Textbook of Regional Anesthesia 2003 EDITION P. PRITHVI RAJ MD Professor of Anesthesiology Co-Director of Pain Services International Pain Institute Texas Tech University Health Sciences Center School of Medicine Lubbock, Texas
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NOTICE Anesthesiology is an ever-changing field. Standard safety precautions must be followed, but as new research and clinical experience broaden our knowledge, changes in treatment and drug therapy may become necessary or appropriate. Readers are advised to check the most current product information provided by the manufacturer of each drug to be administered to verify the recommended dose, the method and duration of administration, and contraindications. It is the responsibility of the treating physician, relying on experience and knowledge of the patient, to determine dosages and the best treatment for each individual patient. Neither the Publisher nor the editor assumes any liability for any injury and/or damage to persons or property arising from this publication. THE PUBLISHER
Library of Congress Cataloging-in-Publication Data Raj, P. Prithvi. Textbook of regional anesthesia/P. Prithvi Raj. p. ; cm. ISBN 0–443–06569–1 1. Conduction anesthesia. I. Title. [DNLM: 1. Anesthesia, Conduction—methods. WO 300 R161t 2002] RD84 .R35 2002 617.9′64—dc21 2001037149 Acquisitions Editor: Allan Ross Project Manager: Robin E. Davis Senior Editorial Assistant: Josh Hawkins TEXTBOOK OF REGIONAL ANESTHESIA ISBN 0–443–06569–1 Copyright © 2002 Elsevier Science (USA). All rights reserved. No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopy, recording, or any information storage and retrieval system, without permission in writing from the publisher. CHURCHILL LIVINGSTONE and the Sail Boat Design are registered trademarks. Printed in the United States of America. Last digit is the print number: 9 8 7 6 5 4 3 2 1 II
Contributors ELI ALON MD Professor of Anesthesiology, University of Zurich, Zurich, Switzerland; Chairman, Department of Anesthesiology, Ospedale Civico and Ospedale Italiano, Lugano, Switzerland Efficacy Outcome of Regional Anesthesia Techniques in Obstetrics SUSAN R. ANDERSON MD Assistant Professor, Director of Education, Advanced Pain Centers of Alaska, Anchorage, Alaska Drugs Used in Regional Anesthesia: Chemical Neurolytic Agents; Continuous Regional Analgesia; Epiduroscopy; Discography and Intradiscal Electrothermal Annuloplasty; Vertebroplasty JOSE DE ANDRÉS MD Associate Professor of Anesthesia, Valencia University Medical School; Director, Pain Management Center, Department of Anesthesiology and Critical Care, Valencia University General Hospital, Valencia, Spain Aids to Localization of Peripheral Nerves; Common Techniques for Regional Anesthesia: Subarachnoid and Epidural Anesthesia DOUGLAS R. BACON MD Associate Professor of Anesthesiology, Mayo Medical School; Senior Associate Consultant, Mayo Clinic Rochester Minnesota Beyond Blocks: The History of the Development of Techniques in Regional Anesthesia
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RONALD BANISTER MD Resident, Department of Anesthesiology, Texas Tech University Health Sciences Center School of Medicine, Lubbock, Texas Aids to Localization of Peripheral Nerves ALDO BARBATI MD Staff Anesthesiologist, Department of Anesthesia and Intensive Care, Cardarelli Hospital, Naples, Italy Equipment and Techniques SHAUNA BAUGHCUM CPC Business Manager, International Pain Institute, Texas Tech University Health Sciences, Center School of Medicine Lubbock Texas Appendix A: Selected Pain Management Billing Codes; Appendix B: Selected Diagnoses for Pain Management DIEGO BELTRUTTI MD Head, Department of Anesthesia and Resuscitation, Pain Control Center, Santo Spirito Hospital, Bra, Italy Organization of Chronic Pain Services; Organization of Palliative Care Services JAY B. BENDER MD Pain Fellow, Department of Anesthesiology, University of Texas M.D. Anderson Cancer Center, Houston, Texas Chronic Pain: Outcomes Using Procedures for Nociceptive Pain HONORIO T. BENZON MD Professor of Anesthesiology, Northwestern University Medical School; Chief Division of Pain Medicine, Northwestern Memorial Hospital Chicago, Illinois Acute Situations: Trauma
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HEMMO A. BOSSCHER MD Assistant Professor of Anesthesiology, Texas Tech University Health Sciences Center School of Medicine, Lubbock, Texas Epidural Steroids CHRISTOPHER M. BURKLE MD Instructor in Anesthesiology, Mayo Medical School; Senior Associate Consultant in Anesthesiology, Mayo Clinic, Rochester, Minnesota Beyond Blocks: The History of the Development of Techniques in Regional Anesthesia ALLEN W. BURTON MD Associate Professor of Anesthesiology, Section Chief of Cancer Pain Management, University of Texas M.D. Anderson Cancer Center, Houston, Texas Chronic Pain: Outcomes Using Procedures for Nociceptive Pain JEFFREY CARRUTH MD Chief Resident, Department of Anesthesiology, Texas Tech University Health Sciences Center, Lubbock, Texas Radiographic Imaging in Regional Anesthesia VINCENT W. S. CHAN MD Associate Professor of Anesthesia, University of Toronto; Director Regional Anesthesia Acute Pain Service, Department of Anesthesia University Health Network, Toronto Western Hospital Toronto, Ontario, Canada Training Education of a Physician for Regional Anesthesia MILES DAY MD, DAPBM Assistant Professor of Pain Management/Anesthesiology, International Pain Institute, Texas Tech University Health Sciences Center School of Medicine; Staff Physician, University Medical Center, Lubbock, Texas V
Nerve Root Neurolysis; Sphenopalatine Analgesia FRANCESCO DONATELLI MD Resident, School of Specialization in Anesthesiology, L’Aquila, Italy Economic Impact of Regional Anesthesia; Organization of an Acute Pain Service and Pain Management CLAUDE ECOFFEY MD Professor of Anesthesiology, Centre Hospitalier Universitaire de Rennes, Rennes, France Common Techniques for Regional Anesthesia: Regional Anesthesia in Children SERDAR ERDINE MD Professor, Medical Faculty of Istanbul University; Chairman, Department of Algology, Capa Klinikleri, Istanbul, Turkey Trigeminal Ganglion Procedures P. M. FINCH MD Perth Pain Management Centre, South Perth, Western Australia Sympathetic Neurolysis BRIAN FLANAGAN MD Progressive Pain Management Dallas, Texas Discography Intradiscal Electrothermal Annuloplasty KAREN GALLOWAY MD Instructor, Division of Pediatric Anesthesiology, The Johns Hopkins University School of Medicine, Baltimore, Maryland; Anesthesiologist, Shriners Hospital for Children, Honolulu, Hawaii Chronic Pediatric Pain MELVIN G. GITLIN MD VI
Professor and Interim Chairman, Department of Anesthesiology, Tulane School of Medicine; Director, Pain Management Care, Tulane University Hospital and Clinic, New Orleans, Louisiana Epidural Steroids STEWART GRANT MD Associate Professor of Anesthesiology, Duke University Medical Center Durham, North Carolina Common Techniques for Regional Anesthesia: Peripheral Nerve Blocks ROY GREENGRASS MD Associate Professor of Anesthesiology; Co-Director, Division of Ambulatory Anesthesiology, Duke University Medical Center, Durham, North Carolina Common Techniques for Regional Anesthesia: Peripheral Nerve Blocks PAOLO GROSSI Director, Department of Regional Anesthesia and Pain Treatment, Instituto Policlinico, San Donato Milano, Milano, Italy Aids to Localization of Peripheral Nerves MARC B. HAHN DO Dean, Texas College of Osteopathic Medicine, University of North Texas Health Science Center at Fort Worth Fort Worth, Texas Peripheral Nerve Blockade RICHARD A. HARDART MD Instructor, Department of Anesthesiology, The Johns Hopkins University School of Medicine, Baltimore, Maryland Pediatric Pain Management CRAIG T. HARTRICK MD
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Director, Anesthesia Research, William Beaumont Hospital, Royal Oak, Michigan Regional Anesthesia for Chronic Situations: Nonmalignant Pain; Trauma SAMUEL J. HASSENBUSCH MD Professor of Neurosurgery, University of Texas, M.D. Anderson Cancer Center, Houston, Texas Neuroaugmentative Procedures for Pain JAMES E. HEAVNER DVM, PhD Professor of Anesthesiology and Physiology, Director of Anesthesia Research, Texas Tech University Health Sciences Center School of Medicine, Lubbock, Texas Pain Mechanisms and Local Anesthetics: Scientific Foundations for Clinical Practice CHRISTOPHER J. JANKOWSKI MD Assistant Professor of Anesthesiology, Mayo Medical School; Consultant, Department of Anesthesiology, Mayo Clinic and Foundation, Rochester, Minnesota Neuraxial Anesthetic Techniques MOLLY JOHNSTON RN Texas Wesleyan University, Fort Worth, Texas Organization Function of the Nerve Block Facility ALAN D. KAYE MD, PhD Professor and Chairman, Department of Anesthesiology, Professor of Pharmacology, Texas Tech University Health Sciences Center School of Medicine, Lubbock, Texas Drugs Used in Regional Anesthesia: Local Anesthetics; Epidural Steroids
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HENRIK KEHLET MD, PhD Professor of Anesthesiology, Copenhagen University, Hvidovre Hospital, Hvidovre, Denmark Endocrine-Metabolic Effects STEVEN KLEIN MD Assistant Professor of Anesthesiology, Division of Ambulatory Regional Anesthesia, Duke University Medical Center Durham, North Carolina Common Techniques for Regional Anesthesia: Peripheral Nerve Blocks ADRIENNE E. KNIGHT MD Assistant Professor of Anesthesiology, University of Colorado, Denver, Colorado Acute Situations: Trauma MARK KRAFT MD Private Practice, Las Vegas, Nevada Discography and Intradiscal Electrothermal Annuloplasty ELLIOT S. KRAMES MD Medical Director, Pacific Pain Treatment Centers, San Francisco, California Untreated Pain and Its Cost to Society: What Are Our Options?; Intrathecal Therapies for the Treatment of Chronic Pain DONALD H. LAMBERT MD, PhD Anesthesiologist, Anesthesia Associates of Massachusetts; Boston University Medical Center, Boston, Massachusetts Efficacy of Regional versus General Anesthesia TIM J. LAMER MD Assistant Professor of Anesthesiology, Mayo Medical School, Rochester, Minnesota; Consultant, Department of Anesthesiology, IX
Mayo Clinic Jacksonville, Jacksonville, Florida Cancer Pain ERIC LANG MD Pharmaceutical Licensing Group, Johnson and Johnson, Titusville, New Jersey Clinical Research ALBERT Y. LEUNG MD Assistant Clinical Professor of Anesthesiology, University of California, San Diego, School of Medicine; Faculty, Center for Pain and Palliative Medicine, University of California, San Diego, Medical Center, La Jolla, California Regional Anesthesia for Chronic Situations: Malignant Pain ANDRES LÓPEZ MD Chairman, Department of Anesthesiology and Critical Care, Móstoles Hospital, Madrid Montepríncipe Hospital, Madrid, Spain Common Techniques for Regional Anesthesia: Subarachnoid and Epidural Anesthesia EDWARD A. R. LORD MD Pain Fellow, Department of Anesthesiology, University of Texas, M.D. Anderson Cancer Center Houston, Texas Chronic Pain: Outcomes Using Procedures for Nociceptive Pain LELAND LOU MD, MPH, DABPM Assistant Professor of Pain Management, Anesthesiology, International Pain Institute, Texas Tech University Health Sciences Center School of Medicine, Lubbock, Texas Drugs Used in Regional Anesthesia: Local Anesthetics; Radiographic Imaging in Regional Anesthesia; Spinal Decompressive Neuroplasty via the Caudal and Cervical Approaches
X
DAVID C. MACKEY MD Assistant Professor of Anesthesiology, Mayo Medical School, Rochester, Minnesota; Consultant, Department of Anesthesiology, Mayo Clinic Jacksonville, Jacksonville, Florida Cancer Pain CARLOS B. MANTILLA MD Assistant Professor of Anesthesiology, Mayo Medical School; Senior Associate Consultant, Mayo Clinic, Rochester, Minnesota Cancer Pain FRANCO MARINANGELI MD Researcher, School of Specialization in Anesthesiology, L’Aquila, Italy Economic Impact of Regional Anesthesia; Organization of an Acute Pain Service and Pain Management MICHAEL D. McBETH MD Clinical Instructor (Voluntary), Department of Anesthesiology, Center for Pain and Palliative Medicine, University of California, San Diego, School of Medicine, La Jolla, California; Director, Pain Management Group, Assistant Chief, Department of Anesthesiology, Kaiser Permanente, San Diego, California Regional Anesthesia for Chronic Situations: Malignant Pain COLIN J. L. McCARTNEY MD Assistant Professor, University of Toronto; Staff Anesthesiologist, Toronto Western Hospital, Toronto, Ontario, Canada Training Education of a Physician for Regional Anesthesia XI
ROBERT S. F. McKAY MD Associate Professor of Anesthesiology and Obstetrics/Gynecology, University of Kansas School of Medicine; Medical Director and Chairman, Department of Anesthesiology, Wesley Medical Center, Wichita, Kansas Efficacy and Outcome of Regional Anesthesia Techniques in Obstetrics SEBASTIANO MERCADANTE MD Director, Anesthesia and Intensive Care Unit, Pain Relief and Palliative Care Unit, La Maddalena Cancer Center, Palermo, Italy Equipment and Techniques GENE MORETTI MD Assistant Professor of Anesthesiology, Duke University Medical Center Durham, North Carolina Common Techniques for Regional Anesthesia: Peripheral Nerve Blocks MAURO S. NICOSCIA MD Servizio di Anestesia e Rianimazione, Ospedale S. Carlo, Genova Voltri, Italy Organization of Palliative Care Services KAREN NIELSEN MD Assistant Professor of Anesthesiology, Division of Ambulatory Anesthesiology, Duke University Medical Center, Durham, North Carolina Common Techniques for Regional Anesthesia: Peripheral Nerve Blocks DAVID NIV MD Professor Sackler Faculty of Medicine, Tel-Aviv University; Director Center for Pain Medicine, Tel-Aviv Sourasky Medical Center Tel-Aviv, Israel Clinical Research
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MARK C. NORRIS MD Staff Anesthesiologist, Henry Medical Center, Stockbridge, Georgia Acute Situations: Obstetrics MAURICIO ORBEGOZO MD Comprehensive Pain Care, Calumet City, Illinois Facet Block and Denervation ANTONELLA PALADINI MD Regional Hospital “S. Salvatore” L’Aquila, Italy Economic Impact of Regional Anesthesia; Organization of an Acute Pain Service Pain Management LOUIS M. PANLILIO MD Assistant Professor of Anesthesiology and Critical Care Medicine, The Johns Hopkins University School of Medicine; Director of Acute Pain Medicine, The Johns Hopkins University Hospital, Baltimore, Maryland Chronic Pain: Neuropathic Pain: Outcome Studies on the Role of Nerve Blocks FRANCIS S. PECORARO MD Medical Director, Integrated Pain Rehabilitation, Integrated Pain Management, Concord, California Untreated Pain and Its Cost to Society: What Are Our Options?; Intrathecal Therapies for the Treatment of Chronic Pain RICARDO S. PLANCARTE MD Professor of Postgraduate Medical Especiality in Anesthesia, Intensive Care and Pain Clinic, Universidad Nacional Autónoma de México; Chairman, Pain Clinic and Palliative Care Department, Instituto Nacional de Cancerologia, México D.F. México Monitoring in Regional Anesthesia
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GABOR B. RACZ MD Grober and Murray Professor, Director, Pain Services, Chairman Emeritus, Department of Anesthesiology, Texas Tech University Health Sciences Center School of Medicine, Lubbock, Texas Spinal Decompressive Neuroplasty via the Caudal and Cervical Approaches; Trigeminal Ganglion Procedures P. PRITHVI RAJ MD, DABPM Professor of Anesthesiology, Co-Director of Pain Services, International Pain Institute, Texas Tech University Health Sciences Center School of Medicine, Lubbock, Texas Historical Aspects of Regional Anesthesia; Organization and Function of the Nerve Block Facility; Aids to Localization of Peripheral Nerves; Common Techniques for Regional Anesthesia: Conduction Blocks; Efficacy of Regional versus General Anesthesia; Endocrine-Metabolic Effects; Regional Anesthesia Options in Surgical Specialties SRINIVASA N. RAJA MD Professor of Anesthesiology, Critical Care Medicine, The Johns Hopkins University School of Medicine; Director of Pain Research, Division of Pain Medicine, The Johns Hopkins University Hospital, Baltimore, Maryland Chronic Pain: Neuropathic Pain: Outcome Studies on the Role of Nerve Blocks NARINDER RAWAL MD Professor, University Hospital, Örebro, Sweden Organization of an Acute Pain Service and Pain Management MIGUEL ANGEL REINA MD Department of Anesthesiology and Critical Care, Móstoles Hospital, Madrid Montepríncipe Hospital, Madrid, Spain Common Techniques for Regional Anesthesia: Subarachnoid and Epidural Anesthesia XIV
FRANCISCO JAVIER MAYER RIVERA MD Assistant Professor of Postgraduate Medical Course in Pain Clinic, Universidad Nacional Autónoma de México; Coordinator of Palliative Care Service Pain Clinic and Palliative Care, Instituto Nacional de Cancerologia México D.F. México Monitoring in Regional Anesthesia RICARDO RUIZ-LÓPEZ MD Clinica del Dolor de Barcelona, Barcelona, Spain Organization of Chronic Pain Services; Organization of Palliative Care Services; Radiofrequency for the Treatment of Chronic Pain RAJ SABAR MD Resident Physician, Department of Anesthesiology, Texas Tech University Health Sciences Center, Lubbock, Texas Drugs Used in Regional Anesthesia: Local Anesthetics XAVIER SALA-BLANCH MD Staff Anesthesiolgist, Servicio de Anestesiologia y Reanimacion, Hospital Clinic de Barcelona, Universidad de Barcelona Barcelona, Spain Aids to Localization of Peripheral Nerves ROBERT P. SANDS JR. MD Clinical Assistant Professor of Anesthesiology, State University of New York at Buffalo; Director, Resident Education, Roswell Park Cancer Institute, Buffalo, New York Beyond Blocks: The History of the Development of Techniques in Regional Anesthesia PHILLIP S. SIZER JR. MEd, PT, MOMT, PhD(c) Texas Tech University Health Sciences Center, Lubbock, Texas Facet Block and Denervation
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SUSAN STEELE MD Associate Professor of Anesthesiology, Director, Division of Ambulatory Anesthesiology, Medical Director, Ambulatory Surgery Center, Duke University Medical Center Durham, North Carolina Common Techniques for Regional Anesthesia: Peripheral Nerve Blocks CARL A. TANDATNICK MD Attending Physician, Diagnostic Clinic, Largo, Florida Peripheral Nerve Blockade PRABHAV TELLA MPH Research Program Coordinator, The Johns Hopkins University School of Medicine, Baltimore, Maryland Chronic Pain: Neuropathic Pain: Outcome Studies on the Role of Nerve Blocks ATHINA N. VADALOUCA MD Assistant Professor of Anesthesia, Pain Management, University of Athens; Aretaeon Hospital Athens, Greece Organization of Palliative Care Services; Drugs Used in Regional Anesthesia: Adjuvant Drugs GIUSTINO VARRASSI MD Professor of Anesthesiology, University of L’Aquila Medical School, L’Aquila, Italy Economic Impact of Regional Anesthesia; Organization of an Acute Pain Service and Pain Management RAMANI VIJAYAN MD Professor of Anaesthesiology, University of Malaya; Consultant Anaesthesiologist, University of Malaya Medical Centre, Kuala Lumpur, Malaysia The Practice of Regional Anesthesia in Developing Countries
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MARK S. WALLACE MD Associate Professor of Clinical Anesthesiology, Fellowship Program Director, University of California, San Diego, School of Medicine; Program Director, Center for Pain and Palliative Medicine, University of California, San Diego, Medical Center, La Jolla, California Regional Anesthesia for Chronic Situations: Malignant Pain MICHAEL A. WEAVER MD Assistant Professor of Anesthesiology, Pennsylvania State University College of Medicine; Milton S. Hershey Medical Center, Hershey, Pennsylvania Peripheral Nerve Blockade BRANKO M. WEISS MD Consultant, Department of Anesthesiology, University Hospital, Zurich, Switzerland Efficacy and Outcome of Regional Anesthesia Techniques in Obstetrics JACK L. WILSON MD Assistant Professor of Anesthesiology, Mayo Medical School; Consultant, Department of Anesthesiology, Mayo Clinic Rochester, Minnesota Cancer Pain CYNTHIA A. WONG MD Assistant Professor, Northwestern University Medical School; Chief, Section of Obstetric Anesthesiology, Division of Pain Medicine, Northwestern Memorial Hospital, Chicago, Illinois Acute Situations: Obstetrics GILBERT Y. WONG MD Assistant Professor of Anesthesiology, Mayo Medical School; XVII
Consultant, Department of Anesthesiology, Division of Pain Medicine, Mayo Clinic, Rochester, Minnesota Cancer Pain CHRISTOPHER L. WU MD Associate Professor of Anesthesiology, Critical Care Medicine, The Johns Hopkins University School of Medicine; Director, Acute Pain Service, Director, Regional Anesthesia, The Johns Hopkins University Hospital, Baltimore, Maryland Efficacy of Neuraxial and Peripheral Nerve Blocks in Acute Pain Management MYRON YASTER MD Professor of Anesthesiology, Critical Care Medicine, and Pediatrics, The Johns Hopkins University School of Medicine, Baltimore, Maryland Pediatric Pain Management
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Foreword Dr. Raj painstakingly has assembled a stellar roster of internationally recognized experts to put the stamp of credibility and currency on Textbook of Regional Anesthesia . Sweeping changes have modernized the practice of regional anesthesia since Dr. Raj first published Handbook of Regional Anesthesia in 1985: unheard-of imaging techniques, safer local anesthetics, cuttingedge laboratory experiments, innovative clinical studies, streamlined practice methods, and (at least in the United States) increasingly restrictive regulation of medical practice that rewards haste, hustle, and false economy over individualized patient care. All these happenings—the good, the bad, the new, the challenging, and the basics—have been addressed in this fully current comprehensive text, a work with a sweeping mandate that promises to set the global gold standard of regional anesthesia for the present and years to come. Textbook of Regional Anesthesia is a seminally mature work of awesome breadth and depth— truly the capstone of a lifetime of research, graduate teaching, clinical experience, and worldwide travel. The contributors, likewise, are established scholars in their own right whose global representation makes this not just another North American text, but a learning and teaching resource of international proportions. Dr. Raj has the uncanny knack of picking rising young talent and for offering them the opportunity to prove their worth. Some of the old war horses return to contribute the seasoned traditional expertise that lends structure and backbone to any comprehensive text. But the input from younger, less-established voices is refreshing; their chapters contribute the new blood that gives regional anesthesia currency and nurtures its growth, and they pass on the hard-gained nuggets of clinical science to the next generation of physicians now in training, but soon to be in independent practice. Ten section editors groomed the eight discrete sections to include not just the traditional how, what, when, and why of regional anesthesia but also the newly emerging trends, such as the hard data from clinical outcome studies and the ongoing shift toward evidence-based medical practice. The detailed sections on procedural fundamentals and advanced interventional techniques will prove of particular interest to busy clinicians. The resulting 54 chapters, contributed by the editors with the assistance of many international collaborators, span the field of regional anesthesia from past history, through current practice, to future directions to form a monumentally defining work. With its handsome modern design and contemporary ambience, Dr. Raj’s Textbook of Regional Anesthesia once more demonstrates that the art of regional anesthesia—crafted and refined over the decades by grand masters such as Labat, Bier, Bonica, Macintosh, and so many others—lives on to flourish and grow. As one of Dr. Raj’s contemporaries and former pupils, I am honored to recommend this fine textbook to my colleagues, and I am proud yet humbled to have been asked to introduce this, the crown jewel of his collective works. RUDOLPH H. DE JONG, MD Professor (Hon), University of South Carolina, Columbia, South Carolina
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Preface Textbook of Regional Anesthesia is a further progression of regional anesthesia books I have published along with the publisher, Churchill Livingstone. This book presents a fresh look at the dynamic field of regional anesthesia. The format and content of the textbook are innovative. The book has new authors and contains new material, new sections, and updated chapters from the last book I published on this subject, Clinical Practice of Regional Anesthesia . The idea of writing this book arose because apart from Neural Blockade in Clinical Anesthesia and Management of Pain , edited by Cousins and Bridenbaugh, there wasn’t another regional anesthesia textbook available to clinicians. Rapid advances are occurring in regional anesthesia and pain management. The aim of Textbook of Regional Anesthesia is to provide updated content in this field to all clinicians. This book presents a new organizational structure. Even though I have remained as the chief editor, well-recognized international authorities in regional anesthesia were asked to be section editors and provide advice on the topics included. Section editors Christopher Wells, Diego Beltrutti, James E. Heavner, David Niv, Richard L. Rauck, Honorio T. Benzon, Gabor B. Racz, Carol Warfield, Peter S. Staats, and Serdar Erdine were chosen for their expertise and international reputations. Great care has been taken to see that all aspects of regional anesthesia are included in this edition. Advanced regional anesthesia techniques and outcome sections are the special features of the book. Many thanks are to be offered for the completion of this book. The publisher comes to mind first. Everyone at Churchill Livingstone has been very understanding of my needs and, despite changes in ownership, support from them has remained solid. The section editors are especially to be thanked for their foresight, perseverance, and expertise in getting this edition completed. Illustrators and copy and manuscript editors have been working extremely hard for a prolonged period, when the demands for completing their tasks were numerous and incessant. I am indebted especially to Susan Raj for her coordinating efforts and to Marla Hall for her assistance in getting the manuscripts ready. I congratulate the authors for completing their chapters and maintaining a high quality of scientific content. I hope readers will find this book current and useful in their practice. P. PRITHVI RAJ, MD
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Section I - Development of Regional Anesthesia
Chapter 1 - Historical Aspects of Regional Anesthesia
Section I - Development of Regional Anesthesia Christopher Wells
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Section I - Development of Regional Anesthesia
Chapter 1 - Historical Aspects of Regional Anesthesia
Chapter 1 - Historical Aspects of Regional Anesthesia P. PRITHVI RAJ
Regional nerve blocks are based on the concept that pain is conveyed by nerve fibers, which are amenable to interruption anywhere along their pathway. The idea that pain is conducted in the nervous system originated with the specific theory of Johannes P. Müller, described in 1826. This was followed by the alternate intensity theory of Erb in 1874 (Dallenbach, 1939), an idea that later culminated in the gate theory of pain by Melzack and Wall in 1965. [1]
[2] [3]
Regional anesthesia was not available when general anesthesia was first successfully administered in 1846. It had to wait until 1855, when Rynd described the idea of introducing a solution of morphine hypodermically around a peripheral nerve. Because he did not have a needle or a syringe, he improvised by introducing a trocar and cannula into the region and then allowing the solution to reach the nerves by gravity. Wood, in 1855, was the first person to perform a subcutaneous injection with a graduated glass syringe and a hollow needle, a device developed initially by ( Fig. 1-1 ). Pravaz for injection of ferric chloride into an aneurysm to produce a coagulation [4]
[5] [6]
Efforts to Produce Analgesia Before the Discovery of Regional Anesthesia Primitive man, seeing in illness and pain the work of evil spirits that had taken possession of the body, tried to get rid of such invaders by methods based on effects on the patient’s imagination. Incantations, charms, amulets, special ceremonies, and faith in the power of medicine men and sorcerers made more or less deep impressions on the subject. In many cases, these methods probably contributed to the alleviation, or even abolition, of pain. A kind of local anesthesia was, therefore, able to be established, which was found valuable in connection with surgical interference, especially in minor operations. From early times, mankind has very often used analogous methods, although the procedures have changed with our supposedly—or perhaps actually— increased understanding of nature and of man himself. Thus, religion has played a role in this connection and still does to some extent, as well as the personal influence of prominent men (e.g., laying on of hands by kings and prophets). Physicians and charlatans have both found similar methods useful in numerous cases, and it has often been difficult to differentiate between the two types of practitioners. The main difference between them seems to be that the physician, with his better knowledge of the nature of illnesses and resources to combat them, has a clearer understanding of the limitations of the psychic methods. A classic example of the influence of psychic factors in alleviating pain is the well-known story of J. Mesmer (1734–1815) and his pretended use of “animal magnetism,” which was an effort to apply to living matter proof of the great progress that had just recently been made in those days with regard to electrical and similar phenomena. Mesmer’s methods were soon severely criticized, and an official commission, with Lavoisier as one of its members, concluded, “Imagination does everything, magnetism nothing.” There was certainly, however, a kernel of truth in Mesmer’s work, insofar as the practical results were remarkable. The mystery may have increased the effects. In 1843, Elliotson, the first holder of a medical professorship at the University College in London and “one of the eminent Victorians,” described the successful use of “the mesmeric state” to abolish pain in clinical operations ( Fig. 1-2 ). His results were interesting and indicated a close connection between bodily functions and the mental state. Unfortunately, he supported Mesmer’s idea of some “fluid” (in modern language, radiation) as the link between the doctor and the patient. After meeting with strong opposition, he resigned his professorship and continued to work on the problem, without convincing even his surgical colleagues of the usefulness of “mesmerism” in reducing or preventing the pain of operations. [7]
Three years later, Esdaile, who had been inspired
2
Section I - Development of Regional Anesthesia
Chapter 1 - Historical Aspects of Regional Anesthesia
Figure 1-1 Syringe and needle as used in 1855.[6]
by Elliotson’s work, published a paper on his experience with “mesmerization” in India. He had obtained “complete suspension of sensibility to external impressions of a most painful kind.” Among his successful cases were the amputation of an arm and the removal of an 80-pound tumor. He had a total record of 261 painless operations (with 5.5% mortality) under mesmerization. After returning to Scotland, however, Esdaile found it impossible to repeat his excellent results of India, thus demonstrating the varying susceptibility to the treatment as well as the role played by racial characteristics in this field. [8]
In his comprehensive work on hypnosis, Braid also dwelled on its power to alleviate or prevent pain in surgery. He mentioned that he himself had painlessly extracted teeth from six patients, and that, in other cases, patients experienced only a little pain under the influence of hypnosis. There were others whose experiences accorded with those of Braid, as described in the following quotation (translated from the original) from a book by the well-known Swiss psychiatrist Forel: [9]
I have arranged extraction of teeth during hypnosis. I have removed a corn and made deep stabs without the hypnotized having felt anything. It was sufficient to assure that the pertinent part of the body was dead, insensible. Surgical operations and even parturitions are possible, though less often, under hypnosis. … If one succeeds in suggesting a thorough anesthesia, painless surgical operations are always possible, if they are not too protracted. But the anxiety before the operation, especially if the patient sees the extensive preparations, usually destroys the suggestibility. There lies the greatest difficulty. [10]
The limitations of the method and the great individual variations mentioned are clearly illustrated in the passage in the preceding paragraph. On the other hand, psychological considerations in connection with other factors will always be important. This may be seen in a report by McGlinn, who says: It was for the reasons of unpleasant reaction from drugs and the fear of complete loss of consciousness when using spinal anesthesia that led me to look for some method that would obviate these objections and allay the fears of the conscious patient. Anything which would appeal to the senses sufficiently to keep the minds of the patients occupied would divert from them the thought of operation. Music best fulfilled the requirements. … Music has been used for untold ages during operations and childbirth … to divert the mind of the sufferer. … We have been using music for a year and have been well satisfied with the results and feel that it is a valuable addition to the operating room. [11]
Mention should also be made of acupuncture, which has been used in China since approximately 2700 B.C. and which was introduced somewhat later in Japan (Fig. 1-3 (Figure Not Available) ). This method consists of inserting It has been used against numerous diseases (e.g., metal needles at certain points of the skin to varying depths. sciatica, other kinds of neuritis), with the aim of counteracting pain and other symptoms. According to Hume, Hun T’O, “the most famous surgeon in Chinese medical history,” who was born about A.D. 190, “used few drugs and needles, and he used cautery in only a few places. If the disease proved resistant to acupuncture and if drugs proved unavailing, he then first caused the patient to swallow wine containing an anesthetic effervescent powder, which produced intoxication and complete insensibility.” He could then perform [12] [13]
[14]
3
Section I - Development of Regional Anesthesia
Chapter 1 - Historical Aspects of Regional Anesthesia
Figure 1-3 (Figure Not Available) Ming Dynasty acupuncture chart showing puncture points along meridians of the body, which apply to treatment for various organs, often quite distant from the point. This important Chinese medical technique has been in continual use for thousands of years. (From Lyons AS, Petrucelli JR: Medicine: An Illustrated History. New York, Albans, 1978.)
the desired operation. This shows that although acupuncture was also used as a local anesthetic, it was not always reliable. It has been noted that the method of acupuncture is used today in places where there is a shortage of modern chemical anesthetics. Acupuncture has gained a certain level of acceptance in Europe, but it seems to have been insufficiently studied by modern methods. Its efficacy has been partly explained as a kind of “referred pain,” but probably there is also some psychological factor contributing to the effect. [15]
NERVE COMPRESSION Pressure on nerves to produce local anesthesia may well be of ancient origin, especially in limb amputations. If the pressure is sufficiently strong, the innervated area becomes anesthetized. In such cases today, we speak of conduction, or regional anesthesia. Corradi considered it probable that compressions were used by ancient healers to stop bleeding, but whether this also led to abolition of pain, as he assumed, is doubtful. However, the famous military surgeon A. Paré (1510–1590) gave a good description of the use of compression for amputation, mentioning three advantages derived from firm ligation above the seat of operation. First, because the muscles were simultaneously pushed proximately, the bone could be better covered after the amputation and recovery was more rapid; second, bleeding was prevented; and, third, pain was greatly diminished. [16]
In 1784, a young English surgeon, J. Moore, tried to improve the compression method ( Fig. 1-4 ). In experiments on himself, he found that complete insensibility of the whole leg and loss of power to move it could be obtained in about half an hour after he had applied compression to the sciatic as well as the crural and obturator nerves. He constructed a special apparatus that facilitated compression of two opposite areas while still permitting a certain flow of blood. In this case, complete insensibility extended only to below the knee. The method was tried in combination with the tourniquet, which had produced insensibility in a patient whose leg was amputated below the knee by no less a person than J. Hunter. The operation seems to have been successful, but Moore clearly saw the necessity for further trials. His work, however, demonstrated the relative difficulties in obtaining the desired result, which could hardly have had a stimulating influence. Furthermore, discussions arose as to whether the anesthesia after compression was due to ischemia or to direct action on the nerve. Such a discussion was published after a communication by Le Fort. The introduction by Esmarch, another prominent military surgeon, of his “bandage”—a rubber tube that was greatly stretched and then wound four or five times around the limb above the place of operation—was a revival [17]
[18]
[19]
Figure 1-4 Apparatus designed by J. Moore for compression of nerves (1784).
of Paré’s method. When cocaine was introduced as a local anesthetic, it seemed desirable to use the Esmarch bandage in conjunction with it in order to lower the rate of absorption of the cocaine and thus to prolong its effect. The method of arresting the local blood flow before the injection of a relatively weak solution of cocaine close to the regional nerves (e.g., those of the fingers and toes), was adopted by several workers, among them M. Oberst at the surgical clinic in Halle, as described by Pernice. The question again raised was whether the complete stoppage of blood flow to the limb itself contributed to the change in sensibility. [20]
Valuable insight has been obtained on compression and other kinds of anesthesia by studies of the order in which different nerve fibers are affected. As early as 1881, Lüderitz observed that in animal experiments the motor fibers [21]
4
Section I - Development of Regional Anesthesia
Chapter 1 - Historical Aspects of Regional Anesthesia
were less resistant to pressure than the sensitive fibers, and he therefore assumed that some physiologic difference existed between the fibers. Boeri and di Silvestro studied the corresponding situation in humans with respect to the sensitive fibers, using the ulnar and sciatic nerves. During pressure, tactile sensations were blocked first, whereas thermal stimuli were less influenced and pain impressions were the least affected. The same order was found after application of the Esmarch bandage. Refrigeration, however, first affected pain and then thermal sensations, and finally tactile stimuli became inefficient. The order was thus the reverse of that observed under constriction. [22]
REFRIGERATION Hunter, who as a military surgeon took a great interest in the prevention of pain, performed experiments on animals and men to study the effect of refrigeration. Here is a typical example of his observations: I have taken a bucket of cold spring water with me when I made an attempt on a wasp’s nest, and put my hand into it after having been stung; and while my hand was in the water I felt no pain, but when I took it out again the pain was greater than when I put it in. [23]
Furnas mentions that D. J. Larrey (1766–1842), the famous surgeon-in-chief to the Grande Armée, “recounted the anesthetic effects of exposure to freezing battlefield conditions in his memoirs; the −19°C temperature allowed him to perform painless amputations on the half-frozen soldier-patients.” The only references given are the four volumes of Larrey’s great work from the battles (Larrey, 1812). Braun and Killian, in their respective handbooks, reported that Larrey, in February 1807, at the battlefield of Prussian-Eylau painlessly amputated numerous wounded soldiers with good results. The battle itself (1812) was characterized by Larrey as the most terrible that had ever occurred, and he complained several times about the cold, which once went down to a low of −19°C and became so intense that the instruments often fell from the hands of the pupils who were to serve him during the operations. He does not mention, however, that insensibility had occurred in the patients, although this is very probable. [24]
[25]
The most obvious effects of a cold environment on sensibility to pain appear more or less locally in peripheral parts of the body such as the limbs, ears, and nose, where circulation may be impaired at the same time. There is probably also some influence on the central nervous system, as is apparent from Larrey’s reports. This may indirectly be of importance, because it may diminish shock symptoms. The introduction of general anesthesia through inhalation of ether or chloroform was hailed as one of the greatest advances in the history of medicine. Early experience of death under the influence of the anesthetics, however, gave renewed urgency to the question of substituting local anesthetic agents for those of general action. In an article from 1848, Simpson, famous for the introduction of chloroform, emphasized that “if we could by any means induce a local anesthesia, without the temporary absence of consciousness which is found in the state of general anesthesia, many would regard it as a still greater improvement in this branch of practice.” He had tried localized effects of vapors from chloroform, ether, carbon disulfide, and even hydrocyanic acid. Although a reversible local action could be obtained, especially in lower animals, the results in mammals were less convincing. In the human subject, the local effect of chloroform vapors was not sufficiently deep to allow the part to be cut or operated on without pain, and it would probably have been dangerous. [26]
Simpson’s article led Arnott to call attention to the benumbing effect of cold, which he had described before. A bladder, taken from a small pig, containing tepid water was placed so as to cover the skin to be rendered insensible; ice and salt were then gradually “dropped in” to bring the temperature considerably below the freezing point. After 15 to 20 minutes, all sensations generally having disappeared, the operation could begin. Arnott added the following remark: “Perhaps … so low a degree of cold as I have mentioned is not required to produce the requisite degree of insensibility, and if pressure is conjoined with cold, so as to squeeze blood from the part, and check the circulation, the effect would certainly be more rapid, complete and extensive.” [27]
Richardson found that a frozen nerve showed a considerably lessened conductivity of electric current, and the same was observed when mechanical pressure was applied. The nerve was thus temporarily disorganized, but if it was frozen until all the water had been converted to ice, transmission of the current was stopped completely and permanently. This is, of course, in agreement with the fact that the metabolic processes in the cells are highly dependent on the temperature. At a few degrees above zero, the metabolism of a warm-blooded animal is only a few percentage points less than its value at normal body temperature. [28]
5
Section I - Development of Regional Anesthesia
Chapter 1 - Historical Aspects of Regional Anesthesia
In conformity with these results are those obtained by Trendelenburg. In 1914, his interest was aroused by a very unusual case of an 8-year-old boy suffering from tetanus infection. When the boy was brought to the hospital, he was seized within a short time by three heavy attacks of convulsions, with fixation of the thoracic cage, increasing cyanosis, and, in one of the attacks, unconsciousness. Both phrenic nerves were divided, so that artificial respiration with oxygen could be applied when needed. This, together with careful supervision and the use of chloral hydrate, made it possible to save the boy’s life, but owing to the operation he did not regain his diaphragmatic respiration. This case inspired Trendelenburg to investigate whether it would not be possible to break the transmission in motor fibers in such a way that regeneration could take place after a period of time. He froze nerves in cats and dogs by sucking ethyl chloride through a tube positioned around the nerves and thus succeeded in breaking the conductivity of the motor fibers; after several months, regeneration started and became complete after about a year. Further demonstrated that sensory fibers of mixed nerves (e.g., sciatic nerve) were put out of action at a experiments much lower degree of freezing than the motor fibers; hence, graded freezing could be used in cases of gunshot wound neuritis and for relieving patients from intolerable pain (the work was performed during World War I) and some other conditions. Perthes confirmed the beneficial effects of this treatment in humans. [29]
[30] [31]
[32]
Development of Regional Anesthesia The idea that drugs might diminish local pain not only by their action on the central nervous system but also by their direct effect on the nerve endings or on the nerves themselves was put to trial after syringes for injection were made available in the middle of the 19th century. Thus, ethyl alcohol, in relatively high concentrations (>50%), was used to treat patients with neuritis. The injection of alcohol into the affected nerve killed it, resulting in alleviation of the patient’s pain. The method is still recommended today in certain cases. Injections of opium suspensions and, later, of solutions of morphium chloride into the vicinity of the nerves were also tried, but results were poor. As was demonstrated by Macht and his collaborators, the peripheral action of opium alkaloids is—in contrast to the central effect—not prominent, and it was also shown that morphine had a lesser effect in this respect than papaverine and narcotine. [15]
[33] [34]
Cocaine
Long before the conquest of Peru by Francesco Pizarro in 1532, the Incas knew that the leaves of the coca bush could be used to stimulate a general feeling of well-being and prevent hunger. A small quantity of an amorphous mixture of coca leaves was prepared by Gaedcke, which on somewhat uncertain grounds, he believed to be an alkaloid that he called erythroxyline. He thought erythroxyline might be related to caffeine, but he was unable to prove it. A few years later, Niemann obtained from coca leaves a crystalline alkaloid to which he gave the name cocaine. He found that on degradation the substance gave rise to a weak base, ecgonine, and also to benzoic acid. After Niemann’s death, the work was continued by Lossen, who also split off methyl alcohol. [35]
[36] [36A]
[37]
It has been suggested that the Incas knew about the anesthetic properties of coca leaves, which they used to diminish local pain during certain surgical procedures. Thus, Singer and Underwood stated, “From early times, the natives of Peru knew about the anesthetic qualities of the coca plant, and they used to chew leaves and allow the saliva to run over the part of the body which had to be cut.” Killian goes further and says, “It seems that the juice of the leaves of the coca plant was dropped into painful wounds in order to decrease pain when trephining the skull.” Some time earlier, Leake, in a historical review, made the following statement: [38]
[25]
[39]
Local anesthesia was established upon a firm basis with the demonstration of the local anesthetic properties of cocaine. The aboriginal inhabitants of the highland of South America were acquainted with these properties. Roy L. Moodie has reconstructed an early surgical operation among the Incas, showing a blanket-clad shaman using a cautery to make a cruciform incision in the scalp of a woman suffering from melancholia. The operator chewed a cud of coca leaves, the juice from which he could drop upon the wound if the pain became severe. To this might be added that another picture of trephining in ancient Peru, as imagined by R. A. Thom, depicts the corresponding situation without the use of the coca leaves, nor is it mentioned in the accompanying text (written by Bender and checked by the historian E. H. Ackerknecht). No reference to early observations of the actual use of coca leaves for the purpose mentioned has been given by any of the authors quoted. Nor was Dr. S. H. Wassén of the Ethnographical Museum of Gothenburg, who kindly consulted the ethnographic literature to ascertain whether any mention was made of this point, able to find any indication that such was the case. It seems that the whole story is only the result of imagination rather than definite knowledge. [40]
Even if the aborigines of Peru had applied coca leaves in any form to wounds for the purpose of allaying pain, such a practice would undoubtedly have been completely forgotten shortly after the conquest of Peru by the Spaniards. It is, of course, possible that loss of this knowledge could have been a consequence of the intense efforts by the
6
Section I - Development of Regional Anesthesia
Chapter 1 - Historical Aspects of Regional Anesthesia
representatives of the Church to eradicate what they considered to be superstitious behavior. As is well known, the Church’s disapproval resulted for some time in the prohibition of chewing of coca leaves as a stimulating agent. Later, it was demonstrated that chewing coca had a considerable stimulating effect on the working capacity of Indian laborers, and the ban on chewing coca leaves was lifted, but there may not have been any understanding of the value of the juice in lessening sensibility. [41]
Niemann described that cocaine on the tongue caused a kind of anesthesia, so that it became temporarily insensible to touch. He tried it on his own eye and observed no effects from it. Eight years later, Moréno y Maiz, who later became the physician-in-chief of the Peruvian army, wrote a fairly extensive paper on cocaine. Using frogs and guinea pigs, he confirmed an increased irritability of the brain manifested by convulsions. Moreover he also observed in experiments on himself the effects of cocaine on his general feeling of well-being, leading him to conclude that “these were the most blessed moments of my life.” He also observed a peripheral effect leading to insensibility after local injection of the alkaloid into the calf muscle. Although he did not closely follow up on this finding, he understood its possibilities, because he remarked in a footnote, “Could we use it as a local anesthetic? It is not possible to give an answer after such a small number of experiments; the future will have to decide this.” [42]
Bennett carried out a comparative study of caffeine (and the identical substance, theine), guaranine, theobromine, and cocaine and found that they were to all appearances identical in pharmacologic action. In small doses, they produced cerebral excitement and partial loss of sensibility; in large doses, complete paralysis. Nothing is mentioned about local effects. With this background, it is perhaps not so remarkable that a British medical commission in 1881 reported on cocaine as merely being a poor substitute for caffeine. [43]
[44]
In the same year, a detailed report by von Anrep was published in which he described a number of experiments with the new substance on mammals, birds, and even himself. He confirmed earlier findings on the general stimulating effects on animals. About the studies on himself he said: [45]
Local Action. (a) On cutaneous nerves, I have injected a weak solution (0.003–0.5 percent) under the skin of my arm, and at first experienced a feeling of heat; then insensibility to rather strong pinpricks at the place of injection; after about 15 minutes, the skin became quite red; and after about 25 to 30 minutes, all these manifestations disappeared again. (b) On the nerves of the tongue: Painting the tongue with a somewhat stronger solution (0.005–0.5 percent) acts anesthetizing on the taste nerves; after 15 minutes, I was unable to differentiate between sugar, salt, and acids. Pinpricks gave not rise to pain, whereas the other, not painted side of the tongue reacted normally.… (c) On the pupil: With local use on the pupil in mammals, there always sets in mydriasis. In frogs not constantly.… von Anrep concluded his report on the experiments in the following terms: I have had the intention after the study of the physiological effects of cocaine on animals also to make experiments on man. Other engagements until now have prevented me from doing so, and the animal experiments do not permit practical conclusions. In spite of this, I would like to recommend cocaine as a local anesthetic and in melancholiacs. Thus, von Anrep has pointed very definitely to the possibility of using cocaine for local anesthesia as well as for its psychological effects. When one remembers that the disappearance of hunger after chewing coca was considered to be the result of a local anesthetic effect on the mucous membrane of the stomach, it seems very remarkable that von Anrep’s advice did not lead to anything for several years, especially because some valuable results in the treatment of pain had been obtained with cocaine even before von Anrep’s paper. Thus, Collin reported on experiments by Ch. Fauvel on the anesthetic action of coca on the mucous membrane of the mouth and also by him and others on the useful application of preparations containing cocaine, especially in cases of granulatomatous pharyngitis and tonsillar angina. The preparations used were made by A. Mariani, who had erected a plantation of coca bushes close to Paris and who made the Mariani brand wine as well as paste and lozenges. The wine was Bordeaux and was thought to be especially valuable. Einhorn mentioned—without any reference to Mariani—that Bordeaux wine often causes local anesthesia of short duration on the tongue; he supposed that this was owing to the presence of esters of aromatic acids, although he did not think their existence had been proved. One is tempted to question the remark made by Clark when he discussed the history of general anesthesia: “Indeed, an enemy of our profession might claim that it showed extreme slowness and conservatism in accepting the gift offered by science.” [46]
[47]
[48]
7
Section I - Development of Regional Anesthesia The Birth of Regional Anesthesia
Chapter 1 - Historical Aspects of Regional Anesthesia
The decisive step in the development of regional anesthesia was taken by C. Koller (1858–1944), a young Viennese physician who had been working for some time in S. Stricker’s experimental pathology laboratory, and who also devoted himself to the study of ophthalmology ( Fig. 1-5 ). Both these circumstances were of importance, because Koller became familiar with experimental methods and also had personal experience with the need for using local anesthesia when operating on the eyes. He had observed the unsuitability of general narcosis for eye operations, because not only is the cooperation of the patient greatly desirable in such operations but the sequelae of general narcosis— vomiting, retching, and general restlessness—are frequently so severe that they could constitute a grave danger to the operated eye. This was especially true at a time when narcosis was not skillfully administered by trained experts, as it is now. During Koller’s time, eye operations were performed without the use of any anesthesia whatsoever. The information is from Koller’s retrospective survey written many years later. He, therefore, experimented with chloral hydrate, bromide, morphine, and other substances, but without success. For a while, he gave up his experiments. [49]
In the summer of 1884, Sigmund Freud (later to achieve fame as a psychiatrist) was attached to the general hospital in Vienna as a “Sekundararzt.” He had been treating a colleague who was a morphine addict by substituting cocaine, and he asked Koller to cooperate in some studies evaluating the effect of cocaine on muscular strength and degree of fatigue as measured by a dynamometer. Koller thus became familiar with cocaine and decided to try it on the eye. Some interesting details have been told by Koller’s daughter, who quotes an untitled paper from 1919 written by her father. Koller noted that the numbing effect of cocaine on the tongue suddenly made him realize that he was carrying in his pocket the local anesthetic he had searched for years earlier. He immediately went to Stricker’s laboratory with the well-known result. This story is supported by the only witness to the discovery, the assistant of the laboratory, J. Gaertner. [50]
[51]
Freud was planning a vacation, and before he left, he asked his friend L. Königstein, an assistant professor of ophthalmology, to try cocaine in patients with eye diseases. When Freud returned from his vacation, the preliminary communication by Koller had already been made. Thus, in 1884, Koller’s famous communication about cocaine as a local anesthetic took place. He was naturally very anxious to report his findings as soon as possible, and because he was unable to go in person to the German Ophthalmological Society’s meeting in Heidelberg on September 15 and 16, he invited Dr. Brettauer from Trieste to read the communication at the session. This brief classical report is quoted in full from the translation published in Archives of Ophthalmology: [52]
It is a well-known fact that the alkaloid cocaine, which is obtained from coca leaves (Erythroxylon coca) makes the mucous membrane of the throat and mouth anesthetic when brought in contact with it, and this led me to investigate the action of this agent on the eye. I have reached the following conclusions: After a few drops of cocaine hydrochloride (I used a 2% watery solution of cocaine in my experiments) are applied to the cornea of a rabbit or a dog, or after the solution is instilled into the conjunctival sac in the usual manner, a stage of irritation develops which generally lasts from 1/2 to 1 minute, as shown by the contraction of the eyelids, and the cornea and the conjunctiva of the eyeball become insensitive to contact. All reflexes, which usually develop on touching the cornea, such as closure of the lid, eversion of the eyeball, and drawing back of the head, are eliminated. Insensitiveness is complete and lasts 10 minutes. During this time the cornea can be scratched with a needle, punctured, or cauterized with silver nitrate until it becomes white, or deep incisions can be made without the animal reacting in any way. Not until the aqueous escapes or the iris is touched is there a sensation of pain. Whether additional drops of cocaine hydrochloride applied after a corneal section, or cocaine administered by some other procedure, will also produce anesthesia of the iris has not been investigated on account of the difficulties of examining sensation in animals. In my experiments with animals, I found that when anesthesia ceases there exists a moderate and not always well-pronounced dilatation of the pupil. As these experiments on animals succeeded, I tried the action of cocaine on myself and on a colleague, with the following results: The immediate effect of the instillation of 1 or 2 drops of a 2% solution of cocaine was a moderate burning, which lasted for 1/2 minute and was succeeded by a feeling of dryness. The palpebral fissure appeared wider than that of the untreated eye. If the cornea or the conjunctiva of the eyeball was touched with the head of a pin 1 or 2 minutes after beginning the experiment, this contact was appreciated only to the slightest degree. When the sensation and the reflexes were not completely exhausted, this effect could be obtained by the instillation of additional drops of cocaine hydrochloride. A depression could be produced in the cornea by pressure on the conjunctiva, or the eyeball could be grasped with the forceps without producing any sensation whatever. The state of anesthesia lasted 10 minutes. This was followed by a weakened sensitivity, which was lost after several hours. During the period of anesthesia, the function of the eye was in no way disturbed. After 20 or 30 minutes
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Section I - Development of Regional Anesthesia
Chapter 1 - Historical Aspects of Regional Anesthesia
following the instillation, the pupil began to dilate. The dilatation increased during the course of an hour to a moderate grade; in the second hour, it gradually disappeared, and after several more hours (up to 12 hours) was entirely overcome. During this entire period, the pupil reacted promptly to light and to convergence. The weakness of accommodation disappeared earlier than the difference in the size of the pupil. I have not had any opportunity to perform experiments on diseased eyes, though I could convince myself that the anesthetic action of cocaine also took place in animals in which I had produced keratitis by the introduction of a foreign body. Perhaps it is not too bold to hope that cocaine can be used with success as an anesthetic in the removal of foreign bodies from the cornea as well as in more extensive operations, or as a narcotic in diseases of the cornea and conjunctiva. As I performed these experiments only during the past 2 weeks, I shall have to take up in a later publication the work which has previously been done on this subject. [53]
Mrs. Koller-Becker placed a facsimile of the original German text at the disposal of Dr. Brettauer. This communication, a model of scientific accuracy, cautious conclusions, and hopeful optimism, was obviously very well received by the meeting, especially after demonstrations by Brettauer of the remarkable anesthetic effect of a 2% solution of cocaine hydrochloride on the cornea and conjunctiva of one of the patients at the Heidelberg Eye Clinic. The detailed publication mentioned by Koller took the form of a lecture before the Viennese Medical Association on October 17, 1884. He could then report that his results had already been confirmed in various places in Germany, and he pointed out that “for us Viennese, cocaine has become a favorite topic because of the thorough review and interesting therapeutic work of my colleague at the general hospital, Dr. Sigmund Freud.” He could also add several important observations, such as the fact that ischemia occurred in the normal conjunctiva after cocaine administration. He saw that the widening of the palpebral fissure preceded the actions on the muscles in the iris and the ciliary body, and, therefore, should be attributed to removal of stimuli, which determine the width of the fissure by acting on the cornea and the conjunctiva. He also concluded from the late effects on the pupil and on accommodation that a slow absorption had taken place. He never saw any signs of stimulation after the administration of cocaine to the eye. [54]
In Vienna, Koller’s findings were confirmed immediately after his lecture by Königstein, and Koller persuaded Jellinek to try cocaine in the field of laryngology, so that he could publish a report on its useful application in the extirpation of polypous and papillomatous growth. Fränkel soon afterwards found that cocaine was well suited for anesthetizing the genital mucosa, even if it was inflamed. However, this was only the beginning. Before the end of the year, numerous “letters from the readers” appeared about the subject in England in Lancet; in other countries as well, interest was obviously very great. [55]
[56]
Perhaps this is best illustrated by the response in the United States. As early as on October 11, 1884, a report about the Heidelberg meeting, written by H. D. Noyes, a professor of ophthalmology in New York, was published in a well-known medical journal. He expressed enthusiasm about Koller’s discovery, and a stream of communications on the subject soon poured forth. As shown in the careful retrospect by Matas, the first use in the United States of cocaine as an anesthetic for the eye had already taken place on October 8, as a consequence of a letter from Noyes (the case had not yet been published). Knapp, also a professor of ophthalmology in New York and editor of the Archives of Ophthalmology, published at the end of the year an article starting with the following words: [57]
[58]
“No modern remedy has been received with such general enthusiasm, none has been so rapidly popular, and scarcely any one has shown so extensive a field of useful application as cocaine, the local anesthetic introduced by Dr. C. Koller of Vienna.” Knapp then gave the translation mentioned earlier, “not only as an acknowledgment of a debt of gratitude we all owe to him, but also as an appropriate introduction.” In conclusion, he said that cocaine had been found useful in ophthalmology, otology, rhinolaryngology, pharyngology, urology, gynecology, and also in general surgery. It was, of course, to be expected, especially after von Anrep’s experiments, that the subcutaneous application of cocaine would also be of value. This was definitely shown by Halsted, who in the year 1884 also successfully established the efficacy of regional anesthesia by blocking the corresponding nerve, as evident from a letter to the New York Medical Journal by his collaborator. In the autumn of 1885, Halsted, during a visit to Vienna, demonstrated how to use cocaine, with the result that A. Wölffler, assistant at Billroth’s clinic, who had at first declared cocaine to be without value in surgery, now wrote an enthusiastic article about it in a daily paper. Regional anesthesia with cocaine was also demonstrated in Vienna by Halsted. Because of his unfortunate ignorance of the dangers associated with cocaine, Halsted later became an addict as a result of numerous experiments on himself. In 1885, he published the first part of an article on the use and abuse of cocaine, but the last part of it never appeared. He had become a victim of his scientific enthusiasm, and only after great difficulties did he succeed in recovering from the addiction. In 1885, Corning called attention to the considerable prolongation [59]
[60]
[61]
[62]
[63]
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Section I - Development of Regional Anesthesia
Chapter 1 - Historical Aspects of Regional Anesthesia
of the effect of cocaine injections in the arm brought about by the application of a tourniquet shortly after the injection. [64]
It is of interest to discuss the criticism of Koller by Jones in his chapter, “The Cocaine Episode.” His opening remark was: “When publishing the paper he had read in Vienna in October 1884, he quoted Freud’s monograph as dating from August instead of July, giving thus the impression that his work was simultaneous with Freud’s and not after it.” This can be countered with the fact that Koller in his article mentions Freud’s review, pointing out that it and the therapeutic papers had brought cocaine to the notice of Viennese physicians. The careful reader must understand that he had no intention of giving the impression insinuated by Jones. It was easy for Koller to make such a slip. Königstein, in his article of October 19, 1884, made the same mistake. Furthermore, Koller stated in the Heidelberg report that he had performed his experiments “during the past 2 weeks,” thus mainly in September. Jones continued his criticism with the following statement: “As time went on, Koller presented the discrepancy in still grosser terms, even asserting that Freud’s monograph appeared a whole year after his own discovery, which was, therefore, made quite independently of anything that Freud had ever done.” This is completely wrong. The paper referred to by Jones was presumably the letter written in 1941 to M.D. Seelig, in which Koller says: “The facts are that Freud did not have anything whatever to do with cocaine anesthesia, nor did he write a single word about cocaine in 1885 (whereas my work dates from 1884) that had not been done better and more scientifically by Anrep in 1878.” Obviously, Koller was not concerned with Freud’s “monograph” at all, the indirect influence of which he but with the reports of 1885 on Freud’s own somewhat illhad already mentioned on various earlier occasions, Jones erroneously assumed that Koller must have meant the literary review of fated experimental work. 1884. A psychoanalyst might find it interesting to analyze the several mistakes made by Jones. [49]
[49] [52] [53]
[65] [65A] [65B] [65C]
Although there can be no doubt about the importance of Koller’s work, it is often stated, even in modern literature, that Koller started his work at the suggestion of Freud. This is quite erroneous as is evident already from the wellestablished fact that Freud had turned to Königstein, the elder of the two ophthalmologists and the one with better opportunities for working on patients, and it would have been very remarkable if Freud had asked both to do the same job. Moreover, we have Freud’s own words that Koller made his discovery on his own initiative and without any suggestion from Freud. On the other hand, Koller, as we have seen, emphasized that Freud’s work on cocaine and his review had influenced interest in cocaine in Vienna.
[15]
[66]
[65]
It is not surprising that Freud personally regretted that he had missed the opportunity of making the great discovery that fell on Koller. However, it is probably true, as pointed out by Jones, that “it is not altogether likely that Freud, even with more time at his disposal, would have thought of the surgical application, one foreign to his interests.” The similarity between the two great discoveries discussed here was also reflected in the unusually rapid acceptance of new possibilities and in the early observation of danger, which led to new progress on the foundation that had been laid. However, it also happened that the men who had fought for the new methods were fated personally to suffer disagreeable hardships. As was common with the pioneers of general anesthesia, Morton died in poverty, exhausted from his efforts to get the appreciation he had hoped for, Wells committed suicide, and Jackson’s life ended in an asylum. Only Long had a peaceful life, but he never fought for the new discovery, preferring to keep it for himself. The fate of Koller was certainly influenced by the work he had performed. The difficulties he encountered in Vienna, which he refers to as “distress and continuous humiliating enmities,” were added to the fact that he did not even get the position of assistant at the eye clinic as he—with good reason one might say—had hoped. He finally emigrated to the United States, where he at last found a refuge. [67]
DEVELOPMENT OF COCAINE ANESTHESIA Cocaine came into general use in 1884, not only for application to mucous membranes but also for subcutaneous injections, and because of its suitability for blocking nerves, it found use in regional anesthesia. New methods for cocaine administration were soon added to those mentioned. Thus, in 1885, Corning published a paper in which he described experiments he had conducted on dogs, injecting 1.18 mL of a 2% solution of cocaine hydrochloride into the space “situated between the spinous processes of two inferior dorsal vertebrae,” with the result that the animal did not react for several hours, even if a stimulus was applied from a powerful faradic battery or if the hind limbs were pinched or pricked ( Fig. 1-6 ). One human experiment produced a similar local effect, and the author concluded: “Whether the method will ever find an application as a substitute for etherization in genitourinary or other branches of surgery, further experiments alone can show.” Corning came back to the problem 3 years later. His main interest was, however, the alleviation of pain in certain nervous diseases, and from the last of the papers mentioned, it is obvious that he succeeded with this in four cases. The reservations that were entertained about his first publication—it seemed uncertain whether he had really been in the subarachnoidal space—were removed, and there can be little doubt that Corning was the first to apply cocaine (and some other substances) to the nerves at their origin in the spinal cord. However, the pioneer in introducing the method for surgical purposes was Bier, who was [64]
[68]
[69]
10
Section I - Development of Regional Anesthesia
Chapter 1 - Historical Aspects of Regional Anesthesia
of the opinion that this kind of “spinal anesthesia” was in response to an action on the unmyelinated fibers and perhaps also on the ganglion cells ( Fig. 1-7 ). He carefully described six patients on whom he had operated for osteomyelitis, resections, and so forth, with success under spinal anesthesia, obtained with 0.005–0.015 g cocaine injections. However, because several of the patients had suffered from considerable postoperative effects (e.g., headache, vomiting), he decided to do some experiments on himself. Because much of Bier’s cerebrospinal fluid had escaped during administration of the solution, and because part of this had also been lost, the experiment was continued on his assistant, Dr. Hildebrandt. The two subjects confirmed that injection of as little as 5 mg of cocaine into the lumbar theca reduced the sensibility in approximately two thirds of the body to such an extent that major operations without the patient feeling any pain would have been feasible. It was also found, however, that some very unpleasant after-effects occurred. The work of Bier stimulated the interest of many surgeons, and soon spinal anesthesia was tried by others as well. The after-effects were sometimes mild or absent, but the fact that sometimes they were severe, or even fatal, caused hesitation in its use. Presumably, the effects were due to attack on the medulla oblongata by the cocaine that had diffused into the liquor as well as the slow normal circulation of the liquor, which after being “secreted” in the choroid plexus slowly passed via the ventricles into the epidural space and back through the subarachnoid space, ending in the pacchionian bodies, where it was partly transferred into the blood. This circulation takes several hours and is greatly influenced by the body position. In sitting or standing positions, the pressure of the cerebrospinal fluid increases greatly, and the circulation time consequently increases. This may partly explain the fact that in the cases of Bier and Hildebrandt it took a longer time for the after-effects to appear and disappear than in patients who were lying in bed. In order to counteract such effects, Pitkin added to the solution of the anesthetic—procaine—a mucilaginous substance and ethyl alcohol in such proportions that the specific gravity and viscosity of the “spinacene” could be held above those in the cerebrospinal fluid. Solutions of high specific gravity were used when the upper part of the body was elevated and those with low specific gravity when the operation took place with the pelvis in a high position. Special measures were also taken to prevent excessive decreases in blood pressure. [70]
A different method was indicated for other cases. Sicard, having used the method of Bier, tried a less dangerous technique. After trials on dogs, he found it possible to reach the nerve trunks at their exit from the medulla by injecting into the extradural space (i.e., between the dura and the bone). He injected cocaine in this way into 9 patients suffering from pains of various kinds (lumbar, sciatic, and even tabetic), who obtained relief of varying duration. Sicard pointed out that it was the surgeon’s prerogative to ascertain whether the method (“sacral anesthesia”) could be improved sufficiently to evoke analgesia of the lower limbs. Shortly thereafter, Cathelin reported similar animal experiments. He also claimed that he had tried the method in four patients with inguinal hernia, but the resulting reduction in sensibility was not sufficient for serious operations. This, he pointed out, was probably due to the fact that the nerves passing through the extradural space were still surrounded by a cover of dura. Because complete analgesia had occurred in the dog, the same result would be expected in the human if the dose were increased or if the solution were diluted. [71]
[72]
Several workers tried sacral anesthesia in human subjects without any evident success, until, in 1910, Läwen solved the problem. He used a 2% solution of procaine-bicarbonate, varying the amount of the injected fluid according to the desired degree of anesthesia. Gros had demonstrated that the effect of some local anesthetics (e.g., cocaine, procaine) is highly dependent on the pH; therefore, the effect would decrease if the acidity rose, a fact observed by Königstein in 1884. Owing to its greater lipid solubility, the free base probably penetrates much more easily into the nerve than salts such as hydrochloride. By injecting in this way, he obtained better penetration into the nerve. Together with von Gaza he proved that procaine applied intradurally in rabbits was considerably more toxic than when introduced extradurally; therefore, the prospects for useful application of sacral block were greatly improved. That variations in the amount of fluid injected determine the area affected is illustrated by the fact that 10 mL provided saddle block, whereas 50 mL caused the anesthesia to reach as far as the nipple. [73]
[74]
[75]
[15]
Other new and modified methods of application of anesthetics are available, such as paravertebral, parasacral, venous, and arterial injections, but they need not be discussed here. The heavy toll exacted by cocainization for surgical purposes (grave intoxications and even several deaths) during the early years of its general use caused great distrust of the new methods, especially when the substance was injected or applied to certain mucous membranes where it was easily absorbed. However, these unfortunate occurrences led to important investigations that aimed to reduce the amount of cocaine applied without unduly decreasing the anesthetic effect. Careful studies in this area were made by Reclus, who was able to show that the concentration of the solutions could be considerably lowered ( Fig. 1-8 ). Whereas in the early days cocaine solutions of 2% to 5% were used in general surgery and on certain mucous membranes even as high as 20%, Reclus found 1% to 2% to be enough. In fact, he communicated that he had performed about 3200 operations using these [76]
11
Section I - Development of Regional Anesthesia
Chapter 1 - Historical Aspects of Regional Anesthesia
dosages, without a single death, and even without disturbing the physical equilibrium of his patients. Some technical changes were necessary with use of the lower concentrations, such as anesthetizing successive layers as the operation proceeded and waiting longer for the anesthetic effect to become strong enough. Even concentrations as low as 0.5% were sometimes sufficient. The idea of using still more dilute solutions was further developed by Schleich[ ] [ ] with the introduction of “infiltration anesthesia.” He used three solutions, one[ ] for general purposes and two for special occasions. 77
77A
2
Solution 1
Solution 2
Solution 3
Cocaine hydrochloride
0.2
0.1
0.01
Morphine hydrochloride
0.02
0.02
0.005
Sodium chloride 0.2
0.2
0.2
100.0
100.0
Distilled water to 100.0
Schleich had observed the well-known phenomenon that the injection of water first caused heavy pain followed by local anesthesia. Because physiologic saline (0.9%) has no pain-inducing action, he tried to find an intermediate concentration that would cause no pain but that would still produce some swelling in the surrounding cells, with consequent disturbance in the functional activity of the nerve endings and decreasing sensibility. The effect was intended to be a summation of the actions of hypotonicity and cocaine; morphine has so small a peripheral effect that it seems impossible to prove that it has any effect in this instance. Schleich tried the method of infiltrating tissues with these solutions and found a good level of anesthesia, permitting performance of many operations without pain. Schleich’s work was at first met with the greatest distrust, but Braun (1897) showed convincingly that the method had great potential for use, even in fairly large operations. He denied the results obtained with 0.2% saline, and he preferred eukaine B to cocaine, but there was no doubt that the principle of infiltration with low concentrations was correct.
DEVELOPMENT OF OTHER LOCAL ANESTHETICS It was only natural that discoveries in organic chemistry, both analytic and synthetic, should have led to efforts to find preparations with good anesthetic properties and without the drawbacks of cocaine. Besides its highly acute toxicity and the risk of addiction (which came to play a greater role as time went by), cocaine is easily decomposed when the solution is sterilized. It is also expensive. As emphasized by Willstätter, the vegetable bases, such as cocaine, are often so complex that the imagination of the chemist is not equal to the task of shaping them without the natural model, “at least in our time.” The constitutional formula of cocaine and its synthesis were not completed before 1934, 60 years after the isolation of the alkaloid by Niemann. For a long time, the ideas about the structure of the base ecgonine were erroneous, but this did not prevent great progress from being made in the field of new local anesthetics. The points of departure were the discoveries of the products split from cocaine, namely, benzoic acid and methyl alcohol. As early as 1887, Filehne called attention to a certain analogy between cocaine and atropine—an ester between tropic acid and the complex organic base tropine or tropanol. According to Filehne, a weak local anesthetizing effect is exercised by atropine, and this was increased if mandelic acid was substituted for tropic acid (homatropine). If the still simpler benzoic acid is introduced into the molecule instead of tropic acid, the compound obtained (benzoyltropine) becomes a strong local anesthetic. With ecgonine—obtained from Lossen himself—no anesthetic action at all was observed. Benzoyl derivatives of several alkaloids, such as quinine and morphine, on the other hand, were highly active. Benzoic acid must, therefore, play a fundamental role in the anesthetic effect of cocaine. Soon after, Poulsson found that the local anesthetic effect of cocaine disappeared if the esterifying alcohol group was removed; the general effects then changed, and the toxicity decreased considerably, especially for mammals. If an ethyl or propyl group was introduced instead of the methyl group, the usual cocaine activity remained, on the whole, unchanged; therefore, esterification of the acidic group was of great importance for the anesthetic action. A second methyl group, attached to a nitrogen atom, can be removed without any loss of activity; indeed, its removal increases cocaine’s activity. Ehrlich confirmed that mice fed on cakes containing varying amounts of cocaine developed pathologic liver changes (substantial enlargement and vacuolization) and that this effect was much influenced by changing special groups in the molecule. The intermediate compounds leading from ecgonine to cocaine were only about frac120; as toxic as cocaine itself. Soon after, Ehrlich and Einhorn observed that the esterifying methyl group in cocaine was not the only group that could be substituted by other alcoholic radicals; the benzoyl group could also be replaced by other acidic groups belonging to the aliphatic or the aromatic series, without the loss of anesthetic action. These [78]
[79]
[80]
[81]
[82]
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Section I - Development of Regional Anesthesia
Chapter 1 - Historical Aspects of Regional Anesthesia
observations combined with the imperfect knowledge of the structure of ecgonine led to the development of hundreds of new synthetic anesthetics, many of them less toxic than cocaine relative to their anesthetic action. It is, of course, impossible to go into the details here, and the reader is referred to the works of Poulsson, Laubender, Drill, Braun and Läwen, and Killian for more specific information. Only a few typical examples illustrating the trend of the evolution are given here. [80]
[13]
[84]
[83]
[25]
Einhorn and Heinz found that even relatively simple derivatives of amino esters were anesthetic, but although their salts could not be used owing to their acidity and consequent irritating effects, the free amino esters produced excellent local anesthesia on wounds. Because the preparations were made soluble in water only with difficulty, the effect lasted for a long time, which was highly desirable for the type of treatment needed. Many of the new substances, in contrast to cocaine, caused no contraction of the blood vessels, which led to fairly rapid absorption. Thanks to the important discovery by Braun that the addition of small amounts of adrenaline to these solutions could often act as a “chemical tourniquet,” an increase in anesthetic action could be obtained. [85]
[86]
As another example, it should be mentioned that Einhorn and Uhlfelder described a new product, p-aminobenzoic acid diethylaminoethylester, or Novocaine (procaine), which was carefully tried on humans by Braun, who produced wheals on the skin of the forearm by injection and could state that the new compound exhibited potent local anesthetic action with practically no irritation. The general toxicity was relatively lower than that of cocaine, its solution could be boiled without decomposition, and the effect was potentiated with adrenaline. Numerous modifications of procaine have since been developed, but it is still a valuable anesthetic in many cases. [87]
[88]
When the final steps in the synthesis of cocaine had been taken by Willstätter and his collaborators, the former also succeeded in synthesizing a number of its numerous optical isomers. These were studied pharmacologically by who found the dextrorotatory cocaine (with cis-transisometry) to be somewhat less toxic than the Gottlieb, natural product, probably because the “unnatural” isomers are often metabolized more rapidly than those occurring in nature. At the same time, dextrorotatory cocaine is about twice as active as cocaine on the sciatic nerve of the frog, which is explained by its greater lipid solubility; it also has the advantage that the solution can stand sterilization well. In contrast to cocaine, however, it caused no contraction of the blood vessels, but this could be changed by Brown’s method. Psicaine, as the product was named, seemed to be suitable, at least for use on mucous membranes. On the whole, however, the intimate knowledge of the structure of cocaine did not yield the harvest one had hoped for with regard to new and better local anesthetics. [78]
[89] [90]
A valuable impetus in the search for new local anesthetics came from an unexpected quarter. In 1935, von Euler and Erdtman in a study on the structure of the alkaloid gramine, observed that although this substance had no anesthetic effect, its isomer, isogramine, or 2-(dimethylaminomethyl)-indole at first tasted bittersweet and then caused anesthesia on the tongue. This discovery was duly appreciated, and a series of investigations were started, beginning with Erdtman and Löfgren. Numerous compounds with local anesthetic action were synthesized, but often they also caused irritation or had other effects that precluded practical use. Löfgren and associates (Löfgren, 1946 and 1948) continued the work with great energy, and after more than 100 compounds had been investigated, they found 2-diethylamine-2′,6′-acetoxylidide (lidocaine [Xylocaine]), a preparation which marked a considerable It had great stability, no irritating action, and good anesthetic effects. These findings were confirmed by advance. extensive pharmacologic studies, especially by Goldberg and also by Björn, who evolved an elegant method for estimating the effect of local anesthetics in dentistry. In collaboration with Huldt, Björn demonstrated the value of lidocaine in dentistry, whereas Gordh and others made corresponding communications from surgical quarters. At present, lidocaine is used extensively throughout the world. [91]
[92]
[66] [93]
[94]
[95]
[96]
[97]
Development of the Technique of Regional Anesthesia In 1908, August Bier devised a very effective method of bringing about complete anesthesia and motor paralysis of a limb. He injected a solution of procaine into one of the subcutaneous veins that was exposed between two constricting bands in a space that had previously been rendered bloodless by an elastic rubber bandage extending from fingers or toes. The injected solution permeated the entire section of the limb very quickly, producing what Bier called direct vein anesthesia in 5 to l5 minutes. The anesthesia lasted as long as the upper constricting band was kept in place. After it was removed, sensation returned in a few minutes. [98]
Interestingly, the first spinal anesthesia occurred 5 years before the first lumbar puncture. The term spinal anesthesia was introduced by Corning in his famous second paper of 1885. Unfortunately, what he had in mind was neither spinal nor epidural anesthesia as presently understood. Corning was under the mistaken impression that the interspinal blood vessels communicated with those of the spinal cord, and his intention was to inject cocaine into the minute interspinal vessels and have it carried by communicating vessels into the spinal cord. He made no mention of cerebrospinal fluid, nor of how far he introduced the needle into the spinal space.
