Textbook Of Neurointensive Care

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Saunders An Imprint of Elsevier

The Curtis Center Independence Square West Philadelphia, Pennsylvania 19106

TEXTBOOK OF NEUROINTENSIVE CARE Copyright © 2004, Elsevier Inc. All rights reserved.

ISBN: 0-7216-9418-7

No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopying, recording, or any information storage and retrieval system, without permission in writing from the publisher. Permissions may be sought directly from Elsevier’s Health Sciences Rights Department in Philadelphia, PA, USA: phone: (+1) 215 238 7869, fax: (+1) 215 238 2239, e-mail: [email protected]. You may also complete your request on-line via the Elsevier Science homepage (http://www.elsevier.com), by selecting “Customer Support” and then “Obtaining Permissions”.

NOTICE Medicine 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 licensed prescriber, relying on experience and knowledge of the patient, to determine dosages and the best treatment for each individual patient. Neither the publisher nor the authors assume any liability for any injury and/or damage to persons or property arising from this publication.

Library of Congress Cataloging-in-Publication Data Textbook of neurointensive care / [edited by] A. Joseph Layon, Andrea Gabrielli, and William A. Friedman.—1st ed. p. ; cm. ISBN 0-7216-9418-7 1. Neurological intensive care. I. Layon, A. Joseph. II. Gabrielli, Andrea. III. Friedman, William A. (William Alan) [DNLM: 1. Central Nervous System Diseases. 2. Intensive Care. 3. Perioperative Care. WL 300 T355 2004] RC350.N49T49 2004 616.8¢0428—dc22 2003066791 Executive Editor: Allan Ross Senior Editor: Natasha Andjelkovic Assistant Editor: Peter McEllhenney Printed in the United States of America Last digit is the print number: 9 8 7

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To all who struggle for humanity, peace, and justice To our people and their heroic aspirations To our families To the memory of our indefatigable friend and colleague, Peter Safar Hay hombres que luchan un dia y son buenos. Hay otros que luchan un año y son mejores. Hay quienes luchan muchos años y son muy buenos. Pero hay los que luchan toda la vida: Esos son los imprescindibles Die Schwachen kämpfen nicht. Die Stärkeren Kämpfen vielleicht eine Stunde lang. Die noch stärker sind, kämpfen viele Jahre. Aber die Stärksten kämpfen ihre Leben lang. Diese Sind unentberlich. Bertolt Brecht Kantate zu Lenins Todestag, #7 Gesammelte Werke 9, Ffm, Suhrkamp, 1966, 691

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Contributors

Bizhan Aarabi, MD, FACS, FRCSC Associate Professor of Neurosurgery, Department of Neurosurgery, University of Maryland School of Medicine; Director of Neurotrauma, University of Maryland Medical System Baltimore, MD Shahram Amini, MD Visiting Scholar, University of Florida College of Medicine Gainesville, FL Assistant Professor of Anesthesiology; Chief, Division of Critical Care; Associate Professor for Education; Khatam-al-anbia Hospital School of Medicine Zahedan, IRAN John L. D. Atkinson, MD, FACS Professor of Neurosurgery, Mayo School of Medicine; Consulting Neurosurgeon and Co-Director, Neurosurgery/Neurology Intensive Care Unit St. Mary’s Hospital Rochester, MN Issam A. Awad, MD, MSc, FACS The Ogsbury-Kindt Chair in Neurosurgery, Professor of Neurosurgery, Neurology, and Pathology, University of Colorado Health Sciences Center Denver, CO

Matthew V. Burry, MD Endovascular Fellow, Department of Neurological Surgery, University of Florida College of Medicine Gainesville, FL Lawrence J. Caruso, MD Associate Professor of Anesthesiology and Critical Care, University of Florida College of Medicine Gainesville, FL Jie Deng, MD Department of Neuroscience, McKnight Brain Institute, Powell Gene Therapy Center, University of Florida College of Medicine Gainesville, FL Howard M. Eisenberg, MD Professor and Chair, Department of Neurosurgery, University of Maryland School of Medicine; Chief of Neurosurgery, University of Maryland Medical System Baltimore, MD Richard G. Fessler, MD, PhD Professor and Chief, Section of Neurosurgery, University of Chicago School of Medicine Chicago, IL

Joella Beard, MD Rehabilitation & Sports Medicine, LLC Anchorage, AK

Kelly D. Foote, MD Assistant Professor, Department of Neurological Surgery, University of Florida College of Medicine Gainesville, FL

Wilhelm Behringer, MD Department of Emergency Medicine, Vienna General Hospital Vienna, AUSTRIA

Cory M. Franklin, MD Professor of Medicine, Director, Medical Intensive Care Unit, Chicago Medical School Chicago, IL

Corinna Burger, PhD Assistant Professor, Department of Molecular Genetics and Microbiology, University of Florida College of Medicine Gainesville, FL

William A. Friedman, MD Professor and Chair, Department of Neurological Surgery, University of Florida College of Medicine Gainesville, FL vii

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Contributors

Andrea Gabrielli, MD Associate Professor of Anesthesiology and Surgery, Medical Director, Hyperbaric Center; Medical Director, Respiratory Care, University of Florida College of Medicine Gainesville, FL Robin L. Gilmore, MD Neurology Center of Middle Tennessee Columbia, TN Eric H. Gluck, MD, FCCP, FCCM Associate Chair of Medicine, Finch University of Health Sciences, Chicago Medical School; Chief, Pulmonary and Critical Care Medicine, North Chicago Veterans Affairs Medical Center North Chicago, IL

Ricardo Morales Laramendi, MD Professor of Internal Medicine, Division of Critical Care Medicine, Saturnino Lora Provincial Teaching Hospital, Instituto Superior de Ciencias Medicas de Santiago de Cuba Santiago de Cuba, CUBA A. Joseph Layon, MD, FACP Professor of Anesthesiology, Surgery, and Medicine, University of Florida College of Medicine; Medical Director, Gainesville Fire Rescue Service Gainesville, FL Dean Lin, MD, PhD Resident, Department of Neurological Surgery, University of Florida College of Medicine Gainesville, FL

Dietrich Gravenstein, MD Associate Professor of Anesthesiology, Jerome H. Modell Professor and Chair, Department of Anesthesiology, University of Florida College of Medicine Gainesville, FL

Emilio B. Lobato, MD Associate Professor, Department of Anesthesiology, University of Florida College of Medicine; Chief, Cardiac Anesthesia, Shands Hospital Gainesville, FL

Nikolaus Gravenstein, MD Professor of Neurosurgery, University of Florida College of Medicine Gainesville, FL

Michael E. Mahla, MD Associate Professor of Anesthesiology and Neurosurgery, University of Florida College of Medicine Gainesville, FL

David M. Greer, MD, MA Assistant Professor, Harvard Medical School; Instructor in Neurology, Massachusetts General Hospital Boston, MA

Ronald J. Mandel, PhD Department of Neuroscience, McKnight Brain Institute, Powell Gene Therapy Center, University of Florida College of Medicine Gainesville, FL

Bernard H. Guiot, MD, FRCSC Attending Neurosurgeon, Colorado Neurological Institute Denver, CO Hugh C. Hemmings, Jr., MD, PhD Professor of Anesthesiology and Pharmacology, Vice Chair for Research in Anesthesiology, Weill Medical College of Cornell University New York, NY Daniel Huddle, DO Associate Professor of Radiology and Neurosurgery, University of Colorado Health Sciences Center Denver, CO

Richard J. Melker, MD, PhD Professor of Anesthesiology, Pediatrics, and Biomedical Engineering, University of Florida College of Medicine Gainesville, FL Ehud Mendel, MD Associate Professor, Department of Neurosurgery, University of Texas, MD Anderson Cancer Center Houston, TX Robert A. Mericle, MD Assistant Professor, Department of Neurological Surgery, University of Florida College of Medicine Gainesville, FL

Ahamed H. Idris, MD Professor of Emergency Medicine, University of Texas, Southwestern Parkland Medical Center Dallas, TX

Chet Morrison, MD Fellow, Department of Critical Care, University of Maryland Shock Trauma Center, University of Maryland School of Medicine Baltimore, MD

Pascal M. Jabbour, MD Resident in Neurosurgery, University of Colorado Health Sciences Center Denver, CO

Lorenzo F. R. Muñoz, MD Section Chief, Pediatric Neurosurgery, Rush Presbyterian–St. Luke’s Medical Center Chicago, IL

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Contributors

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Katrina Murphy, MD, PhD Chief Resident, Department of Neurosurgery, University of Maryland Medical System Baltimore, MD

Albert L. Rhoton, Jr., MD Professor of Neurosurgery, University of Florida College of Medicine Gainesville, FL

Antoˆnio C. M. Mussi, MD Clinical Instructor, Department of Neurology, University of Sao Paulo Sao Paulo, BRAZIL

Steven A. Robicsek, MD, PhD Assistant Professor, Department of Anesthesiology, University of Florida College of Medicine Gainesville, FL

David A. Peace Medical Investigator, Department of Neurological Surgery, University of Florida College of Medicine Gainesville, FL

Edgardo Rodriguez, PhD Graduate Assistant Research, Department of Neuroscience, McKnight Brain Institute, University of Florida College of Medicine Gainesville, FL

Carmen E. S. Peden, BS Department of Neuroscience, McKnight Brain Institute, Powell Gene Therapy Center, University of Florida College of Medicine Gainesville, FL Emily Piercefield, MD Department of Neuroscience, McKnight Brain Institute, Powell Gene Therapy Center, University of Florida College of Medicine Gainesville, FL David W. Pincus, MD, PhD Assistant Professor, Department of Neurological Surgery, University of Florida College of Medicine Gainesville, FL Ronald G. Quisling, MD Professor, Department of Radiology; Director, Section of Neuroradiology, University of Florida College of Medicine Gainesville, FL Alejandro A. Rabinstein, MD Assistant Professor of Neurology, University of Miami School of Medicine Miami, FL Kenneth H. Rand, MD Professor of Pathology and Medicine, University of Florida College of Medicine; Director of Clinical Pathology, Director of Clinical Microbiology, Shands Hospital at the University of Florida Gainesville, FL Paul J. Reier, PhD Eminent Scholar, Department of Neuroscience, McKnight Brain Institute, University of Florida College of Medicine Gainesville, FL

