columbia on February 1, 2003. The Columbia Accident Investigation Board identified a number of contributing latent factors that resulted in complacency within the


National Aeronautics and Space Administration (NASA), including the acceptance of “normal deviation” and the loss of checks and balances that should have guided NASA safety efforts; many of these latent factors resulted from the lack of serious events in the years immediately preceding the loss of Columbia.36 Reason’s commentary about creating effective defenses against accidents fits well for anesthesia: If eternal vigilance is the price of liberty, then chronic unease is the price of safety. Studies of high-reliability organizations—systems that have fewer than their share of accidents—indicate that the people who operate and manage them tend to assume that each day will be a bad day and act accordingly. But this is not an easy state to sustain, particularly when the thing about which one is uneasy has either not happened or has happened a long time ago, and perhaps in another organization. Nor is this Cassandra-like attitude likely to be well received within certain organizational cultures….33

Models of Human Error/Failure The modern theory of accident causality and safety views the human as a component of a system. Most experts now tend to play down the operator’s responsibility for accidents, perhaps because so often the attention and blame has been so heavily directed at those who are at what Woods and Cook term the “sharp end” of the pyramid of accident control.37 In fact, there is substantial evidence about human error and how humans interact with systems in diverse ways to either help or hinder the accident process. This is a topic of serious study that applies to all of society, and numerous textbooks of general and specific areas are available.9,38 Whereas the vast majority of research has been in industry, most notably aviation and nuclear power applications, there has been substantial study in anesthesia specifically, where the earliest studies and discussions of human error and human factors in healthcare are found. The studies of critical incidents mentioned earlier identified the basic issue of human error as a component of what were termed “mishaps.” Factors associated with mishaps, what would now be called latent factors, were identified,

such as lapses in training, equipment design weaknesses, and the contribution of fatigue. In these and other areas, the science of human performance and human factors has revealed much more about the weaknesses of humans and the many ways in which we can fail, including how system design and other factors can influence our performance and conspire to weaken even the most expert clinician. There has been a strong reliance on “vigilance” during anesthesia as the primary approach to error prevention, so much that the word is the motto of the ASA. Vigilance means sustaining attention.39 It has been defined as having 3 components: alertness, selection of information, and conscious effort. It is a much more complex process than is immediately apparent, and vigilance is the subject of much investigation in many fields that require sustained attention to assure safety and performance. The observant practitioner is aware of some of the many ways that vigilance can be thwarted and performance degraded. Furthermore, vigilance is only one task of a complex set of tasks that compromise safe anesthesia practice. Human error in general is the subject of intense investigation in the fields of human factors, ergonomics, and industrial psychology. Again, we look to James Reason for a overview of the subject.9 Reason built on the work of Rasmussen in defining and characterizing human performance and error. Performance is defined in 3 levels: skill based, rule based, and knowledge based. Error is defined as the failure of planned actions to achieve their desired ends without the intervention of some unforeseeable event. Errors are divided into 2 main types: slips and mistakes (Box 3–2). These definitions do not of themselves help prevent errors, but the thoughtful practitioner will consider that his or her slips and mistakes vary in type and cause, most of all recognizing that all forms of error require efforts toward prevention and mitigation of the consequences of those errors that occur despite the best of efforts. Many factors influence vigilance and performance (performance-shaping factors), including fatigue and sleep deprivation, environmental influences, production pressures, human-interface design, and teamwork. Other factors associated with adverse events in

BOX 3–2. Slips and Mistakes Slip: The plan is adequate but the actions fail to go as planned. These are unintended failures of execution, also referred to as lapses, trips, or fumbles. They are further divided into attentional slips of action and lapses of memory. Mistake: The actions conform to plan but the plan is inadequate to achieve its intended outcome. Mistakes are divided into rule based (e.g., misapplication of normally good rules but not correct for this situation) and knowledge based (e.g., incorrectly thinking out a solution for which there is not a prepackaged solution). anesthesia that either may promote errors or foster their propagation have been identified.20,21 We consider some as examples of the kinds of issues that anesthesia providers must address to maintain accident-free performance throughout a professional career. Measures to prevent performance decrement or to help maintain optimal performance are described in Creating Safety at the Organizational and Department Level below.

Fatigue and Sleep Deprivation There is recent evidence (in trainees) that shows a clear association between sleep deprivation and human errors, including lack of attention to task, serious auto accidents, and medical errors involving both diagnosis and treatment.40–42 There are many examples of large-scale industrial accidents where sleep deprivation or fatigue was identified as a major contributing factor. Howard et al. reviewed the literature on sleep and fatigue with particular reference to anesthesia.43 Among the key findings were the following: (a) Inadequate sleep degrades performance; (b) Individuals require different amounts of sleep to feel awake and alert; (c) The failure to obtain adequate sleep results in a sleep “debt” that is cumulative and can only be diminished by sleep to pay back the debt; (d) Circadian rhythms have an important influence both on the tendency to sleep and the ability to sleep. The circadian lull associated with degraded performance is between 2 and 6 A.M. and 2 and 6 P.M.; and (e) Stimu-

25


lants such as caffeine can aid in maintaining alertness and wakefulness, but side effects must be understood in order to use these effectively.44 26

Transitions Among Care Providers (“Handoffs”) There are conflicting findings about the impact of handoffs among anesthesia providers to mitigate the effects of fatigue, boredom, hunger, and so forth. Cooper et al. examined critical incidents associated with relief of one anesthesia provider by another.45 They concluded that, overall, relief provided more benefit from detecting undiscovered problems than harm from transferring responsibility to a provider with less serial knowledge of the specific patient and procedure. These conclusions were verified by interpretation of data from a similar study by Short et al.46 More recently, Arbous et al. found that a change of anesthesiologists was associated with a greater incidence of severe morbidity and mortality.47 Yet, routine breaks are generally found to be useful and necessary in anesthesia and in high-hazard industries. Provisions for adequate transfer of critical information and situational awareness are required. Cooper suggested a specific set of guidelines for conduct of handoffs, which was recently updated.48,49 The hazards of transitions in care are now more widely recognized in healthcare and receiving increasing attention for remediation. More handoffs now occur among trainees as a result of the recent ACGME work-limitation requirements that are intended to mitigate the consequences of sleep deprivation and fatigue.

Environmental Factors Many environmental factors can affect the performance of the anesthesia provider. Among these are noise, extremes of temperature and humidity, lighting, and toxic vapors.39 Listening to music or reading during anesthesia administration are controversial issues with conflicting tradeoffs.50,51 There are no robust studies in healthcare, nor simple extrapolations from studies in other fields, to guide the development of evidence-based standards. Rather, good judgment appears to be the best guideline. Background music can alleviate stress and boredom, but different musical tastes may lead to different effects among all on the operating team. Loud music or other noises can obscure verbal communications

and be especially disruptive during periods of high workload or management of critical events. Similarly, reading in the operating room could alleviate boredom during uneventful intervals, but it could also foster a lack of vigilance and alertness. Reading appears especially problematic intuitively, and would be difficult to justify during an accident investigation involving pilots, air traffic controllers, or anesthesia providers, among others.

Human Factors and Human Interface Design Human factors engineering (HFE) is a broad topic that encompasses all of the different aspects of the ways in which humans interact with systems.38 The importance of human factors, especially the design of the human– machine interface, is well known in other fields, but greatly underappreciated in healthcare.10 Human error can be either encouraged or discouraged, depending on the attention given to understanding human limitations and the ways in which humans interact with the machines and technologies. The goal of HFE is to “design tools, machines, and systems that take into account human capabilities, limitations, and characteristics.”52 Given that anesthesia is very technologyintensive, human factors issues play an important role in prevention of errors and adverse outcomes. Several studies have examined the anesthesia work environment, the tasks of anesthesia providers, and how the design of displays and alarms impact on ease of use and errors.39,53,54 The results indicate that technology is not generally well designed to accommodate the ways people use it. There are numerous examples of how the design of a device interface can be especially dangerous.55–57 The design of anesthesia monitors is particularly problematic, especially when the anesthesia provider works in facilities that have various models or different suppliers of devices. Software complexity, for example, the depth of menus, excessive flexibility in options for alarms, and displays, can cause confusion and distract the provider from other important tasks that should be higher priority.

Production Pressure Production pressure refers to “overt or covert pressures and incentives on personnel to place production, not safety, as their primary priority.”58

Based on a survey of anesthesiologists in California, Gaba et al. reported that nearly half of the respondents had witnessed instances of what they believed to be unsafe actions by an anesthesiologist because of production pressure.58 These included internal pressures (e.g., to foster good relations with a surgeon, accrue personal income) and external pressures (e.g., proceed rather than cancel a case to appease patient or family, accept an unfamiliar patient or procedure to foster facility throughput).

Teamwork The importance of good teamwork and communication is now more widely recognized in healthcare, especially for surgical teams. A substantial body of literature from high-hazard domains, especially aviation, and in healthcare, demonstrates the value of teamwork for successfully preventing and managing critical situations.59–61 Gaba et al. were the first to develop teamwork and crisis management training techniques for healthcare, adapting crew resource management (CRM) techniques from aviation for applications in anesthesia.62 These approaches have since been extended to nearly all healthcare settings but are particularly applicable to those where rapid action is required to successfully treat acute complex events, such as dire surgical emergencies.63 A team can be defined as “two or more individuals who have specific roles, perform interdependent tasks, are adaptable, and share a common goal.”59 Box 3–3 lists some characteristics of effective teams.59,64,65 These definitions and characteristics, derived from other industries, generally apply to healthcare and to anesthesia practice. Anesthesia providers have a varying dependency on others, depending on the setting and circumstances. Good teamwork can prevent errors or prevent them from propagating. Teamwork is vital to the successful management of critical events. The team within which anesthesia providers work varies depending on the setting, but it typically has a surgeon, a circulating nurse, a surgical technician, and other support personnel, including environmental workers, technicians (e.g., blood bank, laboratory, or radiology), and clerical personnel. Within the broad system of care, the team can include those who provide care preand postoperatively and specialists,


BOX 3–3. Some Effective Practices of HighPerformance Teams Introduce all members of the team to each other at the start of each procedure. Regularly conduct preoperative briefings with the entire operative team, which can be done via a specific checklist as described by Lingard.64 Use specific communication protocols within the team (SBAR is gaining increasing acceptance. It calls for a specific sequence for describing the patient’s status: describe the Situation, the Background, Assessment, and Recommendations [SBAR]).65 Establish communication standards such as “read-back” of all verbal orders, e.g., medications. Conduct debriefings with the team following unusual occurrences, near misses, or critical events. Establish an environment that encourages cross-monitoring and backup behaviors across the entire team. Create a language that signifies recognition of potential hazards. Practice for emergency situations (Box 3–4).

such as radiologists, pathologists, and intensivists. The immediate operative team has been given the most attention for training and research. Surgical teams have several distinguishing features that create obstacles to effective performance. The hierarchy in surgical care places physicians above other workers. It is common for surgeons to be accorded higher status and to assume a self-designated role of “captain of the ship.” Whereas leadership is a key feature for team success, the person in that role should vary depending on the situation. Similarly, anesthesia providers may treat other team members as subordinates rather than colleagues. High-reliability organization (HRO; see The Elements of Safe, High-Quality Anesthesia Care/ The High-Reliability Organization Model) theory, which is based on characteristics of organizations that function at high levels of safety, calls for a nonhierarchal culture in which the leader is the one with the most expertise, not the

highest status. Conflict among these roles can be problematic in management of acute operative events, especially when the care team does not work together regularly (e.g., during nights and weekends when the care team consists of “night call” personnel from various work rosters). CRM techniques have been applied for training teamwork skills and performance. There are now many different approaches to such training but the principles are generally the same. Teamwork needs should be assessed for the specific environment; all team members must be motivated and engaged in accepting the need for teamwork and agree about skills and behaviors they will adopt; those behaviors must be taught and practiced via drills; and the behaviors assessed and periodically reinforced via more drills and didactic sessions.59 In anesthesia, simulation of the patient and environment in which anesthesia is administered has been employed, both for motivation and for training of technical and nontechnical teamwork skills.66,67 The level of realism (fidelity) employed varies depending on the training objectives and philosophy.68 One of several models of computer-controlled mannequin is used to simulate the patient, whose physiology, anatomy and life signs can be varied to simulate normal or abnormal situations.66,69 In high-fidelity simulation, props and actors are employed to create realism, which is believed to strengthen the engagement of the learners. The early applications were for the anesthesia “crew” of the larger surgical team. More recently, simulations have involved training for entire operative teams. CRM concepts are the basis for training in behavioral skills. Prominent among these is the concept that all team members are expected to communicate openly, ranging from confirming a directive (e.g., “heparin, xx units, has been administered,” “I’m confirming that these are Mrs. Jones’ radiographs”), to speaking out when a concern for safety exists (e.g., “Are you sure you should be prepping the right hand? The consent says left.” or “Have you noticed that this patient’s blood pressure has been falling over the past several minutes?”). Training sessions use patient-care scenarios to elicit treatment responses from the individuals or teams being trained. Debriefing using videotapes of the session are

conducted to review actions. There is some evidence that such sessions can effectively instill good team behaviors.70 Team training without simulation also is effective, as is the combination of both approaches.61,71

SOME SPECIFIC HAZARDS ASSOCIATED WITH ANESTHESIA There are a seemingly infinite number of case reports of specific hazards and complications of anesthesia that were largely preventable, although a litany of isolated cases is perhaps less helpful than a series of organized observations. Studies of closed malpractice claims, funded by the ASA, have examined many of these events in a more systematic manner, one that assists in developing action plans for reducing risks. These closed claims studies have explored several categories of adverse outcomes, the most notable addressing errors related to airway management, monitoring, sudden cardiac arrest during spinal anesthesia, equipment failures, or nerve injuries.25,72,73 The Australian Incident Monitoring project analyzed 4000 critical events and developed an algorithm (COVER ABCD: A Swift Check) that accounts for the majority of common anesthetic emergencies (Box 3–4)74. Use of the mnemonic will prevent injury in the majority of cases if specific practices are followed. A detailed review of even a substantial subset of these concepts is beyond the scope of this chapter. Rather, we present here examples of the types of failures that establish an argument for having organized principles for general prevention of errors. Analysis of these types of events also suggests tactics that could reduce the likelihood that these would become a trigger or propagator of an accident chain.

Adverse Respiratory Events Events associated with management of respiration are the most serious remaining hazards in anesthesia, as evidenced by data from the ASA closed claims analyses.73 The three most common causes of death and brain damage are inadequate ventilation, esophageal intubation, and difficult tracheal intubation. The large majority of cases in the first 2 causes were judged to have been preventable

27


BOX 3–4. Crisis Management Algorithm—Memorize and Practice: An Explanation of Each Cue in the Mnemonic COVER ABCD74 C1

Circulation

C2

Color

O1 O2

Oxygen Oxygen analyzer

V1

Ventilation

V2

Vaporizer

E1

Endotracheal tube

E2

Elimination

R1

Review monitors

R2

Review equipment

A

Airway

B

Breathing

C

Circulation

D

Drugs

28

Establish adequacy of peripheral circulation (rate, rhythm, and character of pulse). If pulseless, institute cardiopulmonary resuscitation (CPR). The core algorithm must still be completed as soon as possible. Note saturation. Examine for evidence of central cyanosis. Pulse oximetry is superior to clinical detection and is recommended. Test probe on own finger, if necessary, while proceeding with O1 and O2. Check rotameter settings, ensure inspired mixture is not hypoxic. Adjust inspired oxygen concentration to 100% and note that only the oxygen flowmeter is operating. Check that the oxygen analyzer shows a rising oxygen concentration distal to the common gas outlet. Ventilate the lungs by hand to assess breathing circuit integrity, airway patency, chest compliance, and air entry by “feel,” careful observation, and auscultation. Also inspect capnography trace. Note settings and levels of agents. Check all vaporizer filler ports, seatings, and connections for liquid or gas leaks during pressurization of the system. Consider the possibility of the wrong agent being in the vaporizer. Systematically check the endotracheal tube (if in use). Ensure that it is patent with no leaks or kinks or obstructions (see suggested protocol in Anaesth Intensive Care 1993;21:615). Check capnograph for tracheal placement and oximeter for possible endobronchial position. If necessary, adjust, deflate cuff, pass a catheter, or remove and replace. Eliminate the anesthetic machine and ventilate with self-inflating (e.g., Ambu®) bag with 100% oxygen (from alternative source if necessary). Retain gas monitor sampling port, but be aware of possible problems. Review all monitors in use (preferably oxygen analyzer, capnograph, oximeter, blood pressure, electrocardiograph, temperature and neuromuscular junction monitor). For proper use, the algorithm requires all monitors to have been correctly sited, checked, and calibrated. Review all other equipment in contact with or relevant to the patient (e.g., diathermy, humidifiers, heating blankets, endoscopes, probes, prostheses, retractors, and other appliances). Check patency of the nonintubated airway. Consider laryngospasm or presence of foreign body, blood, gastric contents, or nasopharyngeal or bronchial secretions. Assess pattern, adequacy, and distribution of ventilation. Consider, examine, and auscultate for bronchospasm, pulmonary edema, lobar collapse, and pneumo- or hemothorax. Repeat evaluation of peripheral perfusion, pulse, blood pressure, electrocardiograph, and filling pressures (where possible) and any possible obstruction to venous return, raised intrathoracic pressure (e.g., inadvertent peak end-expiratory pressure) or direct interference to (e.g., stimulation by central line) or tamponade of the heart. Note any trends on records. Review intended (and consider possible unintended) drug or substance administration. Consider whether the problem may be a consequence of an unexpected effect, a failure of administration, or wrong dose, route, or manner of administration of an intended or “wrong drug.” Review all possible routes of drug administration.

Runciman WB, Kluger MT, Morris RW, et al. Crisis management during anaesthesia: the development of an anaesthetic crisis management manual. Qual Saf Health Care 2005;14(3):e1. With permission from the BMI Publishing Group.

if “better monitoring” had been employed. For management of the difficult airway, prevention is more challenging. Peterson et al. reported that “Persistent failed attempts at intubation were associated with an outcome of death or brain damage in claims in which a ‘cannot ventilate and cannot intubate’ emergency situation developed prior to surgical incision.” 75 They concluded that this was confirming evidence for limiting conventional ventilation efforts to 3 attempts before using other strategies. Despite substantial advances in technologies that aid endotracheal intubation and some

helpful, although far from foolproof, methods of airway assessment, there remain many opportunities for unanticipated difficulties with airway management, tracheal intubation, and effective ventilation (see Chaps. 12 and 35). Each is an opportunity for a serious adverse outcome. Although airway management skills are greatly emphasized during training, there is great variance in experience and abilities among anesthesia providers, as are the opportunities to practice emergency skills. Thus, periodic retraining and practice in the application of difficult airway management protocols is pru-

dent. (This is an example of the value of simulation as a tool for learning and maintaining skills that may be needed infrequently, but which are essential for patient safety.)

Monitoring and Alarms Failure to monitor the patient adequately is an important contributor to anesthesia adverse events, both in critical incident studies and in the closed claims studies. Aside from failures of vigilance, which are often related to performance-shaping factors, monitoring technology design and lack of experience with technology can contribute


to adverse outcomes. There are numerous ways in which pulse oximetry, capnometry, and automated noninvasive blood pressure monitors can give false information, leading to missed or incorrect diagnoses. The failure to use alarms has led to a requirement in the relevant standard that when a pulse oximeter is used, the variable pulse pitch tone and low-threshold alarm of the oximeter must always be audible.76 Similarly, when capnography or capnometry is used, the end-tidal CO2 alarm must be audible.

Medication Errors Medication errors are among the most frequent errors in anesthesia, and in healthcare practice in general.21 Similarity of drug names, containers, and label colors contribute to the ease by which such errors can be made, especially during periods of high stress. Dosing errors are also common and related to the frequent need for individual numerical calculations when drawing and mixing drugs for bolus administration or intravenous infusion. Choosing the wrong form of drug (e.g., among various insulin formulations), flushing a catheter with a solution containing another potent drug, and confusion in the programming of infusion pumps are other examples of ways in which patients can be injured. An obvious recommendation for prevention of some medication errors is to admonish the provider to read the label carefully.77 Another tactic is to read each label 3 times. Yet, human factors issues are widely recognized as contributing greatly to medication errors, especially because of similarity of drug names, the small or obscure print on vials or ampules, and the failure to organize medication carts optimally to avoid errors. Distractions and production pressure also are likely contributors to medication errors. No universal remedy for prevention has been identified. There is a standard for label colors and grouping by drug type, but some argue that it is unlikely to be effective and, if anything, all drug labels should be in black and white to force careful reading of the drug identity and concentration.78

ing the management of critical events. Gaba has described 3 forms of fixation errors, including “this and only this” (fixating on a single diagnostic possibility to the exclusion of others, a form of “tunnel vision”), “everything but this” (searching among many possibilities but not including the real explanation) and “everything’s OK” (persistent belief that there is no problem in spite of substantive signs that there is a problem).62

Equipment Errors and Failures Current anesthesia machines and associated technology incorporate substantial safety features (see Chap. 38), which have been developed over decades in response to specific series of patient injuries associated with failure or misuse of equipment. Equipment failure is frequent and can occur in many ways, but rarely causes injury directly.21,79,80 When there is an equipment-associated injury, it is more likely to be from misuse than from overt failure of a device. Whereas the end user may be at fault, human factors research dictates that causes related to the design of technology and the lack of training and practice are equally, if not more, responsible. Among the legendary failures associated with poor human factors are the failure to turn on a ventilator that was briefly suspended during measurement of cardiac output or performance of radiologic studies, or the accidental, unnoticed disconnection of an intravenous or arterial pressure cannula leading to blood loss or failure of fluid or drug administration. Users can reduce hazards by ensuring they obtain adequate training before using a new device, conducting a systematic preuse inspection of devices, and using backup monitoring devices as aids to vigilance. Never turning off an alarm is an essential precept to safe care.

Errors Associated with a Lack of Standard Practice and Unusual Situations

Errors in Diagnosis

The complexities of anesthesia create many opportunities for preventable adverse events caused by unusual circumstances or pitfalls. GoldhaberFeibert and Cooper, taking from a convenient sample of clinician experiences, offers numerous examples)49:

Diagnostic errors are likely underreported because of the difficulty in their identification. Yet it is likely that diagnostic errors occur, especially dur-

• A Passy-Muir valve (PMV), a form of “talking” tracheotomy tube, left on a tracheostomy when inflating the

cuff to deliver positive-pressure ventilation causes repeated inflation of the patient’s lungs with no mechanism for exhalation. • An emergency can arise during transport of the intubated patient if the tracheal tube is accidentally dislodged. • Administration of undiluted phenytoin (Dilantin) by rapid intravenous infusion can cause refractory hypotension, arrhythmias, and death. • Administration of undiluted potassium by rapid intravenous infusion can cause ventricular fibrillation and cardiac arrest. • Neostigmine given without an antimuscarinic drug (e.g., glycopyrrolate) can cause asystole/severe bradycardia and atrioventricular (AV) block, and can be fatal. • Inadvertent intravascular injection of local anesthetics during a nerve block can cause neurologic and cardiac toxicity, which can be fatal (especially with bupivacaine). • Air embolism can occur during the placement or removal of central venous catheters. • Limb necrosis can develop if the tourniquet used for intravenous placement or blood draw is left on the anesthetized patient for a prolonged period. • Intracranial pressure (ICP) may be increased if a ventriculostomy drain is connected to a pressurized bag of heparinized saline (in a patient who likely already has a high ICP). Even though these situations are likely obvious to experienced clinicians, they might occur under periods of stress and might not be obvious to the uninformed neophyte. Learning may arise haphazardly in the absence of a systematic approach to training.

THE DIMENSIONS OF QUALITY Despite the widespread use of the term by both the public and the professions, quality in healthcare continues to have multiple meanings, depending especially on the views of the beholder. However, few would deny that the concept of quality care has gained increasing importance over the past 2 decades, as both health professionals and the public have focused greater

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process of meeting the rational expectations of others who interact with the providers of healthcare services. Two major concepts are inherent in the IOM definition of quality: measurement (i.e., “outcomes”) and evidencebased care (i.e., “current professional knowledge”). Inherent in the definition of quality is the view that safety is the essential foundation for quality, and that high quality practice cannot be achieved in the absence of safe practice. Figure 3–2 illustrates these concepts. Donabedian, a leader in the genesis of the quality movement, proposed that quality could be evaluated by examining its major components: structure, process, and outcomes.12 Structure involves the facilities and environment in which care is delivered (e.g., governance, policies and procedures, and specific details, such as cleanliness, attractiveness, ease of access, noise levels, privacy); process involves how care is actually delivered, including the interactions between clinicians and patients (e.g., the elements of communication including listening, sensitivity, compassion, the development of trust); outcomes involves measures of results of the care provided (e.g., mortality, morbidity, speed of recovery). Inherent in these evaluations of quality are the patients’ perspectives on each of these areas, whereas historically, both clinicians and facilities focused primarily on the

Customization (Meeting patientspecific needs)

Increasing quality

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attention on this aspect of healthcare delivery. A discussion of all aspects of quality goes beyond the bounds of this chapter, but focus on some of the key concepts is appropriate if anesthesia providers are to become full participants in the quality movement, a prominent force in the early 21st century. Our comments are limited to some of the essential features of quality and its application to anesthesia practice. What is quality as applied to healthcare? “Quality” is an abstract concept, with little intrinsic meaning. Rather, it represents the extent to which the expectations of healthcare consumers are met by healthcare providers, whether that consumer is the patient, a professional colleague, the payer, or the facility that provides resources for the care delivery. In this context, the “consumer” of anesthesia services includes not only the patient, but the surgeon or other operator who requires anesthesia services to perform a diagnostic or therapeutic procedure. Numerous definitions of quality exist, but perhaps the most widely accepted definition is that of the IOM, which we noted earlier: Quality is the “extent to which health services for individuals and populations increase the likelihood of desired health outcomes and are consistent with current professional knowledge.”4 Thus quality represents not a distinct entity or end point, but a continuum in the

Evidence based current practice (‘‘Best practices’’)

Patient safety (‘‘First, do no harm’’)

Safe

Effective

Patient centered

Care processes FIGURE 3–2. The relationship between safety and quality and the process of care.

technical aspects of care delivery. Thus the role of the consumer (especially the patient) in the evaluation of healthcare quality has increased considerably in recent years. Building on these concepts, the IOM has gone further in defining quality, by identifying 6 desired characteristics of healthcare. Thus high-quality care should be safe, timely, effective, efficient, equitable, and patient-centered (often abbreviated as STEEEP, for ease of recall). Here, also, the concepts of measurement and current knowledge are apparent throughout. Although recent quality initiatives have focused on the patient–provider relationship, there are other dimensions of healthcare delivery that require attention for both safe and high quality practice. The relationships among providers are key elements in the care process, especially in an era when complex care management is provided by specialists and subspecialists who focus on specific aspects of care. That complexity often leads to communication lapses and fragmentation without subsequent integration into a coordinated system of care that focuses on the patient’s needs for understanding, planning, and decision making. Thus patients often rate communication as one of the most important components in the evaluation of quality healthcare, whereas physicians often rate technical abilities as considerably more important than communication.81 Eliminating these lapses in communication is essential for both patient compliance and patient satisfaction; eliminating the lapses benefits both process and outcome in the delivery of care. Furthermore, it minimizes the frustrations that patients and families experience as a result of conflicting or inadequate communications among professionals, leading to mistrust of the provider by the consumer. Finally, the development of relationship-centered care teams, wherein all parties have developed a pattern of open communication and mutual respect and trust, increase both safety and quality in multiple industries, including healthcare.82 These concepts apply as much to the discipline of anesthesiology as to other disciplines in the healthcare delivery process. Anesthesia providers, as individuals and departments, must institute these principles, including practical measurement of outcomes


and the development of relationshipcentered clinical teams, if they expect to practice at the higher levels of the quality spectrum (i.e., beyond the fundamental level of safe practice).

THE ELEMENTS OF SAFE, HIGHQUALITY ANESTHESIA CARE Creating a safe, high-quality practice of anesthesia depends on a combination of broad strategies and effective tactics for day-to-day work. Many models for establishing safe environments and practices and for ensuring quality have been described, but there is no empirical evidence from controlled studies to demonstrate that a specific model is superior to other models. Still, there is face validity from qualitative studies in specific industries and organizations to suggest that having an overall systematic approach leads to both safer and higher quality care. Indeed, a recent combined report from the National Academy of Engineering and the IOM emphasized that systems approaches to healthcare delivery were most likely to transform healthcare to deliver the goals of safe, timely, effective, efficient, patient-centered care in the future.83

The High-Reliability Organization Model Although several models have been promulgated for managing quality (see Chap. 25), there are fewer directed primarily at safety. For the latter, the concept of the HRO was formulated from observations in highly hazardous industries that, despite operating under conditions of high risk, have many fewer serious accidents than expected.84,85 Such industries included naval aviation, nuclear power, and offshore oil platforms. Weick and Sutcliffe further describe how organizations can be successful if they appropriately “manage uncertainty.”86 Gaba applied these concepts to healthcare.34 Although there is no single, accepted model of an HRO, Weick lists the following elements that characterize a typical highly reliable organization: • Preoccupation with failure—Despite its good safety records, an HRO will constantly be on the lookout for any signs of weak systems or impending failure. An HRO assumes that failure is imminent and plans for the worst. In anesthesia, this extends to organizational and individual plan-

ning for potential failures or problems in every procedure. • Reluctance to simplify interpretations— Managers often look for simple answers to problems. In an HRO, interpretations are more nuanced and skepticism about apparent explanations is encouraged. Rather than simply blaming the people who are the proximal agents in a causal chain of events, an HRO seeks to understand the latent failures that led to an individual’s failure to perform flawlessly. • Sensitivity to operations—An HRO pays close attention to how work actually gets done on the frontline rather than merely proposing solutions that appear reasonable from a distance. Cook wrote about the danger of ignoring the ways in which workers must act to do their jobs, often needing to circumvent rules made by managers or regulators who do not understand the complexity and challenges in healthcare systems.37 • Commitment to resilience—The HRO understands that regardless of its best efforts, things do go wrong and people do make mistakes. An HRO “develop[s] capabilities to detect, contain, and bounce back from those inevitable errors that are part of an indeterminate world.” In the operating room, this translates to ensuring adequate backup of personnel, supplies, and equipment. • Deference to expertise—During a crisis in an HRO, decision making falls to the person most experienced in dealing with that kind of problem, not to the most senior person. A good leader seeks out that expertise rather than squelching disagreement or demanding loyalty. Another critical feature of an HRO is that safety is the highest priority over all other concerns. That is, the interests of production and speed are not allowed to supersede the need to ensure safety.34 Another element of HROs, one that has direct implications for anesthesia practice, is the need for intensive and regular training, especially with simulation.87 For high-hazard industries that face rare events requiring expertise to avoid an adverse outcome, frequent training and practice are essential; all of these conditions are met in the practice of anesthesiology.

HROs are also noted for organizational learning, especially from accidents and near misses. Healthcare recently embraced the process of root cause analysis (RCA).11 An RCA is applied to unusual, potentially harmful events in an effort to understand the many elements that contribute to an event and use the findings to design and implement corrective interventions (see Chap. 25 for more detail on RCA). Failure mode and effect analysis (FMEA) is one of several industry techniques to study new processes proactively, before an adverse event occurs.88 The FMEA is used to identify potential failure modes and key points where barriers are needed to minimize the potential for failure (see Chap. 25 for a more detailed discussion of RCA and FMEA as risk-reduction strategies). Vaughan described the concept of “normalization of deviance” that arises when an otherwise safe organization drifts into unsafe conditions.89 In analyzing the sociologic features of the disintegration of the Challenger orbiter (“shuttle”) in 1988, Vaughan identified how NASA, under intense financial and political pressures, evolved from an organization that had once highly valued safety to one that gave production a higher priority. This led to what she called a “normalization of deviance” in the way engineers made decisions about safety issues. Rather than demanding that assurance of safety was the highest priority at each step, the “burden of proof” had shifted—to cancel or delay a launch, engineers were asked to prove that conditions were unsafe, where previously, to allow a launch, they were required to prove that each item was safe. This critical shift in emphasis has direct applications to anesthesia and surgery. To ensure safety, strategies and tactics must be implemented at all levels throughout an organization, from senior management to bedside provider. That process has 2 major elements of responsibility: the organization and the individual.

Creating Safety at the Organizational and Department Level The organization is responsible for creating a safe culture throughout its various levels. Culture is the “shared values and beliefs that interact with an organiza-

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tion’s structures and control systems to produce behavioral norms.”33 More simply stated, it is “the way we do things around here.” Cultural characteristics are usually deeply ingrained, not immediately visible, and often difficult to modify. Yet, it is the culture that defines the overall commitment to safety of an organization. Although highest reliability can likely only be achieved within a consistent culture of safety across an organization, the perioperative subcultures and anesthesia practices and departments can establish strong safety cultures within their sphere of influence. Batalden refers to these smaller elements as “microsystem environments,” and emphasizes that safety and quality must be applied at these levels, as well as in the more global “macrosystems environments” (i.e., it must be brought from the corporate or departmental office to the bedside to be effective).90 In contrast, the individual practitioner working in various environments (e.g., locum tenems practice), will find it difficult to achieve an overall high-quality, safe practice in an organization that gives only lip service to safety. There is a growing literature about safety culture (also referred to as “climate”; the terms are similar but not synonymous) in healthcare.91,92 One means to assess the organizational culture is to conduct periodic surveys. Little is written about the perioperative or anesthesia department patient safety culture or what should be its defining characteristics. Helmreich reported on use of one survey instrument, the Operating Room Management Questionnaire, and compared attitudes of surgeons to pilots, whose safety culture is generally believed to be superior to that found in many industries as a result of long-standing attention to safety training and interventions.93 (Others, less reverently, attribute the safety focus of pilots to the observation that they are usually first on the scene of aviation accidents!). Although there are many similarities with pilots, surgeons appear to have attitudes that are not aligned with safety science, such as a perception that their performance is not affected by fatigue. Flin reported on results of a survey from anesthesia departments in the United Kingdom with a similar finding about the effects of stress and fatigue.94 Also, for example, although perceptions of teamwork were generally positive, only 65% of

respondents perceived that operating room personnel worked well together as a team. Respondents also reported variable compliance with procedures and policies. The Joint Commission on Accreditation of Healthcare Organizations (JCAHO) presumes to assess the organizational and department level of safety through its process of accreditation, which lists many requirements for anesthesia services. Included among those are processes to credential individual practitioners, processes for evaluating unusual clinical events (quality assurance or quality improvement), policies and procedures for common procedures, and a program for ensuring that individuals are trained on the technologies they use.95 Periodic inspections are used to assess the compliance with the JCAHO requirements, but these requirements are generally viewed by practitioners as bureaucratic and of limited value in ensuring that safety is deeply ingrained in ongoing practices. Extrapolating from the earlier descriptors of an HRO, we can imagine that a safe perioperative culture demonstrably places safety as its priority with regular meetings of the group and teams; organizational learning via reporting systems that are open, fair, and nonpunitive; a formal and active quality improvement process; by implementing corrective actions on learning of unsafe practices; having policies and procedures defining standard operations; have regular training for common emergencies; being nonhierarchical during emergencies; rewarding those who raise safety concerns and have open discussions about those concerns; having processes for briefing and debriefing about near misses and adverse events; having standard processes for communication among providers especially for transitions in care; and use other similar processes and attributes. Amazingly, few organizations have these attributes, especially those related to multispecialty analyses of the causes of errors and adverse events; too often these analyses take place in parallel processes that result in the allocation of blame rather than resolution of the root causes that are embedded in the larger system, or the interfaces between services or providers. The safe organization ensures that its workers practice safety and provides the support and resources to

enable them to do so. It is then the responsibility of the individual to develop and maintain a continuous personal commitment to safety by adopting a spectrum of safe practices as outlined in the next section.

Practical Elements for the Practitioner for Producing Safe, High-Quality Patient Care Importance of Instilling Values of Patient Safety, Quality and Patient Centeredness Safety demands that each individual, as well as the organization, make preventing any injury or harm to the patient the highest priority. For the individual clinician, a continual commitment to safe practice includes avoidance of unnecessary risk taking and avoidance of corner cutting, an almost unending anticipation of what might go wrong, projection of actions in anticipation of failure and, above all, mindfulness. Weick describes mindfulness for HROs as organizing in such a way as to “better notice the unexpected in the making and halt its development.”86 The concept applies equally well to the individual practitioner or member of the perioperative care team. Weick goes on to say that “[m]indfulness preserves the capability to see the significant meaning of weak signals and to give strong responses to (them). This counterintuitive act holds the meaning to managing the unexpected.” Being patient-centered includes placing the patient’s needs above all others, especially protecting the patient from harm. Thus, patient safety and patient centeredness are intimately connected and the hallmarks of high-quality practice.

Maintaining Vigilance and Mitigating Performance Decrement Although vigilance cannot be relied on solely to protect the patient from harm, it remains the strongest underpinning of safety in anesthesia. This means that the anesthesia provider must maintain alertness and be aware of, compensate for, and counteract the forces working against vigilance. This, too, requires mindfulness about the state of one’s own vigilance. Fatigue and sleep deprivation are probably the most common causes of lapses in vigilance. Howard et al. have recommended several “fatigue


countermeasures.”43 Among these are education about the effects of fatigue on vigilance, employing good sleep hygiene (regular bedtime and wakeup time; restricting alcohol, caffeine, and nicotine use; creating good conditions for sleep), rest breaks, strategic napping, and selected medications, if necessary. There is no evidence to support any specified time between breaks, but awareness of a fatigued state can suggest when a break is needed. Naps are often inconsistent with daily clinical routines, but may be appropriate when routines are disrupted or during “on call” intervals. Optimal nap times are on the order of 45–60 minutes to improve alertness while minimizing sleep inertia on awakening. Napping is best done when circadian rhythms are enabling sleep (between 2:00 and 6: 00 P.M. and 2:00 and 6:00 A.M.), and is more difficult to do when circadian rhythms are encouraging wakefulness. The evidence that napping improves performance of flight crews is strong enough that appropriate napping is recommended during long duration flights.96 Caffeine can be used judiciously to compensate for fatigue.43 Excessive use or inappropriate timing of caffeine use can have the negative consequence of preventing subsequent sleep. Relief breaks, either during a procedure or at a change of shift, are a double-edged sword, providing an opportunity to identify an undiscovered problem or to create a new problem because of lesser situational awareness by the relieving provider.45,46 A preplanned protocol should be followed to optimize information transfer during the handoff.48,49

Practice in a System of Care Anesthesiologists must identify and integrate into the larger system of care in which they operate. Safe care depends on the effective work of many others working as a team, and understanding their constraints and processes can go far toward creating an environment of safety. This includes learning how to operate within a team rather than primarily as an individual. If the anesthesiologist can determine how the surgeon, consultant physicians, nurses, allied health professionals, and laboratory support personnel and systems function, and where “glitches” may develop in these systems, then the anesthesiologist can

be prepared to mitigate or interrupt cascades that lead to adverse events. For example, understanding how and under what conditions delays in delivery of laboratory information might occur, knowing when nursing turnovers occur, and understanding what factors affect surgical judgment can alert the anesthesia practitioner to strategies that might reduce errors. An example is failure to transfuse when blood loss is excessive (e.g., a system of events where estimation of blood loss by the nurses is interrupted by change of shift, laboratory reports are delayed due to time pressures in the laboratory and the surgeon “hopes” that the bleeding is controlled; this sequence is a classic example of the “holes in the Swiss cheese” aligning in a way that fosters medical error). Integrating anesthesia practices into the overall system, rather than acting in isolation, is more likely to result in safe and efficient processes for the entire patient-care experience.

Teamwork Although teamwork can be seen as a subset of working within a system of care, it also includes specific practices for optimizing safety. Box 3–3 lists some of the recommended practices of high-performance teams in nonhealthcare domains.

Preparation The failure to adequately prepare for anesthesia administration often contributes to anesthesia critical incidents.20,21,97 Preparation encompasses a large set of issues, including complete preoperative assessment (see Preoperative Assessment and Planning below); ensuring availability of emergency drugs, equipment, and supplies; checking out the function of equipment (especially using the FDA recommended procedure for ensuring functionality of the anesthesia machine98); and ensuring communication pathways in the event of an emergency.

Preoperative Assessment and Planning Preoperative assessment and planning involves evaluation of the patient and development of the anesthesia plan that includes the anesthetic technique, the requirements for monitoring, and the plans for postoperative care, all of which must be consistent with the wishes of the patient and the needs of the surgeon or other operator (e.g.,

radiologist, cardiologist), and the resources of the facility. The evaluation must be thorough and appropriate for the procedure and the patient; most especially, it must include a systematic evaluation of comorbidities or other factors that might lead to adverse outcomes. Even in healthy patients, there may be conditions that can lead to adverse events, such as difficult airway access, family history of relevant disease, or the recent use of nonprescription or illicit drugs. (Preoperative evaluation is considered in Chap. 4, and for specific conditions in Chaps. 6–23.) Similarly, an anesthetic plan must be developed that is consistent with both patient wishes and operator requirements, and with the plans for postoperative care. The anesthetic plan should never be based on a rote formula that depends on the procedure only; it should be tailored to the needs of patient, operator, and facility, including the environment and plans for postoperative care. Chapter 5 addresses the development of the anesthetic plan in detail.

Monitoring Because failure to monitor is so often associated with adverse outcomes, this issue deserves special attention. The safe practitioner follows the standards promulgated by the ASA except in truly extraordinary situations, and should those occur, documents the reason for noncompliance. Critical alarms should never be disabled.

Control for Human Factors Although the individual anesthesia provider has little control over the design of equipment and local systems, he or she does have substantial control over many of the human factors features that are part of the environment. Attention to the organized arrangement of supplies and drugs, especially adherence to consistent labeling of drugs, and establishing and adhering to local standards are examples. Care to keep arterial and intravenous cannulae and monitoring cables orderly, ensuring reasonable lighting, and reducing clutter, noise, and distractions are general, sound, safety practices. Control of noise levels and background music can be contentious issues among staff, surgeons, and anesthesia providers, who sometimes are urged to compromise the principle that patient safety takes preeminence.

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Reasonable efforts should be made to reach compromise and music should be discontinued during management of critical events.

mia and reduced by increased perioperative oxygen administration.102,103

Applying Systematic Crisis Management Techniques

The ASA has established a large set of practice standards and guidelines.104 Standardizing practices across providers is widely accepted as a critical component for safety and reliability. Box 3–5 lists common practice standards. Each practitioner is obligated to be familiar with such guidelines and apply them appropriately in his or her practice. Similarly, healthcare facilities are required to establish local polices and procedures to ensure standardization of basic practices. These, too, must be known and followed.

Anesthesia crisis resource management (ACRM) is an organized set of principles for managing crisis situations in anesthesia. Adapted by Gaba et al. from CRM in aviation, it consists of several founding principles for effective management of acute events.62,70,99,100 Although there is no single adopted standard, the following principles are generally applicable: • Seek assistance early and quickly— inform others on the surgical team and call for extra assistance as soon as unusual circumstances are recognized. • Establish clarity of roles for each person involved in management of the event; especially identify who will manage the event (event manager). • Use effective communication processes, including reading back of instructions, being clear to whom directions are being given. • Use resources effectively and identify what additional resources (people, supplies, equipment, transportation, etc.) are available to manage the situation. • Maintain situational awareness and avoid fixations, which is perhaps the most challenging task as situational awareness is difficult to retrieve once it is lost. Having one person act as event manager, observing the big picture rather than becoming immersed in the details, is thought to be effective. The algorithm of ABCD COVER swift check discussed earlier (Box 3–4) should be available for reference.

Infection Control Care in the safe use and sterility of all anesthesia systems is essential, especially in the modern hospital environment where hospital-acquired infections with resistant organisms (e.g., methicillin- or vancomycin-resistant Staphylococcus aureus organisms) are increasingly common. Adherence to carefully timed protocols for antibiotic administration in the perioperative interval reduces postoperative wound infection.101 Surgical wound infection rates are increased 3-fold by hypother-

Following Standards and Practice Guidelines

Periodic Training Because critical events are relatively rare and demand expert and effective treatment, it is important to practice skills periodically. Schwid demonstrated that advanced cardiac life support (ACLS) skills are generally maintained for only approximately 6 months.105 Periodic training includes practice in management of the unanticipated difficult airway, generic skills in ACRM, and drills for operating room fires and other specific anesthetic emergencies, such as malignant hyperthermia. Simulation is increasingly used for such training. Some practice can be achieved via computer-based simulators and trainers, which are effective for obtaining knowledge in management of acute events.106 Simulation using various forms of simulators, from basic to the most realistic environment, is effective for imparting generic, nontechnical (behavioral) skills in managing critical events.66 Resources for obtaining such training are expanding and the ASA is encouraging its members to maintain their skills in this way. In the future, simulation may become part of evaluation processes of accrediting agencies.

INVOLVING THE PATIENT IN SAFETY AND QUALITY Patients increasingly are being urged to take a role in ensuring the safety of their own care, as well as being involved in patient safety by their healthcare providers.107 Anesthesia professionals should encourage and assist in this because it benefits everyone. Providers should also be concerned with

BOX 3–5. Key Standards of Care of the American Society of Anesthesiologists • Ambulatory Anesthesia and Surgery, Guidelines for—2003 • Basic Anesthetic Monitoring, Standards for—2004 • Clinical Privileges in Anesthesiology, Guidelines for Delineation of— 2003 • Critical Care by Anesthesiologists, Guidelines for the Practice of—2004 • Documentation of Anesthesia Care—2003 • Ethical Guidelines for the Anesthesia Care of Patients with Do-NotResuscitate Orders or Other Directives That Limit Treatment—2001 • Ethical Practice of Anesthesiology, Guidelines for the—2003 • Labeling Pharmaceuticals for Use in Anesthesiology, Statement on—2004 • Nonoperating Room Anesthetizing Locations, Guidelines for—2003 • Obstetrics, Guidelines for Regional Anesthesia Care in—2000 • Obstetrics, Optimal Goals for Anesthesia Care in—2000 • Office-Based Anesthesia, Guidelines for—2004 • Patient Care in Anesthesiology, Guidelines for—2001 • Postanesthesia Care, Standards for—2004 • Preanesthesia Care, Basic Standards for—2005 Data from American Society of Anesthesiologists.104

the patient’s perceptions of the quality of care and consider more than just the needs of the direct surgical process. There are several ways in which these goals can be achieved. To encourage patient involvement, actions can be taken to foster “patientcentered communication,” which has been defined as including the following:108 • Eliciting and understanding the patient’s perspectives—concerns, ideas, expectations, needs, feelings, and functioning. • Understanding the patient within his or her unique psychosocial context. • Reaching a shared understanding of the problem and its treatment with the patient that is concordant with the patient’s values.


• Helping patients share power and responsibility by involving them in choices to the degree that they wish to be involved. What specific things can anesthesia providers do to involve patients in their own care that will not just improve satisfaction but also safety? Consider the following: • Tell the patient as much as practical (assessing how much the patient can handle knowing) about the process of anesthesia care the patient will experience. • Provide information preoperatively about the process of anesthesia care and expectations; several references are available on the Internet in addition to books and pamphlets. • Encourage the patient to speak up if the patient doesn’t understand something or believes something is inappropriate, such as drugs being given, absence of handwashing or glove wearing.

clinical services, and facilities. In short, the delivery of care must be recognized as a complex matrix of interactions among multiple providers, including both clinicians and facilities, all interacting with one another in a system of systems. The specialty of anesthesiology is a leader in the development of patient safety approaches within its discipline; the next steps involve building safety and quality into this larger system of care. Anesthesia providers can contribute significantly to achieving these goals by participating fully in the system-of-systems approach, as well as by building highly reliable microsystems within their department or group. These approaches are best understood by adopting a patient-centered approach, whereby all providers interpret the integrated care process from the patient’s viewpoint, and include that viewpoint in the design and delivery of care.

• Involve the patient’s family members in care whenever practical.

KEY REFERENCES

• Advise the patient to contact you if there are any concerns or possible side effects after the anesthetic.

1. Baker DP, Salas E, King H, et al. The role of teamwork in the professional education of physicians: current status and assessment recommendations. Jt Comm J Qual Patient Saf 2005;31(4):185–202.

• In concert with other providers, disclose errors and adverse events (a strategy that enhances trust and decreases skepticism in concerned patients). • Involve patients on committees that involve the design of anesthetizing locations, and in the process of patient flow and family communication in such facilities.

SUMMARY AND CONCLUSIONS The concepts of quality, safety, and patient centeredness are prominent themes throughout American healthcare, and they have been embraced by patients and affirmed by third-party payers, specialty societies, and healthcare organizations, both governmental and private. Despite the increased focus on these factors, the goals have yet to be met, especially because most initiatives have focused on individual practitioners or within specific disciplines. To achieve the full goals of quality and safety, the processes must include systematic approaches that cross the boundaries of specialties,

2. Cooper JB, Newbower RS, Kitz RJ. An analysis of major errors and equipment failures in anesthesia management: considerations for prevention and detection. Anesthesiology 1984;60(1):34–42. 3. Gaba D, Fish K, Howard S. Crisis Management in Anesthesiology. Philadelphia: Churchill Livingstone; 1994. 4. Gaba DM, Howard SK, Fish K, et al. Simulation-based training in anesthesia crisis resource management (ACRM): a decade of experience. Simul Gaming 2001;32(2): 175–193. 5. Kohn LT, Corrigan JM, Donaldson MSE. To Err is Human: Building a Safer Healthcare System. Washington, DC: National Academy Press, 1999. 6. Reason J. Managing the Risk of Organizational Accidents. Aldershot, Hants, UK: Ashgate Publishing, 1997.

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41. Landrigan CP, Rothschild JM, Cronin JW, et al. Effect of reducing interns’ work hours on serious medical errors in intensive care units. N Engl J Med 2004;351(18): 1838–1834. 42. Lockley SW, Cronin JW, Evans EE, et al. Effect of reducing interns’ weekly work hours on sleep and attentional failures. N Engl J Med 2004;351(18):1829–1833. 43. Howard SK, Rosekind MR, Katz JD, et al. Fatigue in anesthesia: implications and strategies for patient and provider safety. Anesthesiology 2002;97(5):1281–1289. 44. Van Dongen HP, Price NJ, Mullington JM, et al. Caffeine eliminates psychomotor vigilance deficits from sleep inertia. Sleep 2001;24(7):813–819. 45. Cooper JB, Long CD, Newbower RS, et al. Critical incidents associated with intraoperative exchanges of anesthesia personnel. Anesthesiology 1982;56(6):456–461. 46. Short TG, O’Regan A, Jayasuriya JP, et al. Improvements in anaesthetic care resulting from a critical incident reporting programme. Anaesthesia 1996;51(7):615– 621. 47. Arbous MS, Meursing AE, van Kleef JW, et al. Impact of anesthesia management characteristics on severe morbidity and mortality. Anesthesiology 2005;102(2):251–252. 48. Cooper J. Do short breaks increase or decrease anesthetic risk? J Clin Anesth 1989;1:228–231. 49. Goldhaber-Feibert SN, Cooper JB. Safety in anesthesia. In: Dunn P, ed. Clinical Anesthesia Procedures of the Massachusetts General Hospital 7th ed. Philadelphia: Lippincott Williams & Wilkins, 2007:127–134. 50. Hawksworth C, Asbury AJ, Millar K. Music in theatre: not so harmonious. A survey of attitudes to music played in the

57. Vicente KJ, Kada-Bekhaled K, Hillel G, et al. Programming errors contribute to death from patient-controlled analgesia: case report and estimate of probability. Can J Anaesth 2003;50(4):328–332. 58. Gaba DM, Howard SK, Jump B. Production pressure in the work environment. California anesthesiologists’ attitudes and experiences. Anesthesiology 1994;81(2): 488–500. 59. Baker DP, Salas E, King H, et al. The role of teamwork in the professional education of physicians: current status and assessment recommendations. Jt Comm J Qual Patient Saf 2005;31(4):185–202. 60. Simon R, Salisbury M, Wagner G. MedTeams: teamwork advances emergency department effectiveness and reduces medical errors. Ambul Outreach Spring 2000;21–24. 61. Morey JC, Simon R, Jay GD, et al. Error reduction and performance improvement in the emergency department through formal teamwork training: evaluation results of the MedTeams project. Health Serv Res 2002;37(6):1553–1558. 62. Gaba D, Fish K, Howard S. Crisis Management in Anesthesiology. Philadelphia: Churchill Livingstone, 1994. 63. Grogan EL, Stiles RA, France DJ, et al. The impact of aviation-based teamwork training on the attitudes of health-care professionals. J Am Coll Surg 2004;199(6):843– 848. 64. Lingard L, Espin S, Rubin B, et al. Getting teams to talk: development and pilot implementation of a checklist to promote interprofessional communication in the OR. Qual Saf Health Care 2005;14(5): 340–346.


65. Leonard M, Graham S, Bonacum D. The human factor: the critical importance of effective teamwork and communication in providing safe care. Qual Saf Health Care 2004;13(Suppl 1):i85–i90. 66. Gaba DM, Howard SK, Fish K, et al. Simulation-based training in anesthesia crisis resource management (ACRM): a decade of experience. Simul Gaming 2001; 32(2):175–193. 67. Gaba D. Simulators in anesthesiology. Adv Anesth 1997;14:55–92. 68. Beaubien JM, Baker DP. The use of simulation for training teamwork skills in health care: how low can you go? Qual Saf Health Care 2004;13(Suppl 1):i51–i56. 69. Gaba D. Anesthesia simulations in an actual operating room environment. Anesthesiology 1987;67(3A):A467. 70. Blum R, Cooper JB, Feinstein D, et al. Sustaining development of crisis resource management training for academic faculty: a new approach to continuing education. Anesth Analg 2003;97(S2):S10. 71. Small SD, Wuerz RC, Simon R, et al. Demonstration of high-fidelity simulation team training for emergency medicine. Acad Emerg Med 1999;6(4):312–323. 72. Caplan RA, Ward RJ, Posner K, et al. Unexpected cardiac arrest during spinal anesthesia: a closed claims analysis of predisposing factors. Anesthesiology 1988;68(1):5–11. 73. Caplan RA, Posner KL, Ward RJ, et al. Adverse respiratory events in anesthesia: a closed claims analysis. Anesthesiology 1990;72(5):828–833. 74. Runciman WB, Kluger MT, Morris RW, et al. Crisis management during anaesthesia: the development of an anaesthetic crisis management manual. Qual Saf Health Care 2005;14(3):e1. 75. Peterson GN, Domino KB, Caplan RA, et al. Management of the difficult airway: a closed claims analysis. Anesthesiology 2005;103(1):33–39. 76. American Society of Anesthesiologists. Standards for basic anesthetic monitoring, 2005. Available at: http://www.asahq.org/ publicationsAndServices/standards/02.pdf. Last accessed May 30, 2006. 77. Orser BA, Byrick R. Anesthesia-related medication error: time to take action. Can J Anaesth 2004;51(8):756–760. 78. ASTM International. ASTM D4774– 1997;94(2000) standard specification for user applied drug labels in anesthesiology, 2000. Avaiable at http://webstore.ansi.org/ ansidocstore/default.asp. Last accessed January 31, 2007. 79. Caplan RA, Vistica MF, Posner KL, et al. Adverse anesthetic outcomes arising from gas delivery equipment: a closed claims analysis. Anesthesiology 1997;87(4):741–748.

80. Weinger MB. Anesthesia equipment and human error. J Clin Monit Comput 1999;15(5):319–323. 81. Sofaer S, Firminger K. Patient perceptions of the quality of health services. Annu Rev Public Health 2005;26:513–559. 82. Safran DG, Miller W, Beckman H. Organizational dimensions of relationship-centered care. Theory, evidence, and practice. J Gen Intern Med 2006;21(Suppl 1):S9–S15. 83. Reid P, Compton WD, Grossman JH, et al. Building a Better Delivery System: A New Engineering/Health Care Partnership. Washington, DC: National Academies Press, 2005. 84. Rochlin GI, La Porte TR, Roberts KH. The self-designing high-reliability organization: aircraft carrier flight operations at sea. Naval War Coll Rev 1987;40(4):76–79. 85. Roberts KH, Rousseau DM, La Porte TR. The culture of high reliability: quantitative and qualitative assessment aboard nuclear powered aircraft carriers. J High Tech Mgmt Res 1994;5:141–161. 86. Weick K, Sutcliffe KM. Managing the Unexpected. San Francisco: Jossey-Bass, 2001. 87. Gaba DM. Safety first: ensuring quality care in the intensely productive environment—the HRO model. Anesthesia Patient Safety Foundation Newsletter 2002;18:1–4. 88. DeRosier J, Stalhandske E, Bagian JP, et al. Using health care failure mode and effect analysis: the VA National Center for Patient Safety’s prospective risk analysis system. Jt Comm J Qual Improv 2002; 28(5):248–246. 89. Vaughn D. The Challenger Launch Decision: Risky Technology, Culture And Deviance at NASA. Chicago: University of Chicago Press, 1996. 90. Mohr J, Batalden P, Barach P. Integrating patient safety into the clinical microsystem. Qual Saf Health Care 2004;13(Suppl 2):ii34–ii38. 91. Gaba DM, Singer SJ, Sinaiko AD, et al. Differences in safety climate between hospital personnel and naval aviators. Hum Factors 2003;45(2):173–178. 92. Colla JB, Bracken AC, Kinney LM, et al. Measuring patient safety climate: a review of surveys. Qual Saf Health Care 2005; 14(5):364–366. 93. Helmreich RL, Merritt AC. Culture at Work in Aviation And Medicine. Aldershot, UK: Ashgate, 1998. 94. Flin R, Fletcher G, McGeorge P, et al. Anaesthetists’ attitudes to teamwork and safety. Anaesthesia 2003;58(3):233–242. 95. Joint Commission for Accreditation of Healthcare Organizations: 2004, 2005, and 2006 Comprehensive Accreditation Manual for Hospital: The Official Handbook (CAMH). Oakbrook Terrace, IL: Joint Commission Resources, 2006.

96. Rosekind MR, Gander PH, Connell LJ, et al. Crew factors in flight operations X. Alertness management in flight operations. NASA Technical Memorandum #208780. NASA Ames Research Center, 1999. 97. Short TG, O’Regan A, Lew J, et al. Critical incident reporting in an anaesthetic department quality assurance programme. Anaesthesia 1993;48(1):3–7. 98. U.S. Food and Drug Administration. Anesthesia apparatus checkout recommendations. Available at: http://www.fda.gov/ cdrh/humfac/anesckot.pdf. Last accessed May 23, 2006. 99. Howard SK, Gaba DM, Fish KJ, et al. Anesthesia crisis resource management training: teaching anesthesiologists to handle critical incidents. Aviat Space Environ Med 1992;63(9):763–767. 100. Holzman RS, Cooper JB, Gaba DM, et al. Anesthesia crisis resource management: real-life simulation training in operating room crises. J Clin Anesth 1995;7(8):675– 678. 101. Classen DC, Evans RS, Pestotnik SL, et al. The timing of prophylactic administration of antibiotics and the risk of surgicalwound infection. N Engl J Med 1992;326(5): 281–286. 102. Kurz A, Sessler DI, Lenhardt R. Perioperative normothermia to reduce the incidence of surgical-wound infection and shorten hospitalization. Study of Wound Infection and Temperature Group. N Engl J Med 1996;334(19):1209–1215. 103. Greif R, Akca O, Horn EP, et al. Supplemental perioperative oxygen to reduce the incidence of surgical-wound infection. Outcomes Research Group. N Engl J Med 2000;342(3):161–167. 104. American Society of Anesthesiologists. Standards, guidelines and procedures. Available at: http://www.asahq.org/publicationsAndServices/sgstoc.htm. Last accessed May 23, 2006. 105. Schwid HA, O’Donnell D. Anesthesiologists’ management of simulated critical incidents. Anesthesiology 1992;76(4):495– 495. 106. Schwid HA, Rooke GA, Michalowski P, et al. Screen-based anesthesia simulation with debriefing improves performance in a mannequin-based anesthesia simulator. Teach Learn Med 2001;13(2):92–96. 107. Edgman-Levitan S. Involving the patient in safety efforts. In: Leonard M, Frankel A, Simmonds T, eds. Achieving Safe and Reliable Healthcare. Chicago: Health Administration Press, 2004:81–92. 108. Epstein RM, Franks P, Fiscella K, et al. Measuring patient-centered communication in patient-physician consultations: theoretical and practical issues. Soc Sci Med 2005;61(7):1516–1528.

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PART 2 PREPARING FOR ANESTHESIA


PART 2: Preparing for Anesthesia

SECTION A APPROACH TO THE ANESTHESIA PATIENT

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CHAPTER 4 Overview of Preoperative Assessment and Management Bobbie Jean Sweitzer, MD

KEY POINTS 1. Comprehensive preoperative evaluation and management improves patient satisfaction, outcomes, and safety. 2. Inadequate preoperative evaluation and management increase perioperative adverse events.

GOALS AND BENEFITS As the practice of medicine becomes increasingly outcomes-driven and costconscious, clinicians need to reevaluate and streamline methods of patient care. Preoperative assessment and management have evolved as the role of the anesthesiologist has expanded outside of the operating theater and as an increasing number of procedures are performed on patients who are not hospitalized the night before. Reasons for preoperative assessment may entail some or all of the following: 1. To screen for and properly manage comorbid conditions. 2. To assess the risk of anesthesia and surgery and lower it. 3. To identify patients who may require special anesthetic techniques or postoperative care. 4. To establish baseline results for perioperative decisions. 5. To educate patients and families about anesthesia and the anesthesiologist’s role. 6. To obtain informed consent. 7. To facilitate timely care and avoid cancellations on the day of operation.

3. At a minimum, the preanesthesia visit should include an interview with the patient to review the medical history (including medications, allergies, comorbid conditions, and previous operations), an appropriate physical examination, review of diagnostic data, assignment of an American Society of Anesthesiologists physical status score, and a formulation and discussion of the planned anesthetic with the patient. 4. The medical history is the most important component of preoperative assessment. 5. Findings from the history and physical examination determine the need for further diagnostic testing. 6. Diagnostic tests should only be ordered if the results will alter the planned anesthetic or procedure or establish an already suspected diagnosis. “Screening” tests are never appropriate. 7. A determination of functional capacity or the patient’s cardiorespiratory fitness can guide further testing and predict a wide range of complications and outcome. 8. Cardiovascular morbidity and mortality are the leading cause of significant perioperative adverse events.


9. Identification and optimization of cardiovascular disease is an important goal of preoperative evaluation. 10. Knowledge of risk factors for cardiovascular disease and familiarity with the American College of Cardiology–American Heart Association guidelines for cardiovascular evaluation for noncardiac surgery is essential. 11. Other “high-risk” patients include those with the following conditions: a. Congestive heart failure b. Murmurs c. Pacemakers and implantable cardioverter-defibrillators (ICDs) d. Pulmonary disease e. Obstructive sleep apnea f. Obesity g. Diabetes mellitus h. Poorly controlled hypertension i. Renal disease j. Hepatic disease k. Substance abuse l. Geriatric patient m. Difficult airway 12. Poor communication is a common source of medical errors and patient dissatisfaction. 13. Practice guidelines can standardize care, decrease delays, and improve outcomes. 14. Anesthesia-directed preoperative evaluation centers can be cost-effective, improve care and patient safety, and offer services beyond history acquisition, physical examinations, and diagnostic testing.

CHAPTER 4: Overview of Preoperative Assessment and Management

8. To motivate patients to stop smoking, lose weight, or commit to other preventive care. 9. To train personnel in the art and science of preoperative assessment and optimization of a patient’s condition. The Australian Incident Monitoring Study (AIMS) found that 3.1% (197 of the first 6271 reports) of adverse events were unequivocally related to insufficient, and 11% to inadequate, preoperative assessment.1 More than half of incidents were considered preventable. An analysis of the first 2000 reports to AIMS found a 6-fold increase in mortality in patients who were inadequately assessed preoperatively.2 Davis concluded that 53 (39%) of 135 deaths attributed to anesthesia involved inadequate preoperative assessment and management.3 Delays, complications, and unanticipated postoperative admissions are significantly reduced by preoperative screening and patient contact. Others have shown that preoperative health status can predict both operative clinical outcomes and resource use. Preoperative preparation and education can facilitate recovery and reduce the incidence of postoperative morbidity. Anxiety, postoperative pain, and length of stay have been positively affected by comprehensive preoperative care. From the patient’s perspective, an opportunity to meet an anesthesiologist (preferably the one providing anesthesia on the day of surgery) is very important. In a study conducted in Canada and Scotland, patients rated meeting the anesthesiologist as the highest priority— above that of information on pain relief, alternative methods of anesthesia, and complications.4 Preoperative evaluation must be efficient for both patient and hospital personnel. It can be cost-effective and can reduce turnover times, cancellations, length of hospital stays, and postoperative complications. Preoperative visits should be comprehensive, including plans for postdischarge patient care. As the numbers of patients undergoing surgery on an outpatient basis or presenting to the hospital on the day of operation increases, anesthesiologists have to adapt to provide patients with the best preoperative services. Many anesthesiologists perform preoperative evaluations, review diagnostic studies (chosen and or-

dered by someone else), discuss anesthetic risks, and obtain informed consent moments before a patient undergoes a major, potentially lifethreatening or disfiguring procedure. This choice offers little opportunity to manage comorbid conditions or alter risk. Legally, morally, and psychologically anesthesiologists and patients are in awkward, and often unpleasant, situations. The effects of extensive disclosure are stressful for patients and families at a time when they may be ill-prepared to consider the implications rationally. An increase in preoperative anxiety may adversely affect postoperative outcomes because increased anxiety correlates with increased postoperative analgesic requirements and prolonged recovery and hospital stay. Anxiety impairs retention of information, which could result in legal action because of inadequate communication or discussion of the risks of anesthesia. At a minimum, the guidelines of the American Society of Anesthesiologists (ASA) indicate that a preanesthesia visit should include the following5: 1. Interview with the patient to review medical, anesthesia, and medication history 2. Appropriate physical examination 3. Review of diagnostic data (laboratory, electrocardiograms, radiographs) 4. Assignment of ASA physical status score 5. Formulation and discussion of anesthesia plan with patient or responsible adult Table 4–1 outlines the criteria and medical conditions of patients likely to benefit from evaluation in a preanesthetic clinic before the day of surgery.

RISK ASSESSMENT AND REDUCTION The current ASA risk classification system was developed in 1941 by Meyer Saklad at the request of the ASA (Table 4–2). This classification was the first attempt to quantify risk associated with anesthesia and surgery. The type of anesthesia and the operation were not even considered in this classification system. Moreover, this system attempted to estimate the mortality rate based only on the patient’s preoperative medical condition. Since

then other studies have corroborated an association of mortality and morbidity with ASA physical status (ASA PS) scores. Studies also have shown a correlation between ASA PS and unanticipated intensive care unit admissions, longer hospital stays for some procedures, and adverse cardiopulmonary outcomes. No correlation was shown between ASA PS class and cancellations, unplanned admissions, and other perioperative complications and cost.6 Fewer studies have evaluated the effect of combining the risk of the surgical procedure and the ASA PS score. Among the first was the Johns Hopkins Risk Classification System.7 Many institutions use a more simplified version of high, intermediate, and low risk.8 Table 4–3 offers one definition of these risk stratifications. Goldman et al. further advanced risk assessment by identifying risk factors and cardiac complications in noncardiac surgery. Several studies followed, culminating in the joint guideline publication by the American College of Cardiology and the American Heart Association (ACC/AHA) in 1996, which was updated in 2002.8 (See Heart Disease below and Chap. 7 for more detailed discussions of the ACC/AHA guidelines.) Some assessment of risk is important to prepare for the anesthetic and surgical procedure. The need for invasive monitoring, blood salvage and hypothermic techniques, postoperative care in the intensive care unit, and special monitoring must be considered. Patients must be informed during the consent process. Risk assessment is useful to compare outcomes, control costs, allocate compensation, and assist in the difficult decision of canceling or recommending a procedure not be done when the risks are too high. Yet risk assessment, at its best, is hampered by individual patient variability.

TIMING OF ASSESSMENT The Practice Advisory for Preanesthesia Evaluation commissioned by the ASA determined that the time of the preanesthesia assessment depends on the patient’s condition, the type of procedure, the health care system, and the patient’s access to care providers.5 The recommendations, which were based on the opinions of experts and random-

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TABLE 4–1. General Criteria and Medical Conditions for Which Preoperative Evaluation is Recommended Before the Date of Surgery

42

Medical Condition

Criteria

General Normal activity inhibited Monitoring or medical assistance at home within 6 months Hospital admission within 2 months Obesity >140% ideal body weight Cardiovascular Angina Coronary artery disease History of myocardial infarction Symptomatic arrhythmias Poorly controlled hypertension Systolic blood pressure >180 mm Hg or diastolic blood pressure >110 mm Hg Congestive heart failure Respiratory Asthma Chronic obstructive pulmonary disease (COPD) requiring medication Exacerbation or progression of COPD within 6 months Previous airway surgery Unusual airway anatomy Airway tumor or obstruction Home ventilatory assistance or monitoring Endocrine Diabetes Adrenal disorders Active thyroid disease Neuromuscular Seizure disorder CNS disease (e.g., multiple sclerosis) Myopathy or other muscle disorders Hepatic Active hepatobiliary disease or compromise Renal Renal insufficiency or failure Musculoskeletal Kyphosis or scoliosis compromising function Temporomandibular joint disorder Cervical or thoracic spine injury/disease Oncology Chemotherapy Significant physiologic compromise

Age >75 years, unless surgery is minor (e.g. cataract) and under monitored anesthesia care Language Patient or parent/guardian cannot hear, speak, or understand English Anesthesia Effects Patient or family has had previous difficult intubation, elevated temperature during anesthesia, is allergic to succinylcholine, has malignant hyperthermia or pseudocholinesterase deficiency or paralysis or nerve damage during surgery Procedure related Intraoperative blood transfusion likely ICU admission likely High risk surgery Pregnancy Patient is pregnant (unless the procedure is dilation and evacuation or dilation and curettage)

The medical condition portion of this table has been adapted with permission from Pasternak LR. Preoperative evaluation of the ambulatory surgery patient. Ambulatory Surgery. Anesthesiol Rep 1990;3(1):8.

ly selected ASA members, favor assessments on or before the day of surgery for low to medium invasive procedures and before the day of operation for highly invasive procedures. The consensus is for assessments before the day of surgery for patients with lesssevere disease if they are scheduled for highly invasive procedures and for lessinvasive procedures in patients with severe disease. For selected patients, evaluations on the day of surgery can be safe and effective. The importance of a visit to the preoperative clinic before a surgical procedure cannot be overstated.9 A Canadian survey found that more than 60% of patients thought it was important to see an anesthesiologist preoperatively, more than 30% thought it was ex-

TABLE 4–2. American Society of Anesthesiologists Physical Status Classification P1

P2

P3

P4

P5

P6

Healthy patient without organic, biochemical, or psychiatric disease. A patient with mild systemic disease, e.g. mild asthma or well-controlled hypertension. No significant impact on daily activity. Unlikely impact on anesthesia and surgery Significant or severe systemic disease that limits normal activity, e.g. renal failure or dialysis or class 2 congestive heart failure. Significant impact on daily activity. Likely impact on anesthesia and surgery. Severe disease that is constant threat to life or requires intensive therapy, e.g. acute myocardial infarction, respiratory failure requiring mechanical ventilation. Serious limitation of daily activity. Major impact on anesthesia and surgery. Moribund patient who is equally likely to die in the next 24 hours with or without surgery. Brain-dead organ donor.

“E” added to the above (P1–P5) indicates emergency surgery. Adapted from American Society of Anesthesiologists. ASA physical status classification system. Available at: www.asahq.org.


TABLE 4–3. Preoperative Testing Guidelines for Healthy Patients, American Society of Anesthesiologists Physical Status 1 Procedure Type

Invasive Status

Testsa,b,c

Low risk, e.g., breast biopsy, knee arthroscopy, cataracts

Minimal

Intermediate risk, e.g., inguinal hernia or lumbar laminectomy

Moderate

High risk, e.g., thoracotomy, colectomy, or other procedures with expected fluid shifts or significant blood loss

High

Baseline creatinine if procedure involves injection of contrast dye Baseline creatinine if procedure involves injection of contrast dye Complete blood count with platelets, electrolytes, blood urea nitrogen, and creatinine

aResults

from laboratory tests within 6 months of surgery are acceptable unless major abnormalities are present or patient’s condition has changed. bRoutine pregnancy test before surgery is not recommended before the day of surgery. A careful history and local practice determine whether a pregnancy test is indicated. cAge alone is not an indication for an electrocardiogram (ECG). Reimbursement for an ECG depends on indication (pallor, dizziness, hypertension) or a diagnosis documented by history or physical examination. No new ECG is needed if results from an ECG within 6 months of surgery are normal and the patient’s condition has not changed.

tremely important, and more than half indicated that the visit should be before the day of operation.10 Anesthesiologists at Massachusetts General Hospital demonstrated that a preoperative visit before the day of surgery was as good as or better than medication in reducing preoperative anxiety and postoperative pain.

DETECTING DISEASE It has been written that the history and physical examination, often referred to as the clinical examination, frequently are all that are required for a diagnosis or elimination of alternative hypotheses. Several studies have proved the usefulness of the history and physical examination in deciding a diagnosis. A study of patients in a general medical clinic found that 56% of correct diagnoses were made with the history alone and rose to 73% with the physical examination. In patients with cardiovascular disease, the history established the diagnosis 66% of the time, and the physical examination contributed to 25% of diagnoses. Moreover, routine investigations, mainly chest radiography and electrocardiography (ECG), helped with only 3% of diagnoses, and special tests, mainly exercise ECG, assisted with 6%.11 History is also the most important diagnostic

method in respiratory, urinary, and neurologic conditions. The skill of performing a clinical examination derives from pattern recognition learned by seeing patients and listening to the stories of their illnesses. The diagnostic acumen of the physician is a result of the ability to assimilate and develop an overall impression, rather than just reviewing a compilation of facts.

Medical History One common problem is the variability of the medical history. Asking and recording symptoms in ordinary words leads to greater interobserver agreement between practitioners. History taking is not simply asking the questions; history taking includes interpreting and carefully recording the answers. Complete and thorough histories not only assist in planning appropriate and safe anesthesia care, but also are more accurate and cost-effective in establishing diagnoses than are screening laboratory tests. The patient’s medical problems, past operations, previous anesthesia-related complications, allergies, and use of tobacco, alcohol, or illicit drugs should be documented. Equally important to identifying the presence of a disease is establishing the severity, the stability, and prior treatment of the condition. A screening review of systems needs special emphasis on airway abnormalities, personal or family history of adverse

events related to anesthesia, and cardiovascular, pulmonary, endocrine, or neurologic symptoms. The patient’s medical problems, previous operations, and responses to questions should elicit further questions to establish the severity of disease, its stability, current or recent exacerbations, and recent or planned interventions. Rarely is a simple notation of diseases or symptoms such as hypertension (HTN), diabetes mellitus (DM), coronary artery disease (CAD), shortness of breath (SOB) or chest pain sufficient. The severity, extent, degree of control, and the activitylimiting nature of the problems are equally important. A determination of the patient’s cardiorespiratory fitness or functional capacity is useful in guiding additional preanesthetic evaluation and predicting outcome and perioperative complications.8,12 Exercise or work activity can be quantified in metabolic equivalents (METS), which refer to the volume of oxygen consumed during an activity. One’s ability to exercise is two-pronged in that better fitness decreases mortality through improved lipid and glucose profiles and reductions in blood pressure and obesity. An inability to exercise may be a result of cardiopulmonary disease. Several studies show that inability to perform average levels of exercise (4–5 METS) identifies patients at risk of perioperative complications. Table 4–4 shows the important components of an anesthesia history. The form can be completed by the patient in person (paper or electronic version), via Internet-based programs, via a telephone interview, or by anesthesia staff. A more detailed discussion of important components of the history for specific medical conditions is presented below (see Medication Instructions).

Physical Examination At a minimum, the preanesthetic examination should include the airway, a heart and lung examination, vital signs, including oxygen saturation, and height and weight. Body mass index (BMI) is one of many factors associated with development of chronic diseases such as heart disease, cancer, and diabetes, and can be calculated from an individual’s height and weight. The two formulas for calculating the BMI are the English and the metric.

43


TABLE 4–4. Sample Patient Preoperative History Patient’s Name Planned Operation Surgeon Cardiologist? 1. Please list all operations (and approximate dates) a. b. c.

44

Age Sex Date of Surgery Primary Doctor

d. e. f.

2. Please list any allergies to medicines, latex, or other (and your reactions to them) a. c. b. d. 3. Please list all medications you have taken in the last month (include over-the-counter drugs, inhalers, herbals, dietary supplements, and aspirin) Name of Drug Dose and how often Name of Drug Dose and how often a. f. b. g. c. h. d. i. e. j. (Please check YES or NO and circle specific problems) 4. Have you taken steroids (prednisone or cortisone) in the last year? 5. Have you ever smoked? (Quantify in ___ packs/day for ___ years) Do you still smoke? Do you drink alcohol? (If so, how much?) Do you use or have you ever used any illegal drugs? (We need to know for your safety.) 6. Can you walk up one flight of stairs without stopping? 7. Have you ever had any problems with your heart? (circle) (chest pain or pressure, heart attack, abnormal ECG, skipped beats, heart murmur, palpitation, heart failure [fluid in the lungs], require antibiotics before routine dental care) 8. Do you have high blood pressure? 9. Have you had any problems with your lungs or your chest? (circle) (shortness of breath, emphysema, bronchitis, asthma, tuberculosis [TB], abnormal chest x-ray) 10. Are you ill now or were you recently ill with a cold, fever, chills, flu, or productive cough? Describe recent changes 11. Have you or anyone in your family had serious bleeding problems? (circle) (prolonged bleeding from nosebleed, gums, tooth extractions, or surgery) 12. Have you had any problems with your blood (anemia, leukemia, sickle cell disease, blood clots, transfusions)? 13. Have you ever had problems with your: (circle) Liver (cirrhosis, hepatitis, jaundice)? Kidney (stones, failure, dialysis)? Digestive system (frequent heartburn, hiatus hernia, stomach ulcer)? Back, neck, or jaws (temporomandibular joint, rheumatoid arthritis)? Thyroid gland (underactive or overactive)? 14. Have you ever had: (circle) Seizures, epilepsy, or fits? Stroke, facial, leg or arm weakness, difficulty speaking? Cramping pain in your legs with walking? Problems with hearing, vision, or memory? 15. Have you ever been treated for cancer with chemotherapy or radiation therapy? (circle) 16. Women: Could you be pregnant? Last menstrual period began: 17. Have you ever had problems with anesthesia or surgery? (circle) (severe nausea or vomiting, malignant hyperthermia [in blood relatives or self], prolonged drowsiness, anxiety, breathing difficulties, or problems during placement of a breathing tube) 18. Do you have any chipped or loose teeth, dentures, caps, bridgework, braces, or problems opening your mouth, swallowing, or choking (circle)? 19. Do your physical abilities limit your daily activities? 20. Do you snore? 21. Please list any medical illnesses not noted above:

22. Additional comments or questions for nurse or anesthesiologist?

YES NO


English formula: £ ¥ Weight in pounds ² -----------------------------------------------------------------´ BMI = ² £ Height ¥ £ Height ¥ ´ × 703 ² ¤ in inches¦ × ¤ ´ in inches¦ ¦ ¤

Metric formula: £ ¥ ² Weight in kilograms ´ BMI = ² -------------------------------------------------------------------Height ¥ × £ Height ¥ ´ ² £¤ ´ in meters¦ ¤ in meters¦ ¦ ¤

or £ ¥ Weight in kilograms ² --------------------------------------------------------------------------------´ BMI = ² £ Height in ¥ £ Height in ¥ ´ × ²¤ ¦ ¤ centimeters¦ ´ ¤ centimeters ¦ × 10,000

See Obesity below for further discussion and for definitions of BMI for adults. Components of the airway examination should include the following13: • Length of upper incisors • Condition of the teeth • Relationship of upper (maxillary) incisors to lower (mandibular) incisors • Ability to protrude or advance lower (mandibular) incisors in front of upper (maxillary) incisors • Interincisor or intergum (if edentulous) distance • Visibility of uvula • Presence of heavy facial hair • Compliance of mandibular space

defense of potential malpractice claims of adverse events. Obesity, HTN, and large neck circumference predict an increased incidence of obstructive sleep apnea (OSA). See Obstructive Sleep Apnea below.

The physical examination contributes 25% of diagnoses in patients with cardiovascular disease. Auscultation of the heart and inspection of the pulses, peripheral veins, and extremities for the presence of edema are important diagnostically and for risk assessment in development of care plans. One should auscultate for murmurs, rhythm disturbances, and signs of volume overload. Murmurs, without a clear etiology (anemia, hyperthyroidism, or pregnancy, with confirmation that the murmur was not present prior to these conditions), warrant further evaluation (see Heart Disease below). The pulmonary examination should include auscultation for wheezing, decreased or abnormal breath sounds, notation of cyanosis or clubbing, and effort of breathing. Observing whether the patient can walk up 1–2 flights of stairs can predict a variety of postoperative complications, including pulmonary and cardiac events and mortality, and aid in decisions regarding the need for further specialized testing such as pulmonary function tests (PFTs) or noninvasive cardiac stress testing.14 For selective patients (e.g., those with deficits or disease who are undergoing neurologic surgery or regional anesthesia) a neurologic examination is necessary to document preexisting abnormalities that may aid in diagnosis or that can interfere with positioning, and to establish a baseline in

PREOPERATIVE TESTING Preoperative testing is performed to evaluate existing medical conditions and to diagnose asymptomatic conditions based on known risk factors for particular diseases. Diagnostic tests can aid in the assessment of the risk of anesthesia and operation, guide medical intervention to lower this risk, and provide baseline results to direct intra- and postoperative decisions. The choices of laboratory tests should depend on the probable impact of the test results on the differential diagnosis and on patient management. A test should be ordered only if the results will impact the decision to proceed with the planned procedure or alter the care plans. The history and physical examination should be used to direct test ordering. Tables 4–3 and 4–5 contain recommendations for testing based on specific medical conditions. Preoperative tests without specific indications lack clinical usefulness and may actually lead to patient injury because of unnecessary interventions, delay of surgery, anxiety, and even inappropriate therapies. The history is

• Thyromental distance • Length of neck • Thickness of neck

Numbering of permanent teeth

• Range of motion of head and neck Because of the relatively frequent incidence of dental injuries during anesthesia, a thorough documentation of preexisting tooth abnormalities is useful. Either a tooth chart (Fig. 4–1) or standard nomenclature (e.g., right upper central incisor, left lower lateral incisor, or right lower bicuspid) can be helpful. A good time to discuss with patients variant options of airway management or techniques other than general anesthesia when applicable, and to prepare patients for possible awake fiberoptic intubation, is after examination of the airway. When challenging airways are identified, advance planning ensures that necessary equipment and skilled personnel are available.

Right upper molar

Left upper molar

1

16 15 14 13

2 Maxillary teeth

3 4 5

12 6

11 7 8 9 10

Right lower molar 32 31 30 29 Mandibular 28 teeth

Left lower molar 17 18 19 20 21 27

22 26

FIGURE 4–1. Dental chart.

25

24

23

45


TABLE 4–5. Preoperative Diagnostic Testing Order Form Healthy patient

䊐

Standard Order CBC w/plt; BUN/Creat; glucose

Standard order for healthy patients having procedure with significant blood loss or in a high-risk category

Disease/therapy/procedure-based indications 46

䊐

AST/AlkP

䊐䊐

`-hCG

䊐

CBC w/plt

䊐

CXR

䊐

ECG

䊐

Electrolytes

䊐

Glucose

䊐

PT/PTT

䊐䊐䊐

Thyroid tests

Cardiovascular, hepatic, intracranial, peripheral vascular, or renal disease; diabetes; morbid obesity; poor exercise tolerance; systemic lupus; use of digoxin, diuretics, steroids; procedures with significant blood loss, with radiographic dye, or in a high-risk category Alcohol abuse, anemia; cardiovascular, intracranial, pulmonary, or renal disease; malignancy; malnutrition; personal or family history of bleeding; poor exercise tolerance; radiation therapy; rheumatoid arthritis; sleep apnea; smoking >40 pack-years; anticoagulant use; procedures with significant blood loss or in a high-risk category Only for active, acute symptoms especially with cardiovascular or pulmonary disease; rheumatoid arthritis; smoking >40 pack-years; systemic lupus; radiation therapy Alcohol abuse; cardiovascular, cerebrovascular, intracranial, peripheral vascular, pulmonary, or renal disease; diabetes; morbid obesity; poor exercise tolerance; rheumatoid arthritis; sleep apnea; smoking >40 pack-years; systemic lupus; radiation therapy to chest or breasts; use of digoxin Cerebrovascular, intracranial, or renal disease; diabetes; malnutrition; use of digoxin, diuretics, or steroids; highrisk procedure Cerebrovascular or intracranial disease; diabetes; morbid obesity; poor exercise tolerance; steroid use Alcohol abuse; hepatic disease; malnutrition; personal or family history of bleeding; use of anticoagulants Thyroid disease; use of thyroid medications

T&S

Procedure with significant blood loss or high-risk category

Urinalysis

Suspected urinary tract infection

BUN/Creat

Alcohol abuse; exposure to hepatitis; hepatic disease; personal or family history of bleeding Possible pregnancy

Abbreviations: AST/AlkP = aspartate transaminase/alkaline phosphatase; `-hCG = `-human chorionic gonadotropin; BUN/Creat = blood urea nitrogen/creatinine; CBC w/plt = complete blood count with platelets; CXR = chest radiograph; ECG = electrocardiogram; PT/PTT = prothrombin time/partial thromboplastin time; T&S = type and screen. With the exception of `-hCG for pregnancy, all tests are valid for 6 months before surgery unless abnormal or patient’s condition has changed. Guidelines may not apply for low-risk procedures where testing is only indicated if the medical condition is newly diagnosed or unstable.

responsible for the diagnosis 75% of the time and is more important than the physical examination and laboratory investigations combined. In addition, the evaluation of abnormal results is costly. Many studies have evaluated the benefits of disease/condition-indicated testing versus screen-

ing batteries of tests. Few abnormalities detected by nonspecific testing resulted in changes in management, and rarely have such changes had a beneficial patient effect.15 At most 1 in 1000 patients has benefited from findings derived from nonindicated testing.16 Blery et al. found that 0.4% of

tests without specific indications provided useful clinical information.15 However, 1 in 2000 preoperative tests resulted in patient harm from pursuit of abnormalities detected by those tests; only 1 in 10,000 was of benefit to the patient.6 It has been suggested that not following up on an abnormal result is a greater medicolegal risk than not identifying the abnormality to begin with. Preoperative ECGs are one of the most frequently ordered and costly noninvasive tests. Preoperative ECGs are ordered because occult heart disease is common in the middle-age population and increases with advancing age; preexisting heart disease increases perioperative risk; and establishing a baseline value is desirable. However, a resting ECG is not a reliable screen for CAD and is a poor predictor of heart disease (without a supporting history) in nonsurgical patients. It appears that only some ECG abnormalities are important in the perioperative period (e.g., new Q waves and arrhythmias). One study found only 2% of patients had one or both of these abnormalities.17 It has been estimated that the frequency of silent Qwave infarctions found only by ECG in men age 75 years or older (the highest risk group) is 0.5%. Gold et al. found that in ambulatory surgical patients, the incidence of abnormal ECGs was 43%. Only 1.6% (12/751) of patients had an adverse perioperative cardiac event and in only half (6/751) of these was the preoperative ECG of potential value.18 Many abnormalities may have implications for anesthesia care beyond the detection of CAD. Arrhythmias, such as atrial fibrillation, which should be detected on physical examination and confirmed by ECG, conduction abnormalities, and left ventricular hypertrophy, may alter anesthesia plans. Adjustments may be necessary to avoid hemodynamic instability, ischemia, or pulmonary edema because of drug interactions or the stress of surgery combined with previous, but not necessarily clinically significant, disease. Plans can be made on the day of operation when monitors are placed in the preoperative area or the operating room rather than incurring the expense of a 12-lead ECG beforehand. Unfortunately, the specificity of an ECG abnormality for predicting postoperative cardiac complications is


only 26%; consequently, a normal ECG does not exclude cardiac disease.19 The ACC/AHA Guidelines for Perioperative Cardiovascular Evaluation for Noncardiac Surgery consider ECG abnormalities (other than Q waves) as a minor predictor of complications.8 History is far more important. An abnormal ECG will be found in 62% of patients with known cardiac disease, in 44% of patients with strong risk factors for ischemic heart disease, and in only 7% of patients older than 50 years with no risk factors. Even more significant is that results are abnormal in only 3% of patients between ages 50 and 70 years without risk factors for heart disease.20 Tait et al. suggested that routine preoperative ECG testing is not indicated in patients without a history of cardiovascular disease and no significant risk factors.21 In summary, the prevalence of abnormalities on ECG may incur costly evaluation, delaying necessary surgery, and the yield of these workups is quite low. Tables 4–3 and 4–5 list the indications for ECG testing. Coagulation studies (platelet count, prothrombin, or activated partial thromboplastin time) are not recommended unless the patient history suggests a coagulation disorder or the procedure is high risk. Given a patient’s negative history for a bleeding disorder, the cost of screening coagulation tests before minor surgery outweighs the benefit. Many practitioners mistakenly believe that a screening prothrombin time (PT) is more likely to be abnormal because of the numbers of patients with liver disease, malnutrition or warfarin use, conditions that should be readily identified by history. If “screening” tests (not based on history) are ordered, a platelet count and activated partial thromboplastin time (aPTT) are indicated to detect the uncommon patient with thrombocytopenia, an acquired anticoagulant (e.g., lupus anticoagulant) or a reduced level of a contact activation factor (e.g., von Willebrand disease or factor VIII, IX, XI, or XII deficiencies). Additionally, a short aPTT may be equally as important as a prolonged aPTT. A short aPTT increases the risk of postoperative thromboembolism. The Centers for Medicare and Medicaid Services (CMS) does not reimburse for “routine” or “preoperative” PT/partial thromboplastin time (PTT) without an appropriate International Classification of Diseases (ICD-9) code.22

There are few data to recommend age-based testing. No correlation has been established, independent of coexisting disease, a positive history, or findings on physical examination, between age and abnormalities in hemoglobin (Hgb), serum chemistries, radiographs, or PFTs.16,23,24 Chest radiographs are indicated only in patients with pulmonary signs or symptoms of undetermined cause or severity. Hgb and hematocrit (Hct) levels are frequently abnormal in otherwise healthy patients, but rarely impact anesthetic care or management unless the planned procedure involves the potential for significant bleeding. Even though ECG abnormalities are more common with advanced age, abnormalities alone do not predict postoperative cardiac complications in the elderly.18,19 Significant abnormalities that impact care are rare in the absence of a history or symptoms of cardiac disease.18 Even the ASA Practice Advisory for Preanesthesia Evaluation states, “The Task Force recognizes that age alone may not be an indication for an electrocardiogram.”5 CMS will not provide coverage for agebased ECGs or simply as a “preoperative” test; one must provide a supporting diagnosis with an acceptable ICD-9 code.22 There is much controversy about and no consensus regarding routine pregnancy testing, especially in adolescents. Surveys show that 30–50% of practitioners mandate testing in females of childbearing age, primarily because of the unreliability of the history, especially from minors, and the concern over the potential harm to the pregnancy or fetus with anesthesia and surgery, with the attendant medicolegal implications.25 Opponents of mandatory testing cite the false-positive rate, cost, the belief that history is reliable if taken in privacy, and the paucity of data establishing risks of anesthesia in early pregnancy. When minors are pregnant, their privacy is governed by state laws. One must be familiar with local statutes and how unexpected positive pregnancy results will be handled. With the high reliability of urine testing, it is best to delay testing until the day of operation instead of testing in the preoperative clinic, unless the patient suspects pregnancy or the menstrual period is delayed. This delay in testing will obviate a negative test days before surgery that

may be positive on the day of surgery. The ASA Preoperative Evaluation Practice Advisory “[r]ecognizes the literature is insufficient to inform patients or physicians on whether anesthesia causes harmful effects on early pregnancy. Pregnancy testing may be offered to female patients of childbearing age and for whom the result would alter the patient’s management.”5 Healthy patients of any age undergoing low- or intermediate-risk procedures without expected significant blood loss are unlikely to benefit from any tests (Table 4–3). Exceptions are a procedure with the injection of contrast (screening blood urea nitrogen [BUN] and creatinine levels are indicated), or the possibility of pregnancy (a pregnancy test should be done). Table 4–5 contains the recommendations for diagnostic tests for patients with coexisting diseases, and taking certain medications, or who are scheduled for a high-risk operation or one in which there is anticipated blood loss. In general, tests are recommended only if their results may • Change, cancel, or postpone the surgical procedure. • Change anesthesia management.

and

medical

• Change monitoring or intra- or postoperative care. • Confirm an abnormality suspected from the history or physical examination. The ASA Task Force states that test results are valid and acceptable for up to 6 months prior to the operation if the medical history has not changed substantially.5 Many facilities have developed diagnostic testing guidelines to improve patient care, standardize clinical practice, improve efficiency, and reduce costs. With implementation of guidelines, one facility reduced the tests ordered by 60%, improved testing by 81%, and saved almost $80,000 per year. The Mayo Clinic reduced preoperative testing and its costs without a change in outcomes. A cost-to-benefit analysis found that routine urinalysis for all knee replacement surgery in the United States would cost $1.5 million to prevent 1 wound infection.26 Interestingly, one study found 50% more routine ECGs and 40% more chest radiographs were done in a feefor-service versus a prepaid practice.27

47


Coronary revascularization within 5 years and NO symptom recurrence or Coronary evaluation (stress test, cath) within 2 years with favorable results and NO symptom recurrence

Functional capacity Poor: 26 Edentulous Age >55 years History of snoring Facial hair Mouth opening/jaw protrusion Mallampati classification Mandibular space Obesity

Likelihood Ratio (LR) That Laryngoscopy Will Be Difficult >2 Factors, LR = 2.546

Limited jaw protrusion (Mallampati Class III), LR = 6.544 Mallampati Class III, IV, LR = 1.5–6.0109,110 Thyromental distance 35, LR = 2112

Data from Pearce A.43

native induction techniques, should eliminate the “unconscious patient, can’t intubate, can’t ventilate” scenario. Consequently, it is a major goal of anesthesiologists to predict the potentially difficult airway in advance of anesthetic induction. Tests to Predict Difficult Laryngoscopy Preoperative airway assessment, with the aim of detecting the anticipated difficult airway, has evolved over the years. Currently, a number of strategies exist for systematic evaluation of the airway and various guidelines endorse the use of such strategies.42 Key elements of the airway examination include neck anatomy, neck flexion and extension, thyromental distance, mouth opening, Mallampati score, and, more recently, jaw protrusion and the presence of a beard. Excellent reviews are available of various tests and strategies commonly used by anesthesiologists to assess physical and symptomatic features that may predict difficult laryngoscopy (Table 5–6).43 Mandibular displacement (upper lip bite test) recently was correlated with difficulty of laryngoscopy and may have clinical usefulness.44 Although these various tests and maneuvers are typically simple to perform, they usually have poor sensitivity and specificity, and hence unreliable predictive value.45 This explains the occasional finding of the “unanticipated difficult airway” after seemingly reliable testing preoperatively predicted otherwise.45 Typically, these tests have attempted to correlate symptomatic (e.g. sleep ap-

nea) and anatomic patient features with difficulty of laryngoscopy.43

Difficult Mask Ventilation Although successful laryngoscopy followed by endotracheal intubation constitutes definitive management for an unconscious and apneic patient, ventilation by mask can be a lifesaving maneuver. Despite this fact, the historical precedent for investigators with an interest in predicting the difficult airway has been to focus on laryngoscopy alone. With the potentially lifesaving importance of mask ventilation in mind, however, investigators are beginning to stress both laryngoscopy and mask ventilation in their predictive strategies. In 2000, Langeron et al. estimated the incidence of difficult mask ventilation and identified several predictive physical features: history of snoring, body mass index (BMI) >26, lack of teeth, age >55 years, and beard.46 In 2004, Han et al. devised a scale for categorizing difficulty of mask ventilation. This 4-point scale elaborates on Langeron’s work , which only noted difficult and impossible ventilation, whereas Han’s scale describes four degrees of assessment of ventilation, similar to scales used for laryngoscopy (Table 5–7). Han et al. noted an incidence of difficult mask ventilation of approximately 1.5% in the 3000 patients studied.47 More recently, a study of more than 41,000 patients confirmed the incidence of difficult ventilation to be approximately 1.5% and that the incidence of impossible ventilation was 0.5%.48 This large study by Kheterpal

CHAPTER 5: The Anesthetic Plan for Healthy Patients

TABLE 5–7. Mask Ventilation Scale 0 1

2

3

4

Not attempted Easy mask ventilation (with and without neuromuscular block) Ventilated by mask with oral airway or other adjuvant (with or without neuromuscular block) Difficult mask ventilation—inadequate, unstable, or required two practitioners Unable to ventilate

Data from Han R, Tremper KK, Kheterpal S, and O’Reilly M.47

et al. noted 6 preoperative independent predictors (four of Langeron’s) of difficult mask ventilation: history of snoring, age >58 years, BMI >30, Mallampati class III or IV, limited jaw protrusion, and the presence of a beard (Table 5–8). It should be noted that the only modifiable risk factor is the presence of a beard. These results suggest that the anesthesiologist might consider recommending that the patient shave

TABLE 5–8. Independent Predictors of Difficult Ventilation and Intubation Difficult Mask Ventilation

P-Value

Beard History of snoring BMI >30 Mallampati III or IV Age >50 years Severely limited jaw protrusion

0.0001 0.001 0.0001 0.001 0.01 0.03

Difficult Mask Ventilationa and Difficult Intubationb Severely limited jaw protrusion Thick neck/mass History of sleep apnea BMI >30 History of snoring

0.0001 0.02 0.04 0.05 0.05

Data from Kheterpal S HR, Shanks A, O’Reilly M, and Tremper KK.48 aDifficult mask is a grade III or IV mask (see Table 5–7). bDifficult intubation is a Mallampati grade III or IV laryngoscopic view.

prior to an elective procedure, especially if the patient has several other risk factors for difficult mask ventilation. Table 5–9 illustrates the standard preoperative airway features that we assess and record via electronic data entry at the University of Michigan.

Anticipated Difficult Airway Strategy When a potential difficult airway is identified, it is the anesthesiologist’s responsibility to develop a strategy to manage the airway in the event that general anesthesia becomes necessary. When a truly difficult airway is known or strongly suspected, and general anesthesia is necessary, the usual management plan entails placement of an oral or nasal endotracheal tube while the patient is awake and spontaneously breathing. Several important steps in planning and patient preparation for this process are worth mentioning. The very thought of a potential airway problem can be anxiety provoking. Often, the source of this anxiety stems from the patient’s perception that theirs is a rare problem that places them in grave danger. To allay much of this anxiety, it is helpful to have a frank discussion with the patient and fully inform the patient about the nature of the problem, and the rationale and plan for safely dealing with it. Patients are reassured knowing that the difficult airway is relatively common and that appropriate management poses no untoward danger. Careful anxiolytic sedation is appropriate preoperatively, to the extent that airway compromise is avoided. Antisialagogue premedication (typically glycopyrrolate 0.4–0.6 mg IV) aids greatly in the ability to anesthetize airway mucosa (typically with 2–4% lidocaine). Profound topical anesthesia of upper airway mucosa, combined with judicious sedation, are the key elements in conducting a safe, effective, and comfortable awake intubation.

Special Preoperative Considerations Preoperative Anesthesia Assessment Clinics Currently, the vast majority of patients who present for elective operations are admitted to the hospital on the day of their procedure. Fortunately, most healthy patients can be seen and assessed by the anesthesia team immediately prior to their opera-

TABLE 5–9. Airway Physical Exam Elements Test

Findings

Dentition

Normal Dentures Edentulous Poor dentition Yes/no ≥3 cm 2 mg/dL in the derivation cohort but not the validation cohort.56

Arrhythmias Arrhythmias are a cause and an effect of ischemia. Generally arrhythmias in and of themselves will not precipitate problems unless the heart is already compromised. Therefore, they are of more concern if there is other evidence of cardiac disease. Conditions that may occur in otherwise healthy persons which are of perioperative concern are Wolff-Parkinson-White (WPW) disease and prolonged QT syndrome. These conditions have a bearing on which drugs are selected to treat arrhythmias that might occur.

Valvular Lesions An increase in the sensitivity of echocardiography a couple of decades ago resulted in a plethora of diagnoses of trivial regurgitation. Trivial regurgitation is just that; it is virtually never of consequence perioperatively, even for consideration of endocarditis prophylaxis. Mitral valve prolapse is also quite common, If asymptomatic, it is generally of no concern perioperatively, except in men older than 40 years of age, who will require prophylaxis against endocarditis.60 Detection of any diastolic murmur requires further investigation. Aortic stenosis is of very grave concern to the anesthesiologist, and the discovery of this condition is a primary objective of preoperative assessment. The history may give evidence of some recent change in exercise capacity if this lesion is becoming significant. However, where aortic stenosis is a possibility, the threshold for investigation of a heart murmur

Anemia The general trend is toward greater tolerance of perioperative anemia. However, patients with CAD are an exception to this.66 If this condition is identified far enough in advance of the operation, arrangements can be made for preoperative erythropoietin and iron, intraoperative isovolemic hemodilution, and special ICU maneuvers.67 With advance preparations, transfusion can be avoided in many situations. In addition to disrupting the supply–demand balance, anemia is a marker for other comorbidities.

Age Age greater than 70 years was an independent risk factor in some multivariate analyses,64,68 but not in others.56,65,69 Age in and of itself is probably not a significant risk factor if it is carefully separated from the associated comorbidities. If an MI does occur, however, mortality is higher.68,70

Markers of Inflammation A recent analysis of more than 14,000 women in the Women’s Health Initiative shows that increased CRP is predictive of adverse cardiovascular events.71 Other studies also show it to be an independent risk factor, and a recent workshop by the Centers for Disease Control and Prevention and the American Heart Association concluded that the high sensitivity test for CRP is the recommended marker of inflammation in atherosclerotic disease.72 Whether it can be used to guide perioperative management is yet to be determined.18 B-type natriuretic peptide is a marker of inflammation that is abnormal in advanced heart failure.73 It has a high negative predictive value and might be useful to select out some high-risk patients who do not need echocardiograms to rule out ventricular dysfunction.74

Albumin Low albumin is a marker of overall debilitation and acute-phase reactants, and thus serves as a very good prognostic test for PCC. Unfortunately, this test result does not offer much guidance in perioperative management, aside from possibly a long delay in surgery to allow improved nutrition.

Depression A recent quantitative review suggests that depressive symptoms contribute a significant independent risk for the onset of coronary disease, a risk (odds ratio [OR] = 1.64) that is greater than the risk conferred by passive smoking (OR = 1.25) but less than the risk conferred by active smoking (OR = 2.5).75 Patients with coronary heart disease who also display depressive symptoms have an increased risk of mortality.76 The Neurological Outcome Research Group conducted a prospective study of 555 CABG patients for 6 months and showed that, after adjustment for other risk factors, depression was associated with a 2- to 3-fold increase in risk of death. Patients who were depressed at the time of surgery, but not depressed at 6 months, did not have the same increased death rate.77 This reminds us of the importance of treating depression discovered preoperatively. Again, cooperation with primary care or consultant specialists is critical.

Genetic Polymorphisms Genetic testing is increasingly commonplace, and there is increasing interest in how this might be applied to perioperative risk stratification. Factor V Leiden is a good example of a common genetic polymorphism. However, with the possible exception of cardiac surgery, routine antithrombotic measures are sufficient to counteract the effects of this condition and routine preoperative testing for this is not recommended.17 Some studies show an association of specific genetic polymorphisms with atherosclerotic complications after CABG,78–80 whereas others have not shown strong associations.81 The Multicenter Study of Perioperative Ischemia Research Group showed that certain polymorphisms for platelet glycoprotein IIIa and the degree of platelet activation are related to levels of troponin after CABG, suggesting

CHAPTER 7: Evaluation of the Patient with Cardiovascular Disease

that this platelet polymorphism contributes to perioperative myocardial injury.82 Inflammatory response is also altered by genetic variability of key inflammatory genes.83–86 Genetic variability in β-adrenergic responses may assist in determining who should receive perioperative β-blockers and who should not.87–89 Although not routinely indicated at this time, genetic testing is a significant frontier in perioperative medicine.

Carotid Stenosis In addition to being a marker for cardiovascular disease, carotid stenosis may predispose a patient to perioperative stroke. A common dilemma is whether or not carotid surgery should precede other operations. The risk of serious stroke in patients undergoing a nonvascular operation is less than 1%. It is no higher in patients with bruits than in those without bruits.90 The benefits of carotid surgery in patients with asymptomatic stenosis is small, and likely achievable only in certain centers.91 In the case of coronary artery surgery, selective duplex ultrasound screening for carotid stenosis does have benefits,92 but there is no evidence to support prophylactic carotid endarterectomy before general surgery.93 Even in cardiac surgery patients, most strokes occur in patients without carotid stenosis.92,94 The exception may be high risk patients—those with stenosis >90% and either a history of transient ischemic attacks (TIAs) or elevated creatinine. These patients warrant carotid surgery whether or not they are scheduled for other surgery.95

the cardiac capacity necessary to endure the stress of surgery. Schein’s large study of 18,189 cataract surgery patients showed that foregoing preoperative testing did not result in any change in outcome. The critical element of this study, which is sometimes missed, is that all of these patients were assessed by their primary care practitioners, and any tests required for general health maintenance were done. This study supports the concept that a clinical examination is the irreplaceable foundation of preoperative assessment, and tests are secondary. The ACC/AHA guidelines categorize surgical risk (Table 7–4). Kumar’s study verifies the profound influence of the type of surgical procedure on perioperative risk.69

al functional capacity,97 the accuracy of this test can be improved by actually observing the stair climbing. Girish observed maximum stair climbing in 83 operation candidates. The overall rate of postoperative complications, including cardiac events, arrhythmias, reintubation, atelectasis, and pneumonia, was 25%. The rate in those who could not complete 1 flight of stairs was 89%. No patient able to climb 7 flights of stairs had a complication.98 It is important that the patient be able to climb 2 flights of stairs without developing dyspnea, chest pain, or leg pain. This helps ensure that a poor anaerobic capacity does not coexist with a good aerobic capacity.99 Biccard recently described this and other limitations of a stair-climbing test.100

Functional Status

Clinical Determination of Need for Specific Preoperative Cardiac Investigations

The remarkably simple tool of asking about the functional status of the patient provides good prediction of risk for PCC. It is a descriptor of how much the risk factors impact the patient, and is most useful as a screening tool to select out patients who are very unlikely to have PCCs. Reilly showed that patients who reported they could not climb 2 flights of stairs or walk 4 blocks had twice as many PCCs as those who reported they could.96 Although patient self-description of exercise capacity correlates well with actu-

TABLE 7–4. Cardiac Riska Stratification for Noncardiac Surgical Procedures High

Surgical Procedure Risk The planned surgical procedure defines the overall requirements for preoperative assessment. High-risk operations, such as an abdominal vascular operation, is almost guaranteed to include significant stress from events such as cross-clamping of the aorta. By definition, a vascular operation occurs in a patient with cardiovascular disease. At this level of surgical risk, it is imperative to know that cardiac function has been optimized. At the other end of the spectrum, low-risk operations, such as cataract removal, entails risks not much different from activities of daily living. If the patient can walk to the surgical suite, the patient has probably demonstrated

Increasingly, the options for testing have outstripped the resources for testing; as a result, it is important to be selective. Testing where it is not needed depletes resources needed elsewhere, and may delay surgery needlessly. Selective testing is cost-effective and safe.36 Similar to other aspects of medicine, preoperative assessment of cardiac status should occur in two stages: through a clinical history that defines general risk, then through se-

Intermediate

Lowb

aCombined

(Reported cardiac risk often greater than 5%) • Emergent major operations, particularly in the elderly • Aortic and other major vascular surgery • Peripheral vascular surgery • Anticipated prolonged surgical procedures associated with large fluid shifts and/or blood loss (Reported cardiac risk generally less than 5%) • Carotid endarterectomy • Head and neck surgery • Intraperitoneal and intrathoracic surgery • Orthopedic surgery • Prostate surgery (Reported cardiac risk generally less than 1%) • Endoscopic procedures • Superficial procedure • Cataract surgery • Breast surgery

incidence of cardiac death and nonfatal myocardial infarction. not generally require further preoperative cardiac testing. Reproduced with permission from Eagle KA, Berger PB, Calkins H, et al.42 bDo

105


106

lective tests that further define that risk. The Bayesian theorem states that testing a group with a low prevalence of a given condition results in too many false positives for the information to be useful. The purpose of the clinical assessment is to select patients who have a roughly 5% or greater likelihood of PCCs,101 and in whom further testing will yield a useful change of pretest to posttest probabilities. Applying tests to a lower prevalence (unselected) group is ineffective. A rapid initial assessment of risk can be done by assessing three areas: (a) the number of clinical risk factors present; (b) the type of operation planned; and (c) the functional status of the patient.45 This format is the foundation of the ACC/AHA guidelines, specifically the shortcut to determination of need for cardiac investigation.42 The ACC/AHA guidelines will soon be updated to reflect the increasingly common situation where management of risk does not necessarily need to be preceded by extensive investigation. A modified scheme foreshadowing this is presented below. This is not meant to be yet another competing scheme, but a simplification and refinement of existing schemes. If the patient is not in an emergency situation or experiencing serious cardiac conditions such as unstable coronary syndromes, decompensated congestive heart failure (CHF), significant arrhythmias, and severe valvular disease (all major clinical predicators in the ACC/AHA guideline), then 3 factors will determine the need for preoperative cardiac investigations. Presence of 2 of these 3 factors generally warrants further cardiac investigations (Fig. 7–8).

Functional Status As described above, inability to do 1 flight of stairs is a predictor of increased perioperative risk.96,98 Climbing 1 flight of stairs is equivalent to an aerobic capacity of 4 metabolic equivalents (METS) (Duke Activity Status Assessment)97 and probably represents a capacity to endure postoperative stresses without ischemia.

Presence of Unoptimized Risk Factors Unoptimized risk factors include the conditions categorized as intermediate clinical predictors in the ACC/

Need preoperative cardiac testing if 2 of 3 are present

Angina CAD CHF Diabetes mellitus Renal insufficiency Hypertension

2 Unoptimized risk factors

Poor functional capacity 1 flight of stairs

High risk surgery

FIGURE 7–8. Clinical determination of need for preoperative cardiac investigation.

AHA guidelines (angina pectoris, prior MI, CHF, diabetes, and renal insufficiency) that have not been assessed, managed, and deemed to be under optimal control by a qualified physician. This physician may be the primary care physician, a consultant, or the anesthesiologist. Also considered are other conditions, such as hypertensive urgencies and dyspnea. Often one risk factor that is stable but not fully optimized (e.g., hyperlipidemia, hypertension, smoking) does not warrant further preoperative investigation. Two or more unoptimized risk factors do warrant the change of perioperative management.65,102,103 This is consistent with Lee’s algorithm and the American College of Physicians guidelines where the use of a scoring system results in no further testing unless more than 1 risk factor is present.56,104

Surgical Procedure A planned operation in the high-risk category (Table 7–4) requires consideration of further quantification of risk if there is also poor functional status or presence of 2 unoptimized risk factors. Moderate-risk procedures entail a less than 1% risk of PCC, even in patients with known cardiac disease.32 Very-low-risk procedures such as cataract surgery and diagnostic arthroscopy entail no more risk than activities of daily living; they could be done even with disease that is not fully optimized. Disease management may be required, but could occur postoperatively.

It is important to remember that the patient is an active partner in the risk analysis. If a patient refuses invasive cardiac intervention, then medical optimization is likely all that will be done, regardless of what tests are considered.

PREOPERATIVE CARDIAC TESTS TO FURTHER QUANTIFY RISK If the initial clinical assessment of risk factors shows that further quantification of risk will be useful, it is appropriate to proceed to other tests. These tests are usually good prognostic indicators of outcome, but are not parameters that directly cause risk. The information provided by these second-level tests may not lead to quick, direct modification of risk, as is the case for risk factors. These tests provide prognostic information, and are useful if the information will change the risk above or below some management threshold—for example if the patient is on the threshold for having the operation done at an ambulatory center, or it is not clear whether angina is stable or not. If the patient is already clearly on one side or the other of the threshold, there is no need to apply prognostic indicators. This is another application of the principle that tests are not useful if the pretest probability is very low because the number of false positives (with needless delay of surgery) will be high. Even angiography is imprecise in a low-risk population.40


Resting Cardiac Tests Electrocardiogram An ECG is often done routinely. This test may be useful as a baseline in case of subsequent PCCs, but it is not useful for screening or for diagnostic purposes except in high-risk patients. This is because the specificity of abnormalities is too low. An ECG should not usually be done preoperatively in low-risk operations, unless it would have been done outside of the perioperative period. Having said that, either the presence of 2 risk factors for CAD or diabetes alone warrants having a baseline ECG even in low-risk operations. For baseline purposes, an ECG less than 6 months old is adequate if there have been no clinical changes. If there is a change on the ECG, what does it mean perioperatively? Most studies show that preoperative ST-T– wave changes (ST segment elevation or depression or T-wave inversion) are not associated with worse outcomes.56,108 However, this generalization does not apply to high-risk patients. In a study of exclusively vascular surgery patients, Landesberg showed that ECG changes of LVH and ST depression were predictive of PCCs.52 What about Q waves? Again, if the Q waves would have raised concerns outside of the operation, they should also be investigated before the operation. Liu’s study of surgical patients age 70 years and older suggests ECG changes are not predictive of PCCs. But this study of 386 patients with abnormal ECGs, only 104 (27%) of whom had major Q waves, did not have an adequate sample size to draw firm conclusions.108

Ejection Fraction Transthoracic (2D) echocardiography or radionucleotide ventriculography are used to measure ejection fraction.

Left ventricular dysfunction is a predictor of future cardiovascular events and increased overall mortality.109 Although helpful in monitoring heart failure and valvular disease, if there is concern about ischemia, it is preferable to select other tests.

Measurement of Heart-Rate Variability A decrease in heart-rate variability predicts adverse cardiac outcomes.110 A recent study of high-risk patients showed that a decreased low-frequency-to-high-frequency power ratio before induction of anesthesia predicted adverse cardiac events up to 2 years after the operation.103 A small study by Laitio showed that fractal analysis of certain preoperative heart-variability parameters may be predictive of prolonged postoperative myocardial ischemia in emergency hip operation patients.111 With current analysis methods, the resting cardiac tests give supportive data only. Stress tests are usually needed to define risk or optimization.

Cardiac Stress Tests Cardiac stress tests involve 2 components: a stressor and a test. These can be mixed in any way, but the most common combinations are treadmill ECG, dobutamine echocardiography, and adenosine radionuclide (Table 7–5).

Treadmill Exercise Testing This is the simplest of the stress tests. Treadmill ECG testing is a good firstline test in those patients able to do the exercise.45,112 It is not useful in patients unable to exercise, with ECG changes (left bundle-branch block, pacemaker, WPW, ST elevation at rest), or with a history of revascularization. It produces 30% false positives in women. In practice, if a patient is able to do treadmill

TABLE 7–5. Matching of Stressor and Test in Cardiac Stress Test Test

Stressor

Not all testing is useful. A common case example is a patient with known stable cardiac disease for whom it would be “nice” to have more information. A stress echocardiogram is arranged, and the result is indeterminate. The cardiologist, when faced with the possibility of serious cardiac disease, wants to be sure nothing is missed. This motivation may stem as much from the concern for litigation as from indications for good medical practice. Thus an angiogram is scheduled, and it shows a stenosis amenable to stenting. A stent is placed and clopidogrel started, which means that surgery should be delayed for up to 12 months.47a All this is done for cardiac disease that may have been less hazardous than the indication for operation. Delay of operation is inconvenient at least, probably unnecessary, and possibly dangerous. McFalls showed that there is no benefit in preoperative versus postoperative cardiac intervention in vascular surgery. If this is true for vascular surgery, it is likely even more true for lower-risk operations and lower-risk patients44 (the shortcomings of this study are addressed in Preoperative Invasive Interventions: When Should CABG or PTCA Be Done Preoperatively? below). It is sometimes best to keep a patient off the “cardiac train” of stress test, angiogram, angioplasty, and antiplatelet agent, because once a patient is onboard, the patient is unavailable for elective surgery until the end of the journey. Before purchasing the “ticket” of a stress test, the clinician and patient must be willing to go the full journey. The Dutch Echocardiographic Cardiac Risk Evaluation Applying Stress Echocardiography Group analyzed45 patients with PCCs. They suggest that in intermediate-risk patients, the addition of perioperative β-blockers reduces the risk of PCCs to a level where dobutamine stress echocardiography would not change management.64 Invasive tests, such as angiography, or alternatives, such as intravascular ultrasonography, coronary artery calcium by electron-beam tomography,105,106 cardiac CT,107 or cardiac MRI106 are not discussed. These specialized tests are not generally ordered or interpreted without a cardiology consultation. Second-level tests, for purposes of discussion, are divided into resting cardiac tests, cardiac stress tests, and postoperative tests.

Exercise treadmill Pharmaceutical stimulation (e.g., dobutamine) Vasodilation (e.g., dipyridamole)

ECG

Echocardiogram

Common

Sometimes Common Sometimes

Myocardial Perfusion

Common

107


108

testing, the patient probably does not need further preoperative testing. If further testing is needed, a more accurate test, such as stress echocardiography, is generally preferred. Older has shown that cardiorespiratory exercise testing for anaerobic threshold is useful for identifying highrisk patients who are unlikely to develop diastolic heart failure postoperatively, and therefore are unlikely to need postoperative ICU admissions.25 Unfortunately, few institutions can logistically arrange these tests preoperatively.

Dobutamine Stress Echocardiography This test has the advantage of requiring relatively little time to complete. It is a functional test in that it shows how cardiac function is affected by underlying pathology. Image quality is limited in obesity. Both Kertai’s and Beattie’s meta-analyses show that the receiver operating curve of dobutamine stress echocardiography is better than other tests.113 Table 7–6 summarizes the other characteristics in Kertai’s study.114 Beattie’s analysis, which included 68 studies of 10,049 patients, judged that stress echocardiography was superior to thallium imaging because the negative predictive value of stress echocardiography was superior. Because accuracy and availability vary between locations, each institution may have a different preferred test.45

A common dilemma is whether a dobutamine stress echocardiogram should be postponed in the case of a patient taking β-blockers. Weissman’s study in dogs showed that dobutamine was less able to reproduce ischemia if esmolol was administered.115 If the test is being done to assess whether β-blockade will reduce ischemia, then β-blockers should be stopped before the test. If, on the other hand, the purpose is to see if the β-blockade is providing protection from ischemia, the test should be done with β-blockers on board. If we are trying to minimize preoperative stress, stopping β-blockers may be counterproductive, even if it is informative.

nisms of PCCs. Several new tests for this are showing prognostic value for cardiovascular disease in general, and may prove to be useful in the perioperative period. One of these is brachial artery flow-mediated dilation. In this “stress test” of the vasculature, nitroglycerin dilation is the “stressor” and ultrasonic observation of the brachial artery is the test.117

Postoperative Tests As most ischemia occurs postoperatively and is silent, it makes sense to monitor for it. Postoperative ECG changes suggesting ischemia may be predictive of postoperative morbidity and mortality even in low-risk patients.118,119 Postoperative troponin elevation indicates increased risk of cardiac events.8,120 It is more sensitive than ECGs5 or creatine kinase myocardial band (CK-MB),119 and has become the gold standard for identifying postoperative ischemia. Le Manache studied the postoperative troponin levels of 1136 abdominal aortic aneurysm surgical patients, and found that a slightly elevated level was associated with delayed postoperative myocardial infarction. Discovery of elevated postoperative troponin may represent an opportunity to reduce asymptomatic ischemia.10 Landesberg’s study of major vascular surgery showed a similar correlation of troponin and CK-MB and overall mortality.121

Radionucleotide Imaging This test may be more sensitive than others in this category as it will detect flow anomalies that do not yet cause wall-motion abnormalities; however, it is also less specific. Compared with echocardiography, its accuracy is less affected by obesity, but is altered by large breasts.

Cardiac MRI This is a new test that can combine flow studies with wall-motion studies in remarkable resolution. It is useful for complex high-risk cases, but does not yet have a clear role in preoperative screening. Fuster and Kim published a recent review of this technology.116

Tests of Endothelial Dysfunction As described above, endothelial dysfunction is one of the unifying mecha-

TABLE 7–6. Summary of Clinical Characteristics of Cardiac Tests

Type of Test Radionuclide ventriculography Ambulatory electrocardiography Exercise electrocardiography Dipyridamole stress echocardiography Myocardial perfusion scintigraphy Dobutamine stress echocardiography

No. of Studies

No. of Patients

Mean Age (years)

Proportion of Men (%)

History of CAD (%)

Proportion of DM (%)

Sensitivity (%; 95% Cl)

Specificity (%; 95% CI)

8

532

67.0

83

45

25

50 (32–69)

91 (87–96)

8

893

68.0

72

55

32

52 (21–84)

70 (57–83)

7

685

64.5

72

36

28

74 (60–88)

69 (60–78)

4

850

66.8

78

28

33

74 (53–94)

86 (80–93)

23

3119

65.5

78

40

30

83 (77–89)

49 (41–57)

8

1877

67.3

76

37

16

85 (74–97)

70 (62–79)

CAD, coronary artery disease; CI, confidence interval; DM, diabetes mellitus. Tests are sorted according to ascending sensitivities. Kertai MD, Boersma E, Bax JJ, et al. A meta-analysis comparing the prognostic accuracy of six diagnostic tests for predicting perioperative cardiac risk in patients undergoing major vascular surgery. Heart 2003;89(11):1327–1334. Reproduced with permission from the BMJ Publishing Group. 113


MANAGING RISK: WHAT INTERVENTIONS? Anesthesiologists are well situated to practice perioperative medicine. Increasingly, this includes perioperative optimization of cardiac conditions. Although consultation and cooperation with cardiology specialists are needed for many aspects of this optimization, some interventions are well within the anesthesiologist’s range of skills. This is because it is the anesthesiologist assigned to a case who best knows what information is needed or not needed in order to balance risks, obtain informed consent, and form an anesthesia plan. The anesthesiologist is in the best position to know when detailed investigations would not change any of these decisions, and thus would entail needless delay, expense, and risk. This section focuses on preoperative and postoperative interventions. Interoperative management is addressed in other chapters. Many of the medical interventions for reducing perioperative risk are part of the secondary prevention of cardiac disease. While the perioperative team must limit itself largely to the management required in the perioperative period, this is an ideal time to institute or reinforce long-term cardiac care, especially the simple, proven interventions, such as control of hypertension and diabetes, along with the use of β-blockers and statins.

Preoperative Invasive Interventions: When Should CABG or PTCA Be Done Preoperatively? Because of the known increase in PCCs in patients with cardiac disease, and because initial studies showed increased PCCs after MI, it has been deemed logical to postpone elective operations until the cardiac status is optimized.122 This optimization has generally been either an operation or intensive medical management. Glance, in a decision-tree model, found that proceeding directly to vascular surgery resulted in the poorest 5-year survival (77.4%) compared with 3 screening strategies: (a) screening all patients with a dipyridamolethallium test (86.1% 5-year survival); (b) screening all patients with coronary angiography (87.9% 5-year survival); and (c) selective screening where high-risk patients underwent

preoperative angiography, intermediate-risk patients were screened noninvasively, and low-risk patients proceeded directly to surgery without further testing (86.0% 5-year survival). While the 5-year survival rate was similar in all screening strategies, the cost ($/year of life saved) of selective screening was half that of either nonselective strategy. There was no difference in 30-day outcome between any of the 4 strategies.36 The Asymptomatic Cardiac Ischemia Pilot study randomized 558 patients who had coronary anatomy suitable for revascularization to 3 treatment strategies: (a) angina-guided drug therapy (n = 183); (b) angina plus ischemia-guided drug therapy (n = 183); and (c) revascularization by angioplasty or bypass surgery (n = 192). Two years after randomization, the total mortality was 6.6% in the anginaguided strategy, 4.4% in the ischemiaguided strategy, and 1.1% in the revascularization strategy.123 On the other hand, the following studies raise doubts about the need to revascularize before surgery in reasonably stable cardiac patients. Mason did a decision analysis modeling comparing 3 perioperative strategies for vascular surgery in high-risk patients: (a) proceed directly to vascular surgery with close monitoring of cardiac status and aggressive treatment of myocardial ischemia; (b) perform coronary angiography followed by selective coronary revascularization, then proceed to vascular surgery except in patients with severe, inoperable CAD; and (c) perform coronary angiography followed by selective coronary revascularization, then proceed to vascular surgery in all patients, including those with inoperable CAD. In the best-case analysis of the 4 end points of nonfatal myocardial infarction, stroke, cost, and a successful vascular procedure, the first strategy of proceeding directly to vascular surgery with close monitoring of cardiac status led to better outcomes than either of the coronary angiography strategies.124 McFalls randomized 510 Veterans Administration patients undergoing abdominal aortic aneurysm repair to either coronary artery revascularization before surgery or no revascularization before surgery. Percutaneous coronary intervention was performed in 59%, and bypass surgery in 41%. There was no difference in MI in the first 30 days after surgery or in mortal-

ity at 2.7 years.44 This study excluded patients with more than 50% stenosis of the left main coronary artery from randomization. Drug-eluting stents were not used. This widely quoted study needs to be repeated with these shortcomings addressed. Godet’s group analyzed a cohort of 1152 patients after abdominal aortic surgery in which 78 patients underwent percutaneous coronary intervention. A propensity score analysis was performed. The observed percentages of patients in the percutaneous coronary intervention group with severe postoperative coronary events (9.0% [95% confidence interval (CI), 4.4– 17.4]) or death (5.1% [95% CI, 2.0– 12.5]) were not significantly different than the expected percentages (8.2% and 6.9%, respectively).125 Coronary interventions should be performed as indicated by guidelines used in nonsurgical settings. Whether or not an operation should be delayed depends more on the urgency of the surgery than on the presence of CAD.

Management of Hypertension In 1988, Stone et al. described the effect of a single preoperative dose of β-blocker on mild hypertensives.126 The dramatic reduction in postoperative ischemia made it appear that treatment of hypertension was very important. Subsequent studies suggest the important aspect of this study was not the mild hypertension, but the β-blockers. Hypertension as a risk factor for cardiovascular disease was discussed previously in Specific Risk Factors: Hypertension above. Management is usually elective, and an operation does not need to be delayed unless blood pressure is quite high. There are no evidence-based guidelines on the threshold of hypertension that warrant delay of surgery. The oft-quoted threshold for postponing surgery of 180/110 mm Hg is the result of a recommendation by Goldman and Caldera in their 1979 study which included 5 such patients, none of whom had any complications.68 Rohgi did show an increased risk of cardiac complications in vascular surgery patients whose diastolic blood pressure was >110 despite taking 2 or more antihypertensive medications.37 The important aspect of management of severe hypertension (>180/ 110 mm Hg) is the search for end-

109


110

Medications: What to Start and What to Stop β-Blockers Large studies have demonstrated the benefit of β-blockers after MIs and in heart failure.129,130 There are small studies showing marked benefit from perioperative use. Mangano’s prospective study of 1 week of perioperative βblocker use showed dramatic results in morbidity and mortality extending to 2 years131 (Fig. 7–9).

100 90 Event-free survival (%)

organ damage (cardiac ischemia, renal dysfunction, cerebral impairment). If there is any evidence of end-organ damage, the patient needs emergency care. In the absence of these, the condition is termed a hypertensive urgency, and the treatment goal is to gradually improve blood pressure control. Indeed, rapid reduction of blood pressure has added risks. If these patients are sent to the emergency department, they will be assessed with a clinical examination, ECG, and simple blood tests to rule out end-organ damage. If there is no such damage, they will be started on an oral antihypertensive and sent home. The anesthesiologist can often do this as well as the emergency department. There is probably no need to delay an operation if there is no end-organ damage and improvement in long-term management is underway.51 Blood pressure control must be continued through and beyond the perioperative period.127 Hypertension is the classic condition that may present preoperatively and whose treatment will result in long-term health benefits. Modena has shown that treatment of hypertension results in improvement in endothelial function and reduction in cardiovascular events in 6 months.128 The reasons for treating hypertension may not stem so much from perioperative benefits as from the clear lifelong benefits. Patient compliance is often suboptimal and perioperative attention to this condition by the anesthesiologist will assist greatly in long-term management. Compared to the potent drugs used daily for anesthesia, antihypertensives have great margins of safety. Anesthesiologists need to learn to write prescriptions for long-term hypertension management where needed. Primary care physicians can assume responsibility for titration of medication prescribed perioperatively.

Atenolol

80 70 Placebo

60 50 40 30 20 10 0

0

180

360

540

720

Days after surgery FIGURE 7–9. Event-free survival after surgery: atenolol versus placebo. Event-free survival in the 2 years after noncardiac surgery among 192 patients in the atenolol and placebo groups who survived to hospital discharge. The outcome measure combined the following events: myocardial infarction, unstable angina, the need for coronary artery bypass surgery, and congestive heart failure. The rate of event-free survival at 6 months (180 days) was 100% in the atenolol group and 88% in the placebo group ( P control (INR >2.2) (3 points)

6 points

7–12 points

13–18 points

Nutrition Encephalopathy 224

Albumin Bilirubin Prothrombin time (INR) Total score

Adapted from Pugh RN, Murray-Lyon IM, Dawson JL et al. Transection of the oesophagus for bleeding oesophageal varices. Br J Surg 1973;60:646. Copyright British Journal of Surgery Society Ltd. Reproduced with permission. Permission is granted by John Wiley & Sons Ltd on behalf of the BJSS Lt.

class A. None of the patients in class C survived for more than 1 year, and the overall mortality was 68% at 6 months. Garrison et al.26 reviewed 100 consecutive patients with cirrhosis undergoing intraabdominal surgery (Table 14–6). No patient had variceal hemorrhage. The authors correlated preoperative, intraoperative, and postoperative variables with survival without complications, survival with complications, and in-hospital death. Surgery included open cholecystectomy, common duct exploration, gastrectomy, intestinal resection, liver biopsy, splenectomy, pancreatectomy, vascular surgery, and exploratory laparotomy. Multivariate analysis showed that the features that correlated well with intraoperative and postoperative complications and death were similar to those factors in the Child-Pugh classification. Poor outcome was associated with malnutrition, uncontrolled ascites, late stages of encephalopathy, perioperative sepsis, coagulopathy, and abnormal liver function tests. The average Child-Pugh class (not score) was 2.4 (equivalent to Child-Pugh class C) in nonsurvivors, 1.6 (equivalent to Child-Pugh class B) in survivors with complications, and 1.25 (equivalent to Child-Pugh class A) in survivors without complications. Garrison’s study added two new parameters to those of Child and Pugh that need consideration in evaluating the risk of surgery for patients with chronic liver disease. Sepsis, as evidenced by elevated circulating

white blood cell (WBC) counts and reoperative surgery were highly predictive of complications and death. Their data suggest that patients with chronic liver disease are at high risk for sepsis syndrome whenever they develop respiratory, urinary, or intraabdominal infections in the perioperative period. The mortality rate was 100% for exploratory laparotomy, most likely because these patients had developed spontaneous bacterial peritonitis. Reoperative surgery, for the most part, was performed to control ascites leaking out via the surgical wound, providing another portal of entry for infection. In 1997, Mansour et al. reported results of 92 patients who were undergoing elective and emergency surgery.27 The mortality rate for Child-Pugh class A was 10%; Child-Pugh class B, 30%; and Child-Pugh class C, 82%. For all three groups, mortality rose significantly following emergency surgery (26% overall for elective cases; 50% after emergency surgery). Furthermore, Aranha et al. reported an 83% mortality rate associated with cholecystectomy and common duct exploration for patients with liver disease and a prothrombin time more than 2.5 seconds greater than the control.28 Cholecystostomy and retrograde cholangiography were recommended as options with a much lower mortality (14%).29 There are reports of improved outcome following laparoscopic cholecystectomy in patients with cirrhosis.

Fernandes et al. compared liver disease patients with matched controls.30 The patients with cirrhosis had greater length of stay, longer duration of surgery, greater need for transfusion, more frequent complications, and a higher rate of conversion of open cholecystectomy. Mortality, however, was not significantly greater. There were no ChildPugh class C patients in this series. In fact, 80% were Child-Pugh class A. Shaw reviewed the role for portosystemic shunting and showed a low mortality rate (5–7%) for selected candidates, and for those with early cirrhosis or uncontrolled alcoholism or advanced age precluding transplantation.31

Model of End-Stage Liver Disease The Model for End-Stage Liver Disease (MELD)32,33 has been recommended as a better predictor of outcomes for patients with liver disease than the Child-Pugh strategy for risk assessment. It is widely used for evaluation of the suitability for hepatic transplantation and it is discussed in detail in Chap. 56. The risk of complications and death following major surgery for patients with cirrhosis is high (Table 14–7) and there has been little reduction in these risks despite the advances in surgery, anesthesia, intensive care, and blood component therapy that have evolved over the past 4 decades. Intraabdominal surgery is associated with a highrisk of complications and death in patients with early, moderate, and advanced liver disease. The increased risk is proportional to the extent of liver disease, which is readily estimated by simple clinical and laboratory data. The traditional risk factors of encephalopathy, uncontrolled ascites, malnutrition, abnormal serum albumin and bilirubin, and prolonged prothrombin time should be expanded to include the presence of sepsis and emergency surgery.

BRIEF OVERVIEW OF LIVER DISEASES Congenital and Infantile Liver Disease Biliary Atresia Biliary atresia results from destruction of bile ducts in utero. Infants do not survive childhood with complete atresia. Surgical correction of a distinct

CHAPTER 14: Evaluation of Patients with Hepatic Disease

TABLE 14–7.

TABLE 14–6. Variables Associated with Morbidity and Mortality following Intraabdominal Surgery

Estimated Risk of Major Intraabdominal Surgerya for Patients with Cirrhosis

Preoperative Preoperative Variable

Survivors without Complications

Survivors with Complications

Nonsurvivors

Ascites Malnutrition Emergency surgery Infection Elevated bilirubin Decreased albumin Prolonged PT (> control) Prolonged PTT (> control) Child-Pugh classa

12.5% 7.5% 15% 7.5% 1.2 mg/dL 3.7 g/dL 0.3 sec 3.0 sec 1.25

33% 16.7% 40% 16.7% 2.0 mg/dL 3.3 g/dL 1.5 sec 0.8 sec 1.6

70% 43% 80% 47% 4.1 mg/dL 2.5 g/dL 4.5 sec 7.9 sec 2.4

Operative Variable

Mortality if Present (%)

Mortality if Absent (%)

Ascites Malnutrition Emergency surgery Infection Elevated bilirubin Decreased albumin Prolonged PT Prolonged PTT Child-Pugh class A Child-Pugh class B Child-Pugh class C

58 62 57 64 62 58 47 54 10 31 76

11 22 10 21 17 12 7 18 50 30 18

Postoperative Variable

Mortality if Present (%)

Mortality if Absent (%)

Lung failure Heart failure Renal failure Liver failure Infected ascites Ascitic leak Second operation Blood >2 units FFP

100 92 73 66 85 82 81 69 61

0 8 9 8 16 18 20 22 19

Child-Pugh Classification

Mortality

A B C

10% 30% 80%

aDoes not include orthotopic liver transplantation. Data derived from Child CG and Turcott JG;25 Pugh RN, Murray-Lyon IM, Dawson JL, et al; 11 Garrison RN, Cryer HM, Howard DA, and Polk HC Jr;26 and Mansour A, Watson W, Shayani V, and Pickleman J.27

Operative

Postoperative

Reye syndrome has been tied to salicylate ingestion and the incidence has fallen as acetaminophen is substituted for salicylates in children with viral illness.

Wilson Disease

_1-Antitrypsin Deficiency

Child-Pugh class calculated assigning a numerical value of 1 for class A, 2 for class B, and 3 for class C. FFP, fresh frozen plasma; PT, prothrombin time; PTT, partial thromboplastin time. Adapted with permission from Garrison RN, Cryer HM, Howard DA, and Polk HC Jr.26

Reye Syndrome Reye syndrome is an acute encephalopathy precipitated by aspirin therapy for children with acute viral infection. In the United States, the incidence of

Hemochromatosis Chronic excessive iron exposure causes hepatic fibrosis ( hemochromatosis) irrespective of whether the accumulation is the result of multiple transfusions or abnormal absorption and accumulation of dietary iron. Hemochromatosis leads to cirrhosis and hepatocellular carcinoma. Hereditary hemochromatosis results in macronodular cirrhosis, diabetes from pancreatic fibrosis, and cardiac iron deposition, often with heart failure, conduction abnormalities, and coronary atherosclerosis. This disease is an autosomal recessive metabolic disorder. Although present from birth, tissue injury does not begin until age 30 to 40 years. Iron toxicity is controlled by aggressive removal of blood. Multiple organ (heart, liver, pancreas) transplantation may be required.

aAverage

segment of biliary atresia with a choledochojejunostomy or Kasai procedure (hepatic portoenterostomy) may provide relief from severe jaundice and liver failure until liver transplantation can be performed.

cornea. The plasma ceruloplasmin level is decreased. However, Wilson disease is not a failure to produce ceruloplasmin; it is a failure of copper transport followed by coupling to ceruloplasmin. Penicillamine therapy chelates copper, leading to improvement of the neurologic symptoms and prevention of cirrhosis. Fulminant hepatic necrosis can occur in 25% of cases, and requires urgent liver transplantation. Patients with Wilson disease require uninterrupted penicillamine therapy in the perioperative period.

Wilson disease consists of progressive lenticular degeneration associated with cirrhosis of the liver. It is an autosomal recessive abnormality of copper metabolism and results in characteristic, greenish Kayser-Fleischer rings in the

_1-Antitrypsin is an enzyme inhibitor produced in the liver that inhibits key proteases (such as trypsin) and neutrophil elastase. Two genes (Pi or protease inhibitor gene), one received from each parent, control the produc-

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Potential Complications of Advanced Liver Disease That Should Be Explored during the Consultation with the Patient

226

• Ascites: The patient’s diuretic therapy would suggest that the patient has longstanding ascites with poor control. • Variceal Hemorrhage: The patient has a history of one episode of variceal hemorrhage. This is suggested by the patient’s therapy with propranolol. • Jaundice: The patient has not been jaundiced but jaundice is unusual in patients with autoimmune hepatitis. • Malnutrition: The patient weighs 220 lb and is 74" tall. Some of the patient’s weight is attributable to the patient’s ascites. On examination the patient shows some evidence of muscular wasting. • Encephalopathy: The patient was hospitalized once for grade II hepatic encephalopathy (see Table 14–9). The patient is on a low-protein diet and is being treated with lactulose, both of which suggest that the patient is at risk of developing encephalopathy. • Hepatorenal Syndrome: The patient has no history of renal dysfunction. • Hepatopulmonary Syndromes: The patient has no evidence of hepatopulmonary hypertension or hepatopulmonary syndrome. • Spontaneous Bacterial Peritonitis: The patient has no history of hospitalization for peritonitis or unexplained abdominal pain. • Sepsis: The patient has an infected hip prosthesis. • Hyperdynamic Circulation: The patient’s blood pressure is 105/75 mm Hg, and the patient’s pulse is 85 beats/min. These are consistent with hyperdynamic circulation but confirmation will be obtained at the time of pulmonary artery catheterization.

tion of _1-antitrypsin. There are many alleles but only two are associated with disease. M is the normal allele; S and Z are the two alleles that are clinically significant. Silent genes result in complete lack of _1-antitrypsin production. The normal genotype is PiMM. The abnormal genotype, PiZZ, causes emphysema and, in approximately 20% of patients, cirrhosis. The PiSS and PiMZ do not cause lung disease. The PiSZ genotype presents some increased risk of lung disease.

Liver disease can be associated with the PiMZ and PIZZ genotypes.

Other Inherited Liver Diseases Hereditary tyrosinemia is an autosomal recessive inborn error of metabolism that results in progressive liver disease and possible acute liver failure early in life. There are at least 10 defects in glycogen synthesis or storage that affect the liver, skeletal muscle, and red and white blood cells.34 For the most part

all result in excessive amounts of glycogen stored in these tissues. The mucopolysaccharide storage disorders are a group of lysosomal storage disorders associated with deficiencies of the lysosomal enzymes required for normal sequential degradation of glycosaminoglycans. Abnormal lysosomal enzymes lead to lysosomal storage diseases such as Hurler syndrome, another autosomal recessive abnormality.

Nutritional Liver Disease Nonalcoholic Fatty Liver Disease Nonalcoholic fatty liver disease (NAFLD) is prevalent in the obese population.35 In a prospective study of 1124 asymptomatic patients referred for evaluation of abnormal liver function tests, 73 of 81 patients without markers for liver disease (infection, metabolic, autoimmune, hereditary, alcoholic, toxic) were found to have some degree of steatosis on liver biopsy.36 NAFLD is believed to be the most common cause of abnormal liver function tests in the United States.37 It is most prevalent in morbidly obese patients with type 2 diabetes mellitus.38 Paradoxically, it occurs frequently following bariatric surgery.39 In its earliest stage, NAFLD is manifested by macrovesicular fatty infiltration of less than one-third of hepatocytes (grade 1), mostly in zone 3, with minimal inflammation (Fig. 14–6). Serum transaminases are elevated and ultrasonography demonstrates a diffuse increase of echogenicity. Zone 3

FIGURE 14–6. Histologic findings with nonalcoholic fatty liver disease. A. Photomicrograph shows macrovesicular fatty infiltration, an inflammatory infiltrate, Mallory hyaline deposits, and hepatocyte ballooning. B. This panel shows zone 3 fibrosis in a pattern typical of nonalcoholic liver disease as opposed to that seen in alcoholic liver disease. (Adapted with permission from Angulo P. Nonalcoholic fatty liver disease. N Engl J Med 2002;346:1221. Copyright 2002, Massachusetts Medical Society. All rights reserved.)


TABLE 14–8. Clinical and Chemical Characteristics of Viral Hepatitis

Disease

Viral Particle

Hepatitis A

RNA

Hepatitis B

DNA

Hepatitis D

Defective RNA

Hepatitis C

RNA

Hepatitis E

RNA

Hepatitis G

RNA

Immunization and Treatment

Transmission

Testing

Course

Fecal–oral contamination of food or water Sexual and familial contact Blood products Intravenous drug abuse Healthcare workplace exposure Immunocompromised patients Intravenous drug abuse Blood products Immunocompromised patients Blood products Intravenous drug abuse Sexual contact Healthcare workplace exposure

HVA-AB

Vaccine HIG

HVBsAg HVBeAg HVB-AB HVB-AB HBV DNA

Self-limited icteric disease FHF rare Subclinical anicteric illness, or full recovery in 4–6 months, or chronic active hepatitis High incidence of FHF

HVD-AB HVD RNA

Coinfection with hepatitis B Chronic active hepatitis

Protection with hepatitis B vaccination

HVC RNA

hIG and antiviral therapy (exposure) Interferon No vaccine

Fecal–oral contamination of water in tropical climates Possibly blood products Unknown

HVE-Ag HVE-AB

Subclinical hepatitis Chronic active hepatitis common FHF rare Cirrhosis and hepatocellular carcinoma Self-limited FHF a risk during pregnancy Uncertain May coexist with hepatitis C

Vaccine HIG Corticosteroids Interferon Antiviral therapy

Vaccine pending None

FHF, fulminant hepatic failure; HIG, human immunoglobulin; HVA, homovanillic acid; HVB, hepatitis B; HVC, hepatitis C virus; HVD, hantavirus disease; HVE, hepatitis E. Data from Hoofnagle JH, di Bisceglie AM. The treatment of chronic viral hepatitis. N Engl J Med 1997;336:347.

fibrosis may be focal or extensive (stage 1 fibrosis). Grade 2 steatosis is a more advanced form of NAFLD, involving up to two-thirds of the hepatocytes with extensive fibrosis in the periportal areas. Grade 3 (more than two-thirds of hepatocytes), stages 3 and 4 (bridging fibrosis and cirrhosis), is an advanced form of the disease.40 In this respect, NAFLD is difficult to distinguish from alcoholic liver disease. It is hypothesized that NAFLD is an abnormality of lipid uptake, synthesis, degradation, or secretion resulting from insulin resistance.35 Although NAFLD is an infrequent indication for liver transplantation,41 it has the potential to be a precipitating cause of postoperative liver dysfunction.

Acquired Liver Disease Viral Hepatitis Viral hepatitis is a broad collection of illnesses that have hepatic dysfunction as the only common thread. The etiology, modes of transmission, clinical course, and late complications are different (Table 14–8).42

All forms of viral hepatitis show diffuse acute inflammation with leukocyte and histiocyte infiltration followed by hepatic necrosis and regeneration with recovery. Zone 3 hepatocytes suffer the greatest injury. Inflammation may be limited to zone 3 in mild forms of viral hepatitis, or it may extend to the entire acinus in fulminant hepatic necrosis. When the entire acinus is involved the patients will eventually develop postnecrotic scarring with fibrosis (bridging fibrosis). Hepatitis A is the least severe of the known forms of viral hepatitis. The fecal–oral route as a contaminant of drinking water or food, especially uncooked shellfish, causes hepatitis A. The incubation period for the disease is approximately equal to or greater than 15 days and plasma transaminases and bilirubin levels may not rise until several weeks into the course of disease. Although recovery may take several weeks to months, most patients with hepatitis A have an unpleasant course but uncomplicated recovery. Fulmi-

nant hepatic necrosis with liver failure requiring transplantation is extremely rare with hepatitis A infection. Hepatitis E is a form of viral hepatitis that is very similar to hepatitis A. It occurs in developing countries where there is fecal contamination of the drinking water. Fulminant hepatic failure following hepatitis E infection can be a serious complication of the third trimester of pregnancy.43 Hepatitis B is often an anicteric illness; however, hepatitis B can lead to either fulminant hepatic necrosis and liver failure or chronic hepatitis. Hepatitis B is a viral infection of the liver caused by a complex virion that contains double-stranded DNA, DNA polymerase, a surface antigen (HBsAg), a core antigen, and the e antigen. HBsAg was first identified in two patients who had received multiple transfusions for hemophilia when their serum, which had antibodies to HBsAg, was tested in a panel that contained an antigen from an Australian aborigine. The antigen was called the “Australian Antigen” and was sub-

227


228

sequent identified as the antigen of viral hepatitis B. The antigens and antibodies found in patients with hepatitis B form the basis for both diagnosis and prognosis. HBsAg is present in the bloodstream during the acute phase of the disease and persists for more than 6 months if the patient becomes a carrier of hepatitis B. HBsAg disappears with recovery and is replaced with the antibody (anti-HB) to HBsAg. Antihepatitis antibodies (anti-HBs) persist and are evidence of prior hepatitis B infection or exposure. Serum IgM antibodies to the core antigen (HBcAb) rise during the acute phase of infection and then disappear. Hepatitis B is spread by sexual contact or exposure to blood products. Evidence of exposure to blood products by positive anti-HBs has been a common finding in surgeons and anesthesiologists who have been in practice for years prior to the availability of hepatitis B immunization and the adoption of universal precautions. Today, hepatitis B vaccination of healthcare workers is mandated by institutional regulation. Body fluids, including blood, urine, saliva, and semen, have been shown to carry hepatitis B virus (HBV) DNA in samples obtained from HBsAg-positive patients. HBsAg is found in approximately 0.1% of potential first-time blood donors. In other areas of the world, especially Africa and Asia, the incidence is higher. HBsAg is routinely tested for by radioimmunoassay in all donors in the United States and Europe. High-risk populations are identified by predonation questionnaires. Testing has contributed significantly to the reduction in the risk of viral hepatitis from the transfusion of blood or blood products. There are reports of healthcare workers who become carriers for hepatitis B and have transmitted the disease to patients,44 and of a cardiac surgeon who transmitted hepatitis C virus.45 Hepatitis D is a severe viral infection of the liver that occurs as a coinfection of a patient with acute hepatitis B or as a superinfection in a patient with chronic hepatitis B, but hepatitis D does not cause hepatitis independently. In western cultures, it occurs most often in patients with a history of intravenous drug abuse, but healthcare workers and transfusion recipients are also at risk, as are other

patients who have acquired acute or chronic active hepatitis B. The virus of hepatitis C is an enveloped single-stranded RNA virus. Immunologic identification of infection with the hepatitis C virus (HCV) can be difficult. Antibodies against hepatitis C may not be present for long periods following initial infection. This has important public health implications because of the prevalence of asymptomatic carriers, approximately 0.5–1.0% of blood donors in the United States. Routine testing of donated blood for HCV and HIV by polymerase chain reaction (PCR) has reduced the incidence of transmission of hepatitis C and HIV to approximately 1:2,000,000 transfusions. PCR testing is not available for HBV, thus the incidence is much higher at 1: 75,000. Testing for HBV does include HBsAg and HBcAb. Additional blood testing to meet current FDA and American Association of Blood Banks standards includes screening for syphilis, human T-cell leukemia, anti-HBcore, and HIV-Ab (human immunodeficiency virus antibody). Much like hepatitis B, those patients at increased risk of hepatitis C include recipients of blood products, intravenous drug abusers, hemophiliacs, and healthcare workers following hollow needle sticks. Sexual transmission of hepatitis C may be possible. Hepatitis C rarely causes fulminant hepatic failure; in fact subclinical, chronic, nonicteric infection is fairly common. Unfortunately, about half of the patients with acute hepatitis C infection will have evidence of ongoing hepatitis after 1 year. At least 20% of these patients will eventually develop cirrhosis. These patients are also at high-risk of developing hepatocellular cancer through several possible immunologic and genetic events.46 There is no vaccine yet to prevent hepatitis C infection. An RNA virus has been identified in the serum of blood donors and blood recipients that may be responsible for the remaining portion of cases of transfusion hepatitis. This virus has been classified as non-A, non-B, and non-C.47 However, many of the patients who have received blood products containing this RNA virus did not develop clinical or laboratory signs of hepatocellular injury. In the few cases that have been followed for months to a few years, hepatitis G virus RNA has

been present in the serum of some patients, suggesting the possibility of a persistent viral infection, but the target organ may not be the liver.48 To add to the confusion on this issue, the so-called hepatitis G virus may be an agent that coexists with the hepatitis C virus. Hepatitis can occur from systemic infections caused by other viruses such as the Epstein-Barr virus (infectious mononucleosis) and cytomegalovirus. These are important infections of immunocompromised patients.

Chronic Hepatitis The histologic findings on needle biopsy of the liver will define several types of chronic hepatitis including, in order of severity, chronic persistent, chronic lobular, mild chronic active, and severe chronic active hepatitis. The extent of portal hepatitis, the degree of necrosis, and the presence of fibrosis all indicate increasing severity. Viral hepatitis, autoimmune hepatitis, and drug-induced hepatitis are the most common causes of chronic hepatitis. Of the viral diseases, hepatitis B and hepatitis C are the most important. When all other causes of hepatitis have been eliminated, there remains a group of patients with cirrhosis with no identifiable etiology. These patients are given the diagnosis of cryptogenic cirrhosis, a diagnosis of exclusion, but one with the features of advanced cirrhosis. The role of liver transplantation for the treatment of chronic hepatitis is discussed in Chap. 56.

Toxic Liver Disease Alcoholic Liver Disease The excessive daily consumption of alcohol can lead to alcoholic hepatitis, especially in individuals with a lowcalorie and low-protein diet. Ingestion of 80 g of alcohol a day places the individual at risk for alcoholic hepatitis, a precirrhotic lesion. Chronic consumption of lower doses of alcohol may lead to fatty infiltration of the liver and, eventually, to cirrhosis of the liver. Alcohol is metabolized by alcohol dehydrogenase to acetaldehyde. Acetaldehyde dehydrogenase is the ratelimiting step in eliminating acetaldehyde, but it can be overwhelmed when large amounts of alcohol are ingested. Acetaldehyde, when it cannot be rapidly eliminated, is toxic to a number of


Acetaminophen Toxicity Suicide attempts are the most common cause of acetaminophen-induced hepatic necrosis and subsequent fulminant hepatic failure. The lethal adult dose of acetaminophen is ap-

Sulfate Acetaldehyde

Glucuronide

Alcohol Enzyme induction

Acetaminophen

P450 enzymes mixed function oxidase Inactive metabolites

Glutathione

Mercapturic acid

Acetylcysteine

+

Toxic metabolites

Binding to macromolecules

Hepatocellular injury

Enzyme induction and glutathione depletion

cellular components and can lead to zone 3 hepatic necrosis. Alcohol can also be metabolized by the microsomal ethanol-oxidizing system, an alcoholinducible P450 enzyme that also metabolizes acetaminophen. The metabolism of acetaldehyde alters the reduced form of nicotinamide adenine dinucleotide (NADH):nicotinamide adenine dinucleotide (NAD) ratio in the cytoplasm of hepatocytes. This change in energy metabolism leads to fatty acid accumulation in zones 2 and 3 cells, an early feature of alcoholic hepatitis. Severe hepatitis secondary to alcohol ingestion alone is rare; however, a fatty liver and chronic alcoholic hepatitis will lead to cirrhosis. Advanced cirrhosis secondary to long-term alcohol abuse is irreversible and patients will demonstrate the cardinal features of portal hypertension secondary to obliteration of portal venules. In early stages, patients with alcoholic cirrhosis do well, as compared to other causes of cirrhosis, if they can abstain from alcohol and correct their nutritional deficiencies (primarily vitamins and protein) that are associated with alcohol abuse. However, the 5-year survival rate in patients with ascites, jaundice, and variceal bleeding and who are from higher socioeconomic backgrounds, is 50% overall, 40% with continued alcohol abuse, and 60% with abstinence. With patients in lower socioeconomic groups the chance of survival is lower, as low as 50% at 33 months. Chronic alcohol abuse of greater than 90 g per day for more than 5 years can lead to alcoholic cardiomyopathy in addition to cirrhosis of the liver. Alcohol abuse is the leading cause of nonischemic cardiomyopathy in the United States.49 Cardiac performance may improve with abstinence from alcohol. Many patients with alcoholic cirrhosis often have concomitant risk factors for coronary atherosclerosis, others may have cardiac valvular abnormalities requiring valve replacement. Cardiac surgery performed using cardiopulmonary bypass has a high mortality rate, especially in Child-Pugh class B and class C patients.50

FIGURE 14–7. Mechanism of acetaminophen hepatotoxicity. Acetaminophen can be conjugated to a sulfate or a glucuronide prior to excretion. Alternatively, it can be oxidized to highly reactive compounds by P450 mixed function oxidases. Binding to glutathione inactivates these toxic compounds. When glutathione is depleted, the reactive metabolites bind to hepatocellular macromolecules and cause cell necrosis. P450 enzyme activity is induced by chronic alcohol ingestion. Increased P450 enzyme activity can deplete glutathione and enhance the toxic binding to macromolecules. Acetylcysteine can augment glutathione and prevent hepatic necrosis if given early after the ingestion of a lethal dose of acetaminophen. (Courtesy of Richard A. Wiklund, MD.)

proximately 10 g but this can be greatly reduced in patients with concomitant alcohol abuse or preexisting liver disease. Acetaminophen is metabolized by the P450 system in the macrosomes of hepatocytes to metabolites (N-acetyl-p-benzoquinone) binding to cellular macromolecules (Fig. 14–7). Glutathione normally binds to and clears the metabolites of acetaminophen and its depletion may lead to accumulation of toxic acetaminophen metabolites. Acetylcysteine can increase the production of glutathione and may prevent hepatic necrosis if given within the first few hours after acetaminophen ingestion.51 Fulminant hepatic necrosis and acute liver failure can occur 2–3 days following an acetaminophen overdose. Plasma transaminases are markedly elevated during the first few days after ingestion. Coagulopathy can become severe when the international normalized ratio (INR) increases. Severe coagulopathy and encephalopathy are signs of a poor prognosis. The outcome of acetaminophen-induced hepatic necrosis can be predicted by measuring the plasma level of acetaminophen 4 hours after ingestion. Blood levels greater than 300 +g/mL predict that hepatic necrosis will occur. Blood levels less than 120 +g/mL

usually do not result in hepatic necrosis. Acetylcysteine is most effective when given intravenously or orally within 24 hours after the ingestion of acetaminophen, but it may be effective even if given up to 72 hours after ingestion.

Halothane and Other Halogenated Anesthetics Halothane was the first of the modern generation of nonflammable halogenated anesthetic agents that changed the practice of anesthesiology. Halothane, a halogenated alkane, was introduced in the late 1950s. It was followed by methoxyflurane, the first of the halogenated methyl-ethyl ethers, which now include enflurane, isoflurane, desflurane, and sevoflurane. A series of case reports describing fulminant hepatic necrosis following surgery led to a review of 850,000 halothane anesthetics and the famous report of the National Halothane Study.52,53 After other causes of severe acute liver failure were ruled out, 7 cases were identified wherein exposure to halothane was the probable cause. The controversy about the continued use of halogenated anesthetics gradually faded with the subsequent introduction of isoflurane and the replacement of halothane. As much as

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230

17–20% of an administered dose of halothane undergoes oxidative and reductive metabolism, mostly in the liver. Reactive metabolites bind to hepatocellular proteins as haptens to produce antigens that can rarely provoke an immune response evidenced by the appearance of immunoglobulins, an inflammatory response in the liver, eosinophilia and hepatic necrosis. The immunologic basis of halothane hepatitis has been challenged by other theories suggesting hepatic oxygen deprivation (decreased supply and increased demand) or direct toxicity of metabolites may be responsible. Massive hepatic necrosis was seen more often in patients with prior or frequent exposures to halothane. Few patients survived massive hepatic necrosis believed to be caused by halothane, which usually occurred before the era of liver transplantation.

Drug-Induced Liver Disease Many other drugs are hepatotoxic; their toxicity mimics other liver diseases. Carbon tetrachloride, for one, causes zone 3 hepatocyte necrosis. Valproic acid causes fatty infiltration of the liver. Drugs such as NSAIDs, methyldopa, amiodarone, nifedipine, and isoniazid may mimic acute viral hepatitis and chronic active hepatitis. Methotrexate may cause hepatic fibrosis and portal hypertension. Antibiotics, tranquilizers, and sex hormones may cause cholestasis. Sex hormone therapy may also cause thrombosis of portal and hepatic veins. In most cases of drug-induced hepatic dysfunction, recovery occurs following withdrawal of the drug. Recovery may be prolonged with a drug like amiodarone because of its long half-life and the extremely long time required to eliminate metabolites. Furthermore, some drugs can become “locked” in the enterohepatic circulation by the intestinal reabsorption of their toxic metabolites.

Autoimmune and Inflammatory Liver Disease Autoimmune hepatitis, primary biliary cirrhosis, and primary sclerosing cholangitis appear to result from autoimmune mechanisms.54 At times they are difficult to distinguish from each other or from other inflammatory disease such as viral hepatitis. Patients with these autoimmune diseases often do well following liver transplantation.

Autoimmune Hepatitis Autoimmune hepatitis is a disease characterized by autoantibodies against a variety of liver antigens, including mitochondrial and nuclear antigens. It is most common in young women.55 Blood testing shows elevated a-globulins and positive antinuclear antibodies. Early treatment with corticosteroids and antiinflammatory drugs can slow the progression of this disease and delay or prevent the need for liver transplantation.56 Consequently, it is important to distinguish autoimmune hepatitis from other forms of hepatitis with similar histology on liver biopsy. Patients with autoimmune hepatitis may develop cirrhosis and hepatocellular carcinoma if the autoimmune process is not controlled. Jaundice is not common in autoimmune hepatitis and patients often remain well nourished, making them good candidates for liver transplantation. Corticosteroids may produce a remission in the disease and often reduce plasma bilirubin, transaminases, and a-globulin levels. Azathioprine therapy can be used to decrease the dose and side effects of corticosteroid therapy and may eliminate the need for corticosteroids once remission is achieved.57 Primary biliary cirrhosis (PBC) is an inflammatory disease of the intrahepatic bile ducts.58 Ninety percent of patients are women, with onset occurring between the ages of 30 and 70 years. PBC is characterized by severe jaundice, disproportionate to the other features of liver disease and, thus, higher bilirubin levels are used for the Child-Pugh stratification. Human leukocyte antigens (HLAs) expressed in bile ducts appear to be a target for the lymphocytes. Other ductal glands (lacrimal glands, pancreas) are also targets in this disease. Patients with PBC have high serum cholesterol levels. They develop disabling cutaneous xanthomas of their hands and feet and severe pruritus. They may have other autoimmune diseases, such as rheumatoid arthritis, systemic lupus erythematosus, scleroderma (CREST [calcinosis cutis, Raynaud phenomenon, esophageal motility disorder, sclerodactyly, and telangiectasia] syndrome) and Sjögren syndrome. PBC can also cause interstitial lung disease with giant cell granulomas. Serum bilirubin levels rise dramatically as the disease progresses and are

predictive of the length of survival. Once serum bilirubin levels exceed 6 mg/dL, expected survival is less than 2 years.59 However, these patients appear clinically healthier than patients with similar levels of jaundice secondary to alcoholic cirrhosis. PBC patients can do well after transplantation. It is unclear whether they are at risk of developing recurrent PBC in the transplanted liver. Primary sclerosing cholangitis (PSC) is another inflammatory disease of the intra- and extrahepatic bile ducts of undetermined etiology affecting more men than women.60 It may be difficult to distinguish in the early phases from primary biliary cirrhosis. Serum antimitochondrial antibodies are positive in primary biliary cirrhosis and negative in primary sclerosing cholangitis. This inflammatory disease will eventually obliterate the bile ducts and cause jaundice and eventually liver failure. Cholangiography reveals a characteristic beading and stenosis of the common bile duct. Ulcerative colitis is diagnosed in as many as 70% of patients with primary sclerosing cholangitis.61 In addition, PSC patients are at increased risk of developing cholangiocarcinoma. The only successful treatment of primary sclerosing cholangitis is liver transplantation.

Infiltrative Liver Disease Amyloidosis is often not a singleorgan disease and its variants can involve single or multiple organs.62 Each variant involves infiltration of a fibrillar, insoluble protein with a unique pleated structure.63 The liver is involved in most forms of amyloidosis, but infiltration of the kidneys or heart may produce for most of the clinical symptoms. Treatment includes chemotherapy for primary amyloidosis and treatment of the underlying disease in secondary amyloidosis. The causes of death from the amyloidoses include sepsis from the underlying disease, renal failure, or cardiac failure, but not usually liver failure. In rare cases of slowly progressive primary amyloidosis (multiple myeloma), liver transplantation may be recommended for liver dysfunction.64

Malignant Liver Disease Hepatocellular carcinoma (HCC) is rare in Western countries, but common in Asian and African countries. It can present as a discrete encapsulated


mass (most common in Asian countries), as an infiltrative disease, or as a multicentric disease (most common in the United States). Predisposing factors for HCC include chronic active viral hepatitis and hemochromatosis, although it may also be associated with other forms of cirrhosis. Hepatitis C is the leading risk factor for HCC in the Western world whereas hepatitis B is the leading risk factor in Asian and African patients. Other risk factors for HCC include long-standing heavy alcohol abuse, cigarette smoking, diabetes, and fatty liver.65 The incidence of HCC in Asian and African countries correlates closely with dietary exposure to aflatoxin, a carcinogen produced by Aspergillus flavus, a mold that contaminates food in these continents.66 _-Fetoprotein is a biochemical marker for HCC. Serial plasma levels correlate with the growth of HCC, as well as with improvement following tumor mass resection. Ultrasonography, CT scanning, and MRI are helpful in diagnosing and localizing HCC tumors for diagnosis and biopsy, but their value is decreased in patients with cirrhosis characterized by large areas of fibronodular regeneration. Hepatic resection for HCC in patients with intact synthetic liver function offers a 26% 5-year survival rate. Predictors of survival include excellent preoperative hepatocellular function, the presence or absence of multiple tumors, resection margins free of tumor, and the need for blood transfusion during surgery.67 Liver transplantation as a therapy for limited HCC is now an established therapy (see Chap. 58). Cholangiocarcinoma is a highly malignant disease that is rare in the Western world, but endemic in Asia and those regions where patients are at risk for parasitic infection with the liver fluke (Clonorchis sinensis).68 It is also associated with primary sclerosing cholangitis (see Autoimmune and Inflammatory Liver Disease) and ulcerative colitis. Liver transplantation is contraindicated for patients with cholangiocarcinoma. Patients are often jaundiced and without other signs of liver failure. Diagnosis is established by ultrasonography and CT imaging, and by endoscopic retrograde cholangiopancreatography and biopsy. When the tumor involves the secondary branches of the left and right hepatic ducts it is not resectable, but palliation

can be achieved with stenting of the bile ducts by an endoprosthesis.69

Vascular Diseases of the Liver Hepatic vein thrombosis (Budd-Chiari syndrome) is usually secondary to another systemic disease, often a myeloproliferative disorder.70 This syndrome can be acute or chronic and can be asymptomatic or lead to chronic liver failure. MRI or ultrasonography diagnoses thrombosis of the hepatic vein. Treatment options include anticoagulation in the absence of a coagulopathy, thrombectomy, thrombolysis, transjugular intrahepatic portosystemic shunting (TIPS), or liver transplantation.71,72 Portal vein thrombosis is most often a complication of orthotopic liver transplantation.

Physical Findings Suggestive of Advanced Cirrhosis • Scleral icterus: mild scleral icterus is seen. • Fetor hepaticus: none appreciable • Asterixis: not evident on testing • Neck vein distension: not appreciable • Spider angiomata: angiomata seen on the extremities, thoracic and abdominal walls • Caput medusa: some increased venous distension on the abdominal wall • Abdominal distension with demonstrable fluid wave: present • Palpable liver with appreciable nodular hyperplasia: not appreciated • Splenomegaly: moderate splenomegaly

LIVER FAILURE Acute Liver Failure Acute liver failure or fulminant hepatic failure (FHF) is a catastrophic illness resulting from many of the liver diseases described in this chapter; it develops within 2 weeks of the onset of disease and carries a poor prognosis without transplantation. It occurs so rapidly that patients may not have developed jaundice. Subfulminant hepatic failure, with onset occurring up to 8 weeks after the onset of jaundice, has a better prognosis with some chance of complete recovery. Transaminase levels rise rapidly with FHF but they may fall to normal levels after massive necrosis occurs. Coagulopathy can become progressively more severe. The common features of fulminant hepatic failure include a severe coagulopathy, metabolic acidosis, hypoglycemia, rapidly progressive encephalopathy, and acute renal failure.73 Encephalopathy with severe cerebral edema is the usual cause of death, which may occur while the patient awaits a donor liver (Table 14–9). The most common cause of FHF is acute viral hepatitis (A, B, others). FHF in patients with hepatitis B can be precipitated by suprainfection with hepatitis D. Immunocompromised patients are at high-risk for FHF with acute viral hepatitis, including hepatitis A, B, herpes simplex, Cytomegalovirus, Epstein-Barr, and varicella.74 There is another cause of FHF that needs to be considered in surgical

patients. Alterations of total hepatic blood flow during anesthesia and surgery may precipitate FHF in patients with stable, underlying chronic liver disease. In these patients, acute liver failure is usually noticed on the second or third postoperative day and can be manifested by an unexplained encephalopathy. These patients have adequate hepatocellular function preoperatively but with very little reserve to combat acute stress associated with anesthesia and surgery. Small decreases in hepatic oxygen supply associated with decreased total hepatic blood flow during surgery cause acute hepatocellular ischemic injury and failure. The encephalopathy of FHF is different than that noted with chronic liver failure and the blood ammonia levels are much higher. In addition, amino acids, which can contribute to the encephalopathy, accumulate in the central nervous system and are excreted in the urine as tyrosine and leucine crystals, FHF with grade 3 or worse encephalopathy is associated with an 80% mortality rate. In contrast, two thirds of patients survive if encephalopathy does not proceed beyond grade 2.75 The principal causes of death are cerebral edema, hemorrhage secondary to a severe coagulopathy, and sepsis syndrome secondary to pneumonia. Metabolic derangements seen in FHF may include severe hypoglycemia, hyperinsulinemia, hyponatremia,

231


TABLE 14–9. Grading of Hepatic Encephalopathy Grade

Consciousness

Cognition

Signs

Electroencephalogram (EEG)

0 Subclincal

Normal Normal

Normal Normal

Normal Normal

1

Restless; abnormal sleep pattern Lethargic

Forgetful, confused, agitated Disoriented at times; uninhibited, inappropriate behavior Disoriented, aggressive

None Abnormal on psychometric testing Tremor, ataxia, uncoordinated, impaired handwriting Asterixis, dysarthria, ataxia, hyporeflexia Asterixis, hyperreflexia, Babinski sign, muscle rigidity Decerebration

Abnormal

2 232 3

Somnolent but rousable, confused

4

Coma

None

Abnormal Abnormal

Abnormal

Modified with permission from Riordan SM, Williams R. Treatment of hepatic encephalopathy. N Engl J Med 1997;337:473. Copyright 1997, Massachusetts Medical Society. All rights reserved.

hypokalemia, and lactic acidosis. Respiratory alkalosis may be caused by hyperventilation. Acute renal failure ( hepatorenal syndrome) is seen in as many as 55% of patients with FHF. Acute respiratory failure may be caused by aspiration pneumonitis or form part of the multi-organ failure associated with sepsis. Survival is frequent with transplantation but many patients die while awaiting the availability of a donor organ.

Chronic Liver Failure Chronic liver failure eventually can impair most of the organ systems in the body. Many of the manifestations are caused by the hepatic fibrosis that follows hepatocellular injury. Portal fibrosis produces compression of the portal venules, capillaries, biliary canaliculi and obliteration of hepatocytes. The result is portal hypertension, obstructive jaundice, coagulopathy, encephalopathy and metabolic abnormalities. If the underlying cause of fibrosis is treated effectively, fibrosis of the liver may be reversible.76 In the early stages of chronic liver failure (ChildPugh class A), ascites is controlled with diuretic therapy. In later stages, ascites is uncontrolled and patients develop the protuberant abdomen with a fluid wave on physical examination that is typical of advanced cirrhosis. Portal hypertension leads to abnormal renal function with marked sodium reabsorption in response to a decreased effective circulating plasma volume. Volume receptor stimulation increases renin secretion and

aldosterone production. Urinary excretion of sodium is limited and total body sodium is greatly increased, yet the patients show mild hyponatremia. This forms the basis for therapy with loop diuretics, such as furosemide, and aldosterone antagonists, such as spironolactone. Renal blood flow and glomerular filtration rate can be decreased in chronic liver failure because of the increased intraabdominal pressure caused by ascites, diuretic therapy, and other hemodynamic abnormalities. Ascites is associated with spontaneous bacterial peritonitis (SBP), another life-threatening complication of chronic liver failure. An aerobic gram-negative organism is the usual cause of the peritonitis. It may be truly spontaneous and caused by incidental bacteremia but often follows paracentesis to reduce the volume of ascites. The 30-day mortality rate for SBP is approximately 32%; 1-year mortality 78%.77 Survivors are at high risk of recurrence. Portal hypertension can lead to the development of collateral circulation with large veins in the abdominal and chest walls, the mediastinum, stomach, and esophagus. In extreme cases these venous collaterals can anastomose with pulmonary vessels, leading to portopulmonary shunting. This can produce a high-blood volume, highblood flow state with intrapulmonary shunts, the so-called hepatopulmonary syndrome (HPS). The collateral circulation that occurs with portal hypertension can produce esophageal,

gastric, and intestinal varices that are prone to rupture and bleeding. Obstructive jaundice is a late finding in most forms of cirrhosis and indicates a poor prognosis. Severe jaundice predicts death within a few years. Severe jaundice is usually accompanied by poor synthetic function with coagulopathy, progressive encephalopathy, and severe malnutrition. There are two causes of the coagulopathy associated with chronic liver disease. The first is decreased production of coagulation factors produced in the liver (all except factor VIII); the second

Laboratory Testing Used to Stratify Hepatocellular Function • Emphasized findings are elements of the Child-Pugh classification of liver disease (Table 14–5). • CBC: hemoglobin = 10.2g/dL ; hematocrit = 32%; white blood count = 9500 cells/mm3 • Blood urea nitrogen = 22 mg/dL; serum creatinine = 1.5 mg/dL • Serum sodium = 132 mEq/dL; chloride = 90 mEq/dL; bicarbonate = 28 mEq/dL; potassium = 3.1 mEq/dL INR = 1.4; partial thromboplastin time = 28 seconds • Serum bilirubin = 4.0 mg/dL; albumin = 3.0 g/dL (consider measuring fibrinogen level and factor VII activity) • Aminotransferases: AST = 200 IU/ L; ALT = 300IU/L (aminotransferases are nonspecific; see Fig. 14–3)


is the hypersplenism resulting from portal hypertension. Measuring the INR, plasma fibrinogen level, or direct measurement of coagulation factor activity readily assesses coagulopathy secondary to impaired synthetic function. Hypersplenism with sequestration of platelets is common in advanced liver disease, and results in platelet concentration equal to or less than 70,000/ mm3. Bleeding from thrombocytopenia is uncommon unless it is complicated by other causes of thrombocytopenia, such as active bleeding with either a consumption coagulopathy or a dilutional coagulopathy. Metabolic abnormalities include hypoglycemia, hyperinsulinemia, aminoacidemia and aminoaciduria, respiratory alkalosis, lactic acidosis, hyponatremia, and hypokalemia. If patients require rapid multiple transfusions, hypocalcemia secondary to citrate toxicity may become a problem. Encephalopathy in chronic liver failure is associated with elevation of the plasma ammonia level. However, encephalopathy and neurological manifestations of chronic liver disease are much more complex than simple ammonia intoxication. Ammonia is only one of the many potentially neurotoxic compounds that are produced in the intestines and reach the brain by virtue of the collateral porto-systemic shunting of chronic liver disease. Other compounds that contribute to encephalopathy include octopamine and the aromatic amino acids, tyrosine, phenylalanine, and tryptophan. Normally, the liver extracts all of these compounds from portal vein blood. Central nervous system a-aminobutyric acid (GABA), an inhibitory neurotransmitter, is also increased in chronic liver disease, as are GABA and benzodiazepine receptors in the brain.78 There are other causes of abnormal neurologic findings in chronic liver disease. There can be generalized cortical atrophy and the increased presence of astrocytes often associated with Alzheimer disease. The electroencephalogram (EEG) shows generalized slowing. Vitamin deficiencies can lead to Wernicke encephalopathy (inadequate thiamine and B1), which also contributes to the neurologic findings of chronic liver disease. Portal-systemic encephalopathy is characterized by depressed consciousness, personality changes, slurred speech, apraxia, and a flapping tremor. Severity is graded

from minimal confusion through coma (Table 14–9).79 Grade 4 coma is usually a terminal event. The circulation in chronic liver disease is hyperdynamic and characterized by a markedly increased cardiac index, a low systemic vascular resistance, mild tachycardia, a normal to increased stroke volume, a high mixed venous oxygen saturation, and a poor oxygen extraction ratio. Patients with a normal cardiac index at cardiac catheterization should be considered to have a cardiomyopathy and the differential diagnosis should include ischemic cardiomyopathy, alcoholic cardiomyopathy, and cardiomyopathy secondary to hemochromatosis. Systemic precapillary arteriovenous shunting can cause the hemodynamic changes seen in chronic liver disease. Circulating blood volume is reduced and extracellular fluid volume is often markedly increased. Coronary artery disease in patients with advanced liver disease may require coronary revascularization. Patients who are Child-Pugh class A may tolerate coronary artery bypass grafting (CABG) with cardiopulmonary bypass without an increased mortality, but patients who are class B or C have an elevated risk of death.80 Combined CABG and orthotopic liver transplantation has been performed, but there are insufficient data to support this as a standard approach.81 Two pulmonary syndromes are noted in patients with advanced liver disease. The first is the HPS; the second is portopulmonary hypertension (PPH).82 HPS, as described above, is characterized by pulmonary precapillary and capillary vasodilatation and direct pulmonary arteriovenous communications. This syndrome is associated with 3-fold elevation of exhaled nitric oxide as compared to control subjects.83 The patients are short of breath, cyanotic, and display systemic arterial hypoxemia. Dyspnea with tachypnea and oxygen desaturation is worsened in the upright position, a syndrome described as platypnea and orthodeoxia.84 This is a high-volume/ low-pressure pulmonary blood state with normal right ventricular function and a low pulmonary vascular resistance.85 PPH, on the other hand, is a high-pressure state similar to primary pulmonary hypertension. The right ventricle is often dilated, cyanosis is absent, right ventricular ejection fraction is low, and systemic hypoxia is

rare. These patients may acutely respond to inhaled nitric oxide. Patients with HPS fare better after liver transplantation than do those with PPH.86 Hepatorenal syndrome is a form of renal failure associated with liver disease. It is more common in acute liver failure but also occurs in patients with chronic liver failure. Hepatorenal syndrome is the result of intense renal arteriolar vasoconstriction in response to the functional hypovolemia caused by splanchnic vasodilatation and other physical changes of liver failure.87 Type 1 hepatorenal syndrome typically evolves over less than 1 week and is an indication for urgent liver transplantation.87 Type 2 hepatorenal syndrome develops over a period of months and is less of an emergency. Standard treatment of hepatorenal syndrome includes intravascular volume expansion with administration of albumin, and the reduction of intraabdominal pressure by relieving tense ascites. The prognosis of the hepatorenal syndrome is poor. The administration of a vasopressin analogue, terlipressin, may improve renal function by its action as a splanchnic vasoconstrictor.88 Portal venous pressure reduction by TIPS has been used for hepatorenal syndrome but it is not recommended on the basis of controlled clinical trials.89

APPROACH TO MANAGEMENT Correction of Coagulopathy Fresh-frozen plasma infusion and/or cryoprecipitate administration greatly improve the coagulopathy of either acute or chronic liver failure.90 Recombinant factor VII may also improve the coagulopathy.91,92 Therapy should be guided by measurement of the INR, plasma fibrinogen levels, and specific coagulation factor analysis when available. Patients may require infusion of large volumes of fresh-frozen plasma, which can itself contribute to circulatory overload. If there is evidence of a consumption coagulopathy, aprotinin or ¡-aminocaproic acid can be administered. It is important to avoid the inadvertent administration of small doses of heparin via monitoring lines to patients with a coagulopathy secondary to liver disease. Platelet transfusion is not indicated unless the platelet count is less than 70,000/mm3. Plate-

233


Stratification of the Patient’s Liver Disease Using the Child-Pugh Criteria (Table 14–5)

234

• Ascites: poorly controlled on diuretics = 3 points • Nutrition: mild malnutrition = 2 points • Encephalopathy: well controlled on diet and lactulose = 1 point • INR; moderately prolonged = 2 points • Albumin: hypoalbuminemic = 2 points • Bilirubin: moderately elevated = 2 points • Total = 12 points, Child-Pugh class C, high risk for surgery especially in view of patient’s sepsis

lets can be sequestered in the spleen when the patient has hypersplenism. The coagulopathy can be monitored by the use of the thrombelastogram (TEG).93,94 Coagulopathy (Fig. 14–8) is manifested on the TEG by a delayed onset of coagulation (prolonged R time), decreased or flattened slope (A), and a decreased maximum amplitude (MA). A useful technique to rule out inadvertent heparin administration is to perform a dual assay using heparinase in 1 cuvette of the TEG assay. A normal tracing in the presence of heparinase and an abnormal tracing without suggests a significant heparin anticoagulant effect.

Varices and Variceal Hemorrhage Endoscopic band ligation therapy is the mainstay of treatment to reduce esophageal varices and prevent variceal hemorrhage.95 Treatment with nonspecific `-adrenergic blockers, particularly propranolol and nadolol,96,97 may decrease the size of esophageal varices. However, these agents do not reduce the portal hypertension, which caused the development of the varices. Portal decompression can be accomplished surgically (portocaval shunt, mesocaval shunt, splenorenal shunt) or by means of a transjugular intrahepatic portal vein-to-hepatic vein shunt.98 TIPS has a high complication rate and a mortality rate that is similar to that reported by centers with extensive experience in surgical shunting.99 Preexisting encephalopathy may preclude any form of portal shunting because of the decrease in

abdominal swelling. These procedures include large volumes of fluid removal by paracentesis, peritoneovenous shunting (LeVeen shunt), or TIPS. Large-volume paracentesis leads to progressive wasting of protein but not usually to hemodynamic instability. Slow removal of ascites by paracentesis can relieve the symptoms of massive ascites and improve quality of life for these patients.103 Currently, peritoneovenous shunting is performed infrequently because of the risks associated with the procedure and the lack of advantages over paracentesis and TIPS.104 The risks include hepatic failure secondary to a major surgical procedure in patients with marginal hepatocellular function, the risk of bacterial contamination with subsequent peritonitis, and the risk of a postoperative ascites leak. The procedure can be complicated by thrombosis followed by nonfunction of the shunt. Fluid overload is another consideration in patients who may have a concomitant cardiomyopathy.

ammonia extraction that follows the decrease in portal vein blood flow to the liver.100 Octreotide is a somatostatin analogue101 that has been used for control of nonvariceal upper and lower gastrointestinal bleeding secondary to portal hypertension.102 It is administered as a continuous infusion and produces vasoconstriction of the portal circulation vessels.

Ascites Ascites is the accumulation of an extracellular colloidal fluid in the abdominal cavity as a result of longstanding portal hypertension. It is a consistent finding in patients with cirrhosis, and it is a poor prognostic finding as only 50% of patients with ascites will survive for 2 years.103 The diagnosis of ascites can be made by ultrasonography when it is not apparent on physical examination. Ascites can be controlled by restriction of sodium intake in the diet, by the administration of diuretics, or by abdominal paracentesis. Dietary sodium restriction is often difficult to maintain because of noncompliance. Diuretic therapy includes the use of furosemide and spironolactone or amiloride. Optimal diuretic therapy requires several weeks during which time the balance of sodium intake versus renal excretion of sodium is monitored. Potassium balance is achieved with the use of potassiumwasting diuretics (furosemide) and potassium-sparing diuretics (spironolactone or amiloride). If diuretic therapy is ineffective, invasive procedures may be necessary to relieve tense

Control of Encephalopathy Encephalopathy is present in the majority of patients with cirrhosis, although at times it may only be demonstrated by psychometric testing.105 Because encephalopathy can progress rapidly from subclinical findings to overt coma, it should be anticipated in any patient with cirrhosis undergoing surgery. Encephalopathy is graded according to the level of consciousness, personality and intellectual features, neurologic signs, and electroencephalographic findings (Table 14–6 “Preop-

Parameter R RK MA A LY30

A. Normal B. Coagulopathic

0

1

2

3

4

5

6

7

8

9

10

11

12

13

14

Result 35 mm 55 mm 21 mm 24° 48%

Normal 21–30 mm 35–40 mm 45–54 mm 30–41°

15

FIGURE 14–8. Thrombelastogram. A: Normal onset of coagulation, normal platelet function, no significant fibrinolysis. B: Delayed onset of coagulation (prolonged R value and diminished angle A), evidence of decreased platelet function (diminished maximum amplitude or MA), and early onset of marked fibrinolysis (decreased amplitude at 30 minutes [LY30]). (Courtesy of Richard A. Wiklund, MD.)


erative Values”).79 Standard therapy for the cerebral edema contributing to grade 3 and grade 4 encephalopathy includes endotracheal intubation, moderate hyperventilation, and monitoring and control of intracranial pressure (ICP). ICP monitoring involves substantial risk of intracranial hemorrhage in coagulopathic patients. Control of ICP may prevent seizures, which lead to elevated ICP. Encephalopathy can be improved in the short-term by limiting protein in the diet. Obviously this counters the objective of improving protein nutrition in chronic liver disease, but limitation of protein in the diet will decrease the amount of nitrogenous waste and ammonia produced in the bowel. Ammonia is an uncharged molecule that readily passes into the blood from the gut. It can be converted to ammonium ion in the presence of excess hydrogen ions; ammonium ion does not cross the gut mucosa. Conversion of ammonia to ammonium ion can be achieved by the oral administration of lactulose, an enzyme that increases the acid content of the colon.106 Acidification of the stool traps ammonia as ammonium ion in the gut contents. Neomycin can reduce the number of bacteria producing ammonia from protein. If encephalopathy is life-threatening, charcoal hemoperfusion can be used to eliminate the responsible metabolites from the blood. So can exchange transfusion and extracorporeal organ perfusion.107,108 However, these are experimental therapies used as a strategy that may worsen the coagulopathy and are only a bridge to transplantation.

SUMMARY The liver is a complex organ that serves multiple functions, including protein synthesis, carbohydrate and lipid metabolism, excretion of waste products, drug metabolism, and phagocytosis. Recognizing that each of these vital functions can be impaired with liver disease leads to an understanding of the primary features of liver failure, namely ascites, jaundice, coagulopathy, encephalopathy, altered metabolism, and abnormal fluid balance. Cirrhosis is the final common histologic manifestation of most forms of liver disease.

In the preadmission anesthesia assessment clinic, the severity of liver disease and the risk of surgery can be estimated using the Child-Pugh scoring system, substituting the INR for the prothrombin time. It includes three clinical and three laboratory assessments. The clinical features are the degree of malnutrition, the control of ascites, and the history of encephalopathy; laboratory assessments are determination of the INR, and plasma albumin and bilirubin levels. Each of these 6 parameters can be assessed as normal or near normal (class A), moderately abnormal or fairly well controlled (class B), and markedly abnormal or poorly controlled (class C). The surgical mortality rate, particularly for intraabdominal and other major surgery, is near 10% for patients assessed to be class A, up to 30% for class B, and up to 70% for class C. Preoperative preparation includes correction of coagulopathy by the administration of fresh-frozen plasma or cryoprecipitate, control of ascites with diuretic therapy or paracentesis, and correction of encephalopathy by limiting protein intake and the administration of lactulose. Transfusion of packed red blood cells may be necessary to correct blood loss from bleeding esophageal varices. Preoperative platelet transfusion is usually unnecessary unless the platelet count is less than 70,000/mm3. Prevention of sepsis by minimizing invasive procedures and use of strict sterile technique for the insertion of lines and surgery is extremely important. These steps may reduce the risk of complications or death for surgical patients with acute or chronic liver disease. Acute liver failure should be anticipated in the postoperative period in patients presenting with marginal liver function, especially following intraabdominal procedures, because of the effects of surgery and anesthesia to decrease total hepatic blood flow. Hepatitis B and C viruses are highly infective following exposure. Immunization against hepatitis B virus is critically important for all healthcare workers, especially anesthesiologists and certified registered nurse anesthetists, because it is effective and safe. Hepatitis B can be a fulminant illness with high mortality. Immunization against hepatitis C virus is not available. Exposure caused by accidental hollow-needle sticks can cause acute

hepatitis C infection, which has a high risk of evolving into chronic active hepatitis, cirrhosis, and hepatocellular carcinoma. Most hospitals offer the options for prophylaxis against viral infection following inadvertent needle stick. These include the administration of hyperimmune a-globulin for prophylaxis against transmission of hepatitis C. Universal precautions are effective in controlling the risk of transmission of hepatitis B and C. With current testing standards in the United States, viral infection following the administration of blood products is rare, approximately 1:75,000 to 1: 2,000,000 transfusions.

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CHAPTER 15: Anesthetic Considerations for the Patient with Anemia or Coagulation Disorders

CHAPTER 15 Anesthetic Considerations for the Patient with Anemia or Coagulation Disorders Edwin G. Avery, IV, MD ANEMIA Anemia is a common blood disorder of perioperative patients.1,2 The physiologic consequence of severe anemia to the surgical patient is inadequate delivery of oxygen that may lead to tissue hypoxia, biochemical imbalance, organ dysfunction and ultimately organ damage.3,4 Mismanagement of the anemic surgical patient can adversely affect perioperative morbidity and mortality.5–7 To provide optimal care for anemic surgical patients, the anesthesiologist should understand the laboratory techniques used to assess anemia, as well as the various etiologies and classifications of anemia.

Anemia Defined and Measured Anemia is defined as a reduction of the body’s total red cell mass (RCM). Both hematocrit (Hct) level and hemoglobin (Hgb) concentration measurements reflect the RCM present in the body but do not define it. The Hct level, defined as the fractional volume of sampled blood that erythrocytes occupy, is an indirect measurement of the body’s RCM. The Hct is a simple, inexpensive, commonly used test to indirectly assess the severity of anemia as well as whole-blood viscosity, oxygen-carrying capacity, and RCM.8 Hgb, the predominant component of a red blood cell, serves as the major carrier to transport oxygen within the blood.9 Hgb concentration is a directly measured value that is also used to indirectly assess RCM.10 RCM is most accurately measured using isotopic dilution assays of erythrocytes and albumin that take into account the total volume of red cells and plasma present in any patient. In

everyday clinical practice, Hct level and Hgb concentration are simple assays that are used to estimate RCM because of the impractical nature of using the more costly and complex isotope labeled assays.9,11 Although measurement of Hgb and Hct values generally provide reliable estimates of a patient’s RCM, they inaccurately reflect the total circulating erythrocyte mass under certain conditions.12,13 The importance of considering the measured Hct and Hgb values in the context of overall plasma volume cannot be over emphasized. Hgb and Hct values are influenced by dynamic changes of the plasma volume and thus are subject to error under certain physiologic conditions. Examples of the Hgb or Hct value misrepresenting the RCM are clinical scenarios involving major, acute blood loss. In this situation, the concurrently obtained circulating Hgb and Hct values will overestimate the RCM because the body has not had sufficient time to redistribute fluid from the interstitial space into the intravascular compart-

ment. The Hct and Hgb values will spuriously indicate an increased RCM. A second example of a failure of the Hct and Hgb values to adequately reflect RCM occurs in the physiologic anemia of pregnancy. During normal pregnancy, both the RCM and the plasma volume expand. The plasma volume increases more rapidly and to a greater extent than the RCM and creates an apparent anemia termed the physiologic anemia of pregnancy.13 Beginning in the first trimester of pregnancy, the reduced Hct value does not represent a decrease in RCM. A third pertinent example of Hct and Hgb values misrepresenting the RCM is in the clinical setting of dehydration. In the dehydrated patient an apparently normal or elevated Hct or Hgb value leads the clinician to overestimate the patient’s RCM.8,9 Thus, there are two necessary considerations when attempting to correctly identify anemia in an individual patient. First, the laboratory values of HgbAHgb and/or Hct must be compared to a standard set of age- and sex-

KEY POINTS 1. Anemia is common in surgical patients. 2. Hemoglobin (Hgb) concentration and hematocrit (Hct) level are appropriate tests to rapidly assess the severity of anemia. 3. Treatment of anemia should be based on the physiology and etiology of anemia. Maintenance and restoration of normovolemia and cardiac output are necessary but insufficient aims in treating anemia. 4. Tachycardia and hypotension are important clinical signs of hypovolemia and anemia, but compensatory increases in heart rate and cardiac output may be impeded by insufficient cardiac reserve or anestheticinduced sympathectomy. 5. Consideration of the physiologic signs and laboratory evidence of inadequate tissue oxygen delivery is mandatory before making a decision to transfuse red blood cells (RBCs). 6. Because evidence-based outcomes supporting a specific transfusion trigger level of Hgb or Hct are lacking for perioperative patients, further clinical investigation is needed.


7. Alternatives to transfusion of allogeneic RBCs are available and are appropriate to integrate into a bloodconservation strategy in selected surgical patients. 8. Given the broad range of congenital and acquired disease states as well as the multiple pharmacotherapies that can result in a hypocoagulable state, serious attention to these pathologies are needed by anesthesiologists in order to avoid the adverse effects of transfusions, excessive perioperative bleeding and the depletion of community blood bank resources. 9. The perioperative management of hypercoagulable disorders is also a responsibility of the anesthesiologist in that many of these patients require perioperative management of their anticoagulant regimens. 10. Hematology consultation is indicated for the perioperative management of many of the hypocoagulable and hypercoagulable disorders so as to avoid exposing the patient to unnecessary perioperative morbidity and mortality.

239


TABLE 15–1. Normal Red Blood Cell Values

240

Hemoglobin (g/dL)

Hematocrit (%)

Red Cell Count (1012/L)

MCV (fL)

Age

Mean

–2 SD

Mean

–2 SD

Mean

–2 SD

Mean

Birth (cord blood) 1–3 days (capillary) 1 week 2 weeks 1 month 2 months 3–6 months 0.5–2 years 2–6 years 6–12 years 12–18 years Female Male 18–49 years Female Male

16.5

13.5

51

42

4.7

3.9

18.5

14.5

56

45

5.2

17.5 16.5 14.0 11.5 11.5 12.0 12.5 13.5

13.5 12.5 10.0 9.0 9.5 11.0 11.5 11.5

54 51 43 35 35 36 37 40

42 39 31 28 29 33 34 35

14.0 14.5

12.0 13.0

41 43

14.0 15.5

12.0 13.5

41 47

MCH (pg)

MCHC (g/dL)

–2 SD

Mean

–2 SD

Mean

–2 SD

108

98

34

31

33

30

4.0

108

95

34

31

33

29

3.1 4.9 4.2 3.8 3.8 4.5 4.6 4.6

3.9 3.6 3.0 2.7 3.1 3.7 3.9 4.0

107 105 104 96 91 78 81 86

88 86 85 77 74 70 75 77

34 34 34 30 30 27 27 29

28 28 28 26 25 23 24 25

33 33 33 33 33 33 34 34

28 28 29 29 30 30 31 31

36 37

4.6 4.8

4.1 4.5

90 88

78 78

30 30

25 25

34 34

31 31

36 41

4.6 5.2

4.0 4.5

90 90

80 80

30 30

26 26

34 34

31 31

MCH, mean cell hemoglobin; MCHC, mean cell hemoglobin concentration; MCV, mean cell volume; SD, standard deviations. Reproduced with permission from Felgar RE and Ryan DH.10

normalized reference values (Table 15–1).10,14 Second, the patient’s overall plasma volume status must be assessed to determine if the patient is significantly plasma volume contracted or expanded.