13
Section I - Development of Regional Anesthesia
Chapter 1 - Historical Aspects of Regional Anesthesia
It fell to Heinrich Quincke to perform the first lumbar puncture. He based his approach on the anatomic principle that the subarachnoid spaces of the brain and spinal cord were continuous and ended in the adult at the level of S2, whereas the spinal cord extended only to L2. Thus, a puncture effected in the third or fourth lumbar intervertebral space would not damage the spinal cord. Lumbar puncture was invented as a treatment for hydrocephalus. Quincke acknowledged in his communication that he followed Essex Wynter, who 6 months earlier had described the use of a Southey’s tube and trocar for a similar purpose. This device was originally designed to drain fluid in cases of dropsy. Wynter introduced the tube between the lumbar vertebrae after making a small incision in the skin for the purpose of instituting drainage of the fluid in two patients with tuberculous meningitis. Quincke prescribed bedrest for the 24 hours after the puncture. It is noteworthy that he entered the skin 5 mm to 10 mm from the midline. Thus, the paramedian and not the median approach is the classic one, contrary to what is sometimes taught. [99]
August Bier published his celebrated paper on spinal anesthesia in 1899, under the title “Versuche uber Cocainisirung des Ruckenmarkes” (“Research on Cocainization of the Spinal Cord”). Bier assumed that intrathecal injection of cocaine produced anesthesia by a direct action on the spinal cord. He wanted to apply cocaine anesthesia for major operations and regarded spinal anesthesia as a means of safely producing a maximal area of anesthesia using a minimal amount of drug. It was his opinion that the anesthesia evoked by small amounts of cocaine injected into the dural sac resulted from its spread in the cerebrospinal fluid and that it acted not only on the surface of the spinal cord but especially on the unsheathed nerves that traverse the intramembranous space. The extent of the anesthesia produced was somewhat unpredictable, so Bier decided to try the experiment on himself. His assistant, Hildebrandt, performed a lumbar puncture on Bier, but when the time came to attach the syringe to the needle, a crisis developed; the needle did not fit. A considerable amount of cerebrospinal fluid and most of the cocaine dripped onto the floor. To salvage the experiment, Hildebrandt volunteered his own body. This time there was a good fit and complete success. However, the incident did not end there. Both of them celebrated the success with wine and cigars, but on the next day Bier had an oppressive headache that lasted for 9 days. Hildebrandt’s “hangover” developed even before the night ended. News of Bier’s work spread quickly, and, although he abandoned it himself, his method of subarachnoid spinal anesthesia was soon brought into prominence by Tuffier. In 1900, in a report of 63 operations, Tuffier promulgated the rule, “Never inject the cocaine solution until the cerebrospinal fluid is distinctly recognized.” The sensation caused by Tuffier’s demonstrations is well conveyed by Hopkins, who wrote, “To be able to converse with a patient during the performance of a hysterectomy, the patient all the while evincing not the slightest indication of pain (and even being unable to tell where the knife was being applied) was certainly a marvel, and was well worth crossing the Atlantic to see.” Rudolph Matas, in his description of spinal anesthesia, used cocaine hydrochloride, 10 to 20 mg, dissolved in distilled water. The solution instilled was, therefore, clearly hypotonic. Fowler preferred to have his patients in the sitting position for the injection and, not surprisingly, was often astonished by the rapidity and completeness of the anesthesia. Gravity methods were not yet understood. [100]
[101]
[102]
[58]
[103]
Aseptic precautions were strictly observed, and Lee mentions that the injection he used consisted of 12 to 20 minims of a 2% sterilized solution prepared in hermetically sealed tubes by Truax, Green, and Company of Chicago. This appears to be the earliest published reference to this method of packaging, which represented an important advance, because previously it was necessary for the surgeon to prepare his own solution from tablets and sterilize it. [104]
In 1912, Gray and Parsons of Birmingham, England, undertook an extensive study of variations in blood pressure associated with the induction of spinal anesthesia. They concluded that the bulk of the fall in arterial blood pressure during high spinal anesthesia is attributable to diminished negative intrathoracic pressure during inspiration, which is dependent on abdominal and lower thoracic paralysis. They noted that when the negative pressure in the thorax was increased, the arterial blood pressure also increased. [105]
It was by then quite clear that one of the principal dangers of spinal anesthesia is the lowering of the blood pressure. Smith and Porter found that the quantity of anesthetic solution was more important for diffusion than its concentration; dilute solutions usually spread farther than concentrated ones. The introduction of procaine beneath the dura in the region in which the splanchnic nerves arise caused as profound a fall in blood pressure as was caused by complete resection of the cord in the upper thoracic region. This, they thought, proved that the fall in blood pressure was not due to toxicity of the drug or to paralysis of the bulbar vasomotor center but to paralysis of the vasomotor fibers that regulate the tone of the blood vessels in the splanchnic area. Because these nerve roots originate between T2 and T7, Smith and Porter believed that the main clinical objective was to prevent cephalad diffusion of the drug from reaching this height and paralyzing these nerve roots. [106]
14
Section I - Development of Regional Anesthesia
Chapter 1 - Historical Aspects of Regional Anesthesia
The idea of making the injected solution hyperbaric with glucose to obtain control over the intrathecal spread of the solution originated with Arthur E. Barker. Barker employed stovaine. It was less toxic than cocaine but was slightly irritating and was eventually superseded by procaine. [107]
[108]
Pitkin, in 1928, and Etherington-Wilson, in 1934, experimented with a glass model of the spinal canal to obtain control over the rate of ascent of the drug by making the injected solution hypobaric. Control was achieved by varying the time the model was kept sitting upright after the injection. Pitkin did this by mixing alcohol with the procaine solutions, a mixture he called spinocaine, but he categorically warned against having the patient in the sitting position during injection. He controlled the level of blockade by tilting the table and illustrated this with a figure showing an “altimeter” attachment. [70]
Barker stressed such points of technique as raising the head on pillows. Whenever he injected a heavy fluid intradurally, he kept the level of analgesia below the transverse nipple line. Barker advocated puncture in the midline as being easier and allowing more even spread of the injected fluid than the paramedian approach. He also emphasized that in no case should the analgesic solution be injected unless the cerebrospinal fluid ran satisfactorily. Above all else, perfect asepsis throughout the entire procedure was absolutely necessary. Moreover, no trace of germicides should be left on the skin, because they could be conveyed by the needle into the spinal canal, where their irritating qualities were particularly undesirable. Barker’s rational approach to the use of a hyperbaric solution for spinal anesthesia was apparently forgotten when stovaine was replaced by improved drugs and had to be rediscovered after trials of quasi-isobaric solutions of several new drugs led to unsatisfactory control of levels. The lessons of the past were ignored or forgotten by surgeons and not yet learned by anesthesiologists. Indeed, at that time, there were few anesthesiologists to learn. In 1920, W. G. Hepburn revived Barker’s technique with stovaine, and Sise, an anesthesiologist at the Lahey Clinic, applied it to procaine in 1928 and to tetracaine in 1935. [109]
[110]
Tetracaine’s great advantage as a spinal anesthetic was its relatively prolonged duration of action without undue toxic effects, but this advantage was partially negated by the vagaries of its segmental spread, which resulted from its being used in approximately isobaric solution. Therefore, Sise mixed the solution with an equal or greater volume of 10% glucose and injected it while the patient lay in a lateral position on a table that was tilted head down 10 degrees. The patient was then turned to a supine position with a good-sized pillow inserted under the head and shoulders to flex the cervical spine forward as much as possible; the slope of the table was adjusted during the next few minutes as dictated by the level of analgesia needed. [110]
A refinement of this technique was the saddle-block method described in detail by Adriani and Roman-Vega. Anesthesia deliberately confined to the perineal area was obtained by performing a lumbar puncture and injection of a hyperbaric solution, with the patient sitting on the operating table and remaining so for 35 to 40 seconds after the injection. [111]
The technique of hypobaric spinal anesthesia was published by W. W. Babcock in 1912. He dissolved 80 mg of stovaine in 2 mL of 10% alcohol; thus, a solution was obtained with a specific gravity that was less than 1.000, well below that of the cerebrospinal fluid, which he calculated to be 1.0065. He believed that the anesthesia that resulted was chiefly a nerve root anesthesia and not the “true spinal cord anesthesia” obtained with standard solutions. A method for continuous spinal anesthesia was described by W. T. Lemmon in 1940. It was performed with the aid of a special mattress, a malleable needle, and special tubing, and was proposed for long operations that required abdominal relaxation. In 1907, H. P. Dean wrote of having so arranged the exploring needle that it could be left in situ during the operation and another dose injected without moving the patient more than a slight degree. He proposed that additional injections be made postoperatively to treat pain or abdominal distention. Lemmon’s technique was simplified by Tuohy. He performed continuous spinal anesthesia by means of a ureteral catheter introduced into the subarachnoid space through a needle with a Huber point. [112]
[113]
Tuffier’s favorable experience with spinal anesthesia for surgery on the lower limbs and urogenital organs led O. Kreis of Basel to try it for childbirth. He injected five parturients with 10 mg of cocaine at the L4 to L5 level and claimed that this procedure alleviated pain with little impairment of muscular power or uterine motility; however, he recommended the method particularly for forceps delivery. In the United States, S. Marx quickly followed with several reports praising the efficacy of lumbar cocainization. All of this occurred in the year 1900, but the enthusiasm soon waned. [114]
[115]
15
Section I - Development of Regional Anesthesia
Chapter 1 - Historical Aspects of Regional Anesthesia
Interest in obstetric regional anesthesia was revived when W. Stoeckel developed sacral anesthesia with procaine. The feasibility of injecting a local anesthetic by the caudal route was demonstrated by Fernand Cathelin in 1901. He found that fluids injected into the extradural space through the sacral hiatus rose to a height proportional to the amount and speed of injection. His objective was to develop a method that would be less dangerous but just as effective as subarachnoid lumbar anesthesia. He was successful in reducing the danger, but his efforts to demonstrate the efficacy of the caudal injection for surgical operations were disappointing. [116]
In 1909, Stoeckel described his experience with caudal anesthesia in the management of labor. He wrote that various concentrations of procaine and epinephrine produced predictably varying degrees of success after a single injection. Pain relief averaged 1 to 1½ hours in duration. He warned, however, that the greater the analgesic effect, the greater the hazard of impairing the forces of labor. These reservations, of course, would not apply to the use of caudal anesthesia for surgical operations, and Läwen, in 1910, described how he used Stoeckel’s experience and Cathelin’s ideas to perform a variety of surgical operations in the perineum. [116]
Matas, the eminent American pioneer and historian of regional anesthesia, recorded that Sellheim, injecting close to the posterior roots of T8 to T12 in addition to the ilioinguinal and iliohypogastric nerves, was able to perform abdominal operations successfully. Sellheim was, therefore, credited by Matas as being the originator of the paravertebral method of anesthesia. [58]
Kappis described posterior approaches to the lower seven cervical nerves for the purposes of cervical and brachial plexus block. The method of paravertebral block of the thoracic nerves and the first four lumbar nerves was also described by Kappis and was used in a great many upper abdominal operations. He pointed out that these techniques could be used to treat acute and chronic pain with procaine, or even with alcohol if motor function could be disregarded. Kappis was also responsible for the posterior approach to the splanchnic plexus. [117]
In 1922, Läwen found unilateral paravertebral block of selected spinal nerves useful in the differential diagnosis of intra-abdominal disease. [118]
In 1925, Mandl reported 16 cases of angina pectoris in which he injected procaine, 0.5%, paravertebrally with excellent results. In the next year, Swetlow attempted to destroy the afferent sensory fibers altogether by substituting 85% alcohol for the procaine; for the most part, patients obtained satisfactory relief of pain for several months. [119]
[120]
The pioneer of alcohol injection for the purpose of producing a long-lasting interruption of neural conduction was Schloesser. Schloesser presented the method as a means of managing convulsive facial tic. His patients attained paralysis that lasted from days to months, depending on the quantity of alcohol injected. He suggested that the method would also be useful for supraorbital neuralgia and tic douloureux. [121]
Segmental peridural anesthesia, under the name of metameric anesthesia, was used for the first time in 1921 by Fidel Pagés, a Spanish military surgeon. Dogliotti, however, popularized segmental peridural spinal anesthesia. He emphasized that injecting the anesthetic solution in sufficient quantity (50–60 mL) and under adequate pressure made it quite easy to subject the spinal nerves to the action of the injected fluid throughout their length in the spinal canal and the intervertebral foramina, and even beyond. Dogliotti’s method was easier and, without question, simpler than paravertebral regional block, because only one puncture was needed. He stressed the sudden loss of resistance at the moment when the point of the needle, having pierced the ligamentum flavum, entered the epidural space. The usefulness of this technique was extended further when Curbelo decided to apply the Tuohy armamentarium for continuous spinal anesthesia to continuous segmental peridural anesthesia. In one case, he left the catheter in place for as long as 4 days and administered a total of 10 injections of 15 mL each of 2% procaine solution, producing a continuous sympathetic lumbar block. [122]
[123]
[124]
[125]
It was but a short step from the diagnostic block to the therapeutic block, and the step was indeed taken by von Gaza and by Brunn and Mandl in 1924 in the management of visceral pain. Long-term pain relief by neurolytic injection of alcohol was developed by Swetlow for the interruption of cardiac afferent inflow and subsequently applied to paravertebral sympathetic block in the treatment of severe intractable pain, particularly the pain of malignant disease. Dogliotti, in 1930, took the bold step of injecting absolute alcohol into the subarachnoid space, hoping to produce by simple chemical means a posterior rhizotomy equivalent to that previously attainable only by surgery. At the opposite end of the local anesthetic concentration spectrum, Sarnoff and Arrowood exploited the continuous subarachnoid injection of dilute procaine (0.2%) to obtain a differential block limited to efferent sympathetic fibers and afferent fibers subserving pain. [126]
16
Section I - Development of Regional Anesthesia Conclusion
Chapter 1 - Historical Aspects of Regional Anesthesia
Local anesthesia by chemical means has come to play a great role in surgery. Today, practically no part of the body is inaccessible to this form of pain relief. Whether general or local anesthesia is to be used in an individual case depends on many factors and must be carefully considered by the surgeon. According to Braun and Läwen, the proportion of operations performed under local anesthesia in Germany increased considerably during the first decades of the 20th century; in some clinics, 50% of procedures were performed with regional anesthesia. Demands on anesthetists have increased greatly: They must master several different methods of regional anesthesia as well as the controls that are regularly performed on the patient’s reactions during the operation. These requirements have necessitated special training for anesthetists who practice in modern surgical clinics. [84]
Thus, on the foundation laid by Carl Koller, a new and important branch of medical science has developed. This is an old story about a young man who became fascinated by a great idea and was ready to grasp the opportunity when it presented itself. But it is also an illustration of the truth of Pasteur’s famous saying that chance favors only one whose mind has been prepared. REFERENCES 1. Riese
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Fort L: Anesthésie produite par la compression. Gaz Hop (Paris) 819–820, 1874.
19. von
Esmarch F: Ueber künstliche Blutleere bei Operationen. Volkmann’s Samml Klin Vortr Chir 1:373–384, 1873.
20. Pernice
L: Ueber Cocainanästhesie. Dtsch Med Wschr 16:287–289, 1898.
21. Lüderitz 22. Boeri
C: Versuche über die Einwirkung des Druckes auf die motorischen und sensiblen Nerven. Z Klin Med 2:97–120, 1881.
G, di Silvestro R: Sur la mode de se comporter des différentes sensibilités sous l’action de divers gents. Arch Ital Biol 31:460–464, 1989.
23. Hunter
J: A treatise on the blood, inflammation, and gun-shot wounds, 1793. In The Works of John Hunter (reprint). London, Longman, 1835,
17
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p 265. 24. Braun
H: Die örtliche Betäubung, ihre wissenschaftlichen Grundlagen und praktische Anwendung. Leipzig, JA Barth, 1935.
25. Killian
H: Lokalanästhesie und Lokalanästhetika. Stuttgart, G. Thieme, 1959.
26. Simpson
JY: Local anaesthesia. Lancet II:39–42, 1848.
27. Arnott
J: I. On cold as a means of producing local insensibility. 2. On cold as a means of producing local anaesthesia in surgical operations. Lancet II:98–99, 287–288, 1848.
28. Richardson
BW: On the influence of extreme cold on nervous fibre. Asclepiad 1:33–37, 1885.
29. Trendelenburg
W: Ueber Langdauernde Nervenausschaltung mit sicherer Regenerations fähigkeit. Z Ges Exp Med 5:371–374, 1917.
30. Trendelenburg
W: Weitere Versuche über langdauernde Nervenausschaltung für chirurgische Zwecke. Z Ges Exp Med 7:251–274, 1919.
31. Waters
RM: The evolution of anesthesia. Mayo Clin Proc 17:428–432, 440–445, 1942.
32. Perthes GC: Ueber die Behandlung der Schmerzzustäande bei Schussneuritis mittels der Vereisungsmethode von W. Trendelenburg. Münch Med Wschr 65:1367–1369, 1918. 33. Macht
DI, Herman NB, Levy CS: A quantitative study of the analgesia produced by opium alkaloids, individually and in combination with each other. J Pharmacol 8:1–37, 1916.
34. Macht
DI, Johnson SL, Bollinger HG: On the peripheral action of the opium alkaloids. Effect on the sensory nerve terminals. J Pharmacol 8:451–463, 1916.
35. Gaedcke
F: Uber das Erythroxylin. Arch Pharm (Weinheim) 132:141–150, 1885.
36. Niemann
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36A. Wöhler
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37. Lossen
W: Ueber das Cocain. Ann Chem Pharm 133:351–371, 1865.
38. Singer
C, Underwood EA: A Short History of Medicine, 2nd ed. Oxford, Clarendon Press, 1962, p 349.
39. Leake
CD: The historical development of surgical anesthesia. Sci Monthly 20:304–328, 1925.
40. Bender
GA, Thom RA: Great Moments in Medicine. Detroit, Parke-Davis, 1961.
41. Mortimor 42. Moréno
WG: Peru History of Coca. New York, JH Bvail, 1901.
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43. Bennett A: An experimental inquiry into the physiological actions of caffeine, theine, guaranine, cocaine, and theobromine. Edinburgh Med J 19:323–341, 1873. 44. Sollmann 45. von
T: A Manual of Pharmacology, 8th ed. Philadelphia and London, WB Saunders, 1957, p 323.
Anrep B: Ueber die physiologische Wirkung des Cocain. Pflügers Arch ges Physiol 21:38–77, 1880.
46. Collin
P: De la Coca et ses véeritables propriétés thérapeutiques. Un Méd Prat Franc 24:239–240, 1877.
47. Einhorn 48. Clark
A: Ueber neue Arzneimittel. Fünfte Abhandlung. Justus Liebigs Ann Chem 371:125–131, 1909.
AJ: Aspects of the history of anaesthetics. BMJ II:1029–1034, 1938.
49. Koller
C: Historical notes on the beginning of local anesthesia. JAMA 90:1742–1743 1928. [The article was also published twice in German in the same journal: Wien Med Wschr 78:601–602, 1928; and again, 84:1179–1180, 1934.]
50. Koller-Becker
H: Carl Koller and cocaine. Psychoanal Q 32:309–373, 1963.
51. Gaertner J: Die Entdeckung der Localanästesie. Der neue Tag, 1919. [The article was also published in Neue freie Presse under Unterhaltung. Quoted from Koller-Becker, 1963, p 331.] 52. Koller
C: Vorläufige Mitteilung über lokale Anästhesierung am Auge. Bericht über die 16. Versammlung der ophthalmologischen Gesellschaft. Heidelberg. Beilageheft zu Klin Mbl Augenh 60–63, 1884.
18
Section I - Development of Regional Anesthesia 53. Koller
Chapter 1 - Historical Aspects of Regional Anesthesia
C: Preliminary report on local anesthesia of the eye. Arch Ophthalmol 12:473–474, 1934.
54. Koller
C: Nachträgliche Bemerkungen über die ersten Anfänge der Lokalanästhesie. Wien Med Wschr 85–708, 1935. [The article was also published in English: Koller C: History of cocaine as a local anesthetic. JAMA 117:1284–1287, 1941.]
55. Jellinek
E: Das Cocain als Anaestheticum und Analgeticum für den Pharynx und Larynx. Wien Med Wschr 34:1334–1348, 1364–1367, 1884.
56. Fränkel
E: Über Cocain als Mittel zur Anästhesierung der Genitalschleimhaut. Wien Med Wschr 34:1535, 1884.
57. Noyes
HD: The Ophthalmologic Congress in Heidelberg. Med Rec 26:417–418, 1884.
58. Matas
R: Local and regional anesthesia. A retrospect and prospect. Am J Surg 65:189–198, 362–379, 1934.
59. Knapp 60. Hall
H: On cocaine and its use in ophthalmic and general surgery. Arch Ophthalmol 13:402–448, 1884.
RJ: Letter to the editor. N Y Med J 41:643, 1884.
61. Fulton
JF: Harvey Cushing. A Biography [Letter from Halsted to Cushing]. Springfield, Ill, CC Thomas, 1946, pp 142–144.
62. Halsted
WS: Practical comments on the use and abuse of cocaine. Suggested by its invariably successful employment in more than a thousand minor operations. N Y Med J 42: 294–295, 1885.
63. MacCallum 64. Corning
WG: William Stewart Halsted Surgeon. Baltimore, The Johns Hopkins Press, 1930, pp 54–57.
JL: On the prolongation of the anaesthetic effects of the hydrochloride of cocaine when subcutaneously injected. N Y Med J 42:317–
319, 1885. 65. Freud
S: Ueber Coca. Cbl Ges Ther 2:289–314, 1885.
65A. Freud
S: Beitrag zur Kenntnis der Cocawirkung. Wien Med Wschr 35:129–133, 1884.
65B. Freud
S: (1885) Ueber die Allgemeinwirkung des Cocains. Med-chir Cbl 20:374–375, 1885.
65C. Freud
S: The Cocaine Papers: 1–26, 35–41 and 45–49. Dunquin Press, Vienna and Zürich, 1884. [English translation was published in 1963.]
66. Löfgren
N: Studies in Local Anesthestics. Xylocaine, a New Synthetic Drug. Thesis I. Stockholm, Haeggström, 1948. [Reprinted, Worcester, Mass, 1958.]
67. Liljestrand 68. Corning 69. Bier
G: Briefe von Carl Koller an Erik Nordenson. Arch Gesch Med 49:280–306, 1965.
JL: A further contribution on local medication of the spinal cord. Med Rec (N Y) 33:291–293, 1888.
A: Versuche über Cocainisieurung des Rückenmarks. Dtsch Z Chir 51, 1899.
70. Pitkin
GP: Controllable spinal anesthesia. Am J Surg 5:537–553, 1928.
71. Sicard
A: Les injections medicamenteuses extra-durales par Voie sacro-coccygienne CR Soc Biol (Paris) 53:396–398, 1901.
72. Cathelin
F: Une nouvelle voie d’injection rachidienne. Méthode des injections épidurales par le procédé du canal sacré. Applications à l’homme. CR Soc Biol (Paris) 53:452–453, 1901.
73. Läwen 74. Gros
A: Uber Extraduralanästhesie für chirurgische Operationen. Dtsch Z Chir 108:1–43, 1910.
O: Ueber die Narkotika und Lokalanästhetika. Arch Exp Path Pharmak 63:80–106, 1910.
75. Läwen
A, von Gaza W: Experimentelle Untersuchungen über Extraduralanästhesie. Dtsch Z Chir 111:289–307, 1911.
76. Reclus
P: De l’anesthésie locale par la cocaine. Gax Hebd Méd Chir 27:146–148, 1890.
77. Schleich
CL: Schmerzlose Operationen. Örtliche Betäubung mit indifferenten Flössigkeiten, 4th ed. Berlin, Springer, 1894.
77A. Schleich
CL: Schmerzlose Operationen. Örtliche Betäubung mit indifferenten Flössigkeiten, 5th ed. Berlin, Springer, 1906.
78. Willstätter 79. Filehne
W: Die local-anästhesirende Wirkung von Benzoylderivaten. Berl Klin Wschr 24:107–108, 1887.
80. Poulsson 81. Ehrlich
R: Ueber die Synthese des Psikains. Münch Med Wschr 71:849–850, 1924.
E: Beiträge zur Kenntniss der pharmakologischen Gruppe des Cocains. Arch Exp Path Pharmak 27:301–313, 1890.
P: Studien in der Cocainreihe. Dtsch Med Wschr 16:717–179, 1890.
19
Section I - Development of Regional Anesthesia 82. Ehrlich
P, Einhorn A: Ueber die physiologische Wirkung der Verbindungen der Cocainreihe. Ber Dtsch Chem Ges 27: 1870–1873, 1894.
83. Laubender 84. Braun
Chapter 1 - Historical Aspects of Regional Anesthesia
W: Lokalanaesthetica. Heffter’s Handb Exp Pharmakol (Erg-werk) 8:1–78, 1939.
H, Läwen A: Die örtliche Betäbung, 8th ed. Leipzig, JA Barth, 1933.
85. Einhorn A, Heinz R: Orthoform. Ein Lokalanaestheticum für Wundschmerz, Brandwunden, Geschwüre, etc. Münch Med Wschr 44:931–934, 1897. 86. Braun
H: Ueber die Bedeutung des Adrenalins für die Chirurgie. Münch Med Wschr 50:352–353, 1903.
87. Einhorn
A, Uhlfelder E: Ueber den p-Aminobenzoesäure-diäthyl-amino- and Piperidoäthylester. Justus Liebigs Ann Chem 371:131–142,
1909. 88. Braun
H: Die Lokalanästhesie, ihre wissenschaftlichen Grundlagen und praktische Anwendung. Leipzig, JA Barth, 1905.
89. Gottlieb
R: Pharmakologische Untersuchungen über die Stereoisomerie der Kokaine. Arch Exp Path Pharmak 97:113–146, 1923.
90. Gottlieb
R: Ueber die pharmakologische Bedeutung des Psikains als Lokalanästhetikum. Münch Med Wschr 71:850–851, 1924.
91. von
Euler H, Erdtman H: Ueber Gramin aus Schwedischen Gerstensippen. Justus Liebigs Ann Chem 520:1–10, 1935.
92. Erdtman
H, Löfgren N: Ueber eine neue Gruppe von lokalanästhetisch wirksamen Verbindungen. á-N-Dialkylaminosäureanilide. Svensk Kem T 49:163–174, 1937.
93. Löfgren
N: Studien über Lokalanästhetica. Ark Kemi Mineral Geol 22:1–30, 1946.
94. Goldberg L: Studies on local anesthetics. Pharmacological properties of homologues and isomers of xylocain (alkyl aminoacyl derivatives). Acta Physiol Scand 18:1–18, 1949. 95. Björn
H: Electrical excitation of teeth and its application to dentistry. Svensk Tandläk-T 39(Suppl 4):1–101, 1946.
96. Björn
H, Huldt S: The efficiency of xylocaine as a dental terminal anesthetic, compared to that of procain. Svensk Tandläk-T 40:831–852,
1947. 97. Gordh 98. Bier
T: Xylocain—a new local analgesic. Anaesthesia 4:4–9, 21, 1949.
A: Ueber einen neuen Weg Localanasthesie an den Gliedmassen zu erzeugen. Arch Klin Chir 86:1007, 1908.
99. Wynter
WE: Four cases of tuberculosus meningitis in which paracentesis of the theca vertebralis was performed for the relief of fluid pressure. Lancet 1:981, 1891.
100. Tuffier
T: Analgesie chirurgicale par l’injection sous-arachnoidienne lombaire de cocaine. CR Soc Biol (11th series) 1:882, 1899.
101. Tuffier T: Anesthesie medullaire chirurgicale par injection sous-arachnoidienne lombaire de cocaine; technique et resultats. Semaine Med 20:167, 1900. 102. Hopkins
GS: Anesthesia by cocainization of the spinal cord. Philadelphia Med J 6:864, 1900.
103. Fowler RG: Cocaine analgesia from subarachnoid injection, with a report of forty-four cases together with a report of a case in which antipyrin was used. Philadelphia Med J 6: 843, 1900. 104. Lee EW: Subarachnoidean injections of cocaine as a substitute for general anesthesia in operations below the diaphragm, with report of seven cases. Philadelphia Med J 6:865, 1900. 105. Gray
HT, Parsons L: Blood pressure variations associated with lumbar puncture and the induction of spinal anesthesia. Q J Med 5:339, 1912.
106. Smith
GS, Porter WT: Spinal anesthesia in the cat. Am J Physiol, 38:108, 1915.
107. Barker 108. De
AE: Clinical experiences with spinal analgesia in 100 cases and some reflections on the procedure. BMJ 1:665, 1907.
Lapersonne F: Un nouvel anesthesique local, la stovaine. Presse Med 12:233, 1904.
109. Hepburn 110. Sise
WG: Stovain spinal analgesia. Am J Surg 34:87, 1920.
LF: Spinal anesthesia for upper and lower abdominal operations. N Engl J Med 199:61, 1928.
111. Adriani
J, Roman-Vega D: Saddle block anesthesia. Am J Surg 71:12, 1946.
112. Lemmon
WT: A method for continuous spinal anesthesia. Ann Surg 111:141, 1940.
20
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113. Dean
HP: Relative value of inhalation and injection methods of inducing anaesthesia. BMJ 2:869, 1970.
114. Kreis
O: Ueber Medullarnarkose bei Gebarenden. Zentralbl Gynakol 24:724, 1900.
115. Marx
S: Analgesia in obstetrics produced by medullary injections of cocain. Philadelphia Med J 6:857, 1900.
116. Stoeckel 117. Kappis
W: Ueber sakrale Anasthesie. Zentralbl Gynaekol 33:1, 1909.
M: Erfahrungen mit Lokalanasthesie bei Bauchoperationen. Verh Dtsch Ges Chir 43:87, 1914.
118. Läwen A: Ueber segmentare Schmerzaufhebung durch paravertebrale Novokaininjektionen zur Differentialdiagnose intra-abdominaler Erkrankungen. Med Wochenschr 69:1423, 1922. 119. Mandl
F: Die Wirkung der paravertebralen Injektion bei “Angina pectoris.” Arch Klin Chir 136:495, 1925.
120. Swetlow
GI: Paravertebral alcohol block in cardiac pain. Am Heart J 1:393, 1926.
121. Schloesser: 122. Pagés
Heilung peripharer Reizzustande sensibler und motorischer Nerven. Klin Monatsbl Augenheilkd 41:244, 1903.
F: Anestesia metamerica. Rev Sanid Milit Argent 11:351–365, 1921.
123. Dogliotti
AM: Eine neue Methode der regionaren Anasthesie: “Die peridurale segmentare Anasthesie.” Zentralbl Chir 58:3141, 1931.
124. Dogliotti
AM: A new method of block anesthesia. Segmental peridural spinal anesthesia. Am J Surg 20:107, 1933.
125. Curbelo 126. Sarnoff
MM: Continuous peridural segmental anesthesia by means of a ureteral catheter. Anesth Analg (Cleve) 28:13, 1949. SJ, Arrowood JG: Differential spinal block. Surgery 620:150, 194.
21
Section I -
Chapter 2 -The History of the Development of Techniques in Regional Anesthesia
Chapter 2 - Beyond Blocks: The History of the Development of Techniques in Regional Anesthesia CHRISTOPHER M. BURKLE ROBERT P. SANDS JR. DOUGLAS R. BACON
Regional anesthesia, the art of rendering a part of the body insensible for an operation, traces its roots to Karl Koller of Vienna, who, in 1884, demonstrated the use of topical anesthesia on the eye. However, regional anesthesia would not have progressed much beyond topical application had not many pioneers tried new and different ways of producing regional insensibility. In many ways, the history of techniques in regional anesthesia mirrors the way in which scientific knowledge is obtained: It is an intellectual history of ideas. There are instances in which techniques were developed, discarded, and revived only when “new” local anesthetics or plastic catheters became available, making the technique viable. Other researchers made an intellectual leap by speculating that if the pain of surgery could be ablated by regional anesthetic techniques, such techniques might be used in the treatment of patients with chronic painful conditions. Thus, from surgical anesthetic experience came the first pain clinics. In addition, there was a need to disseminate this new, exciting information to a professional audience. The development of professional organizations devoted to regional anesthesia also underwent this cycle of birth, death, and rebirth. This chapter explores the continuum of regional techniques, from their inception to their current use or abandonment.
Spinal Anesthesia The history of spinal anesthesia demonstrates the cyclical nature of regional anesthetic techniques. The advent of spinal anesthesia has roots that reach much deeper into the past than August Bier’s first administration of cocaine into the subarachnoid space in August 1898. Over 100 years earlier, in 1764, Domenico Cotugno, an Italian anatomist, published an almost complete description of cerebrospinal fluid (CSF) in his dissertation entitled De Ischiade Nervosa Commentarius. This information lay dormant, with little clinical utility, until 1872, when Heinrich Quincke published Zur Physiologie de Cerebrospinalflussigkeit. In this landmark paper, Quincke reported that there had already been a large number of anatomic and experimental examinations performed on the distribution and movement of CSF, citing that Magendie had given attention to Cotugno’s description. Although Quincke has been given credit for having performed the first lumbar puncture, he himself assigned the credit to Essex Wynter who, in 1891, used a Southey tube to perform a lumbar puncture. Although the Southey tube was originally employed to relieve edema of the legs by subcutaneous drainage, Wynter theorized that, by inserting the tube into the subarachnoid space, he could relieve the increased intracranial pressure of tuberculous meningitis. [1]
[2]
[3]
[4]
Also in 1891, Quincke reported his first lumbar puncture in Germany. Two years later, von Ziemssen, a German physician whose main medical interest was infectious disease, reported on the feasibility of injecting drugs by means of a lumbar puncture. He subsequently injected a patient with saline and tetanus antitoxin via the subarachnoid route. In 1895, Quincke published a paper in the annual report of La SociétéFrançaise de Bienfaisance Mutuelle, elaborating on his technique of using lumbar puncture to relieve the pressure of hydrocephalus, based on “the anatomical and experimentally proven fact that the subarachnoid space communicates with the cerebral ventricles.” Later that same year, George Jacoby published his report on the diagnostic use of the lumbar puncture. The technique he described differs little from the procedure that is currently in use. [5]
[6]
[7]
[8]
THE FIRST SPINAL ANESTHETIC? James Corning ( Fig. 2-1 ), a New York City neurologist, heard in 1885 of the local anesthetic properties of cocaine, which had been discovered by the Viennese ophthalmologist, Carl Koller, in 1884. Corning began a series of experiments to determine whether local medication of the spinal cord was within the range of practical achievement. He reasoned that cocaine might be the ideal agent to treat neurologic disease if applied in the vicinity of the venae spinales of the cord. If it were delivered to the spinal region, it could be absorbed and carried to the affected area, having a much greater effect, like that of strychnine when it was injected in the same way. His first subject was a dog. Corning injected cocaine below the spinous processes of two of the inferior dorsal vertebrae. After a few minutes, the dog’s hindquarters became paralyzed. A short while later, he tried the same technique on a young man with seminal incontinence. The young man received 2 mL of a 3% solution of the hydrochloride of cocaine between the spinous processes of T11–12. No effect was seen after 8 minutes, so another 2 mL of the same solution were [9]
22
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injected into the same space. Approximately 10 minutes after the second injection, the man’s legs began to “feel sleepy.” After another 15 to 20 minutes, the intensity of the anesthesia had increased, and although “there were some evidences of the diffusion part of the anesthetic, the impairment of sensibility was principally limited to the lower extremities, the lumbar regions, the penis, and scrotum.” While standing with eyes closed, the man experienced some dizziness, but no incoordination or motor impairment was discernible in his gait. He left the office 1 hour or more after the last injection and seemed “none the worse for the experience.” [10]
Corning performed his experiment and published his paper in 1885. The practicability of dural puncture had not yet been reported, nor would it be made known until Wynter’s and Quincke’s papers appeared in 1891. For that reason, and because CSF was not recovered in the syringe nor mentioned explicitly in his paper, it is believed that Corning performed the first epidural rather than the first spinal administration of anesthetic. [11]
In 1899, 13 years after Corning’s report and 8 years after the first authenticated lumbar puncture, the surgeon Augustus Bier ( Fig. 2-2 ), a professor at the Royal Chirurgical Clinic in Kiel, Germany, used “cocainization of the spinal cord” to provide pain relief for orthopedic operations on the lower extremities and coccyx. He proposed that injected cocaine would spread in the CSF and affect not only the surface of the cord but also the nonmyelinated nerves in the meninges and ganglia. He described the course of six patients ranging in age from 11 to 34 years, who received treatment between August 16 and August 27, 1898. The injections were made in the lumbar area, at an unidentified interspace, with the patients in a lateral recumbent position. He administered a 0.5 mL of a 1% solution of cocaine to the two teenagers, whereas the adults received either 1 mL of a 1% solution or 2 to 3 mL of a 0.5% solution. All of these blocks were successful and proved “that when a relatively small amount of cocaine is injected into the dural sac, large areas of the body can be made insensitive to pain and major operations can be performed in these areas. On the other hand, so many complaints had arisen in association with this method (back and leg pain, vomiting, prolonged headache) that they equaled the complaints usually occurring after general anesthesia.” [12]
[13]
Because of these complaints, Bier decided to experiment on himself. Dr. Hildebrandt, Bier’s assistant, performed the lumbar puncture on Bier after infiltrating the skin and deeper tissues. Bier immediately felt a lancinating pain in one leg; when the syringe did not adapt to the needle, much CSF was lost. Therefore, most of the cocaine did not reach the subarachnoid space, and loss of sensation did not develop, as manifested by Bier’s perception of small skin cuts and needle pricks. [14]
Hildebrandt then volunteered to undergo the same experiment, albeit with a much different outcome. “He first noticed a feeling of warmth and subsequently had no sensual perception to needle pricks to the thigh, tickling of the soles of the feet, a small incision in the thigh, pushing a large-helved needle down to the femur, strong pinching and squeezing with dental forceps, application of a burning cigar, pulling out pubic hairs, a strong blow with an iron hammer against the tibia, vigorous blows with knuckles against the tibia, and strong pressure on a testicle.” Eighteen minutes after the injection, pain sensation was greatly decreased up to the nipple line. After 45 minutes, the effect began to wear off. [14]
After describing the successes in patients and many details of the anesthesia, Bier noted that “other agents related to cocaine might not cause these unpleasant side reactions, or that additions to cocaine might abolish them.…Therefore, it did not seem justified to me to make further experiments on human beings. Experiments with animals might lead to significant results. For these, the dog would be adequate, since it vomits easily, meaning that the important sign of the unpleasant side effects could thus be observed.” In spite of Bier’s reservations, cocainization of the spinal cord attracted widespread attention and immediate use at several centers. [13]
AN AMERICAN TWIST Although Europe was the birthplace of spinal anesthesia, two pioneering surgeons, F. Dudley Tait and Guido E. Caglieri, administered the first spinal anesthetic in America on October 26, 1899. Tait and Caglieri studied 7 cadavers, 11 patients, and an unknown number of cats, dogs, rabbits, guinea pigs, and horses in their efforts to further understand how lumbar puncture could benefit patients. Although they never clearly stated their reasoning, Tait and Caglieri were apparently trying to exploit for some therapeutic gain the lumbar puncture technique discovered independently by Quincke and Wynter. Examination of CSF was undoubtedly useful in certain diagnostic conditions, but the utility of fluid withdrawal or drug injections into the subarachnoid space was still not established. Infectious diseases of the central nervous system, such as syphilis, tuberculosis, tetanus, and gonorrhea were important causes of morbidity around the beginning of the 20th century. Tait and Caglieri experimented in the treatment of tertiary syphilis by subarachnoid injections of mercuric salts and iodides which, when given systemically, were thought to be beneficial in the treatment of syphilis. Their experiments revealed that the
23
Section I -
Chapter 2 -The History of the Development of Techniques in Regional Anesthesia
intravenous administration of these drugs did not lead to subarachnoid accumulation; however, subarachnoid administration did lead to the appearance of these drugs in the bloodstream. [15]
In addition to its usefulness in diagnosis, penetration of the subarachnoid space was reported to have a potential application with administration of spinal anesthesia. The common anesthetic techniques at that time were inhalation of nitrous oxide, chloroform, or ether, or infiltration with dilute concentrations of cocaine. None of these anesthetics provided adequate muscle relaxation. Furthermore, the side effects were serious, ranging from vomiting to prolonged emergence, airway obstruction, and death. Spinal anesthesia presented a technique that permitted the avoidance of these worrisome problems, particularly in ill patients. In April 1900, Tait and Caglieri reported on 11 anesthetic cases in which 5 to 15 mg of cocaine were used intrathecally for procedures below the umbilicus. Two patients reported minor surgical discomfort and three others were outright failures. Regardless, unlike Bier, Tait and Caglieri unequivocally supported the technique of spinal anesthesia. One patient who “had collapsed” with both ether and chloroform anesthesia underwent a bone curettement without complications after intrathecal administration of 10 mg of cocaine. Thus, relative to the constraints under which Tait and Caglieri operated, modest success represented a groundbreaking achievement. [15]
Tait and Caglieri described a few postoperative problems that could be attributed to the administration of cocaine to the subarachnoid space. Some of their practices could have been responsible for this. For example, they recommended the use of a fine needle and slow injection of the cocaine to prevent rostral spread. They also recognized early that the extent of diffusion was influenced by several factors, including the amount of drug injected, the drug’s composition and density, and the pressure under which the drug was injected. The analgesia provided by this procedure was
thought to be sufficient for all operations of the lower limbs and pelvis, and Tait and Caglieri recommended a trial in obstetrics, thus beginning the successful use of the spinal technique during labor, which was later reported by Kreis. They also experimented with the other available derivatives of benzoic acid, eucaine and nirvanin, and found that they offered no advantages over cocaine. One final observation of these investigators is relevant to current practice. When the present day anesthesiologist advises the patient with a postdural puncture headache to “drink plenty of fluids,” it brings to mind Tait and Caglieri’s simple observation that the flow of CSF through an indwelling subarachnoid needle was markedly increased by intravenous administration of saline. A contemporary of Tait and Caglieri, Rudolf Matas of New Orleans ( Fig. 2-3 ), published his report of spinal anesthesia almost simultaneously. Matas agreed with Tait and Caglieri, citing the advantages of spinal over general anesthesia, but he was disappointed with the results. In fact, Matas stopped administering spinal anesthesia until pontocaine became commercially available. Interest in spinal anesthesia waxed and waned over the next decade. In the 1920s, mortality from spinal anesthetics was reported to be as high as one in a hundred patients. Lincoln Sise ( Fig. 2-4 ), working at the Lahey Clinic in Boston, decreased that number to just under one in a thousand. Sise worked hard to delineate the causes of the profound hypotension that accompanied successful spinal anesthesia. He found that ephedrine, given subcutaneously, would block the hypotensive effects of the spinal block. [16]
[17]
[18]
Another problem that plagued spinal anesthesia in the first decades of the 20th century was duration of the block. Procaine lasted about an hour, often less time than the surgeon needed to complete the operation. In 1935, Sise experimented with a new local anesthetic, tetracaine, with a duration of action of about 2 hours. However, tetracaine was unpredictable when injected into the CSF. Blocks would often be too high, leading to respiratory compromise. Sise theorized that it was the baricity of the solution relative to the CSF that caused the block to float. By mixing his tetracaine with 10% dextrose, Sise created a dependable hyperbaric solution. With adjustment of the patient’s position, he could change the height of the block. For example, when the level was too low, placing the patient in the Trendelenburg position raised the level of the block. [18]
Neurologic complications were another concern for patients and anesthesiologists. In the 1920s, it was estimated that 50% of patients suffered debilitating headaches after spinal anesthesia. Sise developed an introducer, a short, large-bore needle that helped facilitate the passage of a smaller needle through the dura and into the subarachnoid space. It would be another 20 years before Leroy Vandam and Robert Dripps published their study of over 9000 spinal anesthetic procedures. [18]
They found that 11% of their patients had postdural puncture headache, with a decreasing incidence with age. Vandam and Dripps correctly identified the risk factors of pregnancy and needle size and concluded that these were due to a decrease in CSF pressure. They also studied long-term neurologic sequelae in regional anesthesia. [19]
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Vandam and Dripps found that outside of postdural puncture headache, neurologic problems were rare. Most of these problems were apparent preoperatively if the anesthesiologist had done a detailed neurologic history. To avoid complications, Vandam and Dripps advocated proper selection of patients. [20]
Perhaps the most famous instances of neurologic complication of regional anesthesia occurred in England on October 13, 1947. That day, two healthy men underwent routine operations: One had a meniscectomy of the knee and the other a radical repair of a hydrocele. Both men developed permanent spastic paralysis after administration of intrathecal anesthesia. Hyperbaric 1:1500 dibucaine was used. At the time, the explanation given was that phenol, which had been used to sterilize the local anesthetic ampules for surgery and which had minute cracks in them, had caused the contamination of the drug. Sir Robert Macintosh supported this theory and testified before the court to this effect. The case had a devastating effect on use of subarachnoid anesthesia, including far-reaching publicity that lingers to this day. Recent scholarship has demonstrated that phenol was unlikely to have been the causative agent; the more likely suspect was the acidic solution used to clean the sterilizer. The fact that Cecil Roe was the first patient anesthetized that Monday morning and that he was more severely affected than Albert Woolley, who was the second case, supports the theory. Finally, pathologic findings support the conclusion that an acidic solution was introduced into the subarachnoid space. [21]
[22]
[23]
[24]
CONTINUOUS SPINAL ANESTHESIA Seven years after Bier’s landmark work on the administration of cocaine via lumbar puncture, Henry Percy Dean, a British surgeon, introduced a modification of the technique called continuous spinal anesthesia. Unfortunately, many of his colleagues who attempted the procedure encountered difficulties such as needle trauma and breakage. Therefore, the technique fell into disfavor, as can be evidenced by the lack of citations referring to continuous spinal anesthesia in the English language medical literature from 1907 to 1939. [25]
[26]
In 1940, all of that changed when William T. Lemmon re-introduced the technique of continuous spinal anesthesia to the anesthesia community with somewhat different results. Lemmon noted that the problems that Dean encountered earlier in the century were still present and that solutions needed to be devised. To do this, he used special equipment for his technique. First, he designed an operating room table mattress that permitted the patient to lie in the supine position without dislodging the needle or tubing. Second, and more importantly, he totally redesigned the spinal needle. His 17-gauge (G) or 18-G needle was constructed of German silver, which made it very malleable. Once the needle was in place, it was connected to the tubing, which was routed through the hole in the mattress to a spot near the patient’s head, where a syringe containing local anesthetic was attached. The tubing was made of hard rubber to prevent bulging on injection and contained exactly the 2 mL of drug that needed to be accounted for when calculating the dose of local anesthetic delivered to the patient. The technique was used with great success on the battlefields during World War II; it was credited, at least in one unit, for decreasing mortality from abdominal wounds from 46% to 12.5%. [27]
Edward B. Tuohy modified the technique when he placed a catheter through the needle into the subarachnoid space to avoid the problem of needle dislodgment from the space. Even with Tuohy’s modification, acceptance of the technique was slow. And, in 1950, Robert Dripps compared the malleable needle technique of Lemmon and the catheter technique of Tuohy with the standard single shot technique used by the majority of practitioners. He compared technical difficulties and absolute failures of all three techniques. Dripps’ results demonstrated that the single injection technique was associated with fewer technical difficulties and absolute failures than the other two. “Because of the number of failures, the technical problems, the degree of trauma, and the increased likelihood of loss of CSF inherent in the methods of continuous spinal anesthesia, it is our belief that such methods should be used less frequently.” Interestingly, with respect to both technical difficulties and absolute failures, the malleable needle was superior to the catheter technique of Tuohy when the two continuous techniques were compared. [28]
[29]
Again, the technique of continuous spinal anesthesia fell into a long period of quiescence. Once again, however, it rose from the ashes! In 1964, Dante Bizzari stated that he feared continuous spinal anesthesia because of the need for large-bore needles and the dural rents they caused. He advocated the use of 20-G or 21-G needles with smaller catheters. Bizzari’s ideas needed technology to catch up with them. In 1987, Hurley and Lambert reported their work on the use of a microcatheter in continuous spinal anesthesia and the decreased incidence of postdural puncture headaches. [30]
[31]
Small-gauge continuous spinal anesthesia quickly grew in popularity. However, problems soon arose. Rigler and colleagues reported on patients developing cauda equina syndrome after receiving treatment via a microcatheter. Maldistribution of local anesthetic was thought to be responsible. Because of the high resistance of the small lumen
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of the microcatheter, it was widely believed that the local anesthetic did not diffuse in the subarachnoid space. It appeared that if the initial dose of local anesthetic failed to provide an adequate block, a second dose would often be given. This resulted in a restricted block, which appeared to be linked to the cauda equina syndrome. [32]
The Food and Drug Administration (FDA) acted on the initial reports of cauda equina syndrome and issued stringent guidelines regarding microcatheter use. Unfortunately, the incidence of cauda equina syndrome did not decline, and, in 1992, all microcatheters were withdrawn from use in the United States by the FDA. Thus, at the time this chapter was written, those practicing the technique of continuous spinal anesthesia had reverted to large-bore catheters until the FDA should complete studies of a new catheter.
Epidural Anesthesia Although Corning may have administered the first epidural anesthetic, Jean Athanase Sicard and Fernand Cathelin in 1901 independently published their account of peridural anesthesia. They approached the epidural space through the sacral hiatus, giving what now would be described as a caudal anesthetic. Marin Théodore Tuffier attempted a lumbar epidural block that same year but had difficulty locating the space. Twenty years later, Fidel Pages described the intraspinous approach to the epidural space and reported satisfactory anesthesia for intra-abdominal procedures. In the early 1930s, Archile Mario Dogliotti, building on Jansen’s discovery of negative pressure in the epidural space, described a practical technique for administering lumbar segmental anesthesia. Using Dogliotti’s work as a foundation, Gutierrez, in 1932, described the hanging drop technique to identify the epidural space. [33]
[34]
[35]
A year earlier, Eugene Aburel placed a silk ureteral catheter in the epidural space and used it to block the pain of women in labor. During World War II in America, Robert Hingson was assigned to care for the pregnant wives of United States Coast Guard seamen. Stationed at a U.S. public heath hospital, Hingson wanted to develop a method whereby he could alleviate the pain of labor in these women. Unaware of Aburel’s work, Hingson took Lemmon’s malleable needle and placed it sacrally, deep to the peridural ligament. This safe and effective method of producing painless childbirth became popularly known as continuous caudal anesthesia. In 1949, Manuel Martinez Curbello modified a silk catheter for continuous spinal anesthesia and inserted it into the epidural space, thus creating the first continuous epidural block. By 1962, the first polyvinyl catheter with a closed tip was introduced, making the continuous epidural block much easier to perform correctly. [36]
[37]
[38]
[39]
Controversy concerning use of epidural analgesia in labor continued. Opponents of the practice claimed it increased the number of instrumental deliveries, but proponents claimed that it did not. By the early 1990s, the combination of dilute local anesthetic and narcotic was demonstrated to be no different from any other form of obstetric pain relief. Currently, epidural analgesia has been combined with subarachnoid narcotics to ease the pain of labor. Combined spinal-epidural anesthesia is one of the leading techniques on obstetric floors at the dawn of the 21st century. [40]
[41]
Brachial Plexus Block In 1884, less than a year after the discovery of the anesthetic properties of cocaine, William Halsted performed the first regional blockade of the brachial plexus. His technique involved surgical exposure of the plexus in the neck with subsequent intraneural blocking of individual nerves. Effectively providing complete anesthesia to the upper extremity, the procedure itself was, at times, nearly as extensive as the surgery for which it was being provided. Unfortunately, an addiction to cocaine, the very drug that Halsted used to block the plexus, befell him, limiting his ability to popularize his approach. [42]
[43] [44]
It was not until 1887, when George Crile exposed the brachial plexus behind the sternocleidomastoid muscle to help control tetanic spasms in a young boy, that the block was used with some regularity. While he was at the Cleveland Clinic, Crile expanded the use of the brachial plexus block to include surgical anesthesia for upper extremity procedures. His original article of 1902, published in The Journal of the American Medical Association, spoke favorably of the block as being superior hemodynamically to general anesthesia for amputations of the shoulder joint. It is noteworthy that at this time in history, shoulder amputations were dangerous surgeries, with large blood loss potential and high subsequent mortality. A procedure that could effectively provide anesthesia as well as limit inherent surgical risk would be a popular discovery. [45]
[46]
[47]
Not until 1911 was the first percutaneous approach to the brachial plexus described by Hirschel. His axillary approach involved injection both below and above the axillary artery, a novel technique still employed with modifications in today’s practice. His knowledge of the anatomy of the brachial plexus stemmed from his
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experience in performing axillary dissections during radical mastectomy procedures. Despite the fact that he injected local anesthetic in a continuum from the entry of the skin up to the posterior section of the axillary artery, Hirschel never reported complications of intravascular injection. Because he understood the importance of retaining a strong concentration of anesthetic in the area of the nerves for as long a period as possible, Hirschel employed a mechanical blockade against dissipation of the anesthetic by use of a rubber ball that was held in place under the pectoral muscles by elastic bandages. Later, he found that simply increasing the volume of local anesthetic resulted in the same efficacy. [45]
In the same year that Hirschel popularized his percutaneous approach to blocking the brachial plexus in the axilla, Kulenkampff in Germany described the first “blind” supraclavicular approach to blocking the brachial plexus. Interestingly, he perfected his technique by trying the block on himself. Others who tried to duplicate Hirschel’s technique for blocking the brachial plexus in the axilla were unable to meet the same level of success that he had described. One explanation was that the axilla technique lacked precision compared with the supraclavicular approach to the plexus. [45]
Greater precision and perhaps improved success rates for blocking the brachial plexus at the axilla were not far off. Capelle in Germany in 1917 wrote of a simplified perivascular approach to blocking the plexus. His knowledge of the anatomy of the brachial plexus in the region of the axilla did not include an understanding of a fascial compartment; however, he was aware that the nerves serving the upper extremity did pass proximal to the axillary artery. Reding in 1921 is thought to have been the first to highlight the importance of the neurovascular sheath in the plexus block at the axilla. His descriptions of the anatomy of the brachial plexus within the axilla include discussion of a fascial sheath surrounding a bundle of nerves. Reding was also aware that the musculocutaneous nerve was not contained within the sheath and that blocking this nerve required injection of local anesthetic within the coracobrachialis muscle. [45]
The techniques of Capelle and Reding were largely ignored, whereas the supraclavicular approach described by Kulenkampff remained popular. It was not until 1958 that Preston Burnham, an orthopedic surgeon, revived the neurovascular sheath approach for blocking the brachial plexus. While repairing an axillary laceration in a child, Burnham noted that the nerves entering the axilla were proximal to the axillary artery. Additionally, a fascial sheath surrounded both nerves and vasculature. If the sheath were entered with one pass of a needle, multiple nerves could be bathed with local anesthetic. Modifications to Burnham’s perivascular approach were made over the years to include increasing the volume of the local anesthetic to be used in order to ensure a more “solid” block. However, Burnham’s initial work in developing the technique of blocking multiple nerves with fewer injections simplified this procedure and subsequently established the popularity that this technique enjoys today.
Preemptive Analgesia George Crile at the Cleveland Clinic came up with the idea that pain could be controlled through the use of regional anesthesia combined with a light general anesthetic. The approach that Crile took to the brachial plexus, for example, became known as “Crile’s technique,” and through its use alone, or as an adjunct to light general anesthesia, he was able to effectively block a patient’s stress response to surgery. He also found that patients did not need deep ether anesthesia with its attendant pulmonary risks for intra-abdominal surgery. It is these findings that helped prompt his belief that there was “anoci-association” between effective anesthesia and hemodynamic changes that occur with surgical procedures. Indeed, it was Crile’s search for a method of anesthesia and surgery without shock that led him to combine regional and general anesthesia. [48]
[49]
To follow Crile’s technique completely was cumbersome and time-consuming. Patients had to be kept quiet preoperatively. Intraoperatively, the plexus of innervating nerves was often dissected under local anesthesia. Crile admonished surgeons to handle tissue carefully and gently. Rough handling caused shock. Gradually, as better local anesthetics made other forms of regional anesthesia reliable and—to some extent—as anesthesia became professionalized, Crile’s technique was abandoned. Especially after the introduction of muscle relaxants by Harold Griffith in 1941, and as shock became better understood after World War II, there was little need for the elaborate planning and slow surgery demanded by anoci-association. [44]
However, in 1983, C. J. Woolf published his animal model experimentation, which demonstrated a central component to post-injury pain hypersensitivity. Investigation confirmed that the central component in the animal model was real and could be blocked by regional anesthetic techniques. The ensuing human studies have been less clear. However, it appears that a block of the affected nerves needs to be present during surgery to blunt the central [50]
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component. What is clear is that regional anesthetic techniques have been demonstrated to aid patients’ recovery from surgery, and regional analgesia is a “new” direction in the evolution of regional anesthetic techniques. [51]
Dissemination of Information Professional interaction is critical for the exchange of ideas and the dissemination of new techniques. Gaston Labat ( Fig. 2-5 ), who left Paris in 1920 and traveled to the Mayo Clinic to bring regional anesthetic techniques there, spent 9 months training the surgeons of the clinic in regional anesthesia. The most notable accomplishment during his time at the Mayo Clinic was the production of Regional Anesthesia. This was the first American textbook to be devoted to regional anesthesia and was immensely popular; the second printing was greater than the first, a rarity in medical publishing. After leaving Rochester, Minnesota, Labat settled in New York City and was affiliated with New York University and Bellevue Hospital. He taught regional anesthesia courses and also administered anesthesia. [52]
[53]
[54]
In 1923, the American Society of Regional Anesthesia (ASRA) was created in New York City. Originally, the society was founded to honor Labat, and the group was a mixture of surgeons, neurosurgeons, and physician anesthetists. Early meetings focused on regional anesthetic techniques, complications, and the matching of blocks to surgical procedures. The proceedings of the meeting and papers presented were published until 1932 in Current Researches in Anesthesia and Analgesia. In 1933, Paul Wood was elected secretary of the organization ( Fig. 2-6 ). He began to mimeograph the minutes and send them to members across the country who could not attend the New York City meetings. Thus, ASRA became a truly national society, and the papers presented before it had excellent exposure to their intended audience. [55]
[56]
[57]
[58]
In the early 1930s, ASRA’s meetings took a slightly different direction. Papers, such as James White’s report on the use of procaine block to predict the therapeutic value of surgical resection in relieving pain and Philip Woodbridge’s review of therapeutic blocks for chronic pain, began to dominate the program ( Fig. 2-7 ). Thus, regional anesthetic techniques were translated into the emerging new field of pain management. Emery Rovenstine ( Fig. 2-8 ) became president of ASRA in 1935 and moved the organization further into pain management. The 1936 clinical demonstrations, held in conjunction with a meeting of ASRA, were three quarters related to pain management. [59]
[60]
[35]
Rovenstine was an active participant in the decision by ASRA to cosponsor the American Board of Anesthesiology ( Fig. 2-9 ). As the necessary second national organization required by the American Medical Association, ASRA was in a unique position to ensure that regional anesthesia was considered a part of the curriculum of every anesthesiologist. On the first written examination, the entire anatomy section was devoted to questions germane to regional anesthesia. There were regional anesthesia questions in the pathology and pharmacology sections as well. Unfortunately, by 1939, interest in the organization had waned, and by 1941, the society was enfolded into the American Society of Anesthesiologists. [61]
[62]
In 1975, several prominent anesthesiologists, among them Alon Winnie, P. Prithvi Raj, and John Rolwson, perceived the need to reintroduce regional anesthetic techniques to anesthesiologists. Without knowledge of the original society, they organized the American Society of Regional Anesthesia. Within 6 months of its organization, the group held a meeting in Phoenix, Arizona, on the day before the International Anesthesia Research Society meeting. The society already had 300 members. Its avowed purpose was to educate and disseminate regional anesthetic techniques. [63]
Within a year of the founding of the society, a journal was published. Regional Anesthesia, now Regional Anesthesia and Pain Medicine, is an important journal covering a wide range of topics germane to regional anesthesia. In addition to an independent 3-day meeting, there are many forums available where a member of ASRA can learn about regional anesthesia. ASRA’s annual meeting was one of the first to have a hands-on workshop demonstrating how to do blocks under the tutelage of meeting faculty members who had mastered the technique. In 2000, ASRA celebrated its 25th anniversary. Regional anesthesia is alive and well and is entering the 21st century in a manner that Gaston Labat could never have imagined.
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Pain Comes of Age Rovenstine’s interest in regional anesthesia and pain medicine was not simply political. He ran a “block” clinic where he tried to help patients with chronic pain problems by applying regional anesthetic techniques. Ralph Waters ( Fig. 2-10 ), his mentor and friend, once chided him by saying that he should not spend “…all of his time in consultation work in regard to diagnostic and therapeutic blocks.” Rovenstine responded that the work in the pain clinic was what he found most stimulating professionally, and that the operating room had lost some of its appeal. The practice of pain medicine and the ability to help patients whose cases were often thought to be hopeless made his work exciting. [64]
[65]
In treating soldiers with pain problems after World War II, John Bonica found the same rewards as Rovenstine. He saw that regional anesthetics provided relief to his patients, but often the pain would return when the local anesthetics “wore off,” or the anesthetics were not at all effective. Bonica noted that some patients in this group needed neurologic evaluation. Often, they also benefited from the intervention of trained mental health professionals, but coordination of care was a problem. From these observations, the idea of a multidisciplinary pain clinic arose. [66]
Bonica would be well remembered for the concept of the multidisciplinary pain clinic, but that was his only accomplishment. In 1953, Bonica published the first edition of his now classic textbook, The Management of Pain. Within the confines of the text, Bonica clearly lays out which blocks work for which painful conditions. In addition, Bonica was active politically and became president of the American Society of Anesthesiologists and the World Federation of Societies of Anesthesiologists. Through his work in organized medicine, he brought pain issues to the forefront of anesthesiology, including regional anesthetic techniques.
[67]
Conclusions The history of techniques in regional anesthesia is replete with names that are instantly recognized as well as those that are somewhat more obscure. And although one person often is awarded credit for the discovery or popularization of a technique, it takes many anesthesiologists to properly apply the method. Al Winnie entitled his Labat address, “Nothing New Under the Sun,” and promptly demonstrated that the issues that were responsible for the formation of the first ASRA were present more than 50 years later when the second was formed. He also traced the history of various regional anesthetic techniques, demonstrating that the late 20th century “discoverer,” without knowledge of the history of regional anesthesia, might have only reinvented what a colleague had done at the beginning of the century. [63]
At the dawn of the 21st century, regional anesthesia and the techniques for accomplishing it are alive and well. From the operating room to the pain clinic and beyond, regional anesthesia is evolving and will remain an important part of patient care. Those who are the Biers, the Criles, and the Cornings of today will leave a rich legacy of caring for patients in ways that we can only begin to imagine. REFERENCES 1. Cotugno
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LD, Dripps RD: Long-term follow-up of patients who received 10,098 spinal anesthetics. JAMA 161:586–591, 1956.
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33. Bromage
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40. Vertommen
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42. Winnie
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43. Fink
BR: History of neural blockade. In Cousins MJ, Bridenbaugh PO (eds): Neural Blockade, 2nd ed. London, JB Lippincott, 1988 pp 3–21.
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45. Winnie
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47. Bacon DR: Regional anesthesia and chronic pain therapy: A history. In Brown DL (ed): Regional Anesthesia and Analgesia. Philadelphia, WB Saunders, 1996, pp 10–22. 48. Crile
GW: Anoci-association in relation to oeprations on the gall bladder and stomach. JAMA 63:1335–1337, 1914.
49. Crile
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CJ: Evidence for a central component of post injury pain hypersensitivity. Nature 308:686–688, 1983.
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59. White
JC: Diagnostic novocaine block of sensory and sympathetic nerves. Am J Surg 9:264–277, 1930.
60. Woodbridge 61. Bacon
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DR, Darwish H, Emery A: Rovenstine and regional anesthesia. Reg Anesth 22:273–279, 1997.
62. Bacon
DR, Lema MJ: To define a speciality: A brief history of the American Board of Anesthesiology’s first written examination. J Clin Anesth 4:489–497, 1992.
63. Winnie
AP: Nothing new under the sun. Reg Anesth 7:95–102, 1982.
64. Letter from Ralph M. Waters, M.D., to Emery Rovenstine, M.D., July 5, 1944. The Collected Papers of Ralph M. Waters, M.D. Steenbock Library Collection, University of Wisconsin Archive, Madison, Wis. 65. Letter
from Emery A. Rovenstine, M.D., to Ralph M. Waters, M.D., July 8, 1944. The Collected Papers of Ralph M. Waters, M.D. Steenbock Library Collection, University of Wisconsin Archive, Madison, Wis.
66. Thompson 67. Bonica
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JJ: The Management of Pain. Philadelphia, Lea & Febiger, 1953.
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Section II - General Considerations for Regional Anesthesia Diego Beltrutti
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Chapter 3 - Economic Impact of Regional Anesthesia GIUSTINO VARRASSI FRANCO MARINANGELI FRANCESCO DONATELLI ANTONELLA PALADINI
One key approach to evaluating medical practice in the future will be based on assessing the effectiveness of the intervention in relation to the cost of providing it. Attempts to evaluate the effectiveness of medical interventions are hardly new. Nearly a century ago, E. A. Codman, M.D., at the Massachusetts General Hospital in Boston, urged that patients should be followed up long enough to determine the success of the treatment. But the efforts today go beyond developing clinical evidence of effectiveness; cost is also a factor. For example, in determining the cost of drug therapy, one must consider not just the price of the drug but also the expense involved in its administration, whether it is given in hospital or to an outpatient, the pharmacist’s time in preparing the prescription, and so on.
The Need for Economic Evaluation The increased interest in cost derives from the fact that in the economically developed countries health coverage is becoming more and more expensive, and the resources absorbed by national healthcare, when extracted from the rest of the economic system, represent a remarkable portion of the gross domestic product. It was reported that U.S. healthcare expenditures in 1998 totaled $838.5 billion, or 14% of the gross domestic products, and more than 40 cents of each dollar spent on healthcare is provided by the government. [1]
The factors mostly responsible for this phenomenon are the laws that rule each type of market. These laws are based on supply and demand. The latter encompasses the increasing attention given to well-being, quality of life, and the needs of an aging population, and the former expresses the development of more advanced medical technology. On the one hand, consumers often find it difficult to correlate their needs with the complex nature of the goods offered, thus delegating decision making to the physician; on the other hand, particularly in industrialized countries, individuals, regardless of their economic condition, have been conditioned to expect a guaranteed right to healthcare, with their communities and governments assuming a large portion of the financial burden. Where this has happened, as in the United States, the citizen has almost always met the costs of illness by means of recourse to private insurance. The result is that the abiding presence of the third-party payer prevents the high price from exercising its action of rationing. Thus, it is the physician and not the consumer who carries out the decision making, often being influenced by factors other than the needs of the patient. Even more remarkable is the fact that neither the physician nor the patient bears the direct economic consequences of the choices made, often preventing the correct distribution of the resources destined for the healthcare system. Hence, it became increasingly necessary to find means capable of creating a more efficient distribution of the budget at the disposal of the healthcare system. Beginning in the year 1960, an attempt was made to develop criteria, tools, and methods that would allow the evaluation, from an economic point of view, of the investments, programs, and products in the healthcare system. Since then, an increasing number of studies that reveal the economic consequences of a specific healthcare choice in the different physician-surgical disciplines have been published in various scientific magazines. For example, studies of ICU use have attempted to identify the types of patients who can benefit maximally from ICU admission. Patients who are not predicted to benefit from ICU services may be excluded from them. This change in practice is intended to save roughly $60 billion per year spent on ICUs in the United States, a figure that represents approximately 24% of all inpatient hospital costs, 9% of overall healthcare expenditures, and 1.1% of the gross national product. [2]
[3] [4]
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Economic Analysis Methods Used in Healthcare Two characteristics are important in economic analysis, each operating from the sectors of activity to which it is applied. The first characteristic is constituted by the resources employed (the costs) and by the results obtained (the consequences). Few of us would be ready to pay a given price for a parcel without knowing its contents. Moreover, few of us would acquire a package, even knowing and desiring its content, before knowing its cost. In both cases, it is the correlation between the costs and the results that influences the decision. Regarding the second characteristic, economic analysis is based upon the available choices. Because one cannot provide reliable effective outcome, the scarcity of resources makes us choose the options based mostly on explicit criteria. The economic analyst strives to identify this set of criteria, which may be useful to the physician for making decisions. Economic analysis can be defined as comparative analysis, in terms of costs and consequences of the series of alternative actions generated by each program. Its primary task, even when applied to the sanitary services sector, consists, therefore, in identifying, measuring, evaluating, and comparing costs and effects of the alternative actions considered. It is possible to outline the various types of economic analysis. In Table 3-1 , two questions are asked: “Are two or more alternatives being compared?” and “Are both the costs and the consequences of each alternative being examined?” The possible answers define a matrix of six boxes, each of which characterizes a situation being evaluated. In boxes 1A, 1B, and 2, only one program is taken into consideration, with no comparison made between different alternatives. In 1A, only the consequences are examined; hence, the box identifies the description of the results obtained, and in 1B, because only the costs are examined, the box is classified as the description of the costs. In box 2, the costs and results produced are described. Boxes 3A and 3B classify situations in which there are two or more alternatives to be compared but in which either the costs or the effects of each alternative are not examined. In 3A, only the consequences of each alternative are compared (evaluations of theoretical or real effectiveness). In 3B, only the costs of the alternatives are examined (analysis of the costs). These analyses do not satisfy the requisites necessary for an economic evaluation; for this reason, it is defined as a partial evaluation. This, however, does not imply that these studies are not important. In fact, they represent important intermediary stages for the comprehension of the costs and consequences of the services or of the programs. Certainly, however, they are not sufficient to solve the problem of efficiency; for this reason, it is necessary to employ the techniques of economic evaluation listed in box 4: • Cost minimization • Cost-effectiveness • Cost-benefit analysis • Cost of utility
COST MINIMIZATION The minimization of the costs consists of comparing two or more alternatives that have identical effects in terms of health but different consumption modalities of the resources necessary to achieve them. It is the simplest method for evaluating efficiency because it highlights, among different alternatives retained of equal effect, which option has the lowest consumption of resources without giving particular attention to the measurement of the same effects. The purpose of this analysis is to answer, for instance, the question, Which therapeutic program for myofascial pain costs less?” The cost of two or more treatments for which a complete equivalence of the effects was ascertained or hypothesized are compared with the aim of identifying the most convenient one.
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Chapter 3 - Economic Impact of Regional Anesthesia TABLE 3-1 -- HAVE COSTS AND CONSEQUENCES FOR EACH INTERVENTION BEEN EVALUATED? No
Have two or more alternatives been compared?
N O
Y E S
Yes
Only the consequences
Only the costs
Costs and consequences
1A Partial evaluation Description of results
1B Partial evaluation Description of costs
2 Partial evaluation Description costs/results
3A Partial evaluation Evaluation of the efficacy
3B Partial evaluation Cost analysis
4 Complete evaluation Cost minimization Cost effectiveness Cost benefit analysis Cost of utility
A comparison of outpatient surgery with inpatient treatment of hernias or hemorrhoids may also be suitable for a cost minimization analysis. If there is strong evidence to suggest that there are no great differences in clinical outcomes for these two defined groups of patients, one can concentrate on identifying the lesser cost option. Much too often, it is assumed that two programs have identical results. If this were really the case, there would be no difference between the minimization of the costs in boxes 3B and 4 of Table 3-1 . It would be wise, however, to furnish some proof to ensure that the results of the two alternatives are equivalent or that they present irrelevant differences.
COST-EFFECTIVENESS Cost-effectiveness analysis compares two or more alternatives that have identical effects from the qualitative point of view but different effects from a quantitative point of view and that involve different modalities of resource consumption necessary to achieve them. The choice does not fall automatically on the least expensive program, except when the best result is also the least expensive choice. A comparison based on cost per unit is always done before the choice is made. For example, there is a range of treatments available for the control of hypertension. These vary in terms of their outcomes, side effects, and so on, but they may all be measured primarily in terms of the reduction in diastolic blood pressure (mm Hg) they achieve. In practice, this analysis measures the cost to reach a determined therapeutic objective, measured in physical units, such as lowered Visual Analogic Scale (VAS) score, increase in the degrees of excursion of an articulation, or years of life earned. The lower the cost of a physical unit obtained, the higher the efficacy of a treatment.
COST-BENEFIT ANALYSIS Cost-benefit analysis evaluates two or more relief alternatives whose effects are not necessarily identical or that lead to a single common effect. This type of analysis tries to go beyond the considerations of the specific effects, individualizing a modality of measurement of all the results of the considered program. One of these measures is the monetary unit that quantifies, in monetary terms, the benefits of the program. It also facilitates cost comparison. Successively, the costs of a pharmacologic treatment are compared with the economic benefits (savings of resources for the reduction of morbidity and mortality rates). The net benefits are calculated from the difference between the total benefits (savings) and the total costs. The greater the savings and the lower the costs of a treatment, the more beneficial it is. Each alternative is compared with the alternative of doing nothing, characterized by additional void costs (i.e., by the maintenance of the status quo). It implicitly allows comparison of each alternative with the choice not to do anything, a choice without costs or benefits. Unlike the analysis of minimization of costs and analysis of cost-effectiveness, this technique of analysis does not subtend any option for a determined objective that could be rejected if the results do not satisfy the preset criteria.
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COST OF UTILITY Another measure of the value of a program, preferred by many analysts, but more difficult to obtain, is utility. Utility refers to the value of one specific level of the state of health and can be measured on the basis of individual or societal preferences for a set of results produced by the healthcare services. The analysis of utility is a relatively new technique in the field of evaluation of services, but it is considered very promising because it even takes into account the quality of life in judging the results of a treatment program. At the same time, it has a common denominator that makes the costs and results of different programs homogeneous and comparable. This common denominator, usually expressed in the formula of days of health or years of life earned and balanced with the relative quality of life, is obtained case per case by multiplying the duration of the result by a coefficient of relative utility of the state of health reached.
Cost Analysis Assessment of cost is essential when performing any evaluation of the economic impact of a healthcare intervention and is similar for all four methods of analysis. Definition of the cost accounting terms are listed in Table 3-2 . Cost assessment varies according to the perspective of the person making the assessment. Common perspectives considered in healthcare cost analyses include those of society as a whole, those of health insurance companies or other payers, those of healthcare providers, and those of the patient. What is relevant from one perspective may be irrelevant from another. Many healthcare economic analysts recommend that wide-ranging policy decisions on drug use should be based on cost assessments that take the widest possible perspective (i.e., society as a whole). Cost considerations from a narrower point of view may overlook shifting cost from one segment of society to another (e.g., early discharge shifts recovery costs from [5] [6]
TABLE 3-2 -- DEFINITIONS OF COMMONLY USED COSTS Term
Definition
Costs
Sacrifice measured as the price paid for the irreversible use of a resource
Direct costs
Cost of the material and labor used for production
Indirect costs
Costs related to the consequences of an event on society or on an individual
Average costs
Total costs divided by the number of units produced
Fixed costs
Costs that remain the same regardless of the number of goods or services produced
Marginal costs
Change in costs for producing one additional unit of output
Variable costs
Costs that change with the number of services provided
the healthcare system itself to patients, their families, and their primary care physicians).
[7]
The total costs associated with a medical intervention consist of direct and indirect costs. The direct costs of a particular treatment include not only the acquisition cost of the amount of drug administered but also the costs of drug wastage, equipment for therapy administration (e.g., intravenous sets, syringes), pharmacy dispensing costs, and the costs of managing any drug-induced side effects. From the patient’s perspective, total costs include nonmedical, direct, out-of-pocket costs (e.g., transportation to the site of therapy, family lodging, home help care) along with indirect costs of wages lost by the patient and the family member who is the caregiver. [8]
The term indirect costs is used differently by physicians, accountants, and healthcare economists. Although some physicians refer to costs of managing side effects and delayed recovery as indirect costs, most healthcare Accountants include all fixed costs in their economists would describe these as associated direct costs. calculation of indirect costs, whereas economists usually refer to indirect costs as the costs related to lost productivity. [9]
[10] [11]
[12]
COSTS OF ANESTHESIA Expenditures controlled by anesthesia providers represent 3% to 5% of the total healthcare costs of the United States. The cost implications of anesthesia care are complex. Not only are there significant costs associated with [13]
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the delivery of anesthesia care (e.g., cost of drugs, equipment, supplies, provider fees), but there can be additional costs associated with care (e.g., perioperative testing, consultation with other providers, complications). Macario and coworkers, reporting on a study elucidating the proportion of anesthesia costs relative to the major hospital departments involved in surgical care, estimated that intraoperative anesthesia hospital costs constituted 5.6% of the total hospital cost of an inpatient surgical procedure. The true fraction of resources consumed was probably higher because some costs outside the operating room (e.g., preoperative laboratory testing) were not allocated to anesthesia but may have been occasioned by decisions related to anesthesia care. [14]
In this study, 49% of total hospital costs were variable and 57% were direct. The largest hospital cost category was the operating room (33%) followed by the patient ward (31%). The greatest savings occurred if interventions addressed variable costs (e.g., intravenous supplies). Even if this study had been performed in a single university hospital using a well-known cost accounting application, and even if the results were not necessarily transferable to other institutions with other cost categories, the proportions of hospital departmental costs are likely to be generalized to other hospitals. It is possible to divide cost components and cost determinants. Cost components include those expenditures that, added together, result in the dollar cost of anesthesia. These cost components accrue directly to patients and payers and are observed in patient bills and records. Cost determinants are the factors that influence the cost components of anesthesia and are difficult to measure directly. Some costs accrue only to society in general and are best studied as determinants and measured in terms of tradeoff. The major charges for anesthesia are derived from three sources: provider services, technology, and site or facility. Minor charges are derived from payer source and side effects. The two major determinants affecting costs of provider services are the supply and availability of providers and their geographic locations. Technology includes the methods for achieving adequate anesthesia. The methods differ among the three basic types of anesthesia: general, regional, and monitored care. The costs of provider services differ insignificantly among these three types, but there are major differences in the costs of technology. Charges for anesthesia technology have three determinants: disposable supplies, equipment, and anesthetic drugs and agents. Some technologies do require skills that may add from $300 to $1000 to the cost of an anesthetic. Complications such as congestive heart failure or the requirement of an ICU stay are very expensive, but whether new techniques prevent them in a cost-efficient fashion is uncertain. The term facility includes the geographic location where anesthesia is performed and all of its associated contextual and environmental features, such as the following: • Elective versus emergency treatment, which determines whether the patient can shop for a surgeon and surgical facility. • Political and legal policies, which determine where anesthesia practitioners can practice and the exclusiveness or competitiveness of these practices. • The organizational structure, which encompasses the policies, procedures, and philosophies of the surgical facility and that affects the way anesthesia is administered (i.e., how much preoperative laboratory work is required, to what extent preoperative consultations are encouraged, and who provides postoperative pain control. • Patient demographics, which include the physical, social, and financial diversity of the general patient population. Patient demographics determine, in part, the level of services needed and the amount of costshifting from full-paying patients required for the facility and provider to continue in business.
Time in Regional Anesthesia The time spent in the healthcare structures, represented by the period spent in the operating room, the ICU, or the ward, constitutes one of the most important variables to study in an examination of the economic impact of any new anesthesia procedure. This is because the major economic impact of the healthcare assistance is made not by materials and equipment but especially by the personnel’s work, which needs to be well organized. In the literature, no studies exist that have dealt with this question from all points of view. In the study by Tessler and coworkers, for example, the authors sought to compare the time efficiency of spinal versus general anesthesia. The purpose of the study was to determine the frequency of converting failed spinal [15]
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anesthesia to general anesthesia and the amount perioperative time needed for patients undergoing spinal or general anesthesia for vaginal hysterectomy. These operations were all elective and required no additional invasive monitoring. This arrangement allowed a pure comparison of anesthetic induction time (spinal vs. general) and a comparison of overall perioperative time that may be related to the choice of anesthetic technique. Their results indicated that spinal anesthesia and general anesthesia were equally time efficient for that type of surgery. The patients in the spinal anesthesia group remained in the postanesthesia care unit (PACU) an average of 27 minutes longer per patient than those receiving general anesthesia alone. However, at their institution, complete recovery from motor block due to spinal anesthesia is a PACU discharge criterion, and this would explain their finding. Other anesthesiologists do not believe full recovery from motor block after spinal anesthesia is necessary before discharge from the PACU. [16]
This study, regardless of costs, does not give any information on the different economic impact that the two different techniques of anesthesia could have. Moreover, the impact (importance, significance) of the 27 minutes spent in the PACU per patient for those undergoing spinal anesthesia still remains unclear. In the light of other criteria of dismissal from the PACU, the results could be inverted. Another study was designed to ascertain whether interscalene block is reliable and efficient for use in same-day surgery compared with general anesthesia for shoulder arthroscopy. The authors retrospectively reviewed patients treated at the University of Connecticut over a 42-month period in the same-day surgery unit. They found that compared with general anesthesia, regional anesthesia required significantly less total nonsurgical intraoperative time use (53 ± 12 vs. 62 ± 13 min) and also decreased PACU stay (72 ± 24 vs. 102 ± 40 min). Interscalene block anesthesia resulted in significantly fewer unplanned admissions requiring therapy for severe pain, sedation, or nausea/vomiting than general anesthesia (0 vs. 13) and an acceptable failure rate (8.7%). [17]
In this case also, the study did not evaluate the various economic consequences of a different clinical choice but concluded only that interscalene block should be considered as a viable alternative to general anesthesia for shoulder arthroscopy in ambulatory surgery patients. Among the studies that have considered the economic consequences of different therapies is that of Nakamura and coworkers. This retrospective study evaluated 67 consecutive patients who underwent an arthroscopically assisted, autogenous bone-patellar ligament-bone anterior cruciate ligament reconstruction that was supervised by the same surgeon. General endotracheal anesthesia was used for 36 patients, and a femoral sciatic nerve block was used in 31 patients. Patients who received regional anesthesia required a significantly longer recovery room stay than those who received general anesthesia. Most of the patients who received general anesthesia had inpatient procedures. In the general anesthesia group, 31 of 36 patients spent at least one night in the hospital. Three of 31 patients who received regional anesthesia required hospital admission. There were no differences in anesthesia-related complications between the groups. The cost saving of performing anterior cruciate ligament reconstruction under regional anesthesia compared with that of general anesthesia was calculated at $2907 per patient and predominantly reflected the outpatient approach used in these cases. Moreover, the use of regional anesthesia was not found to compromise operating room efficiency. [18]
Another study was performed to assess safety, efficacy, and hospital costs related to general anesthesia and regional anesthesia for carotid endarterectomy (CEA). The authors found that patients who received general anesthesia for CEA spent an average of 1.2 days in the PACU and 6.1 days in a regular hospital bed, for an average cost of $4547. The patients who underwent CEA under regional anesthesia had an average of 0.1 PACU day and 4.1 regular hospital days, for a cost of $2067. Regional anesthesia saved $2480 per patient and $124,000 in this study group, with no increase in the rate of mortality and morbidity. [19]
In these studies, the different economic consequences that are reflected on the patient and on the society in general after the administration of the different anesthesiologic techniques remain unknown. Choice of anesthetic may affect the recovery rate of gastrointestinal function and, thus, duration and cost of hospitalization after colonic surgery. A universal complication after major intra-abdominal surgery is postoperative ileus, which prolongs hospital stays and is estimated to have an annual cumulative U.S. healthcare cost of $750 million. Previous studies suggest that multiple factors may affect the rate of postoperative recovery of gastrointestinal function after abdominal surgery. For example, recovery of postoperative gastrointestinal function may be promoted by early oral feeding, by use of low-fat nutrition, by early patient activity, and by administration of nonsteroidal anti-inflammatory agents. The use of epidural analgesia, especially with local anesthetics, may accelerate the recovery of gastrointestinal function through blockade of inhibitory sympathetic reflexes. [20]
[21] [22]
[23]
[25]
[26] [27]
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Liu and coworkers performed a prospective, randomized, double-blind study to examine the effects of different techniques of anesthesia and analgesia on recovery of gastrointestinal function and subsequent duration and cost of hospitalization. Fifty-four patients undergoing partial colectomy procedures were randomized into four groups. All groups received a standardized general anesthetic. Group MB received a preoperative bolus of epidural bupivacaine and morphine followed by an infusion of morphine and bupivacaine. Group M received a preoperative bolus of epidural morphine followed by an infusion of morphine. Group B received a preoperative bolus of bupivacaine followed by an infusion of bupivacaine. Group P received a preoperative bolus of intravenous morphine followed by intravenous patient-controlled morphine postoperatively. [28]
The authors found that epidural analgesia with bupivacaine and morphine provided the best balance of analgesia and side effects. At the same time, this combination of pain relief accelerated postoperative recovery of gastrointestinal function and time to fulfillment of discharge criteria after colon surgery in relatively healthy patients within the context of a multimodal recovery program. Based on average charges at the institution, the use of epidural morphine and bupivacaine potentially generated a net savings of $1200 per patient compared with the use of epidural or patient-controlled analgesia (PCA) morphine. In contrast, a major study found that patients who received epidural bupivacaine did not experience the improved recovery of bowel function experienced by those who were given systemic opioids. However, in this study, epidural local anesthetic was administered for only 24 hours and then patients were provided with analgesia via parenteral or epidural opioids during the time in which gastrointestinal function was beginning to recover. Hence, it seems likely that early discontinuation of epidural local anesthetic administration may account for this negative finding. [29]
In summary, these data support, but do not conclusively prove, that regional anesthesia results in a superior recovery compared to general anesthesia. However, several questions need to be answered. Although the patient may leave the hospital or surgical center sooner after receiving regional anesthesia, how does the patient treat pain at home once the block has worn off? Who, and at which cost, will take care of the patient? Few studies performed a comparison of differences in time efficiency, costs, charges, and complications among regional techniques. Riley and coworkers compared spinal and epidural anesthesia for cesarean delivery with respect to time spent in the operating room and the PACU, complications, and requirements for additional analgesia. The authors found that significantly less time elapsed from entry into the operating room until surgical incision with spinal anesthesia compared with epidural anesthesia. Thus, patients who received spinal anesthesia spent a shorter total time in the operating room than those who received epidural anesthesia. PACU times were not statistically different between the groups. Cost analysis revealed that patients would have been charged an average of $260 more for operating room use and anesthesia professional fees with epidural anesthesia. Charges to patients who had spinal anesthesia were significantly less than those to patients who had epidural anesthesia; however, patient charges do not reflect the true costs of medical procedures and are meaningless in managed or capitated systems. Examining costs is a better way to compare economic advantages among techniques. In this study, the differences in direct costs between the techniques was relatively small (approximately $20). In contrast, the increased indirect costs associated with epidural anesthesia may be of greater consequence. The additional time taken to perform the epidural block occupies not only the anesthesiologist but also the obstetrician, surgical assistant, and nurses. In addition, the operating room is occupied for a longer period, which may be significant in a busy obstetric service. Patient discomfort can also be considered as an additional indirect cost of epidural anesthesia. [30]
Complications in Regional Anesthesia The act of placing an epidural catheter may determine some of the complications with epidural anesthesia. The most common complication from placement of epidural catheters is accidental dural puncture with resultant postdural puncture headache (PDPH). Large surveys encompassing 51,000 epidural catheter placements performed during the Subsequent development of past three decades suggest that the incidence of dural puncture is 0.16% to 1.3%. PDPH depends on several factors and ranges from 16% to 86%. [31] [32]
[33]
Less frequent complications include paresthesias. The incidence of transient paresthesia varies from 5% to 25%.