Richard J. Rogers, MD, PhD Assistant Professor, Department of Anesthesiology, University of Florida College of Medicine Gainesville, FL Peter Safar, MD (Deceased 2003) Distinguished Service Professor, Safar Center for Resuscitation Research, University of Pittsburgh Pittsburgh, PA Jacob Samuel, MD Assistant Professor of Medicine, Rush Medical College Chicago, IL Andreas Sarrigiannidis, MD, FCCP Fellow, Division of Pulmonary and Critical Care Medicine, Finch University of Health Sciences, Chicago Medical School North Chicago, IL Christoph N. Seubert, MD, PhD Assistant Professor of Anesthesiolgy; Director, Intraoperative Neurophysiologic Monitoring Laboratory, University of Florida College of Medicine Gainesville, FL David H. Shafron, MD Pediatric Neurosurgeon, Phoenix Children’s Hospital Phoenix, AZ James W. Simpkins, PhD Professor and Chair, Department of Pharmacology/ Neuroscience; Director, Institute of Aging & Alzheimers Research University of North Texas Fort Worth, TX Lorna Sohn-Williams, MD Assistant Professor of Neuroradiology, Department of Radiology, University of Florida College of Medicine Gainesville, FL

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Contributors

Cheri A. Sulek, MD Associate Professor of Anesthesiology, University of Florida College of Medicine; Associate Professor of Anesthesiology, Malcolm Randall Veterans Affairs Medical Center Gainesville, FL Sean Michael Sullivan, PhD Associate Professor, Department of Pharmaceutics, University of Florida College of Pharmacy; Shands Cancer Institute Gainesville, FL Research Director, Let There Be Hope Research Institute Beverley Hills, CA Trent L. Tredway, MD Chief Resident, Department of Neurological Surgery, Rush Presbyterian–St. Luke’s Medical Center Chicago, IL Arthur J. Ulm, MD Resident, Department of Neurological Surgery, University of Florida College of Medicine Gainesville, FL Margaret J. Velardo, PhD Research Assistant Professor, Department of Neuroscience, McKnight Brain Institute, University of Florida College of Medicine Gainesville, FL Jian Wang, PhD Department of Anesthesia, Stanford University School of Medicine Palo Alto, CA

Max Weinmann, MBBS, MD, FRACP, DipMBM Associate Professor, Medical Director, Critical Care, Department of Anesthesiology, Medical College of Virginia Richmond, VA Robin L. Wellington, PhD Visiting Assistant Professor, Department of Neurosurgery, Rush Presbyterian–St. Luke’s Medical Center Chicago, IL Hung Tzu Wen, MD Clinical Instructor, Division of Neurosurgery, University of Sao Paulo, Hosptial des Clinicas Sao Paulo, BRAZIL Eelco F. M. Wijdicks, MD Professor of Neurology, Mayo Medical School; Chair, Division of Critical Care Neurology, Mayo Clinic, Saint Mary’s Hospital Rochester, MN Jack E. Wilberger, Jr., MD Allegheny University Pittsburgh, PA Shao-Hua Yang, MD Department of Pharmacology and Neuroscience, University of North Texas Health Science Center Fort Worth, TX

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Preface

Whether apocryphal or not, it is said that in the near future, hospitals will be composed of three areas: the emergency department, the operating rooms, and the intensive care unit (ICU). The rationale for such a statement is that managed care is driving medicine in the United States toward outpatient care except in the cases of very ill patients, who are admitted into the ICU. Our experience is that the severity of illness of the patients we care for is greater every year. This is as true in the general ICU population as it is in those individuals with neurologic disease. Partly because of this increased severity of illness in patients with neurologic injury, we conceived the project that led to this book. The book before you is unusual in several respects. It is a textbook, rather than a monograph, of neurointensive care. We initiate the book with a solid review of neurophysiology and neuroanatomy, including anatomy as seen through the “eyes” of our radiology colleagues. We remind the reader of the problems that our neurosurgical colleagues expect to see, even in a well-performed procedure. The body of the book then follows, first with general topics and then with specific disease states. Difficult ethical issues, including topics such as access to health care, alterations of a do not resuscitate order in patients going to the operating room, withdrawal and withholding of therapy, physician-assisted suicide, and brain death are embraced and discussed. We finish the book with clinically relevant research issues that are present on the horizon, beckoning us forward with the unfulfilled promises that make up their potential. The use of evidence-based medicine when such data exist, provision of protocols and algorithms, and honesty when our best approximations and biases are the only data available has served as our credo.

As any authors should, we undertook this book with some hesitation. To write a book—any book—means laying open, for the world to see, one’s biases, flaws, and inadequacies. This is especially true when dealing with an area as broad and complex as treatment of the critically ill patient with neurologic injuries. While others might have written a different book, we undertook this project and offer it, with humility, to our colleagues. Although we live in a society that lionizes—at least rhetorically—the individual and individual exploits, work of any quality is of necessity the culmination of a collective effort. This is true in the case of our textbook. Our coauthors are dedicated clinicians and scientists with whom we are honored to be associated. They have worked diligently in the process of creation of this work. The publishers and printers are remarkable people and true professionals who put up with our foibles and ideas of cover art (we lost on that one). To Allan Ross, Executive Editor, Natasha Andjelkovic, Senior Editor, and Peter McEllhenney, Assistant Editor at Elsevier; Jesamyn Angelica; and Nancy Lombardi at PM Gordon Associates, we offer our heartfelt thanks and appreciation. To Poppy Meehan, the hand that guided the entire project, we can only say thank you. While this is a work of many, we are responsible for any errors or other flaws. We hope you find this text useful. Let us know what you think. There should, after all, be a second edition. A. Joseph Layon, MD, FACP Andrea Gabrielli, MD William A. Friedman, MD

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Foreword

This textbook represents an enormously thorough effort at not only addressing the issue of neurointensive care in the specific treatment mode but also providing the reader with a comprehensive body of knowledge in regard to the anatomy and physiologic function, both normal and abnormal, of the patient suffering from disorders of neurologic systems. Although the editors have authored a number of the chapters themselves, they also have called on other international experts to contribute to this work. The result is a publication that is not only current in its contents, but also contains material presented by experts in the field. Many of the authors have dedicated their lifetime to the study of neurologic systems in health and disease. Others are relatively new to the field and add a breath of enthusiasm for the future. If I were to have one criticism of this publication, it would be that the title is much narrower than the content of the book itself. Thus, in seeing the title, prospective readers may

not appreciate the enormous amount of comprehensive material that is available to them for study and use in treating their patients. As someone who had the distinct pleasure of working with the three editors in their formative years in residency and/or fellowship, I read the prepublication manuscript with enormous pride. There are many who say that the success of educators can best be appreciated by the accomplishments of their students. The supreme compliment is when the students actually surpass their teachers by their deeds and accomplishments. I feel that through the Textbook of Neurointensive Care, Doctors Friedman, Gabrielli, and Layon have, indeed, paid the supreme compliment to Doctor Albert Rhoton, myself, and others who had a significant role in their growth and development as physicians, scientists, and academicians. Jerome H. Modell, MD

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Chapter 1 Basic Neuroanatomy for Neurointensive Care Unit Hung Tzu Wen, MD, Antônio C. M. Mussi, MD, and Albert L. Rhoton, Jr., MD

Introduction The goal of this chapter is to provide the necessary information on the neuroanatomy that enables the neurointensive care unit staff to: (1) perform a concise but precise neurologic examination and be able to establish the location of the event (anatomic diagnosis), (2) understand the major vascular (arterial and venous) territories of the brain and correlate them with the findings of the neurologic examination and the radiologic findings (computed tomography [CT] or magnetic resonance imaging [MRI]), (3) understand the risks and the potential neurologic complications of the most commonly used neurosurgical procedures, and (4) establish the prevention or early detection and treatment of those complications. The adult central nervous system can be divided into eight major components: (1) cerebral hemisphere, (2) basal ganglia, (3) diencephalon, (4) midbrain, (5) pons, (6) medulla, (7) cerebellum, and (8) spinal cord. The cerebral hemispheres plus basal ganglia and the thalamus are collectively called forebrain. In describing the anatomy of the central nervous system of the brain, some confusion can arise when terms such as rostral, caudal, or both, are used instead of anterior or superior, inferior or posterior. The term “rostral” means nose or mouth region and “caudal” means tail. As for spinal cord and the brainstem, ventral means anterior, dorsal means posterior, rostral means superior, and caudal means inferior. However, because of the 110-degree flexure that the human brain undergoes during development, for the cerebrum and diencephalon, rostral means anterior, caudal means

posterior, ventral means inferior, and dorsal means superior (Fig. 1-1).

Cerebrum Lateral Surface: Neural Structures The cerebrum is arbitrarily divided into five lobes: frontal, temporal, parietal, occipital, and the hidden insula.1 On the lateral surface, the central sulcus and the posterior ramus of the sylvian fissure separate the frontal lobe from the parietal and temporal lobes. Posteriorly, the lateral parietotemporal line, which runs from the impression of the parietooccipital sulcus on the lateral surface to the preoccipital notch, separates the occipital lobe from the parietal and temporal lobes. The parietal and the temporal lobes are separated by the posterior ramus of the sylvian fissure and by the temporo-occipital line, which runs from the posterior end of the posterior ramus of the sylvian fissure to the midpoint of the lateral parietotemporal line. The central sulcus starts from the medial surface of the hemisphere and extends on the lateral surface of the hemisphere from medial to lateral, superior to inferior, and posterior to anterior. It ends adjacent to the posterior ramus of the sylvian fissure approximately 2.5 cm behind the anterior ascending ramus of the sylvian fissure.1 As a characteristic of its trajectory, the central sulcus presents a sinuous silhouette, forming a well-defined superior knee with its convexity directed posteriorly “…” and a not constant inferior knee with its convexity directed anteriorly “Ã.” Together they resemble 3

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Section I 

Introduction ral gyri. The inferior temporal gyrus occupies not only the lateral surface of the cerebrum, but it is also the most laterally placed gyrus on the basal surface of the cerebrum (Fig. 1-2A).