Prevalence of Anemia in Surgical Patients

goal of achieving a constant steady state, depending on the rate at which RBCs are being produced and removed or lost. The kidney plays a vital role in this process by producing the hormone erythropoietin. This process is upregulated when the kidney senses a

decrease in receipt of oxygen because of a contracted RCM (Fig. 15–1). Optimal erythropoiesis can only occur when the body possesses sufficient substrate (e.g., folate, iron, vitamin B12 and other nutrients) to produce new erythrocytes.10

The prevalence of anemia in various surgical populations has been reported to range from 5–75%, depending on both the underlying clinical status and the severity of disease.1,2 As one might expect, the prevalence of anemia decreases with more stringent criteria. Anemia may be produced or exacerbated by the surgical procedure and postoperative care.15–17

Red Blood Cell Maturation Normal red blood cells (RBCs) mature by proliferation and differentiation of precursor stem cells in the bone marrow in a process termed erythropoiesis.18 A mature RBC will circulate for a period of approximately 100–120 days, after which time it will be removed from the circulation by the body’s reticuloendothelial system. The body replenishes the total RCM with the

FIGURE 15–1. Regulation of erythropoiesis. Reproduced with permission from Felgar RE and Ryan DH.10


TABLE 15–2. Usefulness of the Reticulocyte Count in the Diagnosis of Anemia

Hemorrhage-Related Anemia

Value

Diagnosis Hypoproliferative anemias Anemia of chronic disease Anemia of renal disease Congenital dyserythropoietic anemias Effects of drugs or toxins Endocrine anemias Iron deficiency Marrow replacement Maturation abnormalities Vitamin B12 deficiency Folate deficiency Sideroblastic anemia Appropriate response to blood loss or nutritional supplementation Hemolytic anemias Hemoglobinopathies Immune hemolytic anemias Infectious causes of hemolysis Membrane abnormalities Metabolic abnormalities Mechanical hemolysis

with the various classes of anemia is summarized in tabular form (Tables 15–2, 15–3, and 15–4).10

Corrected reticulocyte 80 y CAD CVD Fever/hypertension

6 7 8 7 7 6 8 9 8 8

Ward

Circulation

Myocardial Ischemia

PVO2 50%, SVO2 10%

Rel. inc. HR/dec. BP Rel. inc. HR/dec. BP Rel. inc. HR/dec. BP Rel. inc. HR/dec. BP Rel. inc. HR/dec. BP Rel. inc. HR/dec. BP Rel. inc. HR/dec. BP Rel. inc. HR/dec. BP Rel. inc. HR/dec. BP Rel. inc. HR/dec. BP

ST-segment changes ST-segment changes ST-segment changes ST-segment changes ST-segment changes Clinical signs Clinical signs Clinical signs Clinical signs Clinical signs

Yes Yes Yes Yes Yes NA NA NA NA NA

•

CAD, coronary artery disease; CVD, cardiovascular disease; O2ER, oxygen extraction ratio (%); PVO2, partial venous pressure of oxygen (mm Hg); Rel. inc. HR, relative increase in heart rate defined as heart rate >120–130% of baseline or >110–130 beats/min; Rel. dec., relative decrease in systemic blood pressure defined as a mean arterial pressure 3000 Re Facto Genetics Institute (American 11,200–15,500 (albumin-free forHome Products) mulations) Ultrapure Plasma Derived Monoclate P Aventis-Behring >3000 Hemofil M Baxter Hyland >3000 Monarc M Immuno Baxter (using volun>3000 teer donor plasma collected by American Red Cross) Intermediate-Purity and High-Purity Plasma Derived Alphanate SD Alpha Therapeutics 8–30 Humate P Aventis-Behring 1–2 Koate DVI Bayer 9–22 Reproduced with permission from Cohen AJ and Kessler CM.102

249


the incidence is approximately 1–4% in patients with severe factor IX deficiency).105 Recombinant activated factor VII (rVIIa) is FDA approved for the treatment of both hemophilia A and hemophilia B in patients with inhibitors to factors VIII and IX, respectively.106 The anesthetic implications for factor IX deficiency are analogous to those of hemophilia A.

von Willebrand Disease 250

von Willebrand disease (vWD) is a platelet function disorder caused by a deficiency of normally functioning von Willebrand factor (vWF).107 vWD can result in a hypocoagulable state that manifests as bleeding episodes.108 vWD is a congenital disorder with an equal male-to-female distribution ratio that is inherited by an autosomal dominant pattern and occurs with an incidence of approximately 1%. vWF plays two major roles in the hemostatic process. First, vWF acts as a bridge between platelet receptors and exposed collagen in disrupted endothelium. Platelet binding to exposed collagen in disrupted endothelium initially occurs via a glycoprotein Ib–vWF and collagen interaction, and soon thereafter by firmer adhesion of the platelet to the collagen molecule via the glycoprotein IIb/IIIa–vWF and collagen interaction. vWF enables platelets to create a primary plug in the disrupted endothelium and start the hemostatic process at the site of vessel injury. vWF also acts as a bridge between platelet receptors,

specifically between glycoprotein IIb/ IIIa receptors, for the purpose of platelet aggregation.109 Second, vWF circulates in the plasma to create a complex bound to factor VIII and provides protection to factor VIII against proteolytic cleavage.110 There is a broad range of severity in bleeding associated with vWD. Individuals with moderate or severe vWD tend to bleed abnormally in childhood or young adulthood. The majority of affected individuals have only mild or moderate disease. Symptoms of vWD include easy bruising, epistaxis, and bleeding of mucous membranes. Gastrointestinal bleeding and menorrhagia occur in vWD. Severe gastrointestinal bleeding can be life-threatening in vWD.111 Surgical procedures can also be associated with excessive bleeding in patients with vWD.108 The diagnosis of vWD is complex and is made with a battery of tests that includes vWF antigen (accomplished with the enzyme-linked immunosorbent assay), vWF activity (commonly measured as ristocetin cofactor), factor VIII activity (accomplished with a modified aPTT assay), and the bleeding time. These tests are followed by a second series of assays to determine the classification of vWD and include a ristocetin-induced platelet aggregation assay, as well as vWF multimer studies.108,112,113 The treatment of vWD depends on the type of vWD that is diagnosed (Tables 15–10 and Table 15–11). Use of

nonsteroidal antiinflammatory drugs can further impair an already compromised level of platelet function and are contraindicated in vWD. Because the correlation of the degree of diagnostic laboratory test abnormalities in vWD with the severity of bleeding is poor, an empirical goal of treatment is pursued. The treatment goal for the perioperative period should be to increase the activity of vWF and factor VIII to 50–100% of normal, an analogous goal to the treatment of bleeding episodes in vWD.108 vWF and factor VIII activity levels are increased in patients with vWD through the intravenous administration of DDAVP (1-deamino-8-D-arginine-vasopressin or desmopressin) and the administration of vWF-rich plasma-derived blood products. The use of topical hemostatic agents (e.g., fibrin glue, Gelfoam or Surgicel soaked in thrombin) will also promote hemostasis in these patients.108 Alternatively, vWF concentrates (e.g., Humate-P, a heat-treated, highly purified vWF concentrate) can be administered intravenously for patients who do not respond positively to DDAVP therapy. Pregnant patients with vWD merit special consideration. Although evidence-based recommendations for central neuraxial blockade do not exist, consideration must be given to the fact that spinal or epidural hematoma related to instrumentation can be permanently debilitating. vWF levels increase 2–3 times above the baseline

TABLE 15–10. Classification of von Willebrand Disease

Type

Inheritance

Frequency of vWD Type

vWF Activity

RIPA

Multimer Pattern

Type I (classic)

Autosomal dominant

70–75%

?

?

Uniform ? All multimers present

Autosomal dominant (and recessive) Autosomal dominant Autosomal dominant (and recessive) Autosomal recessive Autosomal recessive

10–15%

?

?

5% Infrequent

? ?

B ?

? Large and intermediate multimers ? Large multimers Normal multimers

Infrequent Rare

Normal ??

Normal ??

Type 2 (variant) 2A 2B 2M 2N Type 3 (severe)

Normal multimers Undetectable (usually cannot visualize)

vWD, von Willebrand disease; vWF, von Willebrand factor; RIPA, ristocetin-induced platelet aggregation; ?, decrease; B, increase; ??, marked decrease. Reproduced with permission from Rick ME.108


TABLE 15–11. von Willebrand Disease Treatment Approaches Medication

Dose

Comments

DDAVP (desmopressin)

IV: 0.3 +g/kg in 50 mL saline over 20 min (maximum 20 +g)

Useful in most patients with type 1; variable in type 2; not useful in type 3; patient should have therapeutic trial before invasive procedure; may repeat dose after 12 hours and q24h; tachyphylaxis and hyponatremia may occur—need to monitor patient

vWF concentrates containing all vWF multimers

Nasal spray: Weight >50 kg = 300 +g (1 spray each nostril) Weight 1 mg/kg or dalteparin >120 U/kg) of LMWH before initiating an elective surgical procedure or attempting central neuraxial blockade.165 Although the anticoagulant effect of LMWH can be partially reversed by protamine sulfate,166 one retrospective study of enoxaparin in cardiac surgical patients found that preoperative use was associated with increased red cell and platelet use, early reoperation for bleeding, and higher chest tube output in the first 24 hours postoperatively despite protamine reversal.167 The activated factor X inhibitor fondaparinux (Arixtra) requires interaction with antithrombin to exert its anticoagulant effect. Once bonded with antithrombin the fondaparinux– antithrombin complex selectively increases antithrombin’s ability to inhibit activated factor X by approximately 300fold. The molecule is smaller than that of LMWH and does not elicit formation of or react with the platelet factor 4 (PF4) antibody associated with heparininduced thrombocytopenia type II. The elimination half-life is 17–21 hours. No definite recommendations exist for management of this drug before attempting neuraxial blockade, although it is recommended to use a single-needle atraumatic placement technique and avoid an indwelling catheter if a neuraxial procedure is mandated. Although no evidence-based recommendations exist, delaying an elective operation for approximately 5 half-lives, or 4 days, is a conservative management strategy for patients treated with this drug. Because there is minimal metabolic breakdown and the primary route of elimination is renal, dose adjustment is required in patients with renal insufficiency. Antiactivated plasma factor X levels are not required in the absence of renal insufficiency.168 Direct thrombin inhibitors include lepirudin (Refludan), argatroban, and bivalirudin (Angiomax). They exert their effect by interacting with free or clot-bound thrombin to inhibit conversion by thrombin of fibrinogen to fibrin. Direct thrombin inhibitors do not rely on the presence of antithrombin to exert their effects. They are used for treatment and prevention of thrombotic events, including treatment of patients undergoing percutaneous coronary interventions (PCIs) with, or who are at risk for, heparin-induced thrombocytopenia (argatroban), or for PCI

(bivalirudin).158 The half-lives of these drugs vary (Table 15–12). Bivalirudin was recently demonstrated to be a safe and effective option for anticoagulation of cardiac surgical patients requiring cardiopulmonary bypass.169,170 Although no evidence-based recommendations exist, conservative management suggests that patients on continuous intravenous infusions of direct thrombin inhibitors should have the drug discontinued 5 elimination halflives before an operation or neuraxial blockade. Direct thrombin inhibitors do not elicit formation of, or crossreact with, the PF4 antibody associated with heparin-induced thrombocytopenia type II and are therefore useful to prevent and treat thrombotic events in patients afflicted with this syndrome. Clinical effects of direct thrombin inhibitors are commonly followed with the aPTT or the ACT. Coumarins, a subclass of antithrombotics that are orally administered, exert their anticoagulant effect by inhibiting the hepatic synthesis of vitamin K-dependent coagulation factors. Specifically, coumarins inhibit the synthesis of factors II, VII, IX, and X, as well as proteins C and S. Assessment of the PT or international normalized ratio (INR) can quantify low levels of these specific coagulation proteins. Because these vitamin K-dependent factors participate in the extrinsic and common coagulation pathways (Fig. 15–6), the PT is the best test to assess coumarin effects. PT is reported as an INR to avoid interlaboratory variation in absolute PT results.159 Coumadin is the only coumarin approved by the FDA. It is metabolized by the liver and possesses an elimination half-life of 20–60 hours. Anticoagulant effects of Coumadin take several days to abate, depending on the level of Coumadin effect at discontinuation. Administration of vitamin K decreases the time for the effects of Coumadin to abate, but may make it difficult to reinstitute a therapeutic Coumadin effect, complicating perioperative anticoagulation therapy. Alternatively, administration of fresh-frozen plasma acutely reverses the anticoagulant effects of Coumadin. However, anticoagulation may recur several hours later because of the longer half-life of Coumadin than of the coagulation factor levels that it affects (e.g., the half-life of Coumadin is 20–60 hours whereas the half-life of factor VII is approxi-

TABLE 15–12. Direct Thrombin Inhibitor Elimination Half-Lives

Drug

Half-Life (Minutes)

Argatrobana Bivalirudin (Angiomax)b Lepirudin (Refludan)c

30–51 25 48–120

Data from a Casserly IP, Kereiakes DJ, Gray WA, et al;220 b Thomson MICROMEDEX;222 and c Francis CW and Berkowitz SD.158

mately 6 hours). Excessive operative hemorrhage and neuraxial anesthesia associated with spinal or epidural hematoma may occur if Coumadin is not neutralized. Individuals at increased risk for a serious thrombotic event should be anticoagulated with a second intravenous or subcutaneous antithrombotic agent (e.g., UFH, LMWH or a short-acting direct thrombin inhibitor) before Coumadin is discontinued or neutralized. Titration of antithrombotic therapy is complex in the presence of more than one antithrombotic agent or when a preexisting factor deficiency is present. A hematology consultation should be considered for these patients.

Antiplatelet Agents The 5 subcategories of antiplatelet agents are nonsteroidal antiinflammatory drugs; glycoprotein IIb/IIIa receptor inhibitors; platelet adhesion inhibitors; platelet adenosine diphosphate (ADP)-receptor antagonists and platelet-production-limiting agents. Because platelets can be activated by more than one stimulus, not all antiplatelet agents clearly place surgical patients at increased risk for bleeding. Indeed antiplatelet drugs are beneficial to patients with cardiovascular disease.171,172 The increasing use of herbal medications in the United States has drawn attention to the anticoagulant effects of garlic, ginkgo, ginseng, ginger, dong quai, feverfew, and fish oil; limited evidencebased data exists describing interactions of herbal medications with other medications and their effect on the clinical course of surgical patients.173,174

Nonsteroidal Antiinflammatory Drugs Aspirin exerts its antiplatelet effects by creating irreversible inhibition of platelet cyclooxygenase. This prevents the

255


Arachadonic acid

Acetylation

ASA COX-1 Salicylate

PGG2

PGH2

256 PGI2

TXA2

FIGURE 15–7. Pharmacodynamics of aspirin.

formation of thromboxane A2 from arachidonic acid for the life of the platelet, which, in turn, blocks the platelet activation, aggregation, and internal mediator release that would propagate further platelet activation (Fig. 15–7). Because normal platelets have an average circulating life span of approximately 10 days, it may take up to 5 days for half of the normal platelet function to return after treatment with aspirin, despite measurement of a normal platelet count. Aspirin’s half-life is 15–20 minutes in the plasma and it undergoes primarily hepatic metabolism, although it also undergoes plasma esterase metabolism. Other nonsteroidal antiinflammatory drugs (NSAIDs), such as ibuprofen and naproxen, produce reversible platelet cyclooxygenase inhibition. Thus the return of platelet function correlates with the drug’s half-life and perioperative management of these antiplatelet agents is easily accomplished when one considers that permitting 5 half-lives to elapse following the last dose will eliminate the effects of these particular NSAIDs. For aspirin a separate perioperative treatment strategy is needed. Provided that aspirin blood levels do not exist, antiplatelet effects of aspirin can be overcome by platelet transfusion.160 Doubt exists whether NSAIDs result in significant surgical hemorrhage. If an NSAID is the only inhibitory influence on the coagulation cascade central neuraxial blockade can be safely undertaken.165,175 In selected patients with severe peripheral arterial vascular disease, it is advisable to continue perioperative aspirin.176

Glycoprotein IIb/IIIa Receptor Inhibitors The glycoprotein IIb/IIIa (GP IIb/IIIa) receptor inhibitors are available only in intravenous preparations and are among the most potent inhibitors of platelet function. Currently, the following GP IIb/IIIa receptor inhibitors are approved for clinical use in the United States: abciximab (ReoPro), eptifibatide (Integrilin), and tirofiban (Aggrastat). Platelets are activated by several different stimuli, including thromboxane, ADP, epinephrine, serotonin, and mechanical shear stress. The final common pathway of platelet activation involves platelet aggregation via interaction of GP IIb/IIIa receptors and either fibrinogen or vWF as an intermediate molecule. Complete inhibition of this final step of platelet aggregation could render a patient completely thrombasthenic. Abciximab (ReoPro) is the Fab portion of the chimeric human–murine monoclonal antibody 7E3 that is directed against the platelet GP IIb/IIIa receptor. In therapeutic doses, it creates a marked decrease in the ability of platelets to aggregate. In approximately 1–2% of patients, it produces significant thrombocytopenia.177 Abciximab also inhibits thrombus formation by suppressing tissue factor-induced thrombin generation. It is FDA approved for use as an adjunct in PCI and as an adjunct in the treatment of refractory angina. Abciximab has a 30minute plasma half-life. However, once bound to the platelet GP IIb/IIIa receptor, it remains in the circulation for up to 15 days. The putative mechanism for this is migration from platelet

to platelet. The antiaggregation effect lasts for 12–48 hours. Platelet transfusion may partially restore platelet function if significant bleeding occurs 12–48 hours after infusion.177 Central neuraxial blockade is contraindicated within 24–48 hours of abciximab administration. Delaying a cardiac operation in the stable patient treated with abciximab for 12–24 hours allows the return of platelet function.165 Tirofiban (Aggrastat), a nonpeptide chemical antagonist of the platelet GP IIb/IIIa receptor, produces a greater than 90% reduction in platelet aggregation that is reversible. Tirofiban is FDA approved for the treatment of acute coronary syndrome (ACS) in patients undergoing angioplasty or being medically managed.178 The half-life is reported as 90–180 minutes; it undergoes renal excretion largely as unchanged drug. Central neuraxial blockade should be delayed for 8 hours in patients who are receiving tirofiban.165 It does not appear to confer an increased risk of hemorrhage following emergent or urgent coronary surgery.178 No specific recommendations are available for general surgical patients at this time. Eptifibatide (Integrilin), a heptapeptide molecule that inhibits the platelet GP IIb/IIIa receptor, is a potent inhibitor of platelet aggregation with FDA approval for use in PCI and for the treatment of ACS. The drug is cleared from the circulation by the kidneys with a half-life of 2.5 hours. Approximately 71% of the drug is eliminated unmetabolized.179 A delay of 4–8 hours is recommended after discontinuation of this drug before attempting central neuraxial blockade.165 One large trial suggested that it was safe to perform a coronary operation within 2 hours of the discontinuation of eptifibatide; the drug was also associated with a platelet-sparing effect in these patients.180 No evidence-based recommendations are available for general surgical patients at this time.

ADP Antagonists Clopidogrel (Plavix) and ticlopidine (Ticlid), the only two FDA-approved ADP-receptor antagonists, selectively and irreversibly inhibit ADP-induced platelet aggregation by blocking the P2Y12 ADP receptor on the platelet surface. These oral agents do not affect prostacyclin and thromboxane synthesis and work by preventing the ADP


platelet P2Y12 receptor from transmitting a signal to the platelet to activate its GP IIb/IIIa receptor complexes. Clopidogrel is FDA approved for the reduction of thrombotic events related to recent myocardial infarction, stroke and established peripheral arterial disease. Additionally, clopidogrel is approved for both the medical management and PCI performed for the treatment of ACS. Clopidogrel and ticlopidine both undergo extensive hepatic metabolism. Clopidogrel is excreted in both the urine and feces in a balanced fashion. The half-life of clopidogrel is reported to be 8 hours.181,182 The irreversible nature of clopidogrel’s effect on platelets requires a full 5–7 days to elapse following drug cessation before a population of functional platelets are available to participate in the coagulation process. A delay of 7 full days is recommended following treatment with this drug before attempting central neuraxial blockade.165 Clopidogreltreated patients bleed more and require significantly higher rates of blood product transfusion following cardiac surgery.182 Evidence-based recommendations do not exist for general surgery patients at this time. Ticlopidine is FDA approved for the placement of coronary stents in conjunction with aspirin therapy. Ticlopidine is also FDA approved for the prophylaxis of thromboembolic stroke. At least 1 metabolite of ticlopidine is a potent inhibitor of ADP-induced platelet aggregation. This metabolite is excreted primarily in the urine. Ticlopidine has a reported half-life of 12.6 hours, which increases dramatically to 5 days with repeated dosing. Ticlopidine is used less frequently than clopidogrel because of hematologic toxicity (e.g., neutropenia, agranulocytosis, and thrombotic thrombocytopenic purpura). A delay of 14 days is recommended following discontinuation of this drug before attempting central neuraxial blockade.165 Evidence-based recommendations do not exist for general surgery patients at this time.

Platelet-Adhesion Inhibitors Dipyridamole (Persantine), Aggrenox, and cilostazol (Pletal) are the three available drugs classified as plateletadhesion inhibitors. Their mechanisms of action differ from those previously described. Dipyridamole, available in oral and intravenous prep-

arations, suppresses platelet aggregation by inhibiting the ability of the platelet to take up adenosine. The increased concentration of adenosine local to the platelet stimulates the platelet A2-receptor which potentiates the platelet’s production of cyclic-3',5'adenosine monophosphate (cAMP). Additionally, dipyridamole has been found to inhibit cellular phosphodiesterase activity which is also speculated to increase intraplatelet cAMP levels. The increased intraplatelet levels of cAMP act to inhibit platelet aggregation by blocking the activation of platelets by 3 different stimuli— ADP, platelet-activating factor, and collagen. Dipyridamole also inhibits phosphodiesterase in other tissues and results in vasodilatation as a result of its effects on vascular endothelium.183 It is FDA approved to be used as an adjunct with Coumadin for the prophylaxis of thromboembolic complications associated with cardiac valve replacement and for use with thallium in myocardial imaging studies. It is also employed to prevent thromboembolic events associated with coronary surgery. Dipyridamole primarily undergoes hepatic metabolism and has a reported half-life of approximately 9– 13 hours. Dipyridamole administration is associated with bleeding. The risk is greater when dipyridamole is combined with aspirin therapy.183,184 A combination of dipyridamole and aspirin, Aggrenox, is commercially available. Aggrenox is FDA approved for the prophylaxis of cerebrovascular accidents in patients with a previous history of stroke or transient ischemic attacks. It may be prudent to delay central neuraxial anesthesia for 7 days following Aggrenox therapy to allow for approximately 50% of normal platelet function to return. Published literature does not present the use of dipyridamole alone to be a direct contraindication to proceeding with elective surgery or neuraxial blockade; however, given that dipyridamole works by suppressing the platelet’s ability to be activated by ADP, collagen and platelet-activating factor it may be prudent to avoid elective surgery and neuraxial blockade for 4 days. A meta-analysis concluded that among antiplatelet drugs dipyridamole was associated with the lowest incidence of bleeding complications.185 In one large trial of antiplatelet drugs

used for the prevention of stroke in medical patients, dipyridamole was indistinguishable from placebo in terms of bleeding complications.186 Cilostazol (Pletal) increases intracellular cAMP by inhibiting the enzyme phosphodiesterase III. An increase in levels of cAMP results in the reversible inhibition of platelet aggregation that is normally stimulated by thrombin, ADP, collagen, epinephrine, arachidonic acid, and shear stress. Cilostazol’s phosphodiesterase inhibition also causes systemic vasodilatation. It is FDA approved for the reduction of symptoms of intermittent claudication. It is extensively metabolized by the liver into active metabolites that are primarily cleared by the kidneys and has a reported elimination half-life of 11–13 hours. Because no evidence-based recommendations exist, a conservative management approach may be to delay elective surgery or central neuraxial blockade for 48 hours following administration.187

Herbal Therapies Self-medication with herbal therapies has been increasing in the United States for the past several years.173 Specific herbal therapies are now recognized as having deleterious effects on elements of the coagulation cascade, although there is a paucity of sound research.174 Garlic, ginkgo, ginseng, ginger, feverfew, fish oil, and dong quai have all been implicated in inhibiting normal hemostasis; several of these biologics have been proven to interfere with platelet aggregation.165,174 Anesthesiologists should routinely inquire during the preoperative evaluation whether patients are taking any herbal supplements. Patients taking these supplements should be advised to discontinue their use perioperatively. The current lack of literature makes it difficult to impossible to recommend delaying elective surgical procedures or neuraxial blockade in patients using these supplements.

Hypocoagulable Effects of the Synthetic Colloid Infusions HES, a synthetic colloid solution derived from amylopectin, is a useful volume expander that has a well-recognized profile of anticoagulant effects.38 Hespan, a commercially available HES solution, is FDA approved for use in leukophoresis and as volume expander in hypovolemic adults and children

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undergoing surgery or in patients in shock secondary to hemorrhage or sepsis. The reported half-life is between 67 hours and 17 days, depending on the size of the molecule. As an alternative to banked blood products, it avoids infection, immunosuppression, and transfusion reactions. Patients prone to develop procedure-associated coagulopathy (e.g., cardiac surgery patients undergoing cardiopulmonary bypass or hepatic transplant patients) may be poor candidates for HES. A meta-analysis comparing HES to albumin in patients undergoing cardiopulmonary bypass concluded that HES was associated with greater postoperative blood loss.188 One literature review demonstrated that adhering to the recommended HES dose of 20 mL/kg was still associated with adverse effects, particularly in intensive care and cardiac surgical patients. This review confirmed that bleeding is associated with the administration of artificial colloids and that protracted pruritus is a commonly reported troublesome reaction. Non–life-threatening anaphylactoid reactions are more likely with HES than with albumin. Additionally, the authors concluded that albumin appears to be the safest option among albumin, dextran, HES, and gelatin (unavailable in the United States) for colloid-based plasma volume expanders.189

Hypercoagulable States Thrombophilias, or hypercoagulable states, put surgical patients at increased risk for experiencing a postoperative thrombotic event. Many of these hypercoagulable states are managed with either temporary or lifelong systemic anticoagulation therapy. Environmental influences (e.g., trauma, surgery, infection, or administration of a drug) will increase the likelihood of a patient with either a congenital or acquired hypercoagulable disorder to develop a thromboembolic event and thus will affect the perioperative management of these patients.190,191 Several thrombophilias are currently recognized and anesthesiologists should be familiar with them to aid in the provision of optimal perioperative care. Discontinuation and reinitiation of systemic anticoagulation in the perioperative period is most safely managed in concert with a hematologist.

Antithrombin Deficiency Antithrombin (also termed antithrombin III) is a plasma protein made by the

liver that prevents hypercoagulability by binding to and neutralizing thrombin (factor IIa) and to factors IXa, Xa, XIa, and XIIa (Fig. 15–6).192 Antithrombin (AT) deficiency is associated with a predilection for thrombosis. AT deficiency is a congenital disorder inherited as an autosomal dominant trait that is estimated to occur in the general population with a prevalence of between 1 in 250–500 people.192,193 Individuals with a history of an unexplained thrombotic event should be evaluated to rule out this disorder. AT deficiency may be a result of a decreased synthesis (type I) of the protein or a decreased activity of the protein in the presence of normal levels (type II).194 AT levels are reported to be between 75% and 120% in normal individuals.195 AT levels are measured by a specific assay. Disease states associated with a reduction in AT activity include sepsis, disseminated intravascular coagulation, burns, acute thrombosis, hepatic disease, severe trauma, and nephritis.192 Patients with an AT deficiency have a predisposition to develop deep vein thromboses and therefore are often maintained on Coumadin. Perioperative management of anticoagulation should be tailored to the invasiveness of the planned intervention or surgical procedure. Surgery induces a prothrombotic state and increases the risk of perioperative thrombosis.196 Preoperative discontinuation and postoperative reinstitution of systemic anticoagulation therapy in these patients should be done in conjunction with a hematologist. Anticoagulation with UFH is frequently required for cardiac, endovascular and open vascular surgical procedures. Importantly, many ATdeficient patients exhibit a relative resistance to UFH as UFH anticoagulation requires coupling with AT to induce a several-fold increase in AT’s neutralizing effect on the procoagulant factors IIa, IXa, Xa, XIa, and XIIa.197 ACT or aPTT assays will reveal heparin resistance in patients with an AT deficiency. Heparin resistance in this context is defined as a failure of UFH to produce the expected degree of ACT or aPTT prolongation. Heparin resistance caused by AT deficiency is most efficiently treated with plasmaderived, purified AT III concentrate (Thrombate III). Bolus Thrombate III administration of 50 IU/kg has been

recommended. In practice, 1–2 vials of purified AT concentrate are often administered and the biologic’s effect is ascertained by performing the ACT assay. If Thrombate III is not available (or not desired), heparin resistance can be treated with 2–4 units of fresh-frozen plasma; the effect of this therapy can be verified with the ACT assay.198

Protein C Deficiency Protein C is a hepatically synthesized vitamin K-dependent protein that, when converted to its active form (activated protein C), exerts an anticoagulant effect through interaction with factors Va and VIIIa. Protein C deficiency may be caused by a quantitative or qualitative defect. It is estimated to occur in the general population with a prevalence of between 1 in 200– 500.199 Many individuals with protein C deficiency will exhibit a prothrombotic tendency and hence require systemic anticoagulation. Protein C deficiency is diagnosed by an aPTT-based clotting assay.192 The diagnosis of protein C deficiency in patients who were recently treated with Coumadin is complex.200 Individuals with protein C deficiency presenting for surgical intervention require perioperative modification of their anticoagulation therapy, which is best accomplished in consultation with a hematologist.

Protein S Deficiency Proteins S is synthesized primarily in the liver, and functions as a cofactor for activated protein C.201 Quantitative and qualitative congenital protein S deficiencies have been described.202 Individuals with protein S deficiency can exhibit a prothrombotic tendency and may be maintained on systemic oral anticoagulation as outpatients. Perioperative management should be accomplished in conjunction with a hematologist.

Factor V Leiden (Activated Protein C Resistance) Factor V Leiden, also termed activated protein C resistance, is associated with recurrent venous thromboembolic events.203 It is caused by a single point mutation in the gene that encodes for factor V.204 This mutation is common among patients who experience thrombotic events; Griffin et al. found that 50% of patients with unexplained


thrombotic events demonstrated activated protein C resistance.205 It is commonly diagnosed by an aPTT-based assay. Because individuals with the factor V Leiden mutation may be on either temporary or lifetime systemic oral anticoagulation,206 perioperative management should be determined in consultation with a hematologist.

Prothrombin G20210 Mutation Prothrombin, or factor II, is an essential element of the coagulation cascade. A single base pair substitution mutation results in affected individuals expressing higher plasma prothrombin activity, which is associated with the occurrence of thromboembolic disease in these patients.192,207,208 This disorder is the second most common thrombophilia, with a prevalence of 2% in whites, with considerable geographic variation.209 It is commonly diagnosed using a polymerase chain reaction-based test.192 Hematologic consultation is advisable in the perioperative period.

Heparin-Induced Thrombocytopenia Heparin-induced thrombocytopenia (HIT) involves an immune-mediated response to either LMWH or UFH administration that results in pathologic platelet activation causing arterial and/or venous thrombosis with or without associated tissue ischemia and infarction. There are two types of HIT. Type I is a non–immune-mediated activation of platelets in heparin-treated patients causing a mild reduction in circulating platelets.210 HIT type II, or heparin-induced thrombosis-thrombocytopenia syndrome (HITTS), is immune mediated. It is caused by the interaction of a heparin-dependent IgG antibody with the molecular complex of PF4 and heparin. The heparin-PF4–bound IgG antibody stimulates platelet activation via the platelet FcaIIa receptor.211 Once platelets are activated, they release internal biochemical mediators that induce platelet aggregation and stimulate other platelets to become activated. The same biochemical mediators that are released from the activated platelets also stimulate thrombin generation.212 The heparin-PF4 IgG antibodyinduced platelet aggregation, along with the thrombin that is generated, contributes to the formation of thrombus. Although venous thrombosis oc-

curs most commonly in HIT type II, arterial thrombosis is also observed. Thrombi can cause organ ischemia and/or infarction. Thrombotic emboli may damage organs distant to the site of thrombus formation. Loss of limbs and damage to vital organs, such as renal failure or strokes, are recognized complications of this disorder.213 Numerous features of HIT type II are not well understood. Only a portion of the patients who are exposed to heparin develop the IgG antibody directed against heparin and PF4 (commonly termed the PF4 antibody). Only a small percentage of the patients who develop the PF4 antibody develop thrombocytopenia and a recognized thrombotic event.214 At least a 50% decrease of platelet count from the preheparin administration baseline is required to establish the diagnosis of HIT type II.213 Using the absolute laboratory criterion of less than 150,000 platelets/mm3 is not completely appropriate to diagnose HIT type II. Patients who are generating the PF4 antibody upon initial exposure to heparin characteristically take at least 5 days to develop PF4 antibody sufficient to cause thrombocytopenia. Patients previously exposed to heparin who have generated PF4 antibody in the past 100 days may develop thrombocytopenia more rapidly.215 In contrast, the thrombocytopenic response and thrombotic event can occur several days to weeks following the discontinuation of heparin therapy.216 HIT type II may be diagnosed using either an antigen assay or a platelet activation assay; these tests are indicated in patients with a history of thrombocytopenia temporally related to heparin administration or in patients receiving heparin with previously documented HIT type II. The antigen type assays use the enzyme-linked immunosorbent assay to detect the presence of the PF4 antibody, which has proven to be highly sensitive for PF4 antibody detection.211,217,218 The activation assays detect the PF4 antibodies by detecting their ability to activate platelets in the presence of heparin.211 The platelet serotonin release assay is an example of an activation assay that detects HIT type II by quantifying the release of 14C-labeled serotonin from platelets activated by heparin in the presence of the PF4 antibody.219 Treatment of HIT type II consists of immediate and complete discontinua-

tion of heparin by any routes. Additionally, immediate systemic anticoagulation is indicated in the setting of thrombosis; the current agents of choice are the direct thrombin inhibitors (e.g., argatroban, bivalirudin, or lepirudin). After systemic levels of a direct thrombin inhibitor are achieved, oral anticoagulation with a coumarin may be established and the direct thrombin inhibitor discontinued. Oral coumarin therapy must not be established until effective thrombin suppression has been achieved to avoid precipitating warfarin-induced skin necrosis.210,215 Given the widespread use of heparin, HIT type II is an important consideration for anesthesiologists. Cardiac and vascular anesthesiologists as well as intensivists will be challenged by this clinical disorder on a regular basis.218 Heparin should be scrupulously avoided in patients with HIT type II and an elevated PF4 antibody titer in order to avoid precipitation of a thrombotic event. Patients with a distant history of an elevated PF4 antibody titer should not be treated with heparin unless the clinical situation mandates systemic anticoagulation (e.g., acute need for cardiac surgery requiring cardiopulmonary bypass [CPB] at an institution that is not experienced with using a direct thrombin inhibitor in the same clinical setting). Alternatives for vascular and other noncardiac surgical procedures that require systemic anticoagulation include argatroban and bivalirudin. Argatroban, a univalent direct thrombin inhibitor, is approved by the FDA for systemic anticoagulation in patients diagnosed with HIT type II.220 Bivalirudin (Angiomax), a bivalent direct thrombin inhibitor, is also an option despite lack of FDA approval. Bivalirudin is the first safe and effective alternative to heparin in cardiac surgical patients with HIT type II.169,170,221 No reversal agents are available for either argatroban or bivalirudin; their suppression of activated factor II abates only after the drug has cleared from the circulation. Argatroban is primarily cleared by hepatic metabolism, whereas bivalirudin is partially metabolized by plasma enzymes and then cleared by renal metabolism.222 The use of bivalirudin in CPB surgical procedures is complex and requires both an in-depth understanding of the drug and training for the entire cardiac sur-

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gical team (e.g., cardiac anesthesia, surgery, nursing, and perfusion) in order to be used safely. The use of bivalirudin in patients on CPB mandates that blood continuously flow in all native and extracorporeal circulations to avoid thrombus formation in areas of blood stagnation because the drug is metabolized by thrombin itself. Both argatroban and bivalirudin can be titrated with the aPTT if the desired level of systemic anticoagulation is between 1.5 and 3 times the baseline aPTT.220,222 If higher levels of systemic anticoagulation are desired, then the ACT is currently the preferred method to titrate the effect of these drugs.223

Disseminated Intravascular Coagulation Disseminated intravascular coagulation (DIC) is presently recognized as a deviation from the normal physiologic balance between the processes of thrombus formation and fibrinolysis. Pathologic hemorrhage, pathologic thrombosis, or both may occur in DIC. Numerous disease processes have been identified as being associated with DIC (Table 15–13).224 All of these disease states have in common the production of intense, sustained stimulation of the coagulation axis, achieved by inflam-

matory mediators resulting in dysregulation of coagulation and/or fibrinolysis.225,226 The association of DIC with inflammation helps to explain why this condition can be associated with multiorgan dysfunction syndrome (MODS) and adult respiratory distress syndrome, two disorders that also involve inappropriate regulation of the inflammatory response. The pathophysiologic mechanism of DIC is incompletely understood. Pathologic thrombosis at the microcirculatory level results in organ malperfusion, ischemia, infarction, and dysfunction, as well as pathologic consumption of essential coagulation elements (e.g., platelets, fibrinogen, and soluble coagulation proteins). Dysregulation of fibrinolysis can contribute to DIC-associated thrombosis (i.e., there is oversuppression of fibrinolysis from excessive plasminogen activator inhibitor type 1) or to DIC-associated hemorrhage (i.e., there is overstimulation of fibrinolysis from high levels of inflammatory mediators, including interleukin-1, interleukin-6, interleukin10, and tissue necrosis factor).227,228 The diagnosis of DIC is approached from two vantage points. First, because DIC is the manifestation of a primary disease process, one must investigate potential clinical causes that may give

TABLE 15–13. Processes That Can Induce Disseminated Intravascular Coagulation Tissue Damage Trauma Crush injuries CNS injuries Heat stroke Burns Hemolytic transfusion reaction Acute transplant rejection Neoplasia Cancers Leukemias Cancer chemotherapy Tumor lysis syndrome Infections Gram-positive bacteria Gram-negative bacteria Spirochetes Rickettsia Protozoa Fungi Viruses

Obstetric Conditions Abruptio placentae Placenta previa Uterine atony Therapeutic abortion Toxemia of pregnancy Retained dead fetus syndrome Amniotic fluid embolism Miscellaneous Shock Cardiac arrest Near drowning Fat embolism Aortic aneurysm Giant hemangiomas Snake bites

Reprinted from Kitchens CS. Disseminated intravascular coagulation. In: Kitchens CS, Alving BM, Kessler CM, eds. Consultative Hemostasis and Thrombosis. Philadelphia: WB Saunders, 2002:165, with permission from Elsevier.

rise to DIC (Table 15–13). Second, although DIC is often initially suspected as a clinical diagnosis, central laboratory values may help to establish the diagnosis. Some authorities advocate for the more readily available central laboratory tests including the aPTT, PT, TT, fibrin degradation products (FDPs) level, D-dimer level and complete blood count. Although measured elevation in FDPs, elevation in D-dimers, prolonged aPTT, PT, and TT, and decreased platelet counts are not universally seen in DIC, they can be very helpful in making the diagnosis if a high level of clinical suspicion exists.224,229 The treatment of DIC is most appropriately directed at the underlying cause of the disorder. For example, DIC in a septic patient with an intraabdominal abscess is most effectively treated by abscess drainage. An obstetrical patient who develops DIC in association with abruptio placentae is best treated with uterine evacuation. Exhaustive efforts to correct laboratory abnormalities may not be needed in all cases of DIC, especially those in which patients require surgical treatment. Perioperative goals include maintaining the platelet count in the range of 25,000–50,000/µL and the fibrinogen level greater than 50 mg/dL. However, few data exist on the effective management of the patient with DIC.224 Presently, with the exception of Trousseau syndrome (occurrence of thrombophlebitis migrans with visceral cancer), anticoagulation is not recommended as a treatment for DIC. Intravenous administration of antithrombin concentrate, although advocated by some, is presently not recommended.230–232 Hemorrhaging DIC patients should be volume resuscitated as appropriate to restore intravascular volume to a level consistent with organ perfusion. As previously stated, coagulopathy is not expected to fully correct until the underlying cause of DIC is appropriately addressed.

Hyperhomocysteinemia Hyperhomocysteinemia is an independent risk factor for stroke, myocardial infarction, carotid artery disease, and venous thrombosis.233–236 Plasma homocysteine levels are partially genetically determined, but are also influenced by environmental factors, specifically by dietary intake of folic acid, vitamin B12, and vitamin B6. Hyperhomocysteinemia is present in 10–20% of patients who develop venous thrombosis. Hyperho-


mocysteinemia is diagnosed by measuring plasma levels of homocysteine.196 No specific recommendations exist for the perioperative management of patients with hyperhomocysteinemia, although vitamin supplementation does reduce plasma homocysteine levels in the elderly population.237 However, reduction of homocysteine levels by vitamins does not decrease the risk of vascular disease. It might be prudent to employ postoperative venous thrombotic prophylaxis, especially in patient populations considered at risk for the development of a postoperative thrombosis (e.g., orthopedic surgical patients). However, no specific recommendations as to a particular antithrombotic or antiplatelet treatment regimen currently exist.

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221. Merry AF, Raudkivi PJ, Middleton NG, et al. Bivalirudin versus heparin and protamine in off-pump coronary artery bypass surgery. Ann Thorac Surg 2004;77:925. 222. Thomson MICROMEDEX. Bivalirudin. MICROMEDEX Healthcare Series. Greenwood, CO: Thomson Healthcare, 2006. 223. Casserly IP, Kereiakes DJ, Gray WA, et al. Point-of-care ecarin clotting time versus activated clotting time in correlation with bivalirudin concentration. Thromb Res 2004;113:115. 224. Kitchens CS. Disseminated intravascular coagulation. In: Kitchens CS, Alving BM, Kessler CM, eds. Consultative Hemostasis and Thrombosis. Philadelphia: WB Saunders, 2002:165. 225. Gando S, Kameve T, Nanzaki S, et al. Disseminated intravascular coagulation is a frequent complication of systemic inflammatory response syndrome. Thromb Haemost 1996;75:220. 226. Levi M, ten Cate H. Disseminated intravascular coagulation. N Engl J Med 1999; 341:586. 227. Levi M, van der Poll T, ten Cate H, et al. The cytokine-mediated imbalance between coagulant and anticoagulant mechanisms in sepsis and endotoxaemia. Eur J Clin Invest 1997;27:3. 228. ten Cate JW, van der Poll T, Levi M, et al. Cytokines: triggers of clinical thrombotic disease. Thromb Haemost 1997;78:415. 229. Carr JM, McKinney M, McDonagh J. Diagnosis of disseminated intravascular coagulation. Role of D-dimer. Am J Clin Pathol 1989;91:280.

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230. Minnema MC, Chang CK, Jansen PM, et al. Recombinant human antithrombin III improves survival and attenuates inflammatory responses in baboons lethally challenged with Escherichia coli. Blood 2000;95:1111. 231. Baudo F, Caimi TK, deCataldo F, et al. Antithrombin III replacement therapy in patients with sepsis and/or postsurgical complications: a controlled, double-blind, randomized, multicenter study. Intensive Care Med 1998;24:336.

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232. Wheeler AP, Bernard GR. Treating patients with severe sepsis. N Engl J Med 1999;340:207. 233. Stampfer MJ, Malinow MR, Willett WC, et al. A prospective study of plasma homocyst(e)ine and risk of myocardial infarction in US physicians. JAMA 1992;268:877. 234. Perry IJ, Refsum H, Morris RW, et al. Prospective study of serum total homocysteine concentration and risk of stroke in middle-aged British men. Lancet 1995;346:1395.

235. Selhub J, Jacques PF, Bostom AG, et al. Association between plasma homocysteine concentrations and extracranial carotid artery stenosis. N Engl J Med 1995; 332:286. 236. D’Angelo A, Selhub J. Homocysteine and thrombotic disease. Blood 1997;90:1. 237. Selhub J, Jacques PF, Wilson PWF, et al. Vitamin status and intake as primary determinants of homocysteinemia in an elderly population. JAMA 1993;270:2693.

CHAPTER 16: Evaluation of the Patient with Perioperative Malnutrition

CHAPTER 16 Evaluation of the Patient with Perioperative Malnutrition Jacob T. Gutsche, MD, and Clifford S. Deutschman, MS, MD, FCCM

As a result of advances in medical and surgical care, operative intervention is now provided for older and sicker patients. These individuals frequently suffer the consequences of diseaseinduced altered metabolism and nutritional depletion. Consequently, today’s anesthesiologist requires a solid working knowledge of perioperative metabolic abnormalities and their effects on organ function, drug metabolism, and patient outcome. This chapter addresses (a) definitions of malnutrition, (b) assessment of malnutrition, (c) the incidence of malnutrition in surgical patients, (d) the effects on organ system function, (e) the consequences of attempted reversal on organ system function, and (f) the association of reversal with improved outcome.

DEFINITION AND SCOPE OF PROTEIN-ENERGY MALNUTRITION Inadequate intake of macronutrients (carbohydrate, protein, fat) is referred to as protein-energy malnutrition (PEM). The hallmark of this process is a reduction in lean body cell mass. Original work on PEM centered on children in underdeveloped nations and in adults receiving experimental diets designed to mimic famine or “liferaft” conditions. A brief review of these two different conditions is important because the clinical presentation of the two conditions is different, and because nutritional management principles derived for use in starvation are ineffective (and can lead to complications) in the presence of stress. However, what is most often seen in surgical patients

reflects the interplay of metabolic changes resulting from starvation with those occurring as a result of “stress” (inflammation, infection, surgery, trauma, and neoplasia). In fact, as detailed by Bistrian1 and Bistrian et al.,2 PEM in sick adults represents a broad spectrum of abnormalities.

Starvation In the initial period of fasting, metabolic rate decreases to conserve endogenous substrate, especially nitrogen. Glucose is the predominant fuel of early starvation and continues to be made available to those tissues that require it (brain, fibroblasts, erythrocytes, leukocytes, renal medullary tissue). Other tissues quickly alter metabolism to adapt to alternative substrate. Glucose is derived initially from glycogen, but following the depletion of stores (about 24 hours of fasting) hepatic and renal gluconeogenesis from amino acids supplied by muscle catab-

olism predominate.3 Insulin secretion decreases because gluconeogenesis is unable to maintain blood glucose concentration at prestarvation values.3 Decreased insulin promotes lipolysis (by activation of a hormone-sensitive lipase) and ketonemia. Ketones inhibit pyruvate dehydrogenase and prevent the conversion of pyruvate to acetyl coenzyme A (CoA), thereby blocking use of the end products of glycolysis in the tricarboxylic acid cycle. As a consequence, the primary fuel for most tissues switches to acetyl CoA derived from fat or ketones. This change is reflected in a decrease in the respiratory quotient (carbon dioxide production/ oxygen consumption).3 In addition, the decrease in glucose is associated with secretion of epinephrine, cortisol, and glucagon. The effect of these three “counterregulatory” hormones is stimulation of proteolysis, lipolysis, and gluconeogenesis.3 Muscle-derived gluconeogenesis provides fuel for tissues

KEY POINTS 1. Although the incidence of malnutrition is unclear, the problem in patients presenting for surgery may be widespread. In addition, a large number of patients acquire proteinenergy malnutrition (PEM) during hospitalization, which can alter the response to anesthetics. 2. In contrast to starvation, acute stress metabolism involves extensive neurohumoral modulation. Inflammation, surgery, trauma, or infection activates monokines, lymphokines, prostanoids, hormones, neural pathways, complement, and other endogenous mediators that “drive” metabolism and increase energy expenditure. 3. PEM is a metabolic disorder that affects virtually every organ system. 4. Decreased total circulating albumin has wide implications for drug administration and volume of distribution. 5. As a result of decreased microsomal enzyme activity and altered cytochrome P450/nicotinamide adenine dinucleotide phosphate (NADPH)dependent transport mechanisms protein deficiency may reduce drug metabolism. Decreased transformation of compounds that are hepati-


cally detoxified may lead to pathologic responses that require dosage alteration. 6. A number of studies confirm that decreased serum transport protein levels, anergy, and weight loss are associated with poor postoperative outcomes. 7. Accurate estimation of the presence and severity of PEM remains problematic for the anesthesiologist whose evaluation of the patient is often brief. The most useful tool for assessing a patient’s nutritional status is a well-performed history and physical examination. 8. Abnormalities of plasma proteins are associated with an increased incidence of bowel anastomotic dehiscence. 9. The anesthesiologist should ensure that the patient presenting for elective surgery is in the best possible condition to tolerate the operation and postoperative course. The relatively poor outcome associated with malnutrition, coupled with the apparent benefits of repletion in the severely depleted individual, constitutes one more problem that must be addressed to improve overall patient outcome.

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that are obligate glucose users. If allowed to continue unchecked, such a process would culminate in rapid depletion of endogenous protein, primarily because of the demands of neural tissue. To counter this effect, brain tissue adapts to the use of ketones, permitting a further decrease in glucose demand and some sparing of lean body mass.4 In starvation, adaptation to exogenous substrate is effective; when given glucose, a starved individual responds to the increase in serum glucose by increasing insulin secretion and decreasing levels of counterregulatory hormones. This decreases levels of proteolysis, lipolysis, and gluconeogenesis. The resulting reliance on the externally supplied glucose spares endogenous tissues and decreases ketosis (blocked by insulin).3 Similar patterns are observed when exogenous fuel is supplied as fat or protein. When demand for energy increases, as in exercise, anaerobic metabolism of glucose also increases. Primary use of branched-chain amino acids by muscle may help meet the new demand.3 Lactate from anaerobiosis and amino acids derived from proteolysis (which result, in part, from increased catecholamines) are released by exercising muscle and are recycled by the liver via the gluconeogenic pathway. The newly synthesized glucose can return to skeletal muscle and again be metabolized to lactate. These processes make metabolic rate responsive to tissue demand and exogenous substrate availability with only modest neuroendocrine modulation.5 Prolonged fasting metabolism eventually results in a clinical picture similar to the form of PEM described in children as marasmus. This is characterized by uniform loss of fat and muscle mass in all tissues and a concomitant loss of water in proportion to nonaqueous mass.

Stress Hypermetabolism In contrast to starvation, acute stress metabolism involves extensive neurohumoral modulation.6 Inflammation, operation, trauma, or infection activates monokines, lymphokines, prostanoids, hormones, neural pathways, complement, and other endogenous mediators that “drive” metabolism and increase energy expenditure. Part of the source for this alteration appears to be derived directly from the energy and substrate

demands of hepatic macrophages and the leukocyte infiltrate in wound tissue.7 After a specific injury, this response follows a regulated time course, with a peak in metabolic rate about 2–3 days after the insult and a gradual decline to baseline by postinjury day 7.6,8 The response will persist if a new activating event occurs or if the source of the initial event (e.g., an undrained abscess) is not removed.6,8 The magnitude of the response is proportional to the magnitude of the injury.6,8 The liver responds to neurohumoral stimulation by generating substrate for the increased metabolism. Amino acids from proteolysis, lactate from devascularized tissues and glycerol from lipolysis are directed into gluconeogenic pathways.8 Amino acids are also used to synthesize enzymes and structural proteins, while free fatty acids provide an alternate energy source. Endogenous mediators, stimulated in part by devascularized wound tissue, mediate this process. Because the response is initiated and driven by this internal source, it remains relatively unresponsive to exogenous substrate.9 The hormonal pattern is characterized by increased glucagon, cortisol, and epinephrine that appear to be driven by demands from damaged tissue and infiltrating leukocytes. As blood glucose levels increase, insulin secretion is stimulated. This pattern of metabolism leads to depletion of visceral protein (in excess of muscle mass) and fat and is associated with an expansion of the extracellular fluid compartment.10 Physical findings (edema, hypoalbuminemia, fatty liver) are similar to those noted in childhood kwashiorkor.1

Assessment of Protein-Energy Malnutrition Protein-energy malnutrition can significantly alter perioperative physiology. Therefore, it is important to identify the presence of PEM and quantify it’s severity. This is best accomplished by direct measurement of body cell mass, which, unfortunately, requires the use of multiple isotopic techniques and is not realistic clinically.11 Lessprecise estimates involve the use of indirect parameters that are believed to correlate with body cell mass. Anthropometrics, biochemical markers (most often circulating hepatic-derived proteins), and test of immunologic function all have been used. Un-

fortunately, each is associated with serious limitations that make their validity in the perioperative period questionable. We review each of these methods briefly and recommend how they might be used in clinical perioperative practice. Most anthropometric measures were developed for the assessment of malnutrition in childhood starvation.12 Consequently, parameters that are of key importance in adults but are negligible in children (frame size, build, fat patterning) are neglected and 95% confidence intervals have not been determined.1,12 Furthermore, because edema is a prominent characteristic in stress-induced PEM, the interpretation of anthropometric measurements becomes difficult. Changes in specific hepatic-derived transport proteins (albumin, transferring, prealbumin, retinal-binding protein), also often used to detect PEM, are common in any stress state and reflect the interplay of decreased synthesis, tissue extravasation and extracellular fluid expansion, both from endogenous and exogenous sources.13 The relationship between actual depletion of body cell mass and these biochemical markers is unclear. In stress states, serum proteins will decrease irrespective of the extent of loss of body cell mass.13 Serum protein concentrations are often only mildly decreased in pure starvation PEM despite significant loss in body cell mass because the loss of mass and water is proportional.14 Despite this, serum proteins are frequently used in the metabolic assessment of the chronically malnourished patient. Low serum albumin may be associated with increased mortality in surgical and chronically ill patients.15 Serum albumin has a half-life of 14–20 days making it insensitive to acute changes in nutritional status. It is also affected by albumin transfusion, dehydration, inflammation, and liver disease. Serum albumin less than 3.5 g/dL is suggestive of malnutrition, and less than 2.5 g/dL of severe malnutrition. Serum transferrin is also somewhat useful for evaluating malnutrition. It has a halflife of about 9 days, which is midway between albumin and prealbumin. Unfortunately, unlike albumin and prealbumin, transferrin increases whenever there is bleeding. This decreases its reliability in the perioperative state. Serum prealbumin is the most reliable of the hepatic-derived transport pro-


teins to signal acute malnutrition. It has a half-life of 24–48 hours. Prealbumin is a negative acute phase reactant and in the postoperation setting, prealbumin levels decline. Abnormalities of cell-mediated immunity and absolute lymphopenia have also been touted as indices of PEM. The presence of these abnormalities in such diverse disease states as cancer, collagen-vascular disease, sepsis, uremia, and cirrhosis, as well as the alterations produced by drug administration, make them particularly nonspecific. Finally, all three of these commonly used measures lack specificity and are derived from population studies that may have little bearing on individual patients.12 Alternative approaches have been advocated to overcome the deficiencies inherent in the standard assessment of malnutrition. Forse and Shizgal16 used isotopic techniques to measure the ratio of exchangeable potassium to exchangeable sodium, which should estimate the ratio of extracellular to intracellular mass and thus estimate lean body mass. The problem with this approach is that there may be variability in potassium from tissue to tissue. Studies to determine normal exchangeable potassium values have never been performed. Other individuals have recommended following multiple parameters over time.6 Composite prognostic indices calculated from a series of unrelated variables have been formulated to classify and stratify the extent of PEM.17 Nonetheless, these indices lack specificity. Prognostic indices are capable of identifying patients at risk for complications, but it is not clear that these complications are related to PEM. Several clinicians have proposed that a thorough history and physical examination, coupled with evidence of weight loss or the presence of known “catabolic” disease, is as valid as any sophisticated test or technique.18 New studies are directed at assessing PEM using indirect calorimetry. This technique directly measures oxygen consumption and carbon dioxide production and uses these values to calculate resting energy expenditure. In one small trial, use of indirect calorimetry improved nitrogen balance and outcome.19 Further testing is required to fully assess the usefulness of this modality. Accurate estimation of the presence and severity of PEM clearly remains problematic, especially for the anesthesiologist whose evaluation of the pa-

tient is often brief. The presence of a severe disease producing rapid depletion of body cell mass (e.g., aggressive malignancy) or a prolonged disease that limits intake or absorption (vomiting, diarrhea, upper gastrointestinal obstruction) makes PEM likely. New developments offer promise. Functional testing of recovery time from isolated twitch in somatic muscle, direct measurement of extracellular compartment size, and quantification of T-cell subpopulations, particularly killer cells, are promising techniques and may soon be routinely available. Malnutrition, as detailed in the following sections, is often present in patients presenting for surgery and has profound effects on organ function and physiology, Consequently, the anesthesiologist should suspect the presence of PEM and recognize its potential for precipitating difficulties in perioperative management.

Incidence of Malnutrition in Hospitalized Surgical Patients Malnutrition in the hospitalized patient does not represent a new concern; true recognition of the presence of a serious nutritional problem can be traced to the work of Bistrian et al.2 These researchers identified abnormalities of anthropometrics or biochemical markers consistent with malnutrition in 50% of general surgical patients2 and 44% of general medical patients20 in a large urban hospital. Numerous other investigations confirm these findings in various hospital settings and patient populations. Nonetheless, the use of anthropometrics, biochemical markers and demonstration of altered delayed hypersensitivity as diagnostic criteria for malnutrition is of uncertain specificity and value and may overestimate the extent of the problem. In a study conducted at a Veterans Administration hospital, an abnormality of one or more of these variables was present in 97% of patients.21 Such an estimate seems unreasonable. Symreng et al.22 found that 28% of surgical patients had, on admission to the hospital, three or more abnormalities consistent with depleted body cell mass. This would appear to be a more valid estimate and is consistent with data reported elsewhere. Another study validates this data, noting that 38% of surgical patients admitted for treatment of benign abdominal processes

had biochemical or anthropomorphic evidence of PEM.23 Perhaps of even greater significance is a study noting that 75% of patients admitted to the hospital without PEM developed abnormalities consistent with PEM during hospitalization.24 Together these findings suggest that, although the actual incidence of malnutrition is unclear, the problem exists on a relatively wide scale in hospitalized patients and may develop or worsen over the course of hospitalization. For the anesthesiologist, there are two key points. First, PEM represents a real and not uncommon problem that alters normal physiology. Second, PEM acquired over the course of hospitalization may alter a patient’s response from one anesthetic episode to the next.

Effects of Protein-Energy Malnutrition and Nutritional Repletion on Individual Organ System Function The effects of protein-energy malnutrition and its correction on individual organ systems are reviewed in this section. When possible, human data is cited; otherwise, appropriate animal studies are presented. An attempt has been made to separate the effects of starvation from stress, but the former is disproportionately represented.

Cardiovascular Changes Starvation PEM is associated with morphologic, functional, and electrical abnormalities of the cardiovascular system. Heart size decreases in proportion to loss of body mass25 and the left ventricular free wall is thinned.26 Histologic examination reveals myocardial atrophy and interstitial edema.27 Left atrial, aortic root, and left ventricular end-systolic and end-diastolic dimensions are decreased relative to normal controls valves,28 and left ventricular compliance is reduced.26 Functionally, resting heart rate, blood pressure and pulse pressure are reported to decrease in PEM29 and a subnormal response is noted in each of these parameters during exercise testing.28 Cardiac index and ejection fraction remain at prestarvation levels26,28 and appear to increase appropriately with exercise28 or àdrenergic stimulation.26 On electrocardiography (ECG), amplitude is diminished, axis shows a rightward deviation, PR and QT intervals are prolonged, T waves are inverted to flat-

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tened, ST-T segments are depressed, and nodal escape beats and ventricular tachycardia have been reported.28 Echocardiographic studies done in anorexic patients reveal decreased ventricular mass with associated ventricular dysfunction.30 Also common in the anorexic population is the finding of prolonged QT and QTc with ventricular arrhythmias.31 In one study, treatment and weight recovery resulted in normalization of ventricular mass and improvement in ventricular function in adolescents with anorexia.31 Stress metabolism in cachectic humans is associated with a somewhat different picture than noted in isolated starvation. Heart rate and indexed ventricular mass (per kilogram of body weight) are increased.32 This suggests that stressed myocardium is spared from some of the protein-depleting aspects of PEM. It is logical to assume that the heart in stress can respond normally to increased demand for work even when other tissues are being wasted. This may result, in part, because the heart can use virtually any fuel (glucose, fat ketones, lactate) to support energy requirements. Protein and calorie repletion in previously healthy adults subjected to semistarvation results in a rapid increase in heart size.28 With refeeding, heart rate, blood pressure, and pulse pressures initially increase to above prestarvation levels and gradually return to baseline. Ejection fraction and cardiac output and index may decrease and congestive failure has been reported. The cause of these abnormalities is unknown but may reflect mobilization of interstitial fluid coupled with the inability of depleted cardiac muscle to handle the fluid load. ECG amplitude and QT interval abnormalities persist for variable periods despite repletion.28 To date, only one study has focused on the effects of correction of stress-induced PEM on cardiac function.32 Ventricular mass, heart rate, end-diastolic volume, cardiac output, and ejection fraction all increased, but congestive heart failure developed in 3 of 5 patients and pericardial effusion developed in a fourth patient.

Pulmonary Changes Relative cell mass (lung weight/body weight) appears to increase in cases of PEM, but overall wet and dry lung weights decrease with depletion.33

Morphologic changes similar to those observed in emphysema are characteristic; distances between alveolar walls are increased, the surface area for gas exchange is decreased and air space is grossly enlarged as a result of disruption of alveolar septae.34 Peripheral lung tissue is more affected than central mass and a significant loss of collagen and elastin is noted.34 The phospholipoprotein content of surfactant is grossly depleted.35 In the early stages of depletion, pressure-volume relationships are normal,35 but after prolonged starvation surfactant concentrations decrease, active surface forces increase, and exposure of alveolar surfaces leads to an altered functional residual capacity.36 Diaphragmatic muscle mass decreases in direct proportion to the loss of body weight.37 As a result, the tension developed in isolated diaphragmatic muscle strips is reduced. Mechanical efficiency appears to be unchanged.38 Observed changes in the time to achieve 50% tension reduction following 20- or 100-Hz tetanus indicate that diaphragmatic fatigability is reduced.37 Animal studies indicate a selective depletion of fast (glycolytic) fibers with sparing of the slow oxidative fibers, a finding that supports the notion of decreased fatigability.37 After an acute period of mild starvation in otherwise healthy adult women, forced vital capacity, forced expiratory volume, inspiratory pressure, and maximal voluntary ventilation were normal.39 A prolonged course of severe depletion in both human and animal subjects results in decreases in all lung volumes, maximal pressure generation and maximal ventilatory effort.40 Respiratory rate is decreased, perhaps reflecting altered carbon dioxide production; the ventilatory response to carbon dioxide is preserved but hypoxic ventilatory drive is markedly attenuated.41 The number of alveolar macrophages and their ability to clear aerosolized Staphylococcus aureus is decreased.42 Refeeding in rats leads to a return to normal lung weight and normal levels of lung hydroxyproline, elastin, and surfactant contents.33 Parenchymal emphysematous changes are incompletely reversed.33 Diaphragmatic contractile force is regained as body weight is regained.40 Respiratory muscle function, maximal inspiratory pressure, and phagocytic capacity improve also, but abnormalities of hypoxic ven-

tilatory drive are not prevented despite the provision of amino acid formulas sufficient to prevent negative nitrogen balance.43 The effects of repletion on lung volumes and hypoxic ventilatory drive are unknown.

Renal Changes During starvation, renal mass is lost in proportion to body mass and renal protein content is reduced. Clearance of creatinine and free water are decreased and effective renal plasma flow, glomerular filtration rate, and filtration fraction decrease dramatically, although total renal blood flow is not reduced. The ability to concentrate the urine in response to water restriction is impaired. Total body water is decreased by starvation PEM but exchangeable sodium remains normal, implying that cellular mass and exchangeable potassium are decreased.44 Free water clearance and sodium excretion are increased early in the course of starvation but decline after several days. Renin and aldosterone are increased in this early natriuretic period. Their role in sodium homeostasis during PEM is uncertain. Titratable acid excretion is decreased whereas serum bicarbonate and urinary ammonia concentrations increase. Refeeding following starvation PEM improves glomerular filtration rate, filtration fraction, concentrating ability, and free water clearance.45 Sodium and acid excretion increase, as do plasma and extracellular volume. After a period of refeeding, accompanied by increasing plasma osmolality, interstitial water moves into the intravascular compartment. This is associated with a diuretic phase. Surgical or traumatic stress activates renal mechanisms to conserve salt and water,6,11 and thus expand the vasculature to improve substrate delivery. Both antidiuretic hormone and aldosterone are involved in this response, and plasma volume contraction in this setting can produce a metabolic alkalosis. The effects of prolonged stress are unknown and no data exist regarding repletion.

Gastrointestinal Changes Intestinal mass, a rapid turnover tissue, is lost at a proportionately greater rate than body weight in starved rats.46 Small intestine as a whole, and mucosal cells in particular, have de-


creased contents of DNA, RNA, and nitrogen. Epithelial cell renewal and migration are reduced and villus size and crypt cell number, size, and mitotic rate are decreased. Gastric ulceration, gastric and intestinal atrophy, and mucosal hemorrhage are all present to a great extent, perhaps reflecting mucosal breakdown either as a result of increased lysosomal acid hydrolase47 or failure to synthesize mucosal glycoproteins. Gastrin concentrations decrease. Long-term fasting appears to be required for mucosal changes to occur; Knudsen et al.48 found normal histologic conditions following a 7-day fast in obese individuals. Mucosal transport, reflected in decreased uptake of oral mannitol, may be impaired. Sucrase and maltase (but not lactase) activities are decreased, with these changes most prominent in the proximal gastrointestinal tract. Glucose transfer across the mucosa decreases but mucosal-to-serosal transport of both glucose and histidine increase. Loss of brush border enzymes impairs absorption and promotes bacterial overgrowth. Healing of mucosal ulcerations has been reported in depleted patients with Crohn disease who receive parenteral nutrition. Increased nitrogen retention and improved gastric motility in starved individuals has been noted.49 Cell populations and absorptive capacity improve, activity of brush border enzymes is restored,47 and lysosomal enzyme activities decrease to normal. Enteral feeding seems to be more effective than parenteral nutrition in restoring gastrointestinal function postoperatively.50 Mucosal integrity, brush border enzyme levels, and absorptive capacity all improve rapidly in depleted animal that are refed orally.51 Use of glutamine is implicated in this improvement; it appears that even parenterally administered glutamine (which is not present in most total parenteral nutrition formulas) is of benefit.52 In critically ill patients there is a concern that bacteria may overgrow and translocate from the intestinal lumen to the systemic circulation leading to infection. In theory, part of the benefit of early enteral nutrition in the critically ill is to prevent this overgrowth. While multiple animal studies support this theory, a study by Moore et al. failed to find bacteria or endotox-

in in the blood from the portal vein in severely injured trauma patients.53 Indeed, careful examination of most of the work on translocation in animals demonstrates (a) at least two insults (overgrowth of a single bacterial species and some form of injury) are required for translocation and (b) bacteria translocate to the intestinal lymph nodes and occasionally, the liver but rarely beyond.54 Thus, the clinical importance of translocation is unlikely to be great.

Pancreatic Changes Pancreatic mass decreases in direct proportion to body mass and acinar atrophy, loss of architecture, fibrosis, and exocrine duct dilation are all noted in response to starvation PEM.3 Rough endoplasmic reticulum and mitochondria are decreased. Amylase and trypsinogen content in the pancreas falls and lipase is increased.3 Duodenal aspirates show a sequential decrease in level of lipase, trypsin and amylase as PEM progresses. Bicarbonate secretion also decreases in adults. Loss of structural integrity is reflected in increased serum amylase levels and indices of amylase production in patients with anorexia nervosa.55 Following PEM in rats, the exocrine pancreas shows decreased responsiveness to carbachol stimulation and insulin responsiveness to glucose stimulation is attenuated.56,57 Insulin secretion, exocrine responses to carbachol, and serum amylase and lipase values return to normal after refeeding.57

Hepatic Changes In humans, starvation results in a rapid loss of liver glycogen. Because of defective triglyceride excretion and carnitine-limited uptake, reesterification of free fatty acids in the periportal region occurs.3 Prolonged PEM will eventually deplete even the periportal fat deposits. In chronic protein deficiency in rats, liver mass and rough endoplasmic reticulum are lost.46 Loss of RNA, water, fat, and protein, as well as cellular atrophy, have been reported, but it appears that hepatocytes are remarkably resistant to loss of structure or number.3 Patients with weight loss as great as 55 kg have had histologically normal liver biopsies, although the presence of pigment deposits, fibrosis, and fatty infiltration has also been reported.3 In pure starvation, hepatic enzymes and bilirubin

may be normal or increased;58 albumin synthesis and total albumin content decrease, but concentrations may be normal. Urinary nitrogen loss decreases, reflecting activation of amino acid-conserving enzymes and decreased urea cycle activity.59 Protein deficiency often reduces drug metabolism, reflecting decreased microsomal enzyme activity and altered cytochrome P450/nicotinamide adenine dinucleotide phosphate (NADPH)dependent transport mechanisms.20 Thus, decreased transformation of compounds that are hepatically detoxified may lead to pathologic responses that require dosage alteration. Conversely, compounds that are biotransformed into toxic metabolites are better tolerated.60 Many products of hepatic protein synthesis are altered during stress. Messenger ribonucleic acid (mRNA) is increased for acute-phase products, such as fibrinogen, or _1-antiproteases, whereas synthesis of transport proteins such as albumin is decreased. Liver size and function return to normal with refeeding; gross and ultrastructural morphology are restored after several weeks of repletion. Serum hepatocellular enzymes increase initially with refeeding but then return to normal.61 Effects of repletion on drug metabolism are unknown.

Immunologic Changes Protein-energy malnutrition is associated with a reduction in the mass of lymphoid tissue in excess of loss of body mass. Both small lymphocytes and germinal centers are affected. Total circulating polymorphonuclear (PMN) cell counts are reduced but the fraction of total erythrocytes that are PMNs is increased. Macrophage and PMN chemotaxis, bacterial engulfment, and intracellular killing are impaired. Serum levels and activity of complement components C3 and C5 are normal in stress, but all other components of both the direct and indirect pathways are reduced in stress and all components are reduced in starvation.62 Circulating B-cell numbers are reduced but account for an increased percentage of the total lymphocyte count. Serum immunoglobulin may be low, normal, or high. Impairments of antibody binding and antigen specificity have been reported.63 Impaired cell-mediated immunity is one charac-

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teristic of the malnourished state.63 Absolute numbers of T cells and the ratio of T cells to total leukocytes is reduced.63 The proportion of T-helper and T-suppressor cells is normal in starvation but reduced in stress; Tkiller cells are reduced in both states.64 Lymphoid tissue mass, cell populations, and germinal center populations respond well to nutritional repletion. Phagocytosis and chemotaxis improve, but the effects of refeeding on engulfment and intracellular killing are unknown.63 Delayed hypersensitivity to skin testing,65 antibody levels (circulating or fixed),65,66 and complement levels return to normal with nutritional therapy.66 Short-term repletion has no effect on T-cell subpopulations in stress or starvation.64 The effects of longer treatment are unknown.

Nervous System Changes Peripheral nerve conduction velocity is decreased and associated sensory abnormalities have been reported in PEM.67 In moderate PEM, nerve biopsies are normal but severe depletion is associated with segmental demyelination.67 Chronic malnutrition may lead to lethargy, confusion, and impaired initiative.68 Cerebral atrophy, ventricular dilatation and diffuse electroencephalographic slowing have been noted.3 In adult rats deprived of protein, the phosphatidylglycerol and sphingophospholipid fraction are decreased but other myelin components are present in normal quantities.69 Refeeding appears to restore nerve conduction and structure70 and to improve mental status.68

Anesthetic Implications of Organ System Dysfunction The dysfunctions caused by PEM have important perioperative implications. Cardiac reserve may compromised, as evidenced by subnormal blood pressure and heart rate responses to stress testing, but appropriate increases in cardiac output in response to exercise or `-adrenergic stimulation argue against this. The potential for myocardial depression caused by volatile anesthetics should be considered in patients with PEM. In addition, the partially repleted patient may be at risk for pulmonary edema when mobilization of fluid occurs because the cardiac response to fluid challenges may be inadequate. Cardiac dysfunction and renal abnormalities make it

important to watch fluid balance. Assisting postoperative diuresis may be necessary. Pulmonary disease resembling emphysema may impair gas exchange, whereas respiratory muscle failure may preclude early extubation, especially with residual paralysis. The selective depletion of fast muscle fibers may alter the ability to respond to acute increases in carbon dioxide. It may be prudent to mechanically ventilate the severely depleted patient for some time postoperatively. In the healthy individual, resistance to pulmonary infection is maintained by bacterial clearance (ciliary action and coughing) and macrophage function. Both are impaired in PEM and further decreased by general anesthesia. Renal abnormalities may reduce the clearance of both solute and solvent, resulting in retention of water as well as toxic byproducts. Thus fluid loads may be poorly tolerated and clearance of drugs and cellular debris impaired. Altered gastric motility increases the risk of aspiration. In addition, because of the loss of brush border enzymes and depletion of gastrointestinal mucosa, oral absorption of drugs may be altered. Blood sugar values should be monitored perioperatively because of the relatively impaired insulin response to hyperglycemia. Hepatic drug metabolism may also be altered but this is unpredictable. Clearance of some drugs (e.g., vecuronium) may be impaired, but tolerance for others with toxic metabolites (e.g., nitroprusside) might be noted. Metabolism of inhalational anesthetics may be decreased. Perhaps most important, decreased total circulating albumin has wide implications for drug administration and volume of distribution. Table 16–1 is a partial list of commonly used drugs that might be affected by decreased total circulating albumin. Other effects occur as well. For example, the increased risk of infection mandates the use of careful sterile technique for even routine vascular access. Use of inhalational anesthetics may further depress leukocyte function. Finally, the associated peripheral neuropathy may alter the effects of conduction anesthesia, and mental status changes associated with PEM may impair rapid recovery from general anesthesia.

TABLE 16–1. Commonly Used Drugs That are Plasma-Protein Bound

Drug

Protein Bound (%)

Narcotics Morphine Meperidine Fentanyl Sufentanil Alfentanil

30 60 84 92 92

Barbiturates Thiopental Phenobarbital

72–86 40–60

Benzodiazepines Diazepam Midazolam Lorazepam

96–98 96–98 96–98

Nonbarbiturate Induction Agents Etomidate Propofol

76 98

Local Anesthetics Tetracaine Lidocaine Mepivicaine Bupivicaine Etidocaine Prilocaine

80 70 77 95 95 55

Cardioactive Drugs Digitalis Labetalol Propranolol Nadolol Pindolol Captopril

25 50 90–95 40–60 1:8 is achieved). • Infection in the face of a foreign body that remains in place. The most effective therapy for tuberculosis deploys three bactericidal drugs; isoniazid, rifampin, and pyrazinamide. Such a regimen permits shortening of the duration of therapy, and its use is associated with greater efficacy. If there are no bactericidal regimens that can be formulated for these conditions because of the nature of the invading organism, then high-dose and prolonged bacteriostatic therapy in association with aggressive surgery becomes the alternative management strategy. Modern microbiologic techniques permit not only the isolation and identification of the infecting microbe, but also can determine the susceptibility to different antibiotics, thus guiding the choice of antibiotics for a particular patient. When exposed in vitro to possible therapies, bacteria may be killed or their growth may be inhibited without being killed. The lowest concentration required to prevent growth is termed the minimal inhibitory concentration (MIC) (a variant of which is the MIC90, which is the concentration of drug required to inhibit 90% of strains of the same species); similarly, the minimal bactericidal concentration (MBC), presents the lowest concentration required to kill the bacterial isolate (with the MBC90 defining the lowest concentration of drug needed to kill 90% of isolates of the same spe-

279


280

cies). The MBC is technically much more difficult and time-consuming to determine than the MIC; it is subject to multiple potential errors and is not needed for routine clinical care.16 These in vitro results are then interpreted in terms of blood levels that are attainable when appropriate doses of the antimicrobial agent in question are administered. One of three results is registered: susceptible, resistant, or intermediate. Susceptibility suggests that blood levels attainable with the therapeutic doses of an antibiotic should be effective in the management of infection caused by this organism. Whether such efficacy is obtained depends on other factors, particularly the site of infection; for example, blood levels may not provide adequate concentrations at sites such as the eye, the brain, or the prostate gland. Thus, in vitro susceptibility is only the first step in choosing the appropriate antimicrobial. In contrast to the sometimes complex assessments that are required after a drug is shown to be effective in vitro, resistance is more easily interpreted. The organism in question is not inhibited by usually achievable systemic concentrations of the agent with normal dose schedules and/or fall in the range where specific microbial resistance mechanisms are likely and when clinical efficacy has not been reliable in treatment studies. In other words, prescribing a drug to which resistance has been demonstrated in vitro is strongly associated with therapeutic failure. Intermediate sensitivity means that MICs of the organism(s) in question are higher than blood and tissue levels that are achievable without potential toxicity. For the most part, the use of antimicrobial agents to which the bacterial isolate only exhibits intermediate susceptibility should be avoided. However, particularly when dealing with a broadly resistant infection in the urinary tract, the issue is not attainable blood levels, but rather the relationship between the isolate’s MIC and the attainable urine concentration. For example, Pseudomonas aeruginosa strains isolated from the urine that are “resistant” to routine therapy can often be effectively treated by tetracycline. The reason for this phenomenon is the dissociation between blood and urine levels of tetracycline that can be expected in the blood (5 mg/dL): quinupristin/dalfopristin, chloramphenicol, clindamycin, lincomycin, all the tetracyclines, cefoperazone, ceftriaxone, metronidazole, nafcillin, nitrofurantoin, fusidic acid, isoniazid, rifampin, rifabutin, pyrazinamide, rimantadine, ketoconazole, fluconazole, itraconazole Modified with permission from Amsden GW.132

in the infant and the latter with an increased incidence of psychomotor retardation, myoclonus, and seizures. Metronidazole, ticarcillin, rifampin, trimethoprim, the fluoroquinolones, and the tetracyclines should be avoided completely because of the potential for injuring the developing fetus. In addition, tetracycline use in the pregnant woman is associated with acute fatty necrosis of the liver, pancreatitis, and possibly renal injury.61

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LRI 5% CVS 4% SSI 4%

Pneu 24%

GI 4% SST 3% EENT 2% Other 1%

BSI 17%

286 UTI 36%

FIGURE 17–1. Site distribution of 2321 nosocomial infections in coronary care units, NNIS System, 1992–1997. BSI, primary bloodstream infection; CVS, cardiovascular system infection; EENT, eye, ear, nose throat infection; GI, gastrointestinal infection; LRI, lower respiratory tract infection other than pneumonia; PNEU, pneumonia; SSI, surgical site infection; SST, skin and softtissue infection; UTI, urinary tract infection. (Reproduced with permission from reference NNIS. 131)

PRACTICAL ASPECTS OF DRUG ADMINISTRATION: ANTIMICROBIAL THERAPY OF PARTICULAR CLINICAL SITUATIONS When choosing the appropriate antibiotic therapy it is critical to decide if the infectious process is nosocomially acquired or present at admission, that is,

community acquired. Of the nosocomially acquired infections, the National Nosocomial Infections Surveillance (NNIS) system has demonstrated that almost 80% occur in three sites: 24% in the respiratory system, 17% in the bloodstream, and 36% in the urinary track. The majority of the remaining 19% of nosocomial acquired infections are associated with the gastrointestinal

tract, cardiovascular system, skin and soft tissue, surgical site, or ear, eye, nose, and throat, as shown in Fig. 17–1. Table 17–4 lists the primary pathogens associated with these various sites. It is important to recognize that gram-positive pathogens, particularly Staphylococcus epidermidis, S. aureus, and enterococci are the leading bloodstream pathogens, whereas S. aureus and gramnegatives, particularly P. aeruginosa, are the predominant pathogens associated with nosocomial pneumonia. In addition to S. aureus and P. aeruginosa, E. coli and Candida albicans are the primary pathogens found in urinary tract infections, with the great majority of these being associated with urinary tract instrumentation.62–68 These data are consistent across continents.68 It is of interest that Candida species now account for the fourth most common cause of nosocomial bloodstream infection. Ten years ago it was 24th, a testimonial to the increasing importance of this organism, particularly in ICU patients. The incidence of nosocomial infections is highly associated with the use of devices such as ventilators, vascular access catheters, and urinary cathe-

TABLE 17–4. Primary Pathogens in Nosocomially Acquired Infections Blood Stream Infection Pathogen SCN SA Enterococcus Escherichia coli Enterobacter Candida albicans Klebsiella pneumoniae Serratia marcescens Pseudomonas aeruginosa Other Candida C. glabrata Acinetobacter Other fungi Proteus mirabilis Citrobacter Streptococcus pneumoniae Haemophilus influenzae Other

Pneumonia

Urinary Tract Infection

CCU (n = 1159)

ICU (n = 2971)

CCU (n = 1635)

ICU (n = 4389)

CCU (n = 2321)

ICU (n = 4956)

37 24 10 3 3 2 2 2 2 2 2 1 1 0.6

36 13 16 3 3 6 4 1 3 3 2 2 0.8 0.5 0.58

2 21 2 4 9 6 8 4 14 0.2 3 3 2 2

1 20 2 4 9 5 8 4 21 1 0.2 6 1 2 2

3 3 14 28 4 10 6 1 7 4 3 0.2 5 4

2 2 14 14 5 21 6 0.7 10 5 5 1 8 2 1

0.4 0.1 7

6

2 3 16

14

0 0 8

3

CCU, critical care unit; MICU, medical intensive care unit; SA, Staphylococcus aureus; SNC, coagulase-negative Staphylococcus. Data derived from the National Nosocomial Infections Surveillance (NNIS) database elucidating the relative frequency of various pathogens by site of infection and by type of ICU (MICU vs. CCU). Data were obtained from 1992 to 1997. Adapted from Richards MJ, Edwards JR, Culver DH, et al;65,66 National Nosocomial Infections Surveillance;131 el-Ebiary M, Tomes A, Fabregas N, et al;133 and Kauffman CA, Vazquez JA, Sobel JD, et al.134

CHAPTER 17: Principles of Antimicrobial Therapy

ters. This is likely a result of the breakdown of normal host defenses and clearance mechanisms. In addition, the various devices may support various microorganisms differently. For example, the development of biofilms on urinary and central venous catheters enhances the adherence of certain microorganisms such as E. coli and impairs the penetration of antimicrobials, whereas the condensation of water in ventilator circuits is a conducive environment for Pseudomonas and Acinetobacter.66 The rate of devicerelated infections per 1000 device days also varies by type of ICU from 3.0 (cardiothoracic) to 6.7 (burn) for urinary catheter-associated urinary tract infections; from 2.7 (cardiothoracic) to 7.0 (burn) for central line-associated bloodstream infections; and from 4.9 (medical) to 12.0 (burn) for ventilatorassociated pneumonia.62

Catheter-Related Infections Intravascular access devices are common causes of bacteremia and fungemia. A catheter-related infection is defined as a bacteremia or fungemia in a patient with a central venous catheter who has at least one positive blood culture drawn at a peripheral site, clinical manifestations of an infection and no apparent source for the infection except the catheter. A positive semiquantitative (>15 colony-forming units [CFU]/catheter segment) or quantitative (>1000 CFU/catheter segment) culture of the same organism from a catheter segment (usually the tip) should also be present.69,70 The most widely used diagnostic technique to assay for catheter infection is a semiquantitative method, which involves rolling the catheter tip across an agar plate and then counting the number of CFU after overnight incubation. A positive culture drawn through a catheter is relatively nonspecific but a negative culture generally rules out a catheterrelated infection because of the low false-negative rate. It is difficult to find current data on the risk of bacteremia associated with various vascular devices, probably because of the large variation in type of catheter (antibiotic coated or not), techniques (skin preparation), care of the site, and barrier precautions between regions of the country and hospitals within a region. To put this risk in perspective, it is worth noting that 50,000–100,000 patients in U.S. hospitals develop nosoco-

mial bloodstream infections (BSIs) each year, with 70–90% of these infections being related to central venous catheters of various types.62,71 Such infections are associated with a mortality of 25–35% and a 2- to 3-fold increase in attributable mortality. The Infectious Diseases Society of America has published guidelines for the management of intravascular catheter-related infections, as has the Centers for Disease Control and Prevention (CDC).69,70 Although the guidelines state that “there is a notable absence of compelling clinical data to make firm recommendations for an individual patient,” understanding the pathogenesis and virulence of the typical organisms involved still permits this problem to be approached rationally. For nontunneled central catheters, the organism usually comes from a colonized catheter, often the hub or lumen. These organisms usually reflect the flora of the skin. S. epidermidis, S. aureus, Enterococcus species, and Candida species are the prime culprits, but gram-negative bacilli also cause infection. The latter is particularly true when there is gram-negative infection of the respiratory tract or surgical wounds and drains as they increase the incidence of gram-negative skin colonization and hence the reservoir of organisms from which infection is derived. This pathogenic mechanism explains the increasing infection rate associated with central line position (femoral > internal jugular > subclavian). Presumably, internal jugular catheter infection is more likely than subclavian catheter infection because the former is more likely to be exposed to orotracheal secretions. One solution has been to use antibiotic-impregnated catheters, which have been shown to prevent microbial contamination of the catheter and subsequent bacteremia in some, but not all studies. In one study, catheter-associated bacteremia decreased from 3.4% to 0.3% with the use of a minocycline- and rifampin-impregnated catheter.72 However, these results should be interpreted cautiously because these coatings may lead to false-negative culture results. Initial therapy of suspected intravascular catheter infection usually includes vancomycin because of the high prevalence, in the nosocomial environment, of methicillin-resistant S. aureus and S. epidermidis. Additional coverage directed at gram-negative organisms

should be considered if gram-negative infection is present at other bodily sites or if the patient manifests cardiovascular instability that is thought to be a result of infection. Empiric therapy directed at vancomycin-resistant enterococci is rarely indicated, as this organism is an unusual cause of acute hemodynamic instability. Antifungal therapy is also not initiated unless there is microbiologic evidence of fungal infection. Once the offending bloodstream pathogen is identified and its resistance profile known, focused antimicrobial therapy should be used. There are several important issues to consider in the treatment of the common BSI pathogens. S. epidermidis is often a contaminant. However, when it does cause a BSI, it typically behaves as a relatively avirulent pathogen. Consequently, it usually can be treated with removal of the catheter and a short course of antibiotics. Nonetheless, this organism has a propensity to adhere to prosthetic devices such as cardiac valves and artificial joints. Therefore, when S. epidermidis bacteremia occurs in such a patient, one must carefully evaluate the prosthetic device for evidence of secondary infection. In light of these considerations, patients with indwelling prostheses should be considered at higher risk for consequences of central catheter placement, and they should be discontinued at the earliest opportunity. S. aureus, on the other hand, is an extremely virulent organism, which in the setting of bacteremia, often disseminates and causes osteomyelitis, endocarditis, and other severe, destructive infections. Thus when a bacteremia with this organism is confirmed a careful evaluation for metastatic infection should occur and prolonged therapy (2–4 weeks) is often recommended. Enterococcal BSI behaves in a similar manner as S. epidermidis and typically responds to removal of the catheter. However, endocarditis may occur, particularly in the setting of prolonged bacteremia. The optimal therapy for this organism is ampicillin plus an aminoglycoside although some of the newer antibiotics show therapeutic promise. When C. albicans is cultured from the blood, the patient should be evaluated for metastatic infectious foci (e.g., hepatic, ocular, and skin), the catheter should be removed, and antifungal therapy initiated, typically with

287


fluconazole.73 If metastatic foci of candidal infection are found, the optimal management of these complications will determine the duration of therapy.

Prophylaxis Surgical

288

Need for Prophylaxis The need for antibiotic prophylaxis for surgery depends on the risk of surgical site infection (SSI), generally defined as purulence within the wound. SSIs are related to the wound classification, patient-related factors such as immunocompetence, the bacterial milieu and hospital infection rate for various procedures, and factors relating to the wound itself. Wounds are usually classified as clean (class I), clean-contaminated (class II), contaminated (class III) and dirty-infected (class IV).74 A clean wound is atraumatic in which there has been no break in sterile technique and the respiratory, alimentary, or genitourinary tracks have not been entered. Clean-contaminated wounds result from surgery in areas known to harbor bacteria, such as the biliary, respiratory, alimentary, and genitourinary tracts, when there is no spillage of contents. Contaminated wounds occur with a major break in sterile technique, or with surgery on a traumatic wound, or gross gastrointestinal spillage, or entrance into an infected biliary or genitourinary tract. Dirty-infected wounds are those for which infection existed before the surgery, such as old wounds with devitalized tissue or surgery for patients with perforated viscera. This classification scheme indicates the risk of postoperative infection and is thought to be related to the bacterial burden except for dirty-infected wounds, which are, by definition, already infected. However, careful microscopic examination shows that even clean wounds are contaminated with skin flora.75 Staphylococcus species are the most common wound pathogens for most SSIs. Prophylaxis is debatable for some clean procedures such as an inguinal hernia repair or mastectomy. However, for other clean procedures, especially for cardiothoracic and vascular surgery, hip or knee arthroplasty, and any procedure when bone is excised or a prosthesis is inserted, gram-positive coverage, usually with cefazolin, is recommended. However because of the increasing incidence of methicil-

lin-resistant Staphylococcus not only in hospitals but also in the community, the trend seems to be shifting back toward vancomycin. Prophylactic antibiotics should be administered for all clean-contaminated and contaminated wounds, as well as for hysterectomies and most urologic procedures. Sterilization of the urinary tract is recommended before any urologic procedure if possible. Even with successful treatment of urinary tract infection (UTI), deep-seated infection of the prostate gland can be reactivated by manipulation and/or surgery of the prostate gland. Prophylaxis is advised for high- and moderate-risk patients undergoing procedures involving infected tissues and should include antistaphylococcal antibiotics for cellulitis and osteomyelitis. Similar coverage is advised for patients receiving prosthetic cardiac valves. Patients with urinary tract infections should receive antibiotics active against gram-negative bacilli such as fluoroquinolones, third-generation cephalosporins, or an aminoglycoside. Convincing evidence of prophylactic antimicrobial benefit is also found in patients undergoing endoscopic manipulation of the biliary tree or in patients undergoing manipulation of an infected urinary tract. For these conditions antibiotics such as ampicillin-sulbactam and piperacillin-tazobactam are reasonable choices. Timing of Prophylaxis It is generally believed intravenous administration of prophylactic antibiotics should be initiated no more than 1 hour before incision. The major impetus for this practice comes from Classen’s study that looked retrospectively at the timing of prophylactic antibiotic administration in patients in whom a wound infection was reported.76 The investigators found that patients who developed wound infections were more likely to have received prophylaxis between 24 and 2 hours prior to surgery or postoperatively. Often missed in this study was that the incidence of wound infection was statistically no different if the antibiotics were initiated within the first 4 hours following incision or in the 2 hours before incision. When the data were subjected to a multiple logistic regression, the only variables related to wound infection were underlying disease, nursing service, type of surgery, duration of surgery and time after the start of surgery

for the first dose of prophylactic antibiotics. Notably, of the 41 wound infections, 58% were resistant to the antimicrobial drug used. Thus, although this study is widely quoted as showing that prophylaxis must be given within 1 hour of the incision, these data does not support this conclusion. Moreover, this study does not address when the antibiotic infusions were completed and a prospective study validating these retrospective findings has never been published. Finally, an animal study widely cited as documenting the need to have the antimicrobial given before the incision lacks statistical testing, uses very high inocula and varying doses of antimicrobials.77 Interestingly, a recent study of vancomycin prophylaxis in 2048 cardiac surgical patients indicated that vancomycin initiated from 16 to 60 minutes before incision and administered over 1 hour was associated with the lowest rate of surgical site infections.78 Although it seems logical to have adequate tissue levels of prophylactic antimicrobials before skin incision, supporting data are only inferential and it is likely that the importance depends upon the size of the inoculum. Nonetheless, Classen’s study76 apparently led the Center for Medicare and Medicaid Services to set a standard that all preoperative antibiotics should be administered within 1 hour of skin incision except for vancomycin which can be administered 2 hours prior to skin incision, presumably because it is often infused over 1 hour. These recommendations also specify that therapy should be stopped within 24 hours except in special circumstances, notably cardiothoracic surgery for which it may be extended to 48 hours. The latter exception occurred because of a document drafted by the Society of Thoracic Surgeons that made the following points: (a) although prolonged use of antibiotics can lead to the emergence of resistant infections, there are no data that this can occur with administration for under 48 hours; (b) antibiotic prophylaxis for 48 hours is “clinically effective in minimizing infectious complications in cardiac surgery” and is as effective as prophylaxis administered for more than 48 hours; and (c) antibiotic prophylaxis should not be used for indwelling catheters of any type or chest tubes.79 There is general agreement on this last point for all types of


surgery with the possible exception of transplantation.

ICU Comparable successes with prophylactic antimicrobial regimens in ICU patients have been more difficult to prove as have attempts to prevent infection with selective gut decontamination regimens. The latter involves using either nonabsorbable antimicrobial agents or fluoroquinolones to eliminate the aerobic gram-negative flora while leaving the anaerobic flora intact, which provides some protection against colonization with a variety of potential pathogens, so-called colonization resistance. Similarly, aerosolized antibiotics, particularly polymyxin or aminoglycosides, do not prevent pneumonia. Topical antibiotic ointments do not decrease the incidence of intravenous access related bloodstream infection.

Preemptive Therapy Recently the concept of preemptive therapy has come to the fore. Preemptive therapy was initially defined in transplant patients, where the initiation of ganciclovir therapy in bone marrow transplant patients with evidence of cytomegalovirus (CMV) replication either in the blood or in the respiratory secretions, at a time when they were asymptomatic, prevented the development of otherwise lifethreatening CMV pneumonia. In organ transplant patients, the initiation of preemptive ganciclovir during intensive antirejection therapy markedly decreases the incidence of systemic CMV infection normally associated with such therapy.1,2 The efficacy of prophylaxis for fungal infection has not been well established. Data for fungal prophylaxis suggests that fluconazole may be effective prophylaxis for certain high-risk patients such as bone marrow transplant recipients and patients undergoing reoperation for gastric or upper small bowel perforations that are the anatomic sites where large numbers of Candida species are normally found. However, there is no evidence that this reduces mortality.80,81 Such studies are difficult to interpret, however, because the diagnosis of invasive fungal infection is often difficult and the ability of the clinician to distinguish between candidal colonization and invasion is not very great. Several studies show

that when a patient is colonized at three or more sites, there is a 30–60% incidence of invasive disease, with a high associated mortality. There is some agreement that preemptive therapy should be initiated only following recent abdominal surgery with recurrent gastrointestinal perforations or anastomotic leaks and is not necessary for the initial surgery even if there is soilage, so long as it has not been present for a relatively long period.82 However, this issue is further complicated by the emergence of fluconazoleresistant C. albicans and the change in common fungal species to more resistant yeast such as Candida krusei and Candida glabrata which are sensitive to newer antifungal drugs.

Bacterial Endocarditis Although there are generally agreed upon guidelines for surgical prophylaxis for bacterial endocarditis there are no studies that definitively show that antibiotic prophylaxis prevents bacterial endocarditis during procedures that can produce a bacteremia. Nonetheless, given the consequences of endocarditis and the minimal risk associated with prophylaxis, the use of antibiotics to prevent cardiac infection is sensible in high-risk procedures. A summary of the most recent recommendations is available from the American Heart Association.83 These recommendations are based on the risk of a procedure producing a significant bacteremia with an organism likely to produce endocarditis and the risk of a patient developing bacterial endocarditis with such a bacteremia. They are also predicated on cardiac conditions that are associated with an increased risk of endocarditis even without surgery. Patients considered to be at highest risk of endocarditis are those with prosthetic heart valves, a previous history of endocarditis, complex cyanotic heart disease and those with surgical systemic-pulmonary shunts or conduits. Moderate risk patients include those with uncorrected ventricular septal defects, primum atrial septal defects, patient ductus arteriosus, aortic coarctation, bicuspid aortic valves, acquired valvular dysfunction and hypertrophic cardiomyopathy. Prophylaxis for mitral valve prolapse is an enlightening controversy for several reasons. First, prolapse can occur in normal mitral valves under conditions that reduce the end-

diastolic volume of the left ventricle such as hypovolemia or enhanced contractility, especially in young adults. Second, prolapse without regurgitation is not thought to increase the risk of bacterial endocarditis because the regurgitant jet seems to produce the valvular abnormalities that make bacteria more likely to adhere to the valve. Thus, it is thought that only patients with mitral valve prolapse who also have mitral regurgitation should receive antibiotic prophylaxis. However, this is further complicated by the observation that regurgitation may occur only with exercise. Consequently, it might be missed on routine examination. In addition, men older than age 45 years with mitral valve prolapse are at higher risk for developing bacterial endocarditis. Procedures such as central catheter placement through skin that is otherwise normal and has been cleansed with povidone-iodine or chlorhexidine are not associated with significant bacteremias and therefore do not warrant prophylaxis. In contrast, patients undergoing dental procedures associated with bleeding or patients with poor dental hygiene should receive prophylaxis. Viridans streptococci (_-hemolytic streptococci) are the most common cause of endocarditis in association with dental or oral surgical procedures. A single oral dose of 2 g of amoxicillin given 1 hour prior to the procedure is the recommended prophylaxis. If oral medications cannot be used, intravenous ampicillin or penicillin is recommended. Clindamycin or azithromycin are alternatives for penicillin allergic patients. Other procedures for which similar prophylaxis is recommended include rigid (but not flexible) bronchoscopy, esophageal stricture dilation, and sclerotherapy (but not banding). Surgery that involves the biliary tree or intestinal mucosa or endoscopic procedures of the pancreatic or biliary tree is also associated with bacteremia with organisms that cause endocarditis, especially Enterococcus faecalis. The recommended prophylaxis for high-risk patients undergoing such procedures is ampicillin and gentamicin. Vancomycin may be substituted for ampicillin in penicillin-allergic patients. Gentamicin may be omitted in medium-risk patients. Endocarditis prophylaxis is recommended for some clean procedures such as abdominal and lower-extrem-

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290

ity vascular procedures, craniotomies, orthopedic procedures with hardware insertion and any procedure that includes implantation of permanent prosthetic material. In contrast, the need for prophylactic antibiotics for orthopedic procedures such as laminectomies and spinal fusions is controversial. The rate of endocarditis-causing bacteremia with genitourinary tract surgery or instrumentation is high in patients with urinary tract infections, prostatitis, and prostatic surgery. E. faecalis is the most common bacterial species, but Klebsiella species are also common. Prophylaxis recommendations are the same as for intestinal or biliary tract surgery but attempted sterilization of the urinary tract before any procedure is also thought to be beneficial. Prophylaxis is not recommended for uncomplicated vaginal delivery, cervical biopsy, or manipulation of an intrauterine device in the absence of infection. However, because bacteremia following removal of an intrauterine device is thought to be relatively common, prophylaxis similar to that used for other genitourinary procedures is recommended.

Pneumonia Patients with pneumonia can be divided into two general categories: those with community-acquired and those with nosocomial pneumonia (particularly ICU-acquired).

Community-Acquired Pneumonia It is useful to consider communityacquired pneumonias (CAP), in three different categories. First are the typical pneumonias of conventional bacterial origin, which are characterized by the abrupt onset (within less than 24 hours) of fever, chills, systemic toxicity, cough, purulent sputum production, and dyspnea, often after a preceding viral illness. Second are the atypical pneumonias, characterized by a subacute onset of fever, nonproductive cough, and malaise, with a gradual progression over a several days. Legionnaires disease, which combines features of both, has an abrupt onset of fever, rigors, nonproductive cough, systemic toxicity, and increasing dyspnea, often after a several-day prodrome of gastrointestinal upset, headache, malaise, and encephalopathy. Although there is considerable overlap among these presentations, initial therapy can

TABLE 17–5. Etiology of Community-Acquired Pneumonia Etiology

Incidence (%)

Typical (acute onset or abrupt deterioration after viral prodrome, with productive cough, systemic toxicity, and a lobar infiltrate) Streptococcus pneumoniae Haemophilus influenzae Staphylococcus aureus Enterobacteriaceae Others (Branhamella catarrhalis, anaerobes, Pseudomonas aeruginosa) Atypical (subacute onset, nonproductive cough, interstitial infiltrate) Viral (influenza, RSV, parainfluenza, adenovirus) Mycoplasma pneumoniae Chlamydia pneumoniae Legionella Others (PCP, Q fever, psittacosis RSV, PCP, Pneumocystis jiroveci)

20–60 5–20 2–10 4–8 5–10

30–60 20–40 4–15 1–15 1–2

PCP, Pneumocystis carinii pneumonia; RSV, respiratory syncytial virus.

be guided by such categorization and by considering the different etiologies within each category (Table 17–5). The bacterial species or virus causing CAP is never identified in approximately 40–60% of patients. However, S. pneumoniae is the most common cause, accounting for approximately two-thirds of bacteremic pneumonias. Other relatively common typical bacteria are Haemophilus influenzae, S. aureus with an increasing frequency of methicillin resistant strains, Neisseria meningitidis, and Moraxella catarrhalis. The atypical bacteria are Chlamydia pneumoniae, Mycoplasma pneumoniae, and Legionella species. The most common viruses are influenza A and B, depending on the season, respiratory syncytial virus, and adenovirus.84,85 The choice of appropriate antimicrobial therapy is helped by Gram stain of sputum; urinary Legionella antigen assays that detect more than 80% of cases of pneumonia caused by Legionella pneumophila type I but not other Legionella species or types; polymerase chain reaction (PCR) test for mycoplasma and/or IgM titers for chlamydia; detection of the appropriate antigen for respiratory viruses; and special studies for other pathogens. In most patients, however, antimicrobial therapy needs to be initiated in the absence of clearcut microbiologic information. Patients without a predisposing host defense defect or history of a gross aspirational episode, in whom a typical pneumonia

is suspected as a cause of respiratory failure, should have initial therapy especially directed against S. pneumoniae, H. influenzae, and possibly S. aureus. Recommended empirical therapy for such inpatients is either a `-lactam plus a macrolide, usually azithromycin, or a fluoroquinolone, such as levofloxacin, alone. For ICU patients, the recommended therapy is either a `-lactam plus a fluoroquinolone or a `-lactam plus a macrolide, although the supporting data are very limited. If S. aureus is suspected and the incidence of MRSA in the community is high, adding vancomycin may be appropriate until the organism and its sensitivities are confirmed. If atypical pneumonia is suspected, then a fluoroquinolone such as levofloxacin, or erythromycin, or one of the newer macrolides (azithromycin or clarithromycin), with or without trimethoprim-sulfamethoxazole, would constitute reasonable initial therapy. For patients with a Legionella-like presentation, high-dose erythromycin is the traditional therapy of choice; however, azithromycin or levofloxacin combined with of one of the regimens used for the treatment of typical bacterial pneumonia such as ampicillin-sulbactam or ceftriaxone might be preferable if resistant pathogens are a concern. It is also important to consider viral pathogens because they are a common cause of community-acquired pneumonia; rapid diagnostic tests are available, and the possibility of antivi-


ral therapy exists. Although the initiation of empiric therapy is often obligatory, invasive diagnostic techniques, such as bronchoalveolar lavage or lung biopsy, should be considered for any patient with respiratory failure in whom the etiologic diagnosis is not quickly apparent or in whom there is a failure to respond to therapy. This is especially important for individuals with underlying conditions that predispose them to a broader range of pathogens such as alcoholics and the immunocompromised.

Nosocomial Pneumonia Nosocomial pneumonia can be divided into three groups: hospital-acquired pneumonia (HAP), which occurs at least 48 hours after admission; ventilatorassociated pneumonia (VAP), which occurs at least 48 hours after endotracheal intubation and healthcareassociated pneumonia (HCAP), which occurs at least 48 hours after admission of patients who had a previous infection within 90 days or resided in a nursing home or long-term care facility or received intravenous antibiotics or wound care within the last 30 days.86 These infections can be divided further into early onset, within the first 2–4 days of hospitalization, and late onset, 5 or more days after hospitalization. Early onset nosocomial pneumonia is less likely to result from multidrug resistant (MDR) organisms and has a better prognosis than late-onset pneumonia. Infections in HCAP patients usually are similar to those in late onset HAP or VAP. The etiology of nosocomial pneumonia, especially when acquired within the ICU, is vastly different from the etiology of community-acquired infection. The pathogenesis is typically an extension of a tracheobronchitis into a bronchopneumonia. In the hospital setting, relatively antibiotic-resistant, aerobic, gram-negative bacilli had been the most frequent invading pathogens but this has been surpassed by gram-positive bacteria. This is thought to be a result of the increased rate of oropharyngeal and gastric colonization with these organisms, with such colonization serving as a reservoir for the introduction of this flora into the lower respiratory tract, usually as a result of aspiration, and the impaired ability to clear these organisms. This is especially true among intubated patients, those with previous lung injury, significant atelectasis, and immunocompromised patients.

Although Tables 17–4 and 17–5 list the etiologies of nosocomial pneumonias caused by different bacteria nationally, it should be emphasized that the etiology of nosocomial pneumonia in each individual hospital may be very different from the national average. Although, gram-negative bacillary pneumonia had been the major problem, gram-positive bacteria, especially MRSA, are rapidly overtaking gramnegative bacteria. Regardless, the type of the bacteria causing infection and their antibiotic sensitivity patterns will vary widely in different hospitals and even in different areas within a hospital. Thus, precise antibiotic recommendations for initiating therapy must be based on ongoing surveillance of the resident bacterial flora and antibiotic sensitivities in the particular hospital area. Initial therapy should reflect the ongoing surveillance information and be modified on the basis of sputum examinations including Gram stains that provide important information about the relative importance of a particular organism found on culture. Initial therapy is usually accomplished with a single, advanced-spectrum, anti–gramnegative drug such as ceftazidime, piperacillin-tazobactam, imipenem, ciprofloxacin, or levofloxacin for less-severe disease, and perhaps one of these drugs with an aminoglycoside for patients with more-severe illness.87 Because of the increasing prevalence of MRSA, vancomycin is often appropriate pending more definitive bacterial

identification. As noted previously, clear-cut evidence in humans that twodrug, potentially synergistic therapy is more effective than a single drug is controversial, but such therapy is used by many clinicians in the face of rapidly progressive Pseudomonas or Klebsiella infection.88 Because some species of Klebsiella are sensitive to cefazolin, it can be substituted for the more expensive advanced-spectrum drugs once the sensitivity is confirmed. In immunocompromised patients, pulmonary infection is the most common form of life-threatening infection. Although a detailed discussion of the approach to pulmonary infection in these patients is beyond the scope of this chapter, certain principles are worth noting here in terms of antimicrobial strategies. As outlined in Table 17–6, particular host defense defects are associated with particular infections, and initial therapy should reflect these associations. Even more than other ICU patients, these immunocompromised individuals are especially susceptible to nosocomial infection, both with the resident gram-negative flora and with Aspergillus species. Because of the importance of such infections in these patients, precise diagnosis is essential, using invasive techniques if necessary.

Bacteremia Bacteremias occurring in hospitalized patients can be considered as arising from two separate pathogenic routes. One route is a consequence of definable tissue infection at an anatomic

TABLE 17–6. Frequent Causes of Pneumonia in Patients with Various Defects in Host Defenses and Initial Antimicrobial Therapy Host Defense Defect

Pulmonary Infection

Initial Therapy

Impaired antibody formation or splenectomized

Streptococcus pneumoniae; Haemophilus influenza type B Pneumocystis jiroveci; Mycobacteria species; fungi; Nocardia; Legionella; herpes group viruses; Strongyloides stercoralis Oral bacterial flora; Enterobacteriaceae; Pseudomonas aeruginosa; Aspergillus Oral bacterial flora; Enterobacteriaceae

Levofloxacin, azithromycin or ampicillin + `lactamase inhibitor Trimethoprim-sulfamethoxazole

Depressed cell-mediated immunity

Decrease in the number and/or function of granulocytes Oral and tracheobronchial ulcerations

Ceftazidime, carbapenem, ± an aminoglycoside Ceftazidime, carbapenem

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site. Common causes of bacteremia of this type are biliary and urinary tract sepsis, usually caused by gram-negative bacilli and/or enterococci; peritonitis caused by a disruption of bowel integrity (mixed infection caused by such anaerobic organisms as B. fragilis, the Enterobacteriaceae, especially E. coli, and bowel streptococci, especially enterococci); and pneumonia. The incidence of bacteremia with pneumonia varies according to which organism is causing the infection. For example, 30–50% of patients with pneumococcal infection will have demonstrable bacteremia compared to less than 10% with gram-negative or aspiration pneumonia. In pneumococcal infection, the bacteremia is typically a result of hematogenous seeding from the pulmonary infection, whereas in gram-negative VAP, the bacteremia is likely related to heavy oropharyngeal colonization leading to skin contamination with consequent seeding of a central venous catheter. Thus, in the setting of VAP, all vascular access devices should be carefully evaluated, especially for duration of implantation, exit-site erythema, and drainage, and by blood cultures. The initial antimicrobial therapy of bacteremia secondary to invasive tissue infection is identical to that which would be prescribed in the absence of bacteremia.

Urinary Tract Infection Urosepsis is relatively uncommon unless complicating factors such as obstruction to urine flow, diabetes, advanced age, spinal cord injury or bladder catheterization are present. The likely bacteria are also different than in uncomplicated urinary tract infections, UTI, or asymptomatic UTIs. In these two instances likely organisms are E. coli or other Enterobacteriaceae, and Pseudomonas can be treated with a fluoroquinolone or trimethoprim-sulfamethoxazole. In patients with complicating factors, gram-positive and antibiotic-resistant gram-negative bacteria, including P. aeruginosa, are more common.89 Consequently, therapy should be initiated with broader-spectrum antibiotics, usually fluoroquinolones or advanced spectrum `-lactam agents such as ceftazidime, ampicillin-sulbactam, ticarcillin-clavulanate, aztreonam, and imipenem. As with all infections, antimicrobial therapy should be adjusted so that the spectrum is as narrow as possible.

A more common problem in hospitalized patients, especially those with urinary catheters, is nosocomial bacteriuria. The etiology of such infections is far different from that observed in community-acquired infections. Whereas E. coli account for more than 85% of community-acquired urinary tract infections, it is responsible for only onethird of nosocomial infections. Enterococci, P. aeruginosa, relatively antibiotic-resistant Enterobacteriaceae such as Klebsiella, Proteus, Enterobacter, and Serratia species, as well as Candida species, now account for the majority of these infections.90 Antibiotic therapy can delay the appearance of bacteriuria for a while, but the price to be paid if catheterization is maintained is that when infection does occur, it will be relatively resistant. Treatment of asymptomatic positive cultures when the catheter is still present is generally not indicated because this represents colonization rather than invasive infection and long-term benefits of such therapy are unlikely. However, when to treat critically ill patients may be problematic because they may not be able to relate symptoms. Usually a quantitative colony count of >105 CFU is used as a criterion for treatment with the choice of antibiotic guided by the culture. Treatment if symptoms develop and/or instrumentation of the urinary tract is to be carried out is clearly indicated.

Other Syndromes Clostridium difficile Clostridium difficile is the leading cause of gastrointestinal infection in the nosocomial environment. This pathogen is an important cause of fever and leukocytosis, which may precede the diarrheal phase. The pathogenesis of this disease is typically mediated by enterotoxin A or cytotoxin B and bacteremia is extremely rare. The diagnosis is confirmed with the detection of either of the aforementioned toxins. The spores from C. difficile are extremely hearty and impervious to antimicrobial therapy, which explains the 10% relapse rate in successfully treated patients. Metronidazole is the therapy of choice even in relapsing cases; however, in recalcitrant cases where there is no response to metronidazole therapy, oral vancomycin can be considered. In patients being treated with other antibiotics for an ongoing pyogenic process, the treatment of C. diffi-

cile is particularly vexing. In this setting, where continued broad-spectrum antibiotic use is required, we recommend continuing the C. difficile therapy in parallel with the other antimicrobial agents and extend the course of therapy for C. difficile for several days after completion of the other antibiotics, typically 5–10 days. The extended C. difficile course of therapy is required because of the role of antibiotic therapy in provoking C. difficile disease by altering the normal bowel flora. Future antibiotic therapy needs to be considered with great care in a previously infected patient as C. difficile can be provoked with subsequent antibiotic courses, in part due to the latent spores. In patients who are severely ill from C. difficile several adjuvant approaches should be considered including minimization of other antimicrobial therapy, toxin binding resins such as cholestyramine, fecal enemas, and in severe cases surgical resection of the colon, for example, in the setting of toxic megacolon. In a patient who undergoes a colectomy for C. difficile toxic megacolon, the rectal stump, if one is left behind, may be a source of residual disease. Patients receiving immunosuppressive therapy appear to be at particularly high risk for severe C. difficile disease.

Acute Pancreatitis Antibiotic management in acute pancreatitis is challenging because the severity of illness often indicates a therapeutic emergency so that the traditional markers of infection may not be present and there may be limited supporting clinical data. Depending on the degree of pancreatic injury, these patients may present with septic physiology, including hypotension, tachycardia, hypoxemia, tachypnea, metabolic acidosis, leukocytosis with a left shift, thrombocytopenia, and coagulopathy. These findings are all consistent with the pathogenesis of this disease where an inciting event such as alcohol, gallstones, or trauma leads to pancreatic injury and inflammation which, in turn, leads to autodigestion, liquefaction and, necrosis. This tissue necrosis results in a cytokine release, which can mimic all aspects of septic physiology. If the necrotic pancreatic tissue becomes infected, by biliary reflux, which is often polymicrobial, colonic bacterial translocation or hematogenous seeding, there is an associated increased morbidity


and mortality.91 It is important to note that infection is rarely the inciting event but rather a consequence of pancreatitis and often occurs weeks into the hospital course. Abdominal imaging, with a contrast CT scan, has enabled stratification of those patients at risk for developing superimposed infection with increasing degree of pancreatic necrosis. Infection of the pancreatic bed is extremely rare in the absence of necrosis.91 Unfortunately imaging, like the physical examination and laboratory evaluation, cannot reliably distinguish an infectious from sterile inflammation. The most reliable means of making this determination is through a Gram stain and culture of the peripancreatic fluid. As an infected necrotic pancreas requires surgical debridement in addition to antibiotic therapy and supportive care, a diagnostic procedure, such as an ultrasound-guided fine-needle aspirate is extremely helpful prior to initiating antimicrobial therapy.92 Once cultures have been obtained, the microbiologic results should guide antibiotic therapy, given the high sensitivity of the Gram stain from the pancreatic aspirate (>90% in one study).93 In the critically ill patient in whom it is too risky to delay antimicrobial therapy, targeting the typical infecting organisms, which includes aerobic enteric gram-negative rods and grampositive cocci, is appropriate. A variety of antibiotics have been shown to achieve pancreatic levels above the MIC for the commonly encountered bacteria—fluoroquinolones, imipenem, ceftazidime, cefepime, metronidazole, clindamycin, chloramphenicol, doxycycline, and fluconazole. Two reasonable combinations are (a) ceftazidime, a fluoroquinolone, or piperacillin plus metronidazole or (b) imipenem or a carbapenem.94 Imipenem-cilastatin 500 mg three times a day for 2 weeks is frequently used preemptively in patients with documented pancreatic necrosis because it has been shown to decrease the need for surgical intervention. However, S. aureus species, which are not sensitive to carbapenems, and Candida species, including C. glabrata, which is generally not susceptible to fluconazole, are emerging as significant pathogens in severe acute pancreatitis. If empiric antibiotics were initiated and Gram stain is negative and the microbiologic cultures are sterile, typically at 48–72 hours, then antimicrobial therapy should

be discontinued. Otherwise therapy should be directed at the pathogens identified. Surgical debridement is considered an essential element in documented pancreatic necrosis with infection.

Antiretroviral Therapy in the Patient with HIV Infection and AIDS A remarkable body of information regarding the treatment of HIV infection has emerged since 1981, when AIDS was first recognized. The occurrence of oral thrush, Pneumocystis jiroveci pneumonia, Toxoplasma encephalitis, and other opportunistic infections in apparently healthy gay males was quickly recognized as something unusual; that is, the net state of immunosuppression should not have been great enough to allow such infections to occur. Very quickly the characteristics of this epidemic emerged: profound and progressive immune compromise; efficient transmission from infected individuals by intimate contact, blood transfusion, organ transplantation, intravenous drug abuse, and perinatal transmission. In 1984, the identification of the cause of these events, infection with a unique retrovirus now known as the human immunodeficiency virus (HIV) was reported. HIV is now recognized as the cause of a worldwide pandemic of infection (particularly those caused by opportunistic organisms), Kaposi sarcoma, and other malignancies. More than 30 million individuals are believed to have been infected by HIV since 1981, with devastating consequences.95–97 Three different phases of disease have been recognized once HIV has been acquired98,99: 1. Primary HIV Infection: A mononucleosis-like illness is observed in ~50% of individuals 2–6 weeks after infection. Primary infection is associated with a marked increase in plasma viremia (this can exceed 1,000,000 copies per mL); a significant decrease in the CD4 T-lymphocyte count; and a large increase in the blood CD8 T-lymphocyte count. 2. Chronic Asymptomatic Stage: An extended phase of clinical latency occurs, persisting for 10–12 years in the majority of individuals. An estimated 20% of individuals (“rapid progressors”) have an accelerated course, having full-blown AIDS in

less than 5 years; conversely, ~10% (“slow progressors”) remain free of AIDS for 15 or more years.. At the end of this period the level of viremia rises rapidly and there is a significant fall in the CD4 T-lymphocyte count. AIDS-defining opportunistic infections begin to appear. 3. Overt AIDS: In the absence of effective therapy, there is a progressive decrease in CD4-positive lymphocytes and an increase in viral load. These events are correlated with recurrent opportunistic infection, the occurrence of certain malignancies, and death in 2–3 years. The specifics of anti-HIV therapy are still evolving, although certain principles remain constant: HIV replication remains at a very high level throughout the stages of illness. This high rate of replication is coupled with a remarkable amount of errors in the function of the reverse transcriptase (the daily production of ~108–1010 virions and a mutation rate of 3 × 103). The frequency of these events virtually guarantees the presence and the rapid development of mutants that are responsible for drug resistance. Resistant clones of HIV may be present even before the initiation of any therapy. Such findings mandate that multiple drugs will be needed to effectively treat this infection. The general principle that applies to HIV therapy is “hit early and hit hard,” with multiple drugs being started simultaneously.99–101 Although the precise point when therapy should be instituted is still being studied, at present it is recommended that highly active antiretroviral therapy (HAART), which consists of multidrug regimens, be initiated in asymptomatic patients who have circulating CD4 T-lymphocyte counts 500-fold increase in affinity when compared to binding to cholesterol in mammalian cell membranes). Binding to ergosterol results in increased membrane permeability and cytolysis, the probable mechanism of fungal injury and death. Amphotericin B remains the broadest spectrum antifungal known, producing fungicidal effects against the majority of pathologic fungi, including those that are resistant to other antifungal compounds. The dose-limiting toxicity is to the kidneys, which is particularly important when such nephrotoxic drugs such as gentamicin or cyclosporine are administered to a patient receiving amphotericin. In addition, the administration of amphotericin B usually produces a “cytokine storm” which can include not only fever and chills but also hypotension. These “storms” are usually not a problem after the first several days of therapy. Lipid-associated amphotericin appears to decrease but not eliminate both the febrile reactions and the renal toxicity. However, as with all the amphotericin products the optimal dose (3–5 mg/kg/d for a lipid-associated drug and 0.1–1.5 mg/kg/d for the standard amphotericin molecules) is not known, and the optimal duration of therapy is unclear. Our practice is to

treat until all overt disease is gone and then add a buffer for safety. The duration of this buffer is a clinical decision usually determined by the nature of the original infection and the speed with which the patient responded. • Flucytosine is mentioned in this context because its optimal use is in patients with cryptococcosis in conjunction with amphotericin. This synergistic regimen protects against a single-step mutation to flucytosine resistance. Dose-related hepatic and/ or bone marrow toxicity can occur with the use of flucytosine. A common approach is to administer amphotericin and flucytosine for 7–10 days to gain control of the process, and then complete the course of therapy with oral fluconazole.115,116 Azoles act by blocking the enzyme lanosterol synthetase, a cytochrome P450-associated enzyme. This results in an inhibition of ergosterol synthesis. The effect is fungistatic. There are five azoles that have been approved for the treatment of systemic fungal invasion. • Ketoconazole and miconazole are essentially of historical interest only and are rarely prescribed today. • Fluconazole, in contrast, was a major event, with the only weakness of the drug being a rather narrow spectrum of activity, limited mostly to Candida species and C. neoformans. Pharmacokinetically, the drug is well behaved, able to penetrate the urinary tract, the eye, and the brain, as well as the spleen, liver, and other sites. The bioavailability when given by mouth is complete, and thus the dose given by mouth is the same as the parenteral dose. Side effects are seen, but are relatively uncommon or minor: a measles-like rash, hepatocellular dysfunction, and minimal GI complaints. Fluconazole does interact with cytochrome P450 enzymes, as do all the azoles, and thus can increase the blood levels of such important therapies as cyclosporine and tacrolimus.116 • Itraconazole has an appealing spectrum of activity, including Aspergillus species and other fungal species. The problem has been poor and unreliable drug delivery. With substitution of an oral suspension, more reliable bioavailability has been

295


achieved, and the usefulness of the drug should be reassessed. Up to now, the major use of this drug has been in oral “wrap up” therapy after amphotericin had gained control of the infection.116

296

• Voriconazole is the newest of the azoles. It can be administered either orally or parenterally. It appears that voriconazole is the most effective of the current anti-Aspergillus drugs, as well as has efficacy for other resistant molds. Side effects are similar to other azoles (e.g., rash, hepatocellular dysfunction, nausea). Voriconazole does have a unique side effect, the occurrence of visual effects including bright colors and lights, akin to that seen with digitalis toxicity. Such symptoms appear to be most common with high doses, and appear to be caused by retinal dysfunction. All such symptoms disappear when the drug is stopped, and extensive study has failed to reveal any persistent visual or structural consequences. Voriconazole appears to be the drug of choice for invasive aspergillosis. Treatment with voriconazole, however, carries a small risk of selecting for Mucorales infection (mucormycosis).116,117 The echinocandins are large lipopeptide molecules that damage fungal cell walls by inhibiting B-(1,3)glucan synthase. In vitro these compounds are fungicidal for Candida and fungistatic for Aspergillus species. These molecules appear to have activity against candidal strains that are amphotericin, fluconazole, and itraconazole resistant. On the other hand, species such as C. neoformans and the Mucorales are inherently resistant to echinocandin therapy, presumably because they do not possess significant amounts of B-glucan in their cell walls.118 • Three echinocandins, caspofungin, micafungin, and anidulafungin are approved by the Food and Drug Administration. The echinocandins, with the limited evaluation in the clinical arena that has occurred thus far, appear to be useful in the treatment of both drug-resistant candidiasis and invasive aspergillosis. The results thus far suggest comparable efficacy to that achieved with amphotericin and the licensed azoles. The possibility of achieving better results with combination therapy that includes an echinocandin is

particularly intriguing. The cell wall damage that is caused by echinocandins is reminiscent of synergistic therapy of enterococcal infection with ampicillin and gentamicin with the echinocandin playing the role of a cell wall active agent that potentiates the penetration of additional drugs. Indeed, the echinocandins have been called “the antifungal penicillins.”118–120

The Future of Antifungal Therapy Since the advent of new drugs for the treatment of fungal disease great progress has been made in terms of efficacy and adverse events. What we need now is a new generation of diagnostic tests that will inform us on the appropriate drugs to use, how long to treat, whether multiple drugs should be deployed, and a determination to define microbial load objectively that will allow us to treat preemptively rather than empirically. The present data on the use of (1-3)-B-D-glucan testing in defining the presence or absence of invasive fungal infection suggests that we are getting closer to that possibility.

NEW DIAGNOSTICS One of the greatest frustrations when caring for a potentially septic patient is having to wait 1–2 days for culture results to find out if the patient is infected, and then to wait another 1–2 days to discover the identity and later the susceptibility profile of the infecting organism. With the molecular biologic revolution, new tests have emerged, typically PCR-based technology, enabling the rapid identification of specific pathogens directly from the infected body site. Nonetheless, this technology is prone to interpretation challenges. For example, does a positive result represent colonization or disease? To help both diagnostically and prognostically, the development of new assays are focusing on the levels (or presence) of mediators in the inflammatory cascade or on circulating bacterial moieties, such as endotoxin or nuclear factor-gB, to improve our ability to risk stratify patients or determine the infecting pathogen.121–124 A broad array of pathogens can now be identified by molecular techniques, including viruses (HIV, CMV), fungi (Candida, Aspergillus), and bacteria

(VRE, E. coli, M. tuberculosis, Bacteroides).125–130 As learned for HIV-positive patients, monitoring the HIV viral load has become an important parameter in gauging the success of therapy. The development of technology may allow us to provide pathogen-directed therapy earlier in a patient’s illness enabling more focused narrow spectrum antimicrobial use. This would diminish the selective pressure, which leads to the emergence and dissemination of resistance as well as yielding novel markers to gauge the duration and intensity of therapy.

SUMMARY Antimicrobial therapy is complicated by the increasing incidence of microbial resistance. As a result, a broader range of antimicrobial agents has come into use, with the basic approach to antimicrobial therapy in these patients being front loading broad-spectrum antimicrobials. This therapy is then modified to relatively narrow spectrum specific therapy. The regimens chosen and the doses prescribed are based on the principle that effective therapy is dependent on the delivery of a level of antimicrobial agent to the site of infection that significantly exceeds the MIC of the invading organism. Bactericidal therapy is essential when dealing with cardiovascular infection, CNS infection, prosthesis associated infection, osteomyelitis, and infection in the neutropenic patient. Synergistic therapy may be important when dealing with life-threatening enterococcal, P. aeruginosa, and perhaps other gram-negative infections, but the definition of synergy varies and the clinical efficacy is not firmly established. Finally, it is hoped that a better definition of high-risk patients will permit the more effective use of preemptive antimicrobial regimens. It is clear that many questions remain unanswered and that many therapeutic decisions must be based on a thorough understanding of the properties of antimicrobials and the pathogenesis of infections rather than efficacy demonstrated in clinical studies.

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51. Brun-Buisson C, Legrand P, Philippon A, et al. Transferable enzymatic resistance to third-generation cephalosporins during nosocomial outbreak of multiresistant Klebsiella pneumoniae. Lancet 1987;8554:302–306. 52. Lynch JP, Zhanel GG. Escalation of antimicrobial resistance among streptococcus pneumoniae: implications for therapy. Semin Resp Crit Care Med 2005;26:575– 616. 53. Zirakzadeh A, Patel R. Vancomycinresistant enterococci: colonization, infection, detection, and treatment. Mayo Clin Proc 2006;81:529–536.

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76. Classen DC, Evans RS, Pestotnik SL, et al. The timing of prophylactic administration of antibiotics and the risk of surgicalwound infection. N Engl J Med 1992;326: 281–286.

91. Isenmann R, Rau B, Beger HG. Bacterial infection and extent of necrosis are determinants of organ failure in patients with acute necrotizing pancreatitis [see comments]. Br J Surg 1999;86:1020–1024.

77. Burke JF. The effective period of preventive antibiotic action in experimental incisions and dermal lesions. Surgery 1961; 50:161–168.

92. Rau B, Pralle U, Mayer JM, et al. Role of ultrasonographically guided fine-needle aspiration cytology in the diagnosis of infected pancreatic necrosis. Br J Surg 1998;85: 179–184.

78. Garey KW, Dao T, Chen H, et al. Timing of vancomycin prophylaxis for cardiac surgery patients and the risk of surgical infection. J Antimicrob Chemother 2006;58:645–650. 79. Edwards FH, Engelman RM, Houck P, et al. The Society of Thoracic Surgeons Practice Guideline Series: antibiotic prophylaxis in cardiac surgery, part I. duration. Ann Thorac Surg 2006;81. 80. Lipsett PA. Surgical critical care: fungal infections in surgical patients. Crit Care Med 2006;34(Suppl):S215–S224. 81. Vardakas KZ, Samonis G, Michalopoulos A, et al. Antifungal prophylaxis with azoles in high-risk, surgical intensive care unit patients: a meta-analysis of randomized, placebo-controlled trials. Crit Care Med 2006;34:1216–1224. 82. Eggimann P, Francioli P, Bille J, et al. Fluconazole prophylaxis prevents intra-abdominal candidiasis in high-risk surgical patients. Crit Care Med 1999;27:1066–1072. 83. Dajani AS, Taubert KA, Wilson W, et al. Prevention of bacterial endocarditis. Recommendations by the American Heart Association. JAMA 1997;277:1794–1801. 84. Mandell LA, Bartlett JG, Dowell SF, et al. Update of practice guidelines for the management of community-acquired pneumonia in immunocompetent adults. Clin Infect Dis 2003;37:1405–1433. 85. Bartlett JG, Dowell SF, Mandell LA, et al. Practice guidelines for the management

93. Banks PA, Gerzof SG, Langevin RE, et al. CT-guided aspiration of suspected pancreatic infection: bacteriology and clinical outcome. Int J Pancreatol 1995;18:265–270. 94. Kramer KM, Levy H. Prophylactic antibiotics for severe acute pancreatitis: the beginning of an era. Pharmacotherapy 1999;19:592–602. 95. Carael M, Schwartlander B, Piot P.HIV and AIDS. In: Clumek N, Powderly WG, eds. Infectious Diseases. Philadelphia: MosbyYear Book, 2004:1297. 96. Gottlieb MS, Schroff R, Schanker HM, et al. Pneumocystis carinii pneumonia and mucosal candidiasis in previously healthy homosexual men: evidence of a new acquired cellular immunodeficiency. N Engl J Med 1981;305:1425–1431. 97. Masur H, Michelis MA, Greene JB, et al. An outbreak of community-acquired Pneumocystis carinii pneumonia: initial manifestation of cellular immune dysfunction. N Engl J Med 1981;305:1431–1438. 98. Kahn JO, Walker BD. Acute human immunodeficiency virus type 1 infection. N Engl J Med 1998;339:33–39. 99. Bart PA, Pantaleo G. The immunopathogenesis of HIV-1 infection. In: Clumek N, Powderly WG, eds. Infectious Diseases. Philadelphia: Mosby-Year Book, 2004:1234–1249. 100. Richman DD. Resistance of clinical isolates of human immunodeficiency virus


to antiretroviral agents. J Clin Microbiol 1993;31:2557–2564.

113. Denning DW. Invasive aspergillosis. Clin Infect Dis 1998;26:781–805.

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114. Boutati EI, Anaissie EJ. Fusarium, a significant emerging pathogen in patients with hematologic malignancy: ten years’ experience at a cancer center at a cancer center and implications for management. Blood 1997;90:999–1008.

102. Mellors JW, Rinaldo CR Jr, Gupta P, et al. Prognosis in HIV-1 infection predicted by the quantity of virus in plasma. Science 1996;272:1167–1170.

115. Stamm AM, Diasio RB, Dismukes WE, et al. Toxicity of amphotericin B plus flucytosine in 194 patients with cryptococcal meningitis. Am J Med 1987;83:236–242.

103. O’Brien WA, Hartigan PM, Martin D, et al. Changes in plasma HIV-1, RNA and CD4+ lymphocyte counts and the risk of progression to AIDS. N Engl J Med 334:426–431.

116. Rex JH, Stevens DA. Systemic antifungal agents. In: Mandell GL, Bennett JE, Dolin R, eds. Principles and Practice of Infectious Diseases. 6th ed. New York: Elsevier, Churchill, Livingstone, 2005:502–514.

104. Carpenter CCJ, Fischl MA, Hammer SM, et al. Antiretroviral therapy for HIV infection in 1998: updated recommendations of the International AIDS Society– USA Panel. JAMA 1998;280:78–86. 105. Rubin RH. Clinical Approach to Infection in the Compromised Host. 4th ed. New York: Kluwer/Academic Press, 2003. 106. Jarvis WR. Epidemiology of nosocomial fungal infection with emphasis on Candida species. Clin Infect Dis 1995;20:1526–1530. 107. Pfaller MA. Epidemiology of candidiasis. J Hosp Infect 1995;20(Suppl):329–338. 108. Hopkins CC, Weber DH, Rubin RH. Invasive Aspergillus infection: possible nonward common source within the hospital environment. J Hosp Infect 1989;13:19–35. 109. Paya CV. Fungal infections in solid organ transplantation. Clin Infect Dis 1993; 16:677–688. 110. Rubin RH, Ikonent GJ, Morris R. The therapeutic prescription for the organ transplant recipient: the linkage of immunosuppression and antimicrobial strategies. Transplant Infect Dis 1999;1:29–39. 111. Edwards JE Jr, Bodey GP, Bowden RA, et al. International Conference for the Development of a Consensus on the Management and Prevention of Severe Candidal Infections. Clin Infect Dis 1997;25:43–59. 112. Fraser VJ, Jones M, Dunkel J, et al. Candidemia in a tertiary care hospital: epidemiology, risk factors, and predictors of mortality [see comments]. Clin Infect Dis 1992;15:414–421.

117. Herbrecht R, Denning DW, Patterson TF, et al. Voriconazole versus amphotericin for primary therapy of invasive aspergillosis. N Engl J Med 2002;347:408–415. 118. Deresinski SC, Dam S. Caspofungin. Clin Infect Dis 2003;36:1445–1457. 119. Marr KA, Boeckh M, Carter RA, et al. Combination antifungal therapy for invasive aspergillosis. Clin Infect Dis 2004;39: 797–802. 120. Torres HA, Hachem RY, Chemaly RF, et al. Posaconazole: a broad-spectrum triazole antifungal. Lancet Infect Dis 2005;5: 775–785. 121. Romaschin AD, Harris DM, Ribeiro MB, et al. A rapid assay of endotoxin in whole blood using autologous neutrophil dependent chemiluminescence. J Immunol Methods 1998;212:169–185. 122. Carlet J. Rapid diagnostic methods in the detection of sepsis. Infect Dis Clin North Am 1999;13:483–494. 123. Arnalich F, Garcia-Palomero E, Lopez J, et al. Predictive value of nuclear factor kappaB activity and plasma cytokine levels in patients with sepsis. Infect Immun 2000; 68:1942–1945. 124. Bohrer H, Qiu F, Zimmermann T, et al. Role of NFkappaB in the mortality of sepsis. J Clin Invest 1997;100:972–985. 125. Pfeiffer CD, Fine JP, Safdar N. Diagnosis of invasive aspergillosis using a galactomannan assay: a meta-analysis. Clin Infect Dis 2006;42:1417–1427.

126. Dutka-Malen S, Evers S, Courvalin P. Detection of glycopeptide resistance genotypes and identification to the species level of clinically relevant enterococci by PCR. J Clin Microbiol 1995;33:24–27. 127. Einsele H, Hebart H, Roller G, et al. Detection and identification of fungal pathogens in blood by using molecular probes. J Clin Microbiol 1997;35:1353–1360. 128. Flahaut M, Sanglard D, Monod M, et al. Rapid detection of Candida albicans in clinical samples by DNA amplification of common regions from C. albicans-secreted aspartic proteinase genes. J Clin Microbiol 1998;36:395–401. 129. Kane TD, Alexander JW, Johannigman JA. The detection of microbial DNA in the blood: a sensitive method for diagnosing bacteremia and/or bacterial translocation in surgical patients. Ann Surg 1998;227:1–9. 130. Warwick S, Wilks M, Hennessy E, et al. Use of quantitative 16S ribosomal DNA detection for diagnosis of central vascular catheter-associated bacterial infection. J Clin Microbiol 2004;42:1402–1408. 131. NNIS Hospital Infections Program, National Center for Infectious Diseases, Centers for Disease Control and Prevention. National Nosocomial Infections Surveillance (NNIS) system report, data, summary from October 1986–April 1998. Issued June 1998. National Center for Infectious Disease 1998:1–25. 132. Amsden GW. Tables of antimicrobial agent pharmacology. In: Mandell GL, Bennett JE, Dolin R, eds. Principles and Practice of Infectious Diseases. 6th ed. Philadelphia: Elsevier Churchill Livingstone, 2005: 634–700. 133. el-Ebiary M, Torres A, Fabregas N, et al. Significance of the isolation of Candida species from respiratory samples in critically ill, non-neutropenic patients. An immediate postmortem histologic study. Am J Respir Crit Care Med 1997;156:583–590. 134. Kauffman CA, Vazquez JA, Sobel JD, et al. Prospective multicenter surveillance study of funguria in hospitalized patients. The National Institute for Allergy and Infectious Diseases (NIAID) Mycoses Study Group. Clin Infect Dis 2000;30:14–18.

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CHAPTER 18 Preoperative Assessment of the Newborn 300

Myron Yaster, MD, and Richard A. Elliott, MD The newborn presenting for surgery is among the most daunting and challenging patients facing the anesthesiologist. Critically ill and hemodynamically unstable, these tiny and fragile patients demand a level of specialized knowledge, skill, and attention to detail that is inversely proportional to their size and gestational age. Providing safe anesthesia is only possible when the specialized equipment and techniques necessary to conduct an anesthetic are in the hands of individuals who understand the anatomic, physiologic, and pathologic differences that characterize these patients during their transition from intra- to extrauterine life. The types of surgical procedures in the newborn span a wide variety of lifethreatening congenital anomalies, each with its own set of unique management strategies. Nevertheless, there are many aspects of preoperative and intraoperative anesthetic management common to all neonates. This chapter focuses on neonatal physiology and its impact on anesthetic and surgical techniques. Emphasis is placed on those aspects of preoperative assessment, monitoring, and supportive care that are pertinent to newborn patients in general, with special attention to disease states, anesthetic agents, and surgical interventions that can influence the infant’s transition from fetal to newborn existence. Historically, the newborn has been undertreated for pain and for painful experiences, including surgery. For example, in 2006, healthy newborn males are routinely circumcised without analgesia or anesthesia.1 It is our belief that, except for extraordinary circumstances, all newborns require anesthesia for surgery.2–4 Why this even remains an issue of debate in the 21st century is discussed in detail in Chap. 62.

FAMILY INTERACTIONS AND PREPARATION The parents of critically ill children require substantial support and reassurance that their newborn child will perceive no pain during a procedure and will be as safe as possible. Parents experience an acute emotional crisis when their newborns face surgery. Aside from the deprivation of contact with their child, parents experience anticipatory grief and a profound sense of failure.5,6 When confronted with surgery and anesthesia, many parents undergo a period of mourning for the loss of the perfect infant or anticipate their infant’s death or mutilation. The overwhelming nature of the situation may deafen parents to explanations during the preoperative interview and repetition may be necessary. The child’s parents should be counseled that the overwhelming majority of children not only survive their surgery but grow up to live healthy and productive lives. Without

being inappropriately optimistic or avoiding the issues of informed consent, it is important to emphasize the normal, healthy aspects of the baby and give positive affirmation regarding the correction that will be achieved by surgery. Failure at this may significantly impact the parents future interactions and bonding to their child. The newborn undergoing surgery must be optimally prepared within the constraints of performing an emergent procedure. Essential to this process is a thorough history and physical examination. This evaluation must focus on maternal and peripartum history, neonatal physiology and its relation to anesthesia, as well as the presence of coexisting anomalies in the child.

Maternal and Peripartum History A thorough review of maternal past medical history and prenatal assessments is essential for the preoperative evaluation of the neonate. Maternal

KEY POINTS 1. Except for extraordinary circumstances, all newborns require anesthesia for surgery. 2. Maternal factors associated with increased perinatal risk include hypertension, diabetes, prolonged rupture of membranes, drug abuse (tobacco, alcohol, opioids, amphetamines) and use (antipsychotics, antidepressants, anticonvulsants), collagen vascular disease, and maternal infection (prolonged rupture of membranes) or inflammation. 3. The younger the infant, the more fragile the neurologic, pulmonary, and gastrointestinal systems, and the more likely the severity of complications. 4. The presence of a congenital anomaly should always alert the anesthesiologist to the potential for others. 5. The presence of any midline defect is almost always associated with another defect. 6. The newborn is an obligate nose breather. 7. The narrowest part of the infant’s airway is at the level of the cricoid ring and not the vocal cords.


8. Premature infants are at risk of developing postanesthesia apnea for weeks after birth (48–60 weeks postconception age) whenever a potent vapor or ketamine is used. 9. Arterial hypoxemia, hypercarbia, acidosis, hypothermia, or pain may reverse this transitional circulation and restore the fetal circulatory pattern; it is referred to as either persistent fetal circulation or persistent pulmonary hypertension of the newborn. 10. The newborn’s myocardium is less compliant than that of the adult or older child and cardiac output is primarily heart-rate dependent. 11. The most common cause of bradycardia in the newborn is hypoxia. Unexplained bradycardia in the operating room should always be considered caused by hypoxia until proven otherwise. 12. Hypoglycemia is common in infants born to diabetic mothers and in infants who require resuscitation, are premature, or who are small for gestational age.

CHAPTER 18: Preoperative Assessment of the Newborn

TABLE 18–1.

TABLE 18–2.

Maternal History

Peripartum History

Pregnancy Polyhydramnios High intestinal obstruction, e.g., duodenal atresia, congenital diaphragmatic hernia, omphalocele Central nervous anomalies, e.g., hydrocephalus, spina bifida Respiratory abnormalities, e.g., pulmonary hypoplasia, pleural effusions Genitourinary tract abnormalities, e.g., posterior urethral valves, urethral structure Maternal diabetes Rh-isoimmunization Multiple pregnancy Oligohydramnios Renal failure Hypoplastic lungs Marked crowding of fetal limbs causing multiple skeletal contractures Neonatal infection (chorioamnionitis) Toxemia of pregnancy Frequency associated with decreased placental perfusion and premature separation of the placenta; associated problems include small for gestational age infants, hypoglycemia, and anemia; magnesium used in blood pressure control produces neonatal hypotonia and apnea Diabetes: large for gestational age infants; hypoglycemia despite enormous glucose loading, prematurity (yet > 2,500 gram birth weight); congenital heart disease; anencephaly; sacral agenesis Maternal seizures 2–3 × greater incidence of congenital malformations Intra-uterine infection: prematurity; fetal infection; particularly pneumonia; persistent fetal circulation; heart defects (rubella) Medication: teratogens, e.g., anticonvulsants, warfarin, anti-metabolites; hypoglycemia, floppy infant Drug abuse Fetal alcohol syndrome: growth retardation, mental deficiency, heart defects, flexion contractures Opioid withdrawal: seizures; jittery, irritable infants; hypoglycemia; diarrhea Amphetamines: congenital heart disease Maternal age: trisomy 13, 18, 21 Single umbilical artery: renal malformations

medical history and pathology may indicate the likelihood of an anomaly or be its possible cause (Table 18–1). Maternal factors associated with increased perinatal risk include hypertension; diabetes, prolonged rupture of membranes; drug abuse (tobacco, alcohol, opioids, amphetamines) and use (antipsychotics, antidepressants, anticonvulsants); collagen vascular disease; and maternal infection (prolonged rupture of membranes) or inflammation. Maternal exposures to teratogens such as thalidomide, phenytoin, or ethanol are well described and are associated with specific anomalies. Less dramatic are the effects of tobacco and opioids, which can affect brain development or somatic size. Additionally, maternal intravenous drug addiction, particularly to opioids, can result in acute with-

drawal and seizures or in HIV virus infection in the neonate. Finally, some perinatal conditions provide insight into potential future problems. For example, polyhydramnios is associated with high intestinal obstruction and oligohydramnios is associated with renal and lung hypoplasia (Tables 18–1 and 18–2). The peripartum history is of equal importance for the evaluation of the neonate (Table 18–2). Prolonged labor and premature rupture of membranes are indicators of potential infectious complications in the neonate. Moreover, a traumatic delivery or abnormal fetal presentation can imply fractures or nerve injury. Other factors that can imply coexisting disorders are an abnormal umbilical cord or placenta, and the child’s age, birth weight, and Apgar scores.

Prolonged labor Abnormal fetus, e.g., hydrocephalus, abdominal wall defect, breech presentation Premature rupture of membranes Prematurity Infection, pneumonia Oligo- or polyhydramnios Traumatic delivery Intracranial hemorrhage, skull fracture, vocal cord paralysis, brachial plexus injury General anesthesia Hypotonia, respiratory distress Prematurity (< 37 weeks post-conceptual age or birth weight < 2,500 grams) Hyaline lung disease Hypocalcemia, hypoglycemia, hypomagnesemia Infection Necrotizing enterocolitis Patent ductus arteriosus Hyperbilirubinemia Increased risk of oxygen toxicity to the eyes (retinopathy of prematurity or “retrolental fibroplasia”) Postmaturity (> 42 weeks post-conceptual age) Infants who are asphyxiated at birth must be identified prior to surgery. These newborns have depressed myocardial function and decreased perfusion to the brain and gastrointestinal system. Additionally, a variety of metabolic derangements, such as hypoglycemia, hypocalcemia, and hyperkalemia, occur in asphyxiated newborns. Other problems seen in these infants are clotting abnormalities, meconium aspiration, and intracranial hemorrhage. The latter is particularly devastating and may be a result of impaired autoregulation of the cerebral circulation and/or large swings in blood pressure, cardiac output, and arterial blood gasses.

Gestational Age Babies born at term, 37–42 weeks postconception age, can either be normal in size, small (90th percentile) for gestational age (LGA). SGA and LGA babies often have glucose homeostatic instability and require 10% glucose infusions to maintain normoglycemia (60–100 mg/dL). Additionally, calcium homeostasis may be ab-

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302

normal in these infants. The wellaccepted definition of prematurity is an infant born at 10 g/dL) became the requirement. Elective surgery probably should await attaining this level, short of transfusion. Iron and nutritional support are indicated. In the emergent situation, transfusion therapy may be indicated as directed by patient need, such as anticipated blood loss and cardiorespiratory status. Transfusion should not rely on arbitrary and unsupported boundary of “normal” hemoglobin.73 What are the essential considerations? In a healthy child with normal cardiorespiratory function, a fully saturated hemoglobin of 10 g/dL would require a cardiac index of 3.4 L/min/m2 to provide an oxygen delivery 3 times the average oxygen consumption. If the child’s hemoglobin were 7 g/dL (hematocrit approximately 20%), a cardiac

CHAPTER 19: Evaluation of Children

TABLE 19–11. Mean Hematocrit and Hemoglobin versus Age

Age 1–3 days 2 weeks 1 month 2 months 6 months 6–24 months 2–6 years 6–12 years 12–18 years Adult

Hct (SD) %

Hgb (SD) g/dL

56 ± 5 53 ± 4 44 ± 5 35 ± 4 36 ± 3 36 ± 2

18.5 ± 2.0 16.6 ± 1.6 13.9 ± 1.6 11.2 ± 0.9 12.6 ± 0.7 12.0 ± 0.8

37 ± 2 40 ± 3 43 ± 4 41 ± 2

12.5 ± 0.5 13.5 ± 1.0 14.5 ± 0.7 14.0 ± 1.0

From Rowe PC. Laboratory values. In Oski FA, De Angelis CD, Feigin RD, et al, editors: Principles and practice of pediatrics, Philadelphia, 1990, JB Lippincott.

index of 4.8 L/min/m2 is required to maintain the same level of oxygen delivery. This is well within a healthy child’s cardiac reserve and should represent no major difficulty. The assumptions underlying this are that the child remains 100% saturated, receives no cardiac-depressant drugs, and loses little blood. These circumstances frequently cannot be guaranteed during surgery and anesthesia, and this lack of guarantee is the key issue. The major concern is not for healthy children having minor surgery, but when surgery will result in blood loss and lower this margin of reserve further. A child whose hemoglobin drops to 5 g/dL from 10 g/dL should double cardiac output to around 6.6 L/min/m2 to maintain oxygen delivery. This remains well within the average child’s cardiac reserve. If a child’s hemoglobin drops to 2 g/dL from 7 g/dL intraoperatively, the child requires a cardiac index of nearly 17 L/ min/m2 to maintain a marginal oxygen delivery, which is beyond the ability of even the healthy child’s cardiovascular system to compensate for, especially when anesthetized. A third issue that frequently is raised is adaptation. The classic teaching is that children with renal disease tolerate lower hematocrits because they have had time to adapt. There is little evidence to demonstrate this is so; 2,3diphosphoglyceric acid may not be increased in children with renal disease, and there is no reason to suggest that

they have a shift in the oxyhemoglobin dissociation curve. The concept that they can adapt to lower levels of oxygen delivery or consumption is unsupported. If serious blood loss is expected perioperatively, the margin of safety is considerably less in patients who begin with low hematocrit. As mentioned above, there are no absolute guidelines for preoperative hematocrit, and at present, each anesthesiologist should decide on a standard for each child. Motoyama and Glasner69 found that a hemoglobin of 7.5–8.5 g/dL will deliver oxygen to the tissues of children equivalent to what a hemoglobin of 10 g/dL will in adults. In neonates, 12–13 g/dL is necessary. This is largely related to shifts in the P50 (partial pressure of oxygen at which hemoglobin is 50% saturated).69 It seems reasonable that a hemoglobin of 8 g/dL in an ASA PS P1 child may be acceptable if no major perioperative blood loss is expected. A child who has chronic restrictive lung disease and is about to undergo scoliosis repair probably should have a hemoglobin higher than 10 g/dL (at least initially). Many abnormalities can be discovered during preoperative laboratory screening.48 These abnormalities fall into two categories: those that are relevant to the anesthetic management of the child and those that are relevant to the child’s general health. The degree to which a preanesthesia screening clinic wishes to be responsible for the general healthcare of children needs to be determined by each facility. There is a responsibility to ensure followup evaluation for abnormal laboratory tests that may be discovered coincidentally with preoperative assessment. O’Connor and Drasner74 reported that 17% of children who had a complete blood count (CBC) were anemic or had a microcytosis. Only 2 of these children had surgery cancelled because of anemia (hemoglobins 45 mm Hg) in the absence of known causes of hypoventilation. OHS is seen in up to 10% of morbidly obese patients. Clinical features are similar to those seen with OSA and include excessive daytime somnolence, fatigue, and morning headaches. In addition, daytime hypercapnia and hypoxemia are associated with pulmonary hypertension and right-sided congestive heart failure (cor pulmonale), resulting in substantial morbidity and mortality.18 OHS patients have an increased sensitivity to the respiratory depressant effects of general anesthetics. Epi-

377


Upper Airway Anatomy

Nasal vestibule

Soft palate Velopharynx or Nasopharynx

Hard palate Mandible

Oropharynx

Genioglossus

378

Epigtottis

Hyoid bone Larynx

Laryngopharynx or Hypopharynx

Action of the Upper Airway Dilator Muscles

Tensor palatine

Velopharynx or Nasopharynx Oropharynx

Genioglossus Hyoid muscles

Epigtottis Laryngopharynx or Hypopharynx

Sites of Obstruction During Sleep Apnea

Velopharynx or Nasopharynx Oropharynx

Laryngopharynx or Hypopharynx Airspace FIGURE 22–3. Airway obstruction during sleep apnea. (Reprinted from Benumof JL. Obstructive sleep apnea in the adult obese patient: implications for airway management. J Clin Anesth 2001; 13:144, with permission from Elsevier.)

sodes of central apnea from progressive desensitization of respiratory centers to hypercapnia initially are limited to sleep but eventually leads to a progressive reliance on hypoxic drive for ventilation. Pickwickian syndrome,19 characterized by obesity, hypersomnolence, hypoxia, hypercapnia, right ventricular failure, and polycythemia, is the end result of OHS. Pulmonary, metabolic, neuromuscular, and genetic diseases should

be excluded before making the diagnosis of OHS. Daytime hypoxemia and increased alveolar oxygen gradient found in these patients suggest that ventilation/perfusion inequalities as well as alveolar hypoventilation are an intrinsic part of this condition. Chronic daytime hypoxemia may be a better predictor of pulmonary hypertension and cor pulmonale than the presence and severity of OSA.20 There is a strong correlation between increasing

BMI >40 kg/m2 and the likelihood of developing OHS.21 Many obese patients with OHS also have OSA, but the reverse is not always true, suggesting that OHS is an autonomous disorder.22 Arterial blood gas (ABG) analysis should be obtained in any morbidly obese patient with unexplained hypoxemia or features of cor pulmonale, because pulse oximetry detects oxyhemoglobin desaturation without considering contribution from hypercapnia. This results in inappropriate treatment with supplemental oxygen alone that does not reverse the hypoventilation.17 An ABG confirms the presence of daytime hypercapnia and usually reveals compensated respiratory acidosis and hypoxemia. Elevated bicarbonate level is consistent with chronic hypercapnia. Treatment of OHS with weight reduction, tracheostomy, or nocturnal positive-pressure support improves daytime hypercapnia and hypoxia without changing the abnormal ventilatory responses.

Cardiovascular System The increased morbidity and mortality of obesity largely result from cardiovascular problems, including hypertension, ischemic heart disease, cardiac failure, cardiomyopathy, arrhythmias, dyslipidemia, and sudden cardiac death.23 Total blood volume is increased in the obese but is less than in nonobese individuals when compared on a volume-to-weight basis (50 mL/kg compared to 70 mL/kg). Most of the extra blood volume supplies adipose tissue. Excess adiposity requires an increase in cardiac output to parallel the increase in oxygen consumption, leading to a systemic arteriovenous oxygen difference that remains normal or slightly above normal. Cardiac output increases with increasing weight (20– 30 mL/kg of excess adipose tissue) because of ventricular dilation and an increase in stroke volume. Left ventricular dilation results in increased left ventricular wall stress leading to eccentric hypertrophy that leads to reduced left ventricular compliance, impairment of left ventricular filling (diastolic dysfunction), elevation of left ventricular end-diastolic pressure (LVEDP), and eventual pulmonary edema. The dilated left ventricle has a limited capacity to hypertrophy so, when left ventricular wall thickening fails to keep pace with dilation, systolic dysfunction (“obe-

CHAPTER 22: Evaluation of the Obese Patient

OSA/OHS

Increased total blood volume

Hypoxia

Increased pulmonary blood volume

Increased cardiac output

Pulmonary hypertension

Increased LV workload

Increased RV workload

LV hypertrophy

Systemic hypertension

RV hypertrophy

LV failure

Coronary artery/ ischemic heart disease

RV failure

FIGURE 22–4. Interrelationship of cardiovascular and pulmonary sequelae of obesity. LV, left ventricle; OHS, obesity hypoventilation syndrome; OSA, obstructive sleep apnea; RV, right ventricle. (From Ogunnaike and Whitten97 with permission.)

sity cardiomyopathy”) results with eventual biventricular failure (Figure 22–4). Increased workload on the heart is suggested by an increase in cardiac weight with increasing BMI. The increased cardiac work may result in cardiomyopathy and cardiac failure, independent of other coexisting diseases such as hypertension, diabetes mellitus, or atherosclerosis. Cardiac weight decreases with weight loss. Obese subjects compensate for the increased workload by utilizing cardiac reserve, especially in the presence of hypertension. Systemic vascular resistance (SVR) usually is within normal limits in morbidly obese patients, suggesting that hypertension and obesity can coexist with a normal SVR. Obesity accelerates atherosclerosis; however, because of reduced mobility, morbidly obese patients appear asymptomatic in the face of significant cardiovascular disease; symptoms such as angina and exertional dyspnea occur only during periods of significant physical activity.24 Cardiac output rises faster in response to exercise in the morbidly obese and often is associated with a rise in LVEDP and pulmonary capillary wedge pressure. Increase in cardiac output during exercise is achieved

by increases in heart rate without a concomitant increase in stroke volume or ejection fraction but with an increase in filling pressures. Similar changes occur during the perioperative period. The expanded blood volume of the obese patient is distributed between the peripheral and central circulations, with both ventricles distended at end-diastole leading to the increase in stroke volume. This situation accounts for the increased cardiac output and the consistent increase in left ventricular stroke work. With the exception of renal and splanchnic blood flows, which increase with obesity, organ blood flow does not change significantly because the additional cardiac output is diverted to perfuse excess fat. Blood volume and cardiac output are approximately twice the values predicted for those with IBW, but when they are normalized for body surface area, they are within normal limits or slightly below normal. The chronically elevated preload causes dilation and hypertrophy of the left ventricle (eccentric hypertrophy). Systolic performance as well as compliance will suffer as workload of the heart increases correspondingly. Chronically increased cardiac output and blood

volume may cause SVR to increase over time. A high SVR and high preload combination may lead to early left ventricular dysfunction and congestive heart failure. Obesity is an independent risk factor for ischemic heart disease (IHD) and eventual heart failure. Cardiovascular disease is strongly associated with central (android) distribution of fat. Angina may actually be a direct symptom of obesity given that a significant number of obese patients with angina do not have demonstrable coronary artery disease.25 The risk of heart failure increases by 5% for men and 7% for women for every 1 kg/m2 increment in BMI.26 Coronary blood flow reserve in obese patients is limited because of ventricular mass and metabolic demands of the myocardium. Weight loss reduces left ventricular volume and diastolic pressures during exercise and at rest. Body oxygen consumption, blood volume, cardiac output, stroke volume, and blood pressure also decrease. Intraoperative cardiac failure can occur from rapid intravenous fluid administration (indicating left ventricular diastolic dysfunction), negative inotropy of anesthetic agents, or pulmonary hypertension precipitated by hypoxia or hypercapnia. Cardiac arrhythmias can be precipitated by fatty infiltration of the conduction system, hypoxia, hypercapnia, electrolyte imbalance, coronary artery disease, increased circulating catecholamines, OSA, and myocardial hypertrophy. ECG findings frequently seen in morbidly obese patients include low QRS voltage, multiple criteria for LVH and left atrial enlargement, and T-wave flattening in the inferior and lateral leads.27 In addition, there is a leftward shift of the P-wave, QRS complex, and T-wave axes, lengthening of the corrected QT interval, and prolonged QT interval duration. Substantial weight reduction can reverse many of these ECG abnormalities by shifting the mean P-wave, QRS, and T-wave axes rightward, significant reduction in the frequency of low QRS voltage, lower frequency of LVH, and marked decrease in T-wave flattening in the inferior and lateral leads.28 Echocardiography usually shows increased cardiac output, increased LVEDP, and LVH in otherwise healthy obese subjects. Mild to moderate hypertension is common in obese patients. Hyperten-

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sion leads to a significant increase in cardiovascular mortality, especially in those with hypercholesterolemia or diabetes.29 There is a 3–4 mm Hg increase in systolic arterial pressure and a 2 mm Hg increase in diastolic arterial pressure for every 10 kg of weight gained. Their expanded blood volume causes increased cardiac output with a lower calculated SVR for the same level of arterial blood pressure. The renin–angiotensin–aldosterone system (RAAS) has been implicated in the hypertension of obesity. Circulating levels of angiotensinogen, aldosterone, and angiotensin-converting enzyme (ACE) increase. As little as 5% reduction in body weight leads to a significant reduction in activity of the RAAS in both plasma and adipose tissue, contributing to a reduction in blood pressure.30 With obesity, most tissues have a normal to increased level of sympathetic nervous system activity. An increased basal level of sympathetic activity predisposes to insulin resistance, dyslipidemia, and hypertension.31 Obesity-induced insulin resistance enhances the pressor activity of norepinephrine and angiotensin II.29 Hyperinsulinemia further activates the sympathetic nervous system causing sodium retention and contributing to the hypertension of obesity.32 Hypertension causes concentric hypertrophy of the ventricle in normalweight individuals but causes eccentric dilation in obese subjects.33 It is associated with increased preload and stroke work. The combination of obesity and hypertension causes left ventricular wall thickening and a larger heart volume and, therefore, increased likelihood of cardiac failure (Figure 22–5). A hypofibrinolytic and hypercoagulable state predisposes the obese patient to cardiovascular disease.34 Obese patients have higher levels of fibrinogen (a marker for the inflammatory process of atherosclerosis), factor VII, factor VIII, von Willebrand factor, and plasminogen activator inhibitor-1 (PAI-1).34 Increased fibrinogen, factor VII, and factor VIII levels and hypofibrinolysis as a result of increased PAI-1 levels are associated with hypercoagulability in obese patients. Significant decrease in fibrinogen concentration requires substantial (>40%) weight loss.35 High factor VIII coagulant activity levels are associated with increased cardiovascular mortali-

Lean Normotensive

Preload

Afterload

Obese Normotensive

Lean Hypertensive

Dilatation

Hypertrophy

Obese Hypertensive

Dilatation and hypertrophy

Congestive heart failure FIGURE 22–5. Adaptation of the heart to obesity and hypertension. (Reprinted from Messerli FH. Cardiovascular effects of obesity and hypertension. Lancet 1982;1:1165, with permission from Elsevier.)

ty. High fasting triglyceride levels also correlate with increased factor VII concentrations, whereas postprandial lipemia causes activation of factor VII. Factor VII levels are decreased by weight loss via a decrease in plasma triglyceride levels. Visceral (abdominal) fat is associated with increased levels of factor VIII and von Willebrand factor. Endothelial dysfunction induced by insulin increases von Willebrand factor and factor VIII levels, predisposing to fibrin formation. PAI-1 is secreted by the endothelium, vascular smooth muscle cells, hepatocytes, and adipocytes. Increased secretion of PAI-1 is associated with visceral obesity and inhibits the fibrinolytic system.

PAI-1 is a significant cardiovascular risk factor because it decreases fibrinolysis and increases the risk of coronary artery disease.36

Gastrointestinal/ Hepatic System Gastric volume and acidity are increased, hepatic function altered, and drug metabolism adversely affected by obesity. A significant number of fasted morbidly obese patients have gastric volumes >25 mL and gastric pH 3.5 kg/m2 increase in BMI is associated with a 2.7-fold increase in risk for developing new reflux symptoms.43 Weight loss, including that through surgery, significantly improves GERD symptoms.44 The combination of hiatal hernia, gastroesophageal reflux, and delayed gastric emptying, coupled with increased intraabdominal pressure and a high-volume, low-pH gastric con-

tent, puts the obese at risk for increased incidence of severe pneumonitis should aspiration occur. Peculiar morphologic and biochemical abnormalities of the liver associated with obesity include fatty infiltration, inflammation, focal necrosis, and cirrhosis. Fatty infiltration reflects the duration rather than the degree of obesity. Histologic and liver function test abnormalities are relatively common in the obese, but clearance usually is not reduced. Abnormal liver function tests are seen in up to one third of obese patients who have no evidence of concomitant liver disease; increased alanine aminotransferase (ALT) is most frequently seen. Weight loss results in sustained improvement in liver enzymes in direct proportion to the extent of weight reduction.45 Despite these histologic and enzymatic changes, no clear correlation exists between routine liver function tests and the capacity of the liver to metabolize drugs.46 Hepatic decompensation can occur after Roux-en-Y gastric bypass, which necessitates careful assessment for preexisting liver disease in candidates scheduled to undergo this procedure because of a high prevalence (63%) of nonalcoholic fatty liver disease (NAFLD) and cirrhosis.47 Obesity is a major risk factor for NAFLD and nonalcoholic steatohepatitis (NASH). NAFLD is a group of liver abnormalities associated with obesity and insulin resistance. Hepatomegaly, elevated liver enzyme levels, and abnormal liver histology (including steatosis, steatohepatitis, fibrosis, and cirrhosis) are intrinsic components of this disease.48 NAFLD is the most common liver disease worldwide. The more progressive forms of NAFLD, NASH, and associated hepatic fibrosis are strongly associated with obesity and the metabolic syndrome.49 Up to 95% of morbidly obese patients have NASH.50 NASH is an aggressive form of NAFLD that can progress to cirrhosis or hepatocellular carcinoma. Insulin resistance and features of metabolic syndrome are good predictors of NASH.51 Fatty liver disease often represents the hepatic component of the metabolic syndrome characterized by obesity, hyperinsulinemia, peripheral insulin resistance, diabetes mellitus, hypertriglyceridemia, and hypertension.52 Massive weight loss in nondiabetic, nonalcoholic morbidly obese subjects leads to significant improvement in NASH and

liver fibrosis.53 Major improvements have been demonstrated in the biochemical and histologic features of liver disease associated with obesity and metabolic syndrome after surgical weight loss. Those with metabolic syndrome have greater initial histologic abnormalities and greater improvement with weight loss.54 The incidence of gallbladder disease, including cholelithiasis, is significantly increased in morbidly obese subjects; the relative risk appears to be positively correlated with increasing BMI.55 Obesity, particularly in male patients, results in earlier onset of biliary disease and an increase in its prevalence.55 After intestinal bypass surgery, patients have a particularly high prevalence of hepatic dysfunction and cholelithiasis; abnormal cholesterol metabolism is partially to blame.

Renal, Endocrine, and Metabolic Systems Impaired glucose tolerance in the morbidly obese is reflected by a high prevalence of type 2 diabetes mellitus as a result of the resistance of peripheral fatty tissues to insulin. The severity of diabetes mellitus depends on the degree and duration of the obesity. A significant number of obese patients have an abnormal glucose tolerance that predisposes them to wound infection and an increased risk of myocardial infarction.56 Exogenous insulin may be required perioperatively to oppose the catabolic response to the stress of surgery, even in obese patients on oral hypoglycemic agents. Abnormal serum lipid profiles may explain the high prevalence of ischemic heart disease. Gastric bypass surgery improves or even cures type 2 diabetes mellitus by substantially improving insulin resistance through an unknown mechanism. Marked improvement in insulin resistance or complete loss of insulin resistance has been seen as early as 6 days following gastric bypass surgery; suggesting that bypass of the stomach and duodenum results in physiologic changes that either inhibit the stress response to surgery, or more likely, alleviate insulin resistance to such an extent that postsurgical insulin resistance is not manifest.57 Subclinical hypothyroidism occurs in approximately 25% of all morbidly obese patients.58 Thyroid-stimulating hormone (TSH) levels are frequently elevated, suggesting the possibility that

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obesity leads to a state of thyroid hormone resistance in peripheral tissues.59,60 Hypothyroidism should be considered in any obese patient who displays perioperative cardiovascular or respiratory instability. Hypoglycemia, hyponatremia, and impaired hepatic drug metabolism are other adverse consequences of hypothyroidism. Reduction of thyroxine requirements is seen with a decrease in BMI.61 Obesity is a major risk factor for end-stage renal disease (ESRD) and essential hypertension. It induces high blood pressure through increased renal tubular sodium reabsorption, impaired pressure natriuresis, volume expansion resulting from activation of the sympathetic nervous system and renin–angiotensin system, and physical compression of the kidneys, especially when visceral obesity is present. Renal vasodilatation and glomerular hyperfiltration initially serve as compensatory mechanisms to maintain sodium balance in the face of increased tubular reabsorption. These changes, plus the increased systemic arterial pressure, create a hemodynamic burden on the kidneys leading to glomerular injury.62 Chronic obesity results in increasing urinary protein excretion and gradual loss of nephron function that worsens with time and exacerbates hypertension. Kidney disease progresses much faster when type 2 diabetes mellitus and other metabolic problems supervene. Weight loss is an essential first step in managing the hypertension and renal disease of obesity. Obesity-related glomerular hyperfiltration decreases after weight loss, which decreases the incidence of overt glomerulopathy.63 Up to a 10-fold increase in the biopsy incidence of obesity-related glomerulopathy has been documented.64 Obesity-related glomerulopathy is defined as focal segmental glomerulosclerosis and glomerulopathy or glomerulopathy alone. Increased BMI in men is associated with an increased risk of development of ESRD, independent of blood pressure and proteinuria; maintenance of optimal body weight reduces the risk of ESRD.65 Despite the negative association of obesity and kidney disease, a “reverse epidemiology” model has been documented in obese patients undergoing maintenance hemodialysis for ESRD whereby the association of obesity and renal disease occurs in the opposite direction, with obesity

conferring survival advantages to hemodialysis patients.66

gested to be a leptin-resistant state given that leptin levels are elevated in most obese individuals.70

The Metabolic Syndrome Obesity plays a major role in the development of the metabolic syndrome, a clinical entity resulting from the interaction of genetic, hormonal, and lifestyle factors. Components of the syndrome include insulin resistance, diabetes mellitus (or impaired glucose tolerance), hypertension, coronary artery disease, peripheral vascular disease, stroke, and hyperlipidemia.67 The metabolic syndrome can be perceived as a prediabetes state because it takes into account the two major outcomes: cardiovascular disease and type 2 diabetes mellitus.68 According to the International Diabetes Federation, a person diagnosed with metabolic syndrome must have central obesity (defined as WC >94 cm for men and >80 cm for women) plus any two of the following four factors69: 1. Raised serum triglyceride level (≥ 1.7 mmol/L) 2. Reduced serum high-density lipoprotein (HDL) cholesterol level (30 kg/m2 are similar to those of nonobese adolescents in the same age group when calculated based on TBW.79

Nondepolarizing Muscle Relaxants Nondepolarizing muscle relaxants should be administered according to LBM to prevent delayed recovery because of increased Vd and impaired hepatic clearance. The effects of obesity on the pharmacodynamics of nondepolarizing relaxants vary with the composition and distribution of body fat. There is no alteration in the pharmacokinetics of rocuronium in obese female patients when compared to normal weight patients; similarly, the Vd, distribution and elimination halflives, plasma clearance, and mean residence are not different. Pharmacodynamic parameters of rocuronium, including onset time, duration, and recovery times, also are comparable.78 The duration of action of rocuronium in obese patients is significantly longer when dosed according to TBW, prompting the recommendation that rocuronium be administered to morbidly obese patients on the basis of IBW.80 Vecuronium pharmacokinetics and pharmacodynamics in obese patients are consistent with dosing on the basis of IBW because the Vd, plasma clearance, and elimination half-life of vecuronium are not different between obese and nonobese patients.81 However, vecuronium action is prolonged when dosed according to TBW because of the excess dose administered; obesity does not alter the distribution or elimination of the drug. The


Vd, absolute clearance, and elimination half-life of atracurium are unchanged by obesity. However, if dosed according to TBW, atracurium concentrations are higher in obese patients than in the nonobese with no increase in recovery times. The median effective dose is higher; therefore, dosing can be based on TBW with some reduction in the total dose.82 The duration of action of cisatracurium is prolonged in the morbidly obese when dosed according to TBW, suggesting that dosing based on IBW is optimal in this group of patients.83

Opioids All synthetic opioids are highly lipophilic drugs. Application of non– weight-based pharmacokinetic models for fentanyl derived from normalweight patients overestimates the plasma concentration of fentanyl as body weight increases from normal to morbid obesity. Fentanyl dosing based on a derived “pharmacokinetic mass” (derived pharmacokinetic body weight for dosing) is clinically more useful than that based on TBW because of the strong linear correlation between this derived mass and total body clearance.84 Administration of fentanyl according to TBW overestimates fentanyl dose requirements in obese patients. Pharmacokinetic mass is the dosing weight for fentanyl that reflects the influence of TBW on clearance.84 Fentanyl dosing for postoperative analgesia also correlates with pharmacokinetic mass.85 Sufentanil is highly lipid soluble and distributes extensively in excess body fat as well as in lean tissues. It has an increased Vd and a prolonged elimination half-life that correlates positively with the degree of obesity. However, plasma clearance is similar in obese and nonobese patients; therefore, loading dose should account for total body mass, whereas maintenance and infusion dosing should be reduced and dosed according to IBW. Pharmacokinetic parameters derived from nonobese subjects accurately predict plasma sufentanil concentrations in morbidly obese subjects, but overestimation of plasma sufentanil concentration rises in patients with BMI >40 kg/m2.86 Remifentanil is a fentanyl congener that is hydrolyzed by blood and tissue esterases, leading to rapid metabolism and inactive products. No difference has been reported in the estimates of

Vd of remifentanil between obese and nonobese subjects, but the Vd is less than expected for lipid-soluble molecules with only modest distribution into body tissues.87 Remifentanil pharmacokinetics is more closely related to LBM than to TBW; therefore, dosing should be based on IBW.87

Dexmedetomidine Dexmedetomidine is a highly specific α2-adrenergic agonist with an eight times higher affinity than clonidine for the α2-adrenoceptor.88 It has sedative–hypnotic, anesthetic-sparing, analgesic, and sympatholytic properties. Dexmedetomidine lacks significant effects on respiration, making it ideally suitable as an analgesic adjuvant in morbidly obese subjects in whom opioid-induced respiratory depression may be catastrophic.89 α2-Agonists produce transient hypertension at higher doses; therefore, slow intravenous loading over 10–20 minutes is recommended to reduce these effects on heart rate and blood pressure. At infusion rates of 0.2–0.7 μg/kg/h, dexmedetomidine produces clinically effective sedation with decreased analgesic and anesthetic requirements.

MEDICAL AND SURGICAL THERAPY FOR OBESITY Antiobesity medications are formulated to reduce energy intake, increase energy utilization, or decrease absorption of nutrients. Indications for drug treatment include BMI ≥30 kg/ m2 or BMI between 27 and 29.9 kg/m2 in conjunction with an obesity-related medical complication. The combination of phentermine and fenfluramine (Phen-Fen) previously was popular for obesity treatment until evidence indicated its association with valvular heart disease and pulmonary hypertension. Sibutramine and orlistat are recently approved antiobesity medications for long-term use that have not yet been associated with such detrimental side effects. Sibutramine inhibits the reuptake of both serotonin and norepinephrine to increase satiety after the onset of eating rather than reduce appetite; it does not promote the release of serotonin, unlike fenfluramine and dexfenfluramine, which primarily increase the release of serotonin in brain synapses and also inhibits reup-

take to produce anorexia. Sibutramine does not deplete the neural synapses of catecholamines; therefore, dangerous hypotension that is unresponsive to indirectly acting vasopressors, seen with fenfluramine and dexfenfluramine, does not occur. Orlistat blocks the absorption and digestion of dietary fat by binding lipases in the gastrointestinal tract. It improves cardiovascular risk factors associated with obesity, such as hypertension, WC, fasting blood glucose levels, and lipid profile.90 Low-density lipoprotein (LDL) and total cholesterol levels also decrease. An increase in the anticoagulant effect of warfarin is seen with chronic dosing of orlistat because of its side effect of decreasing absorption of fat-soluble vitamins, including vitamin K.91 This results in an abnormal plasma thromboplastin time (PTT) because of deficiency of clotting factors II, VII, IX, and X. Obesity (bariatric) surgery is generally classified into malabsorptive, restrictive, or combined. Malabsorptive procedures, which include jejunoileal bypass and biliopancreatic diversion, are rarely used today. Restrictive procedures include the vertical banded gastroplasty and the adjustable gastric banding. The Roux-en-Y gastric bypass combines gastric restriction with a minimal degree of malabsorption. Roux-en-Y gastric bypass is the most commonly performed bariatric procedure in the United States today. It involves anastomoses of the proximal gastric pouch to a segment of the proximal jejunum, bypassing most of the stomach and the entire duodenum. It is the most effective bariatric procedure for achieving safe shortand long-term weight loss in morbidly obese patients. Patients who have undergone Roux-en-Y gastric bypass lose an average of 50–60% excess body weight and decrease their BMI by approximately 10 kg/m2 during the first 12–24 postoperative months. Type 2 diabetes mellitus resolves in >90% of patients after Roux-en-Y gastric bypass.92 Adjustable gastric banding requires placement of an adjustable inflatable band around the proximal stomach to limit stomach capacity. Adjustments can be made to meet a patient’s individual needs by adding to or removing saline from the silicone band, making it tighter or looser. All of these procedures can be performed under laparoscopy.

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Rhabdomyolysis has been documented in morbidly obese patients undergoing prolonged procedures such as laparoscopic bariatric surgery; the main risk factor is prolonged duration of surgery. Elevations in serum creatinine and creatine phosphokinase (CPK) levels unexplained by other reasons and complaints of buttock, hip, or shoulder pain in the postoperative period should raise the suspicion of rhabdomyolysis.93 386

PREOPERATIVE EVALUATION Evaluation of the cardiovascular and pulmonary systems is important because obese patients have significant derangement of these systems. Previous experiences as detailed by the patient and anesthetic records are useful sources of information. Explanation of perioperative anesthetic problems associated with morbid obesity has a significant effect on the type of anesthesia chosen by most obese patients. The majority (>50%) of patients would chose to attempt to lose weight before elective surgery if given the choice, rather than be subjected to the increased risk of anesthesia.94 Obese patients should be evaluated for systemic and pulmonary hypertension, signs of right and/or left ventricular or congestive cardiac failure, and ischemic heart disease. Excess adiposity may make signs of congestive cardiac failure difficult to elucidate. The chronicity of pulmonary impairment, including OSA and OHS, makes pulmonary hypertension common in morbidly obese patients. Tricuspid regurgitation noted on echocardiography is the most useful confirmatory test of pulmonary hypertension but should be combined with clinical features such as exertional dyspnea, fatigue, and syncope, which reflect inability to increase cardiac output in response to activity.95 Features of RVH, such as tall precordial R waves, right axis deviation, and right ventricular strain pattern may be seen on ECG. Sensitivity of the ECG features correlates well with the degree of pulmonary hypertension. Chest radiographs may show evidence of underlying lung disease and prominent pulmonary arteries. Patients who have previously undergone bariatric surgery should be screened for long-term metabolic and

nutritional abnormalities during their preoperative visit. Common deficiencies include vitamin B12, iron, calcium, and folic acid. A collective form of postoperative polyneuropathy, known as acute post–gastric reduction surgery (APGARS) neuropathy, could result from these deficiencies.96 Patients with APGARS neuropathy present with protracted postoperative vomiting, hyporeflexia, and muscular weakness. Differential diagnoses of this disorder include thiamine deficiency (Wernicke encephalopathy, beriberi), vitamin B12 deficiency, and GuillainBarré syndrome. Because of the associated hyporeflexia and muscular weakness, close attention should be paid to dosing and monitoring of neuromuscular blocking agents.97 Electrolyte and coagulation indices should be checked before surgery, particularly in patients who have been chronically taking diuretics and weight loss medications and in those who are acutely ill or poorly compliant with vitamin and nutritional supplements. Chronic vitamin K deficiency can result in coagulation abnormalities requiring vitamin K analogue or fresh-frozen plasma. Evidence for OSA and OHS should be sought during the preoperative visit because these conditions are frequently associated with difficult laryngoscopy and intubation. Inquiry should be made about snoring or apnea during sleep, frequent arousals, and daytime somnolence. History of hypertension or neck circumference >40 cm correlates with an increased probability of OSA. OSA is a legitimate reason to delay elective surgery in order to obtain a proper workup.15 A formal sleep study may be indicated for quantifying its severity. Patients requiring general anesthesia should be treated as having severe OSA. Regional anesthesia should be considered if it is technically feasible. OSA patients should generally be treated as inpatients; however, outpatient surgery can be considered in the following circumstances: mild OSA, local or regional anesthesia with minimal or no sedation, 23-hour observation in the postanesthesia care unit (PACU) following surgery, and patients taking oral medication at the time of discharge. Patients on continuous positive airway pressure device (CPAP) at home should be encouraged to bring the device to the hospital because it may be needed postoperatively. The

possibility of invasive monitoring, prolonged endotracheal intubation, and postoperative mechanical ventilation should be discussed during the preoperative evaluation. Specialized tests such as pulmonary function tests and liver function tests need not be routinely obtained because they are not cost effective in asymptomatic morbidly obese patients. Blood glucose abnormalities should be corrected if present.

Preoperative Medications All current medications should be continued until the time of surgery; with the possible exception of insulin and oral hypoglycemic agents. Antibiotic prophylaxis is important because of an increased incidence of wound infection in obese patients partly as a result of a decrease in tissue oxygenation.98 Both bariatric and general elective surgeries carry an equivalent risk of postoperative wound infection in morbidly obese patients.99 Oral benzodiazepines are reliable for anxiolysis and mild sedation; intravenous midazolam can be titrated in small doses during the immediate preoperative period. Prophylaxis against both aspiration pneumonitis and deep venous thrombosis (DVT) should be addressed during the preoperative period. H2-receptor antagonists, nonparticulate antacids, and proton pump inhibitors all reduce gastric volume, acidity, or both, reducing the risk and severity of aspiration pneumonitis. Obesity is a major independent risk factor for DVT and subsequent morbidity and mortality from postoperative pulmonary embolism.100,101 Minidose subcutaneous heparin 5000 IU administered before surgery and repeated every 8–12 hours until the patient is fully mobile reduces this risk. The incidence of clinically evident DVT after laparoscopic Roux-en-Y gastric bypass is low when the procedure is accomplished in a relatively short time, with the initiation of calf-length pneumatic compression hose before induction of anesthesia and with routine early ambulation.102 Meeting these conditions precludes any form of mandatory heparin anticoagulation except in patients with a history of prior DVT, those with a known hypercoagulable state, or with a significant family history of DVT. Preoperative inferior vena cava (IVC) filter placement is recommended for bariatric


surgery patients with prior pulmonary embolus, prior DVT, evidence of venous stasis, or hypercoagulable state.103 Four important risk factors are significant in the development of postoperative venous thromboembolism: venous stasis disease, BMI ≥60, truncal obesity, and obesity hypoventilation/sleep apnea syndrome. If all of these factors are present, prophylactic IVC filter placement is highly recommended.104 Many bariatric surgeons prefer low-dose unfractionated heparin as their primary method of thromboprophylaxis.105 The use of a protocol for heparin dosing in gastric bypass patients as opposed to a fixed dose is the preferred method. Dose calculations based initially on height and weight and later adjusted according to peak anti–factor Xa activity result in better thromboprophylaxis and fewer side effects.106 Low-molecularweight heparins (LMWHs) have become popular for thromboembolism prophylaxis in bariatric surgery patients because of their bioavailability when injected subcutaneously. Subcutaneous enoxaparin, 40 mg every 12 hours, decreases the incidence of postoperative DVT without increasing bleeding complications.107 Other authors have recommended that enoxaparin dosing in obese patients be varied according to age and LBM.108

AIRWAY History obtained from the obese patient and examination of previous anesthetic records may divulge previous airway management difficulties. Anatomic changes of obesity that contribute to a potentially difficult airway include limitation of movement of the atlantoaxial joint and cervical spine by upper thoracic and low cervical fat pads, excessive tissue folds in the mouth and pharynx, short thick neck, suprasternal, presternal, and posterior cervical fat, and a very thick submental fat pad. Obese patients with OSA are significantly more difficult to intubate than patients without OSA; however, there is no relationship between the severity of sleep apnea and the occurrence of difficult intubation.109 A short thick neck is significantly more related to difficult intubation, whereas obesity and a short thick neck are significantly related to each other, in addition to both being related to OSA.

Patients with OSA have excess adipose tissue deposits in their pharyngeal area, including the tonsils, tonsillar pillars, uvula, tongue, aryepiglottic folds, and lateral pharyngeal walls.15 This fat deposition is most pronounced in the lateral pharyngeal walls and may not be noticed during routine airway examination. Even with the presence of these anatomic changes and pathology, the magnitude of BMI does not correlate with the difficulty of laryngoscopy. Such difficulty correlates better with increased age, male sex, temporomandibular joint pathology, Mallampati classes 3 and 4, history of OSA, and abnormal upper teeth.110 Neck circumference has been identified as the single biggest predictor of problematic intubation in morbidly obese patients.111 A larger neck circumference is associated with the male sex, higher Mallampati score, grade 3 views at laryngoscopy, and OSA. The probability of a problematic intubation is approximately 5% with a 40-cm neck circumference compared with a 35% probability with a 60-cm neck circumference.111

PSYCHOLOGY OF THE OBESE The general public often stigmatizes obesity. The belief that weight can be controlled and that obesity is a manifestation of character deficits makes the general public openly unkind to the obese. Obese people demonstrate poor well-being associated with psychological problems mainly because of discrimination. Increased anxiety, symptoms of depression, and a lower positive mental attitude toward life are some of the psychological problems. The health-related quality of life is worse in the severely obese than in other groups of patients with chronic diseases.112 Bariatric surgery is currently the most viable option for successful weight loss and maintenance; however, postsurgical drastic weight loss and alleviation of medical risks are accompanied by remarkable psychosocial changes.113 Not all morbidly obese patients seeking surgery have elevated levels of psychopathology; however, postoperative improvements in mood have been consistently found despite the lack of preoperative psychopathology findings.113 A positive correlation exists between presurgical severity of

depression and 1-year success at weight loss after bariatric surgery.114 More depressed individuals tend to lose more weight compared to less depressed individuals. Depression, anxiety, and poor self-esteem are prominent psychosocial symptoms that are part of the etiologic factors of obesity; however, the obese population generally does not manifest more severe psychopathology than does the nonobese population, and psychological symptoms are more likely a result of obesity rather than its cause.115

OBESITY AND AMBULATORY ANESTHESIA The Royal College of Surgeons of England issued guidelines in 1992 that deemed patients with BMI >30 kg/m2 unsuitable for ambulatory surgery.116 Subsequent evaluation of adherence to these guidelines discovered that >85% of ambulatory surgery units in England and a significant number in other countries continued to routinely anesthetize patients with BMI >30 kg/ m2.117,118 More than 75% of anesthesiologists responding to a survey believe that morbidly obese patients with comorbidities and no patient escort will be unsuitable for ambulatory anesthesia because many of them are in suboptimal health.119 The presence of cardiovascular or respiratory comorbidity significantly reduces the willingness of anesthesiologists to provide ambulatory care to the obese.119 An excess of adverse cardiovascular events has not been found in obese patients undergoing ambulatory surgery despite a prevalence of cardiovascular disease in this patient population; however, adverse intraoperative and postoperative respiratory events, including arterial oxygen desaturation and bronchospasm, are common.120 Individual evaluation is the most prudent way to choose which obese patients can undergo ambulatory anesthesia and surgery. If an obese patient will require ambulatory anesthesia, the proper equipment and procedures for positioning and monitoring, including difficult airway and resuscitation equipment, should be readily available. Arrangements for transfer to a 23-hour observation unit or full admission unit should be in place. Ambulatory anesthesia for morbidly obese patients without significant comorbidities does

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not increase risk. Obese patients do not have a higher incidence of contact with healthcare professionals after discharge from the ambulatory surgery unit; neither do they have a higher postambulatory surgery unplanned hospital admission rate than does the general population.121 Although obesity is associated with higher regional block failure and complication rates during ambulatory regional anesthesia, the rates of successful blocks and overall satisfaction are high, enough that obese patients should not be excluded from ambulatory regional anesthesia procedures.122

INTRAOPERATIVE CONSIDERATIONS Positioning Obese patients may require specially designed tables or two regular operating tables for safe anesthesia and surgery. Regular operating tables have a maximum weight limit of approximately 205 kg, but wider and highercapacity operating tables that can hold up to 450-kg patients and accommodate the extra girth are available. Electrically operated or motorized tables facilitate maneuvering into various surgically favorable positions. Use of belts, straps, and malleable bean bags helps keep obese patients from falling off the operating table. Pressure areas on the body should be protected with care to avoid neural injuries and possible pressure necrosis. Brachial plexus and lower-extremity nerve injuries are frequent. A documented association between ulnar neuropathy and increasing BMI quoted a >30% incidence of ulnar neuropathy in patients with BMI ≥38 kg/m2 compared with only 1% in the control group.123 Peripheral neuropathy occurs more frequently after bariatric surgery than after other abdominal surgery. Intraoperative neural compression or stretching from improper positioning is one of the most common etiologies. Malnutrition may be an important contributing factor; inflammation and altered immunity also play some role.124 Other associated risk factors include greater absolute weight loss, a faster rate of weight loss, lower serum albumin and transferrin concentrations, prolonged postoperative gastrointestinal symptoms (nausea and vomiting, diarrhea, and dumping syn-

drome), and reduced vitamin and calcium supplementation.124 Attention to patient positioning and duration of immobility during surgery helps to reduce the incidence of compression injuries and rhabdomyolysis during bariatric surgery. Micronutrient deficiencies (e.g., vitamins B6, B12, D, and E, folate) and mineral deficiencies (e.g., calcium, magnesium, phosphorus, selenium, and copper) contribute to nonmechanical peripheral neuropathies, especially in nutritionally noncompliant patients undergoing post– bariatric surgery procedures.125 Nerve compression injury is more likely to occur in patients with micronutrient deficiencies. Supine positioning of the obese patient causes aortic and IVC compression and leads to ventilatory impairment with further decrease in FRC and oxygenation. Trendelenburg positioning, further worsens FRC and should be avoided whenever possible. A simple change of the obese patient from the supine to sitting position causes a significant increase in cardiac output, oxygen consumption, and pulmonary artery pressure. The head-up (semirecumbent) or reverse Trendelenburg (semi-Fowler) position unloads the weight of the intraabdominal contents from the diaphragm, leading to increased pulmonary compliance and improved FRC and oxygenation. Both intraoperative positive end-expiratory pressure (PEEP) and reverse Trendelenburg position significantly decrease alveolar–arterial oxygen tension difference and increase total respiratory compliance to a similar degree in the obese, but reverse Trendelenburg position results in lower airway pressures. However, both maneuvers decrease cardiac output significantly, which partially counteracts their beneficial effects on oxygenation.126 Prone positioning in the obese patient should be correctly performed with freedom of abdominal movement to prevent detrimental effects on lung compliance, ventilation, and arterial oxygenation. Prone positioning increases intraabdominal pressure, worsening IVC and aortic compression and further decreasing FRC. Lateral decubitus positioning allows for good diaphragmatic excursion during mechanical ventilation because the panniculus is displaced off the abdomen, reducing intraabdominal pressure.127 Changing from sitting to lateral decubitus posi-

tion after placing an epidural catheter may cause catheter dislodgment, resulting in inadequate analgesia because movement from sitting to lateral position increases the distance from the skin to the epidural space.128

Monitoring Noninvasive blood pressure measurements can be falsely elevated if a cuff is too small for the limb. The blood pressure cuff bladder should encircle a minimum of 75% of the upper arm circumference or, preferably, the entire arm. Forearm blood pressure is a fairly good predictor of upper arm blood pressure in most patients; however, forearm measurements with a standard cuff may overestimate both systolic and diastolic blood pressures in obese patients.129 Invasive arterial pressure monitoring is not always necessary but may be indicated for the morbidly obese with severe cardiopulmonary disease and for those with poor fit of the noninvasive blood pressure cuff. Central venous and pulmonary artery catheters may be indicated in patients undergoing extensive surgery in whom significant fluid shifts are anticipated and in those with significant cardiopulmonary impairment. Perioperative intravenous access can be problematic in this patient population and is another indication for central venous catheterization. Routine insertion of a central venous catheter is not necessary in obese patients because insertion of peripheral lines almost always is successful.130

Induction, Intubation, and Maintenance Obese patients desaturate rapidly after loss of consciousness because of increased oxygen consumption and decreased FRC; therefore, adequate preoxygenation is vital prior to the induction of anesthesia. Application of positive-pressure ventilation during preoxygenation decreases atelectasis formation and improves oxygenation in morbidly obese patients.131 Four vital capacity breaths with 100% oxygen within 30 seconds have been suggested as superior to the usually recommended 3 minutes of 100% preoxygenation in obese patients.132 Preoxygenation in the head-up or sitting position is more effective and significantly extends the tolerance to apnea in obese patients when compared with


FIGURE 22–6. “Stacking” using towels and blankets. (From Ogunnaike and Whitten97 with permission.)

the supine position.133,134 This position provides the longest safe apnea period during induction of anesthesia.135 The extra time gained helps preclude hypoxemia if intubation is delayed. Obese patients may require larger doses of induction agents because blood volume, muscle mass, and cardiac output increase linearly with the degree of obesity. However, cardiovascular and respiratory depression may result from larger doses. Any of the intravenous induction agents is suitable after considering problems peculiar to individual patients. An increased dose of succinylcholine is necessary because of an increase in pseudocholinesterase activity. Myalgia following succinylcholine is not frequently seen in morbidly obese patients; therefore, succinylcholine is highly recommended for tracheal intu-

bation.136 If difficult intubation is anticipated, awake intubation under topical or regional anesthesia is a prudent approach. During awake intubation, sedative–hypnotic medications should be reduced to a minimum on order to prevent cardiorespiratory depression. An experienced colleague who is immediately available or, better still, is present in the room during induction and airway management can help with mask ventilation or further attempts at intubation. During endotracheal intubation under general anesthesia, hypoxia and aspiration of gastric contents should be prevented at all costs. Preparation should be made for the possibility of difficult intubation, and a surgeon capable of surgically accessing the airway should be readily available. Towels or folded blankets under the shoulders and head can compensate

FIGURE 22–7. A. The preformed Troop head elevation pillow. B. Proper head-elevated laryngoscopy position (HELP) placement with the head elevation pillow combined with a standard intubating pillow. (From Ogunnaike and Whitten97 with permission.)

for the exaggerated flexed position of posterior cervical fat (Figure 22–6). The object of this maneuver, known as “stacking,” is to position the patient so that the tip of the chin is at a higher level than the chest to facilitate laryngoscopy and intubation. The head-elevated laryngoscopy position (HELP), or “ramped” position,137,138 is a step beyond “stacking.” It significantly elevates the obese patient’s head, neck, upper body, and shoulders above the chest to a point where an imaginary horizontal line can be drawn from the sternal notch to the external ear to better improve laryngoscopy and intubation. To facilitate proper HELP placement, the preformed Troop Head Elevation Pillow (C&R Enterprises, Frisco, TX, USA) in combination with a standard intubation pillow can be used in place of folded towels or blankets (Figure 22–7). The advantage of the preformed pillow is that it can be prepositioned, inserted, and removed much faster with less effort than that required to build and dismantle a ramp made from blankets and towels.139 Continuous infusion of a short-acting intravenous agent such as propofol, any of the inhalational agents, or a combination can be used to maintain anesthesia. Desflurane, sevoflurane, and isoflurane are minimally metabolized and therefore are useful choices in obese patients. Desflurane may provide better hemodynamic stability.140 Sevoflurane provides rapid recovery, good hemodynamic control, prompt regaining of psychological and physical functioning, and infrequent incidence of nausea and

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vomiting when compared to isoflurane.141 A bispectral index (BIS)-guided study demonstrated an insignificant difference between sevoflurane and desflurane with respect to emergence and cognitive psychomotor recovery characteristics when careful anesthetic titration was used.142 Obese patients have been found to awake significantly faster after desflurane than after sevoflurane anesthesia; desflurane also resulted in higher oxygen saturation on arrival in the PACU.143 Propofol–nitrous oxide anesthesia adjusted to a BIS level of approximately 60 combined with thoracic epidural analgesia provides intraoperative hemodynamic stability and prompt recovery during laparotomy for gastric bypass surgery.144 Overall, the evidence on significant delayed recovery and awakening from all currently available volatile anesthetic agents in obese patients when compared to the nonobese is conflicting. Metabolism of volatile anesthetics is greater in obese than in normal-weight patients, which is reflected by a greater increase in serum inorganic fluoride level, including during anesthesia with sevoflurane, whose biotransformation has not been shown to result in significant differences in plasma fluoride levels or in differences in preoperative and postoperative liver function and renal function tests between obese and nonobese patients.145 In obese patients, a potentially hepatotoxic reductive pathway metabolizes halothane, resulting in an increased incidence of “halothane hepatitis.” Fortunately, halothane is rarely needed in modern practice. Rapid elimination and analgesic properties make nitrous oxide an attractive choice for anesthesia in obese patients, but high oxygen demand in this patient population limits its use. This high oxygen demand is the result of excess metabolically active fat tissue and an increased workload on muscles and other supportive tissue that significantly increases mean oxygen consumption. Short-acting opioids such as remifentanil at the lowest possible dose, combined with a low-solubility inhalation anesthetic, facilitates a more rapid emergence without increasing opioid-related side effects.146 Cisatracurium possesses an organ-independent elimination profile and is a favorable nondepolarizing muscle relaxant for maintenance of anesthesia in the obese patient with high prevalence of renal and hepatic compromise. Vecuronium and rocuronium are other use-

ful choices.147 Dexmedetomidine, an α2-agonist with sedative and analgesic properties, provides hemodynamic stability without myocardial depression. It has no clinically significant adverse effects on respiration, which makes it an attractive agent for use as an anesthetic adjunct in obese patients. Furthermore, it reduces the postoperative opioid analgesic requirements and their subsequent detrimental respiratory depressant effects.89 Ventilatory tidal volumes >13 mL/ kg offer no added advantages during ventilation of morbidly obese patients during anesthesia. Increasing the tidal volumes further only increases airway pressures and lung compliance without significantly improving arterial oxygen tension but results in severe hypocarbia that increases shunt fraction at PaCO2 left) Septic embolization Hematoma Ischemic vasculitis (cocaine or amphetamines) Vascular thrombosis Mycotic aneurysm Pulmonary Septic pulmonary embolism (tricuspid valve endocarditis) Community-acquired pneumonia Tuberculosis Pneumocystis pneumonia (HIV) Neurologic Brain or spinal cord abscesses Cerebral infarction Cerebral mycotic aneurysm Meningitis Encephalopathy Vertebral osteomyelitis Botulism Tetanus Hepatic/gastrointestinal Viral hepatitis (all forms) Hepatic abscess Hepatic granulomatosis (talc) Spontaneous bacterial peritonitis Renal Nephrotic syndrome (hepatitis B, HIV) Nephritic syndrome (hepatitis C) Rhabdomyolysis Immunologic HIV/AIDS

duce cutaneous or muscular ischemic necrosis at the injection site and contribute to the development of superinfection or ulcer formation. Infections of large skeletal muscles (pyomyositis), most often produced by S. aureus, are also associated with injection drug use in patients with HIV. Treatment of abscess, ulcer, or pyomyositis usually requires the combination of intrave-

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nous antibiotics and surgical incision and drainage. Necrotizing fasciitis is associated with substantial morbidity and mortality, and aggressive surgical intervention is required to effectively manage this devastating complication of injection drug use.

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A common complication of injection drug abuse is endocarditis.23 The frequency of injection and the presence of simultaneous HIV infection are risk factors for the development of infective endocarditis. Interestingly, concomitant alcohol abuse may actually reduce the risk of the disease. Mortality in patients with infective endocarditis resulting from injection drug abuse may exceed 35%,24 and is probably higher in immunocompromised patients. The overall incidence of infective endocarditis has been estimated at 1.5–20 cases per thousand personyears among active injection-drug users.25 Endocarditis may affect any heart valve, but infection of right- as compared to left-heart valves is more frequent and also is associated with lower mortality.26 In patients from the general population, infective endocarditis most often develops as a result of transient bacteremia seeding a preexisting left-heart valvular abnormality resulting from congenital, rheumatic, or myxomatous disease. In contrast, injection drug use more commonly produces infection of structurally normal right-heart valves. The tricuspid valve is most often affected in injection-drug users. The reasons for this clinical presentation appear to be multifactorial and include toxic effects of a drug or its contaminants on valvular endothelium, an enhanced susceptibility of right-heart valves to particular skin organisms, and preexisting thickening of the tricuspid valve leaflets.25 Streptococcus viridans and enterococcus are typically identified as the bacteria responsible for endocarditis in patients without a history of substance abuse, but more virulent species, most notably S. aureus (with or without methicillin-resistance), are most often implicated in injection-drug users with endocarditis. A higher incidence of endocarditis resulting from gram-negative bacilli and fungi also occurs in patients who use injection drugs as compared to those who do not. Endocarditis is characterized by the presence of persistent bacteremia, and

the diagnosis of the disease follows standard criteria.27 Transthoracic or transesophageal echocardiography is commonly used during evaluation of the patient with suspected endocarditis to provide direct visual evidence of a vegetation that consists of platelets, fibrin, and sequestered bacteria usually located on the valve surface. Notably, a normal echocardiogram alone does not definitively exclude the diagnosis. The clinical presentation of endocarditis is typified by persistent fever, a variety of cardiac abnormalities (e.g., new murmur, valvular insufficiency, congestive heart failure, intraventricular conduction defects), evidence of septic embolization from the affected valve, bacterial seeding of other organ systems (e.g., meningitis, brain abscess, osteomyelitis), and immune complex-related complications (e.g., glomerulonephritis, Roth spots, Osler nodes). In contrast to findings in the general population, injection-drug users with endocarditis often present with cough, pleuritic chest pain, and bilateral pulmonary infiltrates that occur as a consequence of septic embolization from the tricuspid valve. Necrotizing or cavitary pulmonary defects produced by these septic thromboemboli may also be complicated by bronchopleural fistulae, hemoptysis, pneumothorax, empyema, or invasion of a major bronchial structure. Primary treatment of endocarditis with organism-specific antibiotics or antifungal drugs also may require simultaneous surgical intervention to manage the cardiovascular or neurologic sequelae of the disease. Vascular infections frequently occur in injection-drug users. Contaminated injection equipment, hematoma surrounding a direct vascular injury, local ischemic damage from vasoactive drug injection (e.g., cocaine, amphetamine), or thrombosis may contribute to the development of thrombophlebitis or the formation of arteriovenous fistulae. Intravenous drug administration using contaminated supplies may also produce thrombophlebitis and septic embolization. When such emboli lodge in the vasa vasorum of an arterial wall, a mycotic aneurysm may be produced. Right- or left-heart valve endocarditis-induced septic embolization is the most frequent cause of pulmonary or brain mycotic aneurysm formation, respectively. Regardless of the embolic source, the vast majority

of these infected, mushroom-shaped, arterial defects resolve with intravenous antibiotic treatment directed against the primary underlying organism. Nevertheless, some patients with mycotic aneurysms may develop signs and symptoms despite appropriate antibiotic treatment. The clinical presentation of a mycotic aneurysm is typified by the presence of a painful, pulsatile mass accompanied by a bruit, thrill, surrounding cellulitis or abscess formation, or frank rupture. In many cases, surgical excision is required for definitive treatment of the infection or to prevent rupture.