[34]
Neurologic damage, which may be long-lasting or even permanent, is the most feared complication of regional anesthesia. There are several causes of such damage, such as trauma (needle, catheter, injection), arteriosclerosis, hypotension, the accidental injection of toxic substances such as povidone-iodine (Betadine), hypocoagulation, and bacteremia. The incidence of these complications is likely to be 0.01% to 0.001%. [34]
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Paraplegia appears to result most commonly from the formation of an epidural hematoma. Puncture of epidural vessels during placement of epidural catheters occurs in approximately 3% to 12% of cases. The incidence of symptomatic epidural hematoma associated with epidural analgesia is difficult to estimate, but combined case series of more than 100,000 epidural anesthetics have been reported without a single epidural hematoma. Currently, the risk of epidural hematoma formation after administration of epidural analgesia appears to be increased if patients are receiving anticoagulant agents or have a coagulation disorder. However, several large series have documented safe use of epidural analgesia in patients receiving antiplatelet therapy, warfarin sodium, and high or low doses of heparin. [35]
[36]
[37]
[36] [37] [38]
[39]
[40]
[41] [42]
Evaluation of the economic consequences of such complications is not simple. The rarity with which they occur renders their economic weight almost uninfluential for the healthcare structures. Administration of local epidural anesthetics for surgical anesthesia frequently results in multiple hemodynamic changes, including decreases in chronotropism, inotropism, dromotropism, systemic vascular resistance, cardiac output, and myocardial oxygen consumption. The economic consequences of these hemodynamic changes are far from being calculated. [43]
Another dangerous complication of epidural administration of opioids is delayed respiratory depression. Although virtually all opioids commonly used for epidural analgesia have been reported to cause respiratory depression, morphine is associated with the highest risk. Nonetheless, the incidence of delayed respiratory depression after epidural administration is small. In a prospective survey of 1062 patients receiving epidural analgesia, there were 1131 episodes in which a local anesthetic and opioid mixture was used, and 160 instances in which opioids alone were used. Local anesthetic was not used without opioids. Twenty-three percent of catheters were removed prematurely because of catheter-related problems including accidental dislodgment (13%) and skin site inflammation (5.3%). No epidural abscess or hematoma was identified. In 14% of the total number of episodes, there was either no demonstrable block or complications occurred that required a change of solution: 30% of this group were salvaged after intervention by the acute pain service. The incidence of respiratory depression was 0.24%. There was no case of delayed respiratory depression. [44]
[45]
For epidural analgesia, fentanyl, because of its greater lipophilic nature, offers a number of advantages over morphine, including a lower incidence of side effects and reduced risk of delayed-onset respiratory depression. The relatively short duration of action of epidural fentanyl makes this agent more ideally suited for continuous infusion or patient-controlled epidural analgesia (PCEA). [46]
Although morphine and fentanyl remain the predominant epidural opioids, sufentanil offers some unique advantages. Because of its greater lipophilic action and µ-receptor binding capacity, sufentanil has a faster onset of action and longer duration than epidural fentanyl. Compared with morphine, sufentanil has been associated with a lower incidence of side effects, particularly delayed respiratory depression. [47]
[47]
Combined case surveys including more than 20,000 patients suggest that the incidence of this complication is less than 1%. Even in this case, the related economic impact of this complication has not been calculated. [48]
Outcome and Regional Anesthesia Perioperative morbidity and mortality rates are mainly influenced by the type and duration of surgery as well as the patient’s preoperative state of health. Anesthesia, however, may also result in severe perioperative pathophysiologic changes, which may be either desirable (e.g., analgesia, vasodilatation in vascular surgery) or detrimental (e.g., hypothermia, ventilatory depression) and which may differ depending on the anesthetic technique used (e.g., general anesthesia vs. regional anesthesia). Epidural anesthesia has been reported to exert beneficial effects in surgical procedures. In a retrospective study of 90 consecutive high-risk thoracic surgical procedures performed using a combined technique of epidural anesthesia with light general anesthesia, the outcome of this technique has been examined. The mortality rate for the group of patients was 2.2% due to myocardial infarction occurring on postoperative days 3 and 4. Morbidity developed in 3.3% of the patients, including the 48-hour requirement of mechanical ventilation in one patient and pneumonia in two other patients. This approach appears to be preferable to use of general anesthesia alone, in which American Society of Anesthesiologists (ASA) class II patients have a predicted mortality rate of 5.4% for elective high-risk procedure. [49]
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On the contrary, in another study comparing general anesthesia combined with epidural anesthesia with general anesthesia for major abdominal surgery, results were equivocal. In fact, the authors found only transient quantifiable differences in recovery characteristics. [50]
Two major periodical reviews of the effects of regional anesthesia on postsurgical morbidity rate and postoperative organ dysfunction have been published. The former concluded that regional anesthesia appears to reduce the early postoperative mortality rate after acute hip surgery for fracture, but long-term survival is dependent on factors other than the choice of anesthesia. The large amount of data suggests that regional anesthesia should be used whenever possible. The latter, a more recent review, confirms what the previous study underlined: Reduced mortality rate appears to have been demonstrated under an epidural regimen for postoperative analgesia in high-risk patients undergoing thoracic, abdominal, and vascular procedures. [51]
[52]
Several studies have attempted to identify the most appropriate anesthetic technique for patients with hip fracture. A significantly lower mortality rate for spinal anesthesia compared with general anesthesia was demonstrated by one group of researchers, but this has not been confirmed. In the largest published study on patients undergoing anesthesia for hip fracture surgery, 1333 patients were studied prospectively to assess the effects on outcome of general and spinal anesthesia. It was demonstrated that the excess mortality rate in some groups was correlated with age and preexisting medical conditions rather than with the type of anesthesia, and there were no significant differences between the groups in the length of hospital stay. [53]
[54] [55]
[56]
In another study, the mortality rate after surgical correction of upper femoral fractures was investigated in 578 patients randomly allocated to receive spinal or general anesthesia. Thirty days after surgery, the mortality rate was 6% after spinal anesthesia and 8% after general anesthesia. Six months to 2 years after surgery the mortality rate was identical in the two groups. The estimated blood loss was smaller in patients receiving spinal anesthesia. Regardless of the anesthetic technique, a high short-term mortality rate was related to age, male sex, and trochanteric fracture, whereas excess long-term mortality rate was related to male sex and high ASA scores. However, the patients in this study had a much shorter period in hospital than the patients in other studies. At the same time, mortality rate during the first year has been reduced from 27% to 19%, suggesting the possibility of a beneficial effect of early ambulation and discharge. [57]
[58]
The perioperative morbidity rate may be modifiable in high-risk patients by the anesthesiologist’s choice of either regional or general anesthesia. Outcomes between epidural and general anesthesia have been compared, with a study made of 100 patients scheduled for elective vascular reconstruction of the lower extremities who were randomized to receive either epidural anesthesia followed by epidural analgesia or general anesthesia followed by intravenous PCA. Cardiac ischemia, myocardial infarction, unstable angina, and cardiac death were identified by a cardiologist. Other major types of morbidity were determined at the time of hospital discharge and at 1 and 6 months after surgery. The major finding of this study was that the rate of reoperation for graft occlusion was higher in patients randomized to receive general anesthesia than in those randomized to receive epidural anesthesia, but no statistically significant differences were found in overall incidence of death, major cardiac disease, or myocardial ischemia. [59]
These findings have been confirmed in the largest prospective randomized trial to date, which was designed to evaluate the effects of regional anesthesia techniques (spinal or epidural) versus general anesthesia on perioperative cardiac morbidity rate and overall mortality rate in patients undergoing peripheral vascular surgery. The authors, in fact, found that the choice of anesthesia, when correctly delivered, does not significantly influence cardiac morbidity and overall mortality rates in patients undergoing peripheral vascular surgery, but it decreases the incidence of peripheral vascular graft thrombosis. [60]
Also, general anesthesia in carotid endarterectomy has not caused an increase in either mortality or morbidity rates. Nevertheless, patients who underwent carotid endarterectomy under regional anesthesia saved $2480 each.
[61]
Therefore, many trials that aimed at comparing the impact of different anesthetic techniques on the incidence of postoperative complaints have been performed in the past. No significant advantage of either technique has been identified up to now with respect to postoperative mortality rate or severe morbidity. This finding may be due to at least three factors; • Many side effects related to anesthesia—due to close postoperative monitoring—are detected and treated early in the postoperative phase (e.g., in the recovery room), thereby preventing serious complications. • Postoperative mortality rate, related exclusively to anesthesia, is probably so low that huge patient numbers would be required to demonstrate any significant differences between different techniques.
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• Besides the factor of anesthesia, many other factors (e.g., anesthetists) contribute to the anesthesia-related morbidity and mortality rates, which are scarcely quantified. The fact that clear advantages for a single technique have not yet been demonstrated must not, however, result in anesthetic nihilism. Rather, there may be good reasons in the individual patient (e.g., lack of a recovery room) to prefer one anesthetic technique or drug over another, in order to lower the individual’s anesthesia-related risk. Intraoperative blood loss has been attributed to multiple clinical variables, including age, physical status, type of surgery, surgeon, and anatomic and physiologic differences between patients. Nearly 12 million red blood cell units are transfused to approximately 3.5 million patients annually in the United States. Approximately 20% of all homologous blood transfusions have resulted in some adverse effect in the recipient. The unit cost has varied from $60 to $150. In another study, the mean cost for all blood components transfused per patient has been evaluated to be $397 ± $244. The advantages of regional anesthesia with regard to intraoperative blood loss compared with those of general anesthesia have long been debated. Although the literature has not demonstrated less bleeding with either anesthetic technique, it is commonly believed that epidural or spinal anesthesia results in less intraoperative bleeding. [62]
[64]
[65]
[63]
[66]
[67]
[68]
[69]
[70]
[56] [57]
More correctly, it seems that positive pressure ventilation increases bleeding during general anesthesia. This was demonstrated by comparing the mean blood loss in 100 patients receiving either epidural anesthesia, combined epidural and general anesthesia, or general anesthesia alone. Mean blood loss in the epidural anesthesia group was significantly less than that in either the combined epidural and general anesthesia group or the general anesthesia alone group. Significantly less blood was transfused during surgery in the epidural group compared with the remaining two groups. [71]
The decrease in blood loss associated with epidural anesthesia with lower transfusion requirements results in significantly reduced frequency of deep venous thrombosis compared with results after general anesthesia. Venous thromboembolic disease is still one of the main causes of postoperative morbidity and death. It is also commonly believed in this case that continuous lumbar epidural anesthesia could exert a beneficial effect in reducing the incidence of such an event. Possible explanations for these differences include increased circulation in the lower extremities, less tendency for intravascular clotting to occur, and more efficient fibrinolysis in association with epidural anesthesia. [72]
The socioeconomic consequences of routine administration of low-molecular-weight heparin (LMWH) as thromboprophylaxis in patients undergoing total hip arthroplasty has been evaluated on the basis of data from a Despite the higher direct costs associated with LMWH, this regimen was more costnumber of clinical studies. effective in preventing thromboembolic complication than no prophylaxis, dextran 70, or low-dose unfractionated heparin. [73] [74]
[73] [74]
Analgesic Consumption and Regional Anesthesia The consumption of analgesic drugs in the postoperative period is another important factor in evaluating the economic impact of an anesthesiologic technique. Epidural local anesthetics may be superior to systemic opioids in the dose range used and in reducing postoperative analgesic requirements because they decrease pain perception in patients. The changes in central neuron excitability induced by a noxious injury stimulus usually outlast the stimulus duration and may persist beyond the expected tissue healing period. Consequently, it has been suggested that surgery in humans may lead to alterations in response properties of central neurons, as in sensitization, similar to the ones produced in experimental animals, resulting in amplification and prolongation of postoperative pain. To date, relatively few studies have examined the effects of intraoperative neuraxial block with either local anesthetics or opioids on postoperative analgesic requirements. One of these studies compared postoperative pain and analgesic demand in patients who underwent radical prostatectomy and received general anesthesia alone and in those who underwent prostatectomy and received epidural anesthesia with bupivacaine, either alone or in combination with general anesthesia. During surgery, patients in the epidural group received a significantly greater epidural bupivacaine dose compared with the epidural general anesthesia group. On postoperative day 1, PCA requirements in the three groups were similar. On postoperative day 2, PCA demand in the epidural general anesthesia group and in the general anesthesia group was significantly greater than in the epidural anesthesia group. The same differences continued on postoperative days 3 and 4. The results were not statistically analyzed because only seven patients still received epidural PCA on postoperative day 5. [75]
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Other studies[ ] [ ] have confirmed these findings, suggesting that analgesic requirements, time of postoperative surveillance, and frequency of treatment of postoperative complaints after both lower abdominal surgery and lower limb surgery can be significantly decreased if surgery is performed with use of subarachnoid anesthesia. Furthermore, the results were more interesting when general anesthesia was compared with triple nerve block (three in one) during surgical correction of fractured femur neck. The nerve blocks significantly reduced the quantity of opioid administered after the operation; 48% of these patients required no additional analgesia in the first 24 hours. 76
77
[78]
Conclusions Anesthesia costs are a small portion of the overall costs associated with a surgical patient’s hospital encounter. Greater cost savings may come with improving operating room efficiency as well as those processes of care that reduce length of hospital stay. Many studies have observed better pain relief with epidural analgesia than with systemic opioids. analgesia is particularly evident when local anesthetics and opioids are combined.
[79] [80]
Improved
[80]
Improved analgesia, however, may not be the only mechanism for improved outcome, at least not through a direct cause-and-effect-relationship. Epidurally administered analgesics may also produce beneficial effects through other mechanisms such as inhibition of efferent pathways or inhibition of neural reflex arcs. This study indicates that use of regional anesthesia and analgesia may be associated with reductions in incidence and severity of many perioperative physiologic perturbations. Perioperative coagulability can be decreased with epidural analgesia, and this effect may significantly reduce the incidence of venous and arterial thromboses. Similarly significant improvements in gastrointestinal motility may result in a more rapid functional recovery from surgery. Despite the obvious need, there are few studies of the costs and economic consequences of alternative anesthetic strategies. Healthcare and cost containment strategies and policies often are developed and implemented before their wider effects are assessed and understood. When designing outcome studies, it is necessary to strike a balance between two opposing goals: first, the scientific need to investigate effects of a single intervention by keeping all other aspects of care constant; and second, the clinical reality that postoperative recovery is a multifactorial event and that a solitary intervention is unlikely to alter the outcome. Although many of these outcomes are relatively subjective and difficult to evaluate, it is necessary to expand the horizon beyond the intraoperative or even intrahospital period to see whether and to what degree clinical interventions influence ultimate patient recovery. The changing economic environment means that it is no longer sufficient for anesthesiologists merely to determine the best method of postoperative analgesia or merely to believe that patients will do better. In the future, it will be necessary to demonstrate that every kind of anesthetic-analgesic technique is cost-effective. REFERENCES 1. Final
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Moiniche S, Bulow S, Hesselfedt P, et al: Convalescence and hospital stay after colonic surgery during balanced analgesia, enforced oral feeding and mobilization. Eur J Surg 7:628–633, 1995. 25. Grass JA, Sakima NT, Valley M, et al: Assessment of ketorolac as an adjuvant to fentanyl patient controlled epidural analgesia after radical retropubic prostatectomy. Anesthesiology 78:642–648, 1993. 26. Ahn H, Bronge A, Johansson K, et al: Effect of continuous postoperative epidural analgesia on intestinal motility. Br J Surg 75:1176–1178, 1988. 27. Jayr C, Thomas H, Rey A, et al: Postoperative pulmonary complications. Epidural analgesia using bupivacaine opioids versus parenteral opioids. Anesthesiology 78:666–676, 1993. 28. Liu SS, Carpenter RL, Mackey DC, et al: Effects of perioperative analgesic technique on rate of recovery after colon surgery. Anesthesiology 83:757–765, 1995. 29. Wallin G, Cassuto J, Hogstrom S, et al: Failure of epidural anesthesia to prevent postoperative ileus. Anesthesiology 65:292–297, 1986. 30. Riley ET, Cohen SE, Macario A, et al: Spinal versus epidural anesthesia for cesarean section: A comparison of time efficiency, costs, charges and complications. Anesth Analg 80:709–712, 1995. 31. Tanaka K, Watanabe R, Harada T, et al: Extensive application of epidural anesthesia and analgesia in a university hospital: Incidence of complications related to technique. Reg Anesth 18:34–38, 1993. 32. Stride PC, Cooper GM: Dural taps revisited: A 20 year survey from Birmingham Maternity Hospital. Anesthesia 48:247–255, 1993. 33. Kopacz DS, Neal JM, Pollok JE: The regional anesthesia “learning curve.” What is the minimum number of epidural and spinal blocks to reach consistency? Reg Anesth 21:182–190, 1996. 34. Kane RF: Neurodeficits following epidural or spinal anesthesia. Anesth Analg 60:150–161, 1981. 35. Schmidt A, Nolte H: Subdural and epidural hematomas following epidural anesthesia: A literature review. Anesthesist 41:276–284, 1992. 36. Schwander D, Bachmann F: Heparin and spinal or epidural anesthesia: A decision analysis. Ann Fr Anesth Reanim 10:284–296, 1991. 37. Sage DJ: Epidurals, spinals and bleeding disorders in pregnancy: A review. Anaesth Intensive Care 18:319–326, 1990. 38. Jorgensen LN: Lumbar analgesia in patients receiving anticoagulant therapy: Pro et contra. Ugeskr Laeger 153:1491–1494, 1991. 39. Horlocker TT, Wedel DJ, Offord KP: Does preoperative antiplatelet therapy increase risk of hemorrhagic complications associated with regional anesthesia? Anesth Analg 70:631–634, 1990.
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40. Odoom JA, Sih IL: Epidural analgesia and anticoagulant therapy. Anaesthesia 38:254–259, 1983. 41. Willie JP, Jorgensen LN, Rasmussen LS: Lumbar regional anaesthesia and prophylactic anticoagulant therapy: Is the combination safe? Anaesthesia 46:623–627, 1991. 42. Bergqvist D, Linblad B, Matzsch T: Low molecular weight heparin for thromboprophylaxis and epidural/spinal anesthesia: Is there a risk? Acta Anaesthesiol Scand 36:605–609, 1992. 43. Cousins MJ, Bromage PR: Epidural neural blockade, neural blockade in clinical anesthesia and management of pain. Cousins MJ, Bridenbaugh PO (eds): Neural Blockade. Philadelphia, JB Lippincott, 1988, pp 253–260. 44. Morgan M: The rational use of intrathecal and extradural opioids. Br J Anaesth 63:165–188, 1989. 45. Burstal R, Wegener F, Hayes C, Lantry G: Epidural analgesia: Prospective audit of 1062 patients. Anaesth Intensive Care 26:165–172, 1998. 46. Grass JA: Fentanyl: clinical use as postoperative analgesic— epidural/intrathecal route. J Pain Symptom Manage 7:419–430, 1992. 47. Grass JA: Sufentanil: Clinical use as postoperative analgesic— Epidural/intrathecal route. J Pain Symptom Manage 7:271–286, 1992. 48. Morgan M: Epidural and intrathecal opioids. Anaesth Intensive Care 15:60–67, 1987. 49. Temeck B, Schafer W, Park WJ, et al: Epidural anesthesia in patients undergoing thoracic surgery. Arch Surg 124:415–418, 1989. 50. Handley GH, Silbert BS, Mooney PH, et al: Combined general and epidural anesthesia versus general anesthesia for major abdominal surgery: Postanesthesia recovery characteristics. Reg Anesth 22:435–441, 1997. 51. Scott NB, Kehlet H: Regional anaesthesia and surgical morbidity. Br J Surg 75:299–304, 1988. 52. Liu S, Carpenter R, Ncal JM: Epidural anaesthesia and analgesia. Their role in postoperative outcome. Anesthesiology 82:1474–1506, 1995. 53. McLaren AD, Stockwell MC, Reid VT: Anaesthetic techniques for surgical correction of fractured neck of femur. Anaesthesia 33:10–14, 1978. 54. Davis FM, Woolner DF, Frampton C, et al: Prospective, multicentre trial of mortality following general or spinal anaesthesia for hip fracture surgery in the elderly. Br J Anaesth 59:1080–1088, 1987. 55. Moore DP, Quinlan W: Mortality and morbidity associated with hip fractures. Irish J Med Sci 158:40–42, 1989. 56. Sutcliffe AJ: Mortality after spinal and general anaesthesia for surgical fixation of hip fractures. Anaesthesia 49:237–240, 1994. 57. Valentin N, Lomholt B, Jensen JS, et al: Spinal or general anaesthesia for surgery of the fractured hip? Br J Anaesth 58:284–291, 1986. 58. McKenzie PJ, Wishart HY, Dewar KM, et al: Comparison of the effects of spinal anaesthesia and general anaesthesia on postoperative oxygenation and perioperative mortality. Br J Anaesth 52:49, 1980. 59. Christopherson R, Beattie C, Frank SM, et al: Perioperative morbidity in patients randomized to epidural or general anesthesia for lower extremity vascular surgery. Anesthesiology 79:422–434, 1993. 60. Bode RH, Lewis KP, Zarich SW: Cardiac outcome after peripheral vascular surgery. Anesthesiology 84:3–13, 1996. 61. Godin MS, Bell WH, Schwedler M, et al: Cost-effectiveness of regional anesthesia in carotid endarterectomy. Am Surg 55:656–659, 1989. 62. Chin SP, Abou Madi MN, Eurin B, et al: Blood loss in total hip replacement: Extradural vs phenoperidine analgesia. Br J Anaesth 54:491– 495, 1982. 63. Moir DD: Blood loss during major vaginal surgery. A statistical study of the influence of general anaesthesia and epidural analgesia. Br J Anaesth 52:1117–1121, 1968. 64. Thorburn J: Subarachnoid blockade and total hip replacement. Effect of ephedrine on intraoperative blood loss. Br J Anaesth 57:290–293, 1985. 65. Sorenson RM, Pace NL: Anesthetic techniques during surgical repairs of femoral neck fractures. A meta analysis. Anesthesiology 77:1095– 1104, 1992. 66. Valley MA, Bourke DL, Hamill MP, et al: Time course of sympathetic blockade during epidural anesthesia: Laser Doppler flowmetry studies of regional skin perfusion. Anesth Analg 76:289–294, 1993. 67. Surgenor DM, Wallace EL, Hao SHS, et al: Collection and transfusion of blood in the United States, 1982–1988. N Engl J Med 322:1646– 1651, 1990. 68. Walker RH: Special report: transfusion risks. Am J Clin Pathol 88:374–378, 1987. 69. Kyriopoulos JE, Michail-Merianou V, Gitona M: Blood transfusion economics in Greece. Transfus Clin Biol 2:387–394, 1995. 70. Goodnough LT, Soegiarso RW, Birkmeyer JD, Welch HG: Economic impact of inappropriate blood transfusions in coronary artery bypass graft surgery. Am J Med 94:509–514, 1993.
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71. Shir Y, Raja S, Frank S, et al: Intraoperative blood loss during radical retropubic prostatectomy: Epidural versus general anesthesia. Urology 45:993–999, 1995. 72. Modig J, Borg T, Karlstrom G, et al: Thromboembolism after total hip replacement: Role of epidural and general anesthesia. Anesth Analg 62:174–180, 1983. 73. Borris LC, Lassen MR: Thromboprophylaxis with low molecular weight heparin after major orthopaedic surgery is cost effective. Drugs 52(Suppl 7):42–46, 1996. 74. Bergqvist D, Matzsch TShir Y: Cost-effectiveness of the prevention of postoperative thromboembolism. Orthopade 22:140–143, 1993. 75. Raja S, Frank S: The effect of epidural versus general anesthesia on postoperative pain and analgesic requirements in patients undergoing radical prostatectomy. Anesthesiology 80:49–56, 1994. 76. Wang JJ, Ho ST, Liu HS, et al: The effect of spinal versus general anesthesia on postoperative pain and analgesic requirements in patients undergoing lower abdominal surgery. Reg Anesth 21:281–286, 1996. 77. Standl T, Eckert S, Schulte J, et al: Postoperative complaints after spinal and thiopentone-isoflurane anaesthesia in patients undergoing orthopaedic surgery. Acta Anaesthesiol Scand 40:222–226, 1996. 78. Hood G, Gerrish SP: Postoperative analgesia after triple nerve block for fractured neck of femur. Anaesthesia 46:138–140, 1991. 79. Benzon HT, Wong HY, Belavic AM, et al: A randomized double-blind comparison of epidural fentanyl infusion versus patient controlled analgesia with morphine for postthoracotomy pain. Anesth Analg 76:316–322, 1992. 80. Negre I, Gueneron JP, Jamali SJ, et al: Preoperative analgesia with epidural morphine. Anesth Analg 79:298–302, 1994.
46
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Chapter 4 - Organization of an Acute Pain Service and Pain Management
Chapter 4 - Organization of an Acute Pain Service and Pain Management GIUSTINO VARRASSI FRANCESCO DONATELLI FRANCO MARINANGELI ANTONELLA PALADINI NARINDER RAWAL
In spite of increasing interest in pain and its management, most patients undergoing surgery do not receive adequate analgesia. Recent surveys show that a large proportion of patients still receive inadequate postsurgical analgesia; this problem is international in character. Analgesia techniques such as patient-controlled analgesia (PCA), spinal opioids alone or in combination with local anesthetics, and other regional analgesic techniques provide superior pain relief compared with intermittent intramuscular (IM) injection of opioids. However, such techniques carry their own risks and, therefore, require special monitoring. The first line of defense against serious complications is an organization that provides appropriate education and policies that permit nurses and physicians to safely care for patients. National guidelines for management of postoperative pain have been published in several countries; however, the impact of these guidelines on patient care is unclear. The available data are not encouraging. In the United Kingdom, 4 to 5 years after publication of professional guidelines, less than half of the hospitals surveyed had implemented a key recommendation to introduce an acute pain service (APS); the principal obstacles were financial constraints and newly qualified doctors who were still undereducated about the management of acute pain. Thus, pain relief remained inadequate. Similar problems have been identified in the United States, in Germany, and in 17 European nations. One of the many reasons for their limited impact is the complexity of the published guidelines. [1]
[2]
[3] [4]
[5]
[6]
The APS, using a multidisciplinary team approach, has received widespread acceptance and formal support from many institutions and organizations such as the United Kingdom Royal Colleges in 1990, the Australian Faculty of Anaesthetists in 1991, the U.S. Acute Pain Management Guideline Panel in 1992, the International Association for Study of Pain in 1992, and the German Society of Anaesthesiologists and Surgeons in 1997. The key recommendations of the United Kingdom Working Party are shown in Table 4-1 . Similar recommendations have been made by other institutions. [7]
[8]
[9]
[10]
[5]
Postoperative Pain Management Postoperative pain can be partially or completely relieved by either or both of the following methods: • Systemic administration of analgesics • Regional analgesia achieved with analgesics or local anesthetics
SYSTEMIC ADMINISTRATION OF ANALGESICS Nonopioid analgesics are an important class of drugs in the management of postoperative pain. A nonsteroidal antiinflammatory drug (NSAID) or acetaminophen as the sole analgesic may be adequate in the treatment of mild postoperative pain, and for moderate to severe
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TABLE 4-1 -- UNITED KINGDOM WORKING PARTY KEY RECOMMENDATIONS 1. Need for education and training in changing antiquated staff attitudes and practice, together with adequate resources. 2. Systematic recording of patients’ pain, as with blood pressure/ heart rate. 3. A named member of staff to be responsible for a hospital policy toward postoperative analgesia, subject to continuous audit and appraisal. 4. All major hospitals performing surgery should introduce an acute pain service using a multi-disciplinary team approach with input of medical, nursing, pharmaceutical and psychological expertise. The anesthetist has a primary role to play. 5. There is a need for powerful, safe analgesics and long-acting nontoxic local anesthetics. Modified from Royal College of Surgeons of England and the College of Anaesthetists Commission on the Provision of Surgical Services. Report of the Working Party on Pain after Surgery. London, September 1990.
pain these drugs can produce significant analgesia to reduce opioid requirements by 20% to 40%.
[11]
This effect is not surprising, because much of the pain is a result of the liberation of algogenic substances whose synthesis is impaired by NSAIDs. These drugs act through a mechanism of cyclooxygenase inhibition, a step in the synthesis of prostaglandins. The decreased concentration of prostaglandins blocks the transduction of the painful stimulus at the levels of the nociceptor, where the tissue injury is converted into an electrical signal. The mechanism of action of acetaminophen is still incompletely understood. There are several hypotheses suggesting a central inhibitory effect on prostaglandin interactions, a central serotoninergic effect, effects on nitric oxide mechanisms, and possible peripheral anti-inflammatory activity. [12] [13] [14] [15] [16]
The use of NSAIDs or acetaminophen as adjunctive therapy to opioid analgesics can significantly potentiate analgesia without increasing opioid-related effects because their mechanisms of action are completely different, and the two types of drugs block transmission of pain at different levels. NSAIDs must be used with caution in patients with a history of renal insufficiency, peptic ulcer, or hepatic disease. The introduction of NSAIDs formulated for parenteral administration (ketorolac) has significantly increased the use of these analgesics in the early perioperative period. Ketorolac is the most commonly used intravenous (IV) NSAID in the management of postoperative pain. It has been demonstrated to produce potent analgesia in adults at doses of 7.5 mg to 30 mg every 6 hours. Higher doses do not provide significantly better analgesia. Older patients and those at risk for NSAID-related complications should be treated with the lowest effective doses (7.5 mg to 15 mg every 6 h). [17]
[18]
When oral administration is possible, it is preferred because it is less expensive but not less effective than IV administration. In this case, the most frequently used NSAID is ibuprofen in doses of 1600 to 3200 mg per 24 hours administered in divided doses every 6 to 8 hours. To enhance the gastrointestinal tolerance of orally administered NSAIDs, these drugs should be taken with food. Acetaminophen is usually administrated at doses of 4 to 6 mg per 24 hours in divided doses. It has been associated with a significant opioid-sparing effect of up to 40%, especially in patients undergoing orthopedic surgery. [19]
In a double-blind study, propacetamol and ketorolac combined with PCA morphine show similar analgesic efficacy after gynecologic surgery. Morphine consumption and pain scores were comparable in both groups of patients. The authors concluded that propacetamol is as effective as ketorolac and has an excellent tolerability after gynecologic surgery. [20]
Contraindications for acetaminophen use are related primarily to hepatotoxicity when used in high doses or in patients with preexisting liver disease and possible nephrotoxicity. Opioid analgesic administration remains the most commonly used method of delivery of postoperative analgesia. The immense popularity and widespread use of these drugs are a result of their ready availability in most countries, their ease of use, their low cost, and, when properly used, their effective relief of pain. Unfortunately, as previously mentioned, these drugs are often improperly used. Consequently, many patients do not derive effective pain relief. The most common errors are routine administration without regard to the intensity of the pain and associated phenomena, the emotional makeup, the physical status, and the age of the patient. These errors occur because of the traditional practice of ordering narcotics pro re nata, without first evaluating the efficacy of the initial dose. Different narcotics in different individuals show a great variability in analgesic efficacy and in side effects. To eliminate variability in the peak plasma concentration and in the time taken to reach this peak, narcotics should be given intravenously rather than intramuscularly. In addition to eliminating the variability of absorption, the IV route has important advantages:
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• Rapid onset of action • Early occurrence of the peak effects, which facilitates the titration • Rapid decline of the blood concentration upon withdrawal of the drug, which limits the occurrence of undesirable effects The most important feature of providing optimal analgesia with systemic opioid analgesics involves the titration of the drug dose to the individual patient’s analgesic requirement. Because individual opioid analgesic dosage needs can vary widely, titration to individual patient requirements is essential. In the immediate postoperative period, opioid analgesia may be initially established through the intermittent IV injection of opioid (2 to 5 mg morphine equivalents) every 10 minutes. In some patients, this initial IV titration may require 15 to 20 mg of morphine equivalents or more to establish analgesia. After this initial IV titration, analgesia is more easily maintained with small, intermittent doses of opioid throughout the postoperative period. Although this technique may provide the best pharmacologic model for titration of opioid dose and analgesic effect, it is labor-intensive, requiring immediate access and administration of opioid analgesic doses on patient demand. The best option for systemic narcotic analgesia is use of a system that permits “on demand” PCA. The patient must be thoroughly informed about the procedure and given instruction in how to use the device. Individual analgesic consumption remains almost constant throughout the PCA period. Most patients establish and maintain a pseudosteady state plasma concentration by triggering new doses as the plasma concentration drops to a critical level of minimum effective analgesic concentration. The safety of PCA, especially in relation to respiratory depression, has been addressed by a number of investigators. serial blood gas analyses showed normal values in patients using PCA. The quality of analgesia In two studies, with PCA has been consistently reported as superior or equal to that attained with use of IM opioids. Less PCA opioid use compared with that of IM control groups is frequently observed, and satisfaction of patients and nurses is high. The principal advantages of PCA to patients are high-quality analgesia, autonomy, elimination of delay in decisions to medicate for pain, and freedom from painful intramuscular medication. It may take less nurse time to provide for the analgesic needs of postoperative patients using PCA. [21] [22]
The prescription of PCA involves physician-determined selection of: • Opioid analgesic • Dose on demand • Lockout interval • A 1-hour (or 4-hour) total dose limit Morphine, meperidine, and hydromorphone are among the most commonly prescribed opioid analgesics for PCA. In a patient with an uncomplicated medical history and no previous history of adverse reaction to opioid administration, there is little evidence to support improved efficacy or reduced side effects of any opioid analgesic over those of morphine. [23]
Several studies have investigated the appropriate PCA dose. A dose of between 1.0 and 2.0 mg of morphine (or morphine equivalents) has generally been found to be the most appropriate starting dose for postoperative pain. The dose should be reassessed with respect to analgesic effect and side effects throughout the first several hours of PCA therapy, and it should be adjusted to patient-specific analgesic requirements. [24]
The lockout interval is the minimum time interval between delivery of successive dose demands. This should be determined according to the time needed to reach peak analgesic effect for the opioid dose. For most opioid analgesics, the peak time is approximately 10 minutes. The 1-hour (or 4-hour) dose limit is a secondary overriding safety parameter that limits the total dose delivered within a specified period of time. The use of postoperative systemic opioid analgesia can range from providing pain relief with only opioid analgesics throughout the entire postoperative period to a combination with other techniques. Such a multimodal approach includes the use of locoregional analgesia and opioid and nonopioid analgesics. The concomitant use of other analgesic techniques that allow reduced dosage and administration of opioid analgesics appears to have significant benefits in terms of reducing postoperative morbidity associated with opioid medication related side effects. A report of adverse drug events leading to increased hospital morbidity rates and lengths of stay identified opioid analgesics as among the most common drugs involved in hospital medical-related complications. [25]
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SPINAL ANALGESIA Spinal analgesia refers to the use of opioids and analgesic concentrations of local anesthetics to produce pain relief by either intrathecal or epidural administration. The epidural route has been used much more extensively for postoperative pain control. Reasons include popularity of the technique along with, or in combination with, light general anesthesia during surgery; willingness to leave an epidural catheter in place for extended periods to maintain analgesia; familiarity with postoperative analgesia using epidural local anesthetics; and freedom from the risk of post-lumbar puncture headache. Spinal opioid analgesia, or selective analgesia, is produced by modulation of nociceptive transmission at the level of the spinal dorsal horn in the absence of sensory, motor, or sympathetic neural blockade. Segmental analgesia is produced by the epidural administration of local anesthetics and opioid analgesics, in that the extent of analgesia spread is related to the spinal segmental level of administration and the volume and concentration of local anesthetic or opioid administered. Spinal anesthesia used for surgery produces positive respiratory, cardiovascular, and neuroendocrine effects; reduced thromboembolic complications and blood loss; and reduced convalescence. These observations have been extended to postoperative pain management. Patients receiving postoperative epidural morphine have reported superior analgesia, earlier ambulation, fewer pulmonary complications, earlier return of bowel function, and earlier discharge from the hospital than patients receiving IM morphine. In another study, patients were randomized in two groups: The first received general anesthesia and IV opioids for postoperative pain management, and the second group received combined general/epidural anesthesia and epidural opioids for postoperative pain. Mortality rate, overall complication rate, infection rate, time to extubation, and hospital costs were significantly lower in the epidural group. [26]
[27]
Preservative-free morphine was the first opioid to gain approval by the U.S. Food and Drug Administration (FDA) for epidural and intrathecal use. Its duration of action is longer than that of other opioid analgesics as a result of its hydrophilic physiochemical properties. Although experience with morphine has primarily involved intermittent injection, it has been used with success as a continuous infusion. Effective doses may range from less than 0.1 to 1.5 mg per hour. Its early use in relatively large doses was associated with reports of cases of severe and delayed respiratory depression, and this led to exploration of the use of less hydrophilic opioid analgesics, including meperidine, fentanyl, and sufentanil. A lipophilic drug such as fentanyl is useful when rapid onset of epidural analgesia is important. Intermittent epidural boluses of 50 to 75 µg can be used to promptly achieve analgesia in the immediate postoperative period if the initial epidural morphine dose is not adequate. Used as the sole opioid, a 25- to 100-µg epidural bolus can be followed by a continuous infusion of 25 to 100 µg per hour with an accurately calibrated pump. As with other opioids, respiratory depression can occur. Until it is possible to identify and eliminate the factors that occasionally lead to severe respiratory depression in patients receiving intraspinal opioids, it must be assumed that all patients offered these techniques are at risk. To prevent serious injury or death, there is no substitute for a high level of vigilance. A nurse trained to check at frequent intervals the rate and depth of respiration as well as the general status and level of consciousness may provide this level of care. Respiratory rate alone is not an adequate indicator of ventilatory status in postoperative patients receiving epidural opioids. A more global assessment is necessary, particularly during the first 24 hours of treatment. This evaluation should include assessment of the level of consciousness, because increasing sedation (presumably due to central drug effect and CO2 narcosis) has been noted with advanced respiratory depression. [28]
For maximal analgesic effect with minimal drug injection, the epidural catheter should be placed at a spinal cord level corresponding to the dermatomal distribution of the surgical pain stimulus. With the epidural catheter advanced 3 cm to 5 cm beyond the needle tip into the epidural space, the corresponding vertebral levels for optimal epidural catheter placement for various surgical procedures are as follows: • C7–T2 for upper extremity surgery • T4–8 for thoracic surgery • T8–10 for upper abdominal surgery • T10–12 for lower abdominal and pelvic surgery
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• L2–4 for lower extremity surgery As previously stated, the combination of epidurally administered analgesic concentration of local anesthetics and opioid analgesics can be expected to produce the greatest balance of analgesia as well as the fewest postoperative side effects after numerous major surgical procedures. Bupivacaine, in analgesic concentrations up to 0.25%, is the most commonly used local anesthetic agent. Infusions of bupivacaine concentrated greater than 0.125% via lumbar epidural catheter are frequently associated with lower extremity motor blockade. [29]
There is considerable interest in combining the potent analgesic effects of drugs delivered into the epidural space with the pharmacologic and nonpharmacologic advantages of patient participation associated with the PCA concept. All the commonly used opioid analgesics have been used for patient-controlled epidural analgesia (PCEA) alone or in combination with bupivacaine. Some favor the use of the more lipophilic opioid analgesics for PCEA because of the more rapid onset of effect. [30] [31]
Role of the Acute Pain Nurse As a result of advances in pain management techniques and technology, anesthesiologists are now offering patients new and highly effective forms of postoperative analgesia. However, it is the responsibility of trained bedside nurses to deliver these analgesic therapies and to monitor and treat associated adverse effects. Because anesthesiologists generally have limited understanding of ward policies, an acute pain nurse (APN) can serve as an important link between anesthesiologists and bedside nurses. Increasingly, specialist nurses with particular training in pain management are being appointed, frequently as part of an acute pain team or pain management service. They make an invaluable contribution to patient care, bridging the gap between doctors and nurses and their areas of knowledge and responsibility. They can help to direct resources, educate nurses and doctors in pain management techniques, give necessary support to the primary nurse, and help to initiate and supervise analgesia. Some APNs are nurse anesthetists with special training in pain management ( Table 4–2 ).
THE NURSE’S ROLE IN PATIENT EDUCATION Nurses are in a unique position to help patients in pain, because they spend more time with patients than any other health team member does. As new techniques of pain management are developed, nurses must update their knowledge to provide safe and effective care. Many nurses who are already overwhelmed with new techniques and equipment may react with skepticism and resistance to changes in the traditional approaches to pain management. Even if the changes will eventually save nursing time, new techniques or pieces of equipment, such as epidural anesthesia and
TABLE 4-2 -- ORGANIZATION OF ACUTE PAIN SERVICES AT ÖREBRO MEDICAL CENTER HOSPITAL, ÖREBRO, SWEDEN Health Care Member “Pain Representatives”
Responsibility
• Acute pain anesthesiologist
Responsible for coordinating hospital- wide acute pain services and in- service teaching
• Section anesthesiologist
Responsible for pre-, peri- and postoperative care (including postoperative pain) for his/her surgical section
• “Pain representative” ward surgeon
Formally responsible for pain management for his/her surgical ward.
• “Pain representative” day nurse
Responsible for implementation of pain management guidelines and monitoring routines on the ward *
• “Pain representative” night nurse • Acute pain nurse (nurse anesthetist)
• Daily rounds of all surgical wards • Check visual analogue scale (VAS) recording on charts (every patient VAS≤3) • “Trouble-shoot” technical problems (PCA, epidural) • Refer problem patients to section anesthesiologist (link between surgical ward and anesthesiologist) • Daily “bedside” teaching of ward nurses
This organization benefits about 20,000 patients a year (VAS≤3) and has been functioning satisfactorily since 1991. Cost per patient is U.S. $2 to
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TABLE 4-2 -- ORGANIZATION OF ACUTE PAIN SERVICES AT ÖREBRO MEDICAL CENTER HOSPITAL, ÖREBRO, SWEDEN Health Care Member “Pain Representatives”
Responsibility
$3 (excluding drug and equipment costs). * Patients are treated on the basis of standard orders and protocols devel oped jointly by chiefs of anesthesiology, surgery, and nursing sections. Pain representatives meet every 3 months to discuss and implement improvements in surgical ward pain management routines.
PCA, are stressful for the staff nurses until they become familiar with them. Background knowledge, skills, and experience of nursing staff influence pain management. Many responsibilities for pain management rest with the nurse who cares directly for the patient; however, many nurses have, in fact, had little formal education on the subject of pain management. The nurse on the ward must be informed of the requirements of an analgesic technique and confident about putting them into practice. This proficiency can be achieved through education and experience in a supportive environment. Protocols should be constructed in conjunction with nursing colleagues and modified as necessary to allow for local nursing practices. Nursing education is widely recognized as an important priority in pain management. Postgraduate training courses on pain management for practicing nurses are increasingly available, and education on pain management is becoming more prominent in basic nursing training. Educational devices such as algorithms to guide analgesic administration can lead to substantial improvements in quality of pain relief. The attitude of the staff toward pain management has an important influence on the effectiveness of pain relief. The APS is best served by developing a small range of standard analgesic techniques to achieve a common level of understanding, familiarity, and confidence. [1]
[2]
Patients are unlikely to be aware of the standard of care they can expect to receive or what they can demand, and their attitudes toward pain and analgesia are believed to influence strongly the effectiveness of their pain relief. Inadequate patient education is associated with a low standard of postoperative pain relief. Patient education is particularly important when drugs are administered by techniques such as PCA. [32]
It is essential that pain be made visible. Pain should be routinely documented in the patient’s notes in a manner similar to that used to record blood pressure and heart rate. This process should be simple and convenient for nursing and medical staff. Documentation also provides data for audit and facilitates review and improvement of care.
AUDIT OF THE ACUTE PAIN SERVICE An audit should be carried out regularly with regard to the process of pain management, patient experience, and cost; the service should be modified according to the outcome. It is essential that pain be regularly evaluated to ensure that it is effectively managed. The minimum standard should be at least an annual determination of the number of patients whose pain scores were above the predetermined threshold, and the reasons for the elevated scores should be identified. The audit method should be developed to meet local conditions. The outcome of an audit should be reviewed regularly, and the service should be modified to rectify any shortfalls identified. Adverse effects of treatment should also be assessed and documented, and the dose or dose interval should be adjusted accordingly.
ACUTE PAIN SERVICE IN THE UNITED STATES Although the concept of the APS was first introduced in Europe, the APS seems to be better established in the United States. Most major institutions in the United States have an anesthesiology-based APS. The comprehensive pain management teams usually consist of staff and resident anesthesiologists, specially trained nurses, pharmacists, and physiotherapists. Sometimes, biomedical and infusion pump dispensing personnel are included. Secretarial and billing personnel are also a part of the APS in the United States. Patients under the care of an APS are visited and assessed regularly by members of the team. Although pain management is often very satisfactory, the economic costs of such [33]
[34]
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services are high; therefore, the benefits are not available to all surgical patients because of reimbursement regulations. Anesthesiologist-based APS organization models usually provide high technology pain management services. This approach is not surprising because anesthesiologists have special expertise in the field of advanced analgesic techniques such as epidural anesthesia and PCA. Therefore, most APSs in the United States are essentially PCA and epidural services. Although the implementation of an anesthesiologist-based APS has had a considerable impact on pain management on surgical wards, only a small percentage of patients receive the benefits of an APS. A good APS organization is one that ensures optimal pain management for every patient who undergoes surgery, including children and those undergoing surgery on an ambulatory basis. Furthermore, the record of the U.S. APS in implementing hospital-wide quality assurance measures such as frequent recording of pain intensity and recording of treatment efficacy (visual analogue scale [VAS] before and after treatment) has been generally unimpressive so far. Additionally, the costs of a U.S. APS are very high. It is not surprising that such costs are being increasingly questioned by healthcare payers. Downsizing of many APSs is taking place in the United States; further reductions are predicted by many. The fee-for-service reimbursement system seems to be reversing the gains made by the introduction of the APS. A more important issue with U.S. anesthesiologist-based APS is a lack of continuity, because the anesthesiologist performing the preoperative evaluation (which includes patient information about the proposed postoperative analgesic technique) and epidural block (operating room anesthesiologist) is not the same physician who provides pain management postoperatively (APS anesthesiologist). The role of an anesthesiologist in any APS model is pivotal. However, in my opinion, such a role is professionally more satisfying as a teacher, supervisor, pain expert, and performer of regional blocks in a APN-based anesthesiologist-supervised model.
DEVELOPMENT OF AN ACUTE PAIN NURSE SERVICE It is becoming increasingly clear that simpler and less expensive models must be developed if the aim is to improve the quality of postoperative analgesia for every patient who undergoes surgery. The organization should also include patients who undergo outpatient surgery. Furthermore, in countries with state-financed health services and budgetary restraints, the overstaffed U.S.-style anesthesiology-based comprehensive, multidisciplinary, postoperative pain control teams appear unrealistic for most institutions. At Örebro Medical Center Hospital, our pain nurse-based, anesthesiologist-supervised model is based on the concept that postoperative pain relief can be greatly improved by provision of inservice training for surgical nursing staff, optimal use of systemic opioids, and the use of regional analgesia techniques and PCA in selected patients. Regular recording of each patient’s pain intensity by VAS every 3 hours and recording of treatment efficacy on the vital signs chart form the cornerstone of this model. A VAS higher than 3 is promptly treated. Participation by the surgeon and ward nurse is crucial in this organization. A specially trained APN makes daily rounds of all surgery departments. The APN’s duties are described in Table 4–2 . In this organization, the treatment of individual patients is based on standard orders and protocols developed jointly by the section anesthesiologist, the surgeon, and the ward nurse. This approach gives nurses the flexibility to administer analgesics when necessary. The section anesthesiologist has the overall responsibility for preoperative, perioperative, and postoperative anesthesia care of these patients; this responsibility includes postoperative pain management. The anesthesiologist selects the patients for special pain therapies, such as PCA and epidural or peripheral nerve blocks, based on departmental policy. During regular working hours, this anesthesiologist is available for consultation or any emergency; during other shifts, the anesthesiologist on call has the same function. The “pain representatives” from each surgical ward meet four times a year under anesthesiologist and APN supervision to discuss improvements in APS. In the organization described here, the only additional cost is that of the APN. At our hospital, where about 18,000 to 20,000 surgical procedures are performed each year, our low-cost ($2 to $3 per patient excluding drug and equipment costs) organization is designed to benefit all these patients. This organization has been functioning satisfactorily since 1991; it can easily be modified for nonsurgical wards. The safety of newer techniques such as PCA, peripheral nerve blocks, and epidural analgesia on surgical wards is dependent on nurse and physician education. An independent audit in 1996 showed that 95% of the surgical patients were satisfied with their postoperative pain management. [35]
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Challenges for the Future The need for multidisciplinary APS teams involving anesthesiologists, surgeons, nurses, and other staff to optimize postoperative pain management is not in doubt. An APS addresses important issues such as improvement in quality of analgesia and efficacy and safety of (current and future) analgesic techniques. Any future APS organization will have to include the following: Regular pain assessment and documentation (“make pain visible”); outpatients and children; active cooperation with surgeons and ward nurses for development of protocols; and bedside teaching of ward nurses for provision of safe and cost-effective analgesic techniques such as PCA and epidural and peripheral nerve blocks. These components are relatively noncontroversial; the challenge is to incorporate them in an APS model that exploits the full potential of invasive and expensive techniques such as epidermal anesthesia for aggressive postoperative patient mobilization, which can be expected to improve outcome. The current system of acute pain management often does not integrate pain management with the overall perioperative care and postoperative rehabilitation of the patient. The role of cooperation and a team approach featuring interaction among anesthesiologists, APNs, surgeons, ward nurses, and physiotherapists will become increasingly important. The role of a good APS in developing cost-effective pain treatment strategies for different surgical procedures cannot be overemphasized. A designated staff member should be responsible for implementing pain management policies in each unit. Patients should be fully informed preoperatively about the range of treatments available and their adverse effects. Patients undergoing outpatient surgery should have their pain assessed and documented in the same way as inpatients. Outpatients should be given a contact number so that they can discuss their pain relief needs after discharge and review written information about the use of analgesics.
Summary In spite of unprecedented interest in understanding pain mechanisms and pain management, a significant number of patients continue to experience unacceptable levels of pain after surgery. Surveys show that there has been no apparent improvement since the first study in 1952. It is increasingly clear that the solution to the problems of postoperative pain management will be found not so much in the development of new techniques but in the development of an organization to exploit existing expertise. [36]
The most obvious members of an acute pain team are anesthesiologists, surgeons, nurses, and physiotherapists. Protocols encourage consistent standards of safe and effective care and should be used as a framework to individualize treatment. The concept of skilled pain therapists collaborating to provide improved postoperative analgesia within the framework of an organized APS appears to be universally applicable. APS models have been described from the United States, the United Kingdom, Germany, Switzerland, and Sweden. The U.S. model, which consists of anesthesiologist-based comprehensive pain management teams, is quite effective but too selective and too expensive. It is not transferable to Europe. A recent U.K. survey showed that there is a large degree of variation in what is thought to constitute an APS in the United Kingdom. A nurse-based, anesthesiologist-supervised APS in which pain is evaluated in every patient who undergoes surgery has been developed in Sweden. Pain higher than 3 on the 10-grade VAS is promptly treated. Clearly, neither the anesthesiologist nor the APN guarantees good pain management on wards; the quality of ward nursing is most important. In this low-cost model, the anesthesiologist’s role is teaching and training ward nurses, supervising the APN, and selecting patients for special pain therapies such as PCA and epidural and peripheral nerve blocks. All senior anesthesiologists (section chiefs) working in the operating room are part of this APS. [37]
The means of providing satisfactory analgesia are already present in most hospitals. Careful planning and a multidisciplinary approach to pain management will ensure that resources are optimally used and that the quality of pain management is consistently maintained. REFERENCES 1. Gould TH, Crosby DL, Harmer M, et al: Policy for controlling pain after surgery: Effect of sequential changes in management. BMJ 305:1165– 1166, 1992. 2. Oats
JDL, Snowman SL, Jason DWH: Failure of pain relief after surgery. Attitudes of ward staff and patients to postoperative analgesia. Anesthesia 49:755–758, 1994.
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3. Warbled
CA, Kahn CH: Acute pain management. Programs in US hospitals and experiences and attitudes among US adults. Anesthesiology 83:1090–1094, 1995.
4. Tittle M, McMillan SC: Pain and pain-related side effects in an ICU and on a surgical unit: Nurses’ management. Am J Crit Care 3:25–30, 1994. 5. Ulf
H, Neugebauer E, Maier C: Die Behandlung akuter perioperativer und posttraumatischer Schmerzen. Empfehlungen einer interdisziplinaeren Expertenkommission. Stuttgart, G. Thieme, 1997.
6. Rawal
N, Allvin R, EuroPain Acute Pain Working Party: Acute pain services in Europe: A 17-nation survey of 105 hospitals. Eur J Anaesth 15:354–363, 1998.
7. Royal
College of Surgeons of England and the College of Anaesthetists Commission on the Provision of Surgical Services: Report of the Working Party on Pain after Surgery. London, September 1990.
8. National
Health and Medical Research Council (Australia): Management of Severe Pain. Canberra, Australia, NHMRC, 1988.
9. U.S.
Department of Health and Human Services: Acute Pain Management. Clinical Practice Guidelines. AHCPR Publications No 92-0032. Washington, DC, U.S. Department of Health and Human Services, 1992.
10. International
Association for the Study of Pain (IASP): Management of Acute Pain. A Practical Guide. Task Force on Acute Pain. Seattle, IASP Publications, 1992.
11. Joris
J: Efficacy of nonsteroidal anti-inflammatory drugs in postoperative pain. Acta Anaesthesiol Belg 47:115–123, 1996.
12. Piguet
V, Desmeules J, Dayer P: Lack of acetaminophen ceiling effect on R-III nociceptive flexion reflex. Eur J Clin Pharmacol 53:321–324,
1998. 13. Pelissier
T, Alloui A, Caussade F: Paracetamol exerts a spinal antinociceptive effect involving an indirect interaction with 5hydroxytryptamine-3 receptors: In vivo and in vitro evidence. J Pharmacol Exp Ther 278:8–14, 1996.
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Raffa RB, Codd EE: Lack of binding of acetaminophen to 5-HT receptor or uptake sites. Life Sci 59:L37–L40, 1996.
15. Bjorkman R: Central antinociceptive effects of non-steroidal antiinflammatory drugs and paracetamol: Experimental studies in the rat. Acta Anaesthesiol Scand 103(Suppl):1–144, 1995. 16. Honer P, Buritova, J Besson JM: Aspirin and acetaminophen reduced both Fos expression in rat lumbar spinal cord and inflammatory sign produced by carrageenan inflammation. Pain 63:365–375, 1995. 17. Mather LE: Do the pharmacodynamics of the nonsteroidal antiinflammatory drugs suggest a role in the management of postoperative pain? Drugs 44(Suppl 5):1–12, 1998. 18. Reuben SS, Connelly NR, Lurie S, et al: Dose-response of ketorolac as an adjunct to patient controlled analgesia morphine in patients after spinal fusion surgery. Anesth Analg 87:98–102, 1998. 19. Peduto VA, Ballabio M, Stefanini S: Efficacy of propacetamol in the treatment of postoperative pain: Morphine-sparing effect in orthopedic surgery. Italian Collaborative Group on Propacetamol. Acta Anaesthesiol Scand 42:293–298, 1998. 20. Varrassi G, Marinangeli F, Agro F, et al: A double blind evaluation of propacetamol versus ketorolac in combination with patient controlled analgesia morphine: Analgesic efficacy and tolerability after gynecologic surgery. Anesth Analg 88:611–616, 1999. 21. White WD, Pearce DJ, Norman J: Postoperative analgesia: A comparison of intravenous on-demand fentanyl with epidural bupivacaine. BMJ 2:166, 1979. 22. Tamsen A, Hartvig P, Fagerlund C: Patient-controlled analgesic therapy: Clinical experience. Acta Anaesthesiol Scand 26(suppl 74):157, 1982. 23. Plummer JL, Owen H, Ilsley AH, et al: Morphine patient-controlled analgesia is superior to meperidine patient-controlled analgesia for postoperative pain. Anesth Analg 84:794-799, 1997. 24. Owen H, Plummer JL, Armstrong I, et al: Variables of patient-controlled analgesia: 1. Bolus size. Anaesthesia 44:7–10, 1989. 25. Classen DC, Pestotnik SL, Evans RS, et al: Adverse drug events in hospitalized patients: Excess length of stay, extra costs, and attributable mortality. JAMA 277:301–306, 1997. 26. Rawal N, Sjostrand U, Christofferson E, et al: Comparison of intramuscular and epidural morphine for postoperative analgesia in the grossly obese: Influence on postoperative ambulation and pulmonary function. Anesth Analg 63:583, 1984. 27. Yeager MP, Glass DD, Neff RK, et al: Epidural anesthesia and analgesia in high risk surgical patients. Anesthesiology 66:729, 1987. 28. Rawal N, Wattwil M: Respiratory depression after epidural morphine—an experimental and clinical study. Anesth Analg 63:8, 1984. 29. Liu SS, Carpenter RL, Mackey DC, et al: Effects of perioperative analgesic technique on rate of recovery after colon surgery. Anesthesiology
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83:757–765, 1995. 30. Veercauteren MP, Van Den Bergh L, Kartawiadi SL, et al: Addition of bupivacaine to sufentanil in patient-controlled analgesia after lower limb surgery in young adults. Reg Anesth Pain Med 23:182–188, 1998. 31. Liu SS, Allen HW, Olsson GL: Patient-controlled epidural analgesia with bupivacaine and fentanyl on hospital wards: Prospective experience with 1,030 surgical patients. Anesthesiology 88:124–129, 1998. 32. Kuhn S, Cooke K, Collins M, et al: Perceptions of pain relief after surgery. BMJ:300:1687–1690, 1990. 33. Maier C, Kibbel K, Mercker S, Wulf H: Postoperative pain therapy at general nursing stations. An analysis of eight year’s experience at an anesthesiological acute pain service. Anaesthesist:43:385–397, 1994. 34. Ready LB: How many acute pain services are there in the US and who is managing patient-controlled analgesia? (Letter) Anesthesiology:82:322, 1995. 35. Rawal N, Berggren L: Organization of acute pain services—a low cost model. Pain:57:117–123, 1994. 36. Papper EM, Brodie BB, Rovenstine EA: Postoperative pain, its use in the comparative evaluation of analgesics. Surgery 32:107–109, 1952. 37. Windsor AM, Glynn CJ, Mason DG: National provision of acute pain services. Anaesthesia:51:228–231, 1996.
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Chapter 5 - Organization of Chronic Pain Services RICARDO RUIZ-LÓPEZ DIEGO BELTRUTTI
Since the initial organization of pain centers carried out in the 1960s by J. J. Bonica in the United States, S. Lipton in the United Kingdom, and a few other specialists in Western countries, the enormous necessity of this type of health service has become clear, along with the difficulty of its comprehensive organizational approach in order to be effective for the diagnosis and therapy of this patient population. [1] [2] [3] [4]
The foundation in 1974 of the International Association for the Study of Pain (IASP) strengthened the development of pain facilities in the United States and around the world. Consequently, in response to the proliferation of pain centers during the last 2 decades, various medical associations have defined and classified the types of such facilities. [5] [6] [7]
According to the scope of the therapeutic approach, pain centers can be classified into three models: 1. 2. 3.
Pain centers following the medical model, in which pain is treated as a symptom of a disease to be diagnosed Pain centers working with the behavioral model, in which pain behavior and associated impaired function are considered as important as the underlying pathophysiology Pain centers with a predominant focus on the cognitive-behavioral model, in which patients are considered to develop aberrant convictions in regard to their functional capacities and prognoses [8]
Today, particularly in Europe and Australasia, chronic pain conditions are treated by a combination of intervention and the behavioral-rehabilitation model, as reports of the efficacy of cognitive-behavioral programs for the treatment of chronic pain conditions have shown variable outcomes in comparison with the selection criteria of interventional approaches, which are better defined. [9] [10] [11] [12] [13]
In the United States, all three models have been established during the past three decades, although recent changes introduced in managed healthcare have modified in many cases the approach of preexisting pain facilities. This chapter will cover the following topics: • Pain treatment facilities • Pain medicine as a new specialty • Administrative issues Appendixes with related recommendations can be found at the end of the chapter.
Pain Treatment Facilities Pain treatment facilities were established to treat chronic, refractory pain related to conventional medical, surgical, and rehabilitative modalities. Multidisciplinary pain centers were developed to treat specifically a group of patients mainly suffering from chronic back pain that did not improve with conventional treatment, causing them to remain disabled. These patients showed, in addition to the existence of chronic pain, behavioral and psychosocial impairment that required the intervention of a multidisciplinary team approach that would deal with the patient’s problem simultaneously. Regardless of the therapeutic approach, the lack of regulation of pain centers and the various clinical structures that used the term indiscriminately forced the American Society of Anesthesiology (ASA) and the IASP to classify the different pain facilities according to their professional composition, modalities of treatment, organization, pain conditions being treated, clinical or basic research, and teaching potential. Thus, the ASA classifies pain centers into four types : [6]
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Major comprehensive pain centers Comprehensive pain centers Modality-oriented pain clinics Syndrome-oriented pain clinics
Overall, it is important to note that the function and organization of these pain centers rely greatly on the training, beliefs, expertise, and specialty of the director; the composition of the staff; and the type of institution. [1]
The variation in staff makeup and available therapeutic modalities has caused both physicians and the public to have misinformation about differences among the pain syndromes and the types of pain centers or clinics. Another step in the process of defining chronic pain services was reached by the Commission on Accreditation of Rehabilitation Facilities (CARF) with the establishment of a certification process for pain clinics for one type of treatment model (i.e., chronic pain management programs). [10] [14]
Because of this lack of definition, the IASP established guidelines and characteristics for four types of pain treatment facilities ( Table 5-1 , Appendix 5-1 ). [15]
This classification makes a clear distinction between the multidisciplinary pain centers and clinics (MPC) and those facilities without multidisciplinary orientation. The only difference between the multidisciplinary pain centers and multidisciplinary pain clinics is that the former have to develop research and teaching activities. Nevertheless, both types of centers must provide inpatient and outpatient treatment, and the teams must contain diversified staff members, including more than one physician specialty and a psychologist or psychiatrist.
TABLE 5-1 -- INTERNATIONAL ASSOCIATION FOR THE STUDY OF PAIN CLASSIFICATION OF PAIN FACILITIES Modality-oriented clinic Provides specific type of treatment (e.g., nerve blocks, transcutaneous nerve stimulation, acupuncture, biofeedback) May have one or more healthcare disciplines Does not provide an integrated, comprehensive approach Pain clinic Focuses on the diagnosis and management of patients with chronic pain or may specialize in specific diagnoses or pain related to a specific region of the body Does not provide comprehensive assessment or treatment Institution offering appropriate consultative and therapeutic services would qualify but never an isolated solo practitioner. Multidisciplinary pain clinic Specializes in the multidisciplinary diagnosis and management of patients with chronic pain or may specialize in specific diagnoses or pain related to a specific region of the body Staffed by physicians of different specialties and other healthcare providers Differs from a multidisciplinary pain center only because it does not include research and teaching Multidisciplinary pain center Organization of healthcare professionals and basic scientists that includes research, teaching, and patient care in acute and chronic pain Typically a component of a medical school or a teaching hospital Clinical programs supervised by an appropriately trained and licensed director Staffed by a minimum of physician, psychologist, occupational therapist, physical therapist, and registered nurse Services provide integrated care based on interdisciplinary assessment and management Offers both inpatient and outpatient programs Adapted from Loeser JD: Desirable characteristics for pain treatment facilities: Report of the IASP taskforce. In Bond MR, Charlton JE, Woof CJ (eds): Pain Research and Clinical Management, vol. 4. 1991, pp. 411–415.
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Pain Medicine: A New Specialty Scientific inquiry into the anatomy and physiology of pain perception increased, and with the discovery of opiate receptors in animal and human tissues, the actions of peptides on endogenous opioid receptors, the development of new therapies for the alleviation of pain, and the classification and description of chronic pain syndromes, some essential pieces were added that support modern pain therapy. [16] [17] [18]
The emerging specialty of pain medicine has been increasingly recognized over the last 2 decades by medical organizations, regulatory agencies, and third-party payers. This specialty is formed by a distinct and unique body of knowledge and a defined clinical application that supports a clinical practice. Moreover, pain medicine has fostered growth of scholarly knowledge and research and fills a recognized gap in health professional training ( Table 5-2 ). In its official policy statement, the American Academy of Pain Medicine (AAPM) defines pain medicine as follows:
The specialty of pain medicine is concerned with the prevention, evaluation, diagnosis, treatment, and rehabilitation of painful disorders. Such disorders may have pain and associated symptoms arising from a discrete cause, such as postoperative pain or pain associated with a malignancy, or may be syndromes in which pain constitutes the primary problem, such as neuropathic pains or headaches. The diagnosis of painful syndromes relies on interpretation of historical data; review of previous laboratory, imaging, and electro-diagnostic studies; behavioral, social, occupational, and avocational assessment; interview and examination by the pain specialist; and may require specialized diagnostic procedures, including central and peripheral neural blockade or monitored drug infusions. The special needs of the pediatric and geriatric populations are considered when formulating a comprehensive treatment plan for these patients. The pain physician serves as a consultant to other physicians, but is often the principal treating physician and may provide care at various levels, such as direct treatment, prescribing medication, prescribing rehabilitative services, performing pain-relieving procedures, counseling of patients and families, (directing a) multidisciplinary team, (coordinating) care with other healthcare providers, and (providing) consultative services to public and private agencies pursuant to optimal healthcare delivery to the patient suffering from a painful disorder. The pain physician may work in a variety of settings and is competent to treat the entire range of painful disorders encountered in the delivery of quality healthcare.
However, the official establishment of pain medicine as a medical specialty needs a process of accreditation that could be obtained, as in other specialties, through any of several, well-defined medical boards. Until now, in the United States only one medical association—the American Board of Pain Medicine
TABLE 5-2 -- PAIN MEDICINE: OPERATIONAL CRITERIA A distinct and unique body of knowledge as evidenced by texts and journals; clinical applicability sufficient to support a clinical practice Ability to generate scholarly knowledge and support research Ability to meet numerical standards for training programs, trainees, and practicing diplomats De facto recognition as clear subject area by governmental bodies (e.g., NIH, NCI, AHCPR) and nongovernmental organizations (e.g., WHO, IASP, AAPM, APS, WIP) Fills a recognized gap in health professional training Adapted from Carr DB, Aronoff GM: The future of pain management. In Aronoff GM (ed): Evaluation and Treatment of Chronic Pain, 3rd ed. Baltimore, Williams & Wilkins, 1998. AAPM, American Academy of Pain Medicine; AHCPR, Agency for Health Care Policy; APS, acute pain service; IASP, International Association for the Study of Pain; NCI, National Cancer Institute; NIH, National Institutes of Health; WIP, World Institute of Pain, WHO, World Health Organization.
(ABPM), recognized by the American Medical Association—offers training and accreditation in pain medicine
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through rigorous procedures. The ABPM has been granted full recognition in California by the American Board of Medical Specialties. In Europe, the situation differs because there is no medical association that links the numerous countries through the territory, and the lack of homogeneous legislation represents a practical barrier for the recognition of any new medical specialty. Only a few exceptions to this situation exist, such as in Turkey, where there has been official recognition of treatment of pain as a medical specialty since 1993, with specific resources for training, research, education, and clinical practice throughout the country. In the rest of the world, academic regulatory obstacles and paucity of resources limit the process of accreditation and the recognition of this specialty. In an effort to strengthen a world initiative in the process of education and training of physicians interested or involved in pain medicine, the World Institute of Pain (WIP), an international association of pain centers founded in 1994, defines different goals that meet a common interest for pain physicians: 1. 2. 3. 4. 5. 6. 7.
Educate and train personnel of member pain centers, including local hands-on training, international seminars, and exchange of clinicians. Update pain centers with state of the art pain information, including a newsletter, scientific seminars, interlinked telecommunications, and publication of a journal and books. Develop common protocols for efficacy and outcome studies. Communicate administrative and patient-related matters on a regular basis by way of a newsletter, a telephone hookup, a world directory of pain centers (region by region), and video conferencing (including patient consultation). Categorize and credential pain centers by mail correspondence, local information, and the industry’s medical representatives. Develop an examination process for pain centers to test trainees and provide information about the examination process. Encourage interested industrial parties to provide information on pain medicine to each region of the world; bring local pain physicians into contact with industry for education about new techniques and training in their use; and formulate a fellowship training program.
Despite the fact that pain clinicians are treating chronic pain on a daily basis, education on pain is absent at the various levels of the medical career, whether at medical schools or at postgraduate levels. Formal education and training are essential so that fellowship programs can be set up to precede the establishment of full residency programs in pain medicine. Residency programs should include specific training in the different areas involved in the field, including surgical training for interventional procedures and education in the important fields related to management of chronic pain and cancer pain, such as psychology, oncology, and symptomatic relief. Many issues and questions remain to be answered or resolved by the scientific community. These include but are not limited to such areas as the epidemiologic figures on chronic pain, whether associated with disability or not; the existence of pain in degenerative syndromes and in advanced incurable diseases; the predisposing factors for suffering pain; the neuromatrix of pain transmission and modulation; the role of the autonomic nervous system in the neurophysiology of pain; the development of more selective drugs for central and peripheral nervous system action; the role of affectivity and the psychological processes that are involved in the perception of pain and suffering; the development of more selective and minimally invasive techniques for pain control; the improvement in understanding the maturation and aging of the nervous system; and the measurement, assessment, and validation of pain. Finally, some attention is due to the administrative issues burdening the clinical practice of pain medicine, because many difficulties have appeared that complement the above-mentioned situations.
Administrative Issues The increasing public demand on healthcare services is rapidly changing the shape and characteristics of pain facilities, much as in other medical specialties in which providers of healthcare services are at the crossroads between pressure exerted by consumers and the managed care rules. [19]
Patients have acquired an enormous amount of information through the media; specifically, the Internet is becoming the most popular means of information gathering. In addition, the public has a growing skepticism about the
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traditional sources of medical information. Chronic pain patients are a very vulnerable population with a large percentage of malpractice victims. Many of them in desperation look for relief by trying pseudoscientific approaches, typically by self-referral. In that scenario, demystification of medicine through health education that provides accurate information to patients and families is a principal goal of the pain physician. The lack of understanding by the patient of the diagnostic evaluation, treatment modalities, and prognosis contributes to confusion among patients and health providers. Healthcare systems have finite resources; that is, the innovations in pain management are viewed quite favorably by insurers and policy makers who see potential cost savings in a patient’s rapid return to normal function after surgery or in home care rather than hospital care for a patient with a chronic or terminal illness. [20]
Several Western countries, including the United Kingdom, Canada, and Australia, require economic justification for approval of any new drug, and there is an increasing trend to apply these criteria to clinical trials by means of cost analyses through diverse perspectives. Extrapolating this concept to the area of pain management, studies should be developed in terms of cost-benefit analysis of therapies and their cost-effectiveness and cost of use, in which benefit is defined in terms of quality of life. [21] [22]
However, findings that can be applied to many medical disciplines in regard to managed care seem to be distorted in the environment of patients with chronic and complex illnesses. These persons often require advanced comprehensive care services, well beyond what the primary care physician can generally provide. Such patients often require well-trained subspecialists or referral to complex comprehensive systems of care. The cost of such services is often far beyond the customary cost, and only by assuming the challenge of normalization and accreditation of health services can pain medicine survive. [23] [24]
Pain physicians must be aware that there is a need for moving away from treatment algorithms to a strategy based on levels of care. REFERENCES 1. Bonica JJ: Evolution of pain programs. In GM Aronoff (ed): Pain Centers: A Revolution in Health Care. New York, Raven Press, 1988, pp 9– 32. 2. Crue BL, Pinsky JJ: Chronic pain syndrome: Four aspects of the problem. In Ng LKY (ed): New Approaches to the Treatment of Chronic Pain: A Review of Multidisciplinary Pain Clinics and Pain Centers. Rockville, Md: National Institutes of Drug Abuse, 1981, pp 137–168. 3. Seres
JL, Newman RI: Results of treatment of chronic low-back pain at the Portland Pain Center. J Neurosurg 45:32–36, 1976.
4. Rosomoff
HL, Rosomoff RS: Comprehensive multidsciplinary pain center approach of the treatment of low back pain. Neurosurg Clin North Am 2:877–890, 1991.
5. Brena
SF: Pain control facilities: Patterns of operation and problems of organization in the USA. Clin Anesth 3:183–195, 1985.
6. Modell
J: Directory of Pain Clinics. Oak Ridge, Ill, American Society of Anesthesiologists, 1977.
7. Curron
H: International Directory of Pain Centers/Clinics. Oak Ridge, Ill, The American Society of Anesthesiologists, 1979.
8. Long
DM: The Development of the Comprehensive Pain Treatment Program at Johns Hopkins. In Cohen MJM, Campbell JN (eds): Pain Treatment Centers at a Crossroads: A Practical and Conceptual Reappraisal. Seattle, IASP Press, 1996.
9. Flor
H, Fydrich T, Turk DC: Efficacy of multidisciplinary pain treatment centers: A meta-analytic review. Pain 49:221–230, 1992.
10. Aronoff 11. Wells 12. Turk
GM, Evans WO, Enders PL: A review of follow-up studies of multidisciplinary pain units. Pain 16:1–11, 1982.
JCD, Miles JB: Pain clinics and pain clinic treatment. Br Med Bull 47:762–785, 1991.
DC, Rudy TE, Sorkin BA: Neglected topics in chronic pain treatment outcomes studies: Determination of success. Pain 53:3–16, 1993.
13. Sanders
SH, Brena SF: Pain management program in the United States: A problem of image and credibility. Focus Pain 1:3, 1993.
14. Commission
on Accreditation of Rehabilitation Facilities: Program evaluation in chronic pain management programs. Tucson, CARF, 1987.
15. International Association for the Study of Pain: Desirable characteristics for pain treatment facilities and standards for physician fellowship in pain management. Seattle, IASP, 1990. 16. Ghia
JN: Development and organization of pain centers. In Raj PP (ed): Practical Management of Pain, 2nd ed. St. Louis, Mosby, 1992, pp
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16–39. 17. Schwartz
DP: Appropriate referral to inpatient vs. outpatient pain management programs: A cliniciaňs guide, Pain Dig 1:2–6, 1991.
18. Merskey H, Bogduk N (eds): Classification of Chronic Pain: Descriptions of Chronic Pain Syndromes and Definition of Pain Terms, 2nd ed. Seattle, IASP Press, 1994. 19. King
RB, Moore B: Managed care: Past, present and future. Arch Neurol 53:851–855, 1996.
20. Carr
DB, Aronoff GM: The future of pain management. In Aronoff GM (ed): Evaluation and Treatment of Chronic Pain. Baltimore, William & Wilkins, 1998.
21. Bootman
LJ, Townsend RJ, McGhan WF (eds): Principles of pharmaeconomics, 2nd ed. Cincinnati, Whitney, 1995.
22. Ruiz-López
R: Continuous care of cancer pain patients. In Aronoff GM (ed): Evaluation and Treatment of Chronic Pain, 3rd ed. Baltimore, Williams & Wilkins, 1998.
23. http://www.jcaho.org/standard/pm_npfrm.html 24. Chapman
CR: New JCAHO standards for pain management: Carpe diem! APS Bull 10:2–3, July/Aug 2000.
APPENDIX 1: Desirable Characteristics of Pain Treatment Facilities
[15]
DEFINITION OF TERMS The following terms are defined briefly in this section; a more complete description of the characteristics of each type of facility appears in subsequent portions of this chapter. 1. 2.
3.
4.
5.
Pain Treatment Facility. This generic term is used to describe all forms of pain treatment facilities without regard to personnel involved or types of patients served. Pain unit is a synonym for pain treatment facility. Multidisciplinary Pain Center. This organization of healthcare professionals and basic scientists includes research, teaching, and patient care related to acute and chronic pain. This type of center is the largest and most complex of the pain treatment facilities and ideally would exist as a component of a medical school or teaching hospital. Clinical programs must be supervised by an appropriately trained and licensed clinical director. A wide array of healthcare specialists is required, such as physicians, psychologists, nurses, physical therapists, occupational therapists, vocational counselors, social workers, and other specialized healthcare providers. The range of disciplines required of healthcare providers is a function of the varieties of patients seen and the healthcare resources of the community. The members of the treatment team must communicate with each other on a regular basis, both about specific patients and about overall development. Healthcare services in a multidisciplinary pain clinic must be integrated and based upon multidisciplinary assessment and management of the patient. Inpatient and outpatient programs are offered in such a facility. Multidisciplinary Pain Clinic. This healthcare delivery facility is staffed by physicians of different specialties and other nonphysician healthcare providers who specialize in the diagnosis and management of patients with chronic pain. This type of facility differs from a multidisciplinary pain center only because it does not include research and teaching activities in its regular programs. A multidisciplinary pain clinic may have diagnostic and treatment facilities to serve outpatients, inpatients, or both groups. Pain Clinic. This clinic is a healthcare delivery facility that focuses on the diagnosis and management of patients with chronic pain. A pain clinic may specialize in specific diagnoses or in pains related to a specific region of the body. A pain clinic may be large or small, but it should never be a label for a solo practitioner. A single physician functioning within a complex healthcare institution that offers appropriate consultative and therapeutic services could qualify as a pain clinic if chronic pain patients were suitably assessed and managed. The absence of interdisciplinary assessment and management distinguishes this type of facility from a multidisciplinary pain center or clinic. Pain clinics can, and should be encouraged to, carry out research, but it is not a required characteristic of this type of facility. Modality-Oriented Clinic. This healthcare facility offers a specific type of treatment and does not provide comprehensive assessment or management. Examples include nerve block clinic, transcutaneous nerve stimulation clinic, acupuncture clinic, and biofeedback clinic. Such a facility may have one or more healthcare providers with different professional training; because of its limited treatment options and the lack of an integrated, comprehensive approach, it does not qualify for the term “multidisciplinary.”
DESIRABLE CHARACTERISTICS OF A MULTIDISCIPLINARY PAIN CENTER
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A multidisciplinary pain center (MPC) should have on its staff a variety of healthcare providers capable of assessing and treating physical, psychosocial, medical, vocational, and social aspects of chronic pain. These therapists work with occupational therapists, vocational counselors, social workers, and any other type of healthcare professional who can make a contribution to patient diagnosis or treatment. At least three medical specialties should be represented on the staff of a multidisciplinary pain center. If one of the physicians is not a psychiatrist, physicians from two specialties and a clinical psychologist are the minimum required. An MPC must be able to assess and treat both the physical and the psychosocial aspects of a patient’s complaints. The need for other types of healthcare providers should be determined on the basis of the population served by the MPC. The healthcare professionals should communicate with each other on a regular basis both about individual patients and about the programs offered in the pain treatment facility. There should be a director or coordinator of the MPC. He or she need not be a physician, but if not, there should be a director of medical services who is responsible for monitoring the medical services provided. The MPC should offer diagnostic and therapeutic services that include medication management, referral for appropriate medical consultation, review of prior medical records and diagnostic tests, physical examination, psychological assessment and treatment, physical therapy, vocational assessment and counseling, and other services as appropriate. The MPC should have a designated space for its activities. The MPC should include facilities for inpatient and outpatient services. The MPC should maintain records on its patients so as to be able to assess individual treatment outcomes and to evaluate overall program effectiveness. The MPC should have adequate support staff to carry out its activities. Healthcare providers active in an MPC should have appropriate knowledge of both the basic sciences and clinical practices relevant to chronic pain patients. The MPC should have a medically trained professional available to deal with patient referrals and emergencies. All healthcare providers in an MPC should be appropriately licensed in the country or state in which they practice. The MPC should be able to deal with a wide variety of chronic pain patients, including those with pain resulting from cancer and other diseases. An MPC should establish protocols for patient management and assess their efficacy periodically. An MPC should see an adequate number and variety of patients for its professional staff to maintain their skills in diagnosis and treatment. Members of an MPC should carry out research on chronic pain. This does not mean that everyone should be doing both research and patient care. Some function only in one arena, but the institution should have ongoing research activities. The MPC should be active in educational programs for a wide variety of healthcare providers, including undergraduate, graduate, and postdoctoral levels. The MPC should be part of or closely affiliated with a major health sciences educational or research institution.
DESIRABLE CHARACTERISTICS OF A MULTIDISCIPLINARY PAIN CLINIC The distinction between an MPC and a multidisciplinary pain clinic is that the former has research and teaching components that need not be present in the latter. Hence, items 15, 16, and 17 in the foregoing list are not required for a multidisciplinary pain clinic. All other items should be present.
DESIRABLE CHARACTERISTICS OF A PAIN CLINIC 1. 2. 3. 4. 5. 6. 7.
A pain clinic should have access to and regular interaction with at least three types of medical specialties or healthcare providers. If one of the physicians is not a psychiatrist, a clinical psychologist is essential. The healthcare providers should communicate with each other on a regular basis both about individual patients and about programs offered in the pain treatment facility. There should be a director or coordinator of the pain clinic. If he or she is not a physician, there should be a director of medical services who is responsible for the monitoring of medical services provided to the patients. The pain clinic should offer both diagnostic and therapeutic services. The pain clinic should have designated space for its activities. The pain clinic should maintain records on its patients so as to be able to assess individual treatment outcomes and to evaluate overall program effectiveness. The pain clinic should have adequate support staff to carry out its activities.
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8.
Healthcare providers working in a pain clinic should have appropriate knowledge of both the basic sciences and clinical practices relevant to pain patients. 9. The pain clinic should have trained healthcare professionals available to deal with patient referrals and emergencies. 10. All healthcare providers in a pain clinic should be appropriately licensed in the country and state in which they practice.
APPENDIX 2: Joint Commission on Accreditation of Healthcare Organizations Standards for Pain Management [21] [22]
The new standards for pain assessment and management of the Joint Commission on Accreditation of Healthcare Organizations (JCAHO) apply to ambulatory care facilities, healthcare networks, behavioral healthcare facilities, home care, hospitals, long-term care organizations, long-term care pharmacies, and managed behavioral healthcare organizations. These standards recognize pain as a condition that requires specific assessment and management and is finally recognized inside the main frame of patient rights with consequent organizational responsibilities. In summary, the standards point out the various aspects of pain care with which the healthcare organizations must comply: • Explicit recognition of the right of patients to appropriate assessment and management of pain. • Screening for the existence of pain and assessment of the nature and intensity of pain in all patients. • Recording the results of the assessment in a way that facilitates regular reassessment and follow-up. • Determining and ensuring staff competency in pain assessment and management, and addressing pain assessment and management in the orientation of all new staff. • Establishing policies and procedures that support the appropriate prescription or ordering of effective pain medications. • Educating patients and their families about effective pain management. • Addressing patient needs for symptom management in the discharge planning process. • Maintaining a pain control performance improvement plan. These new standards have started to be scored for compliance in 2001, and many key professional organizations and accredited healthcare organizations will discuss their experiences in managing pain in order to finalize the guidelines. APPENDIX 3: Standards for Physician Fellowship in Pain Management 1. 2. 3.
4.
[23]
Definition. A physician fellowship in pain management is a specialized postgraduate program of study in assessing and managing patients with chronic pain of all types and understanding the sciences basic to the practice of pain management. Duration. A fellowship in pain management should require a minimum of 1 year of full-time clinical training. Additional research training may be desirable, depending on the fellow’s career goals, but should not erode the clinical training period. Prerequisites for Fellowship in Pain Management. To be eligible for a fellowship in pain management, the candidate must be board-eligible or board-certified in one of the recognized specialties of medicine; furthermore, the specialty area must involve experience with patient care. The fellow must be a graduate of an approved school of medicine. The fellow must provide at least three letters of a reference and a curriculum vitae when applying for a fellowship position. The fellow must be licensed to practice medicine by the appropriate governmental agencies. Resources. The fellowship must occur within a medical institution capable of providing a suitable educational environment. At least three recognized patient care specialty areas must be offered at the same institution. The institution must have a medical library with appropriate resources for this level of training. The clinical pain treatment program or its parent institution must be accredited by the appropriate governmental agencies. The pain treatment facility must have suitable space allocated for its clinical and educational activities. It must have a sufficient volume and variety of patients to provide the fellow or fellows with adequate educational opportunities. The pain treatment facility must see at least 100 new patients per year per fellow; there must be at least 500 patient visits per year per fellow. Pain treatment facilities that specialize in one region of the body or one type of disease are by themselves not adequate as a training resource.
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Director. There must be a designated director of the pain management fellowship. The director shall be a physician who participates in the diagnosis and treatment of patients within the pain management facility offering the fellowship in pain management. The director of the fellowship need not be the administrative or medical chief of the pain treatment facility, but the fellowship director and administrative and medical chiefs, if they are not the same, must demonstrate the ability to interact in such a way as to be conducive to the education of fellows. The director shall be responsible for the design and implementation of the fellowship; he or she shall be responsible for certifying that a fellow has successfully completed his or her training period and has mastered the requisite knowledge, skills, and attitudes. The director must be a member of the International Association for the Study of Pain (IASP) and a national chapter. It is desirable that the director have extensive experience in the management of patients with the complaint of pain; it is also desirable that he or she have educational and administrative experience above and beyond the fellowship in pain management. The director shall be responsible for maintaining an up-to-date file on each fellow, documenting his or her educational progress and any deficiencies. Faculty. There shall be at least three members of the pain treatment facility staff who are designated as faculty in addition to the director. Faculty members shall be appropriately certified in a patient care specialty. If one of the faculty is not a psychiatrist, an additional faculty member must be a licensed clinical psychologist who has expertise in pain management. Faculty members shall also be members of the IASP and a national chapter. Faculty members of a fellowship in pain management shall represent at least three healthcare delivery specialties. Other types of healthcare providers in addition to physicians and psychologists may also be members of the faculty. Faculty members must spend a major part of their professional time working within the pain treatment facility.
CLINICAL TRAINING SUBJECTS Although not every fellow will be fully trained in every area listed here, every fellow should at least have had some exposure to patients whose care involves all these areas. I.
II.
III.
IV.