Figure 1-1. Midsagittal section displaying the differences between the spatial orientation of the cerebrum and the brainstem.

the shape of an inverted letter “S” that is best identified near the midline. Frontal Lobe The two main sulci are the superior and inferior frontal sulci, which are anteroposteriorly oriented and extend from the precentral sulcus to the frontal pole. These two frontal sulci divide the lateral surface of the frontal lobe into three gyri: the superior, the middle, and the inferior frontal gyri. The inferior frontal gyrus is divided into three parts by the anterior horizontal, the anterior ascending and the posterior rami of the sylvian fissure: pars orbitalis, triangularis, and opercularis. The apex of the pars triangularis is directed inferiorly toward the junction of three rami of the sylvian fissure; this junctional point coincides with the anterior limiting sulcus of the insula in the depth of the sylvian fissure. It also marks the anterior limit of the basal ganglia and the location of the anterior horn of the lateral ventricle. Temporal Lobe The temporal lobe is limited superiorly by the posterior ramus of the sylvian fissure and posteriorly by the temporooccipital and the lateral parietotemporal lines. It presents two main sulci: the superior and the inferior temporal sulci, which divide the lateral surface of the temporal lobe into three gyri, the superior, the middle, and the inferior tempo-

Parietal Lobe The parietal lobe is limited anteriorly by the central sulcus, medially by the interhemispheric fissure, inferolaterally by the sylvian fissure and the temporo-occipital line, and posteriorly by the lateral parietotemporal line. Its two main sulci are the postcentral and the intraparietal sulci. The postcentral sulcus is very similar to the central sulcus, except for the “inverted S” morphology and for its variable continuity. It is the posterior limit of the postcentral gyrus. The intraparietal sulcus starts at the postcentral sulcus and is directed posteriorly and inferiorly toward the occipital pole; its direction is often parallel and 2 to 3 cm lateral to the midline. The intraparietal sulcus divides the lateral surface of the parietal lobe into two parts: the superior parietal lobule, which is the superomedial and the smaller part, and the inferior parietal lobule, which is the inferolateral and the larger part. The inferior parietal lobule is constituted by the supramarginal and the angular gyri. The supramarginal gyrus is the posterior continuation of the superior temporal gyrus that turns around the posterior ascending ramus of the sylvian fissure to become the most posterior operculum of the sylvian fissure on the parietal side. The angular gyrus is the posterior continuation of the middle temporal gyrus and turns superiorly and medially up to the intraparietal sulcus; it is sometimes limited between the two posterior terminations of the superior temporal sulcus, the angular and the anterior occipital rami (Fig. 1-2B). Occipital Lobe The occipital lobe is located behind the lateral parietotemporal line and is composed of a number of irregular convolutions that are divided by a short horizontal sulcus, the lateral occipital sulcus, into the superior and inferior occipital gyri. As important as the knowledge of the superficial anatomy of the cerebrum is, its correlation to the neural structures located in the depth of the cerebrum is equally as important. The precentral gyrus begins at the medial surface of the cerebrum, just above the level of the splenium of the corpus callosum; it then runs from medial to laterally, and from posterior to anteriorly to pass above the body of the lateral ventricle, thalamus, posterior limb of the internal capsule, and the posterior part of the lentiform nucleus to finally reach the sylvian fissure midway between the anterior and the posterior limits of the insula (Fig. 1-2C). The functional map of the lateral surface of the hemisphere is shown in Figure 1-2D. Sylvian Fissure The sylvian fissure is not merely a complex fissure that carries the middle cerebral artery and its branches, and sep-

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Basic Neuroanatomy for Neurointensive Care Unit

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D C Figure 1-2. A, Lateral surface of the right hemisphere: 1 = central sulcus; 2 = superior precentral sulcus; 3 = superior frontal sulcus; 4 = intraparietal sulcus; 5 = postcentral sulcus; 6 = precentral sulcus; 7 = postcentral sulcus; 8 = inferior precentral sulcus; 9 = superior frontal gyrus; 10 = angular gyrus; 11 = supramarginal gyrus; 12 = middle frontal gyrus; 13 = inferior frontal sulcus; 14 = posterior ramus of the sylvian fissure; 15 = pars opercularis; 16 = Heschl’s gyrus; 17 = superior temporal gyrus; 18 = pars triangularis; 19 = pars orbitalis; 20 = middle temporal gyrus; 21 = inferior temporal gyrus. B, Posterolateral view of the right hemisphere: 1 = central sulcus; 2 = intraparietal sulcus; 3 = postcentral gyrus; 4 = superior parietal lobule; 5 = supramarginal gyrus; 6 = angular ramus; 7 = posterior ramus of the sylvian fissure; 8 = angular gyrus; 9 = anterior occipital ramus; 10 = superior temporal gyrus; 11 = superior temporal sulcus; 12 = middle temporal gyrus. C, Anterosuperior view of the precentral gyrus with its functional mapping. D, The functional mapping of the lateral surface of the right hemisphere.

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Introduction

arates the frontal and the parietal lobes from the temporal lobe. From a neurosurgical viewpoint, the sylvian fissure can be considered as the gateway connecting the surface of the anterior part of the brain to its depth with all the neural and vascular components along the way. The extensive spectrum of the neural and the vascular structures within the reach of the transylvian approach includes insula, basal ganglia, the lateral ventricle, middle cerebral artery, temporal operculum, frontal and parietal opercula, uncus, orbit, anterior cranial fossa, optic nerve, internal carotid artery and branches, lamina terminalis, and interpeduncular fossa. The sylvian fissure starts on the basal surfaces and extends to the lateral surface of the cerebrum. On both surfaces, the sylvian fissure presents a superficial and a deep part.2 The superficial part of the sylvian fissure presents a stem and three rami. The stem extends medially from the uncus, between the frontal and temporal lobes to the lateral end of the sphenoid ridge, where the stem divides itself into anterior horizontal, anterior ascending, and the posterior rami. The deep (cisternal) part is divided into an anterior part, “sphenoidal compartment,” and a posterior part, “operculoinsular compartment,” The sphenoidal compartment arises in the region of the limen insulae, and extends posteriorly to the sphenoid ridge between the basal frontal and the temporal lobes (Fig. 1-3A). The operculoinsular compartment is formed by two narrow clefts, the opercular cleft between the opposing lips of the frontoparietal and the temporal opercula, and the insular cleft, which has a superior limb located between the insula and the frontoparietal opercula, and an inferior limb between the insula and the temporal operculum (Fig. 1-3B). The opercular cleft—the gyri that constitute the frontal and parietal opercula of the sylvian fissure—are (from posterior to anterior): the supramarginal, the postcentral, and the precentral gyri, pars opercularis, triangularis, and orbitalis The gyri that constitute the temporal operculum of the sylvian fissure are (from posterior to anterior): planum temporale, Heschl’s gyrus, and the planum polare.3 Each gyrus of the frontoparietal opercula is closely related to its counterpart on the temporal side; the supramarginal gyrus is in close contact with the planum temporale; the postcentral gyrus to Heschl’s gyrus, and the precentral gyrus, pars opercularis, triangularis, and orbitalis are related to the planum polare. The site on the posterior ramus of the sylvian fissure where the postcentral gyrus meets Heschl’s gyrus is projected in the same coronal plane of the external acoustic meatus. The medial wall of the sylvian fissure is the insula or island of Reil, which can only be seen when the lips of the sylvian fissure are widely separated. The insula has the shape of a pyramid with its apex directed inferiorly, and it connects the temporal lobe to the posterior orbital gyrus via limen insulae. The limen insulae

is composed of fibers of the uncinate fasciculus covered by a thin layer of gray matter. “Limen,” meaning threshold, was introduced to indicate that the limen insulae serves as threshold between the carotid cistern medially and the sylvian fissure laterally.4 The insula is encircled and separated from the opercula by a deep furrow called the circular or limiting sulcus of the insula, which presents the superior, anterior, and inferior parts. From the limen insulae, the sulci and gyri of the insula are directed superiorly in a radial manner. The deepest sulcus, the central sulcus of insula, is a constant sulcus that extends upward and backward across the insula, in the general line of the central sulcus of the cerebrum. It divides the insula into a large anterior part that is divided by several shallow sulci into three to five short gyri, and a posterior part that is formed by anterior and posterior long gyri. From microsurgical and radiologic viewpoints, the insula represents the external covering of a mass constituted by the extreme, external, and internal capsules, claustrum, basal ganglia, and thalamus. The superior, anterior, inferior, and posterior limits of the insula on the lateral projection correspond to superior, anterior, inferior, and posterior limits of the previously mentioned mass (Fig. 1-3C). Lateral Ventricles Wrapping the previously described mass are the lateral ventricles. These are C-shaped cavities located close to the midline, one on each side of the hemisphere. Each ventricle has five components: frontal horn, body, atrium, and occipital and temporal horns.5 The frontal horn is located in front of the foramen of Monro, and presents roof; floor; and anterior, lateral, medial, and posterior walls. The roof is constituted by the transition between the genu and the body of the corpus callosum, the narrow floor by the rostrum of the corpus callosum, the medial and the posterior walls by septum pellucidum and the thalamus, respectively. The majority of the lateral wall of the frontal horn is represented by the head of the caudate nucleus, except for its most anterior part, constituted by the most anterior part of the anterior limb of the internal capsule, and it is in close relation to the anterior limiting sulcus of the insula. The body of the lateral ventricle is located behind the foramen of Monro, and extends to the point where the septum pellucidum disappears and the corpus callosum and fornix meet. It presents roof, floor, and lateral and medial walls. The roof is formed by the body of the corpus callosum, the medial wall by the septum pellucidum above and the body of the fornix below, the lateral wall by the body of the caudate nucleus, and the floor by the thalamus. The caudate nucleus and the thalamus are separated by the striothalamic sulcus, the groove in which the stria terminalis and the thalamostriate vein course.