Lung Community-acquired pneumonia is very common in injection-drug users and is a major cause of hospital admission in this patient population. Several factors contribute to this enhanced susceptibility including increased aspiration risk resulting from drug-induced depression of airway protective mechanisms, poor nutritional status, diminished immunologic responses, and compromised mucociliary and phagocytic function associated with tobacco smoking.28 Residence in homeless shelters or incarceration in the penal system may also predispose drug users to developing pneumonia because of more frequent exposure to other infected individuals. Injection drug users with HIV are particularly susceptible to community-acquired pneumonia and have a risk of developing the disease that is approximately five times greater that drugs users who do not have HIV.29 Streptococcus pneumoniae and Haemophilus influenzae are the most frequently identified pathogens responsible for pneumonia in injection-drug users with or without HIV infection. Other bacteria, including Legionella species, Chlamydia pneumoniae, Pseudomonas aeruginosa, and S. aureus, are also more commonly encountered in injection-drug users with pneumonia as compared to the general population. HIV-positive patients with AIDS are especially susceptible to opportunistic pulmonary infection with Pneumocystis carinii, Mycobacterium tuberculosis, Mycobacterium avium intracellulare, and cytomegalovirus. Tuberculosis is also common in injection-drug users, especially in those users who are coinfected with HIV.30 Injection-drug users have a prevalence of latent tuberculosis infection that is

CHAPTER 23: Evaluation of the Patient with Alcohol or Drug Addiction

3–5-fold higher than that observed in the general population (approximately 5%). The mechanism responsible for reactivation of tuberculosis or whether active drug use plays a role in this reactivation remains unknown. It appears highly likely that many of the previously discussed factors that predispose injection-drug users to develop other infectious diseases may also contribute to the reactivation of latent tuberculosis. The immunosuppression that characterizes advanced HIV infection promotes reactivation of latent tuberculosis and contributes to the development of extrapulmonary manifestations of the disease including vertebral osteomyelitis, meningitis, and empyema that may occur in as many as 80% of these patients. Notably, reduced delayed hypersensitivity responses to tuberculin are also observed in immunocompromised patients that complicate interpretation but do not necessarily preclude use of these important diagnostic skin tests. Standardized treatment of tuberculosis has been established and usually involves drug therapy with isoniazid, rifampin, ethambutol, and pyrazinamide.31 Rifampin stimulates methadone metabolism, and opioid addicts in methadone maintenance programs often require dosing adjustments to avoid withdrawal.32 This drug interaction between rifampin and methadone also has potentially important ramifications for the anesthesiologist when using opioids during the perioperative period. Rifampin and pyrazinamide have also been reported to exacerbate preexisting hepatitis or contribute to the development of severe liver dysfunction in injection-drug users with tuberculosis.

Central and Peripheral Nervous System Signs and symptoms of acute intoxication or withdrawal often complicate the diagnosis of neurologic infection in injection-drug users. Meningitis, brain abscess resulting from septic embolization, cerebral infarction, or rupture of a mycotic aneurysm may occur in as many as 40% of injection-drug users with endocarditis. These central nervous system consequences of endocarditis may be accompanied by bacteremia-induced vertebral osteomyelitis with extension into the epidural space. The resulting epidural abscess may compromise spinal cord integrity. Al-

ternatively, central nervous system infections may be produced by bacterial invasion from ear, sinus, or mastoid infections, bacteremia resulting from another infectious source, or traumatic injury. Management of most of these bacterial complications requires appropriate antibiotic therapy and surgical intervention. Immunosuppressed injection-drug users infected with HIV are particularly susceptible to central nervous system infections produced by unusual pathogens such as tuberculosis, Cryptococcus, Aspergillus, and Toxoplasma gondii. Viral hepatitis may also produce encephalopathy independent of liver dysfunction. Injection drug users are also susceptible to the development of two major neurotoxin-mediated infectious diseases. Botulinum toxin is released by subcutaneous or intramuscular injection sites infected with Clostridium botulinum and produces blurred vision, dysphagia, descending bilateral flaccid paralysis, and respiratory failure as a result of irreversible inhibition of acetylcholine release. Treatment with antitoxin may limit the progression of the disease until regeneration of axons occurs. Several cases of wound botulism were recently reported in drug abusers from California who had injected black tar heroin. Injection drug use is also a major risk factor for the development of tetanus. Tetanolysin produced by the anaerobic bacterium Clostridium tetani irreversibly blocks release of inhibitory transmitters in spinal motor neurons, and as a result, causes spastic paralysis characterized by trismus, dysphagia, hydrophobia, and profound, unrelenting muscle contraction in the upper and lower extremities. Neutralization of circulating tetanus toxin with hyperimmune globulin precedes surgical debridement so as to avoid the release of additional tetanolysin from the infected injection site. Like botulism, recovery of neural function from tetanus requires axonal regeneration.

Hepatitis Drug abuse is strongly associated with the development of all known forms of viral hepatitis. Collectively, these diseases have potentially devastating consequences for drug users and also pose substantial risks of transmission to anesthesiologists and other health professionals who are responsible for their care. Hepatitis A virus (HAV) is

the most common form of viral hepatitis in the United States, and drug abuse has been identified as a major risk factor for the transmission of the virus. Antibodies directed against the HAV are present as many as 60% of injection-drug users. Fecal–oral transmission of the RNA-based HAV may occur in drug users by inhalation, intranasal, or oral routes of administration, or by sharing of contaminated injection equipment. Under most circumstances, hepatitis A is a self-limited disease characterized by fever, fatigue, gastrointestinal complaints, jaundice, hepatosplenomegaly, and nonspecific abnormalities in liver function tests concomitant with the presence of IgE followed by IgG anti-HAV antibodies that confer immunity against subsequent infection. In contrast to the findings in many patients with hepatitis B virus (HBV) infection, a carrier state does not occur with HAV infection, extrahepatic manifestations of the disease are unusual, and most cases require only supportive care. However, acute HAV infection has been reported to cause fulminant hepatic failure and death in a subset of patients who are coinfected with hepatitis C virus (HCV) or those affected by other chronic hepatic pathology.33 Transmission of the DNA-based HBV among drug abusers most often occurs as a result of sharing contaminated injection supplies or high-risk sexual activity. Drug abuse is responsible for as many as 20% of new HBV cases that are reported annually in the United States, and HBV antibodies are present in between 50% and 80% of all injection-drug users. The duration of injection drug use is strongly correlated with the presence of HBV infection, but infection with the virus most often occurs relatively early in the history of injection drug use. Acute infection with HBV has a widely variable clinical course. Many patients infected with HBV remain completely asymptomatic, and less than half develop the classical signs of jaundice, hepatosplenomegaly, and elevated serum transaminases. Although the vast majority of these patients require only supportive care, a very small number ( ALT). MDMAinduced hepatic injury may be associated with acute drug toxicity or may occur days or even weeks after ingestion, possibly because of delayed drug metabolism by cytochrome P450 2D6 in susceptible patients with reduced enzymatic activity or as a result of an immunologically mediated mechanism. The clinical presentation of hepatic failure is often associated with hypovolemia, hyperthermia, and rhabdomyolysis. Methamphetamine use is associated with the development of HAV. Amphetamine abuse alters kidney perfusion by virtue of the actions of these drugs on arterial blood pressure and may produce acute and chronic renal failure. Accelerated hypertension and acute renal failure have been observed in methamphetamine and MDMA abusers. Necrotizing vasculitis with microaneurysm formation and thrombosis mimicking polyarteritis nodosa has also been reported in patients who abuse amphetamine that contributes to ischemia and chronic renal insufficiency. Rhabdomyolysis and acute tubular necrosis often accompany MDMA abuse, especially in the presence of hyperthermia and hypovolemia induced by intense physical activity. Interestingly, many MDMA abusers recognize the risk of developing acute hypernatremia under these conditions and attempt to prevent this complication by ingesting large quantities of water, thereby inadvertently causing neurologically significant hyponatremia.

Marijuana Marijuana or hashish use is associated with increases in heart rate and cardiac output, reductions in systemic vascular resistance, and relative maintenance of arterial blood pressure. These hemodynamic effects occur in parallel to plasma concentrations of 69-tetrahydrocannabinol (the psychoactive drug in marijuana and hashish), are more pronounced following inhalation as compared to

other routes of administration, and may be accompanied by the occurrence of premature ventricular ectopy. The cardiovascular actions of marijuana are usually well-tolerated by healthy individuals, but may have important consequences for patients with heart disease. Marijuana-induced tachycardia enhances myocardial oxygen consumption, and elevated levels of carboxyhemoglobin resulting from smoking the drug also reduce myocardial oxygen supply. Thus, patients with coronary artery disease may be at risk of developing myocardial ischemia or infarction in association with marijuana abuse. In fact, the incidence of acute myocardial infarction was reported to be approximately 5-fold higher within the first hour after marijuana use as compared to other times.83 Disruption of myocardial oxygen supply–demand relations may also compromise cardiac performance in marijuana users with heart failure resulting from ischemic cardiomyopathy. Marijuana smoking is associated with several pulmonary complications that are similar to those produced by tobacco smoking. Chronic bronchitis and emphysema have been reported in marijuana smokers, and concomitant tobacco smoking further contributes to the development of these chronic pulmonary diseases. Marijuana smoking results in greater tar deposition and substantially higher concentrations of carboxyhemoglobin than tobacco smoking,84 effects that are partially related to deep, sustained inhalation and intense breath-holding performed to maximize drug delivery. Similar to the findings in tobacco smokers, pulmonary defenses against pathologic organisms are compromised by marijuana smoking as indicated by alveolar macrophage dysfunction, reduced cytokine formation, and diminished ability to combat oxidative stress. Chronic, heavy marijuana smoking may also precipitate the development of lung or oropharyngeal cancer. Marijuana is often contaminated with fungi (e.g., Aspergillus) or actinomycetes, and inhalation of these substances during smoking may cause infections or hypersensitivity reactions. Immunosuppressed marijuana users (such as those with advanced HIV infection) appear to be particularly susceptible to aspergillosis pneumonia.

Hallucinogens Phencyclidine and lysergic acid diethylamide (LSD) cause cardiovascular sym-

pathomimetic effects, and complications similar to those produced by cocaine and amphetamines are associated with abuse of these drugs. Thus, phencyclidine or LSD ingestion may be associated with myocardial ischemia and infarction resulting from increased myocardial oxygen consumption, coronary vasoconstriction or vasospasm, and prothrombotic effects. Severe hypertension, left ventricular hypertrophy, and malignant ventricular arrhythmias have also been observed in phencyclidine and LSD abusers. Notably, the mechanisms by which phencyclidine and LSD stimulate the sympathetic nervous system are at least partially distinct from than those responsible for the sympathomimetic actions of cocaine or amphetamines, and as a result, cardiovascular cross-tolerance between phencyclidine or LSD and these other stimulants may not occur. In addition to cardiovascular consequences, phencyclidine and LSD abuse also produce several important neurologic complications. Like ketamine, phencyclidine causes an acute dissociative state that bears striking similarity to schizophrenia. Thus, the phencyclidine abuser may present in a highly agitated state characterized by delusions, hallucination, and paranoia, or, conversely, may demonstrate frank catatonia. LSD also produces hallucinations that may compromise patient compliance with treatment. LSD users often report “flashbacks” (i.e., recurrence of hallucinations that are temporally remote to the original abuse event). Abuse of large quantities of phencyclidine, LSD, or other hallucinogens (e.g., mescaline) may produce seizures, myoclonus, and coma. Phencyclidine or LSD abuse is also associated with ischemic or hemorrhagic stroke concomitant with cerebral vasoconstriction or hypertensive crisis, respectively. A syndrome of pronounced hyperthermia accompanied by acute submassive liver necrosis that resembles the clinical presentation of malignant hyperthermia has been described in conjunction with phencyclidine use.85 Rhabdomyolysis and acute tubular necrosis has also been reported in phencyclidine abusers.

Inhalants Inhalants are volatile hydrocarbons (e.g., hexane, xylene, toluene) contained in a wide variety of common products including paints, solvents, and adhesives. Because they are readily commercially available, inhalants

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are frequently abused by teenagers. Inhalants may be directly sniffed or forcefully inhaled using an airtight container (termed “huffing”), producing rapid intoxication. Inhalant abuse is associated with several respiratory complications. In addition to respiratory depression resulting from sedation, inhalant abuse may contribute to the development of bronchospasm in the presence or absence of preexisting asthma, airway mucosal irritation, hemoptysis, hypersensitivity pneumonitis, aspiration, and barotrauma.86 Methemoglobinemia and the cyanosis that it precipitates may occur in association with abuse of amyl nitrate or related compounds (termed “poppers”). Asphyxiation resulting from respiratory depression or suffocation on a plastic bag used as a container for the inhalant has also been reported. Toluene inhalation may result in a white matter dementia characterized by extrapyramidal signs and symptoms, cerebellar ataxia, and oculomotor effects. Inhaled toluene also causes a nonanion gap metabolic acidosis and hypokalemia that occurs as a consequence of generation of hippuric acid, a product of toluene metabolism. Lead encephalopathy has also been described in individuals who inhale gasoline. A progressive sensory-motor polyneuropathy (“glue sniffer’s neuropathy”) may occur in conjunction with inhalation of hexane-containing adhesives.

ALCOHOL AND DRUG WITHDRAWAL Signs and symptoms of withdrawal are commonly encountered during the perioperative period in alcohol or drug abusers, and prophylaxis against withdrawal should be instituted before surgery in patients with a history of recent heavy use. Alcohol withdrawal is associated with substantial increases in postoperative morbidity and mortality.87 Alcohol withdrawal typically begins within 24 hours after the last drink and produces a wide spectrum of clinical consequences. Interestingly, the severity of withdrawal does not appear to be correlated with the total quantity of alcohol ingested or duration of alcohol consumption. Early alcohol withdrawal is characterized by constitutional complaints including headache, anxiety, nausea, vomiting,

diarrhea, and sleep disturbances (Table 23–3). These symptoms are frequently associated with physical signs, including fever, diaphoresis, tachycardia, hypertension, hyperreflexia, and tremor. Visual, auditory, or tactile hallucinations may also be present, but the patient may initially be able to recognize that these hallucinations do not reflect reality. In the vast majority of patients, alcohol withdrawal resolves spontaneously without advancing to seizures or delirium (also known as delirium tremens or DTs). As discussed previously, alcohol withdrawal seizures are usually single grand mal events, correlate closely with maximal increases in electroencephalographic activity, and occur in between 10% and 33% of alcohol abusers in the absence of prophylactic treatment with benzodiazepines.88 Alcohol withdrawal-induced status epilepticus occurs in less than 3% of patients who develop seizures.89 Notably, the incidence of alcohol withdrawal seizures increases in patients who have experienced multiple episodes of abuse and withdrawal. Delirium tremens usually occurs 3–4 days after the last drink and is characterized by exaggerated signs and symptoms of withdrawal concomitant with vivid hallucinations that cannot be discerned from reality, profound confusion, disorientation, and marked agitation. Alcohol withdrawal delirium usually resolves after 2–3 days, is more frequent in older patients, and continues to carry a mortality rate of approximately 1% because of delayed or inadequate treatment and the presence of coexisting diseases. Comprehensive descriptions of the pathophysiology and treatment of alcohol withdrawal are beyond the scope of this chapter. Briefly, alcohol abuse is hypothesized to chronically stimulate inhibitory GABA-mediated neurotransmission and attenuate autonomic nervous system sensitivity. In response, an upregulation of GABAergic and central and peripheral adrenergic receptors occurs. Thus, anxiety, tremor, hyperreflexia, and a reduction in seizure threshold occur alcohol withdrawal because GABA receptors are no longer stimulated and central nervous system excitatory neurotransmission is relatively unopposed. In addition, sudden abstinence from alcohol consumption causes rebound activation of the sympathetic nervous system, producing

TABLE 23–3. Common Signs and Symptoms of Alcohol or Drug Withdrawal General Fever Chills Headache Diaphoresis Myalgias Fatigue Piloerection (opioids) Cardiovascular Tachycardia Hypertension Gastrointestinal Nausea Anorexia Vomiting Diarrhea Ophthalmologic Lacrimation (opioids) Pupillary dilation (opioids) Otolaryngologic Rhinorrhea (opioids) Neurologic Anxiety, irritability, and agitation Mood disorders Depression (cocaine, amphetamines) Drug Craving Sleep disturbances Insomnia (alcohol, sedative– hypnotics, marijuana) Hypersomnolence (cocaine, amphetamines, hallucinogens) Hyperreflexia Tremor Disorientation (alcohol, sedative– hypnotics) Delusion (alcohol, sedative– hypnotics) Hallucination (alcohol, sedative– hypnotics) Seizure (alcohol, sedative– hypnotics) Delirium (alcohol, sedative– hypnotics) Coma and death (alcohol, sedative–hypnotics)

the characteristic findings of fever, diaphoresis, tachycardia, and hypertension observed during withdrawal. Benzodiazepines (e.g., lorazepam, chlordiazepoxide, oxazepam) are the primary drugs used to treat alcohol withdrawal because these agents activate GABA receptors and thereby en-


hance inhibitory neurotransmission. Beta1- (e.g, metoprolol) or _2-adrenoceptor (e.g., clonidine) agonists may also be used to control the clinical manifestations of increases in sympathetic nervous system tone. Frequent evaluation of the signs and symptoms of alcohol withdrawal using a previously validated instrument such as the revised Clinical Institute Withdrawal Assessment Scale for Alcohol should be used to guide pharmacologic management and supportive care. The clinical ramifications of sedative–hypnotic withdrawal are very similar to those observed during alcohol withdrawal, largely because the primary site of action of these drugs is also the GABA receptor. Abrupt discontinuation of benzodiazepines or barbiturates is characterized by fever, tachycardia, hypertension, gastrointestinal complaints (e.g., nausea, vomiting, diarrhea), and evidence of neurologic excitability (e.g., anxiety, agitation, tremor, hyperreflexia). More severe withdrawal from these drugs is associated with hallucinations, seizures, delirium, and death. The onset of the withdrawal syndrome is dependent upon the elimination half-life of the abused drug. The type, dose, potency, and duration of sedative–hypnotic use are the major factors that determine the severity of withdrawal. In contrast to the findings during alcohol withdrawal, the duration of sedative–hypnotic withdrawal may be very prolonged, often extending from several weeks to months. Barbiturates and benzodiazepines are frequently abused by patients who are addicted to alcohol or other drugs, and signs and symptoms of sedative–hypnotic withdrawal are exaggerated by simultaneous withdrawal from other substances of abuse. Other factors that contribute to the severity of sedative–hypnotic withdrawal include coexisting psychiatric conditions (particularly anxiety disorders and depression), family history of alcohol abuse, age, and female gender. The addition of an acute surgical stress response may also increase the severity of benzodiazepine or barbiturate withdrawal. As a result, continued use of the abused sedative–hypnotic or initiation of an equivalent dose of a crosstolerant alterative drug is recommended throughout the perioperative period so as to avoid withdrawal. Prompt recognition and appropriate treatment of opioid withdrawal are

important clinical objectives during the perioperative period in the opioid abuser. In contrast to alcohol or sedative–hypnotic withdrawal, mortality rarely occurs during opioid withdrawal unless significant comorbid medical conditions are present. Nevertheless, the signs and symptoms of withdrawal are so intensely uncomfortable that untreated opioid abusers will often leave the hospital against medical advice in order to seek and abuse illicit opioids. In fact, many opioid addicts report that continued drug use is at least partially motivated by a strong desire to avoid withdrawal symptoms, and not because of a specific euphoric effect per se. Acute opioid withdrawal is characterized by fever, anxiety, irritability, intense drug craving, altered thermoregulation, rhinorrhea, piloerection, pupillary dilation, and gastrointestinal complaints (e.g., nausea, vomiting, diarrhea). Hypertension and tachycardia also occur in response to activation of the sympathetic nervous system. The onset of acute opioid withdrawal is dependent on the elimination halflife of the abused drug. For example, signs and symptoms of opioid withdrawal usually occur within 6 hours after heroin abuse, but the onset of withdrawal may be delayed if the patient abuses methadone or a sustainedrelease opioid (e.g., oxycodone, morphine). Similarly, the pharmacokinetics of the abused opioid are also responsible for the total duration of the withdrawal syndrome. The duration of abuse, dose of drug, and route of administration (intravenous > inhaled) are the major determinants of the severity of opioid withdrawal. The pharmacologic management of opioid detoxification and withdrawal is complex, and several approaches have been proposed that are not reviewed in detail here. During the perioperative period, the easiest and most effective strategy for managing opioid withdrawal is methadone substitution therapy90 using a validated withdrawal evaluation tool to guide treatment. Briefly, an oral or intravenous loading dose of methadone is administered at the onset of withdrawal, and subsequent doses are titrated until symptoms are adequately controlled and a stable daily dose is established. This methadone dose may either be continued unchanged throughout the hospital course or gradually reduced as signs and symptoms of opioid with-

drawal improve. Notably, methadone substitution therapy for acute opioid withdrawal should not be confused with pain management. Perioperative opioid withdrawal may also be treated independent of substitution therapy using the combination of a benzodiazepine and an _2-adrenoceptor agonist administered on a scheduled basis to control anxiety and sympathetic nervous system activation, respectively. Regardless of the approach, consultation with an addictionologist is strongly recommended to guide perioperative therapy and establish plans for postoperative addiction treatment. Cocaine or amphetamine withdrawal is characterized by drug craving, depression, anhedonia, and hypersomnolence.91 These symptoms of abrupt discontinuation of stimulant abuse are usually self-limited but may initially be severe (known as a “crash”), usually may be treated with supportive care alone, and most often do not require pharmacologic intervention. Notably, the appearance of cocaine or amphetamine withdrawal symptoms (particularly hypersomnolence) during the perioperative period may be confused with a neurologic complication. Abrupt cessation of marijuana use is associated with anxiety, irritability, insomnia, and gastrointestinal complaints in a minority of patients. Treatment of these symptoms is primarily supportive, but antidepressant medications (e.g., trazodone) may benefit some patients. Specific phencyclidine or hallucinogen withdrawal syndromes also have not been described, but a minority of patients report constitutional complaints, including anxiety, fatigue, hypersomnolence, depression, and anhedonia. These acute symptoms and the delayed psychiatric sequelae (“flashbacks”) of phencyclidine or hallucinogen abuse most often respond to supportive care, but some patients with severe manifestations may benefit from a trial of benzodiazepines or specific serotonin reuptake inhibitor antidepressants.

GENERAL PRINCIPLES OF PERIOPERATIVE MANAGEMENT A detailed description of the perioperative management that is unique to each of the substances that might be abused by the active alcohol or drug

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abuser is beyond the scope of this chapter. Rather, the broad pharmacologic diversity of drugs of abuse combined with the wide range of complications that accompany substance abuse requires that the anesthesiologist have a firm understanding of ramifications of substance abuse, and apply this understanding to the specifics of each perioperative experience. As in the case of any patient affected by a chronic disease, the anesthetic approach to the patient with addiction varies depending on the type, location, and duration of the anticipated surgical procedure and the presence, severity, and relative stability of alcohol- or drugrelated comorbidities. However, several general principles should guide the perioperative care of the patient with active substance abuse (Table 23–4). Historical evidence of abstinence from alcohol and other drugs of abuse, confirmed by timely laboratory evidence to assure the validity of the historical information, is strongly recommended before a patient undergoes elective surgery because of the well-recognized increases in the rate and severity of perioperative complications and the potentially life-threatening consequences of unanticipated withdrawal perioperatively. Cessation of drug use before elective surgery also promotes stabilization of many abuse-related medical complications and may increase the probability that the patient will comply with postoperative instructions upon discharge (e.g., followup appointments, wound care, physical therapy). In some patients, abstinence before elective surgery may be facilitated by frank discussions with the anesthesiologist and surgeon regarding the consequences of continued abuse preoperatively. Other patients may require the assistance of an addiction medicine specialist in order to achieve abstinence before an elective procedure. Unfortunately, attaining preoperative abstinence may be an unrealistic goal for many alcohol or drug abusers, especially those who are undergoing urgent or emergent surgery. Under such circumstances, perioperative alcohol or drug withdrawal must be anticipated, and appropriate measures (e.g., drug prophylaxis guided by history and laboratory tests, anticipated admission to an intensive care unit) should be instituted well before the expected onset of withdrawal signs and symptoms. Vigilance about the poten-

TABLE 23–4. General Recommendations for Perioperative Management Preoperative Supportive, nonjudgmental but firm approach Obtain a urine drug screen and blood ethanol concentration Achieve abstinence and stability of medical comorbidity before elective surgery Anticipate and treat alcohol or drug withdrawal, especially in alcohol or drug abusers undergoing urgent or emergent surgery Consult an addiction medicine specialist Assure that anxiety and pain are appropriately treated Intraoperative Consider regional or local anesthesia or nerve blocks if possible Anticipate hyperalgesia, especially in opioid abusers Use general anesthesia or opioids as clinically indicated Postoperative Plan postoperative analgesia including alternative approaches before surgery Use continuous local anesthesia, nonopioid analgesics, or alternative pain approaches if possible, but do not avoid opioids if clinically indicated Use scheduled but not “as needed” administration of opioids Frequently assess behavioral and functional responses to pain therapy Integrate initiation for addiction into the discharge plan

tial for drug withdrawal is essential for all patients with a history of recent substance abuse, and the benefits of proactive intervention cannot be overemphasized. A straightforward, nonjudgmental approach to the patient by physicians and nursing personnel will often encourage the alcohol or drug abuser to cooperate with the treatment plan. Patients should be assured repeatedly that withdrawal symptoms, anxiety, and pain will be addressed appropriately. A clear plan for postoperative pain management should be discussed before surgery. Use of continuous local

anesthesia, nerve blocks, nonopioid analgesics, neuraxial techniques, or alternative analgesic modalities may be employed for postoperative pain management, but opioids administered on a scheduled basis should be used as clinically indicated. As discussed previously, it is critically important that pain be promptly and adequately treated so as to avoid the development of a “mutual mistrust” relationship between the alcohol or drug abuser and healthcare providers.16 The anesthesiologist and other clinicians must recognize that hyperalgesia is common in patients with substance abuse disorders, and all must be prepared to manage pain accordingly. A continuous evaluation of the adequacy of pain management, based on the behavioral and functional responses of the patient, should be conducted throughout the perioperative period. The active participation of an addiction medicine specialist throughout the entire hospital course is strongly advised because the addictionologist may contribute substantially to the evaluation and treatment of alcoholor drug-related coexisting diseases, provide guidance about the management of perioperative alcohol or drug withdrawal, and serve as an additional resource for pain management strategies. Perhaps most importantly, the addictionologist also facilitates the transition to addiction treatment during postoperative discharge planning. The anesthesiologist and surgeon should recognize that the perioperative experience provides a unique opportunity to intervene in cases of substance abuse, and to facilitate the initiation of a plan for treatment of patient’s addictive disease.

THE RECOVERING PATIENT Recovery is a complex process requiring intense, continuous personal effort that not only involves abstinence but also requires a series of changes to maintain sobriety (Table 23–5). Successful recovery requires acquisition of knowledge about substance abuse disorders, renewal of self-esteem and personal responsibility, development of sober living abilities and social interactions, identification with sources of inspiration, and a unified approach to guide these changes.92 The terms “cured,” “former,” “recovered,” and “ex-”


TABLE 23–5. Therapeutic Objectives in Addiction Management Affective Manage anxiety, depression, shame, and guilt Increase coping skills Increase emotional awareness of negative consequences of use Behavioral Eliminate drug use behaviors Expand healthy behaviors Cognitive Reduce denial Enhance personal awareness of addictive disease in self and others Increase recognition of negative consequences of use Physiological Treat withdrawal symptoms and medical consequences of alcohol or drug abuse Encourage healthy activities Reestablish personal responsibility for health Social Increase personal responsibility Increase honesty, reliability, and trustworthiness Establish sober social networks Increase social coping skills Spiritual Increase self-esteem and reduce self-loathing Reestablish personal values Increase appreciation of transcendence Adapted with permission from May JA, White HC, Leonard-White A, et al. The patient recovering from alcohol or drug addiction: special issue for the anesthesiologist. Anesth Analg 2001;92:1604, Table 1.

alcoholic or addict are inappropriate to describe the recovering patient. The incidence of relapse appears to be inversely related to the duration of recovery, but return to use has been observed in patients with decades of recovery. Abstinence alone does not constitute recovery because effective skills for coping with stress independent of drug ideation (e.g., craving) or use may not have been developed. Whether an abstinent individual has more difficulty coping with the perioperative experience than a patient in a well-established recovery program is unknown, however. Mutual-help orga-

nizations including Alcoholics Anonymous (AA) and other twelve-step programs, individual psychotherapy, behavioral modification, and pharmacologic therapy may all be effective in the management of addictive disease. The standard of care in addiction treatment in the United States is based on the Minnesota model,93 a multidisciplinary approach that includes involvement in a twelve-step program, individual and group psychotherapy, patient and family education, vocational rehabilitation, and spiritual renewal. Treatment within the Minnesota model relies primarily on the experience of other recovering patients. Alcoholics Anonymous and related groups are fellowships of recovering patients who help each other maintain sobriety. The twelve steps are the central tenet of the Alcoholics Anonymous program that serve as guidelines for recovery. Other components of recovery within Alcoholics Anonymous include regular meeting attendance and sponsorship that increase the probability of maintaining sobriety. Several medications are presently used in sobriety maintenance therapy that may have important implications for the anesthesiologist (Table 23–6). Strategies include alteration of a drug’s metabolic consequences (e.g., disulfiram in alcoholism), reduction of drug reward (e.g., acamprosate in alcoholism), receptor antagonism (e.g., naltrexone in opioid addiction), and drug substitution therapy (e.g., methadone in refractory opioid addiction). Several drugs have documented efficacy in the treatment of patients with alcohol or opioid addiction, but effective pharmacologic therapy for addiction to other drugs of abuse has yet to be demonstrated. A more frequent incidence of anxiety, psychotic, and affective disorders is also observed in recovering patients. Psychoactive drugs used to treat these concurrent disorders reduce the incidence of relapse by decreasing self-medication of psychiatric symptoms, and may also have anesthetic consequences that are reviewed elsewhere. Disulfiram is an alcohol-sensitizing drug that is still occasionally used in the treatment of alcoholism. Disulfiram inhibits aldehyde dehydrogenase, leading to acetaldehyde accumulation and a severe aversive reaction when alcohol is ingested. Disulfiram also irreversibly inhibits other sulfhydryl-

based enzyme systems responsible for drug metabolism. Inhibition of dopamine `-hydroxylase by disulfiram reduces presynaptic neuronal synthesis of norepinephrine and may produce an attenuated cardiovascular response to indirect-acting sympathomimetic amines. Disulfiram also reduces the clearance of diazepam, midazolam, and chlordiazepoxide, and interferes with the metabolism of barbiturates, tricyclic antidepressants, phenytoin, and warfarin by inhibiting hepatic microsomal enzymes. Calcium carbimide is another alcohol-sensitizing drug used clinically in Europe and Canada that reversibly inhibits alcohol dehydrogenase and may cause less-pronounced drug interactions. The + opioid receptor antagonists, naltrexone and nalmefene, reduce alcohol ideation and decrease the incidence of relapse in recovering alcoholics.94 Clinical experience with naltrexone and nalmefene has been less successful in opioid addiction, but may be used as “insurance” in abstinence-based recovery. Naltrexone and nalmefene increase the threshold dose of opioid required to produce euphoria. The recovering patient who continues to receive an opioid antagonist during the perioperative period will have an increased requirement for opioid analgesics. Conversely, the + receptor is upregulated during chronic opioid antagonist treatment, and withdrawal of naltrexone or nalmefene is associated with increased sensitivity to opioid agonists. Acamprosate is an amino acid derivative that substantially reduces ideation95 and improves treatment retention in recovering alcoholics. Acamprosate decreases neuronal hyperexcitability caused by chronic alcohol abuse by altering GABA- and glutamate-mediated neurotransmission. These actions reduce drug craving, a major cause of relapse in recovering alcohol abusers. To date, the anesthetic implications of acamprosate have not been described. Antiepileptics (e.g., carbamazepine, valproate, gabapentin) also attenuate alcohol- or opioid-mediated drug craving.96 Carbamazepine and other antiepileptics hasten recovery from intermediate- and long-acting nondepolarizing muscle relaxants by enhancing the clearance of these drugs, increasing plasma concentrations of _1-acid glycoprotein, and producing proliferation of postsynaptic acetylcholine receptors. Selective serotonin reuptake inhibitors appear to reduce

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TABLE 23–6. Pharmacological Therapy in Relapse Prevention Medication

Drug of Abuse

Pharmacology

Mechanism of Action

Anesthetic Implications

Disulfiram; calcium carbimide

Alcohol

Enzyme inhibition

Adverse side effects

Naltrexone; nalmefene

Alcohol

Modulation of drug reward Direct receptor antagonist Modulation of drug reward Modulation of drug reward

Decrease drug ideation

Altered response to sympathomimetics; alerted drug metabolism; discontinue disulfiram 10 days before surgery Altered response to opioid agonists; discontinue 3 days before surgery

Opioids

418 Acamprosate

Alcohol

SSRIs

Alcohol? Benzodiazepines? Barbiturates? Alcohol; opioids

Antiepileptics Methadone; LAAM; buprenorphine

Opioids

Reduce neuronal excitability Direct receptor agonist

Decrease euphoric threshold to opioids Decrease drug ideation Decrease drug ideation; decrease consumption in active users Decrease drug ideation Decrease drug ideation, positive reward, and withdrawal symptoms

Unknown Rare; may cause hypotension and bradycardia Prolonged duration of neuromuscular blockers Continue maintenance dose

Abbreviations: LAAM, levomethadyl acetate; SSRIs, selective serotonin reuptake inhibitors. Reproduced with permission from May JA, White HC, Leonard-White A, et al. The patient recovering from alcohol or drug addictions; special issue for the anesthesiologist. Anesth Analg 2001;92:1604, Table 3.

drinking in alcoholics with depression and may also prevent relapse in recovering patients with anxiety or affective disorders.97 Profound bradycardia and severe hypotension during anesthesia have been rarely reported in patients treated with these drugs. Methadone, the long-acting + agonist levo-_-acetyl-methadol (LAAM), and the partial agonist buprenorphine have been used effectively in the treatment of patients with opioid addiction as substitution pharmacotherapy in combination with behavioral interventions. Methadone, LAAM, and buprenorphine decrease withdrawal symptoms, inhibit drug ideation, and attenuate the positive reward associated with subsequent opioid use. Clearly, patients chronically treated with methadone, LAAM, or buprenorphine remain physically dependent on opioids despite attenuation of addictive behavior. Thus, verification of the dose of methadone, LAAM, or buprenorphine with the patient’s addiction specialist before surgery and unconditional administration of the drug throughout the perioperative period to prevent withdrawal are required. Patients receiving opioid substitution therapy may experience exaggerated pain responses to nociceptive stimuli because of drug tolerance.15 These patients often require

large quantities of additional opioids for the control of surgical pain, and may benefit from alterative pain control modalities. Substituting a new opioid for methadone, LAAM, or buprenorphine for maintenance therapy during the perioperative period is inappropriate. Increasing the dose or frequency of administration of these drugs to manage acute pain is also not recommended because the boundaries between treatment of addiction and pain may be obscured. Anesthesia and surgery may expose the recovering patient to several potential obstacles that increase the possibility of relapse. Numerous anecdotal descriptions of profound drug craving or frank relapse have been reported after brief perioperative exposure to sedatives or opioids in recovering patients with years of sobriety, but the precise incidence of such phenomena has not been defined. Anxiety about the perioperative experience may be heightened in the recovering patient because of concerns about the possibility for relapse and the fear that pain will not be adequately treated because of the history of addiction. Anxiety and pain have been identified as important precipitants of relapse, and inadequate treatment of pain precipitates drug ideation.98 Recovering

patients may also display abnormal behavioral responses to stress that increase the risk of relapse.99 Similar to the active alcohol or drug abuser, the recovering patient may encounter surgeons or anesthesiologists during the perioperative period who remain cynical about the sincerity or efficacy of the recovery process. Conversely, other apparently well-intentioned physicians may withhold or restrict pain medication from the recovering patient, fearing that a relapse will be inadvertently provoked. The recovering patient may be left inadequately treated, a situation that may be further complicated if justified requests for additional analgesics are misinterpreted as addictive behavior. The preoperative evaluation allows the anesthesiologist to obtain a detailed history of addiction and recovery and provides an opportunity to reduce anxiety about the operative experience. Many patients will openly disclose their addictive disease and recovery, but others may be reticent to acknowledge this history because they are apprehensive about the stigma that is still associated with the disease. Under these circumstances, the history of addiction and recovery may be elicited by tactfully asking direct questions in response to negative answers to routine


inquiries about alcohol or drug use. The history of alcohol or drug abuse, type and quality of and compliance with a recovery program, and participation in mutual-help groups are important components of the past medical history. Involvement of an addictionologist, rehabilitation counselor, or sponsor in the patient’s recovery should be noted, the duration and relative success of recovery explored, and the history of and apparent factors responsible for triggering relapse episodes identified. Encouraging the patient to intensify the practices of their recovery program has been recommended because the patient’s support system is a powerful defense against relapse during periods of stress.98 Much of the end-organ damage that occurs as a result of chronic substance abuse is reversible with long-term abstinence, but some permanent pathology that requires further evaluation or stabilization before surgery might remain. A urine drug screen may be indicated to exclude drug use and identify the need for further referral. Most recovering patients are aware that many drugs used for premedication have abuse potential and may refuse premedicants on these grounds. Patients familiar with biofeedback, guided imagery, or meditation may want to use these relaxation techniques instead of drug therapy. Euphoria-associated premedication before surgery may theoretically stimulate drug ideation, but use of anxiolytics to control anxiety may be more important because apprehension and exaggerated stress responses are common in the recovering patient. Twelve-step meetings and increased sponsor contact may also be useful anxiolytics for the recovering patient. Clear strategies for the conduct of anesthesia and the management of postoperative pain should be established with the recovering patient before surgery. Reassurance that the history of addiction will not be an obstacle to anesthetic technique and the adequate treatment of postoperative pain should be provided. The anesthesiologist’s broad expertise in pain management also deserves strong emphasis during preoperative discussion with the recovering patient. The anesthesiologist should also discuss evaluation of the recovering patient’s behavioral responses to pain management with the nursing staff before surgery. This dis-

cussion should emphasize that abnormal attitudes or conduct that signify drug ideation or loss of control over pain medications needs to be immediately identified and reported. However, unusual behavior specifically related to pain therapy may instead indicate the presence of pseudoaddiction, a phenomenon that refers to drug-seeking behavior related to inadequate analgesia. In contrast to true addiction, pseudoaddiction is characterized by extinction of aberrant behavior when adequate analgesia is achieved. Analgesics without abuse potential may initially be proposed for the relief of postoperative pain. These drugs may be used with or without continuous regional local anesthesia or selective nerve blocks in some recovering patients to provide adequate pain control and may also serve to reduce opioid analgesic requirements. Alternative pain modalities might also be considered. Importantly, the potential benefits of these methods must be weighed against the risk of inadequate analgesia, a significant factor in precipitating relapse. Opioids remain the most efficacious clinically available analgesics for treatment of surgical pain. Use of opioids should be guided by specific clinical indications. The selection of the specific type of opioid and the route of administration may be less important than the scheduling of administration. Mixed opioid agonist–antagonists theoretically offer a reduced risk of abuse than pure + agonists, but these drugs are not completely devoid of abuse potential and do not provide clear benefits over + agonists for postoperative analgesia. Neuraxial administration of opioids has been advocated because of theoretical reductions in the incidence of euphoria and the potential for associated drug craving, but this hypothesis has not been rigorously investigated. Scheduled administration of opioids or patient-controlled analgesia (administered by intravenous or epidural routes) may provide benefits over intermittent dosing in the recovering patient by simplifying the pain management plan for nursing staff, reducing delays in drug administration that contribute to inadequate analgesia, and eliminating patient requests for opioids that may be misinterpreted as addictive behavior. However, the use of patient-controlled analgesia in recovering patients is controversial be-

cause of the dynamics of self-administration. Prescription of opioids solely on an “as-needed” basis is not recommended in order to reduce associations between pain symptoms and the administration of a reinforcing drug that may increase overall pain perception and inappropriately justify greater drug use.

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PART 3 SAFETY AND RISK REDUCTION IN ANESTHESIA PRACTICE


PART 3: Safety and Risk Reduction in Anesthesia Practice

CHAPTER 24 Anesthesia Risk Fredrick K. Orkin, MD, MBA, MSc, and David E. Longnecker, MD, FRCA

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“What is the risk of anesthesia?” patients often wonder. Their concern really is multipart. First, how likely is something to go wrong? then, what “bad things” could happen? and finally, what can be done to reduce the risk to me and to others following me in the future? Anesthesia care providers try to allay patients’ concerns by noting that most anesthesia side effects are common and may be annoying, but fortunately they are transient. Serious, lifethreatening complications now are uncommon, if not rare. Whereas such comments may offer comfort, they do little to specify the magnitude and types of risks that a given individual faces, nor do they indicate that we know how to reduce the risks. Yet both have been active topics of ongoing research and efforts to improve anesthesia safety. What lends poignancy to an otherwise arcane consideration of anesthesia risk is the recognition that an anesthetic usually confers no therapeutic benefit to the patient but rather facilitates other therapeutic or diagnostic interventions. This facilitation results from one of the most widely heralded humanitarian achievements of modern medicine, yet anesthesia care is accompanied by an ever-present possibility of harm. The potential for harm is expressed quantitatively by a variety of risk metrics, most commonly as the incidence rate for an adverse event. These metrics allow investigators to estimate the contributions of various aspects of anesthesia care (e.g., anesthesia methods and drugs, clinical care sites, temporal periods) to overall anesthetic risk. These findings allow clinicians to formulate approaches to care that are built on knowledge gained from past experience and to benchmark the impact of changes in care using quantitative metrics.

Anesthesia risk has been a critical concern since the first demonstrations of clinical anesthesia 160 years ago, when anesthesia was particularly hazardous. Over decades, interest in identifying, characterizing, and decreasing anesthesia-related harm has increased. These efforts have included inquests, case reports, case series, study commissions, registries, cohort studies (some with multi-institutional and geographically diverse data), clin-

ical trials, clinical practice guidelines and standards, establishment of the multidisciplinary Anesthesia Patient Safety Foundation (emulated in Australia and elsewhere), and use of simulation for clinical training, among other initiatives (see Chaps. 3 and 25 for additional information). The intensity of these myriad efforts illustrates the specialty’s commitment to decreasing the occurrence of adverse events and thereby improving

KEY POINTS 1. Anesthesia risk estimates are wholly dependent on the circumstances in which they are generated; estimates developed in one clinical setting or selected population may not be relevant to other settings or specific patients. 2. The risk of death related primarily to anesthesia is estimated to be as low as approximately 1:200,000 anesthetics in large populations. 3. Such a very low anesthesia-attributable mortality rate reflects improvement of perhaps two orders of magnitude over more than 50 years. 4. Despite the very low anesthesiaattributable mortality rate, the very large and increasing number of anesthetics engenders a substantial burden of mortality and morbidity, much of which may be preventable. 5. Approximately 75% of risk actually relates directly to patient-specific characteristics, including age, gender, and comorbidity; 20% to surgical issues, such as experience and judgment; and the remaining 5% to anesthesia factors, including experience, board certification, pharmacologic issues, and overall management of care. 6. The overall anesthesia-attributable mortality rate is now so low that demonstrating further improvement is no longer logistically feasible. However, there are opportunities for meaningful advances in selected subpopulations of high-risk patients or high-risk procedures. 7. The very low anesthesia-attributable mortality should not be a cause for complacency but rather an impetus toward a wider emphasis on improving anesthesia-related morbidity in


selected populations and even broader outcomes of care. 8. Although randomized clinical trials have rightly become the “gold standard” for establishing efficacy in clinical research, randomized clinical trials have a limited role in studying anesthesia risk, particularly because they cannot conveniently, efficiently, and at reasonable cost unravel the confounding clinically relevant variables. 9. Whereas much of what has been learned about both anesthesia risk and studying risk comes from large prospective cohort studies of mortality, such studies cannot fully capture the multidimensionality of anesthesia risk and risk-related nuances that require adoption of a broader definition of anesthesia care and often the study of large observational datasets. 10. The study of observational data requires rigorous attention to methodology, lest bias enter to impair the risk estimates, and multivariable statistical modeling to deal with confounding among clinically relevant variables. 11. The American Society of Anesthesiologists physical status classification correlates with risk for mortality and morbidity, but it is somewhat subjective and, without embellishment with other clinical information, is not as strong a predictor of poor outcomes than other, morbidity-specific measures. 12. Well-conducted studies of observational clinical data reveal that anesthesia risk is influenced much more by how the anesthesiologist provides care rather than specifically what methods are used.

CHAPTER 24: Anesthesia Risk

anesthesia safety. An almost 100-fold decrease in estimates of anesthesiaattributable mortality among studies over the past 5 decades documents the specialty’s high level of professionalism and leadership toward ever-greater patient safety, which has been cited by the Institute of Medicine as a model for the rest of healthcare.1 The risk of death related primarily to anesthesia has been estimated to be as low as approximately 1:200,000 anesthetics in large populations.2 (This chapter emphasizes that such estimates vary greatly depending on circumstances of the given study, and that no rate can be considered representative of all clinical settings.) Yet the now very frequent administration of anesthesia—almost 48 million surgical procedures3 in the United States plus an uncertain number of diagnostic procedures undertaken with anesthesia—engenders several hundred anesthesia-associated deaths each year. Many more—perhaps 10–15 times as many—perioperative deaths occur in circumstances where perioperative anesthesia management, surgical care factors, and/or patient-specific characteristics jointly contribute to poor outcomes. Moreover, an even greater prevalence of anesthesia-associated morbidity poses a substantial burden of individual suffering and societal costs. Thus, despite substantial improvement in anesthesia safety, potentially preventable anesthesia-associated mortality and morbidity remain “of sufficient magnitude to constitute a public health problem,” as Beecher and Todd4 noted more than 50 years ago. The effort to decrease anesthesia risk has been a major focus of scholarly activity, resulting in more than 3000 English-language, MEDLINE bibliographic citations on “anesthesia risk” since 1966 and many more citations relating to the risk of specific morbidities. As might be expected, this literature can be unwieldy, confusing, sometimes contradictory, and often uneven in scientific quality, leaving the practitioner little guidance about what can be applied in practice or conveyed to patients with confidence. Rather than exploring those studies in detail, this chapter surveys the factors that must be considered when evaluating the literature on anesthesia risk. We review the definition of risk, the special problems in studying anesthesia risk, the relevant study designs,

and the salient findings from selected studies of mortality and morbidity that inform us about anesthesia risk analysis. We see how characteristics of the system of care, including the patient, the procedure, and the clinical setting, may influence outcomes, and where opportunities for further risk reduction may lie. The goal is to inform and educate the practitioner so that anesthesia practice can be guided by an understanding of the principles of anesthesia risk, without great reliance on equations and statistical formulas that are the basis of epidemiology and risk analysis. We see how our understanding of anesthesia-associated risk has developed historically and intuitively, from a single-minded focus on the risk of death associated with anesthetic administration to the multifaceted potential role of anesthesia in a continuum of care management that includes myriad healthcare factors that act collectively to influence patient outcomes, all with the goal of improving care.

WHAT IS ANESTHESIA RISK? A seemingly simple concept, risk often is misunderstood, perhaps in part because of inconsistent and imprecise usage of the terms “risk” and “risk factors.”5,6 The resultant confusion is not trivial, given the recent controversy regarding when the celebrated decrease in anesthesia risk may have occurred7,8 and even whether it actually occurred.9,10 Thus, it is appropriate first to define risk. Risk is a probabilistic term that expresses the likelihood of an outcome. Risk is a ubiquitous, natural part of life, because everything we do, including doing nothing, poses an uncertain outcome. In common usage, anesthesia risk connotes an undesirable or negative occurrence, such as death or injury. However, colloquially, in addition to referring to the chance of an outcome (e.g., risk of death during anesthesia), we occasionally use the term to refer to the outcome itself (e.g., death as one risk of anesthesia). A detailed analysis of the many possible anesthesia-associated adverse outcomes is beyond the scope of this chapter. Thus, this chapter focuses on developing an understanding of the probabilistic concept of risk, which may be applied either broadly or in

subspecialty areas. Risk is defined as the probability of an outcome within a population.5,6 This definition quantifies the occurrence of a specific outcome within a specified population that is exposed to a specific hazard (e.g., anesthesia, air travel, etc.) under specific conditions. For example, the population receiving general anesthesia might share “exposure” to a hazard (e.g., loss of protective airway reflexes) during the period of observation; however, only some among the population develop the adverse outcome (e.g., aspiration pneumonitis) that is associated with this hazard. (Note the distinction between hazard and risk: hazard is a characteristic of the system, whereas risk is a statistical probability; thus the terms cannot be used interchangeably.) Although the definition of risk is precise, differences in risk estimates among reports that purport to have studied the same outcome can vary widely to the casual observer. These differences usually result from differences in study design, not from differing definitions of risk. Careful reading of a report often reveals possible sources of the differences (Box 24–1). Although the bulk of the anesthesia risk literature relates to estimates of risk (including identification of risk factors), an important subset of our risk literature relates to the other, less

BOX 24–1. Common Sources of Differences in Anesthesia Risk Estimates Across Studies Characteristics of study population (e.g., age, gender, comorbidities, genomics) Magnitude or duration of the exposure Definition of the outcome Sensitivity and specificity of the diagnostic methods used to identify the outcome Surveillance interval following exposure Method of attributing outcome to anesthesia management Characteristics of the healthcare setting Sampling variation (especially with small sample size) Other factors that might affect the likelihood of the occurrence of the outcome

425


experience

BOX 24–2. Factors Associated with Decreased Tolerance for Risk

Surgery age

physical status

“major”? emergency Clinical outcome

Patient diseases

gender

technique

drugs

Anesthetic “human factors” FIGURE 24–1. Traditional model of the determinants of the patient’s clinical outcome after surgery and anesthesia care. (Modified from Orkin,158 Fig. 1.)

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common usage of risk: descriptions of specific adverse outcomes. Examples include case reports, case series (e.g., critical incident studies11), and registries such as the American Society of Anesthesiologists (ASA) Closed Claims Project.12 Because such reports do not include information on the “at-risk” or “exposed” population, incidence rates cannot be estimated and risk factors for the occurrence of the outcomes cannot be identified. Yet such reports are widely used to alert us to possible, but still unquantified, risks, and they have been especially useful in developing initiatives to improve safety (see Chaps. 3 and 25).

How Does Anesthesia Risk Differ from Anesthesia Safety? Risk and safety often are discussed colloquially as if they were closely related, yet they are not. Whereas risk is an objective, probabilistic term, safety connotes personal and/or social value judgment about the acceptability of a given level of risk.13,14 We generally regard as safe that which poses an acceptable level of risk, given that nothing is risk-free.14,15 The acceptability of a given risk level is a function of each individual’s risk tolerance, which, in turn, is influenced by factors characterizing the adverse outcome, exposure, and perceptions of the individual evaluating the risk (Box 24–2).13,16 The perceptions of risk, and the tolerance for risk, vary considerably among individuals and over time. Some might consider the risks of space flight as unacceptable, whereas astronauts and recent space tourists do not. Similarly, many Americans reassessed their risk tolerance for commercial aviation immediately after the events of September 11, 2001, with many preferring to drive even though commercial

air travel posed lower risk. Some even purchased firearms, although evidence indicates that the risks from firearm accidents are far greater than the chance of being killed by a terrorist.16 Not surprisingly, parents are generally much more concerned about the safety of anesthesia for their children than for themselves, even though the risk of injury is generally similar.

HOW IS ANESTHESIA RISK MEASURED? Models for Studying Anesthesia Risk The perspective taken in studying anesthesia risk may be narrow or broad— the latter approach has evolved more recently. Most investigators who published before the late 1980s probably were guided by the more restrictive model depicted in Fig. 24–1. In this approach, a population of patients is “exposed” to the dual “hazards” of anesthesia and surgery, and the model counts clinical outcomes (deaths, adverse events) that result from this experience. A revisionist model (Fig. 24–2), consistent with studies of anesthesia risk undertaken since the latter 1980s, recognizes that anesthesia care and surgery occur in a complex matrix of administrative, cultural, and clinical processes, all of which can add hazards to the system. The revisionist model also includes a far broader array of outcomes, well beyond those purely clinical (Box 24–3). Although most of the anesthesia risk literature focuses on clinical outcomes, such as death or morbidity, it also is important to explore the influence of anesthesia care on other outcomes, such as cost, patient performance (e.g.,

A. Features of the adverse outcome 1. Greater versus lesser severity 2. Permanence versus reversibility 3. High versus low frequency 4. “Dread disease,” especially social and economic implications 5. Immediate versus delayed onset 6. Occurrence in all people versus only in sensitive people 7. Relationship to intervention known with certainty versus not well established B. Characteristics of exposure (intervention) 1. Optional (e.g., cosmetic services, treatment for self-limited disease) versus essential (e.g., therapy for life-threatening disease) 2. Related to exposure versus its absence 3. Alternatives available versus only available intervention 4. Imposed versus voluntarily assumed 5. Misuse is likely versus unlikely C. Perceptions of evaluator regarding circumstances of exposure 1. New versus established 2. Synthetic or imposed versus natural 3. Greater uncertainty versus highly predictable result 4. Less knowledge of situation 5. Less personal control versus more control 6. Less trust in the circumstances versus greater trust 7. Relates to one’s child versus oneself versus a stranger Modified from Strom BL. Pharmacoepidemiology, ed 4. Copyright © 2005, John Wiley & Sons Ltd. Reproduced with permission; and Ropeik and Gray.16

quality of life), quality of service, and patient satisfaction. These assume greater importance now with the growing call throughout medicine for greater patient-centered care (see Chap. 3).

Quantifying Anesthesia Risk If exposure to a “hazard” increases the likelihood of an adverse outcome, then duration (or dose) of exposure should be a better predictor of development of the outcome than just occurrence of exposure. Indeed, this intuitive notion


communication

experience

The setting

BOX 24–3. Taxonomy of Outcomes

strength of medical staff

other sociomanagerial factors

resources

experience Surgery age

physical status

“major”? emergency

Outcomes

Patient diseases

gender

functional satisfaction

technique

drugs

clinical

economic

Anesthetic “human factors” FIGURE 24–2. Revisionist model of the determinants of the patient’s outcomes after surgery and anesthesia care. This model acknowledges that the outcomes are far broader than purely clinical and that the care setting also has diverse influences on the care and its results. (Modified from Orkin,158 Fig. 2.)

is the basis for the investigative approach in toxicologic and epidemiologic studies of health hazards. Time-related exposure risks (e.g., 1-year odds) of real-world health hazards have been tabulated.16 Runciman and Moller17 applied this notion to quantify the mortality risk of anesthesia and complex surgery in relation to a variety of realworld hazards (Box 24–4). Although the mortality rates they present for various hazards are only approximations, the relative risks are informative for both providers and patients: having anesthesia is as risky as being hospitalized, 20 times more hazardous than commercial flight, but 10 times safer than parachute jumping! Despite the intuitive appeal and potential empirical value, examples of anesthesia risk studies examining timerelated hazards are few. This may reflect both lack of interest in time-related hazards, as several well-conducted studies suggested that outcome differences among general anesthetics are minimal, if any,18,19 and historically the lack of equipment for detecting and recording time- and dose-related delivery of anesthetics (e.g., minimum alveolar concentration-hours of desflurane). Many studies note an association between greater duration of anesthesia (or surgery) and poorer outcome, but longer duration of anesthesia is not necessarily equivalent to a greater total anesthetic dose and probably reflects longer surgery, among other factors discussed when considering sources of risk. However, Monk et al.20 have reported that greater cumulative deep hyp-

notic time—estimated as the time when the bispectral index is 0.01 in their percentage form (e.g., the risk of perioperative death in relation to cardiac surgery is “3.0%” rather than “0.03”). For smaller

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TABLE 24–1.

BOX 24–4. Average Fatal Accident Incidence Rates (Deaths per 100 Million Hours of Exposure)

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Being pregnant Traveling by train Working at home Working in agriculture Testing positive for human immunodeficiency virus after receiving one unit of blood Being in traffic (overall, in any capacity) Working in the construction industry Flying in a commercial aircraft Being a patient in an Australian hospital Being anesthetized Parachute jumping Having elective abdominal aortic surgery Having emergent abdominal aortic surgery Modified from Runciman and ble 1.17.

Risk Metrics and the Epidemiologist’s 2 × 2 Table

1 5 8 10 10

Risk Metric Relative risk (RR)

Definition Proportion of original risk present with new intervention Proportion of outcome risk removed by intervention

50

Relative risk reduction (RRR) Absolute risk reduction (ARR) Number needed to treat (NNT) Odds ratio (OR)

Number of persons treated with intervention to save one

67 100

Exposure

2,000 2,000 20,000 200,000 2,000,000

Moller,17

Outcome Absent Present a b c d

Ta-

risk values, we often express the risk in either the scientific notation (e.g., 5 × 10–6 rather than 0.000005) or, more commonly, the ratio of 1 to the smallest number of individuals whose exposure to the hazard would result in one case (e.g., risk of death primarily related to anesthesia is “1 in 200,000” or “1: 200,000” rather than “0.000005”). Third, by definition, the calculated risk is the risk faced by the population under study, whereas we are often interested in the risk faced by a particular individual or perhaps a specific group of individuals who were not part of the study population and may have special characteristics that might place them at greater or lesser risk. Thus, risk estimates in the literature, especially some very low mortality rates widely touted in public media, may not relate well to the person(s) we are concerned about. Again, risk estimates are very much the products of the circumstances in which they are generated (Box 24–1). Fourth, this simple and common risk calculation is but one approach to expressing the magnitude of risk. The magnitude of risk can be expressed in alternative ways, some of which are

Present Absent

Proportion of persons spared outcome by intervention

Ratio of proportion of persons with outcome to those without outcome

Calculation a/(a + b) c/(c + d) c/(c + d) – a/(a + b) c/(c + d) c a – c+d a+b 1 ARR a/b c/d

Modified from Jaeschke R, Guyatt G, Barratt A, et al. Therapy and understanding the results: measures of association, In: Guyatt G, Rennie D, eds. Users' Guides to the Medical Literature: A Manual for Evidence-Based Clinical Practice. Chicago: AMA Press, 2002:351. Copyright 2002, American Medical Association. All rights reserved.

particularly useful in understanding clinical trial results and comparing treatment benefit or harm across studies (Table 24–1).21 Such risk metrics are easily computed from summary results presented in the literature (Box 24–5).22

Risk Values Are Estimates If 5 of a 10-patient cohort receiving a new antiemetic regimen experience postoperative vomiting, we conclude that the emesis rate is 0.5. To increase our confidence in the results, we study another

BOX 24–5. Calculating Risk Metrics Often, we can extract greater risk-related information from studies, particularly clinical trials, by calculating a set of risk metrics (Table 24–1).21 The first step is to express the study results in an epidemiologist’s “2 × 2 table” and then compute a set of risk metrics. The computations are simple but error-prone. An interactive, Internet-based calculator is available.22 Example 1: How effective is intensive insulin therapy in intensive care? Van den Berghe et al.23 reported that an intensive insulin regimen was associated with a 48% decrease (P = 0.005) in mortality among those receiving more than 5 days’ intensive care. Such a decrease certainly appears very meaningful, yet we recognize that a small P value is not a measure of clinical significance and is influenced by sample size. Creating a 2 × 2 table from their results (a = 22, b = 208, c = 49, d = 243), we can calculate the risk metrics, including a number needed to treat (NNT) of 13.6. Such a very low NNT value indicates that the intensive insulin regimen is a very potent intervention. Example 2: Reconciling perioperative, prophylactic atenolol recommendations. Mangano et al.24 recommended prophylactic, perioperative atenolol for all patients at risk for coronary artery disease, but more recently Lindenauer et al.25 have suggested that β-blocker use be reserved for patients at high risk because lowerrisk patients are harmed. Can we reconcile the two recommendations? One hypothesis is that Mangano et al. studied higher-risk patients. From a 2 × 2 table constructed from Mangano’s principal results (a = 9, b = 90, c = 12, d = 89), we calculate risk metrics, including an NNT of 36 and odds ratio of 0.74. These risk metrics approximate those for the highest-risk patients studied by Lindenauer et al., thus supporting our hypothesis.

cohort of 10 patients. Naïvely, we expect the same rate as the circumstances are unchanged. The second cohort’s rate is 0.6. Still seeking confirmation, we study a third and fourth cohort, whose rates are 0.2 and 0.5. Now we are confused! Our experience teaches us four important additional lessons about studying risk in small clinical studies. First, the clinical experience of each 10patient cohort is but a sample of the experiences of a universe of patients whom we rarely can study. The observed adverse-event rate in any sample is only an estimate of the true adverse-event rate in the much larger population. If the true emesis rate in the population receiving this anesthetic regimen is 0.5, we are likely to observe this rate in many cohorts, but we may not because of sampling variation. The second lesson is that the rates calculated from small samples can vary greatly. Thus, for our sample of 10 patients, there is a finite set of possible rates (i.e., 0, 0.1, 0.2, ... 0.9, 1.0). Related is our third lesson: with larger samples, the set of possible rates grows, with the values closer to each other (e.g., for a sample of 20 patients, the possible rates are 0, 0.05, 0.10, 0.15, etc.). The fourth and most informative lesson is that rates calculated for successive cohorts hover around the population’s rate and that one may compute a likely range (confidence interval [CI]) for the rates calculated for successive cohorts. As the cohort’s sample size increases, the CI for the rate narrows, enhancing the precision of the rate estimate (Fig. 24–3 and Box 24–6).26 Thus, other things being equal, we intuitively regard rates calculated from larger cohorts as more reliable than those from smaller studies, and the statistics support our intuition.

WHAT ARE THE CHALLENGES IN ESTIMATING ANESTHESIA RISK? Generic Challenges in Studying Anesthesia Risk Identifying the Outcomes of Interest Diagnostic Problems Diagnosing or identifying an adverse event is critical to the assessment of risk and is not a trivial problem. Identifying the occurrence of death might seem inordinately simple, but postanesthesia death may not be recognized if the defined surveillance interval is brief, such as the first

Confidence interval for risk estimate


10

Risk estimate 0.5 0.01 0.001

10-1 10-2 10-3 10-4 10-5 10

100

10,000 1000 Sample size

100,000 1,000,000

FIGURE 24–3. Span of 95% confidence interval (vertical bar) as a function of risk estimate (horizontal line in vertical bar) and sample size. Smaller risk estimates require sharply increasing sample size for precision.

48 hours postoperatively or during hospitalization only. This “ascertainment bias” results in underestimation of the true mortality rate. Even greater challenges are posed by specific adverse events, such as pulmo-

nary aspiration, pulmonary edema, myocardial ischemia, or myocardial infarction (MI), which often present in a graded fashion, from barely detectable to life-threatening. This raises the possibility that differences in the observed

BOX 24–6. Calculating Confidence Intervals When perusing medical literature, physicians hone in on P values, looking specifically for values “less than 0.05” that are commonly accepted to denote “statistical significance.” The latter is not the same as clinical significance, and a smaller P value does not indicate a stronger basis for clinical decision making. Indeed, the P value tells whether the study result could have happened by chance (not necessarily of great relevance to the clinician), and the size of the P value is itself sensitive to the study’s sample size (i.e., smaller P value for same “effect size” with larger sample size). Instead, recognizing that study results vary, the clinician is most interested in knowing the range in which the study result is likely to lie, were the study to be repeated. The 95% confidence interval (CI) is the range in which the result would lie in 95 of the next 100 repeat studies.26 A special situation arises when an outcome of interest (e.g., a complication) does not occur, in which case the rate obviously is 0. But we can have little confidence that the true rate is 0%. Clearly, the lower limit of the confidence interval is 0%, but what is the upper limit? Although we can resort to statistical software or tables, there is a handy “Rule of 3” for computing an estimate of the upper limit of the 95% CI: the quotient of 3 divided by the sample size in which no event was observed.27 (Similarly, there is a “Rule of 5” for estimating the upper limit of the 99% CI.) Example 1: Among 9152 gastroenterologic endoscopies in an ambulatory surgery center where nurses administered propofol sedation, using an anesthesiologist-furnished protocol, there were 7 (0.08%) cases of “respiratory compromise” (3 prolonged apnea, 3 laryngospasm, 1 aspiration requiring hospitalization).28 What is the likely variation about this rate? Using statistical software, we compute the 95% CI to be 0.03–0.16%, suggesting that these important complications are likely to continue to be rare. Example 2: A clinical trial of gastroenterologist-administered sedation for advanced upper endoscopy compared propofol in 38 patients to meperidine/midazolam in 37 patients.29 Apart from brief, transient respiratory depression monitored by capnography, no major complications occurred. How confident can we be about the risk of major complications? Using the Rule of 3, we compute the upper limit of the 95% CI as approximately 8% (statistical software: 9.5% and 9.3%, respectively). Thus, with the risk of a severe complication as high as 1:11, this small trial does not instill a sense of safety.

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risk (incidence rate) of these and other outcomes might be influenced greatly by the prevalent diagnostic methods or definitions. For example, the observed rate of myocardial ischemia is greater if the diagnosis is made by continuous Holter monitoring than by clinical symptoms such as angina. Such imprecision constitutes an important source of systematic error (ascertainment bias, information bias) that can lead to failure to recognize outcome occurrences (misclassification bias) and inaccurate risk estimates. Diagnostic challenges often are compounded by problems with the definitions and classifications that are inherent in clinical information systems and administrative databases. Institutional clinical information systems may use nonstandard definitions for data elements, such as adverse events, diagnoses, surgical procedures, and thresholds for abnormalities among laboratory values. Administrative databases, which classify the diagnoses, complications, and surgical procedures relating to care in a standard procedure coding system, typically have few anesthesia-specific categories [e.g., “E” codes in the International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) system], and some can be quite arcane (e.g., ICD-9-CM code 968.3: poisoning by intravenous anesthetics). Surrogate End Points Even if the outcome of interest (e.g., death, specific adverse event) can be identified accurately, it may occur so infrequently that the proposed study may not be feasible. ( We consider the statistical basis later.) Not unexpectedly, investigators have opted for alternative end points that are surrogates or intermediate variables—symptoms, signs, clinical events, laboratory values, and even process variables—which occur more often than the outcome and are believed to be linked to that outcome. Thus, blood pressure is used as an end point in clinical trials because high blood pressure is a known risk factor for stroke and MI; similarly, myocardial ischemia is commonly used as a surrogate for MI. Such approaches are appropriate only if the surrogate end point truly predicts the occurrence of the outcome. However, this requirement is often not met, possibly because the outcome may occur via some pathway(s) not mediated by the surro-

gate.30 Among recent examples is ventricular ectopy as the surrogate end point in the evaluation of drugs to prevent sudden death. Food and Drug Administration approval of a new class of antiarrhythmic drugs followed clinical trials demonstrating their efficacy in treating ventricular ectopy, but a subsequent trial revealed a greater risk for sudden death among those receiving the new drugs, and the drugs were withdrawn.31 Problematic surrogate end points in anesthesia have included the interval to eye opening after general anesthesia, which does not correlate well with earlier discharge after ambulatory surgery, lower rate of unplanned hospital admission after ambulatory surgery, greater patient satisfaction, and overall lower cost of care.32 Broadened Array of Outcomes The end points of interest have expanded from “clinical outcome,” such as mortality or specific adverse events or complications,18,33–35 to a broader and more comprehensive set of “outcomes” that reflect many facets of the care process, including the results of the care particularly from the patient’s perspective, or administrative end points such as the cost of services (Box 24–3). Studies of anesthesia risk already include some nonclinical outcomes, such as unplanned hospital admission after ambulatory surgery36,37 and poorer quality of immediate postoperative recovery.38 Undoubtedly, more studies will include measures of what has been termed “health-related quality of life,”39,40 increasingly termed “patientreported outcome measures.”41 As the terminology suggests, the patient is the direct source of the information. These measures take the form of a large number of generic health scales (e.g., Medical Outcome Study’s SF-36 Health Survey42) and disease- and condition-specific specific scales (e.g., Visual Analog Scale for Pain,43 McGill Pain Questionnaire44). Such instruments have been validated in large populations, typically with chronic disease, for use in longitudinal and cross-sectional studies,45 and are beginning to be used in settings such as chronic pain clinics. Apart from their possible use as outcome measures, patient-reported measures may also be used as patient descriptors (e.g., quantitating severity of a symptom or disability).

Patient-Specific Descriptive Data Risks are not distributed randomly. Some individuals are more likely to experience health problems as a result of diverse factors, including genetics, coexisting disease, personal health behaviors (e.g., smoking, diet, exercise), socioeconomic status, and environmental setting. Thus, estimating anesthesia risk requires accurate information to characterize each patient, including nonclinical information. Such information enables categorizing patients by likelihood of poor outcome (risk stratification) and “risk adjusting” their data for outcome comparisons.46 The ASA physical status classification originally was advanced to standardize terminology and group patients in six categories for review of clinical outcome.47 Subsequently, it was reformatted to five categories by Dripps et al.48 and adopted by the ASA.49 Only later was it found to correlate with clinical outcomes.18,33–36 In addition, the Charlson Comorbidity Score,50 a disease-specific classification system, is increasingly used in anesthesia risk studies. (We consider these metrics in detail when exploring the patient’s role in risk.) With growing interest in healthcare disparities, noting the patient’s race and ethnicity accurately will be important. Although multiple formats are available for recording such information, the prevailing guidance is that the patient’s self-designated race and ethnicity be noted, using categories from the US Census Bureau (White; Black or African American; Hispanic or Latino; Asian or Pacific Islander; or American Indian or Alaskan Native).51

Duration of the Surveillance Interval Intuitively, we know that the longer we watch for problems, the more likely we are to capture all such occurrences. Too short a surveillance interval risks missing some occurrences and, thus, can lead to systematically underestimating risk (ascertainment bias). Yet, as the time between the “exposure” (e.g., administration of anesthesia) and event increases, the greater the chance that the occurrence may be associated with circumstances partially or totally independent of the exposure. These other circumstances might include even chance patientspecific factors (e.g., MI that might have occurred 2 weeks preoperatively


while walking the dog). This dualism of comprehensiveness versus precision plagues most cohort studies in the anesthesia risk literature. Variation in length of the surveillance interval is especially apparent in the early studies of anesthetic-associated mortality. Bodlander,52 Harrison,53 Tiret et al.,54 and Dornette and Orth55 considered a death eligible for further evaluation as possibly “anesthesiarelated” only if it occurred during or within 24 hours of administration of the anesthetic or after failure of the patient to regain consciousness after anesthesia. Turnbull, et al.56 Hovi-Viander,57 Lunn and Mushin,58 Marx et al.,59 Cohen et al.,19 Dripps et al.,48 Monk et al.,20 and Mangano et al.24 extended the surveillance interval progressively to 48 hours, 3 days, 6 days, 7 days, 30 days, 1 year, and 2 years, respectively. Beecher and Todd4 adopted an empirical approach, using the duration of the surgical hospitalization. Extending the surveillance interval captures the delayed deaths from complications that may have their origin with anesthetic care, such as MI, which historically has occurred most commonly several days postoperatively, or pulmonary aspiration with subsequent pneumonia and terminal respiratory failure days or weeks after our care, and thus would escape our recognition if the surveillance interval were short. Even the approach of Beecher and Todd4 using the duration of the surgical hospitalization can be problematic if the patient dies shortly after an early discharge. Of note, Warner et al.60 found that 39% of major morbidity occurred more than 2 days but within 30 days after ambulatory surgery among 45,090 adults, including 2 of 5 cases of respiratory failure, 5 of 14 cases of MI, and 3 of 5 cases of pulmonary embolism. Their study population was not sufficiently large to differentiate observed adverse-event rates from those estimated in the catchment population; however, it is clear that substantial numbers of events would have been missed had the surveillance interval been limited to the immediate postoperative period. Although there are no formal guidelines on duration of the surveillance interval, a 6-week period had been used in the National Halothane Study,61 30 days has been adopted by the Veterans Affairs (VA) National Surgical Quality Improvement Project

(NSQIP) database,62 and 30 days is commonly used with Medicare data. At least for most procedures, this interval represents a reasonable compromise between too short an interval (which overlooks adverse events that may be temporally related to surgical and anesthesia care), and too long an interval (which introduces significant logistic problems for followup and perhaps captures adverse events unrelated to the hazards of surgery and anesthesia). Although one might naïvely expect that the derived mortality rates would increase uniformly with the surveillance interval, such a facile relationship often does not exist, presumably because multiple technical differences among studies (Box 24–1).

Assessing the Relationship with Anesthesia Care Problem of Attribution The late Emanuel Papper, an esteemed, mid20th century leader of American anesthesiology, fondly recounted that, as chair of a preeminent department, he was often asked to personally administer anesthesia to notables. One such morning, as he was about to induce anesthesia, he was interrupted by a colleague summoning him to an urgent phone call in his office. Apologizing to the patient and others eager to get underway, Dr. Papper excused himself, and, when he returned 15 minutes later, cardiopulmonary resuscitation was underway! Attributing causation is inherently problematic. Most cohort studies of anesthesia-associated mortality have included a panel of blinded case reviewers who were asked to attribute the death to one of several possible causes. Was anesthesia care the primary cause of death? Or was anesthesia management a contributory cause (along with patient- and surgery-related factors) to the death? Or was the poor outcome unrelated to anesthesia care? Panels were often composed mostly or wholly of anesthesiologists. However, recognizing the complexity of the care process and the multifactorial etiology of many adverse events, some study panels have been more balanced. The review committee used by Holland63 had six anesthesiologists, three surgeons, an obstetrician, a general practitioner, and a medical administrator. Holland assigned cases to one of four categories: wholly related to anesthesia or anesthetic management; probably re-

lated to anesthesia or anesthetic management; related to both anesthesia and surgery; or entirely due to surgery. Lunn and Devlin2 sent a questionnaire to the patient’s anesthesiologist and surgeon; the forms were reviewed by blinded assessors who adjudicated differences of opinion and obtained further information if needed to make assignments of attribution. Unmasking Biases Even without close proximity to care, the mere occurrence of a poor outcome that may be related to anesthesia management can bias our judgments regarding quality and appropriateness of care.64 As Keats65 noted more than 25 years ago, an underlying assumption in much of the anesthesia risk literature has been the belief that a poor outcome is presumptive evidence of error on the part of anesthesia providers. He emphasized that high interrater reliability in peer review does not assure that judgments are accurate. Review panel determinations are necessarily products of their collective current knowledge of practice at the particular time, as well as numerous other biases that result from inadequate study designs, limited statistical capabilities, and the complexity of phenomena being studied. Despite these limitations and the resulting widely ranging risk estimates, many important insights about risk, and the study of risk, evolved from this literature.

Characterizing the Population Our discussion thus far has focused largely on patients experiencing an outcome of interest ( becoming “cases”) after exposure to a “hazard.” However, if we do not give due consideration to the larger “at-risk” population from which these cases emerge, we have only a set of cases and cannot quantify the risk. Fortunately, the intellectual basis for estimating anesthesia risk developed in tandem with the early development of anesthesiology. Pioneers in establishing what would become the field of epidemiology recognized the importance of relating the cases to the larger population to estimate risk and compare estimates across different populations (Box 24–7).66 Ecology of Care Later investigators extended the interest in characterizing the at-risk population by noting that a large population is not homogeneous with regard to health status or the

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BOX 24–7. Epidemiologic Pioneers in Developing Mortality Rates

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Victorian England had become infatuated with the potential use of statistics to help solve diverse societal problems by the 1830s. Three individuals emerged—in close proximity to each other and to the embryonic field of anesthesiology—to provide what would become foundations of epidemiology.66 Shortly before the demonstration of clinical anesthesia, William Farr began collecting what we now term vital statistics (e.g., births, deaths) and undertook Britain’s first census. He classified people according to age and occupation groups, and diseases according to crude etiologies. Farr’s early example of health data collection and classification undoubtedly aided pioneer anesthesiologist John Snow (who administered chloroform obstetrical anesthesia to Queen Victoria) in his parallel interest in fighting the British cholera epidemics of 1849 and 1853. He classified cholera cases by London district, juxtaposed the populations of those districts, and calculated cholera death rates as the quotient of the cases and “exposed” populations. The resultant district-specific death rates enabled identification of “high-risk” districts. He then focused on water supply to those districts, particularly in relation to locations of cholera cases. When he noted the association of the highest mortality on Broad Street with service by the water company with especially high rates, he famously curtailed the epidemic by removing the handle of the Broad Street water pump, as well as proved his hypothesis that a water-borne agent was responsible for cholera transmission. At the same time, Florence Nightingale, another Farr collaborator, was nursing the wounded during the Crimean War. She used similar data collection to develop mortality rate estimates, coupled with innovative analyses and graphics, to lobby successfully for British Army healthcare reform by showing that mortality rates relating to infectious disease, poor nutrition, and unsanitary conditions were greater for English solders than for civilians.

need for healthcare services. In describing “the ecology of healthcare,” they noted a hierarchy in which the need for health services and, by implication, poorer health status or greater patient acuity, increases sequentially in the spectrum from the unselected general population to outpatient care settings to community hospital settings, and finally to the academic medical center (Fig. 24–4A).67 Surgical care is delivered in a similar spatial distribution (Fig. 24–4B). Thus, risk estimates derived in one setting may differ from those in another environment (Berkson fallacy).68 Recognizing these relationships can help reconcile seemingly disparate risk estimates from studies undertaken in widely differing clinical settings.

Statistical Problems in Studying Anesthesia Risk Dealing with Low-Incidence Phenomena Although some anesthesia-related events may occur frequently (e.g., postoperative nausea), most severe adverse events do not. The incidence rates may be so low that estimating

rates of occurrence with acceptable precision (i.e., narrow CI) or demonstrating meaningful differences in occurrence (e.g., comparisons of drug regimens or sites of care) can be problematic (Fig. 24–5 and Box 24–8). The most obvious remedy is merely using a larger sample size. Yet, even when feasible, a larger sample usually connotes a longer patient accrual period, during which other countervailing circumstances may arise (e.g., deterioration in quality of data collection because of study team turnover or loss of enthusiasm, emergence of better technology that obviates study, information that alters or invalidates earlier results, changes in concurrent care processes that affect the event being studied). Other options include using a more sensitive end point, repeated measurements, matched cases and controls, multiple controls, lower statistical certainty (‘power’), a higher-risk population, or concurrent multicenter trials. Multiinstitutional studies, such as the 10-hospital Beecher-Todd study,4 34-hospital National Halothane Study,61 or the 460-hospital study by Tiret et al.54 in France, offer the added benefit of enhancing the external va-

lidity (applicability to other settings, termed “generalizability” in epidemiology) of the results, particularly if the cooperating institutions have different patient populations, surgical mixes, and/or administrative characteristics. Yet multiinstitutional designs may introduce additional logistical and managerial challenges, to assure that the study is conducted the same way in each setting, and a sufficiently large sample size may be too costly. Alternatively, investigators may opt to study the occurrence of a surrogate end point (e.g., myocardial ischemia) that is associated with the outcome of interest (e.g., MI) but occurs more frequently. As noted earlier, the linkage between the surrogate and outcome may not be sufficiently tight for reliable, meaningful, or even valid results.30,32 One especially productive approach involves consortia that jointly collect large amounts of data prospectively for purposes other than a single study. Mangano’s Multicenter Study of Perioperative Ischemia Group comprises more than five dozen hospitals throughout the developed world, each contributing the same data elements to a growing database on patients having cardiac and noncardiac surgery. For more than 15 years, this group has studied important perioperative risk topics, including the long-term risk of cardiovascular events,70 atrial fibrillation after cardiac surgery,71 mortality reduction with prophylactic use of βadrenergic blocking agents,24 aspirinrelated mortality from cardiac surgery,72 and risks related to use of aprotinin in cardiac surgery.73 Similarly, in the early 1990s, the dozen US Department of Veterans Affairs hospitals that performed cardiac surgery joined to create a common database,74 which became the model for an expanded project covering all major surgery in more than 120 VA hospitals, the VA NSQIP.75 This database has contributed greatly to risk assessment and acquisition of clinical data for measuring outcomes and quality of care62,75,76 and has been adopted by the American College of Surgeons for national use. Anesthesia-specific data elements are few and limited (e.g., principal anesthesia method); however, the VA NSQIP database includes prospectively defined comorbidities and postoperative complications for thousands of patients having each surgical procedure and is begin-


1000 Persons

800 Reported symptoms 327 Consider seeking medical care 217 Visit a physician’s office (113 visit a primary care physician’s office) 65 Visit a complementary or alternative medical care provider 21 Visit a hospital outpatient clinic 14 Receive home health care 13 Visit an emergency department 8 Are hospitalized 10° and lithotomy position. Because lithotomy position is frequently combined with head-down tilt for improved surgical access, the cardiopulmonary status of the patient must be taken into consideration to minimize cardiac decompensation. The mean arterial pressure (MAP) at a measurement site varies by 2 mm Hg with each vertical inch above or below the atrium. Enderby9 clearly demonstrated the variations in MAP with positional changes (Fig. 26–8). This is particularly important in older patients (with peripheral vascular disease, diabetes, and hypertension) when compressive stockings are used and the patient is situated in lithotomy position for a prolonged period. Inadequate perfusion pressure to the lower extremities in such a situation can lead to ischemic complications of the skin and muscles, resulting in skin necrosis and myoglobinuria. Under general anesthesia, with the assumption of the lithotomy position the tidal volume decreases by 3%. With a 10° head-down tilt, tidal volume decreases another 14%.10 Although conscious patients usually can compensate and tolerate this change in tidal volume because of improved resting position of the diaphragm, anesthetized patients breathing spontaneously may develop basilar atelectasis and hypoxia. Patients with obesity, hiatal hernia, and gastroesophageal reflux disease may have decreased lower esophageal sphincter tone and barrier pressure, increasing the risk for regurgitation and aspiration of gastric contents in the lithotomy position. Compartment syndromes have been associated with use of the lithotomy position lasting >5 hours.11 Anatomic compartments are relatively rigid osseofascial partitions in the extremities comprised of muscles, nerves, blood vessels, and connective and ad-

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FIGURE 26–6. Exaggerated lithotomy position. (Redrawn from Martin and Warner7 with permission.)

ipose tissues. A certain amount of perfusion pressure, 9–15 mm Hg in the lower extremity,12 is required for normal perfusion of tissues in these compartments. If the pressure in the compartment rises as a result of external forces (dependent pressure, casts, stockings, tight dressings) or internally by edema/bleeding, the vascular driving pressure (MAP) must increase concurrently to prevent ischemic complications. Inadequate tissue perfusion and ischemia of the contents of these compartments lead to varying degrees of injury (endothelial injury, tissue necrosis, and myoglobinuria) that potentially could result in death. Because pain is the most specific symptom for diagnosis of compartment syndromes, a high index of suspicion should be maintained for patients at risk while receiving regional analgesia. The respiratory complications of the lithotomy position are similar to those of the supine position. The lithotomy position can be an additional factor when diaphragmatic excursion is restricted as a result of excessively flexed thighs or a steep head-down tilt. The duration of the use of the lithotomy position and the body mass index of the patient are reliable predictors for complications pertaining to nerve injuries, respiratory problems, and the compartment syndromes.11

Sitting Position FIGURE 26–7. Tilted lithotomy position. (Redrawn from Martin and Warner7 with permission.)

An operative surgical site is intentionally elevated above the level of the heart

FIGURE 26–8. Effects of gravity on perfusion pressure in the lower extremities in the lithotomy position. MAP, mean arterial pressure. (Redrawn from Martin11 with permission.)

CHAPTER 26: Positioning of Patients for Operation

to decrease bleeding in the operative field and to provide better surgical conditions. Although popular in the 1980s and early 1990s for posterior fossa neurosurgical procedures, sitting position now is commonly used for surgical procedures on the shoulder. Advantages of the sitting position to the anesthesiologist include easier ventilation because of unimpeded diaphragmatic excursion, easier access to the endotracheal tube and airway, unimpeded access to the chest wall for resuscitative measures, and unobstructed view of the face for monitoring cranial nerve function. Disadvantages include the need for a coordinated effort from the operating team (nursing, surgical, and anesthesia) to establish this position safely, hypotension and venous air embolism (VAE), consequences of excessive neck flexion (kinking of endotracheal tube and swelling of face and tongue), nerve injuries, pneumocephalus, and blindness.

Pathophysiology of the Sitting Position Gravity and anesthetic agents have significant effects on cardiovascular function in the sitting position. In a healthy adult patient, stroke volume and cardiac output are decreased by approximately 12–20%, and cerebral perfusion pressure reduces by 15% without much change in HR.13 There is an overall increase in ventilation with increased VC and FRC. However, with positive-pressure ventilation and relative hypovolemia there is reduced perfusion in the nondependent lung fields leading to an increase in physiologic dead space. During neurosurgical procedures, loss of cerebrospinal fluid (CSF) occurs upon opening of the arachnoid membrane. The loss of CSF allows air to enter the intracranial CSF pathway, leading to pneumocephalus and downward displacement of the brain. Although this gravitation of the brain may be tolerated in most patients, those with thin cerebral mantles may suffer from subdural hematoma.6 While positioning the patient, care should be exercised with the following basic principles: maintaining normal body alignment, protecting and padding all pressure points, avoiding placement of rigid oropharyngeal airways and excessive flexion of the neck, exercising care with extremities so that their limits of passive range of motion are not exceeded, establishing

final position slowly to allow time for hemodynamic compensation, and exercising extreme caution with the horseshoe frame if used for support of the head (Fig. 26–9). Complications The frequent and most common complications are related to the hemodynamic and ventilatory effects as described in the section on Lithotomy. Neurologic complications pertaining to neuropathies and blindness are detailed at the end of this chapter. Venous air embolism The incidence of VAE in posterior fossa surgery in the sitting position is reported to be 41– 45% with routine monitoring.14 However, with the use of Doppler ultrasound the reported incidence is as high as 42–85%.15 VAE often is clinically undetected and frequently not of serious concern in a healthy patient if the volume and rate of air entrainment are minimal. The amount of entrained air that is reported to be lethal in humans is approximately 300 mL.16 Children generally have greater clinically significant hemodynamic derangement from VAE than do adults. Significant morbidity and mortality from VAE is now 60°) of the head and neck can have significant deleterious effects on the flow patterns in cerebral circulation. Complete obstruction of the contralateral vertebral blood flow with rotation of the head >80° in humans has been reported.25 Care must be exercised during rotation of the head because patients can have significant asymptomatic occlusive cerebral vascular disease and/or congenital variations in cerebral vascular anatomy (circle of Willis). Exaggerated rotational movements in such situations can compromise blood flow in the region of the vertebrobasilar systems, leading to neurologic dysfunction. Other complications related to prone postioning include injury to the eyes, ocular edema and blindness, compressive ischemic injuries to facial structures, compartment syndrome, VAE, breast and genital injuries, thoracic outlet syndrome, neuropathies, ostomy injuries, and hypothermia.

Lateral Decubitus Position Lateral decubitus positions are described as right or left, depending on

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the side of the body on which the patient lies. For example, patients are said to be positioned in right lateral decubitus position when they lie with their right side down. In the classic lateral decubitus position, the patient is positioned on the side with his/her back perpendicular to the surface of the table. The head is supported such that the cervical spine is properly aligned with the rest of the body, and a supportive device (axillary roll or chest pad) is placed under the dependent thorax just caudad to the axilla to prevent compression and injury to the axillary neurovascular bundle. The dependent lower extremity is flexed at the hip and knee joints, and the nondependent leg is straightened in such a manner that the pelvis is stabilized and ventral tilt (forward roll) of the torso is avoided. Adequate padding is ensured to protect all the pressure points (pillow between the legs, foam for the dependent greater trochanter, fibular head and lateral malleolus) of the lower extremities. The dependent arm is flexed and supported on a padded arm board while the nondependent arm is slightly abducted and flexed at the shoulder and elbow joints such that the scapula is drawn away from the thorax (Fig. 26–12). Once the patient is positioned optimally, care should be exercised to avoid injuries related to restraint devices (bean bag, hook and loop straps). The “kidney position” is a variation of the lateral decubitus position that is commonly used for renal procedures. In this version of the lateral decubitus position, the patient’s dependent ilium is placed over the flexion point between the torso and thigh sections of the table. The table is then flexed, and the transverse elevating bar of the table (kidney bar) is raised until the lateral flexion has caused the muscles of the upper flank to become tight. During and immediately after the final position, all measures must be taken

to avoid inferior vena caval and dependent rib cage compression.

Pathophysiology of the Lateral Decubitus Position For the most part, the lateral decubitus position has minimal effects on major organ function when the patient is carefully positioned. Sudden postural changes are poorly tolerated by deeply anesthetized and hypovolemic patients because of dosedependent depression of carotid and baroreceptor function under general anesthesia. Gentle changes in position with frequent monitoring of blood pressure is indicated in elderly, hypovolemic, and hypertensive patients. Mediastinal shift to the dependent hemithorax and rotation of the heart on its longitudinal axis in the lateral position could impair venous return and decrease cardiac output. Impediment of venous return usually is not a problem except in lateral jackknife (venous pooling in lower extremities) or kidney positions (caval compression). The right lateral decubitus position appears to have greater propensity for caval compression and reduced venous return with kidney rest because of the closer proximity of the vena cava to the right flank. Vital capacity in normal awake subjects decreases by a comparable 10% in the lateral and supine positions compared to the erect posture. The kidney position can decrease the vital capacity by another 5–10%. Most of this decrease is thought to result from reduced movement of the ribs and diaphragm. Although vital capacity and FRC are reduced, better ventilation– perfusion matching results from increased perfusion in the dependent lung and corresponding increase in ventilation from the stretched dependent hemidiaphragm. However, general anesthesia with or without spontaneous ventilation in the lateral decubitus position causes an increased mismatch

FIGURE 26–12. Lateral decubitus position. (Redrawn from Martin and Warner7 with permission.)

in ventilation–perfusion ratios compared to that in awake subjects. This is further complicated by the institution of paralysis and mechanical ventilation, addition of PEEP, opening of the pleura in thoracic procedures, pathologic processes in the dependent and nondependent lung, and use of medications (vasodilators) that affect hypoxic pulmonary vasoconstriction. Complications from the lateral decubitus position include pressure injuries (ischemic), muscular and ligamentous strain, whiplash-like injury to the cervical spine, neurologic injuries, and ocular complications (corneal abrasions, pressure effects, dependent edema, and blindness).

Nerve Injuries Associated with Positioning Perioperative peripheral nerve injuries are a significant source of morbidity for the patient and unfortunately will be encountered by even the most conscientious anesthesia provider. It is the second most common cause (after death) of professional liability among anesthesiologists, accounting for 16% of claims in the ASA closed claims database.26 The claims secondary to nerve injuries have steadily increased in the last decade, and unfortunately the relationship between current conventional perioperative care with positioning and development of postoperative nerve injury is poorly understood. Injuries to the ulnar nerve, brachial plexus, and lumbosacral roots account for most of the claims, with ulnar being the most commonly reported nerve injury during the perioperative period. Cited mechanisms for nerve injury during the perioperative period include compression, stretch, ischemia, direct trauma, and laceration. Although injuries to the brachial plexus and lumbosacral roots may be secondary to stretch or compression with malpositioning of the patient, those to ulnar nerve usually are unexplained and often puzzling. Ulnar nerve injury may occur despite protective padding and careful positioning. In fact, 27% of cases of ulnar nerve injury in the ASA closed claims database occurred despite documentation of adequate padding at the elbow.26 A retrospective review from the Mayo Clinic reported a 0.04% incidence of persistent ulnar neuropathy in noncardiac surgery, with 9% of


reported injuries in this study being bilateral.27 Initial symptoms in most cases were noted only after a 24-hour period, and the distribution of sensory-only and mixed sensory and motor loss injuries was equal. More recent prospective data from the same authors report a higher incidence (approximately 0.5%) of perioperative ulnar neuropathies.28 The incidence may be even higher in patients undergoing cardiac surgery. The most consistent risk factors appear to be male gender, prolonged hospitalization, and extremes of body habitus.27 Morell et al. reported significant changes in ulnar nerve sensory thresholds with elbow flexion in human volunteers. In the flexed position, nearly all volunteers reported ulnar nerve paresthesias. All the volunteers reporting paresthesias had a significant increase in C fiber sensory threshold without any change in either Aα or Aβ fiber function. It could be that most hospitalized patients spend a considerably greater time with their elbows flexed, accounting for the finding that prolonged hospitalization is an independent risk factor for nerve injuries. Prielipp et al.29 studied the effects of arm positioning on the pressure exerted at the elbow. They showed that the pressure exerted over the ulnar nerve was greatest when the forearm was pronated. It was also noted that up to 50% of male volunteers who experienced pressure on the ulnar nerve sufficient to impair electrophysiologic function did not perceive concurrent paresthesia in that nerve distribution. Thus, a significant number of male patients could be at increased risk for failure to respond to potentially damaging compression injury over the ulnar nerve during the perioperative period. An additional risk factor may be the sedated state of patients in the immediate postoperative period as a result of residual effects of anesthetics and narcotic medications. Injury to the brachial plexus is the second most common perioperative nerve injury, with an estimated incidence of 0.2–0.6%.30 The anatomy of the brachial plexus—long and mobile course of its components through the limited space between the first rib and the clavicle—makes it susceptible to stretch and compressive injury. Careful attention to arm positioning during supine position (abduction 2 hours) in the lithotomy position, and almost all of the reported injuries were sensory in nature. Paresthesia in the affected nerve distribution was the most common complaint. Symptoms in all of their patients were noted within 4 hours. The obturator was the most commonly affected nerve, with lateral femoral cutaneous, sciatic, and peroneal nerve injuries following in order. Sciatic nerve injury is most common after lithotomy positioning or some variant of it. Hyperflexion of the hip with extension at the knee along with external rotation of the thigh during positioning of the legs can produce excessive stretch of the sciatic nerve and result in injury. The common peroneal nerve is particularly vulnerable to compression injury because it wraps around the head of the fibula. Femoral neuropathy is more commonly associated with surgical factors, although ischemic injury could result from extreme abduction and external rotation of the thighs during lithotomy positioning. Anesthesiologists should be familiar with and follow the recommendations of the ASA practice advisory for prevention of perioperative neuropathies (Box 26–1). For particularly long procedures, consideration should be given to minimizing the time spent in a position that amplifies physiologic perturbations or injury to the patient. It may be advisable to look for and document symptoms of nerve dysfunction preoperatively in high-risk patients (those with risk factors for perioperative neuropathies or those coming for high-risk surgery, i.e., long procedures or surgical positions at risk for injury). A description of the intraoperative positioning and measures taken to prevent injury should be documented in the anesthetic record at the beginning of the procedure and thereafter on a regular basis.

Visual Injury Postoperative visual complications constitute a broad group ranging from temporary loss of visual acuity to devastating permanent loss of visual function. Corneal abrasions, periorbital and conjunctival edema, ocular hemorrhage, vitreous loss, retinal detachment, central retinal artery occlusion, and ischemic optic neuropathy are the range of complications that are encountered in the perioperative period. The reported incidence of perioperative visual injury varies widely (< 0.06– 25.6%). The American Association of Nurse Anesthetists (AANA) Foundation closed malpractice claims study32 reports an incidence of 3.3%, and the ASA closed claims analysis33 reports a similar 3.47% for all types of eye injury. In both closed claims projects, corneal abrasions are the most common complications encountered. Patient movement, chemical irritation from prep solutions, direct trauma from face mask, pressure from the laryngoscopic blade, pressure effects on the globe from lateral and prone positioning, prolonged procedures on the spine in prone position, intraoperative hypotension, and anemia all have been implicated as the reasons. Lateral, prone, and Trendelenburg positions increase the risk for visual complications during the perioperative period. In all these positions, venous pressure in the eye can increase from direct pressure, edema, and/or stasis, leading to decreased choroidal perfusion and increased risk for ischemic optic neuropathy. Other associated factors for visual complications during the perioperative period include prolonged operations on the spine, large-volume blood loss, significant decreases in hemoglobin levels, and intraoperative hypotension. Contributing patient comorbid conditions include hypertension, diabetes, obesity, smoking history, hypercholesterolemia, alcohol abuse, atherosclerosis, anemia, Graves disease, and renal transplantation.34 Shaw et al.35 reported that 40 of their 312 patients scheduled for coronary artery bypass grafting procedures had preexisting ophthalmologic abnormalities on examination. Currently, preoperative screening ophthalmologic examination of surgical patients to predict postoperative visual complications is not common practice.

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BOX 26–1. Summary of ASA Task Force Consensus on Prevention of Perioperative Peripheral Neuropathies

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Preoperative assessment • When judged appropriate, it is helpful to ascertain that patients can comfortably tolerate the anticipated operative position. Upper-extremity positioning • Arm abduction should be limited to 90° in supine patients; patients who are positioned prone may comfortably tolerate arm abduction >90°. • Arms should be positioned to decrease pressure on the postcondylar groove of the humerus (ulnar groove). When arms are tucked at the side, a neutral forearm position is recommended. When arms are abducted on armboards, either supination or a neutral forearm position is acceptable. • Prolonged pressure on the radial nerve in the spiral groove of the humerus should be avoided. • Extension of the elbow beyond a comfortable range may stretch the median nerve. Lower-extremity positioning • Lithotomy positions that stretch the hamstring muscle group beyond a comfortable range may stretch the sciatic nerve. • Prolonged pressure on the peroneal nerve at the fibular head should be avoided. • Neither extension nor flexion of the hip increases the risk of femoral neuropathy. Protective padding • Padded armboards may decrease the risk of upper-extremity neuropathy. • Use of chest rolls in laterally positioned patients may decrease the risk of upper-extremity neuropathies. • Padding at the elbow and at the fibular head may decrease the risk of upperand lower-extremity neuropathies, respectively. Equipment • Properly functioning automated blood pressure cuffs on the upper arms do not affect the risk of upper-extremity neuropathies. • Shoulder braces in steep head-down positions may increase the risk of brachial plexus neuropathies. Postoperative assessment • Simple postoperative assessment of extremity nerve function may lead to early recognition of peripheral neuropathies. Documentation • Charting specific positioning actions during the care of patients may result in improvements of care by (a) helping practitioners focus attention on relevant aspects of patient positioning; and (b) providing information that continuous improvement processes use can lead to refinements in patient care. From Practice advisory for the prevention of perioperative peripheral neuropathies: a report by the American Society of Anesthesiologists Task Force on Prevention of Perioperative Peripheral Neuropathies. Anesthesiology 2000;92:1168–1182. Reprinted with permission of publisher.

Therefore, it is imperative for anesthesia providers to be highly cognizant of the potential for visual complications in high-risk patients. Anesthesia providers should pay special attention to avoid pressure effects on the globe and to maintain adequate oxygen delivery to the optic disk and retinal structures. A report by the ASA Task Force on Perioperative Blindness is an excellent source of current information and consensus expert opinion on this devastating problem (approved by the ASA house of delegates October 2005).36

KEY REFERENCES 1. Martin JT, Warner MA. Positioning in Anesthesia and Surgery. 3rd ed. Philadelphia: WB Saunders, 1997. (Highly recommended) 2. Lumb AB, Nunn JF. Respiratory function and ribcage contribution to ventilation in body positions commonly used during anesthesia. Anesth Analg 1991;73:422–426. 3. Warner MA, Warner ME, Martin JT. Ulnar neuropathy. Incidence,

outcome, and risk factors in sedated or anesthetized patients. Anesthesiology 1994;81:1332–1340. 4. Prielipp RC, Morell RC, Walker FO, et al. Ulnar nerve pressure: influence of arm position and relationship to somatosensory evoked potentials. Anesthesiology 1999;91:345– 354. 5. Warner MA, Warner DO, Harper CM, et al. Lower extremity neuropathies associated with lithotomy positions. Anesthesiology 2000;93: 938–942. 6. Rupp-Montpetit K, Moody ML. Visual loss as a complication of nonophthalmologic surgery: a review of the literature. AANA J 2004;72:285–292. 7. Cheney FW, Domino KB, Caplan RA, et al. Nerve injury associated with anesthesia: a closed claims analysis. Anesthesiology 1999;90: 1062–1069. 8. A report by the American Society of Anesthesiologists Task Force on Perioperative Blindness. Chicago: American Society of Anesthesiologists, 2005.

REFERENCES 1. Ward RJ, Danziger F, Bonica JJ, et al. Cardiovascular effects of change of posture. Aerosp Med 1966;37:257–259. 2. Pae EK, Lowe AA, Sasaki K, et al. A cephalometric and electromyographic study of upper airway structures in the upright and supine positions. Am J Orthod Dentofacial Orthop 1994;106:52–59. 3. Froese AB, Bryan AC. Effects of anesthesia and paralysis on diaphragmatic mechanics in man. Anesthesiology 1974;41: 242–255. 4. Lumb AB, Nunn JF. Respiratory function and ribcage contribution to ventilation in body positions commonly used during anesthesia. Anesth Analg 1991;73:422–426. 5. Fairley HB. Airway closure. Anesthesiology 1972;36:529–532. 6. Craig DB, Wahba WM, Don HF, et al. “Closing volume” and its relationship to gas exchange in seated and supine positions. J Appl Physiol 1971;31:717–721. 7. Martin JT, Warner MA. Positioning in Anesthesia and Surgery. Philadelphia: WB Saunders, 1997. 8. Kopman EA, Sandza JG Jr. Hemodynamic effects of head-down lithotomy position in patients with coronary artery disease. Obstet Gynecol 1979;53:237–240.


9. Enderby GE. Postural ischaemia and blood-pressure. Lancet 1954;266:185–187. 10. Jones JR, Jacoby J. The effect of surgical positions on respiration. Surg Forum 1954;5:686–691.

19. Sibbald WJ, Paterson NA, Holliday RL, et al. The Trendelenburg position: hemodynamic effects in hypotensive and normotensive patients. Crit Care Med 1979;7:218–224.

11. Martin JT. Compartment syndromes: concepts and perspectives for the anesthesiologist. Anesth Analg 1992;75:275–283.

20. Shenkin HA, Scheuerman WG, et al. Effect of change of position upon the cerebral circulation of man. J Appl Physiol 1949;2:317–326.

12. Reneman RS. The anterior and the lateral compartmental syndrome of the leg due to intensive use of muscles. Clin Orthop Relat Res 1975;113:69–80.

21. Sing RF, O’Hara D, Sawyer MA, et al. Trendelenburg position and oxygen transport in hypovolemic adults. Ann Emerg Med 1994;23:564–567.

13. Marshall WK, Bedford RF, Miller ED. Cardiovascular responses in the seated position—impact of four anesthetic techniques. Anesth Analg 1983;62:648–653.

22. Johannsen G, Andersen M, Juhl B. The effect of general anaesthesia on the haemodynamic events during laparoscopy with CO2-insufflation. Acta Anaesthesiol Scand 1989;33:132–136.

14. Young ML, Smith DS, Murtagh F, et al. Comparison of surgical and anesthetic complications in neurosurgical patients experiencing venous air embolism in the sitting position. Neurosurgery 1986;18:157– 161. 15. Gildenberg PL, O’Brien RP, Britt WJ, et al. The efficacy of Doppler monitoring for the detection of venous air embolism. J Neurosurg 1981;54:75–78. 16. Gottlieb JD, Ericsson JA, Sweet RB. Venous air embolism: a review. Anesth Analg 1965;44:773–779. 17. Matjasko J, Petrozza P, Cohen M, et al. Anesthesia and surgery in the seated position: analysis of 554 cases. Neurosurgery 1985;17:695–702. 18. Weil MH, Shubin H, Rosoff L. Fluid repletion in circulatory shock: central venous pressure and other practical guides. JAMA 1965;192:668–674.

28. Warner MA, Warner DO, Harper CM, et al. Ulnar neuropathy in medical patients. Anesthesiology 2000;92:613–615. 29. Prielipp RC, Morell RC, Walker FO, et al. Ulnar nerve pressure: influence of arm position and relationship to somatosensory evoked potentials. Anesthesiology 1999;91: 345–354. 30. Cooper DE, Jenkins RS, Bready L, et al. The prevention of injuries of the brachial plexus secondary to malposition of the patient during surgery. Clin Orthop Relat Res 1988;228:33–41. 31. Warner MA, Warner DO, Harper CM, et al. Lower extremity neuropathies associated with lithotomy positions. Anesthesiology 2000;93:938–942.

23. Douglas WW, Rehder K, Beynen FM, et al. Improved oxygenation in patients with acute respiratory failure: the prone position. Am Rev Respir Dis 1977;115:559–566.

32. Jordan LM, Kremer M, Crawforth K, et al. Data-driven practice improvement: the AANA Foundation closed malpractice claims study. AANA J 2001;69:301–311.

24. Lamm WJ, Graham MM, Albert RK. Mechanism by which the prone position improves oxygenation in acute lung injury. Am J Respir Crit Care Med 1994;150:184–193.

33. Gild WM, Posner KL, Caplan RA, et al. Eye injuries associated with anesthesia. A closed claims analysis. Anesthesiology 1992;76:204–208.

25. Toole JF. Effects of change of head, limb and body position on cephalic circulation. N Engl J Med 1968;279:307–311.

34. Rupp-Montpetit K, Moody ML. Visual loss as a complication of nonophthalmologic surgery: a review of the literature. AANA J 2004;72:285–292.

26. Cheney FW, Domino KB, Caplan RA, et al. Nerve injury associated with anesthesia: a closed claims analysis. Anesthesiology 1999;90:1062–1069. 27. Warner MA, Warner ME, Martin JT. Ulnar neuropathy. Incidence, outcome, and risk factors in sedated or anesthetized patients. Anesthesiology 1994;81:1332– 1340.

35. Shaw PJ, Bates D, Cartlidge NE, et al. Neuro-ophthalmological complications of coronary artery bypass graft surgery. Acta Neurol Scand 1987;76:1–7. 36. A report by the American Society of Anesthesiologists Task Force on Perioperative Blindness. Chicago: American Society of Anesthesiologists, 2005.

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CHAPTER 27 Electricity, Electrical Safety, and Instrumentation in the Operating Room Robert H. Stiefel, MS and Julian M. Goldman, MD

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The role of technology in medicine has steadily increased during the past few decades, and there is every indication that this will continue. Most of this technology has been in the form of new electronic equipment. Safety has sometimes been overlooked; at other times, specific aspects of safety (notably, electrical safety) are overemphasized. This chapter describes the principles and practices of the safe use of medical equipment. The safe use of modern medical technology depends first on an understanding of the operating principles of the technology. An understanding of electrical hazards also is necessary to operate electrical equipment safely. Such knowledge is based on an understanding of electricity and electronics. The first section of this chapter reviews the basic concepts of electricity and electronics. The second section of this chapter describes and explains the hazards of medical equipment use. Standards and regulations for the use of medical equipment have been promulgated to avoid hazards to patients and personnel. The third section of this chapter describes the organizations that set standards, tells how and why they develop standards and gives an overview of some more important standards. From this information it becomes clear that proper use of standards is to provide safe, and safe use of, medical technology. These three sections of this chapter provide the basis for development of an equipment safety program. The need to understand and apply electrical engineering principles to analyze and avoid equipment hazards, and to apply equipment safety standards, has spawned a new profession in heathcare known as clinical engineering. This field, practiced

by biomedical and clinical engineers and technicians in hospitals, is described in the fourth section. This section concludes with a discussion of technology management—the term used to describe the involvement of clinicians, engineers, and administrators in planning and implementing the use of medical technology in the most effective manner. An understanding and respect for the safe use of medical equipment is particularly important for anesthesiologists. Of the major disciplines of modern medicine, none depends more on technology for direct patient care and safety than does anesthesiology. Many of the devices used at the bedside for diagnosis and treatment of patients were developed first in the operating room by anesthesiologists. Anesthesiologists use the widest variety of medical equipment and routinely use it in the most precarious situations of any of the medical disciplines.

ELECTRICITY Current is the flow of electric charge, with electrons being the most common charge carrier. The unit of measure of current is the ampere or amp, abbreviated A. One ampere is the flow of 1 coulomb per second, and 1 coulomb is 6.2420 × 10l8 units of electric charge. An electron has one unit of negative electric charge. The symbol for current is I; the symbol for charge (in coulombs) is Q.

Voltage, also called potential difference or electromotive force (EMF), is the amount of potential energy available to move electrons (i.e., available for work). It also is the difference in potential energy between two points caused by differences in electrical charge or the energy released when electrons move from higher to lower potential. The unit of measure of voltage is the volt, and the symbol for voltage is V (or sometimes E). One volt represents the amount of power or work per unit of time to move 1 coulomb. The zero potential reference point is called ground or earth. Besides being a reference point, ground plays a major role in electrical safety. Hazard currents can be safely drained by connection to ground, as will be discussed later. A conductor is a material through which electrons move easily (e.g., copper), and an insulator is a material through which electrons move poorly (e.g., glass). A semiconductor is a material that normally is an insulator but acts like a conductor when certain conditions are met (e.g., silicon crystals with a particular impurity added).

Direct Current Direct current (DC) is unidirectional current and is constant in magnitude. Batteries provide a constant DC. By convention, the direction of current is from the more positive to the more negative voltage (Fig. 27–1). This was based on a guess by Benjamin Franklin when he needed to assign algebraic signs in equations describing electrical

KEY POINTS 1. Hazards to patients from medical equipment include fibrillation and burns, equipment failure, and misuse. Electrical safety concerns originating in the 1960s have led to the development of safety and performance standards, improved equipment designs, and in-house clinical engineering programs. 2. Medical equipment standards are promulgated by a variety of national and international organizations. Understanding and complying with these standards requires clinical engineering expertise.


3. Clinical engineering departments in hospitals help to ensure the safety and performance of medical equipment by providing evaluations, testing, maintenance, and training programs. 4. Safe and effective use of medical equipment involves the cooperation of clinicians, administrators, support staff, and manufacturers. A clinical engineer usually is best able to orchestrate these efforts. 5. A hospital-wide technology management program combines individual equipment programs and improves efficiency and quality.

CHAPTER 27: Electricity, Electrical Safety, and Instrumentation in the Operating Room

Ι

Ι

0 †

A 0 †

FIGURE 27–3. Alternating current.

FIGURE 27–1. Direct current.

charges and forces. Unfortunately, his guess was incorrect. Electrons actually flow from negative to positive, opposite to the convention for current that was accepted before the discovery of electrons. Resistance is the opposition to the flow of current. The unit of measure of resistance is the ohm, abbreviated 1, and the symbol for resistance is R. A resistor is an electrical component designed to provide a specific value of resistance. Voltage, current, and resistance are related by Ohm’s law, which states that voltage is directly proportional to current and to resistance (Fig. 27–2). Power is work per unit time or the rate at which electrical energy is used. Its unit of measure, the watt (abbreviated W), is equivalent to 1 joule per second. The symbol for power is P, and it is calculated P equals IV equals I2R.

Alternating Current Alternating current (AC) differs from DC in that its polarity reverses periodically. As a result, its magnitude is constantly changing. A cycle is one complete wave pattern (from 0–A in Fig. 27–3). A period is the time of one cycle. The average value of AC for one period is zero. Frequency (f ) is the number of cycles per second (cps) and is the inverse of the period. The unit of measure is the hertz, abbreviated Hz. By

definition, 1 Hz is equal to 1 cps. There are 360° in one cycle, and the phase is the number of degrees between two AC waveforms at the same time. Common household voltage (that available at electrical receptacles in the home) and the voltage at most hospital receptacles is nominally 120 volts AC (VAC) and has a 60-Hz sinusoidal waveform (period of 16.7 ms). (In most of Europe, Asia, and Africa, 50 Hz and 220 V are used.) The voltage given is the root mean square (RMS) value, which is 0.707 (1/32) of the peak value or 0.354 of the peak-to-peak value of the voltage waveform (Fig. 27–4). The RMS value of AC voltage provides the same wattage as the same value of DC voltage. DC and AC are additive. Combinations of DC and AC can make virtually any desired waveform. Conversely, any electrical waveform can be described as a series of sine waves, each at a single frequency; this technique is called Fourier analysis. AC adds a number of refinements (or complications) to the management of electricity. In contrast to DC, resistance is no longer the only opposition to AC. Reactance is the opposition to current that varies with frequency (resistance is constant). Together, resistance and reactance are called impedance. Impedance is measured in ohms, but its symbol is Z. Reactance also is composed of two parts: capacitive reactance and inductive reactance. Reactance has the symbol X; capacitive reactance is XC, and inductive reactance is XL. Impedance is calculated as follows: Z = R2 + (XL – XC )2, V

V=I×R

FIGURE 27–2. Ohm’s law (for direct current).

V = I × Z. A capacitor is an electrical component designed to provide a specific value of capacitance, which is the property of storing separated charges when a voltage is present between conductors. In construction, a capacitor is two conductive plates separated by an insulating material called a dielectric. The symbol for capacitance is C. Capacitance is measured in farads, abbreviated F. More often, values are given in microfarads (microfarads = +F, although mF also is used). Capacitance is related to current and voltage by the following formula: I = C [dV/dt]. An inductor is an electrical component designed to provide a specific value of inductance, which is the property of a varying electric current to induce a voltage in a circuit. An inductor is a coil of wire, often around a metallic core. The symbol for inductance is L, and the unit of measure is the henry, abbreviated H. Inductance is related to current and voltage by the following formula: V = L [di/dt]. An important application of inductance is in transformers. A transformer is constructed by placing two coils close to each other. An AC source is applied to one coil, and a current is induced in the other. Voltage can be

Peak value

Ohm’s law (for direct current): (volts) where V = voltage (amps) I = current R = resistance (ohms)

and Ohm’s law becomes:

RMS value

†

0 Peak-to-peak value FIGURE 27–4. Root mean square (RMS) voltage.

477


adjusted up or down by selecting the ratio of turns of wire in the two coils: V1/V2 = Nl/N2,

478

where N is the number of turns of wire (Fig. 27–5). AC is used for transmission from electrical generators because transformers can convert AC voltages but not DC voltages. Increasing and decreasing high voltages is practical only with transformers. High voltage is more efficiently transmitted over long distances. If current is cut in half, the voltage must be doubled to transmit the same power (recall that P = IV). This reduces the power loss in the transmission lines to one quarter (I2R, where R is the resistance of the transmission line).

AC versus DC Sixty hertz was chosen for AC frequency for engineering reasons. Transformers work efficiently at 60 Hz. At higher frequencies, transmission losses increase. At lower frequencies, lights would flicker perceptibly. Unfortunately, 60 Hz also is in the middle of the range of frequencies to which muscles and nerves are most susceptible (see Hazards of Electricity below). An interesting historical note on the selection of AC rather than DC involves William Kemmler, the first man legally electrocuted.1 In 1879, Thomas Edison invented the electric light. He then developed a DC distribution system, most of which was installed in the 1880s. George Westinghouse developed an AC distribution system late in the 1880s. Edison and Westinghouse waged an economic battle over whether AC or DC would become the standard for electrical distribution systems. The advantage of AC was that it could be transmitted at a high voltage for long distances without the unacceptably high losses that AC and DC suffer at low voltage, and then it could be dropped to a lower, safer voltage with a transformer for local distribution. Edison and others could show that AC was more dangerous. In animal experiments, AC voltages of 200 V were lethal, but DC was relatively safe at that level. On June 4, 1888, Governor David Hill of New York signed a law making electrocution the method of execution for capital crimes committed after January 1, 1889. Electrocution had been selected by a commission assigned the

FIGURE 27–5. Example of a transformer.

task of finding an effective, humane means of execution to replace hanging. In March 1889, an electrical engineer, Harold Brown, was contracted to provide execution systems for the Auburn, Sing Sing, and Clinton prisons. Brown previously had published reports on the dangers of AC and the comparative safety of DC. He naturally chose Westinghouse AC generators, although he had to purchase them used because Westinghouse tried to prevent him from obtaining them (Westinghouse did not want his name associated with electrocution). The first system was installed in Auburn state prison in central New York State in June 1889. Meanwhile, on March 29, 1889, in Buffalo, New York, William Kemmler killed his girlfriend after a drunken argument. On May 10, a jury found him guilty, and on May 14, he was sentenced to death by electrocution. Kemmler’s attorney appealed on the grounds of cruel and unusual punishment. Hearings were conducted in New York City and Buffalo during July 1889. The defense attempted to prove that death by electric current was uncertain because people recovered after being struck by lightning. Brown testified on behalf of the State, describing his electrocution experiments on ani-

mals. Edison also was called by the State to testify. He opined that death by electrocution should be instantaneous. Kemmler’s appeals ultimately were denied, and he was electrocuted on August 6, 1890.

Circuits A circuit is any connection of electrical components. A complete circuit is one that starts and ends at the same point and is required for current to flow (Fig. 27–6). A series circuit has two-terminal components connected end to end, and the total current in the circuit passes through each component (i.e., the current is constant through a series circuit). If one light bulb in a series of bulbs burns out, they all go dark. A parallel circuit has two-terminal components connected side by side. The current divides between the components, but the voltage drop across each component is the same (i.e., the voltage is constant across a parallel circuit; Fig. 27–7). If one light bulb in a parallel circuit burns out, the others will be unaffected.

Semiconductors Electricity becomes more interesting and useful—and more complicated— with semiconductors. Resistors, capacitors, and inductors are two-terminal,

FIGURE 27–6. Direct current (DC) circuit and an alternating current (AC) circuit.

CHAPTER 27: Electricity, Electrical Safety, and Instrumentation in the Operating Room

Analog and Digital Circuits

FIGURE 27–7. Series and parallel circuits.

linear, passive devices. In a linear device, a change in the input signal produces a proportional change in the output signal. A passive device is one with no built-in power source. A junction diode is the simplest semiconductor. It is a two-terminal, passive component, but it is nonlinear. It allows current in one direction and blocks current in the other Fig. 27–8). This characteristic is used to convert AC to DC—rectification. A zener diode is a diode that can conduct in the reverse direction when a sufficiently large reverse voltage is applied (Fig. 27–9). This voltage is called a zener point, and a zener diode is used as a voltage regulator, which establishes a fixed voltage. I

V

FIGURE 27–8. Current versus voltage in a junction diode.

A transistor is a three-terminal, nonlinear, active device. Active means that the output can have more power than the input. This characteristic permits amplification of signals. The extra power comes from an external power supply. Characteristics that are controlled by transistor circuits are input and output impedances, current and voltage gains, and phase and frequency responses. Types of transistors include bipolar-junction transistors and field-effect transistors. The symbols for resistors, capacitors, inductors, diodes, and transistors (as they appear in schematic drawings) are shown in Fig. 27–10. Integrated circuits (ICs) are single semiconductor “chips” into which numerous transistors and passive components have been etched. A single IC can be a complete amplifier, a chip capable of storing thousands of bytes of digital memory, a computer’s microprocessor, or any of hundreds of different analog or digital circuits. ICs account for the miniaturization of instruments and computers and for their phenomenal speed and versatility. For example, the IC that serves as the central processing unit of a modern personal computer contains over 1,000,000,000 transistors. Their reduced power requirements are another important advantage.

Circuits that manipulate continuous waveform voltages are called analog circuits. Signals can have a range of magnitudes. Natural phenomena typically are analog. Bipolar digital circuits have only two discrete voltage values, called high and low (or 1 and 0). Analog data can be converted to digital, and vice versa, by analog-to-digital (A/D) and digital-to-analog (D/A) converters. Data need to be in digital form to be used by digital computers. Digital data also have greater immunity to electrical noise. Spurious voltages added to an analog signal will alter the signal’s value. Digital low and high signals need only be within 1.5 V of their nominal values of 0–5 V to be dependably interpreted.

Leakage Current An unavoidable and undesirable side effect of electrical circuitry is leakage current. It is virtually impossible to contain all electrical energy within the wiring and components of electrical equipment. The primary source of leakage current is stray capacitance. Two conductors separated by insulation and air act like a capacitor, and AC current is conducted between them. The electrical power cord usually has the greatest amount of stray capacitance because of the length and proximity of the wires. Interestingly, leakage current will flow in the ground wire of a power cord even when a device is not turned on because AC voltage is present in the power cord as long as it is plugged in. There also is resistive leakage because insulation is less than perfect. Although resistive leakage current is a

Resistor

I

Capacitor Inductor Anode

Zener point

v

Cathode Collector Emitter

Gate

Zener diode Bipolar junction transistor

Base

npn

FIGURE 27–9. Current versus voltage in a zener diode.

Junction diode

pnp Junction field-effect transistor

Drain

Source n-channel

p-channel

FIGURE 27–10. Electronic symbols.

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480

minor source, it tends to increase as equipment ages. In addition to the degradation of insulation, there can be a buildup of dirt, dust, and moisture inside the equipment. The ground wire in a three-wire power cord conducts leakage current from the chassis of equipment to ground. It also shunts fault currents (caused by damaged insulation, wiring, or components) to ground. If a fault current is large enough, it will cause a fuse or circuit breaker to open, preventing shocks to patients or operators and further damage to equipment. If a ground wire is missing or broken, leakage current or fault current energizes the chassis until it finds an alternative path to ground. This alternative path can be a patient or an operator. This is one of the more important considerations in electrical hazards, which is the topic of the section on Hazards of Electricity.

Isolated Power In a conventional power distribution system, three wires feed into a circuit breaker box. These three wires are called hot, neutral, and ground. (This discussion is limited to 120 VAC systems.) The hot wire supplies current at 120 VAC, and the neutral wire provides the return path. The ground wire is for safety (i.e., for shock and fire protection from electrical faults). The circuit breaker box distributes power to branch circuits through individual circuit breakers. Each branch circuit feeds electrical receptacles, overhead lighting, or installed equipment (e.g., radiograph view box; Fig. 27–11). An isolated-power system (or floating system) is a more specialized type of power distribution system. In an isolated-power system, the hot and neutral wires are not ground referenced. An isolation transformer and a line-isolation monitor (LIM) are installed directly in front of the circuit breaker box (Fig. 27–12A). Neither of the output leads from the isolation transformer is connected to ground. The output leads are referred to as line 1 and line 2. Isolated-power sometimes is called ungrounded, but it is important to realize that a ground wire still is used. In this context, ungrounded simply means that neither of the power lines is connected to ground. The LIM monitors the degree of isolation of the isolated-power system by measuring the amount of current that would flow

FIGURE 27–11. Conventional power distribution system. Note the connections of neutral wires to ground terminals on both sides of the transformer and in the circuit breaker box.

to ground if either power line were connected directly to ground (total hazard current). If this current exceeds a preset limit, the monitor lights and sounds an alarm (Fig. 27–12B). If adding a device to the circuit triggers an alarm, the hazard current display can be used to assist troubleshooting by measuring the contribution of a device to the total hazard current as the device is added and removed from the circuit. In a conventional power distribution system, a ground fault (a short circuit from the hot conductor to ground) allows a large current to flow until the circuit breaker opens (circuit breakers typically are rated at 15 or 20 A). An ideal isolation transformer would not allow any current to flow from either power line to ground. A direct fault from either power line to ground would merely convert the isolatedpower system to a conventional power distribution system. A second fault, from the other power line to ground, would be required for a large current to flow to ground. No isolation transformer is ideal. Capacitance between the transformer wiring creates a high-impedance path to ground. Additional high-impedance paths to ground exist within the LIM and the power distribution wiring. Altogether, these allow up to 1.5 mA of leakage current. Each device connected to the system contributes its own inherent leakage current (generally 6 mA is detected, indicating that current from the hot conductor is returning to ground via any other pathway—including a potential victim of electrocution—the GFCI immediately interrupts the circuit. The GFCI reaction time varies inversely with the leakage current. For example, Underwriters Laboratories (UL) standard 943 specifies that at a leakage current of 250 mA, the GFCI must activate in 100 documented lines of text, proved difficult. In the paper environment, intubation difficulty was documented in a specific location on the anesthesia record, and the clinician circled a “0,” “1,” or “2.” This linear analog score had proved useful over the years and was replicated in the electronic record, but it now was just one more event in what appeared to be an endless list of events. The solution was to force intubation difficulty to the top of the event list (Fig. 28–16). In addition, if a difficult intubation was documented on the preoperative assessment, this would be carried forward to all subsequent evaluations (i.e., it would be automatically documented as a difficult intubation on every future preanesthetic evaluation), and a warning window would be displayed when the assessment was opened. Unfortunately, this safety solution was short lived because the PIMS migrated away from printing a paper anesthetic record to the information being available only electronically. The solution to this problem was found with the use of another electronic form, very similar to the invasive line form discussed earlier (Fig. 28–14). An airway management form was developed that not only has the advantages of additional granularity to more fully document how the patients airway was managed, but when the documentation is complete and saved, the system generates a structured text message that is forwarded to the electronic progress notes. This way, every clinician can easily find and read the details of airway management during the pa-

tient’s anesthetic course by merely accessing the progress notes. This has proved very useful for downstream users, particularly the critical care service when they are deciding on when to wean and extubate a patient. A more difficult problem was seen with spinal and epidural opioids. Initially, the regional anesthesia form (Fig. 28–13) required that the clinician document whether neuraxial opioids were administered and, if so, via what route (Fig. 28–17 ). The regional anesthesia form cannot be saved or exited without documentation of whether neuraxial opioids were delivered and, if so, by which route. This was then printed, always in the same location, on the anesthesia record. Unfortunately, some patients who had received neuraxial opioids were missed by the service and/or nursing, received additional parenteral narcotics, and had respiratory depression requiring intervention. Several solutions were attempted, including changing the location of the information on the anesthesia record and automated e-mails triggered by patient transfer. None of these solutions worked. Finally, a hospital-specific Internet site was created that listed every patient who had received opioids in the last 48 hours and included the patient’s medical identification (ID) number and the time, date, and route of administration. This site is accessed throughout the day by the acute pain service, and it is their responsibility to see every patient and ensure that appropriate pain medication orders are written. This example highlights the fact that although computer-based solutions can be very powerful, they will not work unless they are coupled with achievable policies and procedures and that the solu-

tions are evaluated to determine whether they are working (i.e., postimplementation review). A major problem in all medical centers is difficulty errors in correctly identifying patients, particularly in environments where patients cannot speak for themselves. This is particularly true in the operating room where the patient not only is unable to answer questions but, after surgical preparation and draping, cannot even be visually identified. The traditional solution is to place an armband on the patient, but this solution is only as good as the individuals who are comparing the armband to another piece of documentation. Another safety project made use of a bar code reader and the addition of a bar code on the patient’s armband. Currently, prior to entry into the operating room, the PIMS is launched, and the patient’s name and medical ID number are entered into the system. The software compares the entered name and ID number via an interface with the hospital information system to determine if the name and number match. If the name and number are correctly linked, the PIMS starts recording vital signs and other objective data, but no charting may be done. When the patient arrives in the operating room or procedure room, a bar code reader inputs the information on the armband bar code, which consists of the patient’s medical ID number (Fig. 28–18). If the medical ID number on the armband matches the information that had been entered into the system, the PIMS launches the anesthesia record and documents anesthesia start, and

FIGURE 28–17. Close-up of the regional anesthesia form (Figure 28–13), which documents whether neuraxial opioids were administered and, if so, by which route (i.e., spinal or epidural). One of the three choices must be picked before the form can be saved and the clinician returned to the PIMS.

CHAPTER 28: Perioperative Information Management Systems

FIGURE 28–20. Screen displayed by the PIMS if the bar code identification of a blood product matches that of the patient on the operating room table.

FIGURE 28–18. Bar code identification of the patient. When the patient enters the operating room, the bar code, which consists of the patient’s medical ID number, is read with a hand-held device. This number is compared to the medical ID number the clinician entered earlier, which was confirmed to match the patient’s name.

FIGURE 28–19. Bar code identification of blood products. The clinician reads the bar code on the blood product bag, which consists of the medical ID number of the intended recipient, with a hand-held device. This is compared to the confirmed medical ID number of the patient on the operating room table.

charting is enabled. This process ensures that the EMR on the computer is actually that of the patient on the operating table. Unfortunately, this process does not always work. Some patients come to the operating room from the emergency department without identification. Some armbands are unreadable because the ink has worn off. Sometimes the patient has taken the armband off. These are just a few examples of how the system can be defeated. Therefore,

the system allows the clinician to bypass the bar code identification but requires the user to document the reason for the bypass and to attest to the fact that he or she used other reliable means of identifying the patient. This bypass proved to be the source of several incorrect patient identifications, usually when there was a rush of getting the patient into the room, the bar code was not working for whatever reason, and the anesthesia personnel was assured of the

identity of the patient. After a few near misses, the bar code ID bypass was refined. The system now has two requirements: (1) the clinician who is in the room must sign in with his/her name and password and document as performed previously, and (2) an anesthesia supervisor, either an attending physician or senior nurse, must enter the operating room and document that correct identification has been done. A similar process was added to the PIMS for positive blood product identification. The blood identification process also makes use of bar code identification. When blood products are brought into the operating room, the clinician scans a bar code on the blood product bag (Fig. 28–19). Like the patient’s armband, the bar code on the blood product bag contains the intended recipient’s medical ID number. The system compares the ID number on the blood product bag to that of the patient, who had been identified earlier via a bar coding process. If the medical ID number of the patient matches that of the blood product, the system clearly informs the clinician of the fact, both via text and color (i.e., green; Fig. 28–20). If there is a mismatch between the patient and the blood product, the clinician is also informed via text and color (i.e., red; Fig. 28–21). Since the bar code blood product identification system was installed, no patient has received an incorrect unit of any blood product, although the rare near miss (i.e., wrong blood product is brought into the operating room) does occur. The various patient safety projects demonstrate the fundamental fact that the failure to correctly communicate (i.e., transfer information from one clinician to another) is commonly the

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PART 4: Managing Anesthesia Care

FIGURE 28–21. Screen displayed by the PIMS if the bar code identification of a blood product does not match that of the patient on the operating room table.

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foundation upon which error and, at times, patient harm occur. The various safety projects that a PIMS allows decrease the opportunity for those errors of communication to occur. For example, if the patient in the operating room is not the same patient the clinician believes was brought in to the OR (i.e., the patient the clinician initially entered into the PIMS), the system does not allow charting to occur, clearly communicating that the wrong patient is in the operating room. Part of the solution to these kinds of medical errors is taking the human brain out of the process, because human neurophysiology is structured to draw rapid conclusions based on incomplete datasets, thus leading clinicians to see what they expect to see (e.g., patient and blood ID). These procedures are a subset of the ongoing efforts to leverage the electronic environment to decrease the opportunities for clinicians to draw wrong conclusions that lead to errors and harm.

RETURN ON INVESTMENT There is an understandable concern that EMRs broadly, and PIMS specifically, may not be worth the cost. These systems are expensive, with estimates between $20,000–$40,000 per bed. This cost includes the software, hardware, interfacing, furniture, and so on. The return on this investment can be difficult to tease out of the complex dynamics within a medical facility. Nonetheless, we can point to a number of significant benefits associated with the introduction of EMRs.

One of the most obvious benefits of EMRs is availability. With paper records, the paper chart must accompany a patient arriving on the ward or in the operating suite. In the context of an inpatient episode of care, the current chart commonly is placed on a clipboard or other device that holds the pieces of paper together. When the patient is moved, it is a simple task to merely place the chart on the gurney or to have the patient hold the record on his/her lap while th wheelchair is pushed. This becomes more complicated in an outpatient context and even more difficult when the patient has pertinent medical records from a previous episode of care. When the record is not with the patient, it must be sent for. This generates a time delay as well as an expense. The internal estimates at Mayo Clinic assessed a $7 cost every time a record was sent for or moved (i.e., cost of having a clerk find the record and then transport it), and it was twice as expensive to access a radiology image. If the chart is not in the expected location but instead is on another physician’s desk (e.g., to be summarized or reviewed for research purposes), the time delay often can be substantial, if the record can be found at all. The consequence of these delays not only is less efficient care delivery but also possibly less effective care. Depending on the medical situation of the individual patient as well as the time demands on the clinician, decisions may be made without access to important medical information. When we analyzed our critical care practice more than a decade ago, we concluded that as much as 25% of laboratory and radiographic results were never seen by clinicians because they either could not find the results or were unaware that the studies had been done. Once a fully integrated EMR is installed, there is virtually no delay in accessing current and historic medical information, although there is a transition period when the legacy, paper chart will be accessed. The access to old records decreases fairly rapidly over time as their value erodes and the electronic records increasingly contain historic information. Instead of having to call for a chart or waiting until a colleague has completed his/her charting task, all a clinician has to do is access a computer terminal, enter his/ her ID information, and then access

the patient’s medical record. This ready access also assists in the direct delivery of care because clinicians can discuss cases while they have access to the record. The clinician who receives a phone call from an ICU nurse is not constrained by what the nurse sees on the record or the monitor. The clinician can access the record from a distant location and discuss the patient’s management while having access to the patient’s real-time physiologic data. Although we initially had worked very hard to produce a printed anesthesia record that was as similar as possible to the handwritten record, once the rest of the medical center was up and running, we were able to abandon the printout entirely. The advantages to the anesthesia team of having complete access to a patient’s medical record, particularly previous anesthesia records, everywhere in the medical center are substantial. Having this kind of ready access to medical information is associated with a real economic advantage. An immediate cost savings is associated with not having to store and transport paper records. The efficiencies gained from virtually immediate access to medical information can be translated into improved access to medical care and the ability to evaluate and treat more patients per day. Not only does an electronic record provide near immediate access, anywhere in the medical center, to the patient’s medical record, it provides that information in a legible form. Fig. 28–22 shows an example of a handwritten record. It is both difficult (some would say impossible) and time consuming to obtain information from handwritten records. At times the difficulty in reading a handwritten record is an even greater barrier to understanding a patient’s medical history than is the impact of a delay in obtaining the record. For an anesthesiology department, rapid electronic access to legible medical information means faster and more comprehensive preanesthesia assessments. It also increases the likelihood that preexisting conditions that could complicate the perioperative course (e.g., difficult intubation, pseudocholinesterase deficiency) are identified and the associated complications prevented. New findings in an electronic format are available more rapidly. For example, digital radiology can makes images available as soon as they taken. Preventing periop-

CHAPTER 28: Perioperative Information Management Systems

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FIGURE 28–22. Example of a handwritten anesthesia record.

erative complications offers significant cost savings, and holding down costs is imperative in an environment of bundled pricing for procedures. As noted earlier, the PIMS communicates directly with the billing office at the end of every anesthetic procedure. The information forwarded is a subset of the anesthetic record, and the system determines whether all the required information for billing has been provided. If any required item is missing or incomplete, the system blocks transfer of the patient until the required documentation has been entered. Our estimate is that anesthesia

billing has increased 5–10% with this electronic process. Billing for reimbursable procedures (e.g., central line placement, postoperative regional analgesia) has also improved with the addition of electronic forms that ensure that these procedures are documented with adequate granularity, thereby allowing for appropriate billing and reimbursement. This process decreases opportunities for incomplete documentation, which has given us confidence that we not only are complying with the various billing requirements but we also are compliant with regulatory requirements. This substan-

tially reduces the economic risks associated with regulatory audits. Considering the fact that each incidence of noncompliance could be fined as high as $10,000, the value of mitigating such a risk is significant. These are just a few examples of the business case for a PIMS. Rapid access to a patient’s medical information that is presented in a legible form is of unquestionable value. EMRs decrease costs by eliminating the need to store and transfer paper records. Care is delivered in a more efficient manner because there are no delays in accessing information. Care is delivered


more effectively because all information about a patient is available and legible. System design facilitates the clinician’s ability to identify critical information, thereby decreasing the likelihood of avoidable perioperative complications, whether secondary to misidentifying the patient, blood products, previous complications, or critical underlying pathophysiology. A PIMS allows for electronic transfer of billing information that is complete and comprehensive. This allows the organization to receive reimbursement for all delivered services. Finally, the PIMS ensures that the records are complete with regard to regulatory requirements. Therefore, an EMR, including a PIMS, decreases the costs of delivering care, increases productivity, increases revenues, and mitigates regulatory risks.

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BARRIERS TO ADOPTION One of the most important issues hindering adoption of a PIMS is cost. As discussed earlier, the business case can clearly be made and the return on investment can be substantial, depending on the specific issues a PIMS can improve in the medical center. Nonetheless, the capital costs are substantial. As a general statement, a PIMS almost always will be part of a larger EMR project that is supported and funded at the institutional level. Although some anesthesiology practices may decide to go it alone in order to obtain the benefits of an electronic record for their practice, this model will be the exception and not the rule. The benefits of a standalone project can make a PIMS project worth pursuing (e.g., mitigation of litigation and regulatory risks, improved billing), but a more comprehensive project allows for greater benefit and broadens the risk across the medical facility. Concern with artifacts is a common reason for opposing a PIMS. Physicians and nurses express the fear that inaccurate recordings of physiologic parameters (e.g., blood pressure, oxygen saturation) not only will produce an inaccurate record that may mislead clinicians carrying for the patient but also could put them at increased risk during litigation. We have found these concerns to be unfounded. Although artifacts do occur (e.g., arterial blood pressure >300 when arterial line is

flushed), they almost always are obviously artifactual and of no concern. The reason these incorrect data are transparently artifactual is human physiology. The PIMS records information every minute and records in the database every 30 seconds. For example, it is impossible for the blood pressure to be steady at 120/70 for many minutes, then briefly >300 (flushing) or LVEDP Mean LAP > LVEDP PADP > PAOP = LAP > LVEDP PAOP > LAP PAOP > LAP PADP > PAOP

Ignoring intrapericardial pressure Obstruction to flow across mitral valve Retrograde systolic v wave Antegrade systolic v wave Short diastole creates pressure gradients Expansion of West lung zones 1 or 2 Occlusion of distal catheter lumen Increased pressure gradient over pulmonary circulation

EDP, end diastolic pressure; LAP, left atrial pressure; LVEDP, left ventricular end-diastolic pressure; PADP, pulmonary artery diastolic pressure; PAOP, pulmonary artery occlusion pressure.

Ventricular Compliance Because the pressure-volume relationship of the left ventricle is curvilinear, the same change in ventricular volume can produce either a small or large change in LVEDP, depending on the position on the compliance curve over which the left ventricle is operating. Also, conditions causing a marked shift in the compliance curve may result in pressure and volume changing in opposite directions, that is, increased LVEDP associated with decreased LVEDV (Fig. 29–11). In the perioperative period, myocardial ischemia, right ventricular failure causing interventricular septal shift, and inotropic drug effects, can all induce rapid changes in ventricular compliance. Catheter-Tip Position West et al. divided the lung into three zones according to gravity-dependent differences in perfusion and ventilation that affect the relationship of pulmonary arterial pressure (Pa), alveolar pressure (Palv), and pulmonary venous pressure (Pv).45 The PAC tip needs to reside in zone 3 (Pa > Pv > Palv) so that a continuous column of blood exists and the pressure measured by the catheter tip will reflect vascular rather than alve-

olar pressure. In a supine, spontaneously breathing subject, this is rarely a problem. However, with hypovolemia (low Pv) or positive-pressure ventilation (high Palv), zone 2 or zone 1 conditions might appear. This may be suspected when the PAOP trace demonstrates excessive respiratory variation in the pressure waveform (Fig. 29–12).46 Changes in body position will also influence the distribution of lung blood

flow and the anatomic locations of the different lung zones. This may be an important consideration in a patient who has a PAC inserted while supine, but later is positioned in the lateral, prone, or steep head-up or head-down positions. Ventilatory Pressure Influences With large cyclic variations in intrathoracic pressure, as occurs during labored

Abnormal diastolic compliance

25 Pressure (mm Hg)

arterial wall, occluding the distal lumen of the PAC.

Normal diastolic compliance

20 D

15

C

10 B

5 0 0

A 20

40

60

80

100

120

Volume (mL) FIGURE 29–11. The effect of change in left ventricular compliance on pressure–volume relationship. The normal relationship (light blue curve) is curvilinear. Depending on the starting point, the same change in the true preload, that is, end-diastolic volume, will cause a markedly different change in left ventricular end-diastolic pressure, and hence in the pulmonary artery occlusive pressure (A to B vs. B to C). When ventricular compliance decreases (red curve), an increase in filling pressures (from A to D) does not necessarily reflect increased end-diastolic volume. (Modified with permission from Mark JB. Atlas of Cardiovascular Monitoring. New York: Churchill Livingstone, 1998: Figs. 15.1 and 15.2.)

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ΔPAP

Balloon inflation

ΔPAOP

mm Hg

30 ΔPAP < ΔPAOP

10 1 sec 0

FIGURE 29–12. Pressure trace recorded during positive pressure mechanical ventilation from a pulmonary artery catheter located in West lung zone 1. Pressure swings in the pulmonary artery occlusion pressure (ΔPAOP) reflect changes in airway pressure and are significantly higher then swings in pulmonary artery pressure (ΔPa), which result from changes in pleural pressure. (Modified with permission from Teboul JL, Pinsky MR, Mercat A, et al. Estimating cardiac filling pressure in mechanically ventilated patients with hyperinflation. Crit Care Med 2000;28(11):3631–3636.)

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respiration, coughing, Valsalva maneuver, or positive-pressure ventilation, both intracardiac and intrapericardial pressures are affected. The PAC will reflect the increased intracardiac pressures, although the true transmural pressure which determines cardiac preload, has not been changed.47 Consequently, the PAOP should be measured at end-expiration, a time point when intrathoracic pressure approximates atmospheric pressure, whether the patient is breathing spontaneously or mechanically ventilated. Visual inspection of the waveform display is more accurate than reliance on digital display for identifying end-expiratory pressures. During spontaneous breathing, inspiratory pressures are negative and the end-expiration point corresponds to the higher vascular pressure values. The opposite is true under positive-pressure ventilation. Application of positive end-expiratory pressure (PEEP) will also alter intrathoracic pressure and hence PAOP measurements at end-expiration. The magnitude of these effects depends on the level of PEEP used and the pulmonary and chest wall compliance.42 As a simple rule of thumb, the increase in measured PAOP is usually less than one-half the value of the PEEP applied. As lung compliance deteriorates, however, the transmission of airway pressure to the pleural space is attenuated. Therefore the effect of high PEEP, commonly employed in these situations, is minimized.48

Diagnostic Use of the PACDerived Pressure Waveform In addition to the quantitative hemodynamic data provided by pressure measurements and cardiac output, the

analog pressure waveform can be diagnostic of several pathologic cardiovascular conditions. Although echocardiography has mostly supplanted the PAC for clinical diagnosis of most of these disorders, initial clinical clues can be provided by PAC monitoring (Fig. 29–13).49

Complications of PAC Monitoring Complications associated with PAC arise from central venous cannulation (Box 29–2), initial PAC placement and positioning, and from continued presence and use of the catheter within the body. Frequency varies greatly between various reports and most complications have been described only in case reports or small case series.35 Although minor complications occur in up to 50% of cases, recent practice guidelines concluded that the incidence of serious life-threatening complications is much lower, and estimated to be 0.1–0.5%.35 Two large, prospective registries of PAC complications in surgical patients support this estimated risk, showing major morbidity in 0.12– 0.16% and mortality of 0.016% of catheterized patients.50,51 Factors suggested as important to minimize complications include the expertise and experience of the attending physician, close supervision of trainees, and attention to detail during pulmonary artery catheterization and usage.

cant dysrhythmias, such as complete heart block, ventricular tachycardia and ventricular fibrillation, are much rarer— approximately 3% of patients.50,52 Transient right bundle-branch block occurs in up to 5% of patients during PAC insertion.53 Therefore, patients with preexisting left bundle-branch block are at risk of developing complete heart block.54 In these patients, a margin of safety can be provided by using a PAC with a pacing port, having transcutaneous pacing readily available, or, rarely, a prophylactic placement of a transvenous pacing wires. In patients with severe aortic stenosis and other conditions associated with severe left ventricular hypertrophy, effective external cardiac massage is hard to achieve. When cardiac surgery is performed in these patients, many anesthesiologists delay flotation of the PAC until after sternotomy, which enables open cardiac massage to be performed in the event of a lifethreatening dysrhythmia.

Catheter Knotting Possible risk factors for looping and knotting of catheters within the heart include low cardiac output states, rightheart dilation, and excessive length of catheter inside the heart.55 The PAC might also become entangled with intracardiac pacing wires or anatomic structures such as chordae tendinae.56,57 If knots occur, they can usually be disentangled under fluoroscopic guidance. Alternatively, the knot may be pulled tight and the catheter removed with its sheath.58

Thromboembolism and Pulmonary Infarction Minor thrombi associated with the PAC were almost universal in the past, but became uncommon with the use of heparin-coated catheters.59 Major pulmonary embolism associated with PAC use has been reported in 0.9% of patients receiving PAC versus none in the control group.60 Pulmonary infarction following PAC can also result from prolonged balloon inflation or distal catheter migration.61

Dysrhythmias

Catheter-Related Infections

Transient dysrhythmias, most commonly premature ventricular contractions (PVCs), accompany passage of the PAC through the heart in up to 70% of patients.50 PVCs can also occur during removal of the catheter. Clinically signifi-

For central venous catheters and PACs alike, catheter-related infections usually result from skin organisms colonizing the introducer sheath.22 Heparin-coated PACs and regular central venous catheters carry a similar risk of

CHAPTER 29: Hemodynamic Monitoring

1 sec

A 90

R v

1 sec

B

R v ECG

R

PAP

60

Valvular Damage and Endocarditis

200

Case reports have described PAC-associated injury of the tricuspid valve62 and the pulmonary valve,63 but these injuries appear to be very rare events. The PAC balloon must be completely deflated prior to catheter withdrawal to avoid valvular injury. Even with proper catheter management, endocarditis, either septic or thrombotic, has been described in autopsy studies, probably representing occult endocardial injury.64

ART

30 PAOP

0 0 PAOP

100

a v 0

1 sec

C

v x

CVP

ECG

a

20

R

y

Pulmonary Vascular Injury

0 200

1 sec

ART

D

ART

120

0

0

100

30

PAP

CVP

a cv x 0

PAOP

a v ∗

ECG

a v ∗ 20

1 sec

E

0

45 PAP

CVP

infectious complications (2.6 infections per 1000 catheter days), whereas non–heparin-coated PACs carry a 2fold increased risk.22 Leaving the PAC in place for more then 5–7 days also increases the risk of infection.

PAOP

0 0 FIGURE 29–13. Pressure waveforms morphology in various clinical situations. A. Acute mitral regurgitation—giant v waves are seen in the pulmonary artery occlusion pressure (PAOP) trace, as well as distorting the nonwedged pulmonary artery pressure (PAP) trace. While the wedged (PAOP) pressure can be mistaken to be a PAP trace, the timing of the main pressure wave relative to the electrocardiographic T wave can help in correct identification. B. Right ventricular infarction—note prominent CVP waves with increased mean value (16 mm Hg) almost equal the PAOP pressure (18 mm Hg). C. Constrictive pericarditis—equilibration of end-diastolic pressures across the heart: PAOP, diastolic Pa, and CVP a wave, all about 25 mm Hg. Also note the W-shaped CVP trace with the mid-diastolic plateau wave (marked by *). D. Cardiac tamponade—relatively low blood pressure (84/55 mm Hg) and elevated CVP with dominant x descent but attenuated y descent. E. Pulmonary hypertension—increased pulmonary pressure (42/20 mm Hg) with markedly lower PAOP (13 mm Hg), caused by increased pulmonary vascular resistance. (Reproduced with permission from Mark JB. Atlas of Cardiovascular Monitoring. New York: Churchill Livingstone, 1998: Figs. 17.11, 12.15, 18.1, 18.5, and 6.11.)

Pulmonary vascular injury and pulmonary artery rupture are rare, life-threatening complications of pulmonary artery catheterization. Pulmonary artery rupture has an incidence of 0.02–2.0% but carries a mortality of 40–70%.60,65,66 Risk factors for this catastrophic complication include patient characteristics (advanced age, female gender, hypothermia, anticoagulation therapy, and pulmonary hypertension) as well as operator errors (overdistension of the balloon, unrecognized distal migration of the catheter, and balloon inflation when the catheter tip is wedged).65,66 In patients with risk factors, consideration should be given to using the PADP as an estimate for PAOP and avoiding repeated balloon inflation. Sudden hemoptysis is the most common presentation of pulmonary artery rupture. Other signs include hemothorax, hypoxemia, and cardiovascular collapse.65,66 Maintaining oxygenation and achieving rapid control of bleeding are initial therapeutic goals. Endobronchial intubation with a double-lumen tube or intentional mainstem intubation allows selective lung ventilation and isolation of the bleeding segment.67 Ancillary treatment includes lowering pulmonary artery pressure, reversing anticoagulation, and performing bronchoscopy for endobronchial toilet and identification of the bleeding site. Definitive control of bleeding may be achieved by transcatheter selective pulmonary artery embolization,68 but surgical lung resection is required when more conserva-

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BOX 29–4. Common Indications for Pulmonary Artery Catheterization • Hemodynamic monitoring in high-risk patients undergoing major surgery, including preoperative optimization • Differential diagnosis and management of shock (hypovolemic, septic, cardiogenic) • Diagnostic evaluation of major cardiopulmonary disorders (e.g. myocardial ischemia, pulmonary hypertension, intracardiac shunt, pulmonary edema) • Titration of therapy in unstable hemodynamic conditions (e.g. hypervolemic therapy in subarachnoid hemorrhage, management of eclampsia) • Optimization of ventilatory support (PEEP titration) 532 tive treatments fail or if life-threatening bleeding develops.65,66

Indications for Use and the Controversy Surrounding Pulmonary Artery Catheterization Box 29–4 summarizes the common indications for the PAC. However, studies show that factors other than medical indications affect the decision to use the PAC, including institutional, geographical, organizational, demographical, and individual preferences.69,70 In 1996, Connors et al., in a retrospective study in critically ill patients, concluded that PAC use is associated with a 20% increased mortality.71 This study ignited a major controversy regarding the role of the PAC in clinical medicine.31,32 Although earlier studies shared problems of inadequate methodology, unequal case mix and small sample size,35,36 several more recent, large, well-designed clinical trials have been published and have helped to better define the role of the PAC in perioperative medicine. In patients undergoing major noncardiac surgery, a large observational study showed that PAC use was associated with a 2.2fold increase in risk of cardiac complications,72 and a large randomized study found no benefit for PAC-guided goal-directed therapy compared to standard care without PAC.60 In moderate-risk vascular surgery, both ran-

domized controlled studies73 and a meta-analysis74 demonstrated no benefit associated with routine use of the PAC. Lastly, a large prospective randomized trial in patients undergoing coronary artery bypass surgery compared routine use of PAC versus CVP monitoring, and showed no difference in outcome.75 Several recent, large, randomized studies also have been performed in nonsurgical populations, including patients with severe congestive heart failure,76 patients with acute lung injury,77 and ICU patients with early shock or multiorgan failure.52,78,79 All found no therapeutic advantage for use of the PAC. However, most randomized studies have looked at the routine use of the PAC in large sequential cohorts of patients with relatively moderate risk of death.80 In most of these clinical trials, specific therapeutic protocols were not mandated and management was left to the physician’s discretion. Patients whose physicians considered them to be too sick to avoid having a PAC placed were also usually excluded.81 In contrast, several recent large, nonrandomized studies suggest that PAC use may benefit especially highrisk patients characterized by age> 65 years, significant physiologic disturbances (i.e., large base deficit) and a high level of disease acuity or injury severity.82–84 In addition, use of the PAC as a “rescue” monitor in patients who remain hemodynamically unstable despite empirical therapy has received little investigation. Several expert panels have been convened to provide guidelines to help standardize clinical practice.35–37 Specifically focused on the perioperative period, the ASA task force practice guidelines for PAC use suggest that preemptive PAC insertion in patients deemed at high-risk is a justifiable practice because of the delay associated with PAC placement once complications have developed, as well as possibly increased vascular and infectious complications related to hasty catheter insertion under suboptimal clinical conditions.35 The guidelines emphasize the role of operator’s experience in preventing PAC-associated complications, and underscore the importance of training and education to improve physician’s knowledge and understanding of cardiopulmonary physiology. According to the ASA guidelines,

the use of the PAC is considered necessary only in high-risk patients undergoing high-risk surgery, and even then is contingent upon a favorable practice environment (i.e., knowledgeable and experienced physicians and ICU nurses). The term high-risk patient generally refers to an ASA class 4 or 5 patient with significant cardiovascular disease, pulmonary dysfunction, renal insufficiency, sepsis, or trauma. High-risk surgery includes procedures commonly associated with large fluid shifts or hemodynamic derangements and high predicted mortality. As new monitoring modalities become clinically available, the need for PAC is expected to decrease even further.

Special Types of Pulmonary Artery Catheter Pacing Pulmonary Artery Catheter Two types of PAC have pacing capability. One has 5 electrodes incorporated in the catheter that allow bipolar atrial, ventricular, or atrioventricular sequential pacing. A second type has an extra lumen through which a pacing wire can be placed into the right ventricle. An obvious target population for these catheters are patients undergoing cardiac surgery using cardiopulmonary bypass, where pacing is frequently required postoperatively for a short period. Other candidates are patients with left bundle-branch block, in whom placing a PAC puts them at risk of developing complete heart block. Successful pacing with these catheters is usually achieved intraoperatively in anesthetized patients,85 but capture becomes less reliable when patients start to move postoperatively. As a result, these catheters are not widely used.

Continuous Mixed Venous Oximetry Measurement of mixed venous oxygen content in the pulmonary artery blood provides an assessment of the balance between total body oxygen supply and consumption.86 Assuming the contribution of dissolved oxygen is negligible, the mixed venous oxygen saturation can be expressed by rearrangement of the Fick equation (Box 29–5). This relationship highlights that venous saturation increases when arterial oxygen saturation, hemoglobin concentration, and cardiac output increase, and decreases when oxygen consumption increases.


BOX 29–5. Mixed Venous Oxygen Saturation SvO2 = SaO2– Where SvO2 SaO2 V˙O2 Hgb CO 1.36

(

•

)

V O2 × 100 CO × 1.36 × Hgb

= mixed venous oxygen saturation (%) = arterial oxygen saturation (%) = oxygen consumption (mL O2/min) = hemoglobin concentration (g/mL) = cardiac output (mL/min) = the amount of oxygen carried by hemoglobin (mL/g)

Hence, under conditions where oxygen consumption, hemoglobin concentration, and arterial oxygenation remain stable, mixed venous oxygen saturation continuously reflects changes in cardiac output. Mixed venous oxygen saturation can be measured intermittently using a PAC by sampling blood from the distal pulmonary artery lumen. Cooximetry should be used to directly measure saturation rather than calculate it from the blood oxygen partial pressure owing to the steep hemoglobin–oxygen saturation curve at partial pressures normally seen in venous blood. Continuous measurement of mixed venous saturation can be achieved using oximetric PACs that employ “reflectance spectrophotometry”: transmitting light through a fiberoptic bundle, measuring the light reflected from the blood, and calculating the amount of light absorbed by the hemoglobin. Similar to plethysmography, this technique is based on the differential absorption of various wavelengths of light by oxyhemoglobin and deoxyhemoglobin. Oximetric PACs have several technical limitations that should be recognized. They may show a drift artifact, requiring recalibration every 24 hours with a pulmonary artery blood sample, and they may be inaccurate at venous oxygen saturations below 50%. Other technical problems include thrombus formation on the catheter tip or excessive proximity to the vessel wall that may result in inaccurate readings. Most systems will warn of a reduction in light signal quality under these conditions. Last, if

the catheter is wedged, arterialized blood with high oxygen saturation will be sampled rather than mixed venous blood. Although continuously monitoring venous oximetry can reliably reflect changes in cardiac output during cardiac surgery,87 this is not the case in situations associated with rapid changes in oxygen consumption, like graft reperfusion during liver transplantation,88 aortic cross-clamp removal,89 and highdose therapy with catecholeamines.90 Two recent studies, performed in patients with early sepsis91 and in patients undergoing cardiac surgery,92 demonstrated that therapeutic interventions aimed at achieving venous oxygen saturation above 70% result in improved outcome. This contrasts with negative results of an older study performed in critically ill patients,93 supposedly emphasizing the importance of early monitoring and therapy. Recently developed oximetric central venous catheters allow continuous measurement of central venous oxygen saturation in the superior vena cava. Because the brain normally is the major oxygen consumer, central venous oxygen saturation (70–75%) is usually slightly lower than mixed venous oxygen saturation (75%).86 With hypoperfusion, splanchnic blood flow suffers before cerebral blood flow, and oxygen saturation in the inferior vena cava decreases first. Under these situations, central venous saturation will be higher than mixed oxygen saturation by approximately 5–8%.94 Despite these complicated relationships, central venous oximetry does correlate with severity of injury and blood loss in trauma patients with otherwise stable hemodynamic parameters,95 and has been used successfully to guide therapy in early sepsis.91 Experience with this type of catheter in the perioperative period has been very limited to date.

Right Ventricular Ejection Fraction PAC This modification of the PAC allows measurement of right ventricular ejection fraction (RVEF) using a fast-response thermistor that measures beatto-beat changes in pulmonary artery blood temperature.96 Similar to the continuous cardiac output PAC, the RVEF PAC incorporates a heating filament that delivers a thermal bolus into the bloodstream. Distal temperature is measured in the pulmonary artery,

and from the beat-to-beat temperature decay curve and successive diastolic temperature plateaus, RVEF is computed. Right ventricular end-diastolic volume (RVEDV) can be calculated from RVEF and stroke volume, and this derived variable has been used as an index of cardiac preload. Studies demonstrate acceptable accuracy of the thermal technique for RVEF measurement compared to radionuclide ventriculography.97 Right ventricular dysfunction may result from right ventricular ischemia or acute pulmonary hypertension. These events are not rare during cardiac surgery, especially after weaning from cardiopulmonary bypass (CPB) and protamine neutralization of heparin. Indeed, RVEF monitoring in patients following CPB can identify patients with significant right ventricular dysfunction.98 In patients with septic shock, depressed RVEF better predicts prognosis than does cardiac output or cardiac filling pressures,99 as well as indicating the need for inotropic support rather than fluid resuscitation alone.100

CARDIAC OUTPUT MONITORING Cardiac output is determined by cardiac preload, afterload, contractility, and heart rate. As such, cardiac output is a global index of circulatory status. Using cardiac output and other hemodynamic measurements, a variety of useful parameters can be derived, including vascular resistances, oxygen delivery to the tissues, and oxygen consumption (Table 29–3). Measurement of cardiac output and its response to therapeutic interventions are commonly employed therapeutic protocols in critically ill patients. While thermodilution cardiac output (TDCO) using the PAC is generally considered the gold standard in both clinical medicine and research, studies comparing it with the Fick method have not shown good agreement.101 For clinical purposes, however, the absolute cardiac output might be less important than changes in cardiac output and assessing its adequacy in terms of oxygen supply and demand.102 Even though TDCO measurement remains the reference method, other less invasive cardiac output measurement techniques are gaining in popularity.103 Like the PAC, each of these newer

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BOX 29–6. The Modified Stewart-Hamilton Equation for Calculation of Cardiac Output CO = VI × ( TB – TI ) × K ∞

∫ ΔTB(t)dt

0

Where CO VI TB TI K

cardiac output (L/min) injected volume (mL) blood temperature injectate temperature computation constant ∞ integral of temperature ΔT (t)dt ∫ B 0 change over time The computation constant adjusts for characteristics of the injectate (volume, specific heat capacity, and density) and catheter (specific heat capacity, dead space).

534

= = = = = =

monitoring modalities requires education and training for effective use.

The Thermodilution Technique TDCO measurement is based on the indicator dilution principle, wherein a known amount of substance is injected into the circulation and its concentration measured over time at a downstream site. For TDCO, a thermal bolus is used as the indicator and a thermistor incorporated into the catheter 4 cm proximal to the tip measures the change in pulmonary artery blood temperature. Based on these measurements, cardiac output is calculated using the modified Stewart-Hamilton equation (Box 29–6).104 TDCO, therefore, measures right ventricular output, which, at steady-state conditions and in the absence of intracardiac shunts, equals left ventricular output. The computation constant adjusts for characteristics of the injectate (volume, specific heat capacity, and density) and catheter (specific heat capacity, dead space). In clinical practice, 10 mL of room temperature saline or D5W (0.15 mL/ kg in children)105 is injected rapidly and uniformly through the proximal port of the PAC into the SVC or right atrium. The injectate temperature should be measured at the point of injection, to obviate the influence of injectate rewarming in the syringe. The results from 2–3 consecutive measurements are usually averaged, deleting measurements varying more than 10%. The reproducibility of the TDCO

technique is not high; therefore at least 15% change in cardiac output between two time points is required to be considered clinically significant.104 When comparing TDCO results derived with different cardiac output computers, the measurement variability is even higher, in the range of 20%.106 Right and left ventricular loading conditions, as well as pulmonary artery blood temperature, all vary considerably during the respiratory cycle.107 While synchronizing cardiac output measurement to end-inspiration or end-expiration might decrease measurement variation and increase reproducibility, a more truly representative mean value for cardiac output is obtained by averaging multiple measurements performed throughout the respiratory cycle.108 Similarly, while using ice-cold rather than room-temperature injectate can increase the signal-to-noise ratio of the thermal bolus, this has not been shown to be clinically significant.109 Technical errors during TDCO measurement are common and may go unrecognized. A real-time display of the pulmonary artery blood temperature curve is an important aid to identify spurious measurements (Fig. 29–14).104 Fluid boluses, given either peripherally or through the PAC introducer sheath, behave as additional positive or negative thermal sources and will affect TDCO measurement accuracy.110 In the immediate postcardiopulmonary bypass period, both a rapid drift and an exaggerated respiratory variation of the pulmonary artery blood temperature can introduce clinically significant errors in TDCO measurement.111,112 Right-sided valvular regurgitation, especially tricuspid regurgitation, can have a significant and unpredictable effect on the accuracy of TDCO measurement by causing recirculation of the thermal bolus.113 Because positive pressure ventilation with high levels of PEEP can either induce or exacerbate tricuspid regurgitation,114 this may limit the accuracy of TDCO measurement in a large group of critically ill patients. It is also important to remember that intracardiac shunts invalidate TDCO as a measure of systemic cardiac output, because under these conditions right and left ventricular outputs are not equal. Additionally, either recirculation (in left-to-right shunts) or injectate bypassing the thermistor (in right-to-left shunts) will in-

troduce errors in the calculation of cardiac output. Lastly, in low flow states, TDCO might overestimate true cardiac output owing to excessive heat loss from slow transit of the injectate.115 Notwithstanding its limitations, the TDCO technique is simple to perform repeatedly and quickly, does not require blood sampling, and uses a nontoxic, nonrecirculating, and nonaccumulating indicator. For these reasons, TDCO is extensively used as the preferred method in a variety of clinical settings. However, because TDCO measurement requires pulmonary artery catheterization, it is a highly invasive monitoring technique.

Transpulmonary Thermodilution Cardiac Output Measurement Transpulmonary thermodilution replaces the PAC with a special thermistor-tipped arterial catheter that measures blood temperature change in the systemic circulation (either femoral or axillary artery) following bolus administration of ice-cold injectate through a central venous line.116 Unlike standard TDCO measurement, this technique requires iced injectate owing to higher thermal noise and greater thermal loss from the longer path that the thermal bolus must traverse from venous injection to systemic arterial detection. Compared to TDCO, this measurement is made over a longer time period, which eliminates the problem of respiratory variation in cardiac output.117 Both in patients after cardiac surgery and in critically ill patients, transpulmonary thermodilution cardiac output agreed well with standard TDCO, although the transpulmonary values tended to be about 0.3–0.5 L/min higher, possibly reflecting loss of heat during transfer through the lungs.118,119

Lithium Dilution Cardiac Output Measurement Another indicator dilution technique employs intravenously injected ionized lithium as the indicator. The dilution curve is built by drawing blood from a standard arterial line over a lithium-sensitive electrode.120 Similar to transpulmonary thermodilution, respiratory influences are eliminated with this method because cardiac output is measured over several respiratory cycles. Another advantage of this technique is that the injection


D Interrupted injection

PA temperature

PA temperature

A Normal thermodilution curve

Time

Time E Tricuspid regurgitation

PA temperature

PA temperature

B High cardiac output

Time

Time Baseline temperature drift F (e.g. following cardiopulmonary bypass)

PA temperature

PA temperature

C Low cardiac output

Time

Time

FIGURE 29–14. Thermodilution curves recorded from the thermistor at the tip of the pulmonary artery catheter after injection of cold saline. Because the injectate temperature is usually colder than body temperature, the temperature along the y axis is decreasing. The cardiac output is inversely related to the area under the curve, as demonstrated by curves A to C. Curve D shows the effect of a nonsmooth injection. In tricuspid regurgitation (curve E ), incomplete mixing of the indicator within the right ventricle and subsequent recirculation between the right atrium and right ventricle will distort the descending limb of the thermodilution curve, usually leading to an increased area under the curve and underestimation of cardiac output. After discontinuation of cardiopulmonary bypass (curve F ), blood temperature gradually decreases as blood flow resumes to body parts that are cold (e.g., the lungs). The drift in baseline temperature will decrease the area under the curve and lead to an overestimation of cardiac output.

of the lithium indicator can be done through a peripheral vein, removing even the requirement for central venous catheterization.121 In small children, lithium-dilution cardiac output compares favorably with transpulmonary thermodilution cardiac output.122 In several studies that compared lithium-dilution cardiac output with TDCO in postoperative patients in the critical care unit, a good agreement was found,

although the lithium-dilution technique tends to underestimate TDCO by 0.2– 0.5 L/min.120,121 The lithium-dilution technique has several limitations. It cannot be used in patients who are allergic to or receiving lithium. Nondepolarizing neuromuscular blocking agents can interfere with the lithium electrode, which requires a 15–30-minute wait period before measuring cardiac output.

Partial CO2 Rebreathing This noninvasive method employs a modification of the Fick principle to measure cardiac output in mechanically ventilated patients. In the modified Fick partial rebreathing method, CO2 production and end-tidal CO2 are measured at baseline and during brief periods of rebreathing, which allows calculation of pulmonary capillary blood flow.123 The rebreathing is achieved by intermittently diverting exhaled gas through a loop connected to the ventilatory circuit. While this technique does not involve invasive vascular catheterization, it generally requires a tracheally intubated, mechanically ventilated patient. It provides a semicontinuous cardiac output measurement, as the rebreathing period can be automatically repeated. A major theoretical drawback of the technique is that it only measures blood that participates in gas exchange, ignoring shunted blood. To account for this, the CO2 rebreathing measurements can be adjusted by estimating shunt fraction based on FiO2 (fraction of inspired oxygen) and either arterial oxygen partial pressure or saturation. Clinical studies of the partial rebreathing method in surgical patients have been mainly limited to patients undergoing or recovering from coronary artery bypass grafting (CABG). These small trials have generally shown acceptable bias and precision compared to TDCO,124 although accuracy at higher cardiac output is reduced.125 Newer software versions allow use of the partial rebreathing method in modes of ventilation that allow spontaneous breathing and might improve its performance in patients in the intensive care unit. Because arterial PCO2 increases 2–5 mm Hg during each rebreathing measurement period, the use of the CO2 rebreathing technique is relatively contraindicated in neurosurgical patients who have increased intracranial pressure.

Continuous Thermodilution Cardiac Output Measurement The continuous thermodilution PAC incorporates a thermal filament around the right ventricular portion of the catheter, approximately 20 cm from the tip. This filament is intermittently warmed to about 111.2°F (44°C), and a thermodilution curve is recorded by the thermistor at the tip of the PAC in

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the pulmonary artery. Because this warm thermal signal is much smaller than the cold thermal signal of standard TDCO measurement, a stochastic system controls filament heating, switching it on and off with pseudorandom timing, thereby enhancing the signal-to-noise ratio.126 The displayed cardiac output is updated every 30 seconds and represents the averaged measurement over the previous 3–6 minutes, eliminating respiratory variations. Current commercial systems have a “fast” mode that displays the result of each measurement cycle as it is performed, allowing earlier detection of acute changes, but at the price of accentuated random variations and errors. Because of the very small thermal signal involved, this method is more susceptible to interference by other sources of heat, such as rapid intravenous fluid infusion or the temperature changes that occur immediately following cardiopulmonary bypass.127 Continuous thermodilution has been quite extensively validated against standard TDCO, mainly in patients undergoing cardiac surgery.119,128 Although this method is termed continuous thermodilution, current devices only provide semicontinuous measurement that is averaged over a several-minute interval, and therefore have an obligate delay of approximately 10 minutes in identifying acute hemodynamic changes.129 However, compared to TDCO measurements performed only every several hours, continuous thermodilution might still allow earlier recognition of hemodynamic problems.130 Thus far, no studies have demonstrated that patient outcome is improved by using these more expensive continuous cardiac output catheters.

Pulse Contour-Derived Cardiac Output Pulse contour methods calculate stroke volume from the area under the arterial pressure waveform. The pressure waveform as measured in the large arteries is a combination of a forward pressure wave produced by the contraction of the heart and a backward pressure wave reflected from arterial branch points and arterial–arteriolar junctions. The magnitude of wave reflection is affected by changes in arterial resistance and compliance and needs to be taken into account in the calculation algorithm.131,132 Available

commercial devices are based upon different models of the circulation, and generally require intermittent (every 4– 8 hours) calibration with a cardiac output reference to establish accurate monitoring in an individual patient, by accounting for differences in vascular resistance, compliance, impedance, and wave reflectance.133 While the pulse contour method only requires an arterial line for monitoring, the needed calibration methods might require additional invasive procedures. Reliable pulse contour measurement requires a reasonably well-defined arterial pressure waveform, in part because the dicrotic notch is often used to identify end-systole. Conversely, it appears that pulse contour cardiac output monitoring remains accurate across arterial pressure-monitoring systems that have a wide range of dynamic response characteristics.134 Other limitations of this technique include the presence of frequent dysrhythmias or severe tachycardia leading to a variable or low stroke volume, respectively. Some investigators have shown that large fluctuations in systemic vascular resistance affect vessel compliance and wave reflectance and require recalibration to maintain accuracy of the pulse contour measurements,134 whereas other studies have shown preserved accuracy despite acute changes in systemic vascular resistance.135 Notwithstanding these shortcomings, the pulse contour method provides a true continuous beat-to-beat measurement of cardiac output, which has acceptable agreement with TDCO and a small mean bias of 0.1–0.3 L/ min.119,132,134 In addition, pulse contour methods can calculate the beat-to-beat variation in stroke volume induced by positive pressure ventilation, which can be used to evaluate volume status.

Esophageal Doppler Ultrasound waves reflected from a moving target change their frequency, which allows calculation of the direction and velocity of movement using the Doppler equation (Box 29–7). For cardiac output calculation, circulating red blood cells are used as the moving target. Current Doppler cardiac output technique employs an esophageal probe, similar in size to a standard orogastric tube, which is inserted into the lower esophagus, approximately 35–40 cm from the incisor teeth.136 This position

BOX 29–7. The Doppler Equation V=

Δ f .c 2f0 .cos q

Where V Δf fo θ

c

= blood velocity = change of ultrasound frequency = transmitted ultrasound frequency = angle between the ultrasound beam and velocity vector = velocity of ultrasound in blood (1540 m/sec)

provides a suitable acoustic window to the descending thoracic aorta, because the aorta and esophagus are almost parallel at this anatomic location. With this method, descending thoracic aorta blood flow is calculated from the area under the velocity– time curve and the aortic cross-sectional area. The latter is either derived from a nomogram or continuously measured during the cardiac cycle with a dedicated M-mode echo transducer incorporated into the probe to measure aortic diameter. As might be expected, measuring the aortic diameter gives more accurate results than using the nomogram.137 Because the flow in the descending aorta is only a proportion of total cardiac output, some devices report an estimate of total cardiac output that is derived by multiplying descending thoracic aortic flow by an empirical constant of 1.4.136 In addition to providing a minimally invasive, continuous beat-to-beat estimate of cardiac output, Doppler cardiac output monitors can provide valuable information regarding cardiac preload, contractility, and afterload, all derived from the shape of the velocity–time spectral Doppler waveform (Fig. 29–15).136 The respiratory variation in aortic blood flow velocity can also be used to evaluate preload, similar to systolic blood pressure variation.138 One shortcoming of the esophageal Doppler monitor is its restriction to tracheally intubated, deeply sedated patients. Relative contraindications include patients with esophageal pathology or severe coagulopathy. In addition, frequent repositioning of the Doppler probe is needed, particularly in ICU patients who are not paralyzed,


Preload reduction

Mean acceleration Positive inotropy

Velocity

Peak velocity

Afterload reduction

Flow time Time

Myocardial depression

predominant change

Afterload increase

Preload increase

FIGURE 29–15. Spectral Doppler tracings of descending aorta blood flow recorded using esophageal Doppler cardiac output monitoring. Changes in the velocity–time waveform shape result from alterations in contractility (mainly affect peak velocity and mean acceleration), preload (mainly affect systolic flow time corrected for heart rate [FTc]), and afterload (which affect FTc, mean acceleration and peak flow velocity). (Modified with permission from Singer M. Esophageal Doppler monitoring of aortic blood flow: beat-by-beat cardiac output monitoring. Int Anesthesiol Clin 1993;31(3):99–125.)

anesthetized, and immobile. Additional concerns involve the underlying assumptions on which the technique is based: a fixed ratio between descending aortic blood flow and total cardiac output, a constant thoracic aortic cross-sectional area during systole, a uniform flow profile across the aorta, and absence of significant diastolic antegrade aortic flow. It is unsurprising that esophageal Doppler cardiac output measurements tend to underestimate total cardiac output measured by other methods, although in some trials, the bias was small enough to be clinically insignificant and generally changes in cardiac output over time were reliably tracked.139 Despite all the theoretical concerns regarding the accuracy of the technique, Doppler-derived cardiac output monitoring is one of the few monitoring modalities that have been tested and found to be clinically effective for resuscitating critically ill and surgical patients. Several studies, both in cardiac and noncardiac surgery, used esophageal Doppler monitoring to guide fluid therapy for maximizing cardiac output, and have shown a reduced incidence of perioperative complications and a shorter hospital length of stay.140–144

Gastric Tonometry Gastric tonometry is a unique monitoring modality, which instead of directly

measuring total cardiac output, measures gastric PCO2, serving as a surrogate measure of regional blood flow and tissue perfusion. As gastric mucosal blood flow decreases, CO2 clearance is reduced. With further reduction in blood flow and oxygen delivery, CO2 production increases from titration of H+ ions generated by anaerobic metabolism.145 Increased mucosal tissue levels will be reflected by increased CO2 levels in the gastric lumen because CO2 diffuses freely across membranes. The gastric tonometer monitor consists of a modified gastric tube with a balloon at the tip, which is filled with either saline or air. Carbon dioxide in the balloon equilibrates over time with the gas in the gastric lumen, and samples are intermittently aspirated for measurement using either an arterial blood gases machine (for saline tonometry) or infrared spectroscopy (for air tonometry).146 Calculating the gap between gastric PCO2 and arterial PCO2 controls for the effect of respiratory acidosis on gastric CO2. Most devices can also calculate gastric pH (intracellular hydrogen ion concentration [pHi]) when the arterial bicarbonate level is measured and entered into the monitor. A pHi value below 7.32 is considered abnormal, but the PCO2 gap (gastric PCO2 – arterial PCO2) is currently considered to be a better measure of tissue perfusion.147

During low perfusion states, splanchnic blood flow is the first to be compromised, as the body diverts blood flow to the brain, heart, and kidneys.148 Consequently, gastric PCO2 has been considered to be an early monitor of hypoperfusion. Studies of experimental graded hemorrhage,149 as well as clinical studies in trauma patients,150 support this concept. The effects of gut ischemia may be protean, as it can contribute to bacterial translocation, inflammatory response, and the development of multiorgan failure, independent of the mechanism that caused the ischemia in the first place.151 Indeed, intraoperative gastric hypercarbia was shown to correlate with increased complications, length of stay and mortality after both cardiac and noncardiac surgery.152,153 Lastly, several studies in ICU patients and in patients undergoing noncardiac surgery suggest that therapy guided by gastric PCO2 can reduce morbidity and mortality.154,155 Gastric tonometry is contraindicated in patients with esophageal abnormalities and the measurements might be affected by feeding, gastric insufflation or suctioning and the use of H2 blockers. Finally, not all studies have found gastric tonometry to be useful.156,157

PROBLEM-ORIENTED HEMODYNAMIC MONITORING For clinicians, monitoring choices should always stem from a clinical diagnostic or therapeutic question. Consequently, it is essential to discuss and compare the various existing monitoring modalities in terms of their usefulness in answering specific clinical questions.

Assessment of Acute Ischemia Several studies confirm the association of perioperative myocardial ischemia with postoperative cardiac complications, mainly myocardial infarction and cardiac death.158,159 This highlights the importance of early diagnosis of ischemia in the surgical patient. The most commonly used methods to diagnose ischemia perioperatively are ECG monitoring and echocardiography. Some physicians, however, advocate the use of the PAC to monitor for ischemia.160 Myocardial ischemia typically impairs diastolic relaxation, which leads

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538

to decreased ventricular compliance and increased ventricular end-diastolic pressure.161 This leads to an increased amplitude of the a wave of the PAOP, reflecting left atrial contraction against a nonrelaxed ventricle. Less prominent increases in mean PAOP and PADP can also be seen. When systolic dysfunction occurs, reduced stroke volume, left ventricular stroke work, and arterial blood pressure may ensue. If acute mitral regurgitation occurs as a result of either ischemiainduced geometric changes in the left ventricle or papillary muscle dysfunction, a tall c-v wave can be observed in the PAOP trace. The main limitation of using PAC monitoring for diagnosis of ischemia is that no threshold values have been set as diagnostic criteria. In a study where ischemia was defined as wall motion abnormalities seen on TEE, mean PAOP increased by 3.5 ± 4.8 mm Hg.162 However, a threshold of 3 mm Hg had only a 25% sensitivity and a 15% positive predictive value for ischemia. Another study in patients undergoing CABG used myocardial lactate production to diagnose ischemia and found that a 5-mm Hg increase in mean PAOP had almost 100% specificity, but only 1.6% sensitivity.163 Interestingly, ECG monitoring had only 17.5% sensitivity, demonstrating the lack of a clinically reliable and useful ischemia monitor. Given the numerous factors that can affect PAC pressure measurements, these results are unsurprising. Also, ischemia in small areas of the myocardium might not induce a large enough change in global myocardial compliance to be detected by the PAC. Lastly, the PAOP cannot be continuously monitored because of the risk of pulmonary infarction. To summarize, PAC monitoring should probably not be employed for the sole purpose of diagnosing perioperative ischemia. However, other currently available monitors, namely ECG and TEE, are also limited in their diagnostic usefulness. Information collected from the PAC can help to corroborate the diagnosis of ischemia, evaluate its hemodynamic significance and guide therapy.

Assessment of Pulmonary Edema Pulmonary edema results from the interplay of two different processes: increased pulmonary capillary hydro-

static pressure and increased pulmonary capillary permeability. The critical forces driving edema formation are described by the Starling equation (Box 29–8). Pulmonary edema formation is reduced as pulmonary capillary hydrostatic pressure is lowered (e.g., by diuresis), but at a certain point left ventricular preload reduction will reduce cardiac output without any further benefit in terms of pulmonary edema. In normal alveolar–capillary permeability states, a pulmonary capillary pressure of 18–20 mm Hg is considered to be the threshold beyond which alveolar flooding is promoted.164 Accordingly, pulmonary edema in the presence of a PAOP below 18 mm Hg has traditionally been classified as noncardiogenic edema.165

The Usefulness of the PAOP Clinical reliance on absolute PAOP values such as these can be, however, misleading. First, increased hydrostatic pressure might be transient, as in acute ischemic left ventricular dysfunction or acute neurogenic pulmonary edema. Following such an event, by the time the PAOP is measured, it might already be significantly lower. Second, the PAOP is used as a surrogate for pulmonary capillary pressure, assuming negligible pulmonary venous resistance. However, in conditions of increased cardiac output or increased pulmonary venous resistance (e.g., pulmonary fibrosis, latestage ARDS, high-altitude pulmonary edema, vasopressor therapy), true pulmonary capillary pressure might be significantly higher than the measured PAOP.166 In these patients, pulmonary vasodilators might be beneficial for treating pulmonary edema. Third, positive-pressure ventilation may increase the PAOP while simultaneously increasing the interstitial tissue pressure, resulting in no net increase in the filtration pressure gradient. Last, in patients with acute lung injury and increased capillary permeability, the Starling equation indicates that pulmonary capillary pressure might play even a greater role in edema formation because as Kd decreases, protein concentration in the interstitium increases and the oncotic pressure gradient decreases (Box 29–8). Under these conditions, pulmonary capillary pressures less than 18 mm Hg might still promote formation of pulmonary edema. Indeed, pulmonary capillary pres-

BOX 29–8. Starling’s Equation for Fluid Flux across Membranes Fluid flux = Kfc × ( Pcapillary – Pinterstitium ) – Kd × ( πcapillary – πinterstitium ) Where: P = π= Kfc = Kd=

hydrostatic pressure oncotic pressure capillary filtration coefficient reflection coefficient

sure is a major determinant of fluid flux across the alveolar capillary membrane regardless of the degree of capillary permeability. The “safe” level of PAOP in patients with increased alveolar capillary permeability remains elusive.167 However, a large randomized study in patients with acute lung injury has found some clinical advantage to a restrictive fluid therapy (aiming at PAOP 600 mL/min/m2 VO2 >170 mL/min/m2 DO2 >600 mL/min/m2

Fluids, blood, dobutamine

37% vs. 18%

Dopexamine

22.7% vs. 5.7%

PAOP >12 mm Hg Hb >11 g/dL SaO2 > 94% DO2 >600 mL/min/m2 DO2 >600 mL/min/m2

Fluid, blood, oxygen, adrenaline/dopexamine Dobutamine

17% vs. 3%

CI >2.8 L/min/m2 SVR 70% Lactate 600 mL/min/m2

Fluids, dopexamine

60

Esophageal Doppler

Maximize stroke volume

Fluids

Femur neck fracture

40

Esophageal Doppler

Maximize stroke volume

Fluids

Noncardiac surgery with estimated blood loss >500 mL

100

Esophageal Doppler

Maximize stroke olume

Fluids

3% vs. 1% (p nonsignificant, but significantly shorter hospital stay and fewer complications) 9.7% vs. 10% (p nonsignificant, but significantly shorter hospital stay and fewer complications) Not reported, but significantly shorter hospital stay and fewer complications 10% vs. 5% (p nonsignificant, but shorter hospital stay) Not reported, but shorter hospital stay

50% vs. 15.7%

CI, cardiac index; DO2, oxygen delivery; Hb, hemoglobin concentration; PAC, pulmonary artery catheter; PAOP, pulmonary artery occlusive pressure; SaO2, arterial oxygen saturation; SvO2, mixed venous oxygen saturation; SVR, systemic vascular restistance; VO2, oxygen consumption. aFor all results, p is significant at 0.05 levels unless stated otherwise.

have a prognostic value,218 and many studies of goal-directed therapy demonstrate their clinical usefulness (Table 29–5). However, these studies also demonstrate that the “optimal” level of cardiac output or oxygen delivery in the perioperative period is not necessarily the “normal” level. With the changes in oxygen requirements resulting from anesthesia on the one hand, or the systemic inflammatory response on the other hand, the same

oxygen delivery might be too high, too low, or just right. The development of “oxygen debt” after major surgery is associated with both survival and the incidence of complications.219

metabolic markers include either global measures such as base excess, blood lactate level, and venous oxygen saturation, or regional perfusion measures, such as cerebral oximetry and gastric tonometry.

Metabolic Indices Considering the shortcomings of flowbased monitoring methods, metabolic indices might supply the required information about the adequacy of oxygen delivery or cardiac output. These

Lactic Acidosis Elevated blood lactate and metabolic acidosis indicate anaerobic metabolism, presumably related to hypoperfusion leading to tissue ischemia. Indeed, various studies

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confirm the prognostic significance of serial lactate and base deficit measurements,220,221 and the potential of using lactate level as a guide for directing therapy.92,222 Several pitfalls need to be acknowledged. Lactate levels may increase as a consequence of isolated organ damage such as limb ischemia or mesenteric thrombosis, where surgical intervention, rather than medical therapy to increase oxygen delivery, is warranted. Also, because there are various other etiologies for both hyperlactatemia and metabolic acidosis, lactic acidosis is probably a more specific index for hypoperfusion than either measure alone.223

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Venous Oximetry Because increased oxygen extraction can initially compensate for reduced oxygen delivery, anaerobic metabolism usually does not occur before venous oxygen saturation has decreased to 30–40%.224 Therefore, monitoring venous oximetry, in either mixed pulmonary or central venous blood, might allow early detection of hypoperfusion before tissue ischemia develops. Reduced venous oxygen saturation better predicts adverse outcome after cardiac surgery than does cardiac output or oxygen delivery,225 while treating low cardiac output in patients with a normal venous oxygen saturation might be counterproductive.226 Indeed, venous oxygen saturation may be one of the more important monitors for judging the adequacy of the hemodynamic status and determining whether the measured pressureand flow-based indices are acceptable, in the context of the individual patient’s oxygen requirements.227 Regional versus Global Perfusion A major drawback of lactate, base deficit, and venous oxygen saturation is their global nature. Lactate production and increased oxygen extraction induced by ischemia in an isolated organ might be diluted and therefore masked when whole-body lactate or mixed venous oximetry are measured. Consequently, a place exists for also monitoring regional perfusion, the best example being gastric tonometry. Other regional monitors include jugular bulb oximetry, sublingual capnography, near-infrared light spectroscopy, tissue oxygen electrodes, and cytoscan imaging.228,229 To summarize, a systematic approach to hemodynamic monitoring that combines relatively easily measured metabolic indices with classical

Resuscitate to a mean arterial pressure of > 65 mm Hg SvO2

Normal (≥ 70%)

Low (< 70%)

Do nothing

SaO2

Low (hypoxemia)

Normal (> 95%) (Increased O2ER)

Oxygen therapy, increase PEEP

Cardiac output

High (>2.5 L/min.M2)

Low (8 g/dL Stress, anxiety, pain (high VO2)

< 8 g/dL Anemia

>18 mm Hg Myocardial dysfunction

< 18 mm Hg Hypovolemia

Analgesia sedation

Blood transfusion

Inotropes

Fluid challenge

FIGURE 29–20. A systematic approach to assessment and treatment of hypoperfusion. Perfusion assessment by measuring mixed venous oxygen saturation (SvO2) starts after restoration of perfusion pressure (which can be done using fluids and vasopressors). O 2ER, oxygen extraction ratio; SaO2, arterial oxygen saturation; VO2, systemic oxygen consumption. (Reproduced with permission from Pinsky MR, Vincent JL. Let us use the pulmonary artery catheter correctly and only when we need it. Crit Care Med 2005;33(5):1119–1122.)

hemodynamic measurements might allow early detection of tissue hypoperfusion and undertaking of appropriate corrective measures (Fig. 29–20).

Preemptive Goal-Directed Therapy Monitoring alone cannot influence patient outcome unless it is used to guide effective therapeutic interventions. Usually, these interventions are illdefined and highly variable between practitioners, contributing to the difficulty in assessing the usefulness of various monitoring modalities, most notably the PAC.3,32 The “goal-directed therapy” approach, in contrast, defines a priori a set of interventions aimed at achieving specific values for monitored physiologic parameters. In an early retrospective trial in high-risk surgical patients, mostly trauma vic-

tims, survivors were found to achieve higher levels of cardiac output (>4.5 L/min/m2), oxygen delivery (>600 mL/min/m2), and oxygen consumption (>170 mL/min/m2) compared to nonsurvivors.218 This was followed by a successful prospective interventional trial aimed at treating patients to achieve these “supranormal” values preoperatively through use of fluids, blood transfusion, and vasoactive drugs.230 Many similar trials followed, and most of them confirmed a significantly decreased morbidity and mortality in the goal-directed treatment group (Table 29–5). However, a recent, large, multicenter, randomized study tested early goal-directed therapy in surgical patients and did not find any benefit.60 This study, however, included relatively low-risk patients (mortality in the control group was


only 7.7%), the goals chosen differed from those in previous positive studies, most patients did not achieve the therapeutic goals prior to surgery, and the interventions were not rigorously defined. In contrast to perioperative management of surgical patients or treatment of patients in early stages of sepsis,91 goal-directed therapy has been less successful when applied to critically ill medical and surgical patients who have an established systemic inflammatory response syndrome, sepsis, or multiorgan failure.93,231 The main early pathophysiologic disturbance in trauma and perioperative patients is occult hypovolemia, which can be ameliorated with fluids alone.232 In contrast, the pathophysiologic disturbances in critically ill septic patients with multiorgan failure may be much more profound and involve abnormalities at the level of the microcirculation and mitochondria. These critically ill patients might not be able to increase oxygen use regardless of oxygen delivery.233,234 Goal-directed therapy in the perioperative period is still an area of ongoing research and considerable uncertainty. Several retrospective studies suggest that the large fluid volumes required for increasing cardiac index and oxygen delivery to supranormal values might result in congestive heart failure72 and increased abdominal pressure leading to gastric hypoperfusion and acute renal failure.235 Positive inotropic agents might increase systemic oxygen consumption owing to their thermogenic effect, hence paradoxically decreasing venous oxygen saturation despite increased cardiac output.90 Increasing myocardial oxygen consumption might also trigger acute ischemic events.72 For perioperative goal-directed therapy to have a beneficial effect on mortality, treated patients need to be at a very high-risk group (at least 15–20% predicted mortality, according to a recent meta-analysis236). Older patients (above 65 years) with coexisting cardiorespiratory diseases may be one such group.237 A low anaerobic threshold on preoperative cardiopulmonary exercise testing or a clinical assessment of the ability to climb 2 flights of stairs might also help identify patients who will not be able to increase oxygen delivery perioperatively without aggressive therapeutic interventions.238,239 Patients with lower mor-

tality risk might still benefit from goaldirected therapy by having a reduced complication rate or shortened hospital length of stay. To provide any benefit, hemodynamic goals must be achieved early, either pre- or intraoperatively. In most patients, optimization of volume status is all that is required. Patients with known cardiac dysfunction may require inotropic therapy in addition to fluid resuscitation, guided either by cardiac output or venous oxygen saturation. Clinical attention to development of fluid overload and increased oxygen consumption may reduce potential complications of goal directed therapy. When performed properly and applied to appropriate patient cohorts, perioperative hemodynamic optimization may not only improve outcome, but also may prove to be a cost-effective intervention as the reduction in complications compensates for the increased monitoring costs and ICU use.240

Discrepant Clinical Data and Troubleshooting Monitoring Problems One of the more important roles played by the anesthesiologist in the care of the critically ill patient is to determine that the monitored data are accurate and, based on these data and the rest of the patient’s history, physical findings, and testing results, to arrive at a clinical diagnosis. A common challenge arises when monitoring results provide discrepant data or are otherwise inconsistent with the clinical condition of the patient and the working clinical diagnosis. In these circumstances, a methodical approach is helpful, one that is based upon a good understanding of monitoring equipment and patient physiology. Box 29–9

BOX 29–9. Standard Steps for Troubleshooting Unexpected Monitored Values • Recognize clinical urgency • Address technical considerations • Confirm digital values with accompanying waveforms • Confirm measurements using another technique • Cross validate measurements with another monitored variable • Consider physiologic and pathophysiologic explanations • Consider iatrogenic causes

summarizes the recommended steps in the evaluation of discrepant data. These steps can be performed rapidly and some even simultaneously. Although less common, there are certainly clinical situations wherein apparently normal monitored values are in fact spurious. Recognition of these problems begins with knowledge of the clinical condition of the patient and the clinical context in which the monitored value is observed.

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CHAPTER 30 Intraoperative Transesophageal Echocardiography: A Systematic Approach

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Larry C. Field, MD, George D. Lappas, MD, Angus A. Christie, MD, Andrew Green, MD, Steven T. Morozowich, MD, Tamas Szabo, MD, Ph D, Qin Zhang, MD, Stephen P. Murphy, MD, Ravi Bissessar, MD, and Solomon Aronson, MD

Intraoperative echocardiography now is considered an essential part of modern cardiac surgery. It can be performed using transesophageal, epicardial, epiaortic, and transthoracic approaches. Its clinical applications are numerous, including assessment of left ventricular (LV) and right ventricular (RV) function, assessment of preload, measurement of cardiac output, detection of myocardial ischemia, assessment of valvular function, detection and assessment of various congenital heart diseases, and evaluation of aortic atheromatous disease prior to cannulation. Intraoperative echocardiography serves as an important diagnostic tool, as well as a monitor, for cardiac surgical patients.

INDICATIONS FOR PERIOPERATIVE TRANSESOPHAGEAL ECHOCARDIOGRAPHY Since 1996, when evidence-based practice guidelines for perioperative transesophageal echocardiography (TEE) initially were published (see Fig. 30–1), support for the superiority of intraoperative TEE over other techniques

(e.g., electrocardiograms or pulmonary artery catheters) for specific diagnostic information has steadily increased. The indications for a TEE examination should be based on each patient’s condition rather than a specific surgical procedure. In addition, the dynamics of each case should dictate when a TEE examination may reduce critical diagnostic work or distract from it. Table 30–1 provides some published recommendations.

LIMITATIONS TO AND CONTRAINDICATIONS FOR TEE One of the most important limitations to performing an intraoperative TEE examination is the expertise or attention of the physician. Substantial patient harm can result from inappropriate fixation of the anesthesiologist’s attention on the TEE examination rather than on the patient. Although performing a useful TEE examination while simultaneously caring for the patient often is possible, a more appropriate practice would be having a colleague perform the TEE examination while the primary anesthesiologist focuses on caring for the patient (especially if a more comprehensive TEE examination is desired or the patient is unstable). There are few absolute contraindications to performing a TEE examination in an anesthetized patient. A history of dysphagia, esophageal varices, severe gastroesophageal reflux disease, odynophagia, unstable cervical spine injuries, prior mediastinal radiation, and upper airway pathology should be sought prior to probe insertion and are considered relative contraindications. Although TEE has been proven safe, it should be undertaken only by experienced operators in cases with a clear indication for TEE use. In anesthetized patients, the probe can be inserted blindly or with laryngoscopic visualization. It is

helpful to have an assistant support the probe during insertion. A bite guard should always be used to protect the patient as well as the probe. Proper insertion of the probe requires skill and judgment. Major complications of TEE are rare (0.2–0.6% of insertion attempts in prospective studies),1–3 and most examples are based on published case reports. The transducer should never be forced through resistance upon entry into or during passage through the esophagus. Insertion and manipulation of the TEE probe can result in oral, esophageal, or pharyngeal trauma and arrhythmias. Another important danger of performing a TEE examination is misrepresenting a finding as abnormal when it is actually a normal variant (Table 30–2). Understanding the normal variants will enable better diagnostic accuracy when detecting abnormal structures. Significant clinical experience is required for the echocardiographer to be able to confidently make this distinction.

TERMINOLOGY Table 30–3 lists the terminology used to describe probe manipulation, with the patient lying supine, with reference to the heart.

BASIC PRINCIPLES OF ECHOCARDIOGRAPHY Two-dimensional (2D) echocardiography displays the intensity of reflected ultrasound waves as brightness along the axis of the scan plane to reconstruct a representative 2D image. This is useful for identifying tissue structures but does not allow for full assessment of hemodynamics. Doppler ultrasound, however, can be used to assess hemodynamics. Doppler ultrasound uses the principle of

KEY POINTS 1. TEE is an essential component of cardiac anesthesia care. 2. A complete diagnostic examination should include the standard set of views (at a minimum) suggested by the ASE/SCA guidelines.


3. Intraoperative evaluation of acute persistent and life threatening hemodynamic disturbances in which ventricular function is uncertain and unresponsive to treatment is a Category I indication for TEE.