Medical diagnosis and therapy A. History and physical examination B. Measurement of pain C. Physical therapies D. Vocational and rehabilitation assessment and management E. Participation in multidisciplinary assessment and treatment F. Anesthesiologic procedures (when appropriate for the fellow’s prior training) G. Surgical procedures (when appropriate for the fellow’s training) H. Other procedures appropriate to the fellow’s prior specialty training Psychological diagnosis and therapy A. Use of diagnostic tests B. Collection of data from interview and standard forms C. Comprehensive assessment D. Treatment options 1. Individual, group, and family psychotherapy 2. Cognitive-behavioral therapies 3. Biofeedback and relaxation techniques 4. Hypnotherapy Pharmacotherapy A. Analgesics 1. Nonopioids 2. Opioids 3. Adjunctive drugs B. Antidepressants C. Sedative-hypnotics D. Benzodiazepines E. Others Specific types of painful conditions to be included in the fellow’s educational program A. Pain associated with cancer, including issues of death and dying, palliative care, and hospice care B. Postoperative and post-trauma pain C. Pain associated with nervous system injuries D. Pain associated with chronic disease E. Pain of unknown causation
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F. Pain in children G. Pain in the elderly Regional pain syndrome to be included in the fellow’s educational program A. Headache B. Facial pain syndromes C. Neck and upper back pain D. Low-back pain E. Extremity pain syndromes F. Pelvic and perineal pain
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Chapter 6 - Organization of Palliative Care Services RICARDO RUIZ-LÓPEZ DIEGO BELTRUTTI ATHINA N. VADALOUCA MAURO S. NICOSCIA
During the past decade, medical ethical considerations regarding the consequences of developments in healthcare and medical oncology have led to the general assumption in Western societies that promoting the quality of life (QOL) and alleviating suffering are almost as important as preserving life. [1]
Moreover, the increasing concerns about economic growth and development of healthcare and the perception that healthcare policies are determined on the basis of cost-benefit analysis, lay a solid groundwork for the implementation of multidisciplinary and interdisciplinary teams for the management of patients with advanced diseases, whose QOL is considered the principal goal of medical therapy. Palliative care units and hospices are found today in every country of the Western world. There are practical variations in most countries because these services have been modified appropriately to meet specific cultural needs and models of local healthcare systems. This chapter covers the definition of QOL, the relief of pain and other symptoms as a major issue in the management of cancer pain, the structure and functions of the palliative care team, and the integration of levels of care.
Definition of Quality of Life The concept of QOL was introduced as one of the goals of medical treatment in the late 1970s as a result of surveys This concept emerges from the development of Western health policies over the conducted in the United States. past 50 years, ranging from restoration of welfare to objectives related to psychosocial needs. [2] [3] [4]
Although there is no universally accepted definition for this concept, QOL could be considered the functional effect of an illness and its therapy on a patient as perceived by the patient. The World Health Organization’;s definition of health as being “a state of complete physical, mental, and social well-being and not merely the absence of disease” focuses on the issue of the wholeness of life and the importance of the psychosocial component. [5]
Although some definitions indicate that terms such as happiness and satisfaction are integral elements, others mention that measures of sociopersonal balance or QOL should include physical, social, and emotional functions, attitudes toward illness, and personal features of the patient’;s daily life, including family interactions and the cost of illness. Some definitions of QOL treat it as related to the individual’;s own perception, emphasizing that the breadth of the term covers many aspects of life. [6]
[7]
When applied to patients with cancer pain, the term should encompass different clinical dimensions, providing a framework in which physical toxicity (physical impairment, body image, and function) as well as psychological, social, spiritual, cultural, and philosophical factors interact in a way specifically individualized to the patient and changing with the evolution of the disease. Therefore, QOL measures the difference, during a particular period of time, between the individual’;s hopes and expectations and the individual’;s actual experience. According to Calman, four stages of action are required to modify the QOL: [8] [9]
1. 2.
[9]
The problems and priorities of the individual must be assessed and defined. The patient should be fully involved in formulating the plan of care. This step involves a comprehensive discussion with patient and family and requires the patient’;s insight into the dynamics of the situation.
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The action plan must be implemented by either the patient or the caring team. This goal may be accomplished by lessening the patient’;s physical symptoms, altering the patient’;s psychological status, or reducing expectations but allowing the patient to retain hope. An evaluation must be made of the results of the intervention and the patient’;s situation must be reassessed. TABLE 6-1 -- COMMONLY IDENTIFIED DIMENSIONS OF QUALITY OF LIFE
Physical concerns
Treatment satisfaction
Functional ability
Future orientation
Family well-being
Sexuality/intimacy
Emotional well-being
Occupational functioning
Spirituality
Social functioning
From Cella DF, Tulsky DS: Measuring quality of life today: Methodologi cal aspects. Oncology 4:29–38, 1990.
A comprehensive view of palliative medicine requires that QOL be considered with regard to the specific disease and the treatment of symptoms. This involves not only patients in advanced stages of the disease but also those in the early stages, when more aggressive therapies are usually performed. Calman described QOL in relation to the size of the gap between an individual’;s expectations and the reality of those expectations: the smaller the gap, the better the QOL. According to this model, a patient’;s QOL can be influenced either by a change in the actual condition or by a change in expectations. There are many ways of conceptualizing QOL, and, during the past years, a number of questionnaires have been developed. Cella and Tulsky define 10 distinct issues to be measured, although these dimensions need to be categorized and validated in a hierarchy model ( Table 6-1 ). [8]
The Relief of Pain and Other Symptoms as a Major Issue in Cancer Care Various surveys show that pain is experienced by 30% to 60% of cancer patients during the active period of the therapy and by more than 75% of patients with advanced disease. Thus, alleviation of pain is directly linked to achievement of QOL, because pain interferes with physical functioning and social interaction and is associated with psychological distress. [10]
[11] [12] [13]
Continuous pain can interfere with the patient’;s ability to eat, sleep, think, and interact with others. Unbearable pain, whether “difficult” or “refractory,” is a major risk factor in cancer-related suicide. [14]
[15]
[16] [17]
The effective alleviation of pain in cancer and other advanced stages of degenerative diseases is acknowledged by the World Health Organization (WHO) as a major goal of medicine and medical care, requiring knowledge of ethical principles and specific training in pain medicine. [18]
The right to alleviation of avoidable pain is derived from the universal concepts of maximal respect for human beings and is attached to the concept of human ethics. Thus, the relief of pain in cancer and other progressive diseases in advanced stages is a collaborative task among the different agents involved in patient care. This interaction includes government agencies, medical and nursing schools, hospitals, healthcare organizations, physicians, nurses, and other health professionals. The selection of potentially harmful therapies that may occasionally prolong life, such as radical radiotherapy or systemic chemotherapy in patients with advanced incurable disease, may cause harm to most patients, and ethical issues may not be properly addressed. In such cases, treatment protocols must be planned, comprehensible patientfamily information packages must be provided, and clearly worded consent procedures must be offered. Emphasis on QOL criteria is considered essential. [19] [20] [21] [22] [23] [24] [25] [26]
Leaders in both palliative care and other aspects of cancer are reluctant to encourage integration of their respective areas. Oncologists and palliative medicine physicians may think that collaboration or clinical integration could distort therapeutic objectives and lead to dilution of resources. This confusion can provoke an unfair situation that affects both patients and families, being a source of misinformation and establishing an unavoidable barrier to appropriate care. [27]
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The relief of pain and palliation of symptoms has been traditionally considered as a medical treatment for the last days of life, when symptoms are much more prominent and more difficult to control. The WHO, in its definition of palliative care, states: “Palliative care … affirms life and regards dying as a normal process, … neither hastens nor postpones death, … provides relief from pain and other distressing symptoms, … integrates the psychological and the spiritual aspects of care, … offers a support system to help patients live as actively as possible until death, … offers a support system to help the family cope during the patient’;s illness and in their own bereavement.” This expanded definition of palliative care relates to the previous WHO definition which affirms, “The goal of palliative care is achievement of the best quality of life for patients and their families. Many aspects of palliative care are also applicable earlier in the course of the illness in conjunction with the anticancer treatment.” [18]
Structure and Functions of the Pain and Palliative Care Team Specialized care of persons with cancer and other irreversible diseases has undergone major changes during the past three decades ( Table 6-2 ). Although the concept of medical effectiveness can be greatly modified by both physicians’; attitudes and environmental concerns, the organizational issues and the philosophy of a modern pain and palliative care team are not dissimilar
TABLE 6-2 -- SCHEMATIC ORGANIZATION AMONG PAIN AND PALLIATIVE CARE SERVICES; LEVELS OF CARE AND PATIENTS
From Ruiz-López R: Continuous care of cancer pain patients. In Aronoff GM (ed): Evaluation and Treatment of Chronic Pain. 3rd ed. Baltimore, Williams & Wilkins, 1998.
to those postulated by J. J. Bonica in his early work, when he stated, “Complex pain problems can be treated more effectively by a multidisciplinary/interdisciplinary team, each member of which contributes with his or her specialized knowledge and skills to the common goal of making a correct diagnosis and developing the most effective therapeutic strategy.” [28]
The development of the hospice movement over the past 50 years has provided interdisciplinary care to patients and families at home, establishing inpatient units for palliative care in local hospitals or in specialized institutions. In either type of setting, the multidisciplinary/interdisciplinary team plays a major role in providing medical treatment and psychosocial support as well as attending to the spiritual needs of patients and their families. [29] [30] [31]
[32]
[33] [34] [35]
THE MULTIDISCIPLINARY TEAM Multidisciplinary care of cancer pain patients must be active and continuous. Their physical, psychological, social, and spiritual needs should be considered, because the multiple issues that these patients and their families encounter usually exceed the expertise of a single practitioner or caregiver. In this type of team, members with diverse training interact as a group of individuals, with the common purpose of working together and sharing the main goal of improving the QOL of the patient. Team members have particular expertise and training and make individual decisions within their area of responsibility. Teamwork does not mean
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joining healthcare workers together in one room; nor is it the same as collaboration. Information must be the key issue for interaction of members and must be shared by the vehicle of the clinical record. [36]
Structure of a Multidisciplinary Team
The structure of the multidisciplinary team varies with the development of the program of care, its objectives and goals, the availability of resources, and the type of setting, be it in home, hospice, or hospital. The patient and family should be considered as members of the team. PHYSICIAN
The most important challenge—and the first to be considered—is the relief of pain and other symptoms. Thus, the physician plays a central role on the team. The physician must be competent in general medicine, know the principles and practice of care, and understand malignant disease and any other disease represented in the patient population, such as acquired immunodeficiency syndrome or degenerative neurologic diseases. Ideally, the physician should have specific training in palliative medicine and skills in pain management, including surgical and anesthesiologic procedures. This assertion suggests that a team must be comprised of physicians from a wide variety of specialized backgrounds, such as anesthesiology, neurosurgery, oncology, psychiatry, internal medicine, and family medicine among others. Physicians may play various roles, which include managing pain and symptoms for an individual patient, being responsible for medical assessment and coordination, training and supporting the multidisciplinary team, and ensuring coordination of care of the individual patient. Other physicians may act only as consultants, being coordinated by the attending physician of the patient. PSYCHOLOGIST
The role of the psychologist is to perform a first evaluation of the status of patient and family, focusing on personal problems of illness, disability, and impending death. The psychologist must deal with the patient’;s and relatives’; emotional needs. The psychologist should cover the patient’;s and family’s understanding of diagnosis, prognosis, and expectations, the strengths and resources available to the family, the problems precipitated by the terminal illness, past losses and the way they were handled, particular cultural factors, and expectations and plans for the future. The psychologist should help the team when there is dysfunction within the family and participate in the patient’s symptom control by teaching and assessing relaxation techniques, imagery, distraction techniques, and strategies for coping. NURSE
The nurse is the team member who is most likely to visit the patient and family at home or in the inpatient institution. The nurse’s role begins with examination of the details of physical care: bathing, control of odor, pressure areas, mouth care, bladder care, bowel care, diet, and fluids. The nurse also provides any information needed to maintain good hygiene. The nurse’s other responsibilities include organizing the patient’s environment to minimize loss of control, observing what brings comfort and relief, reporting the patient’s response to medical treatments or secondary effects, and instructing the patient and family about the medication plan. SOCIAL WORKER
The social worker’s goals are to assist the patient to develop skills in dealing with the social problems of illness, disability, and impending death; to link the patient with the community; and to establish practical aid for peer support. CHAPLAIN
A sympathetic chaplain who is a skilled listener is a key team member. Sometimes, the patient has feelings of guilt about past events, a sense of meaninglessness, and a perception that life is unjust. Faith may be questioned. The role of the chaplain is to listen, facilitate past recollection, deal with regrets, offer spiritual counseling, and help to make the patient ready for what lies ahead.
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For a patient with an established tradition of religious rituals and sacraments, the chaplain’s role on the team can be very meaningful. Therefore, pastoral counseling should be made available, and pastoral care members should become familiar with information about community resources that provide spiritual care and support. PHYSICAL THERAPIST
Rather than attempting to improve the patient’s function, the goal of the palliative care physiotherapist is to help plan activity oriented to maximizing the patient’s diminishing resources. This can be accomplished by active or passive range of motion exercises that the bedridden patient can perform to prevent contractures and improve circulation, massage to relax aching muscles, treatment of lymphedema, instruction in transfers or positioning, and the use of physical therapy for the alleviation of pain. OCCUPATIONAL THERAPIST
The occupational therapist’s role is to maintain autonomous functions such as control of self-care needs, including such activities as grooming, feeding, dressing, and moving about. The occupational therapist also assesses functions with which the patient needs assistance and those that the patient can still perform autonomously. The therapist should provide adaptive equipment or functional splints, and treatments should be changed in accordance with the patient’s status. In the inpatient setting, the focus of the occupational therapist on leisure can help to restore a sense of normal living through the introduction of corrective measures to help the patient adapt residual capacities to maintain the activities of daily life. VOLUNTEER
The volunteer’s roles vary according to the patient’s setting, although the focus is on improving the QOL, to provide a supportive presence that may facilitate communication, and to assist with the normal activities of daily living. Volunteers should be carefully selected and specifically trained by the pain and palliative care team.
Cancer Pain and Palliative Care: The Continuum Hospital-Hospice Model One of the most challenging tasks in care of patients with cancer pain is to ensure the delivery of specialized services throughout the different settings where the patient will be managed during the course of the disease. Most patients need specialized care in two or more settings because there is an increasing movement in industrialized countries to enable persons with advanced disease to live until death at their maximal potential, letting patients end their lives in the setting most appropriate to them and their families. Therefore, a major objective of care in cancer pain management is, whenever possible, to help patients to reach the limit of their physical and mental capacities with the highest level of autonomy in their own environments. The provision of continuity of care with such terms is conditioned by the availability of resources and, mainly, by an effective communication within the team, including the patient and family. The place of death and quality of care are among the most important concerns for the patient and family. Until the 19th century, people died where they had spent their lives or where they wished. During the 20th century, because of different conceptual assumptions, in Western societies, the place of dying has changed from the home to the hospital, which, in many cases, is not the preference of the patient. In 1965, in the United Kingdom, 63% of deaths occurred in the hospital compared with 73% in 1987. In the United States, in 1957, 70% of deaths occurred in the hospital. In Italy, 72% of the deaths occurred in the hospital in 1986 as opposed to 67% in 1990. In Israel, 29% of terminal patients currently die in hospital, 41% at home, and 31% at institutions for chronic diseases. The availability of home care services in Western Australia has allowed 70% of patients to die at home. If the patients are asked where they would like to spend the last days of their lives, the majority answer that they want to be at home.
HOSPITAL Since the 19th century, technology and industry have developed enormously, and life expectancy has doubled. In the 20th century, the hospital setting became a place designed to recover health and manage treatable diseases. Healing
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and prolongation of life have been assumed to be the hospital’s main objectives. There seems to be no time or space for patients who do not get well. On the other hand, society seems to be trying to eliminate death from its style of life, and dying persons are sent to the hospital to keep them far from the center of the family. Today, the hospital setting has to be considered as one important step for the multidisciplinary team in some circumstances. The hospital is the place where specific palliative therapies can be administered (e.g., radiation therapy, transfusions) and where difficult-to-control symptoms such as pain can be managed. In some cases, an admittance to the hospital is needed to perform a surgical procedure, such as nerve block, for the alleviation of pain. A patient with delirium sometimes requires hospital admission so that a quick and correct diagnosis of the cause of the delirium can be made and so that treatment can be provided if it is feasible. Severe dyspnea stemming from pleural effusion or other causes can require thoracocentesis in hospital. Difficult ulcers (paraneoplasic vasculitic syndromes), ischemic complications, or other miscellaneous conditions can be more effectively controlled in a hospital setting. In any case, the hospital stay should not be prolonged. Other causes of hospital admission can arise from the family situation, such as poor coping or extreme anxiety as well as distressing symptoms such as severe dyspnea, neoplasic ulcers, or agony. The patient who lives alone and has no means to acquire a caregiver sometimes requires hospital or hospice admission. Finally, the patient may make the decision to stay in the hospital. The best way to achieve good results, without the disadvantages of a hospital setting for a terminally ill cancer patient, is to create a palliative care unit (PCU) in a local hospital. Some hospitals have a PCU, which avoids many of the problems of the traditional hospital model. To resolve problems that appear during the disease, the team members must be trained in the treatment and control of the advanced disease and in the integral care of the patient and family. Communication skills are vital; loss of communication usually means that the patient becomes merely a care receiver instead of an active participant in the decision making. The team must have time to dedicate to the patient and family. The patient has to become familiar with the PCU team. The environment must be adequate to allow some degree of independence, and privacy must be maintained. Usually, the hospital is a hostile place for the patient who ignores hospital regulations. Also, privacy during family conferences is important, and a special room for this purpose is desirable to avoid discussions in the corridor. The PCU must have special equipment but not sophisticated technology. The concept of “nothing more can be done” must be abandoned, and inadequate therapeutic attempts or prolongation of agony should be avoided.
HOSPICE The first hospice where modern medicine was applied to terminal patients in a rational and scientific manner was St. Christopher’s Hospice in London ( Table 6-3 ). The human component was not forgotten, and pain management was fundamental. It was the beginning of palliative care as we know it today, and from this beginning the hospice movement expanded throughout the world. [35] [36]
The main purpose of the hospice is to take care of the human being who is ill with no possibility of healing. Its principal objective is to treat patients as whole
TABLE 6-3 -- LIST OF ELEMENTS BROUGHT TOGETHER AT ST. CHRISTOPHER’s HOSPICE Beds integrated in local community Development and monitoring of symptoms control Family support Bereavement service Home care Research and evaluation Education and training From Saunders C, Bains M: Living with Dying: The Management of Terminal Disease. Oxford, England, Oxford University Press, 1983.
persons, enabling them and their families to participate in decision making. The major principles of the hospice setting are symptom control; rehabilitation; attention to psychological and spiritual needs; allowing patients and families together to choose where patients will live during the final phase of their diseases and where they will die;
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maintaining good communication among team members, including patients and their families; and giving support during agony, providing accessibility to staff, and allotting enough time to comfort patients. Palliative care teams have developed skills that have enabled previously hospital-bound patients to return home, with use of techniques such as spinal analgesic delivery systems, pump-delivered subcutaneous medications, and continuous care of regular symptom management by doctors and nurses at the patients’ homes. Data on 3362 patients cared for by St. Christopher’;s Hospice between 1972 and 1977 showed that only 1% reported continuous pain, although more than three quarters of the patients had arrived at the hospice with pain. Cicely Saunders recognized that the achievement of such results, however, can provoke “staff pain,” resulting from prolonged exposure to the suffering of patients and families who are facing death. Although she acknowledged and described the need for formal staff support, she argued that, “The resilience of those who continue to work in this field is won by a full understanding of what is happening and not by a retreat behind a technique.” [31]
[32]
HOME The home setting offers several advantages for the patient. It helps patients to maintain their social and family roles, to use their time as they wish, and to develop personally satisfying eating and sleeping habits. Changing habits in the final days of life can lead to suffering and stress. Furthermore, patients at home can preserve privacy, can go on with occupational activities, and are in a familiar environment. Family members feel more satisfied because they can actively participate in giving care and in showing respect for the patient’;s wishes. Home care as a part of continuous care of the cancer patient benefits the health system by decreasing the number of hospital admissions, shortening hospital length of stay, and providing quality of care according to modern ethical principles. For a patient to be kept in the home, some conditions must be fulfilled ( Table 6-4 ): round-the-clock specialized care by the palliative care team must be available; the patient and relatives must be instructed on all issues related to the illness and its complications; information about home remedies for the appropriate management of pain and other symptoms must be provided; appropriate technical support for medical equipment must be given; and there must be written information about the use of medication. The patient and family must be assured that admittance to an institution is available if the clinical situation cannot be controlled at home. A bereavement program that provides care of the family after the patient’;s death is crucial. If a family has specific difficulties immediately after the patient’;s death, referral to community peer support groups or specialized counseling must be given.
Conclusions The importance of palliative medicine is expected to increase in upcoming years. For full coverage of the population, a rational approach is needed that stresses public health rather than institutionalized involvement. Gaining support for public health involvement should be a priority for the individuals, organizations, and countries in the worldwide network involved in implementing existing knowledge in palliative care. [37]
The implementation of the WHO recommendations in regard to palliative care could have a major impact on the QOL of cancer patients. However, strong political motivation and leadership are required to ensure a full involvement of healthcare systems without extreme expense (Appendix 6–1). Palliative care in Western societies is considered to be a human right when curative interventions are no longer indicated. For a large number of less developed
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24-hour specialized care available Patient and relatives taught about the disease Information about home remedies Appropriate technical support Written information on the use of medication
countries, palliation should be made available now, even before maturation of the country’;s economy can provide technical services. An important effort has to be made to encourage legislation that will at least make essential drugs—including opioids—available to the global population. Education of physicians and health workers in developing countries must be improved so that these countries can implement their own palliative care teams and training centers. REFERENCES 1. Aristotle:
Ethics. Harmondsworth, England, Penguin Books, 1976.
2. Aaronson
NK, Beckmann J (eds): The Quality of Life of Cancer Patients. New York, Raven Press, 1987.
3. Andrews
FM, Withey SB: Social Indicators of Well-Being. New York, Plenum Press, 1976.
4. Campbell 5. World
A, Converse PE, Rodgers WL: The Quality of American Life. New York, Sage, 1976.
Health Organization Constitution. Geneva, WHO.
6. Spitzer WO, Dobson AJ, Hall J, et al: Measuring the quality of life of cancer patients: A concise QL-index for use by physicians. J Chronic Dis 34:585–597, 1981. 7. Krupinsky
J: Health and the quality of life. Soc Sci Med 14a:203–211, 1980.
8. Calman KC: Definitions and dimensions of quality of life. In Aaronson NK, Beckman J (eds): The Quality of Life of Cancer Patients. New York, Raven Press, 1987, pp 1–9. 9. Calman
KC: The quality of life in cancer patients—an hypothesis. J Med Ethics 10:124–127, 1984.
10. Bonica
JJ, Ventafridda V, Twycross RG: Cancer pain. In Bonica JJ (ed): The Management of Pain, 2nd ed. Philadelphia, Lea & Febiger, 400– 460, 1990.
11. Bond 12. Daut
MR, Pearson IB: Psychosocial aspects of pain in women with advanced cancer of the cervix. J Psychosom Res 13:13–21, 1969. RL, Cleeland CS: The prevalence and severity of pain in cancer. Cancer 50:1913–1918, 1982.
13. Fishman
B: The treatment of suffering in patients with cancer pain: Cognitive behavioral approaches. Adv Pain Res Ther 16:301–316, 1990.
14. Feuz A, Rapin CH: An observational study of the role of pain control and food adaptation of elderly patients with terminal cancer. J Am Diet Assoc 94:767–770, 1994. 15. Massie MJ, Holland JC: The cancer patient with pain: Psychiatric complications and their management. Med Clin North Am 71:243–258, 1987. 16. Breitbart
W: Suicide in the cancer patient. Oncology 1:49–54, 1987.
17. Cleeland
CS: The impact of pain on the patient with cancer. Cancer 54:2635–2641, 1984.
18. World
Health Organization: Cancer pain relief and palliative care. Technical Report Series 804. Geneva, WHO, 1990.
19. Questions
and Answers About Pain Control: A Guide for People with Cancer and Their Families. Washington D.C., American Cancer Society and the National Cancer Institute, 1992.
20. Ferrell
BR, Rhiner M, Ferrell BA: Development and implementation of a pain education program. Cancer 72(Suppl 11):3426–3432, 1993.
21. The
Wisconsin Cancer Pain Initiative: Cancer Pain CAN Be Relieved: A Guide for Patients and Families. Madison, Wis, The Wisconsin Cancer Pain Initiative, 1989.
22. The
Wisconsin Cancer Pain Initiative: Jeff Asks About Cancer Pain: A Booklet for Teens About Cancer Pain. Madison, Wis, The Wisconsin
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Cancer Pain Initiative, 1990. 23. Dolore
da Cancro e Cure Palliative: Collana Rapporti Tecnici 804. Organizzazione Mondiale de la Sanità. Ginevra, 1990.
24. Manual
of Care for Terminally Ill Cancer Patients: Tokyo, Ministry of Health and Japan Medical Association, 1989.
25. Facing
Forward: A Guide for Cancer Survivors. Rockville, Md, U.S. Department of Health and Human Services, Public Health Service, National Institutes of Health, National Cancer Institute, 1990.
26. Teamwork: 27. Scott
The Cancer Patient’;s Guide to Talking with Your Doctor. Silver Spring, Md., National Coalition for Cancer Survivorship, 1991.
J: Canadian Brief on Palliative Care. Presented to Cancer 2000 on behalf of the Canadian Palliative Care Association, Silver Spring, Md.,
1990. 28. Bonica,
JJ: General clinical considerations (including organization and function of a pain clinic). In Bonica JJ, Procacci P, Pagni CA, et al (eds): Recent Advances on Pain: Pathophysiology and Clinical Aspects. Charles C. Thomas, Springfield, Ill, 1974, pp 274–298.
29. Saunders
C: Care of patients suffering of terminal illness at St. Joseph’;s Hospice, Hackney, London. Nurs Mirror February 14:vii–x, 1964.
30. Saunders
C: The challenge of terminal care. In Symington T, Cater R (eds): The Scientific Foundations of Oncology. London, Heineman,
1964. 31. Saunders
C: The philosophy of terminal care. In Saunders C (ed): The Management of Terminal Disease. London, Edward Arnold, 1979.
32. Saunders
C: Current views on pain relief and terminal care. In Swerdlow M (ed): The Therapy of Pain. Philadelphia, J.B. Lippincott, 1981.
33. Ventafridda 34. Parkes
V: Continuing care: A major issue in cancer pain management. Pain 36:137–143, 1989.
CM, Parkes J: Hospice versus hospital care: Reevaluation after ten years as seen by surviving spouses. Postgrad Med J 60:120–124,
1984. 35. Saunders
C, Baines M: Living with Dying: The Management of Terminal Disease. Oxford University Press. Oxford, England, 1983.
36. Saunders
CMS: Terminal care. In Weatherall DJ, Ledingham JGG, Warrell DA (eds): Oxford Textbook of Medicine. Oxford, England, Oxford University Press, 1983, p 288(1–28.13).
37. Stjernswärd J: Palliative Medicine—a global perspective. In Doyle D, DWC Hanks DWC, Macdonald N (eds): Oxford Textbook of Palliative Medicine. Oxford, England, Oxford Medical Publications, 1994.
Suggested Reading Brody BA (ed): Suicide and Euthanasia: History and Contemporary Themes. Dordrecht, The Netherlands, Kluwer, 1989. Cassell EJ: The Nature of Suffering and the Goals of Medicine. New York, Oxford University Press, 1991. Foucault M: The Birth of the Clinic: An Archaeology of Medical Perception. New York, Vintage Books, 1975. Numbers RL, Amudsen DW: Caring and Curing: Health and Medicine in the Western Religious Traditions. New York, Macmillan, 1986. APPENDIX 1: WHO Palliative Care Recommendations A WHO expert committee on the relief of cancer pain and palliative care has made the following recommendations to countries for achieving effective palliative care: 1. 2. 3. 4. 5.
Governments should establish national policies and programs for palliative care. Governments of member states should ensure that palliative care programs are incorporated into their existing healthcare systems; separate systems of care are neither necessary nor desirable. Governments should ensure that healthcare workers (physicians, nurses, pharmacists, or other categories appropriate to local needs) are adequately trained in palliative care. Governments should review their national health policies to ensure that equitable support is provided for programs of palliative care in the home. In the light of the financial, emotional, physical, and social burdens carried by family members who are willing to care for cancer patients in the home, governments should consider establishing formal systems of recompense for the principal family caregivers.
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Governments should recognize the singular importance of home care for patients with advanced cancer and should ensure that hospitals are able to offer appropriate backup and support for home care. Governments should ensure the availability of both nonopioid and opioid analgesics, particularly morphine for oral administration. Further, they should make realistic determinations of their opioid requirements and ensure that annual estimates submitted to the INCB reflect actual needs. Governments should ensure that their drug legislation makes full provision for the following: • Regular review, with the aim of permitting importation, manufacture, prescribing, stocking, dispensing, and administration of opioids for medical reasons • Legally empowering physician, nurses, pharmacists, and, where necessary, other categories of healthcare workers to prescribe, stock, dispense, and administer opioids • Review of the controls governing opioid use, with a view to simplification, so that drugs are available in the necessary quantities for legitimate use
9.
With pressure for the legalization of euthanasia likely to increase, governments should make strenuous efforts to keep fully informed of all developments in the fields of cancer pain relief, palliative care, and management of terminal cancer.
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Chapter 7 - The Practice of Regional Anesthesia in Developing Countries RAMANI VIJAYAN
About three quarters of the countries of the world fall into the category of “developing countries,” and four fifths of the world’s population lives in them. How does one categorize these countries? What is the politically correct definition of a developing country? The concept of the Third World emerged after World War II as a category to identify political neutrality in the context of the Cold War, with the distinction originally based on ideologic commitment rather than conditions of economic development. However, the term quickly became associated with economic status and degree of richness or poverty. Hence, the industrial market economy of Western Europe, North America, Australia, New Zealand, Israel, and Japan made up the First World. The centrally planned economies of Eastern Europe made up the Second World. Finally, the remaining countries of the world, such as those in Africa, Asia, the Middle East, the Pacific, Latin America, and the Caribbean, made up the nonaligned Third World. [1]
[2]
In the last two decades, the term developing countries has been used largely to identify those countries that have not yet reached the sophisticated status of industrialized nations such as those of Western Europe and North America. It also denotes that these countries, in particular the low-income countries, have not achieved an advanced level of infrastructure development with regard to the provision of clean water, electricity, housing, healthcare, and education for the large majority of their population. Typically, they have been plagued by poverty, high rates of population growth, low growth rates of gross domestic product (GDP) and industrialization, high dependence on agriculture, high rate of unemployment, and uneven income distribution. There is, of course, a very wide range in the GDP and per capita income in developing countries. The Overseas Development Administration of the United Nations divides them into two lists. Part I covers countries such as Bangladesh and Ethiopia that are characterized as low income (per capita gross national product [GNP] less than U.S. $675 in 1992); low- to middle-income countries such as Papua New Guinea and Armenia; and upper- to middle-income countries that are relatively rich such as Greece, Malaysia, and Argentina. Part II covers countries in transition, such as the countries of Central and Eastern Europe. [3]
Any discussion of the practice of regional anesthesia in developing countries must also take into account the vast differences in healthcare budgets in developing countries. The main differences between anesthesia in the prosperous, developed countries and the less affluent developing countries are related to manpower, training, facilities, equipment, drug availability, and cost of drugs. This difference can be seen even in different parts of the same developing country. In some middle-income countries, more favorable national statistics disguise wide disparities between the conditions of the rural/urban poor and the more affluent urban dwellers who are better educated and have better access to health services that closely resemble those of industrialized countries. [4] [5]
[4] [6]
Anesthesia cannot be separated from the framework of the healthcare system in any given country. It is also linked to the percentage of the population that lives in rural areas, and the degree of rural development. It is not uncommon in many rural areas for a pregnant mother to be transported to a health center 100 to 150 km away, crossing a river or two without bridges. However, the cities and towns in that same country may have excellent facilities typical of large, thriving communities. When rural facilities and other amenities are scarce, doctors generally congregate in urban areas, and anesthetic services tend to be provided primarily by trained nurses or other paramedical staff, who may or may not be taught regional anesthetic techniques. [6]
There are more than 200 developing countries in which the overall population had surpassed 4 billion by the end of the 20th century. It is estimated to pass 5 billion by 2010. There is marked cultural, economic, and political diversity among these countries, and it is difficult to generalize or attempt to categorize the practice of regional anesthesia without running the risk of being either too superficial or too pedantic. This chapter is a review of some of the salient and interesting work that has been undertaken in developing countries and published in indexed journals. It also includes the results of a survey that was conducted in Asian countries in 1999 as well as comments and personal communications garnered from it. [7]
Regional anesthesia, particularly spinal and nerve blocks, have been practiced for many years in developing countries. International anesthetic literature, however, does not quite reflect this practice. The reasons for this could be multifactorial. Papers are often published in local journals, which may not be indexed, and often in languages other than English. Research and writing require time, sufficient staff, and facilities, all or some of which may not
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be easily available in many parts of the developing world. The acute shortage of anesthesiologists and the heavy workload are also not usually conducive to undertaking much research work. Since 1990, however, many of the countries of East Asia and Latin America have seen phenomenal economic growth. In tandem with this growth, there have been vast improvements in healthcare allocation and increased sophistication in healthcare delivery systems. The recent increase in the number of publications from these countries could reflect their growing affluence. Regional anesthesia covers a large number of different techniques. It ranges from simple procedures such as local infiltration with local anesthetic agents practiced by surgeons to those that are more complex, such as the combined-spinal epidural technique.
Regional Anesthesia Administered by Surgeons Surgeons all over the world use local infiltration anesthesia for minor and intermediate surgery. In many parts of the developing world, about 30% to 40% of all surgery is performed under local or local-regional anesthesia. The majority of dental extractions and ophthalmic surgeries are performed under regional anesthesia. Surgeons routinely use retrobulbar or peribulbar blocks for cataract extraction, which may or may not be supplemented by sedation. Peribulbar injection, which avoids the serious complications of retrobulbar injection, is widely used for intraocular surgery and lens implantation. All commonly available local anesthetic drugs, such as lignocaine, bupivacaine, and the newer drug, ropivacaine, have been used with or without the addition of hyaluronidase for ophthalmic surgery. [8] [9]
[10]
[11]
[12]
[13] [14]
Groin surgery accounts for nearly 15% of all general surgery procedures in developing countries and forms a considerable proportion of the surgical workload. Local-regional anesthesia administered by surgeons is used extensively for inguinal hernia repair. When anesthetic services were not available, Nicholls from the Seychelles continued to perform inguinal herniorrhaphy using regional anesthesia only. He found the technique was well tolerated by patients and economical, and he continued using it even after anesthesia became available. Other reports Soukup and have also shown that there is widespread use of regional anesthesia for inguinal hernia repair. Vomacka successfully used local infiltration anesthesia supplemented by sedation in 203 patients undergoing percutaneous nephrolithotomy in Czechoslovakia. [15]
[16]
[17] [18] [19]
[20]
Limiting explosive population growth is a national priority in many developing countries, and female sterilization is one of the more popular methods of family planning. Minilaparotomy to perform tubal ligation under local anesthesia has been found to be a safe, simple, low-cost, and widely applicable technique suitable for even rural areas. It has been used extensively in many developing countries, such as Thailand, India, and the Philippines. Apelo and coworkers from the Philippines reported using local anesthesia in a majority of 2488 women undergoing tubal ligation. Local anesthesia was supplemented with sedation initially in the first 650 women but was omitted in later patients because it was not needed. Of 1546 patients undergoing voluntary sterilization in Nigeria, local anesthesia was used in 996 patients (64.4%). Occasionally, entire teams of healthcare personnel set up mobile hospitals in remote areas to cater to certain specific needs of the rural population. Reichart and coworkers were able to successfully perform outpatient laparoscopic tubal ligation on women under local anesthesia in a remote part of Nicaragua. [21]
[22]
[23]
The administration of local anesthetic drugs into the subarachnoid space is technically easy because most doctors are familiar with lumbar puncture. Spinal anesthesia is therefore the regional anesthetic technique that is most often used by nonspecialists. In many countries, surgeons, medical officers, and nurse anesthetists administer spinal anesthesia because of the general shortage of trained anesthetists. More than 20 years ago (1977), Ajao and Adeloye from Nigeria reported their series of 95 patients in whom major abdominal surgery was accomplished with minimum complications under spinal anesthesia administered by surgeons. They suggested at that time that all surgeons working in “peripheral” hospitals should learn to give spinal anesthesia and deal with its side effects! Inadequate specialist anesthesia service continues up to the present with surgeons providing spinal and epidural anesthesia for surgery in several parts of the developing world. [24]
[25] [26] [27]
Spinal Anesthesia For several decades, spinal anesthesia has enjoyed great popularity in developing countries. In 1966, El-Shirbiny and coworkers from Cairo University reported a large series of 20,000 patients who had surgery under spinal anesthesia with mepivacaine (carbocaine). The list included all types of general surgical (upper and lower abdominal), gynecologic, urologic, and orthopedic procedures. High spinal blocks were performed using 2 mL (80 mg) of mepivacaine with the patient placed in a 10-degree to 15-degree Trendelenburg position. Vasopressors were required only for midlevel and high spinal blocks. A 1976 report from Hungary cites the use of spinal anesthesia with bupivacaine in 240 patients who required surgery after trauma. There were no serious complications, even though one third of the patients were elderly and a quarter were in poor general condition. Kosumian from Russia [28]
[29]
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(1985) reported successful use of spinal anesthesia in 2402 patients in a central regional hospital. Gueguen from Senegal reported that 86% of all surgery is performed under spinal anesthesia in his hospital because it has been found to be a simple and inexpensive technique. [30]
[31]
SPINAL ANESTHESIA AND HYPOTENSION (NONOBSTETRIC) Hypotension is a well-recognized problem associated with spinal anesthesia, and a couple of studies have addressed this issue. Kafle and colleagues from Nepal investigated the efficacy of oral ephedrine in reducing the incidence of hypotension. Two hundred patients undergoing lower abdominal surgery were randomized to receive either oral ephedrine (30 mg) or placebo half an hour before spinal anesthesia with 3.2 to 3.6 mL of 0.5% heavy bupivacaine. Both groups had a volume preload with 10 mL/kg of crystalloid solution. The total dose of intraoperative intravenous (IV) ephedrine supplement was significantly less (P < 0.01) and the number of patients requiring the supplement was significantly less in the group given oral ephedrine (P < 0.01). None of the patients in the treated group exhibited any signs of excitation. Prophylactic oral ephedrine appears to be a simple method of curtailing hypotensive episodes in patients undergoing spinal anesthesia who are classified by the American Society of Anesthesiologists (ASA) at levels I and II. [32]
Baraka and coworkers from Lebanon compared the influence of prehydration with either hypertonic saline (3% NaCl solution, 7 mL/kg) or normal saline (7 mL/kg) on hemodynamic changes and serum sodium concentration in 33 patients undergoing transurethral resection of the prostate under spinal anesthesia. The incidence of hypotension was less with hypertonic saline, but the difference was not significant. The central venous pressure was significantly elevated before spinal anesthesia in the hypertonic group, but there was no difference in the serum sodium levels between the two groups. Although hypertonic saline can be used to prevent the dilutional hyponatremia associated with surgery for transurethral resection of the prostate, caution should be exercised in the presence of left ventricular dysfunction. [33]
VOLUME AND BARICITY OF LOCAL ANESTHETIC DRUGS There appears to be considerable debate about the optimal volume and baricity of local anesthetic solutions that are needed to provide spinal anesthesia. Several studies have been published to determine the most effective volume and type of local anesthetic drugs that can ensure adequate spinal anesthesia for various types of surgery. Table 7-1 shows a summary of studies that have investigated the extent of sensory and motor blocks with different volumes and types of local anesthetic agents. Attygalle and Rodrigo used the sitting position to administer hyperbaric cinchocaine (2 mL), diluted to either 6 or 8 mL, to two groups of patients who were taller than 150 cm. A significantly higher level of sensory block was noted with the 8 mL volume (P < 0.001), but there was no correlation with the height of the patient. In a subgroup of patients shorter than 150 cm who were given 6 mL of diluted cinchocaine, there was a significant correlation between the patient’s height and the upper level of sensory block achieved. The study showed that the height of a patient should be taken into consideration for short patients when deciding the volume of anesthetic solution in spinal anesthesia. Tay and coworkers investigated three different volumes of dilute bupivacaine 0.125% (obtained by diluting 0.5% bupivacaine with normal saline) in 30 patients undergoing postpartum tubal ligation. The bupivacaine was administered with the patients in a lateral position. A sensory level up to T10 was reliably obtained with 8 and 10 mL for the duration of the surgery, but not with 6 mL. The incidence of high sensory blockade was higher with 10 mL. The optimal volume of bupivacaine 0.125% was found to be 8 mL, and this volume could be recommended as a test dose for epidural analgesia for labor. [34]
[34]
[35]
Amponsah studied the effect of different volumes of lignocaine 2% for spinal anesthesia in 70 patients undergoing lower abdominal and lower limb surgery. The volumes used were 3.0, 3.5, and 4 mL. The levels of sensory blockade were adequate for the intended surgery, and there was no significant difference in the mean levels of analgesia and duration of sensory and motor blockade among the three groups. In another study using plain lignocaine 2%, Imbelloni and Carneiro from Brazil investigated the effect of posture on the extent of sensory blockade. One hundred patients were divided into two groups to receive a fixed dose [36]
[37]
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TABLE 7-1 -- SPINAL ANESTHESIA: THE EFFECT OF DIFFERENT VOLUMES AND CONCENTRATION OF LOCAL ANESTHETIC DRUGS ON THE EXTENT OF BLOCK Local Anesthetic Investigated
Type of Surgery Number of Patients
Investigation
Result
Cinchocaine hyperbaric 2 mL Diluted with CSF 3 groups: up to 8 mL, 6 mL, 6 mL (80%). Both hospitals that responded from the People’s Republic of China (Shanghai and Beijing) reported a rate between 59% and 60%, and the lowest rate ( ropivacaine > mepivacaine > lidocaine > procaine and 2-chloroprocaine. This suggests that the bond between the local anesthetic molecule and the sodium channel receptor protein may be similar to that of local anesthetic binding to plasma proteins; that is, similar areas of amino acid sequences are present. [25]
The degree of protein binding of a particular local anesthetic is concentration-dependent. As the transition from AAG binding to albumin binding occurs, the degree of protein binding becomes consistently less. For example, the commonly accepted value for the degree of protein binding in plasma for lidocaine is 65% (see Fig. 13-6 ); this assumes a concentration of 1 to 2 µg/mL. As the concentration of lidocaine increases to 5 to 10 µg/mL, the protein binding decreases to 40% to 50%. In the case of bupivacaine, at the usually achieved clinical concentration of 1 to 2 µg/mL, the drug is about 95% bound. As the concentration increases to toxic levels (4 to 6 µg/mL), the binding decreases to 80% to 85%. Thus, the free active fraction increases from 5% at the low concentrations of bupivacaine to 15% to 20% at the higher concentrations. Thus, high plasma concentrations of drug potentiate toxicity by markedly increasing the amount of active available drug. [26]
The amide-linked local anesthetics are, in general, degraded by the hepatic endoplasmic reticulum, by the initial reactions involving N-dealkylation, and by subsequent hydrolysis. However, with prilocaine, the initial step is hydrolytic, forming o-toluidine metabolites that can cause methemoglobinemia. Caution is indicated in the extensive use of amide-linked local anesthetics in patients with severe hepatic disease. The amide-linked local anesthetics are extensively (55% to 95%) bound to plasma proteins, particularly α1-acid glycoprotein. Many factors increase the concentration of this plasma protein (cancer, surgery, trauma, myocardial infarction, smoking, uremia) or decrease it (oral contraceptive agents). This results in changes in the amount of anesthetic delivered to the liver for metabolism, thus influencing systemic toxicity. Age-related changes in protein binding of local anesthetics also occur. The neonate is relatively deficient in plasma proteins that bind local anesthetics and therefore has greater susceptibility to toxicity. Plasma proteins are not the sole determinant of local anesthetic availability. Uptake by the lung also may play an important role in the distribution of amide-linked local anesthetics in the body. [27]
[4]
Protein binding is also influenced by the pH of the solution (plasma) so that the percentage of drug bound decreases This is important, because with the development of acidosis (as when a seizure occurs), the as the pH decreases. amount of free active drug remains the same. For example, with lidocaine in the adult, binding at pH 7.4 at a concentration of 5 to 10 µg/mL is 50%, whereas protein binding with a decrease in pH to 7.0 is only 35%. [29] [30]
Compared with lidocaine, the consequences of acidosis on protein binding of bupivacaine are much greater. As the binding decreases from 95% to 70% with acidosis, the amount of free bupivacaine increases from 5% to 30% (a factor of 6), even though the total drug concentration is unchanged. Because of this increase in free drug, acidosis renders bupivacaine markedly more toxic. AAG plasma concentrations are also decreased in pregnant women and in newborns. This lowered concentration effectively increases the free fraction of bupivacaine in plasma, and it may contribute to the observations made several decades earlier that (1) bupivacaine toxicity was more prevalent in pregnant patients and (2) the number of cardiac arrests that took place with inadvertent overdoses of bupivacaine was highest in pregnant women. With the intermediate-duration local anesthetics, such as lidocaine and mepivacaine, smaller changes in protein binding occur during pregnancy, and these agents are not associated with any increased risk of cardiac toxicity during pregnancy. [31]
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Plasma Concentration of Local Anesthetics Plasma concentration is dependent on the following: • The dose of the drug administered • The absorption of the drug from the site injected, which depends on the vasoactivity of the drug, site vascularity, and whether a vasoconstrictor such as epinephrine has been added to the anesthetic solution • Biotransformation and elimination of the drug from the circulation Peak local anesthetic blood levels that develop are directly related to the dose administered at any given site. Doubling of the dose in the same individual at the same site approximately doubles the blood level achieved. Administration of the same dose, however, at different sites results in marked differences in the peak blood levels seen ( Fig. 13-8 ). These differences in blood levels result from differences in the vascularity of the site injected and the vasoactivity of various concentrations of the local anesthetic used. [32] [33]
Generally, the administration of a 100-mg dose of lidocaine in the epidural or caudal space results in approximately a 1-µg/mL peak blood level in an average adult. When this dose is injected into less vascular areas (e.g., for brachial plexus blockade using an axillary approach or for subcutaneous infiltration), a peak blood level of approximately 0.5 µg/mL occurs even
Figure 13-8 Peak blood levels of lidocaine. Average blood levels seen with the injection of 400-mg lidocaine at different sites.(From DeFazio C, Woods A, Rowlingson J: Drugs commonly used for nerve blocking: Pharmacology of local anesthetic. In Raj P [ ed]: Practical Management of Pain, 3rd ed.
though the 100-mg dose has been the same. In contrast, when lidocaine is injected into a highly vascular area (e.g., for an intercostal block), a peak blood level of approximately 1.5 µg/mL occurs with administration of this same 100-mg dose. Peak blood levels after injection into extravascular spaces (e.g., brachial plexus, epidural space, intercostal region) occur 10 to 30 minutes after administration. Peak blood levels achieved may also be affected by the rate at which the local anesthetic drug undergoes biotransformation and elimination. In general, this is the case only for very actively metabolized drugs, such as 2chloroprocaine, which has a plasma half-life of about 45 seconds to 1 minute. Rapid biotransformation of 2chloroprocaine occurs in plasma after absorption, and very low plasma levels result. For amide-linked local anesthetic drugs, such as lidocaine, peak blood levels achieved with regional anesthesia primarily result from absorption. Compared with esters, amide local anesthetic biotransformation is much slower and is a minor contributor to peak plasma levels. Lidocaine biotransformation half-life is approximately 90 minutes. To undergo biotransformation, these drugs must get to the liver, a factor limited by hepatic blood flow. Most of the lidocaine absorbed into the blood stream undergoes redistribution to vessel-rich tissues (e.g., muscle, heart, brain), and only that portion going to the liver is subjected to biotransformation. Renal excretion of lidocaine is small and amounts to approximately 3% to 5% of an injected dose in a 24-hour period. It is important to be aware of the systemic effects of the local anesthetic blood levels that result after various routes of administration. For lidocaine, blood levels of 1 to 5 µg/mL are considered therapeutic in the treatment of patients
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with cardiac arrhythmias and as a supplement to general anesthesia. Blood levels of 3 to 5 µg/mL produce systemic symptoms that include circumoral numbness and buzzing or ringing in the ears. The effects of lidocaine blood levels on the brain are triphasic and are summarized as follows: • At low blood levels, the drug has an anticonvulsant action. • As the concentration of the drug in blood and brain increases, seizures occur.
Undesired Effects of Local Anesthetics In addition to blocking conduction in nerve axons in the peripheral nervous system, local anesthetics interfere with the function of all organs in which conduction or transmission of impulses occurs. Thus, they have important effects on the central nervous system (CNS), the autonomic ganglia, the neuromuscular junction, and all forms of muscle. The danger of such adverse reactions is proportional to the concentration of local anesthetic achieved in the circulation. [28]
[34] [35]
CENTRAL NERVOUS SYSTEM After absorption, local anesthetics may cause stimulation of the CNS, producing restlessness and tremor that may proceed to clonic convulsions. In general, the more potent the anesthetic, the more readily convulsions may be produced. Alterations of CNS activity are thus predictable from the local anesthetic agent in question and the blood concentration achieved. Central stimulation is followed by depression; death is usually caused by respiratory failure. The apparent stimulation and subsequent depression produced by applying local anesthetics to the CNS presumably is due solely to depression of neuronal activity; a selective depression of inhibitory neurons is thought to account for the excitatory phase in vivo. Rapid systemic administration of local anesthetics may produce death with no, or only transient, signs of CNS stimulation. Under these conditions, the concentration of the drug probably rises so rapidly that all neurons are depressed simultaneously. Airway control and support of respiration are essential features of treatment in the late stage of intoxication. Benzodiazepines or rapidly acting barbiturates administered intravenously are the drugs of choice for both the prevention and arrest of convulsions. The benzodiazepines can be administered as a premedication. Although drowsiness is the most frequent complaint that results from the CNS actions of local anesthetics, lidocaine may produce dysphoria or euphoria and muscle twitching. Moreover, both lidocaine and procaine may produce a loss of consciousness that is preceded only by symptoms of sedation. Whereas other local anesthetics also show the effect on the CNS, cocaine has a particularly prominent impact on mood and behavior. [28]
CARDIOVASCULAR SYSTEM After systemic absorption, local anesthetics act on the cardiovascular system. The primary site of action is the myocardium, where decreases in electrical excitability, conduction rate, and force of contraction occur. In addition, most local anesthetics cause arteriolar dilatation. The cardiovascular effects usually are seen only after high systemic concentrations are attained and effects on the CNS are produced. However, on rare occasions, lower doses cause cardiovascular collapse and death, probably due to either an action on the pacemaker or the sudden onset of ventricular fibrillation. However, it should be noted that ventricular tachycardia and fibrillation are relatively uncommon consequences of local anesthetics other than bupivacaine. The effects of local anesthetics such as lidocaine and procainamide, which also are used as antiarrhythmic drugs, are not discussed in this chapter. Finally, it should be stressed that untoward cardiovascular effects of local anesthetic agents may result from their inadvertent intravascular administration, especially if epinephrine also is present. [28]
NEUROMUSCULAR JUNCTION AND GANGLIONIC SYNAPSE Local anesthetics also affect transmission at the neuromuscular junction. Procaine, for example, can block the response of skeletal muscle to maximal motor-nerve volleys and to acetylcholine at concentrations where the muscle responds normally to direct electrical stimulation. Similar effects occur at autonomic ganglia. These effects are due to block of the ion channel of the acetylcholine receptor. [36] [37]
SMOOTH MUSCLE
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The local anesthetics depress contractions in the intact bowel and in strips of isolated intestine. They also relax vascular and bronchial smooth muscle, although low concentrations may initially produce contraction. Spinal and epidural anesthesia, as well as instillation of local anesthetics into the peritoneal cavity, cause sympathetic nervous system paralysis, which can result in increased tone of gastrointestinal musculature. Local anesthetics may increase the resting tone and decrease the contractions of isolated human uterine muscle; however, uterine contractions seldom are depressed directly during intrapartum regional anesthesia. [38]
[28]
Metabolism of Local Anesthetics The metabolic fate of local anesthetics is of great practical importance, because their toxicity depends largely on the balance between their rates of absorption and elimination. As noted earlier, the rate of absorption of many anesthetics can be reduced considerably by the incorporation of a vasoconstrictor agent in the anesthetic solution. However, the rate of destruction of local anesthetics varies greatly, and this is a major factor in determining the safety of a particular agent. Because toxicity is related to the free concentration of drug, binding of the anesthetic to proteins in the serum and to tissues reduces the concentration of free drug in the systemic circulation and, consequently, reduces toxicity. For example, in intravenous regional anesthesia of an extremity, about half of the original anesthetic dose is still tissue-bound 30 minutes after release of the tourniquet; the lungs also bind large quantities of local anesthetic. [27]
ESTER LOCAL ANESTHETICS Ester-linked local anesthetics are hydrolyzed at the ester linkage in plasma by the plasma pseudocholinesterase. This plasma enzyme also hydrolyzes natural choline esters and the anesthetically administered drug succinylcholine. The rate of hydrolysis of ester-linked local anesthetics depends on the type and location of the substitution in the aromatic ring. For example, 2-chloroprocaine is hydrolyzed about four times faster than procaine, which in turn is hydrolyzed about four times faster than tetracaine. In the case of 2-chloroprocaine, the half-life in the normal adult is 45 seconds to 1 minute. In individuals with atypical plasma pseudocholinesterase, the rate of hydrolysis of all the ester-linked local anesthetics is markedly decreased, and a prolonged half-life of these drugs results. Therefore, whereas the potential for toxicity from plasma accumulation of the ester-linked local anesthetics (e.g., 2chloroprocaine) is extremely remote with repeated dosing of the drug in normal individuals, this likelihood should be considered with the administration of large doses or repeated doses to individuals with the atypical pseudocholinesterase enzyme. [39]
The hydrolysis of all ester-linked local anesthetics leads to the formation of para-aminobenzoic acid (PABA) or a substituted PABA. PABA and its derivatives are associated with a low but real potential for allergic reactions. A history of an allergic reaction to a local anesthetic agent should be considered primarily as resulting from the presence of PABA or derived from ester-linked local anesthetics. Allergic reactions may also develop from the use of multiple-dose vials of amide-linked local anesthetics that contain PABA as a preservative. Allergic reactions to amide-linked local anesthetics without preservatives are rare. [40]
AMIDE LOCAL ANESTHETICS In contrast to the ester-linked drugs, the amide-linked local anesthetics must be transported by the circulation to the liver before biotransformation can take place. The two major factors controlling the clearance of amide-linked local anesthetics by the liver are (1) hepatic blood flow (delivery of the drug to the liver) and (2) hepatic function (drug extraction by the liver). Factors that decrease hepatic blood flow or hepatic drug extraction result in an increased elimination half-life. For example, drugs such as general anesthetics, norepinephrine, cimetidine, propranolol, and calcium channel blockers (e.g., diltiazem) all can decrease hepatic blood flow and increase the elimination half-life of the amidelinked local anesthetics. Similarly, decreases in hepatic function caused by a lowering of body temperature, immaturity of the hepatic enzyme system in the fetus, or liver damage (e.g., cirrhosis) lead to a decreased rate of hepatic metabolism of the amide local anesthetics. Renal clearance of unchanged local anesthetics is a minor route of elimination. For example, the amount of unchanged lidocaine excretion in the urine in the adult is small, roughly 3% to 5% of the total drug administered. For bupivacaine, the renal excretion of unchanged drug is also small but somewhat higher, in the 10% to 16% range of the administered dose.
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Lidocaine metabolism occurs after uptake of the drug by the liver. The primary biotransformation step for lidocaine is a dealkylization reaction in which an ethyl group is cleaved from the tertiary amine ( Fig. 13-9 ). Interestingly, this primary step in lidocaine’s biotransformation appears to be only slightly slower in the newborn than in the adult, indicating functional maturity of this particular enzyme system in the newborn. However, an approximately twofold increase in the elimination half-life of lidocaine is seen in the newborn, which is believed to result not from enzymatic immaturity but, instead, to reflect the larger volume of distribution for lidocaine in the newborn. A larger volume of distribution means that a given dose of drug achieves a lower plasma concentration; thus, less drug would be delivered to the liver for metabolism per unit time and to the kidney for excretion. Thus, it takes longer to clear a drug from the body when the drug has a larger volume of distribution. As with the biotransformation of lidocaine, that of
Figure 13-9 Metabolism of lidocaine illustrating a dealkylating reaction.
bupivacaine progresses with a dealkylization reaction as the primary step ( Fig. 13-10 ). Again, in the newborn, an increased volume of distribution is present for bupivacaine and a longer half-life is thus anticipated compared with those expected in the adult. Other reactions in the biotransformation of amide-linked local anesthetics include hydrolysis of the amide-link portion and oxidation of the benzene-ring portion of the drug. The metabolites thus formed can be cleared by the kidney as unchanged or conjugated compounds. For example, when hydroxy derivatives are formed from the oxidation of the benzene ring, they are conjugated and excreted as the glucuronide or sulfate conjugate. With mepivacaine, the primary metabolic pathway is the oxidation of the benzene ring portion of the molecule, producing 3-hydroxy and 4-hydroxymepivacaine. Because this oxidation metabolic pathway is less well developed in the newborn, mepivacaine metabolism occurs more slowly in the newborn than in the adult. Ropivacaine metabolism in humans has been studied extensively ( Fig. 13-11 ). At low plasma concentrations, the drug is primarily metabolized by ring oxidation to 3-hydroxyropivacaine, which is conjugated and excreted in the urine. Significantly less drug is metabolized by dealkylation at low concentrations to PPX. At high concentrations in vitro, dealkylation to PPX becomes an important pathway. The metabolites formed are much less active than ropivacaine, the parent compound. Renal clearance of ropivacaine also is relatively small, with only about 1% of the administered dose excreted unchanged in the urine. [41]
[42]
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The metabolism of local anesthetics, as well as that of many other drugs, occurs in the liver by the cytochrome P450 enzymes (CYP-450). This enzyme family has been subdivided into a number of isoenzymes, with those predominantly involved in local anesthetic biotransformation reactions being CYP-1A2 and CYP-3A4. The predominant cytochrome P-450 isoenzyme present in the human liver is CYP-3A4. This isoenzyme accounts for approximately 30% to 60% of the total cytochrome P-450 content in the liver. It is primarily responsible for the dealkylation reaction in drug metabolism, which, in the case of lidocaine, produces monoethylglycinexylidide (MEGX); with bupivacaine and ropivacaine, PPX is produced. As noted, the dealkylation reaction is the predominant metabolic reaction in the metabolism of lidocaine and bupivacaine. This isoenzyme also metabolizes many other drugs, including nifedipine, felodipine, diazepam, warfarin, and cyclosporine. The other major isoenzyme in the liver is CYP-1A2, which accounts for approximately 10% of the total cytochrome P-450 present in the liver. This isoenzyme produces primarily the hydroxymetabolites of the local anesthetics through an oxidation of the benzene ring. This is a primary pathway in the metabolism of mepivacaine and ropivacaine. Despite the presence of large amounts of the CYP-3A4 isoenzyme in the liver, it is not always the predominant pathway for drug metabolism, because it apparently has a lower affinity for local anesthetics than CYP-1A2. The higher affinity for ropivacaine has been identified with the CYP-1A2 isoenzymes and, with ropivacaine, the predominant biotransformation pathway leads to the formation of a 3-hydroxyropivacaine derivative. Similar predominant CYP-1A2 activity [41]
Figure 13-10 Metabolism of bupivacaine.
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Figure 13-11 Schematic diagram showing the two major pathways of ropivacaine metabolism.
is likely for mepivacaine, because the metabolites for this drug are the 3-hydroxy and 4-hydroxy derivatives of the parent compound. The possibility of clinical drug interactions at the cytochrome P-450 enzyme level exists when other drugs administered at the same time are preferentially metabolized by the CYP-1A2 isoenzyme. This probably occurs because of the low content and high drug affinity of this isoenzyme in the liver. In contrast, the liver has a large capacity for metabolizing drugs by the CYP-3A4 catalyzed reactions. This makes drug interactions with the CYP3A4 isoenzyme very unlikely. The CYP-1A2 isoenzymes also are inducible by many substrates, and the activity of this isoenzyme may increase after the administration of enzyme inducers. Potent inhibitors of this isoenzyme include fluvoxamine, which is available in Europe as a psychotropic drug. Coadministration of local anesthetics metabolized by CYP-1A2 and such inhibitors can lead to marked decreases in drug metabolism. [43]
Biotransformation of local anesthetics such as bupivacaine and lidocaine, which involves a dealkylation reaction as the primary step produced by the cytochrome CYP-3A4 isoenzyme, can occur in newborns at essentially the same rate as in adults.
Central Nervous System Toxicity
HISTORY The long history of spinal anesthesia and the safety of local anesthetics are aptly documented by the Phillips and coworkers, and, more recently, Horlocker and classic studies of Dripps and Vandam, colleagues. The Horlocker study (data collection stopped as of June 1990) reported a frequency of persistent sensory and motor deficits in the range of 0.005% to 0.7%, as had the previous, large-survey studies. None of these reviews encompassed the recent period of time, when serious questions have surfaced about the neurotoxicity of local anesthetics. Previous consideration had been given to this issue with regard to 2-chloroprocaine, but this was settled by a change in the drug’s formulation that In a 1985 rabbit study of the toxicity of clinically used anesthetics, eliminated the offending agent. Ready and associates seemed to exonerate the commercial preparations of local anesthet- ics, although supernormal concentrations of lidocaine and tetracaine in their model did produce irreversible neural injury and histologic change. [44] [45]
[46]
[47]
[48] [49]
[50]
Selander argued in 1993, based on a review of reported complications and animal data, that all local anesthetics could be neurotoxic and suggested that the concentration of the drug and the time of exposure were crucial factors in the pathologic changes. He commented that neural trauma and ischemia were additional factors to be considered (while acknowledging that most cases of alleged neurotoxicity are multifactorial). [51]
The 1991 sentinel report of Rigler and coauthors concerning cauda equina syndrome (consisting of varying degrees of bladder and bowel incontinence, perineal sensory loss, and lower extremity weakness) after continuous spinal anesthetic genuinely refocused scientific and clinical attention on the significance [52]
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of local anesthetic neurotoxicity. The practice of placing microbore catheters for continuous spinal anesthesia had become popular. In this report, three patients who received 175 to 300 mg of intrathecal lidocaine and one who received a total of 37 mg of tetracaine manifested signs and symptoms of cauda equina syndrome. The contributory factors highlighted were nonhomogenous spread of the injectate secondary to slow injections through small needles or catheters, with high concentrations of local anesthetic subsequently being present secondary to the directional spread of the local anesthetic solution proportional to the hyperbaricity. Since the mid-1990s, many reports have been published about the clinical manifestations of local anesthetic toxicity, variously called transient neurologic syndrome (TNS) or transient radicular irritation (TRI). Schneider and coworkers published four more cases of possible transient neurologic toxicity associated with the use of hyperbaric 5% lidocaine in four women undergoing short gynecological surgical procedures in the lithotomy position. It was particularly significant that these patients received low-volume injections of lidocaine that were further diluted in cerebrospinal fluid rather than the high total doses through microbore catheters received by the patients in the Rigler study. The etiologic possibilities for TNS were amplified by the Schneider study, which suggested that positional stretching of the cauda equina was contributory because the position could increase the vulnerability of certain nerve roots to the drugs. Even after enough data had been accumulated that the United States (U.S.) Food and Drug Administration (FDA) removed microbore catheters from clinical practice in May 1992, reports of local anesthetic toxicity did not disappear. [53]
[54]
Hampl and colleagues reported on 270 patients who had undergone gynecologic or obstetric procedures under spinal anesthesia with either 5% lidocaine in 7.5% glucose or 0.5% bupivacaine in 8.5% glucose. When TNS symptoms were sought on postoperative day 3, 37% of the patients who had received lidocaine but only one of 150 patients who had received bupivacaine had such symptoms. It was suggested that the symptoms were related to a specific drug. More important, a standardized description of TNS was proposed: “Transient neurologic symptoms were defined as pain and/or dysesthesia in the buttocks, thighs, or lower limbs occurring after recovery from the anesthetic.” This study was critically reviewed by Carpenter, who detailed variations in anesthetic technique, surgical procedure, and intraoperative management; the lack of randomization of patients in the drug groups; and the nonuse of equipotent doses of local anesthetics as factors to be considered in the interpretation of the results. He also raised the pertinent question as to the actual significance of the syndrome, because no neurologic deficits or functional impairments have been reported and symptoms do not persist. [54]
[55]
Pollock and coauthors performed a prospective, randomized, double-blind study of 159 patients undergoing arthroscopy or inguinal hernia repair with equipotent doses of 5% hyperbaric lidocaine, 2% isobaric lidocaine, or 0.5% bupivacaine. TRI symptoms were not present for more than 4 days in any of the patients. The authors’ findings that only patients who received lidocaine had TRI symptoms and that the incidence was higher in patients having arthroscopy seemed to maintain attention on spinal lidocaine and also suggested that surgical positioning might be a factor in the incidence of the syndrome. The were reports documenting that concentrations of lidocaine less than 5% do not eliminate TRI supported by the Pollock study, in that 16% of patients in both groups receiving lidocaine had TRI symptoms. If one chooses to avoid lidocaine because of concerns about neurotoxicity, it is not reassuring to note that TRI has been reported with bupivacaine, tetracaine, and hyperbaric mepivacaine. In 1998, Hampl and coinvestigators suggested that prilocaine might be a suitable alternative to lidocaine when a short-acting local anesthetic is needed. In their study, the incidence of TRI was equivalent for bupivacaine and prilocaine and definitely less than that associated with lidocaine. [56]
[57] [58]
[56]
[59]
[61]
[60]
[62]
It is prudent to question whether the additives in the local anesthetics used clinically contribute to Initially, epinephrine was not considered to be associated with TRI, but more recent neurotoxicity. basic science data have raised suspicion. Sakura and coworkers provoked the same concerns about phenylephrine (Neo-Synephrine). The glucose that is added to local anesthetics to make them hyperbaric potentially creates a hyperosmolar injury, but this has not been confirmed in studies by Sakura or Hampl and their colleagues. [63] [64]
[65]
[66]
[67] [68]
Large-scale studies should be able to continue to chronicle the safety of regional anesthesia. Auroy and coworkers reported on more than 100,000 regional anesthetic procedures in a survey of French anesthesiologists from whom detailed reports of serious complications from regional anesthesia were sought. In part, the study showed that spinal anesthesia is still associated occasionally with cardiac arrest and neural injury. Two thirds of patients with neural injury had pain on injection or paresthesias. Eisenach, commenting on this report, declared that the data showed that regional anesthesia was safe [68]
[68]
[69]
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and that complications occurred rarely, even when the needle was being placed by an inexperienced practitioner. This conclusion reconfirms that when regional anesthesia is attentively provided, most patients experience little other than the expected effects. Occasionally, and sometimes for reasons not completely understood, unexpected clinical situations arise. We must then maintain our vigilance to observe such events, our integrity to report such events, and our scientific curiosity to seek to explain them.
PHARMACODYNAMICS OF CENTRAL NERVOUS SYSTEM TOXICITY In humans, blood levels of lidocaine associated with the onset of seizures appear to be in the range of 10 to 12 µg/mL. At these blood levels, inhibitory pathways in the brain are selectively impeded, and facilitatory neurons can function unopposed. The seizures that result appear to originate in the amygdala and hippocampus. With lidocaine, prodromal symptoms appear before the onset of seizures and usually include slow speech, jerky movements, tremors, and hallucinations. Although these prodromal symptoms are diagnostically helpful before lidocaine CNS toxicity, they are less consistently seen when other local anesthetics approach their seizure threshold. As the blood levels of lidocaine are increased further, respiratory depression becomes significant at 20 to 25 µg/mL, and at much higher levels, cardiotoxicity is manifest. In contrast, for bupivacaine, blood levels of approximately 4 µg/mL result in seizures, and blood levels of approximately 4 to 6 µg/mL are associated with cardiac toxicity. This is reflective of a much lower therapeutic index for bupivacaine compared with lidocaine in terms of cardiac toxicity. [70]
Treatment of seizures resulting from local anesthetics consists primarily of preventing the detrimental effects of hypoxia that result from seizure activity. The primary concern should be for adequate ventilation with 100% oxygen. Secondarily, suppression of the seizures can be achieved by raising the seizure threshold with a small intravenous dose of either thiopental, 50 to 100 mg, or a benzodiazepine, such as midazolam, 1 to 2 mg, or diazepam, 5 to 10 mg. Because cardiac output and cerebral blood flow are markedly increased during seizure activity when cardiotoxicity has not developed, high levels of local anesthetics in the brain rapidly dissipate and are redistributed to other tissue compartments; however, if drug levels are high enough to cause significant cardiotoxicity, cardiac output is greatly diminished and redistribution is delayed and less helpful. The use of thiopental in this situation can be of concern because it may further depress myocardial function and should be administered judiciously if at all. For patients with severe toxicity, rapid tracheal intubation is performed, usually facilitated by a rapid-acting neuromuscular blocking drug. An additional benefit of muscle paralysis is the cessation of the acidosis produced by tonic-clonic seizure muscle activity. Failure to stop seizure activity can lead to progressive acidosis, which can further potentiate the toxicity of the circulating and intracellular local anesthetic by decreasing the fraction of drug bound to proteins and thus increasing the active free fraction (and concentration) of the local anesthetic. [71] [72] [73]
Cardiotoxicity Concern by anesthesiologists for the cardiotoxicity of the long-acting local anesthetics, such as bupivacaine and etidocaine, followed reports of cardiac arrests with difficult resuscitations in a number of patients. These effects Apparently, these patients had high blood levels of local anesthetic occurred predominantly in pregnant patients. from an unintended intravascular injection of large amounts of drug. Most frequently, this occurred while an epidural anesthetic was being administered or resulted from tourniquet failure during intravenous regional anesthesia. [74] [75]
In subsequent animal studies of local anesthetic cardiotoxicity, all local anesthetics caused a dose-dependent depression of contractility of cardiac muscle. This cardiodepressant effect on contractility paralleled the anesthetic potency of the local anesthetic in blocking nerves. Therefore, bupivacaine, which is four times more potent than lidocaine in blocking nerves, is also four times more cardiodepressant on cardiac contractility. Cases in which the patient died with a bupivacaine overdose, however, have been characterized by a progressive prolongation of ventricular conduction as evidenced by a widening of the QRS complex followed by the sudden onset of arrhythmias such as ventricular fibrillation. Possibly, the delay in ventricular conduction predisposes the patient to reentrant phenomena, leading to ventricular dysrhythmias. [76]
[77]
Experimental in vitro studies have shown that all local anesthetics can produce a dose-dependent depression of cardiac conduction velocity, including the intra-atrial, atrioventricular nodal, His-Purkinje, and intraventricular
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pathways. When the potential for producing this electrophysiologic toxicity was evaluated, bupivacaine was approximately 16 times more toxic than lidocaine. This effect, therefore, is out of proportion to the anesthetic potency of the drug in blocking peripheral nerve conduction. [75]
In studies comparing bupivacaine and ropivacaine, bupivacaine was approximately twice as toxic as ropivacaine in producing these cardiotoxic effects. Recent experimental studies evaluating the S isomer of bupivacaine, in contrast to the racemic mixture of bupivacaine (the commercial preparation), have shown that the S isomer of bupivacaine also is less arrhythmogenic than the R isomer or the racemic mixture of bupivacaine. Further studies are ongoing to assess the commercial potential for the S-bupivacaine. [78]
[79]
In vitro studies have demonstrated that local anesthetics block cardiac sodium channels as well as cardiac calcium channels, and the blockade of these channels is better tolerated for lidocaine than for either bupivacaine or ropivacaine. The best explanation for the differences in toxicity for the local anesthetics was given by Clarkson and Hondeghem, who demonstrated that with depolarization, lidocaine rapidly enters and leaves the open cardiac sodium channels and thus has little long-term cardiac-blocking effects at slow or normal rates. This is described as a fast-in, fast-out effect of the drug. In contrast, bupivacaine also rapidly enters the sodium channel, but because of differences in binding, it is slow to leave and has been classified as a fast-in, slow-out local anesthetic. Thus, bupivacaine strongly blocks inactivated open cardiac channels, and the unbinding of the drug from the channel proteins is slow and thus does not allow an adequate time for recovery during diastole. Both slowed and differential nerve conduction predispose to reentrant dysrhythmias and ventricular fibrillation. [80]
Studies comparing levobupivacaine to racemic bupivacaine indicate that these drugs produce a similar depressant effect on cardiac contractility but different effects on conduction. At high concentrations, racemic bupivacaine was associated with QRS widening and ventricular fibrillation, whereas similar doses of levobupivacaine failed to produce the fatal dysrhythmias seen with the racemic mixture. This has been interpreted as indicating that Rbupivacaine is the major culprit in the cardiotoxicity of this drug. [79]
Some investigators have also speculated that cardiac dysrhythmias may be mediated by local anesthetic effects on the CNS. This is based on animal studies in which the local anesthetic was infused directly into the ventricles of the These arrhythmias were more common when bupivacaine rather than brain and cardiac arrhythmias occurred. lidocaine was used. Although the CNS effects cannot be excluded, these effects are less likely to be the primary event in the production of arrhythmias. In a separate study using an animal model in which the local anesthetic was injected directly into the left anterior descending coronary artery (LAD), the direct effects of various drugs on the left ventricle were evaluated. Independent of the very small CNS effects, local anesthetics administered in the LAD caused slowing of ventricular conduction and, with sufficient doses, produced ventricular fibrillation. [81] [82]
[75]
Increases in the cardiotoxicity of local anesthetics can also be further enhanced by the presence of acidosis, hypoxia, With major overdoses of bupivacaine, a clinical picture of cardiovascular hypercarbia, and hyperkalemia. collapse may result in which the drug-induced myocardial depression is accompanied by systemic vasodilatation and extreme hypotension. It is unlikely that this vasodilatation is produced by the circulating local anesthetic, because in animal studies, these agents produce vasoconstriction at concentrations associated with clinical toxicity. In these studies, vasodilatation did not occur until the concentrations used were several orders of magnitude higher. It is more likely that the peripheral vasodilatation resulted from severe hypoxia and acidosis. This makes it all the more important to take action to reverse these physiologic derangements as rapidly as possible by providing adequate ventilation, seizure termination, fluid support, vasopressor therapy, antiarrhythmic therapy (i.e., with bretylium or magnesium), and inotropic support of the myocardium. [72] [73]
[83]
As a result of bupivacaine administration, cardiotoxicity may be increased during pregnancy. In one study, lower doses of bupivacaine were required to produce cardiovascular collapse in pregnant compared with nonpregnant sheep. When this study was repeated, however, this initial finding was not confirmed. [78]
[84]
CNS convulsions occurred in sheep with significantly lower doses of bupivacaine than with ropivacaine. Similarly, cardiotoxicity required markedly larger doses of ropivacaine than bupivacaine. Successful animal resuscitation after massive bupivacaine overdoses has required multiple doses of epinephrine and atropine. It is beneficial to administer epinephrine directly into the central circulation in patients with shock and hypoperfusion. In the absence of a central venous catheter, this can be achieved by the administration of more drug to the heart than when administration is through a peripheral intravenous catheter. Bretylium has also been suggested for the treatment of serious ventricular tachycardias arising from a local anesthetic overdose of bupivacaine. [85]
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Local Anesthetics These drugs are classified as either ester or amide agents. Clinically useful ester agents are cocaine, procaine, 2chloroprocaine, and tetracaine.
COCAINE Chemistry
Cocaine occurs in abundance in the leaves of the coca shrub and is an ester of benzoic acid and methylecgonine. Ecgonine is an amino alcohol base closely related to tropine, the amino alcohol in atropine. It has the same fundamental structure as the synthetic local anesthetics. Pharmacologic Actions and Preparations
The clinically desired actions of cocaine are the blockade of nerve impulses as a consequence of its local anesthetic properties, and local vasoconstriction secondary to inhibition of local norepinephrine reuptake. Toxicity and the potential for abuse have steadily decreased the clinical uses of cocaine. Its high toxicity is due to block of catecholamine uptake in both the CNS and peripheral nervous system. Its euphoric properties are due primarily to inhibition of catecholamine uptake, particularly dopamine, at CNS synapses. Other local anesthetics do not block the uptake of norepinephrine and do not produce the sensitization to catecholamines, vasoconstriction, or mydriasis characteristic of cocaine. Currently, cocaine is used primarily to provide topical anesthesia of the upper respiratory tract, where its combined vasoconstrictor and local anesthetic properties provide anesthesia and shrinking of the mucosa with a single agent. Cocaine hydrochloride is used as a 1%, 4%, or 10% solution for topical application. For most applications, the 1% or 4% preparation is preferred to reduce toxicity. Because of its abuse potential, cocaine is listed as a schedule II drug by the U.S. Drug Enforcement Agency.
PROCAINE Procaine (Novocain), introduced in 1905, was the first synthetic local anesthetic and is an amino ester ( Fig. 13-12 ). Although it formerly was used widely, its use now is confined to infiltration anesthesia and, occasionally, diagnostic nerve blocks. This is because of its low potency, slow onset, and short duration of action. Although its toxicity is fairly low, it is hydrolyzed in vivo to produce PABA, which inhibits the action of sulfonamides. Thus, large doses should not be administered to patients taking sulfonamide drugs.
2-CHLOROPROCAINE 2-Chloroprocaine (Nesacaine), an ester local anesthetic introduced in 1952, is a chlorinated derivative of procaine (see Fig. 13-12 ). Its major assets are its rapid onset and short duration of action and its reduced acute toxicity due to its rapid metabolism (plasma half-life approximately 25 s). Enthusiasm for its use has been tempered by reports of prolonged sensory and motor block after epidural or subarachnoid administration of large doses.
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Figure 13-12 Local anesthetic chemical structures illustrating ester linkage.
This toxicity appears to have been a consequence of low pH and the use of sodium metabisulfite as a preservative in earlier formulations. There are no reports of neurotoxicity with newer preparations of chloroprocaine, which contain calcium ethylenediaminetetraacetic acid (EDTA) as the preservative, although these preparations also are not recommended for intrathecal administration. A higher-than-expected incidence of muscular back pain after epidural anesthesia with 2-chloroprocaine also has been reported. This back pain is thought to be due to tetany in the paraspinal muscles, which may be a consequence of Ca2+ binding by the EDTA included as a preservative; the incidence of back pain appears to be related to the volume of drug injected and its use for skin infiltration. [86]
Pharmacology and Pharmacodynamics
2-chloroprocaine is procaine with the addition of a chlorine group to the benzene ring. This drug has a very rapid onset of action and a short duration of activity (30–60 min). Once absorbed into the circulation, the drug is rapidly metabolized. The approximate half-life in plasma in adults is 45 seconds to 1 minute; hence, it is the most rapidly metabolized local anesthetic currently used. Because of this extremely rapid breakdown in plasma, it has very low potential for systemic toxicity and has been particularly attractive to obstetric anesthesiologists for use when elevated maternal blood levels of local anesthetic can cause major problems for the fetus and mother. This drug is also frequently used for epidural and peripheral blocks in an ambulatory care setting when short duration of anesthesia is needed and rapid recovery is highly desirable. The epidural use of this drug, however, has been limited because of several reported problems. Prolonged and profound motor and sensory deficits occurred with the unintentional subarachnoid injection of the original 2chloroprocaine commercial preparation marketed with the preservative bisulfite. The classic work by Gissen and coworkers and Wang and colleagues demonstrated that bisulfite in the presence of a highly acidic solution releases sulfur dioxide (SO2 ), which equilibrates in solution into sulfurous acid, which is neurotoxic. Gissen postulated that the injection of the highly acidic commercial 2-chloroprocaine (pH 3) solution into the spinal sac resulted in the slow formation of and prolonged exposure to sulfurous acid, causing spinal cord damage. More recently, a 2-chloroprocaine preparation was released in which the bisulfite was removed and EDTA was substituted as the preservative. This change, however, has not been totally satisfactory because there appears to be a significant occurrence of back muscle spasm after epidural application of this formulation. It has been postulated that the EDTA in this commercial preparation binds calcium and causes spasm in the paraspinal muscles. [48]
[87]
[88]
A new 2-chloroprocaine commercial preparation has been released from which all preservatives have been removed. Initial studies with this formulation appear to be promising. No preparations of 2-chloroprocaine are recommended for either spinal or intravenous regional anesthesia.
TETRACAINE Tetracaine is the butyl amino derivative of procaine (see Fig. 13-12 ). Tetracaine (Pontocaine), introduced in 1932, is a long-acting amino ester. It is significantly more potent and has a longer duration of action than procaine.
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Tetracaine has an increased toxicity because it is more slowly metabolized than the other commonly used ester local anesthetics. Currently, it is widely used in spinal anesthesia when a drug of long duration is needed. Tetracaine also is incorporated into several topical anesthetic preparations. With the introduction of bupivacaine, tetracaine is rarely used in peripheral nerve blocks because of its slow onset and toxicity. The drug is a potent long-acting local anesthetic and has been widely used mainly for spinal anesthesia in a dose of 6 to 15 mg in adults. Clinically, such drug administration produces a high degree of motor blockade. Tetracaine has also been used as a 0.2% to 0.5% solution for epidural anesthesia; however, it is not consistently considered adequate for this purpose because of its slow onset of action and its tendency to produce spotty sensory anesthesia. Many otolaryngologists use this drug to produce topical anesthesia in the upper airway.
Amide Local Anesthetics LIDOCAINE Lidocaine (Xylocaine), introduced in 1948, is now the most widely used local anesthetic. The chemical structure of lidocaine is shown in Figure 13-13 . Pharmacologic Actions
The pharmacologic actions that lidocaine shares with other local anesthetic drugs have been described widely. Lidocaine produces faster, more intense, longer lasting, and more extensive anesthesia than does an equal concentration of procaine. Unlike procaine, it is an aminoethylamide and is the prototypical member of this class of local anesthetics. It is a good choice for individuals sensitive to ester-type local anesthetics. Absorption, Fate, and Excretion
Lidocaine is absorbed rapidly after parenteral administration and from the gastrointestinal and respiratory tracts. Although it is effective when used without any vasoconstrictor, in the presence of epinephrine, the rate of absorption and the toxicity are decreased, and the duration of action usually is prolonged. Lidocaine is dealkylated in the liver by mixed-function oxidases to monoethylglycine xylidide and glycine xylidide, which can be metabolized further to monoethylglycine and xylidide. Both monoethylglycine xylidide and glycine xylidide retain local anesthetic activity. In human beings, about 75% of xylidide is excreted in the urine as the further metabolite, 4-hydroxy-2,6dimethylaniline. [27]
Toxicity
The side effects of lidocaine seen with increasing dose include drowsiness, tinnitus, dysgeusia, dizziness, and twitching. As the dose increases, seizures, coma, and respiratory depression and arrest will occur. Clinically significant cardiovascular depression usually occurs at serum lidocaine levels that produce marked CNS effects. The metabolites monoethylglycine xylidide and glycine xylidide may contribute to some of these side effects. Clinical Uses
Lidocaine has a wide range of clinical uses as a local anesthetic; it has utility in almost any application in which a local anesthetic of intermediate duration is needed. Lidocaine also is used as an antiarrhythmic agent.