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Figure 1-3. A, Basal view: 1 = lateral orbital gyrus; 2 = anterior orbital gyrus; 3 = medial orbital gyrus; 4 = rectus gyrus; 5 = olfactory tract; 6 = posterior orbital gyrus; 7 = temporal pole; 8 = lateral olfactory striae; 9 = medial olfactory striae; 10 = optic chiasm and infundibulum; 11 = anterior perforated substance; 12 = tuber cinereum and mamillary bodies; 13 = uncus; 14 = limen insulae; 15 = amygdala; 16 = rhinal sulcus; 17 = head of hippocampus; 18 = posterior perforated substance; 19 = crus cerebri; 20 = inferior temporal gyrus; 21 = lateral mesencephalic sulcus; 22 = medial geniculate body; 23 = tegmentum of the midbrain; 24 = parahippocampal gyrus; 25 = collateral sulcus; 26 = pineal and the splenium of the corpus callosum; 27 = fusiform gyrus; 28 = occipitotemporal gyrus; 29 = atrium; 30 = basal parietotemporal line. B, Frontal view: 1 = corpus callosum; 2 = body of the caudate nucleus; 3 = septum pellucidum; 4 = superior limiting sulcus of insula; 5 = frontal operculum; 6 = internal capsule; 7 = thalamostriate vein; 8 = putamen; 9 = superior cleft of the insular compartment; 10 = opercular compartment; 11 = third ventricle; 12 = globus pallidus; 13 = amygdala; 14 = inferior cleft of the insular compartment (inferior limiting sulcus of insula); 15 = head of the hippocampus. C, Lateral view of the right insula and lateral ventricle: 1 = cingulate gyrus; 2 = corpus callosum; 3 = septum pellucidum; 4 = bulb of the callosum; 5 = superior limiting sulcus of the insula; 6 = calcar avis; 7 = glomus; 8 = last short gyrus of insula and the central sulcus of insula. D, Superior view: 1 = frontal lobe; 2 = genu of the corpus callosum; 3 = frontal horn; 4 = septum pellucidum; 5 = head of the caudate nucleus; 6 = anterior limb of the internal capsule; 7 = body of the caudate nucleus; 8 = foramen of Monro; 9 = genu of the internal capsule; 10 = lentiform nucleus; 11 = striothalamic sulcus; 12 = posterior limb of the internal capsule; 13 = thalamus; 14 = internal cerebral vein; 15 = collateral eminence; 16 = glomus; 17 = pineal gland; 18 = collateral trigone; 19 = straight sinus.

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Introduction

The atrium and the occipital horn together form a roughly triangular cavity, with the apex pointing posteriorly in the occipital lobe and the base anteriorly on the pulvinar. The atrium has roof; floor; and anterior, medial, and lateral walls. The roof is formed by the body, splenium, and the tapetum of the corpus callosum; the floor by the collateral trigone, a triangular area that bulges upward over the posterior end of the collateral sulcus. The medial wall is formed by two roughly horizontal prominences: the upper prominence is the bulb of the callosum, which is formed by the large bundle of fibers called the forceps major, and it connects the two occipital lobes; the lower prominence is the calcar avis, which overlies the deepest part of the calcarine sulcus; the lateral wall has an anterior part, formed by the caudate nucleus as it wraps the lateral margin of the pulvinar, and a posterior part, formed by the fibers of the tapetum as they sweep anteroinferiorly along the lateral margin of the ventricle. At this part of the lateral ventricle, the tapetum separates the ventricular cavity from the optic radiation; the anterior wall has a medial part composed of the crus of the fornix as it wraps the posterior part of the pulvinar, and a lateral part formed by the pulvinar of the thalamus. The occipital horn extends posteriorly into the occipital lobe from the atrium. It varies in size from being absent to extending far posteriorly in the occipital lobe. Its medial wall is formed by the bulb of the callosum and the calcar avis, the roof and lateral wall are formed by the tapetum, and the floor by the collateral trigone. The temporal horn extends forward and inferiorly from the atrium into the medial part of the temporal lobe, and presents roof; floor; and anterior, lateral, and medial walls. The roof is formed by tapetum, the tail of the caudate nucleus, part of the retrolentiform and sublentiform components of the internal capsule, and the amygdaloid nucleus. The retrolentiform component in the roof of the temporal horn is the posterior thalamic radiation that includes the optic radiation; the part of the sublentiform component in the roof of the temporal horn is formed mainly by the acoustic radiation. The amygdaloid nucleus constitutes the most anterior part of the roof of the temporal horn, and is located just above the head of the hippocampus, anterior to the inferior choroidal point, which is the most anterior site of attachment of the choroid plexus in the temporal horn.6 There is no clear separation between the roof of the temporal horn and the thalamus because all fibers of the optic radiation come from the lateral geniculate body. The lateral wall is formed by the tapetum and the optic radiation, and the anterior wall by the amygdaloid body, the posterior two thirds of the medial wall by the choroidal fissure, and the anterior one third of the medial wall by the head of the hippocampus.6 The floor is formed medially by the hippocampus and laterally by the collateral eminence, which is the prominence overlying the collateral sulcus (Fig. 1-3C and D).

On discussing the lateral ventricle, several related elements can be mentioned: foramen of Monro, internal capsule, corpus callosum, fornix, thalamus, caudate nucleus, hippocampus, temporal amygdala, and choroidal fissure. Foramen of Monro. The foramen of Monro communicates

the lateral ventricle to the third ventricle. It is bounded anteriorly and superiorly by the fornix and posteriorly by the thalamus; the elements that run close to the foramen of Monro are the anterior septal vein superior and medially, choroidal plexus posterior and medially, and the thalamostriate vein lateral and posteriorly (Fig. 1-4A). Internal Capsule. The internal capsule has five parts:7,8 ante-

rior and posterior limbs, genu, retrolentiform, and the sublentiform parts. The anterior limb is located between the head of the caudate nucleus and the lentiform nucleus, it contains frontopontine fibers; the posterior limb is located between the thalamus and the lentiform nucleus, and contains corticospinal tract, frontopontine, corticorubral fibers, and fibers of the superior thalamic radiation (somaesthetic radiation) (Fig. 1-4B). The genu comes directly to the ventricular surface and touches the wall of the lateral ventricle immediately lateral to the foramen of Monro in the interval between the caudate nucleus and the thalamus, where the thalamostriate vein usually drains into the internal cerebral vein; the genu contains corticonuclear fibers and anterior fibers of the superior thalamic radiation. The retrolentiform part is located posteriorly to the lentiform nucleus and contains mainly parietopontine, occipitopontine, occipitocollicular, and occipitotectal fibers and the posterior thalamic radiation that includes the optic radiation. The sublentiform part is located below the lentiform nucleus and contains temporopontine, parietopontine fibers, acoustic radiation from the medial geniculate body to the superior temporal, and transverse temporal gyri. Corpus Callosum. The corpus callosum is the largest transverse commissure connecting the cerebral hemispheres. It contributes to the wall of each of the five parts of the lateral ventricle. The corpus callosum has two anterior parts, the rostrum and genu; a central part, the body; and a posterior part, the splenium. The rostrum is located below and forms the floor of the frontal horn. The genu gives rise to a large fiber tract, the forceps minor, which forms the anterior wall of the frontal horn as it sweeps obliquely forward and laterally to connect the frontal lobes. The genu and the body of the corpus callosum form the roof of both the frontal horn and the body of the lateral ventricle. The splenium gives rise to a large tract, the forceps major, which forms a prominence called bulb in the upper part of the medial wall of the atrium and occipital horn as it sweeps posteriorly to connect the occipital lobes. Another fiber tract, the tapetum, which arises in the posterior part of the body and splenium, sweeps

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Figure 1-4. A, Anterolateral view of the right foramen of Monro: 1 = anterior septal vein; 2 = choroid plexus; 3 = thalamus; 4 = thalamostriate vein; 5 = fornix. B, Superior view displaying the distribution of the fibers in the internal capsule; the fibers from the corticospinal tract occupy approximately the anterior half of the posterior limb of the internal capsule: 1 = frontal horn; 2 = anterior limiting sulcus of insula; 3 = head of the caudate nucleus; 4 = claustrum; 5 = lentiform nucleus; 6 = insula; 7 = foramen of Monro; 8 = thalamostriate vein; 9 = thalamus; FT = frontothalamic fibers; FP = frontopontine fibers; S = sensory fibers; TP = temporopontine fibers; V&A = visual and auditory fibers. C, Superior view of the right temporal lobe and temporal horn: 1 = planum temporale; 2 = rhinal sulcus; 3 = anterior segment of the uncus; 4 = apex of the uncus; 5 = posterior segment of the uncus; 6 = head of the hippocampus; 7 = collateral eminence; 8 = Heschl’s gyrus; 9 = inferior choroidal point; 10 = parahippocampal gyrus; 11 = body of the corpus callosum; 12 = tail of the hippocampus; 13 = collateral trigone; 14 = planum temporale. D, Superolateral view of the right lateral ventricle: 1 = left head of the caudate nucleus; 2 = splenium of the corpus callosum; 3 = body of fornix; 4 = thalamus; 5 = foramen of Monro; 6 = bulb of the callosum; 7 = crus of fornix; 8 = lateral geniculate body; 9 = lentiform nucleus; 10 = occipital horn; 11 = calcar avis; 12 = fimbria of fornix and tail of the hippocampus; 13 = collateral trigone; 14 = fimbria and the body of the hippocampus; 15 = head of the hippocampus.

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Introduction

laterally and inferiorly to form the roof and lateral wall of the atrium and the temporal and occipital horns. The tapetum separates the fibers of the optic radiations from the temporal horn and the atrium. Basal Ganglia. Although macroscopically fused and gathered into a “mass” that is involved laterally by insula, the basal ganglia and the thalamus are embryologically and functionally distinct structures. The basal ganglia are telencephalic structures and the thalamus is a diencephalic structure. The basal ganglia consist of four nuclei: (1) striatum (caudate nucleus, putamen and the nucleus accumbens), (2) globus pallidus, (3) substantia nigra, and (4) subthalamic nucleus. The basal ganglia play a major role in voluntary motor movement; however, they do not have direct input or output with the spinal cord. They receive their primary input from the cerebral cortex and send their output to the brainstem, and, via the thalamus, back to the prefrontal, premotor, and motor cortices. The motor activity of the basal ganglia is therefore mostly mediated by motor areas of the frontal lobe. Disturbance of the basal ganglia is usually characterized by: (1) tremor and other involuntary movements, (2) changes in posture and muscle tone, and (3) poverty and slowness of movement without paralysis. The caudate nucleus is another C-shaped structure that wraps around the thalamus; it has a head, body, and tail. The head and the body are lateral walls of the frontal horn and the body of the lateral ventricle. The tail extends from the atrium into the roof of the temporal horn and is continuous with the amygdaloid nucleus. Thalamus. The thalamus is located in the center of the

lateral ventricle. Each lateral ventricle wraps around the superior, inferior, and posterior surfaces of the thalamus. The anterior tubercle of the thalamus is the posterior limit of the foramen of Monro; the posterior part, called pulvinar (pillow) of the thalamus is the wall of three different compartments in the cerebrum: the posterolateral part of the pulvinar is the lateral half of the anterior wall of the atrium; the posteromedial part is covered by the crus of the fornix, and is part of the superolateral wall of the quadrigeminal cistern; the inferolateral part of the pulvinar is the roof of the wing of the ambient cistern. The medial part of the thalamus is the lateral wall of the third ventricle. The thalamus is not a relay station where information is simply passed on to the neocortex—the thalamus acts as a gatekeeper for information to the cerebral cortex, preventing or enhancing the passage of specific information depending on the behavioral state of the person. The thalamus is composed of more than 50 nuclei, which can be divided into specific or relay and nonspecific or diffusely projecting nuclei. The relay nuclei have a specific relationship with a particular region of the neocortex, and are clas-