CHAPTER 30: Intraoperative Transesophageal Echocardiography: A Systematic Approach

FIGURE 30–1. Probe manipulation of guidelines modified from “ASE/SCA guidelines for performing a comprehensive intraoperative multiplane transesophageal echocardiography examination: recommendations of the American Society of Echocardiography Council for Intraoperative Echocardiography and the Society of Cardiovascular Anesthesiologists Task Force for Certification in Perioperative Transesophageal Echocardiography.”4

Doppler effect to display the velocities of moving structures (red blood cells or myocardium). When ultrasound is reflected from a moving target, the ultrasound frequency is slightly changed from the transmitted frequency (i.e., Doppler shift). Red blood cells moving toward the probe return a slightly increased frequency of ultrasound waves, and those moving away from the probe return a slightly decreased frequency of ultrasound waves. The magnitude of Doppler shift is proportional to the velocity of the moving structure. These velocity measurements can be translated into the pressure differences that generate them (Bernoulli equation), allowing for hemodynamic assessments. Modified Bernoulli: ∆P = 4(V22 – V12). Simplified Bernoulli: ∆P = 4V22 (assuming V1 30%). Severe hypokinesis refers to only slight wall movement and 20%. In clinical practice, simple visual estimation by the echocardiographer often is the source of the reported EF. The reliability of visual estimation of EF by an experienced echocardiographer appears to be similar to wallmotion index and EF calculations using the Simpson rule.6 New image

processing modes, such as secondary harmonic imaging, Doppler tissue imaging, and contrast agents, can help delineate subendocardial borders and improve the image. Volumes may soon be obtained from real-time 3D echocardiography with automated border detection programs. Neither FAC nor EF is a pure index of myocardial contractility because both are dependent upon loading conditions, especially at the extremes of preload and afterload. Attempts have been made to measure load-independent indices of ventricular function. Generation of pressure–volume loops at different loading conditions results in a linear end-systolic relationship, the slope of which is termed end-systolic elastance. The area within pressure–volume loops is stroke work, which can be plotted against the corresponding end-diastolic volumes to obtain preload-recruitable work. These measures are much more complex and include measuring intraventricular pressures or their surrogates and thus are principally used for research purposes at this time. Less load-dependent measures that are easier to obtain, although rarely reported, include the peak systolic pressure-end systolic volume ratio and cardiac power. Mean cardiac power is the product of stroke volume, mean arterial pressure, and heart rate. Peak instantaneous power also can be calculated. These measures can be corrected for end-diastolic volume to make them load independent. If MR is present, dP/dt of the MR jet is a relatively load-independent measure of

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E FIGURE 30–7. Ejection fraction calculated using the disk summation method from four-chamber end-diastole (A), two-chamber end-diastole (B), four-chamber end-systole (C), and two-chamber end-systole (D) tracings. E. Depiction of a single Simpson disk with elliptical diameters measured from midesophageal four-chamber and two-chamber views. Using the software package of the transesophageal echocardiography machines, the volume of each theoretical disk is automatically calculated separately in this way and then summed together to obtain the left ventricular volume in both end-diastole and end-systole, allowing for calculation of ejection fraction.

contractility, which is otherwise difficult to assess when ventricular work is lost into the lower-pressure LA. Myocardial performance index is the sum of isovolumic contraction time and isovolumic relaxation time, divided by ejection time. It combines systolic and diastolic function into one easily obtainable and reproducible index that has good prognostic value.7 All of these measures have the benefit of being independent of ventricular geometry and the subjective determination of endocardial borders.

Diastolic Function Diastole is divided into four distinct phases: isovolumic relaxation, early rapid filling, diastasis, and atrial contraction (Fig. 30–8). Isovolumic relax-

ation begins with closure of the aortic valve (AV). The chamber relaxes, and the pressure within the chamber decreases. Once the pressure falls below the pressure in the atrium, the MV opens, ending the period of isovolumic relaxation. Isovolumic relaxation is an active, energy dependent process; therefore, abnormalities in systolic function usually are accompanied by abnormalities in isovolumic relaxation. Blood flowing through the MV initiates the early rapid filling phase. The rapid filling of the chamber (early diastole) is dependent on both LV relaxation (an active process) and chamber compliance (a passive property). As volume fills the ventricle, the pressures between the atrium and the ventricle equalize, and the flow begins to

slow. This period is referred to as diastasis because there is little blood flow between the chambers. The MV leaflets remain in an open position, and the duration of diastasis is dependent on heart rate and chamber compliance. With the onset of atrial contraction, atrial pressures become greater than ventricular pressures, so again there is a net flow of blood into the ventricle. In normal individuals, atrial contraction contributes approximately 20% to the end-diastolic ventricular volume. The atrial contraction phase is dependent on the chamber compliance, LA function, and the electrical conduction system. From the preceding discussion, one can conclude that flow is driven primarily by pressure gradients between


LV

Pressure

Aorta

LA

ERF

IVRT

Systole

D A

Diastole

Systole

Contraction Relaxation Filling

FIGURE 30–8. Pressure tracings from a normal cardiac cycle. Pressure differences (which cannot be measured directly by transesophageal echocardiography) between chambers drive the corresponding flow velocities (which we measure with transesophageal echocardiography to calculate pressure differences). A, Atrial contraction; D, diastasis; ERF, early rapid filling; IVRT, isovolumic relaxation time; LA, left atrium; LV, left ventricle.

the atrium and the ventricle. For a given pressure, if LV relaxation is brisk, the result is a large, early pressure gradient (often even a suction effect) that drives filling during early diastole. This results in less filling in late diastole. On the other hand, if ventricular relaxation is sluggish, early diastolic filling declines and a greater proportion of diastolic filling is seen in late diastole. In the latter situation, there is a greater dependence on atrial contraction for filling. It follows, then, that a decrease in LV relaxation and/or compliance will lead to a compensatory increase in LA pressures to maintain end-diastolic ventricular volume. Because the rate of LV relaxation and increase of LA pressures is a continuum, many different transmitral pressure gradients and LV filling patterns are possible. This leads to a challenge in quantifying diastolic dysfunction over the continuum of varying patient conditions. Doppler echocardiography, by virtue of its ability to evaluate flow patterns across valves and in large blood vessels, allows the clinician to diagnose diastolic dysfunction. Two-dimensional echocardiographic inspection of

the ventricular systolic function may provide an alternative cause for a patient’s heart failure or suggest that diastolic dysfunction is likely. For example, if a patient with the clinical picture of heart failure is found to have normal ventricular systolic function and volumes but LV hypertrophy (end-diastolic wall thickness >1.1 cm) is present, diastolic heart failure is likely. Combined systolic and diastolic failure may be present, or a patient may have ventricular hypertrophy without measurable diastolic abnormalities. Therefore, 2D findings are neither sensitive nor specific for diastolic dysfunction, and further investigation is warranted. Two-dimensional echocardiography, then, is most useful in helping to quantify systolic function and to differentiate isolated diastolic dysfunction from combined systolic–diastolic dysfunction. To fully assess diastolic function, use of Doppler echocardiography techniques is necessary. The period required for isovolumic relaxation (first phase of diastole) is the isovolumic relaxation time (IVRT). IVRT is measured as the time interval from closure of the AV to opening of

the MV. IVRT can be obtained from the deep TG long-axis (LAX) view (multiplane angle at 90°) with a PWD sample at (or CWD through) the junction of the MV inflow and the LV outflow tract (LVOT). Normally, IVRT lasts 60–90 msec and reflects the rate of myocardial relaxation. Impaired relaxation delays the drop in ventricular pressure below that of the atrium, resulting in prolonged IVRT. It probably is the most sensitive Doppler index for detecting impaired relaxation because it is the first to become abnormal, but it is dependent on afterload and heart rate. If a PWD sample is acquired near the coaptation point of the MV leaflets, transmitral flow velocities can be mapped and measured, corresponding to early diastolic filling. Flow at this time is directed away from the transducer ( below the baseline). This wave is the early or E wave. The time required for the flow velocity to return to zero (from the peak of the E wave back to the baseline) is the deceleration time. For a brief time, there is no flow across the MV, and the velocities will remain zero (diastasis). Soon after, the LA contracts, and flow once again begins. Plotting these velocities versus time will yield the atrial or A wave. The total duration of the A wave (from the end of diastasis to the return of zero flow) is termed A-wave duration (Adur). Normally, most diastolic filling occurs in early diastole so that the E/A ratio is >1 (Fig. 30–9A). However, mitral flow velocity curves vary with loading conditions, age, and heart rate. In healthy young patients, the E/ A ratio may be as high as two. As people get older, LV relaxation slows; there is a gradual decrease of the peak E-wave velocity and an increase of the A-wave component. In most individuals, E and A become approximately equal in the sixth decade of life. Because relaxation is impaired beyond what is “normal” for age, early diastolic filling decreases. With diastolic dysfunction, the volume that remains in the atrium at the end of the early filling phase increases, and a progressively vigorous compensatory atrial contraction (“atrial kick”) occurs. This results in a reversed E/A ratio (E/A 220 msec) and IVRT is increased (>100 msec).

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562 FIGURE 30–9. A. Normal transmitral flow velocities. B. Pseudonormal transmitral flow velocities in a patient with regurgitant mitral flow. C. Restrictive diastolic dysfunction in a patient with mitral regurgitation. A, A wave of atrial contraction; E, E wave of early diastolic filling; MR, regurgitant mitral flow velocities (aliasing, a limitation of pulsed-wave Doppler, is also demonstrated, with some mitral regurgitation velocities incorrectly displayed below the baseline as forward velocity).

With further diastolic dysfunction, LV compliance is even lower, and filling pressures begin to increase. This leads to a compensatory increase of LA atrial pressure that results in increased early filling velocities despite impaired relaxation. The filling pattern appears relatively normal (termed pseudonormalization), and the E/A ratio returns to approximately 1 (Fig. 30–9B). Pseudonormalization represents abnormalities of both relaxation and compliance and can be distinguished from normal filling by a shortened deceleration time. In patients with severely decreased LV compliance, LA pressure is markedly elevated and drives vigorous early diastolic filling velocities despite impaired relaxation. This restrictive filling pattern (E/A >1.5) is consistent with an abnormal rise in LV diastolic pressure and an abrupt deceleration of early diastolic flow (deceleration time D-wave velocity) as the MV annulus is pulled downward (Fig. 30–10A). During diastole, additional blood flows from the pulmonary veins into the LA, which is simultaneously emptying into the LV. During atrial contraction, blood is ejected into the LV, with a small amount of retrograde flow into

the pulmonary veins. The smaller A wave is in the opposite direction to the S and D waves. As pressure in the LA increases (compensating for advancing diastolic dysfunction), systolic flow decreases (decreased S-wave velocity) and flow occurs predominantly in diastole (increased D-wave velocity; Fig. 30–10B). The absolute values of the S and D waves do not necessarily provide any additional information. Because they are dependent on the volume status of the patient, the absolute values of the S and D waves can vary significantly even under normal conditions. Pulmonary venous flow patterns help to differentiate normal transmitral filling patterns from pseudonormal patterns. In the pseudonormal pattern, the atrium contracts against an increased afterload in the LV due to an elevated diastolic filling pressure and a stiff LV. More blood will be ejected along the “path of least resistance” back into the pulmonary veins. As a result, the A wave in pseudonor-


FIGURE 30–10. A. Normal pulmonary venous flow velocities (S wave > D wave). B. Abnormal pulmonary venous flow velocities (D wave > S wave) from diastolic dysfunction. A, Retrograde atrial flow wave; D, diastolic phase wave; S, systolic phase wave.

mal diastolic dysfunction is tall (often >0.35 m/s) and prolonged. Both transmitral and pulmonary venous flow patterns are affected by the patient’s volume status. Color Mmode Doppler echocardiography is a relatively new modality that can be used to assess diastolic function in a preload-independent manner. When using color M-mode, an “ice pick” scan line is used to display color Doppler velocity information versus time. By placing the scan line through the mitral inflow jet of the LV, two distinct flow profiles are obtained. The displayed profiles correspond to the E and A waves from PWD. The slope of the first (E) wave’s aliasing velocity is the propagation velocity (Vp), which is an indication of the velocity at which blood travels from the mitral annulus to the apex during early ventricular filling (Fig. 30–11). Vp correlates to the degree of diastolic dysfunction and is independent of preload and heart rate. Another advantage of color M-mode Doppler echocardiography is that it provides a superior combination of temporal, spatial, and velocity resolution. Propagation velocities 30 years) persons, whereas Vp 10 is consistent with diastolic dysfunction. E/E' then can be used to differentiate normal from pseudonormal transmitral flow pattern. E/E' >15 has been shown to be highly specific for elevated LA pressures, whereas E/E' 2:1 relationship.8,9 The mitral annulus is a 3D, saddle-shaped, ellipsoid structure that changes shape and decreases in area as it descends during systole (Fig. 30–14). Coaptation

of the two leaflets is curvilinear, and both leaflets join at the anterolateral and posteromedial commissures (Fig. 30–15). The subvalvular apparatus consists of two papillary muscles and chordae tendineae. The anterolateral papillary

FIGURE 30–13. Transesophageal evaluation of diastolic dysfunction. A, Peak late diastolic transmitral flow velocity; A', peak late diastolic tissue velocity; Ar, peak pulmonary venous (PV) atrial reversal flow velocity; D, peak diastolic PV flow velocity; E, peak early diastolic transmitral flow velocity; E', peak early diastolic myocardial velocity; S, peak systolic PV flow velocity; Vp, flow propagation velocity.


FIGURE 30–14. Anatomic view of the mitral valve viewed from the base of the heart looking toward the left ventricular apex. Orientation of the leaflets and commissures is shown using the Carpentier naming system for mitral segments. The left (L), right (R), and noncoronary (NC) aortic valve leaflets are shown.

muscle supplies chordae to the anterior aspect of both the anterior and posterior mitral leaflets; the posteromedial papillary muscle supplies chordae to the posterior aspect of both valve leaflets. Three groups of chordae exist, named in accordance with their insertion points on the MV leaflets (Figs. 30–16 and 30–17). First-order chordae attach to the free edge of the leaflets, second-order chordae attach to the body of the leaflets, and third-order chordae attach near the base of the posterior leaflet only.10 More than 120 chordal tendons subdivide as they project from each papillary muscle to attach to the free edge and body of both MV leaflets.8 The subvalvular apparatus is responsible for maintaining valve integrity during systole and plays a crucial role in preserving the overall structure–function relationship of the LV. The MV shares a close anatomic, and at times pathophysiologic, relationship with the AV. In particular, the fibrous skeleton of the heart that gives rise to the anterior MV annulus is intimately associated with both the left and noncoronary cusps of the AV. In order to accurately diagnose MV pathology, it is crucial to be able to relate TEE images of this valve to specific anatomic regions. Three approaches to 2D examination of the MV by TEE have been published. Although these approaches all have strengths and limitations, they all emphasize the importance of concise, systematic 2D evaluation of the MV in multiple scan planes and from multiple points of view.

FIGURE 30–15. Midesophageal commissural view of a normal mitral valve. A2 segment of anterior leaflet is seen between the commissures, with P1 and P3 segments lateral to commissures. LA, Left atrium; LV, left ventricle.

In the early 1980s, Carpentier introduced a functional classification of mitral insufficiency (Fig. 30–16).11 Type I MR has normal motion of the leaflets, with MR due to leaflet perforation, usually from endocarditis, or annular dilation, often accompanying LV dysfunction. Type II MR has increased leaflet motion, typically from myxomatous change, leading to either leaflet prolapse or a flail leaflet. Leaflet prolapse, a result of leaflet redundancy and chordal elongation, is defined as doming of the leaflet body above the level of the mitral annulus in systole with the leaflet tip still directed toward the LV. With myxomatous change, the annulus often is significantly dilated in addition to the defect in leaflet tip coaptation. This regur-

TABLE 30–4. Normal Doppler Values Parameters

Adults 55y

Peak mitral flow velocity (E) (cm/s) Peak mitral filling rate (A) (cm/s) Mitral E/A Mitral E deceleration time Isovolumetric relaxation time (ms) Peak pulmonary venous AR wave (cm/s) Peak pulmonary venous S wave (cm/s) Peak pulmonary venous D wave (cm/s

76 ± 13 38 ± 8 2.1 ± 0.6 184 ± 24 74 ± 26 18 ± 3 41 ± 10 53 ± 10

63 ±11 52 ± 9 1.3 ± 0.3

25 ± 5 60 ± 10 38 ± 10

E/A, E wave/A wave ratio. Reprinted from Rakowski H, Appleton C, Chan, KL, et al. Canadian consensus recommendations for the measurement and reporting of diastolic dysfunction by echocardiography: from the Investigators of Consensus on Diastolic Dysfunction in Echocardiography. J Am Soc Echocardiogr 1996;9:736–760, with permission from Elsevier.

Mitral Regurgitation

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FIGURE 30–16. Normal, prolapsed, flail, and restricted mitral leaflets. The classification of chordae tendineae is also shown.

566

FIGURE 30–17. Midesophageal long-axis view showing subvalvular chordae (arrows). Ao, Aorta; LA, left atrium; LV, left ventricle; LVOT, left ventricular outflow tract; RV, right ventricle.

gitant lesion usually evolves slowly and ranges in scale from trivial to severe. A flail leaflet has a leaflet tip directed toward the LA throughout systole. This regurgitant lesion usually is severe with abrupt onset and is

poorly tolerated by the patient. Type III MR is characterized by restricted leaflet motion. Type IIIa dysfunction involves restricted leaflet motion during diastole and systole due to rheumatic changes. Type IIIb dysfunction

correlates to restricted leaflet motion during systole secondary to papillary muscle displacement in ischemic or dilated cardiomyopathy. Mitral insufficiency due to global LV dysfunction appears to result from a distorted geometric relationship between the MV leaflets and the papillary muscles. At the gross level, the LV is seen to transform from its usual ellipsoid shape into that of a sphere, causing widening of the interpapillary angle and restriction or tethering of leaflet motion.12 The valve may appear morphologically normal on 2D imaging, but with loss of the usual systolic leaflet overlap or with a visible coaptation defect. With dilated cardiomyopathy, the regurgitant jet usually is central (Fig. 30–18). Dilation of the annulus may contribute to regurgitation, most notably in the region of the P2 segment, but in most cases is not the major mechanism of regurgitation. With ischemic MR, dilation of specific areas of myocardium may lead to asymmetric tethering and an eccentric regurgitant jet. Papillary muscle rupture, which most frequently affects the posteromedial muscle, is an occasional complication of myocardial infarction and can result in severe bileaflet regurgitation. The papillary muscle and chordae tips can often be seen flinging into and out of the LA. In hypertrophic obstructive cardiomyopathy, the regurgitant jet usually is directed posteriorly as the anterior leaflet is pulled into the LVOT (systolic anterior motion of the anterior leaflet), resulting in a coaptation defect (Fig. 30–19).

FIGURE 30–18. A. Midesophageal two-chamber view with color flow Doppler showing mild mitral regurgitation from left ventricular dilation. B. Midesophageal long-axis view with color flow Doppler showing moderate mitral regurgitation. Ao, aorta; LA, left atrium; LV, left ventricle; RV, right ventricle.


FIGURE 30–19. Midesophageal long-axis view with color flow Doppler revealing mitral regurgitation caused by hypertrophic obstructive cardiomyopathy. Ao, Aorta; IVS, interventricular septum (hypertrophied); LA, left atrium; LV, left ventricle; RV, right ventricle.

MV endocarditis can affect native valves and result in regurgitation because of perforation or deformation of the valve leaflets (Fig. 30–20). Vegetations commonly arise on the upstream side of a valve, which are generally areas of slower flow and therefore are usually seen in the LA. The finding of MV endocarditis mandates careful inspection of the other heart valves to rule out their involvement. Leaflet perforation is identified by the appearance of one or more regurgitant jets that do not seem to arise from the coaptation line. A clue to this particular pathology is the presence of multiple convergence zones on color Doppler. Echocardiographic examination of the insufficient MV should involve inspection of other structures in the heart that may be altered as a result of the regurgitant process. LA dilation is commonly found in chronic MR of at least moderate severity but is not a feature of acute MR. Left-to-right bowing of the IAS due to elevated LA pressure often can be appreciated in the ME four-chamber or ME bicaval view. Signs of pulmonary hypertension, such as RV and RA enlargement, often accompany progressive MR. As a significant portion of the systolic volume is unloaded into the LA with severe MR, normal systolic function should appear like a hypercontractile LV. Therefore, an LV with apparently normal systolic function may actually have significant systolic dysfunction. Spherical enlargement of the LV with eccentric hypertrophy signifies longstanding MR in which the compensatory processes of the ventricle are failing.

The severity of MR can be assessed with TEE in a number of ways. One caveat that must be emphasized is that such severity often can be difficult to interpret in the intraoperative period because of the relatively deranged hemodynamic profile of the patient undergoing general anesthesia. Altered loading conditions and cardiac contractility can lead to varying degrees of MR that may be different from those seen in the awake, physiologically normal state. Furthermore, application of severity estimation methods is dependent on the technical expertise of the imaging staff, the complexity involved with the measurement technique, associated limitations with the individual method, and time constraints. A number of grading systems using CFD have been described, including

regurgitant jet length, jet area, jet area as a percentage of LA area, and width of the vena contracta (narrowest diameter of the regurgitant jet at the site of jet formation). The vena contracta is considered the most useful CFD grading system because it effectively estimates the diameter of the regurgitant jet orifice.13 A vena contracta ≥ 6 mm identifies angiographically severe MR with sensitivity of 95% and specificity 98%. Eccentric regurgitant jets imaged by CFD commonly appear to occupy less overall area compared to jets of similar flow rates directed centrally within the LA.14 An eccentric jet has a different observed morphology compared to free jets secondary to limited expansion because of impingement of the jet along the atrial wall. Consideration of jet morphology in the CFD assessment is important to avoid underestimating the degree of regurgitation. A proximal isovelocity surface area (PISA) may be seen on the LV side of the MV during systole as blood flow accelerates toward the regurgitant orifice, causing aliasing with CFD. The product of PISA and the aliasing velocity provides the flow rate through the valve during the measurement. According to the continuity principle, dividing the peak flow rate by the peak regurgitant velocity, as measured by CWD, provides quantitative assessment of the effective regurgitant orifice (ERO): ERO = PISAMR * (Aliasing velocity)/ (Peak regurgitant velocity), where PISAMR = 2Pi*r2, and r = radius of semicircular shell of color change at the set Nyquist limit.

FIGURE 30–20. Midesophageal four-chamber view with color flow Doppler demonstrating mitral regurgitation caused by mitral valve endocarditis (arrow). LA, Left atrium; LV, left ventricle; RA, right atrium; RV, right ventricle.

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568

The continuity principle also can be used to derive regurgitant fractions by determining stroke volumes through various other sites in the heart (notably the LVOT, AV, and pulmonic valve). Stroke volume is calculated as the product of the velocity–time integral (VTI) through an orifice and the calculated orifice area at the same location. Alterations in the pulmonary venous Doppler profile are useful in quantifying the severity of MR. Trivial or mild regurgitation is generally associated with a normal flow velocity pattern (peak S wave > peak D wave), moderate regurgitation is associated with systolic blunting (peak S wave < peak D wave), and severe regurgitation is associated with S-wave reversal (S wave directed away from transducer as regurgitant blood flows retrograde into the pulmonary vein).15 It is advisable to interrogate at least one pulmonary vein from each side of the LA because regurgitant jets may preferentially affect the pulmonary venous profile of one side over the other. Peak E-wave velocity is another parameter that can be used to qualitatively assess the degree of MR. When the degree of MR increases, the added regurgitant volume across the MV increases the pressure gradient between the LA and the LV. This increase in pressure gradient subsequently increases early mitral inflow velocity. Ewave velocity >1.2 m/s identified patients with severe MR with sensitivity of 86%, specificity 86%, positive predictive value 75%, and negative predictive value 92%.16

FIGURE 30–21. Midesophageal four-chamber view with color flow Doppler demonstrating mitral stenosis from mitral valve endocarditis (arrow). LA, Left atrium; LV, left ventricle; RA, right atrium; RV, right ventricle.

Mitral Stenosis Most cases of hemodynamically significant native MV stenoses are due to rheumatic heart disease. Uncommon causes include severe mitral annular calcification, obstructing lesions such as LA tumors and endocarditis vegetations (Fig. 30–21), and congenital deformities such as parachute MV or cor triatriatum. Surgical correction can involve either open commissurotomy or valve replacement. In addition to confirming the severity of the stenosis, it is equally if not more important to evaluate the heart for evidence of LA thrombus (particularly within the LA appendage), RV and LV function, presence and severity of tricuspid regurgitation (TR), and degree of residual stenosis or regurgitation following valve repair or replacement.

Common echocardiographic findings of rheumatic MV stenosis (Fig. 30–22A) include leaflet thickening and calcification, leaflet restriction, and subvalvular involvement (shortening, tethering, and calcification of the chordae). The resulting failure of leaflet coaptation causes a regurgitant jet that is directed toward the side of the lesion (Fig. 30–22B). These leaflet changes are best seen in the ME four-chamber and long-axis (LAX) views. Subvalvular involvement usually is best visualized from the TG two-chamber view. The TG basal SAX view may reveal calcification in the region of the commissures. Rheumatic heart disease also may involve the pericardium, myocardium, and other heart valves. Associated findings in mitral stenosis include atrial dilation, pronounced

FIGURE 30–22. A. Midesophageal four-chamber view with turbulent flow through a stenotic rheumatic mitral valve. B. Midesophageal four-chamber view with color flow Doppler demonstrating mitral regurgitation in a patient with rheumatic heart disease. LA, Left atrium; LV, left ventricle; RA, right atrium; RV, right ventricle.


left-to-right bowing of the IAS, spontaneous echo contrast in the LA (with or without atrial thrombus), and signs of pulmonary hypertension (right-heart dysfunction). A number of methods are available to the echocardiographer for assessing the severity of mitral stenosis. Mean transmitral pressure gradients are easily estimated from the transmitral CWD profiles using the simplified Bernoulli equation: Mean pressure difference = 4(Mean transmitral velocity)2. Severe MV stenosis is associated with mean transvalvular gradients >12 mm Hg. The pressure half-time denotes the rate of diastolic pressure decline across the MV, specifically the time required to reach 50% of the peak pressure gradient. Normally the diastolic E wave undergoes rapid deceleration due to the abrupt fall in transmitral pressure gradient as the LV fills during early systole. However, in mitral stenosis, the pressure gradient is sustained much later in diastole, giving rise to a greatly prolonged E-wave deceleration and thus longer pressure half-time. Angiographic experiments have shown that an MV area of 1 cm2 corresponds to a pressure half-time of 220 ms; thus, the area of the stenotic orifice can be estimated by dividing 220 by the pressure half-time in milliseconds.17 The continuity equation can be used in conjunction with the peak transmitral E-wave velocity and PISA measurements to estimate the stenotic orifice area. Providing there is no significant aortic or pulmonary regurgitation or interventricular shunts, the continuity equation also can use stroke volumes of the LVOT, AV or pulmonary valve, and the measured VTI of transmitral inflow to estimate the area of the stenotic mitral orifice.

according to the adjacent coronary artery (i.e., left, right, and noncoronary cusps and sinuses). Four standard views allow examination of the AV and LVOT. Beginning with the imaging depth set at 10–12 cm, the ME AV SAX view is obtained by advancing or withdrawing the probe with a multiplane angle of 30– 50° until the AV appears in the center of the screen (Fig. 30–23). All three cusps should be seen symmetrically by rotating the multiplane angle and slightly anteflexing the probe. The general morphology of the AV (bicuspid, tricuspid) is noted as well as the thickness and mobility of the leaflets. CFD is applied to detect flow disturbances indicating aortic regurgitation or stenosis. The AV orifice may be traced to measure valve area. The ME AV LAX view is obtained by rotating the multiplane angle forward 90° from the ME AV SAX to visualize the LVOT, AV, and proximal ascending aorta in long axis (Fig. 30–24). The AV leaflets appear as two thin lines opening parallel to the aortic walls. The right coronary cusp, being farthest from the probe, is visualized toward the bottom of the display. The left or noncoronary cusp (depending on the imaging plane), located closer to the probe, is seen toward the top of the display. The diameters of the LVOT, aortic annulus, sinotubular junction, and ascending aorta can be measured in this view. The annulus is measured where the leaflets insert into the aorta. The proximal ascending aorta should be evaluated for calcification, atheroma, intimal flap or dissec-

tion, and aneurysmal dilation. CFD is again applied to detect the flow pattern through the LVOT, AV, and ascending aorta. Turbulent LVOT flow in this view should prompt further evaluation for hypertrophic obstructive cardiomyopathy or another obstruction to LVOT flow. Systolic anterior motion of the MV (often a fluttering motion into the LVOT, but sometimes apparently occluding the LVOT), associated MR, premature AV closure, and thickened interventricular septum (>1.2 cm, disproportionate from the free wall) confirm hypertrophic obstructive cardiomyopathy. The deep TG LAX view can be obtained by advancing the probe tip deep into the stomach and then anteflexing to create an imaging plane originating from the LV apex with the AV appearing in the far field. Alternatively, the TG LAX view is obtained from the TG midpapillary SAX view by rotating the angle forward to 90–110° until the AV comes into view in the far field to the right side of the image. Both of these TG views allow for parallel alignment of the ultrasound beam through the AV, making them most useful for measuring Doppler flow velocities through the LVOT and AV rather than visualizing anatomy. Positioning the PWD sample volume in the center of the LVOT allows Doppler flow measurement in the outflow tract. Flow velocity through the AV is measured with CWD. Either or both of these TG views may be difficult to obtain in some patients, and a severely stenotic AV may make Doppler interrogation difficult. CFD may be helpful in detecting

Aortic Valve High-resolution images of the AV are provided by TEE because the valve and probe are separated by the LA, which acts as an excellent acoustic window. The AV is composed of three leaflets or cusps that are suspended from the aortic wall along three crescent-shaped lines. The junctions of the free edges of the cusps are called the aortic commissures. Behind each leaflet is the respective sinus of Valsalva, a pouch-like dilation of the aortic root. The leaflets and sinuses are named

FIGURE 30–23. Midesophageal aortic valve long-axis view. Arrow indicates sinotubular junction. Asc Ao, Ascending aorta; LA, left atrium; LVOT, left ventricular outflow tract; RCS, right coronary sinus behind right cusp of aortic valve; RVOT, right ventricular outflow tract.

569


FIGURE 30–24. A. Midesophageal aortic valve short-axis view with color flow Doppler showing central aortic insufficiency in a dilated aortic valve. B. Midesophageal aortic valve long-axis view with color flow Doppler demonstrating aortic insufficiency. Ao, Aorta; IVS, hypertrophied interventricular septum; LA, left atrium, LC, left aortic valve cusp; LV, left ventricle, NCC, noncoronary aortic valve cusp, PA, pulmonary artery, RA, right atrium, RC, right aortic valve cusp, RV, right ventricle, RVOT, right ventricular outflow tract.

flow through the stenotic orifice, facilitating appropriate placement of the Doppler beam. 570

Aortic Insufficiency Acute or chronic regurgitation may result from abnormalities of the AV and the aortic root (Fig. 30–23). Aging, rheumatic heart disease, endocarditis, or congenital bicuspid or unicuspid AV all may lead to aortic regurgitation. Dilation of the aorta resulting from connective tissue diseases (Marfan syndrome, Ehlers-Danlos syndrome), sinus Valsalva aneurysm, aortic root abscess, and hypertension are other causes of aortic insufficiency (AI). Two-dimensional imaging should be applied in the ME AV SAX and LAX views to detect congenital abnormalities or acquired defects such as myxomatous degeneration and vegetations. The aortic root should be assessed for dilation, and measurements of the LVOT, AV annulus, sinotubular junction, and ascending aorta should be obtained. The area of the end-diastolic gap between the aortic cusps, measured by planimetry, correlates with the severity of AI (mild 0.4 cm2). The vena contracta should be measured by CFD in the ME LAX view with the imaging depth reduced. A vena contracta 0.6 cm signifies severe AI. The ratio of the regurgitant jet area to the LVOT area also can be measured by CFD in the ME LAX view. Similarly, the width of the regurgitant jet can be compared to the width of the LVOT. Values >60% and

>65% for area and width, respectively, indicate severe AI. The pressure half time (PHT), described previously to grade mitral stenosis, can be applied to grade the severity of AI. The more severe the AI, the shorter the PHT because the aortic diastolic pressure gradient declines more rapidly. PHT is best obtained in the TG LAX or deep TG LAX views with CWD. PHT >500 msec indicates mild AI, whereas PHT 4 m/s (Fig. 30–27A). The VTI of the traced spectrum is calculated and corresponds to the distance traveled by a column of blood during the stroke cycle. This allows use of the continuity principle to calculate the effective AV cross-sectional area (CSAAV). The continuity principle is based on the conservation of flow over time between two conduits within a closed circuit (AV and LVOT in this example). Because flow is the product of the cross-sectional area of the conduit and the VTI through the conduit: CSALVOT × VTILVOT = CSAAV × VTIAV, where CSA = πr2, and r = radius of the respective conduit. The radius of the LVOT can be measured in the ME LAX view. VTILVOT can be obtained in the TG LAX or deep TG LAX views using PWD. VTIAV can be directly measured with CWD from the deep TG view. Alternatively, a “doubleenvelope” technique can be used to simultaneously measure LVOT and AV VTIs by CWD in the TG LAX or deep TG LAX views (Fig. 30–27C). Because the velocity of flow through the smaller AV must accelerate from that of the larger-diameter LVOT, the larger envelope must correspond to the VTI of the AV, and the smaller, but denser, envelope represents the VTI of the LVOT.

cm. It is divided anatomically into four segments: ascending aorta, transverse aortic arch, descending thoracic aorta, and abdominal aorta. The ascending aorta begins at the level of the aortic annulus and the aortic valve. Just distal to the aortic annulus, the ascending aorta dilates to form a segment known as the aortic sinus of Valsalva, which includes the respective left coronary, right coronary, and noncoronary sinuses. Distal to the aortic sinuses, the aorta has a brief segment with a reduced diameter called the sinotubular junction. In adults, the ascending aorta is approximately 5 cm in length. After originating from the AV annulus, the ascending aorta extends rightward around the main pulmonary trunk and crosses the right pulmonary artery anteriorly. It then ascends rightward and anteriorly until it meets the aortic arch at the origin of the innominate artery

(at the level of the second intercostal space). The proximal or near aortic arch is poorly visualized with TEE because of the anatomic interposition of the trachea between the esophagus and the aorta at this level. Whereas the innominate and left common carotid arteries are in close proximity to the trachea, the left subclavian artery lies to the left of the trachea and can be visualized more easily with TEE. The descending thoracic aorta begins distal to the left subclavian artery at the level of the ligamentum arteriosus. This is an area of narrowing referred to as the aortic isthmus. The ligamentum arteriosus is a fibrous connection between the pulmonary artery and the aorta, a remnant of the ductus arteriosus during fetal life. Inferior to the isthmus, the descending aorta courses to the left lateral side of the body of the fourth thoracic vertebrae. The descending aorta is relative-

Aorta The aorta is the largest artery in the body with a normal diameter up to 3.5

FIGURE 30–26. Deep transgastric long-axis view with aortic valve leaflets (arrow) seen on the left. LA, Left atrium; LVOT, left ventricular outflow tract.

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FIGURE 30–27. A. Continuous-wave Doppler through deep transgastric long-axis view of the aortic valve showing severe aortic stenosis (velocity >4 m/s). B. Continuous-wave Doppler through deep transgastric long-axis view of the aortic valve in a patient with hypertrophic obstructive cardiomyopathy (note sharp “ice pick” contour). C. Continuous-wave Doppler through the aortic valve with velocity–time interval measured at the left ventricular outflow tract (inside tracing) and aortic valve (outside tracing) simultaneously.

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ly transfixed to the vertebral column here. Therefore, deceleration injuries often occur at the level of the isthmus. The descending aorta continues along a slightly anterior and rightward path as it approaches the diaphragm, where it lies directly posterior to the esophagus. Therefore, at the level of the lower esophageal sphincter, the heart and the aorta are on opposite sides of the esophagus. The Society of Cardiovascular Anesthesiologist and the American Society of Echocardiography have defined six views for interrogating the thoracic aorta by TEE.4 Multiple imaging planes from within similar views may be necessary to accurately define aortic pathology. The ME ascending aorta SAX view is obtained in the 0–30° imaging plane with the probe approximately 25 cm from the lips. In this view, an SAX view of the ascending aorta along with the main pulmonary artery, right pulmonary artery, and SVC is obtained. Qualitative analysis of the aortic anatomy and wall thickness can be obtained in this view. The ME ascending aorta LAX view is obtained between 110° and 140°. This

view is easily obtained after starting with the ME AV SAX view (“MercedesBenz” view), which is easily recognized at the ME level with the multiplane angle at 20–50°. Once the “MercedesBenz” view is obtained, rotating the imaging plane forward an additional 90° and withdrawing the probe slightly yields the ME ascending aorta LAX view (Fig. 30–28). This view is useful in defining wall thickness, aortic dimensions, and blood flow patterns in the ascending aorta. From the ME ascending aorta views, turning the probe to the left with a multiplane angle of 0° produces an SAX image through the descending aorta. Once the aorta is visualized, the depth of the image should be optimized so that the aorta is in the center of the screen. Inserting the probe to the level of the diaphragm (where the image disappears) and then slowly withdrawing the probe allows scanning of the entire descending thoracic aorta. The SAX view is useful for defining wall thickness, determining atherosclerotic severity, and measuring aortic dimensions (Fig. 30–29A). From the SAX view, rotating the plane to 90° produces an LAX view of

the descending aorta (Fig. 30–29B). These views are useful for defining spatial relationships of SAX findings, interrogating aortic flow patterns, and identifying branch vessels. With the scan plane at 0°, withdrawal of the probe following the aorta to an upper esophageal window with a rightward rotation produces an LAX view of the aortic arch. This view is used to define aortic dimensions, wall contour, and branch vessels. Advancing the multiplane angle to 90° in the upper esophagus produces an SAX view of the arch. At the proximal arch, the main pulmonary artery and right pulmonary artery may be seen if the depth is sufficient (Fig. 30–33A). At the distal arch, multiple views of the arch and its branch vessels may be obtained. Even using all of these views, TEE does not image the entire thoracic aorta. A “blind spot” in the distal ascending/proximal arch is created by the trachea. The aorta also is subject to echocardiographic artifacts and dropout caused by calcifications. With every image, the examiner should describe the morphology, dimensions, and integrity of the aortic wall. Evalu-


FIGURE 30–28. Midesophageal ascending aorta long-axis view. Asc Ao, Ascending aorta; RPA, right pulmonary artery.

ation for spontaneous echocardiographic contrast or turbulent flow also is recommended. Any fluid collection should be noted. The association between atherosclerosis of the aorta and systemic embolization is prevalent in the literature. Katz et al.18 showed a link between the severity of atherosclerotic atheroma and the incidence of perioperative stroke. In addition, atherosclerosis of the ascending aorta is an independent predictor of long-term neurologic outcomes and morbidity following cardiac surgery.19 If atheroma is not detected by TEE examination of the aorta, then significant atheroma in the ascending aorta (where cannulation, crossclamping, and most aortic manipulation occurs for cardiopulmonary bypass) is unlikely.20 Conversely, if significant atheroma is found in the thoracic aorta upon TEE examination, then there is a 34% chance of significant atheroma in the ascending aorta,

and epiaortic scanning should be strongly considered. Many different classification systems for aortic atheroma severity have been proposed. The most widely used system was proposed by Katz et al.,18 consisting of a five-grade classification system. A grade I atheroma has minimal or no intimal thickening. A grade II atheroma has severe intimal thickening without a protruding element. A grade III atheroma has intimal thickening protruding 5 mm into the lumen. A grade V lesion is any atheroma with a mobile component. Although currently there is no consensus as to the size of plaque that should warrant alteration of the surgical procedure, large atheromas and atheromas with mobile elements should warrant discussion with the surgeon. Direct ultrasound of the aorta via a high-frequency probe placed directly

on the aorta (epiaortic scanning) can be used to gain additional information during procedures that use a sternotomy. An epiaortic probe is guided into a sterile sleeve on the operating field. Gel or water is used to create a standoff from the probe to the aorta in order to visualize the anterior wall of the aorta. The aorta is best visualized in both the LAX and SAX views. The image should be optimized so that the aorta is in the center of the screen. The cross-clamp site and antegrade cardioplegia site should be interrogated. These sites often fall in the region of the aorta that is difficult to image with TEE because of the interposed trachea. If atherosclerotic lesions that could be embolic sources are present, manipulation of these areas should be avoided. TEE is useful for diagnosis and classification of thoracic and abdominal aneurysms (Fig. 30–30). An aneurysm of the aorta involves an increase in the luminal diameter of all three layers of the aorta. A pseudoaneurysm involves an interruption of the intima and media at the level of the aneurysmal sac and its communication with the native aorta. An ascending aortic diameter >4 cm, descending thoracic aneurysm >6 cm, or abdominal aortic aneurysm >5 cm in diameter is considered an indication for surgical intervention. Dissection of the aorta is a process in which the intima separates from the adventitial layer. It is characterized by the presence of an intimal flap and resulting false and true lumens. Aortic dissection can result from intimal rupture followed by cleavage formation and propagation of the dissection into the media. Additionally, aortic dissec-

FIGURE 30–29. A. Descending aorta short-axis view with atheroma (arrow). B. Descending aorta long-axis view with atheroma (arrow). Ao, Lumen of aorta.

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FIGURE 30–30. Short-axis (A) and long-axis (B) views of a descending thoracic aorta aneurysm with ulcerated atheroma.

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tion can result from intramural hemorrhage and hematoma formation in the media, subsequently followed by perforation of the intima. The presence of an intimal flap is the most characteristic feature of aortic dissection. The pathogenesis of dissection is complex. Medial degeneration tends to be more extensive in older individuals and in patients with hypertension, Marfan syndrome, and bicuspid AVs.21 The true lumen diameter typically is smaller than the false lumen diameter (Fig. 30–31A), and spontaneous contrast can often be seen in the false lumen. However, PWD should be used to confirm forward flow in the presumed true lumen during systole (Fig. 30–31B). Aortic dissection is divided into acute and chronic types, depending on the duration of symptoms. Acute aortic dissection is present when the diagnosis is made within 2 weeks after the initial onset of symptoms. Approxi-

mately one third of patients with aortic dissection fall into the chronic category, in which symptom duration is >2 weeks. The most common site of initiation of aortic dissection is the ascending aorta (50%), followed by aortic regions in the vicinity of the ligamentum arteriosum. Anatomically, aortic dissection has been classified by two schemes. The DeBakey classification consists of the three types: type I includes both the ascending and the descending aorta, type II includes only the ascending aorta, and type III includes only the descending aorta. The Stanford classification consists of two types: type A involves the ascending aorta regardless of the entry site location, and type B involves the aorta distal to the origin of the left subclavian artery. Any dissection involving the ascending aorta (DeBakey types I and II or Stanford type A) is an indication for repair, whereas dissections confined to the

descending aorta can be medically managed, at least initially. Endovascular repair of the aorta has gained popularity as a reliable alternative to conventional repair. TEE is used to supplement intraoperative angiography in guiding placement of thoracic endografts. During endovascular repair, TEE is the most sensitive imaging modality currently available for diagnosing endoleaks immediately after graft deployment. The ability to use intraoperative TEE for visualizing the thoracic and abdominal aorta and monitoring cardiac function makes it an invaluable tool during these procedures.22

Right Ventricle The RV is crescent shaped, thin walled, and compliant. It is less contractile compared to the LV. Its oxygen requirements are lessened by its reduced muscle mass and lower afterload. The right coronary artery (RCA)

FIGURE 30–31. A. Descending aorta short-axis view of an aortic dissection. B. Descending aorta long-axis view of an aortic dissection at the level of an intimal tear (arrow).


supplies the RV free wall, the posterior descending artery supplies the inferior RV wall, and the anterior RV wall has a dual blood supply from the conus branch from the RCA and the moderator branch from the left anterior descending artery.23 The RV is a low-pressure system, with an average pressure of 20/5 mm Hg. Therefore, coronary flow to the RV from the aorta follows this favorable pressure gradient, resulting in perfusion during both diastole and systole, unlike the high-pressure LV, which is perfused only during diastole.24,25 RV contraction resembles peristaltic motion, which functions to prolong ejection time by ejecting blood even as proximal RV pressures decline, thus minimizing end-diastolic pressure and promoting venous return.26 RV ejection results primarily from RV free wall inward motion, with a smaller contribution from descent of the base of the heart. The RV is sensitive to changes in afterload and susceptible to coronary air embolism because of the anterior location of the RCA takeoff. Furthermore, the RV t is difficult to protect during cardiac surgery. Evaluation of the RV is a necessary part of a comprehensive TEE examination because RV dysfunction in cardiac surgery correlates with mortality.27 However, because of its anterior position far from the TEE probe and its geometric complexity due to its crescent shape and twisting contraction, assessment of the RV with TEE is more challenging than that of the LV. TEE examination of the RV is primarily performed qualitatively by as-

sessing the RV in long axis with the ME four-chamber (Figs. 30–2B and 30–32B) and TG RV inflow views, as well as in short axis with TG mid-SAX (Fig. 30–34) and ME RV inflow–outflow views (Fig. 30–3B). The RV free wall is best viewed from the ME fourchamber and TG mid SAX views. When assessing RV function, RV dilation, presence of interatrial and/or interventricular septal shift to the left, RV wallmotion abnormalities, significant tricuspid insufficiency, and IVC engorgement indicate dysfunction.28–30 RV hypertrophy is defined as end-diastolic free wall thickness >0.5 cm (or greater than half the thickness of the LV). RV dilation is indicated by an RV diastolic diameter that exceeds the LV diastolic diameter in the TG mid-SAX view. RV dilation also can be graded from the ME four-chamber view. The normal-sized RV will not form part of the heart apex. If the apex of the heart includes the RV apex, then moderate RV dilation is present; if the apex is entirely formed by the RV, then severe dilation is present.31 Semiquantitative assessment of RV systolic function is described by the RV fractional area of contraction in the ME four-chamber view and the tricuspid annular plane systolic excursion (descent of the tricuspid annulus) in the ME four-chamber view. In a retrospective study, RV fractional area of contraction 25 mm correlates with normal RV EF.33 However, because of the complexity of the RV anatomy, these measurements may be

inaccurate, so a comprehensive qualitative assessment must be performed.

Tricuspid Valve The tricuspid valve (TV) consists of anterior, posterior, and septal leaflets; the largest is the septal leaflet (Fig. 30–32A). In the presence of normal leaflets, TR is termed functional and is commonly due to RV dilation and/or dysfunction. In contrast, TR due to leaflet abnormalities is rare. Like the RV, the TV lies in the far field, making 2D imaging difficult. In the ME four-chamber view, the anterior (or sometimes posterior) and septal leaflets are seen. In the ME RV inflow– outflow view, the posterior and anterior leaflets are seen on the left and right of the image screen, respectively (Fig. 30–3B). In the TG RV inflow view, the posterior leaflet is in the near field, and the anterior leaflet is in the far field. Grading TR should consider many factors, including RA and RV size, hepatic flow patterns, vena contracta, and jet area. Severe TR correlates well with systolic flow reversal in the hepatic veins, a vena contracta measuring >6.5 mm in the apical four-chamber view , and TR jet area more than two thirds of RA area.34,35 In addition, TV annulus >4 cm and tricuspid inflow velocity >1 m/s by CWD is associated with severe TR.36 In the absence of pulmonic stenosis, the pulmonary artery systolic pressure can be estimated if TR is present. To accomplish this, the peak pressure gradient is calculated and added to the measured central venous pressure. To

FIGURE 30–32. A. Transgastric short-axis view with rightward rotation at the level of the tricuspid valve leaflets. Arrow indicates septal tricuspid leaflet poorly visualized in this plane. B. Midesophageal four-chamber view showing severe right ventricular dilation and associated tricuspid regurgitation. AL, Anterior tricuspid leaflet; LA, left atrium; LV, left ventricle; PL, posterior tricuspid leaflet; RA, right atrium; RV, right ventricle.

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FIGURE 30–33. A. Upper esophageal aortic arch short-axis view with pulmonary artery and pulmonary valve in the far field. Leftward arrow indicates pulmonic valve. Ao, Aorta with branch vessel (downward arrow); PA, main pulmonary artery. Left pulmonary artery and branch point are not within this two-dimensional ultrasound plane. B. Upper esophageal ascending aorta short-axis view at level of pulmonary artery branch point. Asc Ao, Ascending aorta; IV, innominate vein; MPA, main pulmonary artery; RPA, right pulmonary artery; RVOT, right ventricular outflow tract.

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obtain the peak pressure gradient across the TV, the modified Bernoulli equation is applied to the peak TR jet velocity measured by CWD. With regard to tricuspid stenosis, a mean inflow pressure gradient 6 mm Hg is severe. CWD is used to measure TV inflow velocities, which are used to determine pressure gradients. Multiple views should be interrogated to obtain the best alignment with diastolic inflow and, therefore, more accurate measurements.

Pulmonic Valve The pulmonic valve is trileaflet, consisting of anterior, left, and right leaflets. Significant pulmonic disease in the adult without congenital heart disease is rare. As with the other rightsided structures, the pulmonic valve is anterior and difficult to image with TEE. The best views for visualizing the pulmonic valve are the ME RV inflow– outflow view (Fig. 30–3B) and upper esophageal aortic arch SAX view (Fig. 30–33A). In the adult, pulmonic regurgitation usually is due to pulmonary hypertension and annular dilation. The examination should include the regurgitant jet vena contracta, jet length, RV size, and degree of CWD flow deceleration. Holodiastolic flow reversal in the main pulmonary artery (measured with PWD in the upper esophageal aortic arch SAX view) is indicative of significant pulmonic insufficiency. Pulmonic stenosis is rare in the adult and is classified as valvular, sub-

valvular, or supravalvular. CWD is used in the upper esophageal aortic arch SAX view to obtain a peak pressure gradient (mild stenosis 64 mm Hg).

Pulmonary Artery Evaluation of the main and right pulmonary arteries is performed from the upper esophageal ascending aorta SAX view. The left pulmonary artery is difficult to image because it usually is obscured by air in the left mainstem bronchus. In the adult, the main pulmonary artery is approximately 5 cm in length. The normal main and right pulmonary artery dimensions are 0.9– 2.9 cm and 1.2–2.2 cm, respectively. TEE has 80% sensitivity and 100% specificity for the diagnosis of pulmo-

nary embolus, but its low negative predictive value of 53% makes this modality unsuitable for ruling out pulmonary embolus.37

Pericardium The pericardial sac is a potential space between visceral and parietal pericardium. Pericardial effusion is a syndrome in which fluid accumulates in the pericardial sac. A wide variety of disease processes can lead to pericardial effusion. Depending on the size and speed of accumulation, a pericardial effusion can compromise venous return and lead to low cardiac output. Tamponade occurs when pericardial pressure exceeds the distending pressure of the cardiac chambers, resulting in impaired diastolic cardiac filling. Echocardiography is helpful for diag-

FIGURE 30–34. Transgastric short-axis view revealing a significant pericardial effusion (arrow). The right ventricle (RV) is enlarged, and the D-shaped left ventricle (LV) indicates elevated right ventricular pressures.


nosing pericardial effusion and cardiac tamponade, but cardiac tamponade ultimately is a clinical diagnosis. Pericardial effusions can be visualized as an echolucent space surrounding the echogenic external border of the heart chambers (Fig. 30–34). A thorough TEE examination, including ME four-chamber, ME two-chamber, ME LAX, and TG basal SAX views, should be performed for evaluation of pericardial cavity and surrounding structures. Effusions that separate the visceral pericardium from the parietal pericardium by 2-cm separation are large. Characteristic echocardiographic findings of cardiac tamponade are RA systolic collapse, RV diastolic collapse, abnormal ventricular septal motion, and reciprocal respiratory variation in ventricular volumes. RA systolic collapse usually develops before RV diastolic collapse. Because of the tethering effect of the pulmonary veins, LA collapse is rare and implies the presence of a large effusion. PWD of mitral inflow velocity and pulmonary vein flow velocity also show a pronounced respiratory variation pattern in cardiac tamponade.

CONCLUSION Intraoperative echocardiography has rapidly evolved over the last 3 decades since its introduction in the early 1970s and has become a standard of practice for cardiac anesthesia care. In addition, it now holds a place as an important and increasingly routine adjunct to noncardiac anesthesia practice. Whereas modalities such as 3D, tissue Doppler, and contrast have enabled expanded application of this diagnostic imaging technique for intraoperative anatomic, physiologic, and hemodynamic capabilities, new systems that are less expensive, portable, and user friendly have enabled the expansion of intraoperative echocardiography to a greater variety of settings. Today, hand-held as well as portable systems allow for use of ultrasound in the preoperative clinic, postanesthesia care unit, and ICU and have stimulated a new generation of ultrasound uses. It is our hope that this chapter with its systematic approach to TEE examination will help grow and stimulate further use of this unique and important modality.

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26. Mebazaa A, Karpati P, Renaud E, Algotsson L. Acute right ventricular failure-from pathophysiology to new treatments. Intensive Care Med 2004;30:185–196. 27. Reichert CL, Visser CA, van den Brink RB, et al. Prognostic value of biventricular function in hypotensive patients after cardiac surgery as assessed by transesophageal echocardiography. J Cardiothorac Vasc Anesth 1992;6:429–432. 28. D’Arcy B, Nanda NC. Two-dimensional echocardiographic features of right ventricular infarction. Circulation 1982;65:167–173. 29. Goldberger JJ, Himelman RB, Wolfe CL, et al. Right ventricular infarction: recognition and assessment of its hemodynamic significance by two-dimensional echocardiography. J Am Soc Echocardiogr 1991;4:140–146. 30. Vieillard-Baron A, Prin S, Chergui K, et al. Echo-Doppler demonstration of acute cor pulmonale at the bedside in the medical intensive care unit. Am J Respir Crit Care Med 2002;166:1310–1319. 31. Daniel MT, Martin A, Bruce AB, et al. Practice guidelines for perioperative transesophageal echocardiography. A report by

the American Society of Anesthesiologists and the Society of Cardiovascular Anesthesiologists Task Force on Transesophageal Echocardiography. Anesthesiology 1996;84: 986–1006. 32. Maslow AD, Regan MM, Panzica P, et al. Precardiopulmonary bypass right ventricular function is associated with poor outcome after coronary artery bypass grafting in patients with severe left ventricular systolic dysfunction. Anesth Analg 2002;95:1507–1518. 33. Rafferty T, Durkin M, Harris S, et al. Transesophageal two-dimensional echocardiographic analysis of right ventricular systolic performance indices during coronary artery bypass grafting. J Cardiothorac Vasc Anesth 1993;7:160–166. 34. Shapira Y, Porter A, Wurzel M, et al. Evaluation of tricuspid regurgitation severity: echocardiographic and clinical correlation. J Am Soc Echocardiogr 1998;11:652–659. 35. Tribouilloy CM, Enriquez-Sarano M, Bailey KR, et al. Quantification of tricuspid regurgitation by measuring the width of the vena contracta with Doppler color flow imaging: a clinical study. J Am Coll Cardiol 2000;36:472–478. 36. Moukarbel GV, Ayoub CM, Abchee AB. Valvular regurgitation. In Mathew JP, Ayoub CM, eds. Clinical Manual and Review of Transesophageal Echocardiography. New York: McGraw-Hill, 2005:137– 161. 37. Pruszczyk P, Torbicki A, Kuch-Wocial A, et al. Diagnostic value of transoesophageal echocardiography in suspected haemodynamically significant pulmonary embolism. Heart 2001;85:628–634.

CHAPTER 31: Monitoring Respiratory Function

CHAPTER 31 Monitoring Respiratory Function Dean R. Hess, PhD, RRT, and Robert M. Kacmarek, PhD, RRT Monitoring is the continuous, or nearly continuous, evaluation of the physiologic function of a patient in real time to guide diagnosis and management decisions, including when to make therapeutic interventions and assessment of those interventions.1 Many physiologic parameters can be monitored during mechanical ventilation, including both invasive and noninvasive monitoring. Respiratory monitoring is an integral part of the care of mechanically ventilated patients in the operating room and in the intensive care unit. Arterial blood gases are also commonly used to assess respiratory function. This chapter reviews the use of blood gases and monitors for assessment of respiratory function.

ARTERIAL BLOOD GASES Arterial blood gases refer to measurements of PCO2 and PO2. The measurement of pH is also included with blood gases. Measured hemoglobin saturation with oxygen (O2Hgb), carboxyhemoglobin (COHgb), and methemoglobin (metHgb) may be included. Many laboratories also report calculated values of oxygen saturation, bicarbonate concentration, and base excess. These measurements assess oxygenation, ventilation, and acid–base status.

Oxygenation Hypoxemia results from decreased delivery of oxygen from the atmosphere to the arterial blood, and hypoxia refers to decreased delivery of oxygen to the tissues (Table 31–1). Oxygen content is a combination of dissolved oxygen and that bound to hemoglobin. The amount dissolved in plasma is small and directly related to PO2. The normal range of arterial PO2 (PaO2) is 80–100 mm Hg in healthy young

adults breathing air at sea level. PaO2 normally decreases with increasing age and increasing altitude. Hypoxemia occurs when the lungs fail to adequately oxygenate arterial blood. PaO2 is often a reflection of lung function and not of hypoxia per se. Hypoxia can occur without hypoxemia and vice versa. Adequate PaO2 in acutely ill patients is unknown, but most clinicians agree that PaO2 >60 mm Hg usually is acceptable.

Alveolar Gas Equation The alveolar PO2 (PAO2) is calculated from the alveolar gas equation: PAO2 = (FIO2 × EBP) – (PaCO2 × [FIO2 + (1 – FIO2 )/R]), (31–1) where FIO2 = fraction of inspired oxygen, EBP = effective barometric pressure (barometric pressure minus water vapor pressure), and R = respiratory quotient. For calculation of PAO2, R = 0.8 is commonly chosen. For FIO2 *0.6, the effect of R on the alveolar gas equation becomes the following: PAO2 = (FIO2 × EBP) – (PaCO2 ). (31–2) For FIO2 0.75 at any FIO2. PaO2/FIO2 is the easiest of the indices of oxygenation to calculate. The acute respiratory distress syndrome (ARDS) is associated with PaO2/FIO2 70% if the COHgb level is 30%. Methemoglobin is produced when the iron in the hemoglobin molecule is converted from its common reduced state (Fe++) to its oxidized state (Fe+++). Hemoglobin can carry oxygen only if the iron is in the reduced state. Thus, metHgb decreases the ability of hemoglobin to transport oxygen.

Shunt The right-to-left shunt fraction is the gold standard index of oxygenation efficiency in the lungs. It is calculated from the shunt equation:

Saturation (%)

Causes of Hypoxemia and Hypoxia

Acidosis Hypercarbia Hyperthermia Increased DPG

80 70 60 50 40 30 20 10

0 0

25

50

75 100 PO2 (mm Hg)

125

150

FIGURE 31–1. Oxyhemoglobin dissociation curve. Physiologic conditions that shift the curve to the left and to the right are indicated. Note that a shift to the left increases oxygen saturation for a given PO2 (increased affinity) and a shift to the right decreases oxygen saturation for a given PO 2 (decreased affinity).

Q S/Q T = (CV–O2 – CaO2 )/(CV–O2 – CV–O2 ), (31–5) where CV–O2 = pulmonary capillary oxygen content (mL/dL), CaO2 = arterial oxygen content, and CV–O2 = mixed venous oxygen content. Oxygen content is calculated as follows: CO2 = (1.34 × Hgb × HgbO2 ) + (0.003 × PO2 ). (31–6) To calculate CV–O2, the pulmonary capillary PO2 is assumed to equal the alveolar PO2, and the pulmonary capillary hemoglobin oxygen saturation is assumed to be 100%. If measured when the patient is breathing 100% oxygen, Q S/Q T represents shunt (i.e., blood that flows from the right heart to the left heart without passing gas-exchanging alveoli). If measured at FIO2 50% represents severe respiratory failure, whereas 5% approximates the normal value.

Ventilation Arterial PCO2 (PaCO2 ) reflects the balance between carbon dioxide production (V ˙ CO2 ) and alveolar ventilation ( V˙ A ): PaCO2 = V ˙ CO2/V˙ A. (31–7) Thus, PaCO2 varies directly with carbon dioxide production and inversely with alveolar ventilation. Note that

PaCO2 is determined by alveolar ventilation and not total minute ventilation per se. Minute ventilation affects PaCO2 only to the extent that it affects alveolar ventilation. Clinical causes of hypoventilation (increased PaCO2 ) and hyperventilation (decreased PaCO2 ) are listed in Table 31–2. Because alveolar ventilation is determined by minute ventilation ( V ˙ E ) and the ratio of dead space to total ventilation (VD / VT ), the relationship can be derived as follows:

˙ CO2/[ V˙ E × (1 – VD /VT )]. PaCO2 = V (31–8) TABLE 31–2. Clinical Causes of Hypoventilation and Hyperventilation Hypoventilation • Respiratory center depression: pathologic, iatrogenic • Disruption of neural pathways affecting respiratory muscles: neuropathy, trauma • Neuromuscular blockade: disease, paralyzing agents • Respiratory muscle weakness: fatigue, disease Hyperventilation • Respiratory center stimulation: hypoxia, anxiety, central nervous system pathology • Metabolic acidosis • Iatrogenic: mechanical ventilation


300 250 PaCO2 (mm Hg)

PaCO2 increases with an increase in VD /VT, an increase in V ˙ CO2, and a decrease in V ˙ E (Fig. 31–2). Although a goal of mechanical ventilation traditionally has been to normalize PaCO2, at times an elevated PaCO2 (permissive hypercapnia) may be more desirable than the high alveolar pressure required to normalize PaCO2 in patients with acute respiratory failure.

200

Dead space is that portion of the minute ventilation that does not participate in gas exchange.2–4 It consists of anatomic dead space and alveolar dead space. Dead space is calculated using the Bohr equation: VD /VT = (PaCO2 –

PE–CO

2 )/PaCO2,

(31–9) where VD /VT = fraction of total ventilation that is dead space, and PE–CO2 is the partial pressure of CO2 in mixed exhaled gas. The normal value of VD/VT ranges from 0.2 to 0.4. Causes of an increased VD / VT include pulmonary embolism, positive-pressure ventilation, pulmonary hypoperfusion, and high-rate, low-tidal-volume ventilation. Increased VD /VT has been associated with a high mortality rate in patients with ARDS.5 Increased VD/ VT also has been associated with a lower rate of weaning from mechanical ventilation.6 The traditional method for determining PE–CO2 was to collect mixed exhaled gas in a large bag for 5 to 15 minutes. During the gas collection, the patient is undisturbed, with a stable V ˙ E, and an arterial blood sample is obtained to assess PaCO2 during this time. Many current-generation mechanical ventilators have a constant bias gas flow through the circuit, which complicates the collection of mixed exhaled gas to calculate VD /VT. In this case, PE–CO2 can be calculated from V ˙ CO2 and V˙ E: PE–CO2 = (V ˙ CO2/V˙ E ) × PB. (31–10) Because dead space determinations require a leak-free system, they cannot be measured in patients with a bronchopleural fistula or with a leaking uncuffed tracheostomy tube. From the exhaled CO2, V ˙ E, and barometric pressure (PB), V ˙ A can be calculated as follows:

VCO2 0.2

150

100 VCO 0.3 2 VD/VT 0.8

50 0

Dead Space Ventilation

VCO2 0.3

VCO2 0.2

3

5

VD/VT 0.4

7 9 11 13 Minute ventilation (L/min)

15

FIGURE 31–2. Relationship between PaCO2, minute ventilation, VD/VT, and V˙CO2.

V ˙ A = V˙ E × PE–CO2 /PB. (31–11) V ˙ A also can be calculated from VD /VT as follows: V ˙ A = V˙ E– (V˙ E × VD /VT ). (31–12)

Acid–Base Balance Acid–base balance is explained by the Henderson-Hasselbalch equation: pH = 6.1 + log[HCO3–]/(0.03 × PCO2). (31–13) Metabolic acid–base disturbances are those that affect the numerator of the Henderson-Hasselbalch equation, and respiratory acid–base disturbances are those things that affect the denominator. The pH is normal (7.40) whenever the ratio [HCO3–] /(0.03 × PaCO2 ) is 20:1. The metabolic component of acid–base interpretation usually is given as [HCO3–]. The metabolic component also can be expressed as base excess (BE). BE can be estimated as: BE = [HCO3–] – 24. In other words, [HCO3–] 24 mmol/L corresponds with a positive BE. Clinical causes of metabolic acid–base disturbances are listed in Table 31–3, and the degree of compensation for acid–base disturbances is given in Table 31–4. The strong ion difference (SID) is a method of evaluating acid–base disturbances based on the Stewart physiochemical approach to acid–base chemistry.7 Using this approach, the only variables that affect pH are PCO2, SID, and the concentration of unmeasured strong ions. The normal value for SID is 40 mmol/L and is calculated as follows:

SID = [HCO3–] + 0.28 × [Albumin (g/L)] + [Inorganic phosphate (mmol/L)]. (31–14) Metabolic acidosis is associated with a decreased SID, and metabolic alkalosis is associated with an increased SID ( Table 31–5). The anion gap is useful to differentiate causes of metabolic acidosis. Metabolic acidosis can be associated with a normal anion gap (hyperchloremic acidosis) or with an increased anion gap (normochloremic acidosis). The anion gap is calculated as follows: Anion gap = [Na+] - ([Cl–] + [HCO3–]). (31–15)

TABLE 31–3. Clinical Causes of Metabolic Acidosis and Metabolic Alkalosis Metabolic Acidosis • Lactic acidosis (e.g., hypoxia) • Ketoacidosis (e.g., uncontrolled diabetes) • Uremic acidosis (e.g., renal failure) • Loss of base from lower gastrointestinal tract (e.g., diarrhea) • Loss of base from kidneys (e.g., acetazolamide, renal tubular acidosis) • Poisons (e.g., methanol, ethylene glycol, aspirin) Metabolic Alkalosis • Hypokalemia • Loss of acid from upper gastrointestinal tract (e.g., vomiting, gastric suction) • Bicarbonate administration

581


TABLE 31–4. Expected Compensation for Acid–Base Disturbances Respiratory acidosis:

Respiratory alkalosis:

Metabolic acidosis: Metabolic alkalosis:

6HCO3– = 0.10 × 6PaCO2 (acute) 6HCO3– = 0.35 × 6PaCO2 (chronic) 6HCO3– = 0.2 × 6PaCO2 (acute) 6HCO3– = 0.5 × 6PaCO2 (chronic) PaCO2 = 1.5 × HCO3– + 8 PaCO2 = 0.9 × HCO3– +15

If the acid–base status exceeds the expected level of compensation, a mixed acid–base disturbance is present.

582

A normal anion gap is 8–12 mmol/ L. Causes of metabolic acidosis with an increased anion gap include lactic acidosis, diabetic ketoacidosis, and azotemic (renal) acidosis. Causes of metabolic acidosis with a normal anion gap include loss of bicarbonate from the gastrointestinal tract (e.g., diarrhea), acetazolamide (Diamox) therapy, and excessive chloride administration (e.g., HCl, NH4Cl). The osmolality (osmol gap) is the difference between the measured osmolality of the plasma and that calculated as follows: Osmolality = 2 [Na+] + [Glucose]/18 + [BUN]/2.8 + [Ethanol]/4.6, (31–16) where BUN = blood urea nitrogen. If the measured osmolality is >10 mOsm/L above the calculated value (osmol gap >10 mOsm/L), osmotically active particles whose metabolites may be organic acid may present. Metabolic acidosis with an osmol gap is consistent with the presence of the toxins methanol, ethanol, and ethylene glycol.

Temperature Correction of Blood Gases Blood gases and pH are measured in the laboratory at 37°C. If the patient’s temperature is abnormal, the in vivo blood gas and pH values will differ from those measured and reported by the blood gas laboratory. Using empiric equations, the blood gas analyzer can adjust the measured values to the patient’s body temperature. Two ven-

TABLE 31–5. Classification of Acid–Base Disturbances Using the Steward Approach

Respiratory Metabolic Water excess or deficit Chloride excess or deficit Unmeasured strong ion excess

Acidosis

Alkalosis

BPCO2

?PCO2

?SID, ?Na+ ?SID, BCl– ?SID, Bunmeasured ions

BSID, BNa+ BSID, ?Cl–

SID, strong ion difference.

tilation strategies for hypothermic acid–base management have been suggested (usually during cardiopulmonary bypass)8–13 During _-stat management, PaCO2 is maintained at 40 mm Hg when measured at 37°C. Thus, the dissociation fraction of the imidazole moiety of histidine is constant, whereas pH changes parallel to the neutral pH point of water. During pH-stat management, PaCO2 is corrected to the patient’s actual body temperature. Because of increased gas solubility during hypothermia, the _-stat strategy results in relative hyperventilation. This issue is becoming increasingly important with the use of induced hypothermia after cardiac arrest and in the treatment of focal cerebral ischemia. Animal studies suggest that pH-stat management, as compared with _-stat management, results in improved cerebral blood flow and neurologic outcomes. The pH-stat approach allows differentiation of temperature-related changes from physiologic changes. Temperature-adjusted values should be used to compare blood gas levels with exhaled gas values (e.g., end-tidal PCO2 [PETCO2]) and to calculate oxygen content indices (e.g., right-to-left shunt) or tension indices [e.g., P(A-a)O2].

Point-of-Care Measurement of Blood Gases Point-of-care blood gas monitoring is performed near the site of patient care (e.g., operating room, intensive care unit). Point-of-care analyzers are available to measure blood gases and pH. These analyzers also can make other important useful measurements at the bedside, including levels of electrolytes, glucose, lactate, urea nitrogen, and hematocrit, and clotting studies [activated clotting time (ACT ), prothrombin time (PT ), and partial thromboplastin time (PTT )]. Point-of-care an-

alyzers are small and portable (some are hand-held), they require minute blood volumes (several drops), and they provide rapid reporting of results (a few minutes). They are relatively easy to use (e.g., self-calibrating) and typically incorporate a disposable cartridge that contains the appropriate biosensors. The cost–benefit of these devices is unclear. Further, appropriate documentation for compliance with hospital standards is necessary. This requires appropriate quality control checks and instrument maintenance.

Venous Blood Gases Arterial blood gases primarily reflect lung function, whereas venous blood gases reflect the adequacy of tissue oxygenation and tissue carbon dioxide clearance. A low mixed venous PO2 level (70% was reported to be associated with a survival benefit.14


SaO2 >85% and a falsely elevated SpO2 if SaO2 80%, the accuracy of pulse oximetry is approximately ±4–5%. Below 80%, their accuracy is far worse, but the clinical importance of this is questionable.

To appreciate the implications of the limits of accuracy of pulse oximetry, one must consider the oxyhemoglobin dissociation curve. If the pulse oximeter displays an SpO2 of 95%, the true saturation could be as low as 90% or as high as 100%. If the true saturation is 90%, the PaO2 will be approximately 60 mm Hg. If the true saturation is 100%, however, one does not know how high the PaO2 might be. Also, a shift of the oxyhemoglobin dissociation curve can change the SpO2, although no change in PaO2 has occurred. • Misunderstanding by those who use pulse oximetry: Although pulse oximetry is commonly used, it may be misunderstood by those using it. For example, it has been reported that a large percentage of junior physicians and staff nurses lacked knowledge and made serious errors in the interpretation of SpO2.15 However, this problem may have improved in recent years.16 • Differences between devices and probes: The pulse oximeter is unique in that it requires no user calibration. However, manufacturer-derived calibration curves programmed into the software vary from manufacturer to manufacturer and can vary among pulse oximeters from a given manufacturer. Moreover, the output of the LEDs can vary from probe to probe. • Penumbra effect: If the finger pulse oximeter probe does not fit correctly, light can be shunted from the LEDs directly to the photodetector. This will cause a falsely low SpO2 if

• Dyshemoglobinemias: Because traditionally available pulse oximeters use only two wavelengths of light, they are only able to evaluate oxyhemoglobin (O2Hgb) and deoxyhemoglobin (HHgb). Abnormal elevations of carboxyhemoglobin (COHgb)17 and metHgb18 both result in significant inaccuracy in pulse oximetry, and pulse oximetry should not be used when elevated levels of these abnormal hemoglobins are present. It is noteworthy that a new pulse oximeter design that measures COHgb and metHgb in addition to O2Hgb now is available. This design should be useful for patients with suspected elevations in COHgb and metHgb. Fetal hemoglobin19 and sickle cell anemia20 do not affect the accuracy of pulse oximetry. • Endogenous and exogenous dyes and pigments: Intravascular dye administration can affect the accuracy of pulse oximetry, with methylene blue having the greatest effect.21 Nail polish also can affect the accuracy of pulse oximetry and should be removed before pulse oximetry is begun.22 Hyperbilirubinemia does not appear to affect the accuracy of pulse oximetry.23 • Skin pigmentation: Several studies have found that the accuracy and performance of pulse oximeters are affected by deeply pigmented skin.24–26 • Perfusion: Pulse oximeters require a pulsating vascular bed to function correctly. Under conditions of low flow (e.g., cardiac arrest or severe peripheral vasoconstriction), pulse oximetry becomes unreliable. Under these conditions, an ear probe may be more reliable than a finger probe. • Anemia: Although pulse oximeters are generally reliable over a wide range of hemoglobin levels, they become less accurate and reliable with conditions of severe anemia (hematocrit 70% TOF ratio of 67 minutes (Tables 33–10 and 33–11).44 Cisatracurium recovery indices are unaffected by total dose of relaxant or method of administration. In contrast

0

to atracurium, doses of cisatracurium as great as eight times the ED95 have been administered rapidly without any evidence of histamine release.

Doxacurium Doxacurium is a long-acting bisquaternary benzylisoquinoline diester that is poorly metabolized by plasma cholinesterase. Its ED95 is 25–30 µg/kg.52 Unlike the other benzylisoquinolines, organ elimination is required for its metabolism. This drug is excreted by

0:15

0:35

0:45

the kidney as the major pathway of elimination, and its action is prolonged in renal failure.53 It also is excreted unchanged in the bile.53 Doxacurium exhibits no dose-related cardiovascular side effects. It is useful in long cases wherein extubation is not needed immediately postoperatively, in patients who would benefit from its lack of cardiovascular effects, and perhaps as an adjunct to permit ventilation for short periods in sedated patients in the ICU.

1:00

100

50

0 0.1

Atracurium 0.5 mg/kg

1:15

1:30

1:45

0.1

0.1

2:00

0.1 FIGURE 33–9. Initial dose of atracurium was 0.5 mg/kg, followed by four increments of 0.1 mg/kg every 15 minutes. Note when T 1 spontaneously recovered to control height and train-of-four ratio was 0.74 and increased to 0.85 in the next 4 minutes. (From Ali HH, Miller RD. Monitoring of neuromuscular function. In Miller RD, ed. Anesthesia, vol. 2. 2nd ed. New York: Churchill-Livingstone, 1986, with permission from Elsevier. Copyright 1996.)

CHAPTER 33: Monitoring and Managing Neuromuscular Blockade

TABLE 33–10. Pharmacodynamics of Cisatracurium Dose (mg/kg) ED95 Routine intubation Rapid intubation Primed intubation Infusion (µg/kg/min) aAfter bAfter

0.05 0.2 0.4 — 1.6a

Onset (min)

Time to 25% Recovery


7.6 ± 1.4 2.7 ± 0.1 2.7 ± .01 —

68.3 ± 2.4 91.3 ± 3.3 —

87 ± 4.3 121 ± 5.9 — 33.2 ± 1.8b

0.1 mg/kg bolus. infusion stopped.

TABLE 33–11. Pharmacokinetics of Cisatracurium

Normal Renal failure Hepatic failure Cirrhosis Biliary obstruction Elderly Neonates Children

Vdss (mL/kg)

Clearance (mL/ kg/min)

Elimination Half-Life (min)

121 ± 22 — 195 ± 38 — — 190 (141–238) — —

4.66 ± 0.67 — 6.6 ± 1.1 — — 4.55 — —

25.5 ± 4.1 — 24.4 ± 2.9 — — 28.4 — —

631

All doses for balanced anesthesia.

Steroidal Muscle Relaxants (Fig. 33–10) Vecuronium Vecuronium (Tables 33–12 and 33–13, Fig. 33–4) is the monoquaternary analogue of the steroidal relaxant pancuronium.54 Vecuronium is a more potent NMBD than pancuronium,55 with half to one third of its duration of action by demethylation at the 2-position of the D ring, the position of the steroid nucleus that is responsible for its potency. It is a lipophilic compound that is easily absorbed by the liver and excreted into the bile mostly as the unchanged drug, the predominant method of elimination.55 The action of this drug can be prolonged in patients with liver disease.56 Vecuronium is metabolized in the liver to 3-desacetylvecuronium, 17-desacetylvecuronium, and 3,17-desacetylvecuronium.57 The 3-desacetylvecuronium has neuromuscular blocking properties at approximately half the potency of vecuronium. This metabolite is eliminated by the kidneys, which may account

for the prolonged block when vecuronium is given as a continuous infusion to facilitate mechanical ventilation of patients in the ICU who have compromised renal function.58,59 Recovery times are increased in infants younger than 1 year, based on their increased sensitivity to vecuronium and larger volume of distribution and decreased clearance rate.60 Vecuronium does not have effects on heart rate and blood pressure through modification of the A ring of the steroidal nucleus.61 At doses >0.1 mg/kg, it may inhibit the enzyme histamine-N-methyltransferase,62 which may contribute to occasional reports of histamine-like reactions to vecuronium.63,64 This may be a concern especially when other drugs that release histamine (e.g., the antibiotic vancomycin) are administered or when histamine-rich organs are manipulated during a surgical procedure.62

Rocuronium Rocuronium (Tables 33–14 and 33–15) is the 2-morpholino, 3-desacetyl 16-N-

FIGURE 33–10. Chemical structure of steroidal class neuromuscular blocking drugs.

allylpyrrolidino derivative of vecuronium.65 It was developed specifically to have a rapid onset of action. It achieves this effect partly by being approximately six times less potent than vecuronium and by having a similar molecular weight.16 This results in a larger number of molecules reaching the neuromuscular junction per circulation time and may contribute to the more rapid development of its neuromuscular blockade. Rocuronium undergoes rapid uptake by the liver because of its relative lipophilicity. Unchanged rocuronium has been found in the urine (8.7%) and in the bile (>50%), indicating dual pathways for its elimination.66 The rapid redistribution of rocuronium from the


TABLE 33–12. Pharmacodynamics of Vecuronium

ED95 Routine intubation Rapid intubation Primed intubation Prime: 0.01 mg/kg Time: 4 min Infusion (µg/kg/min)

Dose (mg/kg)

Onset (min)

Time to 25% Recovery (min)


0.05 0.08–0.1 0.2 0.1–0.15

3.5 2.3 1.5–2.0 1.5

30–40 45–60 60–80 45–80

50–60 60–80 80–120 60–120

1–2

—

12–15a

30a

All doses for balanced anesthesia. aAfter infusion stopped.

TABLE 33–13. 632

Pharmacokinetics of Vecuronium

Normal Renal failurea Hepatic failurea Cirrhosis Biliary obstruction Elderly Neonates Children

Vdss (mL/kg)

Clearance (mL/kg/min)

Elimination Half-Life (min)

190 240 (295) (232) 300 290 180 357 204

3.0 2.5 (2.1 vs 4.3) (3.6 vs 54.1) 2.7 2.4 3.7 (5.6 vs 5.2) (5.9 vs 5.2)

79.5 97.1 (148 vs 84) (70 vs 49) 84 98 58 (64.7 vs 70)b (41.0 vs 70)b

aValues bMean

in parentheses include 3-desacetyl vecuronium metabolite. residence time: 66 minutes for infants, 34 minutes for children, vs 52 minutes for

adults.

TABLE 33–14. Pharmacodynamics of Rocuronium

ED95 Routine intubation Rapid intubation Primed intubation Infusion

Dose (mg/kg)

Onset (sec)

Time to 25% Recovery (min)

0.30 0.60 1.2

210 ± 55 89 ± 33 55 ± 14

20(14–28) 37 (23–75) 73 (38–150)

10a

All doses for balanced anesthesia. aAfter 0.45 mg/kg bolus. bAfter infusion stopped.

13 ± 4b


46 ± 19b

neuromuscular junction contributes to its intermediate duration of action at lower doses. The pharmacokinetics of this drug have been reported to be altered in patients with major renal67 and hepatic68 disease. In both infants and elderly patients, the changes in the pharmacokinetics of rocuronium increases the duration of action.69 Rocuronium does not produce alterations in heart rate and blood pressure.70 The ED95 of rocuronium is 0.3 mg/ kg, with a recovery index of 8 minutes and a clinical duration of 50%) and to not attempt to reverse until a plateau of recovery has been reached. Vecuronium and rocuronium by infusion have been used with considerable success. After maintaining steadystate paralysis of approximately 95% and then discontinuing the infusion, mean recovery time to 25% is approximately 13 minutes, and mean 5–95% recovery times are approximately 32 minutes.77 However, there is an agedependent decrease in the steady-state drug infusion requirement and an increased recovery time required for patients older than 60 years.58 These and other findings suggest that disease states or age that alter organ elimination generally decrease maintenance drug infusion requirements and slow the speed of recovery to some extent with vecuronium. This is especially true for long-term infusions in patients with renal failure, because the 3desacetyl metabolite of vecuronium, which is a potent neuromuscular blocking compound, is eliminated by the kidney.59,78 Atracurium and cisatracurium have similar recovery characteristics after infusions in healthy patients. The 25% recovery time after infusion is approximately 12.5 minutes, and the 5–95% mean recovery time is 26.6 minutes during oxygen/nitrous oxide/narcotic anesthesia. Unlike vecuronium, atracurium and cisatracurium show no tendency toward prolonged recovery in disease states, such as renal failure, cirrhosis, and hepatic failure, or at the extremes of age because of its spontaneous degradation by the Hofmann elimination reaction and metabolism by nonspecific plasma cholinesterases. Mivacurium, because of its metabolism by human plasma cholinesterase at 70% the rate of SCh, has significant clinical potential for maintenance of blockade by continuous infusion. During balanced anesthesia, the time from discontinuing the infusion of mivacurium to 25% recovery was 5.7 minutes, with a 5–95% recovery time of 13.6 minutes.40 Its recovery characteristics are much shorter than those of atracurium, cisatracurium, vecuronium, and rocuronium and compare favorably with the short recovery times achieved with SCh.

RELAXANTS IN THE INTENSIVE CARE UNIT NMBDs in the intensive care unit can be valuable adjuncts for managing intubated and mechanically ventilated patients.79 Neuromuscular blockade may be helpful for diminishing the risk of barotrauma by reducing peak airway pressures, minimizing oxygen consumption in hypothermic patients by preventing shivering, decreasing intraabdominal pressure, and stopping respiratory activity that is asynchronous with the ventilatory cycle when all other treatments have failed. NMBD also can be given to help mechanically ventilated patients with unusual problems (status epilepticus, tetanus, botulism) that are resistant to conventional methods of treatment. The use of NMBD in critically ill patients must be balanced with the most serious side effect of severe myopathy.59,79–81 This critical illness myopathy is characterized by marked atrophy of type I and type II muscle fibers, little evidence of inflammation, and sparing of the motor and sensory nerves.82 Although the steroidal muscle relaxants have been implicated because the myopathy associated with their use is similar to the myopathy caused by exogenous corticosteroid administration,59,83 all classes of NMBD contribute to myopathy. In the ICU, the underlying complex systemic disease processes (including sepsis and burns), prolonged immobility, ventilator dependence, use of various drugs that may affect the neuromuscular system, and the initial more frequent use of the steroidal muscle relaxants as compared with the benzylisoquinolines in ICU patients have confounded studies of myopathy caused by prolonged neuromuscular blockade.79 Atracurium and cisatracurium can be given to critically ill patients with renal failure.84 The epileptogenic effects of laudanosine, a metabolite of the Hofmann degradation, have not been reported in patients receiving atracurium infusions. The highest plasma concentrations of laudanosine measured in human plasma during continuous infusions in the ICU are 0.9 has been advocated.91 The return of TOF toward baseline should be considered only one criterion in concert with the sum total of multiple clinical observations such as respiratory function and the ability to follow com-


TABLE 33–18. Criteria of Adequate Recovery Criteria used depend on whether the patient is awake or somnolent. Patient Is Awake Opens eyes widely to command and denies diplopia Sustains tongue protrusion Swallows effectively Sustains a head lift for 5 seconds Sustains a firm hand grip Has an effective cough Has a vital capacity of at least 15 mL/kg Can generate an inspiratory force of at least 30 cm H2O Patient Is Somnolent Can generate an inspiratory force of at least 30 cm H2O Responds to nerve stimulator appropriately, including sustained tetanic response to 50 Hz for 5 seconds TOF or DBS stimulus yields ratio >0.7 or no discernible fade of fully abducted thumb DBS, double-burst stimulation; TOF, train of four.

0

to allow successful extubation usually is present within 20 minutes. In lieu of acetylcholinesterase inhibitors, drugspecific cyclodextrins may provide reversal of neuromuscular blockade in the future. A γ-cyclodextrin, sugammadex, has been synthesized to reverse a profound neuromuscular blockade after rocuronium administration.95,96 This is accomplished by encapsulating rocuronium, decreasing its free concentration in the plasma, and thereby removing this NMBD from the neuromuscular junction. The sugammadex– rocuronium complex is cleared by the kidney. Although sugammadex is specific for rocuronium, it is tempting to speculate that similar encapsulating agents for the other steroidal and benzylisoquinoline NMBD will be synthesized.

mands (Table 33–18) as an indication of adequate recovery from neuromuscular blockade. Reversal of neuromuscular blockade by the administration of an anticholinesterase (e.g., neostigmine or edrophonium) is routinely needed in the operating room or PACU (Fig. 33–11). Through inhibition of acetylcholinesterase activity, the concentration of ACh will increase and be available to compete with the nondepolarizing NMBD. A muscarinic antagonist is simultaneously administered to limit any untoward effects of ACh (bradycardia, bronchospasm, or gastrointestinal hyperactivity). Because the anticholinesterase and muscarinic antagonist should have similar durations, the usual drug pairs that are commonly given are neostigmine/glycopyrrolate or edrophonium/atropine. The timing of the administration of anticholinesterases is important. Profound neuromuscular blockade with NMBD that is dependent on organ elimination may require up to 80 minutes for full recovery.92–94 In routine clinical practice, upon return of the TOF to a single twitch, adequate recovery from neuromuscular blockade

0:15

0:30

0:45

KEY REFERENCES 1. Ali HH. Criteria of adequate clinical recovery from neuromuscular block. Anesthesiology 2003;98: 1278.

1:00

1:15

100

50

0 0.02

Vecuronium 0.12 mg/kg

1:30

0.02

1:45

2:00

0.02

2:15

0.02

2:30

0.02

2:45

A = 0.02 mg/kg N = 0.04 mg/kg

FIGURE 33–11. Tracing of an evoked thenar electromyography after administration of vecuronium. After the initial dose, supplemental vecuronium was given in 15-minute increments. Spontaneous recovery of the first train-of-four (TOF ) response to control height took approximately 30 minutes. The fourth response to the TOF occurred 15 minutes later (dark shadow) and required reversal with neostigmine and atropine to achieve a ratio of 0.9.

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2. Ali HH, Savarese JJ, Lebowitz PW, et al. Twitch, tetanus and trainof-four as indices of recovery from nondepolarizing neuromuscular blockade. Anesthesiology 1981;54: 294. 3. Bevan DR, Smith CE, Donati F. Postoperative neuromuscular blockade: a comparison between atracurium, vecuronium, and pancuronium. Anesthesiology 1988;69: 272. 4. Debaene B, Plaud B, Dilly MP, et al. Residual paralysis in the PACU after a single intubating dose of nondepolarizing muscle relaxant with an intermediate duration of action. Anesthesiology 2003;98: 1042.

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5. Eriksson LI, Sundman E, Olsson R, et al. Functional assessment of the pharynx at rest and during swallowing in partially paralyzed humans: simultaneous videomanometry and mechanomyography of awake human volunteers. Anesthesiology 1997;87:1035. 6. Hayes AH, Mirakhur RK, Breslin DS, et al. Postoperative residual block after intermediate acting neuromuscular blocking drugs. Anaesthesia 2001;56:312. 7. Martyn JA, Richtsfeld M. Succinylcholine-induced hyperkalemia in acquired pathologic states. Etiologic factors and molecular mechanisms. Anesthesiology 2006;104: 158. 8. Naguib M, Flood P, McArdle JJ, et al. Advances in neurobiology of the neuromuscular junction: implications for the anesthesiologist. Anesthesiology 2002;96:202. 9. Schow AJ, Lubarsky DA, Olson RP, et al. Can succinylcholine be used safely in hyperkalemic patients? Anesth Analg 2002;95:119. 10. Watling SM, Dasta JF. Prolonged paralysis in intensive care unit patients after the use of neuromuscular blocking agents: a review of the literature. Crit Care Med 1994;22:884.

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muscular junction: implications for the anesthesiologist. Anesthesiology 2002;96:202. 2. Katz RL. Neuromuscular effects of dtubocurarine, edrophonium and neostigmine in man. Anesthesiology 1967;28:327. 3. Martyn JA, Richtsfeld M. Succinylcholineinduced hyperkalemia in acquired pathologic states. Etiologic factors and molecular mechanisms. Anesthesiology 2006;104:158. 4. Ali HH. Monitoring of neuromuscular function. Middle East J Anesthesiol 1989; 10:261. 5. Ali HH, Savarese JJ. Stimulus frequency and dose-response curve to d-tubocurarine in man. Anesthesiology 1980;52:36. 6. Ali HH, Savarese JJ, Lebowitz PW, et al. Twitch, tetanus and train-of-four as indices of recovery from nondepolarizing neuromuscular blockade. Anesthesiology 1981;54: 294. 7. Ali HH, Utting JE, Gray TC. Quantitative assessment of residual antidepolarizing block. I. Br J Anaesth 1971;43:473. 8. Ali HH, Utting JE, Gray TC. Quantitative assessment of residual antidepolarizing block. II. Br J Anaesth 1971;43:478. 9. Ali HH. Criteria of adequate clinical recovery from neuromuscular block. Anesthesiology 2003;98:1278. 10. Viby-Mogensen J, Howardy-Hansen P, Chraemmer-Jorgensen B, et al. Posttetanic count (PTC): a new method of evaluating an intense nondepolarizing neuromuscular blockade. Anesthesiology 1981;55:458. 11. Drenck NE, Ueda N, Olsen NV, et al. Manual evaluation of residual curarization using double burst stimulation: a comparison with train-of-four. Anesthesiology 1989; 70:578. 12. Engbaek J, Ostergaard D, Viby-Mogensen J. Double burst stimulation (DBS): a new pattern of nerve stimulation to identify residual neuromuscular block. Br J Anaesth 1989;62:274. 13. Pino R, Ali HH. Monitoring neuromuscular blockade. Curr Opinion Anesth 1995; 8:348. 14. Eikermann M, Groeben H, Husing J, et al. Accelerometry of adductor pollicis muscle predicts recovery of respiratory function from neuromuscular blockade. Anesthesiology 2003;98:1333. 15. Viby-Mogensen J, Jensen NH, Engbaek J, et al. Tactile and visual evaluation of the response to train-of-four nerve stimulation. Anesthesiology 1985;63:440. 16. Bartkowski RR, Witkowski TA, Azad S, et al. Rocuronium onset of action: a comparison with atracurium and vecuronium. Anesth Analg 1993;77:574. 17. Kopman AF. Pancuronium, gallamine, and d-tubocurarine compared: is speed of onset inversely related to drug potency? Anesthesiology 1989;70:915. 18. Donati F, Meistelman C, Plaud B. Vecuronium neuromuscular blockade at the adductor muscles of the larynx and adductor pollicis. Anesthesiology 1991;74:833.

19. Donati F, Meistelman C, Plaud B. Vecuronium neuromuscular blockade at the diaphragm, the orbicularis oculi, and adductor pollicis muscles. Anesthesiology 1990;73:870. 20. Mehta MP, Choi WW, Gergis SD, et al. Facilitation of rapid endotracheal intubations with divided doses of nondepolarizing neuromuscular blocking drugs. Anesthesiology 1985;62:392. 21. Ali HH, Lien CA, Witkowski T, et al. Efficacy and safety of divided dose administration of mivacurium for a 90-second tracheal intubation. J Clin Anesth 1996;8: 276. 22. Pino RM, Ali HH, Denman WT, et al. A comparison of the intubation conditions between mivacurium and rocuronium during balanced anesthesia. Anesthesiology 1998;88:673. 23. Miller RD. The priming principle. Anesthesiology 1985;62:381. 24. Mak PH, Irwin MG. The effect of cisatracurium and rocuronium on cisatracurium precurarization and the priming principle. J Clin Anesth 2004;16:83. 25. Naguib M, Abdulatif M, Gyasi HK, et al. Priming with atracurium: improving intubating conditions with additional doses of thiopental. Anesth Analg 1986;65:1295. 26. Schwarz S, Ilias W, Lackner F, et al. Rapid tracheal intubation with vecuronium: the priming principle. Anesthesiology 1985;62:388. 27. Taboada JA, Rupp SM, Miller RD. Refining the priming principle for vecuronium during rapid-sequence induction of anesthesia. Anesthesiology 1986;64:243. 28. Naguib M, Samarkandi AH, Abdullah K, et al. Succinylcholine dosage and apneainduced hemoglobin desaturation in patients. Anesthesiology 2005;102:35. 29. Levano S, Ginz H, Siegemund M, et al. Genotyping the butyrylcholinesterase in patients with prolonged neuromuscular block after succinylcholine. Anesthesiology 2005;102:531. 30. Whittaker M. Plasma cholinesterase variants and the anaesthetist. Anaesthesia 1980;35:174. 31. Schow AJ, Lubarsky DA, Olson RP, et al. Can succinylcholine be used safely in hyperkalemic patients? Anesth Analg 2002; 95:119. 32. Donlon JV. Succinylcholine and open eye injuries. Anesthesiology 1986;65:526. 33. Libonati M, Leahy J, Ellson V. The use of succinylcholine in open eye surgery. Anesthesiology 1986;64:517. 34. Vachon CA, Warner DO, Bacon DR. Succinylcholine and the open globe. Tracing the teaching. Anesthesiology 2003;99: 220. 35. Savarese JJ, Ali HH, Basta SJ, et al. The clinical neuromuscular pharmacology of mivacurium chloride (BW B1090U). A short-acting nondepolarizing ester neuromuscular blocking drug. Anesthesiology 1988;68:723.


36. Savarese JJ, Ali HH, Basta SJ, et al. The cardiovascular effects of mivacurium chloride (BW B1090U) in patients receiving nitrous oxide-opiate-barbiturate anesthesia. Anesthesiology 1989;70:386. 37. Cook DR, Stiller RL, Weakly JN, et al. In vitro metabolism of mivacurium chloride (BW B1090U) and succinylcholine. Anesth Analg 1989;68:452. 38. Gatke MR, Viby-Mogensen J, Ostergaard D, et al. Response to mivacurium in patients carrying the k variant in the butyrylcholinesterase gene. Anesthesiology 2005;102:503. 39. Basta SJ. Clinical pharmacology of mivacurium chloride: a review. J Clin Anesth 1992;4:153. 40. Ali HH, Savarese JJ, Embree PB, et al. Clinical pharmacology of mivacurium chloride (BW B1090U) infusion: comparison with vecuronium and atracurium. Br J Anaesth 1988;61:541. 41. Caldwell JE, Heier T, Kitts JB, et al. Comparison of the neuromuscular block induced by mivacurium, suxamethonium or atracurium during nitrous oxide-fentanyl anaesthesia. Br J Anaesth 1989;63:393. 42. Basta SJ, Ali HH, Savarese JJ, et al. Clinical pharmacology of atracurium besylate (BW 33A): a new non-depolarizing muscle relaxant. Anesth Analg 1982;61:723. 43. Hughes R, Chapple DJ. The pharmacology of atracurium: a new competitive neuromuscular blocking agent. Br J Anaesth 1981;53:31. 44. Lien CA, Schmith VD, Belmont MR, et al. Pharmacokinetics of cisatracurium in patients receiving nitrous oxide/opioid/ barbiturate anesthesia. Anesthesiology 1996;84:300. 45. Fisher DM, Canfell PC, Spellman MJ, et al. Pharmacokinetics and pharmacodynamics of atracurium in infants and children. Anesthesiology 1990;73:33. 46. Ward S, Neill EA, Weatherley BC, et al. Pharmacokinetics of atracurium besylate in healthy patients (after a single i.v. bolus dose). Br J Anaesth 1983;55:113. 47. Fahey MR, Rupp SM, Fisher DM, et al. The pharmacokinetics and pharmacodynamics of atracurium in patients with and without renal failure. Anesthesiology 1984; 61:699. 48. Brandom BW, Stiller RL, Cook DR, et al. Pharmacokinetics of atracurium in anaesthetized infants and children. Br J Anaesth 1986;58:1210. 49. Kent AP, Parker CJ, Hunter JM. Pharmacokinetics of atracurium and laudanosine in the elderly. Br J Anaesth 1989;63:661. 50. d’Hollander AA, Luyckx C, Barvais L, et al. Clinical evaluation of atracurium besylate requirement for a stable muscle relaxation during surgery: lack of age-related effects. Anesthesiology 1983;59:237. 51. Scott RP, Savarese JJ, Basta SJ, et al. Atracurium: clinical strategies for preventing histamine release and attenuating the

haemodynamic response. Br J Anaesth 1985;57:550. 52. Basta SJ, Savarese JJ, Ali HH, et al. Clinical pharmacology of doxacurium chloride. A new long-acting nondepolarizing muscle relaxant. Anesthesiology 1988;69: 478. 53. Dresner DL, Basta SJ, Ali HH, et al. Pharmacokinetics and pharmacodynamics of doxacurium in young and elderly patients during isoflurane anesthesia. Anesth Analg 1990;71:498. 54. Savage DS, Sleigh T, Carlyle I. The emergence of ORG NC 45, 1-[2 beta,3 alpha,5 alpha,16 beta,17 beta)-3, 17-bis(acetyloxy)-2-(1-piperidinyl)-androstan-16-yl]-1methylpiperidinium bromide, from the pancuronium series. Br J Anaesth 1980; 52(Suppl 1):3S.

67. Szenohradszky J, Fisher DM, Segredo V, et al. Pharmacokinetics of rocuronium bromide (ORG 9426) in patients with normal renal function or patients undergoing cadaver renal transplantation. Anesthesiology 1992;77:899. 68. Khalil M, D’Honneur G, Duvaldestin P, et al. Pharmacokinetics and pharmacodynamics of rocuronium in patients with cirrhosis. Anesthesiology 1994;80:1241. 69. Matteo RS, Ornstein E, Schwartz AE, et al. Pharmacokinetics and pharmacodynamics of rocuronium (Org 9426) in elderly surgical patients. Anesth Analg 1993;77:1193. 70. McCoy EP, Maddineni VR, Elliott P, et al. Haemodynamic effects of rocuronium during fentanyl anaesthesia: comparison with vecuronium. Can J Anaesth 1993;40:703.

55. Fahey MR, Morris RB, Miller RD, et al. Clinical pharmacology of ORG NC45 (NorcuronTM): a new nondepolarizing muscle relaxant. Anesthesiology 1981;55:6.

71. Magorian T, Flannery KB, Miller RD. Comparison of rocuronium, succinylcholine, and vecuronium for rapid-sequence induction of anesthesia in adult patients. Anesthesiology 1993;79:913.

56. Duvaldestin P, Saada J, Berger JL, et al. Pharmacokinetics, pharmacodynamics, and dose-response relationships of pancuronium in control and elderly subjects. Anesthesiology 1982;56:36.

72. Khuenl-Brady K, Castagnoli KP, Canfell PC, et al. The neuromuscular blocking effects and pharmacokinetics of ORG 9426 and ORG 9616 in the cat. Anesthesiology 1990;72:669.

57. Marshall IG, Gibb AJ, Durant NN. Neuromuscular and vagal blocking actions of pancuronium bromide, its metabolites, and vecuronium bromide (Org NC45) and its potential metabolites in the anaesthetized cat. Br J Anaesth 1983;55:703.

73. Duvaldestin P, Agoston S, Henzel D, et al. Pancuronium pharmacokinetics in patients with liver cirrhosis. Br J Anaesth 1978;50:1131.

58. d’Hollander A, Massaux F, Nevelsteen M, et al. Age-dependent dose-response relationship of ORG NC 45 in anaesthetized patients. Br J Anaesth 1982;54:653. 59. Segredo V, Caldwell JE, Matthay MA, et al. Persistent paralysis in critically ill patients after long-term administration of vecuronium. N Engl J Med 1992;327:524.

74. Stanley JC, Mirakhur RK. Comparative potency of pipecuronium bromide and pancuronium bromide. Br J Anaesth 1989;63: 754. 75. Stanley JC, Carson IW, Gibson FM, et al. Comparison of the haemodynamic effects of pipecuronium and pancuronium during fentanyl anaesthesia. Acta Anaesthesiol Scand 1991;35:262.

60. Fisher DM, Castagnoli K, Miller RD. Vecuronium kinetics and dynamics in anesthetized infants and children. Clin Pharmacol Ther 1985;37:402.

76. Ramsey FM, Lebowitz PW, Savarese JJ, et al. Clinical characteristics of long-term succinylcholine neuromuscular blockade during balanced anesthesia. Anesth Analg 1980;59:110.

61. Morris RB, Cahalan MK, Miller RD, et al. The cardiovascular effects of vecuronium (ORG NC45) and pancuronium in patients undergoing coronary artery bypass grafting. Anesthesiology 1983;58:438.

77. Shanks CA, Fragen RJ, Ling D. Continuous intravenous infusion of rocuronium (ORG 9426) in patients receiving balanced, enflurane, or isoflurane anesthesia. Anesthesiology 1993;78:649.

62. Futo J, Kupferberg JP, Moss J. Inhibition of histamine N-methyltransferase (HNMT) in vitro by neuromuscular relaxants. Biochem Pharmacol 1990;39:415.

78. Miller DR, Wherrett C, Hull K, et al. Cumulation characteristics of cisatracurium and rocuronium during continuous infusion. Can J Anaesth 2000;47:943.

63. Durrani Z, O’Hara J. Histaminoid reaction from vecuronium priming: a case report. Anesthesiology 1987;67:130.

79. Pino RM. Neuromuscular blockade studies of critically ill patients. Intensive Care Med 2002;28:1695.

64. Lavery GG, Hewitt AJ, Kenny NT. Possible histamine release after vecuronium. Anaesthesia 1985;40:389.

80. Hansen-Flaschen J, Cowen J, Raps EC. Neuromuscular blockade in the intensive care unit. More than we bargained for. Am Rev Respir Dis 1993;147:234.

65. Mayer M, Doenicke A, Hofmann A, et al. Onset and recovery of rocuronium (Org 9426) and vecuronium under enflurane anaesthesia. Br J Anaesth 1992;69:511. 66. Khuenl-Brady KS, Pomaroli A, Puhringer F, et al. The use of rocuronium (ORG 9426) in patients with chronic renal failure. Anaesthesia 1993;48:873.

81. Watling SM, Dasta JF. Prolonged paralysis in intensive care unit patients after the use of neuromuscular blocking agents: a review of the literature. Crit Care Med 1994;22:884. 82. Gooch JL, Suchyta MR, Balbierz JM, et al. Prolonged paralysis after treatment with

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neuromuscular junction blocking agents. Crit Care Med 1991;19:1125. 83. Giostra E, Magistris MR, Pizzolato G, et al. Neuromuscular disorder in intensive care unit patients treated with pancuronium bromide. Occurrence in a cluster group of seven patients and two sporadic cases, with electrophysiologic and histologic examination. Chest 1994;106:210. 84. Prielipp RC, Coursin DB, Scuderi PE, et al. Comparison of the infusion requirements and recovery profiles of vecuronium and cisatracurium 51W89 in intensive care unit patients. Anesth Analg 1995;81:3. 85. Chapple DJ, Miller AA, Ward JB, et al. Cardiovascular and neurological effects of laudanosine. Studies in mice and rats, and in conscious and anaesthetized dogs. Br J Anaesth 1987;59:218. 86. Bevan DR, Smith CE, Donati F. Postoperative neuromuscular blockade: a comparison between atracurium, vecuronium, and pancuronium. Anesthesiology 1988;69:272. 87. Debaene B, Plaud B, Dilly MP, et al. Residual paralysis in the PACU after a single intubating dose of nondepolarizing

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muscle relaxant with an intermediate duration of action. Anesthesiology 2003;98: 1042. 88. Hayes AH, Mirakhur RK, Breslin DS, et al. Postoperative residual block after intermediate-acting neuromuscular blocking drugs. Anaesthesia 2001;56:312. 89. Murphy GS, Szokol JW, Franklin M, et al. Postanesthesia care unit recovery times and neuromuscular blocking drugs: a prospective study of orthopedic surgical patients randomized to receive pancuronium or rocuronium. Anesth Analg 2004; 98:193. 90. Brand J, Cullen D, NE W, et al. Spontaneous recovery from nondepolarizing neuromuscular blockade: correlation between clinical and evoked response. Anesth Analg 1977;56:55. 91. Eriksson LI, Sundman E, Olsson R, et al. Functional assessment of the pharynx at rest and during swallowing in partially paralyzed humans: simultaneous videomanometry and mechanomyography of awake human volunteers. Anesthesiology 1997; 87:1035.

92. Kirkegaard H, Heier T, Caldwell JE. Efficacy of tactile-guided reversal from cisatracurium-induced neuromuscular block. Anesthesiology 2002;96:45. 93. Kopman AF, Chin WA, Moe J. Doseresponse relationship of rocuronium: a comparison of electromyographic vs. acceleromyographic-derived values. Acta Anaesthesiol Scand 2005;49:323. 94. Magorian TT, Lynam DP, Caldwell JE, et al. Can early administration of neostigmine, in single or repeated doses, alter the course of neuromuscular recovery from a vecuronium-induced neuromuscular blockade? Anesthesiology 1990;73:410. 95. de Boer HD, van Egmond J, van de Pol F, et al. Reversal of profound rocuronium neuromuscular blockade by sugammadex in anesthetized rhesus monkeys. Anesthesiology 2006;104:718. 96. Sorgenfrei IF, Norrild K, Larsen PB, et al. Reversal of rocuronium-induced neuromuscular block by the selective relaxant binding agent sugammadex: a dose-finding and safety study. Anesthesiology 2006;104: 667.

CHAPTER 34: Perioperative Electrolyte Abnormalitites, Acid–Base Disorders, and Fluid Replacement

CHAPTER 34 Monitoring and Managing Perioperative Electrolyte Abnormalities, Acid–Base Disorders, and Fluid Replacement Patrick J. Neligan, MD, and Jiri Horak, MD The human body is an aqueous soup containing carbohydrates, protein, fat, ions, and trace elements bundled into and around cellular structures built on an exoskeleton. Fundamental to the structure and function of the body are the chemical properties of water. Patients who are undergoing surgery or suffering with critical illness undergo dramatic changes in the volume, distribution, and composition of body water. Patients undergoing the most minor of procedures will undertake a period of fasting, rehydration with intravenous fluids and neurohormonal changes in fluid distribution. To understand strategies and implications of perioperative fluid administration, it is important that one understands the homeostatic mechanisms by which the body maintains its internal milieu. Homeostasis refers to the capacity of the human body to maintain a stable constant condition by means of constant dynamic equilibrium adjustments controlled by a medley of interconnected regulatory mechanisms. The concept dates from the foundations of scientific medicine, specifically the work of Claude Bernard (1813–1878). Multiple systems exist in the body to test and control deviations from the normal range in vital functions, including the autonomic nervous system, the renin– angiotensin–aldosterone–vasopressin axis, and the hypothalamic–pituitary– adrenal axis. The body thus self-regulates to maintain a variety of physiologic and metabolic variables in the state of equilibrium, despite a staggering range

KEY POINTS 1. Water is the single most abundant compound in the body, constituting approximately 50–70% of body weight. 2. One third of body water is extracellular, representing approximately 20% of body weight. Of this one third is located within the intravascular compartment, and two thirds is extravascular or interstitial. 3. Electrolytes are characterized by their degree of dissociation (strong or weak ions), the number of particles present (millimoles), the number of electrical charges per unit (milliequivalents), and the number of active molecules per unit volume (milliosmoles). 4. Although osmolality is equal through each of the body’s compartments, electrolyte composition varies. Sodium and chloride are principally extracellular. Potassium, phosphate, magnesium, and calcium are principally intracellular. 5. Perioperative patients undergo a predictable “stress” response during which there is significant fluid and electrolyte flux. The magnitude and timing of these changes are key to management strategies. 6. Changes in extracellular sodium concentrations often, but not always, reflect body water composition. Hyponatremia is indicative of free water overload, whereas hypernatremia is indicative of dehydration. 7. Depletion of serum concentration of principally intracellular ions (potassium, phosphate, magnesium, and calcium) reflects significant total body electrolyte depletion. 8. All acid–base abnormalities can be explained in terms of strong ion difference, weak acid concentration, PaCO2 and extracellular free water. 9. The six primary acid–base abnormalities are acidosis because of increased PaCO2, acidosis because of reduced strong ion difference (SID), acidosis because of increased ATOT, alkalosis associated with reduced


PaCO2, alkalosis because of increased SID, and alkalosis because of reduced ATOT. 10. A variety of tools are available for interpreting acid–base abnormalities. These include the base deficit excess, the corrected anion gap, the strong ion gap, and the base deficitexcess gap. 11. Treatment of acid–base abnormalities should be directed at correcting the underlying cause. 12. Initial perioperative or emergency fluid resuscitation strategies involve crystalloid resuscitation to replace insensible loss and restore interstitial volume, lost as a consequence of transcapillary refill. 13. Upper GI losses should be replaced with isotonic saline. Lower GI and extracellular fluid losses should be replaced with balanced salt solutions. Blood loss can be initially be replaced with crystalloid in a 1:3–5 ratio, but as blood loss increases, the volume of crystalloid required increases geometrically. 14. Overresuscitation with crystalloid may lead to poor perioperative outcomes. “Normal saline” solution, given in significant volume, causes metabolic acidosis and hyperchloremia may reduce splanchnic blood flow. 15. Colloid solutions restore circulating volume more rapidly than crystalloid, with less tissue edema. Their use remains controversial. 16. Volume replacement strategies for major surgery should not be formula based, but dynamic and goal directed, using volume- and flow-monitoring devices. 17. Patient outcomes appear to be optimal when the patient is resuscitated fully on the day of surgery or injury and resuscitation efforts rapidly decelerate. 18. Consideration should be given to postoperative fluid restriction, in particular in patients undergoing lower intestinal resection.

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of variations in the level of human activities and externalities. A key part of homeostasis is maintenance of body water in terms of circulating volume, volume distribution, and composition. The systems involved in homeostasis are dedicated to maintaining the delicate balance of homeostatic function despite externalities such as tissue trauma or surgery. The anesthesiologist is in a unique position to manipulate these systems for the good of the patient. Key to the understanding of homeostasis is the role of water and ions in body fluids. Changes in water and electrolyte distribution lead to significant physiologic upset, often manifest as acid–base abnormalities. Acid–base abnormalities all result from changes in carbon dioxide tension, water and electrolyte distribution, and extracellular protein concentration. Intravenous fluids, administered to the majority of perioperative patients have significant effects on water and electrolyte distribution and also impact acid–base balance. Initial perioperative or emergency fluid resuscitation strategies involve crystalloid resuscitation to replace insensible loss and restore interstitial volume. Overresuscitation with crystalloid may lead to poor perioperative outcomes. “Normal saline” solution causes metabolic acidosis and the associated hyperchloremia may reduce splanchnic blood flow. A careful dynamic or goal-directed approach to fluid administration is supplanting traditional formulaic approaches. Furthermore, widely established practices such as fluid administration to replace third space losses and postoperative maintenance fluid administration are undergoing rigorous evaluation. This chapter sequentially reviews these concepts.

ity—molecules clumping together—is responsible for important chemical properties of water. Water has a high surface tension, low vapor pressure, high specific-heat capacity, high heat of vaporization, and a high boiling point. These factors have enabled life on this planet. Water is a powerful ionizing solvent—substances dissolved in water separate into component parts. Water is slightly ionized: when molecules collide, enough energy is produced to transfer a proton from one water molecule to another. Thus water slightly dissociates into a negatively charged hydroxylated (OH) ion and positively charged protonated (HnO+) ion.1 All metabolic activity in the body occurs in this aqueous medium. Thus compounds ingested or administered to the body are impacted by the chemical properties of water.

Water Distribution in Body Compartments Water is the single most abundant compound in the body, constituting approximately 50–70% of body weight. Males contain relatively more water (on average 60%) than do females (on average 50%). There is an inverse relationship between total body fat and total body water (TBW). Females have less skeletal muscle and have more subcutaneous fat, thus lower TBW. TBW varies dramatically, depending on the age of the individual. Neonates have very high TBW (70–80%). Conversely, elderly patients have relatively lower TBW (52% for males, 45% for females). Body water is neither liquid nor easily accessible. It is divided into two separate compartments: the intracellular and the extracellular compartments (or spaces). Two-thirds of body water is intracellular, principally in skeletal muscle. One-third of body water is extracellular, representing approximately

20% of body weight. Of this one third is located within the intravascular compartment, and two thirds is extravascular or interstitial. To place this in context, a 75-kg male has a TBW of 45 L, of which 15 L is extracellular and 5 L is intravascular (Fig. 34–1). The interstitial fluid contains ultrafiltrated plasma (intravascular water), transudated plasma, and fluid and electrolytes actively pumped out of cells (transcellular fluids). Water freely moves from the intracellular to the extracellular space, but dissolved ions cannot do so. Consequently, the clinician should be aware that administration of electrolyte-rich solutions may have a dramatic impact on extracellular ionic composition and, indeed, on acid–base chemistry.2,3 Most of the fluid in the interstitium is derived from filtration and diffusion from the capillaries. The extracellular space is a matrix made up of collagen fiber bundles and proteoglycan filaments. Fluid is entrapped in the minute spaces between the filaments, taking the form of a gel (“tissue gel”). Fluid does not flow easily through this gel. Indeed, fluid diffuses through the gel, molecule by molecule. There is little “free fluid” in the interstitium. Free fluid exists only as small rivulets that course along the collagen fibers or cells. When there is significant extravascular fluid expansion, such as in volume overload or congestive heart failure, these rivulets turn into pockets, then rivers, of free flowing water. As a consequence, tissues feel boggy or edematous.

Ionic Constituents of Body Compartments Charge Compounds introduced into aqueous solutions dissociate into their component parts, depending on the ion dissociation constant (pKa ).4 This describes the tendency of the molecule or ion to

WATER AND IONS Physical Chemistry of Water The human body is composed principally of water. Water is a simple triatomic molecule composed of 2 molecules of oxygen and 1 molecule of hydrogen, bound covalently. There is an unequal charge distribution; oxygen nuclei have a particularly strong attraction for electrons. This results in a H-O-H bond angle of 105°. Thus water behaves like a charged molecule, a dipole, with a negative oxygen and positive hydrogen end. This polar-

Major Body Fluid Compartments in a 75 kg Male

Intracellular fluid 30 L

Intracellular compartment 30 L 40% of body weight 2/3 total body water FIGURE 34–1. Body fluid compartments.

Interstitial fluid 10 L

Intravascular fluid 10 L

Extracellular compartment 15 L 20% of body weight 1/3 total body water

CHAPTER 34: Perioperative Electrolyte Abnormalitites, Acid-Base Disorders, and Fluid Replacement

keep a proton at its ionization center. Strong ions, characterized by low pKa, rapidly split into their component parts. Examples of strong ions include sodium (Na+), chloride (Cl), potassium (K+), magnesium (Mg2+) and lactate. The physiologic and chemical activity, and thus the importance, of electrolytes depend on several variables. These include the number of particles present per unit volume (in terms of moles or millimoles), the number of electrical charges per unit volume (in equivalents or milliequivalents), and the number of osmotically active molecules per unit volume (in osmoles or milliosmoles). It is important that the clinician be aware of these properties and distinguishes each from the others when managing and monitoring fluids and electrolytes in perioperative care. It is also important to be aware of the physiologic functions of the most important ions. The chemical composition of the body’s various fluids is described in terms of chemical combining activity or chemical “equivalents.” When the concentrations of different ions within each fluid compartment are expressed in this way, the sum of all positive ions (cations) exactly equals the sum of all negative ions (anions). This is the law of electrical neutrality. The atomic weight of an element is approximately the sum of protons and electrons in the nucleus: the weight of 1 atom of oxygen is 16. The weight of 1 atom of hydrogen is 1. The molecular weight of a compound can be determined by the chemical formula of the compound, and then adding together the atomic weights of all the elements constituting that compound. One mole (1 mol) of any substance is its molecular weight expressed in grams (i.e., gram-molecular weight) and contains 6.023 × 1023 molecules (the Avogadro number). A millimole (mmol) of a substance is 1/1000 of a mole, or the substance’s weight expressed in milligrams. In addition, 1 mol of any gas (e.g., oxygen, carbon dioxide) under standard conditions occupies a constant volume of 22.4 L and 1 mmol/L of gas occupies 22.4 mL. Regardless of whether a substance is ionized or nonionized, organic or inorganic, the terms mole and millimole are applicable. Electrolytes combine with each other strictly in proportion to their ionic valencies. Originally, oxygen was chosen

as the standard of reference; 8 g of oxygen will combine with 1 g atomic weight of hydrogen. By convention, the chemical standard of reference for combining power is the electric charge (+) of 1 atomic weight (1 g) of hydrogen. Thus 1 equivalent (1 Eq) of an ion is that amount that can combine with 1 g of hydrogen and thus is chemically equivalent to 1 g of hydrogen. One equivalent of hydrogen consists of 6.023 × 1023 particles, weighs 1 g, and carries a positive charge. This quantity of hydrogen ions neutralizes or balances 1 Eq of hydroxyl ions, which consists of 6.023 × 1023 particles, weighs 17 g, and carries a negative electric charge. The result of this neutralization is the formation of 1 mol of water weighing 18 g. Such ions are termed univalent and balance each other in a 1:1 ratio. For all univalent ions, 1 Eq equals 1 mol. Certain ions (e.g., calcium Ca2+, magnesium Mg2+, sulfate SO42) are divalent and carry either 2 positive charges (divalent cations) or 2 negative charges (divalent anions). These multivalent ions have greater chemical-combining power than do univalent ions. As electrochemical neutrality must be maintained in all reactions, 1 divalent cation (e.g., Ca2+) will react with 2 univalent anions (e.g., 2 × Cl). In other words, 1 mol of divalent cation (6.023 × 1023 particles) supplies 2 Eq and will offset 2 mol (1 Eq each) of univalent anion.

The ionic concentrations present in body fluids are relatively small and are expressed in terms of milliequivalents (mEq) rather than equivalents. In the case of univalent ions, 1 mEq is equal to 1/1000 of the gram-atomic weight (i.e., atomic weight expressed in mg); is the same as 1 mmol of the ion in question; and consists of 6.023 × 1020 particles. For divalent ions, 1 mEq consists of 3.012 × 1020 particles and weighs 1/2000 of the gram-atomic weight. One mmol of divalent ions equals 2 mEq. An equivalent (or milliequivalent) of any ion is its atomic weight expressed in grams (or milligrams) divided by the valence. Electrolytes do not combine gram for gram or milligram for milligram; they combine equivalent for equivalent or milliequivalent for milliequivalent of opposite polarity. Therefore, in any given fluid compartment or intravenous solution, the number of milliequivalents of cations is balanced by precisely the same number of milliequivalents of anions.

Distribution There are different electrolyte concentrations in each body fluid compartment; Table 34–1 lists the average values. In the extracellular compartment, the major cation is sodium and the principal anions are chloride and bicarbonate. Sodium and chloride are free in solution, but appreciable fractions of calcium and magnesium are

TABLE 34–1. Ion Distribution in Different Compartments

Electrolyte Cations Sodium Potassium Calcium Magnesium Total Anions Chloride Bicarbonate Phosphate Sulfate Organic acids Protein Total

Plasma

Plasma Water

Interstitial Fluid

Intracellular Fluid

(mEq/L)

(mEq/L)

(mEq/L)

(mEq/kgL)

142 4 5 3 154

152 4 5 3 164

145 4 3 1 153

10 156 3 26 195

103 27 2 1 5 16 154

109 29 2 1 6 17 164

114 30 2 1 5 1 153

2 10 108 20 55 195

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bound to protein. Interstitial fluid represents a partial ultrafiltrate of plasma devoid of platelets and erythrocytes and with a lower concentration of protein. The principal plasma protein, albumin, carries a significant a negative charge at pH 7.4, and its diffusion across capillary endothelium is restricted. Consequently, because of the greater protein content (i.e., organic anions) in plasma, the total plasma concentration of cations is greater and the concentration of inorganic anions is less than in the interstitial fluid. Electroneutrality is maintained within each fluid compartment, but because of protein distribution, there is an asymmetry of ion distribution between plasma and the interstitium. Within each fluid compartment, the total cations must equal the total anions, but a greater number of diffusible ions reside in the compartment containing the most organic anions. As a result, a slight osmotic pressure gradient is established, which, under normal conditions, is counterbalanced by capillary hydrostatic forces. This is an example of the Gibbs-Donnan principle, which describes the unequal distribution of diffusible ions on either side of the cell membranes bordering these fluid compartments. The ionic concentrations for plasma water differ from those of plasma because of the exclusion of solids, notably lipids and large proteins, which total approximately 7%. Plasma proteins occupy a volume far out of proportion to the few milliequivalents of anion they represent. One liter of plasma contains about 940 mL of water. The remaining volume is occupied, for the most part, by protein. Ions are generally dissolved in the aqueous phase of plasma, so that concentrations in plasma water exceed those in whole plasma by a factor of 1000/940. Clinical laboratories usually report electrolyte values as the ionic concentration in a given volume of whole plasma or serum, and, although slightly inaccurate, this is generally accepted. However, if the lipid or protein content of plasma is significantly increased, there will be a corresponding decrease in the reported concentration of ions per liter of plasma (e.g., pseudohyponatremia). The volume of water in the sample may be significantly less than the total volume; therefore the ionic concentrations will be underestimated.

Within the intracellular compartment, potassium and magnesium are the predominant cations, whereas phosphate, sulfate, and protein are the most abundant anions. There is a marked difference between intracellular and extracellular water in terms of ionic concentrations. The ratio of intracellular to extracellular potassium is almost 30:1. Likewise, sodium and chloride are portioned along a steep concentration gradient in the opposite direction. There are more ions in the intracellular compartment than the extracellular compartment. Significant proportions of intracellular ions are bound to protein or cellular constituents and are osmotically inactive. Many biologic processes are dependent on the presence of transcellular impediments to ion transport. Large polyvalent protein and organic phosphate anions are confined intracellularly because of their absolute membrane impermeability. For smaller ions, maintaining different ionic concentrations across cell membranes is in part, dependent on the active accumulation and extrusion of certain ions from within cells. Active, energy-dependent “ion pumps” (contained within cell membranes) generate the ionic concentration gradients observed among the various fluid compartments. For example, the tendency for sodium ions to diffuse from extracellular fluid ( high concentration) into cells ( low concentration) is opposed by the active transport of sodium ions out of cells. Similarly, the tendency for potassium ions to diffuse along a concentration gradient from the intracellular fluid ( high concentration) to the extracellular fluid ( low concentration) is opposed by an active accumulation process. For the anesthesiologist this means that when fluids are administered perioperatively, sodium and chloride remain in the extracellular space. Ionic distribution results in electrical polarization across cells. Sodium is predominantly extracellular and cells are far more permeable to potassium than to sodium. Thus, potassium ions tend to diffuse down a concentration gradient and out of a cell. The result is an increasing negative charge within the cell that tends to counteract this diffusion, restraining further potassium movement. Membrane polarization is largely a function of the difference in potassium concentration on either side of the membrane. For most

cells under normal conditions, the resting transmembrane potential difference is 60 to 90 mV. Alterations in the distribution of ions, particularly in the extracellular space, can result in a change in this resting potential and cellular dysfunction. Hypoxia, in particular, destroys this delicate charge balance and leads to unopposed diffusion of ions along concentration gradients. This results in cellular swelling, a result of sodium and water entering cells, and hyperkalemia, as a result of outward leakage of potassium.

Concentration of Ions By convention, the concentrations of most intravenous solutions are expressed as percentages (usually weight in grams or milligrams per 100 mL of solution). For example, 0.9% saline solution (normal saline) represents 0.9 g sodium chloride/100 mL water. In the United States, laboratory measurements of, for example, glucose, albumin, and creatinine, continue to be expressed as milligrams percent (i.e., mg/100 mL of blood, serum, or plasma). The major limitation of this measurement technique is the impact of temperature on substance volume. Internationally, molality and molarity are widely used to describe concentration. Molality is the number of moles of solute per 1000 g of solvent. It is independent of temperature. A molal solution of saline will contain 58.5 g of sodium chloride dissolved in 1000 g of water. The molar concentration is the number of moles of solute per 1000 mL of solution (usually water) at a specified temperature. In clinical practice, millimoles are used. Thus, we use millimoles per kilogram of solution (millimolal [mmol]) and millimoles per liter of solution (millimolar [mM]).

Water Distribution and Movement Cell membranes are permeable to water. Water molecules continuously move between fluid compartments in the body. Water movement is governed by hydrostatic and osmotic pressures. Hydrostatic pressure is dynamic and results from pulsatile blood flow. This pressure gradually reduces from a mean in the aorta of 90–95 mm Hg, to a mean of 30–40 mm Hg in the capillaries. Hydrostatic pressure is higher in the lower limbs in the erect patient. The capillary network is fe-


nestrated, and the hydrostatic pressure within the capillary is sufficient to push fluid through these fenestrations into the interstitium. Once in the capillary system, however, osmotic forces are more important than hydrostatic forces. Osmosis is the movement of water thru a semipermeable membrane from a location in which solute is in low concentration to a location in which solute is in high concentration. The membrane is permeable to solvent, not solute, resulting in a pressure gradient. Osmotic pressure is the hydrostatic pressure that must be applied to the solution of greater concentration to prevent water movement across the membrane. Osmotic pressure is dependent on the number of osmotically active molecules in solution and not their molecular weight, electric charge, or valence number. Small numbers of large molecules are less osmotically active than large numbers of small molecules. One gram molecular weight (i.e., 1 mol) of a nondissociating compound (e.g., glucose, urea) consists of 6.023 × 1023 molecules and is termed 1 osmole (Osm). For nondissociating compounds, 1 mmol is equivalent to 1 mOsm; 1 mOsm of any solute dissolved in 1 kg of water will decrease the activity of water by 17 mm Hg. Ionized substances tend to dissociate in solution and thereby generate more osmotically active particles. For example, 1 gram-molecular weight of sodium chloride (NaCl)—consisting of 6.023 × 1023 molecules—dissociates into twice this number of ions in solution and exerts an osmotic effect of approximately 2 Osm. One mole of sodium sulfate (Na2SO4) results in 4 Eq (2 Na+, SO4) but dissociates so as to exert an osmotic effect approaching 3 Osm (Na, Na, SO4). Osmolarity is the number of osmoles of solute per liter of solvent plus solute. Osmolality, on the other hand, is the solute concentration per kilogram of solvent (water). Osmolality is more widely used in clinical practice, as its value is unaffected by the presence of fat and protein in plasma. Osmolality is generally measured with a freezing point osmometer. Extracellular osmolality is approximately 290 ± 10 mOsm/kg H2O, and, presumably, the intracellular osmolality level is identical. As 1 mOsm/kg H2O exerts an osmotic effect equivalent to 17 mm Hg, the osmotic pres-

sure of most body fluids is approximately 300 × 17, or 5100 mm Hg. Quantitatively, osmotic pressures greatly exceed any hydrostatic pressure in the body. The magnitude of these osmotic forces can be appreciated when one realizes that an osmotic pressure difference of only 6 mOsm/L, across a semipermeable membrane, can move as much water as the entire hydrostatic pressure generated by the heart. Osmotic forces throughout the body (with the exception of the renal medulla) are equal, as water can readily cross cell membranes. Thus the osmolality of the intracellular and extracellular spaces equalize, despite differing compositions. This has significant impact in health and disease. Loss of extracellular fluid (ECF) volume leads to increased ECF osmolality and subsequent cellular dehydration. Sodium, chloride, and bicarbonate account for 90–95% of the osmotic activity present in plasma and interstitial fluid. Other ions and organic compounds (e.g., glucose, urea, amino acids) account for most of the remainder. Plasma proteins provide negligible osmotic effect. The major intracellular osmotic solutes are potassium, magnesium phosphate, and protein. Total body osmotic solute is portioned such that two thirds is contained within the intracellular fluid (ICF) compartment and one third resides in the ECF compartment. This localization of total body solute in turn explains the overall distribution of body water. In most situations, the concentrations of certain osmotically active substances can be combined to provide a remarkably accurate (within 10%) estimate of serum osmolality (Sosm): Sosm (mOsm/kg H2O) = (2 × [Na] + [K]) + ([glucose]/18) + ([BUN]/2.8) where glucose and blood urea nitrogen (BUN) concentrations are expressed in mg/dL and sodium concentration [Na+] is in mEq/L. The calculations for BUN and glucose resolve the results into mmol/L. Occasionally, osmotically active compounds are present in the extracellular fluids that are not accounted for by the above calculation. When osmolality is measured, and then calculated, a gap between the two figures becomes evident (osmolal gap). This gap is nor-

mally less than 10 mOsm/kg H2O. Pharmacologically, the gap is increased by the administration of mannitol or alcohol. Pathologically, the gap may be widened by poisoning with ethylene glycol, propylene glycol, or isopropyl alcohol. Tonicity describes the relative osmolality of solutions. A solution is said to be isotonic when it is isoosmotic (i.e., the same osmotic pressure) with the body fluids. Intravenous fluids that are formulated as balanced salt solutions (Normosol-R or Plasma-Lyte) are isotonic with respect to plasma. Normal saline (0.9% NaCl) is slightly hypertonic to plasma. Lactated Ringer solution is slightly hypotonic. However, functionally, these fluids act as isoosmotic solutions and do not impact the size of erythrocytes. Administration of hypertonic fluids (e.g., 3% or 7.5% NaCl, 7.5% sodium bicarbonate, 10% mannitol) leads to a dramatic increase in ECF osmolality and cellular dehydration. Often this is intentional, such as the administration of mannitol or hypertonic saline to head-injured patients. Occasionally, hyperosmolality occurs pathologically, as in diabetes insipidus, diabetic ketoacidosis (caused by ketones and glucose) or nonketotic hyperosmolar syndrome (caused by glucose), and acute renal failure (caused by urea and other nitrogenous waste products). Hypotonic solutions (e.g., 0.45% NaCl) have fewer osmotically active particles per volume compared with the reference solution and tend to produce cellular swelling. Finally, although the terms tonicity and osmolality are frequently used interchangeably, an alteration in one does not necessarily lead to an alteration in the other. The classic example of this is urea. Urea is freely permeable throughout the body water. It does not affect tonicity, but will cause an increase in extracellular osmolality.

ALTERATIONS IN FLUID AND ELECTROLYTE DISTRIBUTION Impact of Surgical Stress Response on Perioperative Fluid Distribution Insensible Losses Perioperative care is characterized by dramatic changes in fluid and electrolyte content and distribution in the various fluid spaces in the body. These

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changes are predictable and follow a characteristic pattern described by Cuthbertson5 and Moore,6,7 widely known as the “stress response.” An understanding of this process is central to understanding the dynamics of fluid and electrolyte flux in the perioperative period and is helpful in guiding therapy. The stress response has traditionally been considered a biphasic “ebb and flow” phenomenon. After an injury or surgical incision, initially there is significant peripheral vasoconstriction, shunting of blood from the periphery to the midline (to preserve vital organs), and a drop in body temperature. Simultaneously, there is a fall in capillary hydrostatic pressure, promoting a rapid shift of protein-free fluid from the interstitium into the capillaries.8 This is known as “transcapillary refill” and it includes mobilization of fluid from the splanchnic circulation, in particular the splanchnic veins.9 This induces a state of absolute hypovolemia in the extracellular space. There is a dramatic increase in the release of vasopressin (antidiuretic hormone) and activation of the renin–angiotensin–aldosterone axis to conserve salt and water. The second phase, the hypermetabolic or “flow” phase, occurs within hours, characterized by a dramatic increase in cardiac output, driven by catecholamines, vasodilatation, increased capillary permeability and an increase in temperature. A generalized catabolic state ensues, characterized by insulin resistance, hypercortisolism, and protein breakdown. Thus the patient develops tachycardia, leucocytosis, hyperthermia, hyperglycemia, and tissue edema. The magnitude of this response is proportionate to the degree of injury or extent of surgery. Significant intracellular fluid deficit may be incurred to maintain circulating volume. A period of fluid sequestration occurs, as a result of extravasation of fluid consequent of widespread capillary leak, urinary output falls, and tissue edema may become evident. Vasodilatation and relative intravascular hypovolemia occurs. During this period, patients typically require administration of resuscitation fluids to maintain blood pressure and circulating volume. Weight gain ensues. Eventually a state of equilibrium arrives, usually day 2 after a procedure, when active sequestration stops. This is followed by a phase of diuresis during which the patient mobilizes

fluid and recovers. Initially there is a precipitous drop in serum albumin. Restoration of albumin levels is associated with recovery. Moreover, intracellular fluid volume returns to normal. Inward shift of fluid from the extracellular to the intracellular space is associated with intracellular movement of ions such as potassium, magnesium, and phosphate. Hence hypophosphatemia, hypomagnesemia, and, in particular, hypokalemia are usually evident on a serum chemistry panel at this time. The practicing clinician must be aware of the stages of the stress response when deciding whether or not to administer fluid and electrolytes. For example, early in the flow phase, significant intracellular and interstitial fluid depletion may exist, despite the appearance of “normal” cardiovascular measurements ( blood pressure, cardiac output, stroke volume). This requires repletion with free water and isotonic crystalloid. During the vasodilatory, hypermetabolic phase, the circulating volume requires support, taking into account the large volume of distribution of administered crystalloid. During the equilibrium phase, the administration of intravenous fluid is dependent on the objective of the clinician. The clinician may choose to continue fluid administration, to keep organs well hydrated, or to stop administering fluid, preventing the formation of further tissue edema. During the diuretic phase, the major objective of the clinician is to allow the patient to return to baseline body weight, and to aggressively replete electrolytes. It can be argued that the administration of anesthesia significantly reduces the ebb or shock phase. Nevertheless, patients undergoing surgery are usually dehydrated secondary to fasting, bowel lavage, or their primary disease (e.g., esophageal cancer). Consequently, the perioperative period should be viewed as follows: (a) dehydration phase, (b) shock phase, (c) relative and absolute hypovolemic phase (as a consequence of vasodilatation, fluid sequestration, and blood loss), (d) equilibrium phase, and (e) diuresis phase. Certain operations are associated with greater blood loss because of overt or microvascular bleeding (vascular surgery); other operations are associated with greater tissue injury because of, for example, bowel handling. Thus, within this paradigm, a “one-formula-

fits-all” approach is neither scientific nor effective. Where extensive fluid shifts are to be expected in the perioperative period, it is worthwhile to obtain a preoperative weight so as to have a baseline goal for the patient’s postoperative diuresis.

Hypovolemia There is little excess water-storage capacity in the human body. With the exception of congestive heart failure, perioperative patients are more than likely to present in a state of relative or absolute hypovolemia. This may be mild dehydration, as a consequence of fasting, or severe dehydration, because of the administration of purgatives (for bowel lavage), persistent diarrhea, nasogastric suctioning, fistula drainage, or the inability to consume water and electrolytes. Clinical findings that may alert the clinician to dehydration include confusion, loss of skin turgor, longitudinal furrowing of the tongue, dry mucus membranes, sunken eyes, collapsed veins, cold extremities, and highly concentrated urine. A 15–30% loss of intravascular volume will lead to resting tachycardia. Blood pressure is usually maintained despite a volume loss of up to 40%, caused by intense vasoconstriction and transcapillary refill. In addition cardiac output and cardiac index remain within normal limits and the only hemodynamic indication of hypovolemia is a reduction in stroke volume.10 On evaluation of the patients’ chemistry panel, a high urea to creatinine ratio (>10:1), hypernatremia, and metabolic (contraction) alkalosis (caused by increased strong ion difference, a consequence of free water deficit) should alert the clinician to an ECF volume deficit. An ECF volume deficit can be confirmed by a urine specimen (assuming normal renal function) that is significantly concentrated (e.g., 500– 1400 mOsm/kg H2O) and that has a high specific gravity and low sodium content (40 mEq/L, and are characterized by the inability of the body to retain sodium. This may be caused by loop, thiazide, or osmotic diuretics, carbonic anhydrase inhibitors, primary aldosterone deficiency (Addison disease or adrenal insufficiency), or cere-

bral salt wasting (associated with subarachnoid hemorrhage). If the urinary sodium is less than 20 mEq/L, then the site of sodium loss is outside the kidney, usually the lower gastrointestinal tract, and associated with diarrhea. The mechanism of hyponatremia is the inbuilt priority of preservation of volume over osmolality. Hence, in this situation there is a dramatic increase in plasma ADH levels. A number of diseases and drugs cause abnormal release of antidiuretic hormone, either as a consequence of ectopic production of ADH (ADH-se-

creting tumors) or increased release of this compound from the posterior pituitary gland (Table 34–2). The result is a paradoxically concentrated urine with dilute blood (the urinary osmolality is higher [>300 mOsm] than the serum osmolality [125, the treatment is water restriction, 500–1000 mL/d If Na concentration is 145 mEq/L represents a hypertonic and hyperosmolar state. There is a net deficit of water in relation to sodium. This implies neither an increase in total body sodium nor a deficit in total body water. Hypernatremia is rarely encountered in routine perioperative patients; however, it is not an uncommon finding in the intensive care unit and, consequently, in patients traveling to the operating room from the ICU for subsequent procedures. When the serum osmolality exceeds 305–310 mOsm/kg H2O, ADH secretion is stimulated and the urine becomes severely concentrated (i.e., osmolality greater than 800–1000 mOsm/kg H2OH2O). The thirst response is activated in an attempt to stem cellular dehydration. Hypertonicity and hypernatremia rarely develop in the presence of an intact thirst mechanism and access to water. However, critically ill patients are often too sedated to express thirst and/or unable to drink water. The imbalance between TBW and sodium that occurs in the hypernatremia may develop from either water loss or sodium gain (Fig. 34–4 and Table 34–5).22 This may result from pure dehydration, the presence of a free water deficit (hypovolemic hypernatremia) such as occurs with administration of loop or osmotic diuretics, excessive evaporative losses (nonhumidified breathing systems), or diabetes insipidus (either cranial or nephrogenic). Patients with diabetes insipidus may present to the operating room in three circumstances. First, patients with traumatic brain injury complicated by diabetes insipidus may present for neurosurgery, for example, for decompressive craniectomy. Second, a patient who has undergone devastating brain injury, either traumatic or hemorrhagic, complicated by diabetes insipidus, may present for organ harvest, following brain death. Finally, a patient who has been chronically treated with lithium, for bipolar disorder, complicated by diabetes insipidus, may present for routine surgery. In each of these situations, the major risk to the patient (or to the patient’s organs) is not hypernatremia but hypovolemia, and the anesthesiologist must be careful to replenish perioperative urinary losses. Hypernatremic hypernatremia is associated with sodium gain, in the

Hypernatremia

Pure water loss

(Hypotonic) sodium loss

(Hypertonic) sodium gain

Large insensible losses Open abdomen Non-humidified gases Burns Diabetes insipidus Neurologic Nephrogenic Polyuria Diabetes Hypokalemia Hypercalcemia Cushing’s syndrome

Excessive diuresis Loop diuretics Osmotic diuretics Polyuric phase of acute renal failure Diarrhea Vomiting Nasogastric drainage Burns Sweating

Sodium bicarbonate Hypertonic saline Massive blood transfusion

FIGURE 34–4. Hypernatremia.

presence of either euvolemia or hypervolemia. This may result from administration of hypertonic saline, sodium bicarbonate, blood transfusion (sodium citrate), or parenteral nutrition (sodium acetate). Hypernatremia may be accompanied by metabolic alkalosis associated with an increase in the strong ion difference, from either dehydration of sodium gain. Hypernatremia can be associated with significant neurologic sequelae; initially, the brain shrinks as a consequence of volume depletion, which makes the blood vessels vulnerable to rupture. The brain adapts to dehydration by expressing more solute, which may lead to cerebral edema, neurologic deficit, or convulsions. The clinical approach to the management of the hypernatremic patient is to identify and treat the source, and replace the free water deficit. To correct hypernatremia, fluid and electrolyte losses must be restored. The rate of correction depends on the duration of hypernatremia. In general, for critically ill patients, correction at a rate of 1 mEq Na/L/h is appropriate; if hypernatremia is prolonged, the 0.5 mEq Na/L/h is more advisable (to reduce the risk of rebound cerebral edema). For young males, the free water deficit is calculated as follows: free water deficit = 0.6 × patient’s weight in kg × ([patient’s sodium/140] – 1) where 0.6 × weight = estimated body water and 140 = desired sodium. (To calculate the free water deficit for females and elderly males multiply the weight in kg by 0.5.) Thus for a 70-kg

young male with a serum sodium of 150 mEq/L, the free water deficit equals 3 L. Either isotonic or hypotonic fluid can be used to replace the free water loss. However, the more hypotonic the fluid administered, the more rapidly the deficit will be replaced. In the example above, if one wished to reduce the patient’s serum sodium by 10 mEq/L, how much of what fluid does one use? This depends on the amount of sodium in the chosen fluid,

TABLE 34–5. Causes of Hypernatremia Pure water loss Large insensible losses: no humidifier on mechanical ventilator Diabetes insipidus Neurologic—associated with head injury, brain hemorrhage, or meningitis Nephrogenic—caused by lithium, demeclocycline, amphotericin B, heavy metal poisoning, hypokalemia, and hypercalcemia Hypotonic fluid loss Excessive diuresis with loop of osmotic diuretics Polyuric phase of acute renal failure Diarrhea Vomiting Nasogastric drainage Burns Sweating Hypertonic sodium gain Sodium bicarbonate infusion Hypertonic saline administration

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TABLE 34–6. Sodium Content of Fluids Used to Treat Hypernatremia

Fluid (Infusate)

Na Content (mEq/L)

Change per Liter in 70 kg Male with Na 150 mEq/L

Dextrose 5% in water 0.2% NaCl in D5W 0.45% NaCl Lactated Ringer solution

0 34 77 130

–3.5 mEq Na/L –2.7 mEq Na/L –1.7 mEq Na/L –0.5 mEq Na/L

Potassium is held intracellularly against the electrochemical gradient by the action of the Na+-K+ ATPase pump that maintains the resting membrane potential. The relative ratio for intracellular to extracellular potassium is responsible for electrochemical activity. Hence abnormalities of potassium concentration directly impact neuromuscular activity.

Hyperkalemia and then applying this figure to the formula below (Table 34–6): change in serum Na per liter = infusate Na (serum Na/ [(weight in kg × 0.6) – 1])

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If one chose D5W (dextrose 5% in water) and planned to correct this patient’s sodium at a rate of 1 mEq/L/h, because each 1 L will correct 3.5 mEq, the rate of fluid infusion would be 1000 mL/3.5 = 285 mL/h. Clearly, for simple hypernatremia, the choice of fluid determines the volume required to correct the sodium abnormality (a much larger volume of lactated Ringer solution than of D5W is required). The administration of free water, for example, via the enteral route, is probably the most effective method for replenishing extracellular water deficit.

Potassium Physiology Potassium is the major intracellular cation in the body and has several roles, the most important being the generation of the resting cell membrane potential and the action potential, as well as protein synthesis, acid–base balance and maintenance of intracellular osmolality. The total body potassium content ranges from 50–55 mEq/kg body weight. Potassium is an intracellular cation, and approximately 98% of the body stores are located within the ICF compartment (i.e., only a total of 60–70 mEq exists in the ECF). A huge concentration gradient exists between the ICF and ECF compartments (150 mEq/L and 3.5–5.5 mEq/L, respectively). The primary mechanism for establishing and maintaining this concentration gradient is the sodium-potassium– activated adenosine triphosphatase (ATPase) “pump,” which is located in the plasma membrane of all body cells. These membrane-bound ionic transport pumps and the selective

permeability characteristics of cell membranes are responsible for the transmembrane electrical potential difference found in all living cells. Potassium is the ion responsible for generating cellular electrical activity. Hence, hypoand hyperkalemia result in significant neuromuscular dysfunction. The total amount of potassium present in the body is approximately 3200 mEq, 90% of which is intracellular, which is regulated by a variety of homeostatic mechanisms. Of total body potassium, approximately 135–150 mEq/L is intracellular, compared to plasma levels of 3.5–5.5 mEq/L. The daily requirement is about 1 mEq/kg/d absorbed from the small intestine. Potassium excretion exactly matches intake and body stores are quantitatively stable. Potassium balance is predominately governed by urinary loss. The kidney can adjust urinary potassium excretion from less than 1 mEq/L to greater than 100 mEq/L. In addition, there is some secretion of potassium in the colon. Two factors impact renal handling of potassium: renal tubular fluid flow and aldosterone. The majority of filtered potassium is reabsorbed in the proximal tubule. The distal tubules then secrete potassium. This is influenced by the intracellular potassium concentration, the rate of urinary flow, and the anionic charge of the urine. As the rate of flow increases, there is a significant increase in potassium excretion. This explains hypokalemia associated with diuresis. Conditions that increase distal tubular sodium delivery promote potassium excretion and sodium reabsorption, particularly in the presence of aldosterone. One of the most important roles of potassium is the resting membrane potential and in the repolarization phase of action potentials. The normal cell membrane is relatively permeable to potassium ions, and impermeable to sodium and anions. The anions generate a negative intracellular potential.

Hyperkalemia is generally defined as a serum potassium concentration of greater than 5.5 mEq/L. There are numerous conditions, diseases, and drugs that produce hyperkalemia by disrupting the normal external and/or internal potassium balance (Table 34–7). Factitious hyperkalemia is associated with hemolysis of the blood sample. Several factors may produce a transient increase in serum potassium concentration as a result of transcellular shift. This includes administration of succinylcholine (0.3–0.5 mEq/L in normal subjects), burns, diabetes, metabolic acidosis, and nonselective β-blockers. Succinylcholine may be associated with significant hyperkalemia in certain

TABLE 34–7. Causes of Hyperkalemia Increased exogenous potassium load Potassium supplements including TPN Enteral potassium administration Red blood cell transfusion Penicillin G administration Increased endogenous potassium load Rhabdomyolysis Impaired excretion Acute or chronic renal failure ACE inhibitors Potassium-sparing diuretics Congestive heart failure Heparin Tacrolimus of cyclosporine Trimethoprim Amphotericin Heparin Intracellular to extracellular exchange Hyperglycemia Metabolic acidosis β-Blockers Succinylcholine Digoxin ACE, angiotensin-converting enzyme; TPN, total parenteral nutrition.


circumstances, such as conditions where there is muscle membrane degeneration (e.g., trauma, burns, or primary muscle disorders) or neural denervation (e.g., stroke, multiple sclerosis, GuillainBarré syndrome or spinal cord injuries). Impaired potassium excretion is associated with acute and chronic renal failure, adrenal insufficiency, hypoaldosteronism (for any reason), and the use of angiotensin-converting enzyme (ACE) inhibitors. In hyperkalemia the resting membrane potential is decreased toward the threshold potential (Fig. 34–5). With mild hyperkalemia (i.e., a serum potassium concentration of less than 6–7 mEq/L) there is increased automaticity as reflected by atrial and/or ventricular ectopy. Progressive hyperkalemia enhances rapid repolarization (phase 3), which causes shortening of the Twave interval and symmetrical peaking of the T wave. If the serum potassium concentration continues to increase, the inward movement of sodium (phase 0) and calcium (phase 2) will diminish; the PR interval becomes prolonged and, eventually, the P waves (atrial phase 0) will disappear. Within the ventricular muscle mass, both conduction velocity and the height of the action potential are reduced. The net result is a widened QRS complex and reduced contractility. If the hyperkalemia progresses, the QRS complex will become smooth, wide, and sinusoidal as it merges with the T wave (serum potassium concentration of >10 mEq/ L). Without treatment, ventricular fibrillation will ensue. Emergency treatment is aimed at quickly stabilizing the myocardium and restoring normal transmembrane electrical potentials; 10–30 mL of 10% calcium gluconate can be administered over 3–5 minutes (or 5–10 mL calcium chloride may be substituted). Calcium reduces both the threshold potential and the excitability of cell membranes. The duration of action is roughly 30– 60 minutes; a second dose may be necessary. Alternative temporizing measures include administration of sodium bicarbonate, nebulized albuterol, or insulin and dextrose in combination. Each has the impact of sending potassium into cells. One unit of regular insulin is recommended for each 2 g of dextrose. For example, 1 ampule of D50 (i.e., 50 mL of 50% dextrose) would be immediately followed by 12 units of regular insulin.

Serum potassium

Serum potassium

5 mEq/L

4 mEq/L

T U

6 mEq/L

1

U

T 3 mEq/L

2

7 mEq/L U

8 mEq/L 2 mEq/L 9 mEq/L

10 mEq/L FIGURE 34–5. Electrocardiogram (ECG) changes associated with progressive hyperkalemia.

More definitive treatment of hyperkalemia can be achieved by administering exchange resins administered orally or rectally. These include calcium or sodium polystyrene sulfonate in combination with sorbitol, that facilitates potassium excretion through colonic exchange of calcium or sodium for potassium. If this approach fails, hemodialysis may be required.

FIGURE 34–6. Electrocardiogram (ECG) changes associated with progressive hypokalemia. Strip 1: normal ECG; strip 2: flattened T wave, prominent U wave; strip 3: prolonged PR interval, prolonged QRS, ST-segment depression, heightened U waves, and prolonged QT interval.

mia include malnutrition, malabsorption, diuretic usage, corticosteroid administration, and Conn syndrome (primary hyperaldosteronism). Potassium depletion causes muscle weakness. The ratio of intracellular to extracellular potassium increases, thereby reducing the resting potential (phase 4) and creating a state of hyper-

TABLE 34–8.

Hypokalemia Hypokalemia is typically considered a potassium level of less than 3.5 mmol/ L, although patients may be asymptomatic until the level is less than 2.5 mmol/L. Although the relative fall in extracellular potassium may appear small (1–2 mEq/L) this represents a significant total body deficit of potassium, up to 500 mEq. On average, plasma potassium decreases by 0.3 mmol/ L for each 100-mmol reduction in total body stores. Acute hypokalemia is associated with either inadequate intake or absolute loss of potassium from the body, governed by the law of mass conservation, or transcellular movement (Fig. 34–6 and Table 34–8). Causes of absolute loss include vomiting, diarrhea, bowel fistulae, loop and osmotic diuretics, and the diuretic phase of acute renal failure. Causes of intracellular potassium shifting include metabolic alkalosis, use of β2-adrenergic agonists, hyperadrenergic states (including the acute stress response), administration of insulin, and hypothermia. Chronic causes of hypokale-

3

Causes of Hypokalemia Altered transcellular (internal) balance Metabolic alkalosis Insulin β2-Adrenergic agonists Following resolution of stress response Anabolism Periodic paralysis Altered external balance Decreased intake Inadequate content in intravenous fluids Malabsorption Malnutrition Increased renal excretion Diuretics Polyuria Hyperaldosteronism Hypomagnesemia Renal tubular acidosis High-dose penicillins Increased gastrointestinal loss Vomiting Nasogastric suctioning Diarrhea

651


652

polarization. When the action potential is initiated (phase 0), it is of supernormal magnitude. The time allotted for calcium entry (phase 2) is shortened, and repolarization (phase 3) is prolonged, leading to a greater relative refractory period. The diminished calcium entry affects skeletal muscle and may lead to myalgia, cramps, and weakness. The smooth muscle components of the bladder, gastrointestinal tract and the peripheral vasculature are also affected leading to urinary retention, ileus, and postural hypotension. The ensuing vasoplegia may be catecholamine insensitive. Hypokalemia impacts cardiac conduction and contractility. Progressive electrocardiographic changes are typical (see Fig. 34–6): T-wave amplitude decreases, QT interval lengthens, the U wave appears or becomes broader and taller, the ST segment sags, and Pwave amplitude and QRS duration increase. Cardiac arrhythmias are relatively common. The most common dysrhythmias are atrial fibrillation and premature ventricular systoles, but supraventricular tachycardia, junctional tachycardia, and Mobitz type I seconddegree atrioventricular block may also occur. Hypokalemia may induce digitalis toxicity (Fig. 34–6). It is probably unnecessary to administer potassium supplements to a patient with mild hypokalemia. If moderate to severe hypokalemia ( 45 mm Hg

BDE < +5

BDE < –5

BDE 0

BDE > +5

Acute respiratory acidosis

Acute metabolic acidosis

Acute respiratory alkalosis

Acute metabolic alkalosis

BDEG

Gap

UMA

666

Lactic acidosis

Correct for chloride

Correct for sodium

Correct for albumin

Hypochloremia

Contraction alkalosis

Hypoalbuminemic alkalosis

No gap

Low sodium = dilutional acidosis

Ketoacidosis

High chloride = hyperchloremic acidosis

Renal acidosis

FIGURE 34–13. Mechanism for solving an acid–base problem. BDE, base deficit or excess; BDEG, base deficit excess gap.

Treating Acid–Base Disturbances Therapeutic treatment of acid–base disturbances is controversial; many regard it as “window dressing” rather than addressing the cause. This refers particularly to the use of sodium bicarbonate in the treatment of lactic acidosis.88 Therapeutic use of sodium bicarbonate has three effects: (a) volume expansion, as the 7.5% solution is hypertonic ( hence the often remarked improvement in cardiovascular performance); ( b) increased SID as a consequence of the administration of sodium without accompanying strong anion;89 and (c) increased CO2 generation. There is no evidence that sodium bicarbonate administration improves outcomes in circulatory shock.88 Much discussion has focused on bicarbonate inducing intracellular acidosis,90 but this is probably clinically insignificant.88,91 Lactic acidosis is treated with volume resuscitation and source control; diabetic ketoacidosis is treated with volume resuscitation and insulin. Hyperchloremic or dilutional acidosis is treated by increasing the SID of infused fluids, for example, by infusing sodium without chloride. Although no such fluid is available commercially, such a fluid can be constructed by

using sodium bicarbonate or sodium acetate. Sodium gain is “chloride sensitive” alkalosis, treated by administration of net loads of chloride—0.9% NaCl, potassium chloride, calcium chloride, and, occasionally, hydrogen chloride. It is important to correct chloridesensitive alkalosis, as the normal compensatory measure is hypoventilation, increasing PaCO2, which may lead to CO2 narcosis or failure to liberate from mechanical ventilation. There is no specific treatment for hypoalbuminemic alkalosis. Renal acidosis is treated with dialysis, which removes fixed acids. However, alteration in SID using sodium bicarbonate or sodium acetate can be used, for patient comfort, as a bridge to dialysis. There has been significant interest in hypercapnic acidosis over the past decade following the introduction of “permissive hypercapnia” in acute respiratory distress syndrome, to prevent ventilator-associated lung injury.92 There is accumulating evidence that hypercapnia has a lung-protective effect, and that reversing the acidosis may have adverse effects.93 Nevertheless, in patients with hypercapnic acidosis and associated cardiovascular instability we recommend the use of

Tris(hydroxymethyl)-aminomethane (THAM).94 THAM titrates hydrogen ions (e.g., lactic acid or CO2) according to the following reaction: R-NH2+ HA → R-NH3+ + A– THAM is a proton acceptor that generates NH3+/HCO3 without generating CO2, and the protonated R-NH3+, along with chloride, is eliminated by the kidneys. THAM has the significant advantage of buffering acidosis without increasing serum sodium or generating more carbon dioxide.

Monitoring Blood Gases: Alpha Stat versus pH Stat Water dissociation is temperature dependent. Thus extracellular pH varies with body temperature, becoming more alkalotic with progressive hypothermia and more acidotic with hyperthermia. Hence patients presenting in a state of hypothermia, or induced hypothermia (for cardiac surgery), would be expected to exhibit significant metabolic alkalosis on a blood gas. Blood gas machines heat the blood sample to an idealized 98.6°F (37°C), enabling the clinician to make inferences regarding the presence or absence of respiratory or metabolic abnormalities from a con-


stant perspective. This “alpha-stat” approach is widely used in perioperative medicine. An unfortunate drawback of this approach is that many clinicians are unaware of the impact of temperature on pH. Incumbent in this hypothesis is that, despite temperature changes, the body is capable of maintaining homeostatic function, and intracellular enzymes and transcellular ion pumps will continue to function. Intracellular pH is 6.8 at 98.6°F (37°C), which is neutral pH at that temperature. Extensive animal investigation has established that intracellular pH remains neutral across a wide array of body temperatures. The reason that this occurs appears to relate to the constant buffering capacity, across pH, of intracellular histidine moieties.95 This neutrality has the effect of maintaining intracellular enzymatic activity. Carbon dioxide becomes more soluble in blood as temperature drops. Moreover, hypothermia is associated with reduced metabolic activity. Consequently, hypothermia results in respiratory alkalosis and reduced cerebral blood flow. Some clinicians believe that pH should be kept constant, despite changes in temperature (the pH-stat hypothesis). Thus, when measuring a blood gas, the patient’s current body temperature is entered into the machine and a series of calculations corrects the blood gas to that temperature. Thus if a patient has a temperature of 82.4°F (28°C), the pH will be reported, for example, at 7.65 and the PCO2 at 22 mm Hg. Poikilothermic animals (reptiles) use an alpha-stat system of pH control, and can function over a broad range of temperatures.96 Hibernating animals, however, use a pH-stat strategy, induced by hypoventilation. The consequent increase in intracellular CO2 content reduces cellular metabolism and may have a protective effect.97 Clinicians that adopt a pH-stat approach will correct the blood pH by adding carbon dioxide during cardiopulmonary bypass. The resulting respiratory acidosis is thought to improve neurologic outcomes in cardiac surgery. For example, cerebral; blood flow decreases 40% during cardiopulmonary bypass at 78.8°F (26°C) using alpha-stat management but remains similar to baseline with pH-stat management.98 The higher PCO2 in pH stat approaches is thought to improve neuro-

logic outcomes by (a) inducing a rightward shift of the oxyhemoglobin dissociation curve promoting O2 unloading to tissues, (b) reducing the cerebral metabolic rate of oxygen and increasing neuronal tolerance to ischemia, and (c) modulating the Nmethyl-D-aspartate receptor that limits the neurotoxic effects of excitatory amino acids.99 There is little data to support the use of the pH-stat approach in adults, and benefit, if it exists at all, is probably confined to infants who are undergoing cardiac surgery.99 We do not recommend the adoption of the pH-stat approach for the majority of perioperative patients.

ESTIMATING PERIOPERATIVE FLUID REQUIREMENTS Traditional approaches to perioperative fluid management have focused on rigorous calculation of fluid deficits; the administration of “maintenance” fluids, calculated on body weight and metabolic activity; repletion of insensible losses and third space losses (dependent on the anatomical region of surgery); and replacement of blood loss with crystalloid (in a 1:3 ratio) or colloid (in a 1:1 ratio). There are many limitations to this approach; chief among them is the potential for significant weight gain and fluid overload. Additionally, the actual presence of third space fluid loss has been questioned. Nevertheless, these approaches continue to be widely advocated in practice and a short description follows.

Preoperative Deficits In adults who are undergoing elective surgery, despite guidelines that water is permissible up to 2 hours preoperatively,100 oral intake is usually restricted for up to 12 hours before the procedure. This period of restricted oral intake may be considerably longer when surgery is scheduled late in the day. The resulting fluid deficit is primarily because of water loss. The traditional approach involves calculating the hourly maintenance fluid rate and multiplying that by the time of restricted fluid intake. The maintenance fluid is calculated using a 4–2–1 system (4 mL/kg/h for the first 10 kg body weight, 2 mL/kg/h for the next 10 kg body weight, and 1 mL/kg/h

beyond that body weight). An alternative system is to administer 1.5 mL/kg. Of this total, 50% of this deficit volume is replaced over the first hour of intravenous fluid therapy and 25% is replaced during each of the ensuing 2 hours. The entire deficit is replaced in 3 hours, which is accomplished by adding the fluid deficit to the basal infusion rate of the maintenance fluids. Simultaneously, account must be taken for insensible losses during and after surgery. This is associated with, for example, evaporation at the site of surgery, hyperventilation, fever, sweating, denuded skin, burns, and the use of nonhumidified oxygen therapy administered at high flow rates. Again, much of this loss is in water not extracellular fluid. Additional preoperative deficits may also occur. The most common is volume loss through the bowel as a consequence of preoperative administration of purgatives (“bowel preparations”). This leads to an absolute deficit of water and electrolytes, principally sodium and potassium, but also chloride as a result of renal compensatory loss. This requires replacement with a balanced salt solution. There is no clear published guideline for the absolute volume that must be replaced to overcome bowel preparation losses, but the majority of anesthesiologists estimate this at 1000–2000 mL. Other preoperation causes of absolute hypovolemia with associated electrolyte loss include vomiting, gastric suction, diarrhea, and ostomy output. Upper gastrointestinal losses should be repleted with chloride-rich solutions, preferably 0.9% saline. Lower gastrointestinal losses should be repleted with balanced salt solutions. Internal losses are volume deficits that cannot be easily quantified as they represent redistribution of fluid within the body. Traditionally these are considered “relocation” losses into cavities and third spaces, but also represent expansion of the extracellular fluid space secondary to capillary leak. The cavitary losses (e.g., pleural, ascitic, and pericardial fluid) are simple transudates of plasma that often require a relatively prolonged period to accumulate in significant quantities. Consequently, the impact on the ECF volume is generally minor, as there is usually some degree of compensation for this redistribution of vascular fluid. Although significant cavitary fluid ac-

667


668

cumulation does occur in hypervolemic states, the most important variant of this genre is ascites. Ascitic fluid, secondary to cirrhosis, ovarian cancer, or carcinomatosis, once drained, inevitably reaccumulates, leading to massive fluid shifts and the potential for significant intravascular dehydration. There are many other causes of fluid redistribution losses in perioperative medicine. These usually involve significant edema in conjunction with injured tissue (as may occur with obstructed, ischemic, or dead bowel), in particular when compartment syndromes occur, and when secretory fluid becomes trapped in obstructed bowel. These “third space” and cavitary losses create a new ECF pool that is sequestered and essentially nonfunctional. Internal blood loss also diminishes the ECF volume. Such losses may be significant when associated with retroperitoneal hematoma, leaking aneurysm, pseudoaneurysm or vascular anastomosis, pelvic or femoral fracture, or splenic rupture. Depending on the acuteness of the hemorrhage, some degree of compensation may have occurred. Typically, this involves transcapillary refill (Figs. 34–14 and 34–15), the movement of extracellular fluid into the vascular space to maintain perfusion of fight-or-flight organs (midline structures and skeletal muscle). Although this may lead to a small drop in the hemoglobin concentration, it is essential to understand that in situations of acute isovolemic blood loss, hemoglobin remains essentially unchanged despite massive blood loss. This may lead to false reassurance, particularly in young patients who have tremendous compensatory capacity through tachycardia and intense vasoconstriction. Clearly, estimation of fluid deficits and ongoing fluid losses differs depending on the nature of the patients and the type of surgery. Emergency procedures are often associated with significant fluid shifts that must be accounted for. Fluid used to replace pure volume losses should be nearly isotonic with respect to plasma and should also contain sodium and chloride. In general, a polyvalent, balanced salt solution (e.g., mildly hypotonic, lactated Ringer solution) is used. Ideally, both internal and external preoperative fluid deficits should undergo total correction before the administration of an anesthetic.

2

1

3

5

4

Arteriole

Capillaries

Venule

Precapillary sphincter

Postcapillary sphincter Lymphatics

1. Precapillary sphincters are relaxed, and blood flows into the capillary bed 2. Fluid is filtered on the arterial side and returns 3. On the venous side or 4. Through lymphatics 5. Blood returns through the postcapillary sphincters to the venous system FIGURE 34–14. The normal microcirculation.

However, an urgent need for surgery may preclude replacement of the entire deficit. Relatively small volume deficits (i.e., less than 20% of the blood volume) can often be replaced with an isotonic or balanced salt solution administered over a period of 15 minutes or less. Although most patients will tolerate this amount of acute intravascular volume expansion, care must be taken in patients with a history of hypertension or diastolic dysfunction. In this case, rapid volume administration may precipitate acute pulmonary edema. Importantly, 40–60% of the infused solution will redistribute to the extracellular compartment within 15– 30 minutes, and 80% will redistribute by 1 hour (Fig. 34–16). If the patient has significant extracellular fluid deficit, this is an effective method of resuscitating that space. However, if blood loss is the problem, significant tissue

Angiotensin II Epinephrine Vasopressin

edema will result from large-volume crystalloid resuscitation to maintain hemodynamic goals.

Intraoperative Fluid Losses Intraoperative fluid losses (similar to preoperative losses) can be categorized as either internal or external. Traditional approaches to intraoperative fluid management involve estimation of distribution volume deficits and repletion of this apparent ECF volume loss with isotonic fluids. Significant volume is lost or sequestered into “third” spaces. It is assumed that the volume of fluid sequestered is proportional to the amount of surgical trauma. Thus major orthopedic procedures, surgery within the chest cavity, bowel resections, and hysterectomies are examples in which a significant quantity of third spacing occurs (i.e., perhaps 4–5% of body weight). The

3

1

2 3

3

4. Transcapillary refill 1. The blood pressure falls, reflex vasoconstriction follows 2. The pre-capillary and post-capillary sphincters contract 3. This reduces the volume and increases the velocity of blood passing through 4. Fluid is sucked back into the circulation by the flow of blood, this process is called “transcapillary refill,” and allows remobilization of fluid FIGURE 34–15. Compensation for hypovolemia.


100%

20%

Increasing interstitial pressure

ing geometrically. At 75% blood loss the ratio reaches 16:1.10 Consequently, consideration should be given to replete blood losses with colloid solutions or blood component therapy.

NaCl

80%

Postoperative Fluid Losses

100%

Both internal and external fluid losses continue into the postoperative period. Depending on the patient’s preoperative status, intraoperative management, and surgical procedure, combinations of volume, concentration, and composition disturbances are not infrequent. Over the first 24–36 hours after a procedure, fluid continues to be sequestered into the extracellular space, principally as a result of capillary leakage (Fig. 34–17).103 Evidence of endorgan hypoperfusion may become apparent, in particular oliguria. Recurrent boluses of fluid may be required to restore organ function. On postoperative day 2, a steady state appears to be reached, followed by fluid mobilization and diuresis. Patients lose up to 1000 mL of water per day in insensible losses, but also gain water from metabolic activity. Although traditional teaching emphasizes the administration of hypotonic glucose-containing intravenous fluids to prevent dehydration and ketosis, there is very little support for this position in the literature. Indeed the controversy of “dry” versus “wet” has existed for as long as intravenous fluid therapy has been available.104 Furthermore, postoperative clear fluid administration may be associated with worse outcomes, and dextrose administration is associated with undesirable hyperglycemia. External losses may persist into the postoperative period as a result of, for example, continued bleeding, nasogas-

Albumin washed out of the interstitium and into the lymphatic system

FIGURE 34–16. Crystalloid extravasation. When isotonic crystalloid fluids are administered to the perioperative patient, up to 80% of the infused volume extravasates into the interstitium.

exact quantity of sequestered fluid is impossible to ascertain, and replacement of these third-space losses is an approximation. Conservative approaches to third space fluid replacement, based on the amount of tissue exposure and degree of tissue trauma, are as follows: minimal trauma, 2–4 mL/kg/h; moderate trauma, 4–6 mL/kg/h; extensive trauma, 6– 12 mL/kg/h. This volume replacement is in addition to maintenance fluids and repletion of preoperative losses. External fluid losses during surgery are predominantly a result of insensible or evaporative losses and blood loss. Significant evaporative losses may occur when either the peritoneal or pleural surfaces are exposed to ambient conditions, depending on the relative humidity of the air in the operating room and the rate of exchange of air within the room. This is free water loss that is almost impossible to quantify. Traditional approaches involve the administration of 1–4 mL/kg/h of fluid to replete these losses, with higher volumes administered depending on the cavity or tissue surface exposed. Patients with extensive burns have massive insensible volume losses, and volume repletion is formula driven, based on the surface area burned. Intraoperative blood loss may lead to significant tissue hypoperfusion and organ injury. It is, however, difficult to quantify as a result of, for example, accumulation in drains, drapes, suction canisters, and administration of lavage fluid. The estimated blood loss almost always underestimated true blood loss. Administration of crystalloid or colloid to fixed hemodynamic

goals will progressively deplete the hemoglobin concentration, providing a useful index of blood loss. However, underresuscitation of the patient is often associated with a falsely reassuring hemoglobin concentration. Traditional approaches to blood replacement have identified a 3:1 ratio of crystalloid to blood loss. This is incorrect.101 With increasing volumes of crystalloid administration the extracellular space becomes progressively more compliant, resulting in a geometric increase in transcapillary leakage that volume replacement for blood loss parallels.102 This process is known as cytopempsis and principally reflects the progressive hypoalbuminemia associated with volume replacement.10 In his original animal study, Moss described a 5:1 ratio of crystalloid replacement to blood loss when losses reached 35% of blood volume, reaching an inflection point at this level, with subsequent ratios increas-

3

2 1

2

1

3

1. There is widespread vaso- and venodilatation 2. The endothelium becomes porous 3. Protein-rich fluid leaks out into the extracellular space causing edema FIGURE 34–17. Extravasation of fluid into the extracellular space due to capillary leak.

669


TABLE 34–27. Composition of Commonly Used Crystalloid Solutions

Solution NaCl 0.45% & dextrose 5% NaCl 0.9% & dextrose 5% NaCl 0.9% Lactated Ringer Lactated Ringer & dextrose 5% Dextrose 5% Dextrose 50% Plasmalyte 148 Normosol

670

Osmolarity (mOsm/L)

Na+ (mEq/L)

Cl– (mEq/L)

406

77

77

50

560

154

154

50

308 273 525

154 130 130

154 109 109

252 2520 294 294

K+ (mEq/L)

4 4

Ca2+ (mEq/L)

Mg2+ (mEq/L)

3 3

Glucose (g/L)

Lactate (mEq/L)

Gluconate (mEq/L)

Acetate (mEq/L)

23 23

27 27

28 50 50 500

140 140

tric suctioning, surgical drains, diarrhea, and evaporative losses. It is imperative that the clinician quantify these losses and replenish them with fluids appropriate for the site of loss (e.g., balanced salt solutions for ECF loss, normal saline for upper GI losses).

FLUID REPLACEMENT CRYSTALLOIDS Nature and Makeup of Crystalloid Solutions Crystalloid solutions are intravenous fluids that involve electrolytes or dextrose dissolved in sterile water (Table 34–27). Crystalloid solutions may be hypotonic, isotonic, or hypertonic. They may have a SID of 0 (dextrose solutions or NaCl 0.9%) or a SID that approximates plasma ( balanced salt solutions, e.g., lactated Ringer solution, Normosol, Plasmalyte). Dextrosebased fluids distribute evenly across total body water. Hypotonic fluids distribute across body water in proportion to electrolyte content. Isotonic fluids, being electrolyte based, distribute evenly through the extracellular fluid, but remain extracellular (Fig. 34–18). Hypertonic fluids remain in the compartment into which they are injected ( bloodstream) and expand that compartment by dragging fluid from the intracellular and extracellular space along the osmotic gradient. The choice of intravenous fluids, used therapeutically, is determined by the clinical indication and prevailing conditions. For example, hypotonic fluids are typically used to replace free water deficits. Isotonic fluids are used to

98 98

5 5

3 3

replace extracellular fluid losses. Slightly hypotonic balanced salt solutions, such as lactated Ringer solution, replace free water and extracellular fluid losses. Hypertonic fluids are typically used as plasma expanders, used in acute resuscitation, but may reduce edema volume. Hypertonic saline is typically used in traumatic brain injury. Table 34–26 is a comprehensive list of crystalloid solutions. The following section addresses the most commonly administered formulations.

Dextrose 5% Water cannot be administered into the intravascular space because red cell lysis results. Dextrose as a 5% solution is isosmotic with plasma, but rapidly becomes free water as the glucose content is metabolized. Consequently, free water therapy has traditionally taken the form of dextrose solutions. Alternative “hypotonic fluids” include 0.45% NaCl + dextrose 5% and 0.25% NaCl. Water, administered as dextrose, distributes to the total body water. Thus when 1000 mL of dextrose is delivered, two-thirds of it enters the

Intracellular space

intracellular space and a tiny fraction remains intravascular. Consequently, dextrose, and all hypotonic fluids, should be avoided when intravascular volume expansion is desired. Dextrose has been used traditionally to treat dehydration losses before and after surgery. However, the caloric content of dextrose is problematic (200 kcal/ L). Glucose cannot be used as fuel in perioperative patients. Administration of glucose results in hyperglycemia as a result of stress catecholamine release and insulin resistance, during the stress response. Perioperative hyperglycemia is associated with increased risk of death, myocardial ischemia, and stroke.105–107 Thus the traditional postoperative fluid regimens, which emphasize the use of glucose to prevent ketosis and replenish free water deficits, require reevaluation.

“Normal” Saline “Normal” saline consists of an equimolar solution of sodium (154 mEq/L) and chloride (154 mEq/L). The solution has an osmolality of 308 mOsm, slightly hypertonic to plasma, and a

Interstitial space

Intravascular space

Dextrose 5% Lactated Ringer NaCl 0.9%, Normosol Hetastarch

FIGURE 34–18. Volume of distribution of crystalloid solutions.


SID of 0. Consequently, administration of moderate to large quantities of this fluid is associated with mild hypernatremia, progressive hyperchloremia, and metabolic acidosis (see Fig. 34–10). Saline continues to be widely used in hospital practice, particularly in neurosurgery, where it is used as a component of osmotic therapy. The widely accepted use of this solution in patients with renal failure has been questioned. Traditionally balanced salt solutions were avoided in this patient population because of concerns regarding accumulation of potassium in renal failure. However, a study by O’Malley et al. demonstrated a 20% absolute risk increase (number needed to treat: 5) for hyperkalemia in patients undergoing renal transplantation who were administered saline rather than lactated Ringer solution.108 Moreover, there was a 30% incidence of metabolic acidosis, requiring treatment, in the saline group, versus 0% in the lactated Ringer group. Although not widely recognized, chloride ion excretion is a primary role of the kidney, as sodium and chloride are absorbed in roughly equimolar concentrations in the diet; a net excretion of chloride over sodium is necessary. Chloride is involved with regulation of renal vascular tone.109 Hansen demonstrated that K+-induced contraction of smooth muscle cells in the afferent arteriole is highly sensitive to chloride.110 Thus chloride is a functional renal vasoconstrictor. Hyperchloremia has been shown to produce dose dependent renal vasoconstriction and a reduction in glomerular filtration rate.111,112 In addition hyperchloremia may be associated with an increased risk of acute renal failure in vulnerable patients, such as those receiving radiographic contrast dye.113 Wilkes et al. demonstrated that, compared with balanced salt solutions, patients who received intraoperative saline-based solutions had significantly reduced splanchnic blood flow,34 as estimated using gastric tonometry. Williams et al. randomized healthy volunteers to 0.9% saline versus an equal volume of lactated Ringer solution. Saline administration was associated with lower pH and longer time to first urination.64 This tendency toward fluid retention may result from the higher chloride content or the higher osmolality of the solution that induces inappropriate ADH secretion by “fool-

ing” the midbrain that the patient is dehydrated.64 Crystalloid solutions of any type enhance coagulation as measured by thrombelastograph analysis and routine coagulation studies.114,115 When patients were hemodiluted up to 30% with saline, coagulation parameters increased.116 The most likely mechanism is an imbalance between the naturally occurring anticoagulants and activated procoagulants, with a reduction in antithrombin III probably being the most important.117 This effect lowers the threshold above which positive feedback into the intrinsic coagulation pathway occurs, leading to the enhanced coagulation. Although it has been suggested that resuscitation with 0.9% normal saline is associated with increased risk of bleeding versus balanced salt solutions,118 there is minimal human data to support this claim. One study of 0.9% saline versus lactated Ringer solution in aortic aneurysm surgery showed no difference in outcome variables, but a higher perioperative blood loss in the saline group.119

Lactated Ringer Solution Lactated Ringer solution is the most widely used balanced salt solution, and is recommended as part of ad-

15 L

vanced trauma life support. Although balanced, it does not fully reflect the electrolyte distribution of the extracellular fluid. The sodium component is relatively low (130 mEq/L) and the chloride level high (109 mEq/L), making the SID significantly lower than plasma. Nevertheless, perioperative patients tend to lose more water than sodium as a result of insensible losses, and as all intravenous fluids dilute albumin, a slightly hyperchloremic solution is favored (Fig. 34–19). Hence studies that looked at the acid–base changes associated with lactated Ringer solution have reported few abnormalities.34,64 The slight hypotonicity may worsen cerebral edema in patients with traumatic brain injury, although this has never been proven. In that circumstance, lactated Ringer solution is generally avoided. Because bicarbonate is unstable in electrolyte solutions, lactated Ringer solution is buffered in lactate. Lactate is metabolized by the liver to carbon dioxide and water. Care must be taken with this fluid in end-stage liver disease because the patient cannot metabolize lactate, which then functions as a strong ion, leading to metabolic acidosis. In addition, lactate may be converted to glucose, leading to hyperglycemia; consequently, this solution is

Extracellular fluid Na+ 140 mEq/L K+ 4.0 mEq/L Cl- 102 mEq/L Albumin 4.0 g/dL SID 44 mEq/L BDE 0

5L LR added Na+ 130 mEq/L Cl- 109 mEq/L K+ 4 mEq/L SID = 25

20 L total volume Outcome Na+ 138 mEq/L K+ 4 mEq/L Cl- 103 mEq/L Albumin 3.1 g/dL SID 38 mEq/L BDE 0 No net acidifying or alkalinizing effect FIGURE 34–19. Extracellular fluid dilution with lactated Ringer solution. Although moderate volumes of this fluid have both acidifying effects (low strong ion difference) and alkalinizing effects (dilution of albumin), these effects offset each other and the net acid–base change is negligible.

671


rarely administered during diabetic crises. An important issue with the use of lactated Ringer solution concerns its interaction with packed red cells for transfusion. First, lactated Ringer solution contains calcium, which may lead to clotting of the blood before it enters the bloodstream. Second, there is the theoretical concern that mixing this hypotonic fluid with blood will lead to hemolysis.

Balanced Salt Solutions

672

A variety of balanced salt solutions are available that attempt to mimic extracellular fluid content. The solutions available in North America are Normosol-R and Plasma-Lyte 148, which are essentially identical. Although attractive in conception, there is little published data to suggest that any of these fluids is superior to lactated Ringer solution. Plasma-Lyte comes in a number of different formulations and different buffering solutions. Normosol is buffered in acetate and gluconate, both weak anion buffers; this suggests a better acid–base profile in liver failure. Both Normosol and Plasma-Lyte 148 contain 140 mEq/L Na, 98 mEq/L Cl, and 5 mEq/L K, with a SID of 47. Administration of either of these solutions leads to progressive metabolic alkalosis (see Fig. 34–10). As calcium is not a component of either of these solutions, Normosol and Plasma-Lyte can be safely administered alongside blood. In choosing a crystalloid solution to administer to a patient, the clinician must take into account the patient’s hydration status, anticipated volume of crystalloid to be administered, and the potential side effects. For the majority of patients, a balanced salt solution such as lactated Ringer (Hartmann) solution should be administered. This has the advantages of relative isotonicity, an electrolyte composition similar to extracellular fluid, minimal impact on acid–base chemistry, universal familiarity, low cost, and a strong safety profile. Concerns about hyperkalemia and renal failure are probably overstated. Lactated Ringer solution is an excellent choice for both resuscitation and rehydration, resulting in neither hypernatremia nor hyperchloremia. Isotonic saline solutions should not be administered in large volume. If blood is to be administered through the same intravenous line as the crystalloid, Normosol-

R or Plasma-Lyte 148 should be substituted for lactated Ringer solution.

Hypertonic Saline Normal plasma osmolality is 280–295 mOsm/L. Any solution whose osmolality exceeds 310 mOsm/L is a hypertonic fluid. In practical terms, this refers to hypertonic saline and sodium bicarbonate solutions (Table 34–28). A variety of different hypertonic saline (HS) solutions are commercially available, the most commonly used are 1.8% HS, 3% HS, 7.5% HS, and 23.4% HS. The latter is not generally used as an intravenous fluid, but is, for example, injected into hydatid cysts. There are two well-defined uses of hypertonic fluids. The first is intravascular volume expansion in patients in hypovolemic shock, as a means of lowvolume high-impact resuscitation. The second is a corollary—intracellular volume depletion. This approach is widely used in neurosurgery and neurocritical care to reduce cerebral volume and intracranial pressure. Hypertonic saline dramatically increases the osmotic pressure in the compartment into which it is injected. Water flows along the osmotic gradient into the compartment, expanding its volume for several hours. In the intravascular space, HS causes endothelial cell shrinkage, arteriolar dilation and reduced viscosity, thereby increasing flow.120 It may also increase myocardial contractility, although there are conflicting data on this issue. The metabolic consequences of HS are hypernatremia, hyperosmolality, and hyperchloremic acidosis.121 The degree of hypernatremia and hyperosmolality is lower than one

would expect because of the relatively low volume administered.122 The logic behind the use of HS in shocked states is based on two observations: (a) isotonic crystalloids are very inefficient plasma volume expanders and result in significant tissue edema; and (b) hypertonic solutions expand the plasma volume by a significantly greater amount than the volume administered. Consequently, significant hemodynamic benefit accrues from relatively low volumes of fluid administered. This may be of particular use in combat situations, where the weight and size of medical supplies of great importance. Numerous small studies and case reports suggest that patients have better hemodynamic profiles when given HS than if administered isotonic crystalloid.123 No study of prehospital administration of HS has shown an overall statistically significant benefit. Indeed, published benefits accrue in statistically weaker subgroup analysis. For example Mattox et al. studied 422 patients in a randomized, doubleblind, multicenter trial of prehospital HS with dextran versus an equal volume of isotonic crystalloid.124 Patients who had been administered HS with dextran and who required surgery had improved survival. Wade et al. reported improved survival in patients with penetrating trauma who were administered HS.125 A meta-analysis by the same group failed to demonstrate a benefit to using HS in trauma patients.126 A more recent large clinical trial failed to demonstrate improved clinical outcomes at 6 months.127 Currently, HS is not used in this setting. The major controversy in trauma is

TABLE 34–28. Characteristics of Hypertonic Solutions

Fluid

Sodium Concentration (mEq/L)

Chlorine Concentration (mEq/L)

Bicarbonate Concentration (mEq/L)

Osmolality (mOsm/L)

0.9% NaCl 1.7% NaCl 3% NaCl 7.5% NaCl 10% NaCl 23.4% NaCl Mannitol 7.5% NaHCO3 8.4% NaHCO3

154 291 513 1283 1712 4004 — 900 1000

154 291 513 1283 1713 4004 — — —

— — — — — — — 900 1000

308 582 1026 2566 3424 8008 1098 1600 2000


not the usefulness of HS, but the timing of use. Hypertonic saline has been used in the perioperative care of cardiac surgical patients. To date, data has revealed only that HS reduces perioperative weight gain and has a diuretic effect.128 HS may be an effective component of a goal-directed approach to fluid resuscitation, but this has yet to be studied. The most frequent indication for HS use has been in traumatic brain injury.129 Death from brain injury is primary, as a direct result of the event, or secondary, because of ischemic brain injury, cerebral edema, and brain herniation. Intracranial hypertension is the clinical manifestation of secondary brain injury. Under normal conditions, the blood–brain barrier limits bulk flow of fluid from cerebral capillaries into brain parenchyma by forming a semipermeable membrane, which is moderately permeable to water and relatively impermeable to small solutes and proteins. The balance of Starling forces (the transcapillary hydrostatic pressure gradient that is counterbalanced by an osmotic pressure gradient) determines the magnitude of flow into the brain substance.128 In areas where the blood–brain barrier is disrupted, this balance disappears, facilitating the flow of proteins and electrolytes across the membrane.129 Hydrostatic pressure becomes the dominant driving force for fluid movement from the intravascular space to brain tissue. This leads to brain swelling with an increase in intracranial pressure, a decrease in cerebral perfusion pressure, cerebral hypoxia, and secondary brain injury. Interruption of this continuing cycle of injury is the basis of treatment in traumatic brain injury.130 Osmotherapy using mannitol has been the therapy of choice in traumatic brain injury for a generation. However, mannitol has several limitations, including hyperosmolality, osmotic diuresis leading to hypotension, and accumulation in brain tissue leading to reverse osmotic effects. Hypertonic saline has reemerged over the past decade as an alternative to mannitol. Permeability of the blood–brain barrier to sodium is low. HS produces a significant osmotic gradient, leading to shrinkage of brain tissue (assuming that the blood–brain barrier is intact) and reduces intracranial pressure. HS improves overall sys-

temic perfusion and, presumably, oxygen delivery, and may modulate the inflammatory response.131

FLUID REPLACEMENT COLLOIDS Colloids and Colloid Oncotic Pressure For the majority of patients undergoing surgery and anesthesia, gentle hydration with crystalloid repletes dehydration losses and mild blood losses. However, significant tissue injury (including major surgery) leads to a slightly different paradigm that involves classic inflammatory stress response associated with increased capillary permeability. This facilitates the extravasation of intravascular fluid into the extracellular space (see Fig. 34–17). Fluid sequestered in this way does not remobilize until the stress response resolves. In these circumstances, up to 80% of crystalloid solutions used as volume replacement collect in extravascular tissues (see Fig. 34–16). This leads to weight gain and tissue edema, particularly in lax tissues and in the abdomen. Oxygen delivery is reduced and the cumulative effect may be worsened perioperative outcomes.16 In addition to increased capillary permeability, there is a reduction in plasma oncotic pressure in surgery, trauma, and critical illness as a result of reduced circulating albumin concentrations, because of dilution, extravasation, and reduced hepatic production (negative acute-phase response). High-molecular-weight solutions are use widely as plasma substitutes. These have the purported advantages of remaining in the intravascular space, plugging leaky capillaries and increasing colloid oncotic pressure, thus expanding intravascular volume.

As compared to crystalloid solutions, lower volumes are required to achieve hemodynamic goals.16 Colloids are homogenous noncrystalline substances, consisting of large molecules or ultramicroscopic particles of one substance dispersed through a second substance.132 Colloid solutions remain in the intravascular space because of their large molecular size, which leads to relative membrane impermeability (Fig. 34–20). The principal biologic colloids are plasma proteins, primarily albumin and globulin. These proteins impart two distinct forces: an osmotic pressure and a GibbsDonnan effect. This refers to an electrochemical effect of the protein: the protein is negatively charged and positively charged cations are held in plasma. The combined effect is a pressure that draws water out of the interstitium and into the plasma: the colloid oncotic pressure (COP). The COP is approximately 50% greater than would be expected from the plasma proteins alone. Albumin, with a molecular weight of 69,000 kDa and a significant negative charge, normally accounts for nearly two-thirds of the plasma COP. Serum albumin falls in the perioperative period and during inflammation from tissue injury or sepsis. Many clinicians mistakenly ascribe hypoalbuminemia as the cause of cause of the edema of critical illness. However, edema occurs secondary to increased capillary permeability and fluid overload. In addition, albumin production falls as a consequence of “hepatic reprioritization” toward inflammatory proteins. The result is maintenance of COP despite low levels of albumin.39 Thus serum or plasma protein concentration is an unreliable predictor of COP. Globulins are larger molecules than albumin, and impart significantly less osmotic effects. COP can be measured

FIGURE 34–20. Colloid therapy. Colloids are hypothesized to remain intravascular despite the presence of widespread capillary leak. Fluid (represented by pink arrows) is drawn back into the circulation as a consequence of increased colloid oncotic pressure.

673


in a laboratory using a colloid osmometer (i.e., oncometer); however, this is rarely measured in modern clinical practice. It is important to note that although colloids have an important role in maintaining intravascular volume, the oncotic effect is significantly less important vis-à-vis extracellular volume than the osmotic effect of electrolytes, such as sodium or chloride. This is a result of the significantly lower total number of osmotically active particles involved. The COP is only one of several factors that determine the fluid flux across a vascular membrane. The Starling equation describes the movement of fluid across the capillary endothelium: Qf = k1[(Pc – Pi) – δ(πc – πi)]

674

where Qf indicates transcapillary fluid flux, k1 is the fluid filtration coefficient, Pc indicates capillary hydrostatic pressure, Pi indicates interstitial hydrostatic pressure, πc indicates intravascular oncotic pressure, πi indicates interstitial oncotic pressure, and is the reflection coefficient. The reflection coefficient in the Starling equation is a function of the permeability and surface area of the capillary bed. The numeric value varies from 0 to 1. For example, the reflection coefficient of the pulmonary endothelium is normally 0.7, but may fall to 0.3 or 0.4 in conditions that increase microvascular permeability.

Increased Capillary Permeability The forces responsible for normal or abnormal fluid flux are the net colloid and hydrostatic pressures on either side of the capillary membrane (Fig. 34–21). The capillary hydrostatic pressure is the driving force for fluid moving out of the intravascular compartment. Because the interstitial hydrostatic pressure is usually negative or zero, the plasma COP is the force primarily responsible for counterbalancing the capillary hydrostatic pressure. Any increment in the forces that enhance filtration may induce changes that then retard further transcapillary fluid loss (e.g., increased tissue hydrostatic pressure, increased plasma COP, and decreased tissue COP). In addition, the lymphatic system provides a means for returning filtered capillary water and protein back to the intravascular compartment. The

Hydrostatic pressure Pc

Oncotic pressure c

Interstitium i Pi

i

Starling equation: QF = k1[(Pc – Pi) – δ(πc – πi)] FIGURE 34–21. The Starling hypothesis.

rate of lymphatic flow appears linked to the filtration characteristics of the capillary wall and interstitium, and the net flow of transcapillary fluid. When these protective adaptations are overwhelmed, the rate of interstitial fluid accumulation may surpass the rate of lymphatic drainage and edema will result. During tissue injury, sepsis, or surgery, there is a significant increase in capillary permeability, with leakage of protein-rich fluid into the interstitial space (see Fig. 34–17). Thus the reflection coefficient of the Starling equation changes and fluid accumulates in lax tissues, leading to edema. The rate of edema formation varies linearly with the volume of crystalloid administered. Colloidal solutions (Table 34–29) are purported to remain intravascular in conditions of widespread capillary leak (see Fig. 34–20). There is some evidence to support this contention.133,134 This leads to more rapid achievement of hemodynamic goals, volume expansion equal to or greater than the volume administered, and reduction in tissue edema. Despite these logical arguments there is a strong counterargument that colloid solutions are expensive, probably leak into the extracellular space,

and impact blood coagulation. Three influential meta-analyses were published in the late 1990s that suggested that colloid solutions may actually worsen patient outcomes.135–137 There is reason to be skeptical of the results of these reviews. A myriad of compounds labelled “colloid” were included, many no longer administered. The studies accrued data over a 30-year period during which fundamental changes occurred in the practices of anesthesia, trauma, and critical care. Moreover, the end points listed in the reviews (principally mortality) were not necessarily end points measured in the studies. The majority of these studies were not carried out in the controlled operating room environment, did not use specific goals for resuscitation, and tended to compare isolated crystalloid resuscitation with isolated colloid resuscitation, not in combination. Most studies of colloids have compared one agent against another, rather than against crystalloid solutions. There is an emerging body of evidence to support the limited use of colloid solutions in perioperative medicine. These data are discussed in the final section of this chapter. The following sections review the most frequently prescribed colloid solutions.

TABLE 34–29. Properties of Colloid Solutions

Fluid

Weight (Average Molecular Weight)

Number (Average Molecular Weight)

Colloid Osmotic

5% Albumin 25% Albumin Plasma 6% Hetastarch 10% Pentastarch 6% Pentafraction 10% Dextran 40 6% Dextran 70

69,000 69,000 119,000 450,000 264,000 280,000 40,000 70,000

69,000 69,000 88,000 70,000 63,000 120,000 26,000 41,000

19 78 21 30 40 28 148 60


Intravenous Albumin Albumin is commercially available in concentrations of 5% (250-mL and 500mL vials) and 25% (50-mL and 100-mL vials). These monodisperse solutions are derived from pooled human blood, serum, or plasma, and have been pasteurized at 140°F (60°C) for 10 hours. In addition, these preparations contain no clinically important antibodies and may be administered without regard to the recipient’s blood group or Rh factor. The more frequently used 5% solution contains 50 mg of albumin per milliliter of physiologic salt solution, whereas the 25% solution has an albumin concentration of 250 mg/mL. All commercial albumin products contain 130–160 mEq of sodium per liter of solution. The 5% solution is isoncotic with respect to human plasma; the 25% solution is 4–5 times more oncotically active than is an equivalent volume of normal plasma. Albumin has a very low incidence of allergic reactions (0.5–1%) and these are usually mild (rash, fever, chills, nausea). Albumin solutions do not appear to directly alter blood coagulation. Albumin administration is associated with a rapid but unpredictable expansion of the plasma volume. In profoundly hypovolemic patients the interstitial compartment should be resuscitated first so the use of albumin should follow initial administration of crystalloid. Albumin has been widely used to minimize weight gain, prevent pulmonary edema, diminish ascites and reduce tissue edema. There is some evidence that this agent may have some impact on improving organ function and facilitating enteral nutrition.138 Beyond this there is no evidence that albumin reduces mortality. Previous concerns that albumin may increase mortality,139 appear to be unfounded. The Saline vs. Albumin Fluid Evaluation (SAFE) study, an Australian randomized controlled trial that recruited >7000 patients, showed no differences in outcome between patients treated with 4% albumin as their resuscitation fluid and those receiving saline.140

Dextrans Dextrans are high-molecular-weight dglucose polymers joined largely by α1,6 bonds into linear-branched macromolecules. They are biosynthesized commercially from sucrose by the B512 strain of Leuconostoc mesenteroides, using the enzyme dextran sucrase.

For clinical purposes, dextrans are designated by their weight-average molecular weights, because these solutions are polydisperse colloids containing both large and small molecules. Dextran 40, with a weight-average molecular weight of 40,000 Da (range: 10,000– 90,000 Da), is available in 0.9% sodium chloride or 5% dextrose, as is dextran 70, which has a weight-average molecular weight of 70,000 Da (range: 20,000–200,000 Da). Dextrans have a strong colloidal osmotic effect: 1 g of dextran 40 retains 30 mL of fluid. Following administration, the lowermolecular-weight particles are rapidly cleared by the kidney. The threshold for the renal excretion of dextran is a molecular weight of roughly 50,000 Da. Particles weighing less than 15,000 Da are rapidly filtered and not reabsorbed. The remainder are excreted through the gut or phagocytosed by cells of the reticuloendothelial system. Within 24 hours after infusion, approximately 70% of dextran 40 and 50% of dextran 70 is excreted unchanged in the urine. Severe renal dysfunction (creatinine clearance 20% above baseline or >110 beats/min yes no Hct > 21

CVP > 15 yes no

Transfuse

Hct > 21 yes

Consider vasopressors

Administer 250 mL colloid

Targets met no FIGURE 34–25. Use of central venous pressure as part of goal-directed volume resuscitation.


ed or CVP-based (conventional) intraoperative fluid management. The CVP-guided protocol aimed at a CVP of 12–15 mm Hg. There was a significant reduction in postoperative stay, shorter time to resuming full diet, and lower incidence of gastrointestinal morbidity in the patients randomized to EDM-guided therapy. Noblett et al.160 recruited 108 patients who were undergoing elective colorectal resection and inserted esophageal Doppler monitors in all. The patients were randomized into fluid therapy that was at the discretion of the anesthesiologist versus protocolized fluid therapy that included colloid boluses. The intervention group had a reduced postoperative hospital stay, fewer intermediate or major postoperative complications, and tolerated diet earlier. In addition, there was a reduced rise in perioperative level of the cytokine interleukin 6 in the intervention group. An alternative approach to flow monitoring, derived from the seminal work of Shoemaker,161 is to use oxygen consumption (or its surrogate, mixed venous oxygen saturation [SVO2]) to determine tissue oxygen flow. Low SVO2 is indicative of excessive extraction per unit volume, which is strongly suggestive of hypovolemia. Rivers et al.162 studied early goal-directed therapy in sepsis, in 263 patients who were randomized to “standard” therapy versus aggressive goal-directed therapy that included the use of an oximetric central venous pressure line. This measured SVO2 in the superior vena cava distribution. The patients in the study group received significantly more fluid than did patients in the control group in the first 6 hours, more red cell transfusions overall, and an equivalent volume of intravenous fluid over the first 72 hours. There was a 16% decrease in 28-day mortality (number needed to treat: 6). The implication of this study is that early aggressive volume resuscitation ensures tissue blood flow. Once goals are met, further resuscitation is not helpful and may be harmful (Fig. 34–26). Taking these data together, it appears that perioperative patients who are undergoing major nonvascular surgery, require early, aggressive, goaltargeted volume resuscitation. Stroke volume monitoring appears to be more effective than CVP, which appears to be more effective than the use

of standard formulaic approaches. Patients appear to do better if resuscitated on the day of surgery, and if colloids are administered to achieve volume goals (Fig. 34–27).

Fluid Restriction One question that arises from these data is whether the convention of administering postoperative maintenance fluids to patients who have undergone major abdominal surgery is helpful or hurtful. Brandstrup et al.163 performed a randomized, observer-blinded, multicenter trial (8 Danish Hospitals) that included 172 patients randomized to restrictive or standard perioperative fluid regimen. All of the patients underwent colorectal surgery. The restrictive therapy received no volume preloading, no adjustment for third space loss, and hetastarch or blood to replace blood losses. Postoperative fluid management was adjusted to prevent weight gain of more than 1 kg. The standard therapy group received formula-driven volume replacement. There was a significant reduction in postoperative (including cardiopulmonary and wound healing) complications in the restrictive therapy group. In another study, 152 patients, with an American Society of Anesthesiologists physical status of I–III who were undergoing elective intraabdominal surgery, were randomized to receive intraoperatively either liberal or restrictive amounts of lactated Ringer so-

lution.164 The liberal protocol group received 10 mL/kg followed by 12 mL/ kg/h. The restrictive protocol group received 4 mL/kg/h and no bolus. The majority of patients underwent lower gastrointestinal surgery. The median volume of fluid administered to the restrictive group was 1230 mL versus 3670 mL in the liberal group. The number of complications was lower in the restrictive protocol group. Return of bowel function was later in that group and their hospital stay was longer. Another group randomized 10 patients who were undergoing surgery for colonic cancer to receive liberal postoperative fluids (≤ 3L water and 154 mmol sodium per day) and 10 to receive a restricted intake (≤ 2 L water and 77 mmol sodium per day). Patients in the fluid-restriction group, that is, a weight gain of less than 3 kg, had an earlier return of gastrointestinal function and shorter duration of hospital stay. A similar study by Tambyraja et al. demonstrated a significant relationship between postoperative sodium and water gain and complications after colonic surgery.165

Summary Perioperative fluid management is a complex process that must take into account the patient’s preexisting disease, preoperative volume status, physiologic reserve, degree of perioperative stress, and perioperative fluid losses.