MEPIVACAINE Mepivacaine (Carbocaine, others), introduced in 1957, is an intermediate-acting amino amide (see Fig. 13-13 ).
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Figure 13-13 Local anesthetic chemical structures illustrating amide linkage and indicating an asymmetrical carbon atom (asterisk) when present.
Its pharmacologic properties are similar to those of lidocaine. Mepivacaine, however, is more toxic to the neonate and thus is not used in obstetric anesthesia. The increased toxicity of mepivacaine in the neonate is related not to its slower metabolism in the neonate, but to ion trapping of this agent because of the lower pH of neonatal blood and the pKa of mepivacaine. Despite its slow metabolism in the neonate, it appears to have a slightly higher therapeutic index in adults than lidocaine. Its onset of action is similar to that of lidocaine and its duration slightly longer (about 20%) than that of lidocaine in the absence of a coadministered vasoconstrictor. Mepivacaine is not effective as a topical anesthetic.
PRILOCAINE Prilocaine (Citanest) is an intermediate-acting amino amide (see Fig. 13-13 ). It has a pharmacologic profile similar to that of lidocaine. The primary differences are that it causes little vasodilatation and thus can be used without a vasoconstrictor, if desired, and its increased volume of distribution reduces its CNS toxicity, making it suitable for intravenous regional blocks (see later). It is unique among the local anesthetics for its propensity to cause methemoglobinemia. This effect is a consequence of the metabolism of the aromatic ring to o-toluidine. Development of methemoglobinemia is dependent on the total dose administered, usually appearing after a dose of 8 mg/kg. In healthy persons, methemoglobinemia is usually not a problem. If necessary, it can be treated by the intravenous administration of methylene blue (1 to 2 mg/kg). Methemoglobinemia after prilocaine administration has limited its use in obstetric anesthesia because it complicates evaluation of the newborn. Also, methemoglobinemia is more common in neonates because of decreased resistance of fetal hemoglobin to oxidant stresses and the immaturity of enzymes in the neonate that convert methemoglobin back to the ferrous state. The amino amide agents are metabolized primarily in the liver. Patient age may influence the physiologic disposition of local anesthetics. [35]
ETIDOCAINE Etidocaine (Duranest), introduced in 1972, is a long-acting amino amide (see Fig. 13-13 ). Its onset of action is faster than that of bupivacaine and comparable with that of lidocaine, yet its duration of action is similar to that of bupivacaine. Compared with bupivacaine, etidocaine produces preferential motor blockade. Thus, although it is useful for surgery requiring intense skeletal muscle relaxation, its utility in labor or postoperative analgesia is limited. Its cardiac toxicity is similar to that of bupivacaine (see earlier). Etidocaine is structurally similar to lidocaine (see Fig. 13-13 ), with alkyl substitution on the aliphatic connecting group between the hydrophilic amine and the amide linkage. This increases the drug’s lipid solubility and results in
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a drug more potent than lidocaine that has a very rapid onset of action and a prolonged duration of anesthesia. Because etidocaine produces rapid profound motor and sensory blockade at all of its clinical concentrations, it is unacceptable for obstetric anesthesia when motor blockade is undesirable. In addition, motor blockade has been observed in many instances to far outlast sensory blockade, thus causing significant postoperative patient anxiety during recovery. Some practitioners have found it helpful to take advantage of the rapid onset of anesthesia and the significant motor blocking effect associated with etidocaine administration by using it for lengthy procedures to induce epidural anesthesia and then substituting bupivacaine or lidocaine for subsequent doses to maintain an adequate sensory level without undue prolongation of motor block on recovery. The addition of epinephrine to etidocaine solutions produces a 50% increase in duration of brachial plexus blockade but only a 10% to 15% increase in duration of epidural blockade. This effect, as with bupivacaine, stems from significant solubility into the high fat content of the epidural space by a highly lipid-soluble drug. [63]
BUPIVACAINE Bupivacaine (Marcaine, Sensorcaine), introduced in 1963, is a widely used amide local anesthetic; its structure is similar to that of lidocaine, except the amine-containing group is a butyl piperidine (see Fig. 13-13 ). It is a potent agent capable of producing prolonged anesthesia. Its long duration of action plus its tendency to provide more sensory than motor block has made it a popular drug for providing prolonged analgesia during labor or the postoperative period. With use of indwelling catheters and continuous infusions, bupivacaine can be used to provide several days of effective analgesia. Bupivacaine was developed as a modification of mepivacaine. Its structural similarities to mepivacaine are readily apparent. Bupivacaine has a butyl (four-carbon substitution) group on the hydrophilic nitrogen. Bupivacaine has made a contribution to regional anesthesia second in importance only to lidocaine. It is one of the first of the clinically used local anesthetic drugs to provide good separation of motor and sensory blockade after administration. The onset of anesthesia and the duration of action are long and can be further prolonged by the addition of epinephrine in areas with a low fat content. Only small increases in duration are seen when bupivacaine is injected into areas with a high fat content. For example, a 50% increase in duration of brachial plexus blockade (an area of low fat content) occurs after the addition of epinephrine to bupivacaine solutions; in contrast, only a 10% to 15% increase in duration of epidural anesthesia results from the addition of epinephrine to bupivacaine solutions, because the epidural space has a high fat content. Toxicity
Bupivacaine is more cardiotoxic than equieffective doses of lidocaine. Clinically, this is manifested by severe ventricular arrhythmias and myocardial depression after inadvertent intravascular administration of large doses of bupivacaine. The enhanced cardiotoxicity of bupivacaine probably is due to multiple factors. Lidocaine and bupivacaine both block cardiac Na+ channels rapidly during systole. However, bupivacaine dissociates much more slowly than lidocaine during diastole, so a significant fraction of Na+ channels remain blocked at the end of diastole (at physiologic heart rates) with bupivacaine. Thus, the block by bupivacaine is cumulative and substantially greater than would be predicted by its local anesthetic potency. At least a portion of the cardiotoxicity of bupivacaine may be mediated centrally, because direct injection of small quantities of bupivacaine into the medulla can produce malignant ventricular arrhythmias. Bupivacaine-induced cardiotoxicity can be very difficult to treat, and its severity is enhanced in the presence of acidosis, hypercarbia, and hypoxemia. [80]
[81]
Clinical Uses
In the United States, bupivacaine is used mainly for obstetric anesthesia and postoperative pain control when analgesia without significant motor blockade is highly desirable and achievable with low bupivacaine concentrations. In contrast to lidocaine, however, when high blood levels occur with bupivacaine, a higher incidence of cardiotoxic effects is seen. Bupivacaine has a poorer therapeutic index than lidocaine in producing electrophysiologic toxicity of the heart. Although bupivacaine metabolism is slower in the fetus and newborn than in the adult, active biotransformation is accomplished by the fetus and newborn. [89]
A second major role of bupivacaine is in subarachnoid anesthesia. It produces very reliable onset of anesthesia within 5 minutes, and the duration of anesthesia is approximately 3 hours. In many ways, it is similar to tetracaine; however, the dose of bupivacaine required is somewhat larger, specifically, 10 mg of tetracaine is approximately equal to 12 to 15 mg of bupivacaine. The onset of sympathetic blockade after spinal anesthesia appears to be more
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gradual with bupivacaine than with tetracaine. Also, the sensory blockade produced by bupivacaine lasts longer than the motor blockade, which is in contrast to what occurs with etidocaine and tetracaine. Bupivacaine can be used for subarachnoid anesthesia in either the glucose-containing hyperbaric solution (0.75%) or with the isobaric solution by using the drug packaged for epidural use as a 0.25% or a 0.5% concentration.
Newer Local Anesthetics: Chiral Forms An area of newfound importance for anesthesiologists is in the use of stereoisomers of drugs to take advantage of differences in activity or toxicity of the isomers. For stereoisomerism to be present, an asymmetrical carbon (a carbon atom in the molecule that has four distinctly different substitution groups) must be present in the molecule. Stereoisomers are possible for the local anesthetics etidocaine, mepivacaine, bupivacaine, prilocaine, and, ropivacaine, and some of these drugs have differences in potency or toxicity for the isomers. For these local anesthetics, the asymmetrical carbons are indicated in Figure 13-14 by an asterisk. In the older literature, isomers were described as L and D on the basis of chemical configuration and as (+) or (−) on the basis of topical rotation (i.e., L [+] or D [−]). More recent literature describes isomers as R or S, and the optical rotation is still included in the parentheses as (+) and (−). R and S basically correspond to the D and L in the older nomenclature. As a rule, when differences between the activity of isomers are present for local anesthetics, the S form is less toxic For instance, anesthesia produced by bupivacaine infiltration was of and has a longer duration of anesthesia. longer duration compared with the R isomer when the S isomer was used. Also, the S isomer had lower systemic toxicity. The mean convulsant dose of R-bupivacaine was 57% of the S-bupivacaine convulsant dose. When the isomers of ropivacaine were evaluated, the S isomer of the drug had a longer duration of blockade and a lower toxicity than its R isomer. Additionally, when cardiac electrophysiologic toxicity was evaluated in animal studies, ropivacaine (the commercial preparation is the S form of drug) at equipotent nerve-blocking doses appeared to have a safety margin that was almost twice that of commercial bupivacaine, which is a mixture of the R and S isomers. Studies with the R and S bupivacaine isomers indicate that the R form is apparently more arrhythmogenic and more cardiotoxic. Further evaluation of the isomers of bupivacaine is necessary before commercial use can be achieved. [90] [91]
[92]
[93]
[93]
[79] [94]
ROPIVACAINE The cardiotoxicity of bupivacaine stimulated interest in developing a less toxic, long-lasting local anesthetic.
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Figure 13-14 Stereoisomers are possible for the aforementioned local anesthetics. The asymmetrical carbons are indicated in this figure by an asterisk.
The result of that search was the development of a new amino ethylamine, ropivacaine ( Fig. 13-15 ), the Senantiomer of 1-propyl-2′,6′-pipecolocylidide. The S-enantiomer, like most local anesthetics with a chiral center, was chosen because it has a lower toxicity than the R isomer. This is presumably because of slower uptake, resulting in lower blood levels for a given dose. Ropivacaine is slightly less potent than bupivacaine in producing anesthesia. In several animal models, it appears to be less cardiotoxic than equieffective doses of bupivacaine. In clinical studies, ropivacaine appears to be suitable for both epidural and regional anesthesia, with duration of action similar to that of bupivacaine. Interestingly, it seems to be even more motor-sparing than bupivacaine. Ropivacaine is a long-acting, enantiomerically pure (S-enantiomer) amide local anesthetic with a high pKa and low lipid solubility, which blocks nerve fibers involved in pain transmission (A∆ and C fibers) to a greater degree than those controlling motor function (Aβ fibers). The drug was less cardiotoxic than equal concentrations of racemic bupivacaine but more so than lidocaine (lignocaine) in vitro and had a significantly higher threshold for CNS toxicity than racemic bupivacaine in healthy volunteers (mean maximal tolerated unbound arterial plasma concentrations were 0.56 and 0.3 mg/L, respectively). Extensive clinical data have shown that epidural ropivacaine (0.2%) is effective for the initiation and maintenance of labor analgesia, and provides pain relief after abdominal or orthopedic surgery, especially when given in conjunction with opioids (coadministration with opioids may also allow lower concentrations of ropivacaine to be used). The drug had efficacy generally similar to that of the same dose of bupivacaine with regard to pain relief but caused less motor blockade at low concentrations.
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Lumbar epidural administration of 20 to 30 mL ropivacaine (0.5%) provided anesthesia of a similar quality to that achieved with bupivacaine (0.5%) in women undergoing cesarean section, but the duration of motor blockade was shorter with ropivacaine. For lumbar epidural anesthesia for lower limb or genitourinary surgery, comparative data suggest that higher concentrations of ropivacaine (0.75% or 1.0%) may be needed to provide the same sensory and motor blockade as bupivacaine (0.5% and 0.75%). In patients about to undergo upper limb surgery, 30 to 40 mL of ropivacaine (0.5%) produced brachial plexus anesthesia broadly similar to that achieved with equivalent volumes of bupivacaine (0.5%), although the time to onset of sensory block tended to be faster and the duration of motor block shorter with ropivacaine. Ropivacaine had an adverse event profile similar to that of bupivacaine in clinical trials. Several cases of CNS toxicity were reported after inadvertent intravascular administration of ropivacaine, but only one case of cardiovascular toxicity has been reported to date. The outcome of these inadvertent intravascular administrations was favorable. The conclusion is that ropivacaine is a well-tolerated regional anesthetic with an efficacy broadly similar
Figure 13-15 It is the S-enantiomer r of 1-propyl-2′, -6′-pipecolocylidide.
to that of bupivacaine. However, it may be a preferred option because of its reduced CNS and cardiotoxic potential and its lower propensity for motor block. Pharmacodynamic Properties
The amide local anesthetic, ropivacaine, reversibly blocks nerve impulse conduction by reducing nerve cell 8.2) and low membrane permeability to sodium ions. In vitro studies have shown that, because of its high pKa ( lipid solubility, the drug preferentially blocks nerve fibers responsible for pain transmission (Aβ and C fibers) rather than motor function (A∆ fibers). In isolated rabbit vagus nerve, ropivacaine caused significantly less blockade of motor fibers than bupivacaine (P = 0.0001) but had a similar effect on sensory fibers. Ropivacaine appears to be less cardiotoxic than equal concentrations of racemic bupivacaine (because of its faster dissociation from cardiac Na+ channels) but more cardiotoxic than lidocaine (lignocaine). The drug had a smaller effect on QRS prolongation than bupivacaine in healthy volunteers (+ 2.4 % vs. + 6%: P < 0.05). CNS toxicity occurs at lower plasma concentrations than cardiotoxicity with all local anesthetics; ropivacaine and bupivacaine caused seizures at lower concentrations than lidocaine in dogs. In healthy volunteers, ropivacaine had a significantly higher threshold for CNS toxicity (lightheadedness, tinnitus, and numbness of the tongue) than bupivacaine, with mean maximum tolerated unbound arterial plasma concentrations of 0.56 and 0.3 mg/L, respectively (P < 0.001). Ropivacaine has a biphasic vascular effect, causing vasoconstriction at low concentrations but not at higher concentrations. Importantly, epidural ropivacaine 0.5% did not compromise uteroplacental circulation in healthy pregnant women. Pharmacokinetic Properties
After epidural administration in women undergoing cesarean section, mean maximum plasma concentrations (Cmax ) of 1.1 to 1.6 mg/L were reached after administration of 20 to 28 mL ropivacaine (0.5 or 0.75%). The drug also underwent a degree of systemic absorption after intercostal, subclavian perivascular, peribulbar, intra-articular, or
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local administration. However, because ropivacaine is extensively (90%–94%) bound to plasma proteins (mostly α1 acid glycoprotein) after systemic absorption. Cmax for unbound drug remained well below the threshold for CNS 0.6 mg/L) regardless of the route of administration. Like bupivacaine, toxicity reported in volunteers ( ropivacaine crosses the human placenta. Mean total body clearance and terminal elimination half-life of ropivacaine after epidural administration in pregnant women ranged from 13.4 to 19.8 L per hour and 5 to 7 hours, respectively. Ropivacaine undergoes extensive hepatic metabolism after intravenous administration, with only 1% of the drug eliminated unchanged in the urine. Two cytochrome P450 (CYP-450) isoenzymes, CYP-1A2 and CYP-3A4, are responsible for the formation of major (3-hydroxy-ropivacaine) and minor metabolites, respectively. Agents that inhibit these isozymes (particularly CYP-1A2) have the potential to affect the pharmacokinetic profile of ropivacaine. Accordingly, coadministration of fluvoxamine, a CYP-1A2 inhibitor, significantly increased total plasma concentrations of intravenous ropivacaine by 16% and delayed its elimination. Anesthesia
Lumbar epidural administration of 20 or 30 mL ropivacaine (0.5%) provided anesthesia of a similar quality to that achieved with bupivacaine (0.5%) in women undergoing cesarean section, without affecting neonatal outcome. The drugs had comparable effects on sensory blockade, but motor blockade tended to be shorter with ropivacaine. Lumbar epidural ropivacaine (0.5% to 1%) also provided effective anesthesia for lower limb or genitourinary surgery, although comparative data suggests that higher doses of ropivacaine (0.75% or 1%) may be needed to provide the same pattern of sensory and motor blockade as bupivacaine (0.5% and 0.75%) in these patients. In patients about to undergo upper limb surgery, 30 to 40 mL ropivacaine (0.5%) produced a pattern of brachial plexus anesthesia broadly equivalent to that achieved with bupivacaine (0.5%) whether administered via the subclavian perivascular, axillary or interscalenic approach. The onset of sensory blockade tended to be faster and the duration of motor blockade shorter with ropivacaine, but between-group differences only reached statistical significance in one study. In noncomparative studies, anesthesia of brachial plexus dermatomes was achieved in greater than or equal to 86% of patients who received 30 to 33 mL ropivacaine (0.5%) via the subclavian perivascular route. Limited data indicate that 25 to 30 mL ropivacaine (0.75%) had an onset of sensory block similar to that of the fast 25 mL) when used for combined sciatic-femoral nerve onset/medium duration local anesthetic mepivacaine 2% ( block for lower limb surgery, but ropivacaine provided longer postoperative analgesia. This advantage was offset by a longer time to resolution of foot motor block. Limited data suggest that ropivacaine (0.5%) has an anesthetic efficacy similar to that of bupivacaine (0.5%) when used for combined lumbar plexus-sciatic nerve block (for knee surgery) and 3-in-1 block (for hip surgery after trauma). Results from a number of well-controlled trials suggest that 5 to 10 mL ropivacaine (1%) (alone or with lidocaine) provides a quality of peribulbar anesthesia at least similar to that achieved with 5 to 10 mL bupivacaine (0.5% or 0.75%) (alone or with lidocaine) in patients undergoing eye surgery. Therapeutic Efficacy
Ropivacaine has been extensively evaluated for use as an analgesic (for labor or postoperative pain) and as a regional anesthetic during a variety of surgical procedures. Analgesia. Epidural ropivacaine (0.2%) provided adequate pain relief when used for the initiation (10 to 18 mL) and maintenance (4 to 10 mL/hr) of labor analgesia and had efficacy generally similar to that of the same dose of bupivacaine with regard to pain relief and motor blockade (mild) in comparative studies. Ropivacaine, like bupivacaine, had no significant effects on neonatal outcome. Coadministration with opioids such as fentanyl and sufentanil improved labor analgesia and allowed a lower concentration of the anesthetic to be used (at these lower concentrations ropivacaine caused less motor blockade than bupivacaine). Lumbar or thoracic epidural ropivacaine (0.1%, 0.2%, and 0.3%) infused at 10 mL per hour for 24 hours after abdominal or orthopedic surgery reduced morphine requirements (the primary end-point) compared with placebo. The incidence of motor block increased with increasing dose but did not differ significantly from that reported in placebo recipients. Results from comparative studies suggest that epidural ropivacaine (0.2%) is more effective than
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patient-controlled intravenous morphine for postoperative pain relief. As for labor pain, combination with opioids is effective and may allow a lower concentration of ropivacaine to be used for the same level of pain relief. Preoperative (along the intended line of the incision) or postoperative wound infiltration of 30 to 40 mL of ropivacaine (0.25% or 0.5%) dose-dependently relieved postoperative pain after hernia repair; a higher concentration (0.75%) was as effective as bupivacaine (0.25%). Evidence published in abstract form suggests that preoperative infiltration of the incision line using ropivacaine may also provide pain relief after thoracic surgery, breast reconstruction, or lower back surgery, and postoperative wound infiltration alleviates pain after shoulder surgery. Evidence indicates that epidural ropivacaine (0.2% and 0.25%) (2 and 2.5 mg/kg) may provide effective postoperative analgesia when given via the caudal route in children undergoing minor surgery, and by the lumbar route in those undergoing major surgery. Importantly, motor block on awakening was minimal with ropivacaine in these studies.
Tolerability
Ropivacaine was well tolerated in clinical trials, although few studies provided detailed tolerability data. Hypotension was the most commonly reported adverse event in studies of epidural ropivacaine, but this was most likely a consequence of sympathetic block (common to all local anesthetics). Other reported events included nausea, vomiting, paresthesia, urinary retention, and bradycardia. The tolerability profile of ropivacaine was similar to that of bupivacaine in comparative studies. Limited evidence also suggests that the drug is well tolerated after brachial plexus block, intrathecal administration, lumbar plexus-sciatic nerve block, local wound infiltration and peribulbar administration. The clinical experiences from 60 studies involving 3000 patients showed that accidental intravascular administration of ropivacaine occurred in six patients. Only one patient convulsed and none showed signs of cardiotoxicity at doses of 75 to 200 mg. The outcome of all six patients to these reactions was good. Consistent with preclinical evidence that cardiovascular toxicity occurs at higher plasma concentrations than CNS toxicity, only one case of cardiovascular toxicity after intravascular administration of ropivacaine has been reported to date. Dosage and Administration
Ropivacaine (0.2%) is recommended for epidural analgesia administered via either lumbar or thoracic routes (6 to 14 mL/hr) after surgery for postoperative pain and via the lumbar route for labor pain (10 to 20 mL bolus and then 6 to 14 mL/hr plus top-up if required). For anesthesia during cesarean section, ropivacaine 0.75% (15 to 20 mL) is recommended. This concentration is also recommended for major or minor nerve block and wound infiltration, whereas ropivacaine (0.75% and 1.0%) can be used for lumbar epidural anesthesia during other types of surgery. Administration of ropivacaine to children younger than 12 years of age or for spinal anesthesia in adults is not yet recommended.
LEVOBUPIVACAINE Levobupivacaine (Chirocaine) injection contains a single enantiomer of bupivacaine hydrochloride, which is chemically described as (S)-1-butyl-2-piperidylformo-2′,6′-xylidide hydrochloride and is related chemically and pharmacologically to the amino amide class of local anesthetics ( Fig. 13-16 ).
Figure 13-16 A single enantiomer of bupivacaine hydrochloride chemically described as (s)-1butyl-2-piperidylformo-2′, 6′-xylidide hydrochloride.
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Levobupivacaine hydrochloride, the S-enantiomer of bupivacaine, is a white crystalline powder with a molecular formula of C18 H28 N2 O − HCl and a molecular weight of 324.9. The solubility of levobupivacaine hydrochloride in water is about 100 mg per mL at 20°C, the partition coefficient (oleyl alcohol/water) is 1624, and the pKa of levobupivacaine hydrochloride is the same as that of bupivacaine hydrochloride and the partition coefficient is very similar to that of bupivacaine hydrochloride (1565). Levobupivacaine is a sterile, nonpyrogenic, colorless solution (pH 4.0–6.5) containing levobupivacaine hydrochloride equivalent to 2.5 mg/mL, 5.0 mg/mL, and 7.5 mg/mL of levobupivacaine, sodium chloride for isotonicity, and water for injection. Sodium hydroxide, hydrochloric acid, or both may have been added to adjust pH. Levobupivacaine is preservative free and is available in 10-mL and 30-mL single-dose vials. Clinical Pharmacology
Mechanism of Action.Levobupivacaine is a member of the amino amide class of local anesthetics. Local anesthetics block the generation and the conduction of nerve impulses by increasing the threshold for electrical excitation in the nerve, by slowing propagation of the nerve impulse, and by reducing the rate of rise of the action potential. In general, the progression of anesthesia is related to the diameter, myelination, and conduction velocity of affected nerve fibers. Clinically, the order of loss of nerve function is as follows: (1) pain, (2) temperature, (3) touch, (4) proprioception, and (5) skeletal muscle tone. Pharmacokinetics.After intravenous infusion of equivalent doses of levobupivacaine and bupivacaine, the mean clearance, volume of distribution, and terminal half-life values of levobupivacaine and bupivacaine were similar. No detectable levels of R(+ )-bupivacaine were found after the administration of levobupivacaine. A comparison of the estimates for plasma area under the curve (AUC) and Cmax between levobupivacaine and bupivacaine in two phase III clinical trials involving short-duration administration of either agent found that neither total plasma exposure or Cmax differed between the two drugs when they were compared within studies. Betweenstudy values differed somewhat, likely due to differences in the injection sites, volume, and total dose administered in each of the studies. These data suggest that levobupivacaine and bupivacaine have similar pharmacokinetic profiles. Between 0.5% and 0.75% of levobupivacaine given epidurally at doses of 75 mg and 112.5 mg respectively, the mean Cmax and AUC0–24 of levobupivacaine were approximately dose-proportional. Similarly, between 0.25% and 0.5% of levobupivacaine used for brachial plexus block at doses of 1 mg/kg and 2 mg/kg respectively, the mean Cmax and AUC0–24 of levobupivacaine were approximately dose-proportional. Absorption. The plasma concentration of levobupivacaine after therapeutic administration depends on dose and also on route of administration, because absorption from the site of administration is affected by the vascularity of the tissue. Peak levels in blood were reached approximately 30 minutes after epidural administration, and doses up to 150 mg resulted in mean Cmax levels of up to 1.2 µg/mL. Distribution.Plasma protein binding of levobupivacaine evaluated in vitro was found to be greater than 97% at concentrations between 0.1 and 1 µg/mL. The association of levobupivacaine with human blood cells was very low (0%–2%) over the concentration range 0.01–1 µg/mL and increased to 32% at 10 µg/mL. The volume of distribution of levobupivacaine after intravenous administration was 67 L. Metabolism.Levobupivacaine is extensively metabolized with no unchanged levobupivacaine detected in urine or feces. In vitro studies using [14 C]levobupivacaine showed that CYP-3A4 isoform and CYP-1A2 isoform mediate the metabolism of levobupivacaine to desbutyl levobupivacaine and 3-hydroxy levobupivacaine, respectively. In vivo, the 3-hydroxy levobupivacaine appears to undergo further transformation to glucuronide and sulfate conjugates. Metabolic inversion of levobupivacaine to R(+ )-bupivacaine was not evident either in vitro or in vivo. Elimination.After intravenous administration, recovery of the radiolabeled dose of levobupivacaine was essentially quantitative, with a mean total of about 95% recovered in urine and feces in 48 hours. Of this 95%, about 71% was in urine, whereas 24% was in feces. The mean elimination half-life of total radioactivity in plasma was 3.3 hours. The mean clearance and terminal half-life of levobupivacaine after intravenous infusion were 39 L per hour and per 1.3 hours, respectively. Pharmacodynamics.Levobupivacaine can be expected to share the pharmacodynamic properties of other local anesthetics. Systemic absorption of local anesthetics can produce effects on the CNS and the cardiovascular system.
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At blood concentrations achieved with therapeutic doses, changes occur in cardiac conduction. Excitability, refractoriness, contractility, and peripheral vascular resistance have been reported. Toxic blood concentrations depress cardiac conduction and excitability, which may lead to atrioventricular block, ventricular arrhythmias, and cardiac arrest, sometimes resulting in death. In addition, myocardial contractility is depressed and peripheral vasodilation occurs, leading to decreased cardiac output and arterial blood pressure. After systemic absorption, local anesthetics can produce CNS stimulation, depression, or both. Apparent CNS stimulation is usually manifested as restlessness, tremors, and shivering, progressing to convulsions. Ultimately, CNS depression may progress to coma and cardiorespiratory arrest. However, the local anesthetics have a primary depressant effect on the medulla and on higher centers. The depressed stage may occur without a prior excited stage. In nonclinical pharmacology studies comparing levobupivacaine and bupivacaine in animal species, both the CNS and the cardiotoxicity of levobupivacaine were less than that of bupivacaine. Arrhythmogenic effects were seen in animals at higher doses of levobupivacaine than bupivacaine. Animal data comparing the difficulty of resuscitation from levobupivacaine- and bupivacaine-induced arrhythmia are not available. CNS toxicity occurred with both drugs at lower doses and at lower plasma concentrations than those doses and plasma concentrations associated with cardiotoxicity. In two intravenous infusion studies in conscious sheep, the convulsive doses of levobupivacaine were found to be significantly higher than for bupivacaine. After repeated intravenous bolus administration mean (± SD) convulsive doses for levobupivacaine and bupivacaine were 9.7 (7.9) mg/kg and 6.1 (3.4) mg/kg, respectively. The associated median total serum concentrations were 3.2 µg/mL and 1.6 µg/mL. In a second study after a 3-minute intravenous infusion, the mean convulsant dose (95% confidence interval) for levobupivacaine was 101 mg (87–116 mg) and for bupivacaine 79 mg (72–87 mg). A study in human volunteers was designed to assess the effects of levobupivacaine and bupivacaine on the electroencephalogram following an intravenous dose (40 mg) that was predicted to be below the threshold to cause CNS symptoms. In this study, levobupivacaine decreased high alpha power in the parietal, temporal, and occipital regions, but to a lesser extent than bupivacaine. Levobupivacaine had no effect on high alpha power in the frontal and central regions, nor did it produce the increase in theta power observed at some electrodes after bupivacaine. In another study, 14 subjects received levobupivacaine or bupivacaine infusions intravenously until significant CNS symptoms occurred (numbness of the tongue, light-headedness, tinnitus, dizziness, blurred vision, or muscle twitching). The mean dose at which CNS symptoms occurred was 56 mg (range 17.5–150 mg) for levobupivacaine and 48 mg (range 22.5–110 mg) for bupivacaine; this difference did not reach statistical significance. The primary endpoints of the study were cardiac contractility and standard electrocardiographic parameters. Although some differences were seen between treatments, the clinical relevance of these is unknown.
Clinical Trials
The clinical trial program included 1220 patients and subjects who received levobupivacaine in 31 clinical trials. Levobupivacaine has been studied as a local anesthetic in adults; administered as an epidural block for surgical cases, including cesarean section; and used in peripheral neural blockade and for postoperative pain control. Although relative potency has not been established, clinical trials have demonstrated that levobupivacaine and bupivacaine exhibit similar anesthetic effects. Epidural Administration in Cesarean Section. Levobupivacaine and bupivacaine (0.50%) were evaluated for epidural block in 62 patients undergoing cesarean section in a randomized, double-blind, comparative trial. The mean (± standard deviation [SD]) time to sensory block measured at T4 to T6 was 10 ± 8 minutes for levobupivacaine and 6 ± 4 minutes for bupivacaine. The mean duration of sensory and motor block was 8 ± 1 and 4 ± 1 hours for levobupivacaine and 7 ± 1 and 4 ± 1 hours for bupivacaine, respectively. Ninety-four percent of patients receiving levobupivacaine and 100% of patients receiving bupivacaine achieved a block adequate for surgery. In a second bupivacaine-controlled cesarean section study involving 62 patients, the mean time to onset of T4 to T6 sensory block for levobupivacaine and bupivacaine was 10 ± 7 minutes and 9 ± 7 minutes, respectively, with 94% of levobupivacaine patients and 91% of bupivacaine patients achieving a bilateral block adequate for surgery. The mean time to complete regression of sensory block was 8 ± 2 hours for both treatments. Epidural Administration during Labor and Delivery. Levobupivacaine (0.25%) was compared with bupivacaine (0.25%) in a randomized, double-blind study using intermittent injections via an epidural catheter in 68 patients
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during labor. The median duration of pain relief in the subset of patients receiving levobupivacaine (0.25%) who had relief was 49 minutes; for bupivacaine patients, the median duration was 51 minutes. After the first top-up injections, 91% of patients receiving levobupivacaine and 90% of patients receiving bupivacaine achieved pain relief. Epidural Administration for Surgery. Levobupivacaine concentrations of 0.50% and 0.75% administered by epidural injection were evaluated in 85 patients undergoing lower limb or major abdominal surgery in randomized, double-blind comparisons with bupivacaine. Anesthesia sufficient for surgery was achieved in almost all patients with either treatment. In patients having abdominal surgery, the mean (± SD) time to onset of sensory block was 14 ± 6 minutes for levobupivacaine and 14 ± 10 minutes for bupivacaine. With respect to the duration of block, the time to complete regression was 551 ± 88 minutes for levobupivacaine and 506 ± 71 minutes for bupivacaine. Postoperative Pain Management. Postoperative pain control was evaluated in 258 patients in three studies, including one dose-ranging study and two studies assessing levobupivacaine in combination with epidural fentanyl or clonidine. The dose-ranging study evaluated levobupivacaine in patients undergoing orthopedic surgery; the highest concentration, 0.25%, was significantly more effective than lower concentrations. The combination studies in postoperative pain management tested levobupivacaine (0.125%) in combination with 4 µg/mL fentanyl and 0.125% levobupivacaine in combination with clonidine (50 µg/hour) for orthopedic surgery. In these studies, the efficacy variable was time to first request for rescue analgesia during the 24-hour epidural infusion period. In both studies, the combination treatment provided better pain control than clonidine, opioid, or local anesthetic alone. Peripheral Nerve Administration. Levobupivacaine has been evaluated for its anesthetic efficacy when used for peripheral nerve block. These clinical trials included brachial plexus block study (by supraclavicular approach), infiltration anesthesia studies (for inguinal hernia repair), and peribulbar block studies. Brachial Plexus Block. Levobupivacaine (0.25% and 0.5%) was compared with bupivacaine (0.5%) in 74 patients receiving a brachial plexus (supraclavicular) block for elective surgery. In the levobupivacaine (0.25%) treated group 68% of the patients achieved satisfactory block, and in the other levobupivacaine (0.5%) treated group, 81% of patients achieved satisfactory block for surgery. In the bupivacaine (0.5%) treated group, 74% of patients achieved satisfactory block for surgery. Infiltration Anesthesia. Levobupivacaine (0.25%) was evaluated in 68 patients in two randomized, double-blind, bupivacaine-controlled clinical trials for infiltration anesthesia during surgery and for postoperative pain management in patients undergoing inguinal hernia repair. No clear differences between the two drugs were seen. Peribulbar Block Anesthesia. Two clinical trials were conducted to evaluate levobupivacaine (0.75%) and bupivacaine in 110 patients who underwent peribulbar block for anterior segment ophthalmic surgery, including cataract, glaucoma, and graft surgery, and for postoperative pain management. In one study, a 10-mL injection of levobupivacaine (0.75%) or bupivacaine produced a block adequate for surgery at a median time of 10 minutes. In the second study, a 5-mL dose of levobupivacaine (0.75%) or bupivacaine injected in a technique more closely resembling a retrobulbar block resulted in a median time to adequate block of 2 minutes for both treatments. Postoperative pain was reported in fewer than 10% of patients overall. Indications and Usage
Levobupivacaine is indicated for the production of local or regional anesthesia for surgery and obstetrics, and for postoperative pain management. In surgical anesthesia, it is used for epidural, peripheral, and neural blockade, and for local infiltration. For pain management, levobupivacaine is used for continuous epidural infusion or intermittent epidural neural blockade as well as continuous or intermittent peripheral neural blockade or local infiltration. For continuous epidural analgesia, levobupivacaine may be administered in combination with epidural fentanyl or clonidine. Contraindications
Levobupivacaine is contraindicated in patients with a known hypersensitivity to this drug or to any local anesthetic agent of the amide type.
Potency of Bupivacaine Stereoisomers Chiral local anesthetics, such as ropivacaine and levobupivacaine, have the potential advantage over racemic mixtures in showing reduced toxic side effects. However, these S-(levo, or “−”) isomers also have reportedly lower
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potency than their optical antipode, possibly resulting in no advantage in therapeutic index. Potency for local anesthetics inhibiting Na+ channels or action potentials depends on the pattern of membrane potential as does the stereopotency ratio. Here, the authors have quantitated the stereopotencies of R−, S−, and racemic bupivacaine, comparing several in vitro assays of neuronal Na+ channels with those from in vivo functional nerve block, to establish relative potencies and to understand better the role of different modes of channel inhibition in overall functional anesthesia. The binding of bupivacaine to Na+ channels was assessed indirectly by its antagonism of [3 H]-batrachotoxin binding to rat brain synaptosomes. Inhibition of Na+ currents by bupivacaine was directly assayed in voltage-clamped GH-3 neuroendocrine cells. Neurobehavioral functions were disrupted by bupivacaine percutaneously injected (0.1 mL; 0.0625%–1.0%) at the rat sciatic nerve and semiquantitatively assayed. Concentration-dependent actions of R−, S−, and racemic bupivacaine were compared for their magnitude and duration of action. Competitive batrachotoxin displacement has a stereopotency ratio of R:S = 3:1. Inhibition of Na+ currents with different prepulse potentials shows S > R potency when the membrane is hyperpolarized, and R > S potency when it is depolarized from normal resting values. Functional deficits assayed in vivo usually demonstrate no consistent enantioselectivity and only a modest stereopotency (R:S = 1.2–1.3) for peak analgesia achieved at the lowest doses. Other functions display no significant stereopotency in either degree, duration, or product (AUC) at any dose. Although the in vitro actions of bupivacaine showed stereoselectivity ratios of 1:3–3:1 (R:S), in vivo nerve block at clinically used concentrations showed much smaller ratios for peak effect and no significant enantioselectivity for duration. A primary role for the blockade of resting rather than open or inactivated Na+ channels may explain the modest stereoselectivity in vivo, although stereoselective factors controlling local disposition cannot be ruled out. Levo(S−)bupivacaine is effectively equipotent to R− or racemic bupivacaine in vivo for rat sciatic nerve block.
Rarely Used Local Anesthetics TETRODOTOXIN AND SAXITOXIN These toxins are two of the most potent poisons known; the minimal lethal dose of each in the mouse is about 8 µg/kg. Both toxins are responsible for fatal poisoning in human beings. Tetrodotoxin is found in the gonads and other visceral tissues of some fish of the order Tetraodontiformes, to which the Japanese fugu, or puffer fish, belongs. It also occurs in the skin of some newts of the family Salamandridae and of the Costa Rican frog Atelopus. Saxitoxin, and possibly some related toxins, are elaborated by the dinoflagellate Gonyaulax catanella and Gonyaulax tamerensis and are retained in the tissues of clams and other shellfish that eat these organisms. Given the right conditions of temperature and light, the Gonyaulax may multiply so rapidly as to discolor the ocean—hence the term red tide. Shellfish feeding on Gonyaulax at this time become extremely toxic to human beings and are Although the toxins are chemically different responsible for periodic outbreaks of paralytic shellfish poisoning. from each other, their mechanism of action is indistinguishable. Both toxins, in nanomolar concentrations, specifically block the outer mouth of the pore of Na+ channels in the membranes of excitable cells. As a result, the action potential is blocked. The receptor site for these toxins is formed by amino acid residues in the SS2 segment of the Na+ channel á subunit (see Fig. 13-7 ) in all four domains. Not all Na+ channels are equally sensitive to tetrodotoxin; the channels in cardiac myocites are resistant, and a tetrodotoxin-resistant Na+ channel is expressed when skeletal muscle is denervated. Blockade of vasomotor nerves, together with a relaxation of vascular smooth muscle, seems to be responsible for the hypotension that is characteristic of tetrodotoxin poisoning. Both toxins cause death by paralysis of the respiratory muscles; therefore, the treatment of severe cases of poisoning requires artificial ventilation. Early gastric lavage and therapy to support the blood pressure also are indicated. If the patient survives paralytic shellfish poisoning for 24 hours, the prognosis is good. [95] [96]
[96]
[11] [97]
[95]
[98] [99]
Clinical Uses of Local Anesthetics Local anesthesia is the loss of sensation in a body part without the loss of consciousness or the impairment of central control of vital functions. It offers two major advantages. The first is that the physiologic perturbations associated with general anesthesia are avoided; the second is that neurophysiologic responses to pain and stress can be modified beneficially. As discussed earlier, local anesthetics have the potential to produce deleterious side effects. The choice of a local anesthetic and care in its use are the primary deterrents of such toxicity. There is a poor correlation between the amount of local anesthetic injected and peak plasma levels in adults. The serum level also depends on the area of injection. It is highest with interpleural or intercostal block and lowest with subcutaneous infiltration. Thus, recommended doses serve only as general guidelines.
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The following discussion concerns the pharmacologic and physiologic consequences of the use of local anesthetics categorized by method of administration. A more comprehensive discussion of their use and administration is presented in standard anesthesiology texts (e.g., Cousins and Bridenbaugh ). [100]
TOPICAL ANESTHESIA Anesthesia of mucous membranes of the nose, mouth, throat, tracheobronchial tree, esophagus, and genitourinary tract can be produced by direct application of aqueous solutions of salts of many local anesthetics or by suspension of the poorly soluble local anesthetics. Tetracaine (2%), lidocaine (2%–10%), and cocaine (1%–4%) are most often used. Cocaine is used only in the nose, nasopharynx, mouth, throat, and ear. Cocaine has the unique advantage of producing vasoconstriction as well as anesthesia. The shrinking of mucous membranes decreases operative bleeding while improving surgical visualization. Comparable vasoconstriction can be achieved with other local anesthetics by the addition of a low concentration of a vasoconstrictor such as phenylephrine (0.005%). Epinephrine, topically applied, has no significant local effect and does not prolong the duration of action of local anesthetics applied to mucous membranes because of poor penetration. Maximal safe total dosages for topical anesthesia in a healthy 70kg adult are 500 mg for lidocaine, 200 mg for cocaine, and 50 mg for tetracaine. Peak anesthetic effect after topical application of cocaine or lidocaine occurs within 2 to 5 minutes (3–8 min with tetracaine), and anesthesia lasts for 30 to 45 minutes (30–60 min with tetracaine). Anesthesia is entirely superficial; it does not extend to submucosal structures. This technique does not alleviate joint pain or discomfort from subdermal inflammation or injury. Local anesthetics are absorbed rapidly into the circulation after topical application to mucous membranes or denuded skin. Thus, it must be kept in mind that topical anesthesia always carries the risk of systemic toxic reactions. Systemic toxicity has occurred even after the use of local anesthetics to control discomfort associated with severe diaper rash in infants. Absorption is particularly rapid when local anesthetics are applied to the tracheobronchial tree. Concentrations in blood after instillation of local anesthetics into the airway are nearly the same as those that follow intravenous injection. The introduction of an eutectic mixture of lidocaine (2.5%) and prilocaine (2.5%) (EMLA) bridges the gap between topical and infiltration anesthesia. The efficacy of this combination lies in the fact that the mixture of prilocaine and lidocaine has a melting point lower than either compound alone, existing at room temperature as an oil that can penetrate intact skin. EMLA cream produces anesthesia to a maximal depth of 5 mm and is applied as a cream on instant skin under an occlusive dressing, which must be left in place for at least 1 hour. It is effective for procedures involving skin and superficial subcutaneous structures (e.g., venipuncture, skin graft harvesting). The component local anesthetics are absorbed into the systemic circulation, potentially producing toxic effects. Guidelines are available to calculate the maximal amount of cream that can be applied and area of skin covered. It must not be used on mucous membranes or abraded skin, because rapid absorption across these surfaces may result in systemic toxicity.
INFILTRATION ANESTHESIA Infiltration anesthesia is the injection of local anesthetic directly into tissue without taking into consideration the course of cutaneous nerves. Infiltration anesthesia can be so superficial as to include only the skin. It also can include deeper structures, including intraabdominal organs when these, too, are infiltrated. The duration of infiltration anesthesia can be approximately doubled by the addition of epinephrine (5 µg/mL) to the injection solution; epinephrine also decreases peak concentrations of local anesthetics in blood. Epinephrinecontaining solutions should not, however, be injected into tissues supplied by end arteries (e.g., fingers, toes, ears, nose, penis). The intense vasoconstriction produced by epinephrine may result in gangrene. For the same reason epinephrine should be avoided in solutions injected intracutaneously. Because epinephrine also is absorbed into the circulation, its use should be avoided in those for whom adrenergic stimulation is undesirable. The local anesthetics most frequently used for infiltration anesthesia are lidocaine (0.5%–1.0%), procaine (0.5%– 1.0%), and bupivacaine (0.125%–0.25%). When used without epinephrine, up to 4.5 mg/kg of lidocaine, 7 mg/kg of procaine, or 2 mg/kg of bupivacaine can be employed in adults. When epinephrine is added, these amounts can be increased by one third. The advantage of infiltration anesthesia and other regional anesthetic techniques is that it is possible to provide satisfactory anesthesia without disruption of normal bodily functions. The chief disadvantage of infiltration
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anesthesia is that relatively large amounts of drug must be used to anesthetize relatively small areas. This is no problem with minor surgery. When major surgery is performed, however, the amount of local anesthetic that is required makes systemic toxic reactions likely. The amount of anesthetic required to anesthetize an area can be reduced significantly and the duration of anesthesia increased markedly by specifically blocking the nerves that innervate the area of interest. This can be done at one of several levels: subcutaneously, at major nerves, or at the level of the spinal roots.
FIELD BLOCK ANESTHESIA Field block anesthesia is produced by subcutaneous injection of a solution of local anesthetic in such a manner as to numb the region distal to the injection. For example, subcutaneous infiltration of the proximal portion of the volar surface of the forearm results in an extensive area of cutaneous anesthesia that starts 2 to 3 cm distal to the site of injection. The same principle can be applied with particular benefit to the scalp, the anterior abdominal wall, and the lower extremity. The drugs used and the concentrations and doses recommended are the same as for infiltration anesthesia. The advantage of field block anesthesia is that less drug can be used to provide a greater area of anesthesia than when infiltration anesthesia is used. Knowledge of the relevant neuroanatomy obviously is essential for successful field block anesthesia.
NERVE BLOCK ANESTHESIA Injection of a solution of a local anesthetic into or about individual peripheral nerves or nerve plexuses produces even greater areas of anesthesia than the techniques described earlier. Blockade of mixed peripheral nerves and nerve plexuses also usually anesthetizes somatic motor nerves, producing skeletal muscle relaxation, which is useful for some surgical procedures. The areas of sensory and motor block usually start several centimeters distal to the site of injection. Brachial plexus blocks are particularly useful for procedures on the upper extremity and shoulder. Intercostal nerve blocks are effective for anesthesia and relaxation of the anterior abdominal wall. Cervical plexus block is appropriate for surgery of the neck. Sciatic and femoral nerve blocks are useful for surgery distal to the knee. Other useful nerve blocks before surgical procedures include blocks of individual nerves at the wrist and at the ankle, blocks of individual nerves such as the median or ulnar at the elbow, and blocks of sensory cranial nerves. There are four major determinants of the onset of sensory anesthesia after injection near a nerve. These are proximity of the injection to the nerve, concentration and volume of drug, degree of ionization of the drug, and time. Local anesthetic never is intentionally injected into the nerve because this is painful and may lead to nerve damage. Instead, the anesthetic agent is deposited as close to the nerve as possible. Thus, the local anesthetic must diffuse from the site of injection into the nerve, where it acts. The rate of diffusion is determined chiefly by the concentration of the drug, its degree of ionization (as ionized local anesthetic diffuses more slowly), its hydrophobicity, and the physical characteristics of the tissue surrounding the nerve. Higher concentrations of local anesthetic result in a more rapid onset of peripheral nerve block. The utility of using higher concentrations, however, is limited by systemic toxicity as well as direct neural toxicity of concentrated local anesthetic solutions. Local anesthetics with lower pKa values tend to have a more rapid onset of action for a given concentration, because more drug is ionized at neutral pH. For example, the onset of action of lidocaine occurs in about 3 minutes; 35% of lidocaine is in the basic form at pH 7.4. In contrast, the onset of action of bupivacaine requires about 15 minutes; only 5% to 10% of bupivacaine is in the basic form at this pH. Increased hydrophobicity might be expected to speed onset by increased penetration into nerve tissue. However, it also increases binding in tissue lipids. Furthermore, the most hydrophobic local anesthetics also are more potent (and toxic) and thus must be used at lower concentrations, decreasing the concentration gradient for diffusion. Tissue factors also play a role in determining the rate of onset of anesthetic effects. The amount of connective tissue that must be penetrated can be significant in a nerve plexus compared with isolated nerves and can serve to slow or even prevent adequate diffusion of local anesthetic to the nerve fibers. Duration of nerve block anesthesia depends on the physical characteristics of the local anesthetic used and the presence or absence of vasoconstrictors. Especially important physical characteristics are lipid solubility and protein binding. In general, local anesthetics can be divided into three categories: those with a short (20–45 min) duration of action in mixed peripheral nerves, such as procaine; those with an intermediate (60–120 min) duration of action, such as lidocaine and mepivacaine; and those with a long (400–450 min) duration of action, such as bupivacaine, etidocaine, ropivacaine, and tetracaine. Block duration of the intermediate-acting local anesthetics such as lidocaine can be prolonged by the addition of epinephrine (5 µg/mL). The degree of block prolongation in peripheral nerves
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after the addition of epinephrine appears to be related to the intrinsic vasodilatory properties of the local anesthetic and thus is most pronounced with lidocaine. The types of nerve fibers that are blocked when a local anesthetic is injected about a mixed peripheral nerve depends on the concentration of drug used, nerve-fiber size, internodal distance, and frequency and pattern of nerve-impulse transmission. Anatomic factors are similarly important. A mixed peripheral nerve or nerve trunk consists of individual nerves surrounded by an investing epineurium. The vascular supply is usually centrally located. When a local anesthetic is deposited about a peripheral nerve, it diffuses from the outer surface toward the core along a Consequently, nerves located in the outer mantle of the mixed nerve are blocked first. concentration gradient. These fibers usually are distributed to more proximal anatomic structures than those situated near the core of the mixed nerve and are often motor. If the volume and concentration of local anesthetic solution deposited about the nerve are adequate, the local anesthetic eventually diffuses inward in amounts adequate to block even the most centrally located fibers. Lesser amounts of drug block only nerves in the mantle and smaller and more sensitive central fibers. Furthermore, because removal of local anesthetics occurs primarily in the core of a mixed nerve or nerve trunk, where the vascular supply is located, the duration of blockade of centrally located nerves is shorter than that of more peripherally situated fibers. [101] [102]
Choice of local anesthetic, as well as the amount and concentration administered, is determined by the nerves and the types of fibers to be blocked, the duration of anesthesia required, and the size and health of the patient. For blocks of 2 to 4 hours, lidocaine (1.0%–1.5%) can be used in the amounts recommended earlier (see Infiltration Anesthesia). Mepivacaine (up to 7 mg/kg of a 1.0%–2.0% solution) provides anesthesia that lasts about as long as that from lidocaine. Bupivacaine (2 to 3 mg/kg of a 0.25%–0.375% solution) can be used when a longer duration of action is required. Addition of 5 µg/mL epinephrine prolongs duration and lowers the plasma concentration of the intermediate-acting local anesthetics. Peak concentrations of local anesthetics in blood depend on the amount injected, the physical characteristics of the local anesthetic, and whether or not epinephrine is used. They also are determined by the rate of blood flow to the site of injection and the surface area exposed to local anesthetic. This is of particular importance in the safe application of nerve block anesthesia, because the potential for systemic reactions also is related to peak free serum concentrations. For example, peak concentrations of lidocaine in blood following epidural injection is 7 µg/mL; the same amount of lidocaine used for block of the brachial plexus results in peak concentrations in blood of approximately 3 µg/mL. The amount of local anesthetic that can be injected must, therefore, be adjusted according to the anatomic site of the nerve or nerves to be blocked to minimize untoward effects. Addition of epinephrine can decrease peak plasma concentrations by 20% to 30%. Multiple nerve blocks (e.g., intercostal block) or blocks performed in vascular regions require reduction in the amount of anesthetic that can be given safely because the surface area for absorption or the rate of absorption is increased. [103]
INTRAVENOUS REGIONAL ANESTHESIA (BIER BLOCK) This technique relies on using the vasculature to bring the local anesthetic solution to the nerve trunks and endings. In this technique, an extremity is exsanguinated with an Esmarch (elastic) bandage, and a proximally located tourniquet is inflated to between 100 and 150 mm Hg above the systolic blood pressure. The Esmarch bandage is removed, and the local anesthetic is injected into a previously cannulated vein. Typically, complete anesthesia of the limb ensues within 5 to 10 minutes. Pain from the tourniquet and the potential for ischemic nerve injury limits tourniquet inflation to 2 hours or less. However, the tourniquet should remain inflated for at least 15 to 30 minutes to prevent toxic amounts of local anesthetic from entering the circulation after deflation. Lidocaine (40 to 50 mL) (0.5 mL/kg in children) of a 0.5% solution, without epinephrine, is the drug of choice for this technique. For intravenous regional anesthesia in adults using a 0.5% solution without epinephrine, the dose administered should not exceed 4 mg/kg. A few clinicians prefer prilocaine (0.5%) to lidocaine because of its higher therapeutic index. The attractiveness of this technique lies in its simplicity. Its primary disadvantages are that it can be used only for a few anatomic regions, sensation (i.e., pain) returns quickly after tourniquet deflation, and premature release or failure of the tourniquet can produce toxic levels of local anesthetic (e.g., 50 mL of 0.5% lidocaine contains 250 mg of lidocaine). For the last reason and because their longer durations of action offer no advantages, the more cardiotoxic local anesthetics, bupivacaine and etidocaine, are not recommended for this technique. Intravenous regional anesthesia is used most often for the forearm and hand but can be adapted for the foot and distal leg.
SPINAL ANESTHESIA Spinal anesthesia follows the injection of local anesthetic into the cerebrospinal fluid (CSF) in the lumbar space. This technique was first performed in human beings and described by Bier in 1899. For a number of reasons, including the ability to produce anesthesia of a considerable fraction of the body with a dose of local anesthetic that
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produces negligible plasma levels, it still remains one of the most popular forms of anesthesia. In most adults, the spinal cord terminates above the second lumbar vertebra; between that point and the termination of the thecal sac in the sacrum, the lumbar and sacral roots are bathed in cerebrospinal fluid (CSF). Thus, in this region, there is a relatively large volume of CSF within which to inject drug, thereby minimizing the potential for direct nerve trauma. A brief discussion of the physiologic effects of spinal anesthesia and those features relating to the pharmacology of the local anesthetics used are presented here. The technical performance and extensive discussion of the physiologic consequences of spinal anesthesia are beyond the scope of this text. [100] [104]
Physiologic Effects of Spinal Anesthesia
Most of the physiologic side effects of spinal anesthesia are a consequence of the sympathetic blockade produced by local anesthetic block of the sympathetic fibers in the spinal nerve roots. A thorough understanding of these physiologic effects is necessary for the safe and successful application of spinal anesthetic. Although some of them may be deleterious and require treatment, others can be beneficial for the patient or can improve operating conditions. Most sympathetic fibers leave the spinal cord between T1 and L2. Although local anesthetic is injected below these levels in the lumbar portion of the dural sac, cephalad spread of the local anesthetic is seen with all but the smallest volumes injected. This cephalad spread is of considerable importance in the practice of spinal anesthesia and potentially is under the control of numerous variables, of which patient position and baricity (density of the drug relative to the density of the CSF) are the most important. The degree of sympathetic block is related to the height of sensory anesthesia; often, the level of sympathetic blockade is several spinal segments higher, because the preganglionic sympathetic fibers are most sensitive to block by low concentrations of local anesthetic. The effects of sympathetic blockade involve both the actions (now partially unopposed) of the parasympathetic nervous system as well as the response of the unblocked portion of the sympathetic nervous system. Thus, as the level of sympathetic block ascends, the actions of the parasympathetic nervous system are increasingly dominant, and the compensatory mechanisms of the unblocked sympathetic nervous system are diminished. As most sympathetic nerve fibers leave the cord at T1 or below, few additional effects of sympathetic blockade are seen with cervical levels of spinal anesthesia. The consequences of sympathetic blockade vary among patients as a function of age, physical conditioning, and disease state. Interestingly, sympathetic blockade during spinal anesthesia appears to be inconsequential in healthy children. [105]
Clinically, the most important effects of sympathetic blockade during spinal anesthesia are on the cardiovascular system. At all but the lowest levels of spinal blockade, some vasodilatation occurs. Vasodilatation is more marked on the venous than on the arterial side of the circulation, resulting in a pooling of blood in the venous capacitance vessels. At low levels of spinal anesthesia in healthy patients, this reduction in circulating blood volume is well tolerated. With an increasing level of block, this effect becomes more marked and venous return becomes gravitydependent. If venous return decreases too much, cardiac output and organ perfusion precipitously decline. Venous return can be increased by modest (10 degrees to 15 degree) head-down tilt or by elevating the legs. At high levels of spinal blockade, the cardiac accelerator fibers, which exit the spinal cord at T1 to T4, will be blocked. This is detrimental in patients dependent on elevated sympathetic tone to maintain cardiac output (e.g., during congestive heart failure or hypovolemia), and it also removes one of the compensatory mechanisms available to maintain organ perfusion during vasodilation. Thus, as the level of spinal block ascends, the rate of cardiovascular compromise can accelerate if not carefully observed and treated. Sudden asystole also can occur, presumably because of loss of sympathetic innervation in the continued presence of parasympathetic activity at the sinoatrial node. In the usual clinical situation, blood pressure serves as a surrogate marker for cardiac output and organ perfusion. [106]
Treatment of hypotension usually is warranted when the blood pressure decreases to about 30% of resting values. Therapy is aimed at maintaining brain and cardiac perfusion and oxygenation. To achieve these goals, administration of oxygen, fluid infusion, manipulation of patient position as mentioned earlier, and the administration of vasoactive drugs are all options. In particular, patients typically are administered a bolus (500– 1000 mL) of fluid before the administration of spinal anesthesia in an attempt to prevent some of the deleterious effects of spinal blockade. As the usual cause of hypotension is decreased venous return, possibly complicated by decreased heart rate, vasoactive drugs with preferential venoconstrictive and chronotropic properties are preferred. For this reason ephedrine (5–10 mg intravenously) often is the drug of choice. In addition to the use of ephedrine to treat deleterious effects of sympathetic blockade, direct-acting á1 -adrenergic receptor agonists such as phenylephrine frequently are administered either by bolus or continuous infusion. Spinal anesthesia exerts a beneficial effect on the intestine, partially mediated by the sympathetic nervous system. Sympathetic fibers originating from T5 to L1 inhibit peristalsis; thus, their blockade produces a small, contracted intestine. This contraction and a flaccid abdominal musculature produce excellent operating conditions for some types of bowel surgery. The effects of spinal anesthesia on the respiratory system mostly are mediated by effects on the skeletal musculature. Paralysis of the intercostal muscles reduces a patient’s ability to cough and clear
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secretions, which may be undesirable in a bronchitic or emphysematous patient and may produce dyspnea. It should be noted that respiratory arrest during spinal anesthesia is seldom caused by paralysis of the phrenic nerves or by toxic levels of local anesthetic in the CSF of the fourth ventricle. It is much more likely to be due to medullary ischemia secondary to hypotension. Pharmacology of Spinal Anesthesia
Currently, in the United States, the drugs most commonly used in spinal anesthesia are lidocaine, tetracaine, and bupivacaine. Procaine occasionally is used for diagnostic blocks for which a short duration of action is desired. The choice of local anesthetic primarily is determined by the duration of anesthesia desired. General guidelines are to use lidocaine for short procedures, bupivacaine for intermediate to long procedures, and tetracaine for long procedures. As mentioned earlier, the factors contributing to the distribution of local anesthetics in the CSF have received much attention because of their importance in determining the height of the block. The most important pharmacologic factors include the amount and, possibly, the volume of drug injected and its baricity. The speed of injection of the local anesthesia solution also may affect the height of the block, just as the position of the patient can influence the rate of distribution of the anesthetic agent and the height of blockade achieved. For a given preparation of local anesthetic, administration of increasing amounts leads to a fairly predictable increase in the level of block attained. For example, 100 mg of lidocaine, 20 mg of bupivacaine, or 12 mg of tetracaine usually result in a T4 sensory block. More complete tables of these values can be found in standard anesthesiology texts. Epinephrine often is added to spinal anesthetics to increase the duration or intensity of block. Epinephrine’s effect on duration of block is dependent on the technique used to measure duration. A commonly used measure of block duration is the length of time it takes for the block to recede by two dermatomes from the maximal height of the block, whereas a second is the duration of block at some specified level, typically L1. In most studies, addition of 200 µg of epinephrine to tetracaine solutions prolongs the duration of block by both measures. However, addition of epinephrine to lidocaine or bupivacaine does not affect the first measure of duration but does prolong the block at lower levels. In different clinical situations, one or the other measure of anesthesia duration may be more relevant, and this must be kept in mind when deciding to add epinephrine to spinal local anesthetics. The mechanism of action of vasoconstrictors in prolonging spinal anesthesia is uncertain. It has been hypothesized that these agents decrease spinal cord blood flow, decreasing clearance of local anesthetic from the CSF, but this has not been convincingly demonstrated. Epinephrine, working via α2 -adrenergic receptors, has been shown to decrease nociceptive transmission in the spinal cord; it is possible that this action contributes to the effects of epinephrine. Drug Baricity and Patient Position
The baricity of the local anesthetic injected determines the direction of migration within the dural sac. Hyperbaric solutions tend to settle in the dependent portions of the sac, whereas hypobaric solutions tend to migrate in the opposite direction. Isobaric solutions usually stay in the vicinity where they were injected, diffusing slowly in all directions. Consideration of the patient position during and after the performance of the block and the choice of a local anesthetic of the appropriate baricity is crucial for a successful block during some surgical procedures. For example, a saddle (perineal) block is best performed with a hyperbaric anesthetic in the sitting position if the patient remains in that position until the anesthetic level becomes “fixed.” On the other hand, for a saddle block in the prone, jackknife position, a hypobaric local anesthetic is appropriate. Lidocaine and bupivacaine are marketed in both isobaric and hyperbaric preparations and, if desired, can be diluted with sterile, preservative-free water to make them hypobaric. Complications of Spinal Anesthesia
Persistent neurologic deficits after spinal anesthesia are extremely rare. Thorough evaluation of a suspected deficit should be performed in collaboration with a neurologist. Neurologic sequelae can be both immediate and late. Possible causes include introduction of foreign substances (such as disinfectants or talc) into the subarachnoid space, infection, hematoma, or direct mechanical trauma. Aside from drainage of an abscess or hematoma, treatment usually is ineffective; thus, careful attention to detail while performing spinal anesthesia is necessary. High concentrations of local anesthetic can cause irreversible block. After administration, local anesthetic solutions are diluted rapidly, quickly reaching nontoxic concentrations. However, concern has been raised that 5% lidocaine (i.e., 180 mM) in 7.5% glucose may be neurotoxic when delivered via small-bore indwelling catheters to areas of stagnant CSF. Spinal anesthesia sometimes is regarded as contraindicated in patients with preexisting disease of the spinal cord. No experimental evidence exists to support this hypothesis. Nonetheless, it is prudent to avoid spinal anesthesia in patients with progressive diseases of the spinal cord. However, spinal anesthesia may be very useful in patients with fixed, chronic spinal cord injury. [52]
A more common sequela following any lumbar puncture, including spinal anesthesia, is a postural headache with classic features. The incidence of headache decreases with increasing age of the patient and decreasing needle diameter. Treatment usually is conservative, with bed rest and analgesics. If this approach fails, an epidural blood
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patch can be performed; this procedure usually is successful in alleviating postdural puncture headaches, although a second blood patch may be necessary. Intravenous caffeine (500 mg as the benzoate salt administered over 4 hours) also has been advocated for the treatment of postdural puncture headache. However, the efficacy of caffeine is less than that of a blood patch, and relief usually is transient. If two epidural blood patches are ineffective in relieving the headache, the diagnosis of postdural puncture headache should be reconsidered.
EPIDURAL ANESTHESIA Epidural anesthesia is administered by injecting local anesthetic into the epidural space—the space bounded by the ligamentum flavum posteriorly, the spinal periosteum laterally, and the dura anteriorly. Epidural anesthesia can be performed in the sacral hiatus (caudal anesthesia) or in the lumbar, thoracic, or cervical regions of the spine. Its current popularity arises from the development of catheters that can be placed into the epidural space, allowing either continuous infusions or repeated bolus administration of local anesthetics. The primary site of action of epidurally administered local anesthetics is the spinal nerve roots. However, epidurally administered local anesthetics also may act on the spinal cord and on the paravertebral nerves. The drugs available for epidural anesthesia are similar to those for major nerve blocks. As for spinal anesthesia, the choice of drugs to be used during epidural anesthesia is dictated primarily by the duration of anesthesia desired. However, when an epidural catheter is placed, short-acting drugs can be administered repeatedly, providing more control over the duration of block. Bupivacaine (0.5% to 0.75%) is used when a long duration of surgical block is desired. Because of enhanced cardiotoxicity in pregnant patients, the 0.75% solution is not approved for obstetric use. Lower concentrations (0.25%, 0.125%, or 0.0625%) of bupivacaine, often with 2 µg/mL of fentanyl added, frequently are used to provide analgesia during labor. They also are useful preparations for providing postoperative analgesia in certain clinical situations. Etidocaine (1.0% or 1.5%) is useful for providing surgical anesthesia with excellent muscle relaxation of long duration. Lidocaine (2%) is the most frequently used intermediate-acting epidural local anesthetic. 2-Chloroprocaine (2% or 3%) provides rapid onset and a very short duration of anesthetic action. However, its use in epidural anesthesia has been clouded by controversy regarding its potential ability to cause neurologic complications if the drug is accidentally injected into the subarachnoid space. The duration of action of epidurally administered local anesthetics is frequently prolonged and systemic toxicity decreased by addition of epinephrine. Addition of epinephrine also makes inadvertent intravascular injection easier to detect and modifies the effect of sympathetic blockade during epidural anesthesia. For each anesthetic agent, a relationship exists between the volume of local anesthetic injected epidurally and the segmental level of anesthesia achieved. For example, in 20- to 40-year-old, healthy, nonpregnant patients, each 1 to 1.5 mL of 2% lidocaine gives an additional segment of anesthesia. The amount needed decreases with increasing age and also is decreased during pregnancy and in children. The concentration of local anesthetic used determines the type of nerve fibers blocked. The highest concentrations are used when sympathetic, somatic sensory, and somatic motor blockade are required. Intermediate concentrations allow somatic sensory anesthesia without muscle relaxation. Low concentrations block only preganglionic sympathetic fibers. As an example, with bupivacaine these effects may be achieved with concentrations of 0.5%, 0.25%, and 0.0625%, respectively. The total amounts of drug that can be injected with safety at one time are approximately those mentioned above in “Nerve Block Anesthesia” and “Infiltration Anesthesia.” Performance of epidural anesthesia requires a greater degree of skill than spinal anesthesia. The technique of epidural anesthesia and the volumes, concentrations, and types of drugs used are described in detail in standard anesthesiology texts. [15] [100]
A significant difference between epidural and spinal anesthesia is that the dose of local anesthetic used can produce high concentrations in blood after absorption from the epidural space. Peak concentrations of lidocaine in blood following injection of 400 mg (without epinephrine) into the lumbar epidural space average 3 to 4 µg/mL; peak concentrations of bupivacaine in blood average 1.0 µg/mL after the lumbar epidural injection of 150 mg. Addition of epinephrine (5 µg/mL) decreases peak plasma concentrations by about 25%. Peak blood concentrations are a function of the total dose of drug administered rather than the concentration or volume of solution after epidural injection. The risk of inadvertent intravascular injection is increased in epidural anesthesia because the epidural space contains a rich venous plexus. [103]
Another major difference between epidural and spinal anesthesia is that there is no zone of differential sympathetic blockade with epidural anesthesia; thus, the level of sympathetic block is close to the level of sensory block. Because epidural anesthesia does not result in the zone of differential sympathetic blockade that is observed during spinal anesthesia, cardiovascular responses to epidural anesthesia might be expected to be less prominent. In practice, however, this is not the case; this potential advantage of epidural anesthesia is offset by the cardiovascular responses to the high concentration of anesthetic in blood that occurs during epidural anesthesia. This is most
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apparent when, as is often the case, epinephrine is added to the epidural injection. The resulting concentration of epinephrine in blood is sufficient to produce significant β2 -adrenergic receptor-mediated vasodilation. As a consequence, blood pressure decreases, even though cardiac output increases owing to the positive inotropic and chronotropic effects of epinephrine. The result is peripheral hypoperfusion and hypotension. Differences in cardiovascular responses to equal levels of spinal and epidural anesthesia also are observed when a local anesthetic such as lidocaine is used without epinephrine. This may be a consequence of the direct effects of high concentrations of lidocaine on vascular smooth muscle and the heart. The magnitude of the differences in responses to equal sensory levels of spinal and epidural anesthesia varies, however, with the local anesthetic used for the epidural injection (assuming no epinephrine is used). For example, local anesthetics such as bupivacaine, which are highly lipid-soluble, are distributed less into the circulation than are less lipid-soluble agents such as lidocaine. High concentrations of local anesthetics in blood during epidural anesthesia are of special importance when this technique is used to control pain during labor and delivery. Local anesthetics cross the placenta, enter the fetal circulation, and at high concentrations may cause depression of the neonate. The extent to which they do so is determined by dosage, acid-base status, the level of protein binding in both maternal and fetal blood, placental blood flow, and solubility of the agent in fetal tissue. These concerns have been lessened by the trend toward using more dilute solutions of bupivacaine for labor analgesia. [107]
[108]
LOCAL ANESTHETICS FOR SKIN AND MUCOUS MEMBRANES Some anesthetics are either too irritating or too ineffective to be applied to the eye. However, they are useful as topical anesthetic agents on the skin, mucous membranes, or both. These preparations are effective in the symptomatic relief of anal and genital pruritus, poison ivy rashes, and numerous other acute and chronic dermatoses. They are sometimes combined with a glucocorticoid or antihistamine and are available in a number of proprietary formulations. Dibucaine
Dibucaine (Nupercainal) is a quinoline derivative. Its toxicity resulted in its removal from the U.S. market as an injectable preparation; however, it retains wide popularity outside of the United States as a spinal anesthetic. It currently is available as a cream and an ointment for use on the skin. Dyclonine Hydrochloride
Dyclonine hydrochloride (Dyclone) has a rapid onset of action and duration of effect comparable to that of procaine. It is absorbed through the skin and mucous membranes. The compound is used as 0.5% or 1.0% solution for topical anesthesia during endoscopy, for oral mucositis pain following radiation or chemotherapy, and for anogenital procedures.
Figure 13-17 A surface anesthetic agent that is not a benzoate ester. Its distinct chemical structure may help to minimize the danger of crosssensitivity reaction in patients allergic to other local anesthetics.
Pramoxine Hydrochloride
Pramoxine hydrochloride (Anusol, Tronothane, others) is a surface anesthetic agent that is not a benzoate ester. Its distinct chemical structure ( Fig. 13-17 ) may help to minimize the danger of cross-sensitivity reactions in patients allergic to other local anesthetics. Pramoxine produces satisfactory surface anesthesia and is reasonably well tolerated on the skin and mucous membranes. It is too irritating to be used on the eye or in the nose. Various preparations are available for topical application, usually including 1% pramoxine. Anesthetics of Low Solubility
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Some local anesthetics are poorly soluble in water and, consequently, too slowly absorbed to be toxic. They can be applied directly to wounds and ulcerated surfaces, where they remain localized for long periods of time to produce a sustained anesthetic action. Chemically, they are esters of PABA, lacking the terminal amino group possessed by the previously described local anesthetics. The most important member of the series is benzocaine (ethyl aminobenzoate, Americaine, others). Benzocaine is structurally similar to procaine; the difference is that it lacks the terminal diethylamino group ( Fig. 13-18 ). It is incorporated into a large number of topical preparations. Benzocaine has been reported to cause methemoglobinemia; consequently, dosing recommendations must be carefully followed.
LOCAL ANESTHETICS FOR EYE SURGERY Anesthesia of the cornea and conjunctiva can be obtained readily by topical application of local anesthetics. However, most of the local anesthetics described earlier are too irritating for ophthalmologic use. The
Figure 13-18 Structurally similar to procaine; the difference is that it lacks the terminal diethylamino group.
Figure 13-19 The most frequently used local anesthetics in ophthalmology.
first local anesthetic used in ophthalmology, cocaine, has the disadvantage of producing mydriasis and corneal sloughing and has fallen out of favor. The two compounds used most frequently today are proparacaine (Alcaine, Ophthaine, others) and tetracaine ( Fig. 13-19 ). In addition to being less irritating during administration, proparacaine has the added advantage of bearing little antigenic similarity to the other benzoate local anesthetics. Thus, it sometimes can be used in individuals sensitive to the amino ester local anesthetics. For use in ophthalmology, these local anesthetics are instilled a single drop at a time. If anesthesia is incomplete, successive drops are applied until satisfactory conditions are obtained. The duration of anesthesia is determined chiefly by the vascularity of the tissue; thus, it is longest in normal cornea and least in inflamed conjunctiva. In the latter case, repeated instillations are necessary to maintain adequate anesthesia for the duration of the procedure. Long-term administration of topical anesthesia to the eye has been associated with retarded healing and pitting, sloughing of the corneal epithelium, and predisposition of the eye to inadvertent injury. Thus, these drugs should not be prescribed for self-administration. REFERENCES
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DT, Morison DH, Covino BG, et al: Comparison of carbonated bupivacaine and bupivacaine hydrochloride for extradural anaesthesia. Br J Anaesth 52:419–422, 1980.
22. Mehta PM, Theriot E, Mehrotra D, et al: A simple technique to make bupivacaine a rapid-acting epidural anesthetic. Reg Anesth 12:135–138, 1987. 23. Fischer
RL, Lubenow TR, Liceaga A, et al: Comparison of continuous epidural infusion of fentanyl-bupivacaine and morphine-bupivacaine in management of postoperative pain. Anesth Analg 67:559–563, 1988.
24. Chestnut
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25. Denson
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26. Tucker
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28. Covino BG: Toxicity and systemic effects of local anesthetic agents. In Strichartz GR (ed): Handbook of Experimental Pharmacology, vol. 81, Berlin, Springer-Verlag, 1987, pp 187–212. 29. Burney
RG, DiFazio CA, Foster JA: Effects of pH on protein binding of lidocaine. Anesth Analg 57:478–480, 1978.
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1981. 31. Wood M, Wood AJJ: Changes in plasma drug binding and alpha-1-acid glycoprotein in mother and newborn infant. Clin Pharmacol Ther 29:522–526, 1981. 32. Katz
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GA, Hoffman BF: The role of local anesthetic effects in the actions of antiarrhythmic drugs. In Strichartz GR (ed): Handbook of Experimental Pharmacology, vol 81, Berlin, Springer-Verlag, 1987, pp 213–251.
36. Neher
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MM, Bredberg E, Arvidsson AT, et al: Metabolism and secretion of ropivacaine in humans. Drug Metab Dispos 24:962–968, 1996.
42. Oda
Y, Furuichi K, Tanaka K, et al: Metabolism of a new local anesthetic, ropivacaine, by human hepatic cytochrome P450. Anesthesiology 82:214–220, 1995.
43. Brosen K, Skjelbo E, Rasmussen BB, et al: Fluvoxamine is a potent inhibitor of cytochrome P450 1A2. Biochem Pharmacol 45:1211–1214, 1993. 44. Dripps RD, Vandam LD: Long-term follow-up of patients who received 10,098 spinal anesthetics: Failure to discover major neurological sequelae. JAMA 156:1486–1491, 1954. 45. Vandam
LD, Dripps RD: A long-term follow-up of 10,098 spinal anesthetics: II. Incidence and analysis of minor sensory neurological defects. Surgery 38:463–469, 1955.
46. Phillips
OC, Ebner H, Nelson AT, et al: Neurologic complications following spinal anesthesia with lidocaine: A prospective review of 10,440 cases. Anesthesiology 30:284–289, 1969.
47. Horlocker
TT, McGregor DG, Matsushige DK, et al: A retrospective review of 4,767 consecutive spinal anesthetics: Central nervous system complications. Anesth Analg 84:578–584, 1997.
48. Gissen
AJ, Datta S, Lambert D: The chloroprocaine controversy: II. Is chloroprocaine neurotoxic? Reg Anesth 9:135–145, 1984.
49. Wang
BC, Hillman DE, Spielholz NI, et al: Chronic neurological deficits and nesacaine-CE: An effect of the anesthetic, 2-chloroprocaine, or the antioxidant, sodium bisulfite? Anesth Analg 63:445–447, 1984.
50. Ready
L, Plumer M, Haschke R, et al: Neurotoxicity of intrathecal local anesthetic in rabbits. Anesthesiology 63:364–379, 1985.
51. Selander 52. Rigler
D: Neurotoxicity of local anesthetics: Animal data. Reg Anesth 18:461–468, 1993.
MI, Drasner K, Krejcie TC, et al: Cauda equina syndrome after continuous spinal anesthesia. Anesth Analg 72:275–281, 1991.
53. Schneider
M, Ettlin T, Kaufmann M, et al: Transient neurologic toxicity after hyperbaric subarachnoid anesthesia with 5% lidocaine. Anesth Analg 76:1154–1157, 1993.
54. Hampl
KF, Schneider MC, Ummenhofer W, et al: Transient neurologic symptoms after spinal anesthesia. Anesth Analg 81:1148–1153, 1995.
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RL: Hypobaric lidocaine spinal anesthesia: Do we need an alternative? Anesth Analg 81:1125–1128, 1995.
56. Pollock
J, Neal J, Stephenson C, et al: Prospective study of the incidence of transient radicular irritation in patients undergoing spinal anesthesia. Anesthesiology 84:1361–1367, 1996.
57. Hampl
KF, Schneider M, Pargger H: A similar incidence of transient neurologic symptoms after spinal anesthesia with 2% and 5% lidocaine. Anesth Analg 83:1051–1054, 1996.
58. Drasner
K: Lidocaine spinal anesthesia: A vanishing therapeutic index? Anesthesiology 87:469–472, 1997.
59. Tarkkila
P, Huhtala J, Tuominen M: Transient radicular irritation after spinal anesthesia with hyperbaric 5% lidocaine. Br J Anaesth 74:328–
329, 1995. 60. Sumi
M, Sakura S, Kosaka Y: Intrathecal hyperbaric 0.5% tetracaine as a possible cause of transient neurologic toxicity. Anesth Analg 82:1076–1077, 1996.
61. Lynch
J, zur Nieden M, Kasper S-M, et al: Transient radicular irritation after spinal anesthesia with hyperbaric 4% mepivacaine. Anesth Analg 85:872–873, 1997.
62. Hampl
KF, Heinzmann-Wiedmer S, Luginbuehl I, et al: Transient neurologic symptoms after spinal anesthesia: A lower incidence with prilocaine and bupivacaine than with lidocaine. Anesthesiology 88:629–633, 1998.
63. DiFazio
CA, Rowlingson JC: Additives to local anesthetic solutions. In Brown DL (ed): Regional Anesthesia and Analgesia. Philadelphia, WB Saunders, 1996, pp 232–239.
64. Rowlingson
JC: Toxicity of local anesthetic additives. Reg Anesth 18:453–460, 1993.
65. Sakura
S, Sumi M, Sakaguchi Y, et al: The addition of phenylephrine contributes to the development of transient neurologic symptoms after spinal anesthesia with 0.5% tetracaine. Anesthesiology 87:771–778, 1997.
66. Sakura
S, Chan VWS, Ciriales R, et al: The addition of 7.5% glucose does not alter the neurotoxicity of 5% lidocaine administered intrathecally in the rat. Anesthesiology 87:771–778, 1997.
67. Hampl HF, Schneider MC, Thorin D, et al: Hyperosmolarity does not contribute to transient radicular irritation after spinal anesthesia with hyperbaric 5% lidocaine. Reg Anesth 20:363–368, 1995. 68. Auroy
Y, Narchi P, Messiah A, et al: Serious complications related to regional anesthesia: Results of a prospective survey in France. Anesthesiology 87:479–486, 1997.
69. Eisenach
JC: Regional anesthesia: Vintage Bordeaux (and Napa Valley). Anesthesiology 87:467–469, 1997.
70. Wagman
IH, deJong RH, Prince DA: Effect of lidocaine on the central nervous system. Anesthesiology 28:155–172, 1967.
71. Moore
DC: Administer oxygen first in the treatment of local anesthetic-induced convulsions. Anesthesiology 53:346–347, 1980.
72. Avery
P, Redon D, Schaenzer G, et al: The influence of serum potassium on the cerebral and cardiac toxicity of bupivacaine and lidocaine. Anesthesiology 61:134–138, 1985.
73. Sage
DJ, Feldman HS, Arthur GR, et al: Influence of bupivacaine and lidocaine on isolated guinea pig atria in the presence of acidosis and hypoxia. Anesth Analg 63:1–7, 1984.
74. Albright
GA: Cardiac arrest following regional anesthesia with etidocaine or bupivacaine [editorial]. Anesthesiology 51:285–287, 1978.
75. Block
A, Covino BG: Effect of local anesthetic agents in cardiac conduction and contractility. Reg Anesth 6:55–58, 1981.
76. Lynch
C III: Depression of myocardial contractility in vitro by bupivacaine, etidocaine, and lidocaine. Anesth Analg 65:551–559, 1986.
77. Feldman
HS, Covino BG, Sage DJ: Direct chronotropic and inotropic effects of local anesthetic agents in isolated guinea pig atria. Reg Anesth 7:149–154, 1982.
78. Stevens
MF, Klement W, Lipfert P: Conduction block in man is stimulation frequency dependent. Anesthetists 45:533–537, 1996.
79. Huang
YF, Pryor ME, Mather LE, et al: Cardiovascular and central nervous system effects of intravenous levobupicaine and bupivacaine in sheep. Anesth Analg 86:797–804, 1998.
80. Clarkson
CW, Hondeghem LM: Mechanism for bupivacaine depression of cardiac conduction: Fast block of sodium channels during the action potential with slow recovery from block during diastole. Anesthesiology 62:396–405, 1985.
81. Thomas RD, Behbehani MM, Coyle DE, et al: Cardiovascular toxicity of local anesthetics: An alternative hypothesis. Anesth Analg 65:444– 450, 1986.
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JE: Cardiac dysrhythmias induced by infusion of local anesthetics into the lateral cerebral ventricle of cats. Anesth Analg 65:133–
138, 1996. 83. Johns
RA, Seyde WC, DiFazio CA, et al: Dose-dependent effects of bupivacaine on rat muscle arterioles. Anesthesiology 65:186–191, 1986.
84. Santos
AC, Arthur GR, Lehning EJ, et al: Comparative pharmacokinetics of ropivacaine and bupivacaine in nonpregnant and pregnant ewes. Anesth Analg 85:87–93, 1997.
85. Kasten
GW, Martin ST: Bupivacaine cardiovascular toxicity: Comparison of treatment with bretylium and lidocaine. Anesth Analg 64:911– 916, 1985.
86. Stevens
RA, Urmey WF, Urquhart BL, et al: Back pain after epidural anesthesia with chloroprocaine. Anesthesiology 78:492–497, 1993.
87. Wang
BC, Hillman DE, Spiedholz NI, et al: Chronic neurologic deficits and Nesacaine-CE: An effect of the anesthetic, 2-chloroprocaine, or the antioxidant, sodium bisulfite. Anesth Analg 63:445–447, 1984.
88. Fibuch
EE, Opper SE: Back pain following epidurally administered Nesacaine MPF. Anesth Analg 69:113–115, 1989.
89. Nath
S, Haggmark S, Johansson G, et al: Differential depressant and electrophysiologic cardiotoxicity of local anesthetics: An experimental study with special reference to lidocaine and bupivacaine. Anesth Analg 65:1263–1270, 1986.
90. Ludena
FP, Bogado EF, Tullar BF: Optical isomers of mepivacaine and bupivacaine. Arch Int Pharmacodyn Ther 200:359–369, 1972.