sically divided into four groups, depending on their position in relation to the internal medullar lamina. The anterior group receives input from the mamillary bodies and from the subiculum of the hippocampal formation. The medial group receives input from the basal ganglia, amygdala, and midbrain, and has been implicated in memory; its major output is to the frontal cortex. The nuclei from ventral group are named according to their position within the thalamus. The ventral anterior and ventral lateral nuclei are important for motor control and carry information from the basal ganglia and cerebellum to the motor cortex. The ventral posterior lateral conveys somatosensory information to the neocortex. The posterior group includes the medial and lateral geniculate nucles, lateral posterior nucleus, and the pulvinar. The medial geniculate nucleus is a component of the auditory system; the lateral geniculate nucleus receives information from the retina and conveys it to the primary visual cortex; the pulvinar seems to be interconnected with parietal, temporal, and occipital lobes. The nonspecific or diffusely projecting nuclei are either located in the midline (midline nuclei) or within the internal medullary lamina (intralaminar nuclei). The largest intralaminar nucleus is the centromedian nucleus, and it projects to amygdala, hippocampus, and basal ganglia. These nuclei are also thought to mediate cortical arousal. Hippocampus. The hippocampus occupies the medial part of the floor of the temporal horn and is divided into three parts: head, body, and tail. The head of the hippocampus, the anterior and the largest part, is directed anterior and inferiorly, and then medially, and is characterized by three or four hippocampal digitations; its overall shape resembles a feline paw.9 Its posterior limit is characterized by the initial segment of the fimbria and the choroidal fissure. Superiorly, the head of the hippocampus is related to the posteroinferior portion of the amygdala, which bulges from the most anterior part of the roof of the temporal horn into the ventricular cavity. The body of the hippocampus has an anteroposterior and inferosuperior direction in the medial part of the floor of the temporal horn, and narrows as it approaches the atrium of the lateral ventricle. At the atrium of the lateral ventricle, the body of the hippocampus changes direction and has its longitudinal axis oriented transversely to become the tail of the hippocampus. The tail of the hippocampus is even more slender and constitutes the medial part of the floor of the atrium; medially the tail of the hippocampus fuses with the calcar avis. Macroscopically, the tail of the hippocampus ends when it meets the medial wall of the atrium, although histologically the terminal segment of the hippocampal tail continues as the subsplenial gyrus, which covers the inferior splenial surface (Fig. 1-4C and D). Amygdala. The amygdala, along with the hippocampus, constitute the core of the limbic system.10 The temporal amyg-

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Chapter 1 

dala is composed of a series of gray matter nuclei classified into three main groups: basolateral, corticomedial, and central. From a neurosurgical viewpoint, the temporal amygdala can be considered as being entirely located within the boundaries of the uncus: superiorly, the amygdala blends into the globus pallidus without any clear demarcation; inferiorly, the posterior portion of the temporal amygdala bulges inferiorly into the most anterior portion of the roof of the temporal horn above the hippocampal head and the uncal recess; medially, it is related to the anterior and posterior segments of the uncus; it also constitutes the anterior wall of the temporal horn (Fig. 1-5A). Choroidal Fissure. The choroidal fissure is one of the most

important intraventricular surgical landmarks for neurosurgeons. The choroidal fissure is a cleft located between the thalamus and the fornix. It is the site of attachment of the choroid plexus in the lateral ventricle. It is a C-shaped arc that extends from the foramen of Monro through the body, atrium, and temporal horn of the lateral ventricle.11 The choroidal fissure is divided into three parts: (1) the body part between the body of the fornix and the thalamus, (2) the atrial part between the crus of the fornix and the pulvinar of the thalamus, and (3) the temporal part between the fimbria of the fornix and the stria terminalis of the thalamus. The choroid plexus of the lateral ventricle is attached to the fornix and to the thalamus via an ependymal covering called taenia; in the body and the atrial parts, the taenia fornicis attaches the choroid plexus to the body of the fornix, and the taenia choroidea attaches the choroid plexus to the thalamus. In the temporal part, the choroidal plexus is attached to the fimbria via taenia fimbriae and to the stria terminalis via taenia choroidea. The choroidal fissure is one of the most important landmarks in microneurosurgeries involving the temporal lobe: it separates those structures located laterally that can be removed (temporal structures) from those structures located medially that should be preserved (thalamic structures). Third Ventricle The third ventricle is a narrow, funnel-shaped, unilocular, midline cavity (Fig. 1-5B). It communicates at its anterosuperior margin with each lateral ventricle through the foramen of Monro and posteriorly with the fourth ventricle through the aqueduct of Sylvius. It has a roof; a floor; and an anterior, posterior, and two lateral walls.12,13 The roof extends from the foramen of Monro anteriorly to the suprapineal recess posteriorly and is constituted from superior to inferior by five layers of neural, vascular, and pial structures:14 the first layer is the fornix; the second layer is the superior membrane of the tela coroidea. The third layer is the vascular layer located in a space between the superior and the inferior membranes of the tela choroidea called velum interpositum, which contains the internal cerebral veins and branches of the medial posterior choroidal arter-

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ies. The fourth layer is the inferior membrane of the tela choroidea, which forms the floor of the velum interpositum. The fifth layer is the choroidal plexus of the third ventricle, usually represented by two parallel strands of choroid plexus projecting downward on each side of the midline (Fig. 15C). The floor of the third ventricle extends from the optic chiasm anteriorly to the orifice of the aqueduct of Sylvius posteriorly, and it is constituted from anterior to posterior by the optic and infundibular recesses, tuber cinereum, mamillary bodies, posterior perforated substance, midbrain, and the aqueduct. The anterior wall is constituted by the lamina terminalis and the posterior wall is represented from inferior to superior by the posterior commissure, pineal recess, habenular commissure, pineal gland, and the suprapineal recess (Fig. 1-5D). The anterior wall and the floor form an acute angle that resembles the shape of the beak of a bird. At the inner angle formed by the roof and the anterior wall is the anterior commissure. Frequently there is another commissure located in the cavity of the third ventricle connecting both thalami called massa intermedia, which is located posterior to the foramen of Monro. The lateral wall of the third ventricle is constituted by thalamus above and by the hypothalamus below; the hypothalamus is separated from the thalamus by hypothalamic sulcus, a shallow groove extending from the foramen of Monro anteriorly to the aqueduct posteriorly. The hypothalamic sulcus is the cephalic continuation of the central canal in the spinal cord and the sulcus limitans in the brainstem. During the development of the central nervous system, the neural tube is divided by the sulcus limitans into two plates: dorsal to the sulcus limitans is the alar plate, and ventral to the sulcus limitans is the basal plate. In the spinal cord and brainstem, the structures evolved from the alar plate bear sensory and coordination functions; the structures evolved from the basal plate bear motor function. However, only the alar plate is evolved in the development of the telencephalon and diencephalon; in the diencephalon, the alar plate is further divided by the hypothalamic sulcus into a ventral and a dorsal part: the dorsal part becomes the thalamus (sensory and coordination) and the ventral part becomes hypothalamus (motor). Even though the neural control of emotion involves several regions, including the amygdala and the limbic association areas of the cerebral cortex, they all work through the hypothalamus to control the autonomic nervous system. The hypothalamus coordinates behavioral response to ensure bodily homeostasis, the constancy of the internal environment, by working through three major systems: the autonomic nervous system, the endocrine system, and an ill-defined neural system concerned with motivation. The third ventricle can be approached from the front, through the lamina terminalis via interhemispheric or pterional approaches; from behind, through the velum interpositum via supracerebellar infratentorial approach; or from

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Chapter 1  Figure 1-5. A, Coronal view: the left thalamus has been removed. 1 = bulb of the callosum; 2 = calcar avis; 3 = choroid plexus; 4 = Heschl’s gyrus; 5 = internal capsule; 6 = thalamus; 7 = tentorial edge and the dentate gyrus; 8 = fimbria of fornix and the tail of the caudate nucleus; 9 = globus pallidus and the anterior commissure; 10 = mamillary bodies (floor of the third ventricle); 11 = crus cerebri and the substantia nigra (midbrain); 12 = limen insulae; 13 = substantia inominata; 14 = amygdala; 15 = head of the hippocampus; 16 = optic chiasm. B, Left anterolateral view of the third ventricle: 1 = corpus callosum; 2 = thalamus; 3 = septum pellucidum; 4 = posterior commissure; 5 = thalamus; 6 = medial and lateral geniculate bodies; 7 = tail of the caudate nucleus; 8 = limen insulae; 9 = pons; 10 = optic nerve; 11 = internal carotid artery; 12 = uncus; 13 = left orbit; 3V = third ventricle; III = oculomotor nerve. C, Coronal section through the body of the lateral ventricle and the third ventricle, to display the five components of the roof of the third ventricle. D, Superior view of the third ventricle: the fornix has been reflected posteriorly. 1 = columns of fornix (cut); 2 = head of the right caudate nucleus; 3 = foramen of Monro; 4 = thalamostriate vein; 5 = choroid plexus; 6 = massa intermedia; 7 = right internal cerebral vein; 8 = superior choroidal vein; 9 = thalamus; 10 = midbrain; 11 = posterior commissure; 12 = pineal; 13 = fornix.