Urinary output < 0.5 mL/kg/hour Systolic blood pressure more than 20% below baseline Heart rate > 20% above baseline or >110 beats/min

Central venous and arterial catheter placement

CVP

< 8 cm H2O

Crystalloid of colloid

Fluid load to 12 cm H2O >12 cm H2O 65 mm Hg

Vasoactive agents

> 65 mm Hg 70% no

Goals achieved

Transfuse to hemoglobin >10 g/L 10 g/L

RBC tranfusion

Dobutamine

FIGURE 34–26. Use of SVO2 (mixed venous oxygen saturation) as part of goal-directed resuscitation.

679


Urinary output < 0.5 mL/kg/hour Systolic blood pressure more than 20% below baseline Heart rate > 20% above baseline or >110 beats/min

EDM + oximetric CVP or oximetric PAC and arterial catheter placement SV < 0.7 mL/kg CVP

Crystalloid of colloid SV

0.7 – 1.5 mL/kg: hold fluids

Fluid load to CVP > 16 cmH2O CVP > 16 SV 1.5 mL/kg: hold fluids & diurese > 0.7 ml/kg

>65 mm Hg

65 mm Hg

Inotrope required

10 g/L

RBC tranfusion

>70%

Goals achieved

FIGURE 34–27. Use of stroke volume and SVO2 (mixed venous oxygen saturation) as part of goaldirected resuscitation. CVP, central venous pressure; EDM, esophageal Doppler monitor; MAP, mean arterial pressure; PAC, pulmonary artery catheter; SV, stroke volume .

For the majority of patients, prehydration with 2 mL/kg/h fasting or 30 mL/kg crystalloid, prior to or at the time of induction, will reduce postoperative nausea, vomiting, pain, and lightheadedness. For patients who are undergoing minor surgery or ambulatory surgery without appreciable blood loss, this is all the intravenous fluid that is required. There is little data available with respect to youthful patients with low American Society of Anesthesiologists physical status scores. A formula-based approach to perioperative fluid management appears reasonable for low-risk patients who are undergoing moderately traumatic surgery (e.g., laparoscopic operations, peripheral vascular surgery, neurosurgery). However, management of patients who are undergoing extensive or highrisk surgery requires a more elegant approach. Patients who underwent bowel resection appear to have worse outcomes when overresuscitated with crystalloid. Patients who underwent major vascular surgery, hip surgery, or extensive upper abdominal operations appear to benefit from a dynamic, flow-based, goal-directed approach to volume resuscitation. This can be achieved (in increasing order of inva-

siveness) using CVP (volume responsiveness; see Fig. 34–25); CVP and mixed venous oxygen saturation (volume responsiveness and tissue flow; see Fig. 34–26) or stroke volume and mixed venous oxygen saturation (dynamic volume responsiveness and tissue flow; see Fig. 34–27). In the latter approach, stroke volume is targeted to 0.7–1 mL/kg of ideal body weight. A stroke volume in excess of 1.0 mL/kg is indicative of overresuscitation and fluids are withheld until the stroke volume drifts back into normal range. If the stroke volume exceeds 1.5 mL/ kg, serious consideration should be given to the administration of diuretics. Respiratory pulse pressure variation is gaining popularity and may emerge as a simple surrogate for stroke volume.166 Intraoperative blood loss should be replaced 1:1 with blood or colloid or with 4:1 with crystalloid; crystalloid requirements to replace blood increase geometrically as blood loss continues. Patient outcomes appear to be optimal when the patient is resuscitated fully on the day of surgery or injury and resuscitation efforts rapidly decelerate. Postoperative fluid management remains a controversial area. Although

transcompartmental fluid sequestration continues for a day or two following surgery or injury (longer if a septic source remains uncontrolled), continued administration of crystalloid leads to increasing tissue edema and weight gain. Conversely, intravascular dehydration may lead to hypoperfusion organ injury, particularly to the kidney. A prudent approach to postoperative fluid administration is recommended. Maintenance fluids are probably unnecessary, unless the period of fasting is prolonged. Evidence of tissue hypoperfusion, as evidenced by low urinary output, low SVO2, or low stroke volume, should be treated with fluid boluses, keeping in mind that lower volumes of colloid are required to achieve the same hemodynamic goals. Once spontaneous diuresis commences, continuous fluid infusions should be discontinued and attention directed toward repletion of intracellular ions, potassium, magnesium, and phosphate. A reasonable goal for perioperative fluid management is restoration of normal body weight by day 7 postoperatively.

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90. Goldsmith DJ, Forni LG, Hilton PJ. Bicarbonate therapy and intracellular acidosis. Clin Sci (Lond) 1997;93:593–598.


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109. Hansen PB, Jensen BL, Skott O. Chloride regulates afferent arteriolar contraction in response to depolarization. Hypertension 1998;32:1066–1070. 110. Hansen PB, Jensen BL, Skott O. Chloride regulates afferent arteriolar contraction in response to depolarization. Hypertension 1998;32:1066–1070. 111. Wilcox CS. Regulation of renal blood flow by plasma chloride. J Clin Invest 1983; 71:726–735. 112. Lobo DN, Bostock KA, Neal KR, Perkins AC, Rowlands BJ, Allison SP. Effect of salt and water balance on recovery of gastrointestinal function after elective colonic resection: a randomised controlled trial. Lancet 2002;359:1812–1818. 113. Merten GJ, Burgess WP, Gray LV, et al. Prevention of contrast-induced nephropathy with sodium bicarbonate: a randomized controlled trial. JAMA 2004;291:2328–2334. 114. Boldt J. New light on intravascular volume replacement regimens: what did we learn from the past three years? Anesth Anal 2003;97:1595–1604. 115. Ruttmann TG, James MFM, Finlayson J. Effects on coagulation of intravenous crystalloid or colloid in patients undergoing peripheral vascular surgery. Br J Anaesth 2002;89:226–230. 116. Ng KF, Lam CC, Chan LC. In vivo effect of haemodilution with saline on coagulation: a randomized controlled trial. Br J Anaesth 2002;88:475–480. 117. Ruttmann TG, Jamest MF, Lombard EH. Haemodilution-induced enhancement of coagulation is attenuated in vitro by restoring antithrombin III to pre-dilution concentrations. Anaesth Intensive Care 2001;29:489–493. 118. Healey MA, Davis RE, Liu FC, Loomis WH, Hoyt DB. Lactated ringer’s is superior to normal saline in a model of massive hemorrhage and resuscitation. J Trauma 1998;45:894–899. 119. Waters JH, Gottlieb A, Schoenwald P, Popovich MJ, Sprung J, Nelson DR. Normal saline versus lactated Ringer’s solution for intraoperative fluid management in patients undergoing abdominal aortic aneurysm repair: an outcome study. Anesth Anal 2001;93:817–822. 120. Mazzoni MC, Borgstrom P, Intaglietta M, Arfors KE. Capillary narrowing in hemorrhagic shock is rectified by hyperosmotic saline-dextran reinfusion. Circ Shock 1990; 31:407–418. 121. Bruegger D, Bauer A, Rehm M, et al. Effect of hypertonic saline dextran on acid– base balance in patients undergoing sur-

gery of abdominal aortic aneurysm. Crit Care Med 2005;33:556–563. 122. Oliveira RP, Weingartner R, Ribas EO, Moraes RS, Friedman G. Acute haemodynamic effects of a hypertonic saline/dextran solution in stable patients with severe sepsis. Intensive Care Med 2002;28:1574– 1581. 123. Nolan J. Fluid resuscitation for the trauma patient. Resuscitation 2001;48:57– 69. 124. Mattox KL, Maningas PA, Moore EE, et al. Prehospital hypertonic saline-dextran infusion for post-traumatic hypotension. The U.S.A. Multicenter Trial. Ann Surg 1991;213:482–491. 125. Wade CE, Grady JJ, Kramer GC. Efficacy of hypertonic saline dextran fluid resuscitation for patients with hypotension from penetrating trauma. J Trauma 2003;54: S144–S148. 126. Wade CE, Kramer GC, Grady JJ, Fabian TC, Younes RN. Efficacy of hypertonic 7.5% saline and 6% dextran-70 in treating trauma: a meta-analysis of controlled clinical studies. Surgery 1997;122:609–616. 127. Cooper DJ, Myles PS, McDermott FT, et al. Prehospital hypertonic saline resuscitation of patients with hypotension and severe traumatic brain injury: a randomized controlled trial. JAMA 2004;291:1350– 1357. 128. Jarvela K, Kaukinen S. Hypertonic saline (7.5%) decreases perioperative weight gain following cardiac surgery. J Cardiothorac Vasc Anesth 2002;16:43–46. 129. White H, Cook D, Venkatesh B. The use of hypertonic saline for treating intracranial hypertension after traumatic brain injury. Anesth Anal 2006;102:1836–1846. 130. Klatzo I. Presidential address. Neuropathological aspects of brain edema. J Neuropathol Exp Neurol 1967;26:1–14. 131. Schmoker JD, Shackford SR, Wald SL, Pietropaoli JA. An analysis of the relationship between fluid and sodium administration and intracranial pressure after head injury. J Trauma 1992;33:476–481. 132. Grocott MPW, Mythen MG, Gan TJ. Perioperative fluid management and clinical outcomes in adults. Anesth Anal 2005; 100:1093–1106. 133. Rittoo D, Gosling P, Burnley S, et al. Randomized study comparing the effects of hydroxyethyl starch solution with Gelofusine on pulmonary function in patients undergoing abdominal aortic aneurysm surgery. Br J Anaesth, 2004;92:61–66. 134. Zikria BA, King TC, Stanford J, Freeman HP. A biophysical approach to capillary permeability. Surgery 1989;105:625– 631. 135. Choi PT, Yip G, Quinonez LG, Cook DJ. Crystalloids vs. colloids in fluid resuscitation: a systematic review. Crit Care Med 1999;27:200–210. 136. Roberts I, Alderson P, Bunn F, Chinnock P, Ker K, Schierhout G. Colloids versus crystalloids for fluid resuscitation in

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CHAPTER 35: Airway Management

SECTION B MANAGING THE AIRWAY

CHAPTER 35 Airway Management P. Allan Klock, Jr., MD, and Andranik Ovassapian, MD

sess the patency and alignment of the air passages and their ability to accommodate airway devices. Key are the relationships of the pharynx to surrounding structures, the architecture of the larynx, and the mobility of the tissues.

The Pharynx Extending from the sphenoid bone to C6, the pharynx parallels the vertebrae, which are covered by the anterior longitudinal ligament and fascial layers beneath the mucosa and constrictor muscles.3,4 Between the more

KEY POINTS 685

The airway conducts gases between the atmosphere and the alveoli. Effective airway management keeps the airway free of secretions, contamination, and obstruction while minimizing complications. Critical illness often causes weakness and obtundation sufficient to impair air exchange. The sedative, narcotic, anesthetic, and relaxant drugs that facilitate surgery predictably compromise airway patency and protection. The Closed Claims Study of the American Society of Anesthesiologists (ASA) Committee on Professional Liability reveals that tragic and costly complications of anesthesia frequently are tied to problematic airway management.1 Some of the most important roles of the anesthesiologist include ensuring that the patient is adequately oxygenated and ventilated and that airway patency is maintained. Mastery of the airway demands familiarity with normal and variant anatomy and the alterations caused by abnormal states. Essential attributes for the expert airway manager include knowledge, sound judgment, skills for a range of techniques, and planning for conceivable contingencies.2,3

APPLIED ANATOMY OF THE AIRWAY To ensure adequate gas exchange, anesthesiologists must continually as-

1. Tracheal intubation can be accomplished using a direct visual (rigid laryngoscopy), indirect visual (fiberoptic laryngoscopy), guided blind (laryngeal mask airway, retrograde, lightwand), or a complete blind (blind nasal) technique. Each technique has its preferred indication and risks and benefits. 2. Airway management without tracheal intubation is becoming more popular with the introduction of the laryngeal mask airway. 3. General anesthesia and muscle relaxants are used to facilitate tracheal intubation. A rapid-acting muscle relaxant is used during rapid sequence induction and intubation. 4. Soft-tissue upper airway obstruction is common after induction of anesthesia. Oropharyngeal airway insertion and application of jaw thrust often are successful for overcoming soft-tissue airway obstruction. 5. Securing the airway under topical anesthesia with or without sedation (an “awake intubation”) provides the optimal approach for patients with severely compromised or difficult airways. 6. Awake intubation should be encouraged, taught, and practiced regularly so that anesthesiologists are comfortable and skilled with the elements of this technique.


7. The availability of a difficult airway cart should be assured for every anesthetizing location. 8. Major anesthetic complications are frequently associated with airway mismanagement, including inadequate ventilation or oxygenation and unrecognized esophageal intubation. 9. Laryngospasm is common with patient stimulation during light anesthesia. Stridor indicates partial blockade of the airway. Lack of stridor may indicate complete closure of the larynx with no air exchange. 10. In patients in whom the upper airway is obstructed, establishing emergency ventilation through the use of a laryngeal mask airway, Combitube, cricothyrotomy, or transtracheal jet ventilation is a must and should be applied as soon as possible to prevent brain injury and death. 11. Esophageal intubation to establish emergency ventilation is more likely to succeed since the introduction of the Combitube. 12. Trauma to laryngeal structures can leave patients with vocal cord paralysis and major voice dysfunction. 13. Airway compromise has been reported during patient extubation. Planned and prepared extubation is a must to minimize airway-related complications.


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superficial buccopharyngeal fascia and the prevertebral fascia, the retropharyngeal space permits free movement of the pharynx during deglutition. Retropharyngeal abscesses may infiltrate through this space and enter the superior mediastinum. The anterior communications of the pharynx give names to its subdivisions (Fig. 35–1). The nasopharynx extends from the skull base to the soft palate at the caudal aspect of the atlas (C1). From here to the caudal aspect of C3 lies the oropharynx, whose forward limit is the junction between the anterior two thirds and posterior third of the tongue. The laryngopharynx or hypopharynx merges at C6 with the esophagus (Fig. 35–2). There, the cricopharyngeus (lower fibers of the inferior constrictor), originating on the cricoid cartilage, encircles the esophagus to form its upper sphincter. In anesthetized patients, the same function is mimicked by pressing the cricoid ring against C6 (Sellick maneuver).5

Nasopharynx and Nose The pharyngobasilar fascia anchors the pharynx superiorly to the occipital and the sphenoid bones. In the presence of basilar skull fractures, passage of nasotracheal and nasogastric tubes may result in their entry into the cranium. Superficial to these bones that roof the pharynx and C1 lies the pharyngeal tonsil (called adenoids when hypertrophied), a site of potential obstruction or hemorrhage during nasal intubation. In patients whose large tongues fill their oral cavities, face mask ventilation permits entry of gas through the nasopharynx into the lungs, but the soft palate, posterior pharyngeal wall, and tongue often form a unidirectional valve that blocks exhalation. Exhalation block is prevented by periodic release of the mandible or by insertion of an artificial airway. Anteriorly, the nasopharynx opens through the choanae, nasal passages, and nostrils. Consequent to septal deformity or mucosal congestion, one passage is commonly smaller than the other. The filtration and humidification functions of the nose are well served by the convoluted surfaces of the three turbinates on each lateral wall (Fig. 35–3). Their fragility assures that intubation attempts will cause epistaxis unless the tube is guided parallel and adjacent to the hard palate and perpendicular to the face

FIGURE 35–1. Diagram of sagittal section of the pharynx illustrating the three subdivisions of the pharynx. (Reprinted from Finucane BT, Santora AH. Principles of Airway Management. 2ed. St. Louis: Mosby Year Book, Inc., 1996, with permission from Elsevier.)

FIGURE 35–2. Posterior view of the pharynx showing subdivisions of the pharynx. (Reprinted from Finucane BT, Santora AH. Principles of Airway Management. 2ed. St. Louis: Mosby Year Book, Inc., 1996, with permission from Elsevier.)


isthmus between the oropharynx and oral cavity, in the seated patient with tongue protruding, suggests easy direct laryngoscopic intubation. Anterior to the fauces is the oral cavity proper, separated from the vestibule by the teeth and gums. Maxillary teeth, especially if prominent, bucked, or capped, can interfere with laryngoscopy and intubation.

Laryngopharynx and Larynx

FIGURE 35–3. Lateral wall of the nasal cavity demonstrating the superior, middle, and inferior conchae (turbinate bones). (Reprinted from Finucane BT, Santora AH. Principles of Airway Management. 2ed. St. Louis: Mosby Year Book, Inc., 1996, with permission from Elsevier.)

through the channel beneath the inferior turbinate.

Oropharynx and Mouth The posterior third of the tongue, muscular for mastication and deglutition, forms the anterior wall of the oropharynx. In the sleeping or anesthetized patient in the supine position, muscle relaxation combined with gravity moves the base of the tongue toward the posterior oropharyngeal wall, causing varying degrees of airway obstruction. Partial airway obstruction is aggravated by negative inspiratory pressure collapsing the loose pharyngeal walls inward. Much of successful airway management amounts to preventing airway obstruction at this level. In the absence of artificial airways, airway patency may be improved by extending the neck or subluxing the mandible anteriorly. This anterior displacement, through stretching of the mylohyoid, geniohyoid, and genioglossus muscles, indirectly relieves oropharyngeal obstructions (Fig. 35–4). Mandibular mobility depends in turn on the hinging and gliding motions of the temporomandibular joint. Successful rigid laryngoscopy requires anterior displacement of the tongue to allow visualization of the larynx. The oropharynx opens to the oral cavity at the palatoglossal folds, marking the division between the anterior two thirds and posterior one third of the tongue. The palatoglossal folds and the more posterior palatopharyngeal

folds form bilateral triangles, called the fauces, which contain the tonsils. Hypertrophy of the tonsils and their confluence with the adjacent soft palate, uvula, and tongue base can challenge an anesthesiologist attempting mask ventilation or intubation. Full visualization of all structures at the faucial

Three single cartilages (epiglottis, thyroid, cricoid) and six smaller, paired cartilages (arytenoid, corniculate, cuneiform) and their mucosal coverings shape the larynx (Fig. 35–5). Presenting the appearance of an obliquely cut vent pipe originating out of a steep roof, the larynx protrudes into the laryngopharynx. The laryngeal inlet or aditus is formed by the cephalad border of the epiglottis, the aryepiglottic fold, and the mucous membranes covering the cuneiform and corniculate cartilages. The rima glottidis is the elongated opening between the true vocal folds (anteriorly) and the arytenoid cartilages (posteriorly). The term glottis (vocal apparatus of the larynx) refers to the true vocal folds and the opening between them. Be-

FIGURE 35–4. Sagittal section of the mouth to illustrate the tongue and its innervation. (Reprinted from Finucane BT, Santora AH. Principles of Airway Management. 2ed. St. Louis: Mosby Year Book, Inc., 1996, with permission from Elsevier.)

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FIGURE 35–5. Diagrammatic illustration of sagittal section of the larynx. The epiglottis, thyroid, cricoid, and arytenoid cartilages and the position of the vocal cord ligaments are demonstrated. (Reprinted from Finucane BT, Santora AH. Principles of Airway Management. 2ed. St. Louis: Mosby Year Book, Inc., 1996, with permission from Elsevier.)

tween the false and true vocal cords lie the laryngeal ventricles. The laryngeal vestibule includes the laryngeal inlet and the false vocal folds. The aryepiglottic folds curve caudally and medially into the larynx to form the vestibular folds or false cords. To each side of the larynx and inferior to the aryepiglottic folds are the piriform recesses, which are separated by a prominence in the anterior laryngopharyngeal wall created by the lamina of the cricoid cartilage (Fig. 35–6).3 The properly positioned laryngeal mask airway (LMA) seals against the cricoid cartilage and cricopharyngeus muscle inferiorly, the base of the tongue superiorly, and the piriform recesses laterally.6 The superior laryn-

FIGURE 35–6. Fiberoptic endoscopic view of the larynx. The piriform recesses are represented by the deepest part of the hypopharynx lateral to aryepiglottic folds bilaterally. (From Ovassapian3 with permission.)

geal nerves, submucosal in these recesses, can be blocked with local anesthetic-soaked pledgets applied to the piriform sinuses. During blind nasal or lightwand intubation, tubes caught in the piriform recesses should be withdrawn a few centimeters and rotated to enter the larynx. The hyoid (Greek, “U-shaped”) bone at C4 suspends the thyroid cartilage by the thyrohyoid membrane, which is penetrated when performing superior laryngeal nerve blocks (Fig. 35–7). Gentle lateral movements by the thumb and index finger applied to opposite sides of the hyoid allow palpation of the cornua of the bone. At C5, at the superior aspect of the 3cm high thyroid cartilage, is the thyroid notch and laryngeal prominence (Adam’s apple), an important landmark that may be subtle in women. The thyroid (Greek, “shield”) cartilage sends superior cornua cephalad toward the hyoid bone and inferior cornua to articulate with the cricoid (Greek, “ring”) cartilage. The cricoid cartilage resembles a graduation ring with its narrower portion facing posteriorly. In the midline at C6, the cricothyroid membrane (ligament) provides an easily palpated and avascular site for emergency cricothyrotomy or

cannulation for instillation of local anesthetics, jet ventilation, or retrograde wire-guided intubation. The vocal ligaments of the true cords attach anteriorly to the medial aspect of the thyroid cartilage, just 1 cm superior to the cricothyroid ligament, and posteriorly to the vocal processes of the arytenoid cartilages (Fig. 35–5).3,4 Just superior to the anterior attachment of the vocal ligaments, the epiglottic cartilage is attached to the medial aspect of the thyroid cartilage. The superior edge of the epiglottis blends with the aryepiglottic folds. The tip of a curved (Macintosh) laryngoscope blade fits into the glossoepiglottic reflection. Two lateral valleculae in this reflection are created by the hyoepiglottic ligament, which keeps the resting epiglottis out of the laryngeal vestibule. Tracheal tubes caught in the valleculae during blind nasal or lightwand intubations may be directed into the larynx by changing their angle of approach or by pulling the epiglottis anteriorly with traction on the tongue. The epiglottic cross-section, crescentshaped in adults, is more curved (omega-shaped) in infants. Superior to the posterior cricoid lamina sit the paired arytenoid (Greek, “ladle”) cartilages with superior, anterior, and lateral projections. The superior projections support the corniculate (Latin, “little horn”) cartilages, and the anterior and lateral projections attach to the vocal cords and various intrinsic laryngeal muscles, respectively (Fig. 37–5). Corniculate and cuneiform cartilages embedded in the aryepiglottic fold form two prominences on the posterior part of rima glottidis. These prominences, commonly referred to as “the arytenoids,” serve as important landmarks for intubation during suboptimal laryngoscopy.

Normal Vocal Cord Movements and Laryngeal Nerve Palsies Normal vocal cord movements include abduction during inspiration, partial adduction during exhalation, and full adduction during phonation. All intrinsic muscles of the larynx are adductors or tensors, with the exception of the posterior cricoarytenoid muscles, which are the sole abductors. All intrinsic muscles of the larynx are innervated by the recurrent laryngeal nerve, with the exception of the cricothyroid, a tensor innervated by the external branch of the superior laryn-


ing deglutition, Valsalva, or laryngeal spasm, the thyroid cartilage and hyoid bone approximate, bulging the epiglottis caudal into the vestibule against the false cords in a ball-valve fashion. Muscle relaxants and maneuvers to elongate the larynx (application of the sniff position, neck extension, and jaw thrust) tend to counteract such closure; in contrast, face mask positive pressure may expand the piriform recesses and compress the aryepiglottic folds, compounding laryngeal closure.

The Lower Airway

FIGURE 35–7. Diagrammatic illustration of the anterior view of the larynx. The larynx is suspended from the hyoid bone by the thyrohyoid ligament. The cricothyroid ligament provides easy and fast access to the larynx. Translaryngeal injection of local anesthetics and transtracheal jet ventilation are performed through this ligament. (Reprinted from Finucane BT, Santora AH. Principles of Airway Management. 2ed. St. Louis: Mosby Year Book, Inc., 1996, with permission from Elsevier.)

geal nerve. Laryngeal nerve palsies are classified as central or peripheral and unilateral or bilateral.7 Simultaneous malfunction of the superior and recurrent laryngeal branches implies a central lesion or a high interruption of the vagus nerve. Central causes include posterior fossa surgery or brainstem infarctions. Peripheral lesions are more commonly caused by neck or cardiothoracic surgery than by endotracheal (ET) tube cuff pressure on the larynx. Damage to the superior laryngeal nerve or its external branch results in an inability to sound a highpitched C note, but the inability improves over time as the contralateral muscle compensates. During phonation, the aryepiglottic folds and glottis are asymmetric. A complete unilateral recurrent laryngeal nerve injury causes hoarseness and a motionless cord that is joined during phonation by the contralateral cord crossing the midline. Brain infarction or a complete vagus nerve interruption causes the cord to assume a flaccid, wavy, partially abducted, or “cadaveric” position more commonly seen as a result of administering muscle relaxants. Incomplete bilateral recurrent laryngeal nerve palsies result in a glottic

opening so small that an emergency surgical airway may be needed. Bilateral complete recurrent laryngeal nerve palsies result in severe hoarseness, but because the cords neither adduct nor abduct, a safe glottic opening may remain. Paradoxical movement of vocal cords, often seen in young anxious female patients, may mimic vocal cord paralysis. Both vocal cords move, but they approximate during inspiration, closing the larynx and causing stridor and airway obstruction.8

Glottic and Laryngeal Closure Three forms of laryngeal airway closure can be distinguished. First, during light anesthesia or phonation, the intrinsic laryngeal muscles approximate the vocal cords during exhalation, causing expiratory stridor or moaning. Second, if the vocal cords are edematous or are resting close together (encountered in some anxious patients), the Bernoulli effect draws the cords together during rapid inhalation, resulting in inspiratory stridor.9 The third kind of closure involves the entire larynx instead of simply the glottis; the thyrohyoid and other strap muscles contract in a forceful, longitudinal compression of the larynx.10 Dur-

The lower airway includes the subglottic larynx, trachea, and bronchi. The subglottic larynx is 2 cm in length and extends from the true vocal folds to the lower border of the cricoid ring. The trachea extends from the lower border of the cricoid ring at C6 to the carina at T5, posterior to the angle of Louis (manubriosternal junction).4 A lightwand-fitted tracheal tube can be positioned with its tip at midtrachea by advancing the transilluminated spot to the sternal notch.11 Neck flexion will advance an ET tube in a caudad direction, whereas Trendelenburg position or laparoscopic pneumoperitoneum can move the carina in a cephalad direction. All of these maneuvers can cause a properly located ET tube to move into a bronchus.12 False reassurance that a tube tip is not in a bronchus often is given by a radiograph taken with the head transiently thrown into extension by removing the pillow while supporting the chest with a film cassette. During fiberoptic examination, the trachea is distinguished from bronchi by its flat, muscular posterior wall, lending a D-shaped cross-section. The right mainstem bronchus is approximately half as long as the 5-cm left mainstem bronchus. Being wider and more in line with the trachea, the right mainstem bronchus is more likely than the left bronchus to be unintentionally intubated. Also, foreign bodies, aspirated material, and suction catheters preferentially wind up in the right bronchus. Tracheobronchial anatomy and other features of the airway differ between infants and adults (Table 35–1).4

EVALUATION OF THE AIRWAY A difficult airway can present as difficult mask ventilation, difficult rigid

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TABLE 35–1.

BOX 35–1. Some Causes of Difficult Airway Management

Comparison of the Infant and Adult Airways Infant (birth to 1 year)

Adult ≥8 years)

Cricoid–carina distance (cm) Trachea–right bronchus angle Trachea–left bronchus angle Narrowest portion of airway Level of glottis Inclination of vocal cords Protrusion of corniculate and cuneiform tubercles into laryngeal aditus Epiglottic cross-section

5–6 30° 45° Cricoid cartilage C3–4 interspace Anteroinferior Prominent

10–20 20° 45° Glottis C5 Horizontal Minimal

Omega-shaped

Glottic–epiglottic angle Ease of mobilizing epiglottis to expose cords

Small Generally awkward, especially with curved blade Almost nonexistent

Crescent-shaped or flat Large Usually easy with curved or straight blade Several millimeters

Feature

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Height of thyrohyoid and cricothyroid ligaments Preferred breathing route Prominence of occiput

Nasal Large (no headrest needed to attain the “sniff ” position)

laryngoscopic intubation, difficult tracheostomy, or combination of all three. The major task during preoperative airway evaluation is to identify patients at risk for a “cannot intubate, cannot ventilate” situation, which is caused by congenital or acquired anatomic variations or by abnormal afflictions of the upper and lower airway (Box 35–1).13,14 A search for these includes reviewing old records, taking a ventilatory history, examining the patient with reference to the normal and desired mobility of airway structures, and reviewing relevant laboratory and radiologic studies.14 Inability to ventilate is a more urgent problem than is inability to intubate with adequate mask ventilation. Independent risk factors for difficult mask ventilation include age >55 years, body mass index >26 kg/m2, facial hair, missing teeth, and a history of snoring.15 Special attention should be paid to syndromes associated with a problematic airway. Details of the airway evaluation are given in Chapter 8. It is important to have an airway management plan that addresses whether the patient will require an airway device such as a supraglottic airway or an ET tube. It also is important to consider whether the airway

Nasal or oral Small (headrest needed)

will be instrumented while the patient is awake or after induction of the anesthetic. Despite a thorough evaluation of the airway, anatomic variants, including supraepiglottic cysts16 and lingual tonsillar hypertrophy,17,18 can lead to an unexpected difficult ventilation and/ or intubation. In addition, the ever present possibility of instrument failure requires backup plans and familiarity with algorithms for handling unanticipated challenges.

VENTILATION DURING ANESTHESIA Alveolar ventilation should deliver the oxygen (O2) consumed by tissues while removing metabolic carbon dioxide (CO2). The average anesthetized adult consumes approximately 250 mL/min of O2 and produces 200 mL/ min of CO2. Because the normal alveolar effluent contains 5% (1/20) CO2, removing 200 mL of CO2 each minute requires 4 L/min (20 × 200 mL/min = 4000 mL/min) of alveolar ventilation. Because one third of minute ventilation is dead space (does not participate in gas exchange), the required total minute ventilation to maintain nor-

Anatomic Features Short, muscular neck Limited neck mobility Prominent maxillary incisors Awkwardly placed, incomplete dentition Long, highly arched palate with narrow mouth Small mouth opening Receding chin Abnormal States Anaphylactic airway edema Arthritis and ankylosis Cervical spine Temporomandibular joint Larynx Congenital syndromes Klippel-Feil (short, fused neck) Pierre Robin (micrognathia, cleft palate, glossoptosis) Treacher Collins (mandibulofacial dysostosis) Endocrinopathies Obesity Acromegaly Hypothyroid macroglossia Goiter Infections Ludwig’s angina (floor of the mouth abscess) Peritonsillar abscess Retropharyngeal abscess Epiglottitis Mediastinal masses Myopathies demonstrating myotonia or trismus Scarring from burns or radiation Trauma and hematomas Tumors and cysts Technical and Mechanical Factors Body cast Halo fixation or cervical collar Airway foreign bodies Leaks around a face mask Edentulous Flat bridge of nose Large face and head Whiskers, beard Nasogastric tube Poor technique, inexperience, or haste mocapnia is 6000 mL/min, or approximately 90 mL/kg/min. Unless the metabolic rate is reduced, alveolar hypoventilation results in hypercapnia.


15 100 10 50 5

0

0 25 50%

Alveolar PCO2 (mm Hg)

150

40%

30%

O2 concentration in inspired gas 25%

20

150

21%

15 100 15%

10

10%

5

50

Alveolar PO2 (mm Hg)

Alveolar PCO2 (kPa)

20

Alveolar PO2 (kPa)

Arterial oxygenation can be sustained during hypoventilation by increasing the fraction of inspired oxygen (FIO2). In the presence of opioids, sedatives, and inhaled anesthetics, the brain’s normal compensatory responses to hypercapnia and hypoxemia are blunted. Thus, the spontaneously breathing patient during general anesthesia will become hypercapnic, although surgical stimuli offset ventilatory depression and tend to return PaCO2 toward normal. Spontaneous ventilation is acceptable during general anesthesia when muscle relaxants are avoided and airway patency is properly maintained. The anesthesiologist assists ventilation by timing the compression of the reservoir bag to the patient’s spontaneously initiated breaths, a task requiring considerable practice.19 Assisted ventilation can test the quality of a face mask or laryngeal mask seal and offset the mechanical loading caused by partial airway obstruction. In the anesthetized patient, apnea may result either from hyperventilation until the PaCO2 drops below the apneic threshold or from a series of breaths large enough to elicit the Hering-Breuer inspiratory reflex. It has been shown that assisting breathing enough to lower the PaCO2 by 5 mm Hg reduces it below the apneic threshold. For this reason, assisted ventilation cannot generally reverse hypercapnia to a meaningful extent without becoming controlled ventilation. In the presence of muscle relaxants, unfavorable position, critical illness, or a requirement for hyperventilation, the anesthesiologist may choose to initiate controlled ventilation. An inhalation induction is performed by allowing a patient to breathe volatile anesthetics, starting with concentrations low enough to avoid airway irritation and gradually increasing as the central effects of the vapors begin to depress cough reflexes. As alveolar ventilation drops off, breaths are assisted with increasing frequency, until ventilation is manually controlled. Inhalation inductions, popular for children, have some merit in adults when the ability to ventilate the patient after induction of anesthesia is uncertain.19 If worsening of airway obstruction is encountered during inhalation induction, the anesthetic can be turned off, thereby awakening the patient. Historically, a well-performed

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0

2

4

6

8

0 10

Alveolar ventilation (litres/min) (BTPS) FIGURE 35–8. Dependency of alveolar oxygenation on alveolar ventilation at low FIO2 values. Supplemental O2 largely frees the PaO2 of its dependency on alveolar ventilation. For example, the broken vertical line shows that a patient breathing room air with an alveolar ventilation of 3.2 L/ min has a PaO2 of 100 mm Hg, which would decrease to 50 mm Hg should the alveolar ventilation decrease by 50%. Yet even at the lower alveolar ventilation, increasing the FIO 2 to 0.4 elevates the PaO2 to 200 mm Hg. (Reprinted from Nunn JF. Applied Respiratory Physiology. 3d ed. Boston: Butterworth, 1987, with permission from Elsevier.)

inhalation induction was even used in patients at increased risk for regurgitation to deepen them enough to obliterate the vomiting reflex while preventing inspiratory attempts against a closed glottis.

Hypoventilation Hypoventilation, consequent to depressed ventilatory drive, laryngeal spasm, or most commonly supraglottic soft-tissue airway obstruction, results in hypercapnia and hypoxemia. Normally, although room air is 21% O2, alveolar gas has an O2 concentration of 16% because of the presence of water vapor and CO2. Arterial O2 desaturation of hypoventilating patients breathing room air occurs in part because increasing alveolar CO2 displaces alveolar O2. Small increases in FIO2 elevate alveolar O2 enough to maintain an acceptable arterial O2 saturation in the presence of hypoventila-

tion; large increments in FIO2 can maintain close to normal arterial O2 saturation despite profound hypoventilation (Fig. 35–8). During apnea, arterial oxygenation can be sustained by apneic oxygenation.20 In this technique, the patient breathes 100% O2 long enough to wash nitrogen from the alveoli, leaving only O2, CO2, and 6% water vapor (47 mm Hg vapor pressure at 37°C). If 100% O2 continues to be available to a patent airway, it will be drawn into the alveoli during apnea. Without exhalation, the alveolar CO2 concentration increases 5 or 6 mm Hg the first minute (equilibration between venous and alveolar PCO2) and 3 to 6 mm Hg/min thereafter (metabolic production). Ten minutes into apneic oxygenation that began with normocapnia, the alveolar composition of gases would be 47 mm Hg of water vapor, 72 mm Hg of CO2, and 641 mm Hg of O2. In the absence


BOX 35–2. Conditions Aggravated by Hypercapnia Preexisting metabolic acidosis (e.g., lactic acidosis, uremia) Hyperkalemia Elevated intracranial pressure Pulmonary hypertension Right-to-left cardiac shunts Cardiac dysrhythmia Poor myocardial contractility

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of metabolic acidosis, the pH would be approximately 7.24. In general, it is the risk of hypoxia that threatens to permanently harm the hypoventilating patient. This realization justifies the popularity of supplemental O2 to lessen the likelihood of hypoxemia during hypoventilation. Except in selected conditions, the consequences of hypercapnia are well tolerated or reversible (Box 35–2).

Denitrogenation Because it is impossible to assure the ability to ventilate any patient about to receive general anesthesia, proper preanesthetic denitrogenation should be undertaken. The 80% of the average 2.5-L adult functional residual capacity (FRC) that starts out as N2 is replaced with O2.21 Should ventilation become impossible, this extra 2 L of O2 may sustain vital organs for up to 8 minutes, which is enough time to establish another means of oxygenation. Because it may make the difference between life and death for the patient, proper denitrogenation (Box 35–3) should be a top priority for an anesthesiologist preparing to induce a general anesthetic.21,22

MONITORING THE ADEQUACY OF VENTILATION AND OXYGENATION The gold standard for assessing the adequacy of ventilation and oxygenation is the measurement of the partial pressures of CO2 and O2 in sampled blood, that is, arterial blood gases. Because of cost and delay, a number of alternative technologies have become popular since 1980. Clinical observations remain invaluable to the anesthesiologist, who should constantly monitor the validity of pulse oximetric and capnographic data.

Clinical Observation Airway management demands constant awareness of the patient’s physiologic status, obtained through observations of skin color, vital signs, chest and abdominal movements, and use of accessory muscles. Even before arterial blood gases deteriorate, anesthesiologists usually are able to detect problems and make adjustments to maintain airway patency and gas exchange (Table 35–2).4,19

Proper Denitrogenation Technique High flow of O2 Fully open pop-off valve Leak-free mask fit to prevent entraining room air Tidal breathing for 2–3 minutes or a series of four vital capacity breaths Confirmatory Observations Reservoir bags empties and refills End-tidal CO2 approaches 40 mm Hg End-tidal O2 approaches 85–90%

Capnometry Capnometry, using one of several detection methods, continuously displays the waveform of end-tidal PCO2 (PETCO2)

TABLE 35–2. Reassuring and Worrisome Signs and Their Implications during Airway Management

Reassuring

Worrisome

Concurrent pectoral and subcostal rising, alternating with falling No retractions

Stepwise expansion of subcostal region

No tug Breathing without accessory muscles

BOX 35–3.

Pulse Oximetry In the majority of patients, pulse oximetry affords reliable but noninvasive measurement of the arterial O2 saturation. Provided that hemoglobin concentration and organ perfusion are acceptable, satisfactory arterial O2 saturation makes organ hypoxia unlikely. The reassurance offered by pulse oximetry allows the anesthesiologist to proceed carefully instead of hurrying during intubation.23 Pulse oximetry is not sensitive to hypoventilation in the presence of a high FIO2 and gives late notification of esophageal intubation after denitrogenation.24 Most failures of pulse oximetry (e.g., movement artifact, vasoconstriction) are obvious. The anesthesiologist may incorrectly assume adequate oxygenation during carbon monoxide poisoning or illumination of the pulse oximeter’s probe by lights of unusual wavelength.

Normal breathing sounds heard with pretracheal stethoscopy Normal vital signs

Rebreathing bag quickly refills during exhalation Volumeter indicates appropriate tidal volumes Sequential fogging and clearing of plastic mask

Subcostal expansion with concurrent pectoral collapse Subcostal rocking with no chest expansion Submandibular, intercostal, or supraclavicular retractions Inspiratory tracheal tug

Use of sternocleidomastoid and trapezius muscles Stertor (snoring)

Stridor (harsh, high pitched) Audible phonation or palpable purring

Implication of Worrisome Sign Stomach filling with gas or unidirectional expiratory obstruction Partial upper airway obstruction or intercostal weakness Complete airway obstruction Partial or complete upper airway obstruction Intercostal weakness with preserved diaphragmatic strength Respiratory muscle fatigue or weakness Soft-tissue obstruction

Laryngeal obstruction Light anesthesia or partial airway obstruction


sampled at the patient end of the breathing circuit. When the tidal volume is large enough, alveolar gas reaches the CO2 sampling site, and the displayed PETCO2 closely approximates PaCO2, affording a noninvasive, breath-by-breath method to judge the adequacy of ventilation. In patients with normal cardiopulmonary physiology, expiratory gas has a PCO2 that is 2–5 mm Hg less than the arterial PCO2. Significant and common clinical events create PCO2 gradients (arterial to alveolar) so that the PaCO2 is normally higher than that displayed on the capnometer measured (Box 35–4). In most patients, end-tidal CO2 suggests better alveolar ventilation than actually exists, resulting from significant amounts of CO2-free inspired gas diluting the sample. For example, during spontaneous face mask ventilation of a patient with elevated intracranial pressure, the peak measured PCO2 displayed by the capnometer may be only 18 mm Hg, but the first few breaths after tracheal intubation may show a PCO2 of 30 mm Hg. The rapid,

BOX 35–4. Increased Gradient between PaCO2 and PETCO2 Arterial-to-End-Tidal Gradients PaCO2 increases, whereas PETCO2 decreases (decreased perfusion relative to ventilation) Decreased perfusion Embolization Pulmonary thromboembolism Air embolism CO2 embolism (laparoscopic insufflation) Hypovolemic shock Right-to-left intracardiac shunting Sudden increase in ventilation-to-perfusion ratio Bronchial intubation PETCO2 > PaCO2 (reversed gradients) Chronic obstructive pulmonary disease Alveolar-to-Sampled Gradient Anatomic or apparatus dead space Rapid, shallow breaths Apparatus dead space (face mask) Dilution at the sampling site of exhaled gas by fresh air Sampled-to-Measured Gradients Calibration errors Slow capnometer response time with rapid breaths

shallow ventilatory pattern prior to intubation prevented transport of undiluted alveolar gas to the capnometer. An important application of capnometry is the confirmation of an intratracheal tube position by the appearance of stable CO2 concentrations in sequential breaths immediately after intubation, as mandated, by the ASA Standards for Basic Anesthetic Monitoring.25,26 Despite tracheal intubation, the expected levels of CO2 may fail to appear if delivery of CO2 to the lungs is limited by low cardiac output, hypovolemia, gas embolization, or cardiac arrest.

AIRWAY MANAGEMENT WITHOUT TRACHEAL INTUBATION The majority of airway-related deaths and severe neurologic morbidity result not from a failure to intubate the trachea but rather from a failure to ventilate and oxygenate.1 Resourceful anesthesiologists command an array of techniques for ventilation without tracheal intubation when the latter is not indicated or has failed. These include face mask ventilation, oral airways, and supraglottic devices such as LMAs or esophageal devices.4,19,27

Face Mask Ventilation Positioning to Facilitate Face Mask Ventilation When the patient is in the supine position, gravity draws the relaxed tongue and epiglottis into configurations that can obstruct the airway. Patients recovering from anesthesia or obtunded and intoxicated emergency room patients may be best observed in a semilateral position, with the dependent leg straight and the other leg bent, the dependent arm flexed, and the dependent cheek on the bed (the tonsillar position). Gravity will draw the tongue away from the posterior pharyngeal wall, and blood or vomitus can drain out the mouth before being aspirated. If the anesthesiologist suspects that gastric contents have entered the pharynx, he or she should turn the patient’s head to the side and quickly position the table head down to maximize drainage while attempting to clear the pharynx with a Yankauer suction catheter. Students of basic life support are taught to overcome upper airway obstruction by extending the head and

neck and by anterior mandibular displacement with jaw thrust. Although these maneuvers move the hyoid and attached structures anteriorly, their effectiveness can be limited by two factors. Some vertebral columns can bow anteriorly and impinge on pharyngeal patency. More commonly, the forceful cervicooccipital extension tightens the strap muscles sufficiently to limit the anterior mobility of the larynx and the mandible. For these reasons, anesthesiologists often favor the sniffing position, in which the occiput rests on a firm pad approximately 10 cm anterior to the scapula. Atlantooccipital extension and jaw thrust maneuvers then are superimposed. The sternomental distance shrinks, so the hyoid and its attached structures can be moved away from the posterior pharynx without tightening the strap muscles. Greater comfort for the awake patient and preparedness for laryngoscopy are additional advantages of the sniffing position. It is provided naturally by the large occiput of infants and small children, obviating the need for a pad. In some patients, the best airway patency is achieved by rotating the head to either side. Airway visualization and manipulation seem easier when the operating room table is elevated so that the patient’s forehead is brought to the level of the anesthesiologist’s xiphoid.

Achieving a Seal The skill of sealing a mask to the face develops only after months of anesthesiology residency training. Although masks consist of a few basic designs, facial contours assume an endless variety (Fig. 35–9). Clear plastic masks with large-volume, low-pressure cushions seal easily to most faces (including patients with a flat nasal bridge) while affording a view of ventilatory condensation and evaporation cycles and early detection of regurgitated gastric contents. Being disposable, they are relatively expensive per use, provide little bracing for the mandible, and can be hard to seal on the furrowed face of an edentulous patient. Black rubber anatomic masks have a formable body between their 22-mm connectors and inflatable cushions. A mask strap hooks around the connectors. These opaque masks may delay the recognition of regurgitation, albeit a rare event. As reusable items, they are inexpensive per use but require individual cleaning and high-level dis-

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FIGURE 35–9. Face masks. Three adult universal masks on the left. The Rendell-Baker pediatric mask is shown on the far right.

infection between uses. Masks are only half of an ensemble that includes a mask strap, which is essential for achieving and sustaining a good fit (Box 35–5). Concern of excessive apparatus dead space in patients with tiny tidal volumes led Rendell-Baker and Soucek to develop pediatric masks without cushions and made from molds of infants’ 694

BOX 35–5. Achieving a Seal with a Face Mask 1. Place the mask strap beneath the occiput. 2. Apply the mask’s nasal groove to the low point of the nasal bridge to avoid pressure on the eyes. 3. Grip the left mandible with the third and fourth fingers of the left hand. 4. Lower the mask so that its inferior rim contacts the face between the lower lip and the mental prominence. 5. If there is a leak between the mask and the cheeks, consolidate the seal by dragging mobile tissue of the left cheek toward and under the mask cushion, stabilizing the tissue with the ulnar margin of the left hand. 6. Bracing the mentum against the mask, pull the mandible up and forward with the third through fifth fingers, while the thumb and index finger grip the mask above and below the connector. 7. Maintaining the left-sided seal, tilt the mask toward the right cheek, consolidating the seal by dragging the mobile tissue forward to the cushion and by keeping it there with one limb of the mask strap. 8. The other limbs of the mask strap may improve the seal, especially for anesthesiologists with small hands. Crossing the lower limbs of the mask strap prevents the mask from riding up the face.

faces. In contrast with the racial and ethnic variability displayed in later life, infants share uniformity of facial contours. Their full cheeks can be pulled up and around the rims of these masks. Undue submandibular pressure by the anesthesiologist’s fingers tends to worsen airway obstruction. When providing mask ventilation for children, it is particularly important to ensure that the anesthesiologist’s third through fifth fingers engage only the mandible and do not compress the soft tissues overlying the tongue. Beards or broad mustaches may hinder a good mask seal, making controlled ventilation simply impossible. For edentulous patients too alert to tolerate airways, the lower margin of the mask can be placed against the mucosal reflection in the vestibule of the mouth while drawing the lower lip over the mask. By inserting an oropharyngeal airway, anesthesiologists can minimize the furrows in the cheeks of edentulous patients. Inserting an oral airway lengthens the distance between the supramental depression and the nasal bridge, necessitating substitution for the next larger mask size. For this reason, it is essential that small, medium, and large masks be available.4,19

Applying Positive Pressure A functioning breathing system (a backup self-inflating resuscitation bag should be present at all anesthetizing locations) and a leak-free mask seal are essential for applying positive airway pressure. Anesthesiologists learn to adjust the pop-off valve and speed of reservoir bag compression to keep airway pressures below the 20–25 cm H2O associated with gastric inflation. Fit patients can tolerate generous doses of intravenous (IV) induction drugs without hypotension. An opioid, benzodiazepine, and hypnotic agent in combination act synergistically and generally render the airway nonreac-

tive for several minutes, during which inhaled anesthetics can be introduced. Large vigorous breaths and rapid escalations in inspired anesthetic concentrations may precipitate hiccups, coughing, breathholding, laryngospasm, and delay induction. Increasing sevoflurane or desflurane vaporizer settings in 0.5% increments every five breaths allows depression of airway reflexes before irritating inspired concentrations are reached. Intubating doses of neuromuscular blockers eliminate upper airway reactivity in short intervals. Positive pressure not only facilitates ventilation but may overcome minor degrees of soft-tissue obstruction of the airway. In a spontaneously breathing patient who is too lightly anesthetized to accept insertion of an airway, 5–15 cm H2O of continuous positive airway pressure achieved by partially closing the “pop-off” valve may relieve airway obstruction and increase the minute ventilation. Well-synchronized intermittent positive-pressure breaths can achieve the same result. Inflation of the stomach with respiratory gases should be avoided because it decreases thoracic compliance and increases the risk of regurgitation.

Pharyngeal Airways An inability to ventilate with a face mask despite proper positioning, jaw thrust, and a good mask seal may be caused by laryngeal spasm in response to light anesthesia or by soft-tissue upper airway obstruction resulting from deepening anesthesia and the onset of muscle relaxation (Box 35– 6).2,3 If an assessment suggests simple supraglottic obstruction, insertion of pharyngeal airway to separate soft tissues from the posterior pharyngeal wall is a logical next step (Fig. 35–10). Success confirms that the soft tissue had been obstructing the airway, whereas persisting or worsening obstruction often is indicative of active closure of the larynx that may be relieved by administering muscle relaxants or deepening the anesthetic depth with intravenous agents. The anesthesiologist should minimize the trap created by the pathologic causes of obstruction that may be worsened by the loss of muscle tone. Until the arrival of the LMA and esophageal devices, oropharyngeal or nasopharyngeal airways were the best ways to relieve simple supraglottic obstructions. They remain inexpensive,


BOX 35–6. Causes of Inability to Ventilate Laryngeal spasm or vocal cord adduction Light anesthesia Supraglottic soft-tissue relaxation (obstruction) Soft palate and pharyngeal walls Tongue Epiglottis Chest wall rigidity Breathholding Narcotic-induced Pathologic, glottic, and subglottic Foreign body Enlarged lingual tonsil Edema Infection Tumor and hematoma Congenital Superior vena cava syndrome Bilateral vocal cord palsy Tracheal stenosis Tracheal and bronchial compression Great vessel anomalies Mediastinal mass Equipment failure Selector valve accidentally in the “ventilator” position safe, and generally effective.19,27 Trial and error often are necessary for even the experienced anesthesiologist to select an oropharyngeal airway long enough to anteriorly displace the base of the tongue without pushing the epiglottis into the laryngeal inlet. The forward portion of the oropharyngeal airway separates the teeth or gums; its flange keeps the device from dropping into the hypopharynx. Displacing the tongue into the hypopharynx is avoid-

ed by drawing it anteriorly with a tongue blade held in the left hand while the right hand opens the mouth and inserts the oropharyngeal airway. The onset of soft-tissue relaxation and airway obstruction usually heralds depression of cough and gag reflexes sufficient to tolerate pharyngeal stimulation. Swallowing or gagging triggered by a tongue blade or airway touching the base of the tongue suggests deferring insertion pending greater obtundation; the stimulus itself often restores airway patency. Coughing and breathholding after uneventful placement of an oropharyngeal airway suggest airway irritation by anesthetic vapors and may remit with turning down the vaporizer and temporarily abandoning attempts at positive-pressure ventilation or deepening the depth of anesthesia with intravenous agents. A nasopharyngeal airway can be inserted in a patient with a clenched jaw, a need that often occurs when soft-tissue obstruction complicates premature extubation. Unfortunately, unless precautions are taken (Box 35–7), epistaxis may complicate the hasty introduction of an airway through the nasal passages. Because of alignment with the glottic opening, blind tracheal suctioning may be possible by passing a catheter through a nasopharyngeal airway, although the need for and tolerance of repeated tracheal suctioning usually are indications for intubation.

Laryngeal Mask Airway Developed in the 1980s by Dr. Archie Brain,6 the classic LMA (Fig. 35–11) has achieved great popularity for addressing simple, supraglottic airway obstruction in a variety of contexts.28–30 Its unique capabilities (Boxes 35–8 and

FIGURE 35–10. Artificial oropharyngeal and nasopharyngeal airways.

BOX 35–7. Precautions for Introducing Nasopharyngeal Airways Prepare the larger nasal passage with a vasoconstrictor Choose a soft, blunt-tipped nasopharyngeal airway Soften it by warming (not applicable for some materials) Lubricate the airway To protect the turbinates, point the bevel medially Direct the device directly posteriorly, parallel to the hard palate and beneath the inferior turbinate If resistance is encountered, withdraw, rotate 90°, and re-advance with gentle, steady pressure Ease difficult passage by using a soft suction catheter as an introducer 35–9), relative ease of use, and low incidence of serious complications has assured the LMA a place in the anesthesiologist’s armamentarium.31–34 Several studies have indicated that trained but inexperienced resuscitators are more likely to be successful at proper placing an LMA than at tracheal intubation.35 Lacking an experienced mentor, practitioners can initiate their own LMA experience based on the instructional videotape and manual that accompany the product. Becoming adept at proper LMA insertion requires consideration of anatomy, patience, and practice.29,36 Even when using suboptimal insertion technique, providers will have a high success rate with the LMA, allowing many practitioners to develop poor habits. Adherence to proper technique will maximize success and reduce complications. The LMA should be deflated with finger pressure on the dorsal aspect of the cuff so that the totally flattened cuff curves away from the aperture (Fig. 35–12). Water-soluble lubricant smeared on the dorsal surface of the cuff should be kept from drying. The recommended technique for LMA placement is summarized in Figure 35–13.37 When the epiglottis is dragged downward, the aperture bars of the LMA prevent impaction of epiglottis into the LMA and possible obstruction. Obstacles to LMA insertion include the soft palate, uvula, tonsillar fauces, oropharyngeal angle, tongue, and epiglottis. These areas are negotiated by the sniffing position with marked cervi-

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BOX 35–8. Clinical Use of Laryngeal Mask Airway

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FIGURE 35–11. Various laryngeal mask airways and endoscopic views of them. Shown from left to right are the LMA Unique, Classic, ProSeal, and Fastrach. The two epiglottic bars of the LMA Unique and Classic prevent entry of epiglottis inside the lumen of LMA. The LMA ProSeal dose not have epiglottic bars, but the drain tube supports the epiglottis and prevents it from impacting inside the LMA tube. In the LMA Fastrach, the epiglottis bar elevates epiglottis as the endotracheal tube passes into the trachea.

cooccipital extension, permitting laryngeal structures to move forward and accommodate the mask. A gloved hand flattens the tip of the mask against the hard palate to start it on a path that will not engage the epiglottis. Intravenous propofol doses of 2–2.5 mg/kg usually provide an appropriate depth of anesthesia for LMA insertion, but insertion can proceed during any adequately deep general anesthetic or after topical anesthesia in conscious patients. Although careful placement, cuff inflation, and adaptation time improve the seal, leakage often occurs at 20 cm H2O airway pressure with the classic LMA. Obesity, head-down tilt, abdominal insufflation, airway obstruction, or any other conditions necessitating ventilation with high airway pressures increase the risk of hypoventilation, gastric insufflation, and regurgitation. The LMA Classic is particularly well suited for the lightly anesthetized, spontaneously breathing ambulatory pa-

tient. Compared with face mask or endotracheal anesthesia, there seems to be less need for deep anesthesia beyond that required for the surgery itself.29 Patients seem to tolerate a lighter depth of anesthesia with less chance of coughing, breathholding, stridor, or laryngeal spasm.38 Increasing anesthetic depth usually manages episodes of movement, tachypnea, or hyperpnea. Finally, patients tolerate a return to consciousness with the ability to follow commands while the inflated LMA is still in place. Positive-pressure ventilation can be applied through the LMA; however, the tidal volume, respiratory rate, and inspiratory to expiratory ratio (I:E) should be adjusted to avoid high airway pressures. Newer anesthesia ventilators that can provide synchronized positive-pressure breaths are particularly well suited for use in the patient with a supraglottic airway in place. The LMA ProSeal is an advanced form of the LMA Classic consisting of two

Indications Surgical anesthesia without intubation Repeated anesthetics Emergency ventilation when intubation has failed Improving airway seal without tracheal intubation Patient with facial hair Edentulous Assisting tracheal intubation Providing a patent airway with minimal changes in blood pressure, heart rate, intraocular or intracranial pressure, or bronchial tone Contraindications High risk of aspiration (relative contraindication) Glottic or subglottic obstruction Supraglottic pathology interfering with its placement Extremely limited mouth opening or neck extension Prone position (relative contraindication) Need for high airway pressure ventilation

BOX 35–9. Benefits and Limitations of Laryngeal Mask Airway (LMA) Benefits Permits ventilation when face mask and intubation have failed Permits lighter anesthesia and faster emergence Facilitates blind or fiberoptic tracheal intubation Provides better airway for fiberoptic bronchoscopy Easier to learn than tracheal intubation Limitations Proper position of the LMA may be difficult to achieve Probably gas leak with LMA Classic when airway pressure >20 cm H2O Limited protection against aspiration No protection against laryngospasm tubes; an airway tube and a drain tube.39 When properly positioned, the drain tube communicates with the upper esophageal sphincter and permits insertion of a gastric tube to decompress the stomach. The LMA ProSeal also has a second posterior cuff that provides a


FIGURE 35–12. Diagram of a deflated laryngeal mask airway. The cuff of the laryngeal mask airway is deflated before its insertion. The rim of the cuff should evenly face away from mask aperture, with no folds near the tip.

better seal between the LMA and the larynx, allowing for positive-pressure ventilation with higher airway pressures than the LMA Classic.29 The LMA ProSeal introducer is provided to aid insertion of the LMA ProSeal without the need to place fingers in the mouth. The technique of LMA ProSeal placement with the introducer is similar to LMA Fastrach placement. Whereas the LMA Classic can be used with low-pressure positive-pressure ventilation, the LMA ProSeal has

been designed for use with positivepressure ventilation at higher airway pressures. The drain tube will direct the regurgitated fluid to the outside, minimizing the risk of aspiration of gastric contents.29,40 One of the best emergency uses of the LMA ProSeal is to establish ventilation and to decompress the distended stomach when intubation has failed and the stomach is distended because of difficult face mask ventilation. The anesthetic can be continued with the ProSeal, or the

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FIGURE 35–13. Technique for placing a laryngeal mask airway (LMA) described by Brain. A. The LMA is held by the index finger and the thumb facing the bowl of LMA caudally toward the larynx. The index finger is positioned between the shaft of the LMA and the deflated cuff. The occiput is stabilized with the left hand. B. The deflated and lubricated LMA is placed into the open mouth pressed against the hard palate. C. The LMA is advanced behind the tongue and into the oropharynx using the index finger. D. The LMA is pushed further down deep into the hypopharynx using the tip of the index finger. E. The index finger is removed. The LMA is pushed farther down to its final position by holding the tube of the LMA with the left hand. Without holding the tube of the LMA, the cuff is inflated with the recommended volume of air. The LMA may protrude slightly on inflation of the cuff. Final position of the LMA with cuff inflated. A bite block made of sponges is placed between molars and taped to the LMA tube to prevent patient biting. (LMA Airway Instruction Manual. San Diego: LMA North America, 2005. Courtesy of LMA.)


BOX 35–10. Progression of Steps to Manage Difficulty in Ventilating a Patient

FIGURE 35–14. Combitube. A. Combitube positioned in the esophagus. Ventilation is performed via the blue lumen, marked number 1. B. Combitube positioned in the trachea. Ventilation is performed via the clear lumen, marked number 2. (From Ovassapian3 with permission.)

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device can be exchanged for an ET tube. Using the LMA in an unfavorable setting increases the likelihood of unfortunate results. The LMA does not protect as effectively as an ET tube against pulmonary aspiration of gastric contents.41,42 The incidence of aspiration with the laryngeal mask is reported to be similar to that of mask anesthesia and very close to that of ET intubation.29,43 Application of cricoid pressure impedes placement of the LMA.44 Reported but rare complications include twelfth cranial nerve paralysis,45 unilateral hypoglossal nerve paralysis,46 and transient bilateral vocal cord paralysis.47

Esophageal–Tracheal Airway The esophageal–tracheal Combitube (ETC; Fig. 35–14) is intended for establishing emergency ventilation when there is simple, supraglottic obstruction or when the operator lacks the skills for face mask ventilation or tracheal intubation.48–50 This device differs from the earlier esophageal obturator airway in that it permits ventilation whether it enters the esophagus or the trachea. When the lubricated ETC is passed through the pharynx of a comatose or anesthetized patient, a neutral position or slight flexion of the neck generally directs the device to follow the posterior pharyngeal wall and into the esophagus. Approximately 4–6% of the time, the ETC enters the trachea. A large l00-mL balloon seals the oropharynx, and a smaller balloon seals the esophagus. The ETC has two channels. One lumen is open at the tip of

the ETC. If the ETC enters into the esophagus, this channel can be used to decompress the stomach. If the ETC enters the trachea, this lumen can be used to ventilate the patient, avoiding the necessity of removal and reinsertion. The second lumen opens into multiple pharyngeal ports and is used to ventilate the patient during the more common scenario when the tip of the ETC is placed in the esophagus. Lifesaving ventilation has been provided by this device.48

Other Extraglottic Airways After successful introduction of the LMA, several other extraglottic airway devices have been introduced. Some are commercially available, but none have been studied as extensively as the LMA. Examples are the laryngeal tube airway (VBM Medizintechnik, GmbH, Sulz, Germany), the streamlined pharyngeal airway liner, the intubation laryngeal airway developed by Cookgas, and the Cobra (see reference 29).

Complications of Nonintubated Airway Management Improperly conducted and monitored airway management can result in hypercapnia and/or hypoxic organ damage, although supplemental oxygen and pulse oximetry reduce the incidence of the latter.1 Hypercapnia is nearly always well tolerated; however, in rare situations hypercapnia can cause morbidity (Box 35–2). Laryngeal spasm is an airway reflex that presents as a sustained, disinhibit-

Confirm that the machine’s selector valve is set to “bag” and that the reservoir is not twisted Without exceeding 25 cm H2O, increase airway pressure while intensifying jaw thrust and observing for ventilation or gastric distension If blood pressure is adequate and if awakening the patient is unnecessary, deepen anesthesia with a rapidly acting IV drug (e.g., thiopental, propofol) If depth of anesthesia is judged adequate, insert an oropharyngeal or nasopharyngeal airway If O2 saturation decreases, maximize FIO2 Consider whether it would be safest to awaken the patient Administer 5–20 mg of IV succinylcholine Consider the wisdom of a full dose of relaxant to facilitate tracheal intubation Consider using laryngeal mask airway or Combitube Consider establishing a transcricothyroid airway

ed glottic closure resulting from insufficient anesthesia and precipitated by instrumentation, fluid irritation, or illtimed stimulation of the larynx or other body parts (e.g., moving or examining the patient at a light plain of anesthesia). The anesthesiologist should consider a wide variety of causes (Box 35–6) when treating a patient who is difficult to ventilate (Box 35–10). Although anesthesia deep enough to obliterate airway reflexes eliminates active vomiting, passive regurgitation can occur anytime during the care of the anesthetized or critically ill patient. Repeated inspiratory efforts against an obstructed airway and gastric distension by air are predisposing factors to regurgitation.51,52 When regurgitation occurs, liquids should be removed from the pharynx by rapidly lowering the head, turning it to the side, and suctioning with a rigid-tipped (e.g., Yankauer) catheter. Subsequent pulmonary aspiration of fluid, solid, or acid may result in bronchospasm and O2 desaturation, tracheobronchial obstruction, and/or chemical pneumoni-


BOX 35–11. Indications for Tracheal Intubation Anesthesia Controls the airway Provides an unobstructed leak-free airway for prolonged ventilation Minimizes aspiration risk Facilitates resuscitation of the moribund patient Permits attention to complex diagnostic and therapeutic matters Has preemptive utility if it is feared that ventilation and intubation may later become impossible Ventilates with thoracoabdominal surgery Permits flexible positioning Affords the anesthesiologist distance from the head Allows full range of positions (e.g., prone, sitting, lateral, head down) Keeps blood and secretions out of the trachea during airway surgery Critical Care Establishes airway patency Protects against pulmonary aspiration Facilitates tracheobronchial toilet Provides a route for airway pressure therapy (e.g., IPPV, IMV) IPPV, Intermittent positive pressure ventilation; IMV, Intermittent mandatory ventilation.

tis. Although the ASA Closed Claims Study indicates that aspiration is rare in modern anesthetic practice, the consequences are significant enough to require that the possibility of aspiration be considered in every patient and that thoughtful planning and preparation be undertaken.1 Using a face mask with straps presents risk of traumatic pressure to the eyes or branches of the facial nerve. Upper airway laceration may precipitate mucosal bleeding severe enough to render laryngoscopy impossible.

AIRWAY MANAGEMENT WITH TRACHEAL INTUBATION Tracheal intubation is undertaken for reasons of physiology, pathology, or convenience (Box 35–11). Reflecting an appreciation of the consequences of hypoventilation, hypoxia, and aspiration and the desire to free the anesthesiologist’s hands for other tasks, the prevalence of tracheal intubation during anesthesia had increased until

the introduction of the LMA in the 1980s, leading to a reduction in the proportion of anesthetics used with ET intubation. Visualization of the pharyngeal and glottic structures assures the greatest likelihood of successful tracheal intubation. Tracheal intubation is optimally undertaken after setup in an operating room or critical care area with custom-stocked carts (Box 35–12). Alternative techniques of intubation and ventilation may be lifesaving when suboptimal circumstances prevent visualized tracheal intubation.

Endotracheal Tubes Most ET tubes are disposable and made of clear, bioinert polyvinyl chloride (PVC) that molds to the contour of the airway after softening at body temperature. Lengths are marked in centimeters, and internal diameters are indicated in millimeters. Implantation testing in animals has shown these materials to be nonirritating by the standards of the American Society for Testing and Materials’ Committee F-29 on Anesthetic and Respiratory Equipment. Because combustion of PVC in the presence of supplemental O2 during airway laser surgery produces hydrochloric acid and other pulmonary toxins, tubes in this setting tend to be made of metal, metal-wrapped red rubber or silicone.53 Although the resistance of a small ET tube can impair the ventilatory weaning of a critically ill patient, it generally is not necessary in the operating room to use the largest possible tube. In many cases, a 7.0- or 7.5-mm internal diameter ET tube is chosen for female patients and an 8.0-mm ET tube is used for men. The clinical setting dictates even smaller tubes for patients with airway edema (e.g., preeclamptic), nasal intubation, and blind intubation. Pediatric ET tube sizes are predicted by an age-related formula and tested for leaks in situ. Use of cuffs often is avoided in children until they are 8 to 9 years old, when the cricoid ring ceases to be the narrowest, edema-prone portion of the airway. Cutting ET tubes renders them less obtrusive and easier to handle, but 26 cm of length should be sufficient for adult oral tubes, allowing 3 cm more for nasal tubes. The 15-mm adapter can be firmly affixed by wiping it with alcohol and twisting it firmly into place in the ET tube.

BOX 35–12. Preparation for Tracheal Intubation Skilled assistance Equipment for face mask ventilation Source of positive-pressure oxygen Anesthesia machine Self-inflating bag Tongue blade and oropharyngeal or nasopharyngeal airways Bright laryngoscope Straight blade(s) Curved blade(s) Stiff (tonsil-style) suction device Position and environment Access to patient’s head Patient’s face near anesthesiologist’s xiphoid Occipital elevation (sniffing position) Adequate light Monitors Intubation stylet or introducers Local anesthetics Injectable Nerve block Laryngotracheal spray Transcricothyroid spray Topical Spray Ointment for tongue Viscous Nebulized IV access for Sedation or anesthetic induction Neuromuscular blockers Relaxants Volume administration Cardioactive drugs (e.g., antiarrhythmic) Intubating (Magill) forceps Backup equipment for unanticipated difficult intubation or ventilation (difficult airway cart)

High-volume cuffs contact the trachea over a broad area, minimizing the pressure on the mucosa and improving the seal, which helps minimize aspiration risk. The pressure in the cuff is estimated by squeezing the pilot balloon, or the pressure is set to Pfat. •

•

748 inhaled anesthetic (Palv) so that blood exiting from the pulmonary vein has a partial pressure close to Palv. Anesthetic then is distributed to various tissues via systemic arterial blood. Delivery of anesthetic to each tissue is determined by its blood flow rate, its anatomic volume, and its tissue/blood partition coefficient (Table 37–2). The effective volume (Veff) for uptake of anesthetic in a given tissue is the product of its anatomic volume and λtissue/blood. The time it takes for anesthetic partial pressure in a given tissue to equilibrate with Palv is decreased when tissue perfusion is high and increased when Veff is large. Highly perfused tissues include the brain, spinal cord, kidney, liver, and heart, which compose less than 10% of an adult body’s mass while receiving approximately 70% of the normal cardiac output. Highly perfused tissues equilibrate within a few minutes with the arterial (alveolar) anesthetic partial pressure (Fig. 37–10 and Table 37–2). As a result, the alveolar partial pressure of anesthetic, which can be measured in end-tidal gases, usually is close to the brain and spinal cord partial pressures (unless the anesthetic concentration in alveolar gas is changing rapidly). Muscle represents a large anatomic volume (average 35–40% of body mass) and the muscle/blood partition coefficient for all inhaled agents ranges from 1.2–3.1. Because muscle nor-

mally receives only approximately 10% of cardiac output at rest, the anesthetic partial pressure in muscle rises slowly, and equilibration with Palv takes hours for most anesthetics used clinically (Table 37–2). Fat receives approximately 13% of cardiac output and represents approximately 25% of body mass in the average adult, with considerable variation. In addition, the potent volatile agents partition highly into fat (λfat/blood range 27–51) so that the effective volume for uptake of volatiles into fat is extremely large (Table 37–2). For the volatile anesthetics, uptake into fat is so slow that equilibration of the partial pressure with Palv never occurs under normal clinical conditions. The only commonly used inhaled anesthetic with a low fat solubility is N2O (λfat/blood = 2.3), for which the equilibration time constant is approximately 2 hours. The vessel-poor group of tissues include skin, ligaments, tendons, cartilage, and cortical bone. These tissues represent approximately 14% of the average adult’s body mass and receive less than 2% of cardiac output. As a result, their contribution to anesthetic uptake is negligible.

Other Factors Affecting Uptake and Distribution of Inhaled Anesthetics Intrapulmonary right-to-left shunts (perfused but nonventilated lung regions)

do not participate in anesthetic uptake. They slow the rate of uptake into blood and make Palv rise more quickly, especially for the more blood-soluble anesthetics. At the same time, pulmonary shunting results in an arterial admixture of mixed venous blood with blood from gas-exchanging lung regions. As the fraction of pulmonary blood flow passing through right-to-left shunts rises, Part, the direct upstream anesthetic pressure source for the nervous system, drops relative to Palv. For the highly soluble anesthetics, the increased Palv somewhat compensates for admixing, and Part rises only slightly slower than normal (Fig. 37–11). With insoluble agents, the impact of shunt on uptake from lung (Palv) is smaller and there is less compensation for admixing. Anatomic and physiologic dead space (ventilated but nonperfused lung regions) effectively reduces alveolar ventilation relative to minute ventilation. Therefore, the impact of increasing dead space on anesthetic uptake is equivalent to reducing minute ventilation of lung regions without dead space. An increased dead space reduces agent delivery to alveoli and results in a slower rate of Palv rise. Systemic arteriovenous (left-to-right) shunting causes the anesthetic partial pressure in mixed venous blood to increase rapidly, slowing the uptake of anesthetic agent from alveolar gas. Therefore, alveolar anesthetic partial pressure rises more rapidly, compensating for the reduced uptake rate. Overall, the impact of arteriovenous shunting is to modestly increase the rate of rise in Palv and the highly perfused tissues. Systemic right-to-left shunting, like that in the lung, causes downstream arterial admixing. Thus, intracardiac shunts, such as patent foramen ovale or patent ductus arteriosus, result in regional Part lower than Palv. Patent ductus arteriosus shunting may result in different anesthetic partial pressures delivered to the brain and spinal cord. The overall effect of shunting can be difficult to predict because total cardiac output may also increase to compensate for the shunt. Anesthetic-induced changes in cardiac and respiratory function affect the rate of anesthesia induction with volatile anesthetics. When spontaneous ventilation is maintained, the uptake of inhaled drug is reduced as anesthetic is absorbed and minute ventilation

CHAPTER 37: Pharmacology of Inhalational Anesthetics

Shunt Palv

0.8

Shunt Part P/Pcirc

0.6 No shunt Palv = Part 0.4

0.2

0.0

0

10

20 Minutes

30

40

FIGURE 37–11. Impact of pulmonary right-to-left shunting on alveolar and arterial anesthetic concentrations. The impact of a 30% left-to-right shunt was calculated using a modified model from Figure 37–4. Pulmonary right-to-left shunting reduces alveolar uptake, increasing P alv, and mixing of shunted blood results in a lower Part. However, the increased Palv compensates for admixing so that, compared with the zero shunt model, Part is only approximately 10% reduced by the 30% shunt.

falls. Anesthetic depression of cardiac output is another dynamic factor that alters both uptake and distribution of anesthetic (see Anesthetic Uptake into Pulmonary Blood and Fig. 37–9).

Concentration Effect and Second Gas Effect N2O represents a special case in clinical anesthesia, because it is often the major constituent of the inhaled gas mixture. As a result, uptake of N2O from the alveolar space into blood produces significant shifts of alveolar gas volume.10 As alveolar gas volume

diminishes, the concentration of N2O is maintained (the concentration effect), and the concentrations of other gases increase (the second gas effect). Consider a single breath of a gas mixture of 70% N2O, 29% O2, and 1% isoflurane (Iso) near the start of an anesthetic when mixed venous blood does not contain N2O (Fig. 37–12). When half of the alveolar N2O is taken up into blood, the remaining alveolar gas volume will be 65% of the original volume with relative concentrations of 35 N2O:29 O2:1 Iso = 54% N2O:45% O2: 1.5% Iso. Because of the reduction in

Inhaled gas mixture

Additional gas mixture

1% Iso

1.3% Iso 29% O2

39% O2

44% O2

70% N2O 1.5% Iso

54% N2O

60% N2O

N2O uptake

FIGURE 37–12. Concentration and second gas effects. When nitrous oxide is inspired at high concentrations, transfer from the lung into pulmonary blood causes the volume of alveolar gas to drop, drawing in more of the gas mixture and concentrating the remaining gases. This concentration effect on nitrous oxide itself results in a sustained alveolar driving pressure and more rapid uptake. The alveolar concentration of other gases, such as isoflurane and oxygen, become higher than the inspired concentrations, which increases their uptake as well—the second gas effect.

alveolar gas volume, the alveolar N2O concentration (and partial pressure) is more than half its original concentration (if 100% N2O were inhaled, uptake would not reduce the alveolar concentration at all). Therefore, the concentration effect maintains the pressure gradient for uptake and increases the rate of rise of Palv for N2O toward the inspired concentration. The second gas effect is illustrated in Fig. 37–12. With N2O uptake, the alveolar concentrations of both oxygen and isoflurane will become higher than the inspired concentration, accelerating their uptake into blood.11

Nitrous Uptake into Airspaces in the Body Inhalation of N2O at high concentrations leads to important effects on airspaces within the body. Airspaces usually contain mostly nitrogen (79% of air), which has a low solubility in blood (λb/g = 0.015), such that bulk transfer of trapped nitrogen gas cannot occur on the time scale of most anesthetics. N2O (λb/g = 0.45) is delivered to airspaces 30 times faster than nitrogen leaves. As N2O diffuses into the preexisting airspace, the volume and/or pressure in the airspace increases. In most cases, both airspace volume and pressure will rise, but examples where one or the other effect dominates are useful for illustration. A compliant airspace, such as a small air embolus or pneumothorax, can increase its volume with minimal pressure change. It will continue to expand until the partial pressure of N2O within the airspace equals that in surrounding blood. Theoretically, at 50% inspired N2O, the preexisting volume of the gas bubble would double (half of its gas volume would then consist of N2O). Similarly, 67% N2O could lead to a tripling of volume, and 75% N2O could quadruple the volume (Fig. 37–13). Small venous air emboli then may become easier to detect with Doppler and echocardiographic monitors but may create more physiologic problems by obstructing blood vessels.12,13 A small pneumothorax could expand to compress mediastinal structures and impair oxygenation or create hemodynamic compromise. The rate of airspace expansion depends on the volume, geometry, and compliance of the airspace as well as the blood flow delivering N2O to it. Small venous air emboli may expand within seconds,

749


N2O

N2O

N2 N2 N2

N2O

N2O PN2 = 1.0 atm PN2O = 0 atm PTot = 1.0 atm V = V0

N2O

N2O

N2

N2O

N2O N2O N2 N2 N O 2

N2O N2O N2O

PN2 = 0.5 atm PN2O = 0.5 atm PTot = 1.0 atm V = 2.0 × V0

N2O

N2

N2O

N2O N2O N2O N2 N2O N2O N2O N2 N2O

N 2O N2O N 2O

PN2 = 0.33 atm PN2O = 0.67 atm PTot = 1.0 atm V = 3.0 × V0

FIGURE 37–13. Expansion of venous air emboli by nitrous oxide. Nitrous oxide enters air pockets far faster than nitrogen leaves (because of low blood nitrogen-carrying capacity), causing airspace expansion. Expansion continues until the partial pressure of N2O inside the air bubble matches that in surrounding blood. Thus, at 50% N2O (PN2O = 0.5 atm), air emboli can double in volume, and at 67% N2O (PN2O = 0.67 atm), they can triple in volume. Expansion of small venous air emboli can lead to occlusion of pulmonary capillaries, compromising both blood flow and gas exchange.

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and a pneumothorax can expand toward equilibrium in less than 1 hour, whereas airspaces in bowel take may considerably longer to expand. N2O diffusion into noncompliant airspaces can create clinical problems. In a noncompliant space, volume does not change, so pressure increases as N2O enters. For example, following intravitreal injection of sulfur hexafluoride (SF6) or perfluoropropane (C3F8) gases, N2O administration can result in rapid increases of intraocular pressure, compromising retinal blood flow.14,15 Intracranial air bubbles (after craniectomy or pneumoencephalography) and the inner ear also represent airspaces in noncompliant body compartments. Other commonly used inhaled anesthetics also diffuse into airspaces, but their low concentrations in clinical settings result in negligible impact upon airspace volume and pressure. Xenon is an experimental anesthetic inhaled at high concentrations (60– 70%) and, like N2O, is associated with airspace expansion.16

Elimination of Inhaled Anesthetics via Ventilation Removal of inhaled anesthetics via the lungs is essentially the reverse of uptake, and many of the factors that affect induction also affect elimination rates. High FGF promotes faster washout of anesthetic from the circuit, enhancing the gradient for removal from the lung (Fig. 37–5). High minute ventilation clears alveolar anesthetic, reducing Palv and providing a gradient for movement of anesthetic from the blood to the alveoli (Fig. 37–7). Highly blood soluble

anesthetics are retained longer than insoluble drugs because the effective volume of blood is higher as λ b/g increases (Fig. 37–8). Similarly, increasing the cardiac output retards recovery. Increased delivery of anesthetic from tissues to the lung tends to maintain Palv, which reduces the gradient for removal from the blood (Fig. 37–9). Some aspects of anesthetic elimination do not mirror the uptake during anesthetic induction. The use of overpressure to accelerate anesthetic induction has no parallel during recovery, because the delivered concentration or partial pressure of anesthetic agent cannot fall below zero. Also, prior to induction the inhaled anesthetic partial pressure in all tissues is zero, whereas different tissues will typically have reached different partial pressures when anesthetic delivery is discontinued. In particular, the partial pressures in muscle and fat may be far lower than Palv after a brief anesthetic. Because anesthetic will continue to be transferred into tissue as long as Palv > Ptissue, these compartments may continue to absorb drug even after delivery ceases. This effect is illustrated in Fig. 37–10, where fat continues to take up isoflurane from blood long after delivery is discontinued, until Palv < Pfat. This uptake helps reduce the anesthetic partial pressure within the highly perfused tissues and can reduce recovery time. The longer anesthesia is maintained, the more drug is absorbed into muscle and fat, which are characterized by a slow uptake and release of agent. Thus, clearance of inhaled an-

esthetics is context sensitive: the longer the anesthetic, the slower the clearance. If fat and muscle reach high partial pressures (after many hours for most potent agents), recovery from anesthesia may be significantly delayed. Therefore, obese patients and those with a higher than normal muscle mass are at risk for slowed emergence after long exposures to soluble anesthetics.

PHARMACODYNAMICS OF INHALED ANESTHETICS Therapeutic Effects and Anesthetic Depth Although general anesthesia results in a multitude of physiologic alterations, there is no consensus among clinicians and researchers as to which actions are essential to the state of general anesthesia.17 Our view is that the common desired outcomes of general anesthesia include hypnosis (loss of awareness), amnesia (loss of memory), and immobility (suppression of movement in response to pain). Some have argued that analgesia is also an essential component.18 Pain is unquestionably a critical consideration in perioperative care, but the potent sedative/hypnotic effects of most general anesthetics confound the assessment of pain. Hypnosis and amnesia are produced via drug effects on neural networks within the brain, whereas immobility is primarily mediated by the spinal cord. In short, the major therapeutic actions of volatile anesthetics take place in the CNS. Beneficial and toxic effects of inhaled anesthetics on other physiologic systems (e.g., cardiovascular function, respiration) thus can be regarded as secondary. In this section, we discuss various measurements of anesthetic effects in the nervous system, as well as their limitations. Because general anesthesia is defined as the loss of normal responses to environmental stimuli, anesthetic depth is most rigorously defined by stimulus–response testing using stimuli that range from benign (e.g., spoken commands) to noxious (e.g., laryngoscopy or surgical incision).19 In addition, certain consistent pharmacologic effects of anesthetics that are stimulus independent are useful signs of anesthetic depth. Traditionally, both


1.4

Classic Stages and Planes of Inhalational Anesthesia Stage 1 is defined as the time between normal waking state and the loss of consciousness (hypnosis) due to an anesthetic agent. There is also mild analgesia in Stage 1 anesthesia. Stage 2 is associated with loss of awareness and recall (amnesia). Stage 2 is associated with the undesired effects of cardiovascular instability excitation, dysconjugate ocular movements, and emesis. Stage 3 is defined as surgical anesthesia, a state where movement in response to pain in suppressed. Various planes of anesthesia were described by Guedel, based on additional physiologic signs: Plane 1 is associated with deep respiration, coordinated thoracic and diaphragmatic muscular activity, and papillary constriction. Plane 2 is associated with diminished respiration, as well as fixed midline and dilated pupils. Plane 3 is associated with continued diaphragmatic movement, diminished thoracic movement, and further papillary dilation. Plane 4 is associated with thoracic immobility and diminished diaphragmatic movement. Stage 4 is associated with cessation of spontaneous respiration and medullary cardiac reflexes and may lead to death. desired and undesired clinical effects have been associated with the various stages and planes of anesthesia introduced by Snow20 and modified by Guedel.21 These descriptions (Table 37–3) were developed during the era of ether and chloroform anesthesia and therefore are not fully applicable to modern practice.

Minimum Alveolar Concentration, Minimum Alveolar Concentration– Awake, and Minimum Alveolar Concentration for Blockade of Autonomic Responses Minimum Alveolar Concentration In 1965, Eger introduced the concept of minimum alveolar concentration (MAC) as a stimulus–response meas-

Fraction of MAC at age = 40

TABLE 37–3.

1

0.8

0.6 0

20

40 60 Age (years)

80

100

FIGURE 37–14. Minimum alveolar concentration (MAC) varies with age. MAC is maximal in the first year of life and drops with age. The figure shows the relationship on a semilogarithmic scale. The equation of the line is MAC/MAC40 = 1.32 × 10–0.00303Age, or a 6.7% drop in MAC per decade (Eger24).

ure of anesthetic potency.22,23 MAC is the alveolar concentration of inhaled anesthetic that prevents movement in half of subjects in response to a surgical incision. Thus, MAC is the equivalent of a median effective dose (ED50) for inhibition of movement in response to a specific noxious stimulus. If different noxious stimuli (e.g., varying point pressures or electric shocks) are used, the concentration of inhaled anesthetic required to suppress movement increases with stimulus intensity. Thus, MAC is most useful for comparing potency among different inhaled agents under the same conditions, with potency being inversely related to MAC. During measurement of MAC, equilibrium between the alveolar compartment and the nervous system must first be established. Other drugs that modulate pain sensation (e.g., opioids) or movement (muscle relaxants) cannot be present. MAC as originally defined depends on atmospheric pressure, but when agent concentration is expressed as a partial pressure, MAC becomes independent of ambient pressure. The MAC values of common inhaled agents in oxygen (Table 37–2) show that N2O is least potent, followed by desflurane, sevoflurane, enflurane, isoflurane, and halothane. By definition, an exclusively inhalational anesthetic to a level of 1 × MAC is inadequate to prevent movement in half of patients. The ED95, which is approximately 1.3 × MAC, may be a more clinically useful value. The ED95 corresponds to 0.9% for hal-

othane, 1.68% for isoflurane, and 1.88% for enflurane. Physiologic, genetic, and pharmacologic conditions may alter MAC. MAC decreases with age (Fig. 37–14). MAC was first measured in patient populations with an average age of approximately 40 years. Further studies showed that MAC is highest within the first year of life (age 6–12 months) and decreases with advancing age24,25 Physiologic factors such as temperature influence MAC. For each 1°C decrease in core temperature, anesthetic requirements decrease by 5%. Other physiologic extremes that affect CNS function (hypoxia, hypercapnia, acidosis, hypotension) also decrease MAC. Whether MAC is affected by gender is controversial. Elderly Japanese women require 26% less xenon than do elderly Japanese men. In young men and women, however, MAC for desflurane does not significantly differ.26 MAC is reduced in the parturient.27 Increases in either progesterone or endogenous opiates (endorphins) during pregnancy have been proposed to account for increased anesthetic sensitivity, but these theories have not been substantiated by experiments. Pharmacogenomic factors play a role in determining MAC. Mice of varying genomic backgrounds are differentially susceptible to volatile anesthetics such as halothane, isoflurane, and sevoflurane.28 In humans, natural redheads have a significantly higher desflurane MAC than do other patients (Fig. 37–15).29 Ninety percent of the

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Desflurane MAC (%)

7

6

5

4 Dark hair

Red hair

FIGURE 37–15. Minimum alveolar concentration (MAC) values are increased in natural redheads. On average, redheads require about 20% higher alveolar concentrations of desflurane to prevent movement. Anesthetic requirements for individuals are represented by circles; means are represented by squares; bars indicate 95% confidence intervals. (From Liem et al.29 with permission.)

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redheads tested had mutations reducing expression of the melanocortin-1 receptor gene. Genetically altered (knock-out) mice lacking the melanocortin-1 receptor gene also display a modest increase in MAC for desflurane, isoflurane, sevoflurane, and halothane.30 Pharmacologic factors alter MAC. The addition of 70% N2O reduces the anesthetic requirements of other inhaled agents by 55–70% (Table 37–2). MAC is an additive phenomenon when two or more inhaled agents are combined.31 Adjunct opiate or benzodiazepine administration reduces MAC. Acute alcohol intoxication reduces MAC, whereas chronic intake of alcohol or sedatives can increase resistance to anesthetics, a phenomenon known as cross-tolerance.32 MAC reflects the effects of inhaled anesthetics in the spinal cord. In animal models, MAC has been shown to be primarily dependent on anesthetic effects on the spinal cord and not on the brain.33,34 Anesthetic-induced immobility is likely due to suppression of spinal motor neuron function, observed as a diminished Hoffmann reflex (H-reflex) and F-wave amplitudes.35,36 Suppression of movement and H-reflex amplitude by sevoflurane follow similar dose–response relationships in humans.37

Minimum Alveolar Concentration–Awake Minimum alveolar concentration–awake (MAC–awake) is the concentration of inhaled anesthetic that inhibits appropriate

responses to spoken commands in half of patients.24 MAC–awake has been measured both during induction of anesthesia (loss of response) and during emergence from anesthesia (recovery of response). The ratio of MAC–awake to MAC is not uniform for all inhaled agents. It is fairly constant for the halogenated volatiles (≈0.35 × MAC) and significantly higher for N2O,38 which likely reflects differing mechanisms of action (see Chapter 36). Functional recovery from anesthesia is determined by MAC–awake for the specific agent as well as by its elimination kinetics. Therefore, the time needed to wake up after an anesthetic, especially a long one, depends on what concentration of anesthetic was inhaled relative to its MAC–awake. If the inhaled concentration was 2 × MAC– awake, then only a 50% reduction in Palv will be needed before the patient awakens, which usually is rapidly achieved for most agents. If higher concentrations were inhaled, then recovery may be more than proportionately slowed because the slower phases of agent elimination will have a more dominant effect (see Elimination of Inhaled Anesthetics via Ventilation above). Like MAC, MAC–awake is reduced in the elderly, by hypothermia, and by the presence of other drugs with hypnotic activity (ethanol, benzodiazepines, anticonvulsants, antidepressants).24 MAC–awake also is reduced by neuraxial blockade (spinal or epidural), despite intact cranial nerve function.39–42 This effect is believed to be due to diminished ascending signals from the spinal cord, which stimulate cortical arousal via the brainstem. MAC–awake is decreased by high doses of opiates, but this effect is smaller than the reduction of MAC.43 MAC–awake (hypnosis) is associated with volatile anesthetic effects on the cerebral cortex, γ-range (40-Hz) signals from different cortical regions become desynchronized during the transition from conscious to unconscious states.44 Synchrony among widespread cortical networks is believed to be associated with higher cognitive function, and its interruption may account for loss of consciousness.45 Loss of “functional connectivity” among different cortical networks during anesthesia has been demonstrated by functional brain imaging studies.46,47 Low concentrations of inhaled anesthetics block memory more than aware-

ness.38 When inhaling agents at MAC– awake, only a small fraction of “aware” experimental subjects (those responding to spoken commands) can recall events.48 Amnesia is likely due to effects on the limbic network, including the amygdala and hippocampus. Lesions in the basolateral amygdala produce resistance to the amnestic effects of sevoflurane in animals.49 Volatile anesthetics both attenuate hippocampal activity and inhibit long-term potentiation of hippocampal synapses that is associated with memory formation.50,51

Minimum Alveolar Concentration for Blockade of Autonomic Responses Minimum alveolar concentration for blockade of autonomic responses (MAC– BAR) is the alveolar anesthetic concentration that suppresses cardiovascular responses to surgical incision in half of patients.52 MAC–BAR typically is greater than MAC. For example, MAC–BAR for desflurane is 1.66 × MAC.52 Like MAC and MAC–awake, MAC–BAR is reduced by opiates.19

Limitations on Traditional Anesthetic Depth Measurements Stimulus–response testing usually is impractical in clinical settings. Neuromuscular blocking drugs ablate motor responses to both painful (MAC) and benign (MAC–awake) stimuli. Techniques for maintaining a motor response capability are laborious. As a result, autonomic signs such as blood pressure, heart rate, diaphoresis, tearing, and pupillary responses often are the only accessible data for assessing depth of anesthesia. These signs are valuable but unreliable guides to anesthetic depth. They also are confounded by drugs and diseases that impair cardiac and/or autonomic nervous system functions. Numerous factors affect anesthetic sensitivity (including unknown genetic factors), resulting in widely varying individual anesthetic requirements. Too little anesthetic puts patients at risk for intraoperative awareness (see Intraoperative Awareness and Recall). Conversely, deep anesthesia (>1.5 × MAC) for all patients is neither feasible nor advisable. Deep inhalational general anesthesia in patients with cardiac disease, hypovolemia, and critical illnesses predictably causes profound hypotension and organ hypoperfusion. Healthy patients may tolerate deep anesthesia, but this practice results in slow emergence


Given that the modern practice of general anesthesia frequently includes neuromuscular blockade to provide immobility, narcotics to provide analgesia, and other drugs to control autonomic activity, the essential therapeutic effects of general anesthetics are hypnosis and amnesia (ablation of awareness and memory). These effects, which are mediated in the brain, are the most difficult to assess clinically. Monitors that analyze electrical signals from the brain can provide anesthetists with more data to individualize the titration of general anesthetics to achieve these end points. A number of techniques based on electroencephalography (EEG) have been developed and used. Fourier transformation of raw EEG data enables the derivation of median power and spectral edge frequencies.55 Other EEG analyses assess bispectral phase relationships, burst suppression, and entropy. The bispectral index (BIS; Aspect Medical Systems, Natick, MA) is a proprietary algorithm based on burst suppression, near burst suppression, α-band power, and phase relationships between δ and θ waves.56 The patient state index (PSI; Physiometrix, Inc., North Billerica, MA) is based on EEG component relationships between the frontal and occipital regions.57 Entropy monitors (e.g., S/5, Instrumentarium Corp. [Datex-Ohmeda], Helsinki, Finland) analyze entropy (randomness in frequency and phase relationships) using both EEG and frontal electromyography.58 Some of these monitors are available for intraoperative use for assessing hypnosis and detecting undesired consciousness. The concentration-dependent effects of volatile anesthetics correlate with EEG indexes such as BIS and spectral entropy (Fig. 37–16).59 Auditory evoked potentials (a stimulus–response method) also have been used to assess anesthetic-induced

100

Entropy/BIS index values and BSR

Electroencephalographic Measurement of Anesthetic Depth

A

SE RE BIS BSR

90 80 70 60 50 40 30 20 10 0 00:00

05:00

10:00

15:00 20:00 Time (min)

25:00

30:00

35:00

B 6

Sevoflurane concentration (vol %)

and a high incidence of side effects. Research also suggests that excessively deep general anesthesia may accelerate the pathogenesis of neurodegenerative diseases such as Alzheimer’s dementia53 and may be associated with increased late mortality.54 The delivery of sufficient but not excessive anesthesia together with optimal surgical conditions represents a central challenge facing the anesthetist.

Cet Ceff

5

4

753

3

2

1

0 00:00

05:00

10:00

15:00

20:00

25:00

30:00

35:00

Time (min)

FIGURE 37–16. Correlation between processed electroencephalographic (EEG) parameters and volatile anesthetic concentration. A. Time course of state entropy (SE), response entropy (RE), bispectral index (BIS), and burst suppression ratio (BSR) of a single patient. Each symbol represents an EEG parameter of a 5-second epoch. B. End-tidal sevoflurane concentration (Cet) and calculated effect site concentration (Ceff) during the same time course in the same patient. (From Ellerkmann et al.59 with permission.)

unconsciousness and can be used in conjunction with other EEG parameters.60,61 Nonetheless, all of these monitors have important limitations. Further research in identifying neural and EEG correlates of consciousness may improve their utility to assess the depth of anesthesia.

INTRAOPERATIVE AWARENESS AND RECALL The variability in patient sensitivities to general anesthetics and the uncertainty in clinical assessment of anesthetic depth inevitably result in some patients receiving either supratherapeutic or subtherapeutic doses of anes-

thetic agents. Inadequate anesthesia can result in awareness and explicit recall of intraoperative events, a problem that is a subject of clinical, public, and scientific attention.62

Incidence of Awareness with Recall during General Anesthesia Large studies in both Sweden63 and the United States64 have used multiple postoperative interviews (Table 37–4) to elicit reports of intraoperative awareness. In a total of 31,360 combined patients, 40 cases of “definite” and “probable” awareness with recall were identified, an incidence of 0.13%. Assuming 30 million general anesthetics are administered, the number of patients experiencing


TABLE 37–4. Modified Brice Interview 1. What is the last thing you remember before anesthesia? 2. What is the first thing you recall after waking up? 3. Do you recall anything in between? 4. Did you have any dreams during surgery? 5. What was the worst thing about your surgery and anesthesia? Data from Brice DD, Hetherington RR, Utting JE. A simple study of awareness and dreaming during anaesthesia. Br J Anaesth 1970;42:535-42.

awareness with recall is approximately 40,000 per year in the United States.

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Patient Reports and Posttraumatic Stress Disorder after Intraoperative Awareness Spontaneous reports by patients of intraoperative awareness are rare, emphasizing the need to ask about these events using a structured interview.65 Patients report a variety of intraoperative experiences following general anesthesia. A high proportion of these experiences are vague and dreamlike, whereas others are explicit recollections of intraoperative events. Explicit recollections may include hearing conversations among operating room personnel, pain associated with intubation or surgery, and extreme anxiety, particularly in paralyzed patients. These experiences can lead to postoperative psychological problems, the most severe being posttraumatic stress disorder (PTSD). PTSD is characterized by recurrent episodes of anxiety, irritability, anger, and vigilance, often associated with flashbacks or nightmares, avoidance of cues related to the trauma, and sleep disturbances.66 The incidence of PTSD following intraoperative awareness is not known, but it is likely dependent on the length of the awareness episode and on the presence of pain, anxiety, and preexisting psychological problems. In a small study of 16 postawareness patients, more than 50% developed symptoms of PTSD requiring psychotherapy.67

Risk Factors for Awareness During General Anesthesia The factors that contribute to intraoperative awareness include the use of mus-

FIGURE 37–17. Causes and consequences of awareness during anesthesia. (From Ghoneim 68 with permission.)

cle relaxants, patient resistance to anesthetics, surgical situations where “light” anesthesia typically is used, and errors by the anesthesia care team (Fig. 37–17).68 Awareness with recall has been reported in patients who were anesthetized without muscle relaxants, but these cases are rarer than in patients in whom muscle relaxants were given.69 Furthermore, severe psychological problems seem to develop primarily in patients who experience “awake paralysis” with anxiety and pain.70 Patients receiving chronic therapy with sedatives, opiates, and some anticonvulsants can develop tolerance (resistance) to anesthetic drugs and require higher

than normal anesthetic doses. Pharmacogenomic factors are likely to play a role, and patients with either a personal or a family history of awareness during general anesthesia may be at increased risk. Surgical procedures associated with high incidences of intraoperative awareness include major trauma, thoracoabdominal, and cardiac surgery. In these settings, hemodynamic instability often precludes the use of sufficient anesthetic agent concentrations to block awareness, resulting in reported incidences of awareness ranging from 1–40%.71,72 Caesarean section under general anesthesia, where a “light” anesthetic is provided to reduce depression


of the newborn, also is associated with a high incidence of awareness (0.4%).73 Inadequate dosing, misuse of equipment, and distraction of the care team can lead to patient awareness. Many cases of awareness appear to occur during prolonged attempts at airway intubation, when the hypnotic effect of intravenous induction agents wears off before muscle relaxants. Other reports have described awareness when vaporizers were empty or when drug pumps were not delivering proper doses of hypnotic agents. Reviews of awareness during general anesthesia incidents report that most cases were preventable.74

EEG Monitoring for Intraoperative Awareness To date, use of one EEG-based monitoring technique (BIS) has been evaluated for its ability to reduce the incidence of awareness. In a follow-up to Sandin et al.,63 Ekman et al.75 interviewed 4945 patients who received BIS-guided general anesthesia with intubation and/or muscle relaxants. Two cases of awareness (0.04%) were found, an incidence 80% below that of the historical control group. Myles et al.76 conducted a prospective, randomized, double-blinded, multicenter trial of 2463 patients at high risk for awareness with recall, who were assigned to either a standard care or a BIS-guided anesthesia group. Postoperative interviews identified two patients (0.16%) who experienced awareness with recall in the BISguided group and 11 (0.9%) in the highrisk control group. Of note, use of the BIS monitor in this study did not reduce the total number of reports of intraoperative experiences in the subjects tested (including reports judged as “possible awareness” or “no awareness”) but only those with “confirmed” awareness with recall. A number of confounding factors can affect the BIS, resulting in the possibility of reassuring monitor values with concomitant awareness. These factors include electrical artifact from electrocautery devices, physiologic alterations such as hypoglycemia, low-voltage EEG due to genetic variation or drugs, and neurologic abnormalities such as Alzheimer’s dementia.77 A common confounding factor that can alter BIS and spectral entropy values is electromyographic (muscle) activity and its reduction with neuromuscular blockade.78,79 Furthermore, as with any monitor, ap-

propriate interpretation and response are required for efficacy. In an incidence study by Sebel et al.,64 approximately 40% of patients underwent BIS monitoring, yet this subset of patients did not have a reduced incidence of awareness reports.

Prevention and Management of Intraoperative Awareness Preventing intraoperative awareness with recall begins with recognizing and addressing known risk factors. Caregivers must be familiar with their equipment, and they must maintain and use it properly. Amnestics, such as benzodiazepines, can reduce the incidence of awareness with recall and should be considered as premedication for most patients and in intraoperative circumstances where “light” anesthesia is unavoidable. Muscle relaxants should be used judiciously to provide adequate relaxation for surgery and avoided whenever possible. N2O relaxant anesthesia should be supplemented with adequate (1.5–2 × MAC– awake) volatile anesthetics or intravenous hypnotic agents. When intubation is delayed or multiple attempts are required, consider supplementing the induction bolus with additional inhaled or intravenous agents. All patients should be routinely informed of the risk of awareness during general anesthesia. High-risk patients should be monitored using an EEG-based monitor when feasible. EEG monitoring, if used, should be performed according to manufacturer’s guidelines, and monitor values suggesting inadequate anesthesia should result in increased dosage of hypnotic agents, unless other circumstances make this inadvisable. Ideally, all patients should be interviewed in the postoperative period and asked specific questions (Table 37–4) to elicit reports of intraoperative awareness. When awareness is detected, the case should be treated like any complication that results in harm or potential harm to patients. A thorough debriefing of the patient is warranted, and the details of the patient’s experiences should be reported in the medical record. Other members of the operative team should be informed, and patient recollections should be corroborated as thoroughly as possible. The incident should be reported to the departmental Quality Assurance Committee and possibly the hospital legal counsel. A patient reporting awareness during anes-

thesia should be reassured that his/her experience is valid, and an explanation of why and how the intraoperative awareness occurred should be offered. Expressions of sympathy and regret for the patient’s suffering can help maintain a therapeutic relationship, and the patient should be offered professional psychological evaluation and therapy if he/she experiences uncomfortable emotional reactions to the experience. Maintaining contact with the patient with daily visits to his/her hospital room or phone calls can reduce malpractice risk.

SYSTEMIC ACTIONS OF INHALED ANESTHETICS In this section, we summarize both the therapeutic and toxic secondary effects of inhaled anesthetics on important physiologic systems.

Central Nervous System Cerebrovascular and Metabolic Effects The effects of anesthetics on cerebral metabolism and vascular tone are summarized in Table 37–5. Normal cerebral blood flow (CBF) is tightly autoregulated and coupled to cerebral metabolic demands. Volatile anesthetics interrupt this autoregulation by acting as direct vasodilators of the cerebral vasculature.80 Volatile anesthetics dose dependently increase middle cerebral artery blood flow velocity, with sevoflurane causing less vasodilatation than isoflurane or sevoflurane.81,82 Both K+ channels83 and neuronal nitric oxide synthase84 have been linked to these direct actions of anesthetics. Volatile anesthetics also decrease the cerebral metabolic rate (CMR) of oxygen consumption.17,80 Cerebral metabolism is decreased by halothane, isoflurane, sevoflurane, and desflurane.85 The extent to which flow and metabolism are altered depends on the choice of agent. For example, halothane may increase CBF by almost 200%, but reduce CMR by only 10%.86 In contrast, isoflurane increases CBF by approximately 20% but reduces CMR by 45%.87,88 Volatile agents also partially uncouple flow–metabolism relationships and CO2 reactivity.89,90 These agents have not been shown to increase intracranial pressure in normocapnic adults undergoing supratentorial brain tumor resection without a

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TABLE 37–5. Inhaled Anesthetic Effects on Central Nervous System Physiology Effect

Nitrous Oxide

Desflurane

Sevoflurane

Isoflurane

Halothane

Cerebral blood flow Cerebral perfusion pressure Intracranial pressure Metabolic demands CO2 reactivity

↑ ↓ ↑ ↑ ↔

↑ ↓ ↔/↑ ↓ ↔

↑ ↓ ↔/↑ ↓ ↔

↑ ↓ ↔/↑ ↓ ↔

↑ ↓ ↔/↑ ↓ ↔

preoperative midline shift.91 In children, isoflurane, sevoflurane, and desflurane all have been shown to increase intracranial pressure.92 N2O is distinguished from the potent volatile anesthetics in that it increases CBF and CMR and may increase intracranial pressure.93,94 This is partly attributable to its sympathomimetic effects.95

EEG Effects 756

Volatile anesthetics alter the cortical EEG, decreasing high-frequency (γband) activity and increasing slower frequencies. Quantitative EEG analysis demonstrates that power shifts anteriorly.44 In comparison, N2O has little effect or increases the frequency of the cortical EEG.96–98 Indeed, EEG-based monitors do not reliably detect the hypnotic effects of N2O alone or in combination with other anesthetics.99,100 Deep volatile anesthesia (1.5–2 × MAC) leads to burst suppression or isoelectric EEG patterns. Although all volatile anesthetics have been used to suppress seizures, both enflurane and sevoflurane have been reported to augment epileptic brain activity and may induce EEG patterns associated with epilepsy in normal patients.101–103 Enflurane and sevoflurane may be useful during cortical mapping for ablation of seizure foci but should otherwise be avoided in patients with seizure disorders. The effects of anesthetics that are thought to produce the state of general

anesthesia are discussed in this chapter and in more detail in Chapter 36. The long-term effects of anesthetics on cognitive function are reviewed in Chapter 87.

Cardiovascular System The effects of volatile anesthetics on the cardiovascular system are of paramount clinical importance intraoperatively, particularly in patients at risk for end-organ ischemia. They are summarized in Table 37–6.

Mean Arterial Pressure Volatile anesthetics decrease mean arterial pressure (MAP) in a dose-dependent manner by direct vascular and autonomic nervous effects.85 Volatile anesthetics reduce MAP by decreasing systemic vascular resistance, increasing vascular compliance (the change in circulatory volume with changes in pressure), and inhibiting myocardial contractility. Halothane depresses myocardial contractility more than other volatile anesthetics. Isoflurane and desflurane decrease systemic vascular resistance, although halothane, isoflurane, and sevoflurane increase arterial compliance (Table 37–7).104 Desflurane has been found to stimulate sympathetic nervous system activity (especially with rapid increases in vapor concentration), which may account for its minor effect on vascular compliance.105

N2O raises sympathetic activity and systolic blood pressure106 and thus counters the vasodilatory and hypotensive effects of coadministered volatile agents.107

Heart Rate Volatile anesthetics increase heart rate, both by a baroreceptor reflex in response to decreased arterial pressure and by a direct vagolytic effect on the heart. In dogs, desflurane increases heart rate the most, followed by sevoflurane, isoflurane, and halothane.108 Rapid increases in the alveolar concentration of desflurane are associated with increased heart rate and blood pressure (Fig. 37–18),109,110 which are attributed to stimulation of sympathetic activity.105 The minimal effect of halothane on heart rate is associated with its block of the baroreceptor reflex.111 N2O is associated with only modest transient increases in heart rate,112 which reflect its sympathetic effects and preservation of MAP.

Myocardial Contractility Volatile anesthetics cause myocardial depression, in part by inhibiting calcium ion influx in cardiac muscle.113 Halothane causes marked dose-dependent inhibition of myocardial contractility and reduces cardiac output.114,115 Isoflurane, sevoflurane, and desflurane have lesser effects on myocardial contractility. In dogs, all these anes-

TABLE 37–6. Effects of Inhaled Anesthetics on Cardiovascular Physiology Effect

Nitrous Oxide

Desflurane

Sevoflurane

Isoflurane

Halothane

Mean arterial pressure Systemic vascular resistance Heart rate Myocardial function Epinephrine-induced arrhythmia

↔/↑ ↔/↑ ↔/↑ ↓ ↑

↓ ↓ ↑ ↓ ↔

↓ ↔ ↑ ↓ ↔

↓ ↓ ↑ ↓ ↔

↓ ↔ ↔ ↓ ↑


TABLE 37–7. Inhaled Anesthetic Effects on Vascular Resistance and Compliance Comparison to Sodium Nitroprusside Effect

Desflurane

Sevoflurane

Isoflurane

Halothane

Sodium Nitroprusside

Total arterial resistance Total arterial compliance

↓ ↔

↔ ↑

↓ ↑

↔ ↑

↓ ↑

Modified from Lowe et al.104 with permission.

long the QT interval.124125 In dental outpatients, halothane produced more ventricular arrhythmias than did isoflurane.126,127 In pediatric dental outpatients receiving halothane anesthesia, 48% had ventricular dysrhythmias compared to 8–16% of those inhaling sevoflurane.128 Furthermore, sevoflurane-induced arrhythmias were primarily single supraventricular ectopic beats, although ventricular tachycardia was observed in 12% of patients receiving halothane. N2O may induce atrioventricular junctional rhythms129 and can lower the threshold for epinephrine-induced arrhythmias in conjunction with halothane.130

thetics depress myocardial contractility, delay cardiac chamber relaxation, reduce chamber stiffness, and impair left atrial–left ventricular coupling.116,117 N2O administration also decreases intracellular calcium levels and depresses myocardial contractility.118,119 Thus, although N2O minimally affects blood pressure and heart rate, it has negative inotropic effects similar to those of potent volatile agents.

Cardiac Rhythm and Conduction

Isoflurane is a coronary vasodilator and thus can potentially create “coro-

Volatile anesthetics depress respiration through both central medullary and peripheral muscular effects. In general, inhaled anesthetics decrease tidal volume and increase respiratory rate. Halothane, isoflurane, desflurane,

Begin 1% S or 3% D

†

0

*

*

*

*

*

*

3.2 1.0

4.6 1.4

5.8 1.5

7.3 1.8

7.6 2.0

7.9 2.1

Heart rate, h/min

Sevoflurane (S)

25

Desflurane (D)

90

70

*

50

115

*

*

*

*

*

7 % Exp des 0.2 % Exp sevo 0.2

1.9 0.5

95

75

† 55

l e ofo ak Aw Prop

0.5

1.5

2.5

*

*

3.5

4.5

7.5

Min after vaporizer initiated

8.5

9.5

Central venous pressure, mm Hg

Mean arterial pressure, mm Hg

Ventilation

Coronary Artery Perfusion

Begin 3% S or 9% D Begin 2% S or 6% D

75 50

Respiratory System

110

100 bursts 100 cardiac cycles

Muscle sympathetic nerve activity,

Volatile anesthetics affect the function of cardiac ion channels, increasing the risk of arrhythmias.120 Halothane sensitizes the heart to the arrhythmogenic effects of epinephrine,121 although isoflurane, desflurane, and sevoflurane do not.122,123 Halothane, isoflurane, desflurane, and sevoflurane all pro-

nary steal,” a diversion of blood flow away from fixed stenotic lesions.131 The clinical significance of this phenomenon appears to be mostly theoretical. Isoflurane has been found to be safe in patients with coronary artery disease as long as adequate perfusion is maintained. Isoflurane also provides beneficial effects via ischemic preconditioning.132 Desflurane and sevoflurane do not cause coronary steal.133,134

6

†

5 4 3 2

l e ofo ak Aw Prop

0.5

1.5

2.5

3.5

4.5

7.5

8.5

9.5

Min after vaporizer initiated

FIGURE 37–18. Effects of desflurane and sevoflurane on basic cardiovascular parameters in human subjects. Consecutive measurements of neurocirculatory variables (mean ± SEM) during induction of anesthesia with propofol and subsequent mask administration of sevoflurane or desflurane for a 10-minute period. The subsequent administration of sevoflurane did not alter heart rate or sympathetic nerve activity but led to a progressive decline in mean arterial pressure. In contrast, desflurane resulted in significant increases in neurocirculatory variables that persisted throughout the 10-minute mask administration period. (From Ebert et al.110 with permission.)

757


758

and sevoflurane dose dependently reduce tidal volume. The concomitant increase in respiratory rate is more pronounced with halothane, desflurane, and sevoflurane than with isoflurane.133,135–137 Compensatory tachypnea maintains minute ventilation with desflurane up to alveolar concentrations of 1.6 × MAC. Nonetheless, alveolar ventilation is reduced by all volatile anesthetics, resulting in an increased PaCO2. N2O also causes tachypnea and decreased tidal volume, but alone it causes minimal changes in PaCO2. N2O depression of ventilation is additive when given in combination with other inhalational agents.138 Factors that contribute to hypoxia and hypercarbia during inhalational anesthesia include hypoventilation, atelectasis, airway closure, decreased functional residual capacity, and ventilation– perfusion (V ˙ /Q) ˙ mismatch.139 Volatile anesthetics blunt hypoxic and hypercarbic respiratory drive, increasing the risk of severe hypoxia and hypercarbia in spontaneously breathing patients.140– 142 Depression of hypoxic and hypercarbic ventilatory drives occurs even at subanesthetic doses. N2O blunts the respiratory drive to hypoxia and hypoventilation, but its clinical effects are minimal because of its low potency.143 After terminating delivery, rapid elimination of N2O from blood dilutes alveolar gases and, if supplemental oxygen is not supplied, can lead to diffusion hypoxia.144,145

Hypoxic Pulmonary Vasoconstriction Hypoxic pulmonary vasoconstriction (HPV) is a pulmonary vascular mechanism that diverts blood flow away from poorly ventilated areas of the lung, minimizing V ˙ /Q˙ mismatch. The mechanisms underlying HPV are not fully understood, but cyclooxygenase,

calcium channels, and potassium channels appear to be involved.146 N2O has been shown in vivo to inhibit HPV.147 In isolated lung models, halothane, isoflurane, sevoflurane, desflurane, and N2O all dose dependently inhibit HPV.148–150 In many animal studies, however, clinical concentrations of halothane, isoflurane, sevoflurane, and desflurane have not been found to inhibit HPV.151–154 In a few studies of chronically instrumented dogs, isoflurane was found to attenuate HPV.155 The conflicting data regarding isoflurane effects on HPV may be due to different flow conditions in the pulmonary vasculature during different experiments.

Bronchial Tone Most volatile anesthetics, including halothane, enflurane, isoflurane, and sevoflurane, are bronchodilators that decrease respiratory resistance and increase dynamic compliance (Table 37–8).156 At equi-MAC concentrations, respiratory resistance is reduced by sevoflurane > halothane > isoflurane.157 In contrast to the other volatile anesthetics, desflurane is associated with either no bronchodilatory effects or with bronchoconstrictor effects at higher concentrations.158 Inhalational induction with desflurane is associated with coughing and increased risk of laryngospasm, which likely is due to its pungency. Sevoflurane causes the least amount of subjective airway irritation and is well tolerated during inhalational induction.159 N2O has no effect on respiratory resistance.157

Hepatic and Renal Systems Liver Volatile anesthetics reduce overall hepatic perfusion by altering portal venous and/or hepatic arterial inflows. Most agents decrease portal

venous flow. Isoflurane has the least overall effect on hepatic perfusion because of compensatory increases in hepatic artery flow.160 In contrast, halothane causes hepatic artery vasoconstriction and decreases overall hepatic blood flow,161 hepatic oxygen delivery, and hepatic vein blood oxygen saturation.162 N2O causes minimal circulatory effects on the liver. Transient modest increases in liver enzymes are not uncommon following exposure to volatile anesthetics (halothane, desflurane, sevoflurane, and isoflurane). This effect is independent of surgical intervention and almost always is clinically insignificant.163,164 The increase in liver enzyme levels after halothane administration may be due to anaerobic reductive metabolism that generates free radicals.165 More severe hepatic injury (halothane hepatitis) is described in the section on Breakdown of Inhaled Anesthetics and Toxicity of Byproducts.

Kidney Volatile anesthetic agents cause dosedependent decreases in renal blood flow, glomerular filtration rate, and urine output, which can be minimized with preoperative hydration.166–168 Autoregulation of renal blood flow is preserved during halothane anesthesia.167 Decreases in renal blood flow during inhalational anesthesia reflect a reduction in effective circulating volume secondary to increased vascular capacitance. Anesthetics do not directly stimulate antidiuretic hormone (ADH) release, but diminished urine production due to ADH is associated with surgical stress.169 N2O causes minimal effects on renal blood flow and function. Nephrotoxicity can be associated with breakdown of volatile anesthetics (see Breakdown of Inhaled Anesthetics and Toxicity of Byproducts below).

TABLE 37–8. Effects of Inhaled Anesthetics on Respiratory Physiology Effect

Nitrous Oxide

Desflurane

Sevoflurane

Isoflurane

Halothane

Tidal volume Respiratory rate Hypoxic hypercarbic responses Hypoxic pulmonary vasoconstriction (in vitro) Airway resistance

↓ ↑ ↓

↓ ↑ ↓

↓ ↑ ↓

↓ ↑ ↓

↓ ↑ ↓

↓

↓

↓

↓

↓

↔

↑

↓

↓

↓


Other Systemic and Adverse Effects Muscular System Volatile anesthetics potentiate neuromuscular blockade via direct effects on the neuromuscular junction.170 The muscle relaxant effect of volatile agents is stronger than that of intravenous anesthetics; N2O has no relaxant action. In animal models of isolated diaphragmatic muscle, enflurane and sevoflurane enhance fatigability at high concentrations.171,172 This may be mediated in part by cyclic adenosine monophosphate, as administration of the phosphodiesterase inhibitor olprinone attenuates the effects of volatile anesthetics on diaphragmatic muscular fatigue.

Malignant Hyperthermia Malignant hyperthermia is a life-threatening clinical myopathy triggered by all potent volatile anesthetics and/or succinylcholine. It is a pharmacogenetic disorder associated with autosomal dominant transmission of genes encoding mutant forms of the skeletal muscle calcium release channel (ryanodine receptor protein or RyR1).173 Upon exposure to the triggering drugs, patients with malignant hyperthermia develop an exaggerated increase of intracellular calcium resulting in sustained skeletal muscular contracture, which is not affected by neuromuscular blocking agents. Sustained contracture produces a hypermetabolic state, leading to increased CO2 production and eventually hyperthermia. This condition is fatal unless treated aggressively and rapidly with intravenous dantrolene.

Methionine Synthase Inhibition by N2O N2O irreversibly oxidizes the cobalt atom of vitamin B12, which inhibits the cobalamin-dependent enzyme methionine synthase. This pathway is essential for homocysteine breakdown, nerve myelination, methyl substitutions of neurotransmitters, and DNA synthesis. Most patients are unaffected by temporary inactivation of vitamin B12 after N2O. Nonetheless, this reaction can result in pathology in patients with poor nutrition, preexisting vitamin B12 deficiency, or other metabolic diseases that converge on the same metabolic pathways. N2O exposure has led to “anesthesia paresthetica,” which is characterized by paresthesias, ataxias, and poor manual

dexterity.174 In one infant with a preexisting deficiency of 5,10-methylenetetrahydrofolate reductase, another enzyme in the methionine synthetic pathway, it was thought that superimposed exposure to N2O resulted in neuronal damage, status epilepticus, and death.175

Endocrine Function Halothane and enflurane impair glucose tolerance in animal models by reducing both insulin secretion and receptor sensitivity. Isoflurane has been shown to increase endogenous glucose production and decrease glucose utilization.85,176 The selection of anesthetic may also play a role in modulating stress responses to surgery. In a study of 20 women requiring laparoscopic surgery for ovarian cystectomy, sevoflurane was associated with less increase of cortisol and adrenocorticotropic hormone levels compared to isoflurane.177

Immune Function Potent inhalational anesthetics can alter immune cell functions in various ways, which in turn may affect recovery from surgery or tumor viability. Halothane depresses the neutrophil oxidative response to inflammatory mediators of infection, whereas desflurane, sevoflurane, and isoflurane have smaller effects.178 Sevoflurane impairs transcription factors in human lymphocytes, which may reduce the inflammatory response.179 Volatile anesthetics can induce apoptosis in human T-cells in vitro180 and may affect cytokine function.181

Ischemic Preconditioning Volatile anesthetics induce cellular responses that protect against ischemia and biochemical stress mediators. For example, sevoflurane decreases markers of myocardial and renal damage after coronary artery bypass grafting.182 Animal models of renal ischemic injury demonstrate differential preconditioning, with desflurane demonstrating less protective effects against tubular necrosis than sevoflurane, isoflurane, or halothane.183 Volatile anesthetics can protect against neural ischemia in animal models, through pathways involving both nitric oxide metabolism184 and potassium channels.185

and isoflurane produce genotoxicity in proliferating blood lymphocytes in vitro, whereas sevoflurane does not appear to be cytotoxic in an animal model.186 The potential for anesthetic-induced teratogenicity has been studied. Prolonged N2O exposure is teratogenic in a number of embryonic animal models.187 N2O inhibition of B12-dependent DNA synthesis is the likely cause. Because of potential genetic damage after chronic exposure to inhaled anesthetics, it is currently recommended that operating room air contain less than 25 parts per million (ppm) of N2O and less than 2 ppm of halogenated anesthetics. Under these conditions, there is little evidence of significant risk from workplace exposure to inhaled anesthetics.188 Furthermore, approximately 75,000 pregnant women undergo nonobstetric surgery each year. Although there was once controversy over the effects of surgery and anesthesia in this population, volatile anesthesia appears to be safe for both the parturient and the fetus.189

BREAKDOWN OF INHALED ANESTHETICS AND TOXICITY OF BYPRODUCTS Inhaled anesthetics represent a class of drugs that are eliminated largely via nonmetabolic pathways—for the most part, they leave the body as they entered, unaltered and via ventilatory gas exchange. Undesirable effects directly associated with anesthetics are summarized above (see Systemic Actions of Inhaled Anesthetics), whereas others are caused indirectly by chemical decomposition of inhaled anesthetics into toxic byproducts. The breakdown of volatile anesthetics into potentially harmful chemicals can occur in the presence of CO2 adsorbents or via enzymatic biotransformation in the body. In general, greater breakdown of inhaled anesthetics leads to greater toxicity.

Nonmetabolic Decomposition of Inhaled Anesthetics Whereas inhaled anesthetics are chemically stable under normal storage conditions (including within vaporizers), decomposition can occur under certain environmental conditions.

Genotoxicity and Teratogenicity

Sevoflurane Breakdown and Compound A

Halogenated hydrocarbons and ethers can cause DNA damage. Halothane

When sevoflurane contacts CO2 adsorbents containing a strong base (Bara-

759


760

lyme and soda lime), chemical decomposition occurs, releasing volatile breakdown products.190 The major degradation product, compound A [fluoromethyl-2–2-difluoro-1-(trifluoromethyl) vinyl ether], was shown to cause renal injury and death in rats when inhaled at high levels.191 Renal injury is both dose and time dependent, with a threshold for detectable injury in laboratory animals of 150–300 ppm hours. Nonetheless, in human volunteer and clinical studies, blood urea nitrogen and creatinine levels remain unchanged after exposures that sometimes exceed 300 ppm hours. It is thought that humans sustain less renal injury than rats after compound A exposure because of lower levels of renal cysteine conjugated β-lyase enzyme activity.192,193 Special laboratory markers for subtle renal tubular damage in humans are elevated after 300 ppm hours of compound A exposure, and levels normalize within a few days.194 In clinical settings, the inhaled concentration of compound A is proportional to the sevoflurane concentration and inversely related to FGFs. Low gas flows allow compound A to accumulate in the breathing circuit, unlike high gas flows which wash out compound A with waste gases. At FGF ≥ 2 L/min, concentrations of compound A are low enough that the conservative exposure threshold of 150 ppm hours is unlikely to be reached. Sevoflurane package labeling guidelines should be heeded. There is little evidence that sevoflurane is harmful to patients with preexisting renal disease, but other anesthetic agents are more prudent choices.

Volatile Anesthetic Breakdown and Desiccated CO2 Adsorbents All the halogenated volatile anesthetics degrade in the presence of dry alkaline CO2 adsorbents in rebreathing circuits (only sevoflurane breaks down in the presence of moist adsorbent). Decomposition in the presence of dry CO2 adsorbents releases carbon monoxide (CO), formaldehyde, methanol, and heat. These exothermic reactions have resulted in the ignition of breathing circuit components195 and in acute respiratory distress syndrome in patients.196 They also can lead to significant carboxyhemoglobin levels in patients.197 These problems are preventable and arise only when the CO2 adsorbent is desiccated (e.g., if flushed

overnight with high-flow oxygen) and depend on the type and quantity of strong base in the adsorbent [in descending order of reactivity: KOH > NaOH >> Ba(OH)2]. Sevoflurane releases more heat than does desflurane or isoflurane,198 whereas CO production is highest with desflurane > enflurane > isoflurane > sevoflurane > halothane.199,200

Photochemical Breakdown of Anesthetic Waste Gases Waste gases scavenged from anesthesia machines enter the atmosphere, where they are exposed to solar radiation and other gases.201,202 Ultraviolet light catalyzes the reaction between N2O and O2, producing the free radical nitric oxide, which in turn destroys atmospheric ozone. Waste N2O from medical uses is less than 2% of the total added to the atmosphere (the majority results from agriculture and combustion of fossil fuels). All halogenated volatile gases break down when exposed to ultraviolet light to form halogen free radicals, which can deplete atmospheric ozone. Volatile anesthetic waste gases represent only a small portion of total atmospheric chlorofluorocarbons.

Biotransformation of Inhaled Anesthetics Hepatic Drug Metabolism In the liver, enzymes can transform volatile anesthetics by oxidation, reduction, and conjugation. These reactions convert hydrophobic substrates into more hydrophilic metabolites that are excreted via the kidneys. Of these, the most important pathways for volatile anesthetics are oxidative, and the enzymes responsible are various members of the large cytochrome P450 (CYP) family. Neonates lack some enzymes that are present in older humans, and diverse other factors, such as genetic variation, can alter individual metabolic activities. Intrinsic liver disease or hepatic congestion due to heart failure may result in diminished enzymatic capacity, and intrahepatic blood flow shunting may reduce the efficiency with which drugs are enzymatically cleared. CYP enzyme activities may be inhibited by drugs such as cimetidine and amiodarone, or they may be enhanced by prolonged exposure to “inducers” such as phenobarbital, phenytoin, and a

wide range of other compounds, including inhaled anesthetics.

Halothane Hepatitis Among the currently available agents, halothane undergoes the most hepatic metabolism (20–25%) and is associated most frequently with significant toxicity. Usually, less than 1% of halothane metabolism is reductive. Oxidative metabolism of halothane by CYP enzymes generates trifluoracetic acid, bromide, and an intermediate metabolite, trifluoroacetyl chloride, which can covalently modify proteins. Acetylation primarily occurs within the liver, and these modified proteins can act as neoantigens that stimulate the immune system to attack hepatocytes, resulting in fulminant hepatic necrosis. “Halothane hepatitis” occurs in 1:6000 to 1:35,000 adults following halothane anesthesia and is fatal in 50–75% of these cases.203 Genetic factors likely are involved, and females are affected about twice as frequently as males. Many cases of hepatic necrosis occur following multiple exposures to halothane, consistent with an amplified secondary immune response. Halothane hepatitis has been reported in pediatric patients, but its incidence in children is 10–20 times lower than in adults. Other inhaled anesthetics are metabolized by CYP enzymes to reactive acetyl intermediates that can modify hepatic proteins. Rare cases of fulminant hepatic injury following enflurane, isoflurane, and desflurane have been reported, and the incidence for each compound is related to the relative degree of metabolism (2.5%, 0.2%, and 0.02%, respectively).204

Fluoride Nephrotoxicity Metabolism of some inhaled anesthetics releases inorganic fluoride ions (F–), which can cause polyuric renal failure and increased mortality. Clinical findings include hypernatremia, hyperosmolarity, and increased blood urea nitrogen and creatinine. This problem is primarily associated with methoxyflurane, a very blood- and tissue-soluble anesthetic that is no longer used. Metabolic release of fluoride is clearly linked to methoxyflurane nephrotoxicity by dose-relationships and experiments in animals. Renal injury after methoxyflurane is rare at fluoride blood levels below 50 µmol/L, whereas moderate injury is seen at 50–80 µmol/L


and severe injury at higher levels. In rats, clinical and pathologic changes similar to those seen in human fluoride nephrotoxicity can be produced by intravenous administration of fluoride at similar levels. Other fluorinated anesthetics, particularly enflurane and sevoflurane, release readily detectable amounts of fluoride when metabolized in the liver. However, nephrotoxicity is rarely associated with these drugs. Serum fluoride levels during and after enflurane anesthesia usually are below 50 µmol/L, whereas levels during and after sevoflurane anesthesia often peak above 50 µmol/L. However, sevoflurane is much less soluble in blood and tissue than is methoxyflurane. Sevoflurane is eliminated rapidly at the end of anesthesia, which halts fluoride production. In contrast, methoxyflurane is retained in tissues, and fluoride concentrations continue to rise after delivery is halted, reaching peak levels 2–3 days after anesthesia (for review, see Anders205). Methoxyflurane, more than sevoflurane, is decomposed to fluoride within the kidney, so intrarenal fluoride levels are higher than those detected in blood samples.206

INERT GASES: FUTURE ANESTHETICS? Although the safety and speed of inhaled anesthetics have improved greatly since the 19th century, all of the currently used agents are far from ideal because of their toxic effects on various physiologic systems (Table 37–9). The inert gas xenon was shown to produce anesthesia in 1951, and further study has revealed a pharmacokinetic and pharmacodynamic profile that approaches the ideal for an inhalational anesthetic.207,208 Xenon is an odorless, tasteless, nonflammable, nonexplosive gas. Like other noble gases (helium, neon, argon, krypton, and radon), it is entirely chemically inert, undergoes no metabolic transformation, and has no direct negative environmental effects. Xenon does not cause airway irritation, and its blood/gas partition coefficient is 0.14, which makes inhalation induction significantly faster than with N2O or desflurane. Xenon, like N2O, produces minimal cardiovascular or respiratory depression. It produces no direct systemic organ toxicity, and there is evidence that xenon has neuroprotective effects,209 including attenuation of cog-

TABLE 37–9. Advantages and Disadvantages of Inhaled Anesthetics Anesthetic

Advantages

Disadvantages

Nitrous oxide

No odor, taste, pungency Rapid uptake and elimination Analgesic effect Minimal cardiovascular depression Minimal biotransformation Inexpensive Nonpungent

Airspace expansion ↑ Nausea/vomiting Inhibits methionine synthase Environmental pollutant Supports combustion

Halothane

Enflurane

Good muscle relaxation Stable heart rate

Isoflurane

Good muscle relaxation Maintains cardiac output Low biotransformation Inexpensive Rapid uptake and elimination Very low biotransformation

Desflurane

Sevoflurane

Myocardial depression Arrhythmias Halothane hepatitis risk Very slow uptake and elimination Pungent Slow uptake and elimination Epileptogenic Pungent Slow uptake and elimination

Rapid uptake and elimination Nonpungent

Xenon

No odor, taste, pungency Very rapid uptake and elimination Analgesic effect Minimal cardiovascular depression No toxic metabolites Environmentally safe Inhibits combustion

nitive dysfunction after cardiopulmonary bypass in an animal model.210 Because MAC for xenon is approximately 0.7 atm, its use as a sole anesthetic agent is possible. One of its few negative physiologic effects is, like N2O, airspace expansion. Xenon has analgesic effects, which likely are due to inhibition of N-methyl-D-aspartate (NMDA)-sensitive glutamate receptors. Unlike ketamine, an intravenous anesthetic that also acts on NMDA receptors, xenon is not associated with emergence delirium. The main barrier to routine use of xenon is its limited worldwide supply and the prohibitive cost of isolating and concentrating it. Xenon cannot be

Airway irritant Sympathetic stimulant Requires electric vaporizer Breakdown to carbon monoxide in circuit Expensive Breakdown to compound A in circuit Potentially nephrotoxic Expensive Limited worldwide supply Expensive Airspace expansion

synthesized, so these factors are unlikely to change unless new sources are discovered. Energy expended in collecting xenon creates secondary negative environmental impacts. Methods for conserving (closed-circuit delivery) and reclaiming xenon from waste gases may make xenon more economically viable in the future.

KEY REFERENCES 1. Campagna JA, Miller KW, Forman SA. Mechanisms of actions of inhaled anesthetics. N Engl J Med 2003;348:2110–2124.

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2. Eger EI. Uptake of inhaled anesthetics: the alveolar to inspired anesthetic difference. In: Eger EI, ed. Anesthetic Uptake and Action. Baltimore: Williams & Wilkins, 1974: 77–96. 3. Baum JA. Low Flow Anaesthesia: The Theory and Practice of Low Flow, Minimal Flow and Closed System Anaesthesia. 2nd ed. Boston: Butterworth-heinemann, 2001. 4. Stoelting RK, Eger EI 2nd. An additional explanation for the second gas effect: a concentrating effect. Anesthesiology 1969;30:273– 277. 5. Eger EI 2nd. Age, minimum alveolar anesthetic concentration, and minimum alveolar anesthetic concentration-awake. Anesth Analg 2001;93:947–953.

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141. Knill RL, Gelb AW. Ventilatory responses to hypoxia and hypercapnia during halothane sedation and anesthesia in man. Anesthesiology 1978;49:244–251. 142. Groeben H, Meier S, Tankersley CG, et al. Influence of volatile anaesthetics on hypercapnoeic ventilatory responses in mice with blunted respiratory drive. Br J Anaesth 2004;92:697–703.

174. Kinsella LJ, Green R. “Anesthesia paresthetica”: nitrous oxide-induced cobalamin deficiency. Neurology 1995;45:1608– 1610. 175. Selzer RR, Rosenblatt DS, Laxova R, Hogan K. Adverse effect of nitrous oxide in a child with 5,10-methylenetetrahydro-

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folate reductase deficiency. N Engl J Med 2003;349:45–50. 176. Geisser W, Schreiber M, Hofbauer H, et al. Sevoflurane versus isoflurane-anaesthesia for lower abdominal surgery. Effects on perioperative glucose metabolism. Acta Anaesthesiol Scand 2003;47:174–179. 177. Marana E, Annetta MG, Meo F, et al. Sevoflurane improves the neuroendocrine stress response during laparoscopic pelvic surgery. Can J Anaesth 2003;50:348–354. 178. Frohlich D, Rothe G, Schwall B, et al. Effects of volatile anaesthetics on human neutrophil oxidative response to the bacterial peptide FMLP. Br J Anaesth 1997;78:718–723. 179. Loop T, Scheiermann P, Doviakue D, et al. Sevoflurane inhibits phorbol-myristateacetate-induced activator protein-1 activation in human t lymphocytes in vitro: potential role of the p38-stress kinase pathway. Anesthesiology 2004;101:710–721. 180. Loop T, Dovi-Akue D, Frick M, et al. Volatile anesthetics induce caspase-dependent, mitochondria-mediated apoptosis in human T lymphocytes in vitro. Anesthesiology 2005;102:1147–1157.

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181. Giraud O, Molliex S, Rolland C, et al. Halogenated anesthetics reduce interleukin-1beta-induced cytokine secretion by rat alveolar type II cells in primary culture. Anesthesiology 2003;98:74–81. 182. Julier K, da Silva R, Garcia C, et al. Preconditioning by sevoflurane decreases biochemical markers for myocardial and renal dysfunction in coronary artery bypass graft surgery: a double-blinded, placebo-controlled, multicenter study. Anesthesiology 2003;98:1315–1327. 183. Lee HT, Ota-Setlik A, Fu Y, et al. Differential protective effects of volatile anesthetics against renal ischemia-reperfusion injury in vivo. Anesthesiology 2004; 101:1313–1324. 184. Kapinya KJ, Lowl D, Futterer C, et al. Tolerance against ischemic neuronal injury can be induced by volatile anesthetics and is inducible no synthase dependent. Stroke 2002;33:1889–1898. 185. Xiong L, Zheng Y, Wu M, et al. Preconditioning with isoflurane produces dosedependent neuroprotection via activation of adenosine triphosphate-regulated potassium channels after focal cerebral ischemia in rats. Anesth Analg 2003;96:233–237. 186. Szyfter K, Szulc R, Mikstacki A, et al. Genotoxicity of inhalation anaesthetics:

DNA lesions generated by sevoflurane in vitro and in vivo. J Appl Genet 2004;45: 369–374. 187. Fujinaga M, Mazze RI, Baden JM, et al. Rat whole embryo culture: an in vitro model for testing nitrous oxide teratogenicity. Anesthesiology 1988;69:401–404. 188. Burm AG. Occupational hazards of inhalational anaesthetics. Best Pract Res Clin Anaesthesiol 2003;17:147–161. 189. Kuczkowski KM. Nonobstetric surgery during pregnancy: what are the risks of anesthesia? Obstet Gynecol Surv 2004;59:52–56. 190. Fang ZX, Kandel L, Laster MJ, et al. Factors affecting production of compound a from the interaction of sevoflurane with Baralyme and soda lime. Anesth Analg 1996;82:775–781. 191. Gonsowski CT, Laster MJ, Eger EI 2nd, et al. Toxicity of compound a in rats. Effect of a 3-hour administration. Anesthesiology 1994;80:556–565. 192. Iyer RA, Anders MW. Cysteine conjugate beta-lyase-dependent biotransformation of the cysteine s-conjugates of the sevoflurane degradation product compound a in human, nonhuman primate, and rat kidney cytosol and mitochondria. Anesthesiology 1996;85:1454–1461. 193. Sheffels P, Schroeder JL, Altuntas TG, et al. Role of cytochrome P4503A in cysteine S-conjugates sulfoxidation and the nephrotoxicity of the sevoflurane degradation product fluoromethyl-2,2-difluoro-1-(trifluoromethyl)vinyl ether (compound A) in rats. Chem Res Toxicol 2004;17:1177–1189. 194. Eger EI 2nd, Koblin DD, Bowland T, et al. Nephrotoxicity of sevoflurane versus desflurane anesthesia in volunteers. Anesth Analg 1997;84:160–168.

199. Wissing H, Kuhn I, Warnken U, et al. Carbon monoxide production from desflurane, enflurane, halothane, isoflurane, and sevoflurane with dry soda lime. Anesthesiology 2001;95:1205–1212. 200. Keijzer C, Perez RS, De Lange JJ. Carbon monoxide production from five volatile anesthetics in dry sodalime in a patient model: halothane and sevoflurane do produce carbon monoxide; temperature is a poor predictor of carbon monoxide production. BMC Anesthesiol 2005;5:6. 201. Logan M, Farmer JG. Anaesthesia and the ozone layer. Br J Anaesth 1989;63:645– 647. 202. Westhorpe R, Blutstein H. Anaesthetic agents and the ozone layer. Anaesth Intensive Care 1990;18:102–104. 203. Ray DC, Drummond GB. Halothane hepatitis. Br J Anaesth 1991;67:84–99. 204. Weitz J, Kienle P, Bohrer H, et al. Fatal hepatic necrosis after isoflurane anaesthesia. Anaesthesia 1997;52:892–895. 205. Anders MW. Formation and toxicity of anesthetic degradation products. Annu Rev Pharmacol Toxicol 2005;45:147–176. 206. Kharasch ED, Hankins DC, Thummel KE. Human kidney methoxyflurane and sevoflurane metabolism. Intrarenal fluoride production as a possible mechanism of methoxyflurane nephrotoxicity. Anesthesiology 1995;82:689–699. 207. Preckel B, Schlack W. Inert gases as the future inhalational anaesthetics? Best Pract Res Clin Anaesthesiol 2005;19:365– 379. 208. Lynch C 3rd, Baum J, Tenbrinck R. Xenon anesthesia. Anesthesiology 2000;92: 865–868.

195. Wu J, Previte JP, Adler E, et al. Spontaneous ignition, explosion, and fire with sevoflurane and barium hydroxide lime. Anesthesiology 2004;101:534–537.

209. Ma D, Hossain M, Chow A, et al. Xenon and hypothermia combine to provide neuroprotection from neonatal asphyxia. Ann Neurol 2005;58:182–193.

196. Fatheree RS, Leighton BL. Acute respiratory distress syndrome after an exothermic Baralyme-sevoflurane reaction. Anesthesiology 2004;101:531–533.

210. Ma D, Yang H, Lynch J, et al. Xenon attenuates cardiopulmonary bypass-induced neurologic and neurocognitive dysfunction in the rat. Anesthesiology 2003;98: 690–698.

197. Berry PD, Sessler DI, Larson MD. Severe carbon monoxide poisoning during desflurane anesthesia. Anesthesiology 1999;90:613–616. 198. Laster M, Roth P, Eger EI 2nd. Fires from the interaction of anesthetics with desiccated absorbent. Anesth Analg 2004; 99:769–774.

211. Kennedy RR, French RA, Spencer C. Predictive accuracy of a model of volatile anesthetic uptake. Anesth Analg 2002;95: 1616–1621. 212. Mapleson WW. An electric analogue for uptake and exchange of inert gases and other agents. J Appl Physiol 1963;18:197–204.

CHAPTER 38: Anesthesia Delivery System

CHAPTER 38 Anesthesia Delivery System James B. Eisenkraft, MD The anesthesia delivery system is the anesthesiologist’s constant companion in the operating or procedure room. Whether a patient is to receive general anesthesia, regional anesthesia, or monitored anesthesia care, the delivery system must be checked and ready for immediate use. An understanding of the structure and function of the anesthesia delivery system is essential to the safe practice of anesthesia. The anesthesia delivery system has evolved considerably over the past several years. The current voluntary consensus standard describing the features of a contemporary machine is that published by the American Society for Testing and Materials (ASTM) and designated F1850–00. This document, published in March 2000, is entitled Standard specification for particular requirements for anesthesia workstations and their components.1 The term anesthesia workstation is defined as a system for the administration of anesthesia to patients. It consists of the anesthesia gas supply device, anesthesia ventilator, monitoring devices, and protection device(s). This standard supersedes the F1161–88 anesthesia machine standard published in 1989 by ASTM.2 The above standards represent a consensus adopted voluntarily by the machine manufacturers. Certain accrediting and licensing bodies, however, may choose to adopt such standards in whole or in part and make them requirements for machines used in that locality. The reader is referred to the source documents for more details. The recent evolution of the anesthesia workstation and advances in technology have led to many changes in design. While all of the basic operations remain the same, the functions of many of the traditional components are now performed by more technologically advanced components. In many new models, the familiar rotameter tubes are replaced by virtual

KEY POINTS 1. A basic understanding of the anesthesia delivery system and its components is important to the provision of safe patient care. 2. The current voluntary consensus standard describing the features of a contemporary anesthesia workstation is the American Society for Testing and Materials (ASTM) F1850–00, published in 2000. 3. A full oxygen tank (E cylinder) has a pressure of approximately 1900 psig (pounds per square inch gauge) and evolves 660 L of gaseous O2 at atmospheric pressure (14.7 psia [pounds per square inch absolute], 760 mm Hg). 4. By applying Boyle’s law, the pressure gauge can indicate fullness of the O2 tank. 5. Tank O2 supply is regulated to enter the anesthesia machine at 40–45 psig. Pipeline O2 is regulated to 50–55 psig. 6. The pin-index and diameter-index safety systems ensure that the correct medical gas enters the correct part of the machine. 7. The “fail-safe” valve (pressure sensor shut-off valve, O2 failure protection device) only ensures that if the O2 supply pressure is adequate, nitrous oxide (N2O) and other gases may flow to their flow-control valves. This valve does not ensure O2 flow. 8. N2O can exist as a liquid at room temperature. 9. N2O E cylinders have a pressure of 750 psig (the saturated vapor pressure of N2O at 20°C) as long as some liquid N2O remains. 10. Only one flow-control knob should exist for each gas emerging at the common gas outlet. 11. The O2 flowmeter should be located downstream of all other gas flowmeters, that is, it should be the one closest to the common gas outlet. 12. The O2 and N2O flow controls are interlinked so that a gas mixture containing 25% or greater of O2 is created at the flowmeters when N2O and O2 are in use. Use of a third or fourth gas may “defeat” this feature. 13. An O2 analyzer in the patient circuit is essential to detect a hypoxic mixture.


It should be automatically enabled and the low O2 alarm set whenever the machine is capable of delivering an anesthetic gas mixture. 14. Anesthesia vaporizers create a saturated vapor concentration of the anesthetic and then dilute it to clinically useful concentrations. 15. The ideal vaporizer construction material has high specific heat and thermal conductivity. 16. Contemporary vaporizers for halothane, isoflurane, enflurane, and sevoflurane are variable-bypass, concentration-calibrated, and temperature-compensated vaporizers. 17. The volume of gas leaving a vaporizer is greater than that entering it because of the addition of anesthetic vapor. 18. The output of a variable-bypass, concentration-calibrated, agent-specific vaporizer is determined by the splitting ratio created by the dial setting. This determines what flow bypasses the vaporizing chamber (bypass flow) and what flow enters the vaporizing chamber to evolve the agent at its saturated vapor concentration. 19. Vaporizers are agent-specific. Erroneous filling should be avoided, and the use of agent-specific filling devices is encouraged. 20. Desflurane has a vapor pressure of 669 mm Hg at 20°C and boils at 22.8°C. It cannot be used in traditional designs of variable-bypass vaporizers. Desflurane is administered using the Tec 6 or D-Vapor vaporizer, in which the agent is heated to 39°C to form vapor under pressure at 1500 mm Hg and this vapor is added to the fresh gas stream. The ADU Aladin vaporizer is a hybrid variable-bypass and measured-flow design that can be used for all 5 inhaled anesthetics. 21. The anesthesia machine should be checked each day before anesthetizing the first patient and whenever any change has been made to the system. A shortened checkout should precede each administration of anesthesia. The checkout procedure should follow the directions given in the machine’s operation and maintenance manual. Continued

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Key Points—continued 22. Presently, a positive-pressure check for leaks is recommended for traditional Dräger Narkomed machines and a negative-pressure check for Datex-Ohmeda machines. The FDA 1993 preuse checkout recommends the negative pressure leak check for traditional machines. 23. Use of free-standing vaporizers downstream from the common gas outlet can be hazardous and should be avoided. 24. Anesthesia circuits are classified as rebreathing (no CO2 absorption) or nonrebreathing (including a CO2 absorber; e.g., circle system). 25. In all circuits, the higher the fresh gas flow, the closer inspired gas composition approaches that of fresh gas. 768

26. Anesthesia ventilators are traditionally pneumatic and of “bag-in-a-bottle” or “double-circuit” design. The bellows is the interface between the patient circuit and the driving gas circuit. 27. Datex-Ohmeda ventilators are driven by 100% O2, whereas the Dräger AV-E is driven by an air/O2 mixture in the bellows housing. 28. In traditional ventilators a standing bellows design is preferred as it makes a leak in the breathing system more obvious. The bellows descend on inspiration and ascend on expiration. This design requires that the ventilator relief valve incorporate a positive end-expiratory pressure (PEEP) mechanism. 29. Having set the ventilator rate (f) and tidal volume (VT) controls, one must appreciate that patient VT is determined also by fresh gas flow (FGF), inspiratory-to-expiratory (I:E) ratio, circuit compliance, and peak inspiratory pressure: Patient VT =

[

Bellows VT + FGF ×

I × 1 f I+E

]

30. New designs of ventilator use computerized compensation (ADU, Aisys, Smart Vent) or fresh gas decoupling (Apollo, Fabius GS, Narkomed 6400, Anestar) to ensure that VT is delivered as set on the ventilator. 31. Free-standing PEEP valves may be hazardous if added to the circuit incorrectly. PEEP valves are safer when designed as an integral part of the circuit. Addition of PEEP to a circle may decrease the VT; the decrease depends on the position of the PEEP valve in the circle. The ideal position is as close to the ventilator pressure relief valve as possible. 32. Waste anesthesia gases should be scavenged. 33. National Institute for Occupational Safety and Health (NIOSH) recommends that exposure of operating room workers to halogenated agents should be kept below 2 ppm. N2O levels should be controlled so that no worker is exposed at time-weighted average concentrations greater than 25 ppm. The latter guide should result in levels of approximately 0.5 ppm of the halogenated agents. 34. The ASTM F1850–00 standard calls for an integrated and prioritized alarm system, breathing pressure monitoring, and exhaled volume or ventilatory CO2 monitoring. 35. In the event of a severe machine or gas delivery system malfunction, an alternative means for ventilating the patient’s lungs with O2 (or room air) should be immediately available. Thus a self-inflating bag whose function has been checked should be available in each anesthetizing location. 36. Use error is the most common cause of adverse outcomes in relation to anesthesia gas delivery equipment.

Nitrous oxide

Other gas(es)

Oxygen

Flowmeters

37. User education must be emphasized and there must be a thorough inservice whenever there is a new user or new equipment is introduced.

Concentrationcalibrated vaporizer Common gas outlet

– (circuit compliance × peak inspiratory pressure)

flowmeters displayed on a computer screen. The gas flow-control needle valves may be replaced by electronically controlled gas-mixing devices. Because space does not permit a de-

ate some of the changes that have been made in the most recent models. Figure 38–1 depicts the components of a contemporary basic anesthesia delivery system. These include the anesthesia machine itself, which receives the gases oxygen (O2), nitrous oxide (N2O), and perhaps a third and fourth gas (e.g., air, heliox) delivered under pressure. A controlled gas mixture in terms of concentration of O2 and other gas(es), as well as total gas flow rates, is created using the gas flow controls and delivered to a concentration-calibrated vaporizer, where a measured amount of a potent inhaled anesthetic agent may be added. The resulting fresh gas mixture of known composition and metered production rate leaves the anesthesia machine at the common gas outlet and flows continuously to the patient circuit. The patient circuit represents a mini environment that allows respiratory exchange and control of anesthetic and respiratory (i.e., PO2 and PCO2) gas tensions in the patient’s alveoli, blood, and tissues (e.g., brain). An anesthesia ventilator bellows (or in some recent Dräger models, a piston) may be connected to the breathing circuit, by means of which the patient’s lungs can be mechanically ventilated. Excess gases are vented from the anesthesia circuit via either the adjustable pressure-limiting (APL or “pop-off” valve) or the ventilator pressure relief valve. The vented gases enter the waste gas scavenging system and are removed from the operating room, usually through the hospital suction.

Ventilator bellows

tailed description of each model of workstation, the basic components and functions of a traditional anesthesia workstation are described. The reader should then be able to appreci-

Ventilator pressure relief valve

Patient circuit

Patient’s lungs

“Pop-off” valve

Waste gas scavenging system

FIGURE 38–1. Schematic of generic anesthesia gas delivery system.


Presently, in the United States, the two largest manufacturers of anesthesia delivery systems (machines, ventilators, vaporizers, scavenging systems) are Dräger (Telford, PA) and Datex-Ohmeda (Madison, WI). Other manufacturers include Datascope, Blease, and Penlon. This chapter reviews the features of a basic anesthesia gas delivery system, referring to the product from a specific manufacturer where appropriate. The approach used is to trace the flow of gases, from their pressurized storage sources, and vapors through the various components of the delivery sys-

tem, and to understand the function of each component. In this way the reader can more readily appreciate the rationale for the various checkout procedures and have a framework from which to diagnose problems that may arise during use of the equipment. A systematic approach to problems with the delivery system is presented elsewhere.3 The most comprehensive source of reference for any individual model of workstation is the workstation manufacturer’s operator’s and maintenance manuals, and the reader is strongly encouraged to review the manual(s) relevant to the reader’s

equipment. Additionally, an alternative means for delivering O2 or room air to the patient should be kept immediately available in the event of a severe workstation malfunction. Thus a self-inflating (e.g., Ambu) resuscitation bag, previously tested for correct function and, ideally, a full tank of O2 should be immediately available in each anesthetizing location.

BASIC ANESTHESIA MACHINE Figure 38–2 depicts the flow arrangements of a basic two-gas anesthesia

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FIGURE 38–2. Schematic of flow arrangements of contemporary anesthesia machine. “Fail-safe” valve A in Datex-Ohmeda machines is termed a pressure sensor shutoff valve. In Dräger machines, it is the oxygen-failure protection device (OFPD). Second-stage O2 pressure regulator B is used in Datex-Ohmeda (but not Dräger Narkomed) machines. Second-stage N2O pressure regulator C is used in Datex-Ohmeda Modulus and Excel machines with the Link-25 Proportion Limiting Control System; this is not used in Dräger Narkomed machines. Pressure relief valve D is used in Datex-Ohmeda Modulus machines; it is not used in Dräger machines. Outlet check valve E is used in Datex-Ohmeda machines except Modulus II Plus and Modulus CD models; it is not used in Dräger machines. Datex-Ohmeda Excel machines have a pressure relief valve located downstream from the outlet check valve, between this valve and the machine common gas outlet.


machine. The machine receives each of the two basic gases, O2 and N2O, from two supply sources: a tank or cylinder source and a pipeline source.

Oxygen

770

Oxygen has a molecular weight of 32 and a boiling point of –183°C at a pressure of 760 mm Hg (14.7 pounds per square inch absolute pressure [psia]). (Absolute pressure is designated psia and gauge pressure is designated psig [pounds per square inch gauge pressure]. Gauges record pressure above or below existing atmospheric pressure. Thus 1 atmosphere [atm] pressure = 760 mm Hg = 14.7 psia = 0 psig.) Boiling point (the temperature at which O2 changes from the liquid to the gas phase) is related to ambient pressure such that as pressure increases, so does the boiling point of O2. However, a certain critical temperature is reached above which, no matter how much pressure is applied, the liquid O2 boils to a gas. The critical temperature for O2 is –118°C, and the critical pressure that must be applied at this temperature to keep O2 liquid is 737 psia. Because room temperature is normally around 20°C and thus well above the critical temperature, O2 can exist only as a gas at room temperature. This has certain implications for understanding the contents of an O2 tank. Oxygen tanks serve as the primary source of O2 if there is no pipeline in the anesthetizing location, and as a backup supply in case of pipeline failure. Machines are usually equipped with one or two E cylinders, that hang on specific O2 hanger yokes. The medical gas pin-index safety system ensures that the correct medical gas tank is hung in the correct yoke. The system consists of two pins that are fixed in the yoke, and which fit into two corresponding holes in the tank valve. The two pins are in a unique configuration for O2 and should never be removed from the hanger yoke. Specific pin configurations exist for each of the medical gases supplied in small cylinders in order to prevent erroneous misconnections of gas supplies. A tank should never be force-fitted to a hanger yoke. Oxygen tanks are filled at the factory to a pressure of approximately 1900 psig (add 14.7 to convert to psia) at room temperature. Once filled, they contain a fixed number of gas mole-

cules (fixed mass of gas) that obey Boyle’s law (i.e., pressure × volume = constant), provided that temperature does not change. A full E cylinder of O2 at a pressure of 1900 psig will evolve 660 L of gaseous O2 at 1 atm pressure (14.7 psia, or 760 mm Hg). The internal volume (V1) of an E cylinder is therefore approximately 5 L because, by Boyle’s law, P1 × V1 = P2 × V2. Thus 1900 × V1 = 14.7 × 660. If the O2 tank pressure is 1000 psig, the tank is 1000/1900, or 52% full, and will generate only 660 × 52%, or 340 L of gaseous O2 at atmospheric pressure. If such a tank were being used at an O2 flow rate of 6 L/min, it would empty in just under 1 hour (340/6 = 57 minutes). It is important to understand these principles when O2 cylinders are in use to supply the machine or during patient transport. If the anesthesia machine is equipped with two E cylinders of O2, only one should be open and in use at any one time so that both tanks are not emptied simultaneously. There is a check valve in the hanger yoke for each O2 (and other medical gas) cylinder to prevent leakage of gas out through the hanger yoke if no cylinder is hanging in place and the machine is being supplied by the pipeline or from a second O2 tank (Fig. 38–2). If two O2 tanks are hanging, the check valve in the yoke prevents transfilling of gas from one tank to the other. However, these check valves may leak, so if a hanger yoke does not have a tank hanging in it, a yoke plug should be inserted to prevent leakage of gas in the event of an incompetent check valve. These solid plastic block yoke plugs are usually attached to the back of the machine by a chain to prevent their loss. In the Dräger Apollo workstation, the tank pressures are measured using electronic pressure transducers and the values displayed on a screen.4 In many medical facilities the O2 pipeline is supplied from a bulk liquid O2 source. This may be more economical for the institution, depending on rate and volume of O2 used. Liquid O2 is stored at temperatures of around –160°C under pressure in a storage vessel that resembles a large vacuum (Dewar) flask. When gaseous O2 is drawn from the top of the storage vessel, liquid O2 boils to replace it. The boiling (change of phase) helps to keep the remaining liquid O2 cold. Because the O2 gas evolved is very cold, it is

first passed through a heating coil and then through a pressure regulator that maintains the hospital pipeline pressure at 50–55 psig. Alarms and safety devices, including relief valves and shut-off valves, ensure the safe functioning of the bulk O2 storage and pipeline systems. Pipeline systems, although usually reliable, may fail. A recent report describes failure between the bulk liquid oxygen storage vessel and the pipeline, which resulted in the release of 8000 gallons of liquid O2 into the atmosphere.5 Consequently, ensuring that a backup (tank) supply is available is an important part of the preuse checkout. Pipeline O2 is available in the operating rooms usually via gas-specific and manufacturer-specific “quick connectors” or via oxygen-specific diameter-indexed safety system outlets. The operating room wall pipeline “quickconnectors” are both noninterchangeable among medical gases (so that an O2 hose quick-connector cannot be connected to a N2O wall outlet) and are also manufacturer specific (e.g., Schraeder, Datex-Ohmeda, Chemetron). At the machine end of the hose that conducts O2 from the wall outlet to the machine is a connector that is gas specific by a national standard. The diameter-index safety system specifies that at the machine end the medical gas connectors be of different diameter. The diameter- and pin-index safety systems are designed to ensure that the correct medical gas enters the correct part of the anesthesia machine.6 For simplicity, the anesthesia machine is described as consisting of two basic systems, a high-pressure system for each gas, and a common low-pressure system for the gas mixture. Those parts upstream of the gas flow-control (traditionally needle) valves contain gas at relatively high pressures and are considered to be the high-pressure system. Those parts downstream of the flow-control valves (Fig. 38–2) contain gas at low pressure (measured in cm H2O rather than psig) and constitute the low-pressure system. The lowpressure system extends from the flow-control valves to the machine common gas outlet. Although O2 from the pipeline supply enters the machine O2 high-pressure system at a pressure of approximately 50 psig, O2 from a full tank enters the yoke at pressures of approximately 1900 psig. The O2 tank source is therefore regu-


lated (O2 passes through a regulator valve) and enters the machine highpressure system at a nominal pressure of 45 psig (Fig. 38–2). A pressure regulator is a device that reduces a variable high input pressure (in this case, ~1900 psig from the O2 tank) to a constant low-output pressure (in this case, 45 psig) for the gas whose pressure is being regulated. Because the tank supply serves as a backup in case the pipeline fails, once the tank pressures have been checked during the preuse checkout, the tank supply should be turned off if gas from the pipeline source is being used. If the O2 tank(s) remains turned on while the machine is being supplied from the pipeline, O2 is drawn preferentially from the pipeline supply (50–55 psig) because the regulator that controls flow from the O2 tanks only permits flow into the machine high-pressure system for O2 when the pressure in the machine high-pressure system falls below about 45 psig (Fig. 38–2). However, the pipeline pressure at times may fluctuate to below 45 psig, in which case O2 would be drawn from an open tank. Thus, if the machine is being supplied from the O2 pipeline, the O2 tanks on the machine should be turned off to prevent the tank O2 supply being used and the backup tank supply being unintentionally depleted. As long as pipeline supply pressure (50–55 psig) exceeds the pressure downstream of the first-stage O2 (tank supply) regulator, the O2 tank source will not supply the machine. If one wants to use the tank O2 to supply the machine, the O2 pipeline connector should first be disconnected from the wall. Thus, if one should ever suspect that a hypoxic gas (i.e., a gas other than O2) is being delivered through the O2 pipeline system at 50–55 psig (e.g., because of pipeline crossover or misfilling of the bulk O2 supply tank), the machine’s O2 pipeline connection must be disconnected from the wall outlet so as to permit the tank O2 supply to flow into the high-pressure system. Having entered the machine highpressure system for O2 at a pressure of 45–55 psig (from tank or pipeline), O2 may flow or pressurize in 7 directions (Fig. 38–2): 1. It provides the power source for a pneumatically driven anesthesia ventilator. Most anesthesia ventilators (e.g., those on Datex-Ohmeda

Modulus, Aestiva, Excel ADU, and Aisys machines; Dräger Narkomed 2, Narkomed 3, and Narkomed 4, Narkomed GS, Narkomed Mobile) use compressed oxygen as the driving gas. The driving gas is used to compress (“drive” or squeeze the ventilator bellows during the inspiratory phase of positive pressure ventilation. It is important to realize this because if the machine, and therefore ventilator, are being supplied from the tank rather than the pipeline, the tank will be depleted much more rapidly. In general, the volume of oxygen needed to drive the ventilator is at least the minute ventilation (MV) set to be delivered (e.g., VT 500 mL, respiratory rate [RR] 10 breaths/min, gives MV of 5 L). Thus, if the pipeline oxygen supply fails during use of the ventilator and one switches to the tank supply, one should consider ways to limit the rate of use of the tank oxygen by ventilating the lungs using the reservoir bag, having the patient breathe spontaneously if possible, and using the lowest flow of oxygen necessary at the oxygen flowmeter. 2. It supplies the auxiliary oxygen flowmeter that is present on most contemporary machines. This is the separate flowmeter that is commonly used to supply a nasal cannula. 3. It supplies oxygen to an auxiliary oxygen diameter-index safety system fitting. This may be used to power a Sanders injector design of jet ventilator, or a venturi design vacuum–suction system. 4. If the oxygen flush control (valve) is opened by pressing the oxygen flush control button, oxygen flows directly ( bypassing the flowmeters) to the common gas outlet of the machine at a rate of 35–75 L/min and potentially at a pressure of 50 psig. Consequently, the flush must not be activated if a patient is connected to the breathing system and there is no means for pressure relief. For example, activation of the flush during the inspiratory phase of ventilation, during which gas can enter the breathing system but cannot leave, has the potential to cause positive pressure barotrauma. 5. It pressurizes an oxygen supply pressure failure alarm system such that if oxygen pressure in the high pressure system falls (usually to

below 30 psig) an audible alarm sounds. On modern machines, a pressure-operated electrical switch ensures a continuous audible (and visual) alarm when the oxygen supply pressure falls below 30 psig. This will alert to a possible problem with the machine’s oxygen supply pressure, such as pipeline failure or if the tank in use is nearing empty. 6. It pressurizes and opens the “failsafe” valve (Fig. 38–2 item A). This is a pressure-sensitive valve that can decrease or totally interrupt the supply of nitrous oxide and other gases (e.g., heliox, and in some machines air) to their flow-control systems if the pressure of gas in the oxygen high pressure system falls below a threshold level. In the Datex-Ohmeda machines this valve is called the pressure sensor shut-off valve (PSSV). These valves interrupt the gas supplies to the nitrous oxide and other gas flowmeters when the oxygen pressure falls below a nominal 26 psig. In the Datex-Ohmeda machines, these valves are either fully open or fully closed. In the Dräger Narkomed 2, Narkomed 3, and Narkomed 4 machines, the “fail-safe” valve is called the oxygen-failure protection device (OFPD) and there is one interfacing the high-pressure system for oxygen with the high-pressure systems for each of the other gases supplied to the machine (e.g., nitrous oxide). Unlike the DatexOhmeda PSSV “fail-safe” valves, the OFPDs gradually reduce the supply pressure to the nitrous oxide and other gas flowmeters as the oxygen supply pressure decreases. The supply of other gases to their respective flowmeters is completely interrupted when the oxygen supply pressure falls below 12 ± 4 psig. In this way, a hypoxic mixture arising from oxygen supply problems to the flowmeters should be prevented. Thus in Dräger Narkomed, Datex-Ohmeda, and other brands of machines, when the oxygen supply pressure is low, only 100% oxygen is delivered. 7. It passes to the oxygen flow-control valve. In traditional machines this is the needle valve that is connected to the oxygen flow-control knob used to set the oxygen flow at the oxygen flowmeter.

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772

In Datex-Ohmeda machines (e.g., Modulus II, Modulus II Plus, Modulus CD, and Excel models), to reach the oxygen flow-control valve, oxygen in the high-pressure system must first pass through a secondstage regulator valve where the pressure is downregulated to about 16 psig. This second-stage regulator (Fig. 38–2 item B) ensures that the oxygen flowmeter is supplied at a constant pressure of 16 psig. Thus even if the oxygen supply pressure to the machine falls to below 45–50 psig, as long as it exceeds 16 psig, the oxygen flow set at the flowmeter will be maintained. Without this second-stage regulator, if the oxygen supply pressure to the machine were to fall, the oxygen flow would decrease at the flowmeter and, if nitrous oxide were being used also, a hypoxic gas mixture might result at the level of the flowmeters. In summary, in Datex-Ohmeda machines, if the oxygen supply pressure falls below 30 psig, the lowpressure supply alarm sounds (see #5 above); below 20 psig the “failsafe” valve will interrupt the flow of other gases to their flowmeters so that only oxygen can be delivered, and the oxygen flow set on the oxygen flowmeter will not decrease until the oxygen supply pressure falls below 16 psig. Dräger Narkomed 2, Narkomed 3, and Narkomed 4 machines do not use a second stage oxygen pressure regulator (in Fig. 38–2 item B is absent) to supply the oxygen flowmeter at constant pressure. Instead they use OFPDs (see #6 above) to continually interface the pressure of oxygen in the high-pressure system with the pressure of nitrous oxide just upstream of the nitrous oxide flowmeter. A decrease in the oxygen supply pressure causes a proportionate decrease in the pressure of nitrous oxide supplied to its flowmeter. Thus as oxygen supply pressure decreases, the flow of oxygen and that of all other supplied gases will decrease in proportion so as to avoid creation of hypoxic gas mixture.

Nitrous Oxide Like O2, N2O may be supplied to the machine from the pipeline system at a pressure of approximately 50 psig or from a backup E cylinder supply on the

machine. N2O has a molecular weight of 44 and a boiling point of –88°C at 760 mm Hg (14.7 psia) pressure.7 Because it has a critical temperature of 36.5°C (critical pressure: 1054 psig), N2O can exist as a liquid at room temperature (20°C). E cylinders of N2O are factory-filled to 90–95% capacity with liquid N2O. Above the liquid in the tank is N2O vapor. Because the liquid agent is in equilibrium with its vapor or gas phase, the pressure exerted by the gaseous N2O is its saturated vapor pressure (SVP) at the ambient temperature. At 20°C the SVP of N2O is 750 psig.7 A full E tank of N2O generates approximately 1600 L of gas at 1 atm pressure at sea level (14.7 psia). As long as some liquid N2O is present in the tank and the ambient temperature remains at 20°C, the pressure in the N2O tank will remain at 750 psig, which is the SVP of N2O at 20°C. Unlike with O2, the content of a N2O tank cannot be determined by reference to the N2O tank pressure gauge. However, the content can be determined by weighing the tank and subtracting the weight of the empty tank (tare weight) to determine the weight of the remaining N2O. By Avogadro’s volume, one gram molecular weight (i.e., 44 g) of N2O will occupy 22.4 L at standard temperature and pressure (STP: 760 mm Hg; 273.15°K or 0°C). Once all the liquid N2O has been used and the tank contains only gas, Boyle’s law may be applied. In this situation, where the tank pressure is 750 psig (from gas only) and the internal volume of the E cylinder is approximately 5 L (see Oxygen above), the volume of N2O that will evolve at a pressure of 760 mm Hg (14.7 psia) can be calculated. Thus P1 × V1 = P2 × V2; 750 × 5 = 14.7 × V2, or V2 = 255 L. At this point the N2O tank is 255/1600, or 16%, full. At 20°C room temperature, an E tank of N2O with a pressure of 400 psig would deliver (400/750 × 255 L), or 136 L of N2O gas. Nitrous oxide from the tank supply enters the N2O hanger yoke at pressures of up to 750 psig (at 20°C) and then passes through a regulator that reduces this pressure to 40–45 psig (Fig. 38–2). The pin-index safety system is designed to ensure that only a N2O tank may hang in a N2O hanger yoke. As with O2, a check valve in each yoke prevents the back leakage of N2O if no tank is hanging in the yoke.

The N2O pipeline is supplied from a bulk storage container of liquid N2O or from banks of large N2O tanks, usually H cylinders. (Each H cylinder of N2O evolves 16,000 L of gas at atmospheric pressure.) The pressure in the N2O pipeline is regulated to approximately 50 psig to supply the outlets in the operating room. Having entered the anesthesia machine high-pressure system for N2O, N2O must flow past the fail-safe valve to reach the N2O flowcontrol (traditionally a needle) valve and flowmeter (traditionally a rotameter) (Fig. 38–2). In Datex-Ohmeda anesthesia machines that have the Link-25 Proportion Limiting Control System (see next section), a second-stage N2O regulator further reduces gas pressure so that N2O is supplied to its flow-control (needle) valve at a nominal pressure of 26 psig (Fig. 38–2). The actual downstream pressure of this regulator is adjusted at the factory or by a field service representative to ensure correct functioning of the Link-25 Proportion Limiting Control System.

Gas Flow Control Systems (Knobs, Needle Valves, Rotameters, Etc.) The anesthesia machine is used to adjust the proportions of oxygen and nitrous oxide, as well as total gas flows delivered to the patient. For each gas (oxygen, nitrous oxide, etc.) this is achieved in a traditional machine (Fig. 38–3) by means of a control valve and a gas-flow measuring system. The flow control knob is connected to a needle valve whereby gas flow is set and adjusted. Turning the knob counterclockwise opens the valve wider, permitting a greater flow of gas. The flow-control knob for oxygen is larger than those for the other gases, and it is fluted rather than knurled so that it is “touch-coded.” Thus, the oxygen knob feels different than the knobs for the other gases. Traditionally, gas flows on the conventional anesthesia machine are measured using the rotameter flowmeter (Fig. 38–3). There may be one rotameter, or two rotameters in tandem for each gas. If two are present for each gas, the first permits accurate measurement of low flows (usually up to 1 L/min) and the second of flows of 1–12 L/min. In North America, the oxygen rotameter(s) is(are) positioned on the right


oretical exceptions to this would be that at low (laminar) flows, the flow rates of gases with similar viscosities would be read identically (e.g., oxygen and helium have viscosities of 202 and 194 micropoise, respectively) and at high flows gases of similar densities (e.g., nitrous oxide and carbon dioxide, which both have a molecular weight of 44 atomic mass units) would be read identically. Again, it is emphasized that flow meters are not interchangeable among medical gases and are now manufactured such that they cannot be interchanged.

Virtual Flow Meters

FIGURE 38–3. O2 flowmeter and flow-control valve.

side of the rotameter bank. The rotameter is a constant pressure, variable orifice flowmeter, based on the Thorpe tube principle. Each rotameter consists of a vertical tapered glass tube that is of small diameter at the bottom and wider at the top, and contains a ball, float, or bobbin. The cross-sectional area between the outside of the float and the inside of the tapered glass tube represents the variable orifice. A certain pressure difference across the bobbin is required to “float” the bobbin in the upwardly flowing gas stream. As the orifice widens, increasing flows are required to create the same pressure difference across the bobbin, which floats at a higher level in the tapered glass tube. At low gas flow rates, flow is essentially laminar and Poiseuille’s law applies:

Flow = π × P × r4 8×η×L where P is the pressure drop across the bobbin, r is the radius of the tube, η is the viscosity of the gas, and L is the length of the bobbin or float. When the orificial area (r 2) is larger and flows are greater, flow becomes turbulent, in which case: Flow is proportional to the √P, r2, length–1, and density–0.5. Rotameter flowmeters are precision instruments. Flow tubes are manufactured for specific gases, calibrated with a unique float, and for use within a certain range of temperatures and pressures. Flowmeters are not interchangeable among gases and if a gas were passed through a rotameter for which it was not calibrated, the flows shown would likely be incorrect. The-

As mentioned in the opening paragraphs of this chapter, some of the traditional mechanical components are being replaced by more sophisticated devices. For example, in some models of contemporary anesthesia workstation (Datex-Ohmeda S5/ADU; Dräger Fabius GS,), gas flows are still controlled by mechanical needle valves but flows are measured using electronic flow sensors based on the principle of the pneumotachograph. Essentially, the pressure difference is measured across a laminar flow resistor through which the gas flows. Reference to the Poiseuille formula (see Gas Flow Control Systems [Knobs, Needle Valves, Rotameters, Etc.] above) shows that if r, η, and L are constant, P can be used to measure flow. Flows are therefore measured using a differential pressure transducer, and displayed on a screen in the form of a virtual graduated flow meter, together with a digital display. In the Datex-Ohmeda S5/ADU and the Dräger Apollo workstations, the virtual flow displays are color coded (e.g., green column for O2, yellow for air), whereas in the basic Dräger Fabius GS, all the flows are displayed as vertical yellow bars. Advantages of electronic flow sensors are that they are less expensive than rotameters and the data can be used elsewhere in the workstation to record gas and agent consumption or to adjust ventilator bellows tidal volume (as in the Datex-Ohmeda ADU workstation). An obvious concern with any electronically based system is what would happen if electrical power were totally lost. Also, many anesthesiologists are not completely comfortable unless they can see physical evidence of gas

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flowing. For these reasons, the workstation manufacturers offer (e.g., as an option on the Datex-Ohmeda S5/ADU) a rotameter that is placed at the common gas outlet (CGO) of the machine and that displays the approximate total flow of gas leaving the CGO. Some anesthesia workstations offer, as an option, an oxygen flow that cannot be discontinued completely because either a “stop” is provided on the oxygen flow-control valve to ensure a minimum oxygen flow of 200–300 mL/min past the needle valve (DatexOhmeda machines), or a gas flow resistor is provided (Dräger Narkomed 2, Narkomed 3, and Narkomed 4 machines) that permits a similar flow of 200–300 mL/min to bypass a completely closed oxygen flow-control needle valve. In the Dräger Narkomed machines, the minimum oxygen flow feature functions only in the “O2/N2O” mode but not in the “ALL GASES” mode. 774

Oxygen Ratio Monitoring and Proportioning Systems A major consideration in the design of contemporary anesthesia machines is prevention of delivery of a hypoxic gas mixture. The fail-safe system described previously only serves to interrupt (Datex-Ohmeda pressure sensor shut-off valve) or proportionately reduce and ultimately interrupt (Dräger OFPD) the supplies of N2O and (in some models) other gases (e.g., air, He) to their flowmeters if the O2 supply pressure to the machine is reduced. It does not prevent the delivery of a hypoxic mixture to the common gas outlet, making the term fail-safe somewhat of a misnomer. In traditional contemporary machines, N2O and O2 flow controls are physically interlinked either mechanically (Datex-Ohmeda) or mechanically and pneumatically (Dräger), so that a fresh gas mixture containing at least 25% O2 is delivered at the flowmeters when only N2O and O2 are being used.8,9 Datex-Ohmeda anesthesia machines use the Link-25 Proportion Limiting Control System to ensure an adequate percentage of O2 in the gas mixture created.8,10 In this system, a gear with 14 teeth is integral with the N2O flowcontrol spindle, whereas a gear with 29 teeth is allowed to rotate (“float”) on a threaded O2 flow-control valve spindle (Fig. 38–4). The two gears are connected together by a precision

FIGURE 38–4. Datex-Ohmeda Link-25 Proportion Limiting Control System, which ensures at least 25% O2 concentration at the level of the flowmeters when O2 and N2O are being used. When supply pressure to the second-stage O2 regulator falls below a nominal 26 psig, the pressure sensor shutoff valves (“fail-safe” valves) cause the supply of N2O and other gases to be shut off.

stainless steel link chain. For every 2.07 revolutions of the N2O flow-control spindle, an O2 flow control, set to the lowest O2 flow, rotates once because of the 14:29 ratio of gear teeth. Because the gear on the O2 flow-control spindle is thread-mounted so that it can rotate on the control valve spindle like a nut on a bolt (rather than being integral with the spindle), O2 flow can be increased independently of N2O. However, regardless of the O2 flow set, if the flow of N2O is increased sufficiently, the gear on the O2 spindle will engage with the O2 flow-control knob, causing it to rotate and thereby causing O2 flow to increase. If N2O flow is now reduced, the O2 flow remains high unless it is deliberately decreased by the user. The 75% N2O:25% O2 proportioning is completed because the N2O flow-control valve is supplied from a second-stage gas regulator, that reduces N2O pressure to a nominal 26 psig (adjusted as previously described) before it reaches the flow-control valve, whereas the O2 flow-control

valve is supplied at a pressure of 14 psig from a second-stage O2 regulator (Figs. 38–2 and 38–4). The Link-25 Proportion Limiting Control System permits the N2O and O2 flow-control valves to be set independently of one another, but whenever a N2O concentration of more than 75% would be accidentally set, the O2 flow is automatically increased to maintain at least 25% O2 in the resulting mixture. This system thus increases the minimum flow of O2 according to the N2O flow set. The Link-25 Proportion Limiting Control System interconnects only the N2O and O2 flow-control valves. If the anesthesia machine has flow controls for other gases (e.g., He, air) (Fig. 38–4), a gas mixture containing less than 25% O2 could potentially be set at the flowmeters. In Dräger Narkomed 2, Narkomed 3, and Narkomed 4 machines the oxygen ratio monitor controller (ORMC) (Fig. 38–5) serves to limit the N2O flow according to the O2 flow and create a mixture of at least 25% O2 at the flow-


FIGURE 38–5. Dräger oxygen ratio monitor controller (ORMC). See text for details of operation.

meter level when these two gases are being used.9 At O2 flow rates of less than 1 L/min, even higher concentrations of O2 are delivered. In addition, an alarm is activated when the ORMC is functioning to prevent a hypoxic mixture when the Narkomed machine is used in the “O2/N2O” mode, but not in the “all gases” mode (i.e., when air, helium, etc., might be switched into the system). The ORMC works as follows: As O2 flows past its flow-control needle valve and up the rotameter tube, it encounters a resistor that creates a back pressure that is applied to the O2 diaphragm (Fig. 38–5). As N2O flows past its flow-control valve and up the rotameter tube, it also encounters a resistor that causes a back pressure on the N2O diaphragm. The two diaphragms are linked by a connecting shaft, the ultimate position of which depends on the relative back pressures and, therefore, flows of N2O and O2.

The left-hand end of the connecting shaft controls the orifice of a slave valve, which, in turn, controls the supply pressure of N2O to its flow-control valve. When the O2 flow is high, the shaft moves to the left and opens the slave control valve (Fig. 38–5, lower). Conversely, if the N2O flow is increased excessively, the shaft moves to the right, closing the slave valve orifice and decreasing the supply pressure of N2O to, and thereby flow of N2O from, its flow-control valve. When the ORMC is acting to prevent a hypoxic mixture, the leaf spring contacts (Fig. 38–5) are closed, annunciating an alarm. This alarm is disabled if the machine is in the “all gases” mode.9 The Dräger ORMC differs from the Datex-Ohmeda Link-25 Proportion Limiting Control System in several ways. First, the ORMC does not require second-stage O2 and N2O regulators. Second, the ORMC serves to limit the N2O flow according to the O2 flow, whereas

the Link-25 Proportion Limiting Control System increases the O2 flow as the N2O flow is increased. As with the Link-25 Proportion Limiting Control System, the ORMC functions only with N2O and O2 and there is no interlinking of O2 with other gases (e.g., air, He) that might also be deliverable by the machine. Thus when a third or fourth gas is in use, the proportioning systems afford no protection against a hypoxic mixture. Prevention of delivery of a hypoxic gas mixture when a third or fourth gas is supplied to the machine may be achieved by supplying that gas in a tank premixed with O2 (e.g., heliox, a gas mixture of 75% He and 25% O2 ). Although elegant in design, both the ORMC and the Link-25 Proportion Limiting Control Systems are subject to mechanical and pneumatic failure and should be tested according to the manufacturer’s instructions during the preuse machine checkout.9,11 Furthermore, if the systems are functioning correctly, they only ensure adequacy of greater than 25% O2 at the flowmeter level. An O2 leak downstream from the flow-control valves (i.e., from the low-pressure system of the machine) could result in a hypoxic mixture flowing from the common gas outlet. Consequently, an oxygen analyzer in the patient circuit is essential if a hypoxic mixture is to be detected. The controlled flows of O2, N2O, and other gas or gases are mixed in the manifold at the top of the flowmeter bank, and they flow to a concentration-calibrated anesthesia vaporizer (Fig. 38–2).

ANESTHESIA VAPORIZERS A vapor is the gas phase of an agent that is normally a liquid at room temperature and atmospheric pressure. Vaporizers facilitate the change of a liquid anesthetic into its vapor phase and add a controlled amount of this vapor to the flow of gases passing to the patient circuit.

Vapor, Evaporation, and Vapor Pressure Consider isoflurane in a closed container at 1 atm pressure (760 mm Hg) and room temperature 20°C. Although most is in liquid form, some isoflurane molecules escape from the surface of the liquid to enter the space above as a vapor. Under steady-state conditions of temperature, an equilibrium is estab-

775


776

Units of Vapor Concentration Anesthetic vapor presence may be quantified either as an absolute pressure (or tension), expressed in millimeters of mercury (mm Hg), or in volumes percent of 1 atm (i.e., volumes of vapor per 100 volumes of total gas). By applying Dalton’s law, volumes percent is similar to the agent’s fractional partial pressure: Vols % = (Partial pressure of agent/ Total ambient pressure) × 100

Dalton’s Law of Partial Pressures Dalton’s law states that in a mixture of gases (or vapors) the pressure exerted by each gas is the same as that it would exert if it alone occupied the container.7 Each gas (or vapor) exerts its pressure independently of the pressure of the other gases present. For example, in a container of dry air at atmospheric pressure (760 mm Hg), if O2 represents 21% of all gases present, the pressure exerted by the O2 (its partial pressure) is 21% of 760, or 159.6 mm Hg. Now consider air, which is fully saturated with water vapor at 37°C (normal body temperature). Vapor pressure de-

1600 es flu ra n

e

1400 1200

ne ra

lu

f so

D

Vapor pressure mm Hg

lished between the molecules in the vapor phase and those in the liquid phase. The vapor phase molecules are in constant motion, striking the walls of the container to exert a vapor pressure. If the temperature is increased, more isoflurane molecules enter the vapor phase (evaporate), resulting in an increase in vapor pressure. When the gas phase above the liquid contains all the isoflurane vapor that it can hold at that temperature, it is said to be saturated and the pressure exerted by the isoflurane is called its saturated vapor pressure (SVP) at that temperature. The SVP exerted by the vapor phase of a potent volatile agent depends only on the volatile agent and the ambient temperature (Fig. 38–6). The temperature at which SVP becomes equal to atmospheric pressure and at which all the liquid agent changes to the vapor phase is the liquid’s boiling point. The most volatile agents are those with the highest SVPs for any given temperature, and they also have the lowest boiling points (e.g., desflurane and diethyl ether boil at 22.8°C and 35°C, respectively, at an ambient pressure of 760 mm Hg). Boiling point decreases with decreasing ambient pressure, such as occurs at increasing altitude.

I

1000

e

an

th

lo Ha

800 e

ran

flu

600

En

ne

ura

l vof Se

400 200 0

0

5

10

15

20

25

30

35

40

45

50

55

60

65

Temperature °C FIGURE 38–6. Vapor pressure curves for the potent inhaled anesthetics.

pends on temperature. The SVP for water at 37°C is 47 mm Hg. O2 now represents 21% of what remains (i.e., 713, or 760 – 47), having a partial pressure of 21% of 713, or 149.3 mm Hg. Volumes percent expresses the ratio of gas molecules in a mixture, whereas partial pressure is an absolute value. Anesthetic uptake and potency are directly related to partial pressure and only indirectly to volumes percent. This distinction will become more apparent when the use of vaporizers under hyperbaric and hypobaric conditions is considered in a later section (see Changes in Barometric Pressure).

Minimum Alveolar Concentration The minimum alveolar concentration (MAC) of a potent inhaled anesthetic agent that produces immobility in 50%

of patients undergoing a surgical incision is used as a measure of anesthetic potency or depth. MAC is typically expressed as volumes percent of alveolar (end-tidal) gas at 1 atm pressure at sea level (760 mm Hg). Table 38–1 shows how MAC in familiar volumes percent can be expressed as a partial pressure in millimeters of mercury.12 The reader is encouraged to think of MAC in terms of minimum alveolar pressure (MAP) or minimum alveolar partial pressure (MAPP) rather than volumes percent because it is the partial pressure (tension) of the anesthetic in the brain that determines the depth of anesthesia.13,14 The term PMAC1 (Table 38–1) is used to express the partial pressure of a potent inhaled agent at a concentration of 1 MAC. Thus 1 MAC of sevoflurane is equivalent to a PMAC1 of 16 mm Hg.

TABLE 38–1. Expression of Minimum Alveolar Concentration of Anesthetic Agent (MAC) as Partial Pressure at Concentration of 1 MAC (PMAC1) Assuming Ambient Pressure of 760 mm Hg Anesthetic Agent

MAC (vol %)

Halothane Enflurane Isoflurane Methoxyflurane Desfluranea

0.75 × 760 1.68 × 760 1.15 × 760 0.16 × 760 6.0 × 760 7.25 × 760 2.1 × 760

Sevoflurane

PMAC1 (mm Hg) = = = = = = =

5.7 12.8 8.7 1.2 45.6 55.1 16.0

aMAC of desflurane is age-dependent: 18–35 years = 7.25%; 31–65 years = 6.0%. See Rampil et al.15 Reprinted from Eisenkraft JB. Anesthesia vaporizers. In: Ehrenwerth J, Eisenkraft JB, eds. Anesthesia Equipment: Principles and Applications. St. Louis, MO: Mosby-Year Book, 1993:59, with permission from Elsevier.


Latent Heat of Vaporization Energy in the form of heat is needed to transfer molecules from the liquid to the vapor phase. This energy is called the latent heat of vaporization, and is defined as the amount of heat (calories) required to convert unit mass (grams) of the liquid into vapor.7 For example, the latent heats of vaporization of volatile anesthetics at room temperature are 35 cal/g for halothane; 41 cal/g for enflurane and isoflurane; and 58 cal/g for methoxyflurane.16 The heat of vaporization is inversely related to ambient temperature so that the lower the temperature, the more heat that is required. Heat required to vaporize anesthetic agents is drawn from the remaining liquid and the surroundings. As vapor is generated, the temperatures of the vaporizer and remaining liquid fall. This causes the vapor pressure to decrease and would result in decreased vaporizer output if no compensatory mechanism were provided.

Specific Heat Specific heat is the quantity of heat (calories) required to raise the temperature of unit mass (grams) of a substance by 1°C.7 Heat must be supplied to the liquid anesthetic in the vaporizer to maintain its temperature while

heat is being lost in the process of evaporation. Specific heat is also important to vaporizer construction material. Thus materials with high specific heat change temperature more gradually than those with low specific heats for the same amount of heat lost through vaporization. Thermal capacity is defined as the product of specific heat and mass and represents the total quantity of heat stored in the vaporizer body.7 The vaporizer construction material’s ability to conduct heat from the environment through to the contained liquid anesthetic is also of importance. This is called thermal conductivity, defined in terms of how quickly heat is transmitted through a substance. The ideal material for vaporizer construction would have a high specific heat and high thermal conductivity. In this respect, copper comes close to the ideal (thus the Copper Kettle vaporizer). More recently, bronze and stainless steel have been used in vaporizer construction.

Regulating Vaporizer Output: Measured Flow versus Variable Bypass The SVPs of the four potent inhaled agents halothane, isoflurane, enflurane, and sevoflurane at room temperature

are 243, 238, 175, and 160 mm Hg, respectively, and far in excess of those required for clinical anesthesia (Fig. 38–6 and Table 38–2). Consequently, the vaporizer first creates a saturated vapor that must then be diluted by the bypass gas flow to result in clinically useful concentrations. If this were not done, a lethal concentration of agent could be delivered. Contemporary anesthesia vaporizers for halothane, isoflurane, enflurane, and sevoflurane are concentration-calibrated and of the variable-bypass design.2 The vaporizers for desflurane (Datex-Ohmeda Tec 6; Dräger D-Vapor) are of a different design and are described separately in a later section (see Desflurane and the Tec 6 Vaporizer). In a variable-bypass vaporizer (e.g., DatexOhmeda Tec series, Dräger Vapor 19.n series) the total fresh gas flow from the anesthesia machine flow meters passes to the vaporizer. The vaporizer splits the incoming gas flow into both a smaller flow, which enters the vaporizing chamber to emerge with the agent at its saturated vapor concentration, and a larger bypass flow, which when mixed with the vaporizing chamber output, results in the desired or “dialed-in” concentration (Fig. 38–7). In the now rarely used measuredflow (i.e., not concentration-calibrated)

TABLE 38–2. Physical Properties of Potent Volatile Agents Parameter/Agent

Halothane

Enflurane

Isoflurane

Methoxyflurane

Sevoflurane

Desflurane

Structure Molecular weight Boiling point at 769 mm Hg (°C) SVP at 20°C Saturated vapor concentration at 20°C and 1 atmosphere absolute (vol %) MAC at 1 atmosphere absolute (vol %) PMAC1 (mm Hg) Specific gravity of liquid at 20°C Vapor (mL) per liquid at 20°C

CHBrClCF3 197.4 50.2

CHFClCF2OCHF2 184.5 56.5

CF2HOCHClCF3 184.5 48.5

CHCl2CF2OCH3 165.0 104.7

CH2FOCH(CF3)2 200 58.5

CH2HOCFHCF3 168 22.9

243 32

175 23

238 31

20.3 2.7

160 21

669 87

0.75

1.68

1.15

0.16

1.7

6.0–7.25a

5.7 123

12.8 130

8.7 130

1.22 145

12.9 120

46–55a 143

226

196

195

204

182

207

aAge related; see Table 38–1. MAC, minimum alveolar concentration; PMAC1, partial pressure at concentration of 1 MAC; SVP, saturated vapor pressure. Reprinted from Eisenkraft JB. Anesthesia vaporizers. In: Ehrenwerth J, Eisenkraft JB, eds. Anesthesia Equipment: Principles and Applications. St. Louis, MO: Mosby-Year Book, 1993:60, with permission from Elsevier.

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FIGURE 38–7. Variable bypass vaporizer principle. These are concentration-calibrated and are of the flow-over design (see text).

778

vaporizers, such as the Copper Kettle (Foregger/Puritan-Bennett) or VerniTrol (Datex-Ohmeda), a measured O2 flow is set on a separate flowmeter to pass to the vaporizer, from which vapor at its SVP emerges. This is then diluted by a larger measured flow of gases from other (main) flowmeters on the anesthesia machine (Fig. 38–8). In this type of arrangement, several calculations are necessary to determine the anesthetic vapor concentration in the emerging gas mixture. With either type of vaporizing arrangement, an efficient system must exist to create a saturated vapor concentration in the vaporizing chamber. This is achieved by having a large surface area for evaporation of the liquid agent. In flow-over vaporizers (e.g., Dräger Vapor series, Datex-Ohmeda Tec series) the area is increased by the use of wicks and baffles. In bubblethrough vaporizers (e.g., Copper Kettle, Verni-Trol), O2 is bubbled through the

liquid agent. The tiny bubbles, which in the Copper Kettle are created by passage of O2 through a sintered bronze disk, represent large areas of liquid–gas interface over which evaporation of the liquid agent can quickly occur. Desflurane, because of its high saturated vapor pressure at room temperature (669 mm Hg at 20°C), and its low boiling point (22.8°C at 1 atm), cannot be safely delivered using the vaporizing systems described in the preceding paragraphs. The physical properties of desflurane require that a special design of vaporizer (e.g., DatexOhmeda Tec 6; Dräger D-Vapor) be used to deliver this agent in a controlled fashion (see Desflurane and the Tec 6 Vaporizer).

Calculation of Vaporizer Output for Agents Other Than Desflurane Assume that room temperature is kept constant at 20°C. The SVPs of each agent are as follows: halothane, 243

mm Hg; isoflurane, 238 mm Hg; enflurane, 172 mm Hg; and sevoflurane, 160 mm Hg (Table 38–2). If ambient pressure is 760 mm Hg, these vapor pressures represent 243/760, or 32% for halothane; 238/760, or 31% for isoflurane; 175/760, or 23% for enflurane; and 160/760, or 21% for sevoflurane, in terms of volumes percent of each agent at 1 atm. In a variable-bypass vaporizer, a given volume of carrier gas flowing into the vaporizing chamber over time will exit the chamber over the same period. In the vaporizing chamber, however, anesthetic vapor at its SVP constitutes a mandatory fractional volume of the atmosphere (e.g., 32% by volume in a halothane vaporizer at 20°C and 760 mm Hg ambient pressure). Thus the volume of carrier gas entering the vaporizing chamber constitutes the difference between 100% of the atmosphere in the vaporizing chamber and that which results from the anesthetic vapor. With halothane at 20°C and ambient pressure 760 mm Hg the volume of carrier gas at any time represents 68% of the atmosphere in the vaporizing chamber. Thus if 100 mL of carrier gas enters a vaporizing chamber containing halothane, the carrier gas represents 68% (i.e., 100% – 32%) of the atmosphere, and the remaining 32% is halothane vapor. By simple proportions, the latter can be calculated to be 47 mL of halothane vapor ([100/68] × 32). Another way of expressing this is by applying Dalton’s law: SVPagent (mm Hg) = Total Pressure (mm Hg) Agent vapor (x mL) Carrier gas (y mL) + Agent vapor (x mL)

For halothane in the previous example, y = 100 mL/min. Therefore: 243 x = 760 100 + x

FIGURE 38–8. Measured flow vaporizer principle. These are not concentration-calibrated and are of the bubble-through design (see text).

from which x can be calculated to be 47 mL. Conversely, if x is known, the carrier gas flow (y) can be calculated. Thus a larger total volume of gas leaves the vaporizing chamber than enters it, the additional volume being anesthetic vapor at its saturated vapor concentration.


Measured-Flow Vaporizers Although measured-flow vaporizers are not included in the recent anesthesia machine and workstation standards,1,2 it is instructive to first review the function of a measured-flow vaporizer (e.g., Copper Kettle). Assume that 1% (vol/vol) halothane is required at a total fresh gas flow rate to the patient circuit of 5 L/min (Fig. 38–9). This requires that 50 mL halothane vapor be evolved per minute by the vaporizer (1% × 5000 mL). In the vaporizing chamber, halothane represents 32% of the atmosphere by volume, assuming temperature is kept constant at 20°C and therefore SVP is maintained at 243 mm Hg. Now if 50 mL of halothane vapor represents 32% by volume, the carrier gas (O2) must represent the other 68%, or 106 mL (50/32 × 68). Alternatively: 243 50 = 760 y + 50

where y is carrier gas (O2) flow, or 106 mL. Thus if 106 mL/min of O2 flows into a measured-flow vaporizer, 156 mL/min of gas emerges, of which 50 mL is halothane vapor and 106 mL is the carrier gas O2 supplied to the vaporizer. This vaporizer output of 156 mL/min must be diluted by an additional fresh gas flow of 5000 – 156 = 4844 mL/min, to create a precise 1%

halothane mixture (as 50 mL of halothane diluted in a total volume of 5000 mL = 1% by volume). In clinical practice, however, the anesthetist would likely set flows of 100 mL/min to the measured-flow vaporizer and 5 L/min of fresh gas on the main flowmeters, which results in slightly less than 1% halothane (47/ 5147 = 0.91%). Multiples of either of these numbers (100 mL and 5 L) are used to create other concentrations of halothane from a measured-flow vaporizing system. Thus a 100-mL/min O2 flow to the vaporizer and 2500 mL/ min on the main flowmeters would produce approximately 2% halothane (actually 1.78%). It is important to realize that if there is O2 flow only to the vaporizer and no diluent gas flow is set on the main flowmeters, potentially lethal concentrations (approaching 32%) of halothane would be delivered to the anesthesia circuit, albeit at low flow rates. Because halothane and isoflurane have similar vapor pressures at 20°C (Table 38–2), the gas flows required for halothane are essentially the same as those to be set for isoflurane if similar concentrations of isoflurane were to be produced from a measuredflow vaporizing system.