91. Aberg G: Toxicological and local anesthetic effects of optically active isomers of two local anaesthetic compounds. Acta Pharmacol Toxicol 31:273–286, 1972. 92. Akerman B, Hellberg IB, Trossvik C: Primary evaluation of the local anesthetic properties of the amino amide agent ropivacaine (LEA 103). Acta Anaesthesiol Scand 32:571–578, 1988. 93. Reiz S, Haggmark S, Johansson G, et al: Cardiotoxicity of ropivacaine—a new amide local anaesthetic agent. Acta Anaesthesiol Scand 33:93– 98, 1989. 94. Graf
BM, Martin E, Bosnjak ZJ, et al: Stereospecific effect of bupivacaine isomers on atrioventricular conduction in the isolated perfused guinea pig heart. Anesthesiology 86:410–419,1997.
95. Kao
CY: Pharmacology of tetrodotoxin and saxitoxin. Fed Proc 31:1117–1123, 1972.
96. Ritchie 97. Terlau
JM: Tetrodotoxin and saxitoxin and the sodium channels of excitable tissues. Trends Pharmacol Sci 1:275–279, 1980.
H, Heinemann SH, Stühmer W, et al: Mapping the site of block by tetrodotoxin and saxitoxin of sodium channel II. FEBS Lett 293:93–
96, 1991. 98. Ogura
Y: Fugu (puffer-fish) poisoning and the pharmacology of crystalline tetrodotoxin poisoning. In Simpson LL (ed): Poisons of Animal Origin, vol I, New York, Plenum Press, 1971, pp 139–156.
99. Schantz
EJ: Paralytic shellfish poisoning and saxitoxin. In Simpson LL (ed): Poisons of Animal Origin, vol I, New York, Plenum Press, 1971, pp 159–168.
100. Cousins MJ, Bridenbaugh PO (eds): Neural Blockade in Clinical Anesthesia and Management of Pain, 3rd ed. Philadelphia, JB Lippincott, 1995. 101. DeJong
RH: Local Anesthetics. St. Louis, Mosby–Year Book, 1993.
102. Winnie
AP, Tay CH, Patel KP, et al: Pharmacokinetics of local anesthetics during plexus blocks. Anesth Analg 56:852–861, 1977.
103. Covino
BG, Vassallo HG: Local Anesthetics: Mechanisms of Action and Clinical Use. New York, Grune & Stratton, 1976.
104. Greene
NM, Brull SJ: Physiology of Spinal Anesthesia, 3rd ed. Baltimore, Williams & Wilkins, 1993.
105. Greene
NM: Uptake and elimination of local anesthetics during spinal anesthesia. Anesth Analg 62:1013–1024, 1983.
106. Caplan RA, Ward RJ, Posner K, et al: Unexpected cardiac arrest during spinal anesthesia: A closed claims analysis of predisposing factors. Anesthesiology 68:5–11, 1988. 107. Scanlon JW, Brown WU Jr, Weiss JB, et al: Neurobehavioral responses of newborn infants after maternal epidural anesthesia. Anesthesiology 40:121–128, 1974. 108. Tucker
GT, Boyes RN, Bridenbaugh PO, et al: Binding of anilide-type local anesthetics in human plasma. II. Implications in vivo, with special reference to transplacental distribution. Anesthesiology 35:304–314, 1970.
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Chapter 14 - Adjuvant Drugs ATHINA N. VADALOUCA
The use of adjuvant drugs for spinal and epidural anesthesia is intended to improve the success of regional anesthesia by prolonging the analgesia of local anesthetics and preventing the deleterious clinical effects of their toxic doses. The nerve blockade produced must be complete and reproducible and must also produce the desired duration of action. In the past, this goal was attained by means of new local anesthetic drugs with better spread and good separation of motor and sensory effects. At present, the action of a second drug added to the local anesthetic is directed toward decreasing sensory input to the central nervous system; thus, a major advance in improving the success of regional anesthesia has been achieved. These adjuvant drugs act at a secondary site of action different from that of the local anesthetic. The adjuvant drugs used today range from epinephrine and opiates to α2 -agonist blockers and N-methyl-D-aspartate-(NMDA)–receptor antagonists, and to cholinergic agonists and acetylcholinesterase inhibitor receptor agonists. In addition, the role of calcitonin, octreotide (Sandostatin), and adenosine adjuvant drugs for intraspinal and epidural administration is currently under investigation.
Vasoconstrictors For many years, vasoconstrictors were the only adjuvant drugs available, and, even today, they are commonly used. Local anesthetics, with the exception of cocaine, cause peripheral vasodilatation by direct effects on blood vessel smooth muscle, their vascular absorption being enhanced by the local anesthetic’s vasodilator property. The duration of a local anesthetic is considered to be proportional to the amount of time that the drug remains in contact with the nerve. Vascular absorption is delayed with the addition of a vasoconstrictor, with the result that the drug remains in contact with the nerve tissue longer. This not only prolongs the period of blockade by approximately 50% but also decreases the systemic absorption of local anesthetics by approximately one third ( Fig. 14–1 ). In clinical practice, local anesthetic solutions usually contain epinephrine, at a concentration of 5 µg/mL (1:200,000). With lidocaine, this concentration of epinephrine is optimal. Other concentrations of epinephrine have also been evaluated. There is little difference in peak local anesthetic plasma concentration when it is mixed with epinephrine in proportions of 1:200,000, 1:400,000, or 1:600,000 during epidural administration. Using these data, in the case of a preeclamptic patient, [1]
[2]
Figure 14-1 Addition of epinephrine (adrenaline) to the solution containing lidocaine (lignocaine) or prilocaine decreases systemic absorption of the local anesthetic by about one third.(From Scott DB, Jebson PJR, Braid B, et al: Factors affecting plasma levels of lignocaine and prilocaine. Br J Anaesth 44:1040–1049, 1972.)
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a solution containing 1:600,000 proportion of local anesthetic and epinephrine should be a better alternative to the conventional 1:200,000 solution. In a normal pregnancy, neither vascular resistance in the uteroplacental or fetal circulation nor fetal myocardial function is affected adversely when epinephrine, 90 to 100 µg, is added to bupivacaine and administered fractionally for extradural anesthesia. To prevent maternal hypotension, it is, of course, necessary to administer crystalloid volume rapidly. [3]
In a study reported in 1999 to determine whether epinephrine added to a solution of bupivacaine and injected for superficial cervical plexus blockade lowers plasma bupivacaine concentration and whether this addition of epinephrine results in tachycardia, cardiac arrhythmia, or both, the authors found that (1) bupivacaine 0.25% with epinephrine 1:300,000 consistently produced the lowest plasma bupivacaine concentrations compared with bupivacaine 0.25% without epinephrine and bupivacaine 0.5% with or without epinephrine; and (2) the use of epinephrine did not produce untoward cardiac side effects. [4]
Prilocaine with felypressin causes fewer side effects than lidocaine with epinephrine and is therefore the preferred local anesthetic combination for large loop excision of the transformation zone. [5]
The greater lipid solubility of bupivacaine and etidocaine results in a lesser decrease in systemic absorption and a greater increase in duration of conduction blockade than those occurring with lidocaine when administered in conjunction with epinephrine. When epinephrine or phenylephrine is added to bupivacaine or lidocaine in the spinal space, a greater duration of sensory anesthesia in the lower extremities is produced. The efficacy of epinephrine in prolonging spinal anesthesia has been confirmed in the lumbosacral region, and was confirmed in thoracic segments in 1998. In a study reported in 1998, a dose-dependent response and significant prolongation were confirmed with a 0.6-µg dose of epinephrine added to hyperbaric lidocaine, 60 mg, in 7.5% dextrose solution for spinal anesthesia in the thoracic dermatomes. Furthermore, epinephrine added to a low dose of tetracaine (6 mg) increases the rate of success with spinal anesthesia. [6]
[7]
The addition of epinephrine to procaine for spinal anesthesia prolongs sensory and motor blocks by 25%. However, it is associated with a high incidence of nausea. The decrease of systemic absorption of local anesthetic owing to epinephrine’s vasoconstrictive action increases the likelihood that the rate of metabolism may match that of absorption, thus decreasing the possibility of systemic toxicity. [8]
In clinical practice, the administration of a local anesthetic with vasoconstrictors in the presence of inhaled agents has the potential for producing enhancement of cardiac irritability. The addition of epinephrine to local anesthetic solutions has little, if any, effect on the onset rate of local anesthesia. [9]
The duration of peripheral nerve block anesthesia is prolonged more safely by epinephrine than by increasing the dose of local anesthetic, which also increases the likelihood of systemic toxicity. Mepivacaine with epinephrine for axillary block target injections reduces total anesthetic time and provides better spread of analgesia in the hand and forearm. Bupivacaine combined with epinephrine may produce peripheral nerve block anesthesia lasting up to 14 hours. The prolongation of action when epinephrine is added to bupivacaine or ropivacaine has not been documented in reports. [10]
There is little available information regarding the effect of epinephrine on plasma lidocaine concentration during continuous anesthesia. In a study reported in 1999 regarding continuous epidural administration, the addition of epinephrine to lidocaine solutions was ineffective after 2 hours in reducing the potential for systemic toxicity. This is the result of the overall plasma lidocaine concentration and of the insignificant decrease of its principal active metabolite, monoethylglycine xylidide (MEGX). [11]
Opioids The placement of opioids in the epidural or subarachnoid space to manage acute or chronic pain is based on the knowledge that opioid receptors are present in the substantia gelatinosa of the spinal cord. Opium is probably the oldest known medically useful material. Its psychological effects and usefulness in controlling pain and diarrhea were known to the ancient Sumerians (4000 BC) and Egyptians (2000 BC). Opiate is the term used for drugs derived from opium. Morphine was isolated in 1803, followed by codeine in 1832 and papaverine in 1848. Morphine can be synthesized, but it is more easily derived from opium. [12]
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The most interesting actions of morphine and related drugs are those affecting the central nervous system, such as the control of pain and the phenomena of tolerance and physical and psychological dependence, TABLE 14-1 -- CLASSIFICATION OF OPIOIDS, AGONIST-ANTAGONISTS, AND ANTAGONISTS Opioid Agonist-Antagonists
Opioid Antagonists
Morphine
Opioids
Pentazocine
Naloxone
Meperidine
Butorphanol
Naltrexone
Sufentanil
Nalbuphine
Nalmefene
Fentanyl
Buprenorphine
Alfentanil
Nalorphine
Remifentanil
Bremazocine
Codeine
Dezocine
Dextromethorphan Hydromorphone Oxymorphone Methadone Heroin
TABLE 14-2 – EFFECTS OF OPIOID RECEPTORS Effects
µ1
µ2
κ
δ
Analgesia (supraspinal, spinal) Analgesia (spinal) Euphoria Depression of ventilation Dysphoria sedation Low abuse potential Physical dependence Miosis Constipation (marked) Constipation (minimal) Bradycardia Hypothermia Urinary retention Diuresis
which together make up the major undesirable side effect profile of the opiate drugs, namely, narcotic addiction. The development of synthetic drugs with morphine-like properties has led to the use of the term “opioid” to refer to all exogenous substances, natural and synthetic, that bind specifically to any of several subpopulations of opioid receptors and produce at least some agonist (morphine-like) effects. Semisynthetic opioids result from relatively simple modification of the morphine molecule ( Table 14–1 ). Synthetic opioids contain the phenanthrene nucleus of morphine but are manufactured by synthetic rather than chemical modification of morphine. Morphine derivatives (e.g., levorphanol), methadone derivatives, benzomorphan derivatives (e.g., pentazocine), and phenylpiperidine derivatives (e.g., meperidine, fentanyl) are examples of groups of synthetic opioids. There are similarities between the molecular weights (236 to 326) and pKs of phenylpiperidine derivatives and amide local anesthetics. Fentanyl, sufentanil, alfentanil, and remifentanil, which are semisynthetic opioids, are commonly used as supplements to general anesthesia, as primary high-dosage cardiac surgery anesthetic drugs, or as adjuvant drugs in regional anesthesia, despite the fact that the vehicle within remifentanil, when administered epidurally or spinally, has not yet been demonstrated to be safe. These opioids differ in terms of pharmacokinetics and pharmacodynamics. The most important pharmacodynamic differences among these drugs are potency and rate of equilibration between the plasma and the site of drug effect (biophase). [13] [14] [15]
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It is not disputed that opioids act in the central nervous system, particularly the brainstem and the spinal cord. However, several pharmacologic, neurophysiologic, and immunohistologic studies have suggested that exogenous or endogenous opioids also exert antinociceptive effects by acting at peripheral sites. [16]
THE ENDOGENOUS OPIOID SYSTEM Opioid receptors are classified as µ, δ, and κ receptors ( Table 14–2 ). agonists and antagonists on opioid receptors is shown in Table 14–3 .
[17]
The classification of the effect of opioid
These opioid receptors belong to a superfamily of guanine (G) protein–coupled receptors that constitute 80% of all known receptors, including muscarinic, adrenergic, γ-aminobutyric acid, and somatostatin receptors. µ- or morphine-preferring receptors are principally responsible for supraspinal and spinal analgesia. µ Receptors include a subpopulation of µ1 and µ2 receptors. The activation of µ1 receptors produces analgesia, euphoria, and miosis, whereas the activation of µ2 receptors is responsible for hypoventilation, physical dependence, and marked constipation. Exogenous µ-receptor agonists include morphine, meperidine, fentanyl, sufentanil, alfentanil, and remifentanil. Activation of calcium channel–linked κ receptors produces less respiratory depression than µ-receptor activation. However, dysphoria and diuresis may accompany activation of κ receptors. Opioid agonists-antagonists often act principally on κ receptors. δ Receptors respond to the endogenous ligands known as enkephalins, and these opioid receptors may serve to modulate the activity of the µ receptors. Sigma and epsilon receptors were included in the past in the classification of opioid receptors; however, both of them are no longer considered to be opioid receptors. Nonopioid sigma receptors may be identical to receptors that bind drugs, such as ketamine. [18]
Three types of opioid receptors have been cloned (µ, δ, κ); these receptors belong to the family of seven transmembrane G protein–coupled receptors; the molecular basis for the presence of opioid receptor subtypes has not been demonstrated. Cloning of opioid receptors introduces the potential for development of highly selective and subtype-specific receptor agonists. The ideal opioid analgesic would have a high specificity [19]
TABLE 14-3 -- CLASSIFICATION OF THE EFFECT OF OPIOID AGONISTS AND ANTAGONISTS ON OPIOID RECEPTORS
AGONISTS
ANTAGONISTS
µ1
µ2
Κ
δ
Endorphins
Endorphins
Dynorphins
Enkephalins
Morphine
Morphine
Synthetic opioids
Synthetic opioids
Naloxone
Naloxone
Naloxone
Naloxone
Naltrexone
Naltrexone
Naltrexone
Naltrexone
Nalmefene
Nalmefene
Nalmefene
Nalmefene
for receptors, producing good analgesia with few or no side effects. A new opioid receptor (opioid receptor-like 1, ORL-1), which is structurally analogous to the κ opioid receptor, has been identified. It has the peculiarity of not binding to conventional opioids. [20]
ENDOGENOUS OPIOID PEPTIDES The two pentapeptides, Tyr-Gly-Gly-Phe-Met and Tyr-Gly-Gly-Phe-Leu, given the names methionine enkephalin and leucine enkephalin, were identified as the first endogenous molecules with opiate-like (opioid) activity and high affinity for opiate receptors. Approximately 12 peptides with opioid activity have since been discovered, including the endorphins derived from the previously known pituitary hormone, β-lipotropin, and dynorphin, which is a basic peptide containing many lysine and arginine residues, having leucine enkephalin at its N-terminal, and bearing no relation to β-lipotropin. It is now evident that all the known peptides derive from three large precursor proteins: proenkephalin, pro-opiomelanocortin, and prodynorphin, each coded by a separate gene ( Table 14–4 ). Therefore, three genetically independent families of endogenous opioid peptides are identified: enkephalin, βendorphin, and dynorphin, which include more than 20 peptides with opioid-like activity (transmitters). A new family of endogenous opioid peptides (endomorphins 1 and 2), with selectivity for the µ opioid receptors, has been characterized in the brain. After binding to the receptors, endogenous opioid peptides are inactivated in the [21]
[22]
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extracellular space by nonspecific petptidases. Drugs that block or inhibit these inactivating enzymes have been developed and shown to produce analgesia in various animal models and in humans. [23] [24]
NEURAXIAL OPIOIDS The knowledge that opioid receptors are present in the substantia gelatinosa of the spinal cord has led to the [12]
TABLE 14-4 -- OPIOID PEPTIDES AND THEIR PRECURSORS Precursors
Peptides
Proenkephalin
Met-enkephalin Leu-enkephalin Heptapeptide Octapeptide
Pro-opiomelanocortin
α-Endorphin γ-Endorphin β-Endorphin
Prodynorphin
α-Neoendorphin Dynorphin A (1–17) Dynorphin (1–8) Dynorphin B (Rimorphin)
TABLE 14-5 -- INTERACTIONS OF OPIOIDS WITH ENDOGENOUS SUBSTANCES Substance
Enhances (↑) or Reduces (↓) Morphine Effect
Blocks or Reverses Opiate Tolerance
5-HT agonists
↑
—
α2 -Adrenergic agonists
↑
—
↓
Blocks and reverses
No effect
Blocks
CCK-B NMDA antagonists CCK-B, cholecystokinin-B; NMDA, N-methyl-D-aspartate.
clinical use of opioids in the epidural or subarachnoid space in order to ameliorate acute and chronic pain. Analgesia that is seen after epidural or spinal administration of opioids, in contrast to regional anesthesia with local anesthetics, is not associated with sympathetic nervous system denervation, is dose related, and is specific for visceral rather than somatic pain. The main objective in using spinal opioids is to obtain a reduction in the dose (compared with systemic administration) that results in effective analgesia and fewer side effects. The analgesia induced by spinal opioids is produced by several mechanisms and can be summarized as (1) direct inhibitory action on the dorsal horn of the spinal cord, and (2) indirect effects inducing the release of nonopioid inhibitory transmitters or modulators. After systemic administration, the binding of opioids to opioid receptors located in the midbrain and medulla activates descending inhibitory pathways that induce the release of neurotransmitters in the dorsal horn of the spinal cord. Several endogenous substances interact with spinal morphine ( Table 14–5 ). Placing opioids in the epidural space may lead to systemic absorption, with diffusion across the dura into the cerebrospinal fluid (CSF), or the absorption of the opioid into the epidural fat. Considerable CSF concentrations of opioids are produced through epidural administration. The extent of dural penetration is dependent mainly on lipid solubility, but molecular weight may also play a part. The combination of fentanyl with local anesthetics was initially reported in 1982 by Justins and colleagues as a means of producing more complete anesthesia. These drugs are respectively approximately 800 and 1600 times more lipid soluble than morphine. If CSF concentrations are compared after epidural administration of morphine, fentanyl and sufentanil, the peak concentration occurs in about 1 to 4 hours, 20 minutes, and 6 minutes, respectively. [25]
[26]
However, it has been questioned whether the epidural administration of lipophilic opioids actually offers any clinical advantages over intravenous (IV) administration. Opioids, such as morphine, with a low lipid solubility do produce [27]
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a slower onset of analgesia, but their duration of effectiveness is much longer. Lipid solubility is the dominant factor in terms of the cephalad movement of opioids in the CSF. For instance, lipid-soluble opioids such as fentanyl and sufentanil are restricted in their cephalad movement because of their being drawn into the spinal cord, whereas morphine, which is not so lipid-soluble, remains in the CSF and is therefore able to reach more cephalad locations. After epidural administration of highly lipid-soluble opioids, cervical CSF concentrations of the opioids are minimal. On the other hand, substantial cervical CSF concentrations are present up to 5 hours postinjection after lumbar intrathecal morphine administration. Coughing or straining but not body position can affect the movement of the CSF. Morphine, together with epinephrine, enhances intrathecal analgesia compared with morphine alone. In a study reported in 1998, the analysis of the current literature showed that the addition of fentanyl to local anesthetics for intraoperative epidural analgesia was safe and advantageous. [28]
[29]
In obstetric anesthesia, a lower dosage of bupivacaine, combined with sufentanil in epidural analgesia, significantly improves the obstetric outcome compared with a higher dosage of bupivacaine with adrenaline using an intermittent bolus technique. In 1999, Joshi and associates recommended the addition of 1 µg/kg of fentanyl in a low concentration of bupivacaine (0.125%) as the caudal injectate mixture in pediatric patients. Therefore, clinical use has been extensively investigated. [30]
In terms of the treatment of acute postoperative and chronic pain, the peripheral administration of opioids has also been evaluated. The route and site of administration and the type and duration of inflammation appear to be the most significant factors. A number of different routes and sites have been examined. Opiates have been used individually or combined with local anesthetics and administered through axillary block, as well as by regional IV, interpleural, intradermal, intraperitoneal, and intra-articular routes. However, a recent systematic review concluded that only the intra-articular route produces clinically significant changes in intra- or postoperative analgesic efficacy. One possible explanation for the ineffectiveness of other routes could be the presence of an intact perineurium, which may prevent opioids from reaching the opioid receptors presumably present in nerve fibers and terminals. On the other hand, the administration of opiates intra-articularly does produce some level of analgesia. It must be noted, however, that the published results are not always consistent. Many of the studies in the literature focus on the use of intra-articular morphine after knee arthroscopy in terms of the evaluation of pain intensity and postoperative analgesic requirements. The results demonstrate that low doses of intra-articular morphine produce no systemic effects and induce long-lasting analgesia comparable with that of local anesthetics. As the effects are reversed by intra-articular and systemic naloxone, the conclusion can be drawn that analgesia is mediated through opioid receptors located in the knee joint. In a study published in 1997, the authors concluded that IV regional anesthesia using morphine provided no analgesic advantage over the intramuscular route from 6 to 24 hours postoperatively. However, the addition of alfentanil to lidocaine during axillary brachial plexus anesthesia suggests that alfentanil may have a peripheral local anesthetic action. [31]
[32]
[33]
[34]
Side Effects
The typical side effects of neuraxial opioids are caused by the presence of the drugs in either the CSF or the systemic circulation ( Table 14–6 ). The most serious side effect of neuraxial opioids is respiratory depression, which, after conventional doses of perispinal opioids, requires intervention at a rate of 1%, which is the same as that after IV or intramuscular opioids. Obstetric patients appear to be at less risk for ventilatory depression, perhaps because of increased ventilatory stimulation provided by progesterone. The side effects can be managed by the administration of low doses of naloxone. Naloxone in an IV dose of 0.25 µg/kg/hr is effective in attenuating the side effects. Valley and Bailey observed 11 cases of respiratory depression and concluded that “the clinicians should be aware of the increased incidence of respiratory depression.” Thus, for opioids to be used safely and effectively as adjuvant drugs, adequate monitoring of vital parameters is necessary. Controlling respiratory rate is not sufficient by itself to avoid risks, and a continuous pulse oximetry reading, in order to control the oxygen saturation, together with a sedation degree evaluation, are essential. [35]
Ketamine Ketamine is an IV drug with special properties that make it the only agent currently used as anesthetic, sedative, amnesic, and analgesic.
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Nausea and vomiting Pruritus Urinary retention Sedation Depression of ventilation Central nervous system excitation Water retention Gastrointestinal dysfunction Sexual dysfunction Thermoregulatory dysfunction Ocular dysfunction Viral reactivation Neonatal morbidity
Ketamine is a phencyclidine (PCP) derivative, the chloroketone analogue (C1-581) that produces “dissociative anesthesia,” which is characterized by evidence on electroencephalogram of dissociation between the thalamocortical and limbic systems. [36]
Ketamine is a water-soluble molecule (10 times more soluble than thiopentone) with a pK of 7.5 at physiologic pH. Only the racemic form containing equal amounts of the ketamine isomers is available for clinical use; the S(+) isomer produces more intense analgesia, more rapid metabolism, and, as a consequence, more rapid recovery and a lower incidence of emergency reactions than the R(−) isomer. [37]
Both S(+) and R(−) isomers of ketamine appear to inhibit the uptake of catecholamines. This inhibition is a cocainelike effect and takes place in the postgaglionic sympathetic nerve endings. The fact that the isomers of ketamine differ in their pharmacologic properties suggests that this drug interacts with specific receptors.
MECHANISM OF ACTION Glutamate and aspartate are arguably the major excitatory transmitters in the vertebrate central nervous system, whereas GABA is a major inhibitory transmitter. The cell surface receptors that mediate the effects of glutamate release can be found at most excitatory synapses throughout the central nervous system. These receptors; they are divided into the slow, G-protein–coupled metabotropic receptors and the fast, ligand-gated ion channels (ionotropic receptors). The latter class is again divided according to the agonists originally used to characterize them. (S)-2amino-3-(3-hydroxy-5-methylisoxazol-4-yl) propionic acid (AMPA) receptors mediate the majority of fast, excitatory neurotransmission and kainate receptors; they are as yet little understood but are likely to be important in the future. The NMDA receptor, named after the synthetic glutamate analogue and agonist, N-methyl-D-asparate, is perhaps the most interesting glutamate receptor in terms of physiology and pathology. During normal transient processing of nociceptive signals, the NMDA receptors appear to be unimportant, but with prolonged nociceptive stimulation, as a result of prolonged release of glutamate or neurokinin-1, the NMDA receptors become activated. The NMDA receptors are involved in several events, including central sensitization, wind-up, long-term potentiation, and induction of oncogenes. NMDA receptors generate plasticity in many systems, such as memory, motor function, vision, and spinal sensory transmission. Activation of NMDA receptors is accompanied by loss of their Mg2 + plug, followed by calcium influx, which activates several second messenger systems, the most important of which are protein kinase C and nitric oxide systems. Figure 14–2 shows a schematic representation of dorsal horn systems with mechanisms that mediate the processing of nociceptive information, as occurs after tissue injury. [38]
Ketamine is a noncompetitive antagonist of the NMDA receptor calcium pore and, in addition, ketamine interacts with the phencyclidine-binding receptor site, leading to inhibition of NMDA receptor activity. Hurstveit and associates reported that ketamine interacts with µ, κ, and δ opioid receptors, whereas other studies suggested that ketamine may be an agonist of δ receptors and an antagonist of µ receptors. Results of a study published in 1999 proved that opioid receptor blockade by naloxone does not inhibit ketamine-induced reductions of secondary hyperalgesia. On the other hand, the anticholinergic symptoms produced by ketamine suggest that this drug has an antagonist rather than an agonist effect on muscarinic receptors. [9]
[39]
[40]
Muscarinic signals play an important role in memory, consciousness and learning and, therefore, the “ketamine effect” may be the result of muscarinic inhibition. On the other hand, benzethonium chloride, the ketamine preservative, has also been shown to inhibit cholinergic symptoms. [41]
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Figure 14-2 Schematic representation of dorsal horn systems with mechanisms that mediate the processing of nociceptive information. AA, arachidonic acid; COX, cyclooxygenase; EP, epinephine; NK, natural killer; NMDA, N-methyl-D-aspartate; PG, prostaglandin; PKC, protein kinase C; PLA , phospholipase AZ isoenzymes; sP/CGRP, substance P/calcitonin gene-related peptide. 2
Ketamine interacts with the monoaminergic receptors and voltage-sensitive calcium channels. A study published in 2000 examined the effects of in vitro ketamine on synaptic transmission and long-term potentiation in layers II and III of the adult rat visual cortex. Primed-burst stimulation was used for induction of long-term potentiation. The authors concluded that ketamine can interfere with synaptic transmission in the visual cortex through the antagonism of the NMDA receptors “involved in the induction of long-term potentiation in a rat’s visual cortex.” [42]
Ketamine is metabolized extensively by hepatic microsomal enzymes. The active metabolite of ketamine is norketamine. Norketamine is eventually hydroxylated and then conjugated to form more water-soluble and inactive glucuronide metabolites, which are excreted by the kidneys. The administration of ketamine over a long period has the effect of increasing the activity of enzymes that are responsible for its metabolism. This accelerated metabolism may partly explain why some patients receiving repeated doses of the drug develop a tolerance to ketamine’s analgesic properties. Demling and colleagues suggested that burn patients receiving more than two short-interval exposures to ketamine may develop tolerance. The development of tolerance has also consistently been observed in cases of ketamine dependence. [43]
[44]
NEURAXIAL ANALGESIA Ketamine has been used for a long time as a supplement for central blocks with a lower incidence of adverse effects and for IV sedation during regional anesthesia. [45]
[41]
The first study of intrathecal administration of ketamine was in 1984 by Bion. Studies have demonstrated that the intrathecal administration of preservative-free ketamine causes no neurotoxicity. [46]
[47] [48] [49]
Surgical anesthesia can be achieved by intrathecally injected ketamine. However, further study on this topic is required. A study comparing the hemodynamic effects of lidocaine or intrathecally injected ketamine on normoovolemic and hypovolemic pigs showed that the ketamine group had lower hemodynamic alterations than the lidocaine group. The NMDA antagonist effect may be involved. If this were translated to human practice, ketamine could be employed in subarachnoid anesthesia for hypovolemic or hemodynamically unstable patients. [50]
Intrathecal ketamine (without preservative) is a promising analgesic alternative for women in labor, although its use is still at an experimental or very early clinical stage. [51]
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In the 1980s, a number of studies concerning the use of epidural ketamine in humans began to be published. Good postoperative analgesia without respiratory depression or other side effects was reported. [52] [53]
The group at my institution concluded that ketamine be recommended for use as a postoperative epidural analgesic in regional operations, because it offers satisfactory analgesia without any risk to the safety of the patient. More recent studies have shown good postoperative analgesia with ketamine administered epidurally or caudally. [54]
[55] [56]
Semple and associates evaluated the optimal dose of preservative-free ketamine to be added to local anesthetics (0.25% bupivacaine, 1 mL/kg) for caudal epidural blockade in children. They demonstrated the duration of postoperative analgesia to be dose dependent, with the optimal dose being 0.50 mg/kg of ketamine, which produced no adverse effects, as opposed to a dosage of 1 mg/kg. [57]
To compare the effect of ketamine on onset time of regional anesthesia and the degree of sensory and motor block, Yanli and coworkers added ketamine, 25 mg (with benzethonium chloride) or saline to 0.5% bupivacaine plus adrenaline in a randomized, double-blind study. No differences were demonstrated in hemodynamic parameters. Onset time decreased by about 8 minutes, and the anesthetic level was higher in two to three segments of the ketamine group, without differences in motor blockade or postoperative duration of analgesic effects. No adverse effects were found. [58]
Because NMDA is known to be implicated in central sensitization, it is possible that NMDA antagonists may be more effective in inducing preemptive analgesia than µ- and κ-agonist opioids. This has been confirmed in several studies, but all of these studies suffered from a variable number of defects in design. [59] [60] [61]
Ketamine has also been used for patients with chronic pain syndromes such as neuropathic pain, phantom limb pain, postherpetic neuralgia, and cancer pain. Based on clinical case evaluations, ketamine by spinal route and, on occasion, by other means of administration, seems to be a promising drug in the armamentarium for treatment of chronic pain patients whose cases are difficult. [62]
Numerous experiments have shown the synergistic effects of NMDA antagonists and opioids in analgesia, whereas the development of opioid tolerance was prevented. A possible explanation of the analgesic affinity of ketamine is its antioxidative properties, as was shown in a study published in 1998. These results demonstrated that memantine and amantadine act as radical scavengers, as inhibitors of the oxidative function of microsomal cytochrome P450, or as both. The knowledge that antioxidants play a role in pain relief in treatment of patients with chronic pain may indicate a new horizon for analgesic properties of NMDA-receptor antagonists. [63] [64]
[65]
[66] [67] [68]
Another use of ketamine is its topical application. A study reported in 1999 demonstrated that topical morphine tolerance is mediated, at least in part, through peripheral NMDA receptors, which raises the possibility of the clinical use of topical NMDA-receptor antagonists. [69]
Clonidine The centrally acting selective partial α2 -adrenergic agonist clonidine, because of its ability to reduce sympathetic nervous system output from the central nervous system, acts as an antihypertensive drug. Preservative-free clonidine, administered into the epidural or subarachnoid space (150–450 µg), produces dose-dependent analgesia and, unlike opioids, does not produce depression of ventilation, pruritus, nausea and vomiting, or delayed gastric emptying. [9]
[70] [71] [72]
α2 -Adrenergic drugs such as clonidine, dexmedetomidine, and tizanidine exert action on the descending inhibitory monoaminergic tracts, resulting in an antinociceptive effect. Clonidine produces analgesia by activating postsynaptic α2 receptors in the gelatinous substance of the spinal cord. The use of neuraxial clonidine, either to produce analgesia or to prolong the effects of regional anesthesia, may be accompanied by side effects, namely, hypotension and dryness of the mouth. Most evidence about the effectiveness of intrathecal clonidine is provided by studies on postoperative pain. These studies show the effect of a local anesthetic on the duration and intensity of spinal blockade. Moreover, the addition of intrathecal clonidine results in a longer period of postoperative analgesia. [73]
[74]
Van Elstraete and colleagues, in 2000, assessed the analgesic efficacy and side effects of caudally administered clonidine as a mixture of bupivacaine 0.5% with lidocaine, and 2% with epinephrine. They concluded that the [75]
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addition of 75 µg of clonidine increased the duration of postoperative analgesia in adults without affecting mean arterial pressure. On the other hand, Ivani and Lampugnani, in 1998, stated that “the use of clonidine as an adjuvant drug in the field of regional anesthesia both in adults and children seems to be very effective and in the pediatric field is safer with respect to opioids and adrenaline.” In contrast, Breschan and coworkers concluded that the administration of 2 µg/kg of clonidine caudally in neonates for postoperative analgesia could cause respiratory depression. Postoperative pain relief by continous epidural infusion of ropivacaine has been improved by the addition of clonidine. [76]
[77]
[78]
For spinal anesthesia, motor and sensory blocks are prolonged with the addition of clonidine to local anesthetics, but the requirement for ephedrine treatment is not increased. [79]
The combination of clonidine, in a dose of 100 to 150 µg with fentanyl, results in prolongation of fentanyl analgesia. Continuous infusion of clonidine alone produces rate-dependent reduction in the need for other pain medication after surgery. The importance of these infusion rates is that they are not associated with sedation, although blood pressure is slightly decreased compared with placebo. The addition of clonidine to other opioids for continuous epidural infusion reduces the opioid dose by 20% to 60%. It is possible for clonidine to produce postoperative analgesia with either systemic or epidural injection, but the epidural dose of clonidine required is lower than the systemic one. This is in contrast to fentanyl and sufentanil, in which there is no difference in dose between the two routes. There is clear evidence that a fixed dose (150 µg) of clonidine intramuscularly, epidurally, or intrathecally has a clear order of duration: intrathecal > epidural > intramuscular, supporting intraspinal administration. [79]
[80]
Eisenach and colleagues carried out a review of the use of clonidine in regional anesthesia as presented in the international literature of 1995. Most controlled and uncontrolled trials were concerned with epidural or spinal administration, primarily in perioperative and obstetric patients. The findings demonstrated that clonidine, depending on dose and coadministered agents, was able to reduce blood pressure. Furthermore, there have been no reported cases in the literature of life-threatening hypotension or bradycardia. Eisenach and associates argued that it was this factor that was the key benefit of clonidine, considering the small but significant incidence of respiratory depression that occurs with use of epidural and spinal opioids. [81]
[71]
However, clonidine fails to produce surgical anesthesia and is therefore not administered alone during surgery or for the final stages of labor. In addition, clonidine’s side effects, dose-dependent sedation and hypotension, preclude its administration in large doses and have led to a warning label by the U.S. Food and Drug Administration that it not be administered routinely in postoperative and obstetric settings. On the other hand, small doses of intrathecal clonidine have shown much promise for labor analgesia. [82]
In a study reported in 2000, Paech and coworkers concluded that the addition of clonidine to epidural bupivacaine and fentanyl for patient-controlled epidural analgesia in labor improved pain control and the supplementation rate and shivering. Increased sedation and lower blood pressure were not clinically important. [83]
As a sole agent, clonidine, 50 µg, gives about 45 minutes of good analgesia. At 100 to 200 µg, the analgesia is longer but hypotension can be profound. When clonidine, 30 µg, was coadministered with sufentanil (2.5 µg and 5 µg), analgesia was prolonged. The same result happened when clonidine, 50 µg, was added to sufentanil, 7.5 µg, and bupivacaine, 2.5 mg. In these situation, no adverse side were noted and the opioid dose was reduced. [84]
[85]
[86]
Dexmedetomidine Dexmedetomidine is a next generation α2 -adrenergic agonist in clinical trials, although it is not yet available for obstetric use. The blood pressure effects of dexmedetomidine are minimal and there are few systemic side effects, arguably making it the better analgesic of its class. Compared with clonidine, dexmedetomidine is seven times more selective for α2 receptors and has a shorter duration of action. In this regard, dexmedetomidine is considered to be a full agonist among the α2 receptors, whereas clonidine is a partial agonist. However, more research is necessary before it can be used in parturients. [87]
In the last few years, new routes of administration for α2 -adrenergic agonists have received closer attention. Intraarticular administration of clonidine has demonstrated a peripherally mediated analgesic effect in preclinical and clinical trials. To determine whether clonidine or morphine results in better analgesia and whether their combination would provide analgesia superior to that of either drug alone, a study evaluating patients undergoing knee arthroscopy of
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the meniscus under local anesthesia concluded that intra-articular clonidine and morphine improved comfort compared with either drug alone. [88]
A study published in 2000 reviewed current evidence for the efficacy of adding novel analgesic adjuncts to brachial plexus block, the goal of which was to prolong the analgesic effect without the disadvantage of systemic side effects or prolonged motor block. These adjuncts may also allow a reduction in the dose of local anesthetic used. Novel adjuncts studied to date include opioids, clonidine, neostigmine, and tramadol. Twenty-four studies were reviewed and assessed by using specific inclusion criteria, and only those studies satisfying these criteria were included in the final assessment. Clonidine appears to have significant analgesic benefit and to cause minimal adverse effects when used in doses of 150 µg. [89]
On the contrary, according to a study of Erlacher and colleagues, the addition of clonidine to ropivacaine, 0.75%, for axillary perivascular brachial plexus block, does not lead to any advantage of the block in regard to onset time, duration of analgesia, and quality of the block. [90]
A study by Elliott and coworkers has compared local infiltration with clonidine-containing bupivacaine solution with plain anesthetic solution after inguinal hernia repair. The results of the group who received clonidine were not significantly different from those patients in the plain solution group. On the other hand, it has been shown that during intravenous anesthesia, clonidine improves tolerance of the tourniquet. [91]
[92]
The most important use of intrathecal and epidural clonidine is in the treatment of chronic pain. Intrathecal injection of α2 -adrenergic agonists in preclinical studies maintained or increased potency, whereas intrathecal opioids lost potency or efficacy in animal models of neuropathic pain. [93]
Clonidine infused epidurally, at a rate of 30 µg/hr, produces analgesia in patients with cancer and neuropathic pain, and infusion rates of 10 to 40 µg/hr are commonly used in this patient population. Steady state CSF clonidine concentrations of 12 to 45 ng/mL should be produced by these rates within approximately 6 hours. This time period concurs with the relatively fast onset of analgesia from the epidural infusion of clonidine in these patients.
[81]
In conclusion, the evidence clearly suggests that clonidine should be administered epidurally rather than systemically for pain relief. Clinical studies have indicated a close relationship between the amount of clonidine in CSF and the relief of pain, and a spinal site of action of α2 -adrenergic agonists is supported by anatomic and neurophysiologic experiments in animals. Clonidine is less effective in treating acute pain when administered intravenously. Analgesia is produced by α2 -adrenergic agonists, partly by stimulating cholinergic systems in the spinal cord, and, although this mechanism is activated by a small dose of clonidine administered intrathecally, it is not activated by systemic administration. Epidural clonidine produces effective relief of chronic pain, which involves abnormal sympathetic nervous system activity or abnormal responses to sympathetic activity. Thus, it is clear that clonidine administered epidurally is both more effective as an analgesic and produces fewer side effects than systemic administration. [79]
Neostigmine Neostigmine, edrophonium, and physostigmine are the anticholinesterase drugs that are most often administered by anesthesiologists to facilitate speed of recovery from the skeletal muscle adverse effects caused by nondepolarizing neuromuscular blocking drugs. The spinal cholinergic system has gained new interest as a pharmacologic target for accomplishing efficient antinociception without the limitation of opioid-induced side effects, especially delayed respiratory depression.
[94]
Acetylcholine is one of more than 25 neurotransmitters that participate in spinal cord modulation of pain processing. Acetylcholinesterase is one of the most efficient enzymes known and is normally responsible for the rapid hydrolysis of the neurotransmitter acetylcholine to choline and acetic acid. Therefore, the use of cholinergic agonists or acetylcholinesterase inhibitors such as neostigmine were investigated with respect to their specific antinociceptive activity and to any potential side effects and toxicity after spinal administration. It was demonstrated that neostigmine produces analgesia without introducing the ventilatory depression characteristic of neuraxial opioids, although nausea is common. [71] [95] [96] [97]
[98]
The spinal delivery of cholinergic agonists has been shown in animal studies to produce analgesia. This is brought about by the interaction with spinal noradrenergic-cholinergic neurons corresponding with neurons in laminae I and II of the spinal dorsal horn. It appears that muscarinic receptors, as opposed to nicotinic receptors, play a part in [99]
[100] [101]
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producing analgesia. For this reason, it is suggested that M1 and M2 receptors are primarily involved in spinal antinociception. [102]
Neostigmine administered spinally inhibits nociception in a dose-dependent manner by increasing the endogenous neurotransmitter acetylcholine, and thus its analgesic potency is enhanced in specific pain states with tonic release of acetylcholine-like neuropathic pain or inflammatory pain disorders. [103]
In addition, IV opioids stimulate an inhibitory system in the spinal cord that involves the release of acetylcholine, and intrathecal neostigmine enhances analgesia from intravenous opioids in animals and humans. The large potentiation observed between neostigmine and α2 -adrenergic agonists such as dexmedetomidine and clonidine carries important clinical implications. The addition of neostigmine, 50 µg, prolonged the duration of sensory and motor block. However, a high incidence of side effects and delayed recovery from anesthesia with the addition of neostigmine, 6.25 to 50 µg, may limit the clinical use of these doses for outpatient spinal anesthesia. [104]
Klamt and coworkers, in 1996, studied the analgesia produced by intrathecal neostigmine in cancer patients. Although neostigmine produces analgesia in patients with chronic pain and in the postoperative setting, it produces a high incidence of nausea and vomiting in the same doses. [105]
Spinal administration of neostigmine as a nonopioid analgesic appears to provide a potent, long-lasting analgesia. However, its clinical feasibility has still to be assessed with special regard to its side effects, particularly nausea and vomiting. There is a need, therefore, to investigate the ultralow doses of neostigmine combined with other analgesics in order to avoid the undesirable side effects. [82]
In 1999, Lauretti and colleagues reported the epidural administration of neostigmine in combination with lidocaine for postoperative analgesia. These reports have been encouraging because they demonstrate dose-dependent analgesia without nausea for 8 to 12 hours after surgery. This route of administration needs further investigation. [107]
Bórkle and coworkers concluded, based on preclinical and clinical studies, that neostigmine can be used as a potent peripherally mediated analgesic drug. This action, according to Bórkle’s conclusion, may be mainly due to enhanced levels of endogenous accetylcholine at the level of the peripheral afferent nociceptor. [107]
The authors of a study reported in 2000 reviewed the efficacy of adding novel analgesic adjuvants to brachial plexus block. The novel analgesic adjuvant drugs studied included opioids, clonidine, neostigmine, and tramadol. Evidence regarding the analgesic benefit of opioid adjuvants remains equivocal, and more evidence is required before their routine use can be recommended. Clonidine appears to have significant analgesic benefit and causes minimal adverse effects when used in doses of 150 µg. Data regarding the other drugs, such as tramadol and neostigmine, are not sufficient to allow any recommendations to be made, and further studies of these agents are required. [89]
[89]
On the other hand, in a previous study, the authors concluded that peripherally administered neostigmine improved postoperative analgesia in axillary brachial plexus block. [108]
The intrathecal addition of neostigmine and clonidine significantly increased the duration of analgesia with an intrathecally injected bupivacaine-fentanyl mixture during labor, but neostigmine caused more nausea. [109]
Preclinical investigations have demonstrated that sympathetic activity is increased by spinal neostigmine because of the enhanced release of norepinephrine. For this reason, neostigmine has been suggested for use in the prevention of arterial hypotension after delivery of spinal clonidine or bupivacaine. Studies in humans, however, did not succeed in demonstrating the beneficial effect of one dose (75 µg) of neostigmine on blood pressure or heart rate during spinal bupivacaine anesthesia. [110] [111]
[112]
Studies in sheep have demonstrated that epidural injection of clonidine can enhance the release of spinal acetylcholine. For this reason, the analgesic activity of both clonidine and opioids is increased by neostigmine if it is administered together with these agents. Furthermore, there have been no reports of cross-tolerance in the antinociceptive effects for neostigmine, clonidine, or opioids. The only safe conclusion that can be drawn is that the clinical utility of epidural neostigmine, either alone or with local anesthetics or other agents, awaits further study. [105] [113]
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Adenosine Adenosine is an endogenous nucleoside that is present in all body cells. The enzymatic breakdown of either Sadenosylhomocysteine or adenosine triphosphate produces adenosine. The maintenance of the balance between oxygen delivery and oxygen demand in the heart and other organs tends to be the main action of adenosine. [114]
Sawynok and coworkers, in 1986, suggested that one of the main mechanisms of analgesia, after intrathecal opioid injection, is the release of adenosine by stimulation of its receptors. Adenosine receptors are located in the superficial layers of the dorsal horn of the spinal cord, and antinociceptive effects of adenosine and adenosine analogues have been well demonstrated in acute pain models after systemic and intrathecal injections. The antinociceptive effect of adenosine was also demonstrated in rats after chronic nerve injury. The antinociceptive effect is likely mediated through the adenosine A1 receptor subtype. [115]
[116] [117] [118]
[119]
In healthy volunteers, intrathecal adenosine causes a 1000-fold elevation of the CSF concentration. The only complication observed was a transient lumbar pain after injection of a 2000-µg dose in one of the five subjects. The use of adenosine in humans for intrathecal analgesia followed preclinical toxicity testing in Sweden and the United States. The toxicologic studies indicated that adenosine has no toxic effect after weeks of regular administration. [120]
[120] [121]
Adenosine agonists produce dose-dependent analgesia, motor blockade, and sedation in animal models. Adenosine reduced, in a non–dose-dependent manner, the areas of secondary allodynia after skin inflammation (topical mustard oil application) as well as reduced forearm tourniquet ischemic pain ratings. The use of adenosine in intractable chronic pain was published in 1993 and again in 1995. The two case reports concerned patients with neuropathic pain whose treatment with spinal adenosine or adenosine A1 receptor agonist had successfully increased the pain threshold. [122] [123]
Sollevi’s group evaluated the tolerability and efficacy of intrathecally injected adenosine in patients suffering from severe neuropathic pain, including tactile hypersensitivity. The results showed reduced pain in the majority of the patients, with 6 hours’ to 12 days’ duration of clinical beneficial effects of the treatment. [124]
Intrathecal adenosine does not produce hypotension, motor block, or sedation. Adenosine provides analgesia in hypersensitivity states but has little effect against acute nociceptive stimuli; therefore, adenosine has an uncertain role in the treatment of acute and obstetric pain. [82]
In a study published in 2000, the authors tried to determine whether the systemic administration of caffeine, a nonselective adenosine receptor antagonist, would affect the thermal antihyperalgesic efficacy of acute amitriptyline in a rat model of neuropathic pain. The results of this study suggest that the thermal antihyperalgesic effect of acute amitriptyline in this model may involve enhancement of an endogenous adenosine tone. This involvement is important in light of the widespread consumption of caffeine, which may potentially act to reduce the benefits of amitriptyline treatment of neuropathic pain. [125]
[125]
The knowledge that adenosine produces no side effects and no toxic reaction when administered intrathecally can lead to the conclusion that adenosine may, in the future, be a useful drug in the treatment of hypersensitivity in chronic pain and perhaps in the postoperative period. At present, several groups are investigating the diagnostic and potential therapeutic roles of intrathecally injected adenosine in acute and chronic pain states.
Summary In this chapter, the use and efficacy of adjuvant drugs in providing analgesia with regional anesthesia has been examined. The adjuvant agents discussed include vasoconstrictors, opioids, ketamine, clonidine, neostigmine, and adenosine. Although the primary regional anesthesia is achieved at present by local anesthetics, the novel drugs described here give hope that better, prolonged analgesia is in store for future generations if the side effects of these adjuvants can be minimized. REFERENCES 1. Braid
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Chapter 15 - Chemical Neurolytic Agents SUSAN R. ANDERSON
Prolonged interruption of painful pathways may be accomplished by injection of neurolytic agents. This form of chemical neurolysis has been performed for many years. Perineural injections have been used therapeutically since the discovery of cocaine by Koller in 1884. The application of neurolytic substances to provide relief for patients with cancer has been practiced since 1930. The first reported injection of a neurolytic solution in the treatment of pain was probably by Luton, who, in 1863, administered subcutaneous injections of irritant substances into painful areas. Levy and Baudouin (1906) were the first to administer the injection of neurolytic agents percutaneously. Doppler, in 1925, was the first to report the use of phenol for neurolysis. The first use of phenol for subarachnoid neurolysis was reported by Maher in 1955. Today, phenol and ethyl alcohol (ethanol) are the most commonly used agents. Subarachnoid neurolysis is indicated for patients with limited life expectancy and patients who still have recurrent or intractable pain after a series of analgesic blocks. [1]
[2]
[1]
[1]
[1]
[1] [3]
[4]
Important Considerations Diagnostic blocks are considered of prime importance because neurolytic agents have undesirable side effects and there is limited duration of analgesia. Potential side effects include neuritis and deafferentation pain, motor deficit when mixed nerves are ablated, and unintentional damage to nontargeted tissue. Therefore, careful selection of patients and clinical expertise are essential. The following criteria should be considered before peripheral neurolysis is performed. [4]
[4]
1. 2. 3. 4. 5.
Determine and document that the pain is severe. Document that the pain was not relieved by less invasive therapies. Document that the pain is well localized and in the distribution of an identifiable nerve. Confirm that the pain is relieved with a diagnostic block performed with use of local anesthetic. Document the absence of undesirable deficits after administration of the local anesthetic blocks. [5]
[4]
The impermanence of analgesia is thought to be related to the creation by the neurolytic agent of an incomplete lesion on the targeted nerve. Although local anesthetic injected into the general vicinity of a nerve trunk may diffuse through neighboring soft tissue and often result in an effective neural blockade, neurolytic drugs spread poorly and require precise location of the needle on the targeted nerve. This means that the best results are obtained when the neurolytic solution is deposed directly onto the nerve. To avoid complications, the volume and concentration of the injected neurolytic agent must also be carefully controlled. Controlled comparisons between different concentrations and volumes of neurolytic agents have not been carried out. The formation of incomplete lesions and consequent return of partial function may be influenced by these factors. [4] [6]
[4]
[4]
[4]
Neuropathic (causalgic) pain is a feature observed in most ablative procedures.[ ] [ ] [ ] The risk of this type of pain may be minimized by careful patient selection. A patient with a short life expectancy or one who is unlikely to survive the duration of pain relief would be considered the best candidates.[ ] If the patient should survive beyond the duration of pain relief, the neurolysis may be repeated at the same site or more proximally. Use of peripheral neurolysis in patients with benign chronic pain remains controversial. It is imperative that if neurolysis is used in these patients, the informed consent form must state very clearly pertinent information about undesirable side effects. 4
7
8
4
The potential for damage to nontargeted tissue is of concern with any neurolytic procedure. However, it is less likely to occur with peripheral neurolysis than if central or deep sympathetic neurolytic blocks are undertaken. This is particularly true when localization is facilitated by electrical stimulation, radiographic guidance, and/or test doses of local anesthetic. [4]
[4] [9] [10] [11]
Postneurolytic neuritis may develop as a result of the incomplete lesion formation caused by chemical neurolytics. An association between the creation of incomplete or inaccurate lesions and subsequent neuritis is supported indirectly by the work of Roviaro and colleagues, who at thoracotomy injected three neighboring intercostal nerves with 6% phenol in glycerin (1 mL per segment) under direct vision. In the 32 patients treated, neither neuritis nor deafferentation pain was reported at the 1-year follow-up, a finding that is in marked contrast to results after percutaneous neurolytic intercostal blocks.
[4]
[6] [12]
[13]
[4] [14]
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Ethyl Alcohol Ethyl alcohol is commercially available in 1-mL or 50-mL ampules as a colorless solution that can be injected readily through small-bore needles. It is hypobaric with respect to cerebrospinal fluid (CSF). However, specific gravity is not of concern when the peripheral nerve is injected because the injection takes place in a nonfluid medium. Ethyl alcohol is usually used undiluted (absolute or higher than 95% concentration). The perineural injection of alcohol is followed immediately by severe burning pain along the nerve’s distribution, which lasts about a minute before giving way to a warm, numb sensation. Pain at injection may be diminished by prior injection of a local anesthetic. To precede the injection of any neurolytic drug with an injection of local anesthetic optimizes comfort and serves as a “test dose.” The alcohol spreads rapidly from the injection site. When injected into the cerebrospinal fluid only 10% of the initial dose remains at the site of the injection after 10 minutes, and about 4% remains after 30 minutes. Between 90% and 98% of the ethanol that enters the body is completely oxidized. Oxidation occurs chiefly in the liver and is initiated principally by alcohol dehydrogenase. Denervation and pain relief accrue within a few days after injection, usually after 1 week. If no pain relief is present after 2 to 3 weeks, the neurolysis is incomplete and needs repetition. [4]
[4]
[4]
[4]
[28]
[15]
[16]
[4]
Various concentrations and mixtures of alcohol have been studied in an attempt to determine selectivity for sensory nerves. Schlosser studied the effect of alcohol on somatic nerves. He reported that alcoholization was followed by degeneration and absorption of all the components of the nerve except the neurilemma. There is general agreement that with 95% concentration of absolute alcohol, the destruction involves the sympathetic, sensory, and motor components of a mixed somatic nerve; therefore, it is undesirable to block a mixed nerve with such concentrations of alcohol. However, there is a great discrepancy in determining the effects when the alcohol is on motor fibers lower than 80% concentration ( Fig. 15–1 ). [17] [18]
[18]
In 1907, Finkelburg tested the presence of inconsistency by injecting 0.5 mL to 1.5 mL of 60% to 80% alcohol into the exposed sciatic nerve of dogs and rabbits. Persistent paralysis resulted with these concentrations. In 1912, May found that the injection of 0.5 mL of alcohol into the exposed sciatic nerve of the cat was followed by motor paralysis. The duration of the paralysis varied considerably, irrespective of the strength of the alcohol used, provided it was greater than 60%. With 80% alcohol concentration, May observed motor paralysis lasting 91 days in one case and 19 days in another; with 90% alcohol, paralysis lasted 64 days in one case and 88 days in another. The paralysis was always followed by recovery. Postrecovery examination revealed that in some cases, the nerve showed no microscopic evidence of degeneration, whereas in others, there was evidence of degeneration and regeneration. With absolute alcohol, however, May always found considerable fibrosis at the site of injection into a normal nerve, with some regenerative process above and intermingled degeneration and regeneration below the fibrous zone. He also found that a 50% alcohol concentration produced no motor weakness. Gordon, using an 80% alcohol concentration, found that by the 9th day, there was less evidence of motor involvement than on the 29th day, when he observed partial degeneration in some cases and complete degeneration in others. Nevertheless, no animal was completely paralyzed. Nasaroff used a 70% alcohol concentration and never observed complete paralysis. He did note the onset of a temporary paresis at the end of the second week, at which time he found progressive and simultaneous degenerative and regenerative processes. These findings seem to indicate that a 70% alcohol concentration does not cause irremediable damage to somatic nerves. In Labat’s studies, 48% alcohol (equal parts of 95% alcohol and 1% procaine) and 95% alcohol were compared. Labat observed temporary paralysis in all animals with use of both concentrations. The period of time required to recover from the paralysis varied and was inconsistent with the concentration of the alcohol. Thus, in one case, 48% alcohol caused paralysis for 50 days, the same duration of paralysis as in another case in which 95% alcohol had been used. On microscopic examination performed after recovery, no demonstrable nerve changes could be seen. Using 33.3% alcohol, Labat and Greene reported satisfactory clinical results in the management of painful disorders. They did not report any muscular paralysis or even paresis. [18] [19]
[18] [20]
[4]
[18]
[21]
[18] [21]
[22]
[18] [22]
[18] [23]
[8]
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[23]
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Figure 15-1 A, Effects of alcohol on the peripheral nerve, 15 seconds after application. Electron micrograph shows the sciatic nerve of a mouse after topical application of 100% alcohol. Note the swelling of unmyelinated nerve fibers; sc indicates Schwann cell cytoplasm that is clumped and granular—Schwann cell destruction (original magnification ×5000). B, Effect of alcohol on the peripheral nerve, 15 seconds after application. Electron micrograph shows the Schwann cell after exposure to 100% alcohol. The splitting of the myelin sheath (MS) and the dilated endoplasmic reticulum (ER) indicate acute injury to the Schwann cell and myelin sheath (original magnification ×4300). C, Effect of alcohol on the peripheral nerve 1 minute after application. Electron micrograph shows splitting of the myelin sheath after exposure to 100% alcohol (original magnification ×9600). D, Effect of alcohol on the peripheral nerve, 24 hours after a 15-second exposure to 100% alcohol. Note degenerating axons (A) splitting myelin lamellae (M) and beginning of connective tissue reaction (CR) (original magnification ×2200). E, Effect of alcohol on the peripheral nerve, 4 hours after a 15-second exposure to 100% alcohol. (From Woolsey RM, Taylor JJ, Nagel JH: Acute effects of topical ethyl alcohol on the sciatic nerve of the mouse. Arch Phys Med Rehabil 53:410, 1972.)
Despite the inconsistency in results with varying concentrations of alcohol, there is better consensus regarding maximal and minimal concentrations. For complete paralysis, the concentration must be stronger than 95% alcohol. From Labat and Greene, it may be concluded that a minimal concentration of 33% alcohol is necessary to obtain satisfactory analgesia without any motor paralysis. [24]
Histopathologic studies have shown that alcohol extracts cholesterol, phospholipids, and cerebrosides from the nerve tissue and causes precipitation of lipoproteins and mucoproteins. This results in sclerosis of nerve fibers Alcohol produces nonselective destruction of nervous tissue by precipitating cell membrane and myelin sheaths. proteins and extracting lipid compounds, resulting in demyelination and subsequent wallerian degeneration. Because the basal lamina of the Schwann cell tube is often spared, however, the axon often regenerates along its former course. If a ganglion is injected, it may produce cell body destruction without subsequent regeneration. Topical application of alcohol to peripheral nerves produces changes typical of wallerian degeneration. A subarachnoid injection of absolute alcohol causes similar changes in the rootlets. Mild focal inflammation of meninges and patchy areas of demyelination are seen in posterior columns, Lissauer’s tract, and dorsal roots and rootlets. Later, wallerian degeneration is seen to extend into the dorsal horns. Injection of a larger volume can result in degeneration of the spinal cord. When alcohol is injected near the sympathetic chain, it destroys the ganglion cells and thus blocks all postganglionic fibers to all effector organs. A temporary and incomplete block results if the injection affects only the rami communicantes of preganglionic and postganglionic fibers. Histopathologically, wallerian degeneration is evident in the sympathetic chain fibers. [25] [26]
[30] [38]
[38]
[38]
[26] [27]
[26]
[31]
[26]
For subarachnoid block, alcohol concentrations between 50% and 100% are generally selected (Fig. 15–2 (Figure Not Available) ). Alcohol is hypobaric in nature in relation to CSF. Therefore, the patient must be in the lateral decubitus position with the painful site uppermost. The patient must then be rolled anteriorly approximately 45 degrees to place the dorsal (sensory) root uppermost. The reported volumes required for neurolysis range from a minimum of 0.3 mL to a maximum of 0.7 mL of absolute alcohol per segment and from 0.5 mL to 1 mL to a maximum of 1.5 mL per segment. For celiac plexus block, volumes of 10 mL to 20 mL of absolute alcohol [29]
[28]
[18] [30]
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bilaterally may be used. Similar volumes have been reported for lumbar sympathetic block. Often, 100% alcohol is diluted 1:1 with a local anesthetic before injection. [30]
[18]
The most ominous complication associated with the use of alcohol is the possible occurrence of alcoholic neuritis. It has been postulated that alcoholic neuritis is caused by incomplete destruction of somatic nerves. This seems plausible, because neuritis has not been observed after an intraneural injection of a cranial or somatic nerve that produces a complete block. Alcoholic neuritis occurs frequently after paravertebral block of the thoracic sympathetics. The cause of the neuritis may be the close proximity of the sympathetic ganglia to the intercostal nerves. The alcohol, which is intended for the ganglion, inadvertently bathes and partially destroys the somatic nerve. During the period of regeneration, hyperesthesia and intense burning pain with occasional sharp shooting pain occurs. These pains may be more intense than the original complaint. Fortunately, in most instances, these symptoms subside within a few weeks or a month. Occasionally, however, this complication persists for many months, requiring sedation and, in some instances, performance of a subsequent rhizotomy or sympathectomy. As a prophylactic measure, Mandl recommended the injection of a local anesthetic procaine [18]
[31]
[18] [84]
[18]
Figure 15-2 (Figure Not Available) A, Effect of alcohol on the spinal cord, 4 days after neurolytic block. Cross-section through the spinal cord at T4 shows degeneration of the dorsal fascicularis (DF) after injection of 100% alcohol several interspaces lower. B, Effect of alcohol on the spinal cord, 50 days after direct cord injection. Necrosis and degeneration occurred (arrows) after accidental injection of 100% alcohol into the spinal cord. (From Gallagher HS, Yonexawa T, Hay RC, et al: Subarachnoid alcohol block. II. Histologic changes in the central nervous system. Am J Pathol 35:679, 1961. © American Society for Investigative Pathology.)
mixture during the insertion of the needle, at the site of injection before the alcohol is injected, and again when the needle is withdrawn. With use of this technique, he has observed only two instances of alcoholic neuritis. [32]
Slight cases of alcoholic neuritis are treated conservatively with mild analgesics such as aspirin or with small doses of codeine. Moderate cases of alcoholic neuritis may require more active therapy. Intravenous histamine, 2.75 mg dissolved in 500 mL of 5% glucose in distilled water, administered twice daily, has been employed with some success. In some cases, the administration of intravenous local anesthetics has been helpful. Bonica determined that Pontocaine 250 mg dissolved in 500 mL of fluid was superior to procaine. In one case, when intravenous procaine had been administered several times with only transient relief of pain, one infusion of tetracaine effected prolonged pain relief. In some cases, daily sympathetic blocks have been employed with excellent results. In the case of lumbar nerve neuritis after lumbar sympathetic blocks, serial caudal blocks performed at regular intervals can effect complete relief of pain. Severe cases of alcoholic neuritis that do not respond to these conservative methods may require sympathectomy or rhizotomy. De Takats reported on three such patients who required sympathectomy. [18]
[18]
[33]
[18]
[18]
[34]
Hypesthesia and anesthesia of the dermatomal distribution of nerve roots treated with neurolysis are other complications associated with alcohol nerve block. The lack of sensation can overshadow the pain relief afforded by the procedure. Fortunately, this complication is rare, and recovery is relatively quick. Loss of bowel or bladder sphincter tone, leading to bowel or urinary incontinence, has also been reported with intrathecal alcohol neurolysis administered to the lower lumbar and sacral areas. To decrease the risk of these complications, it is recommended that during sacral neurolysis, only one side should be blocked at a time. A complication of lumbar sympathetic neurolysis with alcohol is the development of genitofemoral neuralgia, which can cause severe groin pain. This referred pain is caused by the degeneration of the rami communicantes from the L2 nerve root to the genitofemoral nerve. Paraplegia can result if injection of alcohol causes spasm of the artery of Adamkiewicz. [26]
[26]
[26]
[26] [35] [36] [37]
[26]
Alcohol-induced neurolysis causes a disulfiram-like effect. Umeda and Arai reported a case of an individual undergoing an alcohol celiac plexus block (15 mL of 67% alcohol) who experienced flushing, sweating, dizziness, vomiting, and marked hypotension 10 minutes after the infusion ceased. The authors speculated that the reaction was due to the patient’s being treated with moxalactam, a type of beta-lactam antibiotic reported to inhibit aldehyde dehydrogenase. Other agents share this property, including metronidazole (Flagyl); chloramphenicol; the betalactam type antibiotics; the oral hypoglycemic tolbutamide (Orinase) and chlorpropamide (Diabinese); and, of course, disulfiram (Antabuse). [39]
[38]
[38] [40]
Phenol Phenol is a combination of carbolic acid, phenic acid, phenylic acid, phenyl hydroxide, hydroxybenzene, and oxybenzene. It is not available commercially in the injectable form but can be prepared by the hospital pharmacy. One gram of phenol dissolves in about 15 mL water (6.67%). It is very soluble in alcohol, glycerol, and a number of other organic substances. Phenol is usually mixed with saline or glycerin and may be mixed with sterile water or material used for contrast radiography. Because it is highly soluble in glycerin, phenol diffuses from it slowly. This [15]
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is an advantage of intrathecal injection, which allows limited spread and highly localized tissue fixation. Diffusion also makes phenol hyperbaric relative to CSF. When mixed with glycerin, phenol is so viscid that even when warmed, injection must be made through at least a 20-gauge needle. This mixture must be free of water, or the necrotizing effect is much greater than anticipated. When phenol is mixed in an aqueous mixture, it is a far more potent neurolytic. Phenol oxidizes and turns red when exposed to air and light. The shelf life of phenol is said to exceed 1 year when preparations are refrigerated and not exposed to light. Phenol acts as a local anesthetic at lower concentrations and as a neurolytic agent in higher concentrations. It has an advantage over alcohol because there is minimal discomfort on injection. [15]
[26]
[15]
In 1925, Doppler was the first to use phenol to deliberately destroy nervous tissue. After painting phenol on human ovarian vessels, he noted downstream vasodilatation and flush. Later, he reported treating peripheral vascular disease in the lower extremity by exposing and painting the femoral arteries with a 7% aqueous solution. Twelve patients were reported to improve, and no failure or complication rate was reported. In 1933, Binet, in France, reported painting ovarian vessels with 7% phenol. Doppler and Binet attributed their good results to destruction of perivascular sympathetic fibers. In 1933, Nechaev reported the use of phenol as a local anesthetic. In 1936, Putnam and Hampton used an injection of phenol to perform a neurolysis of the gasserian ganglion. [41]
[41]
[18]
[42]
[43]
In 1947, Mandl suggested injecting phenol to obtain permanent sympathectomy. In 1950, he reported its use in 15 patients, without complications, suggesting that it was preferable to alcohol. The paravertebral injection of phenol for peripheral vascular disease was also reported by Haxton and Boyd and colleagues in 1949. In 1955, Maher introduced phenol as a hyperbaric solution for intrathecal use in intractable cancer pain, by uttering the famous remark, “It is easier to lay a carpet than to paper a ceiling.” Thereafter, he reported epidural use as well. [44]
[18] [32]
[45]
[46]
[47]
[18]
By 1959, phenol was established as a neurolytic agent for the relief of chronic pain. Kelly and Gautier-Smith and Nathan then simultaneously reported the use of phenol for the relief of spasticity caused by upper motor neuron lesions. Phenol in hyperbaric solution was injected intrathecally, with proper patient positioning to “fix” the drug on the anterior nerve roots, and thus relieve spasticity (Fig. 15–3 (Figure Not Available) ). [18]
[48]
[49]
Maher studied various concentrations (3.3%–10%) of phenol in glycerin injected into the subarachnoid space in an effort to determine the ideal neurolytic strength solution. There was a gradation of block according to the concentration. The stronger concentration caused motor damage. Pain was blocked at lower concentrations (5%) than touch and proprioception. The 3.3% phenol concentration was ineffective. Iggo and Walsh determined that 5% of phenol in either Ringer’s solution or oil contrast medium produced selective [47]
Figure 15-3 (Figure Not Available) Effect of phenol on the spinal cord. Micrographs of transverse section at levels L2, L3, L4–L5, and S3 show degeneration of the posterior column after subarachnoid injection of phenol at L3–L4.(From Smith MC: Histological findings following intrathecal injections of phenol solutions for relief of pain. Br J Anaesth 36:387, 1964.)
block of the smaller nerve fibers in cat spinal rootlets. The same conclusions were drawn from the investigations by Nathan and Sears. For a long time thereafter, the idea prevailed that phenol caused selective destruction of smaller nerve fibers with slower conduction rates, the C afferents carrying slow pain, the A-delta afferents carrying fast pain, and the A-gamma efferents controlling muscle tone. [50]
[51]
[18]
Histopathologic studies by Stewart and Lourie demonstrated nonselective degeneration in cat rootlets, with severity parallel to the concentration. Nathan and associates found evidence of A-delta and A-beta damage in their electrophysiologic experiments and confirmed the nonselectivity of damage by histologic examination. [52]
[18]
[53]
At concentrations of less than 5%, phenol produces protein denaturation. Concentrations greater than 5% cause protein coagulation and nonspecific segmental demyelination and orthograde degeneration (i.e., wallerian degeneration). Concentrations of 5% to 6% produce destruction of nociceptive fibers with minimal side effects. Higher concentrations result in axonal abnormalities, nerve root damage, spinal cord infarcts, and arachnoiditis or meningitis. These characteristics may explain the long-lasting results of neurolytic blocks performed with 10% phenol in the sympathetic axis. [38]
[38] [54]
[38]
The block produced by phenol tends to be less intense and of shorter duration than that produced by alcohol. Moller and associates compared various concentrations of alcohol and phenol and concluded that 5% phenol equaled 40% alcohol in neurolytic potency. Axons of all sizes are affected by therapeutic concentrations and, as described for ethyl alcohol, appear edematous. Importantly, the posterior root ganglia are unaffected by phenol. Similar pathologic changes occur in peripheral nerves when they are exposed to phenol. The process of degeneration takes about 14 days, and regeneration is completed in about 14 weeks. After intrathecal phenol injection, the [55]
[56]
[18]
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concentration decreases rapidly—to 30% of the original concentration in 60 seconds and to 0.1% within 15 minutes. [26] [57]
Phenol is efficiently metabolized by liver enzymes. The principal pathways are conjugation to the glucuronides and oxidation to equinol compounds or to carbon dioxide and water. It is then excreted as a variety of conjugates via the kidney. [18]
A higher affinity for vascular tissue than for neuronal tissue has been suggested by Wood. The interference with blood flow is believed to be the etiology for the observed neuropathy. However, Racz and associates studied the morphologic changes that occurred after epidural and subarachnoid injection. They found that massive tissue destruction was present after subarachnoid injection compared with epidural injection despite intact vasculature in areas of spinal cord destruction. These findings support a direct neurotoxic effect of phenol rather than an effect secondary to vascular destruction. [54]
[58] [59]
[60]
[38]
[38] [61]
Large systemic doses of phenol (≥8.5 g) cause convulsions and then central nervous system depression and cardiovascular collapse. Chronic poisoning results in skin eruptions, gastrointestinal symptoms, and renal toxicity. Clinical doses between 1 mL and 10 mL of 1% to 10% solutions (up to 1000 mg) are unlikely to cause serious toxicity.
[38]
[38] [62]
Glycerol Glycerol is used mostly for neurolysis of the gasserian ganglion to treat idiopathic trigeminal neuralgia. Considered a mild neurolytic like other alcohols, it produces localized perineural damage, whereas intraneural injection results in Schwann cell edema, axonolysis, and wallerian degeneration. In one histologic study, intraneural injection of glycerol was more damaging than topical application, although significant, localized, subperineural damage occurred after local application of a 50% glycerol solution. Histologic changes included the presence of many inflammatory cells, extensive myelin swelling, and axonolysis. Myelin disintegration occurs weeks after the injury along with ongoing axonolysis during periods of myelin restitution, indicating an ongoing nerve fiber injury possibly caused by secondary events such as compression of transperineural vessels and ischemia. Electron microscopy shows evidence of wallerian degeneration; with intraneural injection, all nerve fibers are destroyed. [63]
[38]
[38] [64]
[38] [64] [65]
[38]
The mechanism of action is not clear. Sweet and colleagues suggested that glycerol affected primarily small myelinated and unmyelinated fibers. Bennett and Lunsford, using trigeminal evoked-potential studies, concluded that glycerol more specifically affects the damaged myelinated axons implicated in the pathogenesis of trigeminal neuralgia. Because there is no permanent injury to surrounding structures and facial sensation is preserved in most patients, Feldstein considered glycerol superior to radiofrequency rhizotomy for the treatment of tic douloureux. However, potential spread to the subarachnoid space, risk of neuropathy, and poor control of the spread of a fluid agent, have made radiofrequency a continued attractive alternative. With the current use of pulsed radiofrequency, the advantage of a discrete, controlled lesion remains, without the concern for neuritis or loss of facial sensation. However, long-term follow-up on its effectiveness has not been reported. [66]
[38]
[38] [67] [68]
[69]
Hypertonic and Hypotonic Solutions Hypertonic or hypotonic subarachnoid injections have been used for achieving neurolysis. The intrathecal injection of cold (2°C to 4°C) 0.9% NaCl is supposed to have a specific action on the pain-carrying C fibers, sparing the larger fibers that subserve sensory, motor, and autonomic functions. The technique requires the spinal fluid to be withdrawn and replaced with cold saline as rapidly as possible. Up to 40 mL to 60 mL of saline has been injected. Local anesthetic should be used concomitantly or the procedure can be very painful. The pain relief is usually shortterm. [70]
[71]
[18]
[18]
Injections of hypertonic saline can be quite painful; therefore, local anesthetics are generally injected before the saline. The intrathecal injection of hypertonic saline can produce a variety of complications. Some degree of complications occurred in 11% and significant morbidity in 1% of patients. Two deaths were reported secondary to myocardial infarction. During saline injection, sinus tachycardia or premature ventricular contraction have been seen, and localized paresis lasting for many hours and paresthesia extending for weeks have been observed. Other complications reported include hemiplegia, pulmonary edema, pain in the ear, vestibular disturbances, and loss of sphincter control with sacral anesthesia. [15]
[72]
[73]
[74]
[18] [75]
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Pathologic changes caused by hypertonic and hypotonic solutions have been extensively studied. Microscopic changes seen on the peripheral nerves do not correlate with clinical effects of differential C fiber block. However, application of distilled water on the dorsal root ganglia for 5 minutes produced a differential C fiber block similar to that seen with in vitro hypertonic saline. The mechanism of action seems to be the intracellular shifts of water with extracellular change in osmolarity. [18] [76] [77]
[77] [78]
[18]
Ammonium Salts In 1935, Judovich used pitcher plant distillate for long-term analgesia. The active component of the distillate was determined to be ammonium sulfate, ammonium chloride, or ammonium hydroxide, depending on the acid used to Limited pathologic studies suggested that ammonium salts in neutralize the distillate and on the pH. concentrations of greater than 10% caused acute degenerative neuropathy. This degeneration was nonselective, affecting all types of nerve fibers. More recent in vitro studies with pitcher plant distillate attributed the effects to Associated complications such as nausea and vomiting, headache, benzyl alcohol contained in the vehicle. paresthesia, and spinal cord injury have led to the clinical abandonment of ammonium salt solutions, including pitcher plant distillate. [18] [79]
[18]
[18] [80]
[18]
The action of ammonium salts on nerve impulses produces obliteration of C fiber potentials, with only a small effect on A fibers. Limited pathologic studies suggest that injection of ammonium salts around a peripheral nerve causes an acute degenerative neuropathy affecting all fibers. [81] [82]
[18]
Hand reported the use of subarachnoid ammonium salts in 50 patients. Transient complications were nausea and headache, whereas paresthesias or burning sensation occurred in 30% of patients at doses of 500 mg of ammonium salt and lasted 2 to 14 days. [83]
[18]
Conclusion The use of chemical neurolytic agents for the interruption of painful pathways is one option for the treatment of intractable chronic pain. Because of the potential for undesirable side effects, it is imperative that this method be used by an experienced clinician. The use of fluoroscopic or radiographic guidance is strongly encouraged for accurate placement of the needle and the injection of the solution because the lesion created is not discrete. The patients must be carefully selected and given fully informed consent. REFERENCES 1. Jain
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55. Moller JE, Helweg-Larson J, Jacobson E. Histopathological lesions in the sciatic nerve of the rat following perineural application of phenol and alcohol solutions. Dan Med Bull 16:116–119, 1969. 56. Smith
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58. Nour-Eldin 59. Totoki
F: Uptake of phenol by vascular and brain tissue. Microvasc Res 2:224, 1970.
T, Kato T, Nomoto Y, et al: Anterior spinal artery syndrome—a complication of cervical intrathecal phenol injection. Pain 6:99, 1979.
60. Racz GB, Heavner J, Haynsworth R: Repeat epidural phenol injections in chronic pain and spasticity. In Lipton S, Miles J (eds): Persistent Pain, 2nd ed New York, Grune & Stratton, 1985, p 157. 61. Heavner, JE, Racz GB: Gross and microscopic lesions produced by phenol neurolytic procedures. In Racz GB (ed): Techniques of Neurolysis. Boston, Kluwer Academic Publishers, 1989, p 27. 62. Cousins MJ: Chronic pain and neurolytic neural blockade. In Cousins MJ, Bridenbaugh PO (eds): Neural Blockade in Clinical Anesthesia and Management of Pain, 2nd ed. Philadelphia, JB Lippincott, 1988, p 1053. 63. Hakanson
S: Trigeminal neuralgia treated by the injection of glycerol into the trigeminal cistern. Neurosurgery 9:638, 1981.
64. Rengachary SS, Watanabe IS, Singer P, Bopp WJ: Effect of glycerol on peripheral nerve: An experimental study. Neurosurgery 13:681, 1983.
65. Myers RR, Katz J. Neuropathy of neurolytic and semidestructive agents. In Cousins MJ, Bridenbaugh PO (eds): Neural Blockade in Clinical Anesthesia and Management of Pain, 2nd ed. Philadelphia, JB Lippincott, 1988, p 76.
66. Sweet WH, Poletti CE, Macon JB: Treatment of trigeminal neuralgia and other facial pains by retrogasserian injection of glycerol. Neurosurgery 9:3647, 1981.
67. Bennett MH, Lunsford LD: Percutaneous retrogasserian glycerol rhizotomy for tic douloureux: Part 2. Results and implications of trigeminal evoked potentials. Neurosurgery 14:431, 1984.
68. Lunsford LD, Bennett MH: Percutaneous retrogasserian glycerol rhizotomy for tic douloureux: Part 1. Technique and results in 112 patients. Neurosurgery 14:424, 1984. 69. Feldstein GS: Percutaneous retrogasserian glycerol rhizotomy in the treatment of trigeminal neuralgia. In Racz GB (ed): Techniques of Neurolysis. Boston, Kluwer Academic Publishers, 1988, p 125.
70. Hitchcock E: Osmolytic neurolysis for intractable facial pain. Lancet 1:434, 1969.
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71. Lund PC: Principles and Practice of Spinal Anesthesia. Springfield, IL, Charles C. Thomas, 1971. 72. Lucas JT, Ducker TB, Perok PL: Adverse reactions to intrathecal saline injection for control of pain. J Neurosurg 42:557, 1975. 73. McKean MC, Hitchcock E: Electrocardiographic changes after intrathecal hypertonic saline solution. Lancet 2:1083, 1968. 74. Ventafridda V, Spreafico R: Subarachnoid saline perfusion. Adv Neurol 4:477, 1974. 75. O’Higgins JW, Padfield A, Clapp H: Possible complications of hypothermic saline subarachnoid injection. Lancet 1:567, 1970. 76. Hewett DL, King JS: Conduction block of monkey dorsal rootlets by water and hypertonic solutions. Exp Neurol 33:225, 1971. 77. Nicholson MF, Roberts FW: Relief of pain by intrathecal injection of hypothermic saline. Med J Aust 1:61, 1968. 78. Thompson GE: Pulmonary edema complicating intrathecal hypertonic saline injection for intractable pain. Anesthesiology 35:425, 1971. 79. Walti A: Determination of the nature of the volatile base from the rhizome of the pitcher plant., Sarracenia purpurea. J Am Chem Soc 67:22, 1945. 80. Ford DJ, Phero JC, Denson D: Effect of pitcher plant distillate on frog sciatic nerve. Reg Anaesth 5:16, 1980. 81. Davies JI, Steward PB, Fink P: Prolonged sensory block using ammonium salts. Anesthesiology 28:244, 1967. 82. Judovich BD, Bates W, Bishop K: Intraspinal ammonium salts for the intractable pain of malignancy. Anesthesiology 5:341, 1944. 83. Hand LV: Subarachnoid ammonium sulfate therapy for intractable pain. Anesthesiology 5:354, 1944. 84. Woolsey RM, Taylor JJ, Nagel JH: Acute effects of topical ethyl alcohol on the sciatic nerve of the mouse. Arch Phys Med Rehabil 53:410, 1972. 239
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Chapter 16 - Continuous Regional Analgesia SUSAN R. ANDERSON
Infusion techniques in the epidural space as well as on the peripheral nerves are now commonly used for treatment of acute and chronic pain. For acute pain, continuous regional infusion has been found to be beneficial for trauma, after surgery, and in acute medical conditions. Similarly, for chronic pain, the technique has been useful in the rehabilitation of patients with chronic back pain and in relieving pain from reflex sympathetic dystrophy, peripheral neuropathy, and cancer. The first use of this technique was reported in 1949 with a Continuous epidural analgesia is not a new concept. description of intermittent boluses of a local anesthetic administered postoperatively for 1 to 5 days. Although effective analgesia was obtained, significant sympathetic blockade accompanied the pain relief, with a fluctuating level of analgesia as the effect of the bolus began to regress. Continuous epidural analgesia with intermittent bolus injections is labor-intensive and requires skilled personnel to reassess and reinject the patient every few hours. Because of these shortcomings, continuous infusion (CI) of epidural local anesthetics has now become commonplace ( Fig. 16–1 ). [1] [2] [3]
[4]
Continuous Infusion Versus Intermittent Bolus Injection Continuous epidural infusion offers many therapeutic advantages over intermittent bolus injection. The primary advantage is the continuous administration of analgesia compared with intermittent dosages. Although single boluses of opioids such as epidural morphine may provide 12 hours of pain relief, wide variability has been reported in the duration of effective analgesia, ranging from 4 to 24 hours. Thus, it becomes difficult to titrate uniform levels of pain relief. Continuous infusions provide ease of titration, particularly when shorter acting opioids, such as fentanyl and sufentanil, are employed. Epidurally administered fentanyl has an onset of action within 4 to 5 minutes and a peak effect within 20 minutes. This rapidity of onset facilitates adjustment in dosage, because the patient can quickly experience pain relief. [5] [6]
[7] [8] [9]
A significant disadvantage of the intermittent bolus technique is the need for action when pain relief subsides 4 to 6 hours after epidural administration of morphine. A decision needs to be made about whether to inject a second dose of epidural opioid or to supplement the bolus through systemic administration of an analgesic. Another disadvantage of the intermittent technique is that supplementation with parenteral narcotic or sedative drugs increases the risk of respiratory depression in a patient who has had epidural narcotic administered previously. For the intermittent bolus technique to be successful, administration of longer acting agents, such as morphine and hydromorphone, is required to provide a reasonable duration of analgesia. These opioids are associated with a higher risk of delayed-onset respiratory depression. [6]
A third disadvantage of the intermittent bolus injection technique is the tachyphylaxis that develops with repeat boluses. In contrast, continuous infusion of the analgesic with the same dose actually increases the intensity of the block, and the rate of infusion has to be decreased to maintain the same level of analgesia over time. [10] [11]
Continuous epidural infusion of analgesic agents, especially opioids, has the advantage of fewer fluctuations in cerebrospinal fluid concentrations of drug. The fact that it takes several hours to infuse enough of a long-acting opioid such as morphine to provide adequate analgesia represents, however, a major disadvantage. This drawback can be overcome by administration of a 5- to 10-mL “loading” bolus of epidural local anesthetic solution at the beginning of the infusion or by injection of a bolus of short-acting opioid such as fentanyl or sufentanil. It usually takes five half-lives of the infused drug to reach a steady state, which, when calculated for morphine or bupivacaine, is about 15 to 18 hours.