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above, through its roof as in transcallosal interforniceal15,16 and transcallosal transchoroidal approaches.14 Lateral Surface: Venous Relationships The superficial venous system drains the superficial one fifth of the thickness of the cerebrum, while the deep venous system drains the remaining four fifths.17 On the lateral surface of the cerebrum, the superficial venous drainage system is accomplished via venous channels adjacent to the lobes. In the frontal and parietal lobes, the venous drainage can direct superiorly toward the superior sagittal sinus or inferiorly toward the superficial sylvian vein; in the temporal lobe, venous drainage can be superiorly toward the superficial sylvian vein or inferiorly toward the dural sinuses below the temporal lobe. The lateral surface of the occipital lobe is drained by the lateral occipital vein into the superior sagittal sinus. There are no large veins entering the superior sagittal sinus for a distance of 4 to 5 cm proximal to the torcula.18 There are three main anastomotic veins on the lateral surface of the cerebrum. 1. The superficial sylvian vein begins in the surface of the posterior part of the posterior ramus of the sylvian fissure, and runs inferior and anteriorly along the fissure. Along its trajectory, the superficial sylvian vein receives the frontosylvian, parietosylvian, and temporosylvian veins, and commonly anastomoses with the veins of Trolard and Labbé. In the region of the pterion, the superficial sylvian vein enters the dura and runs in the sphenoparietal sinus or sinus of the lesser wing of

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the sphenoid19 to enter the anterior end of the cavernous sinus via the medial end of the superior orbital fissure, then drains into the basilar and the inferior petrosal sinuses. It can also drain into the tentorial sinus located in the dura of the middle fossa and then drains into the tentorium toward the transverse sinus. 2. The vein of Trolard, also called the superior anastomotic vein, is the largest anastomotic vein crossing the lateral surface of the frontal and parietal lobes between the superior sagittal sinus and the sylvian fissure. It is more frequently located at the parietal lobe. 3. The vein of Labbé, also called the inferior anastomotic vein, is the largest anastomotic vein that crosses the temporal lobe between the sylvian fissure and the transverse sinus. It usually arises from the middle portion of the sylvian fissure and is directed posterior and inferiorly toward the anterior part of the transverse sinus, at the level of the preoccipital notch (Fig. 1-6A). The deep part of the sylvian fissure is related to the deep sylvian or middle cerebral vein and its tributaries. The tributaries of the deep sylvian vein come mainly from the sulci on surface of the insula. The deep middle cerebral vein begins as a vein in the central sulcus of the insula, and runs anterior and inferior toward the limen insulae where it joins other insular veins to form a common trunk. Normally the deep middle cerebral vein courses medially into the carotid cistern, under the anterior perforated substance to form the first segment of the basal vein. The deep venous system of the cerebrum is divided into ventricular and cisternal groups; the ventricular group will be discussed here and the cisternal group will be discussed under the basal surface of the cerebrum. The ventricular veins are named mainly according to the location they course. Frontal horn: anterior caudate and anterior septal veins. Body of the lateral ventricle: thalamostriate, thalamocaudate veins, posterior caudate, and posterior septal veins. Atrium and the occipital horn: medial and lateral atrial veins. Temporal horn: inferior ventricular, amygdalar, and transverse hippocampal veins. Deep thalamic veins: anterior thalamic and superior thalamic veins. Superficial thalamic veins: anterior superficial thalamic, superior superficial thalamic, and posterior superficial thalamic veins. Choroidal veins: superior choroidal, and inferior choroidal veins.20 Lateral Surface: Arterial Relationships Most of the lateral surface of the cerebral hemisphere is supplied by the middle cerebral artery. The middle cerebral artery21,22 is divided into four segments. 1. The M1 or sphenoidal segment extends from the bifurcation of the internal carotid artery to the limen insulae. The M1 segment presents two types of

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Chapter 1  Figure 1-6. A, Lateral view of the right hemisphere: 1 = superior sagittal sinus; 2 = vein of Trolard; 3 = frontosylvian vein; 4 = superficial sylvian vein; 5 = vein of Labbé; 6 = Heschl’s gyrus; 7 = frontopolar vein; 8 = deep middle cerebral vein and the limen insulae; 9 = transverse sinus; 10 = right orbit. B, Superior view: 1 = right olfactory tract; 2 = genu of the middle cerebral artery; 3 = anterior cerebral artery; 4 = optic nerve; 5 = anterior clinoid process; 6 = limen insulae; 7 = internal carotid artery; 8 = uncus; 9 = P1 (posterior cerebral artery); 10 = anterior choroidal artery and the P2A (posterior cerebral artery); 11 = head of the hippocampus; 12 = midbrain; 13 = P2P (posterior cerebral artery); 14 = calcarine artery; M1 = sphenoid segment of the middle cerebral artery; M2 = insular segment of the middle cerebral artery; M3 = opercular segment of the middle cerebral artery. C, Basal view, displaying the sulci and gyri and the functional mapping of the basal surface of the cerebrum. 1 = olfactory tract; 2 = rectus gyrus; 3 = medial orbital gyrus; 4 = temporal pole; 5 = optic nerve; 6 = pituitary stalk; 7 = rhinal sulcus; 8 = optic tract; 9 = parahippocampal gyrus; 10 = inferior temporal gyrus; 11 = mamillary body and the posterior perforated substance; 12 = crus cerebri; 13 = medial geniculate body; 14 = tegmentum of the midbrain; 15 = collateral sulcus; 16 = pineal gland and the splenium of the corpus callosum; 17 = fusiform gyrus; 18 = occipitotemporal sulcus; 19 = lingual gyrus; 20 = preoccipital notch; III = oculomotor nerve. D, Basal view: 1 = deep middle cerebral artery; 2 = olfactory vein; 3 = anterior communicating artery; 4 = anterior cerebral vein; 5 = striate segment of the basal vein; 6 = chiasm; 7 = optic tract; 8 = crus cerebri; 9 = interpeduncular fossa and the peduncular vein; 10 = inferior ventricular vein; 11 = pulvinar of the thalamus; 12 = posterior mesencephalic segment of the basal vein; 13 = anterior choroidal artery (plexal segment); 14 = vein of Galen. Small arrows, Heubner’s artery. Arrowhead, peduncular vein joining the striate segment of the basal vein to form the peduncular segment of the basal vein.

䉳 branches: the lateral lenticulostriate arteries that arise mostly from the superior or posterosuperior aspect of the M1 and penetrate the anterior perforated substance to supply the basal ganglia, and early branches that course toward the temporal lobe to supply the temporal pole. 2. The M2 or insular segment extends from the limen insulae to the superior or inferior circular sulcus of insula; it runs in the insular compartment of the sylvian fissure, and is constituted by superior and inferior trunks and their branches. After reaching the superior or inferior circular sulcus of insula, the M2 branches enter the opercular compartment, and are called M3 segment. 3. The M3 or opercular segment runs in the opercular compartment and is related to the frontal and parietal opercula superiorly and to the temporal operculum inferiorly, and it depicts exactly the morphology of the opercula to which it is related. The morphology of the sylvian fissure is mainly determined by the operculum of the temporal lobe. The loop of the most posterior M3

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segment branch that exits from the sylvian fissure is called “M point” or “sylvian point” (Fig. 1-6B).23 Anatomically the sylvian point is located behind the posterior part of the insula, above the medial end of Heschl’s gyrus. The angiographic sylvian point or “M point” not only displays the location of the medial end of the Heschl’s gyrus, but also depicts the posterior end of the insula, and consequently the posterior end of the mass described earlier constituted by basal ganglia, internal capsule, and thalamus. Medially it points toward the atrium of the lateral ventricle, and consequently it points to the posterior end of the thalamus (pulvinar of the thalamus), which is the anterior wall of the atrium. Therefore, the location of the medial end of Heschl’s gyrus, atrium of the lateral ventricle, posterior end of the insula, basal ganglia, and the thalamus can be determined on an anteroposterior angiogram by following the sylvian point. On lateral projection, the M2 and M3 segments form the “sylvian triangle” that depicts the shape of the insula; as the insula is the outer covering of the “mass” that comprises the basal ganglia, thalamus, and the internal capsule, the sylvian triangle shows the anterior, superior, and the inferior limits of this “mass.” 4. The M4 or cortical segment extends from the sylvian fissure to the lateral surface of the cerebrum. Basal Surface: Neural Relationships The basal surface comprises the basal surface of the frontal, temporal, and occipital lobes. The basal surface of the frontal lobe is divided by the olfactory tract and sulcus in two uneven parts, a smaller and medial part is the rectus gyrus, lodged within the olfactory groove; and a larger and lateral part, the orbital surface of the frontal lobe, located above the orbit and composed of orbital gyri. The orbital surface is divided by the orbital sulcus, a complex sulcus that presents a rough configuration of the letter “H,” into quadrants: the anterior orbital, medial orbital, posterior orbital, and lateral orbital gyri. The pars orbitalis of the inferior frontal gyrus is continuous with the posterior part of the lateral orbital gyrus and the lateral part of the posterior orbital gyrus. The posterior part of the rectus, medial orbital, and the posterior orbital gyri, along with the medial and lateral olfactory stria, constitute the anterior limit of the anterior perforated substance. The posterior orbital gyrus also continues posterior and inferiorly into the temporal lobe as limen insulae. The temporal lobe is separated posteriorly from the occipital lobe by the basal parietotemporal line, which extends from the preoccipital notch to the junction between the parieto-occipital and calcarine fissures and presents from lateral to medially the inferior temporal gyrus, occipitotemporal sulcus, fusiform gyrus, collateral sulcus, and parahippocampal gyrus. The inferior temporal gyrus runs

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from the temporal pole anteriorly to the occipital lobe posteriorly. It is the most laterally located gyrus on the basal surface; medial to it is the occipitotemporal sulcus, a lateralto-medial, inferior to superiorly oriented sulcus that points toward the collateral eminence. The occipitotemporal sulcus has an anteroposterior orientation, and frequently fuses anteriorly and posteriorly with the collateral sulcus, delimiting the fusiform gyrus between them. Medial to the fusiform gyrus is the collateral sulcus. The collateral sulcus is an inferior-to-superior, medial-to-laterally oriented sulcus that bulges into the lateral part of the floor of the temporal horn anteriorly (collateral eminence) and the atrium posteriorly (collateral trigone). The collateral sulcus separates medially the allocortical parahippocampal gyrus from the mesocortical fusiform laterally. These gyri are separated anteriorly by the rhinal sulcus, which separates the uncus medially from the temporal pole laterally. The rhinal sulcus is the lateral limit of the uncus. Part of the floor of the third ventricle can also be seen from below: the optic chiasm, infundibulum, tuber cinereum, mamillary bodies, and the posterior perforated substance form the two-thirds anterior part of the floor of the third ventricle. The interpeduncular region, where the basilar artery bifurcates, is determined by two oculomotor nerves, the anteromedial surface, and the apex of the uncus laterally; diencephalic membrane of the Liliequist membrane (the membrane that goes from the dorsum sellae to the mamillary bodies), pituitary stalk and dorsum sellae anteriorly; tuber cinereum, mamillary bodies, and posterior perforated substance superiorly; inner surface of both crura cerebri posteriorly; the prepontine cistern forms the inferior limit of the interpeduncular fossa (Fig. 1-6C). The functional map of the basal surface is also shown in Figure 1-6C. Anterior Perforated Substance The anterior perforated substance (APS) is the entry site for perforating arteries from internal carotid, anterior choroidal, and anterior and middle cerebral arteries to the basal ganglia, the anterior limb, genu, and posterior limb of the internal capsule. It also is the exit site for the inferior striate veins. The APS is a rhomboid-shaped area buried deep in the sylvian fissure, bounded anteriorly by the lateral and medial olfactory striae; posteromedially by the optic tract and posterolaterally by the anteromedial surface of the uncus; laterally by the limen insulae. Medially the APS extends above the optic chiasm to the interhemispheric fissure.24 Intraoperatively, the APS and the carotid bifurcation can be identified by following the olfactory tract posteriorly. The head of the caudate nucleus, the anterior part of the lentiform nucleus and the anterior limb of the internal capsule are located immediately above the boundaries of the anterior perforated substance. Just like the insula can be understood as the outer covering of the basal ganglia and thalamus, the anterior perforated substance can be seen as