Variable Bypass In the foregoing example discussing measured-flow vaporizing systems, it was necessary to calculate both the O2

FIGURE 38–9. Preparation of 1% (vol/vol) halothane by measured-flow vaporizer.

flow to the vaporizer and the total bypass gas flow needed to produce the desired output concentrations of vapor. This is inconvenient and can give rise to errors, but it is helpful to understand the principles underlying the calculations. In the concentration-calibrated variable-bypass (“Tec-type”) design, the vaporizer splits the incoming total flow of gas arriving from the machine flowmeters between a variable-bypass and the vaporizing chamber that contains the anesthetic agent (Fig. 38–7). The ratio of these flows—the splitting ratio—depends on the anesthetic agent, the temperature, and the dialed-in vapor concentration set to be delivered. Figure 38–10 shows the schematic of a contemporary concentration-calibrated vaporizer, the Dräger Vapor 19.1. Anesthetic output concentration is increased by turning the concentration dial, which raises the control cone, allowing more saturated anesthetic vapor to leave the vaporizing chamber. Review of the previous section for accurately delivering 1% halothane from a measured-flow vaporizer reveals that 4950 mL/min of incoming total gas flow must be split so that 106 mL enters the vaporizing chamber and 4844 mL enters the bypass (Fig. 38–9). This results in a splitting ratio of 4844/106, or 46:1 (at a temperature of 20°C). A variable-bypass vaporizer (e.g., Dräger Vapor 19.1), when set to deliver 1% halothane, is, in effect, set to a splitting ratio of 46: 1 (bypass flow-to-vaporizing chamber flow). Concentration-calibrated vaporizers are agent-specific and designed to be used only with the agent for which the unit is designed and calibrated. To produce a 1% vapor concentration, an isoflurane vaporizer makes a flow split of 44:1, whereas a sevoflurane vaporizer makes a flow split of 25:1 (Table 38–3). If an empty sevoflurane vaporizer set to deliver 1% were filled with isoflurane, the concentration of the isoflurane vapor emerging would exceed 1% (44/25 = 1.7%). An understanding of splitting ratios enables fairly accurate prediction of the concentration output of an agentspecific variable-bypass vaporizer that has been erroneously filled with an agent for which it was not designed (see Incorrect Filling of Vaporizers below).

779


780

FIGURE 38–10. Schematic of Dräger Vapor 19.1 vaporizer. When concentration knob ( 3) is in 0 (zero) position, on/off switch (2) is closed. Gas mixture enters vaporizer at fresh gas inlet (1) and leaves through fresh gas outlet (10) without entering the vaporizer’s interior. When concentration knob ( 3) is turned to any volume (%) concentration above 0.2 vol%, the on/ off switch (2) automatically opens and allows fresh gas to enter the vaporizer’s interior. Gas is immediately divided and follows two different routes. One part of the fresh gas moves through a thermostatically controlled bypass ( 7), which compensates for temperature changes and maintains correct volumes percent concentration vapor output as selected with concentration knob ( 3). The other part of the fresh gas moves through a pressure compensator (4), which prevents pressure changes that occur upstream or downstream from the vaporizer to be transmitted into the vaporizer and thus affect volumes percent vapor output. From the pressure compensator, gas continues into vaporizing chamber ( 5). This chamber contains liquid anesthetic agent, which is absorbed and evaporated by a special wick assembly. As fresh gas moves through the vaporizing chamber, it is fully saturated with anesthetic vapor. Saturated gas leaves the chamber through a control cone (6). The cone is adjustable with concentration knob ( 3). Saturated vapor and fresh gas that did not pass through the vaporizing chamber are combined and leave through the fresh gas outlet (10). Combination of the bypass opening ( 7) and control cone opening (6) determines volumes percent vapor output. The expansion element (8) reduces vaporizing chamber gas flow as temperature increases.

Efficiency and Temperature Compensation Agent-specific, variable-bypass, concentration-calibrated vaporizers are located in the fresh gas path between the flow meters (e.g., rotameters) on the anesthesia machine and the machine common gas outlet (Fig. 38–2). The vaporizers must be efficient and produce steady concentrations of the agent over a fairly wide range of incoming gas flows. However, as the

agent is vaporized and the temperature falls, SVP also falls and vaporizing chamber output tends to decrease. Measured-flow vaporizers (e.g., Copper Kettle, Verni-Trol) incorporate a thermometer that measures the temperature of the liquid agent in the vaporizing chamber. A lower temperature translates to a lower SVP in this chamber, and reference to the vapor pressure curves (Fig. 38–6) enables a resetting of vaporizer gas flow, bypass gas flows, or both to ensure correct

output at the ambient temperature. Such an arrangement can be tedious but if done correctly does ensure the most accurate and rapid temperature compensation. Most of the contemporary variablebypass vaporizers (e.g., Datex-Ohmeda Tec series, Dräger Vapor 19.1) have automatic temperature compensation achieved by a temperature-sensitive valve in the bypass gas flow. When temperature increases, the valve in the bypass opens wider to create a greater splitting ratio. More gas flows through the bypass, and less gas enters the vaporizing chamber. A smaller volume of a higher concentration of vapor emerges from the vaporizing chamber. When mixed with an increased bypass gas flow, this volume maintains a reasonably constant vaporizer output when temperature changes are gradual and not extreme. The design of the temperaturesensitive valve varies among the different types of vaporizer. Datex-Ohmeda Tec series vaporizers use a bimetallic strip; a flap valve situated in the bypass flow composed of two different metals that have different coefficients of expansion (defined as change in length per unit length per unit change in temperature). As temperature increases, one surface of the flap expands more than the other, causing the flap to bend in such a way that the valve orifice opens wider.17 The principle of differential expansion of metals is applied similarly in the Dräger Vapor 19.1 vaporizers, in which an expansion element increases bypass gas flow as temperature increases (Fig. 38–10, component 8). The vapor pressures of the potent volatile anesthetics vary nonlinearly as a function of temperature (Fig. 38–6). The automatic temperature compensation mechanisms described are linear in terms of expansion coefficients of materials. When these affect the size of the orifice that they control, however, the compensation mechanisms also become nonlinear. The situation is complex, depending on the geometry of the valves and the nature of the gas flow through them. The result is that the vapor output concentration at any given vaporizer setting remains constant only within a certain range of temperatures. For example, the Dräger Vapor 19.1 vaporizers are specified as accu-


TABLE 38–3. Gas Flow Splitting Ratios at 20°Ca

1% 2% 3%

Halothane

Enflurane

Isoflurane

Methoxyflurane

Sevoflurane

46:1 22:1 14:1

29:1 14:1 9:1

44;1 21:1 14:1

1.7:1 0.36:1

25:1 12:1 7:1

b

aRatios

are not given for desflurane, because the vaporizer for this agent (Datex-Ohmeda Tec 6; Drager D-Vapor) uses a different design from that used for the above agents. bMaximum possible concentration is 2.7% at 20°C; see Table 38–2. Reprinted from Eisenkraft JB: Anesthesia vaporizers. In: Ehrenwerth J, Eisenkraft JB, ed. Anesthesia Equipment: Principles and Applications. St. Louis, MO: Mosby-Year Book, 1993:63, with permission from Elsevier.

rate to ± 15% of the concentration set when used within the temperature range of 15°C to 35°C at normal atmospheric pressure.9,11 At temperatures outside this range, the resulting concentration increases beyond the upper tolerance limit despite continuing compensation. The boiling point of the volatile agent must never be allowed to be reached in the current variable-bypass vaporizers designed for enflurane, halothane, isoflurane, and sevoflurane, as the vapor output concentration would otherwise be totally uncontrolled and potentially lethal.

Incorrect Filling of Vaporizers Modern vaporizers are agent-specific. If an empty vaporizer designed for one agent is filled with an agent for which it was not designed, the vaporizer output may be erroneous for both agent and delivered vapor concentration.

A dangerous situation would result if a vaporizer designed for methoxyflurane (very low SVP of 20.3 mm Hg at 20°C) were erroneously filled (Table 38–2). A methoxyflurane vaporizer filled with halothane and set to deliver 1% methoxyflurane (albeit 6 MAC; Table 38–2) would deliver 14.8% (20 MAC) halothane. Set to 1 MAC (0.16%) methoxyflurane, the vaporizer makes a flow split of 16:1, similar to that of a halothane or isoflurane variable-bypass vaporizer set to deliver 2.7%. Table 38–4 lists the outputs of erroneously filled vaporizers. Erroneous filling affects the output concentration and consequently the MAC (MAP, MAPP) or potency output of the vaporizer. Thus an enflurane vaporizer set to deliver 2% (1.19 MAC) but filled with halothane at 22°C will deliver 3.21% (4.01 MAC) halothane, that is, 3.3 times the anticipated anesthetic potency output.18

TABLE 38–4. Output in Percent and Minimum Alveolar Concentration (MAC) in O2 of Erroneously Filled Vaporizers at 22°C Vaporizer

Liquid

Setting (%)

Output (%)

Output MAC

Halothane

Halothane Enflurane Isoflurane Enflurane Isoflurane Halothane Isoflurane Halothane Enflurane

1.0 1.0 1/0 2.0 2.0 2.0 1.5 1.5 1.5

1.00 0.62 0.96 2.0 3.09 3.21 1.50 1.56 0.97

1.25 0.37 0.84 1.19 2.69 4.01 1.30 1.95 0.57

Enflurane

Isoflurane

Reproduced with permission from Bruce DL, Linde HW. Vaporization of mixed liquids. Anesthesiology 1984;60:342.

Erroneous filling of vaporizers can be prevented by careful attention to the specific agent and the vaporizer when filling is performed. In the United States, agent-specific keyed filling mechanisms are available as options on modern vaporizers; in Canada, keyed filling is a standard. Liquid anesthetic agents are commercially available packaged in bottles that have an agent-specific collar. One end of the agent-specific filling device fits the collar on the agent bottle, and the other end fits only the vaporizer designed for that agent. An agent-specific filling system assumes even greater importance with desflurane (see Desflurane and the Tec 6 Vaporizer and Table 38–2). Keyed filling systems also decrease contamination of the operating room atmosphere during vaporizer filling.

Vaporization of Mixed Anesthetic Liquids A more likely scenario is that an agent-specific variable-bypass vaporizer partially filled with correct agent is topped off with an incorrect agent.18 The situation here is more complex, vaporizer output is less-easily predicted, and large errors in vapor administration can occur. Halothane, enflurane, and isoflurane, when mixed, do not react chemically but do influence the extent of each other’s ease of vaporization. Halothane facilitates the vaporization of both enflurane and isoflurane and in the process is itself more likely to vaporize.19 The clinical consequences depend on the potencies of each of the mixed agents as well as the delivered vapor concentrations. If a halothane vaporizer 25% full is refilled to 100% with isoflurane and set to deliver 1%, the halothane output is 0.41% (0.51 MAC) and the isoflurane output is 0.9% (0.78 MAC) (Table 38–5).18 In this case, the output potency of 1.29 MAC is not far from the 1.25 MAC (1% halothane) expected. However, an enflurane vaporizer 25% full and set to deliver 2% (1.19 MAC) enflurane that is filled to 100% with halothane has an output of 2.43% (3.03 MAC) halothane and 0.96% (0.57 MAC) enflurane (Table 38–5).19 This represents a total MAC of 3.6, or more than twice that intended. In any event, it is important that erroneous filling of vaporizers be avoided, and that if suspected, the vaporizer be

781


TABLE 38–5. Vaporizer Output after Incorrectly Refilling from 25% to 100% Full Vaporizer Outputs Halothane Vaporizer Halothane Enflurane Isoflurane

Setting(%) 1.0 1.0 2.0 1.5

Refill liquid Enflurane Isoflurane Halothane Halothane

% 0.33 0.41 2.43 1.28

Enflurane

MAC 0.41 0.51 3.03 1.60

% 0.64 — 0.96 —

MAC 0.38 — 0.57 —

Isoflurane % — 0.90 — 0.57

MAC — 0.78 — 0.50

Total MAC 0.79 1.29 3.60 2.10

Reproduced with permission from Bruce DL, Linde HW. Vaporization of mixed anesthetic liquids. Anesthesiology 1984;60:342.

Effect of Carrier Gas on Vaporizer Output

3 L/min 70% N2, 30%O2

3

liquid volatile agents. When N2O/O2 first enters the vaporizing chamber, some N2O gas physically dissolves in the liquid agent, and the vaporizing chamber output decreases until the liquid has become saturated with N2O. Conversely, when N2O is discontinued as the carrier gas, the N2O gas that is dissolved in the liquid anesthetic comes out of solution and represents, in effect, additional gas flow to the vaporizing chamber. The solubility of N2O is approximately 4.5 mL per mL of liquid anesthetic. Thus 100 mL of halothane liquid, when fully saturated with N2O, can dissolve approximately 450 mL of N2O. Such a volume of N2O, being added to the vaporizing chamber flow over a brief period when N2O has been discontinued, causes the observed increase in vaporizer output concentration. This effect is not ob-

3 L/min 70% N2O, 30%O2

The carrier gas used to vaporize the volatile agent in the vaporizing chamber may also affect vapor output concentration. Thus when the carrier gas flow through a variable-bypass Ohio enflurane vaporizer (Fig. 38–11) was changed from N2/O2 to N2O/O2, the vapor concentration decreased for about 15 minutes and then returned to normal.21 Once the output concentration is stable with a carrier gas of N2O/ O2, changing back to N2/O2 resulted in an increase in vapor concentration for about 15 minutes. The explanation for this observed effect is the solubility of N2O in the

3 L/min 70% N2, 30%O2

782

Vaporizers should only be filled as directed in their accompanying instructions. Overfilling or tilting of a vaporizer (free-standing or by tilting the whole anesthesia machine) may result in liquid agent entering parts of the anesthesia delivery system (e.g., vaporizer bypass flow) designed for gases or vapors only and might give rise to lethal concentrations of the agent. If a vaporizer has been tilted and there is concern that liquid agent has leaked into the gas delivery system, then with no patient connected to the system, the vaporizer should be purged with a high flow rate of O2 (10 L/min) from the machine flowmeter (not the O2 flush, which bypasses the vaporizer) and with the vaporizer concentration dial set to the maximum concentration setting.20 The most recent models of vaporizer (Datex-Ohmeda Tec 7; Dräger Vapor 2000 series) are designed with antispill mechanisms. Thus to remove a Vapor 2000 vaporizer from the mounting manifold, the concentration dial must be turned past the OFF setting to the T setting, or transport mode. In this setting, the sump that contains liquid agent is completely isolated from the other parts of the vaporizer, which can then be safely tilted. Table 38–2 shows that 1 mL of liquid volatile anesthetic agent produces approximately 200 mL of vapor at 20°C. Thus if small volumes of liquid agent enter parts of the delivery system intended for gas or vapor only, it is easy to see how potentially lethal concentrations of vapor could arise. For example, if 1 mL of liquid halothane entered the patient breathing system,

3 L/min 70% N2O, 30%O2

Filling of Vaporizers

it would require 22.6 L of fresh gas to dilute the resulting vapor to a 1% concentration (1.3 MAC).

% Enflurane

emptied, serviced, purged, and refilled with the correct agent.

2

1

0

0

10

20

30

40 50 Time (min)

60

70

FIGURE 38–11. Effect of carrier gas composition on output of Ohio enflurane variable-bypass vaporizer (see text for details).


MAC, or 1.3 times the anesthetic potency expected.

Hyperbaric Conditions

FIGURE 38–12. Use of variable-bypass halothane vaporizer under hypobaric conditions. Vaporizer is set to 1% (vol/vol) and is being used at ambient pressure of 500 mm Hg.

served with measured-flow vaporizers (e.g., Copper Kettle, Verni-Trol ), as in this type of arrangement the carrier gas is always O2.21

Changes in Barometric Pressure Although vaporizers are most often used at ambient pressures of approximately 760 mm Hg (1 atm at sea level), they may be used under hypobaric (e.g., at increased altitude) or hyperbaric (e.g., in a hyperbaric chamber) conditions.22

Hypobaric Conditions Because few reports discuss the use of vaporizers under hypobaric conditions, the theoretic considerations applying to such use are discussed here. Consider a variable-bypass vaporizer set to deliver 1% halothane (1.3 MAC at 760 mm Hg atmospheric pressure) that is being used at an ambient pressure of 500 mm Hg (equivalent to an altitude of 10,000 feet above sea level) and at a temperature of 20°C (Fig. 38–12). In the vaporizing chamber, halothane has an SVP of 243 mm Hg (at 20°C), but this now represents 243/500 = 48.6 vol%. The vaporizer, set to deliver 1% under normal conditions, creates a splitting ratio of 46:1 (Table 38–3) between bypass and vaporizing chamber flows. If the total gas flow to the vaporizer is 4700 mL/ min (Fig. 38–12), 4600 mL/min enter the bypass and 100 mL/min of carrier gas enter the vaporizing chamber. This 100 mL represents 51.4% of the volume there because halothane represents the other 48.6 vol% (100% – 51.4%). Emerging from the chamber is 100 mL/min of carrier gas plus ([100/

51.4] × 48.6) = 94.6 mL/min of halothane vapor. When the vaporizing chamber and bypass flows merge, the 94.6 mL/min of halothane vapor are diluted in a total volume of 4794.6 mL/min (4600 + 100 + 94.6), giving a halothane concentration of 1.97 vol%, or approximately 2%. This would appear to be double the dialed-in concentration in terms of volumes percent. Now consider partial pressures. If halothane represents 1.97% of the gas mixture by volume, its partial pressure in the emerging mixture is 1.97 × 500, or 9.85 mm Hg. In terms of anesthetic potency, this represents 9.85/ 5.7, or 1.73 MAC, because the PMAC1 of halothane is 5.7 mm Hg (Table 38–1). Thus in theory, when used at an ambient pressure of 500 mm Hg, the variable-bypass halothane vaporizer set to 1% (vol/vol) would deliver twice the dialed-in concentration in terms of volumes percent but only 1.73/1.33

Consider a variable-bypass isoflurane vaporizer set to deliver 2% (1.74 MAC at 760 mm Hg atmospheric pressure) isoflurane vapor used at 20°C and 3 atm (3 × 760 = 2280 mm Hg), as may exist in a hyperbaric chamber (Fig. 38–13). In the vaporizing chamber, the SVP of isoflurane is 238 mm Hg (Table 38–2) and the isoflurane concentration is 10.4 vol% ([238/2280] × 100). A variablebypass isoflurane vaporizer set to deliver 2% creates a splitting ratio of 21:1 for the fresh gas flow (Table 38–3). If the total gas flow to the vaporizer is 2200 mL/min, 2100 mL enter the bypass and 100 mL of carrier gas enter the vaporizing chamber per minute (Fig. 38–13). This 100 mL represents 89.6% (100 – 10.4) of the total gas there; the remainder is isoflurane vapor. The amount of isoflurane vapor evolved is ([100/89.6] × 10.4) = 11.6 mL/min. This volume, diluted in 2100 + 100 + 11.64 gives 11.6/2211.6, or 0.52% isoflurane vapor by volume. This is 0.26 (0.52/2.0) of what was set on the concentration dial in terms of volumes percent. How about potency? The partial pressure of isoflurane in the emerging gas mixture is 11.9 mm Hg (0.52% × 2280). Dividing by the PMAC1 for isoflurane of 8.7 mm Hg (Table 38–1) gives a potency output of 1.37 MAC (11.9/ 8.7). Thus the isoflurane vaporizer, set to deliver 1.74 MAC under conditions of 1 atm pressure, delivers 1.37 MAC at 3 atm, or about 0.80 times the anesthetic potency expected.

FIGURE 38–13. Use of variable-bypass isoflurane vaporizer under hyperbaric conditions. Vaporizer is set to 2% (vol/vol) and is being used at ambient pressure of 2280 mm Hg (3 atm).

783


These examples show that although changes in ambient pressure may have a great effect on vapor concentration output in terms of volumes percent, the anesthetic potency (MAC) output is changed less drastically. In the examples discussed, it was assumed that the set splitting ratios (Table 38–3) would be maintained constant as ambient pressure changed. In reality, changes in gas density occur with changes in ambient pressure and may affect the splitting ratios slightly. The anesthetic potency output expected for any given vaporizer setting is relatively unchanged, by ambient pressure, even though vapor concentration (vol/vol) may be altered considerably.22 Again, vaporizer output concentration expressed in volumes percent is of limited value unless converted to MAC units using the concept of pressures as described in the foregoing examples.12,22 784

Arrangement of Vaporizers Old anesthesia machines had up to three variable-bypass vaporizers arranged in series such that fresh gas from the flowmeters passed through each vaporizer to reach the common gas outlet of the anesthesia machine. Without an interlock system, which permits only one vaporizer to be in use at any time, it was possible to have all three vaporizers turned on simultaneously. Apart from potentially overdosing the patient, the agent from the upstream vaporizer could contaminate the liquid agent(s) in the downstream vaporizer(s). During subsequent use, the output of the downstream vaporizer would be contaminated. The resulting concentrations in the emerging gas and vapor mixture would be indeterminate and might even be lethal.12 With modern workstations, only one vaporizer can be on at any time. The recent standards require that, to prevent cross-contamination of the contents of one vaporizer with an agent from another, a system must be provided that isolates the vaporizers from each other and prevents gas from passing through the vaporizing chamber of one vaporizer and then through that of another.1,2 This specification is met by use of an interlock system. Contemporary Dräger and Datex-Ohmeda anesthesia machines incorporate manufacturer-specific interlock systems.23,24

Calibration and Checking of Vaporizer Outputs Vaporizers should be regularly serviced according to manufacturer’s recommendations and their outputs checked to ensure that a malfunction does not exist. Thus the vaporizer dial is set to deliver a certain concentration. The actual output concentration is measured by an anesthetic agent analyzer that samples gas via a connector placed at the common gas outlet of the anesthesia machine.

Desflurane and the Tec 6 Vaporizer Box 38–1 lists the physical properties of desflurane. With an SVP of 669 mm Hg at 20°C and a boiling point of 22.8°C, this agent is extremely volatile. Clearly, this agent cannot be administered using the conventional variable-bypass design of vaporizer used for halothane, enflurane, isoflurane, and sevoflurane. If such a variable-bypass vaporizer were somehow filled with desflurane, an increase in temperature to above 22.8°C would result in the desflurane boiling in the vaporizing chamber and uncontrolled output from the vaporizer. The consequences of misfilling contemporary agent-specific variable-bypass vaporizers with desflurane at 22°C have been predicted.23 Thus an enflurane vaporizer set to deliver 3 MAC (approximately 5% enflurane) would deliver 16 MAC (approximately 96%) desflurane at 22°C.25 Datex-Ohmeda (Steeton, UK) designed the Tec 6 concentration-calibrated vaporizer for the controlled administration of desflurane. It was designed to make the practical aspects of the clinical administration of desflurane no different from that of other potent inhaled agents using their Tec series of vaporizers (Fig. 38–14).24,25 The principle of operation of the Tec 6 is that liquid desflurane is heated in a chamber (the sump) to 39°C to produce vapor under pressure (~1500 mm Hg or 2 atm absolute) analogous to having a reservoir of compressed gas in a tank (Fig. 38–14). The vapor leaves the sump (item 9) via a variable pressure-regulating valve (item 7), the opening of which is continuously adjusted according to the output from pressure transducers (items 3 and 4) to ensure that the pressure of the desflurane vapor entering the rotary valve in the user-controlled concentra-

BOX 38–1. Desflurane Structure: CHF2OCHFCF3 Molecular weight: 168 Specific gravity: 1.45 Boiling point: 22.8°C at 760 mm Hg SVP: 669 mm Hg at 20°C Odor: ethereal Preservative free MAC: 6–7.25%* at 760 mm Hg PMAC1: 46–55 mm Hg MAC, minimum alveolar concentration; PMAC1, partial pressure at concentration of 1 MAC; SVP, saturated vapor pressure. *Age related; see reference 15 and Table 38–1.

tion dial is the same as the pressure generated by the fresh gas inflow (from the anesthesia machine flowmeters) into a fixed restrictor. The concentration dial and rotary valve control the quantity of desflurane vapor added to the fresh gas flow so that what emerges from the vaporizer outlet is the dialed-in concentration of desflurane. Unlike other concentration-calibrated vaporizers (e.g., DatexOhmeda Tec 5, Dräger Vapor 19.1) which are of variable-bypass design, no fresh gas enters the desflurane sump in the Tec 6. The Tec 6 is calibrated by the manufacturer using 100% oxygen as the fresh gas. As the oxygen enters the vaporizer it flows through a fixed restrictor (Fig. 38–14, item 2, and Fig. 38–15). This is a device that offers a fixed resistance, resistance being defined as change in pressure per unit of flow. The resistance is approximately 10 cm H2O/L/min over a wide range of gas flows. The back pressure created by gas flowing through the fixed restrictor is therefore proportional to the main gas flow (as set on the machine flowmeters) and changes according to Poiseuille’s law (see Gas Flow Control Systems [Knobs, Needle Valves, Rotameters, Etc.] above). By sensing this back pressure (via a pressure transducer) and ensuring that the pressure of the desflurane vapor entering the variable restrictor is always made equal to this pressure (via the control electronics and variable pressure control valve), the variable restrictor provides a means to control


785

FIGURE 38–14. Schematic of the Tec 6 vaporizer for desflurane. 1, Dial and rotary valve; 2, fixed restrictor; 3, pressure control transducer; 4, pressure monitor transducer; 5, heater in vapor control manifold; 6, vapor control manifold assembly; 7, pressure regulating valve; 8, shut-off valve; 9, sump assembly; 10, agent; 11, volume sensor; 12, sump heaters; 13, mains lead; 14, battery; 15, power supply; 16, control electronics; 17, heater electronics PCB; 18, alarm electronics PCB; 19, agent level liquid crystal display; 20, alarm battery low amber light; 21, water-up amber light; 22, low agent amber light; 23, no output red light; 24, operation green light; 25, tilt switch; 26, solenoid in interlock block; 27, heater in valve plate. For details of operation see text.


the concentration of desflurane (Fig. 38–15). Thus, Resistance = ∆ Pressure ∆ Flow (38–1) For the main gas flow of oxygen entering the fixed restrictor, Resistance (main) = Pressure(main) Flow(main) (38–2) or Flow (main) = Pressure(main) Resistance(main) (38–3)

786

But Resistance(main) is a constant, K (10 cm H2O/L/min), so Flow(main) is proportional to Pressure(main). For the desflurane flow entering the concentration dial variable restrictor, Flow(des) = Pressure(des) Resistance(main)

dial [i.e., Resistance(des)], can be calibrated in terms of desflurane concentration. The calibration of the variable restrictor is not linear, however, and equation 38–6 above is an approximation because the value of Flow(des) in the denominator of equation 1 cannot always be ignored. Some examples of vaporizer concentration dial and gas flow settings will illustrate the application of these principles. Example 1 Consider a Tec 6 vaporizer set to deliver 10% desflurane at a fresh gas flow of O2 of 5 L/min (Fig. 38–16). Concentrations(des) = Flow(des) Flow(main) + Flow(des) 10% = 0.10 =

Flow(des) 5000 + Flow(des) (38-7)

Thus, 0.10 × (5000 + Flow(des)) = Flow(des) 0.9 × Flow(des) = 500 mL

Concentrations(des) = Flow(des) Flow(main) + Flow(des) (38–4) If Flow(des) is small compared to Flow(main), we can ignore Flow(des) in the denominator of equation 38–4, thus: Concentrations(des) = Flow(des) = Flow(main)

Flow(des) = 500 = 556 mL/min 0.9 (38-8) Consequently, at a 5 L/min flow of O2 and set to deliver 10% desflurane, the Tec 6 is adding 556 mL/min of desflurane vapor to the main gas flow, that is, 556 556 = = 0.10 = 10% 5000 + 556 5556 (38-9)

Once the main flow (in this case 5 L/min O2) and the desflurane flow (calculated as above) are known, the ratio of resistances of the variable resistor (Resistance(des), in the concentration dial) to the fixed resistor (Resistance(main), in the main gas flow) may be calculated: Resistance(des) = Pressure(des) Flow(des) Resistance(main) = Pressure(main) Flow(main) (38-10) But, Pressure(des) = Pressure(main), therefore, Flow(main) Resistance(des) = = Flow(des) Resistance(main) 5000 = 9:1 556

Resistance(des) may also be calculated as follows: Pressure(des) = Pressure(main), which is 50 cm H2O (because main gas flow is 5 L/min) Flow(des) = 556 mL/min Resistance(des) = Pressure(des) = Flow(des) 50 = 90 cm H2O/L/min 0.556 (38-12) Example 2 Increase fresh gas flow to 10 L/min. Increasing Flow(main) from 5 L/min to 10 L/min causes a temporary imbalance of pressures

Pressure(des) × Κ Pressure(main) × Resistance(des) (38–5) The pressure transducer, control electronics and variable pressure control valve ensure that Pressure(des) = Pressure(main), therefore: Concentration(des) = Flow(des) Flow(main) which is approximately equal to: 1 Resistance(des) (38–6) Thus it becomes apparent that the variable restrictor in the concentration

(38-11)

FIGURE 38–15. Tec 6 vaporizer simplified to illustrate principles. See text for details.


FIGURE 38–16. A. Tec 6 vaporizer (Datex-Ohmeda) for desflurane. B. Close-up to show status warning lights and LCD indicating agent level.

across the differential pressure transducer because Pressure(main) increases from 50 cm H2O to 100 cm H2O (Fig. 38–15). (Remember that Resistance(main) is 10 cm H2O/L/min.) The imbalance is sensed by the differential pressure transducer and the control electronics cause the variable pressure control valve to open wider (i.e., decrease its resistance to desflurane vapor flowing from the sump at a pressure of 1500 mm Hg) so that the pressure of desflurane vapor into the concentration dial variable restrictor increases until Pressure(des) is also 100 cm H2O. The increase in Flow(des) and, thereby, Pressure(des) ensures that the Tec 6 continues to deliver the 10% concentration as set on the dial. Example 3 Increase concentration dial setting from 10% to 15% while maintaining gas flow of 10 L/min. Increasing the concentration dial setting to 15% causes a decrease in Resistance(des). The resulting decrease in Pressure(des) relative to Pressure(main) is sensed by the differential pressure transducer and the control electronics cause the variable pressure control valve to open wider (i.e., decrease its resistance to desflurane vapor flowing from the sump) so that Pressure(des) is increased to once again be equal to Pressure(main). The resulting increase

in Flow(des) ensures that the vapor concentration increases to the desired greater concentration. Example 4 Decrease concentration dial setting from 15% to 5% at 10 L/ min gas flow. Changing the concentration dial setting from 15% to 5% creates an increase in Resistance(des), which causes an increase in Pressure(des). The latter is sensed by the differential pressure transducer because Pressure(des) is now greater than Pressure(main) and the control electronics cause the variable pressure control valve to decrease its opening (i.e., increase its resistance to desflurane vapor flowing from the sump), thereby decreasing Flow(des) until Pressure(des) once again equals Pressure(main).

Special Considerations Design Features of the Tec 6 (Figs. 38–14 and 38–16)The sump, when full, contains 450 mL desflurane. Because the sump is pressurized to 1500 mm Hg, the agent level is sensed electronically and shown on a liquid crystal display (LCD), rather than the sightglass used in variable-bypass vaporizers. When the vaporizer is energized by connecting the power cord to an electrical outlet, a heater in the sump heats the agent to 39°C and maintains that

temperature via thermostatic controls. While the agent is being heated, the sump shut-off valve is held closed, keeping the agent in the sump. During the warmup period, the vaporizer is not operational because the sump shut-off valve remains closed, and a solenoidlocking device prevents the concentration dial from being turned to on. Once operational (i.e., at 39°C), the dial lock is released and when the dial is turned on, the sump shut-off valve is opened, permitting desflurane vapor to flow to the pressure regulating valve.24,25 To prevent condensation (“rain out”) of desflurane vapor, in addition to the heater in the sump, there are heaters in the rotary valve and in the vicinity of the pressure transducers that sense the back pressures caused by the main gas flow and by desflurane. The Tec 6 thus differs considerably from variable-bypass vaporizers. None of the fresh gas flow enters the vaporizing chamber. The Tec 6 requires electrical power and incorporates sophisticated electronics to ensure normal operation and a display panel to inform the user about its operational status. It also has alarms to alert to any malfunction, in the event of which the sump shut-off valve closes (Fig. 38–16). Filling System Because of its high saturated vapor pressure, desflurane is supplied in plastic-coated glass bottles

787


788

to which an agent-specific filling device is firmly attached. The vaporizer incorporates an agent-specific filling system that permits filling of the sump at any time, including when the vaporizer is in use. This may be important because of desflurane’s low blood-to-gas partition coefficient. During filling the bottle is locked to the vaporizer-filling system and the high pressure of vapor in the sump at 39°C is transmitted to the interior of the bottle, which helps to drive liquid desflurane from the bottle into the sump. When filling is complete, the bottle is disconnected from the vaporizer fill system and the valve on the bottle closes to avoid loss or spillage of agent. At this time the bottle contains vapor at 39°C and a pressure of 1500 mm Hg. As the bottle and its contents cool to room temperature, the pressure in the bottle decreases toward atmospheric (760 mm Hg at 22.8°). Effect of fresh gas composition on performance. The Tec 6 is calibrated at the factory using 100% O2. Performance accuracy at 5 L/min oxygen is specified as ± 0.5% of delivered agent or ± 15% of dial setting, whichever is greater.24 Using Poiseuille’s law, laminar flow through a resistor is determined as: Flow = π × P × r4 8×η×L

the least viscous. Thus, changing the main gas flow composition from O2 to O2/N2O decreases gas viscosity and the output concentration of desflurane from that setting on the dial. Differences between the actual concentration produced and the dial setting are greatest (up to 20% of dial setting) with high concentrations of N2O at low gas flow rates. The clinical implications of this are minimal, however, because the anesthetic effect lost by the decrease in desflurane is offset by the effect of the N2O.24 Effects of Altitude on Output The Tec 6 accurately delivers the dialed-in concentration of desflurane in terms of volumes percent, even at altitudes different than sea level. At sea level, 7% desflurane (1 MAC) creates a Pdes of (7% × 760 mm Hg) = 53 mm Hg (the PMAC1; Table 38–2). At altitude, if the ambient pressure were 500 mm Hg, the same 7% desflurane creates a Pdes of only 35 mm Hg (7% × 500), which is only 0.66 of the PMAC1. To compensate for this decrease in potency output at increased altitude, a higher concentration must be set on the dial. Conversely, at higher ambient pressures, a lower concentration dial setting would be indicated. Recommendations as to how the dial setting should be changed at altitude are provided in the operator’s manual.24

Interlock System Although the Tec 6 is manufactured by Datex-Ohmeda and is mountable on their patented Select-a-Tec manifold on a DatexOhmeda anesthesia machine, a version is also available for mounting on Dräger Narkomed anesthesia workstations. Recently, Dräger introduced the D-Vapor desflurane vaporizer to its Vapor 2000 series (Fig. 38–17). The operating principles are the same as in the Datex-Ohmeda Tec 6 but it weighs significantly less. Similar to other vaporizers in their Vapor 2000 series, the D-Vapor is hermetically sealed when removed from an anesthesia system, allowing transport in any position, even when filled. The 300-mL reservoir capacity of the tank can hold the entire contents of a standard anesthetic agent bottle. Like the Tec 6, the D-Vapor is electrically powered, but it also features 5 minutes of emergency battery operation which ensures that dose settings remain constant even during a brief power failure. Penlon (UK) has also exhibited a desflurane vaporizer addition to their Sigma series of vaporizers, but at the time of writing it is not being marketed in the United States.

Aladin Vaporizing System Advances in technology and computerization of the workstation have led to the development of a new design of

where π = 3.142, P is the pressure difference, r is the radius, η is the viscosity of the gas, and L is length Thus, Flow =

P η

or P ≈ Flow × η The Tec 6 design uses back pressure from gas flow through the fixed restrictor to infer flow (Fig. 38–15). If the viscosity of the gas flowing through the fixed resistor were to decrease, then the same flow would result in a lower back pressure. This back pressure is used to determine the pressure of desflurane into the variable restrictor in the concentration dial. A lower pressure results in a lower flow of desflurane vapor through the variable restrictor. Of the gases on the anesthesia machine, O2 is the most viscous and N2O

FIGURE 38–17. Left: Dräger D-Vapor desflurane vaporizer. Right: Dräger Vapor 2000 sevoflurane vaporizer. Note the T position (for Transport mode) on the concentration dial.


variable-bypass, electrically powered Aladin vaporizing system that is used in the Datex-Ohmeda S5 /ADU and Aisys workstations. The principles of operation differ from those of earlier variable-bypass vaporizers and from the Tec 6 design of vaporizers discussed above. The Aladin vaporizer consists of two separate parts that must be joined to produce a functioning vaporizer. One is a sump, the detachable agent-specific Aladin cassette, that can hold up to 250 mL of liquid agent. Each anesthetic agent, including desflurane, has its own cassette made unique by means of an agent-specific fill system (e.g., SafT-Fil for desflurane; key fill or QuickFill for other agents). Thus five different cassettes are available, one for each of the presently available potent inhaled agents. The second part of the vaporizer is a component of the ADU or Aisys workstation and contains the concentration-control hardware and software. The agent-specific cassette identifies itself to the second part of the vaporizer by the arrangements of signature magnets at the top of the cassette. The ADU and Aisys workstations monitor and control gas and vapor at several points. They monitor and control flow through the N2O, O2 and air flowmeters and will not permit the delivered oxygen concentration to fall below 25% at the workstation’s common gas outlet. Gas flow from these sources is delivered to, or bypasses, the anesthetic in the sump. The flow of agent at its saturated vapor concentration issuing from the sump, and the bypass flows are monitored and adjusted by hardware, as governed by software algorithms to produce the dialed-in concentration of anesthetic. The algorithms take into account the anesthetic agent, temperatures and gas pressures in the sump and by pass (each separately measured). The agent wheel (an electronic control) on the front panel of the ADU or Aisys workstation is used to set the desired concentration of agent to be delivered to the breathing system (Fig. 38–18). A green light-emitting diode (LED) indicates that the vaporizer is on (Fig. 38–19). The vaporizer is controlled via a central processing unit (CPU). See Figure 38–20 for principles of operation.26 The flow restrictor in the bypass causes fresh gas from the gas flow controls to be split into a bypass flow and a flow, that passes

FIGURE 38–18. Aladin vaporizing system shown here on a Datex-Ohmeda ADU workstation. The cassette is agent-specific (in this case sevoflurane). The dial to the left of the cassette is the concentration control. The (green) pilot light to the left of the dial indicates that the vaporizer is on. The dialed-in agent concentration is shown at the bottom of the left-hand screen.

through a unidirectional valve (which prevents backflow) to the Aladin cassette. The latter is an agent-specific cartridge that contains liquid anesthetic at its saturated vapor concentration at the ambient temperature (e.g., [160/ 760] × 100% = 21 vols% for sevoflurane at 20°C). Continuous monitoring of temperature and pressure in the cassette means that the agent vapor concentration there is always known. The concentration of anesthetic vapor delivered to the common gas outlet of the machine is determined by the con-

centration of agent vapor in the cassette, and the ratio of cassette outflow to the bypass flow, both of which are measured continuously. The delivered concentration is controlled by the position of the agent proportional valve, which is set continuously according to information from the agent controller (CPU). Each Aladin cassette is essentially a flow-over vaporizer because it contains liquid agent that is vaporized as fresh gas flows between the agentsoaked wicks and baffles. It is equiva-

FIGURE 38–19. Enlarged view of concentration dial and agent display box on screen. Although this is an electronically controlled vaporizing system, agent concentration is increased by turning the dial in a counterclockwise direction, analogous to the dial on a traditional variable-bypass vaporizer (e.g. Tec 7, Dräger Vapor 2000.)

789


790

FIGURE 38–20. Schematic showing principles of operation of the Aladin vaporizing system used on the Datex-Ohmeda ADU and Aisys workstations.

lent to the sump of a traditional variable-bypass vaporizer but because it does not incorporate bypass flow channels, tilting the cassette during handling, changing, or filling is not hazardous (Figs. 38–21A,B). The Aladin cassette for desflurane incorporates an electronic liquid level measuring device so that if 80 —

Ba(OH)2 — — — 4% Zeolite 6.5% Silica CaCl2 CaCl2 —

No longer Yes Yes Yes Yes Yes No Longer Yes No longer

~16

1–3

NA

75–83

—

Yes

14–18

0.5–2

NA

74–82

CaCl2

Yes

— 12–19 —

1

855


dure as well as decrease the required dose of the sedative. Intermittent bolus administration has the additional risk of causing periods of unconsciousness that may be accompanied by diminished or absent airway reflexes. Barbiturates are infrequently used for procedural sedation (except perhaps the use of methohexital during officebased oral surgical procedures). In subhypnotic doses, thiopental has only mild suppressant effects on memory23 (usually considered a desirable effect), and there may be hyperalgesia to pain.

TABLE 40–7. Induction Characteristics for Intravenous Anesthetic Agents

Drug Name

Induction Dose (mg/kg)

Onset (sec)

Duration (min)

Excitatory Activity

Injection Pain

Thiopental Methohexital Propofol Etomidate Diazepam Lorazepam Midazolam Ketamine

4–7 1–3 1–3 0.2–0.3 0.3–0.6 0.03–0.06 0.2–0.4 1–2

30 5–7 10–20 15–20 1 mg/kg) with only oxygen, and a muscle relaxant could be used during cardiac surgery to produce profound analgesia and sleep.87 In patients with left ventricular dysfunction as a consequence of valvular disease, hemodynamics frequently improved because preload and afterload were reduced. This anesthetic technique rapidly became popular for cardiac surgery.

887


Responder Nonresponder

Plasma sufentanil (ng/mL)

30 25 20 15 10 5 0

888

Post intubation

Post sternotomy

Post cannulation

FIGURE 41–18. Presence or absence of hemodynamic response versus plasma concentration of sufentanil at three points during cardiac surgery. Patients undergoing coronary revascularization received only sufentanil, 100% oxygen, and muscle relaxant. Response was defined as a blood pressure increase of 15% or more over control value while awake. Given alone, even extremely high concentrations of sufentanil did not block all responses. (Reproduced with permission from Philbin DM, Rosow CE, Schneider RC, et al. Fentanyl and sufentanil anesthesia revisited: how much is enough? Anesthesiology 1990;73:5.)

Unfortunately, it had a number of drawbacks, including hypotension, histamine release, occasional intraoperative awareness, and prolonged ventilatory depression. Even these large doses of morphine did not block cardiovascular responses to some stimuli (e.g., sternotomy), but increasing the dose to nearly 10 mg/kg created unacceptable hypotension and fluid shifts. Stanley evaluated fentanyl-oxygen “anesthesia” in a variety of cardiac surgical populations,144 and found that 50–100 µg/kg of fentanyl produced only modest decreases in systemic pressure and total peripheral resistance. Unlike morphine, high doses of fentanyl did not release histamine.122 Within a few years, fentanyl had replaced morphine for this indication. Sufentanil was introduced a few years later, and in doses as high as 30 µg/kg, it shared fentanyl’s hemodynamic advantages as an opioid anesthetic.124 Why give such huge doses of these opioids? If no other sedative-hypnotic agents are administered, very large doses are required to produce sleep.9,138 Large doses of opioids have some advantages in the cardiac surgical population: induction is usually smooth and well tolerated, even by patients with limited myocardial reserve; most hemodynamic responses to surgery are suppressed, and there are no dangerous interactions with most vasoac-

tive medications. This type of anesthesia can also block the release of many “stress” hormones (catecholamines, insulin, growth hormone, antidiuretic hormone, cortisol, renin, etc.) during major surgery.17 The long duration of the opioid effect also allows for a smooth transition to mechanical ventilation in the immediate postoperative period. Fentanyl and sufentanil have fewer limitations than morphine, but they should not be considered complete anesthetics: intraoperative awareness is less common, but still a possibility. Recall has been reported after fentanyl doses as high as 90 µg/kg.98 Even very high plasma concentrations of fentanyl or sufentanil will not block all hemodynamic and hormonal responses to surgery112 (Fig. 41–18). Certain reflex cardiovascular responses seem particularly opioid resistant; for example, the reflex hypertension and tachycardia that is elicited by manipulation of the heart and great vessels. The stress hormonal responses that occur during cardiopulmonary bypass are not completely eliminated by opioids.17 In clinical practice, “pure” opioidoxygen anesthesia (without adjuvant anesthetic drugs) is rarely performed. The desire of most clinicians to be flexible and “fast-track” some of their patients makes such a long-lasting anesthetic less desirable. Most patients

receive premedication and moderate doses of opioids; inhalation or intravenous agents are added to control hemodynamics and to ensure unconsciousness during surgery. The addition of hypnotic agents creates a more complete anesthetic, although cardiovascular depression is more likely. Highdose fentanyl, for example, produces a much larger fall in peripheral resistance when the patient has received intravenous diazepam.153 Paradoxically, anesthesiologists rely on opioids during surgery both for suppression and preservation of autonomic function. Opioids suppress autonomic responses to pain, but they are often part of anesthesia for critically ill patients because they preserve myocardial function and many essential hemodynamic reflexes. In an otherwise fit hypertensive patient, the lack of cardiovascular depression can sometimes make it difficult to control intraoperative hemodynamics. Opioids are not substitutes for β-blockers, intravenous vasodilators, or the controlled vasodilatation produced by inhalation anesthesia. This was elegantly demonstrated by Wynands et al., who compared high-dose fentanyl anesthesia in patients with good or poor left ventricular function.167 Plasma concentrations of fentanyl were high in all patients, but hypertensive episodes occurred almost exclusively in those with good left ventricular function. In this study, hypertension was not a sign of insufficient analgesia, it was an indicator of adequate myocardial function! These patients tolerated—and required—supplemental intravenously administered or inhaled anesthetic agents.

OPIOID ANTAGONISTS Naloxone Naloxone, the N-allyl derivative of oxymorphone, was the first pure opioid antagonist to become available for parenteral use (Fig. 41–19A). Naloxone acts as a competitive antagonist at all opioid receptors, but it has greatest affinity for µ receptors. Small doses of naloxone reliably reverse or prevent the effects of pure opioid agonists and most mixed agonist–antagonists. The block is reversible and competitive, so it can be overcome by additional agonist. Naloxone probably has no effect

CHAPTER 41: Pharmacology of Opioid Analgesic Agents

to search for and treat conditions like residual paralysis, bronchospasm, and airway edema. Naloxone is used to reverse opioids in several other clinical settings: • In the delivery suite, naloxone can be used in depressed neonates whose mothers received opioids during labor. Clark showed that 0.01 mg/kg via an umbilical vein catheter was usually sufficient.22 Acidotic infants were slower to reverse and sometimes required a second dose. • In the emergency department, 0.4– 0.8 mg of naloxone is usually administered in cases of suspected heroin overdose. Naloxone is also useful as an aid in the differential diagnosis of coma; if a patient fails to respond to naloxone, nonopioid causes should be considered. • Patients who receive epidural or intrathecal opioids are frequently troubled by side effects like pruritus and urinary retention (see Chap. 46). An IV infusion of naloxone prevents or reverses these side effects, but may also produce an unacceptable reduction in analgesia.57

FIGURE 41–19. Structural formulas of naloxone (A), naltrexone (B), nalmefene (C), methylnaltrexone (D), and alvimopan (E).

on nonopioid anesthetics, although this remains somewhat controversial.40 Given alone, naloxone is nearly devoid of clinically demonstrable effects. In humans, extremely large doses (4 mg/kg) cause a mild increase in heart rate and systolic blood pressure, as well as slowing of EEG alpha-wave activity. Animal studies also show that naloxone can reduce food intake, alter sleep patterns, and improve spatial learning. In some disease states, such as septic shock, large doses can have a pressor effect. This may be the result of antagonism of elevated endogenous opioid peptides.15 Naloxone is widely distributed and rapidly achieves effective concentrations in the CNS. Plasma and brain levels fall precipitously because of rapid redistribution. The drug is rapidly cleared by hepatic biotransformation, mainly to the 3-glucuronide.96 The clearance is very high (approximately 30 mL/kg/min), which suggests that extrahepatic elimination

may be occurring. The terminal halflife is 1–2 hours. The onset of antagonist effect is extremely rapid, but the duration of action is quite brief. An IV dose of 0.4 mg will usually antagonize morphine for less than 1 hour; increasing the dose does not increase the duration appreciably. With the exception of remifentanil, the duration of naloxone is shorter than the opioids it is used to antagonize. The presence of excessive opioid effects is a common problem in the postoperative setting. Small doses of naloxone (0.04 mg in an adult, repeated every 3 minutes) can be given intravenously, usually with dramatic improvement. In many cases there also is partial reversal of analgesia, but this can be minimized by careful dosing. Patients who receive naloxone need continued observation, and possibly repeated doses. Postoperative ventilatory compromise is frequently caused by a combination of factors, and therapy with naloxone does not eliminate the need

Opioid reversal can sometimes have important hemodynamic consequences. Increases in systemic pressure, heart rate, and plasma levels of catecholamines can occur. This may be because of the sudden onset of pain, but these effects have been reproduced experimentally in the absence of painful stimuli.95 There are several case reports of fulminant pulmonary edema, dysrhythmias, and even death in young, previously healthy individuals given naloxone.4 In one case, the dose of naloxone was only 0.1 mg.107 The etiology of this rare, catastrophic response is unknown.

Naltrexone Naltrexone is the N-cyclopropylmethyl derivative of oxymorphone (Fig. 41– 19B). Like naloxone, it is a relatively pure antagonist. The main clinical use of naltrexone is in the treatment of previously detoxified heroin addicts. When high doses are taken chronically, naltrexone will block the euphoriant effects of injected heroin and thus help to prevent relapse. It also decreases drug craving in former addicts. Interestingly, naltrexone recently has been used to maintain sobriety in alcoholics, although the mechanism in this

889


indication is less clear.142 It is available orally and in a depot formulation for intramuscular injection. Naltrexone is rapidly absorbed and undergoes 95% first-pass metabolism to 6-β-naltrexol. This is an active metabolite that probably accounts for most of naltrexone’s activity. The metabolite accumulates during chronic treatment; it has a terminal half-life of 12.9 hours, so significant antagonist effects may persist for 2–3 days after naltrexone is stopped. In the event that a patient on naltrexone requires emergency surgery or treatment for acute pain, the patient should be managed (if possible) with regional anesthesia, nonopioid analgesics, and other nonopioid methods. If opioids are necessary, naltrexone antagonism is competitive and may be overcome with high doses of morphine or fentanyl.

Nalmefene 890

that this action is likely achieved via an intraluminal effect.169 MNTX, like naloxone, has minimal effects on opioid-naïve persons.

Alvimopan Alvimopan is another permanently charged, peripheral opioid receptor antagonist (Fig. 41–19E).43 It is poorly absorbed after oral administration, does not cross the blood–brain barrier, and does not reverse opioid analgesia. Alvimopan has been studied exclusively in an oral formulation for the treatment of OBD and also for the more general problem of postoperative ileus. Its efficacy in postoperative ileus may be because surgical insult releases endogenous opioid peptides in the bowel wall, which accounts for some of the decrease in intestinal motility. In both OBD and postoperative ileus, alvimopan significantly improves various indices of motility. The

improvement in postoperative ileus decreases the time to hospital discharge.166 At this writing, FDA approval for the oral use of alvimopan in postoperative ileus is pending.

OPIOID AGONIST– ANTAGONISTS General Properties The agonist–antagonist opioids are synthetic and semisynthetic analgesics that are structurally related to morphine (Fig. 41–20). They have been used primarily for moderate to severe acute pain, although buprenorphine has now been approved for maintenance therapy in opioid addiction. All these compounds produce some degree of competitive antagonism to morphine and the other pure agonists. Nalorphine, the original agonist–antagonist, is no longer used clinically,

Nalmefene is a potent, extremely longlasting pure antagonist. It is the 6methylene derivative of naltrexone (Fig. 41–19C). Gal and DiFazio showed that 2 mg of nalmefene can block the effects of repeated fentanyl injections for more than 8 hours.47 The long duration of nalmefene is probably because of its extensive distribution and long terminal half-life (9 hours). Reversal with nalmefene can probably cause some of the undesirable autonomic activation seen with naloxone. A single dose of nalmefene should certainly prevent recrudescence of ventilatory depression in most cases, and infusions are unlikely to be necessary. Nalmefene should be titrated carefully, because it can potentially eliminate opioid analgesia for a very long period of time.

N-Methylnaltrexone N-methylnaltrexone (MNTX) is a quaternary analogue of naltrexone that does not achieve significant concentrations in the CNS (Fig. 41–19D). It is being investigated in both parenteral and oral forms as a treatment for OBD.19 In healthy volunteers who were given morphine, intravenous MNTX reversed depression of gastric emptying and intestinal motility, but it did not interfere with analgesia against experimental pain.168 It rapidly relieves constipation in subjects on methadone maintenance and in hospice patients who are taking opioids chronically. Efficacy of the oral formulation suggests

FIGURE 41–20. Structural formulas of pentazocine (A), nalbuphine (B), butorphanol (C), buprenorphine (D), and tramadol (E).


but it has pharmacologic properties that illustrate the most important features of the class: • A strong analgesic effect, sufficient for moderate to severe postoperative pain. • A morphine antagonist effect that depends on the ratio of morphine to nalorphine. At very high doses of nalorphine, the agonist effects predominate. • A very low potential for diversion or abuse. Administration to subjects who are physically dependent on opioids produces a violent “precipitated withdrawal” syndrome. Former heroin addicts given nalorphine do not experience euphoria or perceive the drug as being similar to morphine. • A combination of typical and atypical opioid side effects. Nalorphine produces limited ventilatory depression and GI effects, but analgesic doses can cause severe psychotomimetic reactions. The unusual mental effects—distressing hallucinations and dysphoria—made nalorphine clinically unacceptable as an analgesic, although it was used for many years as an opioid antagonist. Nalorphine was an important milestone in opioid pharmacology because it demonstrated, for the first time, that addiction liability and potent analgesia might be separated. All the more modern agonist–antagonist opioids are products of an intense search for strong analgesics that are less likely to be abused. All of the agonist–antagonists behave as partial agonists; these drugs tend to have shallower dose–response curves and produce lower maximal effects than fentanyl or morphine119 (Fig. 41–1A). This means there is a “ceiling” to the analgesic effects, but the toxic effects also are limited. Most of the clinically available agonist–antagonists bind to both µ and κ receptors, but they have different intrinsic activities at each site: • κ Partial agonists: Pentazocine, butorphanol, and nalbuphine (and nalorphine) produce analgesia and sedation by a partial agonist effect at κ receptors. All of them are competitive antagonists at µ receptors, and therefore reverse the effects of morphine. • µ Partial agonists: Buprenorphine binds to µ receptors with extremely

TABLE 41–4. Agonist vs. Antagonist Potential of Opioid Mixed Agonist–Antagonists

Drug

Analgesic Potency (Morphine = 1)

Morphine Antagonist Potency (Nalorphine = 1)

Pentazocine Nalbuphine Butorphanol Buprenorphine

0.2 1 5 25

0.02 0.25 —a 10

aWeak antagonist;

see text.

The agonist–antagonists are effective in a variety of acute and chronic pain states. They can be given intramuscularly, orally, sublingually, intranasally, intravenously by bolus or continuous infusion, and in patient-controlled analgesia systems. Table 41–1 lists the agents and their recommended intravenous doses. None of these drugs is currently approved for epidural or intrathecal use, although they have all been reported to be effective by this route. The agonist–antagonist opioids have been used during balanced anesthesia, but their partial agonist properties are not a particular advantage in this setting. Even extremely large doses of nalbuphine or butorphanol will not produce the intensity of analgesia one expects from fentanyl or its derivatives.143 Compared with morphine or fentanyl, the agonist–antagonists produce more limited decreases in the requirements for potent volatile anesthetics.99

tion of κ receptors in deeper layers of the cerebral cortex.50 Patients given pentazocine, nalbuphine, or butorphanol may experience floating and dissociation, but usually do not experience mood elevation like that seen with morphine. After analgesic doses these patients often appear extremely sedated, yet remain capable of surprisingly lucid conversation. With pentazocine, patients are increasingly likely to experience “weird” feelings, dysphoria, or even hallucinations as the dose is raised. As stated previously, these unpleasant effects may also be mediated by κ receptors. They occur less frequently with butorphanol or nalbuphine. Most physicians are familiar with the pleasant mental detachment produced by morphine and use it as a sign that the drug is working. Because mood elevation and euphoria do not usually occur with the κ-type agonist–antagonists,71 patient and physician acceptance of these drugs has been somewhat limited. Ironically, lack of a morphine-like mood effect makes these analgesics much less desirable for opioid addicts, and it is thought to be a key factor in their low abuse liability. The sedative effects of some agonist– antagonists may be used to advantage. Butorphanol was evaluated as a premedicant in elective surgical patients, and it produced useful sedation in doses lower than those routinely used for analgesia.28 Its effects on body perception, anxiety, and psychomotor testing were similar to those of midazolam. Unlike the benzodiazepine, it produced very little anterograde amnesia. In this patient population, there was no evidence of dysphoria or hallucinations.

Sedation and Mood Effects

Ventilatory Depression

The subjective effects of buprenorphine are similar to morphine throughout the dose range. The κ-type agonists have been described as producing “apathetic sedation”; this may reflect the localiza-

As stated previously, these opioids are all partial agonists, and their toxic effects are limited in intensity. Ventilatory depression reaches a maximum after about 30 mg of nalbuphine47 or

high affinity but has limited efficacy. When given alone, its effects are similar to those of morphine. When given after morphine, it competes with the full agonist and causes a reduction in opioid effect119 (Fig. 41–1B). Buprenorphine is also an antagonist at κ opioid receptors. These drugs vary widely in their potencies, both as analgesics and antagonists (Table 41–4). Neither agonist versus antagonist potency nor µ versus κ interaction has proved to be a predictor of clinical usefulness or patient acceptance.

Acute Effects Analgesia

891


2–4 mg of butorphanol,103 and even larger doses are well tolerated by most patients. Severe depression is still possible in sensitive individuals, those with concomitant CNS or pulmonary disease, and those receiving other depressant drugs. Ventilatory depression may be reversed with naloxone but not with another agonist–antagonist. A ceiling effect on ventilation has also been demonstrated with the use of buprenorphine. This is important because buprenorphine has very high affinity for µ receptors and is not reliably antagonized by naloxone.46

Smooth Muscle Effects

892

Nalbuphine, butorphanol, and pentazocine do not cause significant elevation of intrabiliary pressure in animals or humans.5,92,119 These agents may be particularly useful for patients who experience biliary colic after morphine. Buprenorphine is believed to cause biliary effects that are slightly more pronounced.152 The agonist–antagonists appear to have small effects on smooth muscle in the intestine and bladder, and they cause less constipation than do drugs that are similar to morphine.

Cardiovascular Effects The cardiovascular effects of buprenorphine and nalbuphine are similar to those of morphine. Pentazocine produces unusual cardiovascular effects, both in normal individuals and in those with ischemic heart disease.2 Unlike morphine, pentazocine may increase heart rate, systemic and pulmonary artery pressure, and left ventricle end-diastolic pressure. These effects may be secondary to elevations in plasma catecholamines. Because these changes are likely to elevate myocardial oxygen consumption, pentazocine may be a poor choice for patients with ischemia or infarction. Butorphanol (2 mg) can also increase pulmonary artery pressure, but heart rate and systemic pressure usually decrease slightly.113 The rise in pulmonary artery pressure apparently does not increase as the dose is raised: In one study, doses of butorphanol greater than 25 mg were used safely during coronary artery bypass surgery.3

Antagonist Effects Table 41–4 lists the approximate agonist versus antagonist potencies of these drugs. Nalbuphine and buprenorphine are strong antagonists, and have been used clinically for this

purpose. The available evidence does not suggest that reversal with an agonist–antagonist is safer or more reliable than reversal with naloxone.70 Administration of an opioid antagonist to an opioid-dependent patient will precipitate withdrawal; this has occurred after therapeutic doses of pentazocine, nalbuphine, and buprenorphine. Butorphanol is a very weak antagonist, and it produces only mild withdrawal in addicts who are maintained on 30 mg/d of methadone.116 A low level of physical dependence may occur in patients who receive opioid agonists over long periods, and this subclinical state may be unmasked by administration of an antagonist. During routine perioperative care, it seems prudent to avoid agonist–antagonists in patients who have had significant prior treatment with morphine, meperidine, oxycodone, and other such drugs.

Chronic Administration In the United States, pentazocine is the only agonist–antagonist available in a typical oral tablet; butorphanol is available as a nasal spray; and buprenorphine is available as a sublingual tablet. It is possible to give these drugs parenterally for long periods of time, but there are few clinical data on such use. Long-term studies on ex-heroin addicts showed that tolerance and physical dependence do occur after repeated administration of agonist–antagonist opioids. Withdrawal is usually qualitatively different from that of morphine and not usually accompanied by intense drug-seeking behavior. There has been renewed interest in chronic sublingual administration of buprenorphine since 2002 when the FDA approved it for maintenance therapy of opioid addicts (see Chap. 23). Chronic administration of buprenorphine in relatively high doses prevents withdrawal and reduces drug seeking.43 Unlike methadone maintenance, buprenorphine treatment of addicts does not have to occur in a specially licensed clinic, although physicians who use it this way must have additional qualifications. The heroin addict is usually switched under supervision to sublingual buprenorphine (the partial agonist properties may sometimes elicit withdrawal symptoms). Chronic dosing is then done by the addict without direct supervision. To reduce the possibility that buprenorphine will be diverted or

abused during chronic maintenance, it is dispensed in a formulation that combines buprenorphine and naloxone (Suboxone). Sublingual administration of the combination produces similar effects to buprenorphine alone, because sublingual naloxone does not achieve high concentrations in blood. If the tablet were inappropriately dissolved and injected intravenously, however, the naloxone would antagonize the euphoriant effect and possibly cause precipitated withdrawal. In the event that a patient taking buprenorphine/naloxone presents for surgery, treatment of acute pain may present a significant problem. These patients are highly tolerant to opioids, and residual levels of the partial agonist may antagonize other opioids for a long time. Regional anesthesia and nonopioid techniques should be used, whenever possible. If opioid treatment is required, large doses of potent opioid agonists may be needed, and advice should be sought from a specialist in addiction medicine.

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151. Tharp MD, Kagey-Sobotka A, Fox CC, et al. Functional heterogeneity of human mast cells from different anatomic sites: In vitro responses to morphine sulfate. J Allergy Clin Immunol 1987;79:646–653. 152. Tigerstedt I, Turunen M, Tammisto T, et al. The effect of buprenorphine and oxycodone on the intracholedochal passage pressure. Acta Anaesth Scand 1981;25:99. 153. Tomichek RC, Rosow CE, Philbin DM, et al. Diazepam-fentanyl interaction—hemodynamic and hormonal effects in coronary artery surgery. Anesth Analg 1983;62:881. 154. Urthaler F, Isobe JH, James T. Direct and vagally mediated chronotropic effects

of morphine studied by selective perfusion of the sinus node of awake dogs. Chest 1975;68:222. 155. Van Ree JM, Versteeg DH, SpaapenKok, et al. Effects of morphine on hypothalamic noradrenaline and on pituitary–adrenal activity in rats. Neuroendocrinology 1976;22:305. 156. Verbeeck RK, Branch RA, Wilkinson GR. Meperidine disposition in man: influence of urinary pH and route of administration. Clin Pharmacol Ther 1981;30:619. 157. Vinik HR, Kissin I. Rapid development of tolerance to analgesia during remifentanil infusion in humans. Anesth Analg 1998; 86:1307–1311. 158. Wang SC, Glaviano VV. Locus of emetic action of morphine and Hydergine in dogs. J Pharmacol Exp Ther 1954;111:329. 159. Ward JW, McGrath RL, Weil JV. Effects of morphine on the peripheral vascular response to sympathetic stimulation. Am J Cardiol 1972;29:656. 160. Way WL, Costley EC, Way EL. Respiratory sensitivity of the newborn infant to meperidine and morphine. Clin Pharmacol Ther 1965;6:454. 161. Wei G, Moss J, Yuan CS. Opioidinduced immunosuppression. In: Yuan CS, ed. Handbook of Opioid Bowel Syndrome. New York: Haworth Medical Press, 2005: 45–57. 162. Weil JV, McCullough RE, Kline JS, et al. Diminished ventilatory response to hypoxia and hypercapnia after morphine in normal man. N Engl J Med 1975;292:1103. 163. Weinger MB, Smith NT, Blasco TA, et al. Brain sites mediating opiate-induced muscle rigidity in the rat: methylnaloxonium mapping study. Brain Res 1991;544:181.

164. Weitz CJ, Faull KF, Goldstein A. Synthesis of the skeleton of the morphine molecule by mammalian liver. Nature 1987;330:674. 165. Westomoreland CL, Hoke JF, Sebel PS, et al. Pharmacokinetics of remifentanil (GI87084B) and its major metabolite (GI90291) in patients undergoing elective inpatient surgery. Anesthesiology 1993;79:893. 166. Wolff BG, Michelassi F, Gerkin TM, et al. Alvimopan, a novel, peripherally acting mu opioid antagonist. Results of a multicenter, randomized, double-blind, placebocontrolled, phase III trial of major abdominal surgery and postoperative ileus. Ann Surg 2004;240:728–735. 167. Wynands JE, Wong P, Whalley DG, et al. Oxygen-fetanyl anesthesia in patients with poor left ventricular function: hemodynamics and plasma fentanyl concentrations. Anesth Analg 1983;62:476. 168. Yuan CS, Foss JF, O'Connor, et al. Methylnaltrexone prevents morphine-induced delay in oral–cecal transit time without affecting analgesia: a double-blind randomized placebo-controlled trial. Clin Pharmacol Ther 1996;59:469–475. 169. Yuan CS, Foss JF, Osinski J, et al. The safety and efficacy of oral methylnaltrexone in preventing morphine-induced delay in oral–cecal transit time. Clin Pharmacol Ther 1997;61:467–475. 170. Zadina JE, Hackler L, Ge LJ, et al. A potent and selective endogenous agonist for the µ-opiate receptor. Nature 1997;386: 499–501. 171. Zelis R, Mansour EJ, Capone RJ, et al. The cardiovascular effects of morphine. The peripheral capacitance and resistance vessels in human subjects. J Clin Invest 1974;54:1247.

CHAPTER 42: Total Intravenous Anesthesia

CHAPTER 42 Total Intravenous Anesthesia John Sear, MA, PhD, MBBS, FFARCS, FANZCA

In 2006, we are still without any one drug that can provide all the requirements of anesthesia (i.e., unconsciousness, analgesia, amnesia, and muscle relaxation). Consequently, administration of several different agents is needed to produce the desired end result. The use of intravenous agents to achieve these goals began with the introduction of the rapidly acting barbiturates in 1934. Despite the disastrous consequences following the use of thiopental at Pearl Harbor in 1941, intravenous anesthesia is now well established as an alternative, and in some circumstances more appropriate, technique than the traditional approaches of volatile anesthetics alone, or balanced anesthesia where volatile and intravenous agents are combined together. The kinetics of the early barbiturates did not render the drugs ideal for the maintenance of anesthesia; the provision of analgesia could not be achieved by the barbiturates alone; and the addition of either meperidine or morphine (both drugs having slow blood–brain equilibration) led to overdosing and hence to poor clinical conditions, especially in the spontaneously breathing patient. The introduction of modern volatile agents, starting with halothane in 1956, with their easy titratability, encouraged the anesthetist to turn away from the intravenous agents for the maintenance of anesthesia. The development of and present interest in total intravenous anesthesia (TIVA) owes much to a number of important studies. From the standpoint of hypnosis, a key contribution was that of Savege et al., in 1975, who used the steroid agent Althesin (alphaxalone and alphadolone acetate) with meperidine to supplement oxygen-enriched air in the spontaneously breathing patient.97 Subsequent drug developments included the use of in-

fusions of thiopental, methohexital, carboxylated imidazole etomidate, propofol, and ketamine. However, with the exception of ketamine, none of these agents probably provided analgesia (although analgesic effects of alphadolone have been described by Goodchild et al.36). The use of morphine to provide anesthesia as a sole agent in patients undergoing cardiac surgery was first described by Lowenstein et al. in 1969, where the hypnotic side effects of large doses of morphine were used to provide sedation.61 However, this method of anesthesia (more popular in the United States and Europe than in the

United Kingdom) was not reliably effective. It was associated with a high incidence of episodes of awareness during anesthesia, as well as intraoperative episodes of hypotension caused by histamine release, resulting in increased intraoperative and postoperative fluid and blood requirements. The selective and highly potent µreceptor opiates (fentanyl, alfentanil, sufentanil, and more recently, remifentanil) have the advantage of less cardiovascular depression, as well as the ability to obtund the hemodynamic responses to laryngoscopy and intubation. However this apparent stability is less evident during major cardiovascu-

KEY POINTS 1. The appearance of new drugs with short blood–brain equilibration times (especially those with an ester linkage) enables the clinician to use anesthetics and analgesics where titratability will be easy and recovery rapid. 2. Total intravenous anesthesia (TIVA) offers some important advantages over inhalation anesthetics, including rapid recovery with minimal hangover and a low incidence of nausea and vomiting. TIVA may be the technique of choice for some operations. 3. Effective delivery of TIVA requires the clinician to have a good knowledge and understanding of pharmacokinetics, pharmacodynamics, and pharmacokinetic–pharmacodynamic (PK-PD) modeling. 4. Important drug characteristics include induction dose, rate of administration and ke0 (rate constant for the elimination of drug from the effect compartment) (drugs with small ke0 values take longer to equilibrate between the blood and the effect compartment or biophase). Thus for a rapid sequence induction, drugs with a large ke0 are preferable (viz., propofol, thiopental, remifentanil, and alfentanil compared with midazolam, ketamine, and fentanyl) 5. Drug interactions are important in TIVA. Excepting ketamine, opiates and hypnotics potentiate each other and can result in synergistic cardiovascular and respiratory depression. This means the doses of each can be


reduced. There is a ceiling to the potentiating effect of the opiates, beyond which there is an increased incidence of adverse side effects and often delayed onset of spontaneous ventilation at the end of surgery. 6. Ketamine is the only hypnotic drug with analgesic properties; there are few data suggesting that the S (+) isomer has major advantages. 7. If the patient shows signs of response during TIVA, there is need for additional IV supplementation by bolus doses or by increasing the targeted concentration if using target-controlled infusion (TCI). 8. The elimination half-life and systemic clearance are not useful in TIVA for determining the offset of IV drugs. The context-sensitive half-time (CSHT) is more relevant, and modeled data and dynamic measurements correlate well. 9. Context-sensitive decrement times are useful indices of recovery from anesthesia. Recovery is influenced by other factors apart from the CSHT, including patient characteristics such as age, gender, body habitus, and disease states. 10. A knowledge of the context-sensitive decrement times for opiates and hypnotics allows appropriate choice of drugs for the maintenance of anesthesia. CSHT also helps determine which infusions should be terminated at the end of anesthesia, and which some time beforehand.

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TABLE 42–1. Adverse Properties of Volatile Agents 1. Organ toxicity is associated with the use of most of our present volatile agents, such as dose-related cardiovascular and respiratory depression; dose-related increases in cerebral blood flow and intracranial pressure; hepatic and renal toxicity; coronary blood-flow steal phenomena; and immunodepression. 2. Environmental issues related to trace concentrations of volatile agents and nitrous oxide as well as the effects of these trace concentrations on the health and work performance of anesthesiologists, surgeons, operating room and recovery area personnel.

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lar surgery, particularly during the period of sternotomy and aortic root dissection in patients undergoing cardiopulmonary bypass, where there are frequent episodes of significant hypertension and tachycardia that are not always remediable by increased doses of the opiates. Thus it became clear that use of high doses of opiates alone was inappropriate to provide anesthesia. Hence attempts to control the hemodynamic effects of surgical stimulation and to reduce the incidence of awareness have used either low inspired concentrations of volatile agents or infusions of a sedative-hypnotic agent as supplements to opiates. Use of TIVA techniques are not without difficulties in these patients as some combinations of opiates, such as fentanyl and diazepam, can result in significant reductions in both cardiac output and systemic vascular resistance. However, the effectiveness of the benzodiazepines in reducing the circulating levels of catecholamines may be important, and greater hemodynamic stability has been found in cardiac surgical patients where the combination of sufentanil with ketamine or midazolam has been employed. In noncardiac surgery, opiates remain popular as the basis of most neurosurgical anesthetic techniques, as they do not alter the carbon dioxide reactivity of the cerebral blood vessels. The kinetics and dynamics of remifentanil (and to a less extent alfentanil) allow the anesthesiologist to titrate dose requirements more closely for a given surgical procedure during abdominal

and other major body surface surgical procedures. Over the past two decades, increased interest in intravenous anesthesia has been prompted both by the availability of newer and more appropriate rapid-onset and short-acting IV sedative-hypnotics (e.g., midazolam, propofol, etomidate), analgesics (alfentanil, sufentanil, remifentanil), and muscle relaxants (atracurium, vecuronium, mivacurium, and rocuronium). All these factors have refocused the anesthetist’s attention on the total provision of anesthesia by the intravenous route. Furthermore, there are also a number of clinical situations where intravenous anesthesia techniques are advantageous, including: • To provide sedation to supplement local or regional anesthetic techniques. • To provide general anesthesia with accompanying minimal cardiovascular depression. • For office or ambulatory surgery, where the speed and completeness of recovery are important. • For situations where volatile-based anesthetics may be difficult to administer because of the unavailability of resources, such as nitrous oxide; at sites of military or nonmilitary trauma; and for anesthesia at increased ambient pressure. • In circumstances where nitrous oxide may either be undesirable (e.g., because of the need for high inspired oxygen concentrations) or contraindicated (e.g., for one-lung anesthesia; for middle ear surgery, some neurosurgical operations, and prolonged abdominal surgery where nitrous oxide can cause closed-space effects as a result of increased volume and pressure; for relief of cardiac tamponade; for airway endoscopies [ bronchoscopy and laryngoscopy]; and for bronchotracheal surgery), or where volatile agents may best be avoided (Table 42–1). • To prevent awareness during cardiopulmonary bypass, and to offer cerebral protection to patients at risk of episodes of brain ischemia. • In malignant hyperpyrexia-susceptible patients. However, the general application of TIVA techniques is not without important considerations and questions. These include the possibility and de-

TABLE 42–2. Ideal Properties of a Hypnotic Drug for Use during Total Intravenous Anesthesia 1. Soluble in aqueous such that use of a solvent is avoided. 2. Stable in solution and on exposure to light for prolonged periods of time. 3. No absorption onto plastic tubing or giving sets. 4. No venous damage (pain on injection, venous phlebitis, or thrombosis) or tissue damage when administered either extravascularly or intraarterially. 5. Sleep in one arm–brain circulation time. 6. Short duration of action, and inactivation by metabolism in either the liver, blood, or other organs of the vessel-rich group of tissues. 7. Inactive, nontoxic, water-soluble metabolites. 8. Minimal cardiovascular and respiratory side effects.

tection of awareness; the possibility of postoperative respiratory depression because of the persistent effects of concurrently administered analgesic agents; the requirement of a separate dedicated IV access site; appropriate infusion pumps; and the observation that some researchers consider depth of anesthesia as uncontrollable as with the volatile agents.

What Are the Ideal Drug Properties for and Advantages of TIVA? Table 42–2 lists the ideal properties of a hypnotic drug for continuous infusion anesthesia. Although none of the present hypnotic or analgesic agents fulfills all of these criteria, some are more suitable than others under differing circumstances. Table 42–3 lists the pharmacologic advantages of TIVA over inhalational agents.

Dosing Strategies for TIVA The administration of hypnotic, analgesic, and neuromuscular blocking components of TIVA can be provided in a number of different ways: • Intermittent bolus doses of the drugs; • Continuous infusions using syringe infusion pumps or similar delivery systems;


TABLE 42–3. Advantages of TIVA 1. Smooth induction of anesthesia without coughing or hiccupping. 2. Easy control of depth of anesthesia when using drugs with short blood–brain equilibration times. 3. With most of the agents there is rapid and predictable emergence with minimal hangover. 4. Low incidence of postoperative nausea and vomiting. 5. Ideal operating conditions for neurologic surgery with reduced cerebral brain flow and cerebral metabolic rate for oxygen. 6. Minimal organ toxicity, although infusions of etomidate cause depression of adrenosteroidogenesis and red cell hemolysis. Infusions of propofol can lead to a metabolic syndrome.

• Through the introduction (in most parts of the world, although not presently in the United States) of targetcontrolled infusion systems (TCI). When given by intermittent bolus doses, there will be fluctuating drug concentrations that are associated with accompanying changes in the depth of anesthesia. Continuous infusions of IV hypnotics, opiates, and muscle relaxants can reduce these swings in drug concentrations, as well as minimize any relative under- or overdosing during drug administration. This offers a number of advantageous features to the anesthetized patient, including greater hemodynamic stability; fewer episodes of hemodynamic breakthrough and other signs of patient responsiveness; reduced need for supplemental anesthetics or vasoactive drugs; more rapid awakening and decreased incidence of requirements for naloxone or need for postoperative ventilatory support; decreased incidence of side effects; and a 25–30% lower total drug dose compared with bolus dosing.4,5,92,139,140 Use of continuous drug infusions may also lead to decreased drug costs. However, because modern IV agents exert profound pharmacologic effects and have short durations of action, frequent adjustments to drug dosage are necessary in order to match anesthetic effect to the varying noxious stimuli being perceived at different

times during surgery, as well as the different noxious intensities of different surgical operations. This requires either frequent additional bolus dosing, or the calculation of new infusion rates to achieve different drug targets. Early studies using IV infusion anesthesia focused on providing fixed rate infusions that were adequate for 50% or more of a given population.5,89 With the passage of time, these have been viewed as being less appropriate and flexible in output because they failed to allow easy titration of the achieved drug concentration to clinical effect in accordance with an individual patient’s requirements. Indeed there is the probability that many patients received an overdosage because of the desire to design regimens that were “all-embracing” to all people! Nevertheless, the work of Prys-Roberts et al. confirmed the usefulness of this approach to the provision of anesthesia with minimal cardiorespiratory depression, and no reported cases of awareness.88,109,110 With the hypnotic drugs currently available for continuous infusion, several manual schema for anesthesia delivery have been developed. For example, there is the regimen for propofol described by Roberts et al. based on an infusion protocol to maintain a plasma propofol concentration of around 3 µg/ mL.93 This was achieved by an initial 1 mg/kg induction dose, then 10 mg/kg/h for 10 minutes, 8 mg/kg/h for 10 minutes, and maintained at 6 mg/kg/h. As this scheme is designed to achieve a fixed plasma propofol concentration, there is often a need for supplementation with additional propofol boluses and/or opiates during abdominal or other major operations. Manual regimens have similarly been described for midazolam by infusion. Persson et al. used an induction dose of 0.25 mg/ kg, followed by a fast infusion of 0.65 mg/kg/h for 15 minutes and maintained with 0.13 mg/kg/h. This provided a hypnotic plasma concentration of between 300 and 400 ng/mL.84,86 In a separate study, Thiel et al. described an infusion of midazolam (0.1–0.15 mg/kg then 0.02 mg/kg/h) supplemented with an opiate infusion of sufentanil for cardiac surgery.126

Pharmacokinetic Principles of TIVA Simplistically, the design of infusion schema for TIVA is based on two important equations which define the

loading dose and the maintenance infusion rate. Loading dose = Vd × Cp Maintenance infusion rate = Cp × Cl where Vd = initial apparent volume of distribution; Cp = the desired plasma drug concentration; and Cl the systemic clearance of the drug. However, these calculations of drug requirements to reach a given target concentration are flawed for several reasons. First, the plasma is not the site of action of IV drugs; the site where the drugs produce their effects is in the brain, and is termed the biophase. To reach the biophase, drug redistributes from the blood to the brain. At the same time, drug is also being redistributed to other tissues of the body. Hence the loading dose necessary to produce a desired pharmacologic effect cannot usually be calculated based on the initial volume of drug distribution (which is primarily the blood volume), but should use the apparent volume of distribution into which the drug has distributed once it has equilibrated with the biophase (i.e., this will, of necessity, be a larger volume). When a drug is given by rapid infusion, there may be a simultaneous pharmacologic effect; however, the measure of drug effect ( be it electroencephalogram [EEG] spectral edge frequency, minute ventilation volume, or change in blood pressure or heart rate) does not always parallel the rapid increase and decrease in the plasma drug concentration. This implies “hysteresis” in the relationship between drug concentration and effect. From studies that provide continuous measurement of plasma drug concentration and effect, it is possible to relate the plasma drug concentration to the effect produced in the biophase,108 and, in turn, to calculate the volume of distribution of this effect compartment. Furthermore, by complex mathematical manipulation, the hysteresis loop can be “collapsed” to derive a linear relationship between concentration and effect. The value that causes the hysteresis loop to collapse represents the rate of equilibration of the drug concentration between the plasma and the biophase. This is termed ke0 or the blood–brain equilibration rate constant. Table 42–4 shows the values of ke0, t1/2ke0, time to peak effect, and the apparent volume of the effect compartment.

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TABLE 42–4. Typical Values for the ke0, t1/2ke0, Time-to-Peak Effect following a Bolus Dose and the Apparent Volume of Distribution Incorporating the Effect Compartment

PROP THIOP ETOM KET MIDAZ REMI ALF FENT SUF

ke0 (min – 1)

t1/2ke0 (min)

Time-to-Peak Effect (min)

Vde

0.291 0.46 0.48

2.4 1.5 1.5

2.2 1.4 2.0

37

0.124 0.46 0.77 0.147 0.227

5.6 1.5 0.9 4.7 3.0

3.0 1.5 1.4 3.6 5.6

5.9 75 89

ALF, alfentanil; ETOM, etomidate; FENT, fentanyl; KET, racemic ketamine; MIDAZ, midazolam; PROP, propofol; REMI, remifentanil; SUF, sufentanil; t1/2 ke0, half-time for blood–brain equilibriation; THIOP, thiopental; Vde, volume of distribution incorporating the effect compartment.

clinicians need to know the time to peak effect when giving IV drugs during both the induction and maintenance phases of anesthesia (Fig. 42–1).

Although the t1/2ke0 is the time for blood–brain equilibration, it also relates closely to the “time to peak drug effect.” For optimal dosing strategies, 900 100

Fentanyl

80 Plasma concentration 60

Effect site concentration

40 20 17% 3.6

Percent of initial plasma concentration

0 100

Alfentanil

80 60

Computerized Drug Administration: TargetControlled Infusions

40 37% 20 0

1.4

100

Sufentanil

80 60 40 20 20% 0 0

For example, during a rapid sequence induction, the anesthesiologist should use drugs with short times to peak effect. The combination of thiopental or etomidate and alfentanil or remifentanil is probably more appropriate than a combination of propofol and fentanyl. With the latter combination, the effect of the fentanyl (if given immediately before the hypnotic agent) would not be maximal by the time of intubation, leading to an initial hypertensive response to the noxious stimulus of laryngoscopy. This might then be followed by a hypotensive response when the peak effect of the fentanyl is achieved and airway stimulation is minimal. In addition, when giving drugs by bolus dosing, the interval between doses needs to be of a sufficient duration to allow the peak effect of one bolus to be observed before the next dose of the drug is administered. For most of the drugs used as the hypnotic and analgesic components of TIVA, plasma (blood) concentration– effect relationships have now been determined. From these, and using appropriate kinetic datasets, the clinician can derive manually controlled dosing schedules (Tables 42–5 and 42–6). However, these schema do not really take account of time delays in the concentration–effect relationship. Hence, many anesthesiologists view TIVA using manually controlled infusion systems and devices as a more complex strategy for maintaining anesthesia than using a vaporizer in the case of volatile agents!

2

5.6 4 6 Minutes since bolus

8

10

FIGURE 42–1. Computer-simulated plasma and effect-site concentrations for fentanyl, alfentanil, and sufentanil for the first 10 minutes after a bolus injection, as a percent of initial plasma concentration. (Adapted with permission from Shafer SL, Varvel JR. Pharmacokinetics, pharmacodynamics and rational opioid selection. Anesthesiology 1990;74:53–63.)

One of the most significant and recent advances in the delivery of infusion anesthesia over the last decade is the introduction of TCI systems that allow the anesthesiologist to set the target concentration of anesthetic. This target can be defined as either the blood or the effect-site (i.e., brain) concentration. In many respects, these systems function in a similar manner to the setting of the inspired concentration of the volatile agents using a vaporizer. A number of publications describe a theoretical approach to attaining and maintaining steady-state drug concentrations,55,106,130,131 with different algorithms employed for targeting blood concentrations,4,22,44,125 and incorporating effect-site concentrations into


TABLE 42–5. Plasma Drug Concentrations of Hypnotics and Analgesics Needed for Provision of Adequate Anesthesia for Different Noxious Stimuli during Surgery in Patients Receiving TIVA

Hypnotics (µg/mL) Propofol Methohexital Thiopental Etomidate Midazolam Ketamine (racemic) Opiates (ng/mL)c Alfentanil Fentanyl Sufentanil Remifentanil

Incision

Major Surgerya

Minor Surgeryb

5–6 5–10 35–45 0.4–0.6 — —

2.5–7.5 5–15 10–20 0.5–1.0 0.05–0.20 —

2–6 5–10 10–20 0.3–0.6 0.02–0.25 1–2

200–300 3–6 1–3 2–6

250–450 4–8 2–5 4–8

100–300 2–5 1–3 2–4

aMajor

surgery includes abdominal and vascular surgery, thoracic surgery, major orthopaedic surgery, and neurosurgery. bMinor surgery is body surface surgery. cIn the case of the opiates, adequate spontaneous ventilation will occur at concentrations ≤200–250, ≤1–2, ≤0.2, and ≤1–3 ng/mL, respectively.

model-driven automated delivery systems.48,114 Several different systems for computerized drug delivery have been described. For example, Schwilden et al. formulated a system to maintain anesthesia using the hypnotic agent etomidate.107 Other systems include the CACI (computer-assisted continuous infusion) system for fentanyl4; the TIAC (target-controlled infusion-based anesthesia) system also for fentanyl5; and the various systems for propofol.19 A TCI system consists of an infusion pump linked to a microprocessor containing the disposition pharmacokinetic

parameters for the drug in question. The equations describing disposition are based on the BET (bolus-elimination-transfer) scheme of Schuttler et al.105 TCI combines sequential BET schemes for maintaining or increasing the target concentration, and periods of discontinuation of the infusion when the target concentration has to decrease. Infusion halts are mandatory if a new lower drug concentration is to be achieved as fast as possible. The first commercially available TCI system is the Diprifusor,35 which was introduced in 1996 and uses prefilled glass syringes

TABLE 42–6. Dosing Strategies (µg/kg or µg/kg/min) of Hypnotics and Analgesics When Given by Manual Infusion Regimens to Achieve the Concentrations (µg/mL) Needed for Major Surgery as Identified in Table 42–5

Hypnotics Propofol Methohexital Midazolam Ketamine (racemic) Opiatesa Alfentanil Fentanyl Sufentanil Remifentanil

Induction or Loading Dose

Maintenance Infusions Rate

1000–2000 1500–2500 50–150 1500–2500

50–150 50–150 0.25–1.5 25–75

50–150 5–15 1–5 0.5–1.0

0.5–3.0 0.03–0.10 0.01–0.05 0.1–0.4

of propofol tagged with a unique metallic strip. More recently “open TCI systems” that allow use of the various available generic formulations of propofol have been developed. Such systems include the Alaris Asena PK system and the Base Primea system of Fresenius. At present, no drugs apart from propofol are licensed for use for TCI; in addition, approval for TCI is still awaited in the United States. However, research or developmental computerdriven delivery systems have been described for both sufentanil and remifentanil.7,10,42,81,100,116 Sufentanil has been administered by TCI in combination with isoflurane, propofol, and midazolam, with targeted concentrations, in most studies, of sufentanil between 0.2 and 1.5 ng/mL for noncardiac surgery and 3–10 ng/mL for cardiac surgery. Most studies report good quality anesthesia with hemodynamic stability and satisfactory times to return of spontaneous ventilation and extubation. Remifentanil by TCI has been assessed in combination with both IV hypnotics and volatile agents,32,41,57,65 the most appropriate kinetic model for drug delivery being that of Minto et al.68 For analgesia, concentrations between 1 and 1.5 ng/mL are needed. In combination with propofol for noncardiac surgery, remifentanil concentrations in the range of 4–8 ng/mL are appropriate. However, these data need confirmation in larger clinical trials. Any TCI drug delivery system has 4 key components: 1. A calculator (computer or microprocessor) and a software program, either separate with cables linking to a syringe pump, or an “all-inone” system (as is the case with the Diprifusor); 2. Datasets of pharmacokinetic parameters for each drug to be infused; 3. An infusion device; and 4. A user interface.

aFor the opiates, the induction of loading dose is best given over 2 minutes to avoid marked cardiorespiratory depression.

For TCI delivery, the anesthesiologist needs to enter the patient’s age and weight into the device, and then select the desired target drug concentration. On pressing “start,” the TCI system delivers precisely the amount of drug to achieve the target drug concentration and then continues to infuse drug at an appropriate rate to maintain that concentration. Unlike using a manual fixed-infusion system, the anesthesiologist can easily either

901


increase or decrease the target drug concentration at any time, thereby facilitating the titration of the drug concentration according to the patient’s response to differing noxious stimuli. One fundamental principle underlies the TCI pump—namely, the relationship between the infusion rate and achieved drug concentration: Drug concentration = Infusion rate Drug clearance

902

If a higher target concentration is selected, the system automatically delivers a further small bolus of drug and then infuses at a faster rate to achieve and maintain the higher drug concentration. When a lower target is chosen, the device discontinues the infusion of drug until the system predicts that the patient’s drug concentration has decreased to the new value (by a combination of drug redistribution and clearance). The system then restarts the infusion at the appropriate rate for the new target concentration. With a TCI system, the anesthesiologist does not control the device’s infusion rates and the size of bolus doses; rather, the anesthesiologist titrates the depth of anesthesia by selecting target drug concentrations appropriate to the patient’s needs. A number of different algorithms are used in the different systems to calculate the required infusion rate.44,45,55,114

Kinetic Model Selection TCI systems tend to incorporate population-averaged pharmacokinetic parameters to drive the infusion pump. This can lead to considerable variability in the observed drug concentration compared with the targeted concentration. The mean variation between these two concentrations (targeted and observed) is usually of the order of 20– 30% with a maximum of 50–60% considered clinically acceptable. It seems likely that greater accuracy is not going to be achievable. The sources of this variability include the differences in the parameter estimates of the polyexponential equation that is used to describe the concentration–time relationship. At the present time, there are several different commercial systems on the market for the delivery of propofol and the opiates sufentanil and remifentanil. Two types of systems can be identified—those incorporating the Diprifusor module, using tagged Dipri-

van prefilled syringes with the fingergrip tag and the original Diprifusor kinetics, and “open” systems that do not require the tagged syringes and use different pharmacokinetic datasets for the delivery of propofol, remifentanil, and sufentanil (Table 42–7).

Effect-Site Targeting Initial drug-targeting technology was based on the plasma concentration; but as this is not the site of anesthetic action, it is more logical to target the effect-site or biophase. This has been described by several authors, and reviewed by Jacobs and Williams.48 Effect-site control should allow for a faster induction time; and during maintenance a more rapid increase in the depth of anesthesia. However, there are some limitations to effect-site compartment targeting, including that of overshoot of the arterial drug concentration with associated adverse consequences. Effect site TCI has been described by a number of different research groups.48,123,138 Wakeling et al. have compared the efficacy of plasma and effect-site targeting.137 Twenty ASA (American Society of Anesthesiologists) classification PS-I or PS-II patients were randomized to receive TCI propofol targeted at one or the other site. In this study, the delivery system was modeled according to the kinetic dataset of Gepts and Camu34 and a ke0 value of 0.63 min–1. At a target concentration of 5.4 µg/mL (the predicted effect-site concentration associated with loss of consciousness in 95% of subjects),117,134 Wakeling found a median time to loss of consciousness of 3.02 minutes in the plasma-targeted group, but only 1.23 minutes in the effect-site targeted group. However, loss of consciousness occurred at the same predicted effectsite concentration in both groups. Other studies of effect-site drug control have found similar results.82,123,138 Although an advantage of these systems is that drug delivery is optimized to a given effect-site concentration, the speed of achieving this concentration varies with the ke0 value incorporated into the different delivery systems. At present, several different models with different ke0 values are in use for the delivery of propofol. If the Diprifusor is used with the Marsh model kinetics, the blood–brain equilibration half-life (t1/2 ke0) is 2.6 minutes (ke0 0.26 min–1).62 However modifications of the Diprifusor algorithm in the two new “open-TCI” systems (the Base

TABLE 42–7. TCI Systems Currently Available for the Delivery of Propofol, Remifentanil, and Sufentanil in the United Kingdom and Other Parts of the Worlda “Diprifusor” TCI systems incorporate use of tagged prefilled syringes: 1. Graseby 3500 system (Graseby Medical, Watford, UK) 2. Vial Medical Master TCI (Fresenius Vial, Brezins, France) 3. Alaris IVAC TIVA TCI (ALARIS Medical Systems, Basingstoke, UK) 4. Terumo TERUFUSION TE-372 TCI TIVA (Terumo Corporation, Tokyo, Japan) Open TCI systems have the advantages of being able to use “generic” formulations of propofol: 1. Alaris Asena PK Syringe Pump. This has the same pharmacokinetic model as in the Diprifusor, with a ke0 of 0.26 min-1. It also incorporates modeling for effect-site control. 2. Base Primea (Fresenius Vial, France). This includes 2 kinetic sets for propofol delivery. There is the kinetic model included in the Diprifusor but with a modified value for ke0 of 1.21 min-1. The second model system is based on the kinetics of Schnider et al.99 where the kinetics are corrected for patient age and weight. The ke0 is also different (0.456 min-1), which leads to a faster rise in brain propofol concentration. 3. B Braun (FM System—“Space Station”) incorporating the “ProTiva” pump system. This was introduced in Europe in 2006. aAt

the time of writing (March 2007), none of these delivery systems are licensed for use in the United States.

Primea and Asena PK systems) with a longer ke0 of 1.2 min–1 gives a t1/2 ke0 of 34 seconds. When the slower ke0 is used, any increase in the target effectsite concentration requires higher blood drug concentrations to generate a bigger gradient to drive drug to the effect-site. A second effect-site model, based on the kinetics of Schnider et al., incorporates additional details into the algorithms (including patient age, height, weight, and calculated lean body mass). In this system, the ke0 varies with the


age of the patient.98 Although most studies suggest that effect-site targeting provides faster control, it is only true if there is an accurate value for ke0! The recent studies of Kazama et al. show that ke0 values have a wide interindividual variability with regard to age, and end point assessed.52 This may be a result of a number of factors, including poor delineation of early distribution kinetics and failure to accurately define the EEG hysteresis effect; this will clearly limit the accuracy of any effectsite TCI delivery system in a given individual. Use of effect-site TCI will, of necessity, lead to an overshoot of the plasma drug concentration, which can result in hemodynamic depression. Although this overshoot has little effect in patients younger than age 60,123 further study is needed in the elderly. As a further development in effectsite targeting, Van Poucke et al. have described modified delivery algorithms that target the effect-site but limit the peak plasma concentration.129 This should have the advantage of reducing the acute hemodynamic effect of intravenous anesthetic drugs on the heart and circulation. Simulations suggest that this approach will reduce the plasma overshoot by approximately 60%, with an accompanying 20% delay in the time to peak effect and hence the onset of drug effect. In vivo studies are clearly needed to confirm the efficacy of this method of TCI delivery.

INDUCTION OF ANESTHESIA WITH TIVA Several factors affect the speed of induction by TIVA, including the size of the induction dose and important drug interactions.

Factors Determining the Induction Dose of Hypnotic Agents The onset of anesthesia requires the brain drug concentration to reach a given level; this can be achieved either slowly or rapidly. Rapid achievement is usually accompanied by significant adverse effects such as hypotension, bradycardia, and respiratory depression. The greater the concentration gradient between the blood and the effect-site, the greater the time needed to induce anesthesia. Conversely, any marked overshoot in the effect-site

concentration leads to a greater incidence and severity of the adverse effects. The transfer of drug from the blood to the effect site is governed by simple diffusion. The time needed to achieve this transfer varies with the concentration gradient and the ke0. The rate of infusion of the induction dose is another determinant governing the size of the induction dose; an infusion rate designed to only just achieve a desired effect-site concentration causes a loss of consciousness but at the cost of a slow onset. The loss of consciousness is only transient, and is maintained only for the duration that the targeted effect-site concentration is maintained. A faster rate of infusion provides a more rapid onset of anesthesia and a longer duration of loss of consciousness, but again involves administration of a larger induction dose and hence a greater likelihood of adverse effects. Variations in induction dose requirements also occur because of interindividual pharmacokinetic differences, and because of pharmacodynamic differences that are the result of age, gender, cardiac output, smoking, concomitant medications, and the presence of coexisting disease states.46

Drug Interactions Because no single IV drug (with the possible exception of ketamine) can provide hypnosis, amnesia, and analgesia, total intravenous anesthesia will be, by definition, provided by a combination of drugs. However, in contrast to the simply additive effects of the different gaseous and volatile anesthetics, IV anesthetics may interact in either additive or synergistic manners (see Chaps. 40 and 41). In the case of most IV agents, this interaction is synergistic. One example used to good effect is the combination of a hypnotic and benzodiazepine or other sedative drug (such as an α2-agonist) for induction of anesthesia (the technique of coinduction). One major advantage of this technique is to provide an adequate depth of anesthesia for a noxious stimuli such as laryngoscopy and intubation without any associated significant cardiovascular depression. Also clinically useful is pretreatment with an opiate (fentanyl, sufentanil, alfentanil, or remifentanil), which will reduce the amount of hypnotic agent needed for loss of consciousness and provide analgesia to

reduce the adrenergic stimulus caused by the instrumentation of the airway (whether by laryngoscopy and intubation, or insertion of the laryngeal mask airway). However, the combination of an opiate with an IV hypnotic agent can cause both positive and negative side effects (namely, cardiovascular stability or profound cardiovascular and respiratory depression). Respiratory depression is of little importance in the mechanically ventilated patient, but is a significant and unwanted effect in the spontaneously breathing individual. Although the combination of benzodiazepines with nitrous oxide produces minimal cardiovascular effects for induction of anesthesia, the combination of benzodiazepines with opiates results in a synergistic depression of most hemodynamic parameters. Because opiates alone are not complete anesthetics, they cannot be used reliably to induce anesthesia and amnesia in the absence of supplements. In clinical practice, a second anesthetic drug (such as an IV hypnotic) should always be given to ensure loss of consciousness. Thus the main functions of opiates are to provide analgesia and potentiate the effects of IV anesthetic agents, both at induction and during the maintenance phase.

Termination of IV Anesthetic Action The duration of drug effect of a bolus dose of IV drugs is terminated predominantly by redistribution of drug from the blood and brain to the lean tissues. This redistribution occurs by a series of different intercompartmental clearances, and to a lesser extent, metabolic clearance, the sum of these being dependent on cardiac output in the case of lipid-soluble hypnotic agents. However, if the dose of the induction agent causes a significant reduction in cardiac output, the offset of the drug effect is delayed.

DRUGS FOR INDUCTION OF ANESTHESIA Thiopental This thiobarbiturate continues to be the most popular of all IV anesthetic induction agents, even though propofol may be more appropriate in circumstances where rapid recovery from anesthesia is a prerequisite (e.g.,

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in ambulatory surgical practice). Thiopental, however, has a number of drawbacks as it is highly alkaline in solution, and therefore extremely irritating if injected extravascularly or intraarterially, and has a low therapeutic index of about 4. When given IV, the barbiturates achieve onset of hypnosis within one arm–brain circulation time. Because of their high lipid solubility and low percentage of ionization at physiologic pH, there is rapid uptake into the brain. The maximum effect of thiopental is seen within about 1 minute of a single induction dose of 3– 6 mg/kg. There then follows a similarly rapid decline in the brain concentration as a consequence of redistribution into the “lean” body tissues, making the duration of effect of an induction dose about 5–10 minutes. However, at the time of awakening, only 18% of the injected thiopental dose will have undergone metabolism (compared with approximately 38% of a dose of methohexital and nearly 70% of propofol). Several different factors influence thiopental elimination. Stanski and Maitre showed that, although age influenced the kinetics of thiopental, it had no effect on brain responsiveness or dynamics when the spectral edge frequency was used as the measure of drug effect.119 The induction dose requirements for thiopental anesthesia vary with patient age and weight, and, most importantly, cardiac output. Lower doses are indicated in the premedicated patient; in patients with severe anemia or burns; in malnourished patients; in patients with uremia or liver failure; and in the hypovolemic individual regardless of cause. Both circulatory failure and hypothermia slow the circulation time, prolonging the induction period for thiopental. Moreover, the total dose needed in such patients is also reduced. The blood–brain equilibration rate constant for thiopental is rapid (0.46– 0.58 min–1). The effect-compartment concentration associated with dropping a loaded syringe is about 17 µg/mL, and the duration of effect of an induction dose of 320 mg is about 4 minutes. Induction with thiopental causes a decrease in cardiac output, and a compensatory 10–15% increase in heart rate. Thiopental also causes venodilation, but has no effect on systemic vascular resistance.96 Another feature of thiopental induction is the decrease in respiratory responsiveness to hy-

poxia and hypercapnia. Opiates potentiate these effects. When anesthesia is induced with the combination of thiopental and midazolam, the two hypnotics act synergistically; when thiopental is given with an opiate such as alfentanil, there is greater potentiation of the antinociceptive response than hypnosis.64

Thiamylal Thiamylal (another thiobarbiturate used mainly in the United States and Japan) has pharmacologic characteristics similar to thiopental with regard to potency, incidence of laryngospasm and respiratory depression, cardiac toxicity, and recovery time. It is formulated as a racemic mixture. The potency of the S enantiomer is about twice that of the R+ form, and there are also kinetic differences. The plasma protein binding of the R+ isomer is 82.5%, and of the S– isomer 88.3%. The elimination half-life of the R+ enantiomer is 20.2 hours; the apparent volume of distribution is 3.66 L/ kg; and clearance is 0.27 L/kg/h. The corresponding values for the S– compound are 24.1 hours, 2.60 L/kg, and 0.15 L/kg/h, respectively.

Methohexital This is an oxybarbiturate with a faster recovery profile than thiopental because of a greater systemic clearance and a shorter elimination half-life. Compared with thiopental, methohexital has a more appropriate kinetic profile for both induction and maintenance of IV anesthesia (elimination half-life of 420– 460 minutes, clearance of 700–800 mL/ min). Because its main metabolite, 4OH methohexital, has no pharmacologic activity (unlike thiopental’s major metabolite, pentobarbital), methohexital may be usefully given by continuous infusion for maintaining anesthesia or sedation (see Drugs for Maintenance of TIVA). Induction of anesthesia with methohexital requires doses of 1–2 mg/kg, giving it a potency of 2.7 times that of thiopental. The side-effect profile of methohexital is more significant than that following thiopental, and includes increased incidences of pain on injection, a tendency to venous thrombophlebitis, and exaggerated involuntary movements, especially in the unpremedicated patient. Inadequate induction doses can also cause excitatory phenomena because the inhibitory

areas of the brain are thought to be depressed at lower drug concentrations.

Etomidate Etomidate is a carboxylated imidazole compound formulated as the R+ enantiomer. The approximate potency ratio of the enantiomers is R+:S– = 1:10.127 As an induction agent, etomidate has important advantages over the barbiturates, showing many ideal properties for an IV agent (cardiostability; reduction of cerebral blood flow, cerebral metabolic rate, and intracranial pressure; no release of histamine and low rate of allergic reactions; only transient and minimal respiratory depression and no inhibition of the hypoxic pulmonary vasoconstrictor reflex), and offers hemodynamic advantages during induction of anesthesia in patients with poor cardiac reserve, and hypovolemia. The drug also has a wider margin of safety in animals, with a high therapeutic index of 26.4. Because it is unstable in water, etomidate is presently solubilized either in 33% propylene glycol or as an emulsion. The drug has a pH of 8.1 and pKa of 4.2. It is a base and approximately 99% of the drug is unionized. Plasma protein binding is approximately 75% (mainly to albumen). Metabolism occurs predominantly in the liver and plasma by esterase hydrolysis, and hence etomidate shows the expected high systemic clearance. Induction doses of 0.2–0.4 mg/kg provide hypnosis for between 5 and 15 minutes, with only minor alterations in cardiovascular parameters in healthy patients and in those with valvular or ischemic heart disease. Little is known about the interaction of etomidate and opiates or other hypnotics for loss of consciousness. Etomidate alone does not obtund the sympathetic responses to laryngoscopy and intubation;39 and for a smooth hemodynamic profile, etomidate is best combined with an opiate or benzodiazepine. However, its use as an induction agent is also associated with a number of minor disadvantages, with significant incidences of pain on injection, thrombophlebitis, myoclonia, and a high incidence of postoperative nausea and vomiting. When given either as a single induction dose or by infusion, etomidate suppresses adrenal steroidogenesis,69 and low plasma cortisol levels are found following use of the agent. Does this matter? In pa-


tients receiving etomidate by infusion for intensive therapy unit sedation, Ledingham et al. found that its use was associated with increased mortality.58 However these findings were not based on a double-blind, randomized, controlled trial. There are no data to support this association when etomidate was administered by continuous infusion to anesthetized surgical patients. As a result of the cortisol suppression, etomidate by infusion is contraindicated in many countries, and any continued use in that way must be considered as off-label. The role of etomidate is further confused by a recent unreasoned and unsupported editorial in Anaesthesia expressing the view that the drug has no place in current anesthetic practice.70 This view is not shared by the present author in the absence of properly conducted clinical outcome trials.

Alternate Formulations of Etomidate Attempts at improving the side-effect profile of etomidate have focused primarily on the solvent. Development of an emulsion formulation does not change the drug’s dynamic properties, but is associated with lower incidences of pain on injection, myoclonus, and local thrombophlebitis.56,128 Another advantage of the emulsion formulation is its lower osmolality and higher pH (400 mOsm/kg and pH 7.6 compared with 4965 mOsm/kg and pH 5.1 for the propylene glycol formation), which means less red cell hemolysis.29,74 A second reformulation of etomidate has used 2-hydroxypropyl-β-cyclodextrin as the solvent.30 Again, there was a lower incidence of myoclonia (17% vs. 92%) and pain (8% vs. 58%), and thrombophlebitis (0% vs. 42%), and no hemolysis. None of these formulations appears to show alterations in the kinetics or dynamics of etomidate. Although it is widely believed that use of etomidate is associated with an increased incidence of postoperative nausea and vomiting, this has not been supported by a recent comparison where etomidate-lipuro and propofol were used for induction of anesthesia to supplement isoflurane/fentanyl in air in patients undergoing orthopedic procedures.122 There were no differences in rates of nausea, vomiting, or the intensity of any nausea during the early postoperative period to 24 hours. However the rates of vomiting after etomidate were higher (27% vs. 10%).

Midazolam Midazolam is the only currently available benzodiazepine that is suitable for induction of anesthesia. It has a faster onset and lower incidence of venous complications than either diazepam or lorazepam, but a slower onset than the other IV hypnotic agents (30–60 seconds for loss of consciousness). Induction of anesthesia (as is the case with the barbiturates) coincides with loss of the eyelash reflex. Induction occurs with doses of 0.1–0.2 mg/kg midazolam given over 20–30 seconds; smaller doses are sufficient in premedicated patients, in the elderly, and in patients of ASA groups PS-III to PS-IV. However, emergence from midazolam-induced anesthesia may be prolonged.79 Midazolam has some advantages over thiopental, including improved perioperative amnesia and hemodynamic stability. However, the combination of midazolam and an opiate can result in significant cardiovascular depression. Although a single induction dose of midazolam does not suppress the adrenal steroidogenesis,27 data from Crozier et al. and Desborough et al. suggest that high doses of midazolam given by infusion prevent the increase in plasma cortisol concentrations in response to surgical stress.24,28 As with etomidate, the significance of this finding during TIVA is uncertain in the absence of appropriate outcome data. Another advantage of midazolam over other hypnotic agents is the availability of a specific antagonist, flumazenil, which is devoid of any intrinsic effects on the respiratory or cardiovascular systems. However, it has a short duration of action, with peak effect occurring 1–3 minutes following IV injection. Because of its shorter elimination half-life (40–70 minutes) and faster clearance rate than midazolam, flumazenil may produce an initial arousal from sedation or anesthesia, followed by resedation.77 Thus, if larger doses of midazolam are used for induction and/or maintenance of anesthesia, flumazenil preferably should be given as the combination of a loading dose and continuous infusion to maintain a plasma drug concentration in excess of 20–40 ng/mL.

Propofol This sterically hindered alkyl phenol was originally formulated as an emulsion containing soybean oil and egg phosphatide (Diprivan). A number of

TABLE 42–8. Different Formulations of Propofol (di-Isopropyphenol) Presently in Preclinical Trials, Current Clinical Practice, or Under Developmenta 1. Original preclinical formulation: 2% propofol in 16% Cremophor EL and 8% ethanol 2. 1% Propofol in 16% Cremophor EL (preclinical) 3. 1% Propofol in lipid emulsion (containing 10% soybean) [ = Diprivan]; emulsion preservatives include ethylenediaminetetraacetic acid (EDTA) and sulfite 4. Ampofol (Amphaster Pharmaceuticals Inc, Rancho Cucamonga, CA) formulated in 1% propofol in 5% soybean [AQ: Please verify this entry. Product not listed at company’s website.] 5. Modified lipid emulsions containing medium-chain triglycerides (MCTs) and 1% propofol: IDD-D propofol (Skye Pharma Inc., New York, NY) and Propofol-lipuro (B Braun, Meslungen, Germany) 6. 6% propofol in MCTs-LCT (longchain triglycerides) (Lipofundin, B Braun) 7. AM 149 (Amrad Operations Pty Lyd, Richmond, Victoria, Australia): 1% propofol in MCT alone 8. Albumin-containing emulsions (under development) 9. Nonemulsion formulations (under development) β-Cyclodextrin Micelle formulations Polysorbate formulation 10. Propofol prodrugs formulated as the hemisuccinate, hemigluratate, hemiadipate, monophosphate, diphosphate aData so far suggest little difference between formulations with regard to pharmacokinetics and pharmacodynamics.

other formulations are either available or undergoing clinical evaluation (Table 42–8). However, the efficacy of these newer formulations in large outcome studies is awaited, but there appears to be little difference in their kinetic and dynamic properties. Propofol (as Diprivan) has a neutral pH of 7.4, and pKa of 11.0; this means that the drug is 99.7% nonionized and highly lipid soluble at pH 7.0. It is rapidly broken down to inactive me-

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tabolites (the glucuronide and the corresponding quinol glucuronide and sulphate) in the liver, and possibly in other organs, such as the lungs.26,40 Other minor metabolites detected in the urine include 2-(ω-propanol)-6-isopropylphenol and 2-(ω-propanol)-6isopropyl-1,4-quinol. It is not known whether any of these have anesthetic potencies. The hydroxylation of propofol by hepatic cytochrome P450 (CYP) involves the isoform 2B6, which shows wide individual variability.21 Another isoform that shows high binding for propofol is CYP 2C9.80 Despite its rapid and complete offset of effect, propofol has a long elimination half-life (of up to 45 or more hours), an apparent volume of distribution of between 1000 and 3940 L, and a systemic clearance between 1.0 and 1.8 L/min. Because of its high extraction ratio, propofol shows flow-dependent clearance, and its own clearance is reduced secondary to its action on myocardial contractility and cardiac output. Population kinetic analyses by Schuttler and Ihmsen indicate weight to be a significant covariate for the elimination clearance, the 2 intercompartmental clearances of a 3-compartment model, and the apparent volumes of the central and 2 peripheral compartments, whereas in older patients (age >60 years), both elimination clearance and the central volume compartment decrease linearly with age.102 Induction of anesthesia with propofol is smooth and associated with a low incidence of excitatory side effects. Doses of 1–2.5 mg/kg (depending on patient age, physical status, and use of premedicant drugs) induce anesthesia in approximately 30 seconds; however, lower induction doses should be used in patients with cardiovascular disease. Loss of consciousness occurs at propofol concentrations between 2.5 and 5.5 µg/mL, with the concentration for loss of response to verbal command being between 2.5 and 3.5 µg/mL. The speed of onset and the dose of propofol needed for induction are dependent on the administration rate. Stokes et al. compared induction times when propofol was infused at 50, 100, and 200 mg/min and as a 2 mg/kg bolus. Times to loss of consciousness were 124, 92, 62, and 32 seconds, respectively, with the corresponding total induction doses being 1.4, 1.96, 2.61, and 2.15 mg/kg.120 The size of the induction dose depends on many physiologic factors.

Kazama et al. determined 4 factors to be independent variables influencing the size of the induction dose (namely age, lean body mass, central blood volume, and liver blood flow).53 When the dynamics of propofol are related to age, 3 functions correlate in a linear manner: the blood–brain equilibration rate constant and time to peak effect; the steepness of the concentration– response relationships for EEG activation and depression; and the effect-site concentration associated with 50% of peak EEG activation.99 The hemodynamic effects following induction doses of propofol are similar to those of the thiobarbiturates, although propofol additionally decreases systemic vascular resistance. In contrast to the barbiturates, propofol has little effect on heart rate. In contrast to the barbituates, propofol has little effect on heart rate; the combination of the drug’s vagotonic effect and the fall in vascular resistance predisposing to significant falls in blood pressure when used in the hypovolemic patient or in patients receiving other vagotonic drugs (e.g., opiates).15 The ventilatory effects of propofol are comparable to those of other hypnotic agents. Induction doses cause significant decreases in tidal and minute volumes, coupled with episodes of apnea often greater than 30 seconds, in 25–30% of patients. Comparative studies indicate the duration of apnea following propofol is longer than with thiopental.118 All induction agents decrease the rib cage and abdominal components of ventilation to a similar amount. The ventilatory depressive effects of propofol are synergistic with those of midazolam and fentanyl, and with the combination alfentanil-midazolam. One advantage of propofol as an induction agent is the greater depression of pharyngeal and laryngeal reactivity than is seen with thiopental, methohexital, or etomidate. This can be of benefit during upper airway instrumentation and insertion of the laryngeal mask airway. Pain on injection is commonly observed during induction of anesthesia with propofol, with incidences of up to 50% when administered into the small veins on the dorsum of the hand. The incidence may be reduced by use of large veins, by mixing with lignocaine (10–20 mg), and by pretreatment with drugs such as fentanyl and alfentanil. Other side effects of induction include excitatory myoclonic phenomena and

occasional epileptiform fits reported during recovery. Like etomidate, propofol appears to have in vitro potential for inhibition of adrenal steroidogenesis, but this is not relevant in clinical anesthetic practice.

Ketamine (2-O-Chlorophenyl2-Methylaminocyclohexanone HCl) This phencyclidine derivative is formulated as a racemic mixture. It is unique among the induction agents in that it produces both dose-related unconsciousness and analgesia. Following induction with ketamine, patients have little recall of surgery or anesthesia. The two stereoisomers, R(–) and S(+), show differing anesthetic potencies (1:3–4), but have similar kinetics. The pH of ketamine is 3.5–5.5, and the pKa is 7.5. At physiologic pH, ketamine is highly lipid soluble, with 12–35% being plasma protein bound, and 44% nonionized. Recovery from ketamine anesthesia occurs as a result of both distribution and degradation by demethylation and hydroxylation by hepatic cytochrome P450. The metabolic breakdown of ketamine is complex, but one metabolite (norketamine; metabolite I) is pharmacologically active with a potency of approximately 30% that of the parent drug, and a longer elimination half-life. The main excretory metabolites are ketamine and metabolite I and II glucuronides. The efficacy of ketamine is enhanced in patients with renal impairment with an accompanying delayed recovery. Most of the ketamine is excreted in the urine as the glucuronides; only 2.5% is unchanged. Ketamine causes rapid induction of anesthesia by the IV route. However, its cardiovascular effects differ from other hypnotic agents; ketamine causes increases in heart rate, blood pressure, and cardiac output. These inotropic and chronotropic effects are seen in both healthy patients and in those with heart disease, and are mediated via central mechanisms. Ketamine blocks the reuptake of noradrenaline by both the uptake 1 (extraneuronal) and uptake 2 (intraneuronal) mechanisms, as well as causes the release of noradrenaline from the sympathetic ganglia. The in vivo effects are obtunded in patients receiving adrenergic antagonists (both α and β) and vasodilators, as well as by pretreatment with benzodiazepines. Ketamine has advantages over propofol and etomidate because it is water


soluble. However, although it lacks the cardiorespiratory depressive properties of other IV agents, its usefulness is limited by high incidences of disturbing emergence reactions (up to 30% of patients). Ketamine also causes increases in intracranial pressure and salivation. The psychomimetic effects of ketamine may be attenuated by benzodiazepine premedication, although these drugs appear to prolong the elimination half-life of ketamine and increase its recovery time.

Stereoisomers of Ketamine The potency ratio for anesthesia is approximately 4:2:1 for S(+) ketamine, ketamine racemate, and R(–) ketamine enantiomers. Some data suggest administration of S(+) ketamine is accompanied by a lower median EEG power spectrum, a greater rise in blood pressure and heart rate, decreased locomotor activity, shortened recovery times, and equipotent analgesia compared with the racemate at similar doses.87,102,104,142

Opiates As already detailed in the section on induction of anesthesia with TIVA, these are not complete IV hypnotics and do not produce anesthesia in the absence of other supplements. However all opiates potentiate the effects of hypnotics when used for induction of anesthesia (this is seen less with thiopental, but is most important with midazolam).

surgical conditions for all patients and all operations. Titration of the infusion rate should reflect the anticipated intensity of the applied stimulus and likely observed patient responses. In general, drug requirements are greatest during endotracheal intubation, and decrease during surgical preparation and draping. The infusion rates will need to be increased prior to skin incision, whereas during anesthesia, drug dosing should be titrated according to signs of patient movement, hemodynamics, and autonomic responses. In the absence of any response over a given period of time, the anesthesiologist may consider reducing the infusion rate by 15–20%. Table 42–9 shows typical infusion regimens used to achieve the steady drug concentrations required to provide analgesia using IV analgesic drugs given by infusion. If the dose of drug administered is clearly too high in the presence of continuing signs of inadequate anesthesia, then the anesthesiologist should examine for a disconnection of the delivery system, or delivery to a subcutaneous rather than vascular site. Other causes could include incorrect programming of pumps, or mechanical errors of the delivery systems. During TIVA, use of combinations of drugs poses questions over which one

to increase or decrease and for what reasons. In general, the dosing of opiates should be aimed at achieving analgesic drug concentrations at the effect site, whereas the hypnotic infusion should be titrated to individual patient requirements and to the intensity of the surgical stimulation. At the end of surgery, the anesthesiologist should reduce the infusion rates of the hypnotic and analgesic during skin closure to allow restoration of spontaneous respiration by the end of surgery.

Thiopental and Thiamylal Early recovery from thiopental occurs because of a decline in the blood (and brain) concentrations as a result of drug redistribution. Following bolus doses and after short or low-dose infusion regimens, thiopental is eliminated by first-order kinetics and the patient promptly awakens. However, at rates in excess of 300 µg/kg/min, thiopental concentrations increase nonlinearly because of the peripheral tissue stores becoming saturated. Maintaining anesthesia with infusions of thiopental requires rates of 150–300 µg/kg/min in combination with an opiate. This will achieve thiopental concentrations of between 15 and 25 µg/mL.22 In the absence of an analgesic supplement, thiopental concentrations of the order

TABLE 42–9.

DRUGS FOR MAINTENANCE OF TIVA In modern anesthesia, the dosing of both hypnotics and analgesics is by titration to clinical effect, measured either by effects on the cardiovascular system or the EEG (or one of its surrogates). The changes in heart rate and blood pressure tend to be “agent specific” (for most IV agents, increasing depth of anesthesia causes a reduction in heart rate and blood pressure, although with ketamine, the heart rate may increase with increasing plasma drug concentrations). However, of all the markers of inadequate anesthesia, patient movement remains the most reliable. Despite the availability of pharmacokinetic-based infusion regimens, it is the dynamic responses of the individual patient to any given surgery that governs the rate of drug infusion. No single plasma drug concentration results in satisfactory anesthetic and

Typical Drug Concentrations and Manual Infusion Regimens to Provide Adequate Analgesia for Major Noncardiac Surgery Under TIVA and Other Target Analgesic Concentrations

Alfentanil Fentanyl Remifentanil Sufentanil

Cp50 (ng/mL) for Surgery

Cp50 (ng/mL) for Adequate Spontaneous Respiration

200–300 4–6 4–6 0.3–0.4

10–30 0.5–1.0 0.5–1.0 0.025–0.05

Dosing strategies

Alfentanil

Fentanyl Remifentanil Sufentanil

Target Concentration (ng/mL)

Loading Dose (mg/kg)

Maintenance Infusion (mg/kg/min)

40 160 320 1 4 6 12–20 0.15 0.5

20 80 160 3 10 1 1–2 0.15 0.5

0.25 1.0 2.0 0.02 0.07 0.02 0.04–1.0 0.003 0.01

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PART 4: Managing Anesthesia Care of 40–50 µg/mL will abolish the response to squeezing the trapezius muscle (which has been equated with the initial surgical incision). Besides the changes in pharmacokinetics, high doses of thiopental also lead to the formation of significant blood concentrations of its active metabolite, pentobarbital. Other inactive metabolites occur following C5 side-chain oxidation. Renal excretion of thiopental is very low (approximately 0.3%). Possible advantages to the use of thiopental infusions include minimal cardiovascular depression and cerebral protection during ischemic episodes, with blood thiopental concentrations on the order of 70 µg/mL resulting in EEG burst suppression.20 There are no published reports in the English-language literature of thiamylal being used as part of infusion anesthesia.

Methohexital 908

Plasma methohexital concentrations of between 3 and 4 µg/mL result in hypnosis, and concentrations between 10 and 12 µg/mL cause EEG burst suppression. Based on dose–response data from Sear and Prys-Roberts,90,112,113 infusion rates of 50–65 µg/kg/min supplemented by opiates or of 100 µg/kg/ min methohexital alone are required for anesthesia. Methohexital infusions depress both blood pressure and cardiac output; they also decrease baroreceptor reflex sensitivity with a resetting of the response to allow a more rapid heart rate at lower arterial pressures than when awake.16 Side effects include excitatory movements, pain on injection, and predisposition to convulsions. Epileptiform activity has been recorded by EEG, but clinical fitting is rare. Methohexital also causes pain if accidentally injected into arteries, but unlike thiopental, this does not normally lead to thrombosis. The combination of methohexital and opiates can cause significant respiratory depression. No untoward effects of methohexital infusions on liver, renal or adrenal function have been described.

Midazolam Continuous infusions of midazolam have been used to provide both sedation and maintenance of anesthesia. When used as the hypnotic component to supplement alfentanil in a TIVA technique, and compared with propo-

fol, Vuyk et al. observed similar hemodynamic effects but slower recovery.135 For the maintenance of anesthesia, infusions on the order of 10 mg/h (resulting in plasma drug concentrations of 200–350 ng/mL) are needed to supplement opiate infusions.24,79,85,86,92 Several of these studies showed that infusions of midazolam and opiates together may cause myocardial depression; this does not appear to be dose dependent and there is an apparent ceiling effect at midazolam concentrations greater than 100 ng/mL. Clinically relevant rates of infusion of midazolam in combination with alfentanil have no significant effect on the plasma cortisol response during lower abdominal surgery.78 A major disadvantage of midazolam for TIVA is the slow recovery. Awakening occurs at drug concentrations around 50–80 ng/mL. Nilsson et al. showed that recovery can be improved by reversal with bolus doses of flumazenil; but resedation may subsequently occur as a consequence of the faster elimination of the antagonist and rebinding of the agonist.77

Ketamine Although widely used throughout the world for the maintenance of anesthesia, there are few concentration-effect data for continuous infusions of ketamine. Most studies suggest hypnotic and analgesic thresholds are about 1.5–2.5 µg/mL and 150–200 ng/mL, respectively. Awakening from anesthesia occurs in the concentration range 600–1100 ng/mL. As sole agent, infusion rates of 60–80 µg/kg/min will provide clinical anesthesia. The use of TCI ketamine for sedation and maintenance of anesthesia was described by Bowdle et al. and Gray et al.14,37 For examination of the psychomimetic effects of ketamine, Bowdle et al. designed a BET delivery scheme based on the kinetic parameters of Domino et al.31 to achieve a stepwise series of plasma target concentrations between 0 and 200 ng/mL. Bowdle et al. showed a good correlation and relationship between the targeted and observed drug concentrations. Increasing ketamine concentrations were associated with greater psychedelic effects for a variety of symptoms. Interestingly, there was no apparent threshold concentration, and no concentration at which these effects plateaued. In the second study, Gray et al. developed a TCI scheme for ketamine to

provide the analgesic component of a TIVA technique with propofol in spontaneously breathing patients undergoing body-surface surgery, using the kinetic parameters of Wieber et al.143 The target concentration of ketamine was 300 ng/mL, with propofol delivered according to the manual BET scheme of Roberts et al.93 Clinically this combination provided good cardiovascular control throughout the surgery, with an average end-tidal carbon dioxide of 5.8 kPa (kilopascals). There were episodes of involuntary movements (although these did not interfere with the surgery being undertaken), and no episodes of recall. However, recovery to giving date of birth was prolonged in some patients. There were no reports of unpleasant dreams or other psychomimetic side effects. Schuttler et al. described a similar technique in patients undergoing lower abdominal surgery under propofol-ketamine anesthesia.103 They describe satisfactory anesthesia without any significant psychic disturbances or cardiovascular stimulation. Recovery was not significantly delayed. A major development in the use of ketamine as part of TIVA has been the separation of the hypnotically active S(+) ketamine enantiomer from the racemic mixture. In a crossover volunteer study, White et al. examined the pharmacologic effects of infusions of racemic, S(+), and R(–) ketamine, with measurement of cardiovascular parameters, the raw EEG, and a battery of psychometric tests.142 S(+) ketamine was approximately 2 times more potent in terms of anesthesia, and was associated with faster recovery compared to both the racemic mixture and the R(–) isomer. This is in agreement with subsequent kinetic studies showing inhibition of metabolism of S(+) ketamine by its R(–) isomer.54 Ketamine enantiomer concentrations at time of regaining consciousness and orientation are consistent with an S-to-R potency ratio of 4:1, while for impairment of psychomotor function, the ratio was between 3:1 and 5:1. When administered at equipotent doses, S(+) ketamine produces longer hypnosis than the R(–) isomer, with the racemate being intermediate. Improved recovery was seen after S(+) ketamine by infusion, compared with the racemate. However, cardiovascular stimulation and psychotomimetic effects are seen with both stereoisomers.


When given alone as part of an anesthetic technique to surgical patients, ketamine can cause considerable side effects. Emergence reactions are commoner after infusions of the R(–) enantiomer than after the racemate and S(+) isomer. However the incidences of dreaming with all three treatment groups were comparable.141 There are no apparent differences between the enantiomers and racemate in their hemodynamic effects, but recovery is faster after the S(+) isomer. The EEG effects of both racemic ketamine and the S(+) isomer are similar; both cause increased fast activity (21–30 Hz) with an accompanying reduction in ∆ power. The IC50 (concentration that inhibits 50%; in this instance, the plasma ketamine concentration necessary to achieve a 50% depression of the maximal EEG median frequency reduction) was 0.8 µg/mL for S(+) ketamine, compared with 1.8 and 2.0 µg/mL, respectively, for the R(–) and the racemic preparations.104 The concentration– effect relationships show the curve for S(+) ketamine to lie to the left of the racemate, and to be steeper.

Propofol Propofol is probably the most used hypnotic for the maintenance of TIVA. Infusion rates of 2–10 mg/kg/h are needed when administered with bolus doses or an opiate infusion, whereas drug concentrations >8 µg/ mL will be necessary if propofol is used as a sole anesthetic agent. Recovery occurs rapidly after cessation of an infusion at blood concentrations of approximately 1.0 µg/mL.15 Because of the wide variability in the therapeutic drug concentration window (related to both age and type of surgery) and intersubject drug kinetics, propofol dosing must be titrated to effect. This is easily achievable as it has a short blood–brain equilibration time (t1/2 ke0). When used to maintain anesthesia, infusions of propofol cause dose-related decreases in blood pressure, cardiac output, and systemic vascular resistance.15 One important difference when compared with methohexital is that infusions of propofol do not show the normal baroreflex increase in heart rate to a decreased blood pressure. Propofol causes a resetting of the baroreceptor reflex such that slower heart rates are seen for a given arterial blood when compared with awake values.25 As well as these central hemodynamic

effects of propofol by infusion, other cardiac effects, including severe bradycardia, sinus arrest, heart block, and asystole, have been reported, which usually occur when propofol is coadministered with vagotonic drugs.15 During TIVA, propofol affects ventilatory control, causing a reduction in the ventilatory response to carbon dioxide, and in the acute ventilatory response to isocapnic hypoxia.73,76 Although bolus doses of propofol have no effect on renal or portal venous blood flows, dose-related changes in liver blood flow have been reported in dogs during graded infusions to concentrations greater than those needed clinically in people.111 However, in patients, clinically relevant infusion rates of propofol appear to cause no significant changes of liver blood flow.72 As well as being an anesthetic agent, propofol has a number of important and advantageous nonhypnotic effects. 1. Mood-altering effects: Subhypnotic doses of propofol administered by a patient-controlled analgesia (PCA) system (10 mg with a 1–5-minute lockout) exerts sedative and anxiolytic effects in anxious patients presenting for ambulatory surgery, and thus can be useful as premedication in ambulatory patients.94 2. Antiemetic effects: Although several authors have suggested an antiemetic effect of propofol (in both hypnotic and subhypnotic doses), the site of this action of the drug remains uncertain.11 It is probable that propofol does not act at dopaminergic receptors. Subhypnotic infusions of the hypnotic are also effective in the prevention of nausea and emesis following cisplatin chemotherapy.11 3. Antipruritic effects: Again subhypnotic doses (10–20 mg IV) of propofol are equally as effective as naloxone in relieving pruritus caused by both epidural and spinally administered opiates.12,95 4. Effects on the central nervous system: Although in vitro studies demonstrate a vasodilating effect of propofol, in vivo measurement shows that infusions of propofol act to decrease cerebral blood flow and intracranial pressure (ICP), and decrease the cerebral metabolic rate. Infusions of propofol have no effect on cerebrovascular autoregulation to

carbon dioxide, although the slope of the curve is decreased. There is some evidence for a cerebral protective effect of propofol, and high doses of propofol have been used to afford protection during cerebral aneurysm surgery in patients requiring cardiopulmonary bypass and deep hypothermic arrest, as well as in patients undergoing nonpulsatile bypass for cardiac surgery.75,121

Propofol–Drug Interactions during TIVA Because TIVA normally depends on the coadministration of more than one IV drug, there is always the opportunity for drug–drug interactions, which may result in changes to drug distribution, metabolism and elimination, or drug dynamics. In vitro, propofol inhibits drug metabolism at clinical concentrations.8,18,49 The magnitude of this inhibition varies from 30–71, with the greatest effect on biotransformations mediated by hepatic isocytochrome P450 2B1. Other cytochromes (P450 1A1 and 2A1) are also inhibited, and Chen et al. showed that clinical concentrations of propofol inhibit renal monooxygenase and defluorinase activities.17 As infusions of propofol decrease liver blood flow,111 they also decrease clearance of flow-dependent drugs. Capacitylimited drug clearance is also decreased by action of propofol on the hepatic extraction ratio.19 These findings are relevant during TIVA, because propofol may decrease the systemic clearance of other coadministered drugs through changes in effective liver blood flow or in the hepatic extraction ratio. However, simulation studies by Schnider et al. suggest that significant changes will not be associated with propofol infusion rates used in clinical practice, as the kinetics of propofol appear linear with regard to infusion rate at those concentrations.98 Schnider’s simulations are in general agreement with the data of Sear and colleagues in an open-chested dog model.111 What happens in vivo? There are data indicating significant interactions between propofol and alfentanil that lead to alterations in drug clearance.67 In male volunteers, the addition of a propofol infusion (at a steady-state concentration ranging between 0.85 and 1.75 µg/mL) to alfentanil infused at 25 µg/ kg/h resulted in a decrease in mean arterial pressure. In turn, this influenced the disposition of the alfentanil,

909


35 No movement Movement

Propofol concentration (µg/mL)

30

25

20

15

10

5

0

910

0

1

2 3 4 5 6 7 Fentanyl concentration (ng/mL)

8

FIGURE 42–2. Increasing concentrations of fentanyl reduces the propofol concentration at which 505 (95%) of patients did not move at skin incision (Cp50i and Cp95i, respectively). Solid lines, logistic regression solution. (Adapted with permission from Smith C, McEwan AL, Jhaveri R, et al. The interaction of fentanyl on the Cp50 of propofol for loss of consciousness and skin incision. Anesthesiology 1994;81:820–828.)

resulting in a 15% decreased systemic clearance, a 68% reduction in the rapid distribution clearance, and a 51% reduction in slow distribution clearance. A similar interaction is seen with the combination propofol-remifentanil, where there is a significant reduction in the initial volume of distribution of the opiate and reductions in both systemic clearance and the intercompartmental distributional clearance. Because this effect is not concentration dependent, it does affect the dosing strategy when using this opiate.13 Of greater importance, however, are the dynamic interactions between the hypnotics and opiates during the maintenance phase of anesthesia. One of the earliest studies examining the hypnotic–opiate interaction was by Smith et al. (Fig. 42–2).117 Other clinical studies and computer simulations by Vuyk et al. from Leiden confirm a synergism between these groups of drugs. They also indicate that regardless of an opiate’s relative potency, the optimal effect-site concentration should be one that (a) prevents responses to noxious stimulation and ( b) allows the rapid recovery of spontaneous ventilation at the end of anesthesia and surgery. Although the original interaction studies focused mainly on the

combination propofol-alfentanil,67,133–136 more recent studies confirm similar interactions for propofol with remifentanil and sufentanil.59,66 A further dynamic interaction is seen between the two groups of drugs, with the frequent need for vasoconstrictor drugs to correct hypotension following the induction of anesthesia.

Adverse Effects of Propofol during TIVA Although widely used as the main hypnotic component of TIVA, propofol exhibits a number of significant adverse effects, including pain on injection (especially when given into small veins and to children), hypotension and bradycardia (which are exaggerated in the presence of other vagotonic drugs such as opioids and hypovolemia), apnea in up to 40% of patients after induction, and reports of epileptiform movements and true convulsions.

α2-Agonists and Other Sedative Drugs α2-Agonist drugs are widely used as part of TIVA techniques in veterinary practice; however, none of these agents are presently licensed for clinical use for sedation or hypnosis in people. Dexmedetomidine (DMD) is

presently undergoing evaluation for both its sedative and hypnotic properties. It can also be seen to have analgesic properties in animals. In humans, DMD interacts with both opiates and hypnotics to reduce drug requirements needed to maintain sedation or anesthesia. Peden et al. examined the combination DMD and propofol.83 They found that an infusion of 3 ng/kg/min of DMD reduced the median effective (ED50) infusion rate of propofol for loss of consciousness from 5.79 to 3.45 mg/kg/h, and the resulting plasma median effective concentration (EC50) from 2.3 to 1.69 µg/mL. however, at these infusion rates, DMD caused significant side effects (with 2 cases of sinus arrest, and 1 of severe postural hypotension persisting for 24 hours postanesthesia). Sinus arrest has also been observed in other studies. Consequently, it is appropriate to pretreat patients (especially those younger than age 40 years) with an anticholinergic agent. At an infusion rate of 3 ng/kg/min, DMD blunted the hemodynamic responses to intubation and surgical incision, with the blood pressure and heart rate remaining stable throughout surgery and into the recovery period. In a separate study, Dutta et al. determined the EC50 of propofol for loss of motor response to an electrical stimulus to be 6.63 µg/mL; when DMD was infused to a steady plasma concentration of 0.66 ng/mL, the EC50 of propofol was reduced by 41% to 3.89 µg/mL.33 A number of other clinical studies describe the use of DMD as part of TIVA techniques. Ramsey and Luterman used variable rate DMD infusions to provide hypnosis for surgery in patients with upper airway pathology.91 When infused at rates up to 10 µg/kg/ h, DMD caused no respiratory depression, none of the patients experienced severe hypotension or bradycardia, and recovery was not excessively prolonged (although the patients, who were ages 50–66 years, required 2–3 hours for complete recovery). Clomethiazole (a derivative of the thiazole part of vitamin B1) has been used as a continuous IV anesthetic to supplement both regional and spinal anesthesia. It permits ease of titration of the depth of sedation and anesthesia, with minimal cardiovascular effects. However, widespread use is limited because of the large fluid loads that

occur when administered as a 0.8% infusion in 4% glucose; increased red cell fragility when given as infusions of >5%; a high incidence of peripheral thrombophlebitis, necessitating central venous administration; and minor side effects of nasal irritation and stuffiness. Following prolonged infusions, recovery may be delayed.63

Opiates Chapter 41 describes the use of infusions of opiates as part of balanced techniques. When used in TIVA, the opiates act synergistically with most hypnotic agents. Studies by Vuyk et al.,65,66,133–136 Glass et al.,117 and Lentschener et al.59 show that even very small doses of opiates can markedly reduce the requirements of the hypnotic component. These studies also demonstrate a significant “ceiling effect”—such that above a given opiate dose or plasma concentration, little further reduction in hypnotic requirement can be achieved. During TIVA, the ability to prevent autonomic responses appears to be largely dependent on increasing the amount of the opiate drug. Examples of “useful” interactions between the hypnotic and analgesic components of TIVA can be found in the work of Vuyk et al. and Mertens et al.66,133,134,136 Table 42–9 shows the typical plasma opiate concentrations needed to obtund responses to noxious stimuli during TIVA (and the associated opiate concentrations needed for adequate spontaneous ventilation in the recovery room), together with the regimens needed to achieve other drug concentrations.

RECOVERY FROM TIVA The rapidity of recovery after TIVA depends on how well the clinician is able to keep the effect-site drug concentrations near to those concentrations found in the awake or spontaneously breathing subject. If intraoperative concentrations are kept at approximately 20% above those associated with wakefulness, rapid recovery will occur.

Context-Sensitive Half-Time In 1992, Hughes et al. offered a different approach to the anesthesiologist’s understanding of the recovery profile following infusions of intravenous anesthetic agents. Rather than relating recovery to elimination half-life or systemic clearance, they defined a new

Context sensitive half-time (minutes)


300 250 Fentanyl 200 Thiopental 150 100

Midazolam

50

Sufentanil

Alfentanil Propofol

0 0

1

2

3 4 5 6 Infusion duration (hours)

7

8

9

FIGURE 42–3. Context-sensitive half-times as a function of infusion duration from computer simulations of pharmacokinetic models. Solid and dashed lines are used only to permit overlapping lines to be distinguished. (Adapted with permission from Hughes MA, Glass PSA, Jacobs JR. Context-sensitive half-time in multicompartment pharmacokinetic models for intravenous drugs. Anesthesiology 1992;76:334–341.)

term: context-sensitive half-time (CSHT).43 Compared to the various half-lives of a kinetic model, the CSHT describes what is happening to the plasma drug concentration. Termination of drug effect is dependent on two separate kinetic processes: drug distribution and drug elimination. An IV drug with a short elimination halflife is not necessarily a short-acting drug, as drug redistribution can affect the dynamic profile of the agent. The CSHT is dependent on the 3 rate constants—kel, k12, and k21—of a 2-compartment mamillary model in which drug elimination occurs only from the central kinetic compartment. The CSHT is a “half-time” rather than “half-life,” as the time needed for plasma or effect-site drug concentration to decrease by 40% will not be twice that required to decrease by 20%! The term “context” refers to the duration of the drug administration, with the half-time measured from the moment of cessation of the infusion (Fig. 42–3). One limitation of the CSHT is that it describes the time to a 50% decrease in the plasma or central compartment drug concentration. This may not be the required decrement in the drug concentration needed to achieve recovery, although the studies of Prysi-Roberts and Sear suggest that it may certainly be appropriate when predicting the behavior of hypnotic agents given by infusion.89 The study of Kapila et al.,51 comparing the modeled CSHT for both alfentanil and remifentanil with values determined from volunteers where the effect measured was that of depression

of minute ventilation, validated the predictive accuracy of the CSHT. The modeled values of the CSHT following a 3-hour infusion were 2.0 and 51.9 minutes, respectively, for remifentanil and alfentanil, compared with measured values of 3.2 and 47.3 minutes, respectively. Youngs and Shafer further elaborated on the concept of CSHT.144 They produced simulations of the time courses not just for a 50% decline in the plasma drug concentration, but also for the 20% and 80% declines after varying-length infusions of 3 opiates (alfentanil, fentanyl, and sufentanil), giving rise to the “20%, 50%, and 80% decrement times.” Examination of the relationship between 6 derived components of a 3-compartment mamillary model (namely V1, V2, V3, Cl10, Cl12, and Cl13) on these decrement times show that increases in the initial volume of drug distribution ( V1) lead to longer decrement times. The reverse is true after increases in the clearance constant Cl10. Similarly, increases in the peripheral volumes of distribution ( V2 and V3) and the intercompartmental clearances Cl12 and Cl13 lead to shorter decrement times when the infusion is of limited duration, but longer times after prolonged infusions. For rapid recovery from TIVA, drugs with a small initial volume of distribution ( V1) and high clearance (Cl10) are the most suitable. After prolonged anesthesia, the fastest recovery times are seen after infusion of drugs with small apparent peripheral volumes of distribution and small intercompartmental

911


80

300

Alfentanil

250

70

200

60

Time (min)

Time (min)

Sufentanil

150

50

100

40

50

30

0

50

100

150

200

250

300

350

20 0

400

50

Duration of administration (min)

400

140

100 Propofol

Midazolam 120 Time (min)

80 Time (min)

100 150 200 250 300 350 Duration of administration (min)

60 40

100 80 26

20

40

912 0

50


400

20 0

50


400

•

FIGURE 42–4. Comparison of mean effect time (MET) ( ) and 50% decrement times (■) as a function of length of administration of sufentanil, alfentanil, propofol, and midazolam when maintained as an infusion maintaining a constant plasma concentration equal to the Cp90 for surgery. (Adapted with permission from Bailey JM: Technique for quantifying the duration of intravenous anesthetic effect. Anesthesiology 1995;83:1095–1103.)

clearances. As the “biophase” concentration is always related to the plasma drug concentration, the “decrement times” are also a good descriptor of drug effect except after bolus doses or very short infusions. Bailey described another descriptor of recovery following intravenous infusions: the “mean effect time.”6 The mean effect time is based on whether or not a patient responds to a given parameter or end point. For a given plasma drug concentration, the “probability (p)” of a given drug effect is described by a logistic regression equation of the type: p = Cg/ Cg50 + Cg where C = drug concentration; C50 = drug concentration at which there is a 50% probability of a given effect; and g = a parameter estimate describing the steepness of the concentration–probability relationship. From this equation, Bailey calculates the mean effect time as the integral of p against time. Whereas the 50% decrement time of Youngs and Shafer will be, by definition, the median recovery value for a given population of patients after a

given dosing regimen, it will also be the mean recovery index based on the probability of that event occurring. A large steepness coefficient g indicates a steep drug concentration–response relationship. Under such circumstances, the difference between the mean effect time and the 50% decrement times will be insignificant. However, if the concentration–response relationship is flatter, recovery times will tend to be right-skewed, and the mean effect time will be significantly greater than the 50% decrement time. Although determination of decrement times is straightforward, the calculation of the 50% value for the intraoperative maintenance drug concentration, or determination of the mean effect time requires the anesthetist to have a clear understanding of the nature of the concentration–response relationship (and hence be able to determine g). For low values of g, the anesthetist needs to “overdose” the patient to make sure that all patients are adequately asleep or pain free. This necessitates a greater decline in the maintenance drug concentration in order to achieve concentrations where there is a 50% probability of recovery

occurring. Alfentanil is an example of a drug with a high g value (9.2), whereas sufentanil, propofol, and midazolam have flatter dose–response curves (g values of 5.99, 3.27, and 3.05, respectively). Thus the mean effect time and the 50% decrement times for alfentanil are similar, whereas those for propofol, midazolam, and sufentanil differ, depending on the duration of drug administration, with the mean effect time being increasingly greater as the dosing time increases6 (Fig. 42–4).

How Do All These Simulation Data Compare with In Vivo Observations for Different IV Agents? Hypnotics Propofol has a CSHT of 24 72

Elimination Renal Renal Renal Renal Renal/hepatic Renal/hepatic Renal/hepatic Renal/hepatic GI tract/hepatic Renal/hepatic Renal

congestive heart failure. They are generally well tolerated, producing few idiosyncratic side effects. They competitively inhibit the enzyme that converts angiotensin I to the potent vasoconstrictor, angiotensin II (Fig. 43–1). This decrease in plasma angiotensin II causes vasodilatation of both venous capacitance and arteriolar resistance vessels without reflex increases in heart rate. ACE inhibitors also decrease aldosterone levels, potentiate the vasodilating kallikrein–kinin system and may affect prostaglandin levels. Side effects include hypotension, acute renal failure, and hyperkalemia.65 Other complications, including cough, bronchospasm, angioneurotic edema, and anaphylactoid reactions, are believed to be related to increased kinin levels because ACE is also kininase. Precipitous reductions in blood pressure may occur following initiation of therapy, particularly in hypovolemic patients. In those with normal renal function ACE inhibitors generally raise plasma potassium concentrations by less than 0.5 mEq/L. More prominent hyperkalemia may be seen in patients with renal insufficiency, concurrent use of a potassium-sparing diuretic or a nonsteroidal antiinflammatory drug, and in the elderly.66 Declines in renal function occur in patients with bilateral renal artery stenosis, hypertensive nephrosclerosis, congestive heart failure, polycystic kidney disease, or chronic renal insufficiency. Nevertheless, as a result of the favorable effects on the progression of diabetic67 and nondiabetic renal disease, an increase in serum creatinine of as much as 35% above baseline is acceptable, unless hyperkalemia develops.68

CHAPTER 43: Cardiovascular Drugs

Angiotensinogen

Prorenin

RENIN

?

Kininogen(s) KALLIKREIN(S) Kinin(s)

Angiotensin I ANGIOTENSIN - CONVERTING - ENZYME Angiotensin II

Inactive fragments Aldosterone synthesis Prostaglandin synthesis

Vasoconstriction antinatriuresis

Vasodilation natriuresis

FIGURE 43–1. Schematization of the renin–angiotensin–aldosterone system and the kallikrein– kinin system and their interaction with the angiotensin-converting enzyme. (Reproduced with permission from Borek M, Charlap S, Frishman WH. Enalapril. Pharmacotherapy 1987;7:135.)

In addition to lowering blood pressure, ACE inhibitors decrease progression of cardiac dysfunction in heart failure, decrease the progression of chronic renal disease,69 improve survival after myocardial infarction with reduced systolic function, and induce regression of left ventricular hypertrophy.70 Consequently, they are frequently the antihypertensive of choice.6 It has also been shown that increased kinin levels may increase insulin sensitivity, which can lower the blood glucose in patients with type 2 diabetes.71 During the perioperative period, patients maintained on ACE inhibitors through the morning of the surgery have increased numbers of hypotensive episodes that require treatment with vasopressors.72

Angiotensin II Receptor Blockers Table 43–6 lists the angiotensin II receptor blockers. There are two well-described subtypes of angiotensin II receptors, designated AT1 and AT2, both of which have a high affinity for angiotensin II.73 The AT1 subtype mediates the vasoconstrictor effect of angiotensin II and may mediate angiotensin II-induced growth in the left ventricle and the arterial wall. The AT2 receptor has a less-well-understood role. ARBs are selective blockers of AT1 receptors on the cell membrane.74 The ARBs have been primarily evaluated for the treatment of hypertension, where they appear to have an

effect similar to monotherapy with other antihypertensive drugs, including ACE inhibitors. In fact, ARBs are more effective than β-blockers in reducing the long-term risk of cardiovascular morbidity and mortality.75 ARBs prolong survival in heart failure76–78 in patients with systolic heart failure who cannot tolerate ACE inhibitors,76 and in those treated with both ARBs and ACE inhibitors.77,78 Two major trials demonstrated a clear benefit in renal protection with ARBs in patients with nephropathy caused by type 2 diabetes, although these trials did not compare ARBs with ACE inhibitors.79,80 The angiotensin II receptor blockers are generally well tolerated. They exhibit side effects similar to ACE inhibitors, with the exception of those mediated by kinins, particularly cough, which is the most common reason that patients discontinue ACE inhibitors. Unlike ACE inhibitors, they are effective and safe in the treatment of hypertensives with symptomatic asthma.81 It should be recognized, however, that

multiple cases of angioedema have been described in patients taking losartan, typically characterized by swelling of the mouth, tongue, pharynx, and eyelids, and occasional laryngeal obstruction.82 Consequently, physicians should proceed with caution when choosing an antihypertensive for patients who have discontinued ACE inhibitors because of angioedema. As with ACE inhibitors, patients taking ARBs might be more prone to developing intraoperative hypotension.83 A study in vascular surgery patients found a statistically significant increase in the number of hypotensive episodes in patients who were treated with ARBs prior to surgery compared with those patients who were treated with β-blockers or calcium channel blockers.84

DIGITALIS More than 200 years after William Withering published “An account of the foxglove and some of its medical uses,” digoxin remains a mainstay of cardiac therapeutics. The mechanism of action of the cardiac glycosides is unique. They bind to and directly inhibit the membranebound sodium-potassium adenosine triphosphatase (ATPase) pump of the myocardial cell, causing increased intracellular sodium and decreased intracellular potassium. The increase in intracellular sodium changes the sodium concentration gradient and produces decreased exchange of extracellular sodium for intracellular calcium. This leads to net increased inward calcium current and intracellular calcium concentration, resulting in enhanced isolated myocyte contractile performance (increased shortening velocity) and left ventricular (LV) systolic function. Digitalis remains the most prominent

TABLE 43–6. Angiotensin II Receptor Blockers Agent

Dosage

Half-Life (hours)

Losartan Valsartan Irbesartan Telmisartan Candesartan Eprosartan

50–100 mg daily BID 80–320 mg daily BID 150–300 mg daily BID 40–80 mg daily BID 16–32 mg daily BID 400–800 mg daily

6–9 9 11–15 24 3–11 5–7

925


926

inotrope available for chronic oral use and has been shown clinically to decrease symptoms of CHF as well as the number of hospitalizations.85,86 Unlike all other inotropes, digitalis use is not associated with increased mortality.87 Cardiac glycosides have substantial electrophysiologic effects. Digitalis substantially enhances parasympathetic tone while causing some decrease in cardiac sympathetic activity. These effects are why digitalis is efficacious in treatment of supraventricular dysrhythmias.88 By affecting the sodiumpotassium ATPase pump, digitalis may also have effects on conduction that are independent of vagal tone. In normal subjects, digoxin has only a small effect on the sinoatrial (SA) node. It may be safely used in patients with sinus bradycardias without decreasing heart rates. However, patients with evidence of sick sinus syndrome given digitalis may have lengthened SA node conduction and recovery times.89 The major effects of digitalis on atrial and atrioventricular (AV) node tissue are also vagally mediated. In humans, therapeutic dosages decrease conduction velocity and either have no effect or increase effective atrial refractory period. Digitalis causes prolongation of both conduction time and the AV node’s effective refractory period. In the accessory pathway of patients with Wolff-Parkinson-White ( WPW) syndrome, digitalis may shorten the refractory period of the antegrade pathway90 without affecting the retrograde pathway. Consequently, it should not be used in patients with WPW syndrome. In the ventricle, digitalis shortens the effective refractory period while having little indirect effect. Digitalis possesses a very low therapeutic index. At toxic levels, in addition to causing anorexia, nausea, fatigue, visual disturbances, and confusion, digitalis may cause severe conduction disturbances. The ECG manifestations may include sinus bradycardia or SA node exit block, AV block, premature atrial contractions, junctional tachycardias, premature ventricular contractions, ventricular tachycardia, and fibrillation. Certain factors, such as renal insufficiency, electrolyte abnormalities (hypokalemia, hypomagnesemia and hypercalcemia), hypothyroidism, pulmonary disease, and pharmacokinetic interactions with other drugs that can affect digoxin metabolism (quinidine, cyclo-

sporine, verapamil, rifampin), can increase the risk of digitalis intoxication. Treatment of digitalis toxicity can include several measures, ranging from simply stopping further dosages to aggressively treating hypokalemia and hypomagnesemia, oral therapy with activated charcoal, or placement of a transvenous pacemaker in patients with symptomatic bradycardia or AV dissociation. It has been suggested, however, that transvenous cardiac pacing might precipitate cardiac dysrhythmias and deterioration, and should, if possible, be avoided.91 Atrial, junctional, and ventricular ectopy are amenable to therapy with phenytoin or procainamide. Ventricular ectopy is usually treated successfully with lidocaine. Anecdotal data suggest that magnesium, bretylium, and amiodarone may suppress severe lifethreatening dysrhythmias although amiodarone itself may increase digoxin levels by 100%. In general, drugs that increase serum digitalis levels (e.g., quinidine, propafenone, verapamil) and administration of calcium salts should be avoided. The availability of digoxin-specific Fab fragments has dramatically changed therapy for severe toxicity. The Fab fragments bind to digoxin intravascularly and in the tissues. The digoxinFab fragments complexes are small, so can be rapidly excreted by glomerular filtration in patients with normal renal function. Multiple studies show favorable response to digoxin-specific antibody fragments.92 The therapeutic indication for digitalis use is to control heart rate in atrial fibrillation or flutter, and symptomatic management of congestive heart failure. The usual dose of digoxin is about 0.25 mg/d, with half that dose prescribed for the elderly (age > 65) and patients with renal insufficiency. When acute therapy is necessary, a loading dose of 1–1.5 mg is given over 24 hours. Digoxin-induced arrhythmias and other toxic manifestations occur at progressively increasing frequency as the plasma digoxin concentration rises above 2.0 ng/mL, the upper limit of normal. Dysrhythmias occur often during the perioperative period. In patients receiving digitalis therapy, the possibility of digitalis toxicity as the dysrhythmia source must always be considered. This could delay introduction of drugs (e.g., verapamil) that substantially in-

crease serum digitalis levels or delay use of cardioversion, which may precipitate ventricular fibrillation in the presence of digitalis toxicity. These considerations become even more significant when one realizes that powerful inotropes and antidysrhythmics with shorter half-lives than digitalis are available for acute administration if necessary.93 Some data suggest that halothane, enflurane, ether, methoxyflurane, ketamine, droperidol, and curare may reduce the likelihood of digitalis-induced ventricular dysrhythmias. Thiopental and fentanyl have no effect, whereas succinylcholine, neostigmine, and diazepam may induce dysrhythmias in patients taking digitalis. No reports are available regarding the interaction of digoxin with sevoflurane or desflurane to our knowledge. More important to any discussion of digitalis-associated dysrhythmias and toxicity is prevention of hypokalemia, acid–base imbalance, hypoxia, hypercalcemia, and catecholamine excess states, and avoidance of medications that acutely increase digitalis serum levels.94

ANTIANGINALS Three groups of drugs—nitrates, βadrenergic blocking agents, and calcium channel blockers—alone or in combination, are effective and are commonly used to manage angina. Choosing a class of drugs, or a particular drug within each class, depends primarily on patient tolerance of side effects, ventricular function, presence or absence of conduction disease, and relative indications or contraindications caused by additional illnesses.

Nitrates Nitrates in many forms have been used in treatment and prevention of angina for more than 100 years. Nitrates are potent dilators of the vascular smooth muscle that affect venous capacitance more than arterial resistance.95 Other hemodynamic effects include decreases in left ventricular end-diastolic pressure, pulmonary artery pressure, pulmonary vascular resistance, and right ventricular enddiastolic pressure. Decreases in mean arterial pressure are usually slight and smaller than the other hemodynamic parameters. Low doses have little effect on cardiac output and heart rate in


patients with normal or increased intravascular volume. Rapid administration or high doses of nitrates, especially in patients with volume-contracted states, may decrease left ventricular end-diastolic pressure, stroke volume, cardiac output, and mean arterial pressure, and cause reflexive increases in heart rate and sympathetic tone.95 Nitroglycerin inhibits hypoxic pulmonary vasoconstriction, but to a lesser extent than nitroprusside. The antianginal use of nitroglycerin stems from its effect on the relationship between myocardial oxygen supply and demand. By increasing venous capacitance, and thus decreasing left ventricular end-diastolic pressure and volume, nitroglycerin decreases systolic ventricular wall tension, which is the major determinant of myocardial energy consumption. An additional benefit of nitrates is improved flow to areas of ischemia. This effect is related to higher myocardial perfusion pressure, resulting from lower left ventricular diastolic pressure and redistribution of coronary blood flow to subendocardial tissue. This results in an increased endocardial-to-epicardial flow ratio, and probably in a decreased resistance to collateral blood flow. Nitroglycerin is a direct coronary arterial vasodilator; especially of large epicardial vessels.96 Dilation of large coronary arteries explains the beneficial effects of nitrates in patients with angina caused by coronary vasospasm. In patients with classic angina caused by coronary insufficiency, net coronary blood flow does not increase following administration of nitroglycerin. It has been postulated that dilation of large epicardial vessels or improvement of cardiac perfusion pressures causes an autoregulated increase in coronary vascular resistance in wellperfused arteriolar resistance vessels distal to large coronary arteries. This increased resistance shunts coronary flow to areas of ischemia where the arterioles are already maximally dilated. Effects of nitrates on coronary blood flow distribution are different (indeed opposite) from those of sodium nitroprusside and dipyridamole. The latter drugs dilate arteriolar resistance vessels and can lead to myocardial steal phenomena. Nitroglycerin’s effects on both systemic and coronary circulations are important. For example, intracoronary

Vascular smooth muscle cell R-SH (Tissue thiols) NO

(CN)5–FeNO (Nitroprusside)

NO

R-SNO (S-nitrosothiol) NO (Nitric oxide)

GTP GC (Guanulate cyclose) cGMP

NO (Nitric oxide) 2H+ R1–SS–R1 (oxydized) Sulphydryl RONO2 NO2– (Organic nitrate) (Inorganic nitrate)

[Ca2+] i

R1–SH (reduced)

R–ONO2 (Organic nitrate)

R1 - SS - R1

Nitrate tolerance Extracellular

Relaxation

NO2– Intracellular

FIGURE 43–2. Cellular mechanism of action of nitroglycerin and nitroprusside. (Reproduced with permission from Ignarro LJ, Lippton H, Edwards JC, et al. Mechanism of vascular smooth muscle relaxation by nitrates, nitroprusside and nitric oxide. J Pharmacol Exp Ther 1981;218:739.)

927 injections of nitroglycerin are not as effective as IV nitroglycerin in treatment of pacer-induced ischemia. Beneficial systemic effect is suggested by the observation that intracoronary injection is less effective despite increased coronary blood flow. Conversely, intracoronary nitroglycerin in doses without systemic effect decreases ST segment elevations, improves systolic and diastolic function, and enhances flow to ischemic tissue.97 Nitrates produce these effects by entering vascular smooth muscle cells, where they are metabolized to 1,2-glyceryl dinitrate and nitrite via mitochondrial aldehyde dehydrogenase, whose sulfhydryl group is required for activity.98 Nitrite is then oxidized to form nitric oxide. Nitric oxide in combination with tissue thiols forms s-nitroso-thiol, an activator of guanylate cyclase, the enzyme that catalyzes the formation of cGMP (Fig. 43–2).99 As a second messenger, cGMP mediates many of the biologic effects of nitric oxide, including the control of vascular tone. Dephosphorylation of light-chain myosin occurs through a cGMP-mediated protein kinase, causing smooth muscle relaxation. Higher intracellular levels of cGMP also mediate bronchial, biliary, gastrointestinal, ureteral, and uterine smooth muscle relaxation. Nitrates also have beneficial antiplatelet and antithrombotic properties. The recently recognized

role that platelet-dependent thrombotic processes play in acute coronary syndromes suggests that the inhibition of platelets by nitrates may offer an additional mechanism by which these compounds improve perfusion to ischemic myocardium. This effect is a result of stimulation of platelet guanylate cyclase by nitrates preventing fibrinogen binding to platelet IIb/IIIa receptors, which is essential for platelet aggregation.100 Clinically, nitrates can be used transdermally or orally for chronic therapy, on an intermittent basis via the sublingual route, or intravenously for acute therapy (Table 43–7). Clinical indications include classic exertional, Prinzmetal , and unstable angina; acute myocardial infarction (MI), and coronary artery spasm. Nitrates can be also useful in patients with congestive heart failure, particularly at night in those with significant orthopnea or paroxysmal nocturnal dyspnea. Tolerance has been a major problem with the use of nitrates as chronic antianginal therapy. How tolerance occurs is incompletely understood, but it is probably a result of attenuation of the vascular effect of nitrates and not of altered pharmacokinetics.101 Common adverse effects in patients taking nitrate therapy are headache, flushing, and hypotension. Nitrates must be used cautiously in patients with severe aortic stenosis and volume depletion.


TABLE 43–7. Nitrate Preparations Nitroglycerin Sublingual tablets—Nitrostat Translingual spray—Nitrolingual Transmucosal tablets—Nitrogard (Forest) Oral extended-release Ointment—2% Transdermal patches Isosorbide Dinitrate Sublingual tablets—immediate release Oral tablets Extended-release tablets and capsules Isosorbide-5-Mononitrate Immediate release

928

Extended-release Pentaerythroid tetranitrate Sublingual Erythritol tetranitrate Sublingual Oral Patients taking nitrates who are to have surgery should continue to receive therapy until and possibly throughout surgery. If a substantial perioperative or postoperative lapse is expected, nitrate ointments or IV nitroglycerin may be used. Perioperatively, IV nitroglycerin may be used for treatment of myocardial ischemia, CHF, acute volume overload, systemic and pulmonary hypertension, and coronary artery spasm. In patients who are undergoing cardiac surgery, nitroglycerin is also used to facilitate infusion of oxygenator reservoir volume by venodilation and transfusion of blood to increase O2carrying capacity. Patients receiving acute nitroglycerin therapy may exhibit exaggerated hemodynamic responses to anesthetics, possibly related to its effects on preload. Prolonged use or excessive doses of nitroglycerin rarely may cause methemoglobinemia,102 but to a much lesser extent than sodium nitroprusside.

β-Adrenergic Blocking Agents β-Adrenergic blocking agents are among the most widely prescribed cardiac medications and have a wide spectrum of therapeutic uses beyond treatment of hypertension, angina, and dysrhythmias.

0.3–0.6 mg PRN (up to 3 tablets) 0.4 mg/spray (up to 3 sprays) 1–3 mg q5h TID 2.5–6.5 BID to QID 1” to 2” q4h for 12–14 h/d 1 patch 12–14 h/d 2.5–10 mg q2–3h 30 mg BID or 20 mg TID in morning and afternoon 40–80 mg once daily to TID 20 mg in morning and afternoon, 7 hours apart 60–120 mg once daily 10 mg PRN 5–10 mg PRN 10–30 mg TID There are at least three distinct types of β-receptors: • Activation of β1 receptors, found primarily in the heart muscle, increases heart rate, contractility, and AV conduction, and decreases AV node refractoriness. • Activation of β2 receptors, present in cardiac muscle but more prominently found in bronchial and peripheral vascular smooth muscle, result in bronchodilatation and vasodilatation. • Activation of β3 receptors, found in adipose tissue and the heart, may induce thermogenesis103 and may have cardiodepressant effects.104 The major therapeutic effects of βadrenergic blockers are on the cardiovascular system. Variations among β-adrenergic blocking agents result from their differing pharmacologic properties in regard to β1 selectivity, α-adrenergic blocking activity, presence of intrinsic sympathomimetic activity (ISA) or membrane-stabilizing activity (MSA), potency, lipid solubility, first-pass effect, half-life, and mode of metabolism and excretion. All β-adrenergic blocking agents competitively block effects of catecholamines on receptors in the

heart, lung, vasculature, kidney, brain, and eye, and their therapeutic value stems from these effects. β-Adrenergic blockers lower blood pressure in patients with hypertension, although the mechanism is still debated. β-Blockers decrease myocardial contractility and heart rate, and thus cardiac output, but even at dosages lower than necessary to cause substantial decreases in cardiac output, they can be effective antihypertensives. βBlockers with ISA such as pindolol, decrease cardiac output less, yet are similarly effective antihypertensives. βBlockers decrease the release of renin from the juxtaglomerular apparatus. This action contributes to the antihypertensive effect. However, even though hypertensive patients with high plasma renin activity (PRA) respond well to propranolol, which decreases PRA, βblockers that do not decrease PRA (e.g., pindolol) are also effective. Evidence suggests that β-blockers cross the blood–brain barrier, and a CNS mechanism involving reduction of receptor-mediated sympathetic outflow has been proposed. On the other hand, lipophilic drugs such as propranolol and metoprolol are no more effective than hydrophilic compounds such as atenolol. Other proposed mechanisms of action include resetting of baroreceptors, attenuation of pressor responses to stress and exercise, and blockade of prejunctional receptors that normally facilitate norepinephrine release.105,106 Despite unclear mechanisms, β-blockers are among the most useful and commonly prescribed cardiovascular medications. With the recent introduction of the so-called third-generation β-blockers, other additional antihypertensive mechanisms have been proposed, such as release of nitric oxide, antioxidant action, Ca entry blockade, opening of K channels.107 In angina pectoris, β-adrenergic blocking agents decrease heart rate, blood pressure, and contractility, and therefore reduce myocardial O2 consumption. They may improve perfusion by increasing diastolic coronary filling time. Although β-blockers have little effect on the factors influencing plaque vulnerability, they may decrease the incidence of plaque rupture by reducing mechanical stress.108 Other mechanisms have been suggested (Box 43–1). Not all the actions of βblockers are beneficial in all patients.


BOX 43–1. Possible Mechanisms by Which β-Blockers Protect the Ischemic Myocardium Reduction in myocardial oxygen consumption, heart rate, blood pressure, and myocardial contractility Augmentation of coronary blood flow Increase in diastolic perfusion time by reducing heart rate Augmentation of collateral blood flow Redistribution of blood flow to ischemic areas Alterations in myocardial substrate utilization Decrease in microvascular damage Stabilization of cell and lysosomal membranes Shift to oxyhemoglobin dissociation curve to the right Inhibition of platelet aggregation Reproduced with permission from Frishman WH. Clinical Pharmacology of the β-Adrenoceptor Blocking Drug. 2d ed. Norwalk, CT: Appleton-Century-Crofts, 1984:306.

In patients with very poor ventricular function, worsening failure may negate other gains. Similarly, in Prinzmetal angina, β-blockade is ineffective and may even be harmful because of unopposed α-tone in the large coronary arteries.109 Treatment of angina pectoris with β-blockers, in combination with nitrates, aspirin, and/or calcium channel blockers, represents the current standard of care, if no contraindications exist. Competitive β-receptor inhibition has useful antidysrhythmic effects. βBlockers decrease the phase IV depolarization slope of the action potential and thus decrease automaticity. They slow the rate of discharge of the sinus and ectopic pacemakers and increase the effective refractory period of the AV node. The membrane-stabilizing effect of β-blockers does not appear to be relevant in the management of arrhythmias as it is manifested at concentrations well above therapeutic levels. βBlockers are particularly effective in dysrhythmias caused by increased circulating catecholamines such as pheochromocytomas, anxiety, exercise, myocardial ischemia, and heart failure caused by cardiomyopathy; in those caused by increased cardiac sensitivity to catecholamines such as thyrotoxicosis; and in the dysrhythmias of mitral

valve prolapse. They control heart rate in atrial fibrillation, flutter, and paroxysmal atrial tachycardia.110,111 β-Blockers reduce sudden death, especially in patients with prior myocardial infarction or heart failure.112 Survivors of myocardial infarctions have decreased morbidity, less sudden death, and fewer recurrent infarctions when treated with β-blockers. Although the reasons for this are not completely clear, a combination of the antiischemic and antidysrhythmic effects seems to play a key role.113 Other cardiovascular syndromes in which β-blocker therapy has proved useful include mitral valve prolapse, preexcitation syndromes, hypertrophic cardiomyopathy,114 tetralogy of Fallot, aortic aneurysm, prolonged QT interval syndromes, and advanced cardiomyopathies. Noncardiac uses have included prevention of bleeding in patients with portal hypertension and treatment of glaucoma, thyrotoxicosis, migraines, essential tremors, delirium tremens, and anxiety. These important drugs are not without significant side effects. βBlockers may precipitate congestive heart failure in patients with preexisting ventricular dysfunction. Patients with sinus node dysfunction or AV block may develop symptomatic bradycardias; consequently, β-blockers are relatively contraindicated in patients with sick sinus syndrome. Stimulation of β2 receptors in lungs causes bronchodilation; conversely, treatment with β-blockers may induce bronchospasm. Even β-blockers with relative β1 selectivity (e.g., metoprolol, atenolol, betaxolol, esmolol, acebutolol, bisoprolol) occasionally induce bronchoconstriction in therapeutic doses. Nevertheless, they are preferred in patients with chronic lung disease.115 β-Blockade may decrease cardiac output and block β2mediated coronary or peripheral arterial dilation, allowing unopposed constriction (e.g., spasm). Symptoms of peripheral vascular disease may worsen after β-blocker therapy, although this concern might be overstated in patients with mild to moderate peripheral vascular disease.116 Additional concerns include impotence, and decreased sympathetic manifestations of hypoglycemia in patients taking insulin or hypoglycemic agents. CNS effects such as depression, psychosis, and obtundation may occur.

Depression, fatigue, and sexual dysfunction are common causes of βblocker discontinuation. Multiple interactions between βadrenergic blocking agents and other drugs have been described, particularly ones that depress myocardial function and automaticity, such as calcium channel blockers and antiarrhythmic drugs. Abrupt discontinuation of β-blockers can result in a withdrawal syndrome caused by upregulation of β-receptors. This increased sensitivity to endogenous catecholamines can result in hypertension, tachycardia, or exacerbation of anginal syndromes, even MI or death. The β-adrenergic blocking agents most frequently used in the United States today are described in the following sections (Table 43–8).

Propranolol Propranolol is the prototype against which all other β-adrenergic blocking agents are measured. It is noncardioselective and has no ISA. Although propranolol possesses MSA, this occurs only at doses far beyond therapeutic and is not clinically relevant except following massive overdoses. Propranolol is almost completely absorbed after oral administration, but undergoes extensive first-pass hepatic metabolism. Thus, the usual oral dosage of propranolol is 40–320 mg/d, whereas the IV dosage is only 0.025–0.15 mg/ kg. Cimetidine decreases hepatic metabolism and blood flow and may decrease propranolol’s therapeutic dose. Propranolol is highly lipophilic and crosses the blood–brain barrier, which may explain its many CNS effects. Its usual oral half-life is approximately 4 hours. Propranolol is available as a long-acting preparation, a marked advantage for treatment of patients with angina pectoris.117 Propranolol may be slowly administered intravenously to patients under anesthesia in incremental doses of 1 mg with frequent monitoring of blood pressure.

Metoprolol Metoprolol is a β1 selective blocker with no ISA or MSA. It is primarily hepatically metabolized, with a halflife of 3–7 hours. When used in low doses, metoprolol may be preferable to propranolol for smokers and other patients who may have bronchospastic diseases but who require therapy with β-blockers. Although relatively cardi-

929


TABLE 43–8. Pharmacologic Properties of β Blockers Elimination Half-Life Charts (hours)

Predominant Mode of Elimination

Oral Dosage (mg)

Agent

Relative β1 Selectivity

ISA

MSA

α Activity

Acebutolol Atenolol

+ ++

+ –

+ –

– –

3–4 6–7

Renal/hepatic Renal

200–600 BID 50–200 daily

Betaxolol Bisoprolol Carteolol Carvedilol

++ ++ – –

– – + –

+ – – +

– – – +

16–22 9–13 5–6 7–10

Hepatic/renal Renal/hepatic Renal Hepatic

Esmolol

++

–

9 min

Red blood cell esterases

10–40 mg daily 10–20 mg daily 2.5–10 daily 3.125–25 mg BID –

Labetalol

–

–

–

+

6–8

Hepatic

200–1200 BID

Metoprolol

+

–

–

–

3–7

Hepatic

50–200 BID

Metoprolol extended release Nadolol Oxprenolol Penbutolol Pindolol Propranolol

++

–

–

–

?

Hepatic

50–400 daily

– – – – –

– + + ++ –

– + – + ++

– – – –

20–24 4–6 5 3–4 4

Renal Hepatic Renal Renal/hepatic Hepatic

Propanolol extended release Timolol

–

–

++

–

10

Hepatic

40–240 daily 40–80 TID 20 daily 5–30 BID 40–320 daily, 0.1–0.15 mg/ kg BID or QID titrated slowly to effect 80–320 daily, BID

–

–

–

–

4–5

Renal

930

oselective, metoprolol still may precipitate bronchospasm. It is less likely than propranolol to mask symptoms of hypoglycemia. Its usual oral dosage is 50–200 mg twice daily, although an extended-release formulation is also available and widely prescribed. Like propranolol, metoprolol is available in IV form, with usual dosage of 0.025– 0.15 mg/kg. Metoprolol is used in the treatment of hypertension, stable angina, acute myocardial infarction, and chronic heart failure. The efficacy of metoprolol in heart failure management was studied in several random-

ized clinical trials, which showed an improved survival, reduced need for hospitalizations as a consequence of worsening heart failure, improved New York Heart Association (NYHA) functional class and beneficial effects on patient well-being.118,119

Atenolol Atenolol is a long-acting, cardioselective β-blocker with no ISA or MSA. It is eliminated by renal excretion, and has a half-life of 6–7 hours. Its usual dosage is 50–200 mg daily. It is available in an IV form, with a recommended

IV Dosage 5–10 titrated at 1 mg/min

0.5–1 mg/kg bolus, then 100–300µg/ kg/min 5–20 mg initially, then 40 mg q10min up to 300 mg as boluses or 2 mg/min as infusion 0.1–0.15 mg/kg titrated slowly to effect

10–30 BID dosage of 5–10 mg given slowly. Besides being cardioselective and requiring only a single daily intake, other possible advantages include relative hydrophilia and minimal blood–brain barrier crossing. Unfortunately, in clinical trials with atenolol, this has not been reflected by a lower incidence of CNS side effects.120

Bisoprolol Bisoprolol is a highly selective, longacting, cardioselective β-blocker, without any ISA or MSA. It is well-absorbed following oral administration and is


eliminated by renal excretion, with 50% unchanged in the urine and the remaining 50% eliminated as inactive metabolites.121 Its half-life of 9–13 hours makes it suitable for once-a-day administration. Recent randomized clinical trials show that bisoprolol prevents major cardiovascular events in patients with CHF.122

Betaxolol Betaxolol is an oral, long-acting, cardioselective β-blocker with no ISA or MSA. Undergoing mainly hepatic metabolism, its half-life of 16–22 hours makes it suitable for once-a-day administration. As with timolol, betaxolol is available for topical ophthalmic use and may be better tolerated by patients with bronchospastic disease because of its β1 selectivity.

Nadolol Nadolol is a long-acting, noncardioselective β-blocker with no ISA or MSA. Unlike propranolol, it is renally excreted, with a half-life of 20–24 hours, allowing for once-a-day administration. The usual dosage is 40–240 mg/d; dosage should be reduced in patients with renal failure.

Timolol Timolol is a noncardioselective βblocker with no MSA or ISA. Its usual dosage is 10–30 mg twice a day, with a half-life of 4–5 hours. It undergoes both hepatic and renal excretion. Otherwise, it is similar to propranolol. Timolol is frequently used as an eyedrop therapy for open-angle glaucoma. In this form, it is often systemically absorbed and produces effects similar to those after oral ingestion.

Acebutolol, Carteolol, Penbutolol, Pindolol Acebutolol, carteolol, penbutolol, and pindolol are nonselective β-blockers with ISA and partial agonist effects. With the patient at rest, these drugs may decrease heart rate to a lesser extent than other β-blockers. They are efficacious in blunting exerciseinduced hemodynamic response. These drugs are thought to produce fewer lipid abnormalities and peripheral vascular complications, with less myocardial depression and bronchospasm. Specifically, pindolol produces less depression of heart rate and fewer nocturnal pauses in patients with sick sinus syndrome compared with agents

lacking agonist effects.123,124 Another possible advantage may be the absence of rebound following discontinuation; however, no large-scale trials are available to support these claims. No data are available to support the use of these drugs after MI. Table 43–9 lists the dosages for these drugs.

Labetalol Labetalol is a nonselective β-blocker unique among β-blockers for its β-adrenergic blocking properties in a ratio of about 7:1(β:α). In addition, labetalol has partial agonist activity at β2 receptors.125 This blocking can be used to decrease arterial pressure with somewhat better maintenance of cardiac output. Labetalol is available in both IV and oral forms and its use is well established in acute therapy of severe hypertension in the emergency room, operating room, and recovery suite, but it is seldom employed as a long-term medication.

Esmolol Esmolol is a highly cardioselective adrenergic blocker with little ISA and no MSA. It has a distribution half-life of 2 minutes and an elimination half-life of 9 minutes, as a result of rapid hydrolysis by red blood cell (RBC) esterases. Its short duration of action makes it particularly valuable in management of perioperative patients. Esmolol is typically used as a bolus, with or without an infusion. Steady-state plasma levels are obtained within 5 minutes. Usual bolus dosages are 0.5–1 mg/kg. Infusion rates of 50–300 µg/kg/min are titrated to clinical effect. On discontinuation of an esmolol infusion, significant recovery occurs within 10–20 minutes, and blood concentrations are undetectable within 30 minutes. Because esmolol is metabolized by red blood cell esterase, plasma cholinesterase inhibitors do not affect metabolism and elimination. Esmolol has been used intraoperatively to attenuate response to intubation, prevent and/or treat tachycardia and ischemia, and produce deliberate hypotension. The time course for attainment of heart rate decreases is faster than for changes in blood pressure.126 It has been used to attenuate the increased heart rate and mean arterial pressure associated with rapidly increased desflurane concentrations.127 Postoperatively, it has been used in treatment of hypertension, myocardial ischemia, and supraventricular dysrhythmias.

Celiprolol Celiprolol is a third-generation cardioselective β-blocker without MSA but with evidence of ISA at the β2 receptor.107 It is an effective drug in the treatment of hypertension and angina.128 It is a weak bronchodilator and vasodilator as a result of its β2 receptor effect. It may prove superior to other β-blockers for asthmatic patients.129

Carvedilol Carvedilol is a nonselective β-blocker that also blocks α1 receptors in a manner similar to labetalol. It has MSA but no ISA. Carvedilol is also a potent antioxidant and antiproliferative, which inhibits vascular smooth muscle proliferation.130 This property makes it useful in the treatment of chronic congestive heart failure. In numerous clinical trials, carvedilol significantly reduced morbidity and mortality in patients with heart failure.131 Favorable effects on the remodeling process in heart failure were seen, with a decrease in left ventricular size and improvement in ejection fraction.132 A recent clinical trial comparing metoprolol and carvedilol in patients with chronic heart failure showed that carvedilol extends survival.133

Bucindolol Bucindolol is a third-generation nonselective β-blocker with α1 blocking and β2-agonist capabilities. In contrast to other β-blockers studied, bucindolol failed to show any significant overall survival benefit in patients with advanced cardiac failure.134

Nebivolol Nebivolol is a highly selective β1 receptor blocker, which can be distinguished from other β-blockers by its hemodynamic profile. It combines β-blocking activity with a vasodilating effect, which is mediated at least in part by endothelial NO. The blood-pressure-lowering effect of nebivolol is linked to a reduction in peripheral resistance and an increase in stroke volume with preservation of cardiac output.135 Recent clinical trials show that it is an effective and welltolerated treatment for heart failure in the elderly (age > 65).136

Anesthetic Considerations Anesthetic considerations regarding βblocker therapy are numerous. Initially, β-blockers and antihypertensives were discontinued before anesthesia

931


TABLE 43–9. Pharmacologic Effects of the Calcium Channel Blockers

932

HR Acute

SA Node

AV Node

Myocardial Contractility

PVR

CO

Diltiazem

↓

↓

↓

↓

↓

V

↓

Bepridil

↓

↓

↓

V

–

V

↓

Verapamil

↓

↓

↓

↓↓

↓

↓

↓

Amlodipine Felodipine

–

–

↓–

↓↓

V

–

–

–

↓↓

V

Isradipine

–

–

–

↓↓

V

Nicardipine

–

–

–

↓↓

V

Nifedipine

–

–

↓–

↓↓

V

Nimodipine Nisoldipine

–

–

–

↓↓

V

–

–

–

↓↓

V

CBF

MVO2

Oral Dosage

Intravenous Dosage

30–90 mg q6–8h 200–400 mg QD 80–120 mg q6–2h

0.25 mg/kg (bolus) then 0.15 ng/kg/hr -

2–6

0.75–0.15 mg/ kg (bolus) then 0.075– 0.15 ng/kg/hr –

3–7

–

2.5–10 mg QD 2.5–10 mg QD

T1/2 (hrs)

24–48

36–45

2.5–10 mg QD 10–20 mg q8h 10–40 mg q8h

–

tri-exponential: 4.8 min; 1.5 h; 9.1 h 6–11

5–15 mg/h

2

–

1.5–5

20–40 mg QD

–

10

↓, decrease; –, no change; AV, atrioventricular; CBF, coronary blood flow; CO, cardiac output; HR, heart rate; MVO 2, myocardial oxygen consumption; PVR, peripheral vascular resistance; SA, sinoatrial; V, variable.

and surgery because of concerns that their effects would be additive with those of general anesthetic agents. Unfortunately, this sudden withdrawal tended to result in rebound effects with worsening of both angina and hypertension.137 The 2002 ACC/AHA Guidelines for Perioperative Cardiovascular Evaluation for Noncardiac Surgery recommend that patients previously on β-blockers should continue these agents perioperatively.5 The recent focus on perioperative βblockade has led to mounting evidence that the prophylactic use of βblockers will reduce cardiac mortality and morbidity. β-Blockers reduce ischemia by decreasing myocardial oxygen demand caused by increased stress and catecholamine release in the perioperative period. It has been shown that in high-risk patients who

have to undergo noncardiac surgery, perioperative β-blockade can reduce mortality and cardiovascular complications.138,139 The ACC/AHA guidelines state that whenever possible βblocker should be started days or weeks before elective surgery in patients at risk for or with evidence of ischemia. The dose should be titrated to achieve a resting heart rate between 50 and 60 beats/min.5 Nevertheless, according to recent studies β-blockers are underused in the perioperative period.140,141 More recent data show that low-risk patients do not benefit, indeed may suffer harm, from perioperative β-blockade. Conversely, highrisk patients may have a greater than 40% reduction in mortality.142 Furthermore, β-blockers lower the incidence of atrial fibrillation after cardiothoracic surgery.143

Because of their pharmacologic effects, β-blockers interact with many anesthetic agents. β-Blockers have additive negative inotropic effects with potent inhalation agents. In dogs at 1.0 MAC of enflurane, propranolol causes mild decreases in myocardial contractility, heart rate, and cardiac output. These changes are more pronounced at deeper anesthetic concentrations. Circulatory depression, although present, is less when halothane or isoflurane are combined with propranolol compared with enflurane. In dogs anesthetized with halothane, isoflurane, or enflurane, propranolol produces additive slowing of heart rate and AV node conduction.144 Patients maintained on β-blockers, particularly when combined with calcium channel blockers, are at risk for


severe bradyarrhythmias when anesthesia is induced with high-dose fentanyl or sufentanil. These bradyarrhythmias especially occur when muscle relaxants lacking vagolytic effects are used. When high-dose narcotics are given to patients who take β-blockers, with or without calcium channel blockers, it is recommended that vagolytic muscle relaxants (e.g., pancuronium) be used.145 β-Blockers are also associated with bradycardia during neuraxial anesthesia.146 The currently available IV β blockers—propranolol, metoprolol, atenolol, labetalol, and esmolol—may be administered perioperatively to attenuate hemodynamic responses to intubation or surgical stress, treat hypertension and ischemia, slow heart rates, or treat dysrhythmias, in addition to the prophylactic uses described above.

Calcium Channel Blockers The calcium channel blockers represent a diverse group of compounds with dissimilar structures and pharmacologic effects (Table 43–9). They inhibit voltage-sensitive calcium channel function (L-type or slow channels), which mediate the entry of extracellular calcium into smooth muscle (Fig. 43–3), cardiac myocytes, and SA and AV nodal cells in response to electrical depolarization. They therefore have vasodilatory properties, especially in arterial beds, and have negative chronotropic and inotropic effects to varying degrees.147,148 Unlike β-blockers, which all depend on blockade of receptors for their activity, the sites and mechanisms of action of the individual calcium channel blockers vary, as do their individual actions on different tissues. They are not nearly as interchangeable as β-blockers. Used predominantly in antianginal and antihypertensive therapy (Fig. 43–4), calcium channel blockers are also used in treatment of syndromes as diverse as paroxysmal supraventricular tachycardia, hypertrophic obstructive cardiomyopathy, Raynaud phenomenon, preterm labor, and migraine headache prophylaxis.114,149,150 The currently available calcium channel blockers can be categorized into 4 groups based on different chemical structures: dihydropyridines (which include nifedipine, nisoldipine, nicardipine, nimodipine, amlodipine, isradipine, felodipine, nitrendipine), verapamil (a phenylalkylamine), diltiazem

Ca2+ 1 Calmodulin

Ca2+–Calmodulin

2 Myosin light chain kinase (inactive)

Actin

Ca2+–Calmodulin-myosin light chain kinase (active)

P-myosin

Myosin

Myosin light chain phosphatase

Contraction

Relaxation

FIGURE 43–3. Activation sequence of mechanical contraction in vascular smooth muscle. The calcium (Ca2|m+ ) calmodulin complex (1) activates myosin light-chain kinase (2), which catalyzes the phosphorylation of myosin (P-myosin). Cross-bridge formation between P-myosin and actin produces mechanical contraction. (Reproduced with permission from Anderson KE, Hogestatt ED. On the mechanism of action of calcium antagonists. Acta Med Scand 1984;681(Suppl):11.)

(a benzothiazepine), and bepridil (a diarylaminopropylamine).

Verapamil Verapamil, which is structurally similar to papaverine, has a complex mode of action. It is a racemic mixture with L-verapamil being a more potent calcium channel blocker than D-verapamil.151 The net effect is depression of both slow channel activation and recovery from inactivation. Via its effects on the calcium channels, verapamil decreases myocardial contractility and dilates coronary and

Inhibition of slow Ca2+ current

peripheral vascular beds, increasing coronary blood flow and decreasing systemic vascular resistance. Reflex tachycardia, secondary to decreased systemic vascular resistance, does not occur as a result of its negative chronotropic effect. Like other calcium channel blockers, verapamil has little effect on venous capacitance vessels in clinical doses. By decreasing heart rate, contractility, and peripheral resistance, verapamil decreases myocardial O2 consumption. By increasing diastolic filling time and coronary blood flow while decreasing coronary

Coronary vessels

Increased coronary flow

Myocardium

Negative inotropism

Conducting, nodal + pacemaker tissue

Negative chronotropism

Smooth muscle

Vasodilation

? Decreased perfusion + reflex tachycardia

Increased O2 and substrate supply + removal of metabolites

Decreased O2 utilization

O2 balance

Decreased O2 supply Increased O2 utilization

FIGURE 43–4. Consequences of calcium channel blockers on myocardial O2 balance. Because of reflex responses, negative chronotropism and inotropism may not be important. (Reproduced with permission from Nayler WG, Dillon JS, Daly MF. Cellular sites of action of calcium antagonists and β-adrenoceptor blockers. In: Opie LH, ed. Perspectives in Cardiovascular Research. Vol 9. Calcium Antagonists and Cardiovascular Disease. New York: Raven Press, 1984:188.)

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934

vascular resistance, it increases myocardial O2 delivery. In patients with congestive heart failure, intravenous verapamil can cause a marked decrease in contractility and left ventricular function. By directly antagonizing coronary vascular spasm, verapamil is useful in treatment of classic and Prinzmetal angina. Verapamil is useful in managing patients after myocardial infarction without congestive heart failure, and its use may decrease long-term mortality.152 The electrophysiologic effects of verapamil are substantial. It slows spontaneous rates of firing and increases SA node recovery time, thereby decreasing heart rate. The velocity of AV node conduction decreases as a consequence of both decreased conduction and increased refractoriness. Because of this effect on the AV node conduction, verapamil can terminate paroxysmal supraventricular tachycardia, slow the ventricular response in atrial flutter, fibrillation, and multifocal atrial tachycardia. It can successfully convert paroxysmal supraventricular tachycardias (PSVTs) to sinus rhythm with an effectiveness of greater than 90%. It is also of prophylactic value in preventing recurrences of PSVT and controlling the ventricular response in atrial flutter and fibrillation during long-term oral therapy.153 It should be noted that in patients with Wolff-Parkinson-White syndrome, verapamil might increase heart rate by preferential AV slowing, which may increase conduction through accessory pathways in patients who develop atrial fibrillation. The net effect of verapamil in lowering both systolic and diastolic blood pressure with few side effects makes it efficacious for treatment of hypertension, although calcium channel blockers are currently not recommended as first-line therapy for hypertension. Possibly as a result of its improvement in diastolic function, verapamil improves exercise tolerance and decreases the severity of symptoms in patients with hypertrophic obstructive cardiomyopathy (HOCM). It is mainly used in HOCM patients who cannot tolerate β-blockers.114 In acute IV therapy, the recommended dose of verapamil is 0.075– 0.15 mg/kg titrated to effect. Peak vasodilatory effect occurs at approximately 5 minutes and may persist for 30 minutes, although the antidys-

rhythmic effect may persist substantially longer. IV distribution half-life is 3.5 minutes and elimination half-life 110 minutes. Anesthetics or other drugs that decrease liver blood flow will increase the half-life of verapamil. The side effects of verapamil are related to its pharmacologic and therapeutic actions. Verapamil may exacerbate SA and AV node dysfunction, especially in patients with underlying disease or those treated with digitalis or β-blockers. Verapamil may worsen symptoms of CHF, especially if used in combination with β-blockers.147 Digitalis levels increase by an average of 70% after initiation of therapy with verapamil.

Diltiazem Diltiazem, a benzothiazepine, is a calcium channel blocker with a spectrum of pharmacologic effects between verapamil and the dihydropyridines. Diltiazem, like all calcium channel blockers, is an effective coronary artery dilator, but has less effect on peripheral vessels than the dihydropyridines. It is a mild negative inotrope, but less so than verapamil.147,154 Reflex tachycardia is also blunted because diltiazem decreases sinus node automaticity and AV nodal conduction, albeit to a lesser extant than verapamil. Although diltiazem can be used in combination with β-blockers, the effects may be additive, causing SA and AV node dysfunction in patients with underlying conduction disease. Diltiazem is approved for rapid conversion of paroxysmal supraventricular tachycardia to sinus rhythm and for temporary control of rapid ventricular rate in atrial flutter or fibrillation. The usual dose of IV diltiazem is 0.25 mg/kg as a slow loading dose, followed by an infusion of 0.15 mg/kg. An additional bolus of 0.35 mg/kg may be given if needed. Oral diltiazem can be used for the chronic management of these problems.

The Dihydropyridines Nifedipine In vitro, nifedipine has significant effects on both smooth muscle and myocardium. In vivo, however, it is an effective coronary and systemic arterial dilator at doses that have little effect on myocardial contractility or conduction tissue. The vasodilatation and increase in coronary artery blood flow result from the blockade of calcium influx, as well as an increase in the

levels of nitric oxide and bradykinin.155 Because of its afterload reduction, nifedipine may cause reflex sympathetic increases in heart rate and cardiac output.156 This sympathetic stimulation is more evident with short-acting preparations than it is with sustainedrelease nifedipine.157 Clinically, with the exception of short-acting formulations, which may occasionally worsen angina, nifedipine effectively improves exercise tolerance, prolongs the time to the onset of angina in exercise and decreases the frequency of episodes of angina.147 Concurrent therapy with nifedipine and a β-blocker is more effective than either agent given alone. Indeed, βblockers eliminate nifedipine’s potentially detrimental reflex increases in heart rate.158 Although it is an effective antihypertensive, nifedipine, and generally all calcium channel blockers are not currently recommended as firstline therapy, unless there are contraindications to other antihypertensives.6 Even though nifedipine has fewer negative chronotropic or inotropic effects than verapamil or diltiazem, in longterm studies hemodynamic deterioration occurred in some patients with congestive heart failure who were treated with dihydropyridines.159 Because it is light sensitive, IV nifedipine is not commercially available in the United States. Nifedipine’s side effects include headaches, pedal edema, hypotension, and exacerbation of angina. Like verapamil, nifedipine increases serum digitalis levels. Because a higher rate of cardiac events was reported among patients who were treated with short-acting nifedipine after myocardial infarction, this preparation is no longer recommended in patients with angina.160

Nicardipine Nicardipine has structural and pharmacologic properties similar to those of nifedipine. Like nifedipine, nicardipine is a potent coronary and systemic vasodilator with little effect on contractility. It is available as an IV agent for treatment of hypertension in acute care settings, including the perioperative period and neurologic emergencies.161–163 An initial intravenous bolus of 2 mg is followed by an initial infusion rate of 5 mg/h, which may be increased in 2.5mg increments every 15 minutes, up to a maximum infusion rate of 15 mg/h. Nicardipine administered intraarterially


reverses vasospasm in subarachnoid hemorrhage and interventional coronary procedures.164,165

Nimodipine Nimodipine, a nifedipine analogue, is a calcium channel blocker with high lipid solubility and apparent preference for cerebrovascular smooth muscle. It is useful in inhibiting cerebral vasospasm and improving outcome in patients with neurologic defects associated with cerebral vasospasm after subarachnoid hemorrhage.166 Its usefulness in patients with acute ischemic stroke has not been proven.167

Amlodipine, Isradipine, Felodipine, Nisoldipine, and Nitrendipine Amlodipine, isradipine, felodipine, nisoldipine, and nitrendipine are structurally and pharmacologically similar to nifedipine, the dihydropyridine prototype. They dilate coronary and peripheral arteries with minimal effect on cardiac conduction and contractility. Like nifedipine, these drugs are used to treat hypertension and angina, and may be safely used in patients with CHF.168 The individual agents are distinct from each other in many ways. Because isradipine has an inhibitory effect on the SA node but not on the cardiac myocytes, it produces little or no reflex tachycardia. Felodipine and nisoldipine have a higher degree of vascular specificity than the rest of the dihydropyridines. Several trials have shown that amlodipine increases exercise duration, decreases the number of anginal attacks, and reduces the consumption of nitroglycerin.169 The Systolic Hypertension in Europe (Syst-Eur) Trial reported that antihypertensive therapy initiated with the nitrendipine reduced the risk of fatal and nonfatal stroke, as well as all cardiovascular events combined, in older patients (age > 65) with isolated systolic hypertension.170

Mibefradil Mibefradil is an antagonist of T-type calcium channels. This arterial dilator has negative chronotropic effects but minimal inotropic effects. Mibefradil is an effective antianginal whose vasodilatory effects are associated with a reduction in heart rate.171,172 There are case reports of QT interval prolongation and ventricular dysrhythmias during treatment with mibefradil.173

Monatepil Monatepil is a calcium channel blocker similar to nifedipine, which also has α1-adrenoreceptor blocking properties. It decreases systolic and diastolic pressure without changes in heart rate. Furthermore, it significantly decreases levels of low-density lipoprotein (LDL) cholesterol, apolipoprotein B, and glycosylated hemoglobin (HgbA1c).174

Bepridil Bepridil is structurally unrelated to other calcium channel blockers. It blocks slow calcium channels in both cardiac and vascular smooth muscles as well as fast sodium channels in cardiac muscle. It has negative chronotropic and dromotropic and mild negative inotropic effects.175 Bepridil reduces blood pressure and heart rate, improves left ventricular performance in patients with angina, and decreases the frequency of exercise-induced angina attacks. Bepridil can prolong QT interval, especially in the setting of hypokalemia or bradycardia, and can precipitate polymorphic ventricular tachycardia.175 Bepridil is also associated with agranulocytosis and pancytopenia. Because of these serious side effects, it should be used only in cases of angina refractory to other therapies.

Anesthetic Considerations There are limited data regarding the risks and benefits of calcium channel blockers in the perioperative setting. Although a classic withdrawal syndrome has not been described, there are case reports of severe coronary vasospasm following abrupt discontinuation of the calcium channel blockers.176 Overall, the continuation of calcium channel blockers in patients already taking them preoperatively is recommended, despite the paucity of information in relation to their interaction with the process of anesthesia and surgery. There is considerable potential for drug interaction between anesthetic drugs and calcium channel blockers. When used in combination with highdose narcotics in patients with normal conduction systems and ventricular function, IV verapamil decreases systemic vascular resistance and mean arterial pressure with no change in cardiac output or pulmonary capillary wedge pressure. Although lengthening of the PR interval has been observed,

neither first-degree nor more advanced AV block has occurred. In combination with inhalation agents, verapamil may produce varying degrees of AV block and must be given carefully in patients anesthetized with enflurane, halothane, and, to a lesser degree, isoflurane in patients with AV nodal block or in patients chronically taking β-blockers.177 Verapamil has many perioperative uses. It has been used for intraoperative control of paroxysmal supraventricular tachycardia. During cardiopulmonary bypass, verapamil terminates refractory ventricular fibrillation following aortic cross-clamp removal. Verapamil successfully treats intraoperative myocardial ischemia refractory to IV nitroglycerin.178 In vitro, diltiazem may depress left ventricular function in the presence of enflurane or desflurane, while the incidence of bradyarrhythmias is higher with enflurane than with equivalent levels of desflurane.179 Combined with enflurane, diltiazem is particularly depressant to conduction. Together, they may cause first-degree AV block, Mobitz I AV block, or sinus node dysfunction.180 Nifedipine administered in dogs during fentanyl/nitrous oxide anesthesia, decreased systemic vascular resistance accompanied by an increase in cardiac index and heart rate. In vitro, the combined treatment of nifedipine and volatile anesthetics, especially enflurane, additively depresses atrial rate and contractility. However, these effects appear less pronounced than the combination of volatile agents with diltiazem and especially verapamil.181 Nicardipine has a longer duration of action in the presence of isoflurane and produces greater initial hypotension with sevoflurane.182 Calcium channel blockers may potentiate effects of depolarizing and nondepolarizing neuromuscular blocking agents, although this is controversial. In contrast with β-adrenergic blocking agents, calcium channel blockers have not been shown to be effective in prevention of intraoperative ischemia.183

Other Antianginals Novel therapeutic strategies have been developed for patients with ischemic heart disease and angina pectoris that were unsuccessfully managed with conventional medical or interventional approaches.