Catheter Location Segmental limitation of epidural analgesia mandates placement of an epidural catheter at a site adjacent to
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Figure 16-1 The assembly of analgesic solution, infusion pump, and catheter connection with a filter for epidural infusion technique.
the dermatome covering the field of pain. This practice reduces dosage requirements and increases the specificity of Suggested interspaces where catheters are usually located for epidural infusion of analgesic spinal analgesia. solutions are shown in Table 16–1 . [12] [13]
Analgesic Agents Epidural analgesia is commonly provided with one of the following choices: • Local anesthetic • Opioid • Opioid combined with local anesthetic
LOCAL ANESTHETICS Local anesthetic agents are best used to provide analgesia and anesthesia for patients undergoing surgery to maintain postoperative pain relief. Lidocaine, bupivacaine, and, more recently, ropivacaine are effective in TABLE 16-1 -- SUGGESTED INTERSPACES FOR CATHETER INSERTION FOR CONTINUOUS INFUSION OF ANALGESIC SOLUTIONS AFTER SURGERY Location of Surgery
Interspace(s) for Catheter
Thorax
T2–T8
Upper abdomen
T4–L1
Lower abdomen
T10–L3
Upper extremity
C2–C8
Lower extremity
T12–L3
In general, lidocaine is limited to use in a bolus form to establish achieving and maintaining adequate analgesia. or rescue a block, whereas bupivacaine is used as an infusion. Ropivacaine is becoming more widely used for infusions owing to its shorter time of onset, shorter duration of motor block, greater selectivity for A delta and C fibers, and decreased cardiotoxicity compared with bupivacaine. A problem inherent in the use of a bolus of local anesthetic through the epidural catheter is the development of tachyphylaxis, which has not been seen when bupivacaine is administered as an infusion. [10] [11]
[14] [15] [16] [17] [18] [19] [20]
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The CI of dilute local anesthetic solutions has simplified maintenance and improved analgesic uniformity; however, concentrations sufficient to produce pain relief usually have resulted in progressive sensorimotor blockade. Such deficits are undesirable because the patient’s ability to ambulate is compromised. The use of local anesthetic agents alone can cause an accumulation of the local anesthetic agent in the systemic circulation, which is more pronounced with the shorter acting amides such as lidocaine than with the longer acting amides. The decrease in systemic effects with longer acting agents has been attributed to their more nonspecific binding in the fat of the epidural space compared with that of shorter acting amides. Even when bupivacaine was infused for 72 hours after abdominal surgery, the serum bupivacaine level increased, peaking at 48 to 60 hours. The toxicity of local anesthetics is less pronounced when the agents accumulate slowly, but there is an ever-present risk of central nervous system depression, convulsions, or cardiac arrest. [10] [21]
[22]
The concentration of local anesthetic influences the analgesia and the profile of side effects. A constant rate of infusion of 0.25% or greater concentration of bupivacaine is associated with hypotension, muscle weakness, sensory block, and the possible accumulation of toxic systemic levels of bupivacaine. Higher plasma levels of the agent may occur in the elderly or frail patient. Side effects may be attenuated by the use of lower concentrations of bupivacaine. The use of a low-dose, constant-rate infusion of epidurally administered bupivacaine (0.03% to 0.06%), close to the dermatomal level desired for pain relief, decreases the incidence of side effects. Although the low dose of bupivacaine is effective, the level of analgesia it provides is less profound than that achieved by combining bupivacaine with low concentrations of epidurally administered morphine or with the use of opioid alone. [10]
[10] [23] [24]
OPIOIDS The ideal intraspinal opiate would be hydrophilic in nature, have a high affinity for the opiate receptor, require occupation of a small percentage of receptors to provide analgesia, demonstrate a prolonged duration of analgesia, and be free of side effects. The drugs commonly used spinally are morphine, meperidine, fentanyl, and sufentanil. Morphine is still the only opiate that has FDA approval for epidural administration. In the postoperative period, morphine sulfate has been administered by intermittent injection and by continuous infusion. Meperidine has also been injected epidurally and possesses local anesthetic properties. The accumulation of its metabolite normeperidine is a cause of concern. Fentanyl has achieved widespread popularity during the past 7 to 10 years. Its advantage over morphine sulfate is that it spreads rostrally less than morphine. Whether the effect after intraspinal injection is spinal or systemic, the rapidity with which analgesia is obtained after epidural fentanyl administration makes it the drug of choice for acute, unacceptable pain. Sufentanil has been used epidurally. The characteristics of fentanyl, which is lipid-soluble, are magnified with sufentanil. Its theoretic advantage results from the strong affinity it has for µ receptors. This characteristic has relevance in cancer management.
COMBINATION OF OPIOID WITH LOCAL ANESTHETIC In an effort to combine the desirable analgesic properties of local anesthetics with those of epidural opioids, several investigators studied the concomitant use of morphine-bupivacaine epidural infusions for pain relief. Studies have demonstrated either additive or synergistic analgesic activity between a variety of opioids and dilute concentrations of bupivacaine. Such combinations appear to provide pain relief of greater magnitude than that attained with either an opioid or bupivacaine alone, and the incidence and severity of side effects are minimized. This advantage may be explained by the different analgesic properties of each class of agent and their ability to block pain at two different sites in the spinal cord. Opioids produce analgesia by specific binding and activation of opiate receptors in the substantia gelatinosa, whereas local anesthetics provide analgesia by clocking impulse transmission at the nerve roots and dorsal root ganglia. [25] [26] [27] [28]
[27] [28] [29]
Bupivacaine has been used most often, in concentrations ranging from 0.03% to 0.125%, with morphine, fentanyl, or meperidine. The use of morphine and bupivacaine has resulted in effective analgesia in the management of patients after thoracic, abdominal, and general surgery. Fentanyl combined with bupivacaine, however, had a lower incidence of side effects compared with the morphine-bupivacaine combination. Bupivacaine, 0.03% to 0.125%, mixed with fentanyl, 2 to 3 g/mL, at a rate of 8 to 10 mL/hour in an adult 70-kg patient, usually achieves excellent analgesia with minimal respiratory depression and sensorimotor blockade. Bupivacaine, 0.03%, with morphine, 0.005%, or fentanyl, 2 to 3 µg/mL, infused at 8 to 10 mL/hour achieves similar results for patients with chronic pain. Ropivacaine may be used in place of bupivacaine, in concentrations ranging from 0.1% to 0.2%, with either morphine or fentanyl. Specific concentrations of drugs and rates of infusion should be tailored to individual patients. For example, one can treat or prevent significant hypotension in patients by (1) decreasing the local [10] [24] [30] [21]
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anesthetic concentration, (2) eliminating the local anesthetic, (3) decreasing the rate of a combined local anestheticopioid infusion, or (4) infusing intravenous (IV) fluids. One can treat sedation or carbon dioxide retention by (1) changing the specific epidurally administered opioid, (2) decreasing the concentration of the opioid, (3) decreasing the overall infusion rate, or (4) eliminating the opioid from the infusion.
Management of Inadequate Analgesia Although continuous epidural infusion techniques provide excellent results in most patients, occasional individuals experience inadequate pain relief. In these cases, the causes of inadequate analgesia should be evaluated and corrected. Most commonly, placement of the catheter is tested in two stages. First, 5 mL of the epidural infusion solution is administered, and the patient’s analgesia is reassessed after 30 minutes. Second, if the analgesia remains inadequate, 5 to 10 mL of 2% lidocaine is administered in two fractionated doses. This test dose generally yields one of three results: 1. 2. 3.
If bilateral sensory block occurs in a few segmental dermatomes, correct catheter placement is confirmed. In this case, insufficient volume of the infusion mixture was the likely cause of inadequate analgesia. This problem can be rectified by increasing the rate of infusion. A unilateral sensory block most likely indicates that the catheter tip was placed too far laterally into the epidural space (i.e., at the foramen). The catheter can be withdrawn 1 to 2 cm, and the test dose repeated. Finally, lack of any sensory block indicates that the epidural catheter is no longer in the epidural space. The catheter is then removed, and the options are placement of another epidural catheter or administration of an alternative therapy.
Complications of Continuous Infusion Epidural Anesthesia Complications of continuous epidural anesthesia include accidental intrathecal administration of the analgesic drug, infection, epidural hematoma, and respiratory depression. To decrease the incidence of these complications, the following guidelines are advocated: 1.
2.
3.
The use of appropriate concentrations of local anesthetics (e.g., bupivacaine, 0.03% to 0.125%) prevents serious hypotension and facilitates diagnosis of subarachnoid catheter migration more readily by providing progressive levels of sensory blockade where none would have been expected. Another safety feature is the combination of dilute local anesthetic solution with half the usual dose of an opioid, such as oral morphine, 0.005% to 0.01%, with fentanyl, 3 µg/mL. Daily examination of catheter insertion sites, monitoring of temperature, and periodic check for neurologic signs of meningism are essential. If findings consistent with infection are present, the catheter should be removed and the patient should be treated appropriately. I have had experience with one case of epidural abscess in 2000 epidural infusion cases. The patient’s infection resolved in 6 weeks with aggressive antibiotic therapy. Infections limited to the cutaneous and subcutaneous tissues can develop and resolve with local conservative therapy. If epidural catheters are placed at least 1 hour before heparinization, the incidence of epidural hematoma is not significant. Epidural catheters may be inserted safely in patients who receive warfarin postoperatively, as long as their coagulation status is normal at the time of catheter insertion.
Limitations of Continuous Epidural Analgesia There are limitations to epidural infusion analgesia. First, this type of analgesia cannot independently control pain that stems from multiple sites. Epidural analgesia normally can provide analgesia for five to seven dermatomal regions in continuity, such as L4 to S5 or T2 to T8. Patients with multiple injuries may require other forms of pain control management. The placement site of the epidural catheter influences the adequacy of pain relief and the maintenance of normal vital function. In general, placing the epidural catheter within the dermatomal distribution of the pain achieves the best result with the smallest amount of drug. For example, pain from a thoracotomy is best treated with a thoracic epidural infusion, and pain in the lower extremity requires a lumbar epidural infusion.
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Patient-Controlled Epidural Analgesia Patient-controlled epidural analgesia (PCEA) has been offered to patients with acute postoperative pain after intraabdominal, major orthopedic, or thoracic surgery and has also been given to patients with chronic pain states such as occur with cancer. The technique has several potential advantages. The patient has the ability to titrate analgesic doses in amounts proportional to the level of pain. Given the large individual variation in the perception of pain and its relief, this control is an important factor in optimizing spinal opioid analgesia. Most of the published work describing PCEA comes from Europe. Chrubasik and colleagues used PCEA technique in comparing three different epidural opioids. These studies were remarkable in that the morphine dosage required to provide effective analgesia with PCEA was much smaller than the amount used with continuous epidural infusion and IV patientcontrolled analgesia (PCA). Serum morphine levels used in these studies were very low. Table 16–2 lists various studies and the opioids used, along with their hourly consumption. Sjostrom and colleagues evaluated morphine PCEA and demonstrated its efficacy. They employed intermittent boluses of 1 mg with a 30-minute lockout period. The average consumption was about 0.5 mg/hour, and serum morphine levels were well below the minimum effective plasma concentrations usually associated with parenteral delivery. Marlowe and coworkers compared constant infusion of epidural opioid with PCEA. They found that the self-administration technique was superior because less [32]
[32]
[33] [34]
[35] [36] [37]
[32]
[38]
TABLE 16-2 -- CONSUMPTION OF OPIOIDS USED WITH PATIENT-CONTROLLED ANALGESIA Study *
Average Consumption (mg/hour)
Morphine sulfate
0.52
[38]
Demerol
18.0
Hydromorphone
0.1
Morphine sulfate
0.47
Morphine sulfate
0.25
Sjostrom et al Marlowe et al
Epidural Opiates
[32]
Walmsley et al[39] † [33] †
Chrubasik and Wiemers
*Superscript number refers to reference number in chapter. †Infusion and patient-controlled epidural anesthesia were both used.
opiate was required to provide similar levels of analgesia. Walmsley and associates reported the high efficacy of PCEA in their evaluation of more than 4000 surgical cases. [39]
The following advantages are given for PCEA over conventional epidural CI analgesia: • Increased efficiency • Higher satisfaction • Decreased sedation • Reduced opioid usage The following advantages are given for PCEA compared with IV PCA: • Self-adjustment by patient • Self-satisfaction and resulting decrease in anxiety • Reduced opioid requirement
PCEA TECHNIQUE USING MORPHINE The following techniques are used for patient-controlled epidural analgesia.
[31]
Loading Dose
Lower thoracic or upper lumbar catheters are placed preoperatively or intraoperatively with use of standard techniques. Patients are “loaded” with preservative-free morphine, 2 to 3 mg, and given a basal infusion of 0.4 mg/hour with a 0.02% solution. Patients are allowed to self-administer morphine, 0.2 mg, every 10 to 15 minutes with a maximum dose of 1 to 2 mg/hour. The “load” is administered only after a local anesthetic test dose (lidocaine 2%, 2 to 3 mL) has demonstrated that the catheter is not located in a subarachnoid space. The optimal loading dose size and the timing of the administration have yet to be determined; however, given morphine’s latency to peak
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effect, one needs to “load” as early as possible. Breakthrough pain is common in these patients during the first 6 to 8 hours postoperatively. Breakthrough pain is treated with epidural morphine boluses, 0.5 to 1.0 mg/hour. If two doses are inadequate to provide analgesia, the catheter needs to be retested with local anesthetic to confirm the epidural placement and to rule out dislodgment. The loading dose can be augmented with epidurally administered fentanyl, 50 to 100 µg. This drug speeds the onset of the analgesia, possibly because of dual action (i.e., rapid vascular uptake) and rapid spinal cord neural uptake. Residual levels of intraoperatively administered local anesthetics augment initial epidural morphine analgesia and contribute to subsequent postoperative pain relief. Lockout
The short lockout period usually set with PCEA is somewhat controversial in view of the longer latency of morphine’s epidural effect. Sjostrom and coworkers thus chose 30 minutes as the lockout period. There are few problems with morphine’s longer latency to peak epidural effect, however, provided that a suitable loading dose has been administered 90 to 120 minutes before PCEA is begun. It is possible that patients perceive early analgesic benefits from the small rise in serum morphine levels occurring soon after a PCA bolus. The shorter latency of response to a single PCA bolus may be related to the “primed” or “loaded” state of spinal cord tissues during infusion and an optimal interval between the load and the initiation of PCEA opioid. Alternatively, patients may be satisfied by the placebo effect associated with all self-administration techniques. [32]
The size of the intermittent PCEA dose should be limited in order to avoid excessive accumulations of morphine. Small boluses with short lockouts are safe and do not lead to accumulation of excessive drug before the initial dose becomes effective. Continuous Infusion
A continuous infusion provides the major portion of epidurally administered morphine. Tolerance to morphine does not develop when continuous infusions are added to PCEA in the typical postoperative patient. Several authors believe that continuous infusions, by avoiding peaks and valleys in cerebrospinal fluid levels, provide more uniform levels of analgesia while reducing the incidence of side effects. [35] [36]
Serum levels at 24 hours are low, with 90% of 20 samples studied being less than 6.5 ng/mL. This finding indicates that the systemic absorption of morphine provides a minimal contribution to the overall levels of analgesia. Breakthrough pain is treated with small morphine boluses. Changing the rate of infusion alone has little effect in the short term, because it requires five half-lives to reach the new equilibrium. [39]
ALTERNATIVE ANALGESIC AGENTS FOR PCEA Lipophilic Opioids
Fentanyl, sufentanil, and hydromorphone may be used with a PCEA infusion technique; however, the amount of drug necessary to provide effective analgesia appears to be much greater than equivalent doses of morphine. The administration of lipophilic opioids by continuous infusion, PCEA, or both has been questioned by several authors. E stok and coworkers showed that fentanyl administered by IV PCA or PCEA provided equivalent analgesia.
[40]
[41]
[41]
Epidurally administered lipophilic opioids are most appropriately administered via thoracic epidural catheters. They may be of special use in the following circumstances: • To speed the onset of epidural opioid analgesia. • In large volumes of dilute solution or combined with local anesthetics. (Cohen and associates compared combinations of fentanyl bupivacaine and buprenorphine-bupivacaine for PCEA. The average hourly doses of opioid were minimized, presumably because of the effective analgesia provided by concurrently administered bupivacaine; therefore, 24-hour serum concentrations were low.) • For breakthrough pain, especially in the first few hours postoperatively. [42] [43]
Local Anesthetics
The use of PCEA with local anesthetics during labor has been reported to be safe and effective. The technique was first described in 1988 by Gambling and colleagues, who compared bupivacaine (0.125%) PCEA with CI alone. They found that PCEA was better for controlling pain than continuous epidural infusion of bupivacaine. Patients in [44]
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the PCEA group required significantly smaller doses of bupivacaine to provide similar analgesia. The technique was believed to be safe and reliable and was not associated with excess sensory blockade. Lysak and associates evaluated bupivacaine, 0.125%, in combination with three different concentrations of fentanyl to find the optimal regimen for PCEA. The control group received continuous infusion of plain bupivacaine. Hemodynamics, sensory level, and duration of labor were monitored. The results suggested that PCEA was safer than plain bupivacaine, and the researchers concluded that the optimal concentration of fentanyl for PCEA hourly dosage was 1 ng/mL. [45]
Bupivacaine-fentanyl administered by PCEA with infusion also demonstrated greater safety and efficacy (i.e., fewer “top-ups” and lower infusion rates) than when administered by CI. Naulty and coworkers used bupivacainesufentanil combinations for relief of labor pain. They demonstrated no particular benefits of PCEA with this combination of drugs; in fact, total drug requirements were higher in the PCEA group. Whether this finding was attributable to the drugs employed or to the PCEA regimen (small volume of self-administered dose) remains to be seen. [48]
Dilute local anesthetic solutions (bupivacaine, 0.03%–0.06%) can be used in selected postoperative patients. So that patients may avoid avoid interference with ambulation, the use of local anesthetics should be limited to the first 12 to 24 hours postoperatively. Local anesthetics are probably best employed with segmentally placed catheters in patients recovering from major upper abdominal or thoracic surgery. A small but definite incidence of hypotension and lower extremity weakness is associated with the PCEA technique.
CONCLUSION Compared with IV PCA, PCEA is a relatively new technique that may offer adequate analgesia with a lower opioid dosage. PCEA provides greater control and higher patient satisfaction than CI. There is also a potential decrease in dose-dependent side effects with use of PCEA. The clinical advantages of PCEA may outweigh the greater cost and invasiveness of the technique. More data need to be analyzed, however, so that the best choice among IV PCA, CI, and PCEA may be made for analgesia in patients with acute and chronic pain.
Continuous Peripheral Regional Analgesia A prolonged peripheral nerve block may be placed as a continuous technique to provide perioperative pain relief for patients with trauma and postoperative pain. This continuous technique is very similar to a single-injection technique. After the needle is placed in the correct position, a catheter may be threaded into the perivascular compartment and secured for up to 7 to 10 days. In addition to perioperative pain relief, these catheters may be placed for a sympathetic block in patients with vascular compromise, intractable pain from complex regional pain syndrome (CRPS) I and II, or phantom limb pain. [49]
[50]
[51]
[52]
CONTINUOUS BRACHIAL PLEXUS INFUSION
[53]
Indications for continuous brachial plexus infusion include perioperative pain for trauma and postoperative pain relief, vascular compromise, intractable pain from CRPS I and II, and phantom limb pain. Anatomy
The brachial plexus is an ideal location for a continuous regional technique because of its well-defined perivascular compartment and the close approximation of the large number of nerves supplying the upper extremity. All techniques of brachial plexus blockade have been described as continuous techniques, but some are easier to achieve than others. The infraclavicular approach is preferred owing to the advantage of maintaining the catheter in the same position for long periods, sometimes as long as 3 weeks. [53]
[53]
Technique
The patient lies supine, with the head turned away from the arm to be blocked ( Fig. 16–2 ). The arm is abducted to 90 degrees and allowed to rest comfortably. The physician stands on the opposite side of the arm to be blocked. The whole length of the clavicle is identified after palpation or fluoroscopic imaging. The midpoint of the clavicle is marked. The brachial artery is palpated in the arm and marked. The C6 tubercle on the same side is palpated in the neck and marked. A line is drawn from the C6 tubercle to the brachial artery in the arm. This line goes through the midpoint of the clavicle and is the surface marking of the brachial plexus. The ground electrode of a peripheral
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nerve stimulator is attached to the opposite shoulder. A skin wheal is raised 2 cm below the inferior border of the clavicle at its midpoint. An 18-gauge (G) needle is used to pierce the skin. A 19-G B-D Longwell needle/catheter (or a 16-G R-K epidural needle with appropriate epidural catheter to follow) is introduced through the skin wheal. The needle point is directed laterally toward the brachial artery (see Fig. 16–2 ). The exploring needle is then attached to either the stem or the hub of the needle with a sterile alligator clip. The current of the peripheral nerve stimulator is set to deliver 3 mA, and the needle is advanced at an angle of 45 degrees to the skin. As the needle approaches the fibers of the brachial plexus, movements of the muscles supplied by those fibers occur. The forearm and hand are carefully observed for these movements. Flexion or extension of the elbow, wrist, or digits confirms that the needle point is close to nerve fibers of the brachial plexus. The current of the impulse is decreased to 0.5 mA. The needle is then advanced. The muscle movement previously seen increases as the needle tip moves closer to the brachial plexus. The needle is advanced until the muscle movements start to decrease. When this happens, the needle tip has passed the nerve. The needle is withdrawn slowly until maximal muscle movements are observed. The needle is held in that position. Water-soluble contrast medium may be injected (approximately 3 mL) to observe the spread in the nerve sheath; lidocaine, 2 mL of 2%, is then injected through the needle, with the 1 impulse per second button on the peripheral nerve stimulator activated (Fig. 16–3 (Figure Not Available) ). If the needle is placed correctly on the nerve fibers, there is a loss of previously seen muscle movements within 30 seconds. If not, the needle should be withdrawn slightly and the process repeated. The catheter is then threaded through the needle and approximately [54]
Figure 16-2 Raj’s technique of the infraclavicular approach. The drawing illustrates the surface markings of the brachial plexus. The needle is directed laterally at 45 degrees to the skin at the point of entry. The point of entry is 1 inch inferior to the midpoint of the clavicle. The artery is identified in the upper arm, and the needle is directed toward it.(From Raj PP, Pai U, Rawal N: Techniques of regional anesthesia in adults. In Raj PP [ed]: Clinical Practice of Regional Anesthesia. New York, Churchill Livingstone, 1991.)
Figure 16-3 (Figure Not Available) A, Radiograph shows needle in final position after infraclavicular block. Note that the needle tip approaches the scapula as it goes deeper. B, The spread of the contrast material (20 mL) when the needle is on the brachial plexus in the infraclavicular region. (From Raj PP, Montgomery SJ, Nettles D, et al: Infraclavicular brachial plexus block: A new approach. Anesth Analg 52:897-904, 1973.)
3 to 5 cm beyond the needle tip. Further confirmation of placement of the catheter can be made with contrast dye. Ropivacaine 0.2%, 20 to 30 mL, is then injected through a bacteriostatic filter in divided doses for immediate pain relief (Fig. 16–4 (Figure Not Available) ). The needle Figure 16-4 (Figure Not Available) Details of 20 mL of contrast solution injected into the infraclavicular region. Note the cephalad spread under the midclavicular region and the filling of the axillary sheath in the upper arm (caudad spread). The spilling of the solution in the midportion suggests a sievelike brachial plexus sheath in the infraclavicular region. The spilling of contrast solution outside the sheath at this level usually blocks the intercostobrachial nerve, an obvious advantage of this block.(From Raj PP, Montgomery SJ, Nettles D, et al: Infraclavicular brachial plexus block: A new approach. Anesth Analg 52:897-904, 1973.)
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is then withdrawn under direct fluoroscopic guidance. The catheter is sutured into place. The site is covered with antibiotic ointment and a bio-occlusive dressing. The brachial plexus catheter is then connected to a constant infusion of ropivacaine, 0.1%, with fentanyl, 5 µg/mL, at 6 to 10 mL/hour. Occasional bolus doses may be required and may be administered by the patient (patient-controlled with 3 mL of the dosage, 15-minute lockout, and a maximum of 6 mL/hour). The CI is reliably efficacious for up to 48 hours. After that period, the efficacy drops precipitously, for A-delta fiber blocking. Sympathetic blocking can still be maintained for up to 2 to 3 weeks with ropivacaine, 0.1% to 0.2%, in a reliably anchored catheter. [53]
Complications
The complications of a continuous brachial plexus infusion are similar to those of a brachial plexus block. They include bleeding, infection, intravascular injection, intrathecal injection, pneumothorax, and phrenic nerve paralysis. The severity and length of phrenic nerve paralysis are related to site of catheter placement (e.g., interscalene, supraclavicular) and choice of local anesthetic. The plasma concentration and pharmacokinetics of the constant infusion in steady state are similar to those observed in epidural infusion. Once steady state is reached, the drugs infused do not accumulate if they are infused at the same rate. The metabolites also remain at an insignificant level without causing any deleterious effect. [55] [56] [57] [58] [59] [60] [61]
[54]
CONTINUOUS SCIATIC NERVE INFUSION Indications
Patients with CRPS I and II, vascular insufficiency, and unilateral leg edema from many causes are frequently managed with lumbar epidural catheters. There are, however, inherent risks with long-term placement of an epidural catheter. The sciatic catheter can be an alternative in such patients. It can eliminate the risk of epidural abscesses, hematoma formation, or catheter erosion of the dura. The unilateral affected limb can be specifically treated without numbing or weakening the opposite limb. Thus, ambulation can be maintained. Contraindications include (1) anticoagulant therapy, (2) septicemia, (3) local infection, (4) recent injury at the site of injection to the nerve, and (5) inability of the patient to lie in the prone position. Anatomy
The sciatic nerve is formed from the nerve roots of L4 to L5 and S1 to S3. After formation at the sciatic notch, the nerve passes through the gluteal region between the greater trochanter and the ischial tuberosity. In the buttocks, it runs posterior to the gemelli and the obturator internus. It lies anterior to the piriformis muscle as it descends to the thigh, as first described by Labat in 1923. My approach is based on the identification of the piriformis muscle and the placement of the catheter on the sciatic nerve in the gluteal region. [62]
Technique
The patient is placed in the prone position. The gluteal regional ipsilateral to the affected side is sterilized and draped. The following landmarks are located by fluoroscopy: (1) posterior superior iliac spine, (2) greater trochanter, and (3) ischial tuberosity ( Fig. 16–5 ). A line is drawn connecting the posterior iliac spine and the greater trochanter. The midpoint is identified and a perpendicular line is drawn in a caudal direction. A second line is drawn from the greater trochanter to the ischial tuberosity. This line is divided into thirds. A line is drawn vertically from the medial third mark upward to intersect the other line. The point of entry is where the two lines meet ( Fig. 16–6 ). A skin wheal is raised at the site with a 25-G needle. A larger needle (16-G or 18-G) can pierce the skin. A blunt, 16-G, 7-inch needle is introduced perpendicularly, approximately 1 cm through the skin to reach the piriformis muscle ( Fig. 16–7 ). A 22-G needle is inserted subcutaneously and attached to a positive lead from the Medtronic test stimulator (or equivalent peripheral nerve stimulator). The Medtronic test stimulator should be set to deliver 6 to 8 V at 1 impulse per second. (If a peripheral nerve
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Figure 16-5 Drawing depicting the landmarks to be identified by fluoroscopy. A, Posterior superior iliac spine. B, Greater trochanter. C, Ischial tuberosity. (From Racz G, Raj P, Lou L, et al: Posterior sacral approach to the sciatic nerve for continuous lidocaine infusion: A new technique. Presented at 1997 ASA Annual Meeting, San Diego, CA.)
Figure 16-6 Surface landmarks and entry point of needle. A, Posterior superior iliac spine. B, Greater trochanter. C, Ischial tuberosity. D, Insertion site. (From Racz G, Raj P, Lou L, et al: Posterior sacral approach to the sciatic nerve for continuous lidocaine infusion: A new technique. Presented at 1997 ASA Annual Meeting, San Diego, CA.)
stimulator is used, the current should be adjusted from 3 to 0.5 mA at 1 impulse per second.) The needle is slowly advanced anteriorly until the piriformis muscle, which is identified by contrast solution, is twitching ( Fig. 16–8 ). The needle is further advanced until the piriformis muscle stimulation stops and foot twitching (dorsiflexion) is observed in the affected limb. A stimulating catheter is then inserted through the needle. The
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Figure 16-7 Surface view of the catheter after placement.(From Racz G, Raj P, Lou L, et al: Posterior sacral approach to the sciatic nerve for continuous lidocaine infusion: A new technique. Presented at 1997 ASA Annual Meeting, San Diego, CA.)
Figure 16-8 Fluoroscopic image of catheter with the piriformis muscle superficially and with contrast solution over the sciatic nerve.(From Racz G, Raj P, Lou L, et al: Posterior sacral approach to the sciatic nerve for continuous lidocaine infusion: A new technique. Presented at 1997 ASA Annual Meeting, San Diego, CA.)
negative lead of the stimulator is attached to the distal connecting wire of the catheter. The catheter is passed to the level of the lesser trochanter for foot movement. The needle is then removed, and the catheter is attached to the hub connector. Confirmation of placement can be made with 3 mL of contrast dye via the catheter ( Fig. 16–9 ). An additional 3 mL of local anesthetic (ropivacaine 0.2%) may be injected, and stimulation of the sciatic nerve should cease. Ropivacaine 2%, 15 to 30 mL, is injected through an attached bacteriostatic filter in divided doses for [63]
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immediate pain relief and nerve blockade. The constant infusion of ropivacaine 0.1% with fentanyl 5 µg/mL may range from 4 to 10 mL/hour. Occasional bolus doses may be required and may be delivered by the patient through the pump with a bolus of 5 mL and a 30-minute lockout. The catheter may be connected to a drug infusion balloon (DIB) for outpatient care through home health services. This DIB delivers 4 mL/hour of the drug to the patient for 24 hours. (The volume of the DIB reservoir is 100 mL.) [64]
Complications
Potential complications with the CI sciatic catheter include bleeding, infection, hematoma, intravascular injection, and residual dyschesia.
Figure 16-9 Fluoroscopic image of the catheter with contrast solution following the sciatic nerve sheath.(From Racz G, Raj P, Lou L, et al: Posterior sacral approach to the sciatic nerve for continuous lidocaine infusion: A new technique. Presented at 1997 ASA Annual Meeting, San Diego, CA.)
LUMBOSACRAL PLEXUS CATHETERIZATION Placement of a lumbosacral catheter with an epidural needle has been reported by Vaghadia and colleagues. Successful blockade of the lumbar and sacral plexuses was achieved for unilateral lower extremity surgery. The catheter is placed between the quadratus lumborum and psoas muscles between the transverse processes of L4 and L5. The technique is not difficult and seems highly successful. The main disadvantage is the volume of local anesthetic needed, which is between 40 and 70 mL. [65]
[66]
FEMORAL NERVE CATHETERIZATION Continuous techniques for the femoral nerve have been used for various surgeries. Edwards and Wright, in 1992, reported significantly lower postoperative pain scores and reduced opioid requirements in patients who underwent total knee replacement with CI (0.125% bupivacaine at 6 mL/hour) within the femoral sheath compared with patients who received analgesia from conventional intramuscular injections of opioids. [67]
The drugs administered for lower extremity infusions follow the same principles as those used for brachial plexus infusions. The concentration of drug infusion depends on the need to block A-alpha, A-delta, or C fibers, and the rate of infusion is usually 10 to 15 mL/hour. Complications include peripheral neuropathy, motor weakness, dysesthesias, and decubitus ulcers secondary to sensory loss. [66]
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Technically, lower extremity infusion is difficult and unreliable. At best, this technique is an alternative to lumbar epidural infusion (when it cannot be performed because of infection or coagulation abnormality). Postoperative knee pain and CRPS I and II may be the best indications for these procedures. [66]
CONTINUOUS SYMPATHETIC INFUSION Some clinicians routinely perform continuous sympathetic infusions, such as continuous stellate ganglion and continuous lumbar sympathetic infusions. The stellate ganglion infusion is often unreliable because of catheter dislodgment. Continuous splanchnic and lumber sympathetic infusions are successful even in outpatients with no significant problems. These techniques are most useful for treatment of patients with visceral pain secondary to cancer, CRPS I, and sympathetically maintained pain. [68]
[66]
[69]
DRUGS The drugs administered for sympathetic infusions follow the same principles as those for brachial plexus infusion. The drug of choice has been bupivacaine (0.125%–0.25%), usually without a narcotic. With the introduction of less cardiotoxic local anesthetics, ropivacaine (0.1%–0.2%) and chirocaine (0.125%), are becoming the drugs of choice. Morphine, fentanyl, and sufentanil have been mixed with the local anesthetic to prolong the analgesia. A solution of 6 mL (stellate ganglion) to 20 mL (splanchnic nerve or celiac plexus [bilateral]) is continuously infused. [66]
[66]
EFFICACY The stellate ganglion infusion is unreliable because of catheter dislodgment. Lumbar sympathetic infusion is quite reliable, although the lumbar plexus is eventually blocked by the diffusion of the local anesthetic solution into the psoas muscle. Hypotension and nausea are rare complications of bilateral celiac plexus infusion. Not enough data are currently available to state that continuous sympathetic infusion is a safe, reliable, and efficacious technique. [66]
Conclusion Continuous regional analgesia, whether central or peripheral, is a safe and efficacious technique. The infusions may use local anesthetics, opioids, or a combination of both. These infusions are performed when prolonged analgesia is required for moderate to severe acute, chronic, or cancer pain. [53]
BIBLIOGRAPHY Lubenow TR: Epidural analgesia: Considerations and delivery methods. In Sinatra RS, Hord AH, Ginsberg B, Preble LM (eds): Acute Pain: Mechanisms and Management. St. Louis, Mosby-Year Book, 1992, pp 233–242. Walmsley PNH: Patient controlled epidural analgesia, In Sinatra RS, Hord AH, Ginsberg B, Preble LM (eds): Acute Pain: Mechanisms and Management. St. Louis, Mosby-Year Book, 1992, pp 312–320. REFERENCES 1. Green
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10. Scott ND, Mogensen T, Bigler D, et al: Continuous thoracic extradural 0.05% bupivacaine with or without morphine: Effect on quality of blockade, lung function and the surgical stress response. Br J Anaesth 62:253–257, 1989. 11. Raj PP, Denson D, Finnason R: Prolonged epidural analgesia: Intermittent or continuous? In Meyer J, Nolten H (eds): Die Kontinuerliche Peridural Anesthesia. 7th International Symposium uber die Regional Anaesthesia AM, Jan. 7, 1982, Minden, Germany. Stuttgart, George Thieme, 1983, pp 26–38. 12. Lubenow TR, Durrani Z, Ivankovish AD: Evaluation of continuous epidural fentanyl/butorphanol infusion for postoperative pain. Anesthesiology 69:381, 1988. 13. Rosseel PMJ, Van Der Broeck J, Boer EC, Prakash O: Epidural sufentanil for intraoperative and postoperative analgesia in thoracic surgery: A comparative study with intravenous sufentanil. Acta Anaesthesiol Scand 32:193–198, 1988. 14. Scott
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16. Akerman B, Hellberg IB, Trossvic C: Primary evaluation of the local anaesthetic properties of the amino amide agent ropivacaine. Acta Anaesthesiol Scand 32:571–578, 1988. 17. Feldman HS, Covino BG: Comparative motor blocking effects of bupicavaine and ropivacaine, a new amino amide local anesthetic, in the rat and dog. Anesth Analg 67:1047–1052, 1988. 18. Reuz S, Haggmark S, Gohansson G, Nath S: Cardiotoxicity of ropivacaine—A new amide local anesthetic agent. Acta Anaesthesiol Scand 33:93–98, 1989. 19. Finucane
BT: Ropivacaine—A worthy replacement for bupivacaine? Can J Anaesth 37(7):722–725, 1990.
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GR, Feldman HS, Covino BG: Comparative pharmacokinetics of bupivacaine, a new amide local anesthetic. Anesth Analg 67:1053– 1058, 1988.
21. Tucker
GT, Cooper S, Littlewood D, Buckley SP: Observed and predicted accumulation of local anesthetics during continuous extradural analgesia. Br J Anaesth 49:237, 1977.
22. Schweitzer
SA, Morgan DJ: Plasma bupivacaine concentrations during postoperative continuous epidural analgesia. Anaesth Intensive Care 15:425–430, 1987
23. Gregory MA, Brock-Utne JC, Bux S, Downing JW: Morphine concentration in brain and spinal cord after subarachnoid morphine injection in baboons. Anesth Analg 64:929–932, 1985. 24. Rawal
N, Sjostrand U, Dahlstrom B: Postoperative pain relief by epidural morphine. Anesth Analg 60:726–731, 1981.
25. Chestnut DH, Owen CL, Bates JN, et al: Continuous infusion epidural analgesia during labor: A randomized double-blind comparison of 0.0625% bupivacaine/0.0002% fentanyl versus 0.125% bupivacaine. Anesthesiology 68:754–759, 1988.
26. Cullen M, Staren E, Ganzouri A, et al: Continuous thoracic epidural analgesia after major abdominal operations: A randomized prospective double-blind study. Surgery 98:718–728, 1985. 27. Fisher R, Lubenow TR, Liceaga A, et al: Comparison of continuous epidural infusion of fentanyl-bupivacaine and morphine-bupivacaine in the management of postoperative pain. Anesth Analg 67:559–563, 1988. 28. Logas WG, El-Baz NM, El-Ganzouri A, et al: Continuous thoracic epidural analgesia for postoperative pain relief following thoracotomy: A randomized prospective study. Anesthesiology 67:787–791, 1987. 29. Hjorts NC, Lunc C, Mogensen T, et al: Epidural morphine improves pain relief and maintains sensory analgesia during continuous epidural bupivacine after abdominal surgery. Anesth Analg 65:1033–1036, 1986. 30. Magora F, Olshwand DL, Eimei D, et al: Observation on extradural morphine analgesia in various pain conditions. Br J Anaesth 52:247–252, 1980. 31. Rutberg
H, Hakannson E, Anderberg B, et al: Effects of extradural administration of morphine or bupivacaine on the endocrine response to upper abdominal surgery. Br J Anaesth 56:233–238, 1984.
32. Sjostrom
S, Hartvig D, Tamsen A: Patient controlled analgesia with extradural morphine or pethidine. Br J Anaesth 60:358, 1988.
33. Chrubasik J, Wiemers K: Continuous-plus-on demand epidural infusion of morphine for postoperative pain relief by means of a small, externally worn infusion device. Anesthesiology 62:263, 1985. 34. Chrubasik J, Wust H, Schulte-Monting J, et al: Relative analgesic potency of epidural fentanyl, alfentanil and morphine in treatment of postoperative pain. Anesthesiology 68:929, 1988.
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35. Downing
JE, Stedman PM, Busch EH: Continuous low volume infusion of epidural morphine for postoperative pain. Reg Anesth 13(Suppl):84, 1988.
36. Planner RS, Cowie RW, Babarczy AS, et al: Continuous epidural morphine analgesia after radical operations upon the pelvis. Surg Gynecol Obstet 166:229, 1988. 37. Rauck R, Knarr D, Denson D, Raj P: Comparison of the efficacy of epidural morphine given by intermittent injection or continuous infusion for the management of postoperative pain. Anesthesiology 65:A201, 1986. 38. Marlowe S, Engstrom R, White PF: Epidural patient-controlled analgesia (PCA): An alternative to continuous epidural infusion. Pain 37:97, 1989. 39. Walmsley PNH, McDonnell FJ, Colclough GW, et al: A comparison of epidural and intravenous PCA after gynecological surgery. Anessthesiology 73:A684, 1989. 40. Loper KA, Ready LB, Sandler AN: Epidural and IV fentanyl infusions are clinically equivalent following knee surgery. Anesthesiology 71:A1149, 1989. 41. Estok PM, Glass PSA, Goldberg JS, et al: Use of PCA to compare IV to epidural administration of fentanyl in the postoperative patient. Anesthesiology 67:A230, 1987. 42. Cohen
S, Amar D, Pantuck CB: Continuous epidural-PCA post-cesarean section: Buprenorphine-bupivacaine 0.03% vs. fentanyl-bupivacaine 0.03%. Anesthesiology 73:A230, 1987.
43. Cohen S, Amar D, Pantuck CB: Continuous epidural-PCA for cesarean section: Buprenorphine-bupivacaine 0.015 with epinephrine vs fentanyl-bupivacaine 0.015 with and without epinephrine. Anesthesiology 73:A918, 1990. 44. Gambling
DR, Yu P, Cole C, et al: A comparative study of patient controlled epidural analgesia analgesia (PCEA) and continuous infusion epidural analgesia (CIEA) during labour. Can J Anaesth 35:249–254, 1988.
45. Lysak SZ, Eisenach JC, Dobson CE: Patient-controlled epidural analgesia during labor: A comparison of three solutions with a continuous infusion control. Anesthesiology 72:44–49, 1990. 46. Gambling
DR, McMorland GH, Yu P, et al: Comparison of patient controlled epidural analgesia and conventional intermittent “top-up” injections during labor. Anesth Analg 70:256–261, 1990.
47. Viscomi
C, Eisenach JC: Patient-controlled epidural analgesia during labor. Obstet Gynecol 77:A685, 1989.
48. Naulty
JS, Barnes D, Becker R, et al: Epidural PCA vs. continuous infusion of sufentanil-bupivacaine for analgesia during labor and delivery. Anesthesiology 73:A963, 1990.
49. Fisher A, Meller Y: Continuous postoperative regional analgesia by nerve sheath block for amputation sugery—A pilot study. Anesth Analg 72:300–303, 1991. 50. Raj P: Continuous brachial plexus analgesia In: Abstract Book, 21st Annual Meeting, American Society of Regional Anesthesia, San Diego, 1996, pp 501–502. 51. Matsuda
M, Kato N, Hosoi M: Continuous brachial plexus block for replantation in the upper extremity. Hand 14:129–34, 1982.
52. Hartrick C: Pain due to trauma including sports injuries. In Raj PP (ed): Practical Management of Pain, 2nd ed. St. Louis, Mosby-Year Book, 1992, pp 409–433. 53. Raj
PP: Continuous regional analgesia. In Raj PP (ed): Practical Management of Pain, 3rd ed. Philadelphia, WB Saunders, 2000.
54. Raj
PP, Moontgomery SJ, Nettles D, et al: Infraclavicular brachial plexus block—A new approach. Anesth Analg 52(6):897–904, 1973.
55. Pere P, Pitkanen M, Rosenberg PH, et al: Effect of continuous interscalene brachial plexus block on diaphragm motion and on ventilatory function. Acta Anaesthesiol Scand 36:53–57, 1992. 56. Urmey
WF, Talts KH, Sharrock NE: One hundred percent incidence of hemidiaphragmatic paresis associated with interscalene brachial plexus anesthesia as diagnosed by ultrasonography. Anesth Analg 72:498–503, 1991.
57. Urmey WF, McDonald M: Hemidiaphragmatic paresis during interscalene brachial plexus block: Effects on pulmonary function and chest wall mechanics. Anesth Analg 74:352–357, 1992. 58. Knoblanche GE: The incidence and etiology of of phrenic nerve blockade associated with supraclavicular brachial plexus block. Anaesth Intensive Care 7:346–349, 1979. 59. Dhuner KG, Moberg E, Onne L: Paresis of the phrenic nerve during brachial plexus block analgesia and its importance. Acta Chir Scand 109:53–57, 1955.
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MD, Scheybani M, Nolte H: Upper extremity block: Effectiveness and complications. Reg Anesth 6:133–134, 1981.
61. Kulenkampff 62. Adriani
D: Die Anasthesia des plexus brachialis. Zentralbl Chir 38:1337–1340, 1911.
J: Labat’s Regional Anesthesia: Techniques and Clinical Applications. Philadelphia, WB Saunders, 1967.
63. Racz G, Raj P, Lou L, et al: Posterior sacral approach to the sciatic nerve for continuous lidocaine infusion: A new technique. Presented at 1997 ASA Annual Meeting, San Diego, CA (and the 1997 PGA, New York, NY and 1998 IARS, Orlando, FL.) 64. Racz G, Raj P, Lou L, et al: Posterior sacral approach to the sciatic nerve for continuous ropivacaine infusion: A new technique. Presented at 1998 PGA, New York, NY. 65. Vaghadia
H, Kapnoudhis P, Jenkins LC, Taylor D: Continuous lumbosacral block using a Tuohy needle and catheter technique. Can J Anaesth 39:75–78, 1992.
66. Raj P: Nerve blocks: Continuous regional analgesia. In Raj PP (ed): Practical Management of Pain, 3rd ed. St. Louis, Mosby-Year Book, 2000, p 719. 67. Edwards ND, Wright EM: Continuous low-dose 3-in-1 nerve blockade for postoperative pain relief after total knee replacement. Anesth Analg 75:265, 1992. 68. Rauck R: Sympathetic nerve blocks: Head and neck and trunk. In Raj PP (ed): Practical Management of Pain, 3rd ed. St. Louis, Mosby-Year Book, 2000, pp 677–678. 69. Racz GB, Noe C, Colvin J, et al: Sympathetic nerve block: Pelvic. In Raj PP, (ed): Practical Management of Pain, 2nd ed. St. Louis, MosbyYear Book, 1992, pp 813–817.
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Chapter 17 - Aids to Localization of Peripheral Nerves P. Prithvi Raj Jose De Andrés Paolo Grossi Ronald Banister Xavier Sala-Blanch
An increasing number of patients in daily clinical practice who are undergoing surgery or who have acute or chronic pain receive nerve blocks for anesthesia, analgesia, or both. The continued popularity of regional anesthesia depends on a high success rate with these blocks. The peripheral nerve stimulator (PNS) can achieve this success rate. In addition to the PNS, other aids to the success of nerve blocks are appearing on the horizon: for example, ultrasonography, radiologic imaging, and “anesthetic line.” This review describes these techniques in some detail.
PERIPHERAL NERVE STIMULATION FOR NERVE BLOCKS P. Prithvi Raj Ronald Banister
HISTORY In 1912, von Perthes became the first to describe the technique of peripheral nerve stimulation. He used an induction apparatus as the source of faradic current. The current was transmitted through a pure nickel needle that was coated with lacquer down to the tip to provide insulation. The following is the original excerpt of von Perthes’ paper translated into English. [1]
About Nerve-Block/Conduction Anesthesia with the Help of Electrical Stimulation Our procedure is based on the following facts: If one pushes forward a cannula coated with an isolating varnish until the furthest/outermost point onto a nerve which exists out of motoric and sensitive fibers, and when one sends a faradic electricity through the needle whereby the electricity is so low that it can only be realized as a very sensitive stimulus, then, when one’s tongue gets in contact with the needle-shaped electrode, a muscle spasm happens. Only there, however, where the nerve is directly touched by the cannula. If the point of the needle is just 1 mm away from the nerve, then the electrical stimulus with the indicated strength of the electric current is ineffective. The spasms that occur when the nerve gets touched do not affect the whole area, which is provided by the nerve with motoric fibers. Rather, one just sees spasms in single muscles or sees the spasms in some fascicles of fibers when a fine cannula is used. This is proving that only these nerve fibers that are directly touched by the point of the needle get stimulated. Those facts were determined at the nerve ischiadicus in the drugged dog and at the open laying nerve peroneus in a human being. Several experiences with patients and a test with my own nerve ulnaris revealed that the electricity of the indicated strength of the electric current is, on the one side, strong enough to cause spasms and abnormal feeling; on the other side, one does not see it as pain. On the basis of these facts, it is possible to inject the anesthetizing solution in the same moment when the spasm of muscle proves that the point of cannula touches the nerve stem. The cannula, which is connected with the cable, is already put onto the Novocaine solution filled jab during the injection so that one can inject the anesthesia as soon as the muscle spasms occur. During the injection, the spasms get weaker or disappear. When this first occurred, there was concern that the cannula point slipped off the nerve during the injection. The beginning of anesthesia, however, convinced me that this was not the case. The test at the open laying ischiadicus of the dog revealed that as soon as 2% of the Novocaine solution touched the fibers, the motoric sensitivity of the fibers toward the electricity at once vanished as soon as the point touched the fibers. It is recommended not to push forward the solution immediately before the injection through the whole cannula or the solution may affect the nerve stimulus.
Block of Nervus Ischiadicus In order to block the nervus ischiadicus , I usually did it in the following way: while the patient was lying on his/her stomach, the tuber ischii was examined. When the patient bends his/her knee, one can feel the muscles that arise from the tuber ischii . At the very least, one can feel the nervus ischiadicus with his/her fingers and move it back and forth. If one starts its injection parallel to the central axis and at the height of the cleft between the buttocks, at the side of the musculus biceps , he can reach the nervus ischiadicus 5 to 6 cm under the skin surface. While pushing the needle forward, one can start the electric current; this causes the nervus ischiadicus to start spasms in the calf or to
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lightly bend the knee. At the same time when the spasms occur, 15 cc of 3% of the Novocaine-suprarenin solution are injected.
Anesthesia of the Plexus Brachialis with the Aid of Electric Stimulus Borchers explains that the method of Kuhlenkampff is perfect in its recent form. I, however, have to confess that following Kuhlenkampff’s method, I did not always receive a satisfying plexus anesthesia. One point of this method I think is not quite right: that the operating doctor has to depend on what the patient tells him. Following Kuhlenkampff’s method, one injects above the clavicula ; one knows that it hits the plexus when the patient tells the doctor that he feels it in his arm. It seems this is something the patient can do, but I realized that most patients are not able to do this. Some patients are so nervous and get so excited when the hives get attached that they are no longer able to express what they feel in their muscles. Sometimes, when the electric stimulus proved that the plexus was reached, the patient still claimed he/she did not feel anything. It seems more appropriate to use the objective method—the motoric stimulus—instead of depending on the word of the patient. Another advantage of this method is that one can put very nervous patients into a doze. I did the plexus anesthesia with the stimulus needle about seven times. I can, however, prove that operations at fingers, hands, and arms, amputations of the lower arm because of sarcoma , etcetera can be done without any pain with an injection—following Kuhlenkampff—of 10 cc of 3% Novocaine-suprarenin. When one touches the plexus with the stimulus cannula, there are spasms of different muscle groups possible when moving the needle a little bit; therefore, it is still open to figure out which position of the cannula is the best for anesthetizing different areas; for example, the hand or the elbow joint. There are also more tries necessary in order to answer the question if the electric current will help to find pure sensitive nerves. I started those tries already in 1905, but, unfortunately, didn’t pursue them. The method is important insofar as a very fine cannula stimulates only a few fibers; therefore, this method can help to figure out the exact topography of the cross-section through the nerve, especially when one thinks of the operation following Stoffel for the Little-disease. At a discussion following Stoffel’s presentation in 1911, I suggested to him my method; he explained that he had already used this method in order to identify the fibers. In his publication one can read that he uses the galvanic current and that he isolates single beams in a radius of 2 cm from their neighbors. At the Congress of 1911, I also suggested to Mr. Foerster the use of electrical stimulus in order to differentiate the motoric and sensitive muscles for the Foerster-operation. Mr. Foerster was very positive toward my suggestion. We finally found a method to treat sciatica with the injection following Jerome Lange after having found the nervus ischiadicus through the unhurt skin. Postscript: After having finished this essay I did some more experiences with this method. Unfortunately, beside good results I also had two partially bad ones and two completely bad ones. This method can, therefore, not yet be called totally successful. I think, however, I should not keep my experiences to myself, since there is no doubt that, thinking of the good results, this principle is very much of high value. In 1955, Pearson located motor nerves by electrical stimulation with an insulated needle, using a heavy transformer, a vacuum-tube stimulator, and an electrophrenic stimulator. In 1962, Greenblatt and Denson constructed a portable transistorized nerve stimulator as a “needle nerve stimulator-locator.” It delivered a square wave impulse of 0.001 second’s duration at 1-second intervals. Its output could be varied from 0.3 to 30 volts. One pole of the output voltage was grounded to a metal plate or needle connected to the patient’s extremity. The negative pole consisted of a clip that was fastened to the metal Luer lock of a standard syringe. A standard needle of the desired size, insulated with plastic paint except at the tip, completed the circuit. To localize the motor nerve, the insulated needle was placed in the vicinity of the nerve to be blocked. The needle then was used as a stimulator probe with 10 volts until motor stimulation of the nerve was initiated. Voltage was decreased progressively and the needle advanced, redirected, or both until the lowest voltage that produced motor stimulation was obtained, usually in the range of 2 to 5 volts. An injection of 2 to 4 mL of local anesthetic agents usually terminated the motor response. If, after further probing, nerve fibers remained that responded to low voltage, they also were injected with 2 to 4 mL of drug. Paresthesias were not sought. [2]
[3]
[3]
In 1969, Wright modified the commercially available Block-Aid monitor for use as a PNS. His modification consisted of two wires with an Eyenard adapter soldered to each end of one of the wires and one end of the second wire and an alligator clamp at the other end of the second wire. The needle was inserted proximal to the nerve and the monitor connected to it. The monitor was switched to the tetanus position and turned on. The voltage selector was turned about midway. If the voltage produced discomfort, it was reduced and the needle advanced further. As the nerve was approached, the current produced stronger paresthesias. However, if the needle was positioned wrong, paresthesia was not elicited or became weaker as the needle was advanced. [4]
In the same year, Koons introduced the Rochester plastic cannula as a needle probe, and Magora and colleagues evaluated the technique of electrical stimulation by comparing obturator nerve blocks either with blind anatomic technique and radiography or electrical stimulation alone. They concluded that electrical nerve stimulation was preferable to blind or radiographic technique (used singly or in combination) for location of the obturator nerve. [5]
[6]
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All the early reports of the use of the PNS for regional anesthesia noted the use of insulated needles. Some of these were intravenous cannulae ; others were specially constructed by insulating a conventional needle with Teflon or lacquer. In 1973, worrying that such needles might alter the feel of the tissues or that the insulation might peel off, Montgomery and colleagues tried using conventional un-insulated needles. They demonstrated the efficacy of the technique and did some experimental work to show that most of the current leaves from the tip of such a needle. They believed that use of coated needles in plastic cannulas could alter the feel of tissues, making accurate anatomic location more difficult than with standard needles. The coating occasionally tears off or curves back and could lead to errors in performance of the block. [5]
[3]
[7]
[7]
ELECTROPHYSIOLOGY OF PERIPHERAL NERVE STIMULATORS Before the middle of the 19th century, nerve fiber conduction was thought to be instantaneous. In 1850, von Helmholz, in a classic series of experiments with an isolated nerve muscle preparation, demonstrated the temporal nature of nerve fiber conduction and paved the way for the elucidation of most of the relevant physiology of peripheral nerve stimulation. Of particular importance is the relationship between the strength and duration of the current and the polarity of the stimulus. [8]
There is a threshold stimulus that must be applied to a nerve fiber to cause it to propagate a nerve impulse. Below this threshold, no impulse is propagated; above this threshold, no increase is produced in the impulse. If a square pulse of current is used to stimulate the nerve, the total charge applied to the nerve is the product of the current (strength) and the length of the pulse (duration). The relationship between the strength and the duration of the charge needed to stimulate a nerve can be expressed by the familiar strength-duration curve. Figure 17–1 shows such a curve obtained from a preparation of cat sciatic nerve. The rheobase is the minimum current required to stimulate the nerve with a long pulse width, whereas the chronaxy is the duration of stimulus required to just stimulate at twice the rheobase. Generally, strength duration curves follow this formula:
I is the current required, Ir is the rheobase, C is the chronaxy and t is the duration of the stimulus. Thus, the
Figure 17-1 Strength-duration curve. Stimulus strength is plotted against the duration of the pulse. The rheobase is the smallest current to stimulate the nerve with a long pulse width. The chronaxy is the pulse duration at a stimulus strength twice that of the rheobase. The curve was obtained from cat sciatic nerve, with the stimulating needle touching the nerve.(From Pither CE, Raj PP, Ford DJ: The use of peripheral nerve stimulators for regional anesthesia: A review of experimental characteristics, technique, and clinical applications. Reg Anesth 10:50, 1985.)
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TABLE 17-1 -- CHRONAXIES OF MAMMALIAN PERIPHERAL NERVES Cat sural nerve
Cat saphenous nerve
A Alpha fiber
50–100 µsec[10]
A Delta fibers
170 µsec[9]
C fibers
400 µsec[12]
current needed to stimulate a nerve depends on the pulse width or the duration of the stimulus. The chronaxie can be used as a measure of the threshold for any particular nerve and is useful when comparing different nerves or nerve fiber types. Table 17–1 shows values obtained for chronaxies for mammalian peripheral nerves. Note that smaller unmyelinated fibers have larger chronaxies. This supports the observation that the larger the fiber, the easier it is to stimulate at any given distance. Thus, it is possible to stimulate the larger A alpha motor fibers without stimulating the smaller A delta or C fibers responsible for pain. In practical terms, this means that a mixed peripheral nerve can be located by a twitch in the muscles it supplies without causing pain (see Table 17–1 ). [9]
MINIMUM VOLTAGE Raj and colleagues raised several questions during their studies of nerve blocks with electrical stimulation. The first question was: What is the minimal voltage of current necessary to stimulate a peripheral mixed nerve for muscle contraction? During axillary block, the needle tip was placed on the median nerve as confirmed by paresthesia. The needle was stimulated with varying voltage, and the muscle contraction in the median nerve distribution was observed. When the compound potential from one of these muscles was recorded, it appeared that the voltage necessary for optimal potential was 2 volts; there was no action potential below 1.5 volts. Amplitude increased with increasing voltage up to 2 volts, but increasing voltage from 2 to 3 volts did not increase the amplitude any further. [13]
MINIMUM CURRENT Magora and colleagues reported that 0.5 mAmp was required for direct stimulation of the obturator nerve. If 1 to 3 mAmp were needed, the block usually was ineffective and delayed. [6]
OPTIMAL DISTANCE OF NEEDLE TIP TO THE NERVE Study 1 Greenblatt and Denson performed experiments to determine the relationship between voltage and the distance of the needle tip from the nerve. During above-knee amputation, a probing needle was inserted through soft tissue [3]
TABLE 17-2 -- DISTANCE–VOLTAGE RELATIONSHIP Touching nerve
1–2 volts
3 mm
3–5 volts
6 mm
10 volts
8 mm
15–20 volts
>8 mm
No stimulation at higher voltage
and the minimal voltages needed to produce motor stimu lation at various distances from the exposed nerve were recorded. Table 17–2 shows the voltage needed to stimulate the motor fibers at varying distances.
Study 2 The second question Raj and coworkers asked was: How can one tell that the needle tip is on the nerve? His group recorded the twitch height of contracting muscles while performing infraclavicular blocks with a PNS. In Figure 17– 2 , it appears that as the needle tip nears the nerve, the twitch height increases and, as it moves away, the twitch [13]
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height decreases. The tip of the needle is presumed to be on the nerve if the twitch height is greatest at the lowest voltage.
Study 3 To confirm that the needle tip was within 5 mm of the nerve, Raj and coworkers performed the following experiment in a group of five anesthetized dogs. Three spinal needles were introduced toward the sciatic nerve at the gluteal region via electrical stimulation. After it appeared that the muscle contraction was maximal at the lowest voltage with all of the needles, one needle was left undisturbed. The second needle was pulled back 1 cm proximally, the third needle was pushed 1 cm deeper, and 0.2 mL of methylene blue stain was injected through each needle. With the needles in place, the stained areas were explored through careful dissection. It was found that the needle that was presumed to be on the nerve, did, in fact, stain the nerve sheath. The other needles, 1 cm distal or proximal to the nerve, stained tissues similar distances away from the nerve. [13]
DISCUSSION The fundamental principle of clinical importance is the variation of stimulus current (at a fixed stimulus duration) with distance from the nerve. As the stimulating tip moves away from the nerve, the relationship between stimulus intensity and distance from the nerve is governed TABLE 17-3 -- CALCULATED VALUES FOR CURRENT REQUIRED TO STIMULATE NERVE AT VARIOUS DISTANCES FROM THE NERVE Distance On Nerve
0.5 cm
1 cm
2 cm
Stimulus
0.1
2.5
10
40
Current
0.5
12.5
50
200
In milliamperes
1.0
25.0
100
400
by Coulomb’s law, E=K(Q/r2 ). E is the current required, K is a constant, Q is the minimal current, and r is the distance. The presence of the inverse square means that a very high stimulus is needed once the tip is some distance away from the nerve. Table 17–3 shows some calculated figures to demonstrate the magnitude of the rise. This can be of clinical concern, because stimulation of the nerve from more than 2 cm can require currents in the region of 50 mA (depending on the pulse width) and currents smaller than this have been reported to cause ventricular fibrillation when applied directly to the heart (so-called microshock); however, if appropriate care is taken in any patient who may have intracardiac electrodes (e.g., pacemaker, Swan-Ganz catheter), currents of these magnitudes are perfectly safe in most individuals. They do become painful, however, presumably because of direct stimulation of nerve endings in the tissues being penetrated and are not recommended for this reason. [14]
PROGNOSTIC VALUE OF MUSCLE TWITCH FOR BLOCK SUCCESS During electrical stimulation to locate nerves, it was observed by Montgomery and others that after good muscle contraction was obtained, 2 mL of local anesthetic would diminish or abolish that muscle contraction within 10 seconds in successful blocks ( Fig. 17–3 ). Conversely, if the muscle contraction did not diminish within 10 seconds, the block usually was patchy and inadequate ( Fig. 17–4 ). It appeared that a 2-mL test dose would indicate the success of the block if muscle twitch was abolished immediately. The mechanism was intriguing because twitch abolition was too rapid for the nerve to be blocked by the injected local anesthetic. [13]
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Figure 17-2 The twitch height recorded during infraclavicular block as the needle tip approaches the nerve.(From Raj PP, Rosenblatt R, Montgomery SJ: Use of the nerve stimulator for peripheral blocks. Reg Anesth 5:14–21, 1980.)
Figure 17-3 The arrow shows the effect of 2 mL of lidocaine, 2%, to the twitch height. This indicates that the needle tip is close to the nerve.(From Raj PP, Rosenblatt R, Montgomery SJ: Use of the nerve stimulator for peripheral blocks. Reg Anesth 5:14–21, 1980.)
DETERMINATION OF THE MECHANISM OF ABOLITION OF TWITCH HEIGHT Raj and associates performed several experiments to clarify this mechanism. In the first experiment, the needle tip was placed on the femoral nerve by the PNS. When the twitch height was maximal at the lowest voltage, 2 mL of air were injected and the twitch was recorded. A decrease in the amplitude of the twitch height occurred within 2 seconds ( Fig. 17–5 ). With continued impulses at 1-second intervals, the twitch height reappeared in 10 seconds. Similar abolition occurred with 2 mL of saline (see Fig. 17–5 A), and the twitch started to reappear at 15 seconds. With 1 mL of 2% lidocaine (Xylocaine), not only did the twitch disappear within 1 to 2 seconds, but it did not reappear for 1½ minutes and then only with a 50-fold increase in the voltage (see Fig. 17–5 B). [13]
These results indicate that the disappearance of twitch with 2 mL of air, saline, or local anesthetic is caused by physical displacement of the nerve via the pressure executed during injection. This removes the nerve from the influence of voltage at the tip of the needle. The reappearance of the amplitude within 30 seconds after air or saline is introduced suggests that this pressure is dissipated very quickly and that the influence of the voltage at the tip of the needle is regained. Delayed reappearance, with the increased voltage necessary supplied with local anesthetic,
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Figure 17-4 The arrow shows that 2 mL of lidocaline, 2%, does not have any effect on the twitch height, which indicates that the needle tip is not close to the nerve.(From Raj PP, Rosenblatt R, Montgomery SJ: Use of the nerve stimulator for peripheral blocks. Reg Anesth 5:14–21; 1980.)
suggests that not only is there physical displacement but that the 2 mL of local anesthetic does, in fact, anesthetize the neural surface.
ELECTRICAL CHARACTERISTICS OF PERIPHERAL NERVE STIMULATORS CURRENTLY AVAILABLE IN CLINICAL PRACTICE [15]
To determine which electrical characteristics of the PNS contributed to the localization of a peripheral nerve, the electrical properties of eight commercially available peripheral nerve stimulators and a Grass S-88 stimulator were measured. The PNS was then used in the laboratory to locate a peripheral nerve in an anesthetized cat. The controlled environment in the laboratory allowed each PNS to be used under nearly identical conditions.
Experiment I: Determination of Output Characteristics of Peripheral Nerve Stimulators To determine the shape and duration of the stimulating pulse, the linearity of the output, and the change in the output in response to a change in load resistance, the peripheral nerve stimulators were connected to a variable resistance and an oscilloscope (Tektronix Type 564B) as shown in Figure 17–6 . The shape, duration, and amplitude of the output were measured on the oscilloscope screen. The linearity of the output was determined by correlating the current output of the PNS with the dial (or slide) setting of the same PNS. The change in the output of the PNS as the load resistance was changed from 1000 Ω to 2000 Ω was monitored on the oscilloscope. The current output of the peripheral nerve stimulator was calculated from the relation, V=I×R. V is the voltage output as measured on the oscilloscope and R is the known load resistance. The known resistance in this experiment is approximately that encountered when the PNS is connected to a patient. Result. The effect of increasing the load resistance on the current and voltage output was determined first. For a twofold increase in resistance, the current delivered by the PNS dropped an average of 10% (range: 1%–24%). Next, the linearity of the peripheral nerve stimulators was determined. A completely linear PNS delivered X5 of its maximal output when the dial was set at x%. As can be seen from Figure 17–7 , some PNSs deviated greatly from being linear, whereas others were quite linear. Finally, all but one of the PNSs studied delivered a square wave of duration between 200 µsec and 1000 µsec. The exception delivered a triangular pulse.
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Figure 17-5 A, Effect of 2 mL of air on amplitude of the compound potential. B, Effect of 2 mL of saline on the median nerve in infraclavicular block. C, Effect of 1 mL of lidocaine on the same nerve. (From Raj PP, Rosenblatt R, Montgomery SJ: Use of the nerve stimulator for peripheral blocks. Reg Anesth 5:14–21, 1980.)
Experiment II To determine how the different electrical properties of the PNS affected the localization of a peripheral nerve, the peripheral nerve stimulators were used in the laboratory to locate a peripheral nerve in an anesthetized cat. Six cats of either sex weighing between 2.5 kg and 3.5 kg were used for this study. The cats were obtained from Kaiser Lake, St. Paris, Ohio, and housed in the Department of Laboratory Animal Medicine until used. On the day of the experiment, the cat was given 100 mg of ketamine and 0.1 mg of atropine intramuscularly. After the appropriate areas for surgery were shared, the cat was intubated and placed on a respirator. Anesthesia was maintained with 0.2% to 0.5% methoxyflurane, 67% N2 O, and the balance of O2 . Venous and arterial lines were established in the external jugular vein and carotid artery, respectively. Blood pressure and heart rate were monitored continuously. Blood gases were taken every 60 minutes to ensure that normal acid-base status was maintained. To monitor evoked muscle twitches produced by the PNS, the sciatic nerve–tibialis muscle preparation of the cat was chosen as a model. The superficial tendons of the tibialis muscle on the dorsal surface of the right hind paw were exposed. After clamping the quadriceps muscle and the paw to immobilize the leg, the most lateral tendon
Figure 17-6 Schematic diagram of the apparatus used in experiment I. The oscilloscope (left), variable resistance (center), and the peripheral nerve stimulator (right) are connected in parallel. (From Ford D, Pither C, Raj P: The use of peripheral nerve stimulators for regional anesthesia. A review of experimental characteristics, technique, and clinical applications. Reg Anesth 9:73–77, 1984.)
was attached to an F-1000 Microdisplacement Muograph, transducer (Norco Biosystems, Inc.). Then the remaining tendons and the Achilles tendon were severed. Finally, the force transducer was connected to a strip recorder (Physiography, Model DMP-4B) to record the evoked muscle twitches ( Fig. 17–8 ). The needle (6.3 cm×22 gauge [G] spinal needle, uninsulated) was mounted in a one-dimensional manipulator and aligned to approach the sciatic nerve through the hamstring muscle. The needle was advanced through the
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Figure 17-7 Linearity of the peripheral nerve stimulators. The percentage of output delivered at a given setting was plotted along the Y axis, and the percentage of dial setting was plotted along the X axis. A linear response is shown by a straight line starting at the origin and going to the (100%) point.(From Ford D, Pither C, Raj P: Electrical characteristics of peripheral nerve stimulators: Implications for nerve localization. Reg Anesth 9:73–75, 1984.)
Figure 17-8 Schematic diagram of the apparatus used in experiment II. The cathode of the peripheral nerve stimulator was attached to the needle (arrow) and the anode to the cat through a 1000 Ω resistance. To measure the current delivered by the peripheral nerve stimulator, the voltage drop across the 1000 Ω resistance was measured on the oscilloscope and related to current by: Current = V/1000. To measure the voltage drop delivered by the peripheral nerve stimulator, the line labeled “Current” was disconnected and connected as shown by the dashed line labeled “Voltage.” The tibialis muscle was attached to a force transducer and the muscle twitches recorded on a strip recorder. (From Ford D, Pither C, Raj P: Electrical characteristics of peripheral nerve stimulators: Implications for nerve localization. Reg Anesth 9: 73–75, 1984.)
skin and each PNS was connected in sequence to the cat and the needle. The voltage output, current output, and dial setting, along with the muscle twitch strength, were recorded. The needle was advanced in 0.5-cm increments and the recording repeated until the femur was reached or the needle was clearly past the nerve. Next, the needle was moved in and out until the position was found where the minimum current caused a muscle twitch. This maneuver simulated the clinical situation of manipulating the needle to find the closest approach to the nerve. At the conclusion of this experiment, with the needle 1 to 2 cm beyond the sciatic nerve, a cutdown to the nerve revealed how closely the needle approached the nerve ( Table 17–4 ). By withdrawing the needle until the tip was again even with the nerve, the depth of the nerve was determined. A repeat series of measurements was made 2 to 3 cm distally on the nerve.
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Result. In rotating the PNS through this series of experiments, five favorable electrical characteristics were discerned. They were (1) a linear output, (2) high and low output ranges, (3) a short stimulation pulse, (4) clearly TABLE 17-4 -- POLARITY OF STIMULATION Anodal vs cathodal current required to stimulate peripheral nerve × 4.57 × 4.3 Data from Ford DJ, Pither CE, Raj PP: Electrical characteristics of periph eral nerve stimulators: Implications for nerve localization. Reg Anesth 9:73–77, 1984; and from BeMent SL, Ranck JB Jr: A quantitative study of electrical stimulation of central myelinated fibers. Exp Neurol 24:147–170, 1969.
marked polarity, and (5) constant current output. In addition, three design features that also contributed to finding a peripheral nerve were noted. These were a large, easily turned dial; a digital output meter; and a battery check.
Experiment III: Strength Duration Curve Because all of the commercial PNSs examined used a stimulus pulse width between 2000 microseconds and 1000 microseconds, it was not possible to determine the effect of a shorter pulse (3 days’ duration), reflecting inhibition of all segments of bowel, especially small bowel activity. A delay in recovery of gastrointestinal function prevents initiation of enteral feeding and may increase neuroendocrine stress response, incidence of septic complications, and decrease of wound healing. [194]
[195] [196] [197]
Postoperative ileus is the result of inhibitory input from central and systemic sources, spinal reflexes, and local factors. The contribution of central and systemic factors to postoperative ileus is not clear. Postoperative release of vasopressin (either through surgical stress or induced by opioid use) may inhibit small bowel contractility, partly by [194]
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decreasing mesenteric blood flow. Spinal reflex inhibition is related to activation of nociceptive afferent and sympathetic efferent nerves. Postoperative pain (nociceptive afferent) initiates spinal reflex inhibition of gastrointestinal motility. In addition, increased sympathetic efferent stimulation (neuroendocrine stress response, inadequate analgesia) after surgery diminishes organized gastrointestinal activity. Local factors contributing to postoperative ileus include absence of normal myoelectric activity resulting from membrane hyperpolarization. Normal gastrointestinal transit is dependent on a characteristic pattern of oscillations (with occasional contractile spike-wave potentials) that proceeds distally in an organized manner as current passes from one cell to the next by ion exchange through intercellular gap junctions. Smooth muscle in the colon lacks intercellular gap junctions and is dependent on external neuronal systems for contraction. Thus, colonic activity may be most susceptible to postoperative inhibition. [194] [198] [199]
[200]
[194]
PHYSIOLOGIC EFFECTS OF REGIONAL ANESTHESIA AND ANALGESIA
Epidural analgesia is the most common regional anesthetic modality for postoperative analgesia after abdominal surgery. By blocking nociceptive afferent nerves, TEA with local anesthetics prevents activation of spinal reflex inhibition of gastrointestinal motility. TEA with local anesthetics blocks sympathetic efferent fibers and provides a predominantly parasympathetic tone (emanating from vagus and pelvic nerves), thus favoring return of gastrointestinal propulsive activity. Increased gastrointestinal blood flow as a result of the sympathectomy from There TEA with local anesthetics also facilitates gastrointestinal motility and promotes anastomotic healing. is no substantial evidence that return of gastrointestinal motility during epidural analgesia results in anastomotic dehiscence. [201] [202] [203]
[203] [204]
In addition, to prevent reflex inhibition of gastrointestinal motility, local anesthetics administered through epidural catheters may be systemically absorbed. Systemic administration of local anesthetics has been shown to facilitate the Mechanisms for facilitating the return of bowel function by return of gastrointestinal motility after surgery. systemic administration of local anesthetics include an increase in intestinal smooth muscle excitation and decrease in amount of opioids used. Systemic absorption of local anesthetics may also prevent reflex inhibition of gastrointestinal motility by blocking nociceptive afferent input (peritoneal irritation). [205] [206]
[206]
[206]
Other than local anesthetics, opioids can be administered through epidural catheters to control postoperative pain after abdominal surgery. Administration of both systemic and neuraxial opioids inhibits gastrointestinal motility and return of bowel function. Epidurally administered opioids compared with local anesthetics are not as effective in facilitating return of bowel function because epidural opioids are not able to block either the afferent or efferent loop of the spinal reflex inhibiting gastrointestinal motility. Epidural opioids may not delay return of gastrointestinal motility to the same degree as systemic opioids. Systemic but not epidural opioids produce inhibitory myoelectric activity in the colon. Furthermore, peripheral mechanisms may be relatively more important than central mechanisms in inhibition of gastrointestinal motility because opioid receptors are found throughout the gastrointestinal system. [31]
[207]
[208]
EFFICACY OF NEURAXIAL BLOCK
TEA with local anesthetics promotes earlier return of gastrointestinal function after abdominal surgery. An overwhelming majority of studies investigating patients who received TEA with local anesthetics demonstrate the accelerated return of postoperative gastrointestinal function (compared with those who received systemic opioids) as demonstrated by several markers of gastrointestinal function, such as passage of flatus, first bowel movement, barium contrast, and myoelectric activity. Compared with systemic opioids, TEA with local anesthetics also provides superior postoperative analgesia, including pain relief with activity, which may be important in facilitating Patients receiving TEA with local anesthetics have postoperative rehabilitation after abdominal surgery. Epidural analgesia should be continued for earlier fulfillment of discharge criteria and a shorter hospital stays. at least 48 to 72 hours postoperatively to provide any benefit in recovery of gastrointestinal motility. [209] [210]
[1]
[178] [209] [211]
[209] [212]
[1]
Epidural administration of opioids may not provide earlier return of bowel function compared with TEA with local anesthetics. Few studies have compared the effect of an epidural with the systemic administration of opioids on Some studies have demonstrated an earlier return of return of postoperative gastrointestinal function. bowel function with use of epidural opioids than with systemic opioids. However, not all studies show a benefit in the return of gastrointestinal function or time until fulfillment of discharge criteria with epidural opioids compared with systemic administration of opioids. [2] [164] [209] [213] [214]
[164] [213]
[2] [209]
Thus, by providing superior analgesia, preventing the inhibitory spinal reflex, and decreasing the amount of opioids used, TEA with local anesthetics facilitates the return of gastrointestinal motility after abdominal surgery. TEA with local anesthetics is superior to epidural and systemic opioids in restoring postoperative bowel function. Compared
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with systemic opioids, epidural opioids may be associated with a lesser degree of delay in gastrointestinal motility; however, the role of epidural opioids in this situation is not clear. Cognitive Function POSTOPERATIVE PATHOPHYSIOLOGY
Postoperatively, patients may exhibit alterations in several aspects of general mental status, such as cognitive function, and they may experience confusion, delirium, or dementia. Although mental function generally reaches a nadir between the second and fifth postoperative days, with recovery to preoperative levels by 1 week after surgery, Along with physical delays in recovery of mental function are associated with poor patient outcomes. parameters, cognitive functional measures are strong predictors of long-term mortality after hospitalization. Delirium is associated with poor outcomes, increased mortality, and longer hospital stays. [215] [216]
[217]
[218] [219]
Postoperative cognitive dysfunction, as measured by neuropsychological tests, may be present in approximately 26% of elderly patients 1 week after major noncardiac surgery. In addition, long-term cognitive dysfunction (3 months postsurgery) may occur in about 10% of patients. Risk factors for the development of early postoperative dysfunction include advanced age and prolonged anesthesia, postoperative infections, and respiratory complications; however, only advanced age is a risk factor for development of late postoperative dysfunction. Interestingly, hypoxemia and hypotension were not significant risk factors (in one large-scale study) for development of either early or late postoperative cognitive dysfunction. Some data suggest no difference in postoperative mental deterioration between elderly and young patients. In addition, higher levels of pain predict a decrease in postoperative mental status. [220]
[220]
[220]
[220]
[221]
[222]
Postoperative delirium may cost Medicare approximately $2 billion per year. Independent correlates for development of postoperative delirium after elective noncardiac surgery include age (>70 years); poor preoperative cognitive and functional status; marked abnormalities in preoperative sodium, potassium, or glucose levels; and thoracic or aortic aneurysm procedures. In addition, perioperative use of psychoactive medications (anticholinergic drugs, meperidine, benzodiazepines) is significantly associated with development of postoperative delirium. Higher levels of postoperative pain at rest are also associated with development of delirium. [223]
[224]
[225] [226] [227]
[228]
The etiology of both postoperative cognitive dysfunction and delirium is unclear. Many factors, including hypotension, hypoxia, and hyperventilation, are believed to contribute to development of postoperative cognitive dysfunction and delirium. CNS catecholamine and cholinergic transmission may also play a role in disruption of postoperative mental function. The effect of anesthetic agents per se on postoperative mental status is also uncertain. [229]
EFFICACY OF REGIONAL ANESTHESIA AND ANALGESIA
Unlike its effect on other organ systems, regional anesthesia does not exert any direct effects on postoperative mental function. Several prospective, randomized studies have compared efficacy of general anesthesia with that of regional anesthesia regarding postoperative mental function. Most studies do not demonstrate any advantage of Only a few regional anesthesia over general anesthesia in preserving postoperative mental function. Although many studies support a beneficial effect of regional anesthesia on postoperative mental function. studies do not demonstrate a clear benefit of regional anesthesia in decreasing incidence of postoperative cognitive deficits or delirium, there are concerns relating to method in evaluation of postoperative mental function. [215] [227] [230] [231] [232] [233] [234] [235]
[226] [229]
One area that may provide potentially beneficial effects on postoperative mental function is use of postoperative analgesia. The effect of postoperative analgesia on mental function has not been investigated. In general, postoperative regional analgesia with local anesthetics provides superior analgesia at rest and with activity compared with systemic opioids. Because higher levels of postoperative pain are associated with postoperative cognitive dysfunction and delirium, using postoperative regional analgesia with local anesthetics may theoretically preserve postoperative mental function. By using postoperative regional analgesia, patients may also receive fewer medications (e.g., meperidine) that may be associated with development of perioperative mental dysfunction. [1]
Because there are many potential etiologies for postoperative decline in mental function, it is unlikely that regional anesthesia and analgesia alone can directly diminish incidence of postoperative alterations in mental function. However, regional anesthesia may alleviate inadequate postoperative pain control, which may contribute to deterioration of postoperative mental function, thus indirectly improving postoperative mental function. At this time, definitive studies comparing efficacy of general anesthesia with regional anesthesia and analgesia on postoperative
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mental function are lacking, but the majority of current studies do not demonstrate a beneficial effect of regional anesthesia on preservation of postoperative mental function. Economic Outcome CONSIDERATIONS IN ECONOMIC OUTCOME ANALYSIS
With escalating pressure on healthcare providers to control costs, there are an increasing number of articles incorporating some type of economic analysis comparing the effects of various treatments or programs. In general, evaluating validity of such studies can be difficult. Regional anesthesia, and postoperative analgesia may provide many economic benefits; however, there are presently several obstacles to determining the economic impact of regional anesthesia and analgesia. The first problem is lack of appropriate, large-scale, controlled trials to definitively determine whether use of regional anesthesia and postoperative analgesia will decrease morbidity and mortality or facilitate patient recovery after surgery and thus improve economic outcomes (see the discussion on current outcome studies). In addition, economic analysis may not even be considered in some studies. [236]
[237]
The second problem in evaluating the economic impact of regional anesthesia and analgesia is the divergence and inconsistency of economic outcome analysis. There are several dimensions of economic analysis, which include the type of analysis (cost-effectiveness, cost-benefit, cost-utility), the types of costs and benefits (direct and indirect, medical and nonmedical), and the perspective for analysis (patient, provider, payer, societal). The economic impact of regional anesthesia and analgesia may be altered depending on the type of analysis used. Furthermore, current economic outcome measurements may not be accurate or applicable. For instance, a decrease in operative or recovery time may not automatically lead to an increase in actual savings because discharge from the recovery room and hospital are typically based on actual discharge times (not when patients are “discharge ready”), and decreases in discharge times may not necessarily allow for reductions in staffing, which account for a significant percentage of recovery room costs. [238]
[239] [240]
Measurement of cost in a study may not be appropriately defined, calculated, or complete, which, consequently, may result in inaccurate conclusions. In general, the cost of a specific service reflects resources used to provide that service. Direct costs of regional anesthesia and analgesia include operational expenditures required for delivery of care, including equipment, catheters, drugs, and personnel. Indirect costs, which include lost income, out-of-hospital expenditures, and decreased productivity, may be increased by complications or decreased by benefits from regional anesthesia and analgesia. Although the (direct) cost of regional analgesia may seem higher than that of systemic administration of traditional analgesic agents, regional analgesia may actually decrease overall (indirect) costs, in part by decreasing incidence of complications or length of stay. Thus, obtaining comprehensive measurements of costs and determining their applicability to different centers are complex tasks. [241]
[238]
EFFICACY OF REGIONAL ANESTHESIA AND ANALGESIA
Despite the difficulty in economic analysis, there is some evidence that regional anesthesia and postoperative analgesia may have a favorable economic impact. Use of intraoperative regional anesthesia is associated with decreased length of stay after both outpatient and inpatient surgery. Regional anesthesia for shoulder surgery decreases total surgical and nonsurgical intraoperative time and length of stay in the recovery room. Adequate postoperative pain control with regional anesthesia may allow certain procedures, such as arthroscopic knee and shoulder reconstruction surgery, which have traditionally required short-stay hospitalizations, to be consistently Inadequate control of postoperative pain after ambulatory surgery may performed on an outpatient basis. necessitate an overnight hospital admission or readmission after discharge. [242]
[243] [244]
[242] [243] [245] [246]
Postoperative epidural analgesia has also been associated with a decreased length of stay in the intensive care unit (ICU) and shorter hospital stays. A randomized trial of patients undergoing colonic surgery revealed that patients receiving postoperative epidural analgesia with bupivacaine fulfilled discharge criteria significantly faster than those receiving systemic opioids. Another prospective study demonstrated that compared with those who received IV patientcontrolled analgesia morphine, patients who received postoperative epidural analgesia had shorter lengths of stay in both the ICU and the hospital after thoracic or abdominal cancer surgery. Retrospective data also confirms that use of postoperative epidural analgesia has been associated with shorter lengths of intensive care unit and hospital stays. [209]
[247]
[248] [249] [250] [251] [252]
Regional anesthesia and postoperative analgesia have also been shown to decrease the incidence of complications. Epidural analgesia is associated with a decrease in postoperative pulmonary complications. Attenuation of the postoperative hypercoagulable state by regional anesthesia decreases incidence of graft failures after vascular surgery. Use of regional anesthesia is associated with a lower incidence of deep venous thrombosis after [5]
[3] [80]
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orthopedic and genitourinary surgery. Regional anesthesia is associated with a lower incidence of postoperative Thus, by decreasing the pulmonary complications in high-risk patients who have undergone abdominal surgery. length of stay and incidence of complications, use of regional anesthesia and postoperative analgesia potentially may result in beneficial economic outcomes. [88] [92]
[96] [164]
Nontraditional Outcome Measurements CONSIDERATIONS IN NONTRADITIONAL OUTCOME ANALYSIS
Healthcare providers, especially those who interact with patients on a more acute basis, are generally more comfortable with traditional outcome measurements (mortality and morbidity) and may be unfamiliar with nontraditional outcome measurements, such as health-related quality of life (HRQL) or patient satisfaction. Popular use of nontraditional outcome measurements is hindered by lack of information with regard to their value and benefits in clinical trials, applicability of measurements to daily clinical situations, and the perception of measurements as being “soft” or “unscientific.” In addition, studies may not incorporate appropriate or standardized instruments in measuring nontraditional outcome measurements. There has been little research on conceptualizing models that elucidate relationships between clinical variables and HRQL measurements and determine the effect of clinical interventions on HRQL. Thus, it may be difficult for clinicians to use nontraditional outcome data to effect appropriate therapeutic interventions. [253]
[254] [255]
[255]
Use of patient satisfaction has become an important measure for evaluating quality of medical care. Despite an increasing amount of research evaluating measurement of patient satisfaction, many problems, such as lack of standardized approaches, comparative studies, consensus, or accepted models of patient satisfaction, create uncertainty in the value of patient satisfaction as a measure of quality patient care. Assessment of patient satisfaction as a clinical end point and indication of quality of care have also been hindered by lack of discrimination, reliability, and validity of current measurements. Results obtained from questionnaires created without proper psychometric construction may not truly reflect patient satisfaction with the aspect of care being examined. [256]
[256]
[254]
Both HRQL measurements and patient satisfaction are important components of patient outcomes. Many concerns with method remain, including standardization and refinement of current measurements. Acceptance of nontraditional outcome measurements by clinicians may be difficult, partly because of concerns about validity and applicability of these measurements. However, nontraditional outcome measurements provide another opportunity for evaluating potential differences in patient outcome between general and regional anesthesia. EFFICACY OF REGIONAL ANESTHESIA AND ANALGESIA
The efficacy of regional anesthesia and postoperative analgesia on nontraditional outcome measurements is unclear because data in this area are lacking. HRQL measurements have not been used extensively in evaluation of regional anesthesia and postoperative analgesia. Some data suggest that use of regional anesthesia and postoperative analgesia in the setting of intensive rehabilitation (early nutrition and mobilization) will facilitate earlier recovery of HRQL measurements to preoperative levels compared with those receiving general anesthesia with postoperative patient-controlled morphine. [257]
Measurements of HRQL in this study were not taken in the immediate postoperative period (within 1 week after surgery) but at 3 and 6 weeks after surgery. Difficulties associated with use of HRQL in the immediate postoperative setting include the nonspecific nature of certain HRQL measurements (generic vs. condition-specific measures) and the possibility that the expected postsurgical decrease in general functional status will overshadow Many issues will need to be any observable HRQL differences between postoperative analgesic treatments. resolved before a meaningful comparison of the effect of general anesthesia with that of regional anesthesia on HRQL measurements can be made. Until that time, no definitive conclusions can be formed regarding the effect of regional anesthesia and analgesia on HRQL measurements. [258] [259]
Despite the limitations of current studies with measurement of patient satisfaction, some data suggest that regional anesthesia and postoperative analgesia may have a favorable impact on patient satisfaction. Twenty-four of 25 patients who received intraoperative regional anesthesia (interscalene block) and had received general anesthesia for previous shoulder surgery preferred regional anesthesia. In two studies of more than 1800 patients, 78% to 93% of patients stated a willingness to undergo a repeat block. Although these studies seem to indicate a favorable association between regional anesthesia and patient satisfaction, many factors influence patient satisfaction and consent to undergo regional anesthesia. [260]
[261] [262]
[263]
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By providing superior analgesia at rest and with activity, postoperative regional analgesia may also potentially affect patient satisfaction as severity of postoperative pain influences the degree of patient satisfaction. Lower postoperative pain ratings are associated with higher levels of patient satisfaction. Higher levels of postoperative pain also interfere with activity and sleep, which may affect other HRQL measurements. However, it may be difficult to assess patient satisfaction with postoperative pain management per se because there is always the question of whether patients are able to differentiate satisfaction with pain control from other aspects of medical care. [264] [265]
[264]
[266]
Although nontraditional outcome measurements have become increasingly popular in evaluating quality of patient care, few data exist on the application of nontraditional measurements, such as HRQL and patient satisfaction, in assessing the effect of regional anesthesia and analgesia on patient outcomes. Until further properly conducted studies are performed, no conclusions can be drawn about efficacy of regional anesthesia and analgesia on nontraditional patient outcomes. Efficacy of Postoperative Analgesia Use of intraoperative regional anesthesia and postoperative regional analgesia will provide many physiologic benefits that may reduce incidence of complications and, ultimately, improve patient outcomes. However, it may be difficult to differentiate to what extent intraoperative anesthesia or postoperative analgesia contributes to any improvements in patient outcomes. Some processes, such as deep venous thrombosis formation, begin intraoperatively. Other complications, including myocardial ischemia and infarction, may peak in the postoperative period. In most instances, physiologic disturbances begin intraoperatively and continue well into the postoperative period, necessitating use of both intraoperative regional anesthesia and postoperative regional analgesia to maximize any benefits on patient outcomes. Thus, the effect of postoperative regional analgesia per se on patient outcomes is difficult to assess. [267]
[127]
Although superior analgesia provided by postoperative regional analgesia in itself may not be adequate to improve patient outcomes, postoperative regional analgesia may be used as part of a multimodal approach to facilitate patient recovery after surgery. Control of postoperative pain is important in this model because analgesic regimens will facilitate early ambulation, decrease ileus, allow early enteral nutrition, and reduce infectious complications. A multimodal approach to control postoperative pathophysiology and to accelerate rehabilitation in patients undergoing abdominal esophagectomy reduces intensive care unit stay and provides economic benefits. Other studies also demonstrate the value of an integrated approach to facilitate postoperative patient recovery. [178]
[178]
[268]
[237] [269]
Conclusions Regional anesthesia and analgesia provide many physiologic benefits in the perioperative period and may improve patient outcomes. Many organ systems, including coagulation, pulmonary, and gastrointestinal, clearly benefit from perioperative use of regional anesthetic techniques. Probable benefits for the cardiovascular system and stress response may be provided by use of regional anesthesia and analgesia. Data on the effect of regional anesthesia on other outcomes are equivocal (mental status) or insufficient (immune system). There are several concerns related to methods that hinder determination of efficacy of regional anesthesia and analgesia on traditional patient outcomes. Future studies using economic and nontraditional outcome measurements may reveal additional benefits of regional anesthesia and analgesia on patient outcomes.