the “floor” of the anterior half of the basal ganglia. The anterior perforated substance can be considered the site where the anterior basal ganglia come to the surface extraventricularly (the caudate nucleus comes to the surface intraventricularly in the frontal horn and in the body of the lateral ventricle). Basal Surface: Venous Relationships The basal surface of the frontal lobe is drained by inferior frontal veins. The inferior frontal veins either drain anteriorly to the superior sagittal sinus (anterior group) or posteriorly to join the deep sylvian vein in the sylvian fissure (posterior group). The temporal lobe is drained by inferior temporal veins. The inferior temporal veins are divided into a lateral group that drains into the sinuses in the anterolateral part of the tentorium, and a medial group that empties into the basal vein as it courses along the medial edge of the temporal lobe. The occipital lobe is drained by the occipitobasal vein, which arises from tributaries that drain the inferolateral part of the lingual and adjacent part of the occipitotemporal and inferior temporal gyri. The occipitobasal vein courses anterolaterally toward the preoccipital notch and frequently joins the posterior temporobasal vein before emptying into the lateral tentorial sinus. The most important deep venous channel on the basal surface is the basal vein of Rosenthal.25 The basal vein originates below the APS by the union of the deep middle cerebral, inferior striate, olfactory, fronto-orbital, and anterior cerebral veins, and it usually drains into the vein of Galen after passing around the midbrain. The basal vein is divided into three segments. The first, also called anterior or striate segment, originates from the junction of the anterior cerebral, inferior striate, olfactory, fronto-orbital, and deep middle cerebral veins under the APS and runs posteriorly under the optic tract, medially to the anterior portion of the crus cerebri. This point denotes laterally the location of the apex of the uncus. The main tributaries of the first segment are the fronto-orbital, the olfactory, the inferior striate, the anterior cerebral, the deep middle cerebral, and the anterior pericallosal veins. The second, also called middle or peduncular segment, starts from this most medial point in the course of the basal vein, usually correspondent to the site where the peduncular vein joins the basal vein. It runs laterally between the upper part of the posteromedial surface of the uncus and the upper part of the crus cerebri, and under the optic tract to reach the most lateral part of the crus cerebri, which corresponds to the most lateral point of the vein as it turns around the crus cerebri, usually where the inferior ventricular vein joins the basal vein. This is called the anterior peduncular segment by Huang and Wolf 25; it then turns medially, superiorly, and posteriorly to the plane of the lateral mesencephalic sulcus behind the crus cerebri to constitute the posterior peduncular segment. The main

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tributaries of the second segment are the peduncular or interpeduncular vein, the inferior ventricular, the inferior choroidal, the hippocampal, and the anterior hippocampal veins. The third, also called posterior or posterior mesencephalic segment, runs medially, superiorly, and posteriorly from the lateral mesencephalic sulcus, and under the pulvinar of the thalamus to penetrate the quadrigeminal cistern and generally drains into the vein of Galen. The main tributaries of the third segment are the lateral mesencephalic vein, the posterior thalamic, the posterior longitudinal hippocampal, the medial temporal, and the medial occipital veins. Sometimes, the precentral cerebellar, superior vermian, internal occipital, splenial, medial atrial, and direct lateral and lateral atrial subependymal veins may drain into the third segment of the basal vein (Fig. 1-6D). Basal Surface: Arterial Relationships The supraclinoid portion of the internal carotid artery, anterior choroidal artery, anterior perforating and the posterior cerebral arteries are better visualized from this surface. The internal carotid artery is divided into five parts: cervical, petrous, cavernous, clinoid, and the supraclinoid portions. Yet recent evidence has shown that the clinoid segment is also located inside the cavernous sinus.26 The supraclinoid portion of the internal carotid artery has been divided into three segments based on the origin of its major branches:27 the ophthalmic segment extends from the origin of the ophthalmic artery to the origin of the posterior communicating artery (PCom); the communicating segment extends from the origin of the PCom to the origin of the anterior choroidal artery (AChA), and the choroidal segment extends from the origin of the AChA to the bifurcation of the internal carotid artery. Each segment gives off a series of perforating branches with a relatively constant site of termination. The ophthalmic artery arises under the optic nerve, usually from the medial one third of the superior surface of the carotid artery, then it passes anteriorly and laterally to become superolateral to the carotid to enter the optic canal and the orbit.28 The perforating arteries from this segment arise from the posterior or medial or posteromedial aspect of the carotid artery and are distributed to the stalk of the pituitary gland, the optic chiasm, and less commonly to the optic nerve, premamillary portion of the floor of the third ventricle, and the optic tract. The superior hypophyseal arteries, which can range from one to five in number, pass medially across the ventral surface of the chiasm to reach the pituitary area, where they intermingle and constitute a fine anastomotic plexus around the pituitary stalk called the “circuminfundibular anastomosis,” which supplies the pituitary stalk and the anterior lobe of the pituitary gland. The posterior lobe is supplied by the inferior hypophyseal artery originated from the meningohypophyseal trunk of the intracavernous carotid artery. The infundibular arteries are

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another group of arteries that arise from the PCom and supply the same area as the superior hypophyseal artery. The PCom arises from posteromedial or posterior or posterolateral aspect of the internal carotid artery and passes posteromedially below the tuber cinereum and above the sella turcica and oculomotor nerve to join the posterior cerebral artery (PCA). In the embryo, the PCom continues as the PCA, but in the adult the PCA becomes part of the basilar system. If the PCom remains the major origin of the PCA, the configuration is termed “fetal.” The perforating arteries from PCom range four to 14 in number, arising predominantly from the proximal half of the artery, course superiorly and terminate in the premamillary area, posterior perforated substance, interpeduncular fossa, optic tract, pituitary stalk, and the optic chiasm. They then reach the thalamus, the hypothalamus, the subthalamus, and internal capsule. The largest branch from the PCom is the premamillary artery or “anterior thalamoperforating artery,” which enters the floor of the third ventricle in front of or beside the mamillary body. The AChA arises either from the posterolateral or from the posterior aspect of the internal carotid artery. The AChA courses posteriorly below the optic tract and above the PCom toward the temporal horn by passing through the choroidal fissure. The AChA sends off branches to the optic tract, the crus cerebri, the lateral geniculate body, and the uncus, and supplies the optic radiation, the globus pallidus, the midbrain, the thalamus, and the retrolenticular and posterior portion of the posterior limb of the internal capsule.29,30 The choroidal segment of the internal carotid artery is the most frequent site of perforating arteries (range, 1 to 9), they arise either from the posterior, posterolateral, or posteromedial surfaces of the internal carotid artery. They terminate in the APS, optic tract, and the uncus. The anterior perforating arteries are those arising from the internal carotid, middle and anterior cerebral, and the anterior choroidal arteries, which enter the brain through the APS. The anterior perforating arteries of the internal carotid artery arise from the choroidal segment (Fig. 1-7A and B). Embryologically, the posterior cerebral artery (PCA)31–35 arises as a branch of the internal carotid artery, but up to birth its most common origin is the basilar artery. The PCA is classified, according to Yasargil and Rhoton, into four segments: the P1 segment extends from the basilar bifurcation to the site where the PCom joins the PCA. The P2 segment extends from the PCom to the posterior aspect of the midbrain. The P2 segment is further divided into P2A (anterior) and P2P (posterior) segments. P2A segment begins at the PCom and courses around the crus cerebri; inferiorly to the optic tract, AchA, and basal vein; and medially to the posteromedial surface of the uncus, up to the posterior margin of the crus cerebri. The P2P segment begins at the posterior margin of the crus cerebri and runs laterally to

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A

B

C

D

Figure 1-7. A, Basal view: 1 = internal carotid artery; 2 = M1 (middle cerebral artery); 3 = posterior communicating artery; 4 = anterior choroidal artery; 5 = P1 (posterior cerebral artery); 6 = P2A (posterior cerebral artery); 7 = anterior inferior temporal artery; 8 = interpeduncular fossa; 9 = short circumflex arteries; 10 = P2P (posterior cerebral artery); 11 = middle inferior temporal artery; 12 = posterior inferior temporal artery. B, Basal view: 1 = internal carotid artery; 2 = middle cerebral artery; 3 = A1 (anterior cerebral artery); 4 = anterior communicating artery; 5 = anterior choroidal artery; 6 = hypothalamic arteries from anterior communicating artery; 7 = posterior communicating artery; 8 = lateral lenticulostriate arteries; 9 = P2P (posterior cerebral artery); 10 = interpeduncular fossa; 11 = anterior inferior temporal artery; 12 = short circumflex arteries; 13 = P2P (posterior cerebral artery). C, Inferomedial view of the left hemisphere: 1 = parieto-occipital sulcus; 2 = isthmus of the cingulate gyrus; 3 = posterior communicating artery; 4 = collicular point; 5 = P3 (posterior cerebral artery); 6 = P2A (posterior cerebral artery); 7 = internal carotid artery; 8 = posterior inferior temporal artery; 9 = P2P (posterior cerebral artery); 10 = calcarine sulcus; 11 = middle inferior temporal artery. D, Medial view: the midbrain has been removed. 1 = anterior choroidal artery entering the temporal horn (inferior choroidal point); 2 = P2A (posterior cerebral artery); 3 = posterior segment of the uncus; 4 = perforating branches from the anterior choroidal artery; 5 = middle cerebral artery; 6 = cisternal segment of the anterior choroidal artery; 7 = anterior cerebral artery; 8 = pons; 9 = P1 (posterior cerebral artery); 10 = posterior communicating artery; 11 = internal carotid artery.