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Ivabradine

936

Ivabradine is the first of a new class of drugs called If inhibitors. It selectively and specifically inhibits If, a sinus node-specific sodium-potassium inward current. It reduces heart rate at rest or exercise without decreasing myocardial contractility, atrioventricular conduction, and ventricular repolarization duration.184 A double-blind trial comparing the antiischemic and antianginal effects of ivabradine to atenolol showed that ivabradine is as effective as atenolol in preventing exercise-induced angina in patients with chronic stable angina.185 Ivabradine has been approved in Europe for the symptomatic treatment of chronic stable angina pectoris in patients with normal sinus rhythm who have a contraindication or intolerance to β-blockers. With the exception of reversible, transient visual symptoms described mainly as increases in brightness in limited areas of the visual field, no other adverse effects are attributed to ivabradine therapy.

Nicorandil Nicorandil is a nicotinamide ester, which activates the adenosine triphosphate (ATP)-sensitive potassium channel. It dilates peripheral and coronary resistance arterioles, and because of a nitrate-like effect, it dilates systemic veins and epicardial coronary vessels. Consequently, nicorandil increases coronary blood flow, reduces preload and afterload, and has antianginal efficacy similar to oral nitrates, β-blockers, and calcium antagonists.186 By opening ATP-dependent potassium channels, nicorandil may also mimic a natural process of ischemic preconditioning, protecting the heart from subsequent ischemic attacks. The IONA (Impact of Nicorandil in Angina) trial showed a significant improvement in outcome as a result of reduction in major coronary events by adding nicorandil to standard antianginal therapy in patients with stable angina.186 Nicorandil is not available in the United States.

Inhibitors of Fatty Acid Oxidation Two agents, ranolazine and trimetazidine, are presently available and represent this new class of drug. During episodes of acute myocardial ischemia, fatty acid levels rise, promoting their uptake and use as energy source by the myocardium. Because

fatty acid oxidation is more oxygen inefficient than carbohydrate oxidation, this abrupt increase in circulating free fatty acids imposes a further deleterious effect on an already imbalanced oxygen supply–demand situation. Inhibition of fatty acid oxidation may increase glucose oxidation, which generates more ATP for each molecule of oxygen than fatty acid oxidation, thereby minimizing lactate accumulation.187 Both drugs are virtually devoid of hemodynamic effects. The efficacy of ranolazine has been studied in several clinical studies, such as the MARISA (Monotherapy Assessment of Ranolazine in Stable Angina) and CARISA (Combination Assessment of Ranolazine in Stable Angina) trials. Both MARISA and CARISA showed that ranolazine increases exercise capacity and provides antianginal effects on symptomatic patients with chronic angina.187,188 Similar benefits were shown in the TRIMPOL (Trimetazidine in Poland) II trial, which studied trimetazidine in patients already receiving metoprolol. The addition of trimetazidine produced significant improvement in exercise stress tests and anginal symptoms relative to metoprolol monotherapy.189 Neither ranolazine nor trimetazidine is available in the United States.

ANTIDYSRHYTHMIC AGENTS Antidysrhythmic agents are indicated for prevention and treatment of symptomatic dysrhythmias and for therapy of asymptomatic dysrhythmias with malignant potential. Reasons for selecting one drug over another are frequently complex; the choice may depend on type of dysrhythmia, a particular drug’s therapeutic index, a medication’s effectiveness during electrophysiologic studies, or a patient’s tolerance to side effects. Antidysrhythmic drugs are classified on the basis of their major pharmacologic effects on myocardial electrophysiology, as originally proposed by Vaughan Williams190 and now modified to include newer agents (Box 43–2). Although now loosely used to group drugs, this classification was originally proposed to rigorously classify patterns of pharmacologic action. This is a subtle but important difference. Many antidysrhythmics, although classified into one group or another, have (a) multiple

actions in a given tissue, (b) different actions in different heart tissues, and (c) active metabolites with different actions than the parent compound. Since the early nineties, the use of most antidysrhythmic drugs has been reassessed and dramatically limited because of increased awareness of their proarrhythmic potential and advances in ablation techniques. Moreover, recent clinical trials have demonstrated negative effects on survival in many situations where these drugs might have been given in the past. Finally, implantable cardiodefibrillators have largely replaced antidysrhythmic medications in the management of ventricular dysrhythmias.191 Agents with class I actions include drugs that affect the fast inward sodium current of phase O, the period of rapid depolarization of the action potential (Fig. 43–5). They have been further divided into three groups: IA, IB, and IC. Class II actions refer to antidysrhythmic effects associated with β-adrenergic antagonism. Therefore, class II agents include all β-adrenergic blocking agents. Class III agents block potassium repolarization currents and increase action potential duration (APD) and effective refractory period (ERP) in atrial and ventricular muscle, as well as in Purkinje fibers. The ERP-to-APD ratio is increased. Class IV agents are represented by blockers of the L-type calcium channel, that is, calcium channel blockers. Among them only verapamil and diltiazem are effective for antidysrhythmic use. Some newer drugs, such as adenosine and ibutilide, do not fit neatly into any of these categories (although ibutilide is categorized by some as a class III drug).

Class IA Agents Antidysrhythmics with class IA action include quinidine, procainamide, and disopyramide (Table 43–10). They all decrease the maximal velocity (Vmax) and amplitude of phase 0 depolarization of the action potential. The ERP, APD, and ERP-to-APD ratio are increased. Automaticity, represented by the decreased slope of phase 4 of the action potential, are decreased with these drugs. These agents produce measurable increases in refractoriness of cardiac tissue and lengthening of the QTc interval on the ECG.


(60–80%) and renal excretion (20– 40%), with a variable half-life of 4–10 hours. The metabolites of quinidine also possess antidysrhythmic activity. Although it is available in an IV form, this route is usually avoided because of profound hypotensive and negative inotropic effects. As with all antidysrhythmics, quinidine may be prodysrhythmic. Patients with CHF are at greater risk. With congenital prolongation of the QT interval or bradycardia associated with hypokalemia, quinidine, by further lengthening the QT interval, may initiate torsade de pointes, a serious, potentially lethal dysrhythmia.194 If torsade de pointes occurs, therapy should include increasing heart rate with isoproterenol or pacing, correction of hypokalemia and hypomagnesemia, and discontinuation of quinidine. Because of its anticholinergic effects on the AV node, quinidine may increase ventricular response in atrial fibrillation and flutter. Consequently, if it is used for conversion of atrial dysrhythmias, digoxin, verapamil, or a βblocker should be administered concurrently. If quinidine therapy is initiated in a patient receiving digitalis, one must be aware that quinidine may double the digitalis plasma concentration, possibly leading to digitalis toxicity. Digitalis dosages should therefore be decreased by half. Evidence of quinidine-induced cardiac toxicity may be manifested by greater than 50% increase in QT interval, widening of QRS complexes, and SA or AV node disturbances. Noncardiac adverse effects typically occur with quinidine. In 30–40% of patients, therapy must be withdrawn because of gas-

BOX 43–2. Vaughan-Williams Classification of Antiarrhythmic Agents IA

IB

IC

Quinidine Lidocaine Procainamide Mexiletine Disopyramide Tocainide Moricizine Phenytoin Class II β blockers Propranolol Atenolol Timolol Metoprolol Acebutolol Esmolol Carvedilol Class III Bretylium Amiodarone Acecainide (N-acetylprocainamide) Dofetilide Ibutilide Azimilide Sotalol Class IV calcium channel blockers Verapamil Diltiazem Bepridil Other agents not formally classified Digoxin Adenosine

Quinidine decreases automaticity in atrial and ventricular tissue and in the His-Purkinje and pacemaker fibers. Quinidine’s direct effects on SA node automaticity are balanced by its anticholinergic effects, which speed conduction through the SA and AV nodes, causing little change in heart rate. ECG changes occur with quinidine; most noticeably, it prolongs the QT interval by up to 25% at therapeutic levels. Quinidine also blocks the rapid component of the K channel, prolonging action potentials in most cardiac cells, especially at slow heart rates.47 It has been used effectively for conversion of atrial fibrillation, atrial flutter,192 and PSVT, and for maintenance of sinus rhythm after conversion.193 In addition, it suppresses ventricular ectopy, tachycardia, and fibrillation. Quinidine is available orally as a sulfate, gluconate, or polygalacturonate salt with 83%, 62%, and 60% quinidine

content, respectively. Quinidine sulfate is typically initiated at 200 mg every 6 hours and increased to 800–2400 mg/d, titrated to drug levels and therapeutic effect. It undergoes hepatic metabolism

ECG mV Transmembrane potential

Quinidine

Flecainide Encainide Propafenone

1 2

0

Action potential

3

0

4

4 -100

Na+ ATP K+

Na+

Ca+

K+

K+

Inside cell CELL MEMBRANE K+ Outside cell

FIGURE 43–5. Schematic of the action potential in a ventricular myocardial cell as it correlates with the electrocardiogram (ECG). Arrows indicate times of major ionic movement across the cell membrane.

937


TABLE 43–10. Class IA Antidysrhythmic Agents Usual Dosage and Interval

Effect on Electrocardiogram

Quinidine

PO: 200–400 mg q4–6h

Prolongs QRS, QT, and PR (+)

Procainamide

PO: 50 mg/kg/d in divided doses q3–4h or q6h (longacting); IV loading no more than 100 mg q5min to 1 g (12 mg kg); IV maintenance 2–4 mg/min PO: 100–200 mg q6h


200–300 mg TID

Prolongs QRS interval

Drug

938

Disopyramide

Moricizine


Adverse Effects

Concentrations

Metabolism

Indications

Half-Life

Diarrhea and other GI symptoms; cinchonism; hepatic granulomas and necrosis; thrombocytopenia; rashes; hypotension; heart blocks; tachyarrhythmias; torsade de pointes; fever; lupus-like syndrome Lupus-like syndrome; confusion; disorientation; GI symptoms; rash; blood dyscrasias; fever hypotension; arrhythmias; torsade de pointes

2–7 µg/ mL

Hepatic (60– 80%); renal (20–40%)

Ventricular and supraventricular arrhythmias, including PAT, AF atrial flutter, WPW, junctional tachycardias

4–10 h; increased in elderly

4–10 mg/ mL NAPA 10–20 µg/mL

Hepatic, excreted in urine by filtration and active secretion

As above

2–5 h; increased in renal failure

Anticholinergic effects; hypotension; heart failure; tachyarrhythmias; torsade de pointes; heart block; nausea; vomiting; diarrhea; hepatic toxicity; acute psychosis; agranulocytosis; constipation; hypoglycemia May be prodysrhythmic; Congestive heart failure; intraventricular conduction delays

2–8 µg/ mL

Hepatic; 50 excreted unchanged in urine

As above

4–10 h; 8–18 h with renal dysfunction

0.2–1.5 µg/mL

Hepatic; biliary and urinary excretion

Ventricular dysrhythmias

9.2 h

AF, atrial fibrillation; NAPA, N-acetylprocainamide; PAT, paroxysmal atrial tachycardia; WPW, Wolff-Parkinson-White Syndrome. Data from Abramowicz M, ed. Drugs for cardiac arrhythmias. Med Lett Drugs Ther 1991;33:60.

trointestinal (GI) intolerance. Quinidine may cause CNS toxicity, as manifested by tinnitus and delirium. Other adverse effects include fever,

rash, anaphylaxis, thrombocytopenia, hemolytic anemia, and agranulocytosis. In surgical patients, quinidine should be continued preoperatively and re-

sumed as soon as possible following surgery. If oral intake is impossible, IV procainamide or lidocaine may be substituted, depending on the original rea-


son for initiating quinidine therapy. Quinidine increases the neuromuscular blockade of succinylcholine and may worsen neuromuscular blockade in myasthenia gravis. Quinidine has fallen into disfavor because it worsens survival in patients with ventricular dysrhythmias.195 Even in the presence of atrial dysrhythmias, where quinidine may be highly successful in maintaining sinus rhythm, it still has a negative effect on survival.196

Procainamide Procainamide, an analogue of the local anesthetic procaine, has a pharmacologic effect and a set of clinical indications similar, but not identical, to those of quinidine. Although both are class IA agents, each may be effective in suppression of dysrhythmias that are unresponsive to the other drug. This is not surprising, since procainamide’s major metabolite, N-acetylprocainamide (NAPA), actually has class III actions.197 In addition, because procainamide is readily available in stable IV form, it is useful for acute management of atrial fibrillation and flutter, PSVT, and dysrhythmias associated with Wolff-Parkinson-White syndrome. It may also be used for acute suppression of ventricular dysrhythmias following acute MI, and in treatment of ventricular tachycardia. When given intravenously, it may produce vasodilatation by a mild ganglionic blocking action; consequently, loading doses should be given slowly over approximately 20–30 minutes while monitoring the QRS duration. A loading dose up to 1 g may be given, followed by an infusion at 1–4 mg/min. Procainamide undergoes acetylation to NAPA, with half the population being fast acetylators. Subsequently, both substances are renally excreted. Therefore, dosage should be adjusted in patients with renal dysfunction. Procainamide and NAPA levels may prove useful to facilitate dosage adjustment. Procainamide has fewer anticholinergic properties than quinidine and disopyramide. As with quinidine, procainamide may be prodysrhythmic and may cause torsade de pointes.194 Consequently, it should not be used in patients with prolonged QT interval, hypokalemia, or history of torsade de pointes. Chronic administration is associated with positive antinuclear antibody titers; however, only 15–20% of patients develop a lupus-like syndrome. It usually resolves with discontinuation of the drug. Preoperatively,

procainamide should be continued until surgery. In the perioperative period, procainamide may be given as an IV infusion and used as a substitute for quinidine or disopyramide in treatment of atrial and ventricular dysrhythmias. Like quinidine, procainamide increases long-term mortality and is seldom used on a chronic basis.195

Disopyramide Disopyramide is used to maintain sinus rhythm in patients with atrial flutter or atrial fibrillation and to prevent recurrence of ventricular tachycardia or ventricular fibrillation. Unlike quinidine and procainamide, it has significant negative inotropic effects. Even more than quinidine, it has substantial anticholinergic effects. If it is tolerated, little additional chronic toxicity occurs. The usual dosage of disopyramide is 100–400 mg, three to four times daily, up to 800 mg total. Its half-life elimination is 4–10 hours and is usually increased in patients with cardiac or renal disease. Fifty percent is excreted unchanged by the kidney and the remainder as an active metabolite. As with all class IA agents, disopyramide should not be used in patients with congenital prolongation of the QT interval, hypokalemia, or history of torsade de pointes. It may cause severe bradycardia in patients with sinus node dysfunction or conduction system disease. Because of negative inotropic effects, disopyramide is contraindicated in patients with CHF. Disopyramide is still used in management of dysrhythmias in patients with HOCM, for which its negative inotropic effect is an advantage. In HOCM, it can decrease the subaortic gradient and ameliorate symptoms without increasing mortality.198 Like other class IA agents, disopyramide has largely been abandoned as a treatment of chronic dysrhythmias. Because of its anticholinergic effects, it is contraindicated in patients with glaucoma and obstructive uropathy. In addition, disopyramide may cause dry mouth, constipation, urinary retention, and esophageal reflux.

Moricizine Moricizine, a phenothiazine derivative, has characteristics of class IA, class IB and class IC agents. Moricizine decreases Vmax to an extent similar to class IA agents. As with IB agents, it shortens APD and increases the ERPto-APD ratio. On the ECG, moricizine prolongs the QRS complex with little

effect on the QT interval, a characteristic of class IC agents. In clinical studies, moricizine has been effectively used for treatment of chronic complex ventricular dysrhythmias and prevention of ventricular tachycardia and fibrillation. However, in the Cardiac Arrhythmia Suppression Trial (CAST) II trial moricizine was shown to increase mortality in patients shortly after a myocardial infarction and did not improve survival during long-term therapy.199 Moricizine use has therefore been largely abandoned. Moricizine is well absorbed orally, undergoes hepatic metabolism, biliary and urinary excretion. In healthy volunteers, the half-life 1.5–3.5 was hours; however, cardiac disease may increase this to as long as 13 hours. Recommended dosages are 600–900 mg three times daily. Adverse reactions include dizziness, nausea, and headaches. Intraventricular conduction delays may occur in up to 9% of patients. Moricizine may be prodysrhythmic or worsen CHF in 2–5% of patients.47 Few data are available about interactions with anesthetic agents.

Class IB Agents Drugs with class IB actions, such as lidocaine, mexiletine, tocainide, and phenytoin, have more moderate effects on phase O of the action potential (Table 43–11). Unlike class IA agents, they shorten APD and ERP and increase the ERP-to-APD ratio in the Purkinje fibers, but have little effect on the refractory periods in sinus node, atrium, and AV node, thus being ineffective against supraventricular tachycardias. They show little ECG effect. They exhibit rapid association and dissociation from the sodium channels.47

Lidocaine Although lidocaine, the prototypical class IB agent, was first introduced as a local anesthetic, it is widely used in acute treatment and suppression of all ventricular dysrhythmias, except those associated with prolonged QT intervals and torsade de pointes. As with all class I agents, lidocaine decreases Vmax to some extent. In addition to its typical type IB effects, lidocaine decreases the slope of phase 4 of the action potential, reducing automaticity. Like other IB agents, lidocaine has little effect on atrial tissue and thus is ineffective against supraventricular tachycardias.

939


TABLE 43–11. Class IB Antidysrhythmic Agents

Drug

940

Usual Dosage and Interval

Effect on Electrocardiogram

Lidocaine (Xylocaine and others)

IV loading: 1 mg/kg given over 2 min, then 2 mg/kg over 20 min or 50 mg given over 1 min and repeated every 5 min × 3 or 20 mg/min infused over 10 min IV; maintenance for 24–30 h 30 µg/kg each min

No significant change

Phenytoin (Dilantin and others)

PO loading: 14 mg/ kg; PO maintenance: 200–400 mg/d; IV loading: 50 mg q5min to total dose of 1000 mg (up to 12 mg/kg); IV maintenance: 200–400 mg/d PO initial dose: 100–200 mg q8h taken with food; PO maintenance: 100–300 mg q6– 12h, maximum 1200 mg/d


PO initial dose: 200–400 mg q8h; PO maintenance: 200–600 mg q8h, maximum 2400 mg/d


Mexiletine (Mexitil)

Tocainide (Tonocard)


Adverse Effects

Usually Effective Plasma Concentrations

Indications

HalfLife

Metabolism

Drowsiness or agitation; slurred speech; tinnitus; disorientation; coma; seizures; paresthesia; cardiac depression, especially with excessive accumulation in heart failure or liver failure or infusions for more than 24 hours Ataxia, nystagmus; drowsiness; coma blood dyscrasias; cardiac toxicity with rapid IV injection; fever; rash; hepatic granulomas and necrosis

1.5–6 µg/ mg

Ventricular dysrhythmias

1.5– 2.0 h

Hepatic; R S>R S>R

S=R S=R S resting. Many investigators have shown that the block of propagation of action potentials is a function of frequency of depolarization, which supports the conclusion that the open state of the sodium channel is the primary target of local anesthetic molecules. This is referred to as “state-dependent block.”

Voltage-Gated Sodium Channels Voltage-gated ion channels are ion channels (Na+, K+, Ca2+, etc.) whose permeability is a function of transmembrane potential. There are a number of sodium channel subtypes that generally are divided into those that are tetrodotoxin sensitive (TTXs) and tetrodotoxin resistant (TTXr).4

TABLE 44–2. Cation-to-Base Ratio

Procaine Lidocaine Mepivacaine Tetracaine Benzocaine Bupivacaine Ropivacaine

pKa

pH 7.4

8.9 7.9 7.6 8.5 3.5 8.1 8.1

32:1 3:1 2:1 13:1 All base 5:1 5:1

CHAPTER 44: Pharmacology of Local Anesthetics

β1 subunit H3N+

α subunit

I

II

β2 subunit

III

IV +

H3N

Outside 1 2 3 4 5

−

6

1 2 3 4 5

6

1 2 3 4 5

6

h

OOC

1 2 3 4 5

6

Membrane Inside

P

COO−

Voltage sensing S4 transmembrane segment

COO−

Inactivation

P

H3N+

P

P

P

A

P

Modulation Closed

Neutral P

Substrate for phoshorylation by cAMP-dependent protein kinase

P

Substrate for protein kinase C Open

Inactivated

B FIGURE 44–7. Structure and function of voltage-gated Na+ channels. A. A two-dimensional representation of the α (center), β1 (left), and β2 (right) subunits of the voltage-gated Na+ channel from mammalian brain. The polypeptide chains are represented by continuous lines with length approximately proportional to the actual length of each segment of the channel protein. Cylinders represent regions of transmembrane α helices. Ψ indicates sites of demonstrated N-linked glycosylation. Note the repeated structure of the four homologous domains (I through IV) of the α subunit. Voltage sensing: The S4 transmembrane segments in each homologous domain of the α subunit serve as voltage sensors. (+) Represents the positively charged amino acid residues at every third position within these segments. An electrical field (negative inside) exerts a force on these charged amino acid residues, pulling them toward the intracellular side of the membrane. Pore: The S5 and S6 transmembrane segments and the short membraneassociated loops between them (segments SS1 and SS2) form the walls of the pore in the center of an approximately symmetrical square array of the four homologous domains (see B). The amino acid residues indicated by circles in segment SS2 are critical for determining the conductance and ion selectivity of the Na+ channel and its ability to bind the extracellular pore blocking toxins tetrodotoxin and saxitoxin. Inactivation: The short intracellular loop connecting homologous domains III and IV serves as the inactivation gate of the Na + channel. It is thought to fold into the intracellular mouth of the pore and occlude it within a few milliseconds after the channel opens. Three hydrophobic residues (isoleucine–phenylalanine–methionine [IFM]) at the position marked H appear to serve as an inactivation particle, entering the intracellular mouth of the pore and binding to an inactivation gate receptor there. Modulation: The gating of the Na+ channel can be modulated by protein phosphorylation. Phosphorylation of the inactivation gate between homologous domains III and IV by protein kinase C slows inactivation. Phosphorylation of sites in the intracellular loop between homologous domains I and II by either protein kinase C P or cyclic adenosine monophosphate (AMP)-dependent protein kinase P reduces Na + channel activation. B. The four homologous domains of the Na+ channel α subunit are illustrated as a square array as viewed looking down on the membrane. The sequence of conformational changes that the Na+ channel undergoes during activation and inactivation is diagrammed. Upon depolarization, each of the four homologous domains undergoes a conformational change in sequence to an activated state. After all four domains have activated, the Na + channel can open. Within a few milliseconds after opening, the inactivation gate between domains III and IV closes over the intracellular mouth of the channel and occludes it, preventing further ion conductance. (Reproduced with permission from Catterall W, Mackie K. Local Anesthetics. In Hardman JG, Limbird LE, Gilman AF, eds. The Pharmacological Basis of Therapeutics. 10th ed. New York: McGraw-Hill, 2001:370.)

Most sensory neurons generate TTXs currents. However, TTXr currents are present in a high proportion of smaller dorsal root ganglion neurons associated with nociceptive Aδ, and C fibers.

Available evidence indicates that channels from both groups are involved in pain states as a result of changes in channel function and expression caused by disease or injury.

Arguments have been put forth that local anesthetics might exert their pharmacologic action not only on Na+ conductance, but also on other ionic conductances (e.g., K+ and Ca2+).5,6

957


TABLE 44–3. Disposition Kinetics in Adult Human

Local Anesthetic

Vdss (L)

Cl (L/min)

T1/2 γ (h)

Hepatic Extraction

Lipid Solubility

Protein Binding

Blood/Plasma Partitioning

Mepivacaine Ropivacaine Bupivacaine Lidocaine Prilocaine Etidocaine

84 59 73 91 261 133

0.78 0.73 0.58 0.95 2.84 1.22

1.9 1.8 2.7 1.6 1.5 2.6

0.40 0.40 0.51 0.72 — 0.74

0.8 2.8 27.5 2.9 — —

78% 94% 96% 60% 55% 94%

0.92 0.69 0.73 0.84 — 0.58

Differential Block

958

Differential block, the block of pain perception without motor block for example, is observed clinically but the mechanism responsible for this is poorly understood. The clinical manifestations of differential block vary depending on the local anesthetic used.7 For many years, differential block was ascribed to smaller axons being more sensitive than large ones to local anesthetics,8 but this “size principle” was challenged.9 Strichartz and Berde7 cite a number of different factors that might contribute to differential block, including anatomical and relative sensitivity to sodium and potassium channels of different local anesthetics. Oda et al.10 suggested that preferential block of TTXr sodium channels by ropivacaine in small dorsal root ganglia neurons (associated with nociceptive sensation) underlies differential block observed during epidural anesthesia with this drug.

Pain Relief by Systemic Administration Another pharmacodynamic puzzle is the mechanism whereby systemically administered local anesthetic relieves pain. Analgesic effect has been reported following intravenous lidocaine administration in many acute and chronic conditions.11–18 Subcutaneously injected bupivacaine reportedly produces analgesia via a systemic effect.19 Normal or altered sodium channels located in various areas of the brain, spinal cord, or dorsal root ganglia, or in peripheral axons, are mentioned most frequently as the action sites. Zhang et al.20 reported that in rats systemic lidocaine delivered via implanted osmotic pump reduces sympathetic nerve sprouting in dorsal root ganglion that is associated with some neuropathic pain behaviors. Takatori et al.21 presented evidence that inhibition of nerve growth factor (NGF)

stimulated tyrosine kinase activity of TrkA, a high-affinity receptor of NGF, might be involved in the suppression of neurite outgrowth by local anesthetics.

Ligand-Gated Ion Channels Ligand-gated ion channels are channels whose permeability status depends upon the interaction between a ligand and a receptor that influences channel function. Many of these receptors interact with G proteins. Local anesthetics effect a number of biologic processes, including inhibition of G-protein coupled receptor signaling, that are potentially important pharmacodynamic actions of value in treating pain.

PHARMACOKINETICS OF INJECTED LOCAL ANESTHETICS Distribution to the Target Site The usual pharmacokinetics parameters (Table 44–3) presented for local anesthetics incompletely describe important details regarding distribution of these drugs from application sites to target and nontarget structures. It is well established that systemic absorption of local anesthetics correlates positively with the vascularity of the injection site (intravenous > tracheal > intercostal > paracervical > epidural > brachial plexus > sciatic > subcutaneous). The spinal cord meninges influence distribution of local anesthetics from the epidural and subarachnoid spaces. Intact skin is nearly a complete barrier to local anesthetic penetration. In the latter case, special local anesthetic formulations (e.g., eutectic mixture of local anesthetics [EMLA] cream, an eutectic mixture of lidocaine and prilocaine) or delivery methods (e.g., electrophoresis) are employed to facilitate transcutaneous transfer. The large number of different injection sites used (e.g., epidural, intrathecal,

intrapleural, intraarticular, intramuscular, perineural, topical) and the variety of dosing methods (e.g., single shot, continuous infusion, intermittent infusion) make comprehensive discussion of all pharmacokinetic considerations beyond the scope of this chapter.

Absorption In addition to the injection site, the vascular absorption of local anesthetic agents is related to dosage, addition of a vasoconstrictor agent, and specific agent employed. The high blood concentrations following intercostal administration are probably related to the multiple injections required for intercostal nerve blocks. As a consequence of this, local anesthetic solution is exposed to a greater vascular area, which results in a greater rate and degree of absorption. After thoracic paravertebral block, ropivacaine demonstrates a biphasic fast and slow absorption pattern.22 The fast phase approximates the speed of intravenous injection and accounts for nearly half of ropivacaine absorption. When epinephrine (5 μg/ mL) is added, systemic absorption and peak plasma concentration of ropivacaine is significantly reduced. For most local anesthetic agents, a linear relationship exists between the amount of drug administered and the resultant peak venous plasma concentration. The mean venous plasma concentration of lidocaine increases from approximately 1.5–4 μg/mL as the total dose administered into the lumbar epidural space is increased from 200–600 mg. Depending on the site of administration, a peak blood concentration of 0.5–2.0 μg/mL is achieved for each 100 mg of lidocaine or mepivacaine injected. Simon et al.23 reported that systemic absorption of ropivacaine following epidural administration was biphasic with higher absorption kinetics in younger than in older


Systemic Distribution The distribution of local anesthetic agents from systemic circulation can be described by a two- or three-compartment model.27 The rapid disappearance (α) phase is believed to be related to uptake by rapidly equilibrating tissues, that is, tissues with a high vascular perfusion. The slower phase of disappearance from blood (β phase) is mainly a function of distribution to slowly equilibrating tissues and the biotransformation and excretion of the compound (Fig. 44–8). The α half-life (T1/2α) of prilocaine is shorter than that of lidocaine and mepivacaine, which indicates that prilocaine is redistributed at a significantly more rapid rate from blood to tissues than either of the other two drugs (Table 44–3). The T1/2α

Alpha phase

Beta phase

8.0

Plasma level (μg/mL)

patients. The absorption kinetics were in the same range as for other longacting local anesthetics. In general, the addition of epinephrine to local anesthetic solutions decreases the rate of vascular absorption of these agents.24 Epinephrine 5 μg/mL (1:200,000) significantly reduces the peak blood concentrations of lidocaine and mepivacaine, regardless of the site of administration. However, peak blood concentrations of bupivacaine and etidocaine are minimally influenced by the addition of epinephrine following injection into the lumbar epidural space. On the other hand, the rate of vascular absorption of these agents is significantly decreased when epinephrine-containing solutions are employed for brachial plexus blockade.25,26 The rate of vascular absorption also varies, and is dependent on the specific local anesthetic agent. Lidocaine is absorbed more rapidly following brachial plexus and epidural blockade than is prilocaine, whereas bupivacaine is absorbed more rapidly than etidocaine. 24,26 Prilocaine is a less-potent vasodilator than lidocaine, which partly accounts for lower blood concentrations of prilocaine. The lower peak blood concentrations of etidocaine compared with bupivacaine may be related to the greater lipid solubility of etidocaine, which results in its sequestration by adipose tissue and a decreased rate of absorption. The differences in absorption rates are of practical clinical significance, as they permit the use of larger doses of prilocaine compared with lidocaine and of etidocaine compared with bupivacaine.

6.0

4.0

2.0

0.0

0

10 20

30

60

90

120

Time (min) Distribution To rapid equilibrating tissues

Distribution To slow equilibrating tissues

+

Metabolism and excretion

FIGURE 44–8. Plasma concentration curve of lidocaine following IV administration showing initial rapid rate of disappearance related to distribution to rapidly equilibrating tissues and slower rate of disappearance caused by distribution to slowly equilibrating tissues and biotransformation and excretion. (Reprinted from Covino BG. Pharmacology of local anesthetic agents. In: Rogers MC, Tinker JH, Covino BG, et al., eds. Principles and Practice of Anesthesiology. Vol. 2. St. Louis, MO: Mosby Year Book, 1993:1245, with permission from Elsevier.)

of lidocaine and mepivacaine are similar. The half-life of the β disappearance phase (T1/2β) of prilocaine is more rapid than that of lidocaine and mepivacaine, suggesting a more rapid rate of biotransformation. A comparison study reveals that etidocaine has a more rapid rate of tissue redistribution and biotransformation than bupivacaine.28 Local anesthetic agents are distributed throughout all body tissues, but the relative concentration in different tissues varies as a function of time, vascular perfusion, and tissue mass. Initially, local anesthetic agents are rapidly extracted by lung tissue so that the whole blood concentration of local anesthetics decreases greatly as they pass through the pulmonary vasculature.29,30 Ultimately, the highest percentage of an injected dose of a local anesthetic agent is found in skeletal muscle, simply because the mass of skeletal muscle makes it the largest reservoir for local anesthetic agents.

Biotransformation and Elimination The degradation of local anesthetic agents varies according to their chemical classification. Amino ester local anesthetic drugs are hydrolyzed in plasma by cholinesterase enzymes. Chloro-

procaine shows the most rapid rate of hydrolysis (4.7 μmol/mL/h), compared with a rate of 1.1 μmol/mL/h for procaine and 0.3 μmol/mL/h for tetracaine.31 Less than 2% of unchanged procaine is found in urine, whereas approximately 90% of p-aminobenzoic acid, which is a primary product of procaine hydrolysis, appears in urine. Only 33% of dimethylaminoethanol, the other hydrolysis product of procaine, is excreted unchanged. The amino amide agents are biotransformed primarily in the liver.32 Prilocaine undergoes the most rapid rate of hepatic metabolism, and lidocaine is biotransformed somewhat more rapidly than mepivacaine. In humans, the hepatic clearance of etidocaine is greater than that of bupivacaine, which suggests a more rapid rate of hepatic biotransformation for etidocaine. Evidence also exists that prilocaine may be biotransformed in the kidney, which would explain the rapid clearance of this agent compared with all other amino amides.33 The biotransformation of the amino amide-type agents results in the formation of a variety of metabolites. The biotransformation of lidocaine has been studied most extensively. The main pathway of lidocaine biotransfor-

959


960

CLINICAL CONSIDERATIONS Routes of Administration The clinical profile of local anesthetic drugs varies, and is dependent on the type of regional anesthetic technique performed (Fig. 44–9). The shortest duration of action occurs following the

Spinal anesthesia—15 mg bupivacaine Brachial plexus blockade—150 mg bupivacaine

12.5

20

10

15

7.5

10

5

5

Time (hr)

25

Time (min)

mation in humans involves oxidative deethylation of lidocaine to monoethylglycinexylidide by cytochrome P450 IIIA4, followed by a subsequent hydrolysis of monoethylglycinexylidide to xylidine. The excretion of the amino amidetype local anesthetic drugs occurs by way of the kidney. Less than 5% of the unchanged drug is excreted via the kidney into the urine. The major portion of the injected agent appears in the urine in the form of various metabolites. The renal clearance of the amino amide local anesthetic agents appears to be inversely related to their proteinbinding capacity. Prilocaine, which has a lower protein-binding capacity than lidocaine, has a substantially higher clearance value than lidocaine.34 Renal clearance also is inversely proportional to the pH of urine, suggesting that urinary excretion of these agents occurs by nonionic diffusion. Patient age may influence the physiologic disposition of local anesthetics. The half-life of lidocaine following IV administration increased from an average of 80 minutes in human volunteers 22–26 years of age to 138 minutes in subjects ages 61–71 years.35 Age-dependent disposition kinetics have been reported for ropivacaine following epidural administration, with elimination half-life significantly longer and clearance significantly decreased in older (>61 years) than in younger patients (18–40 years).23 The elimination of local anesthetic agents also is influenced by the individual patient’s hepatic and cardiac function. For example, an average lidocaine halflife of 1.5 hours was reported in volunteers with normal hepatic function, whereas patients with liver disease demonstrated an average half-life of 5 hours.36 In patients with congestive heart failure (CHF) the IV infusion of lidocaine results in significantly higher plasma concentrations of lidocaine than occurs in patients with normal cardiovascular function, indicating a decreased plasma clearance in patients with CHF.37

2.5

0

0 Onset

Duration

FIGURE 44–9. Comparison of onset and duration of spinal anesthesia and brachial plexus blockade with bupivacaine. (Reprinted from Covino BG. Pharmacology of local anesthetic agents. In: Rogers MC, Tinker JH, Covino BG, et al., eds. Principles and Practice of Anesthesiology. Vol. 2. St. Louis, MO: Mosby Year Book, 1993:1242, with permission from Elsevier.)

intrathecal or subcutaneous administration of local anesthetics. The longest latencies and durations are observed following major peripheral nerve blocks, such as brachial plexus blockade. Intrathecal bupivacaine usually produces anesthesia within 5 minutes and persists for 3–4 hours.38 For brachial plexus blockade, the onset time of bupivacaine is approximately 20–30 minutes, whereas the duration of anesthesia averages approximately 10 hours.39 These variations in the onset and duration of anesthesia result from differences in the anatomy of the injection sites and the amount of drug employed for various types of regional anesthesia. In the subarachnoid space the lack of a nerve sheath around the spinal cord and the placement of the local anesthetic solution in the immediate vicinity of the spinal cord is responsible for the rapid onset of action. The relatively small amount of drug employed for spinal anesthesia probably accounts for the short duration of conduction block. For example, 50–75 mg of lidocaine and 10–15 mg of bupivacaine are usually employed for most spinal anesthetic procedures. The onset of brachial plexus blockade is slow, as the anesthetic agent is usually injected some distance from the nerve roots and must diffuse through various tissue barriers before reaching the nerve membrane. The prolonged blockade is probably related to the decreased rate of vascular absorption from that site and the larger dose of drug employed for this regional anesthetic technique. For example,

400–600 mg of lidocaine and 100–150 mg of bupivacaine are usually employed for brachial plexus blockade.

Clinical Manifestations of Potency In vitro studies show a general positive correlation between lipid solubility of local anesthetics and potency (Fig. 44–10).40,41 This presumably is because the nerve membrane that represents the site of action of local anesthetics consists primarily of lipids. However, the hydrophobicity and anesthetic potency are not as well correlated in intact animals and humans. The EC50 (median effective dose) of lidocaine, for example, is significantly less than that of mepivacaine in an isolated nerve, but in humans, little difference in anesthetic potency is apparent between these agents.24 Etidocaine possesses a lower EC50 than bupivacaine in an isolated nerve, but etidocaine is approximately half as potent as bupivacaine in vivo42,43: 1–1.5% etidocaine is required to achieve a similar degree of epidural blockade as is produced by 0.5–0.75% bupivacaine. The difference between potency in an isolated nerve and in a clinical situation is probably a function of the vasodilator or tissue redistribution properties of the various local anesthetics. Lidocaine is a more profound vasodilator than mepivacaine in humans. More rapid vascular absorption of lidocaine as a result of vasodilatation causing increased blood flow, results in fewer lidocaine molecules being available for neural blockade.


0.4

TABLE 44–4. Mepivacaine Lidocaine Bupivacaine Etidocaine

EC50 (mM)

0.3

0.2

90

304

0.1

0 Partition coefficient (octanol/buffer) FIGURE 44–10. Relationship between concentrations of various local anesthetics required to cause 50% depression in amplitude of isolated nerve action potential (median effective concentration [EC50]) and partition coefficient values. (Reprinted from Covino BG. Pharmacology of local anesthetic agents. In: Rogers MC, Tinker JH, Covino BG, et al., eds. Principles and Practice of Anesthesiology. Vol. 2. St. Louis, MO: Mosby Year Book, 1993:1236, with permission from Elsevier.)

Hence, lidocaine and mepivacaine appear to possess similar anesthetic potencies clinically. The profound conduction-blocking activity of etidocaine in vitro is a result of its high lipid solubility. However, sequestration of etidocaine in adipose tissue in vitro, such as in the epidural space, results in fewer etidocaine molecules being available for neural blockade compared with bupivacaine.

Speed of Onset In isolated nerves,41,44 onset time of conduction block is correlated with the pKa of the various agents (Fig. 44–11) and lipid solubility influences onset of action, too. The pKa of local anesthetics and the pH of the anesthetic solution

determine the degree of ionization of specific agents. This is because the degree of ionization influences the rate of diffusion of local anesthetics across the nerve sheath and membrane. The uncharged base form diffuses more easily than the charged cationic form.45,46 The pKa of all local anesthetics, except benzocaine, varies from 7.6–9.1 and is greater than the physiologic pH (7.4) of tissue (Table 44–4). At a pH of 7.4, approximately 2% of procaine (pKa of 9.1) exists in the base form. In contrast, 35% of mepivacaine, lidocaine, etidocaine, and prilocaine, which possess a pKa of approximately 7.6, are present in the unionized forms. The pH of most local anesthetic solutions is approximately 5–6 because of the rela-

0.4 Lidocaine, mepivacaine, prilocaine, etidocaine Bupivacaine, ropivacaine Tetracaine Procaine, chloroprocaine

Onset (min)

0.3

0.2

0.1

0 pKa

7.7

8.1

8.4

9.1

Base form (%)

35

15

5

1

FIGURE 44–11. Relationship between onset of conduction block in isolated nerve and pKa and percentage of local anesthetic present in base form. (Reprinted from Covino BG. Pharmacology of local anesthetic agents. In: Rogers MC, Tinker JH, Covino BG, et al., eds. Principles and Practice of Anesthesiology. Vol. 2. St. Louis, MO: Mosby Year Book, 1993:1236, with permission from Elsevier.)

Dissociation Constants (Rounded) Local Anesthetic

pKa

Benzocaine Mepivacaine Lidocaine Etidocaine Prilocaine Ropivacaine Bupivacaine Tetracaine Cocaine Dibucaine Procaine Chloroprocaine Hexylcaine Procainamide Piperocaine

3.5 7.7 7.8 7.9 7.9 8.1 8.1 8.4 8.6 8.8 8.9 9.1 9.3 9.3 9.8

tively low solubility of local anesthetics in solutions of higher pH. The inclusion of epinephrine in local anesthetic solutions results in a further decrease in pH to approximately 3–4. Studies in vitro clearly demonstrate the relationship among the pKa of specific agents, the pH of anesthetic solution, and the onset of conduction block.44–46 Agents with a relatively low pKa, such as lidocaine and mepivacaine, show the most rapid onset of conduction block. Procaine, chloroprocaine, and tetracaine, which possess high pKa values, demonstrate a longer latency. The onset of conduction blockade is also reduced by increasing the pH of the bathing solution.45 Clinically, onset time may be influenced by the dose or concentration of local anesthetic employed.43 For example, increasing the concentration of bupivacaine from 0.25– 0.75% results in a significant acceleration in anesthetic effect. Despite its pKa being approximately 9 and its onset of action in isolated nerves being relatively slow, chloroprocaine demonstrates a rapid onset of action in humans. This is because chloroprocaine’s low systemic toxicity allows the use of high concentrations such as 3%. Lidocaine has been shown in some studies to produce a more rapid onset of epidural anesthesia than chloroprocaine when employed at the same concentrations. However, use of a 3% chloroprocaine solution results in a more rapid onset of conduction block compared with 2.0% lidocaine.47

961


related to ropivacaine’s cutaneous vasoconstrictor effects (Fig. 44–13).50,52

12 10 8

Procaine Lidocaine Tetracaine Bupivacaine

95

Differential Sensory/Motor Block 76

6 4 2 0

95 Percent of protein binding FIGURE 44–12. Relationship between duration of brachial plexus blockade of various local anesthetics and their degree of protein binding. (Reprinted from Covino BG. Pharmacology of local anesthetic agents. In Rogers MC, Tinker JH, Covino BG, et al., eds. Principles and Practice of Anesthesiology. Vol. 2. St. Louis, MO: Mosby Year Book, 1993:1238, with permission from Elsevier.)

962

The various local anesthetics have greatly different durations of action and protein binding apparently is a determinant of duration (Fig. 44–12).44 Procaine and chloroprocaine have a short duration of action; lidocaine, mepivacaine, and prilocaine have a moderate duration of anesthesia. Tetracaine, bupivacaine, levobupivacaine, etidocaine, and ropivacaine are associated with the longest durations of anesthesia. Procaine produces duration of brachial plexus blockade of 30–60 minutes—approximately 10 hours of anesthesia has been reported following the use of bupivacaine, etidocaine, and ropivacaine for brachial plexus blockade. Local anesthetics are believed to act by binding to a protein receptor in the sodium channel,3 and thus the greater protein binding of a specific agent presumably results in a longer period of sodium channel blockade and a longer duration of anesthesia. Plasma proteins have been used to measure protein binding of local anesthetics, assuming that binding to membrane proteins is similar to plasma protein binding. Duration of action of the various agents is influenced by their peripheral vascular effects. Local anesthetics except cocaine generally tend to have a biphasic effect on vascular smooth muscle.48–50 These agents cause vasoconstriction at low concentrations and vasodilatation at clinically employed concentrations. The protein kinase C Rho and p44/42 mitogen-activated protein kinase signaling pathways in calci-

um sensitization mechanisms may be involved in the biphasic action.51 Differences exist in the vasodilator activity of the various drugs. Lidocaine is a more potent vasodilator than mepivacaine or prilocaine. In vivo, the duration of anesthesia produced by lidocaine is shorter than that of mepivacaine or prilocaine. If epinephrine is added to solutions of these agents, the duration of action for all three drugs is similar. The duration of action of ropivacaine is similar to that of bupivacaine when the agents are administered for peripheral or central neural blocks.52,53 However, ropivacaine produces a significantly longer duration of infiltration anesthesia than bupivacaine in animals, which appears

Influence of Dose An increase in the dose of local anesthetic usually results in a more profound depth of block, a prolongation of satisfactory anesthesia, and a decrease in the onset of block.43,54 No clinically significant differences in onset, depth, and duration of anesthesia appear to

300 250 Duration (min)

Duration of Action

Differential block is observed clinically but is poorly understood. Local anesthetic agents differ with respect to producing motor versus sensory block. The most significant separation between sensory anesthesia and motor blockades is produced by bupivacaine.43 Depending on the concentration of bupivacaine employed, significant sensory anesthesia may be obtained with little inhibition of motor activity. Ropivacaine appears to provide a similar degree of sensory/motor separation.54 Bupivacaine and etidocaine are notably different in terms of their differential sensor/motor fiber-blocking activity (Fig. 44–14). Bupivacaine is widely used epidurally for obstetric procedures and relief of pain postoperatively because of its ability to provide adequate analgesia with minimal muscle weakness or paralysis, particularly as a 0.125% or 0.25% solution. In contrast, etidocaine shows little separation between blockade of sensory and motor fibers.43

Ropivacaine Bupivacaine

200 150 100 50 0 0.125

0.25 0.5 Concentration (percent)

0.75

FIGURE 44–13. Relationship between duration of infiltration anesthesia and concentration of bupivacaine and ropivacaine. (Reprinted from Covino BG. Pharmacology of local anesthetic agents. In: Rogers MC, Tinker JH, Covino BG, et al., eds. Principles and Practice of Anesthesiology. Vol. 2. St. Louis, MO: Mosby Year Book, 1993:1239, with permission from Elsevier.)


Bupivacaine

Percent

150 100 50 0 0.25

0.5 Concentration

0.75

Etidocaine

Percent

150 100 50 0 0.5

1.0 Concentration

1.5

Frequency of satisfactory sensory analgesia Frequency of complete motor block FIGURE 44–14. Frequency of satisfactory sensory analgesia and frequency of motor block produced by bupivacaine and etidocaine at various concentrations. (Reprinted from Covino BG. Pharmacology of local anesthetic agents. In: Rogers MC, Tinker JH, Covino BG, et al., eds. Principles and Practice of Anesthesiology. Vol. 2. St. Louis, MO: Mosby Year Book, 1993:1239, with permission from Elsevier.)

blockade showed no difference in onset, adequacy, or duration of anesthesia, and onset, depth, and duration of motor blockade if the dose was maintained constant (Fig. 44–15).55 However, the increase in total dose from 300 to 600 mg of prilocaine did result in a more rapid onset, a greater degree of satisfactory anesthesia, and a prolonged duration of anesthesia. Similar studies of spinal anesthesia indicate little difference between the use of varying volumes of 0.5% and 0.75% bupivacaine if the total dose was constant (Fig. 44–16).38 The volume of anesthetic solution may influence the spread of anesthetic in the epidural or subarachnoid space. For example, the level of anesthesia was 4.3 dermatomes higher when 30 mL of 1% lidocaine was injected epidurally compared with 10 mL of 3% lidocaine.56 In general, increased dosage is usually achieved by the use of more concentrated anesthetic solutions, as the volume of solution that can be administered is usually restricted by the anatomy of the specific injection site.

FORMULATIONS exist when the same dose of local anesthetic is administered as a large volume of dilute solution or as a small volume of concentrated solution. A

comparison of 15 mL of 2% prilocaine with 10 mL of 3% prilocaine (300 mg) and 30 mL of 2% prilocaine with 20 mL of 3% prilocaine (600 mg) for epidural

200 180

3% Prilocaine − 20 mL 2% Prilocaine − 30 mL

600 Mg

160

120

100

100

80

80

60

60 40 40 20

20 0

20 30

20 30

20 30

20 30

Onset

Duration

Adequate analgesia

Adequate muscle relaxation

Local anesthetics are mixed with other substances during the manufacturing process or just prior to administration. Some objectives of this practice are to shorten onset time, limit absorption, increase intensity of action, stabilize local anesthetic molecule, and inhibit microbial growth. A 2004 issue of Techniques in Regional Anesthesia and Pain Medicine discussed in detail additives to local anesthetics.57

Mixtures of Local Anesthetics Percent

Time (min)

140

Purpose of Different Formulations

0

FIGURE 44–15. Relationship between onset, duration, and frequency of adequate analgesia and frequency of adequate muscle relaxation produced by prilocaine when used as either a 3% solution or a 2% solution for epidural blockade. (Reprinted from Covino BG. Pharmacology of local anesthetic agents. In: Rogers MC, Tinker JH, Covino BG, et al., eds. Principles and Practice of Anesthesiology. Vol. 2. St. Louis, MO: Mosby Year Book, 1993:1240, with permission from Elsevier.)

Mixtures of local anesthetics have been employed by adding an agent, such as chloroprocaine or lidocaine, which have a relatively rapid onset, to a solution of bupivacaine, which has a slow but long duration of action. A mixture of 3% chloroprocaine and 0.5% bupivacaine was reported to produce a rapid onset and prolonged duration of brachial plexus blockade.58 Subsequent epidural studies indicated that a mixture of chloroprocaine and bupivacaine resulted in a slower onset than chloroprocaine alone and a shorter duration than bupivacaine alone.59 Isolated nerve studies demonstrate

963


were improved when epinephrine 1: 300,000 was added to 0.25% bupivacaine.66 Although the addition of epinephrine may not significantly prolong the duration of surgical epidural anesthesia produced by 0.5–0.75% bupivacaine, a more profound degree of motor blockade has been observed following the use of bupivacaine with epinephrine.64 Epinephrine’s ability to prolong spinal anesthesia may be partly related to a direct antinociceptive effect in the spinal cord. Adrenergic receptor agents exert a direct antinociceptive action in the spinal cord. For example, clonidine, an α2-adrenergic agonist, produces analgesia following epidural administration.67 Epinephrine’s effect on the onset of regional anesthesia is controversial. Some studies demonstrate a more rapid onset of conduction blockade, presumably because of the decreased vascular absorption of local anesthetics.62 Others fail to demonstrate any difference in onset time.68 This is attributed to the low pH of epinephrine-containing local anesthetic solutions, which favor the formation of the local anesthetics cationic form, which does not easily diffuse through nerve sheaths.

Sensory Anesthesia

150

Number of dematomes blocked

Time (min)

200 20

3 ml of 0.5% bupivacaine 2 ml of 0.75% bupivacaine

100

10

50 0

0 Onset

Regression to T12

Spread

Motor Block 150 100 50 50 0

0 Onset

964

Percent

Time (min)

100

Duration

Frequency

FIGURE 44–16. Relationship between onset, duration, and spread of sensory anesthesia and onset, duration, and frequency of motor block produced by bupivacaine when employed as either a 0.5% or a 0.75% solution for intrathecal use. (Reprinted from Covino BG. Pharmacology of local anesthetic agents. In: Rogers MC, Tinker JH, Covino BG, et al., eds. Principles and Practice of Anesthesiology. Vol. 2. St. Louis, MO: Mosby Year Book, 1993:1240, with permission from Elsevier.)

that the addition of a metabolite of chloroprocaine to bupivacaine significantly decreased the duration of conduction block compared with bupivacaine alone (Fig. 44–17).60 To date, no similar antagonism has been demonstrated when lidocaine or mepivacaine is mixed with bupivacaine. One should remember that in terms of the potential systemic toxicity of mixtures of local anesthetics, the toxicity of local anesthetics is additive if an unintentional IV injection occurs.

Use of Vasoconstrictors Epinephrine (1:200,000; 5 μg/mL) is frequently added to local anesthetic solutions to decrease the rate of vascular absorption.24 This allows more anesthetic molecules to diffuse to the nerve membrane and thus improves the depth and duration of anesthesia. Epinephrine 1:200,000 has been reported to be the optimal concentration prolonging the duration of anesthesia of lidocaine for epidural or intercostals use. Other vasoconstrictor agents, such as norepinephrine and phenylephrine, have been used but do not appear to be superior to epinephrine. For example, equipotent concentrations of epinephrine and phenylephrine similarly prolong the duration of spinal anesthesia produced by tetracaine (Fig. 44–18).61 Epinephrine’s ability to prolong the duration of anesthesia depends on the

local anesthetic employed and the injection site. Epinephrine significantly extends the duration of both infiltration anesthesia and peripheral nerve blocks with most agents.62,63 The duration of surgical epidural anesthesia, however, is not greatly prolonged when epinephrine is combined with prilocaine, bupivacaine, or etidocaine, but does result in a significant increase in the duration of epidural blockade produced by agents such as lidocaine.64,65 Diluted solutions of bupivacaine employed for epidural analgesia in obstetric patients may be improved with the addition of epinephrine. The depth and duration of epidural analgesia in obstetric patients

3

Bupivacaine

2

Chloroprocaine

1

CPmet + Bup

0

10

20

Carbonation and pH Adjustment of Local Anesthetics Carbonation of local anesthetics results in a more rapid onset and a more profound degree of conduction blockade in an isolated nerve preparation.45,69,70 The enhanced onset is believed to be related to a more rapid dissociation of the local anesthetic to the base form, a direct depressant ef-

30

40

50

60

50% recovery time (min) FIGURE 44–17. Recovery of conduction blockade in isolated nerve following exposure to bupivacaine alone, chloroprocaine alone, and mixture of a chloroprocaine metabolite and bupivacaine. (Reprinted from Covino BG. Pharmacology of local anesthetic agents. In Rogers MC, Tinker JH, Covino BG, et al., eds. Principles and Practice of Anesthesiology. Vol. 2. St. Louis, MO: Mosby Year Book, 1993:1243, with permission from Elsevier.)


ate. In the original study in which onset time for brachial plexus blockade was significantly reduced, the pH of bupivacaine with epinephrine was increased from 3.9 to 6.4.77 In the subsequent study in which no effect on latency was observed, the pH of plain bupivacaine was increased from 5.5 to 7.0.78 The amount of bicarbonate added to local anesthetic solutions depends on the particular local anesthetic. One milliliter of sodium bicarbonate is added to 10 mL of lidocaine, whereas 0.1 mL of bicarbonate is added to every 10 mL of bupivacaine. The latter agent is insoluble at a high pH, and the addition of excess bicarbonate will result in a precipitation of bupivacaine.

Sensory Anesthesia 12 10

Tetracaine Tetracaine + 0.2 mg epinephrine Tetracaine + 2.0 mg phenylephrine

8

200

6

150

4

100

2

50 0

0 Onset

Duration

FIGURE 44–18. Relationship between onset and duration of spinal anesthesia following use of plain tetracaine, tetracaine with epinephrine, and tetracaine with phenylephrine. (Reprinted from Covino BG. Pharmacology of local anesthetic agents. In: Rogers MC, Tinker JH, Covino BG, et al., eds. Principles and Practice of Anesthesiology. Vol. 2. St. Louis, MO: Mosby Year Book, 1993:1241, with permission from Elsevier.)

fect of carbon dioxide (CO2) on the nerve membrane, and a decrease in the axoplasmic pH from the diffusion of CO2 intraneurally. The lower axoplasmic pH increases the rate of formation of the local anesthetic’s active cationic form within the nerve. Although CO2 clearly enhances the onset of local anesthetic-induced conduction block in an isolated nerve, discrepancies exist among clinical studies in which hydrochloride and carbonated local anesthetic solutions have been compared. Several investigations have demonstrated a significant decrease in the onset of epidural blockade with lidocaine carbonate compared with lidocaine hydrochloride.71,72 However, other researchers have failed to observe a significant reduction in onset of epidural anesthesia with lidocaine carbonate.73 Similarly, differing results concerning onset time have been reported when bupivacaine hydrochloride and bupivacaine carbonate were employed for brachial plexus blocks.74,75 Although controversy may exist regarding the effect of carbonation on onset of anesthesia, most studies show that carbonated solutions do improve the depth of sensory and motor blockade when administered into the epidural space. Also, these solutions produce a more complete blockade of the various nerve roots when employed for brachial plexus blockade. Alkalinization of local anesthetic solutions by the addition of solution bicarbonate has also been reported to decrease the onset of conduction block-

Hyaluronidase, Liposomes, Microencapsulation Hyaluronidase (tissue spreading factor) is sometimes added to local anesthetic solutions to facilitate spread of solution at the injection site, thereby affecting speed of onset and extent of a block. This seems only to be useful when local anesthetic is injected in the orbit preparatory to ophthalmologic surgery. Hyaluronidase may be injected with local anesthetic during epidural neurolysis to treat pain with positive benefit. Various attempts have been made to prolong the duration of action of local anesthetics by loading them into liposomes or microcapsules, but no such formulations have been approved by the FDA for marketing.

ade (Fig. 44–19).76,77 An increase in the pH of the local anesthetic solution increases the amount of drug in the uncharged base form, which should enhance the rate of diffusion across the nerve sheath and nerve membrane. The use of pH-adjusted solutions of bupivacaine or lidocaine has been reported to significantly decrease the latency of brachial plexus and epidural blockade.76,77 Again, controversy surrounds the improved onset of pH-adjusted local anesthetic solutions. Some investigators have failed to demonstrate an improved onset of brachial plexus or epidural blockade with the use of pH-adjusted solutions of bupivacaine or lidocaine.78,79 The differences between these studies might be related to the magnitude of the pH change produced by the addition of bicarbon-

TOXICITY Table 44–5 shows categorizes the toxic effects of local anesthetics.

pH = 3.9

A

pH = 6.4

pH = 4.6

B

pH = 7.2

0

5

10

15

20

25

30

Onset time (min) FIGURE 44–19. Comparison of onset of brachial plexus blockade with bupivacaine (A) and onset of epidural blockade with lidocaine (B) using solutions of varying pH. (Reprinted from Covino BG. Pharmacology of local anesthetic agents. In: Rogers MC, Tinker JH, Covino BG, et al., eds. Principles and Practice of Anesthesiology. Vol. 2. St. Louis, MO: Mosby Year Book, 1993:1243, with permission from Elsevier.)

965


was lower than for other local anesthetics such as lidocaine. Human volunteer studies of doses required to produce early features of CNS and cardiovascular system toxicity by ropivacaine and levobupivacaine demonstrated the doses were about equal and higher than for bupivacaine.87–89 Brown et al.90 reviewed records of patients who had seizures while undergoing brachial plexus, epidural, and caudal regional anesthetics. No adverse cardiovascular, pulmonary or nervous system events were associated with any of the seizures, including in 16 patients who received bupivacaine blocks. In dogs, the relative CNS toxicity of bupivacaine, etidocaine, and lidocaine is 4:2:1,91 which is similar to the relative potency of these agents for the production of regional anesthesia in humans. IV infusion studies in human volunteers have also demonstrated an inverse relationship between the intrinsic anesthetic potency of various agents and the dosage required to induce CNS toxicity.92,93 The rate of IV administration alters the toxicity of local anesthetic agents.93 In human volunteers, an average dose of 236 mg of etidocaine and a venous blood concentration of 3.0 µg/mL resulted in CNS symptoms when 10 mg/ min was infused. When the infusion rate was increased to 20 mg/min, an average of 161 mg of etidocaine, which produced a venous plasma concentration of approximately 2 µg/mL, caused symptoms of CNS toxicity.

TABLE 44–5. Categories of Local Anesthetic Toxic Reactions Localized or Systemic

Systemic

Localized

Allergic reactions

Cardiac/vascular Central nervous system Methemoglobin

Tissue toxicity

966

True allergic reactions are associated with amino ester-linked local anesthetics, not amino amide-linked ones. In a study of anaphylactic and anaphylactoid reactions (n = 789) occurring during anesthesia, Mertes et al.80 found no such reactions to local anesthetics. However, Mackley et al.81 reported that of 183 patients who were patch tested, 4 had positive reactions to lidocaine, 2 of whom had histories of sensitivity to local injections of lidocaine manifested by dermatitis. They concluded that contact-type IV sensitivity to lidocaine might occur more frequently than previously thought. It is common, but inappropriate, to refer to all adverse events as “allergic reactions.”

Tissue Toxicity Tissue toxicity, primarily myotoxicity and neurotoxicity can be produced by all local anesthetics if “high” concentrations are used. Signs and symptoms of varying degrees of neuropathy (e.g. transient neurologic symptoms, cauda equina syndrome) have been reported following spinal anesthesia with, for example, 2% and 5% lidocaine. In a recent systematic review, Zaric et al.82 compared the frequency of transient neurologic symptoms and neurologic complications after spinal anesthesia with lidocaine with that after other local anesthetics. The results showed that the risk for developing transient neurologic symptoms after spinal anesthesia with lidocaine was higher with lidocaine than with bupivacaine, prilocaine, procaine, or mepivacaine.

Systemic Toxicity Methemoglobinemia A variety of local anesthetics reportedly may produce methemoglobinemia. Prilocaine is the local anesthetic for which there appears to be greatest risk for this to occur. A dose–response relationship exists between the amount of prilocaine administered epidurally and the degree of methemoglobinemia. In

general, doses of prilocaine of 600 mg are required for the development of clinically significant levels of methemoglobinemia.83 The formation of methemoglobinemia is believed to be related to prilocaine’s chemical structure. This agent lacks a methyl group in the benzene ring. The metabolism of prilocaine in the liver results in the formation of O-toluidine, which is responsible for the oxidation of hemoglobin to methemoglobin.84 The methemoglobinemia associated with prilocaine is spontaneously reversible or may be treated by IV methylene blue.

Cardiovascular and Central Nervous System As concentration of local anesthetic in systemic circulation increases, various cardiovascular system and central nervous system signs and symptoms appear (Fig. 44–20). The relative CNS and cardiovascular toxicity of local anesthetics has been of interest, especially after Albright85 reported unexpected cardiovascular toxicity of bupivacaine. In animal studies, the ratio of doses of bupivacaine that produced convulsive activity and cardiovascular collapse86

28

C.V.S. depression

26 24 Plasma concentration μg/mL

Allergic Reactions

22

Respiratory arrest

20 18 Coma

16 14 12 10 8 6 4 2

Convulsions Unconsciousness Muscular twitching Visual disturbance Lightheadedness Numbness of tongue

0 FIGURE 44–20. Plasma concentration of lidocaine versus systemic toxicity.


Convulsive threshold (mg/kg)

50 40

PaCO2 = 25–37 mm Hg PaCO2 = 65–81 mm Hg

30 20 10 0 ca

ca in

e

e

in

e

ca

in

iva

iva

do

ep

e

ne

in

ai

oc

ca

p Bu

Li

M

il Pr

o Pr

FIGURE 44–21. Relationship between convulsive threshold doses of various local anesthetics and arterial CO2 tension (PaCO2). (Reprinted from Covino BG. Pharmacology of local anesthetic agents. In: Rogers MC, Tinker JH, Covino BG, et al., eds. Principles and Practice of Anesthesiology. Vol. 2. St. Louis, MO: Mosby Year Book, 1993:1247, with permission from Elsevier.)

Acid–base status can alter the CNS activity of local anesthetic agents. In cats, the convulsive threshold of various local anesthetics is inversely related to the arterial CO2 tension (PaCO2)94 (Fig. 44–21). An increase in PaCO2 from 25 to 40 mm Hg to a range of 65 to 81 mm Hg decreases the convulsive threshold of procaine, mepivacaine, prilocaine, lidocaine, and bupivacaine by approximately 50%. A decrease in arterial pH also decreases the convulsant threshold of these agents. Respiratory acidosis, with a resultant increase in PaCO2 and a decrease in arterial pH, consistently decreases the convulsant threshold of local anesthetic agents. However, an elevation in both PaCO2 and arterial pH, as may occur during metabolic alkalosis, does not increase CNS toxicity to the same degree. Hypercarbia increases cerebral blood flow, which probably results in a greater uptake of local anesthetic by the brain. In addition, diffusion of CO2 into neuronal cells decreases intracellular pH and thus increases the intracellular cationic form of the local anesthetic agents. This form does not diffuse well across the nerve membrane, so ion trapping occurs. Hypercarbia and/or acidosis also decrease the plasma protein binding of local anesthetic agents, which will increase the proportion of free drug available for diffusion into the brain.95,96 On the other hand, acidosis also decreases the percentage of the local anesthetic existing in the base form, which should decrease the rate of diffusion into neuronal cells. Local anesthetics have a direct effect on both cardiac muscle and vascular

smooth muscle. These agents alter the heart’s electrical and mechanical activity. Studies using the intact, isolated mammalian heart in vitro show that highly lipid-soluble, extensively protein-bound, highly potent local anesthetics (e.g., tetracaine, bupivacaine, etidocaine) are much more cardiotoxic than are the less-lipid-soluble, proteinbound, potent local anesthetics (e.g., lidocaine, mepivacaine, prilocaine).97 Bupivacaine has a potent depressant effect on electrical conduction in the heart primarily via an action on voltage-gated sodium channels that generally govern the initial rapid depolarization (phase 0) of cardiomyocytes. The S forms of bupivacaine are less cardiotoxic than the R form. Bupivacaine actions other than on voltage-gated sodium channels probably also contribute to dose-dependent cardiotoxic effect of this local anesthetic. Local anesthetics decrease the maximal rate of depolarization in Purkinje’s fibers and ventricular muscle because of an inhibition of sodium channels in cardiac membranes.98–100 Action potential duration and the effective refractory period are also decreased by local anesthetics. However, the ratio of effective refractory period to action potential duration is increased both in Purkinje’s fibers and in ventricular muscle. Qualitative differences exist between the various local anesthetic agents. Bupivacaine depresses the rapid phase of depolarization (Vmax) in Purkinje’s fibers and ventricular muscle to a greater extent than does lidocaine.98–100 In addition, the rate of recovery from a

use-dependent block is slower in bupivacaine-treated than in lidocaine-treated papillary muscles.101 This slow rate of recovery results in an incomplete restoration of Vmax between action potentials, particularly at high heart rates. In contrast, recovery from lidocaine is complete, even at rapid heart rates. These differential effects of lidocaine and bupivacaine may explain the antidysrhythmic properties of lidocaine and the dysrhythmogenic potential of bupivacaine. Bupivacaine, and to a lesser degree etidocaine and ropivacaine, can produce severe cardiac dysrhythmias, including ventricular fibrillation, in various animal species.86,102–106 Ventricular dysrhythmias are rarely seen with lidocaine, mepivacaine, or tetracaine. Although the dysrhythmogenic action of bupivacaine is probably related primarily to an inhibition of the fast sodium channels in the cardiac membrane, evidence also exists that this agent may block the slow calcium channels.107 These electrophysiologic effects of bupivacaine may result in conduction abnormalities, leading to a reentrant type of dysrhythmia similar to a torsade de pointes dysrhythmia.103 The dysrhythmogenic activity of bupivacaine is believed to result primarily from a direct cardiac effect. Isolated guinea pig hearts perfused with bupivacaine revealed evidence of conduction block, bigeminy, and trigeminy.108 In addition, ventricular fibrillation occurred in intact pigs in which bupivacaine was injected directly into the left anterior descending coronary artery.105 On the other hand, the injection of bupivacaine directly into certain regions of the brain may result in cardiac dysrhythmias, which may indicate a relationship between the CNS and cardiotoxic effects of bupivacaine.109,110 Electrophysiologic studies in intact dogs and in people shown that high blood levels of local anesthetics prolong conduction time through various parts of the heart as indicated by an increase in the PR interval and QRS duration. Extremely high concentrations of local anesthetics depress spontaneous pacemaker activity in the sinus node, resulting in sinus bradycardia and sinus arrest. Local anesthetic agents also depress myocardial contractility. All local anesthetics exert a dose-dependent negative inotropic action on isolated cardiac

967


100

Lidocaine, mepivacaine Etidocaine Bupivacaine

CC dose (mg/kg)

80 60 40 20 0 1 2 3 4 5 Relative in vivo anesthetic potency FIGURE 44–22. Relationship between dose of various local anesthetics that causes cardiovascular collapse (CC) and in vivo anesthetic potency of these agents. (Reprinted from Covino BG. Pharmacology of local anesthetic agents. In: Rogers MC, Tinker JH, Covino BG, et al., eds. Principles and Practice of Anesthesiology. Vol. 2. St. Louis, MO: Mosby Year Book, 1993:1249, with permission from Elsevier.)

caine causes vasoconstriction because of its ability to inhibit the uptake of norepinephrine by storage granules.113 Studies indicate that ropivacaine causes cutaneous vasoconstriction, whereas bupivacaine produces vasodilatation.51 In a review of the cardiotoxicity of modern local anesthetics, Mather and Chang114 concluded that as compared with bupivacaine, although ropivacaine and levobupivacaine may be seen as “safer,” they must not be regarded as totally “safe.”

Factors Influencing Cardiovascular Toxicity Specific Agents Although the CNS is more susceptible to the toxic effects of local anesthetics than the cardiovascular system, differ-

Pregnancy Data regarding the effects of pregnancy on the cardiovascular toxicity of local anesthetic is not conclusive.

Acidosis and Hypoxia Hypercarbia, acidosis, and hypoxia potentiate the negative chronotropic and inotropic action of lidocaine and bupivacaine in isolated cardiac tissue.116 The combination of hypoxia and acidosis greatly potentiates the cardiodepressant effects of bupivacaine. Hypoxia and acidosis also increase the frequency of cardiac dysrhythmias and the mortality rate in sheep following the IV administration of bupivacaine.116 Hypercarbia, acidosis, and hypoxia

60 50 Dose (mg/kg)

968

tissue that is proportional to the conduction blocking potency of the various agents in isolated nerves (Fig. 44– 22).111 For example, bupivacaine, tetracaine, and etidocaine produce the greatest degree of myocardial depression. The agents of moderate anesthetic potency (i.e., lidocaine, mepivacaine, prilocaine) are intermediate in terms of their negative inotropic action. Procaine and chloroprocaine, which are the least-potent local anesthetics, require the highest concentration to decrease cardiac contractility. In dogs, tetracaine is approximately 8–10 times more potent than procaine as a local anesthetic and as a myocardial depressant.112 Hemodynamic studies in closed-chest anesthetized dogs have shown that tetracaine, etidocaine, and bupivacaine caused a 50% decrease in cardiac output at doses of 10–20 mg/kg, whereas doses of 30–40 mg/kg of lidocaine, mepivacaine, prilocaine, and chloroprocaine were required for a similar decrease in cardiac output. A dose of 100 mg/ kg of procaine was needed to reduce cardiac output to 50%. Most local anesthetic agents exert a biphasic effect on peripheral vascular smooth muscle.48,49 Low concentrations of lidocaine and bupivacaine produced vasoconstriction in the cremaster muscle of rats, whereas high concentrations increased arteriolar diameter, indicative of vasodilatation. In vivo studies also demonstrate that low doses of local anesthetics decrease peripheral arterial flow without any change in blood pressure, whereas higher doses increase blood flow. Co-

ences exist in the margin between the dose of various agents that causes convulsions and the dose that results in cardiovascular collapse (Fig. 44–23). A cardiovascular collapse (CC)-to-convulsive (CNS) dose ratio of 7.1 + 1.1 was reported for lidocaine in adult sheep, indicating that 7 times as much drug was required to induce irreversible cardiovascular collapse as to cause convulsions.115 The CC:CNS ratio for bupivacaine was 3.7 + 0.5 and for etidocaine, 4.4 + 0.9. The CC:CNS blood level ratio of lidocaine was 3.6 + 0.3, compared with values of 1.6–1.7 for bupivacaine and etidocaine. At the time of cardiovascular collapse, high concentrations of bupivacaine and etidocaine were present in the myocardium compared with lidocaine, which suggests that the enhanced cardiac toxicity of these more potent agents may result from a greater myocardial uptake.

Convulsive dose Cardiovascular collapse dose

40 30 20 10 0 Lidocaine

Etidocaine

Bupivacaine

FIGURE 44–23. Relationship between dose of lidocaine, bupivacaine, and etidocaine that causes CNS toxicity and dose that produces cardiovascular collapse. (Reprinted from Covino BG. Pharmacology of local anesthetic agents. In: Rogers MC, Tinker JH, Covino BG, et al., eds. Principles and Practice of Anesthesiology. Vol. 2. St. Louis, MO: Mosby Year Book, 1993:1249, with permission from Elsevier.)


occur very rapidly in some patients following seizure activity because of the rapid unintentional intravascular injection of local anesthetic agents.118 Thus the cardiovascular depression observed in some patients following the accidental IV injection of bupivacaine may be related in part to the severe acid–base changes that occur during toxic reactions to this agent. Measures to prevent systemic toxic reactions to local anesthetics include following dose recommendations, injecting aliquots over time, avoiding unintentional intravascular injections, and monitoring vital signs during injection. Blanket recommended doses versus block-specific recommended doses were discussed recently.119,120 Drug administration must be stopped should signs or symptoms of toxicity develop. Seizures induced by local anesthetics are usually self-limiting, and require maintenance of respiratory gas exchange and control of muscle contractions (e.g., intubation, oxygenation, short-acting muscle paralysis). Drugs such as propofol, thiopental, and benzodiazepines are effective against these seizures. Cardiovascular toxicity is treated according to American Heart Association guidelines, depending on the nature of the toxicity. Recent evidence suggests that in some instances, lipid emulsion infusion may be beneficial.121

TABLE 44–6. Generic and Trade Names of Local Anesthetics Generic Name

Trade Name(s)

Benoxinate Bupivacaine Butacaine Chloroprocaine (2-chloroprocaine) Cyclomethycaine Dibucaine Etidocaine Hexylcaine Levobupivacaine Lidocaine Mepivacaine Piperocaine Prilocaine Procaine Proparacaine Ropivacaine Tetracaine

Dorsacaine; Novesine Marcaine; Sensorcaine Butyn Nesacaine Surfacaine Nupercaine; Percaine Duranest Cyclaine Chirocaine Xylocaine; Xylotox Carbocaine; Polocaine Metycaine Citanest Novocain; Planocaine Opthaine; Ocu-Caine Naropin Pontocaine; Pantocaine

As these local anesthetics are administered chiefly as the chloride or sulfate slats, it is more accurate to specify procaine hydrochloride than just procaine. Because the latter is the active species, it is the usually used term. Modified with permission from deJong RH. Local Anesthetics. St. Louis: Mosby-Year Book, 1994.

tetracaine. All of these agents were introduced into clinical practice by 1955.

Procaine Procaine was the first synthetic local anesthetic agent introduced into clinical practice. It is a relatively weak local anesthetic with a slow onset and a short duration of action. Its systemic toxicity

is relatively low because of rapid plasma hydrolysis. Procaine is hydrolyzed to p-aminobenzoic acid, which is responsible for the allergic reactions associated with repeated use of procaine. Procaine is used primarily for infiltration anesthesia, diagnostic differential spinal blocks in certain pain states, and obstetric spinal anesthesia.

SPECIFIC LOCAL ANESTHETICS Local Anesthetics in Clinical Use Table 44–6 lists generic and trade names of local anesthetics. Undoubtedly, lidocaine is most commonly used to prevent procedure-related pain and for diagnostic tests. Intermediate- to longacting local anesthetics, such as ropivacaine, levobupivacaine, and bupivacaine, are used for therapy. Table 44–7 lists topical anesthetics and dosage forms. Most of the forms are available without prescription. A 5% lidocaine patch (Lidoderm) is approved by the FDA for controlling postherpetic neuralgia.

Amino Ester Agents Local anesthetics in this class have an ester linkage to benzoic acid or its derivatives. The amino ester-linked local anesthetics most commonly used clinically are procaine, chloroprocaine, and

TABLE 44–7. Topical: Local Anesthetics and Available Dosage Forms Benzocaine Cream Ointment Topical aerosol Benzocaine and menthol Lotion Topical aerosol solution Butamben Ointment Dibucaine Cream Ointment Lidocaine Film-forming gel Ointment Patch Cream

Lidocaine/prilocaine Cream Lidocaine/tetracaine Patch Pramoxine Cream Lotion Pramoxine and menthol Gel Lotion Tetracaine Cream Tetracaine and menthol Ointment

From http://www.nlm.nih.gov/medlineplus/druginfo/uspdi/202042.html with modification.

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Chloroprocaine Chloroprocaine has rapid onset of action, short duration, and low systemic toxicity. It undergoes hydrolysis by human plasma esterases about 4 times faster than procaine. Chloroprocaine is primarily employed for epidural analgesia and anesthesia in obstetrics because of its rapid onset and low systemic toxicity in the mother and fetus. However, frequent injections are required to provide adequate pain relief during labor. Sometimes, epidural analgesia is established in the pregnant patient with chloroprocaine, followed by a longer-acting agent such as bupivacaine. Chloroprocaine has also proved of value for various regional anesthetic procedures in ambulatory surgical patients for whom surgery is not expected to exceed 30–60 minutes. Concern about potential myotoxicity and neurotoxicity have haunted chloroprocaine. 970

Tetracaine Tetracaine is used primarily for spinal anesthesia. It may be employed as an isobaric, hypobaric, or hyperbaric solution for spinal blockade, although hyperbaric solutions of tetracaine are probably employed most often. Tetracaine provides a relatively rapid onset of spinal anesthesia, excellent qualities of sensory anesthesia, and a profound block of motor function. Plain solutions of tetracaine produce an average duration of spinal anesthesia of 2–3 hours, whereas the addition of epinephrine can extend anesthesia to 4–6 hours. Tetracaine is rarely used for other forms of regional anesthesia because of its extremely slow onset of action and the potential for systemic toxic reactions when larger doses are employed.

Cocaine Cocaine was the first agent successfully employed clinically for the production of local anesthesia. It has limited use in modern anesthesia practice because of its relatively high potential for systemic toxicity and addiction liabilities. It is listed as a schedule II drug in the United States. Cocaine is an excellent topical anesthetic agent and it produces vasoconstriction at clinically useful concentrations. As a result, it is still sometimes employed to anesthetize and constrict the nasal mucosa before nasotracheal intubation and otolaryngologists use cocaine during nasal surgery because of its topical anesthetic and vasoconstrictor properties. It is the only local anesthetic

that inhibits the reuptake of catecholamines in the central and peripheral nervous systems.

Amino Amide Agents Amino amide-linked local anesthetics most commonly used clinically are lidocaine, mepivacaine, ropivacaine, bupivacaine, and levobupivacaine. The first step in the biotransformation of the tertiary amine forms typically is dealkylation of the amino nitrogen by cytochrome P450 in the liver.

Lidocaine Lidocaine, the first of the amino amidetype local anesthetics to be introduced into clinical practice, remains the most versatile and most frequently used drug in this class. It is popular because of its inherent potency, rapid onset, moderate duration of action, and topical anesthetic activity. Solutions of lidocaine are available for infiltration, peripheral nerve blocks, and epidural anesthesia. In addition, hyperbaric lidocaine is useful for spinal anesthesia of 30–60 minutes’ duration. Lidocaine is also used in ointment, jelly, viscous, and aerosol preparations for a variety of topical anesthetic procedures. Lidocaine currently is still the only agent officially approved in the United States for IV regional anesthesia. Lidocaine is sometimes given intravenously as an antiepileptic agent, as an analgesic for certain chronic pain states, and as a supplement to general anesthesia. It is administered intravenously for the treatment of ventricular dysrhythmias.

Mepivacaine Mepivacaine has a local anesthetic profile similar to that of lidocaine. It can produce a profound depth of anesthesia with a relatively rapid onset and a moderate duration of action. Mepivacaine may be used for infiltration, peripheral nerve blocks, and epidural anesthesia, and in some countries, 4% hyperbaric solutions of mepivacaine are also available for spinal anesthesia. It is ineffective as a topical anesthetic agent. The metabolism of mepivacaine is greatly prolonged in the fetus and newborn; thus this agent is not usually employed for obstetric anesthesia. Mepivacaine appears to be somewhat less toxic in adults than lidocaine and has less vasodilator activity than lidocaine. Because of the difference in vasoactivity, mepivacaine provides a somewhat longer duration of anesthesia than lidocaine when used without epinephrine.

Mepivacaine seems to be particularly useful for brachial plexus blockade when large volumes of anesthetic solutions without epinephrine are given.

Ropivacaine Ropivacaine is prepared as the pure S isomer rather than a racemic mixture. Onset of action, potency and duration of sensory nerve blockade appear similar for ropivacaine and bupivacaine, but ropivacaine is a less potent and short-acting agent in terms of motor fiber blockade. Toxicity studies suggest that ropivacaine is less cardiotoxic than bupivacaine, although ropivacaine still possesses some dysrhythmogenic potentia.

Bupivacaine Bupivacaine was the first local anesthetic that combined the properties of an acceptable onset, long duration of action, profound conduction blockade, and significant separation of sensory anesthesia and motor blockade. This agent is used for various regional anesthetic procedures, including infiltration, peripheral nerve blocks, and epidural and spinal anesthesia. The average duration of surgical anesthesia with bupivacaine varies from approximately 3 to 10 hours. Its longest duration of action occurs with major peripheral nerve blocks such as brachial plexus blockade. The major advantage of bupivacaine appears to involve epidural obstetric analgesia for labor when satisfactory pain relief for 2–3 hours is achieved, which significantly decreases the need for repeated injections in the pregnant patient. Moreover, adequate analgesia is usually achieved without significant motor blockade such that the patient in labor is able to move her legs. This differential blockade of sensory and motor fibers is also the basis for the widespread use of bupivacaine for postoperative epidural analgesia and for certain chronic pain states.

Levobupivacaine The clinical profile of levobupivacaine, the S isomer of bupivacaine, is essentially the same as the profile of racemic bupivacaine except with somewhat wider therapeutic index for cardiac toxicity and systemic toxicity.

Prilocaine The clinical profile of prilocaine is also similar to that of lidocaine. Prilocaine has a relatively rapid onset of action while providing a moderate duration of anesthesia and a profound depth of conduction blockade. Because this agent


causes significantly less vasodilatation than lidocaine, it can be used without epinephrine. Prilocaine biotransformation produces aminophenols that oxidize hemoglobin to methemoglobin thus limiting its clinical use. The primary use of prilocaine is in EMLA cream, a eutectic mixture of prilocaine and lidocaine for topical application.

Etidocaine Etidocaine is characterized by very rapid onset, prolonged duration of action, and profound sensory and motor blockade. It has a significantly more rapid onset of action than bupivacaine. Concentrations of etidocaine required for adequate sensory anesthesia produce profound motor blockade. As a result, etidocaine is primarily useful as an anesthetic for surgical procedures in which muscle relaxation is required. Consequently, this agent is of limited use for obstetric epidural analgesia and postoperative pain relief, as it does not provide a differential blockade of sensory and motor fibers. The drug is used infrequently in North America.

Dibucaine Dibucaine is only available for topical anesthesia in the United States. It is more potent than tetracaine, although the onset of action of the two agents is similar. The duration of spinal anesthesia is slightly longer with dibucaine. The degree of hypotension and depth of motor blockade appear to be less in patients receiving intrathecal dibucaine than in those receiving tetracaine into the subarachnoid space, although the spread of sensory anesthesia is similar in the two groups.

Benzocaine This local anesthetic is used exclusively for topical anesthesia. Benzocaine is available in a variety of proprietary and nonproprietary preparations. The most common forms used in an operating room setting are aerosol solutions for endotracheal administration and ointments for lubrication of endotracheal tubes. One should remember that benzocaine also can cause methemoglobinemia.

KEY REFERENCES 1. Hille B. Ionic Channels of Excitable Membranes. 3rd ed. Stamford,

Connecticut: Sunderland, Sinauer Associates, 2001.

3. de Jong RH. Local Anesthetics. St. Louis: Mosby-Year Book, 1994.

2. de Jong RH. Local Anesthetics. St. Louis: Mosby-Year Book, 1994.

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3. Heavner JE, guest ed. Techniques. Reg Anesth Pain Manage 2004;8:105–140.

5. Kindler CH, Yost CS. Two-pore domain potassium channels: new sites of local anesthetic action and toxicity. Reg Anesth Pain Med 2005;30:260–274.

4. Mackley CL, Marks JG, Anderson BE. Delayed-type hypersensitivity to lidocaine. Arch Dermatol 2003; 139:343–346.

6. Xu F, Garavito-Aguilar Z, Pecio-Pinto E, et al. Local anesthetics modulate neuronal calcium signaling through multiple sites of action. Anesthesiology 2003;98:1139–1146.

5. Zaric D, Christiansen C, Pace NL, et al. Transient neurologic symptoms after spinal anesthesia with lidocaine versus other local anesthetics: a systematic review of randomized, controlled trails. Anesth Analg 2005;100:1811–1816.

8. Gisson AJ, Covino BG, Gregus J. Differential sensitivities of mammalian nerve fibers to local anesthetic agents. Anesthesiology 1980;53:467–474.

6. Albright GA. Cardiac arrest following regional anesthesia with etidocaine or bupivacaine. Anesthesiology 1979;51:285–287. 7. Feldman HS, Arthur GR, Covino BG. Comparative systemic toxicity of convulsant and supraconvulsant doses of intravenous ropivacaine, bupivacaine, and lidocaine in the conscious dog. Anesth Analg 1989; 69:794–801. 8. Stewart J, Kellett N, Castro D. The central nervous system and cardiovascular effects of levobupivacaine and ropivacaine in healthy volunteers. Anesth Analg 2003;97: 412–416. 9. Heavner JE. Cardiotoxicity of local anesthetics in the intact isolated heart model: a review. Reg Anesth Pain Med 2002;27:545–555. 10. Mather LE, Chang H-T. Cardiotoxicity with modern local anesthetics. Drugs 2001;61:333–342. 11. Rosenberg PH, Veering BT, Urmey WF. Maximum recommended doses of local anesthetics: a multifactorial concept. Reg Anesth Pain Med 2004;29:564–575.

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84. Hjelm M, Holmdahl MH. Biochemical effects of aromatic amines. Acta Anaesthesiol Scan 1965;2:99–120. 85. Albright GA. Cardiac arrest following regional anesthesia with etidocaine or bupivacaine. Anesthesiology 1979;51:285–287. 86. Feldman HS, Arthur GR, Covino BG. Comparative systemic toxicity of convulsant and supraconvulsant doses of intravenous ropivacaine, bupivacaine, and lidocaine in the conscious dog. Anesth Analg 1989;69:794–801. 87. Stewart J, Kellett N, Castro D. The central nervous system and cardiovascular effects of levobupivacaine and ropivacaine in healthy volunteers. Anesth Analg 2003; 97:412–416. 88. Knudsen K, Beckman-Suurkula M, Blomberg S, et al. Central nervous and cardiovascular effects of I.V. infusions of ropivacaine, bupivacaine and placebo in volunteers. Br J Anaesth 1997;78:507–514. 89. Scott DB, Lee A, Fagan D, et al. Acute toxicity of ropivacaine compared with that

100. Moller RA, Covino BG. Cardiac electrophysiologic effects of lidocaine and bupivacaine. Anesth Analg 1988;67:107–114. 101. Arlock P. Actions of three local anesthetics: lidocaine, bupivacaine and ropivacaine on guinea pig papillary muscle sodium channels (Vmax). Pharmacol Toxicol 1988;63:96–104. 102. deJong RH, Ronfeld RA, DeRosa RA. Cardiovascular effects of convulsant and supraconvulsant doses of amide local anesthetics. Anesth Analg 1982;61:3–9. 103. Kasten GW. High serum bupivacaine concentrations produce rhythm disturbances similar to torsades de pointes in anesthetized dogs. Reg Anesth 1986;11:20–25. 104. Kotelko DM, Shnider SM, Dailey PA, et al. Bupivacaine-induced cardiac arrhythmias in sheep. Anesthesiology 1984;60:10– 18. 105. Nath S, Haggmark S, Johansson G, Reiz S. Differential depressant and electrophysiologic cardiotoxicity of local anesthet-

ics: an experimental study with special reference to lidocaine and bupivacaine. Anesth Analg 1986;65:1263–1270. 106. Sage D, Feldman H, Arthur G, et al. The cardiovascular effects of convulsant doses of lidocaine and bupivacaine in the conscious dog. Reg Anesth 1985;10:175– 183. 107. Coyle DE, Sperelakis N. Bupivacaine and lidocaine blockade of calcium-mediated slow action potentials in guinea pig ventricular muscle. J Pharmacol Exp Ther 1987;242:1001–1005. 108. Tanz RD, Heskett T, Loehning W, et al. Comparative cardiotoxicity of bupivacaine and lidocaine in the isolated perfused mammalian heart. Anesth Analg 1984;63: 549–556. 109. Heavner JE. Cardiac dysrhythmias induced in infusion of local anesthetics into the lateral cerebral ventricle of cats. Anesth Analg 1986;65:133–138. 110. Scott DB. Toxic effects of local anaesthetic agents on the central nervous system. Br J Anaesth 1986;48:732–735. 111. Block A, Covino BG. Effect of local anesthetic agents on cardiac conduction and contractility. Reg Anesth 1982;6:55–61. 112. Stewart DM, Rogers WP, Mahaffrey JE, et al. Effect of local anesthetics on the cardiovascular system in the dog. Anesthesiology 1963;24:620–624. 113. MacMillan WH. A hypothesis concerning the effect of cocaine on the action of sympathomimetic amines. Br J Pharmacol 1959;14:385–391. 114. Mather LE, Chang H-T. Cardiotoxicity with modern local anesthetics. Drugs 2001; 61:333–342. 115. Morishima HO, Pedersen H, Finster M, et al. bupivacaine toxicity in pregnant and nonpregnant ewes. Anesthesiology 1985;623:134–139. 116. Sage DJ, Feldman HS, Arthur GR, et al. Influence of lidocaine and bupivacaine on isolated guinea pig atria in the presence of acidosis and hypoxia. Anesth Analg 1984; 63:1–7. 117. Rosen M, Thigpen J, Shnider S, et al. Bupivacaine-induced cardiotoxicity in hypoxic and acidotic sheep. Anesth Analg 1985;64:1089–1096. 118. Moore DC Crawford RD, Scurlock JE. Severe hypoxia and acidosis following local anesthetic-induced convulsions. Anesthesiology 1980;53:259–260. 119. Heavner JE. Let’s abandon blanket maximum recommended doses of local anesthetics. Reg Anesth Pain Med 2004;29: 524. 120. Rosenberg PH, Veering BT, Urmey WF. Maximum recommended doses of local anesthetics: a multifactorial concept. Reg Anesth Pain Med 2004;29:564–575. 121. Weinberg G, Ripper R, Feinstein DL, et al. Lipid emulsion infusion rescues dogs from bupivacaine-induced cardiac toxicity. Reg Anesth Pain Med 2003;28:198–202.

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SECTION D REGIONAL ANESTHESIA

CHAPTER 45 Incorporating Regional Anesthesia into Anesthetic Practice 974

Richard W. Rosenquist, MD and David L. Brown, MD Incorporating regional anesthesia into an established anesthesia practice demands that the physicians involved understand and make preparations to address the following: • Management of regional anesthesia through the perioperative period; • The clinical indications for the regional anesthetic chosen; • The resources necessary to perform the blocks efficiently and effectively; and • Establishment of an institutional strategy to optimize the introduction of new techniques. Far too often physicians desire to immediately transfer “techniques” they have learned into their own practices. That strategy is often destined to fail as the four areas of understanding clearly need to be managed to predictably and reliably introduce regional anesthesia into established practices. This chapter explores each of these necessary steps for successful introduction of regional anesthesia into a practice and expands on them so that you are able to individualize a plan for your own institution and practice.

CONCEPT OF THE CONTINUUM OF ANESTHESIA CARE: THE PERIOPERATIVE PERIOD Physicians who desire to add regional anesthesia techniques to their own

practice are most successful if they fundamentally are truly outstanding physicians and, as a result, excellent anesthesiologists. These physicians must be true perioperative physicians. They must be

able to understand patient medical problems, surgeons’ operative requirements, and regional anesthesia techniques, as well as recovery pattern, nursing requirements, rehabilitation,

KEY POINTS 1. The one overriding benefit of regional anesthesia techniques is that they do not need to end as the patient leaves the operating room at the end of the intraoperative period. 2. The patient education process is most effective if started in the surgeon’s office at the time of the visit at which the decision for operation is completed. Both the surgeon and the nurses need to understand the general concepts and goals of anesthesia and are often strong coadvocates of better perioperative analgesia for their patients. 3. The perioperative period should be designed so that regional anesthesia does not delay or slow down a surgical day. Surgical delay is one of the most important items to avoid if you desire to successfully add regional anesthetic techniques to your practice. 4. Regional anesthesia techniques should be selected and performed on the basis of clear indications so as to maximize benefit and minimize complications. 5. The preoperative anesthetic note should clearly outline that the patient has been informed of the risks and benefits of the entire anesthetic experience, including the regional anesthetic portion, if that is applicable to the patient. 6. Patients should have regional anesthetics performed in settings where


full monitoring, resuscitation equipment, and supplies are available. 7. When a practice has added continuous regional anesthetic techniques (either epidural or continuous peripheral nerve block techniques), it is important that round-the-clock coverage and followup is available to the patient and hospital if the patient remains as an inpatient. 8. One of the most important technical items in the intraoperative period with regional anesthesia is to recognize that if a block is not 100%, the anesthesiologist should be the only individual aware of that fact. This means that if the block is not working as well as desired, general anesthesia or deep sedation should be added efficiently. 9. If a patient is to be discharged with a continuous catheter technique, a clear understanding of catheter and pump management, limb protection, catheter removal, breakthrough pain control, and contact numbers must be assured. 10. Anesthesiologists need to continue their own regional anesthesia education by attending continuing education conferences and workshops that help them to have a more complete understanding of the topic and learn new techniques for introduction into their practice. This enables anesthesiologists to continue the education of physicians, nurses, and others regarding regional anesthesia advances.

CHAPTER 45: Incorporating Regional Anesthesia Into Anesthetic Practice

and potential complications from the surgical procedure performed. Only if all of these are incorporated into decisions about regional anesthesia will the patient, surgeon, anesthesiologist, and nursing staff be coadvocates of the proposed new technique. In today’s surgical and anesthetic environment, our intraoperative general anesthetic care has advanced to a level where it is unusual to find clear advantages for regional anesthesia when considered during the isolated intraoperative period. There are exceptions, of course. Nevertheless, regional anesthesia may be better termed “regional analgesia,” as one seeks to incorporate that concept into a practice. The one overriding benefit of regional anesthesia techniques is that they do not need to end as the patient leaves the operating room at the end of the intraoperative period. Rather, when effectively chosen, these regional techniques can be extended either through appropriate drug selection, or via catheter insertion and continuous infusion of medication. Either of these choices may help transition the patient from the intraoperative to the postoperative period and to nearly full recovery without significant pain. Examples of this include using new, extended-release depot preparations of morphine in the epidural space to extend analgesia, or by inserting home going peripheral nerve plexus catheters to provide local anesthetic analgesia into the immediate and more distant postoperative period.1–4 A key step in successfully introducing regional anesthesia to an established practice is insuring that preoperative evaluation and education of the patient includes an explanation of regional anesthesia and that realistic patient expectations are established. Far too often patients are under the misunderstanding that because they choose a regional anesthesia technique, they will be “awake” during their surgical procedure. Experts in regional anesthesia are nearly always capable of providing outstanding sedation and anxiolysis for the entire perioperative period for patients undergoing a regional technique. This observation fits with these anesthesiologists being excellent physicians and understanding that it is a rare patient who wants to be, or should be allowed to be, unsedated for a surgical procedure. The patient education process is most effective if

started in the surgeon’s office at the time of the visit at which the decision for operation is completed. Both the nurses and the surgeon need to understand the general concepts and goals of anesthesia, including regional anesthesia techniques. Once they understand these concepts, they are often strong coadvocates of better perioperative analgesia for their patients. When considering patient education, the most important concept is that realistic expectations for both patient and the patient’s family are outlined. The patient’s expectations should be focused around anesthesia, sedation, postoperative analgesia, and what side effects the patient might experience so that, for example, a “numb” arm does not bother the patient on arrival in the recovery room or discharge to the floor or home. In setting these expectations, it is important that the anesthesiologist and institution design an analgesia transition program that addresses resolution of the regional anesthetic. As an example, outstanding brachial plexus anesthesia and analgesia for an upperextremity operation can frustrate a patient and the patient's family if the block abruptly wears off while the patient is expecting to sleep through the night and no oral medication regimen has been planned to ease that transition. When setting expectations for surgeons, a key element is that the perioperative period is designed so that regional anesthesia does not delay or slow down a surgical day. This demands that anesthesiologists and institutional leaders be creative about incorporating regional blocks and techniques into their practices. My experience is that surgical delay is one of the most important items to avoid if you desire to successfully add regional anesthesia techniques to your practice.

CLINICAL INDICATION FOR REGIONAL ANESTHESIA After considering the continuum of anesthesia care in the entire perioperative period, the next step for successful introduction of regional techniques into a practice is to develop clear indications for the use of these techniques. It must be remembered that the dominant focus for regional anesthesia is regional analgesia and the ability to minimize opioids and other intrave-

nous agents in the immediate perioperative period. Additional advantages of regional anesthesia techniques include the ability to avoid airway manipulations in patients who evidence difficult airway characteristics, or those with full stomach considerations. This does not mean that regional anesthetics should be applied in every full-stomach situation, but a mature clinical risk-to-benefit approach to many emergency patients suggests that the use of effective regional anesthesia does modify risk. Finally, there are selected patients in whom specific regional techniques may provide significant physiologic advantages. As example, in a patient with obstructive cardiomyopathy, the intravascular volume shifts from both general anesthesia vasodilatation and/or neuraxial anesthesia vasodilatation may be avoided, to the patient’s advantage, by the use of a brachial plexus nerve block. Another example might be a patient with endstage pulmonary disease, who requires open reduction internal fixation of a hip fracture. This clinical setting might be effectively handled with a continuous spinal anesthetic and minimal sedation, rather than a general anesthetic with tracheal intubation. In a patient who is undergoing regional anesthesia, there must be clear documentation of both the technical procedure and the indications for the regional technique in the patient’s chart. This is another opportunity for the anesthesiologist to educate both surgeons and nurses about the primary reason why the regional anesthesia technique was chosen. In my opinion, anesthesiologists frequently do not take advantage of the educational opportunities present in writing clear and effective progress notes in a patient’s record. The preoperative anesthesia note should clearly outline that the patient has been informed of the risks and benefits of the entire anesthesia experience, including the regional anesthesia portion, if applicable to the patient. The increasing number of drugs being developed that impact coagulation demands that anesthesiologists interested in adding regional techniques to their practice fully understand the implications of these anticoagulants and platelet-active drugs. For example, consensus statements for the use of neuraxial anesthesia techniques in relation to the use of various anticoagu-

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lant and antiplatelet agents were published by the American Society of Regional Anesthesia and Pain Medicine (ASRA) in 2003.5 Recent data outlining a 10-year Swedish experience with anticoagulants and neuraxial anesthesia underscore the need to understand the potential risks and benefits of this drug and technique combination.6 The Swedish results reiterated the danger of using more than one agent with anticoagulant or antiplatelet activity in combination. They also identified subgroups of patients at markedly increased risk; for example, elderly females with osteoporosis undergoing total knee arthroplasty under epidural analgesia and receiving once-per-day low-molecular-weight heparin have a 1 in 1800 incidence of epidural hematoma. The data to develop clear consensus statement guidelines regarding the use of anticoagulants and antiplatelet agents in conjunction with peripheral regional anesthetics is extremely limited. It has been suggested that the ASRA consensus guidelines for neuraxial anesthesia be applied to all regional anesthesia techniques. This may be too restrictive. In most cases, techniques performed in areas that are easily compressed in the event of bleeding may be appropriate. Others, such as paravertebral or subclavian blocks, should be avoided unless coagulation parameters are normal.

RESOURCES REQUIRED FOR EFFICIENT PRACTICE A common stumbling block for practices desiring to add regional anesthesia expertise to their practice is to have too few anesthesiologists skilled in the techniques. There must be critical masses of personnel, resources for the techniques, as well as interest in the techniques, for these to be added successfully to an anesthesia practice. Many practices often seek to have a single individual provide the regional anesthesia expertise. This is nearly always doomed to failure as that individual cannot be present 24 hours a day, year-round. Rather, it seems important to have enough physicians with the technical skills and interest in these anesthesia approaches to be able to provide consistent delivery of regional anesthesia throughout the day, week, and year. In addition to the physician resources, it is often helpful

to have allied health personnel help to prepare patients and supplies for the regional techniques to optimize timing of the technical performance of the regional anesthetic. This may be with a technician who is well trained in assisting the physicians, a nurse anesthetist who is skilled in this area of practice, or a registered nurse who works for the practice or hospital and has an interest in and a desire to grow this part of the practice. For the physicians, there must be a complete understanding of anatomy and regional anesthesia technical skills so as to safely and reliably perform the nerve blocks. Patients should have regional anesthesias performed in settings where full monitoring, resuscitation equipment, and supplies are available. These are major anesthesia techniques and need to be treated as such. Monitoring should meet American Society of Anesthesiologists (ASA) standards for performance of an anesthetic.7 Delays in the surgical day can often be minimized if many of the regional anesthesias are performed outside the operating room itself. This serves two functions. First, it allows the regional anesthesia to be performed while the surgical team is still preparing the operating room. Second, it gives the injected local anesthetic additional time to effectively anesthetize the desired region. This, of course, demands that regional anesthesia block rooms, or at least regional anesthesia block areas, are established outside the operating room. In many practices, this could be accomplished in areas of the preoperative holding or of postoperative anesthesia recovery. The ideal is to have induction rooms near the operating rooms. Within these areas of the hospitals, regional anesthesia carts with supplies easily at hand and with appropriate monitoring and resuscitation gear are critical for effectively caring for these patients. As the regional anesthetic practice is established, allied health staff assisting physicians with the technical features of these nerve blocks need to be trained and to have regional block protocols developed so that they are most effective. This demands significant planning and communication to effectively implement this practice. When a practice has added continuous regional anesthesia techniques (either epidural or continuous peripheral nerve block techniques), it is impor-

tant that round-the-clock coverage and followup are available to the patient and hospital if the patient remains as an inpatient. Even the most successful technical regional anesthetic can be viewed as unsuccessful if this part of the practice is not accounted for in the development phase of adding regional anesthesia to a practice. Other ideas to ease the transition of regional anesthetic techniques into a practice are to use regional anesthesia continuous infusion pumps that differ from general intravenous infusion pumps used throughout the hospital with tubing that has no injection ports. This difference helps to minimize the inappropriate administration of other intravenous drugs through regional block catheters. Drug swaps remain one of the dilemmas of modern medicine and the use of different pumps and tubing helps to minimize this type of error and potential neurotoxicity. New devices with the capability to read barcodes and recognize appropriate or inappropriate drugs for the device may provide additional safety in the future. Successful introduction and continued use of regional anesthetic techniques requires that physicians stay abreast of the latest technologies, such as ultrasound guidance or the use of stimulating catheters for catheter placement.8,9

OPTIMIZING INSTITUTIONAL INTRODUCTION OF REGIONAL ANESTHESIA Once the preceding three major elements are understood and a group decides to move ahead with introduction of regional anesthesia or expansion of regional anesthesia into its practice, strategies need to be developed to optimize this introduction. First, a core group of regional anesthesia physicians who agree, in principle, on the plan must be established. It is most effective if, as a system is rolled out, a small number of surgeons and surgical procedures are used as the initial clinical settings so that “success” can be validated more quickly. One of the easiest ways to cause an introduction of regional anesthesia to a practice to fail is to try to be all things to all patients and all surgeons at the outset. It is important to emphasize that successful introduction of regional anesthesia to a practice demands that all involved perceive that regional anes-

CHAPTER 45: Incorporating Regional Anesthesia Into Anesthetic Practice

thesia is truly an advantage to the patient, to the surgeon, to the anesthesiologist, and to the institution. Collins et al.10 provided clear evidence for this as they examined the impact of a regional anesthesia–analgesia program for outpatient foot surgery. They documented a marked increase in regional anesthesia use, no decrease in operating room efficiency, reduced postanesthesia care unit and discharge time, decreased analgesic use, and decreased nursing interventions for analgesia. An important technical item in the intraoperative period with regional anesthesia is to recognize that if a block is not 100%, the anesthesiologist should be the only individual aware of that fact. This means that if the block is not working as well as desired, general anesthesia or deep sedation should be added efficiently. This demands that anesthesiologists interested in this practice understand enough about regional anesthesia and sedation to blend the two techniques so that patients are effectively sedated and do not have any painful memories of either block insertion or eventual surgical manipulations. The potential for this transition from conscious sedation to deep sedation or general anesthesia should be explained in advance so that patients have realistic expectations regarding the plan of management. Successful use of regional anesthesia also requires education and training of the nursing staff and development of care protocols. This often begins in the postanesthesia care unit where the limb must be protected. If the patient is to be discharged, the patient and family must be educated about how to protect the limb until recovery from the block has occurred. If the patient is to be discharged with a continuous catheter technique, a clear understanding of catheter and pump management, limb protection, catheter removal, breakthrough pain control, and contact numbers must be assured. In some settings, this may require training home health nurses to facilitate the process. On the inpatient side, education regarding limb protection, neurologic evaluations, breakthrough pain,

and issues with anticoagulation and ambulation must be completed. Once the techniques are well established within an institution and the anesthesiologists are interested, the anesthesiologists need to continue their own regional anesthesia education by attending continuing education conferences and workshops that help them to an even more complete understanding of the topic and to learn new techniques for introduction into their practice. This enables these anesthesiologists to continue the education of nurses and others interested in regional anesthesia advances. This is a critical component of successful introduction of the practice of regional anesthesia. Once it is effectively introduced, the registered nurses within an institution often are its most vocal advocates, as they see firsthand the difference between patients having effective regional anesthesia and those having either ineffective regional anesthesia, excessive opioid analgesia, or uncontrolled pain in the perioperative period.

CONCLUSION The introduction of regional anesthesia to an established anesthesia practice is no different than the introduction of any new technique to a practice. There must be expertise, planning, and a group of physicians and support staff interested in the entire perioperative period who can coordinate the necessary personnel and resources to provide state-of-the-art medical care.

KEY REFERENCES 1. Ilfeld BM, Enneking FK. Continuous peripheral nerve blocks at home: a review. Anesth Analg 2005; 100:1822–1833. 2. Horlocker TT, Wedel DJ, Benzon H, et al. Regional anesthesia in the anticoagulated patient: defining the risks. Reg Anesth Pain Med 2003; 28:172–197.

3. Moen V, Dahlgren N, Irestedt L. Severe neurological complications after central neuraxial blockades in Sweden 1990–1999. Anesthesiology 2004;101:950–959. 4. Gray AT. Ultrasound-guided regional anesthesia: current state of the art. Anesthesiology 2006;104:368–373. 5. Collins L, Halwani A, Vaghadia H. Impact of a regional anesthesia program for outpatient foot surgery. Can J Anaesth 1999;46:840–845.

REFERENCES 1. Viscusi ER. emerging techniques in the management of acute pain: epidural analgesia. Anesth Analg 2004;101(5 Suppl):S23–S29. 2. Viscusi ER, Martin G, Hartrick CT, Singla N, Manvelian G, EREM Study Group. Fortyeight hours of postoperative pain relief after total hip arthroplasty with a novel, extendedrelease epidural morphine formulation. Anesthesiology 2005;102:1014–1022. 3. Ilfeld BM, Enneking FK. Continuous peripheral nerve blocks at home: a review. Anesth Analg 2005;100:1822–1833. 4. Ilfeld BM, Wright TW, Enneking FK, Vanderborne K. Total elbow arthroplasty as an outpatient procedure using a continuous infraclavicular nerve block at home: a prospective case report. Reg Anesth Pain Med 2006;31:172–176. 5. Horlocker TT, Wedel DJ, Benzon H, et al. Regional anesthesia in the anticoagulated patient: defining the risks. Reg Anesth Pain Med 2003;28:172–197. 6. Moen V, Dahlgren N, Irestedt L. Severe neurological complications after central neuraxial blockades in Sweden 1990–1999. Anesthesiology 2004;101:950–959. 7. ASA House of Delegates. Standards for basic anesthetic monitoring. 2005. Available at: http://www.asahq.org/publicationsAndServices/sgstoc.htm. Last accessed July 8, 2007. 8. Gray AT. Ultrasound-guided regional anesthesia: current state of the art. Anesthesiology 2006;104:368–373. 9. Boezaart AP, de Beer JF, Nell ML. Early experience with continuous cervical paravertebral block using a stimulating catheter. Reg Anesth Pain Med 2003;28:406–413. 10. Collins L, Halwani A, Vaghadia H. Impact of a regional anesthesia program for outpatient foot surgery. Can J Anaesth 1999;46:840–845.

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CHAPTER 46 Neuraxial Anesthesia Daniel T. Warren, MD, and Spencer S. Liu, MD

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With more than 100 years of use, neuraxial anesthesia has enjoyed much success and endured controversy. With the stage set by the developments of the hollow needle and syringe, the discovery of neuraxial anesthesia was born out of mishap in 1885 when Corning was experimenting with effects of cocaine on the spinal nerves of dogs. Bier brought spinal anesthesia into clinical use for surgery in 1898, but only after self-experimentation and a personal experience with a well-described postdural puncture headache. Epidural anesthesia gained widespread attention in the setting of labor analgesia, maintaining the medical community’s interest in neuraxial blockade despite rapid advancements in techniques for general anesthesia in the 1940s and 1950s. More recently, the introduction of continuous catheter techniques, combined spinal–epidural anesthesia, and various neuraxial anesthetic adjuvants has allowed further opportunities to provide our patients the benefits of neuraxial blockade.

ANATOMY Neural Structures A thorough appreciation for the anatomy of the spinal structures is necessary for appropriate technique, patient selection, and management of neuraxial anesthesia. The spinal structures are identified by cervical, thoracic, lumbar, sacral, and caudal regions (Fig. 46–1). The spinal cord begins at the base of the brainstem and continues caudad terminating as the conus medullaris, typically at the level of L1L2 in the adult. The cord shows cervical and lumbar enlargements to accommodate the increased neuronal supply of the limbs. Rootlets emerge from the dorsal and ventral surface of the spinal cord and converge to form

the respective ventral and dorsal roots of the spinal nerves at each spinal level (Fig. 46–2).

Cerebrospinal Fluid As with the brain, the spinal cord and portions of the spinal nerves are bathed in cerebrospinal fluid (CSF), which provides protection for these structures and participates in maintaining homeostasis. The CSF is secreted mainly by the choroid plexuses located on the roofs of the lateral, third, and fourth ventricles, and reabsorbed mainly through the arachnoid villi which project into the parasagittal venous sinuses and to a much lesser extent through the epidural veins of the vertebral column. It typically has a density range of 1.00028–1.00100 g/ mL.1 CSF volume and its clinical consequences are discussed in the Clinical Pharmacology section below.

Meninges As with the brain, spinal cord, nerve roots and CSF are enveloped by three membranes: the pia mater, arachnoid mater, and the dura mater (Figs. 46–2 and 46–3). The innermost pia mater is intimately lining the surface of the cord and nerve roots. It is a highly vascular and permeable membrane. The arachnoid mater approximates the

outermost membrane, the dura mater. Within the boundaries of the arachnoid is the subarachnoid space, home to the CSF, trabecular network, and dentate ligaments. The subarachnoid space extends laterally with the dura as nerve root “sleeves,” with the accompanying CSF as far as the dorsal root ganglion. The spinal dura mater extends from the level of the foramen magnum, where it is contiguous with cranial dura, to the level of S2 in most adults. Here the subarachnoid space terminates as the dura fuses with the filum terminale (pial extension), and then with the coccygeal periosteum. Between the dura mater and arachnoid mater resides the subdural space, which contains little more than a small amount of serous fluid. This space is often implicated as a culprit in complications such as a total spinal following an intended epidural administration of local anesthetic and failed spinal anesthetics.

Vertebrae The neural structures of the spinal cord are protected by the bony vertebral column comprised of 7 cervical, 12 thoracic, 5 lumbar, 5 sacral, and 4 coccygeal vertebrae (Fig. 46–1). The vertebrae of the sacral and coccygeal regions are fused to form the sacrum

KEY POINTS 1. A systematic and rational approach based on a thorough three-dimensional understanding of anatomy should be used when accessing the subarachnoid and epidural space. 2. Anesthetic doses, agents, and combinations of agents should be individualized so as to optimize neuraxial blockade for a given clinical setting.

5. Evaluating the appropriateness of neuraxial procedures in patients receiving anticoagulant and antiplatelet medications is a challenge. Clinicians should be familiar with the recommendations presented by the American Society of Regional Anesthesia and Pain Management in the consensus statement addressing these issues.

3. Hypotension and bradycardia associated with neuraxial anesthesia should be identified early and treated aggressively in an attempt to prevent cardiovascular collapse and poor outcome.

6. When suspicion of spinal hematoma or abscess is credible, definitive diagnosis with appropriate imaging and prompt decompression within 4–6 hours of onset of neurologic symptoms is crucial to improve chances of recovery of function.

4. Our understanding of potential neurotoxicity and the nature of transient neurologic symptoms (TNS) are continuing to evolve. However, there is growing consensus that TNS may not represent direct neural toxicity.

7. Developing an understanding of the nature of combined spinal–epidural anesthesia and facility with its techniques can expand a clinician’s armamentarium of tools to provide neuraxial anesthesia and optimize patient care.


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FIGURE 46–1. Regions of the spinal column.

and coccyx, respectively. Cervical and lumbar lordotic curves and thoracic kyphotic curves of the normal spine allow for advantageous distribution of mechanical forces and spinal movements. A typical vertebra consists of a pillar-like vertebral body joined by the pedicles to the posterior elements, namely the laminae, superior and inferior articular processes, transverse processes, and the spinous process. The vertebrae have regional characteristics

that are relevant to the techniques used to access the neuraxis in clinical situations. The figures depict relevant features of representative thoracic and lumbar vertebrae (Fig. 46–4).

Intervertebral Disks and Ligaments The endplates of the vertebral bodies are joined to one another by the intervertebral disks (Fig. 46–2), consisting of the outer annulus fibrosus and the

inner nucleus pulposus. Further structural support comes from the anterior and posterior longitudinal ligaments running along the ventral and dorsal aspects of the vertebral bodies respectively. Along with the supraspinous ligament traversing superficially, the deeper interspinous ligament joins the spinous processes to one another (Fig. 46–3). Adjacent lamina are interconnected by the ligamentum flavum, together forming the posterior wall of the


els have a higher rate of failed fusion compared to levels below T3-T4 (as high as 50–70%) and are thus perhaps more difficult for epidural access using the loss or resistance technique.2

Epidural Space

980 FIGURE 46–2. The spinal cord, along with the emerging root structures, are enveloped by the meninges as depicted in this figure.

spinal canal. This ligament forms embryologically from two (right and left) separate neural crest structures. These ligamenta meet in the midline at an acute angle, but have an inconsistent

degree of fusion. Incomplete fusion results in sagittal gaps, which are variable not only between individuals, but also among spinal levels within a given patient. Cervical and upper thoracic lev-

The epidural space (also referred to as extradural and peridural space) lies between the dura and the borders of the spinal canal (Fig. 46–3). Anteriorly, this border is the posterior longitudinal ligament; posteriorly, it is the vertebral lamina and adjoining ligamentum flavum (Fig. 46–3). The spinal epidural space runs from the level of the foramen magnum to the sacral hiatus, which is bound by the sacrococcygeal ligament. The lateral borders of the epidural space are partially delineated by the vertebral pedicles, but this space extends laterally through the intervertebral foramina to communicate with the paravertebral spaces on each side. The epidural space is somewhat compartmentalized by the sections of the dura abutting the ligamentum flavum, vertebral lamina, and other borders of the vertebral canal (Fig. 46–3B). However, these compartments are joined by a “potential space” that is opened by injection of fluid or air, thus connecting the compartments and revealing a more continuous communication.

FIGURE 46–3. A. Cross-sectional view of the lumbar region depicting the location of the epidural space and other anatomical structures associated with neuraxial procedures. As demonstrated in (B), the epidural space is somewhat compartmentalized, but continuous via “potential space” pathways that expand with injection of liquid.


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FIGURE 46–4. Anatomic structures associated with (A) lumbar and (B) thoracic vertebrae.

The contents of the epidural space include epidural fat, venous plexus, and segmental arteries. The epidural fat is largely located in the posterior and lateral aspects of the epidural space. This fat plays a role as a site for depot sequestration of epidurally administered local anesthetics and opioids as a function of the lipid solubility of the drug.3 The plexus of epidural veins (Batson plexus) is principally within the anterior and lateral portions of the epi-

dural space, with rare presence in the posterior aspect. These veins communicate with the azygous system, and thus can become engorged in the setting of increased intraabdominal pressure.

EQUIPMENT Spinal Needles Although many designs have been introduced throughout the history of

spinal anesthesia, the needles commonly used today can be generally classified as either “cutting needles” or “pencil-point needles” (Fig. 46–5). The Quincke-style needle, one of the most frequently used cutting needles, has a medium-length bevel, coming to a sharp point, which cuts through dural and arachnoid structures as it passes to the subarachnoid space. In contrast, pencil-point needles (often called “atraumatic”), such as the Green,


Whitacre, Sprotte, and Gertie-Marx, have a rounded, noncutting tip. The latter three have openings on the side rather than at the tip. Efforts to minimize the incidence of postdural puncture headache have driven the advancement of needle design. More recent designs include tapered needles, and return of stylet-point needles, such as the “Ballpen (Rusch, France) needle.” Needle gauge usually ranges from 27 to 18, with the smaller-gauge needles requiring an introducer needle.

Epidural Needles and Catheters

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Needles for accessing the epidural space need to be able to facilitate catheter insertion and techniques for identification of the epidural space. Currently, the most commonly used needle is the Tuohy needle (Fig. 46–5D). The design of this needle has undergone many modifications, but is characterized by a curved, or Hubber, tip. This curved tip decreases coring of tissue during insertion, but has been employed chiefly to attempt directional control of catheter insertion. Epidural needles are typically 16–20 gauge and accompanied by a tight-fitting stylet. Larger-gauge needles are less likely to be deflected by firm ligaments and osseous structures, and may provide a more reliable “loss-of-resistance” for identification of the epidural space.4 Commercially available catheters for cannulation of the epidural space are composed of polyurethane, nylon, or silicone-based material. Catheters with wire-wound reinforcement are designed to prevent kinking of the lumen and to increase durability, thus making them useful for postoperative analgesic infusions. Several variations of catheters have been brought to the market with options for multiorifice tips, metal stylets, and varying stiffness.

PATIENT SELECTION The success of neuraxial anesthesia begins with proper patient selection and creation of an environment that is conducive to a variety of regional anesthetic techniques. Principally, the surgical procedure should be able to be performed with a sensory block level that is tolerable and safe for the patient under the appropriate positioning, monitoring, and supplemental medication/sedation for the patient’s

FIGURE 46–5. Close-up views of the tips of a “cutting-tip” spinal needle. A. Quincke, and two “pencil-point” needles; (B) Whitacre; (C) Gertie-Marx. Also shown is the tip of a common epidural needle, (D) the 17-gauge Tuohy.

given condition. Lower-extremity, pelvic, and lower-abdominal procedures can be suited for spinal or epidural anesthesia. Procedures in the perineum usually are more suited to spinal anesthesia because of the potential for sacral nerve sparing with epidural anesthesia. Upper abdominal procedures usually require sensory levels that are not comfortably attainable with regional techniques alone, and would require “supplementation” with light general anesthesia. It is imperative that the patient be able to cooperate and tolerate the experience, from placement of the block, to block resolution. This can be accomplished through proper preoperative evaluation of the patient’s maturity and affect, and appropriate informed consent discussions regarding risks, benefits, alternatives, and patient expectations in light of the requirements of the procedure. Absolute contraindications to neuraxial anesthesia are few in number, but include patient refusal, significant hypovolemia, infection at the site of needle entrance, increased intracranial pressure, and significant coagulopathy. Relative contraindications require analysis of the risks and benefits for a given patient and situation. Unfortunately, this often needs to be done in light of the current medicolegal environment. Commonly encountered conditions are minor coagulopathy, sepsis/bacteremia, and preexisting neurologic conditions, such as peripheral neuropathy, multiple sclerosis, and other demyelinating processes.

TECHNIQUE FOR NEURAXIAL ANESTHESIA Patient Positioning and Preparation In addition to confirming patient consent and understanding, one should also verify the availability of equipment and medications to manage airway compromise and hemodynamic perturbations. The patient should have proper monitoring and supplemental oxygen during neuraxial anesthesia. Most patients prefer to have sedation administered prior to beginning neuraxial anesthesia, but judicious use of agents like midazolam and fentanyl should not significantly impair oxygenation or the patient’s ability to reliably report paresthesia or other signs of unintended trauma. The lateral decubitus position (Fig. 46–6) is most often used for spinal anesthesia. The patient should have hips and knees flexed with head approximating the knees in effort to relax the lumbar lordotic curve and accentuate the interlaminar aperture. This position is useful when employing spinal anesthesia for one-sided procedures, placing the operative side down if using hyperbaric solutions, or operative side up for hypobaric preparations (a technique commonly employed for hip surgery). Alternatively, neuraxial access can also be obtained with the patient in the sitting position (Fig. 46–7), bending forward to relax the lordotic curve of the lumbar spine. Advantages of this position are that it facilitates the iden-


FIGURE 46–6. Lateral decubitus position for neuraxial procedures. The patient is positioned with the head tucked down, hips flexed, and back rounded in efforts to maximize the aperture of the interlaminar space. Lines depicting the levels of the iliac crests and scapulae are commonly employed anatomical landmarks to identify the levels of L4 and T7, respectively. However, these landmarks are often unreliable.

tification of the midline in obese or anatomically distorted patients and augments CSF pressure at the needle entrance site, enhancing CSF flow through the needle when performing lumbar puncture. It is also used to accomplish “saddle block” anesthesia for procedures limited to the perineum by administering hyperbaric spinal preparations to the intrathecal space and having the patient remain sitting for at least 5 minutes after injection. If the patient is going to be in the prone position for procedures such as perianal surgery, a hypobaric technique can be employed. This is accomplished by positioning the patient for surgery prone with hips flexed and lumbar

spine relaxed (jackknife) (Fig. 46–8), then accessing the subarachnoid space, using a syringe to aspirate for confirmation of CSF flow. Once a hypobaric solution is administered, it is recommended that the patient remain in a flat or head-down position for at least 30 minutes to prevent unintended rostral “floating” of the anesthetic.

Accessing the Subarachnoid Space Several techniques have been described for inserting a needle percutaneously into the subarachnoid space, each having specific advantages in different clinical situations. By developing skill with multiple techniques, the

FIGURE 46–7. A patient in the sitting position, with the spine curved to relax the lordotic curve on the lumbar region. The approximate range of cord termination in 90% of patients is from T12 to L2.

practitioner can be prepared to adapt to the clinical challenges presented. Despite the position and technique to be used, a standard approach should begin with identifying the midline, and palpating the iliac crests. The intercrest line (Fig. 46–6) is classically described as crossing the level of the fourth lumbar vertebra, or the L3-L4 or L4-L5 interspace. The most commonly used and easily mastered technique for needle insertion is the midline approach. After identification of the desired interspace for lumbar puncture, skin wheal is raised over the interspace and appropriate infiltration of local anesthetic is fanned along the midline. It is useful to firmly place 2 fingers of the nondominant hand parallel to the axis, straddling the lateral borders of the interspace (Fig. 46–9). When using small-gauge spinal needles, an introducer needle is first inserted in the sagittal plane between the spinous processes, initially parallel to the plane of the surface of the back. The introducer is then stabilized by grasping the hub with the digits of the nondominant hand as the spinal needle is passed through the bore of the introducer and advanced in the sagittal plane. The path of travel for the needle in the midline approach is through skin, subcutaneous tissue, supraspinous ligament, interspinous ligament, ligamentum flavum, and, finally, through the dura and arachnoid matter into the subarachnoid space. As the needle tip passes beyond the ligamentum flavum and through the dura, a change in resistance, and possibly a “pop,” can be appreciated. At this point, the stylet is withdrawn from the spinal needle, and the hub is inspected for free flow of CSF. If bone is contacted prior to entering the thecal sac, the practitioner should reassess the angle of projection and ensure that it is within the sagittal plane. If no correction toward the midline is needed, the most fruitful adjustment is usually an attempt to gradually “walk” the needle tip in a cephalad direction until the subarachnoid space is encountered. If free flow of CSF is in question, rotating the bevel or side hole of the needle through the four quadrants can help ensure proper placement of the needle opening. Once satisfied with needle placement, the dosing syringe (typically a Luer slip style), which was previously prepared with the intended agent, is firm-

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FIGURE 46–8. Patient positioned in the prone-jackknife position for surgery to be performed under hypobaric spinal anesthesia. Note that the head is below the level of the hips to ensure that the anesthetic “floats” to the caudad portion of the intrathecal space.

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ly attached to the hub of the spinal needle. Aspiration of CSF into the syringe is final confirmation of subarachnoid placement; the agent is slowly injected while keeping the needle tip immobile. Once the injection is complete, the patient should be placed in the intended position to effect the spread of the agent, or into the appropriate position for surgery. The advantages of the midline approach include simplicity and the stability provided by the relatively avascular sagittal plane through the interspinous ligament. The paramedian technique (Fig. 46–10), although routinely used by some, should be mastered to the same level as the midline technique because of its advantages in common clinical situations. When the midline approach is difficult, the paramedian approach may still allow access to the subarach-

noid space when presented with inability to obtain adequate patient positioning (maintained lumbar lordosis), obesity, term pregnancy, heavily calcified interspinous ligament (common in elderly patients), or scoliosis. This advantage is a consequence of the larger interlaminar aperture presented via the path of the paramedian approach, especially when lumbar lordosis is retained. Although variations have been described, in the lumbar region this approach begins with identification of the superior aspect of the caudad spinous process of the interspace to be accessed. The percutaneous entry point is identified 1 cm lateral to this superior tip of the spinous process. After raising a skin wheal and appropriate infiltration with local anesthetic, the introducer and/or spinal needle are advanced through the anesthetized region, directed approximately 10–15°

FIGURE 46–9. Fingers of the nondominant hand are used to identify the lateral borders of the interspace of interest. This aids in developing a three-dimensional mental image of the anatomical structures to facilitate neuraxial access.

toward midline, and at a slightly cephalad angle. This path will traverse skin, subcutaneous tissue, paraspinous muscle, ligamentum flavum, and dura and arachnoid matter to reach the subarachnoid space. If bone is encountered prior to dural puncture, it is most likely the caudad lamina, in which case the needle should be “walked” cephalad, then medial, until the thecal sac is breached. The Taylor approach (Fig. 46–11) is a variation of the paramedian technique; it capitalizes on the breadth of the L5-S1 interspace (typically the largest interspace) and the palpable and relatively constant location of the posterior superior iliac spines (PSISs). Once a PSIS is identified, a skin wheal is raised 1 cm medial and caudad to its inferior border. After appropriate infiltration of local anesthetic, the spinal needle (typically at least 22 gauge) is directed approximately 45° medial and cephalad toward the L5-S1 interspace. Again, if bone is contacted, the correction needed is a greater cephalad angle to “walk off” of the superior aspect of the sacrum.

Accessing the Epidural Space Although the pathway and approach to the epidural space are the same for the subarachnoid space, the technical skills to correctly and reliably access and identify the epidural space require more experience to develop than those for dural puncture.5 Again, both midline and paramedian approaches are used for needle placement and the patient can be placed in either the sitting or lateral position. In contrast to spinal anesthesia, the epidural space theoretically can be accessed at any vertebral level. Because of the differences in the projecting angles of the spinous processes in the lumbar and midthoracic regions, an angle of approach closer to the plane of the surface of the back is used when performing thoracic epidural placement. With the midline approach, the desired interspace is identified by palpation as described above, and a skin wheal is raised with local anesthetic at the site of intended needle entrance, which should be in the sagittal plane at the midpoint between the spinous processes. The needle is inserted through the skin, subcutaneous tissue, and supraspinous ligament, and into the interspinous ligament. With the blunter tip of the larger-gauge needles used for


FIGURE 46–10. In the paramedian approach for lumbar neuraxial access, an entrance site is identified 1 cm lateral and caudad to the superior aspect of the inferior spinous process. After appropriate local anesthetic is infiltrated, the needle is typically inserted to touch down on the lamina, then walked, first medially, then cranially, to step off of the lamina.

epidural anesthesia, passage into the interspinous ligament is typically met with a “crunchy” sensation. Patients who are not sedated might either hear or feel this “crunching,” and should be reassured if report of this is elicited. If in the sagittal plane, further advancement of the needle should place the tip in the ligamentum flavum, which provides increased resistance to the needle. Alternatively, if the paramedian approach is used, as may be preferable in the thoracic region, the interspinous ligament is not encountered. If attempting access in the thoracic region, the appropriate needle entrance site is 1 cm lateral to the inferior aspect of the superior spinous process of the

interspace desired. The needle is advanced through an anesthetized skin wheal, subcutaneous tissues, paraspinous muscle, and to the lamina of the inferior vertebra, providing a reference depth. The needle tip is walked medially until the base of the spinous process is encountered, which will be noted to have a shallower depth. The needle tip is then marched superiorly until it “walks off” of the lamina, and should encounter resistance as it meets the ligamentum flavum. With either approach, correct passage of the needle tip through the ligamentum flavum and into the epidural space without breaching the dura can be accomplished by employing several different methods for iden-

tifying the epidural space. The most commonly used method is the loss of resistance (LOR) technique using saline or air, although saline may be preferred, given the risk of headache if air is unintentionally injected into the subarachnoid space. A low-resistance syringe made of glass or plastic is filled with 1–2 mL of sterile saline, as well as 1 small (0.2-mL) air bubble (Fig. 46–12). This syringe is attached to the epidural needle once the tip has been placed into the ligamentum flavum. The degree of resistance to injection of the saline is assessed by determining if the bubble compresses without allowing injection of fluid. If little resistance is encountered, the needle tip is either not yet reaching the ligamentum flavum, or perhaps has passed through to the epidural space. If uncertain, careful advancement of the needle by a few millimeters could be considered in an attempt to reach the ligament, but one might wish to withdraw and reattempt placement. Once this ligament is identified, the needle is advanced slowly, with constant pressure on the syringe plunger, until the resistance to injection is reduced. A dramatic loss of resistance is reassuring of the passage of the needle tip just beyond the ligamentum flavum and into the epidural space. An alternative technique is the “hanging drop” of Gutierrez. This relies on a negative pressure in the epidural space to aspirate a visible drop of fluid from the hub of the needle into the lumen of the epidural space itself (Fig. 46–13). This negative pressure is encountered just as the tip of the needle enters the epidural space and is much more reliable in the thoracic and cervical regions. One theory of the nature of this negative pressure is that it is created by the tip of the needle tenting the dura, thus increasing risk of dural puncture. This technique is best used in the thoracic region with a sitting patient. It may helpful in the setting of combined spinal–epidural anesthesia because of minimal saline entering the epidural space and less chance of a “false return” being interpreted as CSF.6 Newer techniques for identifying the epidural space are being described. The use of electrical nerve stimulation via a conducting catheter allows for confirmation of placement of the catheter within the epidural space by confirming appropriate stim-

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CLINICAL PHARMACOLOGY Distribution, Uptake, and Elimination

L5

1 cm 1 cm

Sacrum

Posterior superior iliac spine

Skin entrance 986 FIGURE 46–11. The Taylor approach begins with identification of the posterior superior iliac spine (PSIS). The skin entrance site is 1 cm medial and 1 cm caudad to the PSIS. The needle is then directed approximately 45° medial and cephalad to enter the L5-S1 interspace.

ulation threshold.7 Additionally, the myotomal distribution of the stimulation can lend information regarding the spinal level of the catheter tip. Lechner et al.8 describe an apparatus for use in epidural access that produces both audible and visual indication of the pressure encountered at the tip of

Prior to reaching the site of action, anesthetic agents injected into the subarachnoid space undergo dilution within the CSF via mass effect. It has long been postulated that CSF circulation played a role in distribution of anesthetic agents; however, this has not been reliably demonstrated. The uptake of anesthetic agents by the spinal cord and nerve roots depends on the concentration of agent at a given region and lipid content of the tissue. Elimination of local anesthetics from the subarachnoid space and spinal cord is determined by regional blood flow and vascular reabsorption, not metabolism of the anesthetic within the intrathecal space. Drugs administered in the epidural space must diffuse into the CSF and neural tissues to exert conduction blockade. The epidural fat acts as a reservoir for injected agents with great affinity for lipophilic agents. The elimination of drug from the epidural space is largely dependent on regional blood flow.

Factors Affecting Block Height an attached epidural needle. Using this device allows a two-handed advancement of the epidural needle while awaiting the drop in pressure that is characteristic of entering the epidural space. Further testing and study is needed to determine the appropriate usefulness of these new methods.

FIGURE 46–12. Photo depicting a glass loss-of-resistance syringe attached to an epidural needle. The syringe is filled with saline and a small (0.2-mL) bubble of air. The bubble provides visual indication of “compression” resultant of resistance to injection that is characteristic of the ligamentum flavum.

Spinal Anesthesia The ability to affect and predict block height is important for producing reliable and manageable spinal anesthesia. Many parameters have been studied as potential determinants of block height (Table 46–1). The most significant physiologic parameter related to block height is CSF volume. Unfortunately, easily measurable physical features, such as height, weight, gender, and age, do not correlate well with CSF volume.9 However, it has been observed that obese individuals have lower CSF volumes than those who are not obese. Although some studies show a slight influence of age and height on peak block levels,10,11 these are weak correlations with inadequate predictive power to influence clinical practice. Baricity, drug dose (mass), and patient position relative to baricity of the agent are the most important factors influencing block height. Baricity is defined as the ratio of the specific gravity of the local anesthetic solution to the specific gravity of CSF. Solutions with a density greater than 1.0015 g/mL (3 standard deviations above mean patient CSF density) can be expected to behave as a hyperbaric


Drop of saline

A

B

FIGURE 46–13. The “hanging drop” technique is performed by first placing a drop of saline at the “mouth” of the needle hub ( A). The needle is then advanced while monitoring the drop of fluid. The drop is drawn into the needle when the epidural space is entered ( B).

solution (Table 46–2). Hyperbaric solutions are typically prepared by the addition of dextrose to the solution. However, it should be noted that plain 2chloroprocaine behaves in a hyperbaric fashion. Once injected into the subarachnoid space, hyperbaric solutions migrate “downhill” to the dependent

TABLE 46–1. Various Factors Proposed as Determinants of Spinal Block Height Patient characteristics Height Weight Age Gender Intraabdominal pressure Technical variations Patient positioning Site of injections Speed of injections Direction of bevel Barbotage Cerebrospinal fluid characteristics Volume Density Velocity/circulation Characteristics of the local anesthetic solution Baricity Volume of injection Concentration of solution Drug dose (mass) Temperature

portions of the spinal column. Thus, for a patient in the sitting position, the agent sinks to the sacral regions to produce a “saddle block.” In the supine patient, hyperbaric agents injected at or above the apex of the lumbar lordotic curvature will migrate to the thoracic kyphosis, hence the tendency for a peak block of T4–6 in most supine patients. Manipulation of patient position after hyperbaric subarachnoid injection can enhance either migration of the agent to the thoracic region (head down position), or to the sacral region (head up or sitting position). Isobaric solutions have a density that is clinically equivalent to that of CSF. Thus, once injected into the subarachnoid space, the agent neither sinks nor floats. This can be advantageous because patient position does not affect block height. In such a scenario, peak block height is more determined by dose of anesthetic agent (mass effect), but individual CSF density and volume contribute.16 It should be noted that it may be difficult to achieve block heights above the midthoracic region because of the tendency of isobaric solutions to “stay put” in the lumbar region after injection. Hypobaric solutions have a distinct advantage in perianal surgery or other procedures that require a head down or jackknife position, or for lateralized procedures when the patient cannot lie on the operative side. These preparations are formed by diluting anes-

thetic agents in distilled water, achieving a density of less than 0.9990 g/mL. With a patient in the prone position with the head down, an intrathecal

TABLE 46–2. Baricity of Solutions for Spinal Anesthesia Agent Hypobaric Bupivacaine 0.3% in water Tetracaine 0.2% in water Lidocaine 0.5% in water Isobaric Bupivacaine 0.5% in saline Bupivacaine 0.75% in saline Tetracaine 0.5% in saline Lidocaine 2% in saline Hyperbaric Bupivacaine 0.75% in 8.25% dextrose Tetracaine 0.5% in 5% dextrose Lidocaine 5% in 7.5% dextrose Procaine 10% in water 2-Chloroprocaine 2% in saline

Baricity 0.9946 0.9922 0.9985 0.9983 0.9988 0.9997 0.9986 1.0227 1.0133 1.0265 1.0104 1.0012

Data from Horlocker TT and Wedel DJ12; Bodily MN, Carpenter RL, and Owens BD13; Greene NM14; and Na KB and Kopacz DJ.15

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injection is performed, and subsequently the agent “floats” to the sacral region, giving excellent anesthesia to the perineal and perianal region. As mentioned previously, the patient must be recovered in the head-down position for a reasonable amount of time to prevent unintentional rise of the block.

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Other Factors The volume and concentration of isobaric spinal agents have not been shown to affect block height when using a constant dose.17 In contrast, when using hyperbaric preparations, baricity seems to overcome alterations in dose and volume, showing similar block heights with a range of doses if concentration is held constant. This highlights the propensity for hyperbaric preparations to settle to the dependent portions of the spinal canal. Injection site can influence the nature of spinal blockade. If using hyperbaric preparations, injection low in the lumbar region can cause failure to achieve expected block height and cephalad block density as a result of sacral pooling and absence of agent above the lordotic curve. However, if injection is made at or above L2-3, then block height and success is more reliable. For isobaric solutions, block height can be reduced by as much as 2 dermatomes per interspace when comparing administrations at L2-3, L3-4, and L4-5.11 The manner of injection is thought to have influence on block characteristics. Investigations into the effect of barbotage show no impact on peak block height, although it does seem to reduce the time from injection to achievement of peak block height.18

Epidural Anesthesia In contrast to spinal anesthesia, epidural anesthesia produces a segmental block that is related to the site of injection of local anesthetic. Most procedures that are amenable to spinal anesthesia could also be served by epidural anesthesia that produces a similar block height (Table 46–3). Unless a caudal approach is performed, the potential for sacral nerve sparing with epidural blockade (because of increased epidural fat and nerve root size in the low lumbar and sacral regions) may preclude its use in perineal procedures. When planning an epidural anesthetic, the choice of local anesthetic, dose, and injection site must be appropriate for the given procedure and the clinical scenario.

Injection of local anesthetic into the lumbar epidural space is typically suited for lower-extremity and lower-abdominal procedures, but increasing the dose and volume is necessary to get extension to midthoracic levels. In general, one can think of administering 2 mL of local anesthetic solution for each additional dermatome to be blocked. When administering anesthetic to the thoracic region, the dose is typically reduced by 30–50%, compared to the lumbar region, to accommodate the decreased volume and compliance of the thoracic epidural space and to avoid unwanted cephalad spread. Thoracic epidural injections tend to not extend caudally to the degree that is seen with lumbar injections, thus are reserved for procedures in the thorax and upper abdomen. When considering the ranges that are typically used for surgical anesthesia, concentration of the anesthetic solution has little effect on extent of the epidural block, but increased block density is observed with higher concentrations. Increasing the volume of solution injected for a given total dose will have a minor effect on cephalad spread (about 4 dermatomes when increasing from 10–30 mL), but will compromise density and quality of the block. Patient position also has no demonstrable effect on lateralization of the block or cephalad spread, but is often used clinically. The effect of patient age on epidural block height and dose requirement seems to be only clinically relevant in extremes of age, but some studies suggest as much as a 40% reduction in dose requirement when comparing 60–79-year-old patients with 20–39year-old patients.19 This is attributed to the increased likelihood of spinal canal stenosis and decreased epidural compliance in the older population. In similar scale, the influence of height and weight on the spread of epidural block is small,20 and usually not clinically relevant unless considering the extremes of the spectrum. The effect of pregnancy on the spread of epidural blockade is unclear. Some studies suggest that an observed increased cephalad spread of blockade is a result of an effect of altered abdominal anatomy. However, similar increases seen in early pregnancy suggest that this may be an effect of altered sex steroid levels increasing the sensitivity to anesthetic agents.21

TABLE 46–3. Required Block Height for Common Surgical Procedures

Surgical Procedure Upper abdominal surgery Cesarean section Lower abdominal (appendectomy, inguinal herniorrhaphy) Pelvic procedures Transurethral resection of prostate Obstetric vaginal delivery Hip and lower extremity (with thigh tourniquet) Lower extremity Perineal procedures (limited to exterior)

Block Height T4–5 T6–8

T10

L2–3 S1–2

In summary, physical characteristics seem to have little if any clinical effect on epidural block spread for a narrow range of variability. However, clinical judgment may allow for reducing the initial epidural dose for a patient who is very short, very old, and morbidly obese. Conversely, more aggressive dosing can be used for the patient who is very young, tall, and thin. Comorbidities and other challenges may determine the appropriate dose regimen: a failed technique as a result of inadequate block vs. treating the complications resulting from a block that is higher than intended.

CLINICAL ASPECTS OF NEURAXIAL AGENTS Local Anesthetics Local anesthetic agents are discussed in Chap. 44 in detail, but some clinical points relating to neuraxial anesthesia are addressed here. The choice of neuraxial agents is determined by the nature and estimated time of the surgical procedure, as well as postoperative issues such as disposition. Tables 46–4 and 46–5 list representative durations for doses of spinal and epidural agents. For spinal anesthesia, increasing the dose of agent administered prolongs the block, and unless counteracted by positioning and baricity, it may also increase peak block height. Longer-acting local anesthetics, such as bupivacaine, levobupivacaine, tetracaine, and


TABLE 46–4. Typical Dose-Response Effects of Spinal Local Anesthetics

Local Anesthetic Lidocaine

Bupivacainea

Mepivacaine

Ropivacaine

Procaine Prilocaine 2-Chloroprocaineb

Dose (mg)

Peak Block

Duration of Sensory Block (min)

Duration of Motor Block (min)

Time Until Discharge (min)

Anesthetic Success Rate (%)

30 40 60 80 5 7.5 10 15 30 45 60 8 10 12 14 100 50 30 40 60

T4 (T2–10) T3 (T2–10) T3 (T1–7) T5 (T4–7) T8 (T4–11) T8 (T6–10) T5 (T4–7) T9 (T2–L5) T6 (T2–12) T5 (T2–L1) T9 (T4–L1) T8 (T4–L2) T8 (T4–L1) T9 (T3–L1) T5 (T1–10) T6 (T1–10) T8 (T6–L1) T7 (T3–T10) T4 (C6–T6)

130 (26) 162 (32) 170 (24) 123 (27) 144 (25) 194 (26) 343 (28) 158 (32) 182 (38) 203 (36) 130 (27) 152 (44) 176 (42) 192 (48) 120 (23) 128 (38) 103 (12) 114 (14) 132 (23)

93 (24) 128 (31) 142 (32) 50 (20) 75 (24) 100 (24) 150 (24) 116 (38) 142 (37) 168 (36) 107 (25) 135 (31) 162 (37) 189 (44) 100 (30) 165 (37) 54 (23) 69 (16) 100 (13)

173 (34) 216 (33) 236 (46) 181 (30) 202 (28) 260 (30) 471 (35) 180 (34) 191 (29) 233 (52) 165 (45) 174 (38) 199 (52) 233 (52) 244 (43) 253 (55) 103 (12) 113 (14) 141 (21)

0 90 90 97 75 100 100 100 72 100 100 63 83 93 100 83 100 NA NA NA

NA, Clinical data not available. Increasing doses of spinal local anesthetics increase duration of both anesthesia and recovery. Dose-response data allow selection of appropriate dose for planned anesthetic duration. Isobaric solutions are glucose free. Hyperbaric solutions contain glucose or dextrose aLevobupivacaine is equipotent. b2-chloroprocaine spinal anesthesia is currently an off-label use. Data from Liu SS and McDonald SB,22 except data for 2-chloroprocaine is from Kopacz DJ.38

ropivacaine are typically chosen for longer procedures (greater than 120 minutes). Lidocaine, mepivacaine, and prilocaine are considered to be of intermediate duration. Short-acting local anesthetics include procaine and 2chloroprocaine, which are used for appropriately brief procedures.

Long-Duration Agents Bupivacaine and levobupivacaine have the benefit of having very low incidence of transient neurologic symptoms

(TNS) when used for low-dose spinal anesthesia.23 However, the variability in time to complete resolution of the block and achievement of discharge criteria provides a challenge in the ambulatory setting. Bupivacaine and levobupivacaine are employed in epidural anesthesia when a longer block is desired. The use of 0.5% solutions is typical, but the using 0.75% solutions or adding epinephrine may provide increased motor block. Levobupivacaine is approximately equipotent to bupiv-

TABLE 46–5. Duration of Sensory Block for Commonly Used Local Anesthetics for Epidural Anesthesia

Local Anesthetic

Concentration

Time Until 2 Dermatome Regression (min)

2-Chloroprocaine Lidocaine Mepivacaine Bupivacaine Levobupivacaine Ropivacaine

2–3% 1.5–2% 1.5–2 % 0.5–0.7% 0.5–0.75% 0.5–1%

45–60 60–100 60–100 120–240 105–290 90–180

Time Until Complete Regression 100–160 160–200 160–200 300–460 390–780 240–420

acaine with the exception of less systemic toxicity. Ropivacaine was introduced to reduce the risk of cardiotoxicity that is associated with bupivacaine and was released for clinical use in 1996. When used as a spinal agent, ropivacaine has a clinical profile similar to bupivacaine at equipotent doses (ropivacaine is 60% as potent as bupivacaine) with little risk of TNS.24 Ropivacaine is used in concentrations of 0.5–1% for epidural anesthesia, providing blockade of somewhat shorter duration than bupivacaine. There is some evidence that ropivacaine may have less motor block when compared to bupivacaine when used for labor analgesia.25 Although tetracaine is used less commonly at this time, it remains the agent that provides the most reliable hypobaric spinal block (tetracaine 2% in water). It should be noted that the use of vasoconstrictors might increase the risk of TNS with tetracaine.26

Intermediate-Duration Agents Lidocaine has enjoyed widespread popularity and safety as a neuraxial agent, but it has undergone increasing scruti-

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ny regarding neurotoxicity given the high incidence of TNS seen when used for ambulatory spinal anesthesia (see Neurologic Complications below). To avoid this issue, lower doses of lidocaine have been investigated, usually requiring adjuvant agents to provide suitable reliability of spinal blockade. Lidocaine is used in concentrations of 1.5% and 2% for epidural anesthesia to provide reliable blockade for procedures lasting less than 120 minutes. However, continuous catheter techniques commonly employ lidocaine, with reinjection typically required every 60–90 minutes. Mepivacaine has a clinical profile similar to that of lidocaine when used as a neuraxial agent, although it has higher potency (1.3:1 compared with spinal lidocaine).27 It also seems to have similar concerns regarding the high incidence of TNS when used for outpatient spinal anesthesia, depending on concentration of agent.28 It is used in concentrations of 1–2% for epidural anesthesia, again with similar performance to lidocaine. Prilocaine is an amide local anesthetic with pharmacologic properties similar to those of lidocaine when used as a spinal anesthetic.29 However, it shows a much lower incidence of TNS compared to spinal lidocaine, and thus may be a favorable agent for ambulatory spinal anesthesia. Currently, prilocaine is not available in the United States, but it is used commonly in Europe.

Short-Duration Agents Having a place in history as the first synthesized local anesthetic, procaine has been used for spinal anesthesia since the early 1900s. Procaine provides brief spinal anesthesia, but has limited clinical usefulness given the rate of block failure (see Table 46–4) and the incidence of side effects. For reasons that are poorly understood, spinal procaine carries a higher risk of nausea than do other local anesthetics (odds ratio [OR] 3:1).30 Although it has a lower incidence of TNS than spinal lidocaine (Table 46–6), spinal procaine is clearly not enticing when seeking a suitable agent for outpatient spinal anesthesia. 2-Chloroprocaine has received increased attention in regards to the current issues of ambulatory anesthesia and concerns of relative neurotoxicities of neuraxial agents. One year after its

TABLE 46–6. Typical Incidences of Transient Neurologic Symptoms (TNS) with Outpatient Spinal Anesthesia Local Anesthetic

Patient Position

TNS (%)

Lidocaine 2–5% Lidocaine 3% Lidocaine 0.5% Lidocaine 5% Lidocaine 5% Bupivacaine (0.25–0.75%)

Supine Prone Knee arthroscopy Knee arthroscopy Lithotomy Supine Knee arthroscopy Lithotomy Knee arthroscopy/mixed Mixed Supine Knee arthroscopy Knee arthroscopy Mixed

6 0.4 17 16 24 0–1 0–1 0–1 6–8 30 1 0 6 3–4

Mepivacaine 1.5% Mepivacaine 4% Ropivacaine 0.25% Ropivacaine 0.2–0.35% Procaine 5% Prilocaine (2–5%)

Bupivacaine and ropivacaine consistently result in low incidences of TNS, whereas lidocaine typically results in the highest incidences. Other local anesthetics are intermediate in incidence of TNS. Data from Liu SS and McDonald SB,22 and YaDean JT, Liguori GA, and Zayas VM.28

introduction into clinical use, in 1952, Foldes and McNall described successful use of a preservative-free preparation of 2-chloroprocaine for spinal anesthesia in 214 patients. Subsequently, 2-chloroprocaine enjoyed increasing popularity as an agent for epidural anesthesia, particularly in the obstetric population. Unfortunately, reports of accidental intrathecal injection of large volumes of Nesacaine-CE intended for the epidural space, resulting in several cases of neurotoxicity with lower-extremity paralysis and sacral nerve dysfunction, came to attention in the 1980s. The combination of the antioxidant sodium bisulfite in the presence of low pH was assumed to be responsible for the neurotoxicity,31,32 and the formulation of 2-chloroprocaine was changed. Currently, two of the three commercially available formulations of 2-chloroprocaine (Nesacaine-MPF, Astra Pharmaceuticals, Wilmington, DE, and generic chloroprocaine, Bedford Pharmaceuticals, Bedford, OH) are preservative free and antioxidant free. Given the availability of these new preparations and growing concerns about the TNS associated with lidocaine, 2-chloroprocaine has been reinvestigated for off-label use as a shortacting spinal anesthetic. Work by Kopacz et al. shows 2-chloroprocaine to provide a reliable spinal anesthesia with consistent time to resolution and achievement of discharge criteria without identifiable occurrence of TNS.33–38

It should be noted that 2% 2-chloroprocaine behaves in a hyperbaric fashion,36 and that the addition of epinephrine to spinal 2-chloroprocaine is not recommended because of consistent and disturbing reports of flu-like symptoms in volunteers receiving this combination.33 One should also bear in mind that a recent laboratory study observed direct neurotoxicity from high doses of preservative-free 2-chloroprocaine in a rat model that was equivalent to 2% lidocaine.39 Thus, the complete risk-to-benefit ratio of offlabel use of spinal 2-chloroprocaine is not completely known. The use of 2% and 3% 2-chloroprocaine is an appropriate choice for epidural anesthesia of short duration. Following the release of Nesacaine-MPF containing ethylenediaminetetraacetic acid (EDTA), reports of back pain upon block resolution were associated with high volumes of injected agent (greater than 40 mL).40 This is thought to be caused by tetanic spasm of the paraspinous muscles resulting from chelation of calcium by the EDTA. Given the above concerns, it may be prudent to use only 2-chloroprocaine preparations that are preservative and antioxidant free for neuraxial blockade.

Analgesic Adjuncts Initial interest in adjuvant medications for neuraxial anesthesia centered around increasing the duration and in-


TABLE 46–7. Analgesic Adjuvants for Neuraxial Anesthesia Agent

Dose

Typical Anesthetic Effect

Comments

Clinically Useful Fentanyl

Spinal: 10–25 μg

25% increase in duration of surgical anesthesia 33% increase in anesthetic success with small doses of local anesthetic 60% incidence of easily treated pruritus 2-fold reduction in volatile anesthetic requirements Decreased visceral pain with cesarean section 29% increase in duration of motor block 37% increase in anesthetic success with small doses of local anesthetic Mild perioperative sedation and decrease in heart rate and blood pressure 2–3-fold increase in duration of sensory anesthesia Increased time to first analgesic request Dose-related increase in surgical anesthesia and motor block Increased duration, intensity of block with lidocaine and 2-chloroprocaine Minimal effect with ropivacaine

No delay of anesthetic recovery

Dose-related increase in surgical anesthesia and motor block Dose dependent analgesic effect Increased time to first analgesic request

Dose-related increase in time until recovery of the same or greater magnitude Reports of sedation with higher doses

Epidural: 1–2 μg/kg

Clonidine

Spinal: 15–45 μg

Epidural: 150 μg

Epinephrine

Spinal: 0.1–0.6 mg Epidural: 5 μg/mL

Investigated Neostigmine

Spinal: 6.25–50μg Epidural: 1–4 μg/kg

Bolus administration may act at spinal level, infusions act systemically

No delay of anesthetic recovery

Less oxygen desaturation, pruritus, and urinary retention compared to opioids Dose-related increase in time until recovery of the same or greater magnitude Decreased plasma levels with lidocaine and bupivacaine, but not ropivacaine

Utility and safety of other agents (ketamine, ketorolac, midazolam) not fully determined. Date from references 41, 43–46, 48, 56–57, 60, 62, 65–72, 86, 89, and 94.

tensity of blockade. As the percentage of operations performed in the ambulatory setting increases, interest is shifting to finding adjuncts that will provide faster recovery without compromising anesthetic reliability (Table 46–7).

Opioids The potent analgesic effects of neuraxial opioids have been exploited to improve perioperative analgesia and reduce the supraspinal side effects of sedation and respiratory depression seen with systemic opioids. Neuraxial opioids that diffuse into the spinal cord exert spinal analgesia by modulating A-δ and C-fibers to decrease afferent nociceptive input,41 inhibiting Ca2+ influx presynaptically, and increasing K+ conductance and hyperpolarize ascending neurons postsynaptically.42 Owing to its hydrophilic nature, neuraxial morphine provides highly selective, prolonged spinal analgesia,

but is not typically used to augment intraoperative anesthesia because of slow onset. The lipophilic opioids, such as fentanyl, are more suited for intraoperative use in the intrathecal space because of rapid onset, modest duration, and lower risk of delayed respiratory depression. The addition of 10–25 μg fentanyl to low-dose lidocaine and bupivacaine spinal anesthetics dramatically improves anesthetic success without delaying achievement of discharge criteria for ambulatory patients.43,44 However, when used with the ultrashort-acting spinal anesthetic 2-chloroprocaine, fentanyl can slightly delay discharge (95 vs. 104 minutes) and increase pruritus.35 The administration of epidural fentanyl can reduce volatile requirements more than intravenous fentanyl (more than 2-fold at 2 μg/kg).45 The method of delivery of epidural fentanyl may be important for optimal effect. Gino-

saur et al.46 showed that when epidural fentanyl is given as a bolus, it imparts segmental analgesia consistent with spinal level of action, but if given as an infusion, the analgesia is mediated through systemic uptake and supraspinal effect, as is seen with sufentanil and alfentanil.47

α2-Agonists

Interest in α2-agonists, such as clonidine, has been rising in the field of regional anesthesia given their ability to enhance neuraxial analgesia without the respiratory depression and pruritus common to opioids. As with analgesia, the sedation, hypotension, and bradycardia seen with neuraxial clonidine are dose dependent.48 Additionally, less urinary retention is seen with intrathecal clonidine than with intrathecal morphine.49 Clonidine exerts its analgesic effects by binding to α2-adrenoreceptors (on primary afferent, substantia

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gelatinosa, and several brainstem nuclei attributed to analgesic mechanisms), attenuating A-δ and C-fiber nociception, producing conduction blockade via increased potassium conductance,50,51 as well as increasing acetylcholine and norepinephrine in the CSF, inhibiting the release of substance P.51 Although clonidine rapidly redistributes systemically to the periphery after epidural or spinal administration as a consequence of lipophilicity, the analgesic effect is spinally mediated as evidenced by the lack of correlation between time of analgesia and peripheral blood levels. Through extensive testing for neurotoxicity and safety in several animal models, neuraxial clonidine shows no histopathologic or behavioral evidence of detriment. Although previously investigated as a sole anesthetic,52 the majority of the clinical use of intrathecal clonidine is in combination with a variety of local anesthetics to produce dose-dependent prolongation of both sensory and motor block.53–56 Showing a promising role in ambulatory anesthesia, De Kock et al.57 demonstrated that the addition of as little as 15 μg of clonidine to ropivacaine 8 mg for spinal anesthesia in outpatients undergoing knee arthroscopy produced a considerable increase in anesthetic success (from 70–90%) without significant effect on recovery time. However, increasing the dose to 45 μg increased resolution of motor and sensory block and time to void from 170 to 215 minutes. Adding clonidine to local anesthetics intensifies and prolongs epidural blockade and can reduce local anesthetic dose requirement.58,59 The typical dose of clonidine for addition to local anesthetics for epidural bolus administration is 150 μg, or 2 μg/kg.60–62 Klimscha et al. demonstrated that the addition of 150 μg of clonidine to 10 mL of 0.5% bupivacaine for epidural anesthesia increased the mean duration of anesthesia from 1.8 to 5.3 hours, reduced pain scores, and increased time to first postoperative analgesic request.61 These benefits of clinical doses of neuraxial clonidine typically persist for around 3 hours and can be achieved without increasing hemodynamic instability more than local anesthetic alone or significantly altering responsiveness to resuscitation drugs.62–65

Vasoconstrictors Vasoconstricting agents, namely epinephrine and phenylephrine, are com-

monly added to local anesthetic solutions and have a long history of clinical use with the intention to prolong the anesthetic effect, provide more reliable block, and intensify anesthesia and analgesia.66–69 Vasoconstriction, and thus decreased blood flow, can reduce uptake of local anesthetics into the circulation, thus maintaining concentrations at the site of injection and reducing peak plasma concentrations. Additionally, intrinsic analgesic effects of epinephrine are exerted via stimulation of presynaptic α2 adrenoreceptors found at the terminals of primary afferents. These receptors are also found centrally on neurons in the superficial laminae of the spinal cord and several brainstem nuclei that participate in analgesic mechanisms. For spinal anesthesia, epinephrine is commonly employed in a typical dose of 0.2 mg (although doses of 0.1–0.6 mg have been described), which when added to a bupivacaine spinal anesthetic, increases time of regression to L2 by 25%.70,71 The addition of epinephrine to spinal anesthetics prolongs motor block and delays the return of bladder function, which is problematic for ambulatory surgery patients trying to achieve discharge criteria. Chiu et al.,72 using volunteers, showed that adding 0.2 mg epinephrine to 50 mg hyperbaric lidocaine prolonged surgical anesthesia (as demonstrated by tolerance of transcutaneous electrical stimulation) by 30 minutes, whereas time to void and discharge time were increased by 80 minutes. As for concerns of safety, intrathecal epinephrine by itself, in clinically relevant doses, shows no neurotoxicity in humans. Spinal cord blood flow is well maintained in the dog and cat model in doses up to 0.5 mg.73 However, it is suggested that epinephrine may contribute to the neurotoxicity of local anesthetics. Additionally, epinephrine is associated with a case report of cauda equina syndrome after singleshot lidocaine spinal anesthesia.74 Smith and Kopacz reported consistent flu-like symptoms when epinephrine was added to spinal 2-chloroprocaine in a volunteer study.33 Phenylephrine may increase the risk of TNS as suggested by Sakura et al. in a study of tetracaine spinal anesthesia.26 With epidural anesthesia, the typical use of epinephrine is in concentrations of 1:200,000, or 5 μg/mL. The clinical effect of epinephrine on duration of

anesthesia depends on the local anesthetic used. Epinephrine is more effective at prolonging the anesthetic duration of shorter-acting agents, such as lidocaine and 2-chloroprocaine. Adding 1:200,000 epinephrine to 2% lidocaine will nearly double the time to resolution of blockade.75 Agents with longer duration of action show much less prolongation of anesthesia with the addition of epinephrine. Adding epinephrine to ropivacaine will intensify the block, but will not prolong the duration of epidural anesthesia or affect plasma levels.67 This is likely a result of the inherent vasoconstricting effects of ropivacaine. Other agents do show reduction of plasma levels when epinephrine is added.66,68 Epinephrine 1:200,000 will decrease plasma lidocaine and chloroprocaine levels by 20– 30%, but will decrease plasma bupivacaine levels only by 10–20%. The effect of epinephrine on plasma levels of local anesthetics has long been thought to be caused by constriction of the epidural venous plexus, reducing blood flow and slower uptake of local anesthetics. More recent evidence implies that reduced dural blood flow and increased hepatic clearance may be more important in this phenomenon.76 Its potential to prolong discharge times and delay bladder function limits the usefulness of adding epinephrine to epidural agents for ambulatory surgery. The premixed solutions of local anesthetics with epinephrine that are commercially available are prepared more acidic in efforts to preserve the potency of the epinephrine. Because this lower pH slows the onset of block and inhibits the vasoconstricting actions of epinephrine, adding “fresh” epinephrine to local anesthetic solutions at the time of use is preferred. When phenylephrine is added to epidural solutions, the systemic absorption results in increased vascular resistance without the benefit of increased contractility or chronotropy seen with epinephrine. Minding this, phenylephrine is typically only used in the subarachnoid space.

Neostigmine The acetylcholinesterase inhibitor neostigmine has been investigated as a neuraxial analgesic adjunct because of its ability to provide analgesia without hemodynamic depression. Unfortunately, its tendency to induce nausea and delay recovery from neuraxial


blockade limits clinical use. Intrathecal neostigmine inhibits the breakdown of acetylcholine in the spinal cord via reversible inhibition of acetylcholinesterase. Animal models suggest that acetylcholine plays a role in spinal analgesia through stimulation of cholinergic receptors in the substantia gelatinosa and superficial laminae of the dorsal horn of the spinal cord,77–79 and perhaps through stimulating nitric oxide production in the spinal cord.80 Whereas intrathecal injection of cholinergic agonists stimulates all receptors of a particular class, neostigmine increases endogenous acetylcholine in a manner dependent on the tonic production of this neurotransmitter within each particular region of the spinal cord. Hood et al.81 evaluated safety, analgesic efficacy, and side effects of intrathecal neostigmine in volunteers. All doses produced analgesia without sedation, pruritus, respiratory depression, hypotension, or bradycardia; however, there was dose-related motor weakness, decreases in deep tendon reflexes, urinary incontinence, and nausea and vomiting. Further studies in patients revealed similar responses of nausea and vomiting that proved to be prolonged and difficult to treat.82–86 Liu et al.86 showed that when added to low-dose (7.5 mg) bupivacaine spinal anesthetics, 50 μg of neostigmine enhanced motor and sensory block, but delayed achievement of discharge criteria. Doses of 6.25 and 12.5 μg did not prolong anesthesia but still elicited nausea and delayed discharge. Intrathecal neostigmine does counteract hypotension resulting from bupivacaine spinal anesthesia in rats,87 but these effects are not reproducible in human subjects.88 Low and moderate doses of neostigmine are considered to have little or no cardiovascular effects. Lauretti et al.89 studied the analgesic effect of epidural neostigmine, in doses from 1 to 4 μg/kg added to epidural lidocaine, and showed a doseindependent analgesic effect, increasing time to first analgesic request from 3.5 to 8 hours. Other studies report similar results with doses in the range of 1–10 μg/kg, without reporting increased nausea,90–95 but reporting some suggestion of sedation.94

Ketamine Ketamine is a noncompetitive antagonist of N-methyl-D-aspartate (NMDA) receptors, but also has actions at

monoaminergic receptors, opioid receptors, voltage-sensitive calcium channels, muscarinic receptors, and local anesthetic actions through sodium channel blockade.96 Commercially available as a racemic mixture, the S enantiomer is far more potent at NMDA receptors.97 Though not approved for neuraxial use, animal models suggest that preservative-free ketamine lacks neurotoxicity.98 Ketamine was first used intrathecally as a sole anesthetic by Bion in 1984.99 Hawksworth et al. reported an intolerable rate of anesthetic failure and psychometric side effects at doses of 0.7–0.95 mg/kg.100 Other investigators found similar problems when combining ketamine with bupivacaine for spinal anesthesia.101 Epidural administration of ketamine at 0.5–1 mg/kg does reduce intraoperative102–104 and postoperative102–105 analgesic requirements without increased side effects. Ozyalcin et al. demonstrated decreased pinprick hyperalgesia and touch allodynia in thoracotomy patients receiving epidural versus intramuscular ketamine.104 Further work continues to delineate potential applications for chronic neuropathic pain, preemptive analgesia, and modulation of opioid tolerance.

Ketorolac Ketorolac tromethamine is a nonselective, but cyclooxygenase (COX)-1 preferring, nonsteroidal antiinflammatory drug that has received interest given demonstrated involvement of spinal COX enzymes in postoperative hypersensitivity and pain.106,107 There is evidence that ketorolac may enhance analgesic effects of intrathecal clonidine108 and have analgesic synergy with intrathecal morphine109 in rat models. A phase I safety study of preservative-free ketorolac in healthy volunteers using single bolus doses of 0.5–2 mg showed no immediate or delayed neurologic detriment.110 This study revealed no significant effect on blood pressure or motor function, but also showed no decrease in pain with heat stimuli. Further human investigations are underway with the hope of identifying the clinical role of intrathecal ketorolac.

Alkalinization and Carbonation Alkalinizing local anesthetic solutions to raise the pH closer to the pKa of the local anesthetic, thereby increasing the proportion of the nonionized form available to cross cell membranes, is

thought to speed the onset of epidural anesthesia. Although this is well demonstrated with peripheral nerves in vitro,111 studies attempting to demonstrate this clinically in epidural anesthetics are sometimes conflicting. Most studies show that alkalinization speeds onset of epidural blockade with lidocaine,112–117 bupivacaine,112,118,119 mepivacaine112,120,121 and chloroprocaine122,123 by up to 10 minutes. Ropivacaine seems to not show faster onset with alkalinization,124 but as with the other drugs, there is evidence that alkalinization can intensify epidural anesthesia and improve spread to sacral dermatomes.113,116,117,125 One trend that is noted is that the effects of alkalinization are greatest on solutions containing epinephrine, whether freshly added or prepackaged. This is perhaps a result of pH-dependent vasoconstrictive actions of epinephrine. Alternatively, this may be attributed to the fact that commercially available epinephrine-containing solutions are prepared at lower pH (usually with bisulfite), ranging from 3.2 to 4.2, in efforts to preserve the epinephrine. Typically recommended volumes of 8.4% sodium bicarbonate to be added to local anesthetic solutions are 1 mL per each 10 mL of lidocaine or mepivacaine, 0.1 mL per 10 mL of bupivacaine, and 0.3 mL per 10 mL of 2-chloroprocaine. Because of the tendency to precipitate, it is not recommended to add sodium bicarbonate to ropivacaine solutions. It should be noted that the degree of alkalinization is limited by precipitation and all preparations should be inspected for precipitation before administration. Alternatively, the carbonate salts of local anesthetics have a more rapid onset of epidural blockade than standard hydrochloride preparations.126 However, carbonated drugs are of limited availability and may be more prone to induce hypotension with epidural administration.127

PHYSIOLOGY OF NEURAXIAL ANESTHESIA Neurophysiology Neural blockade by local anesthetics is discussed in Chap. 44, thus this section highlights some of the clinical aspects specific to neuraxial blockade. After intrathecal injection of local anesthetics, drug is found in the spinal cord as

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well as in the spinal nerve rootlets within the CSF. After epidural injection, local anesthetic is found in spinal nerves in the epidural space, spinal nerve rootlets within the CSF, and within the spinal cord. Consequently, conduction blockade may take place at multiple sites along the neural pathway for both spinal and epidural anesthesia, and the exact mechanisms are unknown.128 Previous studies do provide some insight into primary sites of action. After spinal anesthesia, somatosensory evoked potentials from the tibial nerve (peripheral nervous system) are abolished, whereas direct spinal cord stimulation remains unchanged.129,130 These findings lend support to the theory that the spinal nerve rootlets are the primary site of action of spinal anesthesia and not the spinal cord. Animal studies suggest that the mechanism of action of epidural anesthesia is similar to spinal anesthesia. Measurement of evoked potentials in monkeys again indicates that the primary site of action of epidural anesthesia is the spinal nerve rootlets.131 Interestingly, epidural anesthesia does not produce complete conduction block, as measurement of somatosensory evoked potentials from the tibial nerve are only modestly changed following induction of epidural anesthesia. Furthermore, magnitude of change in somatosensory evoked potentials does not correlate with intensity of epidural block.132 This finding is similar to peripheral nerve block, and investigators suggest that anesthesia occurs from loss of information coding inherent in the oscillations of the action potential instead of from complete loss of conduction. Finally, the ability of spinal but not epidural anesthesia to completely suppress somatosensory evoked potentials from the tibial nerve offers objective support for the clinical impression that spinal anesthesia is more intense and complete than epidural anesthesia. In addition to direct conduction blockade within the CNS, spinal and epidural anesthesia produce sedation that is unrelated to systemic levels of agent, but which correlates with block height.133 Animal studies using electroencephalogram (EEG) monitoring and direct brain stimulation during spinal anesthesia suggest this is the result of a decrease in reticular activating system activity from decreased tonic afferent input from the anesthetized region.134

One may note decreased requirements for supplemental sedation during high spinal blockade from this direct sedative effect. Previous clinical studies examining use of propofol and midazolam suggest that spinal anesthesia per se decreases sedative requirements by approximately 30–50% with clinically relevant spinal block heights.135,136 This direct sedative effect of epidural anesthesia also becomes clinically relevant when a combined epidural-general anesthesia technique is performed. The use of epidural anesthesia or analgesia reduces volatile anesthetic requirements by 20–30% during surgery when general anesthesia is titrated to either hemodynamics or bispectral index monitoring.137,138

Respiratory Physiology With spinal or epidural blockade to midthoracic levels, pulmonary function, gas exchange, and control of breathing are generally preserved in patients without preexisting respiratory disease.139 Many patients will report a subjective sensation of dyspnea as a consequence of reduced sensation of expansion of the chest wall with inspiration. However, resting tidal volumes, respiratory rate, minute ventilation, and lung volumes are maintained in healthy patients.140,141 Preservation of gross pulmonary function—even with relatively high thoracic level blocks—is explained by the fact that the diaphragm is the primary muscle of ventilation and is innervated by the cervical plexus (C3-5). In contrast, accessory respiratory muscles (abdominal, intercostal) do play a role in active expiratory function and small block-height-dependent decreases in peak expiratory flow can be observed (11% reduction at T8 vs. 17% reduction at T4).142 Active expiratory function plays a role in ability to cough, thus spinal anesthesia may impair ability to clear secretions.139 Overall, healthy patients easily tolerate these mild changes, but patients with severe pulmonary disease may not. However, previous studies indicate that patients with chronic lung disease do not suffer from significant reductions in vital capacity or forced expiratory volume at 1 second (FEV1) during spinal anesthesia.139 Control of breathing during spinal anesthesia is not altered significantly although earlier studies demonstrated a small decrease in resting end-tidal PCO2.143 While hyperventilation as a

consequence of anxiety may cause lowering of the PCO2, the hypocapnia is speculated to result from a lack of proprioceptive input from the abdomen and chest wall during spinal anesthesia, resulting in an increased drive to breathe.143 It has been reported that spinal anesthesia with bupivacaine in unpremedicated patients increased ventilatory responsiveness to CO2.144 The rare respiratory arrest after spinal anesthesia is thought to result from brainstem hypoperfusion secondary to decreased cardiac output rather than the direct effects of local anesthetics on the brainstem, as the concentration of local anesthetic in the ventricular fluid is not high enough to result in medullary depression. Preoperative discussions usually impart tolerance of the subjective dyspnea, but at times judicious sedation can be used to quell anxieties. It should be noted that sedative medications used to facilitate neuraxial blockade are more likely to impact the patient’s respiratory status than the blockade itself.140 This is likely a result of both reduction in respiratory drive and initiation of paradoxical respiration from upper airway obstruction.

Cardiovascular Physiology The perturbations of cardiovascular function during neuraxial anesthesia are perhaps the most critical factors to consider in evaluating the risk to patients and in preventing adverse outcomes. In the nonobstetrical population, the incidences of hypotension and bradycardia after spinal anesthesia are approximately 33% and 13%, respectively.22,127 Large epidemiology studies from France, Scandinavia, and the United States indicate that the risk of cardiac arrest after spinal anesthesia is approximately 0.1–1:1,000 and 1: 10,000 after epidural anesthesia.145 Although cardiac arrest after spinal anesthesia appears to be distressingly common, a recent study suggests that survival is better for cardiac arrest during neuraxial block than during general anesthesia (65% vs. 31%).146 This may be a result of enhanced vigilance, as several risk factors for bradycardia and hypotension have been identified for spinal anesthesia (Table 46–8). Risk factors for epidural anesthesia are probably similar but have not been fully identified because of the decreased frequency of occurrences. An appreciation for the mech-


TABLE 46–8. Risk Factors for Moderate Bradycardia (Pulse 60 years General anesthesia Spinal anesthesia

Hemodynamic Criteria for Intravascular Injection of 15 μg of Epinephrine HR increase >20 bpm SBP increase >15 mm Hg T-wave amplitude decreased by ≥25% on ECG HR unreliable SBP increase >15 mm Hg HR increase >9 bpm SBP increase >15 mm Hg HR increase >8 bpm SBP increase >13 mm Hg HR increase >20 bpm SBP unreliable

HR, heart rate; SBP, systolic blood pressure. All responses occur within 2 minutes of injection.

dose prior to initiating full epidural anesthesia.208 This test dose is meant to detect unintentional placement of the needle or catheter into either the subarachnoid or intravascular space. A 3-mL volume of local anesthetic is the primary component of a test dose. Theoretically, subarachnoid injection of this local anesthetic will produce a much more rapid and profound sensory and motor block than epidural injection. However, changes can be subtle and will require time to develop. Previous reports indicate that 2–4 minutes are required prior to development of sensory or motor block after subarachnoid injection of 3 mL of 1.5% lidocaine.208,209 Subarachnoid injection of a bupivacaine test dose (3 mL 0.25– 0.5%) produces spinal blocks with highly variable onset time and spread and is probably not a reliable indicator.208 Use of a test dose to detect subarachnoid placement is not without risk, as previous publications have reported high spinal anesthesia requiring tracheal intubation after 3 mL of 1.5% lidocaine or 0.5% bupivacaine.208 The local anesthetic component can also be used to detect intravascular injection by assessing symptoms of CNS irritability such as tinnitus, perioral tingling, metallic taste, and dizziness. Detection ability is limited as the standard 3-mL test dose (45 mg lidocaine or 15 mg bupivacaine) contains insufficient local anesthetic to reliably produce such symptoms. Previous studies suggest that larger doses, such as 100 mg or 1 mg/kg of lidocaine or

>25 mg of bupivacaine, levobupivacaine, or ropivacaine, are required in the unsedated patient.208,210 Administration of even modest doses of sedation further reduces the ability of patients to report these symptoms (40% reduction in sensitivity).211 Epinephrine is commonly added to the local anesthetic dose to increase sensitivity for detection of intravascular injection. Addition of 15 μg is the standard dose of epinephrine; it will consistently produce increases in heart rate and systolic blood pressure and reduction in T-wave amplitude within 60–120 seconds in healthy patients (Table 46–9).208,212 Use of βblockers, advanced age, and addition of general or spinal anesthesia all decrease the hemodynamic response to this dose of epinephrine and reduced criteria should be applied in these circumstances.208,213,214 Intravascular injection of epinephrine may be of concern in patients with hypertension, patients at risk for myocardial ischemia, and in obstetrical patients, and potential risks should be considered in these patients. The best method for avoiding systemic toxicity from local anesthetics is through prevention. Toxic systemic levels can occur by unintentional intravenous or intraarterial injection, or by systemic absorption of excessive doses placed in the correct area. Unintentional intravascular and intraarterial injections can be minimized by frequent syringe aspiration for blood, use of a test dose of local anesthetic (see

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above), and either slow injection or fractionation of the rest of the dose of local anesthetic.215 Detailed knowledge of local anesthetic pharmacokinetics will also aid in reducing the administration of excessive doses of local anesthetics. Ideally, heart rate, blood pressure, and the electrocardiogram should be monitored during administration of local anesthetics. Pretreatment with a benzodiazepine might also lower the probability of seizure by raising the seizure threshold.

CONTINUOUS SPINAL ANESTHESIA

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Because of the density and reliability of spinal anesthetic blockade, attempts to extend the duration and graduate the dosing of agents led to techniques for continuous spinal anesthesia (CSA). Almost a century ago, malleable spinal needles were left within the subarachnoid space to allow redosing during prolonged procedures, and, later, Tuohy placed catheters in the intrathecal space. The development of microcatheters (29–32 gauge) in the 1980s led to a revisiting of this technique with hopes of titrating and prolonging spinal blockade with reduced incidence of PDPH as compared to Tuohy’s 15-gauge catheters. Unfortunately, beyond the problems of breakage and knotting, these catheters are associated with several reports of cauda equina syndrome, usually with 5% hyperbaric lidocaine used as the agent. The hypothesis is that the small-bore catheters led to a “sacral pooling” of the hyperbaric agents, limiting spread and dilution of the drug in the CSF, unmasking the neurotoxic potential of lidocaine at such a concentration. The FDA subsequently removed these microcatheters from the market, as did the Canadian authorities. Although some practitioners still employ continuous spinal anesthesia using larger-gauge catheters, the risks and benefits must be weighed carefully for the given situation. If CSA is to be undertaken, precautions should be taken to not advance the catheter beyond 3 cm within the intrathecal space, avoid dextrosecontaining preparations, give adequate time for spread and distribution of the agent prior to additional dosing, and be prepared to abandon the technique if sacral pooling is suspected.

COMBINED SPINAL–EPIDURAL ANESTHESIA Combined spinal–epidural anesthesia (CSEA) is an increasingly popular technique, with an estimated 10-fold increase in use in the past decade.216 Its advantages include rapid onset, dense neuraxial block, ability to titrate spread and duration of block, and lower total drug dosage when compared to epidural anesthesia. Potential disadvantages include increased time to perform the dual technique, intrathecal migration of epidural drug and/ or catheter, effects of increased epidural pressure from injection of solutions on spinal block, and decreased ability and reliability of epidural test dosing. Although a seemingly simple combination of two routine techniques for neuraxial anesthesia, the interactions between the two can be subtle, can impact clinical management, and have not been fully determined.

Patient Selection and Clinical Applications Obstetrics CSEA has been most widely accepted in the obstetric population. The concept of the “walking epidural” has become popular among patients, where intrathecal opioid allows rapid onset of analgesia without motor blockade. Lipid-soluble opioids, such as fentanyl (up to 25 μg) and sufentanil (up to 10 μg), are commonly used to provide dose-dependent analgesia for 60–90 minutes.217 Opioids are also commonly combined with small doses of local anesthetics, such as bupivacaine, to either prolong this initial spinal analgesia or to reduce side effects by decreasing the required dose of opioids. Previous dose response studies indicate that 2.5 mg of bupivacaine combined with either 15 μg of fentanyl or 2.5 μg of sufentanil provides satisfactory analgesia while reducing incidences of nausea and pruritus, when compared to larger doses of opioid.218,219 Recent comparisons suggest that the newer local anesthetics ropivacaine and levobupivacaine are approximately equipotent for CSEA for labor analgesia and essentially interchangeable with bupivacaine for labor analgesia.220,221 Preservation of motor function is an important goal after CSEA for labor analgesia, and sophisticated testing of positional sense and motor

function after CSEA indicates little effect from the initial spinal dose (2.5 mg bupivacaine + 5 μg fentanyl).222 However, subsequent injection of a standard test dose (45 mg lidocaine + 15 μg epinephrine) to confirm epidural catheter placement or the initiation of continuous epidural analgesia appears to degrade motor function and positional sense.222,223 Addition of other less commonly used adjuncts to standard doses of opioids can also increase duration of analgesia. For example, addition of 200 μg of epinephrine or 50 μg of clonidine to opioid is equivalent to adding 2.5 mg of bupivacaine and can provide an additional 30 minutes of analgesia.217 Despite the apparent preservation of motor function, large clinical trials have not observed a decrease in incidence of cesarean section when CSEA is compared to conventional epidural analgesia, although the incidence is similar to systemic analgesia.224–226 As an anesthetic for cesarean section, CSEA offers a rapid, titratable block, good muscle relaxation, and the ability to use reduced doses of local anesthetic. Several clinical trials have compared CSEA to epidural anesthesia with lidocaine or bupivacaine combined with fentanyl. These studies report more rapid onset, better motor block, decreased anxiety levels, decreased shivering, and greater patient satisfaction with CSEA.227,228 Incidences of side effects were similar in that the severity of hypotension did not differ, nor did the incidence of postdural puncture headaches, backaches, nausea, or vomiting.227,228 When compared to conventional single-shot spinal anesthesia, use of CSEA offers the potential advantage of using a smaller initial dose of spinal anesthetic with the epidural catheter available, should the block be insufficient. Such an approach theoretically offers the advantage of greater individual titration with reduction in side effects and faster recovery from conduction block. However, results from studies are inconsistent, with some trials observing faster motor recovery with this approach229 and others not discerning a reduced dosing need for spinal anesthesia with epidural supplement.230,231 A potential disadvantage of the CSEA technique versus the single-shot technique is an increased incidence of transient paresthesia during placement of the spinal needle. A previous study randomizing


patients undergoing cesarean section to CSEA versus conventional spinal anesthesia observed incidences of paresthesia of 37% versus 9%. There were no long-term complications, and the authors speculated that the CSEA technique might lead to deeper tissue penetration as a mechanism for increased incidence of transient paresthesia.232

Ambulatory Anesthesia The dose of local anesthetic determines both anesthetic success and duration of recovery. Availability of the epidural catheter for a rescue anesthetic allows use of minimal doses of spinal local anesthetic with resultant rapid recovery and discharge (Table 46–4) and represents an alternative or complementary strategy to use of analgesic additives. Several clinical trials have determined minimally effective doses for ambulatory knee arthroscopy using this approach. For example, initial doses of spinal lidocaine 40 mg or mepivacaine 45 mg233,234 have been determined to be optimal doses for CSEA by previous dose–response studies. However, induction of a CSEA technique probably takes more time than conventional spinal anesthesia, and no current data are available to assess relative cost benefit of increased induction time versus decreased recovery time with CSEA. Thus, final conclusions on the role of CSEA in a busy ambulatory surgery center remain to be determined.

Techniques and Equipment The most widespread approach used in the literature is the needle-throughneedle technique. A number of commercial kits are available. The simplest version is a Tuohy needle (or equivalent) through which a long, small-gauge spinal needle (24–30 gauge) is passed. Epidural needles with a “back hole” are also available, configured to allow placement of the spinal needle through a separate conduit so as to avoid angulation of the spinal needle (Fig. 46–15). Recent studies suggest that use of a back-hole needle may offer advantages over a conventional needle through needle technique. A randomized trial in parturients observed decreased incidence of paresthesia (14% vs. 42%) and failure to obtain CSF on the first attempt (8% vs. 28%) with the back-hole needle.235 The separate conduit for the spinal needle may also reduce risk of toxicity from metal fragments caused

A

B

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C FIGURE 46–15. Styles of needles for combined spinal-epidural anesthesia. Depicted are (A) “conventional” Tuohy with a long spinal needle exiting the curved tip; (B) “back-eyed” needle with spinal needle exiting through the eye; and (C) “double-barrel” design, with a separate bore for passage of a spinal needle. Notice the difference in the angle of projection of the spinal needle passing out of the “conventional Tuohy” tip, as compared to B and C.

by needle friction.236 Metal fragments have been proposed as a cause of aseptic meningitis, following the observation of notches in epidural needle tips.237 However, recent evaluations using atomic absorption spectrography and photomicrography did not demonstrate metal fragments even after up to 5 spinal needle passes, and suggest the notches were caused by malleability of the metal.238 As an alternative to the needlethrough-needle technique, the doublesegment method also offers the ability to place the epidural catheter and administer a test dose prior to placing the spinal block. Typically, the epidural and spinal portions are performed at different interspaces. By first introducing the catheter, there exists the potential risk of damaging the catheter with the spinal needle. Furthermore, creating two separate cutaneous punctures could lead to increased incidence of adverse events, including backache, headache, infection, and hematoma.239 A recent study demonstrated greater

acceptance by surgical patients of the needle-through-needle over the double-segment technique (85% vs. 67%).240 That same study also showed a significantly longer time to perform the double-segment technique without decreasing the failure rate of spinal anesthesia, although other studies suggest a higher failure rate with the needle-through-needle technique.240

Potential Complications Failure of Spinal Anesthesia The combined technique is associated with a higher failure rate of spinal anesthesia than conventional spinal anesthesia. The most recent data suggests about a 5% incidence, improved from older reports of 10–25%.216 There are a number of reasons for failure to occur. (a) Smaller-gauge spinal needles with long lengths are typically used. These needles lead to slower return of CSF and a greater resistance to injection. (b) Because the epidural needle has penetrated the tissue


A

B

C

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D FIGURE 46–16. Various reasons for not achieving successful spinal anesthesia when attempting combined spinal–epidural anesthesia. A. Inadequate length of spinal needle, or epidural needle not advanced far enough. B. Spinal needle rents the dura, but does not achieve puncture. C. Angle of advancement deviates too far from midline. D. Successful dural puncture with return of CSF.

planes, there is little to anchor the spinal needle in place. Although a Luer lock apparatus is available, it locks at a fixed needle length and can result in not reaching or traversing the dura.27 (c) Any deviation from midline can lead to missing the dura altogether (Fig. 46–16). (d) If loss-of-resistance technique used saline, a false return of saline in the spinal needle rather than CSF can occur. Kopacz et al. recommend the hanging drop method within the epidural needle to aid identification of dural puncture in this situation.6 Negative pressure from tenting the dura with the spinal needle will cause an inward movement of the drop of fluid followed by return of CSF. (e) Finally, patient positioning and duration between spinal injection and completion of epidural catheter placement can change the characteristics of the spinal block.

Failure of Epidural Anesthesia There are no controlled randomized prospective studies addressing the failure of epidural anesthesia or analgesia with the combined technique.22 The in-

cidence of failure is unlikely to be higher with the combined technique; however, the difficulty in early testing with a needle-through-needle technique may lead to late recognition of a misplaced catheter. Prior injection of spinal anesthetic precludes testing the epidural catheter for intrathecal placement, and epidural injection of a test dose can lead to increased height of spinal block (see Intrathecal Effects of Epidural Agent below).243 Reliability of detecting an intravascular test dose using 15 μg of epinephrine remains intact in healthy individuals using heart rate and systolic blood pressure criteria, although the developing spinal block will reduce the magnitude of hemodynamic response to epinephrine.214

Intrathecal Effects of Epidural Agent The intrathecal effects of epidurally administered drugs can occur through migration of the epidural catheter through the dural puncture, leakage of epidural anesthetic through the dural hole, and pressure effects of epidural injection. The likelihood of passing an

epidural catheter through a dural hole is very small, provided a 24-gauge or smaller spinal needle is used. This has been demonstrated using in vitro models and in vivo epiduroscopy.244 However, intrathecal catheter placement is possible if the epidural needle (17–18 gauge) initially rented the dura. Migration later in the anesthetic course is no more likely than with conventional epidural techniques. Although significant clinical effects of leakage of epidural local anesthetic or opioid through the small-gauge dural puncture is unlikely, significant leakage of epidural agents can occur through large dural rents such as with a “wet tap.” 245,246 Pressure effect is the observation that increasing epidural volume can “squeeze” the CSF compartment and thus raise the cephalad spread of spinal drugs. A recent myelographic evaluation demonstrated that the subarachnoid space’s diameter decreased to 25% after 10 mL normal saline was injected through an epidural catheter.247 The ability to increase dermatomal spread by epidural volume appears to be time dependent. Sensory block extension can be significant (3– 4 dermatomes) if epidural saline or air is injected soon after or before bupivacaine spinal anesthesia.243,248 This block enhancement may be clinically significant, as a recent clinical trial reported that CSEA required 20% less local anesthetic than single-shot spinal anesthesia.249 However, if delayed until two-segment regression has begun, there is no increase in sensory blockade level250; in fact, it can even result in shorter duration of anesthesia.251

KEY REFERENCES 1. Liu SS, McDonald SB. Current issues in spinal anesthesia. Anesthesiology 2001;94(5):888–906. 2. Auroy Y, Benhamou D, Bargues L, et al. Major complications of regional anesthesia in France: the SOS Regional Anesthesia Hotline Service. Anesthesiology 2002;97(5): 1274–1280. 3. Carpenter RL, Caplan RA, Brown DL, Stephenson C, Wu R. Incidence and risk factors for side effects of spinal anesthesia. Anesthesiology 1992;76:906–916.


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8. Lechner TJ, van Wijk MG, Maas AJ, et al. Clinical results with the acoustic puncture assist device, a new acoustic device to identify the epidural space. Anesth Analg 2003;96:1183–1187. 9. Hogan QH, Prost R, Kulier A, et al. Magnetic resonance imaging of cerebrospinal fluid volume and the influence of body habitus and abdominal pressure. Anesthesiology 1996;84:1341–1349. 10. Pitkanen M, Haapaniemi L, Tuominen M, et al. Influence of age on spinal anaesthesia with isobaric 0.5% bupivacaine. Br J Anaesth 1984;56:279–284.

6. Horlocker TT, Wedel DJ, Benzon HT, 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 2003;28(3):172– 197.

11. Taivainen T, Tuominen M, Rosenberg PH. Influence of obesity on the spread of spinal analgesia after injection of plain 0.5% bupivacaine at the L3-4, or L4-5, interspace. Br J Anaesth 1990;64:542–546.

7. Pollock JE. Transient neurologic symptoms: etiology, risk factors, and management. Reg Anesth Pain Med 2002;27(6):581–586.

13. Bodily MN, Carpenter RL, Owens BD. Lidocaine 0.5% spinal anaesthesia: a hypobaric solution for short-stay perirectal surgery. Can J Anaesth 1992;39:770–773.

8. Cook TM. Combined spinal–epidural techniques. Anaesthesia 2000;55:42–64.

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236. Eldor J. The evolution of combined spinal-epidural anesthesia needles. Reg Anes 1997;22:294–296. 237. Eldor J, Guedj P. Aseptic meningitis due to metallic particles in the needlethrough-needle technique. Reg Anesth 1995;20:360. 238. Holst D, Molmann M, Schymroszcyk B, et al. No risk of metal toxicity in combined spinal-epidural anesthesia. Anesth Analg 1999;88:393–397. 239. Rawal N, Van Zundert A, Holmstrom B, et al. Combined spinal–epidural technique. Reg Anesth 1997;22:406–423. 240. Casati A, D’Ambrosio A, De Negri P, et al. A clinical comparison between needlethrough-needle and double-segment techniques for combined spinal and epidural anesthesia. Reg Anesth Pain Med 1998;23:390–394. 241. Backe SK, Sheikh Z, Wilson R, et al. Combined epidural/spinal anaesthesia: needle-through-needle or separate spaces? Eur J Anaesthesiol 2004;21:854–857. 242. Hoffmann VL, Vercauteran MP, Buczkowski, et al. A new combined spinal– epidural apparatus: measurement of the distance to the epidural and subarachnoid spaces. Anaesthesia 1997;52:350–355. 243. Stienstra R, Dilrosun-Alhadi BZR, Dahan A, van Kleef JW, Veering BT, Burm AGL. The epidural “top-up” in combined spinal–epidur-

245. Swenson JD, Wisniewski M, McJames S, et al. The effect of prior dural puncture on cisternal cerebrospinal fluid morphine concentrations in sheep after administration of lumbar epidural morphine. Anesth Analg 1996;83:523–525. 246. Bernards CM, Kopacz DJ, Michel MZ. Effect of needle puncture on morphine and lidocaine flux through the spinal meninges of the monkey in vitro. Implications for combined spinal–epidural anesthesia. Anesthesiology 1994;80:853–858. 247. Takiguchi T, Okano T, Egawa H, et al. The effect of epidural saline injection on analgesic level during combined spinal and epidural anesthesia assessed clinically and myelographically. Anesth Analg 1997;85: 1097–1100. 248. Goy RW, Sia AT. Sensorimotor anesthesia and hypotension after subarachnoid block: combined spinal–epidural versus single-shot spinal technique. Anesth Analg 2004;98:491–496. 249. Goy RW, Chee-Seng Y, Sia AT, et al. The median effective dose of intrathecal hyperbaric bupivacaine is larger in the single-shot spinal as compared with the combined spinal–epidural technique. Anesth Analg 2005;100:1499–1502. 250. Leeda M, Stienstra R, Arbous MS, et al. The epidural “top-up”: predictors of increase of sensory blockade. Anesthesiology 2002;96:1310–1314. 251. Trautman WJ, Liu SS, Kopacz DJ. Comparison of lidocaine and saline for epidural top-up during combined spinal– epidural anesthesia in volunteers. Anesth Analg 1997;84:574–577.

CHAPTER 47: Paravertebral Anesthesia

CHAPTER 47 Paravertebral Anesthesia Holly Evans, MD, FRCPC, and Stephen M. Klein, MD Paravertebral nerve block (PVB) involves injection of local anesthetic close to the spinal nerve roots within the paravertebral space (PVS). The resulting unilateral or bilateral segmental anesthesia and analgesia of thoracic or lumbar dermatomes has multiple applications. This chapter describes paravertebral anatomy and PVB techniques. The physiologic effects are discussed in relation to the advantages, disadvantages, and contraindications for PVBs. The chapter also summarizes the existing literature outlining the use of PVBs for surgical procedures.

PARAVERTEBRAL ANATOMY Thoracic Paravertebral Anatomy The thoracic PVS is a wedge-shaped space that lies on each side of the vertebral column. Detailed descriptions of the anatomic features of the PVS are available.1–7 Figure 47–1 illustrates the boundaries of the thoracic PVS. The space is limited posteriorly by the superior costotransverse ligament. At each dermatomal level, this ligament extends from the lower border of the transverse process above to the upper border of the rib below (Fig. 47–2). Anterolaterally, the thoracic PVS is limited by the parietal pleura. The medial base of the thoracic PVS is defined by the posterolateral segment of the vertebral body, the intervertebral disk, the intervertebral foramen and its contents. The PVS is continuous medially with the epidural space via the intervertebral foramen; in addition, dural sleeves extend into the PVS.1,5,8 Laterally, the thoracic PVS is continuous with the intercostal space lateral to the transverse processes. Communication with the contralateral PVS may occur by contact through the prevertebral9,10 or epidural spaces.2 The PVS is continuous superi-

orly and inferiorly across the heads and necks of adjacent ribs. The precise cranial limit has not been fully elucidated; however, cervical spread of injectate has been observed after thoracic PVB.2 Caudally the thoracic PVS was previously thought to be limited by the origin of the psoas major muscle;11 however, continuity with the PVS below the diaphragm has been supported by studies documenting the lumbar spread of dye following thoracic injection.2,12,13 The contents of the thoracic PVS include the endothoracic fascia, the spinal nerves, the sympathetic chain, the intercostal vessels, lymphatics, and loose fatty tissue (Fig. 47–3). The endothoracic fascia is the deep, fibroelastic fascia of the thoracic cavity.14,15 It is continuous medially with the prevertebral fascia that covers the vertebral bodies and intervertebral disks,15 superiorly with the scalene fascia, and inferiorly with the fascia transversalis of the abdomen.2,14 Karmakar2 described the endothoracic fascia as dividing the thoracic PVS into two potential fascial compartments: the anterior “extrapleural paravertebral compartment” and the posterior “subendothoracic paravertebral compartment.” It appears the anterior compartment contains loose areolar connective tissue (subserous fascia)7 and the sympathetic trunk,2,16 whereas the posterior compartment contains the intercostal nerves.2,16 The spinal nerves emerge from the intervertebral foramina and course through the thoracic PVS as a collection of small nerve rootlets devoid of fascial covering.2,4,17,18 Early in the course of the spinal nerve, the posterior primary ramus branches to supply the posterior vertebral muscles, ligaments, facet joints and the overlying skin (Fig. 47–3). The sympathetic chain traverses anteriorly

within the thoracic PVS2 and communicates with the spinal nerves through the preganglionic white rami communicantes and the postganglionic grey rami communicantes (Fig. 47–3). The intercostal arteries (originating from the descending aorta), as well as the hemiazygos and accessory hemiazygos veins,19 pass through the thoracic PVS. Lymphatic drainage is to local nodes and subsequently to tributaries of the thoracic duct which form a plexiform network around the vertebral bodies.20 Several features of the thoracic spine are important because they serve as landmarks for performing PVBs. Because the spinous processes in the thoracic spine are steeply angulated, they lie in the same transverse plane as the transverse processes of the vertebra below (i.e., spinous process of T5 is at the same horizontal level as the transverse process of T6) (Fig. 47–2). A spinal nerve exits through its intervertebral foramen to enter the PVS caudal to the transverse process of the same name (i.e., T5 nerve root passes inferior to the T5 transverse process). In adults, the thoracic transverse processes project laterally a mean distance of 3.2 cm from midline (range: 2.1–4.2 cm) 8 and the mean depth from skin to thoracic PVS is 55 mm.21 Depth is greater in the upper thoracic spine (mean: 77 mm at T1) compared to the mid- and lower thoracic spine (mean: 50 mm at T6);21 in addition, considerable variation exists as a result of body habitus (mean depth to T1 PVS is 67.5 mm if body mass index [BMI] 30).21

Lumbar Paravertebral Anatomy The lumbar paravertebral region possesses generally unique features. While

KEY POINTS 1. A paravertebral nerve block involves conduction block of the spinal nerve within the paravertebral space. 2. Dense sensory, motor, and sympathetic block results. 3. Unilateral or bilateral, thoracic or lumbar segmental block can be obtained. 4. Common indications include thoracic surgery, breast surgery, and hernia repair.