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267. Sharrock NE, Ranawat CS, Urquhart B, Peterson M: Factors influencing deep vein thrombosis following total hip arthroplasty under epidural anesthesia. Anesth Analg 76:756–771, 1993. 268. Brodner G, Posatzi E, Van Aken H, et al: A multimodal approach to control postoperative pathophysiology and rehabilitation in patients undergoing abdominothoracic esophagectomy. Anesth Analg 86:228–234, 1998. 269. Moinche S, Bulow S, Hesselfeldt P, et al: Convalescence and hospital stay after colonic surgery with balanced analgesia, early oral feeding, and enforced mobilisation. Eur J Surg 161:283–288, 1995.
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Chapter 47 - Trauma CRAIG T. HARTRICK
Each year, tens of millions of Americans suffer serious accidental injuries that result in physiologic compromise, physical disability, and persistent pain. In addition to the obvious personal and social impact on patients and their families, the economic impact secondary to lost productivity and healthcare expenses represents a significant burden to society. The cost of post-traumatic chronic pain alone is conservatively estimated in excess of $85 billion annually. Heightened awareness of the importance of early intervention with effective pain management measures is reflected in both public policy and medical professional guidelines. If morbidity secondary to trauma is to be minimized, guidelines for the treatment of post-traumatic pain must encompass more than the humanitarian concern for analgesic administration. Reduction of stress, restoration of function, and prevention of subsequent complications are all intimately related to post-traumatic analgesia. [1]
[2]
[3] [4]
The role of regional analgesia in the treatment of posttraumatic pain is well established empirically. Best practice recommendations, however, ideally follow critical analysis of multiple prospective, randomized, double-blinded studies designed to examine specific outcomes. The unpredictable nature of nonoperative trauma, with variable degrees of physiologic compromise and stimulus intensity, presents obvious challenges to well-controlled study. Ongoing processes secondary to multiple concurrent injuries further confound analysis. Considerable evidence for improved patient outcomes when regional analgesia is used post-traumatically can readily be inferred from numerous postoperative studies described elsewhere in this text. Outside the operating room, evidence-based outcome analysis has demonstrated the efficacy of regional anesthesia in reducing morbidity in patients after chest wall trauma and in the treatment of patients with post-traumatic musculoskeletal and neuropathic pain. Additional nonoperative evidence for the effectiveness of neural blockade as a means of improving physiologic function, reducing chronic pain, and preventing the subsequent development of chronic pain states in patients after trauma are also reviewed. [5]
Reducing the Stress Response After Trauma The response to trauma involves initiation of intertwined neural and humoral cascades. Afferent neural barrage leading to central sensitization and acting in concert with post-traumatic cytokine elaboration alters physiologic function and leads to neural plasticity. Neuroinflammation with neuroimmune cell activation in the periphery after neural trauma provides another source of ongoing afferent activity, further adding to the central sensitization and the development of persistent pain. Interruption of these cascades can prevent further escalation of the inflammatory response, thus interrupting this positive feedback cycle. [6]
Moller and colleagues demonstrated that preoperative institution of epidural blockade to T4, including adrenal and hepatic innervation, prevented the normal postoperative increase in cortisol and glucose after hysterectomy. Although initial increases were observed when epidural anesthesia was initiated after the incision, no further increases in cortisol or glucose were observed once afferent blockade was established. Although resting endocrinemetabolic activity was not reestablished, a major portion of the stress response was indeed inhibited by posttraumatic conduction blockade. Brandt and associates found that if postoperative epidural block was maintained for just 24 hours, there was a sustained decrease in the negative nitrogen balance over the 4 days of the study period. [7]
[8]
The observation that sympathetic blockade alters immune cell activity clinically is not unexpected, because it is known from experimentation that sympathetic efferents play a role in inflammation. Furthermore, circulating monocytes are recruited in wallerian degeneration associated with neuropathic hyperalgesia. Experimental animal models of mononeuropathy exhibiting neuropathic allodynia develop significant upregulation of TNF-α and IL1-β production from circulating monocytes. Analogous findings in patients with complex regional pain syndrome (CRPS) are currently the subject of investigation. Moriwaki and coworkers suggested that clinical neuropathic pain has two distinct components: a neuropathic response characterized by mechanical allodynia and an inflammatory response with characteristic rubor, calor, tumor, and loss of function that is responsive to corticosteroids. [9]
[10]
[11]
[12]
[13]
[14]
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Respiratory Function After Trauma Oxygenation can be impaired in the trauma patient for a variety of reasons. Pulmonary injury as a result of direct penetrating wounds, parenchymal contusions, aspiration of gastric contents, or parenchymal compression as a result of hemothorax or pneumothorax is frequent. Hypoventilation and atelectasis due to reduced respiratory excursion can result from pain after upper abdominal and thoracic injury or from anatomic disruption of chest wall mechanics with flail chestsecondary to rib or sternal fractures. The severity ofpain from fractured ribs often necessitates tracheal intubation and mechanical ventilation for respiratory insufficiency. Systemic opiate analgesia is problematic because of its respiratory-depressant and coughsuppressant effects. Regional blockade provides excellent analgesia, leaving the patient awake and cooperative, and thus promoting cough, deep breathing, and improved pulmonary toilet. Johnson studied forced vital capacity (FVC) and forced expiratory volume in 1 second (FEV1 ) in patients who had undergone elective thoracic and abdominal procedures. On the first postoperative day, there were reported reductions in preoperative pulmonary function of 75% for those with thoracic incisions, 68% for those with xiphoid to pubic abdominal incisions, 61% for those with paramedian upper abdominal incisions, 53% for those with subcostal incisions, and 38% for those with midline lower abdominal incisions. Postanesthetic respiratory failure was most prominent when surgical insults were complicated by preexisting chronic obstructive pulmonary disease. Blunt chest trauma that causes rib fractures in elderly patients results in twice the morbidity and mortality experienced by younger patients when epidural analgesia is not employed. Pain relief in these patients is often critical to the restoration of pulmonary function, prevention of further deterioration, and weaning from mechanical ventilatory support. [15]
[16]
Intercostal blockade, including all of the rib fracture levels as well as one intercostal nerve above and one below the site of injury, has long been used in these situations. However, multiple levels are frequently involved, necessitating multiple injection sites. Intercostal blocks can be particularly difficult at the uppermost thoracic levels, where paravertebral blocks may be preferable. Furthermore, intercostal blocks must be repeated frequently, even when long-acting local anesthetics are selected. There is also a risk of pneumothorax in patients who may already be in a state of respiratory compromise. However, it is possible to insert a catheter percutaneously into the intercostal space When a minimal number of contiguous ribs and, by injecting a large volume, block several adjacent segments. are involved unilaterally, this approach lends itself to continuous local anesthetic infusion. [17] [18]
Intrapleural administration of local anesthetic via a percutaneously placed catheter provides unilateral thoracic dermatomal analgesia, which is ideally suited to patients with multiple rib fractures. Although the presence of thoracostomy tubes does not preclude use of this technique (the chest tubes can be used to deliver the local anesthetic), it works best in situations in which no such drains are required, because the anesthetic spread is dependent on apposition of the parietal and visceral pleura. [19]
[20]
Thoracic epidural analgesia with local anesthetic, narcotic, or both, can improve diminished compliance, increase vital capacity and functional residual capacity, and decrease high bronchial resistance in these high-risk patients with multiple rib fractures. Use of epidural analgesia has led to a more aggressive approach to the treatment of such fractures, based on the recognition that the problem is primarily a functional rather than an anatomic derangement. [21]
[22] [23]
Regional Anesthesia and Pulmonary Function After Trauma Although Spence demonstrated that nerve block with intercostal or epidural techniques does not affect the reduction of functional residual capacity, hypoxemia, or decreased ventilation, regional block does decrease the retention of secretions, preserve ciliary activity, and make the cough more effective through a reduction in pain. Bromage and colleagues reported improved FEV1 postoperatively, with segmental analgesia produced by epidural narcotics. Benhamou and associates subsequently demonstrated that intravenous morphine after upper abdominal surgery in high-risk patients with respiratory disease was unable to alter any objective pulmonary function, whereas epidural morphine or epidural lidocaine was able to partially restore FVC and FEV1 to preoperative levels. [24]
[25]
[26]
Rybro and coworkers compared morphine administration on demand after upper abdominal surgery between patients who received medication via an intramuscular (IM) or epidural route. The epidural morphine group demonstrated significantly reduced radiographic pulmonary changes and significantly higher PaO2 values, with a slower rise in alveolar-arterial oxygen gradient. Rawal and colleagues compared postoperative pain relief with IM narcotic, bupivacaine intercostal block, and single-bolus epidural morphine and found that postoperative PaO2 and PaCO2 values reflected changes in peak expiratory flow rate. The greatest reductions in peak expiratory flow occurred after IM drug administration, and the least occurred after epidural drug administration. Mankikian and associates [27]
[28]
[29]
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further described improved diaphragmatic function after thoracic epidural block with local anesthetic in patients with upper abdominal wounds. Prospective, randomized studies comparing intravenous opioid administration with epidural analgesia after chest wall trauma have demonstrated a lower incidence of tracheostomy, less dependence on mechanical ventilation, shorter stays in the intensive care setting, and inhibition of cytokine production associated with post-traumatic complications. These studies are consistent with the postoperative experience in which meta-analysis of randomized controlled trials confirmed the superiority of epidural opioids over systemic opioids in reducing postoperative atelectasis and the superiority of epidural local anesthetics over systemic opioids in improving oxygenation and reducing the incidence of both postoperative pulmonary infection and overall pulmonary complications. These effects were less dramatic with intercostal blockade. In one randomized, crossover trial, intrapleural block has been reported to be as effective as epidural analgesia in the management of multiple rib fractures, with fewer adverse effects, but additional controlled studies are needed comparing the two techniques. The best available evidence strongly supports the use of regional analgesia, especially via the epidural route, after the chest sustains blunt trauma associated with sternal or rib fractures. [30] [31]
[32]
[33]
Acute Pain Management and Functional Outcome The benefits of peripheral nerve block for trauma patients are often not fully exploited, either because of inexperience of available personnel, time constraints, or the fear of masking an evolving compartment syndrome. These techniques deserve increased use because they usually produce total and long-lasting analgesia with minimal side effects. Furthermore, in patients requiring immediate surgical intervention, they obviate the need for general anesthesia and shorten the patient's hospital stay. [34]
Outcome after closed reduction of extremity fractures in the emergency department may be assessed by patient satisfaction with analgesia as well as the quality of the subsequent alignment of the bone. Local anesthetics have long been injected into fracture hematomas to facilitate reduction. The use of intravenous regional (Bier) blocks has been compared with fracture hematoma injection in the treatment of Colles' fracture in both adults and children. A prospective, randomized study has demonstrated less pain during manipulation, improved grip strength at 6 months, improved anatomic alignment, and less remanipulation with intravenous regional blockade. [35]
[36] [37] [38]
Brachial plexus block can be accomplished with use of several different approaches. The choice of technique depends on the site of injury and the ability to position the arm. In general, higher lesions (upper arm injury, shoulder) require analgesia extending into the C5 dermatome; this is best achieved with an interscalene block. Shoulder manipulation for treatment of dislocations is a common use. This technique is also suitable for Colles' fracture because the anatomic snuffbox is sometimes difficult to cover adequately in lower approaches to the brachial plexus. [39]
[40]
Continuous infusion of local anesthetic can be used to prolong neural blockade without the tachyphylaxis seen in patients who undergo repeated bolus techniques. The infusion technique also allows the degree of blockade to be modulated by adjusting the concentration of local anesthetic so as to provide analgesia without complete anesthesia. This is particularly useful after reimplantation procedures or other vascular injuries resulting in vasospasm. The prolonged sympathectomy provided permits improved blood flow to the area of injury. Although the axillary approach can be used, the infraclavicular approach lends itself to continuous infusion because the catheter is easily fixed to the pectoral region. The stability of this location has facilitated the use of home infusion devices for In a prospective, randomized study, the introduction of a patient-controlled component outpatient application. to the brachial plexus catheter system represented a further refinement, which was reported to improve patient satisfaction while lowering the total mass of local anesthetic required. [41]
[42] [43]
[44]
Femoral nerve block can be easily performed and provides excellent analgesia for femoral fractures in both adults and children. The quality of the analgesia depends on the fracture site; excellent relief can be obtained for midshaft fractures, good relief for lower third fractures, and partial relief for upper third fractures. The method is also amenable to continuous infusion. By increasing the volume of injectate, femoral nerve block can be extended cephalad, becoming a lumbar plexus block. The inclusion of the lateral femoral cutaneous and obturator nerves can provide improved analgesia for the upper thigh and the knee joint. Modulation of the density of the block is more difficult with the lower than with the upper extremity because the femoral nerve is quite easily blocked with relatively little local anesthetic. Fascia iliaca compartment block has been suggested to provide reliable analgesia in children. Psoas compartment lumbar plexus block is still another alternative. Although nerve block has not been demonstrated to be of similar value in the management of hip fracture, the best available evidence does suggest that the use of regional anesthesia for repair results in reduced short-term mortality. Catheter techniques lend themselves to continuous infusion and PCEA (patient-controlled epidural analgesia) administration. The addition [45] [46]
[47]
[48]
[49] [50]
[51]
[52]
[53]
[54]
[55]
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of a basal infusion to PCEA reduces unwanted side effects such as excessive numbness, hypotension, and sedation by reducing the need for high infusion rates and rescue boluses. Lumbar epidural infusion is a simple yet effective means of producing continuous analgesia for the lower extremity. As such, this approach enjoys widespread usage in hemodynamically stable patients. More importantly, the degree of neural blockade is readily modified by changing the amount of local anesthetic delivered. Continued tissue swelling after crushing or blunt traumatic extremity injury may predispose the patient to subsequent development of a compartment syndrome. Swelling within the confines of a fascial compartment resulting from hemorrhage or reactive edema formation after trauma can produce pressures sufficient to limit the blood supply to both muscle and nerve contained therein. Untreated, these conditions can, within hours, produce permanent neural damage, resulting in significant pain and functional impairment. However, even with prompt surgical decompression through fasciotomy, significant numbers of patients go on to suffer persistent disability secondary to chronic neuropathy. When an analgesic is selected, consideration should be given to the potential masking of evolving neurologic sequelae of both peripheral and central origins. The pain associated with acute compartment syndrome in the lower extremity typically breaks through properly controlled epidural analgesia. Furthermore, if weakness develops during the infusion, the local anesthetic can be removed to facilitate prompt assessment. [56]
[57] [58] [59]
[60]
The quality of physical rehabilitation after injury may well depend in some cases on the efficacy of analgesic therapy immediately after injury. After total knee arthroplasty, improved analgesia allows the patient more active participation in physical measures, which, in turn, promotes improved surgical outcome. In a randomized, controlled trial, both continuous epidural infusion and continuous femoral block maintained for 72 hours resulted in improved analgesia and range of continuous passive motion compared with intravenous patient-controlled analgesia (PCA) therapy. At postoperative day 7, both regional anesthesia groups exhibited significantly greater mobilization. Furthermore, the duration of rehabilitation required was significantly less for both regional anesthesia groups compared with the PCA group. Similarly, a single injection of sustained-release encapsulated epidural morphine with a duration of less than 48 hours has been associated with improved ambulatory tolerance at 72 hours in a double-blinded, randomized, placebo-controlled trial. [61]
[62]
Regional Analgesia and Prevention of Chronic Post-Traumatic Pain CHRONIC PAIN AFTER TRAUMA
Pain persisting beyond the normal recovery period, and often greatly exceeding what might be anticipated relative to the residual pathology, can be considered chronic post-traumatic pain. Although it is widely assumed that psychological factors become increasingly important as acute pain becomes chronic, it is perhaps less well appreciated that a number of pathophysiologic changes also occur in both central and peripheral pain pathways. Consequently, the response of patients with chronic pain to various therapeutic interventions, including the response Modification of to local anesthetic blockade, often varies from what might be expected in the acute pain setting. the approach to treatment is required. [63] [64]
PREDISPOSITION
It is poorly understood why some patients suffer traumatic injuries that result in chronic pain states, whereas other patients with similar injuries escape this fate. Genetic predisposition to chronic neuropathic pain has been suggested and clinical studies. Premorbid psychological factors have also been implicated in the by both experimental subsequent development of chronic post-traumatic pain and are described elsewhere in this text. Nevertheless, the persistence and intensity of acute pain may be crucial to the initiation of processes leading to chronic pain in and low back susceptible individuals. This impression is based on clinical studies involving phantom pain The intensity of acute pain predicted the severity and persistence of pain in these conditions. pain. Overwhelming afferent barrage from severe pain may lead to the pathophysiologic alterations associated with chronic pain in a manner consistent with the central neuroplasticity previously discussed. [65] [66] [67]
[68]
[69]
[70] [71] [72] [73]
[74] [75] [76]
[77]
Site of injury is certainly an important factor in the development of persistent pain. Sports-related injuries that seem more likely to become chronic pain problems include injuries involving the spine and spinal cord, brachial plexus injuries including thoracic outlet syndrome and other syndromes of neurovascular compression, and certain extremity injuries. Mechanical shoulder and knee injuries producing recurrent joint dislocation, bursitis, posttraumatic arthritis or tendinitis, and myofascial dysfunction involving muscle groups about the joint are particularly common. The risk factors predicting musculoskeletal injuries from overuse, however, relate to poor conditioning, predisposing anatomic characteristics, and intensity of activity, but not to “accident-prone” psychological factors. Patients with extremity injuries are also most likely to develop CRPS type I, which is reflex sympathetic
[78] [79]
[80]
[81] [82] [83]
[84]
[85]
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dystrophy (RSD). The sympathetic dysfunction seen in the upper extremity after shoulder injury has long been referred to as shoulder-hand syndrome. RSD of the knee has been more recently recognized to be a fairly common ailment. [86]
[87]
Similarly, chronic pain conditions seem to occur more commonly after surgical trauma involving the extremities, especially the hands and feet. Patients who have undergone spinal surgery, thoracotomy, extensive facial and scalp surgery, cholecystectomy, and radical mastectomy also seem particularly vulnerable to persistent pain problems.
[88] [89]
Chronic post-traumatic pain in the lower abdomen and groin occurs frequently after appendectomy, inguinal herniorrhaphy, varicocele ligation, obstetric or gynecologic procedures with Pfannenstiel incisions, nephrectomy, femoral thrombectomy, femoral-popliteal bypass grafting, vein stripping, lumbar sympathectomy, and uterine suspension procedures. Visceral, myofascial, neuropathic, and psychogenic factors are contributory. Hitchcock and Alvarez reported a 2% incidence of chronic postincisional scar pain. They found the most common sites (in decreasing order) to be the lower abdomen, thorax, lumbosacral area, head and neck, flank, and palm. Neuroma formation was diagnosed in 43.3% of cases, whereas 23.3% had deafferentation pain. Psychological factors were thought to be important in 33.3% of cases. [90]
[91]
[92]
QUALITY OF ACUTE PAIN MANAGEMENT IN THE PREVENTION OF CHRONIC PAIN
As previously mentioned, there is increasing evidence that the quality of acute pain management is an important factor in the subsequent development or prevention of chronic pain after trauma. Melzack and colleagues reported that patients with persistent postsurgical pain tended to be older individuals for whom lower doses of analgesics had been initially prescribed, resulting in ineffective analgesia in the early postoperative days. Pain persisted for a longer period in these individuals than in individuals for whom early analgesic therapy was more effective. Similarly, unrelieved preoperative pain may trigger central sensitization before surgical intervention, thereby thwarting preemptive analgesic efforts. A “critical time interval” has been proposed during which effective acute pain management prevents delayed pain sequelae. This critical period of plasticity may be, in part, mediated by γaminobutyric acid. Reorganization of central dendritic connections through synaptic clustering can be prevented by preemptive intracellular sodium channel, calcium channel, and N-methy-D-aspartate (NMDA) receptor blockade. [93]
[94]
[95]
[96]
[97]
PREEMPTIVE ANALGESIA
This form of pain relief may be defined generally as an antinociceptive treatment that prevents the establishment of altered central processing (which amplifies subsequent pain states). Although numerous animal studies have documented the theoretical usefulness of pretraumatic application of various analgesics, clinical evidence of this phenomenon in humans has been less convincing. Differences between laboratory and clinical settings should not be dismissed as species-specific variation. The disparity in results may instead be accounted for by differences in terminology, target, and timing. Background
The concept of preemptive analgesia was first described clinically by Crile in 1913. It was noted that regional blockade prevented subsequent development of painful scars after surgery. Seventy years later, Woolf provided experimental evidence for the central component in the post-traumatic hypersensitivity theory originally postulated by Crile. The volumes of studies produced since 1983 have elucidated two related yet distinctly different phenomena with respect to preemptive analgesia. [98]
[99]
In the narrowest sense, preemptive analgesia refers to administration, before a noxious stimulus, of antinociceptive agents that seem to be more effective than the same agents applied post-traumatically. This improved efficacy may manifest itself through either enhanced apparent potency or by increased duration, when the treatment effect seems to outlast the expected duration of direct analgesic effect. These hypotheses are most often tested clinically in the setting of acute postoperative pain. In the recent past, acute and chronic pain were thought to arise from very different pathophysiologic circumstances. It is now apparent, however, that the cascade of events initiated after acute injury may, in some individuals, lead to the development of chronic pain. The prevention of long-term painful postoperative sequelae described by Crile was echoed in the report by Bach and associates, who described the incidence of phantom limb pain reduction 1 year after amputation in association with preoperative epidural analgesia. This finding has since been prospectively studied, and although it had been confirmed by some, it was subsequently refuted by data from a randomized, double-blinded trial. Thus, in the broader sense, preemptive analgesia may also refer to the administration, before [70]
[100] [101]
[102]
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injury, of agents that prevent the ensuing cascade of events that could lead to the development of chronic pain. Understanding the pathophysiology of injury is a key factor in the selection of appropriate target agents for study. Target
High-intensity noxious stimulation alters central processing of afferent neural information. Studies elucidating the mechanisms for this central hypersensitivity have documented a host of neurochemical changes, including enhancement of dorsal horn neuronal activity after repetitive C-fiber barrage (wind-up), receptive field expansion with decreased dorsal horn threshold resulting in both temporal and spatial summation, and increased immediate early gene and dynorphin expression. [103] [104] [105] [106] [107] [108] [109]
Primary afferent nociceptor projections to laminae I and V of the dorsal horn are normally associated with small, discrete, receptive fields. Prolonged high-intensity discharge, however, may alter this spinal circuitry, both functionally and anatomically, through synaptic plasticity (sprouting). Stimulation results in the release of substance P, calcitonin gene-related peptide, and glutamate from axon terminals of primary afferent nociceptors. Glutamate then binds NMDA receptors in the dorsal horn. Resultant increases in intracellular calcium cause increased synthesis of a second messenger, nitric oxide. Unlike other neurotransmitters, NO, being a highly diffusible gas, is not restricted to interaction with nerve terminals immediately adjacent to the site of release. Instead, NO disperses freely to surrounding regions of the spinal cord, where, having entered the presynaptic terminals of the primary afferents, it This positive feedback results in hyperalgesia. induces the release of even more substance P and CGRP. Sensitization of wide dynamic range neurons that receive both noxious and non-noxious input gives rise to the development of allodynia. [110] [111]
The generation of these hypersensitive post-traumatic pain states depends on NMDA receptor activation. Further, preemptive NMDA antagonist administration prevents wind-up and the subsequent development of allodynia in experimental animal models and in humans.
[112] [113]
[114]
[115]
Timing
Noxious stimulation potently induces the expression of immediate early genes such as c-fos within minutes of injury. This response coincides with nociceptive behavior and is abolished in parallel with the preemptive application of NMDA antagonists, thereby preventing long-term hyperalgesia. The preemptive administration of a single dose of intrathecal ketamine delays the development of neuropathic pain in the rat for several days, clearly exceeding the expected duration of the analgesic. However, this treatment by itself fails to affect the ultimate severity or frequency of the neuropathic condition. Ongoing neuronal activity likely involves additional factors unrelated to the NMDA receptor. This finding is not unexpected, because tissue trauma results in the elaboration of a host of inflammatory mediators, that, acting in concert, can be characterized as a “sensitizing soup.” [116]
[117]
[118]
[119] [120]
Nociceptive neuronal activity after administration of subcutaneous formalin in rats is known to follow a biphasic response in which an early acute nociceptive phase, responding to opioid or local anesthetic, precedes a second Local anesthetic application after phase 1 period of dorsal horn excitation, known as the inflammatory phase. prevents phase 2 and thus the expression of c-fos. The secondary wave of neural input sustains the hypersensitivity state. NMDA antagonists have been reported to block the second but not the initial phase of this biphasic response. Although a biphasic mechanism has not been demonstrated in a model of neuropathic pain, a similarly complex process seems likely. Thus, successful prevention of long-term consequences of post-traumatic pain may require different antagonists timed appropriately for each phase of the hypersensitivity process. [121] [122]
[123]
Similar results are seen with local anesthetic blockade of afferent input, with improved efficacy when the analgesia is extended to include the early postoperative period. It is now apparent that the complexity of the neurochemical response to trauma necessitates an ongoing treatment process if long-term sequelae are to be prevented. [124] [125]
[126]
[119]
Clinical Studies
Clinical studies have supported a role for local anesthetic blockade, spinal narcotic, nonsteroidal anti-inflammatory drugs, and ketamine administered before noxious stimulus in acute pain studies in humans. A prospective, randomized, double-blinded placebo-controlled study demonstrated an opioid-sparing effect with preemptive dextromethorphan, an NMDA antagonist. However, the notion that multiple simultaneous or sequential neurochemical events are involved in the development of wind-up has led to the prophylactic use of therapies combining analgesics with differing mechanisms of action.
[115] [126] [127] [128] [129] [130] [131] [132] [133] [134]
[135] [136] [137]
[138]
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Choe and colleagues provided clinical evidence for efficacy of preemptive analgesia with use of epidural morphine in combination with epidural ketamine in a randomized, double-blinded study. Significantly improved analgesia was associated with preincisional use compared with postincisional administration. Perhaps the most innovative use of the available experimental evidence to date was a multimodal approach combining epidural local anesthetic and epidural narcotic infusion, a nonsteroidal antiinflammatory drug, and metamizole to induce descending central inhibition. A significant reduction in postoperative analgesic requirements after major abdominal surgery was observed when therapy was administered before incision compared with the institution of this same therapy just before wound closure. A similar preemptive effect was seen when preincisional epidural ketamine, morphine, and bupivacaine were administered in combination in a randomized, single-blinded, placebocontrolled study. [139]
[140]
[141]
However, if the only beneficial effect of preemptive analgesic efforts was that of reducing the amount of supplemental opioid required postoperatively, the clinical usefulness of these efforts would be quite limited in a cost-conscious medical environment. Long-term pain reduction and the prevention of chronic pain, on the other hand, are far more important and potentially cost-effective goals. Evidence is accumulating of long-term Additionally, controlled clinical studies have now consequences after occurrence of unrelieved acute pain. reported reduced chronic pain and improved function after preemptive analgesic interventions. Obata and associates examined the effect of preincisional versus postoperative epidural local anesthetic blockade in a randomized, double-blinded study of post-thoracotomy pain. They reported a significantly reduced incidence of post-thoracotomy pain at 6 months of follow-up when continuous epidural blockade was instituted before incision. [142] [143]
[144] [145]
[146]
Directions for further clinical study depend on preliminary investigations employing animal models. Unfortunately, existing animal models for pain studies imperfectly mimic human chronic pain states. Further, inability to control the intensity of the stimulus or the confounding effects of anesthesia, or to ensure sufficient afferent blockade, add to The greatest limitation, however, may be the inability to predict which subjects are the technical challenges. likely to go on to develop chronic sequelae. [147]
[119] [148] [149]
It has been a widespread belief, despite the paucity of significant supporting evidence, that certain personality traits may be predisposing factors in the development of chronic neuropathic pain. However, there is considerable evidence, based on experimental animal studies, to support a heritable basis for some neurologic conditions, Mailis and Wade have identified HLA antigens associated with RSD in women including neuropathic pain. who failed to respond to sympathetic blocks. They believe that the gene conferring susceptibility to RSD may be located on or near the MHC (major histocompatibility complex) region of the short arm of chromosome 6. The ability to identify patients predisposed to neuropathic conditions would represent a tremendous advance, guiding both further study of the condition as well as judicious use of treatment resources. Nevertheless, the most dramatic application may rely on the precise description of the responsible gene or genes, thus permitting future gene therapy to promote physiologic modulation through altered expression of that gene. [66] [67] [150]
[68]
[151]
Treatment of Chronic Post-Traumatic Pain Frequently encountered post-traumatic chronic pain syndromes are the so-called whiplash injury and CRPS type 1 (RSD). Although evidence-based outcome studies are generally lacking with respect to regional anesthesia and chronic pain, well-controlled trials have been performed for these two maladies and are worthy of mention. In both cases, specific entry criteria predicted successful outcome. Lord and colleagues reported that chronic cervical-zygapophyseal joint pain after whiplash injury is responsive to a specific regional anesthetic treatment strategy using radiofrequency ablation. First, prognostic medial branch blocks were employed in a double-blinded, placebo-controlled fashion to select appropriate study subjects. Then, subjects were randomized in a double-blinded fashion into either active or sham treatment groups. This careful screening process was rewarded when subjects in the active group experienced long-lasting reduction in pain. Hord and coworkers treated patients who had CRPS type 1 (RSD) with intravenous regional bretylium and lidocaine and demonstrated the effectiveness of this combination in a double-blinded, randomized trial. Patient selection criteria included responsiveness to sympathetic block with concurrent abnormalities in response to cold stress testing. Kingery, in a review of controlled trials for neuropathic pain, also suggested support for this technique, as well as limited support for the use of epidural clonidine. [152]
[153]
[154]
Obtaining evidence for the efficacy of sympathectomy in the treatment of patients with chronic pain is confounded by difficulties in selecting appropriate patients. Careful entry criteria are generally lacking in most studies, and many failures are probably secondary to misdiagnosis. Although some authorities have suggested a blinded phentolamine test as prognostic, it can be shown experimentally that sympathetic blockade can reduce pain in animal models that are unresponsive to phentolamine. Conversely, phentolamine may relieve pain that is resistant [155]
[156]
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to permanent sympathectomy. As in the captioned studies described earlier, carefully conducted double-blinded, placebo-controlled, prognostic sympathetic blocks may be most suitable for selection of appropriate candidates for sympathectomy. Recapitulation Use of regional anesthesia clearly improves patient outcome after chest wall trauma. Improved functional outcomes have also been demonstrated in patients who were treated with several other post-traumatic applications using nerve blocks. Evidence continues to accumulate for the notion that effective blockade of acute pain with regional analgesia prevents the development of chronic pain and improves long-term functional outcome. At present, however, there are few outcome studies of sufficient quality to support the general use of regional analgesia for trauma as a standard of practice. Consequently, this chapter provides more questions than answers. Numerous investigators have focused on the superior analgesia provided by regional anesthesia. However, the most compelling rationale for the use of regional anesthesia is provided by the prompt restoration of physical functioning, the reduction in morbidity, and the prevention of delayed post-traumatic sequelae that have been observed in subjects treated with regional anesthesia in the few available studies. Additional well-controlled clinical trials using prospective, randomized, double-blinded designs to examine specific outcomes are needed. REFERENCES 1. APS
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Chapter 48 - Efficacy and Outcome of Regional Anesthesia Techniques in Obstetrics BRANKO M. WEISS ELI ALON ROBERT S. F. McKAY
Outcome and “Seven Pillars of Quality” Avedis Donabedian asserted that the “seven pillars,” or attributes, that define quality in healthcare are (1) efficacy (ability to bring improvements); (2) effectiveness (degree to which the care could attain the level of improvement that studies of efficacy have established as attainable in the clinical practice); (3) efficiency (if two approaches are equally efficacious or effective, the less costly one is the more efficient); (4) optimality (relationship between the health benefit and the cost of care); (5) acceptability (care adapted to the wishes, expectations, and values of patients and their families, who expect and deserve accessibility of care, an effective patient-practitioner relationship, amenities, and individual preferences as to the effects and the costs of care); (6) legitimacy (conformity to the social preferences or features that are important to individuals are of social concern; now, a road to conflicts of interest opens widely); and (7) equity (fair distribution of care and its benefits from the individual and social points of view). Donabedian’s conclusion was that the patient and the social preferences must be taken into account in assessing and ensuring quality. In the real world, the seven pillars of quality may look like an endless conflict of interest. The conflicts involve all components, ranging from patients and families, insurance companies, and medical institutions to the industry, economists, politicians, and society as a whole. In this generation, the healthcare system may not reach an efficacious, effective, efficient, optimal, and patient-acceptable (with all attributes) level that can simultaneously fulfill both individual and social legitimacy and equity. Otherwise, the maternal mortality rate in the United States, France, the Netherlands, and other developed countries would be a concern of the past, and the relative death risk would not be higher for ethnic minorities than for the population of the local majority. Factors involved in the measurable differences in mortality rates among black, Hispanic, and white pregnant women in the United States would be identified and eliminated. The proportion of cases of maternal death in which substandard care is present would not remain constant at about 40% to 50% in the United Kingdom, a country with a traditional triennial audit, known as the Confidential Enquiries into Maternal Death. An aspect of equity emerged from the report spanning 1994 to 1996. There was no evidence of any excess in substandard care for cases involving death of the nonwhite women. In the United States, Australia, and, certainly, other countries, the rates of obstetric and anesthetic intervention among women covered by private and public health insurance would not be, with similar risk profiles, significantly higher in private hospitals. An editorial plea that begged, “Let’s not turn back the clock to the dark ages of the leather wrists straps on the delivery beds, screaming women in pain, and various intravenous or inhalational shots of analgesia,” would be unnecessary. The American College of Obstetricians and Gynecologists (ACOG) would not need to repeat in a news release that “the last thing a woman needs to hear during a painful labor is that her insurance company isn’t going to cover her epidural.” [1]
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[10]
[11]
Evidence-Based Medicine: Epidemiologic Data versus Individual Healthcare Measuring and improving the quality and outcome of healthcare have become high priorities. The collection and interpretation of outcome in the healthcare system have been addressed from individual, institutional, and national and less developed regions. The proper perspectives in both developed countries identification and analysis of reliable evidence (evidence-searched and evidence-based medicine) became a complex process, (over)loaded by methodological, statistical, and analytic difficulties, and unsolved controversies and The critical aspect of evidence-based medicine is the wide gap that exists between the disagreements. value of epidemiologic data for the population in general and applicability of these data to the healthcare requirements of an individual patient. Some medical evidence may not be transferable (again, for various reasons and without any trace of poor clinical practice) between the countries and institutions. Although the developed countries have reached an almost uniform standard of healthcare, the cultural, social, religious, financial, traditional, climatic, and political differences among them remain measurable and, occasionally, relevant. [6] [9] [12] [13] [14] [15] [16] [17] [18] [19] [20] [21] [22] [23] [24]
[25]
[22] [24] [26] [27] [28]
Outcome is considered to denote favorable, adverse, or neutral changes of health status, integrating the physical, psychological, emotional, and social consequences that occur after or during healthcare. Emphasizing positive categories, outcome analysis looks for survival, longevity, activity, comfort, satisfaction, achievement and resilience, and rapid, full restitution to productive business and social life. The medical, financial, political, and social pressures are continually increasing, asking for real (or at least surrogate) improvements in healthcare. Not [12]
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infrequently, a variety of soft, indirect, and biologically or chronologically remote variables (pseudo-outcome variables) are presented as denoting outcome. Although it is easy to differentiate extremely poor from impeccably excellent medical care, a variety of fine details make the definition of outcome rather complex. Frequently, financial, performance, and clinical outcomes, or the patient’s perceived outcome, must be considered from the perspective of The outcome variables may be the specific procedure, the medical institution, or the individual patient. divided, from the epidemiologic point of view, into traditional (morbidity, mortality rates) and nontraditional (patient satisfaction, costs) categories and subcategories. The quality and outcome of healthcare in obstetrics look simple only at first sight; in an individual woman, and particularly in a larger number of subjects, the exact definition may depend on the focus of interest, subjective interpretations and expectations, education, and previous experience, as well as on the construction of questionnaires (called psychometric measurements, if multiple items are included and properly analyzed). [16] [17] [23] [24] [29]
[24] [29]
[29]
David Gaba claimed, following the school of thought of Arthur Keats, that traditional epidemiologic studies are insufficient for assessment of the incidence of adverse events related to anesthesia. The errors, mistakes, and system failures have continued to prevent reduction in negative outcomes related to anesthesia. For accomplishments in patient safety in anesthesiology, Gaba accentuated nontraditional investigation techniques that analyze a small proportion of the events to glean the maximum amount of useful information, such as “critical incident” analysis adapted from aviation, closed malpractice claims, and the Australian Incident Monitoring Study. Unfortunately, the trend in the quality assessment of anesthesia seems to be redirected (again) to the collection of small and largely irrelevant incidents, errors, mishaps, short-term nonvital equipment failures, and The majority of such data are useless for conducting quality assessment at the “abnormal” laboratory findings. institutional or national level. When reviewed individually, the collection and the data imply waste of time and resources. Worse, they confuse the differentiation between “events without any relevance or consequences” (within the bounds of reason) for the anesthesia practice and the critical incidents and near-miss events that constitute or have real potential for anesthesia-related complications and negative outcomes. [30]
[31]
[30]
[30]
[14]
[18]
[18] [32]
Regional anesthesia and techniques of neural blockade present one of the most important aspects of modern clinical anesthesiology and management of pain. Central neuraxial blockades for combatting the pain of labor, delivery, and interventions postpartum became the single most important pillar of quality in obstetric anesthesia. The regional anesthesia techniques in obstetrics (as elsewhere) are not free from complications, controversies, and The controversies originate from different sources and incentives, such as dissensions. improvements in medical knowledge, spread of new and reliable information (evidence), real or surrogate technologic and pharmaceutical innovations, and increased or decreased financial and nonfinancial expenditure in healthcare. They may reflect a changing quality of life or the fashionable trends involving both providers and consumers in the healthcare system. Some attributes of quality and outcome in obstetric anesthesia have been addressed repeatedly, but for many techniques and drugs, “hard” data are missing. The proper assessment of effects, side effects, and complications, as well as their impact on the attributes of quality, remains frequently a matter of subjective interpretation. Even if or when objective outcome studies address a specific topic, regional and national interpretations keep the discussion open. Compared with regional anesthesia techniques, all other pharmacologic and nonpharmacologic methods of pain relief in obstetrics are lagging far behind. Of course, all these alternative avenues are a traditional part of obstetrics and obstetric anesthesia, involving certain attributes of quality. However, they represent only compromises and alternatives to central neuraxial techniques. None are addressed here because detailed reviews are available elsewhere. [33] [34] [35] [36]
[14] [24] [37] [38] [39] [40] [41] [42] [43] [44] [45]
[35] [36] [46]
Maternal Outcome Related to Regional Anesthesia Techniques MATERNAL MORTALITY
From the point of view of the modern healthcare system, it is relatively easy to consider anesthesia-related death as just a marker or “sentinel event” (unusual, unexpected, and very rare outcome) and then assess the percentage of “avoidable/preventable deaths” in a specific population or institution. Mortality data may be even dismissed as Death “resulting” from anesthesia per se is highly problematic and unusable (distorted) indicators of outcome. considered to have dropped dramatically over the past decades by a combination of various reasons and “mechanisms.” Similar to the previous conclusions of Henrik Kehlet, the preliminary data from an overview of the randomized trials indicate—probably the best available outcome analysis for 2000 and beyond—that the use of regional anesthesia techniques, compared with general anesthesia, was associated with risk of death reduced by 30% and risk of severe complications reduced by 30% to 60%. Despite the inherent methodologic and statistical difficulties and the caution required to interpret and extrapolate epidemiologic conclusions to the clinical practice, the outcome differences remain much too high to be ignored. [12] [31]
[22]
[42]
[24]
[24]
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Pregnant women and new mothers die in all countries, and the rate of maternal deaths (or, better, the maternal survival rate) could be considered one of the best indicators of the “quality of life” in a country or a region. In both underdeveloped and undeveloped countries, the mortality rates exceed 50 to 100 cases or even 500 to 1000 cases per It is assumed (an educated guess from the historical perspectives) that the main factors 100,000 maternities. and critical remedies that could lead to decline of maternal deaths in poor countries are improvements in maternal care (easier to accomplish) more than improvements in the standards of living. Currently, pregnant women die in developed countries at the rate of 3 to 25 cases per 100,000 maternities. One analysis concluded that the maternal mortality rate did not change substantially in Canada and the United States between 1982 and 1997. Other developed countries are reaching a plateau, and, in some, increased mortality rates are expected in the near future because of the more advanced age of the pregnant population; regional differences within one country; national, international, and intercontinental migration of the population; omnipresent “human factors and preventable cases”; and improved data collection. The risks of maternal complications and death are specifically increased by women’s greater age and parity, multiple gestations, preeclampsia, emergent cesarean delivery, coincidence of lower socioeconomic status in local minorities and recent immigrants, and by various aspects of The “final” major causes of death are thromboembolism, extrauterine pregnancy substandard care. and bleeding, hypertension, and diseases involving the cardiovascular system and the central nervous system. [25] [47] [48]
[49]
[4] [5] [6] [13] [21] [50] [51] [52] [53] [54]
[20]
[4] [6] [21] [51] [52] [54] [55] [56] [57]
[5] [6] [13] [21]
[50] [51] [52] [53] [58] [59] [60]
Anesthesia-Related Maternal Deaths
The maternal mortality rate is decreasing, but it is still associated with or attributed to anesthetic care. An increasing number of pregnant women are “treated” in one form or another by anesthesiologists. The number of anesthetic interventions (anesthesia denominator) is increasing (changing) over time. The standard calculations, expressing mortality rate as “per 100,000” maternities, deliveries, or live births and using the number of “anesthetic” deaths as a percentage of the total, could present the real or distorted (favorably or unfavorably) rate of anesthesia-related deaths. At a very low number of total cases, 1% to 13% of all direct maternal deaths are considered anesthesia In Massachusetts, the maternal mortality rate decreased from 50 cases to 10 cases per related 100,000 live births between 1954 and 1985, accompanied by a threefold decrease in anesthesia-related deaths. The primary causes were pulmonary aspiration during general anesthesia administered by face mask in the first decade, cardiovascular collapse associated with regional anesthesia in the second decade, and in the third decade, all deaths were associated with general anesthesia and tracheal intubation. The pattern of change and the causes of anesthetic-related death were almost identical in other countries, and certain similarities persist up to the present In the United States, England, and Wales, the mortality rate directly associated with time. In the United Kingdom, one anesthesia decreased to 17 cases per 100,000 in the period from 1988 to 1990. case of anesthetic death was found in the 1994 to 1996 triennium, which made a negligent impact of anesthesia (0.8%) on all direct maternal deaths. Hopkins and coworkers analyzed maternal mortality rates between 1979 and 1992 in the United States. Pregnancy-induced hypertension explained, in part, the higher mortality rate in Hispanics (10.3 per 100,000 live births) compared with non-Hispanic whites (6.0), but the highest mortality rate was found in blacks (25.1). The rates of anesthesia-related death for pregnant white, Hispanic, and black women were 0.1 (3%), 0.3 (4%), and 0.7 (5%), respectively. A Swiss analysis from 1985 to 1994 showed a total maternal mortality rate of 6.7 per 100,000 live births. Four anesthesia-related deaths (all associated with general anesthesia and tracheal intubation) represented a mortality rate of 0.5 per 100,000 or 9% of all direct deaths in the 10-year study period. [3] [5] [6] [13] [21] [22] [50] [51] [52] [58] [61] [62]
[2]
[63]
[6] [13] [14] [21] [50] [52] [54] [61] [62]
[13] [52] [61]
[6]
[5]
[5]
[54]
[54]
Regional Anesthesia and Decreasing Anesthesia-Related Mortality Rate
Regional anesthesia techniques, by reducing the requirement for general anesthesia and tracheal intubation in emergencies, have (combined with other, less visible factors) played a major role in decreasing anesthesiaassociated maternal deaths. In the analysis of anesthesia-related deaths during obstetric delivery, Hawkins and coworkers calculated that the maternal mortality rate decreased 2.5-fold (from 43 to [52] [61] [62] [64]
[61]
TABLE 48-1 -- ANESTHESIA-RELATED OBSTETRIC DEATHS IN THE UNITED STATES 1979-1990 * General Anesthesia (n = 67)
Regional Anesthesia (n = 33)
Airway problems
73
Cardiac arrest
22
6
Cause of death (%)
Local anesthetic toxicity
51
High spinal or epidural block
36
Overdosage
Anaphylaxis
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Chapter 48 - Efficacy and Outcome of Regional Anesthesia Techniques in Obstetrics TABLE 48-1 -- ANESTHESIA-RELATED OBSTETRIC DEATHS IN THE UNITED STATES 1979-1990 * General Anesthesia (n = 67)
Regional Anesthesia (n = 33)
5
6
1979–1984
2.00 (1.77–2.27)
0.86 (0.19–0.94)
1985–1990
3.23 (2.59–4.93)
0.19 (0.18–0.20)
1979–1984
0.23 (0.19–0.29)
referent
1985–1990
1.67 (1.29–2.18)
referent
Unknown Mortality risk of cesarean delivery
†
Case fatality rate
Risk ratio of general vs. regional anesthesia
Modified from Hawkins JL, Koonin LM, Palmer SK, Gibbs Cl’: Anesthesia-related deaths during obstetric delivery in the United States, 19791990. Anesthesiology 86:277,1997. Reproduced with permission. * Additional 29 cases occurred during "sedation" and unknown anesthetic technique. † Rate per 100,000 anesthetics (95% confidence interval).
17 cases per 100,000) in the United States between 1979 and 1990. The majority of deaths were related to cesarean delivery (82%) and use of general anesthesia (52%). The predominant causes were airway/respiratory problems and cardiac arrest with general anesthesia, and local anesthetic toxicity, high level of block, and cardiac arrest with regional anesthesia ( Table 48-1 ). Deaths caused by local anesthetic toxicity decreased abruptly after 1984, temporally related to the discontinuance of 0.75% bupivacaine from the obstetric anesthesia practice. The case fatality rate for cesarean delivery with regional anesthesia was calculated to have decreased by a factor of 4.5 between 1979 to 1984 and 1985 to 1990. With general anesthesia, it increased by a factor of 1.6. The risk of death has been 2.3-fold higher with general than with regional anesthesia until 1984 and almost 17-fold higher in the 1985 to 1990 period (see Table 48-1 ). These results, insufficient methodologic precision notwithstanding, became an almost ironclad argument for regional and against general anesthesia in obstetrics. The authors attempted to define the risk of death more precisely by including cesarean deliveries only to obtain the correct anesthesia denominators. However, the combination of missing and incomplete data, estimates and extrapolations, based on surveys with 50% returns, and underestimation of the number of general anesthetics exaggerated the risk between the two techniques. Hawkins and coworkers recognized the study limitations and suggested that the discrepancy in the mortality rates emerged from different indications and circumstances. General anesthesia may have been used primarily in emergencies and in patients for whom regional block was difficult to administer (obesity) or was contraindicated (coagulopathy, preeclampsia). After 1984, the abrupt decrease of mortality rate caused by local anesthetic toxicity could be considered not only as temporally but also as causally related to the discontinuance of epidural 0.75% bupivacaine from the obstetric anesthesia practice. “The high maternal mortality associated with unrecognized intravenous injection of bupivacaine probably relates to the difficulties involved in resuscitating a parturient, not to the greater intrinsic toxicity of bupivacaine in this population.” Because of the time delay, the cases entering the American Society of Anesthsiologists (ASA) closed claims project after 1995 might be expected to show a similar trend of decreased maternal mortality rate resulting from local anesthetic toxicity. [61]
[62]
[61]
[61]
[65]
[14]
Risk Assessment of General versus Regional Anesthesia
The surveys of national and institutional obstetric anesthesia practice are showing an overall trend toward preferring regional anesthesia techniques. However, the percentage of cases for elective, urgent, and emergent cesarean The detailed delivery is varying widely among countries and among different-sized hospitals. analyses are missing and the absolute number of fatalities in the developed countries is very small. It seems that anesthesia-associated maternal mortality could not be explicitly related to the proportion of deliveries managed with general anesthesia. [64] [66] [67] [68] [69] [70] [71] [72] [73]
[4] [5] [6] [34] [50] [52] [61] [64] [66] [67] [68] [69] [71] [72] [73]
For various reasons, a direct comparison of obstetric regional and general anesthesia remains difficult or almost impossible. The use of general anesthesia tends to be a priori associated with urgent or emergent conditions, failed or refused regional anesthesia, and complicated pregnancy with coexisting diseases. These factors, either combined or isolated, increase (even with experienced practitioners and institutions) the risk of complications and death. David Chestnut, in an editorial, analyzed the data of the Hawkins’ study and addressed a critical point in obstetrics. “As long as obstetricians continue to ask anesthesiologists to provide anesthesia for emergency cesarean section at a moment’s notice, it is unlikely we can reduce the general anesthesia-related mortality to zero.” In a retrospective study from Boston, the proportion of general anesthesia for cesarean delivery was found to have decreased from 7% in 1990 to 4% in 1995, but the procedure was used in parturients with significantly more
[61] [62] [74]
[75] [76] [77] [78]
[61]
[62]
[74]
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maternal diseases. The number of women who refused regional anesthesia increased slightly as did the rate of failed regional (particularly, spinal) techniques. One maternal death resulting from failed intubation was documented among 536 parturients who received general anesthetics. Human error, inexperience, and poor judgment are confounding factors that contribute to the maternal mortality rate. However, presuming that human error, inexperience, and poor judgment are evenly distributed in all obstetric cases, the core message of the Hawkins study and other studies (higher risk of death from general anesthesia in obstetrics) must be taken into account. This risk assessment, cumulatively for the whole population, is a rough indicator of epidemiologic value only and not an absolute parameter for the management of an individual case. Christopher Rout came to the conclusion that “there is epidemiologic evidence of an association between increased use of regional techniques and decreasing maternal mortality.” In normal, healthy women undergoing elective cesarean delivery under the care of an experienced anesthesiologist, “there is probably little difference between general and regional anesthesia in terms of mortality risk. Nevertheless, collective experience suggests that the unpredictable complications of general anesthesia are more likely to result in an adverse outcome compared with those occurring during regional anesthesia.” Conversely, the practice of obstetric and anesthetic care is decisive. A combination of unfavorable circumstances in the local process and structure of antenatal, medical, obstetric, anesthetic, and postanesthesia care, without a specific focus on one or another anesthetic technique or drugs, may explain the vast majority of In the 1994 to 1996 Confidential Enquiries in the United anesthesia-associated maternal fatalities. Kingdom, the single maternal death directly attributed to anesthesia resulted from a massive overdose of several drugs used for a combined spinal-epidural block. Indeed, to suggest that the regional technique per se was a factor in this death would be absurd. The same report provided an analysis of “deaths associated with anaesthesia” in women whose deaths were due to direct obstetric causes (such as eclampsia, amniotic fluid embolism, sepsis, or bleeding) and preexisting concomitant diseases (such as severe cardiac failure, pulmonary hypertension, or pheochromocytoma). Aspects of substandard care and lack of communication were identified and involved (in various combinations) obstetric (dominant), medical, anesthetic, and peripartum intensive care. The “association with anesthesia” was in some cases obvious, but in others it was poorly defined or even lacking ; at any rate, it would be absurd to blame or associate “general anesthesia” per se with these fatalities. The ASA task force concluded that “the literature is insufficient to determine the relative risk of maternal death with general anesthesia compared with other anesthetic techniques. However, the literature suggests that a greater number of maternal deaths occur when general anesthesia is administered.” An additional insight on the topic is provided by the reports massive postpartum bleeding, eclampsia, and describing maternal survival after amnio- or thromboembolism, two cardiac arrests, cardiorespiratory arrest during cesarean delivery under epidural anesthesia or after combined spinal-epidural anesthesia. The reports highlight not only the specific management but also the core of the prevention of anesthesia-related maternal deaths. [74]
[79]
[6] [13] [14] [52] [61]
[64]
[64]
[6] [13] [34] [52] [62] [64] [79] [80] [81]
[6]
[80]
[6]
[6]
[34]
[82] [83]
[84]
[85]
[86]
Maternal Mortality—Incident Reporting and Closed Claims Studies
Heathcliff Chadwick provided the 1985 to 1995 data from the ASA closed malpractice claims project, an ongoing study of the United States insurance company liability files that are closed, and compared the obstetric and nonobstetric files. Although the hard facts are lacking (insurance claims but not a total number of procedures and complications are known), the study provided important data concerning the anesthetic outcome of pregnant women. The most common injury in the files was death, which was found at a significantly lower rate in obstetric than in nonobstetric files, in obstetric regional rather than obstetric general anesthesia cases ( Table 48-2 ), and after vaginal (10%) more than cesarean (23%) delivery. It is of interest that maternal fatalities are completely missing in reports from Australia and Canada. This absence of fatalities shows either an excellent standard of national anesthesia care, a different medicolegal system with different thresholds to trigger a malpractice claim, a different definition of anesthesia-related and unrelated deaths, or an unreliable data collection and incomplete reporting. In a 1990 to 1997 review of closed claims involving Canadian anesthesiologists, no cause of death was identified among the files involving regional anesthesia (13 in obstetrics), in contrast to the 17% mortality rate in other anesthetic files. [14]
[14]
[18]
[87]
[87]
TABLE 48-2 -- ASA CLOSED CLAIMS PROJECT 1985-l995: OBSTETRIC AND NONOBSTETRIC ANESTHESIA FILES All Obstetric Files (II = 434)
Obstetric Regional (n = 290)
Obstetric General (n = 133)
Nonobstetric Files (n = 3099)
Maternal death
83 (19%)
31 (ll%) *
52 (39%)
1111 (36%) †
Headache
64 (15%)
61 (21%) *
2 (2%)
50 (2%) †
Nerve damage
43 (10%)
38 (13%)
*
5 (4%)
523 (17%) †
Pain
37 (9%)
36 (12%)
0 (0%)
27 (1%) †
Back pain
36 (8%)
36 (12%) *
0 (0%)
37 (l%) †
Brain damage
32 (7%)
17 (6%)
14 (11%)
403 (13%)
Emotional distress
31 (7%)
23 (8%)
8 (6%)
115 (4%) †
Maternal Injuries
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TABLE 48-2 -- ASA CLOSED CLAIMS PROJECT 1985-l995: OBSTETRIC AND NONOBSTETRIC ANESTHESIA FILES Maternal Injuries
All Obstetric Files (II = 434)
Obstetric Regional (n = 290)
Obstetric General (n = 133)
Nonobstetric Files (n = 3099)
20 (5%)
2 (1%) *
18 (14%)
58 (2%) †
Pulmonary aspiration
From Chadwick HS: An analysis of obstetric anesthesia cases from the American Society of Anesthesiologists closed claim database. Int J Obstet Anesth 5:258,1996. Reproduced with permission. *P< 0.05 regional vs. general anesthesia in obstetric files. † P < 0.05 obstetric vs. nonobstetric files. MATERNAL MORBIDITY Complications Related to Regional Anesthesia Techniques in Nonobstetric Patients
A retrospective 1987 to 1990 review of 4767 consecutive spinal anesthetics, performed at the Mayo Clinic in the United States, for genitourinary and lower extremity orthopedic procedures, revealed a low incidence of paresthesias during needle placement (6%) and postdural puncture headache (PDPH) (1%). Six patients reported pain after resolution of the block, which slowly resolved 1 week to 24 months later, and, in two cases, spinal infectious complications occurred. A combined retrospective and prospective study analyzed 18,000 central neuraxial blocks performed between 1991 and 1994 at the Lund University Hospital in Sweden. Persistent lesions associated with regional anesthesia (some still involving other cofactors) were identified in 13 patients. Three patients had lesions after a single-shot spinal block (rate 1:2834) and 10 after an epidural block (1:923). [88]
[88]
[89]
[89]
The most detailed data on the incidence and severity of complications related to regional anesthesia were provided by a prospective survey of French anesthesiologists in 1994. Analyzing more than 100,000 spinal, epidural, peripheral nerve, and intravenous regional blocks, Auroy and coworkers identified 89 cases (< 0.1%) of severe complications fully or partially attributed to anesthesia ( Table 48-3 ). The incidence of cardiac arrest and neurologic injury was significantly higher during spinal than during epidural block. The authors concluded that the higher risk of cardiac arrest might be associated with factors other than regional anesthesia (age, procedure), whereas the risk of neurologic injury might have been primarily associated with the type of regional block and the drug used. In most but not all cases (21 of 34) of neurologic symptoms, paresthesias during puncture or pain during injection heralded the complications. All except five patients recovered within 48 hours to 3 months. Nine of 12 patients with neurologic deficit received hyperbaric lidocaine, and in 3 the deficit remained permanent; the neurotoxicity of local anesthetic remained primarily suspected. Three patients after hyperbaric bupivacaine had only transient neurologic symptoms. Seizures occurred in 14 of 23 patients after the use of bupivacaine, but in none did the event result in cardiac arrest. Thus, the study documented a remarkable safety margin, because the risk of neurologic injury lasting longer than 3 months and the risk of death were assessed to be 0.5 and 0.7 per 10,000, respectively, for all regional anesthetic techniques. Even in experienced hands, the serious complications remain unavoidable, and cardiac arrest is the major cause of fatality during regional anesthesia. [90]
[90]
[91]
An analysis of the patient insurance claims in Finland between 1987 and 1993 identified 86 (one obstetric) cases of serious neurologic complications associated with spinal or epidural anesthesia. The rates of complications after spinal (0.45/10,000) and epidural (0.52/10,000) anesthesia, according to the insurance claims in Finland, were as low as those found prospectively in France. A survey of the reports from 1965 to 1994 in the Swedish adverse drug reaction registry identified peripheral neurologic deficits in 21 cases after central neuraxial block. Intrathecal application was involved in 17 and epidural in 4 (1 obstetric patient) cases. The number of cases was extremely low, but 15 of 21 cases were reported between 1992 and 1994. Hyperbaric lidocaine was associated with nine spinal anesthetics, and other iso- or hyperbaric local anesthetics, plain or with epinephrine, in the remaining 12 cases. Pain in the lower extremities and paresthesias were the most frequent symptoms, followed by low back pain, abdominal pain, urinary and fecal incontinence, and erectile dysfunction. The patients with reversible deficit after 2 weeks had no motor deficit, whereas in those with persistent symptoms, some motor dysfunction was present in 50% of cases. [92]
[92]
[90]
[93]
TABLE 48-3 -- REGIONAL ANESTHESIA-RELATED COMPLICATIONS: PROSPECTIVE SURVEY IN FRANCE, 1994 All Regional Techniques (n = 103,730)
Spinal Anesthesia (n = 40,640)
Epidural Anesthesia (n = 30,413)
Cardiac arrest
32 (3.1) (3.9–8.9)
26 (6.4) (3.9–8.9)
3 (l.o) † (0.2–2.9)
Death related to event
7 (0.9) (0.2–1.2)
6 (1.5) (0.3–2.7)
0 (0.0–1.2)
Seizures
23 (2.2) (1.3–3.1)
0 (0.0–0.9)
4 (1.3) (0.4–3.4)
Neurologic injury
34 (3.3)
24 (5.9)
6 (2.0) †
Serious Event *
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Chapter 48 - Efficacy and Outcome of Regional Anesthesia Techniques in Obstetrics
TABLE 48-3 -- REGIONAL ANESTHESIA-RELATED COMPLICATIONS: PROSPECTIVE SURVEY IN FRANCE, 1994 All Regional Techniques (n = 103,730)
Spinal Anesthesia (n = 40,640)
Epidural Anesthesia (n = 30,413)
(2.2–4.4)
(3.5–8.3)
(0.4–3.6)
Radiculopathy
28 (2.7) (1.7–3.7)
19 (4.7) (2.6–6.8)
5 (1.6) † (0.5–3.8)
Cauda equina syndrome
5 (0.5) (0.2–1.1)
5 (1.2) (0.1–2.3)
0 (0.0–1.2)
Paraplegia
1 (0.1) (0.0–0.5)
0 (0.000.9)
1 (0.3) (0.0–1.8)
Serious Event *
From Auroy Y, Narchi P, Messiah A, et al.: Serious complications related to regional anesthesia. Results of a prospective survey in France. Anesthesiology 87:479486,1997. Reproduced with permission. * Number of cases, (rate per 10,000) and (95% confidence interval). † P < 0.05 epidural vs. spinal anesthesia.
Pleym and Spigset concluded that the causal relationship between the neuraxial application of local anesthetic and neurologic deficit remains uncertain, but the number of cases associated with hyberbaric 5% lidocaine (injected through fine-bore needles) are consistent with the suspicion that lidocaine is neurotoxic. [93]
The “safe” use of intrathecal lidocaine abruptly ended in the mid-1990s when numerous studies started to implicate lidocaine as the cause of transient (48– 72 hr) neurologic symptoms (pain and dysesthesias with radiation to the buttocks, thighs, or legs), found in up to one third of patients after an otherwise uneventful spinal anesthesia with Lithotomy position, caudal-oriented injection, outpatient status, and obesity hyperbaric 5% lidocaine. were found to increase the risk, whereas preexisting neurologic disorders, paresthesias during needle placement, or In a multicenter study of 1863 patients, the risk of neurologic symptoms lidocaine dose did not affect the risk. after spinal lidocaine was calculated to be three to five times higher compared with risk after spinal tetracaine and bupivacaine, respectively. The incidence of transient symptoms after spinal anesthesia with hyperbaric lidocaine was significantly higher compared with hyperbaric bupivacaine in patients operated on in a supine position. The negative report of lidocaine escalated, because a suspicion was raised that hyperbaric 5% lidocaine could be the cause of rare but permanent damage to the cauda equina, even after single-shot spinal anesthesia. After a review of six cases of cauda equina syndrome reported in Sweden from 1993 to 1997, Loo and Irestedt repeated the recommendations that hyperbaric (or even isobaric) lidocaine should be administered intrathecally in a concentration not greater than 2% (equipotency ratio of 4:1 to 0.5% bupivacaine) and at a total dose not exceeding 60 mg. Some editorialists questioned the relevance and etiology of transient neurologic symptoms. They requested proof of neurotoxicity and claimed that lidocaine might still be an excellent drug. These investigators warned against reaching any hasty conclusion. [90] [94] [95] [96] [97] [98] [99]
[100] [101]
[100]
[102]
[103]
[104] [105]
Complications Related to Regional Anesthesia in Obstetrics
In obstetrics, the complications result from pregnancy, labor and delivery, preexisting diseases, and conditions arising from or during pregnancy, concomitant medical treatment, obstetric interventions, regional anesthesia techniques per se, or multifactorial combinations (as in other patient populations) of several factors or mechanisms. An objective assessment of the patient’s history; concomitant risks, triggers, and drug treatment; details of obstetric and anesthetic procedure; positioning; course and management postpartum; and clinical and radiologic presentation are required to treat and elucidate the predominant or primary cause and mechanism of A review of the 1988 to 1994 institutional consultations revealed 12 (6 obstetric patients) injury. cases of neurologic complications related to lumbar epidural technique. Yuen and coworkers concluded that neurologic sequelae associated with epidural block are rare but potentially severe in the presence of spinal stenosis or after inadvertent subarachnoidal injection. In another neurologic series, seven women attributed falsely their symptoms to epidural analgesia administered during labor, and five were considering litigation. The example of three cases of severe neurologic damage after administration of general anesthesia is highly didactic. Philip Bromage concluded that “the anesthetic technique was not incriminated in any of these three cases. However, there is a high probability that a cause-and-effect relationship would have been imputed and medicolegal proceedings instituted if spinal or epidural anesthesia had been used.” [37]
[38] [39] [88] [89] [101] [103] [106] [107] [108]
[37] [38] [39] [101] [106] [108] [109] [110] [111]
[112]
[112]
[113]
[37]
Improved Safety of General and Regional Anesthesia
The concept that the anesthesia-related maternal mortality rate is low and decreasing because of the widespread use of regional anesthesia techniques has become implicitly established. The mechanisms and types of complications associated with regional and general anesthesia are different. In a proportion of cases, however, both techniques may have the same type and severity of complications. General anesthesia (in a majority of [14] [18] [52] [61] [62] [87]
[14] [18] [87] [90]
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countries and institutions) remains reserved for high-risk pregnant women who are prone to or who have already had complicated gestation. General anesthesia is predominantly used for cesarean delivery and less frequently for vaginal delivery. Thus, the proportion of cases and indications for regional techniques and general anesthesia in obstetrics remain, quantitatively and qualitatively, widely different. Multiple advantages have been attributed to regional anesthesia techniques. Maintaining consciousness and allowing women to participate in delivery results in high maternal satisfaction, reduced blood loss, lower incidence of minor complications, and prolonged postpartum pain relief, which are all factors that are considered to contribute to a faster and smoother recovery with regard to the use of regional anesthesia in obstetrics. [33] [34] [64] [65] [81] [114] [115] [116] [117]
With the remarkable popularity and safety of regional techniques in obstetrics, it remains neglected that general anesthesia is undergoing a process of safety improvement as well. The following factors contribute to the safety and improved outcome of general anesthesia in obstetrics: [34] [52] [62] [64] [79] [81] [121] [122] [123]
1. 2. 3. 4. 5.
Routine use of prophylaxis against pulmonary aspiration Increased recognition of risk factors associated with difficult intubation Widespread use of capnometry and pulse oximetry A more favorable pharmacologic profile of new anesthetic drugs and muscle relaxants Availability of laryngeal masks, fiberoptic instruments, and other tools for the management of failed intubation or ventilation [118] [119] [120]
In the United Kingdom, with decreased use of general anesthesia for cesarean delivery (from 66% to 83% in the mid-1980s to 23% in the mid-1990s), the incidence of failed intubation remained stable. The majority of cases of failed intubation occurred during the night, over the weekend, in an emergency situation, and in women from minority groups (a sign of nonequity) in whom general anesthesia was used with disproportionate frequency, but none resulted in an adverse outcome. Data from the United Kingdom (1993 to 1998) show that a trend toward more cesarean deliveries and fewer general anesthetics (14% for elective surgeries and 30% for emergency cesarean The incidence of failed intubation (1:249 among 8790 obstetric general anesthetics) deliveries) continues. remained stable in a United Kingdom region. Of 36 cases of failed intubation, 26 were well documented, and none resulted in negative outcome. Six cases were finally managed with an endotracheal tube, 12 were switched to regional anesthesia, and for most other procedures a laryngeal mask was used. In the 24/26 cases, there was either no recording of preoperative assessment, failure to follow an accepted protocol, or no follow-up. [71] [72] [124]
[71]
[73] [125]
[73]
[73]
The risk of pulmonary aspiration is considered to be higher in pregnant women than in the nonobstetric population. However, the risk assessment of aspiration in obstetrics seems to be based more on past than on current practice Widely different practices prevail among and within hospitals and options in obstetric anesthesia. and countries for the following :
[14]
[126]
[14] [81] [126] [127] [128] [129] [130]
[81] [132] [133]
1. 2. 3. 4.
Eating routines in wards, delivery units, and labor rooms Indications for cesarean delivery Definition of elective, semielective, emergent, and urgent procedures The whole process and structure of obstetric and anesthesia care [131]
[132] [133]
[62] [132] [133]
A routine use of antacids, histamine-receptor antagonists, and other measures reduced the risk and the consequences of pulmonary aspiration in obstetrics in a highly efficacious and cost-effective manner. The risk of aspiration is ill defined and needs revision. A mandatory use of endotracheal intubation if general anesthesia is induced intrapartum should be considered, at the least, controversial. In a series of difficult or failed intubations (ideal conditions for These data are rough indicators only and should not be gastric regurgitation), no aspiration was reported. transferred directly to the management of individual cases. A part of anesthesia-related morbidity and mortality seems to be hidden in the inadequately defined risks of both regional and general anesthesia techniques. The quality and outcome of obstetric anesthesia are continuously improving, but this may be true only for institutions that succeeded to define the risks adequately, within their respective structure and process of anesthesia care. [81]
[134]
[18] [71] [72] [73]
Maternal Morbidity: Incident Reporting and Closed Claims Studies
The Australian Incident Monitoring Study is a collection of anonymous and voluntary reports of all anesthesia incidents. In its first 5000 reports, the proportion of obstetric cases was 4% (203 per 5000). The obstetric incidents were over-represented with respect to accidental dural puncture and headache as well as drug incidents involving wrong ampule or syringe swap. The rate of failed intubation was significantly higher in obstetric than in nonobstetric cases, particularly in emergent procedures, but the analysis did not provide the outcome of 12 pregnant women in whom intubation “failed.” Unexpectedly high spinal or epidural blockade was reported in 22 cases, and in 8 cases general anesthesia or ventilatory support was required. In the ASA closed malpractice claims project, [18]
[18]
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[14]
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Chapter 48 - Efficacy and Outcome of Regional Anesthesia Techniques in Obstetrics
nerve damage was more frequently found in the nonobstetric files, but the proportion of cases involving obstetric regional techniques (the third most common maternal claim) was remarkable (see Table 48-2 ). Of 38 nerve injuries after spinal or epidural anesthesia, 21 cases were judged to be caused by the regional block procedure. The most frequent causes were needle or catheter trauma, neurotoxicity, and ischemia. Convulsion (predominantly associated with epidural block resulting in neurologic injury or death to the mother, newborn, or both in 74% of cases), headache, pain during anesthesia, and back pain were the most frequent injury/damaging event leading to claims in obstetric regional cases. Brain damage was evenly distributed between obstetric and nonobstetric files and between obstetric regional and general anesthesia. Difficult intubation and pulmonary aspiration were the leading causes of claims and death in obstetric files. Damaging events related to the respiratory system were more common among obese than nonobese parturients. A Canadian review of the 1990–1997 closed legal actions involving anesthesiologists identified 42 claims (13 in obstetrics) related to the use of central neuraxial block. The outcome in the majority of obstetric cases resulted in no or minor disability, except for one case of paraplegia after cesarean delivery (details of block not provided). The legal outcome was favorable for the patient in 10% of regional anesthesia claims compared with 28% of all anesthesia-related claims. [14]
[87]
[87]
Neurologic Complications Associated with Epidural Anesthesia
In a 1975 to 1983 study from Winnipeg, Canada, the postpartum paresthesias and motor dysfunction were all of transient duration (< 72 hr). The overall rate was 19 per 10,000 deliveries, but primiparas (27.9 vs. 11.7 in multiparas), women who had prolonged labors and forceps/vacuum-assisted deliveries (28.5 vs. 11.0 in spontaneous deliveries), and those who had any type of anesthesia (considered to be a priori at higher risk) were more likely to experience a neurologic deficit. The rate of complications was low (2.4 per 10,000) in women who delivered without analgesia in contrast to delivery under epidural (36.2 or 1 per 277 deliveries) and general anesthesia (34.7 or 1 per 288). Ong and coworkers concluded that neurologic deficits after labor and delivery are rare and that the causal relationship with epidural analgesia is highly unlikely. An inquiry of more than 11,000 women in Birmingham, England, 13 months to 9 years after delivery, from 1978 to 1985, found that women who delivered with epidural anesthesia (compared with those who delivered without) more commonly complained of backache (19% vs. 11%), frequent headaches (5% vs. 3%), migraine (2% vs. 1%), and tingling in hands or fingers (3% versus 2%). Twenty-six women reported numbness or tingling in the lower back, buttocks, and legs, and 23 of them had received epidural anesthesia. The high rate of long-term numbness or tingling postpartum (presumably) associated with epidural analgesia (48 per 10,000) remained an isolated finding of the Birmingham study that was not confirmed by later investigators. A 1982 to 1986 survey of United Kingdom obstetric units identified 108 nonfatal events after 505,000 epidurals (2 per 10,000). The most frequent complications were single nerve neuropathy (rate 0.75 per 10,000; 37 of 38 women recovered), convulsions, prolonged headache after dural puncture, too high level of block, urinary problems, severe backache, and cranial nerve palsy; permanent damage was considered to have occurred in five cases. A United Kingdom 1990 to 1991 prospective survey confirmed that the incidence of reversible neuropathy after obstetric epidural (3.5 per 10,000) and spinal anesthesia (5.4 per 10,000) is low. A series of seven obstetric cases of radiculopathy were encountered within a period of 1 year. A stiff (Teflon) epidural catheter and a direct mechanical trauma were considered the most likely causes of injury. The symptoms remained unresolved in two women from 2 to 9 months later. [135]
[135]
[136]
[136]
[44]
[45]
[137]
Holdcroft and coworkers addressed prospectively all neurologic complications associated with pregnancy in the 1991 to 1992 period. The study covered more than 40,000 deliveries in the Northwest Thames Region, England, and an independent specialist panel analyzed the cases according to notifications from hospital and community specialists. The majority of cases were only identified within the community; thus, an audit restricted to the hospital data would provide a falsely low incidence of morbidity. The neurologic complications associated with pregnancy and delivery and persisting for more than 6 weeks were identified in 19 women (1 per 2530 deliveries). Epidural analgesia was used in 13 women who had neurologic complications. It was considered contributory to a disorder in just one case of more than 13,000 epidurals. In other words, an epidural block was five times less likely to be of cause of injury than pregnancy, labor, delivery, and preexisting diseases. The same proportion of cases involved the upper and lower parts of the body. Higher prepregnant body index was found in 60% of women with pregnancyassociated neurologic problems. The authors concluded that, in contrast to a dramatic decrease in maternal mortality rate in the past decades, “neurological maternal morbidity has remained static, although it can cause serious distress and disability.” Another eight women in the Holdcroft analysis had no identifiable lesion, but their symptoms, suggestive of neurologic dysfunction, such as back pain, stress incontinence, or paresthesias, could not be excluded. These injuries were considered by the panel to be “mechanical rather than neurological.” However, several factors/mechanisms, including regional anesthesia, could be simultaneously involved. Bladder and sphincter disorders have been previously associated with obstetric epidural block. Severe bladder dysfunction (rarely, complete atony) could be encountered after recovery from a central neuraxial block. An interview study revealed a de novo stress incontinence after vaginal delivery in 27% of women who delivered under epidural analgesia, compared with 13% in the control group. In those who had epidural block, the first stage of labor lasted significantly longer. After 1 year, stress incontinence persisted in 7% of the epidural group and 3% of the control group. An [38]
[38]
[38]
[138]
[139]
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analysis of 3364 labors found a low incidence of significant but temporary urinary retention. Twenty-seven of 30 women delivered under epidural block. [140]
A prospective study (1989 to 1994) from an Australian referral obstetric unit and an audit (1987 to 1997) from a district hospital in the United Kingdom each analyzed more than 10,000 epidural cases. The incidence of complications, such as inadvertent intravascular injection, subdural or extra-arachnoid injection resulting in an asymmetrically high block, or inadvertent subarachnoid injection resulting in a rapid, dense, and high spread of local anesthetic, was extremely low (< 0.1% –