5. Benefits include diminished stress response to surgery; decreased opioid consumption; reduced opioidrelated side effects (nausea, vomiting, sedation); hemodynamic stability as well as preservation of pulmonary mechanics; lower-extremity strength; and bladder function. 6. Potential side effects are rare and include pleural puncture, pneumothorax, intrathecal or epidural injection, and local anesthetic toxicity.

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FIGURE 47–1. Transverse section of the thoracic spine depicting the boundaries, contents and structures surrounding the paravertebral space. (Reproduced with permission from Eason MJ and Wyatt R.3)

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the medial boundary of the lumbar PVS is similar to that described for the thoracic PVS, other differences exist. The posterior boundary of the lumbar PVS is formed by the transverse processes

and paravertebral muscles. The anterior margin of the lumbar PVS is formed by the fascia transversalis, which is the fascial lining of the intraabdominal cavity. The fascia transversalis in the abdo-

FIGURE 47–2. Posterior view of the thoracic spine depicting the relationship between the superior costotransverse ligament and the paravertebral space. Reprinted from Greengrass R, Steele S. Paravertebral blocks for breast surgery. Tech Reg Anesth Pain Manage 1998;2:8–12, with permission from Elsevier.

men is continuous with the endothoracic fascia in the thoracic PVS (Fig. 47–4).14 The fascia transversalis blends posteromedially with the anterior layer of the quadratus lumborum fascia and with the psoas fascia (Fig. 47–5).22 The cephalad part of the psoas and quadratus lumborum fascias are thickened to form the medial and lateral arcuate ligaments, respectively. The medial arcuate ligament is attached medially to the body of L2 and laterally to the transverse process of L1. The lateral arcuate ligament passes from the lateral aspect of the L1 transverse process to the inferior border of the twelfth rib. The transversalis fascia is in direct communication with the endothoracic fascia at the medial and lateral arcuate ligaments as well as at the aortic hiatus. And, it is via these communications that there exists continuity between the thoracic and abdominal PVS.2,14,23 The lumbar nerve roots course through the lumbar PVS and subsequently combine to form the nerves of the lumbar plexus. The subcostal, iliohypogastric, ilioinguinal and lateral femoral cutaneous nerves course anterolaterally over the quadratus lumborum muscle. The genitofemoral and, more distally, the femoral and obturator nerves pass over the anterolateral surface of the psoas muscle. Accordingly, local anesthetic injected into the PVS has the potential to block a segment of the lumbar plexus. Several features of the lumbar spine’s bony anatomy deserve men-


FIGURE 47–3. Midthoracic transverse section depicting the contents of the paravertebral space (including the endothoracic fascia) and surrounding structures. (Reproduced with permission from Karmakar MK.2)

tion. The spinous process of a lumbar vertebra projects posteriorly with less angulation than in the thoracic spine (Fig. 47–6). As a result, a given transverse process lies at the same horizon-

tal level as its corresponding spinous process. In addition, the transverse processes in the lumbar region do not articulate with the ribs and are much smaller and thinner in the anteropos-

terior plane in contrast to the thoracic spine.

HISTORY Hugo Selheim, an obstetrician, is credited with the development of paravertebral anesthesia in 1905.2 Arthur Lawen, a surgical resident, subsequently refined Sellheim’s technique2 and performed PVBs on patients presenting with abdominal pain. This provided acute pain relief, which facilitated abdominal muscle relaxation and palpation. Subsequent laparotomy or autopsy allowed identification of the underlying pathology. As a result, detailed information was collected on the segmental innervation of various thoracic and abdominal organs. These pioneers are credited with early development of the familiar segmental dermatome map (Fig. 47–7). Selheim, Lawen, and subsequently Kappis further expanded the use of PVBs for surgical anesthesia in attempt to reduce complications and improve survival in the early years of general and spinal anesthesia.2 The technique fell into disfavor for several decades until a publication by Eason and Wyatt renewed interest in this modality.3

FIGURE 47–4. Thoracoabdominal sagittal section showing the relationship between the endothoracic fascia in the chest and the transversalis fascia in the abdomen. Karmakar MK, Gin T, Ho AM. Ipsilateral thoraco-lumbar anaesthesia and paravertebral spread after low thoracic paravertebral injection. Br J Anaesth 2001;87:312–316. © The Board of Management and Trustees of the British Journal of Anaesthesia. Reproduced by permission of Oxford University Press/British Journal of Anaesthesia.

PARAVERTEBRAL BLOCK TECHNIQUE The patient can be positioned sitting, prone, or lateral decubitus (side to be blocked uppermost). The neck is flexed,

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1012 FIGURE 47–5. Upper abdominal transverse section depicting the relationship between the fascia transversalis and the fascia of the psoas major and quadratus lumborum muscles. Karmakar MK, Gin T, Ho AM. Ipsilateral thoraco-lumbar anaesthesia and paravertebral spread after low thoracic paravertebral injection. Br J Anaesth 2001;87:312–316. © The Board of Management and Trustees of the British Journal of Anaesthesia. Reproduced by permission of Oxford University Press/British Journal of Anaesthesia.

the back is rounded, and the shoulders retracted forward, similar to positioning for a thoracic epidural. Appropriate sedation is useful for anxiolysis and analgesia.

The levels (spinal nerve roots) to be blocked are selected based on the surgical procedure, for example, T1 to T6 for mastectomy and axillary dissection (Ta-

ble 47–1 and Fig. 47–7). The spinal nerve root is located following identification of its corresponding transverse process. In the thoracic spine, a given transverse process is located in the same horizontal plane as the spinous process of the vertebra above (e.g., the T4 transverse process is at the level of the T3 spinous process) (Fig. 47–2). Spinous processes are generally palpable in the midline with the most prominent spinous process in the neck representing C7, the lower border of the scapula corresponding to T7, and the intercristal line marking L4. The superior aspect of the desired spinous process is identified and, in adults, a mark is drawn 2.5 cm lateral from the midline (Fig. 47–8). The skin is cleaned with disinfectant and subcutaneous infiltration of local anesthetic is given at all needle entry sites. A number of techniques have been described to identify the PVS.

Anatomic or Loss-ofResistance Technique

FIGURE 47–6. Oblique views of a thoracic and a lumbar vertebra. (Reprinted from Covino BG, Scott DB, Lambert DH. In: Handbook of Spinal Anaesthesia and Analgesia. Philadelphia, PA: WB Saunders, 1994, with permission from Elsevier.)

Identification of the thoracic PVS can be made when a tactile “pop” is noted as the needle passes through the superior costotransverse ligament. Alternatively, loss of resistance to injected air or saline may be used; however, this end point is more sub-


FIGURE 47–7. Dermatomal distribution of spinal nerves. (Reprinted from Covino BG, Scott DB, Lambert DH. In: Handbook of Spinal Anaesthesia and Analgesia. Philadelphia, PA: WB Saunders, 1994, with permission from Elsevier.)

tle and subjective than with epidural anesthesia. A 10-cm, 22-gauge Tuohy needle is inserted in a horizontal plane 2.5 cm lateral to the midpoint of the superior border of the appropriate spinous process in adults. The needle is advanced to contact the transverse process, withdrawn to the subcutaneous tissue, and then redirected caudal to the transverse process (Fig. 47–9). The needle is slowly advanced until a change in resistance is perceived. This occurs approximately 1 cm past the depth at which the transverse process is contacted. The depth from skin to thoracic PVS varies by vertebral level and patient habitus.21

A cautious approach is warranted if bone is contacted deep to the transverse process as this may represent the rib. Further advancement of the block needle past the rib can result in pleural puncture and pneumothorax. This risk can be minimized when the block needle is redirected caudally after initial bony contact. If the rib is unintentionally contacted first, caudal redirection will bring the block needle in contact with the transverse process at a shallower depth (Fig. 47–10). Subsequently, a more accurate estimation of the depth of the PVS is provided and the risk of pleural puncture is decreased. In contrast, an alternate ap-

proach has been described in which the needle is redirected cephalad to the transverse process. If initial contact is made with the rib, cephalad redirection will not bring the needle into contact with the transverse process. Further advancement of the needle deep to the rib increases the possibility of pleural puncture and resulting pneumothorax. When the thoracic PVS has been located, 3–5 mL of local anesthetic is typically injected at each level. The syringe containing local anesthetic is aspirated for air, blood, or cerebrospinal fluid prior to injection. Injection should occur without resistance. Local anesthetic doses may need to be adjusted when multiple or bilateral PVBs are performed. Nerve block adequacy is confirmed by appropriate thoracic dermatomal sensory block, intercostal muscle motor block, and sympathectomy-related changes such as vasodilatation and increased skin temperature. Lumbar PVBs involve a modification of the thoracic technique. The needle entry site for each spinal nerve corresponds to the spinous process of the same level, making correction for spinous process angulation unnecessary in the lumbar region. In addition, after contact with the lumbar transverse process, the block needle is advanced no more than 0.5 cm anteriorly. This is because the lumbar transverse processes are thinner in the anteroposterior plane compared to the thoracic spine. Finally, the loss of resistance upon entrance into the lumbar PVS is less-well defined compared to that felt in the thoracic spine. This may be related to the lack of the costotransverse ligament in the lumbar region.

Nerve Stimulation The spinal nerve can be located in the PVS using a nerve stimulator and a 10cm, 21- or 22-gauge short-bevel insulated stimulating needle. The needle is inserted as previously described. Direct paraspinal muscle stimulation is observed initially as the needle passes through these muscles. Further advancement caudad to the transverse process brings the stimulating needle in close proximity to the spinal nerve and leads to intercostal or abdominal muscle contractions depending on the level of stimulation. As for other peripheral nerve blocks, appropriate

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TABLE 47–1. Clinical Applications for Paravertebral Nerve Blocks Surgical Procedure

Levels Blocked

Thoracotomy Thoracoscopy Rib fractures

T4–T9 T4–T9 Level of fracture with 1 level above and below T2–T6 bilaterally T2–T6 T1–T6 with superficial cervical plexus block Level of lesion with 1 level above and below T10–L2 T9–T11 bilaterally According to level of repair T8–T12 T8–T12 T6–T10 T10–T12 T1–T2

Cardiac surgery Mastectomy, breast surgery Mastectomy with axillary dissection Breast biopsy

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Inguinal hernia repair Umbilical hernia repair Incisional hernia repair Ileostomy closure Nephrectomy Cholecystectomy Appendectomy Adjunct for shoulder surgery (subdeltoid incision) Adjunct for hip surgery Bone marrow aspiration Iliac crest bone harvesting Labor analgesia Chronic pain

T11–T12 with lumbar plexus block T11–L2 bilaterally T11–L1 T10 bilaterally for first stage of labor According to condition

Data from Karamaker MK;2 Richardson J and Lonnquist PA;23 and Greengrass R, and Buckenmaier CC 3d.102

needle placement is confirmed when muscle contractions persist with a current of 0.5–0.6 mA. Isolated posterior spinal muscle contraction should not be accepted as this may represent direct muscle activation or stimulation of the posterior ramus of the spinal nerve root after it diverges from the spinal nerve. Proponents of this technique describe its usefulness in challenging cases (e.g., morbid obesity, ankylosing spondylitis) and as a way to minimize the occurrence of pneumothorax, although this has yet to be proven.24

Other Techniques Injection of Radiographic Contrast Dye Injection of contrast dye and radiologic examination can be used to confirm proper paravertebral needle location. Dye spread occurs in either a longitudinal distribution or a segmental, cloud-like dispersal (Fig. 47–11).7 Naja et al.25 hypothesized that dye dispersion is dependent on the location of the needle with respect to the endothoracic fascia. They conjectured that needle position posterior to the endothoracic fascia would be associated with segmental, cloud-like dye spread and needle position anterior to the endothoracic fascia with more longitudinal dye distribution.25

Pressure Transduction Pressure measurement has been described to confirm paravertebral needle placement.26 When the needle tip is in the erector spinae muscle, the measured pressure is higher during inspiration (mean: 29.6 mm Hg) than expiration (mean: 19.4 mm Hg).26 This is thought to occur as a result of greater muscle activity during inspiration or as a result of muscular compression caused by the expanding chest cage.23 As the needle is advanced into the PVS, there is a sudden lowering of pressures and expiratory pressure becomes higher (7.6 mm Hg) than inspiratory pressure (3.3 mm Hg).26 Unintentional puncture is identified when subatmospheric pressures are recorded both during inspiration and expiration.

Ultrasound-Assisted Technique FIGURE 47–8. Skin markings for paravertebral blocks performed for left mastectomy. Reprinted from Greengrass R, Steele S. Paravertebral blocks for breast surgery. Tech Reg Anesth Pain Manage 1998;2:8–12, with permission from Elsevier.

Ultrasound imaging can be used to provide an estimate of the location and depth of the transverse process.


Spinal nerves

FIGURE 47–9. Paravertebral nerve block technique. Following identification of the transverse process, the block needle is redirected inferiorly and advanced into the paravertebral space. Reprinted from Greengrass R, Steele S. Paravertebral blocks for breast surgery. Tech Reg Anesth Pain Manage 1998;2:8–12, with permission from Elsevier.

Pusch et al.27 found a close correlation between the needle depth from skin to transverse process and the estimated depth as measured by ultrasound. Moreover, there was also close correlation between the needle depth to the

thoracic PVS and the ultrasound-estimated depth to the parietal pleura.

Continuous PVBs Placing a continuous catheter into the PVS can be used to extend the duration

A

B Skin Pleura Neck of rib

Nerve Superior costo-transverse ligament Inferior costo-transverse ligament Tip of transverse process

FIGURE 47–10. Paravertebral nerve block technique. Longitudinal section depicting insertion of the block needle (A) above and (B) below the transverse process or rib. (Reproduced with permission from Eason MJ and Wyatt R.3)

of postoperative analgesia provided by single-injection PVBs. This is typically reserved for more invasive surgery associated with intense postoperative pain, such as thoracotomy and subcostal incisions. Insertions methods are usually modifications of single injection techniques. A single-injection 22gauge 10-cm Tuohy needle is initially used to estimate the depth of the transverse process and paravertebral space. A larger-bore (e.g., 18 gauge) Tuohy needle capable of accommodating a 20gauge epidural catheter is then substituted. Extension tubing or a hemostatic valve is used to create a closed circuit with the needle to mitigate entrainment of air if the pleura is punctured. The catheter is threaded 1–2 cm into the paravertebral space to minimize the risk of migration. Consequently, a catheter with a single distal orifice is used to reduce leakage of local anesthetic solution outside of the paravertebral space. A novel insertion method described for thoracic surgery is to place the catheter under direct vision in the surgical field (Fig. 47–12).4,23 At the completion of the thoracotomy just prior to chest closure, the surgeon strips away the parietal pleura in the paravertebral gutter at the level of the incision, 2 dermatomes cephalad and 2 dermatomes caudad. A small defect is made in the extrapleural fascia. A Tuohy needle is then introduced percutaneously and a catheter is placed into the PVS through the small defect in the extrapleural fascia. The parietal pleura is repositioned and sutured in place.

Effect of Technique on Distribution of Injectate Paravertebral anesthesia can be provided with one injection using a large volume of local anesthetic deposited at one single level. The theoretic advantage of a single-needle insertion is a reduction in the incidence of side effects such as pleural puncture or pneumothorax. Alternatively, PVBs may be performed with multiple injections using a small volume of local anesthetic at each level injected. The theoretic advantage of this method is more extensive and complete anesthesia of the desired dermatomes. Insufficient evidence exists to determine which technique is most effective; current practice is both institution and practitioner dependent. A single-level paravertebral injection of 10–15 mL of local anesthetic in

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FIGURE 47–11. Chest radiographs taken following injection of radiocontrast dye into the paravertebral space depicting ( A) longitudinal and (B) cloudlike spread. (Reproduced with permission from Naja MZ, Ziade MF, El Rajab M, et al. 25)

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adults,12,28,29 and 0.5 mL/kg in children,7 achieves a mean sensory block of 4–5 dermatomes, independent of age, height, weight, or sex. Few studies have been designed to rigorously investigate the potential effect of dose or volume of injectate on spread within the PVS. One study in adults has shown no association between these variables,28 whereas another study of pediatric patients has found a moderate to strong correlation between in-

jected volume and segmental spread of dye.7 It has been proposed that there may be an age-related loss of connective tissue leading to greater spread of injectate in adults.28 Additional factors do affect the spread of injectate within the PVS. Purcell-Jones et al.8 studied singleinjection PVBs using the loss of resistance technique. They radiographically showed greater craniocaudal distribution of solution (5.5 mL) when

FIGURE 47–12. Placement of a paravertebral catheter under direct vision. The extrapleural fascia is exposed by raising the parietal pleural from the posterior chest wall. The epidural catheter is lying within the paravertebral space (broken line), introduced through the small defect. Reprinted from Berrisford RG, Sabanathan SS. Direct access to the paravertebral space at thoracotomy. Ann Thorac Surg 1990;49:854, with permission from the Society of Thoracic Surgeons.

the PVB was associated with epidural spread. They found sensory anesthesia in a mean 1.43 dermatomes when injectate was confined to the PVS; 2.27 dermatomes when injectate was primarily in the PVS but also spread to the epidural space; 4.66 dermatomes when injectate was confined to the epidural space; and 6.6 dermatomes when injectate was primarily in the epidural space but also spread to the PVS. In all instances, the spread of contrast dye was greater than the observed sensory block. Cheema et al.12 studied patients who received a singleinjection PVB using loss of resistance with 15 mL of local anesthetic and dye. They found that the mean extent of vasodilatation (sympathetic block) was 8 dermatomes, which exceeded the mean sensory block of 5 dermatomes. Interestingly, they also discovered that a greater proportion of the solution injected into the PVS spread in a caudad direction. The distribution of craniocaudal spread is also influenced by the direction in which the solute is injected. Saito et al.29 performed single-injection PVBs with 12 mL of local anesthetic. When all the injectate was given with the needle bevel directed caudally, sensory block developed in a mean of 5.2 dermatomes, whereas when half the injection was made with the needle bevel directed cephalad and half caudad, sensory block developed in a mean 7.7 dermatomes.


TABLE 47–2.

TABLE 47–3.

Local Anesthetic Regimen for Paravertebral Nerve Blocks Single-level injection

Multiple-level injections

Continuous infusion

Children: 0.5 mL/kg up to 20 mL local anesthetic Adults: 10–20 mL local anesthetic (i.e., ropivacaine 0.5% with epinephrine 1:400,000) Thoracic spine: 3–4 mL local anesthetic per segment Lumbar spine: 5–7 mL local anesthetic per segment (i.e., ropivacaine 0.5% with epinephrine 1:400,000) 0.1–0.2 mL/kg/h local anesthetic (i.e., ropivacaine 0.2%)

Cheema et al.12 theorized that stratification of connective tissue within the thoracic PVS may lead to tracking of injectate such that small differences in needle placement could have important consequences. This was supported by Naja et al.25 who hypothesized that the endothoracic fascia affects the spread of injectate and may function as a mechanical barrier to diffusion. This was inferred after two distinct patterns of spread of radiographic contrast dye were observed following thoracic PVB with a nerve stimulator. Longitudinal spread occurred more commonly in association with low nerve-stimulating current (0.5 mA), whereas localized, cloud-like spread occurred more commonly with higher nerve-stimulating current (2.5 mA). Although it was not known with certainty where injections were made relative to the endothoracic fascia, the authors conjectured that longitudinal spread was associated with injection anterior to the endothoracic fascia and that cloud-like spread was associated with injection dorsal to the endothoracic fascia. Because of the unpredictable variability in spread of block, more information about the anatomy, permeability, and importance of the endothoracic fascia within the PVS is required.

to peak arterial and venous concentrations.30 Some practitioners add opioids or clonidine to the local anesthetic mix; 31,32 however, this has not been extensively studied. Table 47–2 outlines standard dosing regimens. A single-level injection is typically performed with 0.5 mL/kg of dilute local anesthetic solution in children, and 10–20 mL in adults. Multiple-level injections are accomplished in adults with 3–4 mL of local anesthetic per segment in the thoracic region, and 5–7 mL per segment in the lumbar area. Continuous PVBs are managed with 0.1–0.2 mL/ kg/h of dilute local anesthetic.

ADVANTAGES Table 47–3 summarizes the advantages of PVBs. PVBs provide block of afferent nerve activity leading to dense body wall anesthesia and postoperative analgesia. Richardson et al.33 performed somatosensory evoked potential testing on patients before and after they received a single-injection block. They discovered complete abolition of the evoked potentials at the level of the paravertebral injection in 100% of patients (Fig. 47–13). They commented

Local Anesthetic Regimen Various local anesthetics can be used for PVBs. Bupivacaine and ropivacaine are the most frequently studied agents and the duration of analgesia is similar to that obtained with brachial plexus anesthesia. Ropivacaine has a sound safety profile and provides analgesia for 12–24 hours. Epinephrine is frequently added to the local anesthetic solution to indicate intravascular injection, to reduce the peak local anesthetic blood level,30 and to improve analgesia. Epinephrine produces a 25% reduction in the mean peak arterial concentration of ropivacaine and delays the time

Beneficial Effects of Paravertebral Nerve Blocks Dense sensory, motor, and sympathetic nerve block Unilateral or bilateral segmental block Wide application for various surgical procedures Decreased stress response to surgery35 Low postoperative opioid requirements41,68,88 Infrequent opioid-related side effects (nausea, vomiting, sedation)41,68,88 Postoperative analgesia similar or better than epidural68,92 Hemodynamic stability43,68 Preservation of pulmonary function65,68 Preservation of lower-extremity motor strength Preservation of bladder function43,68 Enhanced perioperative efficiency31,42 that such reliable afferent block does not often occur following epidural anesthesia34 and they postulated that by this mechanism, PVBs may prevent central sensitization and the development of chronic pain conditions. PVBs also modify the stress response to surgical stimulation. Giesecke et al.35 studied open cholecystectomy patients under general anesthesia and discovered that those who also received a single injection PVB had lower plasma adrenalin and cortisol concentrations (p Ppa > Ppv Ppa

PA

Ppv

Ppa

PA

Vertical distance

Zone 2 Ppa > PA > Ppv

Ppv

In the spontaneously ventilating patient with an open chest, the inspiratory tidal volume in the dependent lung is decreased by the downward displacement of the mediastinum, which leads to impaired ventilation to the dependent lung and paradoxic respiration. Paradoxic respiration refers to the movement of air between the dependent lung and the nondependent lung during respiration and the ambient atmosphere in and out of the open chest cavity. These physiologic changes can affect circulatory performance by decreasing venous return and triggering associated sympathetic reflexes, resulting in a clinical picture similar to that of shock. The reflex symptoms of hypotension, pallor, cold and clammy extremities, and pupillary dilatation can be lessened by local anesthetic infiltration of the pulmonary plexus at the hilum. Most commonly, the ventilatory and circulatory changes associated with mediastinal shift are abolished by positive-pressure ventilation.

Patient Anesthetized, Mechanically Ventilated, Chest Open

Zone 3 Ppa > Ppv > PA

Blood flow FIGURE 53–9. Schematic representation of the effects of gravity on the distribution of pulmonary blood flow in the lateral decubitus position. Vertical gradients in the lateral decubitus position are similar to those in the upright position and cause the creation of zones 1, 2, and 3. Consequently, pulmonary blood flow increases with lung dependency and is largest in the dependent lung and least in the nondependent lung. (Modified from Kaplan JA. Hemodynamic monitoring.)

Opening the chest results in a marked increase in the compliance of the upper lung, with a slight but still important increase in the compliance of the dependent lung. Airway pressure decreases in the dependent and the nondependent lungs. As a result, ventilation of the nondependent lung increases further compared with the closed-chest state.68 The cardiac index increases with opening of the chest

CHAPTER 53: Thoracic Anesthesia

Awake, closed chest distribution of ventilation

Upright position

Lateral decubitus position

V Nondependent lung

PPI

Dependent lung

P

A

B

FIGURE 53–10. Pleural pressure in the awake patient (closed chest) is most positive in the dependent portion of the lung; therefore, alveoli in this region are most compressed and have the least volume. Pleural pressure is least positive (most negative) at the apex of the lung; therefore, alveoli in this region are least compressed and have the largest volume. When these regional differences in alveolar volume are translated to a regional transpulmonary pressure–alveolar volume curve, the small dependent alveoli are on a steep (large-slope) portion of the curve, and the large nondependent alveoli are on a flat (small-slope) portion of the curve. In this diagram, regional slope equals regional compliance. Thus, for a given and equal change in transpulmonary pressure, the dependent part of the lung receives a much larger share of the tidal volume than does the nondependent part of the lung. In the lateral decubitus position (right side of diagram), gravity also causes pleural pressure gradients and therefore similarly affects the distribution of ventilation. The dependent lung lies on a relatively steep portion, and the upper lung lies on a relatively flat portion of the pressure–volume curve. Thus, in the lateral decubitus position, the dependent lung receives the majority of the tidal ventilation.

and pleura, but mean arterial pressure does not change significantly.69 The upper lung eliminates more CO2 shortly after the pleura has been opened.69 The increased elimination of CO2 from the upper lung is proportionately greater than the increase in ventilation. Also, the end-tidal PCO2 measured from the upper lung increases more than that of the lower lung, which reflects a marked increase in

the blood flow to the upper lung. The decrease in airway pressure on opening the pleura, along with the increase in cardiac index, results in increased blood flow to the nondependent lung.

Effect of PEEP Selective PEEP application to the dependent lung can improve oxygenation by decreasing the shunt fraction. The explanation is that PEEP to the

Awake

Anesthetized V

Nondependent lung

Nondependent lung

Dependent lung

Dependent lung

A

P

dependent lung increases the FRC of that lung, moving it to a steeper, more favorable portion on its pressure–volume curve and leading to improved ventilation of the dependent lung. Even if the increase in PVR caused by the application of PEEP shifts blood flow from the dependent to the nondependent lung, that portion of the cardiac output diverted to the nondependent lung still participates in gas exchange as long as it is ventilated or exposed to continuous positive airway pressure (CPAP).

Effects of Surgical Manipulation With the onset of surgical manipulations, compliance and distribution of ventilation to the upper lung decrease dramatically. End-tidal PCO2 and CO2 elimination from the upper lung decrease, but changes in PaCO2 are minimal.69

Summary The anesthetized, paralyzed patient in the lateral decubitus position with an open chest may have considerable V ˙ /Q˙ mismatch. The nondependent lung receives greater ventilation and less perfusion and has V ˙ /Q˙ >1. The dependent lung has more perfusion and less ventilation (i.e., low V ˙ /Q) ˙ and therefore acts as a physiologic shunt. The blood flow distribution is mainly determined by the effects of gravity. Causes of poor ventilation of the dependent lung are (1) loss of FRC because of induction of general anesthesia, (2) compression of the dependent lung by the mediastinum, (3) upward shift of the abdominal contents and paralysis of the diaphragm, (4) suboptimal positioning effects, (5) impaired ciliary clearance of mucus, and (6) absorption atelectasis from the use of high fraction of inspired oxygen (FiO2). Consequently, two-lung ventilation in these patients may result in an increased alveolar-toarterial PO2 difference and less than optimal oxygenation.

B

FIGURE 53–11. Schematic diagram showing the distribution of ventilation in the awake patient (closed chest) in the lateral decubitus position (left ) and the distribution of ventilation in the anesthetized patient (closed chest) in the lateral decubitus position (right ). Induction of anesthesia has caused a loss in lung volume in both lungs, with the nondependent (up) lung moving from a flat noncompliant portion to a steep compliant portion of the pressure–volume curve and the dependent (down) lung moving from a steep compliant part to a flat, noncompliant part of the pressure–volume curve. Thus, in the anesthetized patient in a lateral decubitus position, the majority of the tidal ventilation occurs in the nondependent lung (where there is the least perfusion) and the minority of the tidal ventilation in the dependent lung (where there is the most perfusion).

ONE-LUNG ISOLATION Indications The techniques of lung isolation are used to selectively ventilate the lung within one hemithorax while the nearly motionless lung is operated on in the contralateral hemithorax. Collapse of the nondependent lung produces less

1227


1228

trauma than surgical retraction and offers better exposure of structures within the hemithorax.15,16 The airways of the operated lung can be incised while positive-pressure ventilation continues in the other lung. During thoracoscopic surgery, collapse of the operated lung is essential to provide adequate visualization of structures within the pleural cavity. Although many surgical procedures are facilitated by use of isolation techniques, most procedures are feasible without isolation. Single-lung isolation is indicated under certain clinical conditions. When one lung contains either blood or infectious secretions, isolation of the lungs is imperative to prevent spillage of contents into the unaffected lung. Isolated lung ventilation is essential when a bronchopleural or bronchocutaneous fistula renders positive-pressure ventilation difficult or impossible. Furthermore, directing ventilation toward the healthier lung may result in better oxygenation and ventilation.70 Some procedures require isolated ventilation, including open procedures on the trachea and mainstem bronchi, such as sleeve and carinal resections, and bronchopulmonary lavage for pulmonary alveolar proteinosis.

the tracheal lumen into the other bronchus. Hence, a properly placed double-lumen endotracheal tube permits selective ventilation or collapse of either lung. Double-lumen endotracheal tubes are manufactured with selective bronchial extensions intended for placement into either the left or right mainstem bronchus. The left mainstem

A

Left-sided tube Most proximal acceptable position

MS

Most distal acceptable position Proximal left cuff to tip

Tip of left lumen at left upper lobe

Proximal left cuff to tip

MS LUL

LMS

LMS Proximal surface of left endobronchial cuff just below tracheal carina

MS = LMS – Proximal left cut to left tip B

Mallinckrodt right-sided tube Most proximal acceptable position

Design of Double-Lumen Tubes Isolated lung ventilation usually is accomplished through a double-lumen endotracheal tube. The central shaft of a double-lumen endotracheal tube is cylindrical and contains a septum that divides it into two symmetric Dshaped lumens. At the proximal end of each lumen is a short length of tubing that creates a Y-shape that permits independent attachment for ventilatory apparatus, clamping, or opening to atmospheric pressure. At the distal end, the shaft is surrounded by an inflatable tracheal cuff. The tracheal lumen terminates just below the tracheal cuff. The other lumen has a cylindrical extension, curved to fit into one of the mainstem bronchi, and carries an inflatable circumferential bronchial cuff. After the double-lumen endotracheal tube has been properly placed within the patient’s airway, the bronchial cuff permits use of the bronchial lumen for positive-pressure ventilation or exclusion of the hemithorax in which it resides. The tracheal cuff provides a seal that directs pressurized gas from

bronchus arises at a more acute angle with reference to the tracheal axis, but it is adequately long to easily accommodate the endobronchial extension with its inflatable cuff. In contrast, the right mainstem bronchus is nearly a direct extension of the trachea, but it contains a branch to the right upper lobe bronchus that arises close to the tracheal bifurcation (Fig. 53–12). A

Most distal acceptable position Distal surface of cuff at RUL RUL

MS Proximal surface of right endobronchial cuff just below tracheal carina

RUL

MS RMS

RMS Width of cuff

Length of the right cuff

MS = RMS – Width of right cuff C

Rusch right-sided tube

Diameter of RUL bronchus Length of RUL ventilation slot

MS = Length of RUL – Diameter of Ventilation slot RUL bronchus FIGURE 53–12. Schematic showing the definitions of the most proximal and most distal acceptable positions of left- and right-sided double-lumen tubes and the margin of safety in positioning double-lumen tubes. A. All left-sided double-lumen tubes. B. Mallinckrodt right-sided doublelumen tube. C. Rusch right-sided double-lumen tube. LMS, Length of left mainstem bronchus; LUL, left upper lobe; MS, margin of safety in positioning double-lumen tube; RMS, length of right mainstem bronchus; RUL, right upper lobe.


TABLE 53–5. Choice of Double-Lumen Endotracheal Tube

Patient Height 136–164 cm 4’5.5”–5’4.5” 165–179 cm 5’5”–5’10.5” 180–194 cm 5’11”–6’4.5”

Tube Size (Fr)

Depth of Insertion (cm)

37

27

39

29

41

31

From Brodsky JB, Benumof JF, Ehenworth J, et al. Depth of placements of left doublelumen endobronchial tubes. Anesth Analg 1991; 73:570–572, with permission.

right-sided double-lumen endotracheal tube has a fenestration within the bronchial extension and an elaborately shaped cuff to permit a seal without airflow obstruction. Because of these considerations, right-sided tubes are more difficult to insert and require more maintenance to ensure continuous ventilation of all lobes of the right lung. In the absence of a specific indication for a right-sided double-lumen endotracheal tube, a left-sided tube is strongly preferred.

Placement of Double-Lumen Tubes The type of tube is chosen based on the surgical procedure, and its size is based on the patient’s body habitus (Table 53–5). Direct laryngoscopy with a curved (MacIntosh) laryngoscope blade is preferred because the glottic opening is better exposed compared with a straight blade. The double-lumen endotracheal tube is held with its bronchial curve oriented anteriorly and its tracheal–pharyngeal curve oriented to the right. The tube is advanced through the glottic opening until the bronchial cuff just passes the vocal cords. If a stylet was used, it is removed. Two methods are used for cannulation of the desired bronchus: empiric or “blind placement,” and direct vision using fiberoptic assistance. In the first method, the tracheopharyngeal curve is rotated anteriorly until the proximal end of the double-lumen endotracheal tube just passes the midsagittal axis. The bronchial curve should now be oriented to the side dictated by the tube selected. It then is advanced until moderate resistance to further insertion is encoun-

tered. A bifurcated connector is attached to the two lumens, and the tracheal cuff is inflated. Intubation of the trachea is confirmed by capnography, auscultation, and observation of chest excursion. Once both lungs are determined to be adequately ventilated, it is safe to proceed with confirmation that the tube is positioned to allow isolation of the two lungs. Correct placement can be determined by a series auscultation maneuvers whereby the tracheal and bronchial lumens are ventilated independently. However, this technique is time consuming and may often prove inaccurate. The alternative method uses a bronchoscope to confirm placement. Each lumen of the bifurcated doublelumen endotracheal tube connector is fitted with a fenestrated membrane covered by a removable cap. While the lungs are ventilated with positive pressure, the fenestrated membrane on the tracheal lumen is uncovered, and the bronchoscope is passed through it into the double-lumen endotracheal tube to confirm placement. The alternative method of tube placement, which uses direct observation via a fiberoptic bronchoscope, is the most efficient method for confirming appropriate anatomic placement. The bronchoscope is steadily advanced through the tracheal lumen until its tip just exits from the distal opening. If the tube is properly positioned, the carina should be seen just beyond the opening, and the medial wall of the endobronchial extension should be seen entering the contralateral bronchus. The bronchial cuff should be entirely contained within the contralateral bronchus, while an unobstructed view of the opening into the ipsilateral bronchus is enjoyed. Disposable doublelumen tubes usually feature a prominent band around the endobronchial extension several millimeters above the endobronchial cuff to facilitate positioning. When ideally positioned, the band should lie at the level of the carina. It may be necessary to slightly advance or withdraw the tube to achieve ideal position. Once anatomically correct tube position has been confirmed, it is secured in place, and the endobronchial cuff is gently inflated under direct bronchoscopic visualization to ensure that the cuff does not herniate into the trachea. Each time the patient is repositioned, the position of the double-lumen endotracheal tube should be verified.

An alternative method of tube placement eliminates the possibility of placing the endobronchial extension in the wrong bronchus. The tube is passed through the cords and rotated as for the first method. It is advanced only until the tip of the bronchial extension is 20–22 cm beyond the central incisors as determined by markings on the shaft. The bronchial cuff is inflated to seal against the wall of the trachea. An anesthetic circuit is attached to the connector for the bronchial lumen, and intubation of the trachea is confirmed. The bronchoscope is passed into the bronchial lumen. After the tip of the bronchoscope has entered the trachea, it is advanced under direct visualization past the carina into the desired mainstem bronchus (Figs. 53–13 and 53–14). After the bronchoscope is advanced as far as possible, the bronchial cuff is deflated. Using the bronchoscope as a directing stylet, the double-lumen endotracheal tube is advanced until gentle resistance is met. The bronchoscope is withdrawn and placed in the tracheal lumen to confirm unimpeded access to the ipsilateral bronchus as in the first method. Once placement is confirmed, the tube is secured. Occasionally, double-lumen endotracheal tube is malpositioned. Three possible reasons are (1) the tube is inserted so deeply that the tracheal opening is beyond the carina; (2) the tube is not inserted far enough so that the bronchial cuff is above the carina, and (3) the endobronchial extension has entered the incorrect bronchus so that the tracheal lumen opening is trapped against the lateral wall of the trachea on the ipsilateral side (Fig. 53–15). Gently withdrawing or advancing the tube under direct bronchoscopic visualization should reveal and correct either of the first two causes. If the endobronchial extension is not in the correct bronchus, the tube is repositioned by inserting the fiberoptic bronchoscope in the endobronchial lumen and withdrawing the tube and scope until the carina is encountered. The tube and scope then are advanced down the appropriate mainstem bronchus. Right-sided tubes require more vigilance and confirmation that the fenestration supplying the right upper lobe bronchus is positioned correctly. This is accomplished by passing the bronchoscope into the endobronchial lumen and observing the upper lobe

1229


1230 FIGURE 53–13. Bronchoscopic guide for placement of single lung-ventilation devices. A. The bronchoscope is situated in the distal trachea. In this view, the carina is clearly visualized along with the anterior cartilaginous rings and the posterior striated membranous portion of the trachea. The takeoff of the right mainstem bronchus is more aligned with the trachea, predisposing to endobronchial intubation of the right mainstem bronchus when an endotracheal tube is advanced too far. The easiest way of absolutely identifying the carina is to locate the right upper lobe. Confirmation of the “true” left and right mainstem bronchi is the best way to ensure proper placement of the selective lung ventilation device. B. The bronchoscope is in the right mainstem bronchus, just proximal to the bronchus intermedius, which begins below the origin of the right upper lobe. Origin of the right upper lobe is variable but usually arises 1–1.5 cm past the carina between 2 and 4 o’clock. C. The bronchoscope is in the right upper lobe bronchus. The right upper lobe branches into three segments: apical, posterior, and anterior. These three orifices typically are arranged in “V” pattern, but they also can be oriented in a line. D. The bronchoscope is in the distal bronchus intermedius. The right middle lobe, which is to the right, immediately splits into the lateral and medial segments. It is possible to advance a double-lumen endotracheal tube distal enough down the right side so that the endobronchial lumen will be in the right inferior lobe and the tracheal lumen will expose the right middle lobe. The right middle lobe’s lateral segment orifice could be confused for the right upper lobe orifice, but the right middle lobe’s lateral segment does not subdivide like the right upper lobe. E. The bronchoscope is in the distal left mainstem bronchus. This view reveals the left upper and lower lobe bronchi. It is important to ensure that left-sided double lumen tubes have not been advanced too far, leading to selective intubation of the left upper or lower lobe.

bronchial orifice through the fenestration in the lateral wall of the endobronchial extension (Fig. 53–16). Although confirmation of position through direct visualization with a fiberoptic bronchoscope usually is rapid and definitive, it is not always feasible. Furthermore, although it assures anatomically correct position, it does not ensure functional isolation of the left and right lungs. Functional isolation is tested by selectively ventilating one lung while the other is vented to the atmosphere, and unilateral ventilation of the intended lung is confirmed by auscultation and visual or tactile observation. The opposite lung then is venti-

lated, and the test is repeated. A test for functional isolation should always be used when the double-lumen endotracheal tube is placed to prevent spillage of liquid from one lung to the other.

Complications Complications associated with doublelumen endotracheal tubes can be divided into two types: those resulting from malposition of the tube, and those caused by trauma to the tracheobronchial tree.

Malposition Malposition may lead to failure either to ventilate segments of the depen-

dent lung or to collapse the operative lung. Failure to ventilate segments of the ventilated lung can occur if the bronchial lumen obstructs the origin of the upper lobe bronchus, which frequently manifests as hypoxemia and increased peak airway pressures. A common cause of upper lobe obstruction is distal migration of the endobronchial lumen associated with flexion of the neck. Upper lobe obstruction is more common when a right-sided double-lumen endotracheal tube is inserted. Failure to collapse the nonventilated lung may interfere with the operation. Cephalad migration of the doublelumen endotracheal tube can be caused by surgical manipulation, neck extension, or traction on an inadequately secured tube. As the tube withdraws, the bronchial cuff herniates over the carina into the trachea. When partially herniated, increased cuff pressure may force the cuff further into the trachea. The herniated cuff may partially or fully obstruct the contralateral mainstem bronchus, making that lung difficult or impossible to collapse (or ventilate). Malposition of the tube should be suspected when peak airway pressure suddenly increases, hypoxemia occurs, or inflation of the nonventilated lung is detected. Vigilance should be heightened immediately after the patient is repositioned and during surgical manipulation near the hilum of the lung. At the first suspicion of a malpositioned double-lumen endotracheal tube, tube position should be confirmed immediately by fiberoptic bronchoscopy. If discerning the anatomy during an open thoracotomy is difficult, the surgeon may be able to manually guide the endobronchial lumen of the doublelumen endotracheal tube into the desired mainstem bronchus.

Traumatic Damage Trauma to the tracheobronchial tree by double-lumen endotracheal tubes include minor insults, such as ecchymosis of the mucous membranes, and more severe insults, such as arytenoid dislocation and vocal cord rupture. Catastrophic tracheobronchial rupture has been reported.71–76 The multiplelumen design and relatively large size of double-lumen endotracheal tubes make them stiffer than conventional endotracheal tubes, thus increasing the risk of damage from forceful ad-


A

B

C

FIGURE 53–14. Schematic diagram portraying use of the fiberoptic bronchoscope to insert a left-sided double-lumen tube. A. The double-lumen tube can be put into the trachea in a conventional manner, and both lungs can be ventilated by both lumens. The fiberoptic bronchoscope can be inserted into the left lumen of the double-lumen tube through a selfsealing diaphragm in the elbow connector to the left lumen. This allows continued positivepressure ventilation of both lungs through the right lumen without creating a leak. After the fiberoptic bronchoscope has been passed into the left mainstem bronchus (B), it is used as a stylet for the after-coming left lumen (C). The fiberoptic bronchoscope is then withdrawn. Final precise positioning of the double-lumen tube is performed with the fiberoptic bronchoscope in the right lumen.

vancement against resistance. The stiffness is further increased by use of a rigid stylet during tube placement. Therefore, when use of a stylet is required for intubation of the trachea, it should be withdrawn before the bronchial lumen of the double-lumen endotracheal tube is advanced into the mainstem bronchus. Injuries may result from excessive pressure in either the tracheal or bronchial cuffs, leading to tissue necrosis or rupture. The small size and high pressure of the bronchial cuff increase the risk of tissue injury from overinflation. Cuff pressure should be regularly monitored by palpation of the pilot balloon or by use of a calibrated device. Failure to obtain a complete seal is especially hazardous when the doublelumen endotracheal tube is used to protect one lung from liquid contents within the other. The leak may allow spillage of liquid into the unaffected lung. Liquids include saline during bronchopulmonary lavage, pus from unilateral empyema, and blood from airway hemorrhage.

Contraindications

In too far (on left side)

Left cuff blocks right lumen

Out too far (in trachea)

In too far (on right side)



Left

Right

Left

Procedure

Right

Left

Breath sounds heard

Clamp right lumen (both cuffs inflated)

Left

Left and right

Clamp left lumen (both cuffs inflated)

None or very ↓↓

None or very ↓↓

Left

Left and right

Clamp left lumen (deflate left cuff)

Right

Right None or very ↓↓ Right

FIGURE 53–15. The three major (involving a whole lung) malpositions of a left-sided doublelumen endotracheal tube. The tube can be in too far on the left (both lumens are in the left mainstem bronchus), out too far (both lumens are in the trachea), or down the right mainstem bronchus (at least the left lumen is in the right mainstem bronchus). In each of these three malpositions, the left cuff, when fully inflated, can completely block the right lumen. Inflation and deflation of the left cuff while the left lumen is clamped creates a breath sound—differential diagnosis of tube malposition (see text for explanation). L, left; R, right; –, decreased.

The principal contraindication to use of a double-lumen endotracheal tube is the presence of a luminal airway mass that may be dislodged or may prevent passage of the tube. Relative contraindications include critical dependence on bilateral mechanical ventilation in patients unable to tolerate its interruption, patients requiring rapid placement of an endotracheal tube to avoid aspiration of gastric contents, and patients in whom conventional tracheal intubation is judged to be difficult.

Alternative Methods of Lung Isolation When collapse of the left lung and ventilation of the right are required or use of a double-lumen endotracheal tube is not feasible, a bronchial blocker can be placed in the left mainstem bronchus. This strategy eliminates the risk of losing the airway while changing the endotracheal tube at the end of the case for patients requiring postoperative ventilation. Specific bronchial blockers having a patent central lumen to permit deflation of the distal airway have been developed. The Arndt catheter has a nylon loop that is used to ensnare the distal portion of the fiberoptic scope as it is advanced in the selected mainstem bronchus. The loop

1231


View down left (Tracheal) lumen

View down right (Bronchial) lumen

Tracheal carina

Bronchial carina

Right upper lobe bronchial orifice

Right lumen going off to the right A

B

FIGURE 53–16. Schematic diagram portraying use of a fiberoptic bronchoscope to determine precise right-sided double-lumen tube position. A. When the fiberoptic bronchoscope is passed down the left (tracheal) lumen, the endoscopist should see a clear straight-ahead view of the tracheal carina and the right lumen going off into the right mainstem bronchus. B. When the fiberoptic bronchoscope is passed down the right (bronchial) lumen, the endoscopist should see the bronchial carina off in the distance. When the fiberoptic bronchoscope is flexed cephalad and passed through the right upper lobe ventilation slot, the right upper lobe bronchial orifice should be visualized.

1232 is loosened and advanced distal to the fiberoptic scope. Another variation, the Cohen endobronchial blocker, incorporates a small wheel that is used to deflect the tip of the catheter into the selected bronchus. Under direct vision, the catheter is slowly withdrawn until the inflated balloon is just distal to the level of the carina. In an emergency, an angled Fogarty catheter is inserted through the endotracheal tube under radiographic or fiberoptic guidance into the desired bronchus.77 Absence of a patent lumen extending below the balloon of Fogarty catheters prevents suctioning or oxygen delivery to the occluded lung segment. Endobronchial intubation with a single-lumen tube offers an alternative to the double-lumen endotracheal tube, which can be especially useful in emergencies. Disadvantages of using a single-lumen tube include loss of ability to selectively ventilate or suction the contralateral lung and increased difficulty in placing or ascertaining correct placement of the tube. Endobronchial intubation is especially useful for patients who require emergent tracheal intubation for massive hemoptysis. For adults, endobronchial intubation requires a tube of adequate length, often >31 cm, to ensure that the entire cuff is placed below the carina. Occasionally it is necessary to extend the tube using a length of tubing and a connector. Although endo-

bronchial intubation of the right side is easier, preserving ventilation to the right upper lobe is inherently difficult. Mainstem intubation is facilitated using a fiberoptic bronchoscope as a directing stylet. Blind left mainstem placement can be achieved with a 92% success rate by turning the head to the right after the tube has passed through the vocal cords and then rotating the tube 180° so that the convex curve faces posteriorly before advancing it.78 The Univent tube is a single-lumen endotracheal tube that contains a bronchial blocker that passes through a small channel within the wall of an endotracheal tube. The bronchial blocker carries a low-pressure, high-volume cuff and has an internal lumen that can be used for suctioning the collapsed lung or for providing CPAP or high-frequency jet ventilation (Fig. 53–17).79 Initial tube placement in the trachea is accomplished as for any single-lumen tube; then it is rotated 90° toward the lung into which the blocker will be passed and advanced (Fig. 53–18). The blocker is advanced into the targeted mainstem bronchus, after which the tracheal cuff is inflated and the tube secured. The depth of the blocker is adjusted and confirmed using a flexible bronchoscope passed through the main lumen of the tube. Additional techniques to assist in placing the blocker include rotation of the head and placing the fiberoptic scope

in the opposite lung to divert the blocker into the contralateral side. The tube offers the advantage of allowing easy conversion from one- to two-lung ventilation (and vice versa), and it is suitable for long-term use in an intensive care unit (ICU) setting. The mobility of the blocker and the large volume of its cuff increase the likelihood of proximal migration, with herniation of the cuff into the trachea.

HYPOXIC PULMONARY VASOCONSTRICTION Humans encounter hypoxia throughout their lives. Hypoxia occurs in utero, through disease, and by desire, in our quest for higher altitude. HPV is a widely conserved, homeostatic, vasomotor response of precapillary smooth muscle in the PAs to alveolar hypoxia.80–82 HPV mediates V ˙ /Q˙ matching and, by reducing shunt fraction, optimizes systemic pO2. Although total pulmonary blood flow is directly proportional to right ventricular cardiac output, its distribution within the pulmonary vasculature can be altered dynamically. Hypoxia, caused by either atelectasis or ventilation with a hypoxic gas mixture, diverts blood flow to better ventilated, nonhypoxic lung segments. This phenomenon of HPV, first noted by Von Euler and Liljestrand in 1946, is of importance to the anesthesiologist, particularly during thoracic anesthesia. In the absence of inhibiting factors, HPV can divert blood flow away from nonventilated regions.80 When a patient is in the lateral decubitus position, the dependent lung receives 60% of the cardiac output, whereas the nondependent lung receives 40%. If

FIGURE 53–17. Close-up of the Univent tube shows two lumens. The small tube is retracted into the small lumen before intubation. (Modified from Kamaya H, Krishna PR. New endotracheal tube [Univent tube] for selective blockade of one lung, Anesthesiology 1985;63:342, with permission.)


A

Ventilate 12 mL/kg L

B

R

L

R

Ventilate L

Insert FOB through self-sealing diaphragm and decide R from L mainstem

FOB Intubate with Univent BB tube and inflate Univent cuff

Carina Cartilaginous ring

Self-sealing diaphragm in elbow connector

R

After FOB orientation, deflate cuff slightly and rotate Univent tube toward the side to be blocked and identify BB.

R

L

BB

D

C

Ventilate 12 mL/kg

Posterior membrane E

Ventilate L

R

F


R


R

1233 Advance BB into mainstem bronchus to be blocked

Inflate BB (6–7 mL). See cuff just below carina

Withdraw FOB

FIGURE 53–18. Sequential steps of the fiberoptic-aided method for inserting and positioning the Univent bronchial blocker in the left mainstem bronchus. One- and two-lung ventilation are achieved by simply inflating and deflating, respectively, the bronchial blocker balloon. FOB, fiberoptic bronchoscope.

the nondependent lung is not ventilated and is atelectatic, a maximal HPV response can reduce its blood supply by 50%. As a result, the dependent lung receives 80% of the cardiac output, and the atelectatic nondependent lung receives only 20% of the cardiac output (Fig. 53–19). Therefore, the arterial oxygen tension (PaO2) observed during regional lung hypoxia is much greater than would be expected if the HPV response were not present (Fig. 53–20).

Mechanisms HPV is mediated by the smooth muscle cells throughout the lung. Although modulated by the endothelium, the core mechanism is in the smooth muscle cell. The Redox Theory for the mechanism of HPV proposes the coordinated action of a redox sensor (proxi-

mal mitochondrial electron transport chain) that generates a diffusible mediator (reactive O2 species) that regulates an effector protein [voltage-gated potas-

sium (Kv) and calcium channels]. The subsequent inhibition of O2-sensitive Kv channels, particularly Kv1.5 and Kv2.1, depolarizes PA smooth muscle,

50% HPV response

A

B 40% Blood flow (60%)

20% 1 LV No isoflurane

Blood flow (80%)

FIGURE 53–19. A. Schematic diagram showing that the two-lung ventilation nondependent-todependent lung blood flow ratio is 40%/60%. B. When two-lung ventilation is converted to onelung ventilation (as indicated by atelectasis of the nondependent lung), the hypoxic pulmonary vasoconstriction response decreases the blood flow to the nondependent lung by 50% so that the nondependent-to-dependent lung blood flow ratio is now 20%/80%.


500 FIO2 = 1.0

PaO2 (mm Hg)

300 With HPV 200

Drugs and anesthetics may modulate HPV and interfere with V ˙ /Q˙ matching. Calcium channel blockers and vasodilators, such as sodium nitroprusside, attenuate the HPV response (Table 53–6). These drugs increase the A–a gradient, often leading to hypoxemia perioperatively. Other perioperative conditions, such as hypocapnia and hypothermia, also decrease the normal HPV response.83,85

Effects of Anesthetics 100

With no HPV 0

1234

20 40 60 80 100 Percent of lung hypoxic

FIGURE 53–20. Effect of hypoxic pulmonary vasoconstriction (HPV) on arterial PO2 (PaO2). As the percent of lung that is hypoxic increases (X-axis), PaO2 decreases (Y-axis). When the amount of lung that is 30% to 70% hypoxic, which is in the one-lung ventilation/anesthesia range, the decrease in PaO2 is much greater if there is no HPV compared with the normal expected amount of HPV. (From Benumof JL. One-lung ventilation and hypoxic pulmonary vasoconstriction: implications for anesthetic management. Anesth Analg 1985;64:821, with permission.)

activating voltage-gated Ca2+ channels and causing Ca2+ influx and vasoconstriction.81 A similar mechanism for regulating O2 uptake/distribution exists in simpler organisms and in other specialized mammalian O2-sensitive tissues, including the carotid body and ductus arteriosus.82 Hemodynamic variables can influence the magnitude of HPV. The pulmonary vasoconstrictor response to hypoxia is decreased with increases in PA pressure, cardiac output, left atrial pressure, and central blood volume.83 Increases in pulmonary vascular pressures can mechanically open and recruit closed vessels in hypoxic lung regions, overcoming part of the active pulmonary vasoconstriction.84 An increase in cardiac output can mask the HPV response by recruiting pulmonary vessels or increasing PvO2. Alternatively, HPV may increase PVR and PA pressures as flow is diverted from a proportionately large section of hypoxic lung to a smaller section of normoxic lung.84 When flow is diverted from small hypoxic segments, the high compliance of the pulmonary circulation prevents clinically significant changes in PVR or PA pressure.

Extensive studies have been performed to examine the effect of inhalation and intravenous (IV) anesthetics on HPV. The results and implications of these studies differ according to the type of experimental preparation used. In human studies and in more physiologic in vivo investigations with an intact systemic circulation, inhalation anesthetics produced either no effect or only a mild decrease in HPV.97,98 In part, the discrepancy between the more complex in vivo studies and simpler in vitro models occur because the additional factors that can modulate the HPV response, such as pulmonary vascular pressure, cardiac output, PCO2, and temperature, are absent. In the more biologically complex in vivo models, these factors seem to diminish the inhibitory effect of inhaled anesthetics on HPV.99,100 IV agents such as ketamine and propofol do not significantly affect HPV.99,101 HPV is not directly affected by thoracic epidural analgesia. Any changes that have been observed during epidural may be attributable to alterations in cardiac function and loading conditions.102

Nitric Oxide Nitric oxide (NO) is a unique endogenous compound that is found in endothelium and smooth muscle cells. NO induces vasodilatation by activating

protein kinases and guanylate cyclase and reducing or resequestering intracellular Ca2+. A class of IV vasodilators, including nitroglycerine and nitroprusside, produces muscle relaxation in a similar manner. The most common clinical uses of NO are for management of pulmonary hypertension and V ˙ /Q˙ mismatching. IV therapy nonselectively produces pulmonary and systemic vasodilatation. In contrast, NO administered as an inspired gas selectively dilates the vascular supply to those areas, thereby improving V ˙ /Q˙ matching. NO has been used clinically in cases of primary pulmonary hypertension, lung transplantation, cardiac transplantation, cardiac disease, adult respiratory distress syndrome (ARDS), acute pulmonary hypertension, congenital heart disease, and idiopathic pulmonary hypertension. Its clinical potential has been hampered by the complexity and cost of the gas and its delivery system. Delivery systems require an adequate scavenging system to reduce the risk of occupational exposure and continuous gas concentration monitoring. The potential toxicity of NO focuses on its conversion from the free radical form to NO2, which is associated with lung toxicity, and the formation of nitrosylhemoglobin, which is rapidly converted to methemoglobin.103–106 Clinical reports of NO-associated toxicity include methemoglobin toxicity, paradoxical deterioration in oxygenation related to edema or worsening of right-to-left shunting,79,103,105,107–109 and rebound pulmonary hypertension.103,110,111 Because of these latter responses, the dose of NO should be gradually decreased to avoid prevent in oxygenation or rebound pulmonary hypertension.

Prostacyclin Prostacyclin (PGI2, Epoprostenol, Flolan) is a member of the prostaglandin fam-

TABLE 53–6. Effect of Vasodilators on Hypoxic Pulmonary Vasoconstriction Drug

Effect

References

Hydralazine Nifedipine Verapamil Nitroglycerin Sodium nitroprusside Nicardipine Labetalol

No change Inhibited Inhibited Inhibited Inhibited No change No change

86 86–89 90, 91 93 94 95 96


ily of lipid mediators derived from arachidonic acid. It is synthesized predominantly by endothelial cells, including the pulmonary vascular endothelium.112 PGI2 produces vasodilatation in low-resistance vascular beds such as the pulmonary circulation.113 Not only has PGI2 been shown to stimulate endothelial release of NO,114 but NO has been shown in turn to enhance the production of PGI2 in human PA smooth muscle cells. It has a good safety profile; PGI2 is spontaneously hydrolyzed in plasma to its inactive metabolite, 6-keto-prostaglandin F. The in vitro half-life of prostacyclin in human blood at 37°C and pH 7.4 is approximately 6 minutes.115 Animal studies demonstrate that IV PGI2 has a high clearance (93 mL/min/kg), small volume of distribution (357 mL/kg), and short half-life (2.7 minutes).115 Prostacyclin that can be delivered as an aerosol has replaced NO as the preferred inhaled selective pulmonary vasodilators because of its lower cost and absence of toxic metabolites.112 It has minimal effects of systemic arterial pressure but results in dramatic improvements in arterial oxygenation and lowering of pulmonary arterial pressures. Its use during one-lung anesthesia can improve V ˙ /Q˙ matching, but it is not as effective as CPAP in the nonventilated (nondependent, operative) lung (see Strategies for Improving Oxygenation during One-Lung Ventilation).

STRATEGIES FOR IMPROVING OXYGENATION DURING ONE-LUNG VENTILATION Arterial hypoxemia during one-lung ventilation is difficult to predict clinically. Previous studies have attempted to identify predictive preoperative and intraoperative factors of PaO2 during single-lung ventilation. Some variables (relative perfusion to the operative lung, intraoperative PaO2 during twolung ventilation) were strongly identified as predictors of low PaO2 during one-lung ventilation, whereas other factors (side of operation, preoperative pulmonary function tests) have been controversial.117,118 Interestingly, patients with a hematocrit value >45% are reported to have lower PaO2 values during one-lung ventilation.119 The occurrence of hypoxia mainly depends on factors such as residual shunt to the nonventilated lung, cardiac output,

and degree of pulmonary vasoconstriction. However, strategies for managing hypoxemia during one-lung ventilation are available. The basic principles for management of one-lung ventilation include (1) delaying initiation until after the patient to turned to the lateral decubitus position while still allowing sufficient time for the nondependent lung collapse, (2) confirming correct positioning of the double-lumen tube by fiberoptic bronchoscopy, (3) using high-inspired O2 concentrations to decrease the risk of systemic hypoxemia, (4) using a large tidal volume of approximately 10 mL/kg and adjusting respiratory rate to keep PaCO2 at approximately 40 mm Hg, (5) continuously monitoring oxygenation using pulse oximetry, and (6) continuously monitoring ventilation by noting changes in end-tidal CO2 concentrations and peak inspiratory pressures. Measures for improving oxygenation during one-lung ventilation include one or more of the following strategies: (1) improving V ˙ /Q˙ distribution in the dependent lung (i.e., lung recruitment maneuver, PEEP), (2) increasing alveolar partial pressure of oxygen (PaO2) in the nondependent lung (i.e., CPAP), (3) decreasing blood flow to the nondependent lung (i.e., placement of a ligature on the PA), and (4) increasing blood flow and perfusion to the dependent lung (i.e., prostacyclin or NO).

Recruitment Maneuver Progressive atelectasis associated with decreasing PaO2 is a common problem in patients undergoing single-lung ventilation during thoracic surgery. These patients are at increased risk for atelectasis as a result of single-lung ventilation, lateral decubitus positioning, inhibition of HPV, and periodic disconnection from the ventilator. Recruitment maneuvers are used to reinflate collapsed alveoli, resulting in improved oxygenation and ventilation. A sustained pressure of approximately 35 cm H2O, which is above the tidal ventilation range, is applied for a period of 30–60 seconds in order to inflate lung units. After this maneuver, increasing the tidal volume or PEEP is not necessary because the subsequent lung volumes should be maintained. A successful procedure will result in improved oxygenation, reduced end-tidal CO2, and improved compliance.

Ventilation Using Large Tidal Volumes

Absorption atelectasis, caused by increased FiO2, can be decreased or prevented by ventilation using large tidal volumes, application of PEEP to the dependent lung, and ventilation with FiO2 30% of the hemithorax,190–192 those with progressively en-

FIGURE 53–27. Characteristic radiographic findings of patients with bullous disease. Typical findings in patients with chronic obstructive pulmonary disease include an increased size of lung fields and flattened hemidiaphragms. The appearance of hyperaeration of both apical lung fields (bracketed area), decreased vascular marking in upper lung fields, and compressive atelectasis of the lower lung fields are consistent with severe bullous lung disease.

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TABLE 53–10. Anesthetic Guidelines for Bullectomy and Volume Reduction Pneumoplasty

Indication

Preoperative concerns

Monitors Anesthesia Additional equipment Ventilation Position

Incision 1246 Unique considerations

Intraoperative complications Blood loss Postoperative analgesia Postoperative morbidity

Postoperative care

Bullectomy/Volume Reduction Pneumoplasty

Volume Reduction Pneumoplasty

Bullectomy—large bullae >30% of hemithorax Volume reduction—severe bullous emphysema Review preoperative pulmonary function tests and check arterial blood gases Pulmonary symptoms may mask presence of coronary artery disease Standard monitors and A-line General anesthesia Combined regional/general anesthesia Optional ( jet ventilator)

Severe bullous emphysema

Double-lumen endotracheal tube Bullectomy (lateral decubitus) Volume reduction pneumoplasty (lateral, supine) Bullectomy (thoracotomy, VATS) Volume reduction pneumoplasty (thoracotomy, VATS, median sternotomy) Single-lung ventilation Avoid positive end-expiratory pressure Minimize use of long-lasting respiratory depressants Restrict administration of intravenous fluids Tension pneumothorax Pneumothorax Hypoxia Hypercarbia Minimal 92% on room air Needs O2 to maintain >90% 70%)

Low (< 70%) SaO2

Do nothing Low (hypoxemia)

Normal (> 95%) (Increased O2ER)

Oxygen therapy, increase PEEP

Cardiac output High (> 2.5 L/min.M2) Hemoglobin

>8 g/dL < 8 g/dL stress, anxiety, pain anemia (high VO2) Analgesia sedation

Blood transfusion

High (< 2.5 L/min.M2)

PAOP >18 mm Hg myocardial dysfunction

Dobutamine

< 18 mm Hg hypovolemia

Fluid challenge

FIGURE 82–4. Diagnostic and therapeutic algorithm based on mixed venous oxygen saturation (SvO2) measurements: therapeutic options to be considered are presented in the rectangles. O2ER, oxygen extraction ratio; PAOP, pulmonary artery occlusion pressure; PEEP, positive endexpiratory pressure; SaO2, arterial oxygen saturation; VO2, oxygen consumption. (Reproduced with permission from Pinsky MR and Vincent JL.74)

CHAPTER 82: Hemodynamic Support of the Critically Ill Patient

lactate levels provide valuable information regarding global adequacy or perfusion and oxygenation, they do not provide detail on the adequacy of regional microcirculatory blood flow or oxygen delivery and use, which is believed to be a crucial factor in the development of multiple organ failure in patients with shock. Measuring regional parameters is of particular importance, as they can remain inadequate even when global parameters have returned to normal. However, even though considerable progress is being made in this field, there is as yet no ideal technique that can be used in critically ill patients to assess regional blood flow or oxygenation.

Gut Tonometry The measurement of regional perfusion initially focused on the splanchnic circulation as the hepatosplanchnic circulation is particularly sensitive to changes in blood flow and oxygenation, and may have a higher critical oxygen delivery threshold than other organs. In addition, a countercurrent exchange mechanism operates in the villus, making the tip particularly sensitive to changes in regional flow and oxygenation. However, gastric tonometry is limited by measurement errors, doubts regarding the validity of pHi calculations, and unreliability of results during patient feeding.76 Calculations of gastric pHi were replaced by gastric mucosal PCO2 because this measure is not confounded by arterial bicarbonate, but because gastric mucosal PCO2 is influenced by systemic arterial PCO2, the gastric–arterial PCO2 difference may be of more interest.77 An early trial suggested that tonometry derived parameters may be useful in guiding therapy,78 but these findings were not confirmed in a later study,79 and many investigators have emphasized the limited sensitivity, and especially specificity, of these measurements. Different vasoactive agents have divergent effects on gut PCO2 and pHi that are neither consistent nor predictable.80

Sublingual Capnography The methodologic limitations of gastric tonometry encouraged researchers to look elsewhere for another easily accessible tissue where local PCO2 could be measured, and the sublingual circulation has been suggested for this purpose. Several clinical studies have suggested that sublingual PCO2 (PslCO2) is

a reliable marker of tissue hypoperfusion. However, as with gut PCO2, PslCO2 may also be influenced by arterial CO2 and the gradient (i.e., gap) between PslCO2 and PaCO2 may be more specific for tissue hypoperfusion.81 In a recent study, the PslCO2 gap was found to correlate with the alterations in microcirculatory blood flow seen in patients with severe sepsis.82 Further work is clearly needed to define normal and pathologic PslCO2 levels and to establish whether targeting treatments to restore a normal PslCO2 can improve outcomes.

CONCLUSION: THE GLOBAL PICTURE Multiple organ failure is a serious problem in intensive care unit patients, resulting in high morbidity and mortality and associated resource use and costs. Multiple organ failure can arise from many causes, but a key factor in its development appears to be an imbalance between tissue oxygen requirements and uptake. Tissue oxygen uptake can be limited by inadequate oxygen delivery and availability, and also by altered oxygen extraction ability. Appropriate hemodynamic support can improve both global and regional blood flow and, hence, oxygen delivery. Early studies suggested that those patients with greater cardiac index and oxygen delivery values were more likely to survive conditions associated with the development of multiple organ failure.83,84 This observation was the rationale behind several studies in the early 1990s, which assessed the benefits of increasing oxygen delivery to supranormal values using inotropes and fluids. Although this approach was shown to improve outcomes in some groups of critically ill patients, notably surgical and trauma patients,85,86 routine application to all critically ill patients does not confer a uniform survival benefit and may worsen outcomes in some patients.62,87 However, a protocol targeting adequate oxygen transport, as reflected by the ScvO2, in patients who are at risk of multiple organ failure, has been shown to result in improved survival2 and adequate oxygenation clearly remains an important parameter to target. Unfortunately, at present there is no clear marker of adequate tissue oxygenation so we must rely on surro-

gate markers of tissue perfusion and oxygenation as discussed above. Adequate oxygen delivery is likely to vary among patients and in the same patient over time so that hemodynamic support must be titrated and adjusted carefully based on each individual’s response to the therapy.

KEY REFERENCES 1. Dellinger RP, Carlet JM, Masur H, et al. Surviving sepsis campaign guidelines for management of severe sepsis and septic shock. Crit Care Med 2004;32(3):858–873. 2. Hollenberg SM, Ahrens TS, Annane D, et al. Practice parameters for hemodynamic support of sepsis in adult patients: 2004 update. Crit Care Med 2004;32(9):1928–1948. 3. Vincent JL, Weil MH. Fluid challenge revisited. Crit Care Med 2006; 34:1333–1337.

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al pH in patients with severe sepsis. Crit Care Med 1995;23(7):1184–1193. 76. Creteur J. Gastric and sublingual capnometry. Curr Opin Crit Care 2006;12(3): 272–277. 77. Russell JA. Gastric tonometry: does it work [editorial]? Intensive Care Med 1997; 23(1):3–6. 78. Gutierrez G, Palizas F, Doglio G, et al. Gastric intramucosal pH as a therapeutic index of tissue oxygenation in critically ill patients. Lancet 1992;339:195–199. 79. Gomersall CD, Joynt GM, Freebairn RC, Hung V, Buckley TA, Oh TE. Resuscitation of critically ill patients based on the results of gastric tonometry: a prospective, randomized, controlled trial. Crit Care Med 2000;28(3):607–614. 80. Silva E, De Backer D, Creteur J, Vincent JL. Effects of vasoactive drugs on gastric intramucosal pH. Crit Care Med 1998;26: 1749–1758. 81. Marik PE, Bankov A. Sublingual capnometry versus traditional markers of tissue oxygenation in critically ill patients. Crit Care Med 2003;31(3):818–822. 82. Creteur J, De Backer D, Sakr Y, Koch M, Vincent JL. Sublingual capnometry tracks microcirculatory changes in septic patients. Intensive Care Med 2006;(32):516–523. 83. Bland RD, Shoemaker WC, Abraham E, Cobo JC. Hemodynamic and oxygen transport patterns in surviving and nonsurviving postoperative patients. Crit Care Med 1985; 13:85–90. 84. Bishop M, Shoemaker WC, Appel P, Wo CJ, Zwick C, Kram H, et al. Relationship between supranormal circulatory values, time delays and outcome in severely traumatized patients. Crit Care Med 1993;21: 56–63. 85. Boyd O, Grounds M, Bennett ED. A randomized clinical trial of the effect of deliberate perioperative increase of oxygen delivery on mortality in high-risk surgical patients. JAMA 1993;270:2699–2707. 86. Fleming A, Bishop M, Shoemaker WC, et al. Prospective trial of supranormal values as goals of resuscitation in severe trauma. Arch Surg 1992;127:1175–1181. 87. Gattinoni L, Brazzi L, Pelosi P, et al. A trial of goal-oriented hemodynamic therapy in critically ill patients. N Engl J Med 1995; 333:1025–1032.

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CHAPTER 83 Mechanical Ventilation for the Surgical Patient Robert M. Kacmarek, PhD, RRT, and Dean R. Hess, PhD, RRT

The vast majority of surgical patients do not require support of the respiratory system once they are past the immediate postoperative period. However, others with preexistent chronic respiratory diseases, trauma patients, and patients who require extensive surgical procedures may require more lengthy periods of respiratory support. This chapter focuses on mechanical ventilation of the postoperative patient. The chapter primarily discusses invasive ventilation but also reviews selected data for noninvasive respiratory support and the application of noninvasive positive pressure ventilation (NPPV) and continuous positive airway pressure (CPAP) by mask.

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INDICATIONS FOR INTUBATION AND MECHANICAL VENTILATION The main objectives of mechanical ventilation in the postoperative patient are to decrease the work of breathing and the load on the cardiovascular system, and to reverse life-threatening hypoxemia or respiratory acidosis. Table 83–1 summarizes some of the specific indications for mechanical ventilation.1,2 Esteban et al. reported an international survey of 1638 patients requiring mechanical ventilation. Acute respiratory failure was the indication for mechanical ventilation in the majority of patients (66%), followed by coma (15%), an acute exacerbation of chronic obstructive pulmonary disease (13%), and neuromuscular disorders (5%).3 Included under the heading of respiratory failure were postoperative respiratory failure, acute respiratory distress syndrome (ARDS), heart failure, pneumonia, sepsis, and complications of trauma.3

MECHANICAL VENTILATION TARGETS Pressure Versus Volume Ventilation During all forms of mechanical ventilation the ventilator must be programmed to deliver gas to achieve specific target values. The format for gas delivery in most ventilator modes is to either a targeted pressure or volume (Table 83–2).1 In volumetargeted ventilation (the original approach to ventilatory support), a specific tidal volume is set by the clinician and the ventilator ensures that the volume is delivered regardless of inspiratory pressure (up to a clinicianset limit). In addition to tidal volume, the flow waveform and peak flow or inspiratory time must be set. With this approach to ventilatory support the focus is on ensuring that ventilation is maintained at a targeted level. Pressure ventilation is essentially an opposite approach to ventilatory gas delivery. A peak airway pressure is set, with the result that the peak alveolar

pressure is limited. That is, with each breath pressure increases to the set level before the breath terminates. However, the tidal volume and gas flow are allowed to vary from breath to breath. During pressure ventilation the clinician must set the targeted pressure, and in some modes, the allowed inspiratory time. Flow is provided rapidly at first, then in an exponentially decelerating pattern where the rate of deceleration is dependent upon the patient’s inspiratory demand and lung mechanics.4 Essentially, the ventilator rapidly delivers gas flow to establish the targeted pressure but once the pressure target is met, the flow must decrease to avoid exceeding the set pressure. This approach to ventilatory support focuses on ensuring a targeted pressure is met and never exceeded. As noted in Table 83–3 pressure and volume ventilation respond differently to changes of the impedance to gas delivery. With volume ventilation pressure increases if the patient becomes more difficult to ventilate, whereas with pressure ventilation the tidal volume is decreased. Most modes of ven-

KEY POINTS 1. Patients require mechanical ventilation because of apnea, acute or impeding acute respiratory failure, or severe refractory hypoxemia. 2. The two basic forms of mechanical ventilation are pressure ventilation (peak airway pressure constant, tidal volume variable) and volume ventilation (tidal volume constant, peak airway pressure variable). 3. Although numerous modes of ventilation exist little data is available to differentiate the benefits of one over the other and no mode has been shown to improve outcome. 4. A major concern during assisted ventilation is patient–ventilator synchrony—the ventilator should be set to match the patients ventilatory demands. 5. Autopositive end-expiratory pressure (PEEP) is a common cause of patient–ventilator dyssynchrony; in patients with obstructive lung disease, properly set applied PEEP improves synchrony and decreases patient effort.


6. It is unnecessary to achieve normal PaO2 and PaCO2. In most critically ill patients, a PaO2 ≥ 60 mm Hg is usually acceptable and permissive hypercapnia may be necessary in some patients. 7. Ventilator-induced lung injury is primarily caused by localized overdistension and the opening and closing of unstable lung units. 8. In the vast majority of patients who are ventilated, the tidal volume should be 5–10 mL/kg predicted body weight (PBW) and the plateau pressure should be 50 mm Hg and pH 15 kg or 45 × % min MV/100 if IBW < 15 kg whereas the maximum tidal volume delivered is the targeted MV/5.16 With this information the ventilator determines the optimal breathing pattern that will minimize the work of breathing; that is, a ventilatory pattern that results in minimum work of breathing based on the lung and chest wall mechanics of the patient. With the initial application of ASV the ventilator provides a series of 5 pressure-limited test breaths at a rate of about 10 breaths/min with a maximum pressure of 15 cm H2O. During these breaths, the ventilator measures dynamic compliance, the respiratory time constant, tidal volume, and the patient’s respiratory rate.16 These measurements are used to determine the initial targets for breathing rate and tidal volume. As ventilation con-

tinues the ventilator software recalculates the above variables from each breath and determines the new rate and tidal volume targets. Targets are based on the original work by Otis for estimating the patients’ minimal ventilatory work.18 This mode of ventilation is designed to ensure an ideal ventilatory pattern is maintained and can be used in all phases of ventilatory support. It continually adjusts mechanical ventilation characteristics as the patient’s status changes because it monitors the patient’s lung mechanics on a breathto-breath basis.

Automatic Tube Compensation This mode of ventilation has been referred to as electronic extubation. Automatic tube compensation (ATC) is designed to provide sufficient mechanical ventilatory support during inspiration and sufficient decompression of the ventilatory circuit during expiration to maintain the tracheal pressure equal to the set PEEP level. The ventilator software accomplishes this by having the resistance properties of various endotracheal and tracheostomy tube sizes programmed into its memory and continually measuring gas flow. From this data, the pressure needed to overcome the resistance (resistance = change in pressure divided by flow) of the endotracheal tube is continually calculated and applied.19 Upon activation of the ATC mode, the clinician must indicate the type and size of artificial airway and the desired percentage of automatic tube compensation (20–100% on most ventilators).4,5 In addition, some ventilators only apply the ATC correction during inspiration, others during both inspiration and expiration. The precise clinical indications for ATC are still unclear. Because this mode responds only to the patient’s demand, if demand is low, ventilatory support is low; that is, if the patient generates a low inspiratory effort then little pressure is applied, whereas if the patient generates great effort, the applied pressure is greater.20 ATC, like proportional-assist ventilation, does not force a ventilatory pattern, but is only designed to unload the flow resistive properties of the artificial airway. Its use is recommended for patients ready to wean from the ventilator. If the ATC pressure level is stable and

CHAPTER 83: Mechanical Ventilation for the Surgical Patient

Proportional-Assist Ventilation This mode of ventilation is similar to ATC but the software weighs both the mechanics of the total respiratory system plus the resistive properties of the artificial airway; that is, the ventilator delivers a pressure assist in proportion to the patient’s desired tidal volume (volume assist) and to the patient’s instantaneous inspired flow (flow assist).21 The level of these two aspects of ventilatory assistance are automatically adjusted to meet changes in the patient’s ongoing ventilatory demand. This algorithm is based on the law of motion as it applies to the respiratory system: Pmus + Pappl = (volume × E) + (flow × R) where Pmus is pressure generated by the respiratory muscles,21 Pappl is pressure applied by the ventilator, and E and R are elastic and resistance properties of the respiratory system. Assuming that E and R are linear during inspiration, the instantaneous flow and volume to be delivered are proportional to the resistive and elastic work of breathing respectively. The ventilator measures the instantaneous flow and volume, whereas the clinician must measure and set values for E and R. Ideally, the ventilator should be able to measure on a breath-by-breath basis E and R, and software should adjust gas delivery accordingly by estimating Pmus and assisting Pmus in a proportional manner.22 Thus the patient is the determinant of the ventilatory pattern. Patients are given the freedom to select a ventilatory pattern that is rapid and shallow or slow and deep.22 The ventilator does not force any control variable except the unloading of E and R in a proportional manner. Proportional-assist ventilation (PAV) is only useful in patients with a stable

ventilatory drive who choose an acceptable ventilatory pattern. Of concern is the inability of most mechanical ventilators to reassess E and R on an ongoing basis. As a result, the level of unloading may be inappropriate if respiratory system mechanics are dynamically changing. There are a number of clinical reports that compare the effects of PAV with those of pressure support, and PAV functions equivalently.23,24 In addition, the PAV mode has been shown to be useful during noninvasive ventilation.25,26

Airway Pressure Release Ventilation This mode of ventilation is a combination of pressure-targeted SIMV and inverse-ratio pressure-control ventilation.27 As illustrated in Fig. 83–11, airway pressure release ventilation (APRV) applies two levels of CPAP and allows spontaneous unassisted breathing at each CPAP level. There are two approaches to setting APRV based upon the belief that spontaneous breathing should only occur at the high CPAP level,28 or at both CPAP levels.29 If the clinician desires spontaneous breaths only at the high CPAP level, the time spent at the low CPAP level is kept brief to prevent complete exhalation, hence an inverse ratio between high and low CPAP levels. In this setting, the high CPAP level is set to maintain oxygenation and the lower level assists ventilation by periodically decreasing the lung volume. The alternate approach is to set the low CPAP level to maintain oxygenation (as if setting a PEEP level) and the high CPAP level to provide ventilatory assistance, as in SIMV.29 In this latter approach, the time spent at low CPAP levels is sufficient to allow complete exhalation and spontaneous breathing at the lower CPAP levels. Proponents of APRV cite the salutary benefits of spontaneous unsupported breathing to improve ventilation–perfusion matching, increase cardiac output and reduce the need for sedation.27–29 However, as noted in Fig. 83–12, the effort associated with spontaneous breathing under these conditions can result in very high esophageal pressure swings and a high work of breathing for the patient. Accounting in part for the greater cardiac output.30 In addition, dyssynchrony is common with APRV. Dyssynchrony occurs at the mandatory transition from high-to-low or low-to-high CPAP

Phigh Pressure

remains at a low pressure (5–7 cm H2O), then extubation is indicated. The use of expiratory ATC does raise some concerns when used in patient’s with airways obstruction. The decompression of the airway during early exhalation may precipitate greater airways collapse and obstruction. As with many of these newer modes of ventilation, additional research is required before clinical indications and contraindications can be clearly defined.

Plow Time FIGURE 83–11. Airway pressure release ventilation (APRV). Phigh, high continuous positive airway pressure (CPAP) level; Plow, low CPAP level. Note spontaneous breaths at both levels of CPAP. (Reprinted from Kacmarek RM, Dimas S, Mack C. Essentials of Respiratory Care. 4th ed. St. Louis, MO: Elsevier, 2005: 690–714, with permission from Elsevier.)

levels. If the patient is exhaling when the ventilator increases airway pressure, or inhaling when the ventilator decreases airway pressure, dyssynchrony results. Although this mode of ventilation is most commonly used in the management of acute lung injury or the acute respiratory distress syndrome, it has not been shown to be more beneficial than the assist/control mode.29

Bilevel Pressure Ventilation This is a modification of APRV. As noted in Fig. 83–13, pressure support can be added to spontaneous breaths at either the high or low CPAP level or both.4 This reduces the patient’s effort and esophageal pressure swings but it also increases the mean intrathoracic pressure, negating somewhat the increased cardiac output and beneficial augmentation of ventilation to perfusion matching. In addition, the transition from high-to-low and low-to-high CPAP levels is coordinated with the patient’s muscular effort (as in SIMV), markedly decreasing dyssynchrony. Like APRV, the bilevel ventilation mode is primarily employed in the management of acute lung injury and the acute respiratory distress syndrome.

VENTILATOR SETTINGS AND PATIENT–VENTILATOR SYNCHRONY Patient–ventilator synchrony is a critical issue for every patient triggering the ventilator for a mechanically supported inspiration. A lack of synchrony increases ventilatory effort, respiratory rate, and the patient’s work of breathing as the ventilator is not providing flow to match the patient’s inspiratory demand. Pressure-targeted modes of ventilation are generally better than

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FIGURE 83–12. Airway pressure release ventilation actual patient tracings. A synopsis of airway pressure (Paw ), flow, volume, and esophageal pressure (Pes) is shown. A. Time intervals of the upper (Phigh ) and lower airway pressure (Plow ) set to 2.5 seconds each. B. Time intervals of Phigh = 4.0 seconds and Plow = 1.0 second in the same patient. Note that spontaneous breathing occurs on the upper and lower CPAP levels in A and that tidal volumes varied considerably, depending on the pressure level from which an inspiration started. When Plow was decreased to 1.0 second, as shown in B, spontaneous breaths occurred almost exclusively during Phigh. This results in a more regular breathing pattern as compared with A. Note, however, the large esophageal pressure swings (10–12 mbar or cm H2O) per breath, indicating high patient effort on each spontaneous breath. Breaths are classified as type A, spontaneous breath at the lower CPAP level; type B, spontaneous breath on the upper CPAP level; type C, the pressure increase from the lower to the upper CPAP level triggered by an inspiratory effort of the patient; type D, mechanical breath; and type E, combined mechanical and spontaneous inspiration without a triggered pressure increase from Plow to Phigh. (Newman P, Golisch J, Strohmeyer A, et al. Influence of different release times on spontaneous breathing pattern during airway pressure release ventilation. Intensive Care Med 2002;28:1742, with kind permission of Springer Science and Business Media.)

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Plow Time FIGURE 83–13. Bilevel ventilation upper airway pressure (Phigh ). High continuous positive airway pressure (CPAP) level and lower airway pressure (Plow) low CPAP level. Note spontaneous breaths at both levels of CPAP, but in this case pressure support is applied to the breaths at the Plow . Pressure support could also be applied to Phigh . (Reprinted from Kacmarek RM, Dimas S, Mack C. Essentials of Respiratory Care. 4th ed. St. Louis, MO: Elsevier, 2005: 690–714, with permission from Elsevier.)

volume-targeted modes at reducing the likelihood of dyssynchrony, as pressure ventilation allows the ventilator to deliver a variable flow with each breath based on the patient’s inspiratory demand.31 In addition, most ventilators now allow adjusting the slope of the increase of flow delivery (rise time) to ensure gas delivery is matched to patient’s inspiratory flow demand.5,32 Patient–ventilator synchrony is also affected by the inspiratory time. The ventilator’s inspiratory time and the patient’s inspiratory time should be equal. Trigger sensitivity should always be set to be as sensitive as possible without causing spontaneous autotriggering. In general, flow triggering is to

be recommended over pressure triggering.33 A final factor affecting patient– ventilator synchrony is auto-PEEP,34 which normally is only a problem in patients with airways obstruction, although it is a potential concern in all patients. If the patient’s inspiratory efforts fail to trigger the ventilator, the problem is usually auto-PEEP.35

Peak Flow and Flow Waveform If a patient is spontaneously triggering the ventilator, peak flow delivery during volume ventilation should match the patient’s inspiratory flow demand.36 Most adult patients with moderate to strong ventilatory demands require a peak flow of ≥ 80 L/min. As


Volume

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FIGURE 83–14. A. Depiction of an actual pressure-time curve (dotted line) during volume control ventilation superimposed on the ideal curve reflecting total work of breathing (solid line). B. Note the scooped-out actual pressure waveform when patient demand increases. The hatched area reflects the work performed by the patient during assisted volume-targeted ventilation. (Marini JJ, Rodrigues RM, Lamb V. The inspiratory workload of patient-initiated mechanical ventilation. Am Rev Respir Dis 1986;134:902–909. © American Thoracic Society.)

clearly demonstrated by Marini et al. (Fig. 83–14), if the peak flow does not meet the patient’s inspiratory demand the work of breathing performed by the patient increases. The efficiency of the work may be greater than during spontaneous breathing but the overall patient work may be similar.36 It is important to remember that if the patient is triggering the positivepressure breaths, the work of breathing is shared between the patient and the ventilator. It is for this reason that patients originally receiving assisted ventilation demonstrate altered gasdelivery patterns after they are sedated to apnea. With the transition to controlled ventilation, the peak airway and plateau pressures usually increase during volume ventilation, and tidal volumes decrease in the pressure ventilation mode.37 Because the patient is no longer performing a portion of the work of breathing, the work performed by the ventilator must increase. Most ventilators during volume ventilation mode can deliver gas flow in a decelerating or square wave flow pattern. If the patient is triggering inspiration, we recommend a decelerating flow pattern, especially when a small tidal volume (VT) is being delivered.4,37 A decelerating flow pattern allows a high peak flow to be delivered, but also ensures that the inspiratory time can be adequately set. In patients who are sedated and who are not triggering the ventilator, the

choice of flow waveform is unimportant, and the setting of peak flow is dependent on the predetermined inspiratory time and tidal volume.

Inspiratory Time In patients self-triggering every breath, the set inspiratory time should equal the patients neuroinspiratory time.38 As illustrated in Fig. 83–15, when the inspiratory time is decreased to equal A

B

the patient’s desired inspiratory time and peak flow is increased to match the patient’s demand, then the patient’s work of breathing and effort correspondingly decrease. It is rare that a patient with a moderate to high ventilatory demand desires an inspiratory time less than 1 second.38 In fact, many adults with moderate or high ventilatory demands desire an inspiratory time of between 0.6 and 0.9 seconds.37 Carefully matching the patient’s inspiratory time with the ventilator’s inspiratory time generally markedly improves patient–ventilator synchrony. In patients who are receiving controlled mechanical ventilation, inspiratory time is set based on the tidal volume and the clinician’s perceived optimal time of inspiration. In most settings, an inspiratory time of about 1.0 second is ideal. Some clinicians prefer to lengthen the inspiratory time in ARDS/acute lung injury (ALI), thereby inversing the usual inspiratory-to-expiratory (I:E) time ratio; however, there are no data to indicate that longer inspiratory times result in better oxygenation or better outcomes in these syndromes than an appropriately set PEEP level.39,40 Prolongation of the inspiratory time can have a minor positive effect of increasing CO2 elimination by allowing time for inspired gas C

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FIGURE 83–15. Representative example of the effect of alternations in peak flow and inspiratory time on airway pressure (Paw ), the raw diaphragmatic electromyography (EMG) signal (Raw Edi), the diaphragmatic EMG signal after removal of the electrocardiographic interference and rectification, and the calculated pressure output of the inspiratory muscles (Pmus ). Note the reduction in EMG activity and muscle output as flow increases. (Fernandez R, Mendez M, Younes M. Effect of ventilatory flow rates on respiratory timing in normal humans. Am J Respir Crit Care Med 1999;159: 710–719. © American Thoracic Society.)

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to transfer from fast time constant lung units to adjacent slower time constant units (“pendelluft”). In patients with severe asthma, the inspiratory time may need to be increased to 1.2–1.5 seconds to ensure ventilation passes beyond markedly obstructed airways.37 Note that in asthma the airways resistance is not only increased during exhalation but also during inspiration.

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Over the past 10 years, emphasis has been placed on the relationship between elevated tidal volumes and ventilator-induced lung injury (VILI; see Ventilator-Induced Lung Injury below).41 Recent epidemiologic studies indicate that the most common tidal volume used to manage patients in acute respiratory failure is about 10 mL/kg PBW.42 However, it is also important to emphasize that normal healthy relaxed mammals breathe at a tidal volume of about 6–7 mL/kg of PBW.43 There is no evidence indicating that tidal volumes >10 mL/kg PBW are useful in the management of critically ill patients. In fact, evidence from a recent retrospective review indicates that the development of ALI is linked to large tidal volume ventilation (>10 mL/kg PBW).44,52 As a general rule, all critically ill patients should be ventilated with ≤10 mL/kg PBW of VT regardless of the cause of their acute ventilatory failure. Patients with ALI/ARDS ideally should be ventilated with a VT 4–8 mL/kg of PBW.45

Plateau Pressure The plateau pressure (end-inspiratory equilibration pressure) is a function of the mean peak alveolar pressure and is a reflection of the transpulmonary pressure. Similar to VT, it is unknown if there is a specific plateau pressure that is safe. Because of the high shear forces associated with the ventilation of heterogeneously diseased lung, mechanical lung injury is theoretically possible, even with transpulmonary pressures below 30 cm H2O. However, most clinicians would agree that a plateau pressure less than 25 cm H2O is unlikely to produce an injurious level of alveolar overdistension, and that a plateau pressure in this range and a tidal volume ≤10 mL/kg PBW will not produce VILI regardless of the cause of respiratory failure. However, as plateau pressure increases, the delivered tidal volume should be decreased, re-

gardless of the cause of respiratory failure. VT should be kept ≤8 mL/kg PBW if the plateau pressure is 25–30 cm H2O and VT should be ≤6 mL/kg PBW if plateau pressures are >30 cm H2O. Ideally, all patients should be managed with a plateau pressure of 30 cm H2O may be required and would not be associated with an increased risk of VILI.46 However, in all patients the plateau pressure should ideally be maintained below 40 cm H2O. Alternatively, some have advocated the use of an esophageal balloon to estimate pleural pressure and guide mechanical ventilation strategies to limit transpulmonary pressure.

Auto-PEEP Auto-PEEP, also known as occult PEEP, is defined as an alveolar pressure above the airway opening pressure. Auto-PEEP can be caused by flow limitation, dynamic hyperinflation, a high minute ventilation, expiratory muscle activity, and/or a high intraabdominal pressure (Fig. 83–16).34,47 Occult autoPEEP is a term that is used to describe those lung units with trapped gas that do not communicate with the airway following a prolonged end expiratory pause.48 Occult auto-PEEP is likely a function of airway closure or occlusion secondary to mucus plugging, and can be difficult to clinically diagnose. The performance of an end-expiratory occlusion maneuver can be helpful in estimating auto PEEP levels if the patient is not making expiratory muscle efforts (passive-controlled ventilation). However, the absence of auto-PEEP by this technique should not be completely reassuring, because occult autoPEEP may still be present. In severe asthma, it is frequently better to monitor the level of plateau pressure, as the plateau pressure will increase or decrease as total auto-PEEP increases or decreases.48 Auto-PEEP is a major cause of dyssynchrony. As noted in Fig. 83–17, when auto-PEEP is present, patients

frequently cannot generate a sufficient inspiratory effort to decompress the auto-PEEP and trigger a breath.35,49 Whenever, the patient’s respiratory rate exceeds the ventilator’s response rate, this problem is almost always caused by auto-PEEP. When auto-PEEP is caused by dynamic airflow limitation of exhalation volume as in chronic obstructive pulmonary disease, the application of applied PEEP reduces the patient’s effort to trigger the ventilator;35 that is, applied PEEP can be titrated up to approximately 80% of the measured auto-PEEP without increasing the overall level of air trapping. Applying PEEP in the presence of auto-PEEP caused by dynamic airflow limitation increases central airway pressure without increasing auto-PEEP, so that the pressure change needed to trigger the ventilator is reduced, thereby increasing patient–ventilator synchrony; that is, decreasing the pressure difference across the obstruction. From a practical perspective because auto-PEEP is difficult to measure in the spontaneously breathing patient, the applied PEEP is increased in 1–2 cm H2O steps until every inspiratory effort made by the patient triggers the ventilator. In some patients, this may require more than 10 cm H2O of applied PEEP. During controlled ventilation, a controversy exists over the benefit of applying PEEP to balance the auto-PEEP, because no spontaneous ventilatory efforts are present.

GAS EXCHANGE TARGETS Target blood gas tensions during mechanical ventilation are theoretically the normal range for the individual patient. This is usually a PaCO2 of about 35–45 mm Hg for all patients except those with chronic CO2 retention. In patients with chronically elevated CO2 levels, the PaCO2 should be maintained at the patient’s normal level up to 90 mm Hg.1 If the arterial pH and PCO2 are reset in these patients to “normal” values, the patients may become impossible to wean from ventilatory support, because during spontaneous unassisted breathing they will maintain CO2 levels at their baseline, which now results in an acute acidosis. In patients with ARDS, permissive hypercapnia may be unavoidable, as the effect of increasing the


the acidosis associated with permissive hypercapnia protects the cell from hypoxemic injury.52 In older or cardiovascularly unstable patients, the level of acceptable acidosis must be individually gauged based on the response of the patient’s cardiovascular system. In all patients the more gradual the permissive hypercapnia is allowed to develop, the greater the likelihood it will be well tolerated. Tissue oxygenation is dependent on appropriate blood levels of oxygen and cardiac output. Assuming a normal cardiac output, PaO2 values in critically ill patients need only to be maintained >60 mm Hg, whereas for some patients, because of a lack of alternatives, a PO2 of >50 mm Hg may be acceptable.1 There is no value in the vast majority of patients to maintaining a PaO2 of ≥100 mm Hg.

Expiratory port open to atmosphere A

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FIGURE 83–16. Relationship between alveolar, central airway, and ventilator circuit pressure under (A) normal conditions and (B and C) in the presence of severe dynamic airway obstruction, (B) with expiratory port open, and (C) with expiratory port occluded. Autopositive end-expiratory pressure (PEEP) level is identified by creating an end-expiratory hold, allowing alveolar, central airway, and ventilator circuit pressure to equilibrate. Note that during equilibration, auto-PEEP level can be read on the system manometer. (Pepe PE, Marini JJ. Occult positive end-expiratory pressure in mechanically ventilated patients with airflow obstruction: the auto-PEEP effect. Am Rev Respir Dis 1982;126:166–170. © American Thoracic Society.)

level of ventilation to reduce CO2 levels may produce lung injury. One factor limiting an increase in PaCO2 with a permissive hypercapnic ventilatory strategy is the acidosis induced by the elevated CO2.50 Most

healthy young adults can tolerate a pH as low as 7.20 without adverse effect.51 In fact, in acute lung injury or asthma, the increased cardiac output induced by the acidosis may be beneficial. Some clinicians have proposed that

VENTILATOR-INDUCED LUNG INJURY Although the application of mechanical ventilation can be lifesaving, it has become increasingly clear that the mechanical ventilator can induce lung injury. Laboratory data have defined two primary settings in which the mechanical ventilator can induce lung injury, by producing overdistension of the lung at end inspiration and by collapse and reexpansion of unstable lung regions during ventilation.

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Ventilator Patient FIGURE 83–17. Gas flow, airway pressure, and esophageal pressure during pressure-supported ventilation with marked patient–ventilator dyssynchrony. Pressure spikes at the onset and termination of the breath indicate dyssynchrony, as well as the difference between patient inspiratory efforts (arrows) and the ventilator response (arrows). (Reproduced with permission from Fabry BE, Guttmann J, Eberhard LE, et al. An analysis of dyssynchrony between the spontaneously breathing patient and ventilator during inspiratory pressure support. Chest 1995;107:1387–1384.)

Figure 83–18 depicts the impact of a large tidal volume without PEEP on a rat lung as compared to a rat lung ventilated with a small tidal volume and one with 10 cm H2O PEEP and a large tidal volume.53 One hour of ventilation with a large tidal volume at zero PEEP caused marked hemorrhagic edema of the lung. This type of injury was termed volutrauma by Dreyfuss and Saumon because it is believed that the injury is primarily caused by an excessive tidal volume.54 However, as described above, an excessive tidal volume is accompanied by an excessive transpulmonary pressure, making the distinctions between pressure and volume injury somewhat semantic. VILI is defined as an increase in the permeability of the alveolar capillary membrane, the development of pulmonary edema, the accumulation of neutrophils and protein within the

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FIGURE 83–18. Comparison of lungs excised from rats ventilated with peak pressure of 14 cm H2O, zero positive end-expiratory pressure (PEEP); peak pressure 45 cm H2O, 10 cm H2O PEEP; and peak pressure 45 cm H2O, zero PEEP (left to right). The perivascular groove is distended with edema in the lungs from rats ventilated with peak pressures of 45 cm H2O, 10 cm H2O PEEP. The lung ventilated at 45 cm H2O peak pressure zero PEEP is grossly hemorrhaged. (Webb HH, Tierney D. Experimental pulmonary edema due to intermittent positive pressure ventilation, with high inflation pressure protection by positive end expiratory pressure. Am Rev Respir Dis 1974;110: 556–565. © American Thoracic Society.)

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lung parenchyma and airway, the disruption of surfactant production, and a decreased lung compliance.54 VILI is indistinguishable from human ARDS and can be produced in rats within minutes by large tidal volume ventilation.55 Indeed, VILI caused by inflation with large tidal volumes has been demonstrated in many small- and large-animal models. Parker et al.,56 in isolated perfused dog lungs, demonstrated that ventilatory pressures greater than 30 cm H2O peak alveolar pressure resulted in VILI. Hernandez et al.,57 Egan,58 and Kolobow et al.59 also demonstrated similar injuries in large-animal models. Ventilation of many species with large tidal volumes results in the development of VILI and an increase in the severity of preexisting lung injury. The single factor most responsible for the development of VILI appears to be the transpulmonary pressure (pressure inside minus pressure outside the lung or alveolar minus pleural pressure).55 In a now classic experiment, Dreyfuss et al.55 demonstrated that rats with strapped chest walls were protected from VILI as compared with those ventilated with the same peak pressure but without chest wall binding. In fact the lung injury was similar regardless of the use of positive or negative pressure ventilation provided high transpulmonary pressures were established. As a

result, we reason higher ventilating pressures can be used in the presence of a decreased chest wall compliance without the development of VILI, as the reduced chest wall compliance decreases transpulmonary pressure at peak airway pressure and results in a lower delivered tidal volume.

Recruitment/Derecruitment Injury: “Atelectrauma” As noted in Fig. 83–18, the application of 10 cm H2O PEEP in spite of a peak airway pressure of 45 cm H2O decreased the level of VILI as compared with similar animals ventilated with the same peak pressure but at zero PEEP.61 Only mild interstitial edema developed in animals ventilated at 10 cm H2O PEEP. Similar findings have been reported by Corbridge et al. in dogs with hydrochloric acid-induced lung injury.60 Dogs ventilated with 12.5 cm H2O PEEP and a VT of 15 mL/kg after lung injury had far less pulmonary edema at autopsy than dogs ventilated with 3.2 cm H2O PEEP and 30 mL/kg tidal volumes, in spite of the fact that peak alveolar pressure (33 cm H2O) was the same for both groups during the 5 hours of ventilation.

Biotrauma Slutsky et al.61 has referred to the activation of pulmonary and systemic inflammatory mediators by an inappro-

priate ventilatory pattern as biotrauma. Increasing data from both animal and clinical studies indicate that a traumatic ventilatory strategy can augment the level of the pulmonary and systemic inflammatory response. Tremblay et al.,62 in an ex vivo healthy and injured rat lung model, demonstrated that both pro- and antiinflammatory mediators are activated by ventilatory patterns associated with high peak alveolar pressure and zero PEEP. For ventilated animals in which PEEP was set greater than Pflex (lower inflection point on the respiratory system pressure-volume curve) and overdistension was avoided, minimal mediator activation was observed. Similar data were reported by Bethmann et al. in an ex vivo perfused mouse lung model.63 Hyperventilation at 2.5 times the normal transpulmonary pressure using either positive or negative pressure ventilation resulted in a 1.75-fold increased expression of tumor necrosis factor α (TNF-α) and interleukin-6 messenger RNA (mRNA). Imai et al.64 and Takata et al.,65 studying rats, noted greater TNF-α mRNA expression with conventional ventilation at low peak pressure (30 cm H2O) and low PEEP (5 cm H2O) as compared to high-frequency oscillation at a mean airway pressure of 15 cm H2O (same as with conventional ventilation). Ranieri et al. showed the same effect of ventilatory pattern on pulmonary lavage and plasma TNF-α level in ARDS patients.66 In a randomized comparison, patients ventilated with PEEP set greater than Pflex and peak alveolar pressure kept below the upper inflection point of the pressure-volume curve had reduced TNF-α levels in both plasma and lung lavage fluid after 36 hours. Patients randomized to PEEP based on oxygenation with VT set to produce eucapnia increased their TNF-α levels after 36 hours. In addition the ARDSnet45 demonstrated a lower systemic proinflammatory mediator response in a low tidal volume group of patients as compared to a high tidal volume group. Most recently, Chu et al.67 demonstrated that lung maintained at a high lung volume either by CPAP or ventilated at the same high peak pressure resulted in the same marked activation of inflammatory mediators. Based on these data both Slutsky and Tremblay61 and Dreyfuss and Saumon68 proposed that the lung was the “engine” that drives the development of multisystem organ failure in


ARDS patients. The additional lung injury resulting from inappropriate mechanical ventilation causes the movement of inflammatory mediators into the systemic circulation increasing the systemic production of mediators influencing and damaging the function of distal organs and tissues. As a result, it seems reasonable to conclude, as discussed by Marini,46 that “excessive mechanical forces produce lung damage by at least three mechanisms: (a) the signaling of proinflammatory mediator release by mechanical stress, ( b) trauma to the epithelium of the lung parenchyma by repetitive opening at high pressures and subsequent closing with each breath, and (c) physical stress on the parenchyma by high peak alveolar pressures.” Marini also points out that there is some evidence that high ventilatory frequency69 (higher frequency, greater injury), high pre- and postalveolar microvascular pressures,70 decreased surfactant production,71 supine body position,72 high body temperature,73 and immune suppression74 all enhance the development and severity of VILI.

LUNG-PROTECTIVE VENTILATION As already discussed, a primary aim of ventilatory support of the surgical patient is to achieve “lung protection”; that is, to insure that the process of mechanical ventilation does not amplify the extent of lung injury. Care should always be exercised to ensure that the plateau pressure and tidal volume do not result in overdistension. In general, based on current information the tidal volume should be maintained ≤ 10 mL/kg in all acutely ill patients or patients undergoing anesthesia. In ARDS, as presented in the previous section, it is certain that smaller tidal volumes are required. At least three clinical trials have demonstrated a benefit of ventilating at 6–7 mL/kg (PBW) tidal volumes in ARDS.45,75,76 In conjunction with these small tidal volumes, the plateau pressures should be maintained below 30 cm H2O unless the chest wall is stiff.46 However, the lower the plateau pressure, the less likely tidal volumes of 8–9 mL/kg will present concern. Outside of the clinical setting of ARDS the data are less clear; however, Hubmayr et al. performed a retrospective analysis of data on mechani-

cal ventilation in the ICU44 and intraoperatively77 at the Mayo Clinic, and on data from an international ventilation survey78 that would indicate that small tidal volume (4 weeks) should be given a tracheotomy and will require successful 12–16-hour spontaneous breathing periods before being allowed to breathe without ventilatory support during the night. For COPD patients who are ventilated for short periods, who meet all the criteria for weaning, and who clinically seem ready for ventilator discontinuation but continue to fail spontaneous breathing trials, carefully consider extubation to NPPV.95–97 Some COPD patients can be successful transitioned to ventilator independence using NPPV. (See Weaning and Noninvasive Positive Pressure below.)

Acute Respiratory Distress Syndrome Pathophysiologic Issues ARDS and ALI are acute lung diseases characterized by atelectasis, edema, decreased compliance, and severe arterial hypoxemia. As a result, a most important issue during mechanical ventila-

tion is to avoid inducing greater lung injury either by end-inspiratory overdistension or by the repetitive opening and closing of unstable lung units. Other important issues are the recruitment of lung, the reversal of atelectasis, and the assurance of adequate systemic oxygenation and CO2 exchange while avoiding pulmonary oxygen toxicity. The end-inspiratory plateau pressure should be 180 mm Hg or diastolic blood pressure >90 mm Hg • Increased anxiety • Increased diaphoresis Adapted from Evidence-based guidelines for weaning and discontinuing ventilatory support.98

be adjusted to ensure spontaneous breathing by early morning. A 30–120minute spontaneous breathing trial is performed, and if the patient does not fail the trial based upon the criteria in Table 83–7, consider the patient for extubation.98 After short-term ventilatory support most clinicians do not recommend measuring lung mechanics. Even the rapid shallow breathing index has not proven universally useful in identifying those patients who are ready for weaning. All of the current data indicates that the use of other approaches to weaning simply results in prolongation of the ventilatory support period.95 Patients failing weaning trials should be carefully assessed for the specific factors causing failure. Table 83–8 from Ely lists areas of concern that should be assessed in the patient falling multiple weaning trials.99 Finally, in some patients, the use of NPPV may facilitate the process of transition to unsupported spontaneous breathing.95–97

NONINVASIVE POSITIVE PRESSURE Over the last 15 years increasing emphasis has been placed on the use of noninvasive (without tracheal intubation) positive-pressure to support patients developing respiratory failure.100 Although, much of the emphasis in such studies has focused on the patient with COPD in an acute exacerbation,101 a number of trials over the years have focused on the use of NPPV102 or CPAP for the management of postoperative patients.103–107 The primary mechanism producing arterial hypoxemia after surgery is im-

paired ventilation-to-perfusion matching as a result of the development of atelectasis.107 Atelectasis in this setting is a result of recumbent positioning, ventilation with high oxygen concentrations, diaphragmatic dysfunction, and incisional pain producing impaired secretion clearance.103 Several studies show that mask CPAP ventilation in this setting improves gas exchange, minimizes the development of atelectasis, and increases functional residual capacity.103–107 Most of these studies were case series;103–106 the most recent study, however, was a randomized controlled trial.107 Squadrone et al.107 demonstrated that mask CPAP at 7.5 cm H2O at 0.5 FiO2 for 6 hours in all patients following major elective abdominal surgery with a PO2/FiO2 65 years, ineffective cough, and excessive secretions, 1 or more weaning failures, upper airway obstruction, or more than 1 comorbid condition. Of note, however, very few of these patients were postoperative patients. There is considerable concern over the use of NPPV for the patient developing postextubation hypoxemic respiratory failure. Keenan et al.111 demonstrated no benefit from the use of NPPV as compared to standard therapy in about 160 randomized patients. No differences were observed in the length of mechanical ventilation, hospital stay or hospital mortality. Of even more concern was the increased mortality reported by Esteban et al.112 in patients with postextubation hypoxemic respiratory failure who were managed with NPPV. These authors argue that the primary reason for the increased mortality was the delay in intubating those who were treated with NPPV (12 vs. 2 hours). Based on the current data from these randomized controlled trials, NPPV is best employed for patients passing weaning trials who are at an increased risk of developing respiratory failure as described by Nava109 and Ferrer.110

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nosocomial infections and survival in critically ill patients. JAMA 2000;284:2361– 2357. 102. Auriant I, Jallot A, Herve P, et al. Noninvasive ventilation reduces mortality in acute respiratory failure following lung resection. Am J Respir Crit Care Med 2001; 164:1231–1235. 103. Stock MD, Downs JB, Gauer PK, et al. Prevention of postoperative pulmonary complications with CPAP, incentive spirometry, and conservative therapy. Chest 1985;87:151–157. 104. Dehaven CB, Hurst JM, Branson RD. Postextubation failure treated with a continuous positive pressure airway mask. Crit Care Med 1985;13:46–48. 105. Lindner KH, Lotz P, Ahnefeld FW. Continuous positive airway pressure effect on functional residual capacity, vital capacity and its subdivisions. Chest 1987;92:66– 70. 106. Rusca M, Proitti S, Schnyder P, et al. Prevention of atelectasis formation during induction of general anesthesia. Anesth Analg 2003;97:1835–1839. 107. Squadrone V, Coha M, Cerutti E, et al. Continuous positive airway pressure for treatment of postoperative hypoxemia: a randomized controlled trial. JAMA 2005; 293:589–595. 108. Delclaux C, L’Her E, Alberti C, et al. Treatment of acute hypoxemic nonhypercapnic respiratory insufficiency with continuous positive airway pressure delivered by a face mask: a randomized controlled trial. JAMA 2000;284:2352–2360. 109. Nava S, Gregoretti C, Fanfulla F, et al. Noninvasive ventilation to prevent respiratory failure after extubation in high-risk patients. Crit Care Med 2005;33:2465–2470. 110. Ferrer M, Valencia M, Nicolas JM, et al. Early noninvasive ventilation averts extubation failure in patients at risk. Am J Respir Crit Care Med 2005;173:164–170. 111. Keenan SP, Powers C, McCormack DG, Block G. Noninvasive positive-pressure ventilation for postextubation respiratory distress. JAMA 2002;287:3238–3244. 112. Esteban A, Frutos-Vivar F, Ferguson, N, et al. Noninvasive positive-pressure ventilation for respiratory failure after extubation. N Engl J Med 2004;350:2452– 2460.

CHAPTER 84: Cardiopulmonary Resuscitation

CHAPTER 84 Cardiopulmonary Resuscitation Charles W. Otto, MD, FCCM In the hospital, resuscitation from cardiac arrest depends on the rapid response of a well-trained cardiopulmonary resuscitation (CPR) team that usually includes physicians, nurses, respiratory care providers, and pharmacists. The anesthesiologist is usually a team member and frequently is expected to be the leader. The team must communicate readily and be coordinated. Providing the knowledge base and framework for effective teamwork are the goals of published CPR guidelines and widely taught courses in basic life support (BLS), advanced cardiac life support (ACLS), and pediatric advanced life support (PALS).1 The anesthesiologist must be thoroughly familiar with ACLS protocols to function within the team. Team leadership requires in-depth, current knowledge of physiology, pharmacology, and alternative CPR techniques. This chapter provides the scientific background on which current CPR practice is based. It focuses exclusively on cardiac arrest. Other circumstances requiring cardiovascular support, such as shock and dysrhythmias, are discussed in other chapters. Approximately 50% of patients suffering in-hospital cardiac arrest are resuscitated and 18% of adults and 27% of children survive to discharge.2 The operating room is the location where CPR has the highest rate of success. Cardiac arrest occurs approximately 7 times for every 10,000 anesthesia events.3 The cause for the arrest is anesthesia-related approximately 4.5 times for every 10,000 anesthesia events but mortality from these arrests is only 0.4 per 10,000 anesthesia events. Resuscitation is successful approximately 90% of the time in anesthesia-related cardiac arrests. Excluding the operating room, the best initial resuscitation rates are found in the intensive care unit (ICU), while the best survival rates are for patients arresting in the emergency department.

The in-hospital success is similar to resuscitation and survival rates from out-of-hospital arrest in cities with rapid response emergency medical systems.4 In out-of-hospital arrests, poor outcomes are associated with (a) long arrest times before CPR is begun, ( b) prolonged ventricular fibrillation without definitive therapy, and (c) inadequate coronary and cerebral perfusion during CPR.5 Optimum survival from ventricular fibrillation is obtained only if basic CPR is started within 4 minutes and defibrillation applied within 8 minutes.4 A better outcome might be expected for in-hospital

arrests because of rapid response times and expert personnel. Intercurrent illnesses of hospitalized patients reduce the likelihood of survival and the arrest victim is more likely to be elderly, a factor that may reduce survival. The cause of arrest associated with the best outcome and the most common cause of out-of-hospital arrest is ventricular fibrillation secondary to myocardial ischemia. This initiating event is less common in hospitalized patients. When applying CPR, attention to the details of effective resuscitation is important. However, CPR is only symptomatic therapy; attention should

KEY POINTS 1. In many resuscitation attempts, both in- and out-of-hospital, chest compressions are performed for less than 50% of the time. Interrupting compressions is detrimental to maintaining myocardial perfusion and, therefore, to the ultimate success of the resuscitation attempt. 2. Fluctuations in intrathoracic pressure play a significant role in blood flow during most resuscitations and the cardiac pump mechanism contributes under some circumstances. 3. Cardiac output is severely depressed during cardiopulmonary resuscitation (CPR), ranging from 10– 33% of prearrest values in experimental animals. Nearly all of the cardiac output is directed to organs above the diaphragm. 4. During CPR, measurement of blood gases reveals an arterial respiratory alkalosis and a venous respiratory acidosis because the arterial PCO2 is reduced and the venous PCO2 is elevated. 5. The critical myocardial blood flow is associated with aortic “diastolic” pressure exceeding 40 mm Hg. 6. Exhaled end-tidal CO2 is an excellent noninvasive guide to the effectiveness of standard CPR. 7. Immediate defibrillation is only effective if applied within 4–5 minutes of collapse. Otherwise, a brief period of 2–3 minutes of chest compressions before defibrillation is necessary. 8. Lidocaine and amiodarone are used during cardiac arrest to aid defibrillation when ventricular fibrillation is


refractory to electrical countershock therapy or when fibrillation recurs following successful conversion. 9. Of the drugs used during CPR, only vasopressors have been acknowledged to help restore spontaneous circulation. 10. Outcome studies prospectively comparing standard and high-dose epinephrine have not demonstrated conclusively that higher doses will improve survival. 11. Evidence currently suggests that, like other potent vasopressors, vasopressin is equivalent to but not better than epinephrine for use during CPR. 12. Calcium is not indicated for use during cardiac arrest in adults or children. It may be useful for treatment of hyperkalemia, ionized hypocalcemia, hypermagnesemia, or calcium channel blocker toxicity. 13. Sodium bicarbonate should be considered for use during CPR only in arrests associated with hyperkalemia, severe preexisting metabolic acidosis, and tricyclic or phenobarbital overdose. It may be considered for use in protracted resuscitation attempts after other modalities have been instituted. 14. In contrast to pharmacologic therapy, two studies demonstrate improved neurologic outcome when mild therapeutic hypothermia (89.6–93.2°F [32–34°C]) is induced for 12 – 24 hours in cardiac arrest survivors who remained comatose after admission to the hospital.

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not be paid to the mechanics of CPR only, but also should include a search for a treatable cause of the arrest.

HISTORY

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Discoveries contributing to modern CPR have a long history recorded in many famous works.6,7 They begin with the Bible story of Elisha breathing life back into the son of a Shunammite woman (II Kings 4:34) and continue with Andreas Vesalius’ description of tracheotomy and artificial ventilation, William Harvey’s manual manipulation of the heart, and the teachings of the Society for the Recovery of Persons Apparently Drowned, founded in London in 1774. Nevertheless, the combined techniques of modern CPR are less than 50 years old. Although there were significant contributions from other centers in the United States and Europe, modern CPR developed primarily from the fortuitous assemblage of innovative clinicians and researchers in Baltimore in the 1950s and early 1960s. In the late 1950s, Elam, Safar, and Gordon established mouth-tomouth ventilation as the only effective means of artificial ventilation.8–11 The internal defibrillator was developed in 1933,12 but not applied successfully until 1947.13 It was another decade before general use was made possible by the development of external transthoracic defibrillation.14,15 Despite these advances, widespread resuscitation from cardiac arrest was not possible until Kouwenhoven, Jude, and Knickerbocker described success with closed chest cardiac massage in a series of patients.16 The final major component of modern CPR was added in 1963 when Redding and Pearson described the improved success obtained by administering epinephrine or other vasopressor drugs.17

BASIC LIFE SUPPORT BLS consists of those elements of resuscitation that can be performed without additional equipment: airway management, ventilation, and chest compressions. Physiologically, the objective of performing CPR is to provide oxygen to the vital organs, especially the heart, and the brain until normal circulation is restored. Common practice is to approach a victim with the

BOX 84–1. Basic Cardiopulmonary Resuscitation Airway Assess Call for help Activate EMS system Position Open airway Head tilt/chin lift Jaw thrust Breathing Determine breathlessness Perform rescue breathing Two breaths (1 second each) Circulation

Adult

Child

Infant

Pulse Check Site

Carotid

Carotid

Brachial or Femoral

Placement

Two hands

One hand

Depth of compression

1.5–2 in

1/3–1/2 depth of

Two or three fingers or encircling method —

Rate/min Compression/ ventilation ratio

100 30:2

chest 100 30:2

100 30:2

Chest compressions

ABC (airway, breathing, circulation) sequence although the CAB (circulation, airway, breathing) sequence has been used in some countries with comparable results. Box 84–1 gives the full sequence for initiating CPR in an apparent arrest victim and Fig. 84–1 illustrates the technique of infant chest compressions. If complete resuscitation equipment and expertise in its use is available, the overall priorities of resuscitation may dictate altering this sequence (Box 84–2).

THE IMPORTANCE OF THE TIMING OF INTERVENTIONS DURING CPR It is now clear that cardiac arrest caused by ventricular fibrillation can be characterized in three phases ( Table 84–1).21 The electrical phase occurs during the first 4–5 minutes of the arrest and early defibrillation is critical for success during this time. The hemodynamic phase follows for the next 10–15 minutes when perfusing the myocardium with oxygenated blood is critical. This is followed by what has been called the metabolic phase when the ischemic injury to the heart is so

great that it is not clear what interventions will be successful. What is obvious from this timeline is that early intervention is necessary for resuscitation attempts to be successful. This requires not only rapid response emergency medical systems for out-of-hospital arrests and appropriate code teams for in-hospital arrests, but it requires immediate intervention by bystanders when cardiac arrest victims collapse. Unfortunately, the incidence of bystander CPR has been falling for 3 decades. The reasons for this reluctance to intervene are multiple but seem to be primarily (a) lack of training, ( b) the complexity of the task, and (c) fear of harm. Many of these concerns focus on the mouth-to-mouth ventilation part of the CPR intervention and many experts are now stressing the importance of continuous chest compressions, even at the expense of ventilation, by bystanders and early rescuers. There is no doubt that chest compression-only CPR by bystanders is more acceptable for most, easier to learn and retain, and provides better hemodynamic support. Early studies in anesthetized humans suggested that the airway would not remain open in the unconscious,


FIGURE 84–1. A. Two-finger method of external chest compression in infants. Rescuer places 2 fingers on the sternum and 1 finger-breadth below the line intersecting the nipples and compresses 0.5–1 inch at a rate of 100 compressions per minute. Ventilation is not shown for the sake of clarity. B. Encircling method of external chest compression in infants. Rescuer places thumbs over sternum 1 fingerbreadth below the line intersecting the nipples and clasps hands behind infant’s back.

leading to the teaching that airway control and artificial ventilation must accompany chest compressions.8–11 However, there is now considerable data to suggest that eliminating mouthto-mouth ventilation early in the resuscitation of witnessed fibrillatory cardiac arrest is not detrimental to outcome and may improve survival. Data from the Belgian CPCR Registry demonstrates that 14-day survival and neurologic outcome are the same regardless of whether bystanders initiate full basic life support or only do chest compressions. Both are significantly better than if the bystanders only do mouth-to-mouth ventilation or attempt no CPR.22,23 The necessity for ventilation during basic life support

BOX 84–2. Interventional Priorities during CPR If All Necessary Equipment and Expertise Are Available Diagnose ventricular fibrillation and defibrillate Open airway Begin ventilation Begin chest compressions Administer supplemental oxygen Obtain intravenous access Administer epinephrine or vasopressin Assess adequacy of CPR efforts Secure airway Additional drug therapy

has been studied in animal models. Multiple studies have been reported by two research groups of 169 swine with up to 5 minutes untreated fibrillatory cardiac arrest and 10 minutes of BLS, comparing chest compressions without airway control or ventilation to standard CPR with ventilation.24–26 Both techniques resulted in approximately 75% neurologically normal 24– 48-hour survival. A similar study in an asphyxial arrest model showed that assisted ventilation during bystander CPR was critical for survival.27 The animal studies are supported by a study of telephone dispatcher instructions in CPR techniques to inexperienced bystanders. Instruction in chest compressions only resulted in the same survival as instruction in both compressions and ventilation.28 These observations suggest that when arrest is witnessed, likely to be of cardiac (rather than respiratory) cause, and intubation will be available within a short time, closed chest compressions alone may be as efficacious as com-

pressions and mouth-to-mouth ventilation. In many venues, basic life support teaching for the lay rescuer is being simplified to eliminate mouthto-mouth ventilation. Just as importantly, there is renewed interest in importance of not interrupting chest compressions. Compressions are interrupted for repeated patient assessment, ventilations, intubation, central line placement, changing rescuers, and defibrillation (especially with automatic external defibrillators [AEDs]). In many resuscitation attempts both in- and out-of-hospital, chest compressions are performed for less than 50% of the time. Interrupting compressions is significantly detrimental to maintaining myocardial perfusion and, therefore, to the ultimate success of the resuscitation attempt.

AIRWAY MANAGEMENT The goal of airway management during cardiorespiratory arrest is the

TABLE 84–1. Phases of Cardiac Arrest Phase

Time from Collapse

Intervention

Electrical Hemodynamic Metabolic

4–5 minutes 15–20 minutes >20 minutes

Defibrillation Myocardial perfusion Unknown

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same as during general anesthesia: to provide a clear path for respiratory gas exchange while minimizing gastric insufflation and the risk of pulmonary aspiration. Airway maintenance in an unconscious patient is a basic part of anesthesia practice and all the techniques learned for use during anesthesia are applicable to the cardiac arrest victim. Just as in the operating room, the most commonly used technique for opening the airway is the “head tilt–chin lift” method. If this is ineffective, the “jaw thrust” maneuver is frequently helpful. Oropharyngeal and nasopharyngeal airways are useful for helping maintain an open airway in patients that are not intubated. Care must be used to ensure they are correctly inserted and do not worsen airway obstruction. Insertion in the semiconscious can induce vomiting or laryngospasm. Effective airway management during CPR is a major problem, even for medical professionals. Many individuals cannot manage a self-inflating resuscitation bag and mask effectively. Larger tidal volumes at lower pressures are delivered by mouth-to-mouth or mouth-to-mask ventilation.18 The bag and mask apparatus is more effective if two individuals manage the airway: one to hold the mask and maintain the airway and one to squeeze the bag.19 A number of airway devices designed for blind placement have been described for use by individuals who are not skilled laryngoscopists. The combination esophagealtracheal tube (Combitube) and the laryngeal mask airway (LMA) have been studied for use during CPR. None of these methods allow the degree of airway control that is obtained with an endotracheal tube. However, no method of ventilation has been proven to be superior to the others in promoting successful resuscitation.20 Intubation may be performed in prolonged resuscitations if a skilled laryngoscopist is available. However, it should not be performed until adequate ventilation by other means (preferably with supplemental oxygen) and circulation by chest compressions have been established and defibrillation performed, if appropriate (Box 84–2). When other methods of establishing an airway are unsuccessful, translaryngeal ventilation or tracheotomy by cricothyroid puncture may be lifesaving (Fig. 84–2).

FIGURE 84–2. Cricothyroidotomy. A, Anatomic view. B, Insertion of 14-gauge IV cannula. C, Bag attached to 3.0 endotracheal tube (ETT ) adaptor connected to IV cannula.

VENTILATION Currently, airway management and ventilation remain the standard first steps of CPR. Mouth-to-mouth or mouth-to-nose ventilation is the most expeditious and effective method immediately available. Although inspired gas with this method contains approximately 4% carbon dioxide and only approximately 17% oxygen (composition of exhaled air), it is sufficient to maintain viability. Mouth-tomask ventilation using a simple anesthesia face mask also is very effective. If the mask is fitted with a nipple adapter, a flow of oxygen can also supplement inspired oxygen concentration. The self-inflating resuscitation bag with mask also can be used with or without supplemental oxygen. Recommendations for ventilation are 2 breaths to 30 chest compressions during basic life support, as summarized in Box 84–3. Once an advanced airway (endotracheal tube, LMA, Combitube) is in place, ventilation should proceed at 8–10 breaths/min without

concern for synchronizing ventilation with chest compressions. Do not hyperventilate. Blood flow during CPR slows rapidly when chest compressions are stopped and recovers slowly when they are restarted. Consequently, unless the cause of arrest is hy-

BOX 84–3. Ventilation during Basic Life Support A. Healthcare provider(s) without advanced airway 1. 6–8 breaths/min, each delivered over 1 second 2. Pause 2.0 seconds for 2 breaths after every 30 chest compressions 3. Tidal volume adequate to cause chest rise (~0.5–0.6 L) B. Healthcare provider(s) with advanced airway 1. 8–10 breaths/min adequate to make chest rise (~0.5–0.6 L) 2. Do not pause chest compressions for ventilation 3. Avoid hyperventilation


poxia, emphasis should be on maintaining chest compressions with as little interruption as possible.

Physiology of Ventilation during CPR In the absence of an endotracheal tube, the distribution of gas between the lungs and stomach during mouthto-mouth or mask ventilation will be determined by the relative impedance to flow into each; that is, the opening pressure of the esophagus and the lung–thorax compliance. It is likely that esophageal opening pressure during cardiac arrest is no more than that found in anesthetized individuals (~20 cm H2O) and lung–thorax compliance likely is reduced. To avoid gastric insufflation, inspiratory airway pressures must be kept low. Insufflation of air into the stomach during resuscitation leads to gastric distension, impeding ventilation and increasing the danger of regurgitation and gastric rupture. If gastric insufflation is to be avoided, inspiratory airway pressures must be kept low. Partial airway obstruction by the tongue and pharyngeal tissues often leads to increased airway pressures and gastric insufflation. A useful aid to minimizing gastric insufflation is the use of cricoid pressure (Sellick maneuver).29 Pressure applied over the anterior arch of the cricoid cartilage can prevent air from entering the stomach at airway pressures up to 100 cm H2O.30 Meticulous attention to maintaining an open airway is necessary during rescue breathing. To cause a rise in the chest of most adults, a tidal volume of 0.5– 0.6 L will be needed. Rescue breaths should be given as quickly as possible without causing gastric insufflation.

CIRCULATION Physiology of Circulation during Closed Chest Compressions Two mechanisms of blood flow during closed chest compression have been described.15,31 In the cardiac pump mechanism, the heart is compressed between the sternum and spine, resulting in ejection of blood from the heart into the aorta with the atrioventricular valves preventing backward blood flow. In the thoracic pump mechanism, chest compression raises intrathoracic pressure, forcing blood out of

FIGURE 84–3. Possible mechanisms for blood flow during CPR include direct cardiac compression and the thoracic pump. With direct cardiac compression, an increase in chest compression rate causes an increase in blood flow by squeezing the heart between the vertebral column and sternum. With the thoracic pump mechanism, factors that increase pleural pressure cause an increase in pressure within the heart chambers and, ultimately, an increase in blood flow.

the chest, with venous valves and dynamic venous compression preventing backward flow and the heart acting as a passive conduit. The two mechanisms are not mutually exclusive (Fig. 84–3). Fluctuations in intrathoracic pressure play a significant role in blood flow during most resuscitations and the cardiac pump mechanism contributes under some circumstances. Which mechanism predominates probably varies from victim to victim and even during the resuscitation of the same victim. Cardiac output is severely depressed during CPR, ranging from 10– 33% of prearrest values in experimental animals. Nearly all of the cardiac output is directed to organs above the diaphragm. Brain blood flow is 50– 90% of normal and myocardial blood flow 20–50% of normal, while lower extremity and abdominal visceral flow is reduced to less than 5% of normal. Total blood flow tends to decrease with time but the relative distribution of flow does not change. Flow to the brain and heart are improved by the administration of vasopressors, while flow to organs below the diaphragm is unchanged or further reduced.

Physiology of Gas Transport during CPR During CPR, measurement of blood gases reveals an arterial respiratory alkalosis and a venous respiratory acidosis because the arterial PCO2 is re-

duced and the venous PCO2 is elevated. The cause is not respiratory in origin. Rather, these changes result from decreased cardiac output. During the low-flow condition of CPR, excretion of CO2 (mL of CO2/min in exhaled gas) is decreased approximately to the same extent as cardiac output is reduced. This reduced CO2 excretion is primarily a result of shunting of blood flow away from the lower half of the body. The exhaled CO2 reflects only the metabolism of the part of the body that is being perfused. In the nonperfused areas, CO2 accumulates during CPR. When normal circulation is restored, the accumulated CO2 is washed out and a temporary increase in CO2 excretion is seen. Although CO2 excretion is reduced during CPR, the mixed venous partial pressure of CO2 (PvCO2) usually is increased.32 Two factors account for this elevation. Buffering acid causes a reduction in serum bicarbonate, so that the same blood CO2 content results in a higher PvCO2. In addition, the mixed venous CO2 content is elevated. When flow to a tissue is reduced, not all the produced CO2 is removed, and CO2 accumulates, increasing the tissue partial pressure of CO2. This allows more CO2 to be carried in each aliquot of blood, and mixed venous CO2 content increases. If flow remains constant, a new equilibrium is established where all CO2 produced in the tissue is removed but at a higher venous CO2

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content and partial pressure. In contrast to the venous blood, arterial CO2 content and partial pressure (PaCO2) are decreased during CPR. This accounts for most of the observed increase in arterial–venous CO2 content difference. Although venous blood may have an increased CO2, the marked reduction in cardiac output with maintained ventilation results in very efficient CO2 removal. Decreased pulmonary blood flow during CPR causes lack of perfusion to many nondependent alveoli. The alveolar gas of these lung units has no CO2. Consequently, mixed alveolar CO2 (i.e., end-tidal CO2) will be very low and correlate poorly with arterial CO2. However, end-tidal CO2 does correlate well with cardiac output during CPR. As flow increases, more alveoli become perfused, there is less alveolar dead space, and end-tidal CO2 measurements rise.

Technique of Closed Chest Compression

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Cardiac arrest should be presumed in the absence of a pulse in the major arteries (carotid, femoral, axillary) of an unconscious patient. After opening the airway and providing two ventilations, search for a pulse should be made before starting chest compressions. If weak circulation exists in a patient with a primary respiratory arrest, pulses may return after adequate ventilation and compressions may not be necessary (Box 84–1). Standard chest compression technique consists of the rhythmic application of pressure over the lower half of the sternum. For compressions to be effective in providing blood flow to the brain and heart, the patient must be on a firm surface with the head level with the heart. The rescuer should stand or kneel at the side of the patient so that the hips are on a level with the victim’s chest. Using the weight of the entire upper body, the compression is delivered straight down with enough force to depress the sternum 3.5–5.0 cm in adults and one-third to one-half the depth of the chest in children and infants. Following maximal compression, pressure is released completely from the chest. Chest compressions should be performed at a rate of 100 per minute. They are most effective if the compression and relaxation phases of the cycle are equal in length. This 50% compression time is easier to achieve at faster compression rates.

Alternative Techniques of Circulatory Support Better understanding of circulatory physiology during CPR, especially involving the thoracic pump mechanism, has resulted in several proposals for alternative techniques or adjunct devices in recent years. Most are intended to provide better hemodynamics and extend the duration during which CPR can support viability. Unfortunately, none has proven reliably superior to the standard technique, and no improvement in survival from cardiac arrest has been demonstrated consistently. Initial studies suggested hemodynamic advantages for techniques that raised intrathoracic pressure (simultaneous ventilation/compression, abdominal binding with compression, pneumatic antishock garment). Further investigations found that right atrial pressure and intracranial pressure were raised by these techniques, frequently more than aortic pressure. Consequently, there was no improvement in cerebral or myocardial blood flow. Outcome studies with these techniques found no improvement in resuscitation success compared to standard CPR. They are currently not recommended for support of the cardiac arrest victim.

Interposed Abdominal Compression CPR Interposed abdominal counterpulsation (IAC) CPR consists of a dedicated rescuer providing manual abdominal compression between the xiphoid and umbilicus during the relaxation phase of conventional CPR.33 IAC-CPR increases venous return and compresses the abdominal aorta to produce retrograde aortic flow, closing the aortic valve and augmenting diastolic pressure. Although initial hemodynamic studies were encouraging, a large randomized study of out-of-hospital arrest found no improvement in survival compared to standard CPR.34 Two subsequent in-hospital studies using trained providers found improved return of spontaneous circulation (ROSC) and short-term survival with IAC-CPR compared to the standard technique.35,36 In general, there has not been improvement in long-term survival with the use of this technique. Reports of human studies demonstrate the frequency of complications, including laceration of abdominal viscera or esophageal regurgitation, is not

increased with IAC-CPR. During inhospital resuscitation, IAC-CPR may be considered when there are sufficient personnel trained in its use. Its use for out-of-hospital arrest remains experimental.

Active Compression– Decompression CPR Active compression–decompression (ACD) CPR developed from the anecdotal report of CPR performed with a plumber’s helper applied to the anterior chest wall.37 This suggested that active decompression of the chest wall might reduce intrathoracic pressure during the relaxation phase of chest compressions, leading to improved venous return, increased stroke volume with compression, and better blood flow. Devices that can be applied to the chest wall in order to enable active compression and decompression have been developed but none is currently approved by the FDA for sale in the United States. Hemodynamic studies in animals and humans show that coronary and cerebral perfusion may be somewhat improved with this method compared to standard CPR, although when epinephrine is used, there is no difference between techniques.38,39 Clinical trials have found mixed results, with 4 showing improved resuscitation and 5 demonstrating no difference from the standard technique. A meta-analysis of 4162 patients in 10 out-of-hospital trials and 826 patients in 2 in-hospital trials found no difference in early or late survival with ACD-CPR compared to standard CPR.40

Impedance Threshold Device The impedance threshold device (ITD) is a valve that limits the flow of air into the lungs during the relaxation phase of chest compressions, reducing intrathoracic pressure during chest recoil and enhancing venous return.41 Originally designed for use with an endotracheal tube, it has been adapted for use with a face mask assuming a tight seal with the face is maintained. It has frequently been studied in association with ACD-CPR in the belief that the two techniques would act synergistically to improve venous return. Two randomized trials of the combined techniques found improved ROSC and 24-hour survival compared to the standard technique.42,43 One randomized trial of adding the ITD to standard CPR found improved admission to the ICU


and 24-hour survival.44 No studies have demonstrated improved longterm survival.

Pneumatic Vest CPR and Load-Distributing Band CPR Pneumatic vest CPR is a method of increasing intrathoracic pressure by phasically inflating a bladder around the chest (with or without simultaneous ventilation), without significantly changing the dimensions of the chest.45,46 Experimental animal studies show excellent hemodynamics and the ability to maintain viability for prolonged periods. The technique continues to be investigated with a number of modifications from the original method. A recent modification is the load-constricting band (LCB) device consisting of a pneumatically or electrically actuated constricting band and backboard. One preliminary report using this device found improved survival to emergency department admission compared to standard CPR in outof-hospital cardiac arrest.47

Invasive Techniques In contrast to the closed chest techniques, two invasive methods have been able to maintain cardiac and cerebral viability during long periods of cardiac arrest. In animal models, open-chest cardiac massage and cardiopulmonary bypass (through the femoral artery and vein using a membrane oxygenator) can provide better hemodynamics and myocardial and cerebral perfusion than closed chest techniques.48,49 When performed after 15 minutes of closed-chest CPR, openchest CPR significantly improves coronary perfusion pressure and the rate of successful resuscitation.50 When initiated early (probably within 20–30 minutes of arrest) following failure of closed-chest CPR, open-chest CPR may improve resuscitation.53–55 However, if open chest massage is begun after 30 minutes of ineffective closed chest compressions, there is no better survival even though hemodynamics are improved.56 Preliminary trials of percutaneous cardiopulmonary bypass for refractory human cardiac arrest have been reported51 and this is a technique available in some institutions. Prompt restoration of blood flow and perfusion pressure with cardiopulmonary bypass can provide resuscitation with minimal neurological deficit after 20 minutes of fibrillatory cardiac arrest in canines.52

Monitoring during CPR Assessment of the patient during CPR is similar to other clinical situations; Box 84–4 lists the major points. A basic clinical examination and adherence to basic principles, including inspection, palpation, and auscultation of the patient, are performed. The chest is carefully observed for adequacy of chest expansion with artificial ventilation and for equal and normal breath sounds. In addition, the depth of compression and the position of the rescuer’s hands in performing chest compressions should be reevaluated constantly. Successful resuscitation in experimental models is associated with myocardial blood flows of 15–20 mL/min/ 100 g (Table 84–2).57 Obtaining such flows requires that closed chest compressions generate adequate cardiac output and coronary perfusion pressure. During CPR, coronary perfusion occurs primarily during the relaxation phase (diastole) of chest compression. The critical myocardial blood flow is associated with aortic “diastolic” pressure exceeding 40 mm Hg and coronary perfusion pressure (aortic diastolic minus right atrial diastolic pressure) exceeding 25 mm Hg in animal models.57–67 One report has confirmed similar findings in humans, noting that all patients with successful return of spontaneous circulation had coronary perfusion pressures higher than 15 mm Hg.67 The use of an indwelling arterial catheter, when available, is an invaluable monitor in assessing the arterial blood pressure and estimating these critical perfusion pressures. In addition, an arterial line allows for determination of arterial blood gases. If pressures are below the critical levels (Table 84–2), adjustments should be made to improve chest compressions and/or additional epinephrine should be administered. Greater pressures do not ensure success. Damage to the myocardium from underlying disease may preclude survival no matter how effective the CPR efforts. However, inadequate vascular pressures consistently result in poor outcomes. Although invasive pressure monitoring may be the ideal, exhaled end-tidal CO2 is an excellent noninvasive guide to the effectiveness of standard CPR.68 Carbon dioxide excretion during CPR with an endotracheal tube in place is dependent primarily on flow rather than ventilation. Since alveolar dead

BOX 84–4. Assessment of Patient during Cardiopulmonary Resuscitation A. Inspection Chest rise Depth of compression Position of rescuer’s hands B. Palpation Establish pulselessness Assess peripheral pulses Locate landmarks C. Auscultation Breath sounds Heart sounds D. Monitoring Electrocardiogram Arterial catheter Central venous catheter Pulse oximeter End-tidal CO2 Temperature

space is large during low-flow conditions, end-tidal CO2 is very low (frequently 20 mm Hg during successful CPR). When spontaneous circulation resumes, the earliest sign is a sudden increase in endtidal CO2 to greater than 40 mm Hg. Within a wide range of cardiac outputs, end-tidal CO2 during CPR correlates with coronary perfusion pressure,69 cardiac output,70 initial resuscitation71,72 and survival.73 End-tidal CO2 measured during human CPR has been used to predict outcome. No patient with an end-tidal CO2 10 mm Hg

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pressions. Attempts should be made to maximize the value by alterations in technique or drug therapy. Sodium bicarbonate administration results in the liberation of CO2 in the venous blood and a temporary rise in end-tidal CO2. Therefore, end-tidal CO2 monitoring will not be useful for judging the effectiveness of chest compressions for 3–5 minutes following bicarbonate administration.

ADVANCED LIFE SUPPORT Advanced life support encompasses all technical skills and cognitive resources required to restore spontaneous circulatory function. In addition to BLS skills, it includes use of adjunctive equipment and techniques for assisting ventilation and circulation, electrocardiogram (ECG) monitoring with arrhythmia recognition and defibrillation, establishment of IV access, and drug therapy.

DEFIBRILLATION Duration and Electrical Pattern of Fibrillation

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Ventricular fibrillation is the most common rhythm disturbance in cardiac arrest; it is caused by reentry impulse generation with multiple circuits with changing pattern. The only consistently effective treatment is electrical defibrillation. The fibrillating heart consumes considerable oxygen, increasing myocardial ischemia, and decreasing the time to irreversible cell damage. The longer fibrillation continues, the more difficult it is to defibrillate and the less likely is successful resuscitation.5,53,74–77 During the electrical phase of arrest (within 5 minutes of collapse), defibrillation should be the first priority of resuscitation (Box 84–2). Initial resuscitation success following out-of-hospital fibrillation and survival to hospital discharge are improved the earlier that defibrillation is accomplished.5,76 The application of defibrillation during the electrical phase has been facilitated by the development of AEDs that recognize ventricular fibrillation, charge automatically, and give a defibrillatory shock. Minimally trained individuals can incorporate defibrillation into BLS skills using an AED, thus improving survival in out-of-hospital arrest by

reducing time to delivery of the first shock.5,77–80 The value of public access defibrillation was dramatically demonstrated by the early results of installing AEDs in Las Vegas casinos where there was a 53% survival to discharge from the hospital78 and in Chicago airports where there was a 55% oneyear neurologically intact survival over the first two years.79 Early defibrillation is the paramount intervention during the electrical phase of cardiac arrest. However, in the usual out-of-hospital rescue with EMTs or paramedics doing the defibrillation and in many in-hospital arrests, the first shock frequently is delayed until 6–10 minutes following collapse, well into the hemodynamic phase of arrest. A retrospective analysis in Seattle found that, when response time was greater than 4 minutes, survival was improved if CPR was provided before defibrillation.81 In a randomized trial of 200 out-of-hospital cardiac arrests in Oslo, there was a highly significant improvement in outcome if CPR was provided before defibrillation when the response time was greater than 5 minutes.82 Consequently, it now appears that immediate defibrillation is only effective if applied within 4–5 minutes of collapse. Otherwise, a brief period of 2–3 minutes of chest compressions before defibrillation is necessary. The coarseness of the fibrillatory waves on the ECG may reflect the severity and duration of the myocardial insult and, thus, have prognostic significance.83 Increasing myocardial ischemia results in less-vigorous fibrillation, reduced amplitude electrical activity, and more difficult defibrillation. Low-amplitude and low-frequency fibrillatory waveforms are associated with poor outcome and the median frequency of the waveform correlates with myocardial perfusion during CPR and with success of defibrillation.83,84 Catecholamines with `-adrenergic activity, such as epinephrine, increase the amplitude of the electrical activity but have no influence on the ability to defibrillate.75,85 Consequently, defibrillation should not be delayed for drug therapy.

Defibrillators The modern defibrillator is a variable transformer that stores a direct current in a capacitor until discharged through the electrodes. Until recently, the cur-

rent waveform of most defibrillators used for transthoracic defibrillation was a monophasic (single direction of current flow between paddle electrodes), damped sinusoid, although some delivered truncated exponential waves. Nearly all AEDs and defibrillators sold today deliver a biphasic current (direction of flow reverses during the shock) in either a truncated, exponential, or rectilinear waveform.86 The output of most defibrillators is indicated in energy units ( joules or watt-seconds). At a constant stored energy, the energy delivered to the patient will be inversely related to the impedance (resistance) between the paddle electrodes. For consistency, the energy level indicated on most commercially available defibrillators is the output when discharged into a 50-ohm load.

Transthoracic Impedance Defibrillation is accomplished by the current passing through a critical mass of myocardium causing simultaneous depolarization of the myofibrils. Even at a constant delivered energy, delivered current will be reduced as impedance increases. At high impedance and relatively low energy levels, current could be too low for defibrillation. Transthoracic impedance has been measured at 15–143 ohms in human defibrillation.87 The major determinants of transthoracic impedance are known, and many are under the control of rescuers (Box 84–5). Impedance decreases with increasing electrode size, but concern has been expressed that a too large a paddle size may diffuse the current over too great an area for effective defibrillation. The most common paddle size remains an 8–10-cm diameter for adults and children and a 4.5-cm diameter for infants. The high impedance between metal electrode and skin requires that carefully applied self-adhesive defibrillation pads or electrode paste/gel pads specifically designed to conduct elec-

BOX 84–5. Factors Reducing Transthoracic Impedance during Defibrillation Large paddle size (*8-cm diameter) Defibrillation paste Firm pressure on paddles (*11 kg) Defibrillation during exhalation Successive shocks


tricity in the defibrillation setting be used. When paste or gel is used, it should be applied liberally to the paddle surface to prevent burns and obtain the maximum reduction in impedance. However, it must not form a continuous path from one paddle to the other, allowing the electric circuit to follow the path of least resistance and bypass the heart. Transthoracic impedance decreases with successive shocks, a partial explanation for why an additional shock of the same energy can cause defibrillation when previous shocks have failed. Transthoracic impedance is slightly but significantly higher during inspiration than during exhalation. Air is a poor electrical conductor. Firm paddle pressure of at least 11 kg reduces resistance by improving paddle-skin contact and by expelling air from the lungs.87 Optimum success of defibrillation is obtained by keeping impedance as low as possible. The average transthoracic impedance in human defibrillation is 70–80 ohms. Impedance is probably of little clinical significance when reasonably proper technique and high-energy shocks are used. For lower-energy shocks, great care should be taken to minimize resistance. Defibrillators have been developed that measure transthoracic impedance during the charge cycle, allowing the use of low-energy shocks in appropriate patients and identification of victims needing higher energy.88 Although not clinically available, current-based defibrillation may be a better way describe defibrillation dose.89

Energy Requirements and Adverse Effects The incidence and severity of myocardial damage from defibrillation in humans is not clear. In studies using the traditional monophasic defibrillator, repeated high-level shocks in animals result in dysrhythmias, ECG changes, and myocardial necrosis.90,91 Whether such injuries occur in humans is unknown. In humans, dysrhythmia frequency and the degree of ST-segment depression is greater with increased energy doses.92 Although there is no definitive evidence demonstrating myocardial damage within the range of clinically used doses, it would seem prudent to keep energy levels as low as possible during defibrillation attempts. However, if energy is too low, the delivered current may be insufficient for

defibrillation, especially when transthoracic impedance is high. With monophasic defibrillation, there is a general relationship between body size and energy requirements for defibrillation.93 Children need lower energies than adults, perhaps as low as 0.5 J/kg.94 However, over the size range of adults, body size does not seem to be a clinically important variable.95 Multiple studies have demonstrated high rates of successful defibrillation using relatively low levels (160– 200 J) of delivered energy. Studies of out-of-hospital and in-hospital arrests have demonstrated equal success when using 200 J or less initial energy compared to administering all shocks at energies of 300 J or greater.92,96 Biphasic defibrillators with different waveforms have been demonstrated to be effective over specific dose ranges. AEDs have the shock energy preselected within the defibrillator algorithm. For manual biphasic defibrillation, most manufacturers display the effective dose range on the defibrillator. For biphasic truncated exponential waveforms, initial energies of 150– 200 J have been shown to be successful >90% of the time.1 For rectilinear biphasic waveforms, initial energy of 120 J has had similar success. Escalating doses of biphasic shocks have not been shown to improve success of defibrillation. Immediate defibrillation is indicated if it can be applied within 4–5 minutes of collapse. Beyond that time, results are likely to be better if a brief (~2 minutes) period of chest compressions is provided before defibrillation. The current recommendation in adult patients using a monophasic defibrillator is to give a single shock of 360 J followed by immediate resumption of CPR for 2 minutes before rechecking rhythm and pulse (Box 84–6).1 Because most defibrillations result in asystole or pulse electrical activity (PEA), a period of CPR will be necessary; beginning compressions immediately following the shock minimizes interruption of critical blood flow. With an AED or biphasic defibrillator, use the preset or manufacturers recommended energy. If that is unknown or unclear, a dose of 200 J may be selected. In children, with a manual defibrillator (monophasic or biphasic), an initial dose of 2 J/kg is used. As with adults, CPR is immediately restarted after a shock for 2 minutes

BOX 84–6. Defibrillation Recommendations Adults 2 minutes CPR if >5 minutes since collapse Countershock: Monophasic: 360 J AED: Preset Biphasic: Device recommended (if unknown, 200 J) Immediately restart CPR for 2 minutes Recheck rhythm and pulse Repeat countershock Immediately restart CPR, oxygen, drugs Repeat sequence Children 2 minutes CPR if >5 minutes since collapse First countershock: 2.0 J/kg monophasic or biphasic Immediately restart CPR for 2 minutes Recheck rhythm and pulse Repeat countershock with 4.0 J/kg Immediately restart CPR, oxygen, drugs Repeat sequence, all subsequent shocks: 4.0 J/kg before repeat rhythm and pulse check. If the first shock is unsuccessful, additional shocks of 4 J/kg are given separated by at least 2 minutes of CPR and appropriate drug and other therapy. If defibrillation attempts are unsuccessful, attention should be directed to the oxygenation, acid–base status, and administration of CPR and drugs such as epinephrine. In addition, factors that may increase transthoracic impedance should be evaluated, including pneumothorax, inadequate paddle–chest wall interface, improper paddle position, excessive distance between paddles, and inadequate paddle pressure on the chest. Open-chest defibrillation can be used in the operating room when the thorax is already opened during surgery. Appropriate internal paddle sizes are 6-cm diameter for adults, 4-cm for children, and 2-cm for infants. The paddles are applied with saline-soaked pads, one placed behind the left ventricle and the other over the right ventricle. When defibrillation is performed in this manner, 5 J should be used on the first attempt. If unsuccessful, repeated doses can be used with energy levels up to 50 J.

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Supplemental Therapy Lidocaine and amiodarone are used during cardiac arrest to aid defibrillation when ventricular fibrillation is refractory to electrical countershock therapy or when fibrillation recurs following successful conversion. However, no antiarrhythmic agent has been shown superior to electrical defibrillation or more effective than placebo in the treatment of ventricular fibrillation. Consequently, defibrillation should not be withheld or delayed for drug therapy, but should be applied at the earliest possible time when treating ventricular fibrillation (Box 84–2).

Lidocaine and Amiodarone

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Lidocaine is primarily an antiectopic agent with few hemodynamic effects. It depresses automaticity by reducing the slope of phase 4 depolarization and reducing the heterogeneity of ventricular refractoriness. It tends to restore the ventricular fibrillation threshold decreased by ischemia or infarction. It has no effect on conduction times through the atrioventricular node or on intraventricular conduction time. Amiodarone is a pharmacologically complex drug with sodium, potassium, calcium, and _- and `-adrenergic blocking properties that is useful for treatment of atrial and ventricular arrhythmias. Amiodarone can cause hypotension and bradycardia when infused too rapidly in patients with an intact circulation. This can usually be prevented by slowing the rate of drug infusion, or treated with fluids, vasopressors, chronotropic agents, or temporary pacing. Lidocaine is effective in terminating ventricular premature beats (VPBs) and ventricular tachycardia associated with cardiac surgery, acute myocardial infarction, and digitalis intoxication. It is also effective in preventing and treating ventricular dysrhythmias during cardiac catheterization. Lidocaine is not effective in the treatment of atrial or atrioventricular junctional dysrhythmias (Box 84–7). In contrast, amiodarone is effective in treating multiple types of supraventricular and ventricular dysrhythmias. In cardiac arrest, intravenous lidocaine and/or amiodarone are administered following return of spontaneous circulation for prophylaxis or when ventricular tachycardia or ventricular fibrillation have not responded to or have recurred following epinephrine and defibrillation. There are two ran-

BOX 84–7. Indications for Use of Lidocaine Frequent ventricular premature beats (>10 beats/min) Coupled VPBs Multiform VPBs Ventricular tachycardia Prophylaxis during cardiac catheterization Prophylaxis following resuscitation

domized, blinded, clinical trials in shock-resistant cardiac arrest victims demonstrating improved admission alive to hospital with amiodarone treatment compared to placebo or lidocaine, although there was no difference in survival to discharge.97,98 Amiodarone is initially administered as a 300-mg rapid infusion. Supplemental infusions of 150 mg can be repeated as necessary for recurrent or resistant arrhythmias to a maximum total daily dose of 2 g. Lidocaine is an alternative therapy in refractory fibrillation. To rapidly achieve and maintain therapeutic blood levels during CPR, relatively large doses are necessary. An initial bolus of 1–1.5 mg/kg should be given and additional boluses of 0.5– 0.75 mg/kg can be given every 5–10 minutes during CPR up to a total dose of 3 mg/kg. Only bolus dosing should be used during CPR but an infusion of 2–4 mg/min can be started after successful resuscitation.

Temporary Pacemaker Therapy When emergency pacing is indicated, intravenous or transthoracic pacing can be initiated. Temporary pacing can usually be quickly instituted using external, noninvasive, temporary pacemakers that use large, high-impedance electrodes, allowing relatively nonpainful stimuli.99 Temporary pacing is indicated for patients with preserved myocardial function whose primary problem is impulse formation or conduction, such as patients with severe bradycardia or high-grade heart block who have a palpable pulse. Studies of temporary pacing during cardiac arrest (out-ofhospital or in the emergency department) have found no improvement in admission to hospital or survival. Consequently, withholding chest compressions in patients with asystole to attempt pacing is not recommended.1

PULSELESS ELECTRICAL ACTIVITY AND ASYSTOLE Although ventricular fibrillation is the most common ECG rhythm seen in cardiac arrest, PEA and asystole do occur as either the presenting rhythm or following defibrillation. They are seen more often in children and are associated with a poor outcome. PEA is the circumstance where no palpable pulse is present but an ECG rhythm is detectable. This includes a number of different rhythms, most commonly electromechanical dissociation (EMD; Box 84–8). Asystole is the absence of electrical activity on the ECG. Fine ventricular fibrillation can masquerade as asystole if the ECG lead being monitored is located at right angles to the fibrillatory wave.100 For this reason, the trace from a second lead or from a different position of paddle electrodes should always be inspected before a decision is made not to defibrillate. The predominant cause of primary PEA and asystole is severe myocardial ischemia. These rhythms may represent a failure of myocardial contractility caused by a depletion of intracellular energy stores and carry a very poor prognosis. These ECG patterns also may be secondary, caused by a variety of noncardiac mechanisms that are amenable to treatment (Boxes 84–9 and 84–10). Therapy directed at the underlying disorder may result in a successful outcome. Consequently, consideration of a noncardiac cause for arrest should always be part of the resuscitation sequence when these rhythms are detected (Box 84–11).

DRUG THERAPY During cardiac arrest, drug therapy is secondary to more fundamental inter-

BOX 84–8. Pulseless Electrical Activity Pulseless electrical activity (PEA) includes: EMD Pseudoelectromechanical dissociation Idioventricular rhythms Ventricular escape rhythms Bradyasystoloic rhythms Postdefibrillation idioventricular rhythms


BOX 84–9. Causes of Pulseless Electrical Activity (PEA) Cardiac (primary) Failure of myocardial contractility Noncardiac (secondary) Hypovolemia Tension pneumothorax Cardiac tamponade Massive pulmonary embolism Hypothermia Drug overdose Hypoxia Hyperkalemia Acidosis ventions (Box 84–2). Chest compressions, defibrillation (if appropriate), and ventilation should take precedence over medications. Establishing IV access and administering drugs, although important, should not interrupt sustained chest compressions and ventilation. Of the drugs used during CPR, only vasopressors are acknowledged to help restore spontaneous circulation.1

Oxygen Patients in cardiac arrest or low cardiac output states should receive 100% oxygen as soon as possible. Oxygen will increase arterial oxygen tension and hemoglobin saturation if ventilation is supported and improve tissue oxygenation when circulation is supported.

Vasopressor Agents Mechanism of Action Epinephrine has been used in resuscitation since the 1890s and has been the vasopressor of choice in modern CPR since the studies of Redding and Pearson in the 1960s.17,101 Its efficacy lies entirely in its _-adrenergic properties.64 When epinephrine is administered during CPR, peripheral vasoconstriction results in higher aortic pressure causing an increase in coro-

BOX 84–10. Causes of Asystole Hypoxia Hypothermia Drug overdose Hyperkalemia Hypokalemia Acidosis Myocardial electrical failure

nary and cerebral perfusion pressures and myocardial and brain blood flows.63,102,103 Flow to other organs either does not improve or diminishes further when epinephrine is given, despite the increase in aortic pressure. Animal studies demonstrate that all strong _-adrenergic drugs (epinephrine, phenylephrine, methoxamine, dopamine, norepinephrine) and nonadrenergic vasopressors (vasopressin) are equally successful in aiding resuscitation regardless of the `-adrenergic potency. `-Adrenergic agonists without _ activity (isoproterenol, dobutamine) are no better than placebo.17,59,101,104,105 _-Adrenergic blockade precludes resuscitation, whereas àdrenergic blockade has no effect on the ability to restore spontaneous circulation.61,62 Although it has been suggested that the ability of epinephrine to increase the amplitude of ventricular fibrillation (a `-adrenergic effect) makes defibrillation easier, animal studies show that epinephrine does not improve the success of or decrease the energy necessary for defibrillation.75,85 Retrospective clinical studies show no effect of epinephrine on defibrillation success.83 `-Adrenergic stimulation during cardiac arrest is potentially deleterious. In the fibrillating heart, epinephrine increases oxygen consumption. Myocardial lactate production in the fibrillating heart is unchanged after epinephrine administration during CPR suggesting that the increased coronary blood flow does not improve the oxygen supply-todemand ratio.106 Large doses of epinephrine increased deaths in swine early after resuscitation as a consequence of tachyarrhythmias and hypertension, an effect partially offset by metoprolol treatment.107 Despite these theoretical considerations, survival and neurologic outcome studies show no difference when epinephrine is compared to a pure _-agonist (methoxamine or phenylephrine) or to a nonadrenergic vasopressor (vasopressin) during CPR in animals or humans.108–111

Epinephrine When added to chest compressions, epinephrine helps to develop the critical coronary perfusion pressure necessary to provide enough myocardial blood flow for restoration of spontaneous circulation. If invasive monitoring is present during CPR, an arterial diastolic pressure of 40 mm Hg or coronary perfusion pressure of 20 mm Hg

BOX 84–11. Treatment of Asystole/Pulseless Electrical Activity Begin cardiopulmonary resuscitation ? Intravenous access ? Epinephrine or vasopressin (repeat every 3–5 minutes) ? Consider noncardiac causes ? Consider atropine (repeat every 3–5 minutes up to 3 doses) ? Secure airway without interrupting compressions, when possible must be obtained with good chest compression technique and/or epinephrine therapy (Table 84–1). In the absence of such monitoring, the dose of epinephrine must be chosen empirically. The standard dose used in animals and humans for many years has been 0.5–1.0 mg intravenously. On a weight basis, this dose is approximately 0.1 mg/kg in animals but only 0.015 mg/kg in humans. Animal studies in the 1980s suggested that higher doses of epinephrine in human CPR might improve myocardial and cerebral perfusion and improve success of resuscitation. Case reports on a series of children (with historical controls) were published demonstrating return of spontaneous circulation when large doses (0.1–0.2 mg/kg) of epinephrine were given to patients who had failed resuscitation with standard doses. Outcome studies prospectively comparing standard and high-dose epinephrine do not demonstrate conclusively that higher doses improve survival. Two randomized, blinded animal studies (one with fibrillatory arrest and one with asphyxial arrest) comparing standard and high-dose epinephrine found no difference in 24hour survival or neurologic outcome but more of the high-dose epinephrine animals died in the early postresuscitation period as a result of a hyperdynamic state.107,112 Eight adult prospective randomized clinical trials involving more than 9000 cardiac arrest patients have found no improvement in survival to hospital discharge or neurologic outcome, even in subgroups, when initial high-dose epinephrine (5–18 mg) is compared to standard

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doses (1–2 mg).113–120 Some of the studies (and the cumulative data) suggest that there may be an improvement in immediate resuscitation with highdose epinephrine. None of the studies found improvement in survival to hospital discharge. Because of the long experience with epinephrine, it remains the vasopressor of choice in CPR. It should be administered whenever resuscitation has not occurred after adequate chest compressions and ventilation have been started and defibrillation attempted, if appropriate (Box 84–2). High doses of epinephrine apparently are not needed as initial therapy for most cardiac arrests and potentially could be deleterious under some circumstances. However, the successful case reports were in patients with prolonged CPR and the high doses were given as “rescue” therapy when standard doses had failed. This may be the appropriate place for higher doses of epinephrine in CPR practice. Current recommendations are to give intravenous epinephrine, 1 mg in the adult or 0.01 mg/kg in children, every 3–5 minutes. Higher doses may be indicated in specific circumstances, or if treatment has been delayed and the standard dose seems ineffective.

Vasopressin

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The newest addition to the pharmacologic armamentarium in CPR is arginine vasopressin. It is currently recommended as an alternative to either the first or second dose of epinephrine in a dose of 40 units intravenously. If additional vasopressor doses are needed, epinephrine should be used. Vasopressin is a naturally occurring hormone (antidiuretic hormone) that, when administered in high doses, is a potent nonadrenergic vasoconstrictor, acting by stimulation of smooth muscle V1 receptors. The half-life in the intact circulation is 10–20 minutes, and longer than epinephrine during CPR. Animal studies demonstrate that vasopressin is as effective as, or more effective than, epinephrine in maintaining vital organ blood flow during CPR.121–123 Repeated doses during prolonged CPR in swine were associated with significantly improved rates of neurologically intact survival compared to epinephrine and placebo.124 Postresuscitation myocardial depression and splanchnic blood flow reduction are more marked with vasopressin than epinephrine but

they are transient and can be treated with low-doses of dopamine.125 Clinical studies indicate that vasopressin is as effective as epinephrine, but have not definitively shown it to be superior. A small, randomized, blinded study comparing vasopressin and standard-dose epinephrine in 40 patients with out-ofhospital ventricular fibrillation found improved 24-hour survival with vasopressin but no difference in ROSC or survival to hospital discharge.126 A larger clinical trial of 200 in-patients found no difference between the drugs in survival for 1 hour or to hospital discharge.127 In this study, response times were short, indicating that CPR outcome achieved with both vasopressin and epinephrine in short-term cardiac arrest may be comparable. The hemodynamic effects of vasopressin, compared to epinephrine, are especially impressive during long cardiac arrests. Thus vasopressin may find most use in CPR during prolonged resuscitation. A multicenter, randomized study of 1186 patients comparing vasopressin 40 U and epinephrine 1 mg for the first two doses of vasopressor during resuscitation from out-of-hospital cardiac arrest found no overall difference in survival to hospital admission (36% vs. 31%) or discharge (10% vs. 10%).111 However, in subgroup analysis, in patients presenting in asystole, there was a significant improvement in survival to hospital admission (29% vs. 20%) and discharge (4.7% vs. 1.5%). In those patients who did not resuscitate following two doses of study drug, approximately 60% received additional epinephrine. In these difficult-toresuscitate patients, irrespective of presenting rhythm, those who received vasopressin followed by epinephrine had better outcomes than those who received only epinephrine, suggesting that the combination of the drugs may have advantages. Overall, evidence currently suggests that, like other potent vasopressors, vasopressin is equivalent to, but not better than, epinephrine for use during CPR.

Atropine Atropine sulfate enhances sinus node automaticity and atrioventricular conduction by its vagolytic effects. Atropine is indicated when bradycardia coexists with hypotension, ventricular ectopy, or symptoms associated with myocardial ischemia. The drug can also be used to treat second-degree and

third-degree heart block, and slow idioventricular rates. Although atropine is frequently given during cardiac arrest associated with an ECG pattern of asystole or slow PEA, neither animal nor human studies provide evidence that it actually improves outcome from asystolic or bradysystolic arrest.127–130 The predominant cause of asystole and EMD is severe myocardial ischemia. Excessive parasympathetic tone probably contributes little to these rhythms during cardiac arrest in adults. Even in children, the significance of autonomic tone during arrest is doubtful. The most effective treatment for asystole or PEA is improvement in coronary perfusion and myocardial oxygenation with chest compressions, ventilation, and epinephrine. However, cardiac arrest with these rhythms has a very poor prognosis. Because atropine has few adverse effects, it can be tried in arrest refractory to epinephrine and oxygenation. The recommended dose for bradycardia in adults is 0.5 mg IV every 3–5 minutes to a total dose of 3.0 mg. The pediatric dose for treating bradycardia is 0.02 mg/kg with a minimum dose of 0.1 mg and a maximum total dose of 1.0 mg in a child and 3.0 mg in an adolescent. The dose may be repeated every 3–5 minutes. When treating pulseless arrest in the adult, the dose is 1.0 mg IV every 3–5 minutes to a total dose of 3.0 mg. Atropine is no longer recommended for use in pulseless arrest in children. Full vagolytic doses may be associated with fixed mydriasis following successful resuscitation confounding neurologic examination. Occasionally, a sinus tachycardia following resuscitation may be caused by use of atropine during CPR.

Calcium Salts With normal cardiovascular physiology, calcium increases myocardial contractility and enhances ventricular automaticity. Consequently, calcium salts have been administered during attempted resuscitation of asystole and EMD for many years. However, multiple clinical studies have found that calcium is no better than placebo in promoting resuscitation and survival from asystole or EMD.131,132 Calcium is not indicated for use during cardiac arrest in adults or children. It may be useful for treatment of hyperkalemia, ionized hypocalcemia, hypermagnesemia, or calcium channel blocker toxicity (Box 84–12). If calcium is adminis-


BOX 84–12. Indications for Use of Calcium Hypocalcemia, ionized Hyperkalemia Calcium channel blocker overdose Hypermagnesemia tered, the chloride salt (2–4 mg/kg) is recommended because it produces higher and more consistent levels of ionized calcium than other salts.

Sodium Bicarbonate Although sodium bicarbonate was used commonly during CPR in the past, there is little evidence to support its efficacy. Its use during resuscitation was predicated on the adverse cardiovascular consequences of acidosis, including impaired myocardial function, decreased catecholamine responsiveness, and peripheral vasodilatation. However, most studies have been unable to demonstrate improvement in success of defibrillation or resuscitation with the use of bicarbonate.133–135 The observation that metabolic acidosis develops very slowly during CPR may explain the absence of effect of buffer therapy. Acidosis does not become severe until 15–20 minutes of cardiac arrest have passed.32,136,137 Sodium bicarbonate use during CPR should be restricted not only because of its lack of efficacy but because of the documented complications from excessive use, including hyperosmolality, hypernatremia, metabolic alkalosis and hypercapnia from CO2 liberation (Box 84–13).136,138 These abnormalities are associated with low resuscitation rates and poor survival. However, if sodium bicarbonate is given judiciously according to standard recommendations, no significant metabolic abnormalities should occur.139 Theoretically, sodium bicarbonate could cause a paradoxical worsening of

BOX 84–13. Side Effects from Excessive Use of Sodium Bicarbonate Hyperosmolality Hypernatremia Metabolic alkalosis Hypercapnia Decreased unloading of oxygen from hemoglobin Paradoxical intracellular acidosis

intracellular and intracerebral acidosis as the CO2 liberated during the reaction with acid readily diffuses across cell membranes and the blood–brain barrier whereas bicarbonate diffuses much more slowly. Direct evidence for this effect has not been found. Animal studies have found no change in spinal fluid acid–base status with clinically relevant doses of sodium bicarbonate140 and no worsening of myocardial intracellular acidosis during bicarbonate administration.141 Consequently, paradoxical acidosis from sodium bicarbonate remains a concern primarily on theoretical grounds. Current practice suggests sodium bicarbonate should be considered for use during CPR only in arrests associated with hyperkalemia, severe preexisting metabolic acidosis, and tricyclic or phenobarbital overdose. It may be considered for use in protracted resuscitation attempts after other modalities have been instituted (Box 84–14). These recommendations stem from its unproven efficacy in increasing patient survival and the known side effects. When bicarbonate is used, 1 mEq/kg should be given as the initial dose and no more than half this dose given every 10 minutes thereafter. However, dosing of sodium bicarbonate should be guided by blood gas determination, whenever possible.

Routes of Administration and Vascular Access The preferred route of administration of all drugs during CPR is intravenous or intraosseous. If one of these routes cannot be established rapidly because of technical difficulties, one of the other alternatives—endotracheal or intracardiac—can be used.

Intravenous Access The most rapid and highest drug levels occur with administration into a central vein. Therefore, when a central venous catheter is available during CPR, as is often the case in the operating room, it should be used for drug therapy. However, peripheral intravenous administration also is effective. The antecubital or external jugular vein should be the site of first choice for starting an infusion during resuscitation because starting a central line usually necessitates stopping CPR. Sites in the upper extremity and neck are preferred because of the paucity of blood flow below the diaphragm dur-

BOX 84–14. Indications for Sodium Bicarbonate during Cardiopulmonary Resuscitation Severe preexisting metabolic acidosis Hyperkalemia Tricyclic or phenobarbital overdose Protracted resuscitation ing CPR. Drugs administered in the lower extremity may be extremely delayed or not reach the sites of action. Even in the upper extremity, drugs may require 1–2 minutes to reach the central circulation.142 Onset of action may be speeded if a peripheral drug bolus is followed by a 20–30-mL bolus of intravenous fluid.

Intraosseous Administration The intraosseous route of fluid and medication administration, originally described in 1934,143 has regained popularity recently in the CPR literature. All medications used during CPR and fluids, including whole blood, have been given by the intraosseous route. This technique should be considered a temporary measure during emergencies when other vascular sites are not available. The technique of placing an intraosseous line is straightforward. A standard 16- or 18-gauge needle, spinal needle with stylet, or bone marrow needle is inserted into the anterior surface of the tibia, 1–3 cm below the tibial tuberosity. The needle is directed to a 90° angle to the medial surface of the bone or slightly inferior to avoid the epiphyseal plate. There is a loss of resistance after the needle passes through the bony cortex of the tibia. Placement is successful if the needle is in the marrow cavity as evidenced by the needle standing upright without support and bone marrow can be aspirated into a syringe connected to the needle. It will lose the upright position if it has slipped into the subcutaneous tissue. Free flow of the drug or fluid infusion without significant subcutaneous infiltration also should be demonstrated (Fig. 84–4).144 There are a number of reports of successful intraosseous infusions in children with minimal complications. Animal models have demonstrated successful reversal of hemorrhagic shock,145 effective buffering with sodium bicarbonate,146 and equal hemodynamic response to epinephrine with intraosseous and central intravenous administration.147

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FIGURE 84–4. Intraosseous needle placement. Insert needle at the level of tibial tubercle on the medial portion of the tibia. The needle is aimed carefully and laterally.

Endotracheal Administration

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Drugs that can be absorbed from tracheal mucosa include lidocaine, atropine, naloxone, and epinephrine (Box 84–15). During CPR the rapid establishment of an intravenous line can be difficult, especially in the obese or in infants and small children. The endotracheal route can be used as an alternative following intubation in these settings. The time to effect and drug levels achieved are inconsistent using this route during CPR.148–150 Better results may be obtained by administering 5–10-mL volumes. It is unclear whether deep injection is better than simple instillation into the endotracheal tube.57 Doses 2–2.5 times higher than the recommended IV dose should be administered when this route is used.

POSTRESUSCITATION CARE The major factors contributing to mortality following successful resuscitation are progression of the primary disease and cerebral damage suffered as a result of the arrest. There is growing awareness that any cardiac arrest, even of

BOX 84–15. Endotracheal Administration of Drugs Lidocaine Atropine Naloxone Epinephrine

Do not administer: Sodium bicarbonate Calcium chloride

brief duration, causes a generalized decrease in myocardial function similar to the regional hypokinesis seen following periods of regional ischemia. This is usually referred to as global myocardial stunning and can be mitigated with inotropic agents, if necessary. Active management following resuscitation appears to mitigate postischemic brain damage and improve neurologic outcome without increasing the number of patients surviving in a vegetative state.151 When flow is restored following a period of global brain ischemia, 3 stages of cerebral reperfusion are seen in ensuing 12 hours. There are multifocal areas of the brain with no-reflow immediately following resuscitation. Within an hour there is global hyperemia followed quickly by prolonged global hypoperfusion. Postresuscitation support is focused on providing stable oxygenation and hemodynamics so as to minimize any further cerebral insult. A comatose patient should be maintained on mechanical ventilation for several hours to ensure adequate oxygenation and ventilation. Restlessness, coughing, or seizure activity should be aggressively treated with appropriate medications including neuromuscular blockers, if necessary. Arterial PaO2 should be maintained above 100 mm Hg and moderate hypocapnia (PvCO2 25–35 mm Hg) may be helpful. Blood volume should be maintained normal and moderate hemodilution to a hematocrit of 30–35% may be helpful. A brief 5-minute period of hypertension

to mean arterial pressure of 120–140 mm Hg may help overcome the initial cerebral no-reflow. This frequently occurs secondary to the effects of epinephrine given during CPR. However, both prolonged hypertension (>110 mm Hg) and hypotension are associated with a worsened outcome. Hyperglycemia during cerebral ischemia is known to result in increased neurologic damage. Thus, it seems prudent to control glucose in the 100–300 mg/dL range. Specific pharmacologic therapy directed at brain preservation has not been shown to have further benefit. Although animal trials of barbiturates and calcium channel blockers were promising, large, multicenter trials found no improvement in neurologic status when drugs were given following cardiac arrest.151,152 In contrast to pharmacologic therapy, two studies have demonstrated improved neurologic outcome when mild therapeutic hypothermia (89.6–93.2°F [32–34°C]) is induced for 12–24 hours in cardiac arrest survivors who remained comatose after admission to the hospital.153,154 Both investigations studied only patients whose initial rhythm was ventricular fibrillation and the larger of the trials included only witnessed arrests. Nevertheless, these are the first studies to document improved neurological outcome with a specific post-arrest intervention. The International Liaison Committee on Resuscitation (ILCOR) now recommends “unconscious adult patients with return of spontaneous circulation after out-of-hospital cardiac arrest should be cooled to 32–34°C for 12 to 24 hours when the initial rhythm was ventricular fibrillation. Such cooling may also be beneficial for other rhythms or in-hospital cardiac arrest.”

PROGNOSIS For the comatose survivor of CPR, the question of ultimate prognosis is important. One retrospective study demonstrated that the admission neurologic examination of comatose victims is highly correlated with the likelihood of awakening.155 If there was no pupillary light response and no spontaneous eye movement, and if the motor response to pain was absent or extensor posturing, there was only a 5% chance the patient would ever awaken. A companion study demonstrated


BOX 84–16. Prognosis of Comatose Survivors of Cardiac Arrest Signs predicting death or poor neurologic outcome Absent corneal reflex at 24 hours Absent pupillary response at 24 hours Absent withdrawal response to pain at 24 hours No motor response at 24 hours No motor response at 72 hours that the chance of ever awakening fell rapidly in the days following arrest.156 If the patient was not awake by 4 days following arrest, the chance of ever awakening was less than 20%, and all those awakening had marked neurologic deficits. Most patients who completely recover show rapid improvement in the first 48 hours. A meta-analysis of 11 clinical studies involving 1914 patients identified 5 clinical signs that strongly predict death or poor neurologic outcome (Box 84–16).157

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146. Spivey WH, Lathers CM, Malone DR, et al. Comparison of intraosseous, central, and peripheral routes of sodium bicarbonate administration during CPR in pigs. Ann Emerg Med 1985;14:1135.

132. Stueven HA, Thompson BM, Aprahamian C, et al. The effectiveness of calcium chloride in refractory electromechanical dissociation. Ann Emerg Med 1985;14:626. 133. Federiuk CS, Sanders AB, Kern KB, et al. The effect of bicarbonate on resuscitation from cardiac arrest. Ann Emerg Med 1991;20:1173.

147. Andropoulos DB, Soifer SJ, Schreiber MD. Plasma epinephrine concentrations after intraosseous and central venous injection during cardiopulmonary resuscitation in the lamb. J Pediatr 1990;166:312. 148. McDonald JL. Serum lidocaine levels during cardiopulmonary resuscitation after intravenous and endotracheal administration. Crit Care Med 1985;13(11):914.

120. Sherman BW, Munger MA, Foulke GE, et al. High-dose versus standard-dose epinephrine treatment of cardiac arrest after failure of standard therapy. Pharmacotherapy 1997;17:242.

134. Guerci AD, Chandra N, Johnson E, et al. Failure of sodium bicarbonate to improve resuscitation from ventricular fibrillation in dogs. Circulation 1986;74(Suppl IV):IV-75.

121. Lindner KH, Brinkmann A, Pfenninger EG, et al. Effect of vasopressin on hemodynamic variables, organ blood flow, and acidbase status in a pig model of cardiopulmonary resuscitation. Anesth Analg 1993;77:427.

135. Stacpoole PW. Lactic acidosis: the case against bicarbonate therapy. Ann Intern Med 1986;105:276.

149. Ralston SH, Tacker WA, Showen L, et al. Endotracheal versus intravenous epinephrine during electromechanical dissociation with CPR in dogs. Ann Emerg Med 1985;14:1044.

136. Bishop RL, Weisfeldt ML. Sodium bicarbonate administration during cardiac arrest: effect on arterial pH, pCO2, and osmolality. JAMA 1976;235:506.

150. Hornchen U, Schuttler J, Stoeckel H, et al. Endobronchial instillation of epinephrine during cardiopulmonary resuscitation. Crit Care Med 1987;15:1037.

137. Weil MH, Grundler W, Yamaguchi M, et al. Arterial blood gases fail to reflect acid–base status during cardiopulmonary resuscitation. a preliminary report. Crit Care Med 1985;13:884.

151. Abramson NS, Safar P, Detre KM, et al. Randomized clinical study of cardiopulmonary-cerebral resuscitation: thiopental loading in comatose cardiac arrest survivors. N Engl J Med 1986;314:397.

138. Mattar JA, Weil MH, Shubin H, et al. Cardiac arrest in the critically ill. II. Hyperosmolal states following cardiac arrest. Am J Med 1974;56:162.

152. Brain Resuscitation Clinical Trial II Study Group. A randomized clinical study of a calcium-entry blocker (lidoflazine) in the treatment of comatose survivors of cardiac arrest. N Engl J Med 1991;324: 1225.

122. Lindner KH, Prengel AW, Pfenniger EG, et al. Vasopressin improves vital organ blood flow during closed-chest cardiopulmonary resuscitation in pigs. Circulation 1995;91:215. 123. Wenzel V, Lindner KH, Krismer AC, et al. Repeated administration of vasopressin, but not epinephrine, maintains coronary perfusion pressure after early and late administration during cardiopulmonary resuscitation in pigs. Circulation 99:1379–1999. 124. Wenzel V, Lindner KH, Krismer AC, et al. Survival with full neurologic recovery and no cerebral pathology after prolonged resuscitation in pigs. J Am Coll Cardiol 2000;35:527.

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130. Stueven HA, Tonsfeldt DJ, Thompson BM, et al. Atropine in asystole: human studies. Ann Emerg Med 1984;13:815.

125. Prengel AW, Lindner KH, Keller A, Lurie KG. Cardiovascular function during the postresuscitation phase after cardiac arrest in pigs: A comparison of epinephrine versus vasopressin. Crit Care Med 1996;24:2014. 126. Lindner KH, Dirks B, Strohmenger HU, et al. Randomized comparison of epinephrine and vasopressin in patients with out-of hospital ventricular fibrillation. Lancet 1997;349:535. 127. Stiell IG, Hebert PC, Wells GA, et al. Vasopressin versus epinephrine for in-hospital cardiac arrest: a randomized controlled trial. Lancet 2001;358:105. 128. Iseri LT, Humphrey SB, Siner EJ. Prehospital bradyasystolic cardiac arrest, Ann Intern Med 1978;88:741. 129. Coon GA, Clinton JE, Ruiz E. Use of atropine for bradyasystolic prehospital cardiac arrest. Ann Emerg Med 1981;10:462.

139. White BC, Tintinalli JE. Effects of sodium bicarbonate administration during cardiopulmonary resuscitation. JACEP 1977;6:187. 140. Sanders AB, Otto CW, Kern KB, et al. Acid–base balance in a canine model of cardiac arrest. Ann Emerg Med 1988;17:667.

153. Holzer M, The Hypothermia After Cardiac Arrest Study Group. Mild therapeutic hypothermia to improve the neurologic outcome after cardiac arrest. N Engl J Med 2002;346:549.

141. Kette F, Weil MH, von Planta M, et al. Buffer agents do not reverse intramyocardial acidosis during cardiac resuscitation. Circulation 1990;81:1660.

154. Bernard SA, Gray TW, Buist MD, et al. Treatment of comatose survivors of out-ofhospital cardiac arrest with induced hypothermia. N Engl J Med 2002;346:557.

142. Hedges JR, Barsan WB, Doan LA, et al. Central versus peripheral intravenous routes in cardiopulmonary resuscitation. Am J Emerg Med 1984;2:385.

155. Longstreth WT, Diehr P, Inui TS. Prediction of awakening after out-of-hospital cardiac arrest. N Engl J Med 1983;308:1378.

143. Josefson LM. A new method of treatment—intraossal injections. Acta Med Scand 1934;81:550. 144. Berg RA. Emergency infusion of catecholamines into bone marrow. Am J Dis Child 1984;138:810. 145. Morris RE, Schonfeld N, Haftel AJ. Treatment of hemorrhagic shock with in-

156. Longstreth WT, Inui TS, Cobb LA, Copass MK. Neurologic recovery after outof-hospital cardiac arrest, Ann Intern Med 1983;98:588. 157. Booth CM, Boone RH, Tomlinson G, et al. Is this patient dead, vegetative, or severely neurologically impaired? Assessing outcome for comatose survivors of cardiac arrest. JAMA 2004;291:870.

PART 7 SPECIAL CONSIDERATIONS IN ANESTHESIA CARE


PART 7: Special Considerations in Anesthesia Care

CHAPTER 85 Blood and Blood Component Therapy Ian J. Welsby, BSc, MBBS, FRCA, and Steven J. Bredehoeft, MD HISTORY OF BLOOD TRANSFUSION

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Practical, safe transfusion derives from centuries of experimentation and discovery. Although the first known animal transfusion experiments took place in both England and France in the 17th century, early efforts to translate the technique to humans failed with such spectacular flair that the learned societies on both sides of the English Channel flatly banned the practice. The first “modern” transfusion is attributed to John Syng Physick in Philadelphia in 1795. English physician James Blundell claimed success for 5 of 10 transfused patients during his professional career (1820–1840). The 19th century saw rapid expansion of bacteriology and growing understanding of antisera. In 1900, Karl Landsteiner significantly advanced the cause of blood compatibility with his landmark discovery of the ABO blood groups, with O being derived form the German “ohne” or without, for which he received the 1930 Nobel Prize in Medicine and Physiology. Four decades later, in collaboration with Alex Weiner, Philip Levine, and R.E. Stetson, Landsteiner played an instrumental role in the recognition of Rh(D), a major cause of hemolytic disease of the newborn (HDN) and non–ABO-related hemolytic transfusion reactions. Prior to effective schemes for anticoagulation, Alexis Carrel explored vascular anastomosis as a possible strategy for moving blood from donor to recipient. Although eclipsed by other approaches, this pioneering techniques formed the basis of contemporary vascular anastomoses in solid-organ transplantation and won Carrel the 1912 Nobel Prize. The use of citrate to anticoagulate stored blood by means of calcium che-

lation was a landmark, as heparin was unsuitable to transfuse into bleeding patients, and citrate’s rapid metabolic elimination in vivo proved ideal for purposes of transfusion. Its adoption paved the way for transition from direct to indirect transfusion. By 1916, Rous and Turner introduced glucose in addition to sodium citrate, extending ex vivo storage by several days. The first blood depots were established during the First World War by the British and were stocked prior to major campaigns. The Soviets established the first permanent blood bank in a Leningrad hospital in 1932, and 5 years later Bernard Fantus established the first U.S. blood bank at the Cook County Hospital in Chicago. Although clinical efforts had focused largely on transfusion of whole blood, Professor Edwin Cohn at Harvard explored fractionation of plasma proteins using cold ethanol treatment and centrifugation. By 1940, these techniques yielded concentrated fractions of albumin, immunoglobulins, and fibrinogen. With the outbreak of war in Europe, the U.S. War Department and American Red Cross launched Plasma for Britain, under the direction of Dr. Charles Drew. Despite highly successful initial resuscitation, casualties with significant blood loss treated exclusively with plasma developed “air hunger” from anemia. Improved logistics enabled a shift to use of whole blood. With this transition, volume tolerance emerged as the next constraint to adequate re-

placement of oxygen-carrying capacity. Large-scale availability of red blood cell concentrates (and more general exploitation of blood component therapy) awaited development of the plastic, integrated, blood-collection systems of the 1950s and 1960s. Success was tempered by the identification of transfusion borne infections. “Serum” hepatitis followed approximately 10% of transfusions. Worse, in some communities posttransfusion hepatitis reached rates of 30%, an observation that was explained by reliance on monetarily compensated donors. In parallel with these epidemiologic discoveries, advances in virology and radio-immunochemistry brought to market by 1969 limited supplies of tests for detection of hepatitis B surface antigen (HBsAg, the “Australia Antigen”). With transition in the United States to an allvolunteer blood supply, rates of hepatitis B virus (HBV) transmission fell dramatically, and with full deployment of HBsAg testing in 1972, rates of transfusion-transmitted hepatitis B fell to between 0.3% and 0.9%. Although remarkably high by today’s standards, this represented risk reduction by an order of magnitude. Following the emergence of HIV/ AIDS, an epidemic that transformed public perceptions of blood safety occurred. Lessons learned for dealing with hepatitis led to rapid progress toward securing the safety of the blood supply. The answer to a patient’s question, “Will this transfusion give me AIDS?” is, “No.”

KEY POINTS 1. ABO compatibility remains the major safety consideration for blood transfusion. Clerical errors of patient identification and sample labeling remain the primary cause of mistransfusion of ABO-incompatible units. 2. Prestorage leukoreduction of cellular blood products has greatly reduced, but not eliminated, the incidence of febrile reactions, transfusion-related immunosuppression, and cytomegalovirus transmission, and has led to improved outcomes in surgical patients compared to the use of nonleukoreduced products.


3. Rigorous donor screening, serologic testing and nucleic acid amplification testing have proven extremely effective in reducing the risk of transfusion-transmitted infections in developed nations. However, transfusion-transmitted infection remains a serious concern throughout the developing world. 4. International travel and associated exposure to pathogens not addressed by existing screening mechanisms will increasingly limit suitable blood donors. These and other pressures on the blood supply make imperative strategies for blood conservation and promotion of bloodless surgical techniques.

CHAPTER 85: Blood and Blood Component Therapy

Although infectious risks of blood transfusion have diminished enormously in developed nations, high rates of endemic disease and limited testing resources in developing countries paint a variegated global picture of blood product safety. Today’s tools include effective donor screening and testing. Tomorrow holds promise of pathogen inactivation and improved controls of bedside transfusion practice as further steps on the long path toward safe transfusion.

CLINICALLY AVAILABLE BLOOD PRODUCTS Whole Blood Despite some clinicians’ desires for fresh whole blood, especially for use in pediatric cardiac anesthesiology, the optimal use for a limited resource demands the use of red cells for oxygen-carrying capacity, plasma for coagulation proteins, and platelets for thrombocytopenia or platelet dysfunction. The component therapy approach maximizes the number of recipients benefiting from transfusion and optimally preserves the function of essential blood elements. Colloid replacement can be provided by synthetic colloids, such as gelatins and starches, or albumin products fractionated from plasma. The time required to perform federally mandated testing makes fresh whole blood practically unavailable to most clinicians; consequently, discussion is primarily focused on blood components. A unit of whole blood is collected in citrate-phosphate-dextrose-adenine 1 (CPDA-1) anticoagulant, giving it a shelf-life of 35 days and a volume of approximately 510 mL (450 mL of blood plus 63 mL of CPDA-1). Within 24 hours of collection, the platelets are dysfunctional,1 and several plasma coagulation factors are below optimal levels,2 emphasizing the importance of the component products despite the disadvantage of increased donor exposure.

Red Cell Concentrates Red cell concentrates, or packed red blood cells (PRBCs), are obtained from CPDA-1-anticoagulated whole blood after centrifugation of most of the plasma and platelets. At most blood centers, the red cells are then mixed with 100 mL of an additive nutrient con-

taining an additional dextrose and adenine (NutriCell or AS-3) or dextrose, adenine, and mannitol (Adsol or AS-1) solution that extends the storage period to 42 days3 and results in flow properties similar to those of whole blood. PRBCs from CPDA-1-anticoagulated blood are stored for up to 35 days. Loss of viability during storage is caused by cellular adenosine triphosphate (ATP) depletion, which leads to loss of membrane phospholipids, increased rigidity, and reduced life span, with current standards requiring 75% of transfused cells to survive in the circulation for 24 hours.4 At 35 days, 70% of cells survive in CPDA-1 versus 88% in Adsol, with a pH of 6.7 in both solutions; intracellular ATP is 45% baseline in CPDA-1 versus 75% in Adsol, whereas 2,3-diphosphoglycerate (2,3-DPG) levels are at 10% baseline in both. In vivo, 2,3-DPG levels rapidly normalize over 24 hours and recover to more than 50% within 1 or 2 hours.5 PRBCs are the product of choice for the correction of an isolated defect in oxygen-carrying capacity, as in chronic anemia, with the advantage of lower volume load in this setting. During acute perioperative blood loss, however, attention must be paid to volume status as well as restoring oxygen-carrying capacity using crystalloid or colloid volume expanders. Leukocyte-Reduced Red Cells Leukocyte-reduced red cells (LRRCs) can be prepared by a variety of methods, with varying efficiency of white cell removal. The minimum standard, established by the American Association of Blood Banks (AABB), is a leukocyte number in the final component of 99% leukocyte reduction while depleting 1 blood volume in 24 hours) because of the dilutional coagulopathy arising from the PRBC and crystalloid solutions, both of which lack coagulation factors. A predetermined algorithm for FFP transfusion per units of PRBCs is often unreliable, as dilutional thrombocytopenia also complicates the coagulopathy after massive transfusion.41,42 As recommended in the transfusion guidelines published by the American Society of Anesthesiologists, FFP transfusion should ideally be guided by abnormal PT and PTT results when available as the degree of coagulopathy can be unpredictable. Disseminated intravascular coagulation may be secondary to sepsis, liver disease, hypotension, perioperative hypoperfusion, trauma, obstetric complications, leukemia, or underlying malignancy. Successful treatment of the underlying cause is paramount. Pa-

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PART 7: Special Considerations in Anesthesia Care

tients with DIC leading to coagulopathic bleeding should be given FFP to correct PT and PTT abnormalities, but as in severe liver disease, FFP alone may fail to normalize PT and PTT.43 The need for cryoprecipitate or platelet transfusion should also be evaluated. Rapid Reversal of Vitamin K Antagonists Warfarin (Coumadin) inhibits the hepatic synthesis of vitamin K-dependent clotting factors (II, VII, IX, and X), inducing functional deficiencies of these factors that can correct within 48 hours after drug discontinuation if diet and vitamin K absorption are normal. Vitamin K administration corrects the coagulopathy in 12–18 hours. In an emergency, the deficiency of clotting factors can immediately be corrected by FFP transfusion. However, a large volume of FFP may be required, and if unlikely to be tolerated, smaller volumes of FFP can be augmented with a bypassing agent such as prothrombin complex concentrates or more commonly recombinant activated factor VII.44 In the absence of bleeding, the potential danger of excessively prolonged PTs must be weighed against the risks of FFP infusion, and FFP is rarely indicated.45

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Thrombotic Thrombocytopenic Purpura and Hemolytic Uremic Syndrome In some patients with thrombotic thrombocytopenic purpura (TTP), hemolytic uremic syndrome (HUS), or the syndrome of hemolysis, elevated liver enzymes, and low platelets associated with preeclampsia (HELLP) syndrome, FFP exchange transfusion has been clinically therapeutic; plasmapheresis is preferred if there is concern for fluid overload.46,47 The mechanism of the therapeutic effect of FFP is likely to involve transfused anticoagulant proteins such as protein C and antithrombin III, which may restore endothelial prostaglandin I2 (prostacyclin) production and inhibit the agglutinating activity of the abnormal plasma.48 Alternatively, it may inhibit the release of large-molecular-weight von Willebrand factor (vWF) multimers or restore their normal processing in the circulation by deficient ADAMTS13 enzyme.49 The use of cryo-poor supernatant for refractory TTP has been suggested, but the advantage is unestablished.50 Dosage One unit of FFP derived from a unit of whole blood contains 200–280

mL; apheresis may contain as much as 800 mL. On average, there are 0.7–1 unit/mL of activity of each coagulation factor per mL of FFP and 1–2 mg/ mL fibrinogen. For perioperative use, the FFP dose may be estimated at 8–10 mL/kg and should be ordered as the number of milliliters to be infused for pediatric patients or units for adults. Laboratory measurements and clinical response determine the need for additional doses. Compatibility and Side Effects Fresh-frozen plasma is screened for unexpected RBC antibodies and should be ABO-type compatible as it contains anti-A (groups O and B) and anti-B (groups O and A). Cross-matching is not performed. The Rh(D) type is not always matched because immunization to Rh(D) antigen has rarely been reported as a result of transfusion of Rh(D)-positive plasma to Rh(D)-negative individuals. Hemolytic reactions as a consequence of infusion of an undetected antibody directed toward recipient RBC antigens are rarely seen, as is alloimmunization to RBC antigens.51 Fever, chills, and allergic reactions may occur and are treated symptomatically. Typical urticarial reactions are believed to result from recipient antibodies interacting with donor plasma protein antigens. Rarely, severe allergic reactions occur. Some are believed to be caused by donor antibodies reacting with recipient leukocytes or protein antigens. Anaphylactic reactions may occur after infusion of plasma (containing IgA) into patients with IgA deficiency and antibodies to IgA.52 IgA-deficient plasma from donors in the national registry can be obtained for these occasional patients. Transmission of infectious disease by FFP has been significantly reduced but not eliminated. Cell-associated CMV is not transmitted by FFP.53 Immunoglobulin Preparations Intravenous immunoglobulin (IVIg) is prepared by fractionation of large pools of human plasma. Indications for IVIg use include primary congenital immunodeficiency syndromes, children with HIV infection,54 chronic lymphocytic leukemia complicated by hypogammaglobulinemia, CMV pneumonia complicating bone marrow transplantation (in combination with ganciclovir),55 a possible role in preventing severe graft-versus-host dis-

ease after bone marrow transplantation, acute and chronic idiopathic thrombocytopenic purpura, and mucocutaneous lymph node syndrome (Kawasaki disease).56 Hyperimmune immunoglobulin (HIg) is prepared from large pools of plasma known to contain elevated antibody titers against specific infectious agents. Specifically, CMV HIg is indicated in transplantation recipients seronegative for CMV who receive a seropositive donor organ or in bone marrow transplantation patients with CMV interstitial pneumonia.55 Hepatitis B HIg is used to provide passive immunity to hepatitis B virus associated with inoculation by or a liver transplantation in HBsAg-positive individuals. Rhesus HIg is used when fetal Rh(D)-positive RBCs may have entered the maternal circulation of an Rh(D)-negative mother. Rhesus HIg is given to Rh(D)-negative mothers after abortion or amniocentesis as well as before delivery and again postpartum if the child proves to be Rh(D) positive.57,58 The therapeutic effect is believed to be caused by antibody feedback with T-cell suppression of the Bcell clone responsible for the formation of anti-Rh antibody. Its routine use in obstetrical practice has virtually eliminated alloimmunization of Rhnegative mothers. Antithymocyte globulin (ATG) is purified from the hyperimmune serum of horses immunized with human T lymphocytes. ATG is used in transplant patients as an adjunct therapy in the treatment of graft rejection. Cryoprecipitate Cryoprecipitate is prepared from 1 unit of FFP thawed at 39.2°F (4°C). The precipitate is then refrozen in 10–15 mL of plasma and stored at 0.4°F (18°C) or colder for up to 1 year. Cryoprecipitate contains 80– 100 units of factor VIII, 100–250 mg of fibrinogen, 50–60 mg of fibronectin, 40–70% of normal vWF levels, and anti-A and anti-B antibodies. Cryoprecipitate is effectively the blood component containing the highest concentration of factor VIII, vWF, factor XIII, fibrinogen, and fibronectin. Cryoprecipitate may be used to treat bleeding associated with hypo- or dysfibrinogenemia or factor XIII deficiency states, although an equivalent amount of fibrinogen to the usual adult dose of 100 mL is also found in 4 units of FFP. Its use in vWF and factor VIII deficien-

CHAPTER 85: Blood and Blood Component Therapy

cy has been superseded by individual factor replacement therapy. Indications: Fibrinogen Deficiency Fibrinogen deficiency may be a result of rare congenital afibrinogenemias or dysfibrinogenemias or more commonly as a result of severe liver disease, DIC, or massive transfusion.45 These patients often have multifactorial coagulopathies and may require the coadministration of FFP, platelets, and antifibrinolytic agents. Fibrinogen measurements are an important component of a coagulation screen because levels

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