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the tegmentum of the midbrain within the ambient cistern, parallel and inferiorly to the basal vein, inferolaterally to the geniculate bodies and pulvinar, and medially to the parahippocampal gyrus to enter the quadrigeminal cistern. The P3 segment begins under the posterior part of the pulvinar in the lateral aspect of the quadrigeminal cistern and ends at the anterior limit of the anterior calcarine sulcus. P3 is often divided into its major terminal branches: the calcarine and the parieto-occipital arteries before reaching the anterior limit of the anterior calcarine sulcus. The point where the PCAs from each side are closer to each other is called the collicular or quadrigeminal point. It marks the posterior limit of the midbrain on angiogram. The P4 segment is the cortical branches of the PCA (Fig. 1-7C and D). The main branches arising from the PCA are the posterior thalamoperforating, the direct perforating, the short and long circumflex, the thalamogeniculate, the medial and the lateral posterior choroidal, the inferior temporal, the parieto-occipital, the calcarine, and the posterior pericallosal arteries. The posterior thalamoperforating arteries, which arise from P1 segment and enter the brain through the posterior perforated substance, interpeduncular fossa, and medial crus cerebri, supply the anterior and part of the posterior thalamus, hypothalamus, subthalamus, substantia nigra, red nucleus, oculomotor and trochlear nuclei, oculomotor nerve, mesencephalic reticular formation, pretectum, rostromedial floor of the third ventricle, and the posterior portion of the internal capsule.36 The direct perforating arteries to crus cerebri arise mainly from the P2A segment and supply the crus cerebri. The short and long circumflex arteries to the brainstem arise mainly from P1 segment, and less frequently from P2A segments; the short circumflex artery courses around the midbrain and terminates at the geniculate bodies; the long circumflex artery courses around the midbrain and reaches the colliculi. The thalamogeniculate arteries arise equally from P2A or P2P segments, perforate the inferior surface of the geniculate bodies, and supply the posterior half of the lateral thalamus, posterior limb of the internal capsule, and the optic tract. The medial posterior choroidal arteries arise mainly from P2A and less frequently from P2P and P1 segments, and course around the midbrain, medial to the main trunk of the PCA, turn around the pulvinar of the thalamus to proceed superiorly at the lateral side of colliculi and pineal gland, to enter the roof of the third ventricle through the velum interpositum, and finally course through the foramen of Monro to enter the choroid plexus in the lateral ventricle. The medial posterior choroidal arteries supply the crus cerebri, tegmentum, geniculate bodies (mainly the medial), the colliculi, pulvinar, pineal gland, and medial thalamus. Angiographically on lateral projection, the medial posterior choroidal artery describes the shape of the number “3.” The inferior curve of the “3” is when it turns around the pulvinar, and the superior curve is when it contours the colliculi before

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entering the roof of the third ventricle. Lateral posterior choroidal arteries arise mainly from P2P, and less frequently from P2A segment, and pass laterally to enter the ventricular cavity directly through the choroidal fissure, to supply the choroid plexus in the atrium and the temporal horn. It anastomoses with the AChA and also supplies the crus cerebri, posterior commissure, part of the body and anterior portion of the column of the fornix, the lateral geniculate body, pulvinar, dorsomedial thalami nucleus, and the body of the caudate nucleus. Inferior temporal arteries are distributed to the basal surface of the temporal and occipital lobes. They include the hippocampal artery and three groups of temporal arteries, namely, anterior, middle, and posterior temporal arteries. The anterior temporal artery arises mainly from the P2A segment, while the middle and posterior temporal arteries arise mainly from the P2P segment. Parieto-occipital and calcarine arteries are usually terminal branches of the PCA; they arise predominantly from P3 segment; however, sometimes they may also arise from the P2P segment and course respectively in the parietooccipital fissure and calcarine fissure. As the calcarine fissure reaches laterally to bulge into the medial wall of the atrium and the occipital horn, the calcarine artery also follows laterally into the depth of the calcarine fissure. The splenial or posterior pericallosal artery supplies the splenium of the corpus callosum, and arises from the parieto-occipital artery in 62% of cases, from the calcarine artery in 12%, medial posterior choroidal artery in 8%, posterior temporal in 6%, P2P in 4%, P3 in 4%, and lateral posterior choroidal artery in 4%. Medial Surface: Neural Relationships The medial surface of the cerebrum comprises the sulci and gyri of the frontal, parietal, occipital, and temporal lobes. The general organization of the gyri of the frontal, parietal, and occipital lobes on this surface can be compared to that of a three-layer roll; the inner layer is represented by corpus callosum, the intermediate layer by cingulate gyrus, and the outer layer by the medial frontal gyrus, paracentral lobule, precuneus, cuneus, and the lingual gyrus. The cingulate gyrus is separated inferiorly from the corpus callosum by the callosal sulcus, and superiorly from the outer layer by cingulate sulcus. Several secondary rami ascend from the cingulate sulcus in a radiate pattern and divide the outer layer into several sections; there are two secondary rami of particular importance: the paracentral ramus, which ascends from the cingulate sulcus at the level of the midpoint of the corpus callosum, and separates the medial frontal gyrus anteriorly from the paracentral lobule posteriorly and the marginal ramus, which ascends from the cingulate sulcus at the level of the splenium of the corpus callosum, and separates the paracentral lobule anteriorly from the precuneus posteriorly.

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The parieto-occipital and the calcarine sulci also have the same radiate pattern; the parieto-occipital sulcus separates the precuneus superiorly from the cuneus inferiorly, and the calcarine sulcus separates the cuneus superiorly from the lingual gyrus inferiorly. The marginal ramus of the cingulate sulcus intercepts the postcentral gyrus in almost 100% of the cases.1 The marginal ramus is an important landmark to determine the location of the sensory or motor areas in the lateral convexity through a midsagittal MRI. The paracentral ramus along with the marginal ramus determines the paracentral lobule, which is concerned with movements of the contralateral lower limb and perineal region, and is involved in voluntary control over defecation and micturition. The precuneus along with the part of the paracentral lobule behind the central sulcus forms the medial part of the parietal lobe. The precuneus presents the subparietal sulcus on its surface. This sulcus behaves as a posterior continuation of the cingulate sulcus and separates the precuneus above from the cingulate gyrus below. It has a variable vaguely H-shape where the vertical arms of the H tend to align with the marginal ramus and the parietooccipital sulcus. The parieto-occipital and the calcarine sulci determine the cuneus; the cuneus along with the medial part of the lingual gyrus are the medial portion of the occipital lobe. The calcarine sulcus starts at the occipital pole and directs anteriorly, presenting a slightly curved course with its characteristic upward convexity. The calcarine sulcus joins the parieto-occipital sulcus (only superficially) at an acute angle behind the isthmus of the cingulate gyrus, then continues anteriorly to intercept the isthmus of the cingulate gyrus. The portion of the calcarine sulcus anterior to the junction with the parieto-occipital sulcus is called anterior calcarine sulcus, which is crossed by a buried anterior cuneolingual gyrus and bulges into the medial wall of the atrium of the lateral ventricle as calcar avis. The part of the calcarine posterior to the union is called posterior calcarine sulcus and presents the striate (visual) cortex on its upper and lower lips, and the anterior calcarine sulcus presents the visual cortex only on its lower lip. Anteriorly, the cingulate and the medial frontal gyri wrap around the genu and the rostrum of the corpus callosum. At the inferior end of these two gyri, under the rostrum of the corpus callosum and in front of the lamina terminalis is a narrow triangle of gray matter, the paraterminal gyrus, separated from the rest of the cortex by a shallow posterior paraolfactory sulcus. Slightly anterior to this sulcus, the anterior paraolfactory sulcus, a short vertical sulcus may occur; the cortex between the posterior and anterior paraolfactory sulci is the subcallosal area or paraolfactory gyrus. Frequently two anteroposteriorly directed sulci, the superior and inferior rostral sulci, which are parallel to the floor of the anterior fossa, divide the inferior portion of the medial frontal gyrus into three parts. Posteriorly the cingulate gyrus continues inferiorly with the parahip-

pocampal gyrus through the isthmus of the cingulate gyrus (Fig. 1-8A). The mesial portion of the temporal lobe presents intraventricular and extraventricular elements.6 The intraventricular elements are the hippocampus, fimbria, amygdala, and the choroidal fissure; the extraventricular elements are the parahippocampal gyrus, uncus, and dentate gyrus. The parahippocampal gyrus extends from anterior to posterior, and at its anterior extremity it deviates medially and bends posteriorly to constitute the uncus. Posteriorly, just below the splenium of the corpus callosum, the parahippocampal gyrus is often intersected by the anterior calcarine sulcus, which divides the posterior portion of the parahippocampal gyrus into the isthmus of the cingulate gyrus superiorly, and the parahippocampal gyrus inferiorly, which continues posteriorly as the lingual gyrus. Superiorly the parahippocampal gyrus is separated from the dentate gyrus by the hippocampal sulcus. Laterally, the parahippocampal gyrus is limited by the collateral sulcus posteriorly and by the rhinal sulcus anteriorly. The rhinal sulcus marks the lateral limit of the entorhinal area of the parahippocampal gyrus. Medially the parahippocampal gyrus is related to the free edge of the tentorium and to the contents of the ambient cistern. The various components of the parahippocampal gyrus are the subiculum, presubiculum, parasubiculum, and entorhinal area, with the subiculum as its medial round edge. Uncus, meaning hook, is formed by the anterior portion of the parahippocampal gyrus, which has deviated medially and folded posteriorly. Inferiorly, the uncus is separated from the parahippocampal gyrus by the uncal notch (Fig. 1-8A). Anteriorly, the uncus continues with the anterior portion of the parahippocampal gyrus without a sharp limit; superiorly, the uncus is continuous with the globus pallidus. At the basal surface, the uncus is separated laterally from the temporal pole by the rhinal sulcus, and its medial part is normally herniated medially to the tentorial edge. When viewed from its basal surface, the uncus presents the shape of an arrowhead with its apex pointing medially, featuring an apex, an anterior segment, and a posterior segment. The anterior segment of the uncus is continuous with the parahippocampal gyrus and presents one surface, the anteromedial, which is related to the proximal sylvian fissure and carotid cistern, and is the posterolateral limit of the APS. The posterior segment is related to the hippocampus and has two surfaces: a posteromedial and an inferior surface. The posterior segment is occupied by three small gyri; from anterior to posterior, they are the uncinate gyrus, the band of Giacomini, and the intralimbic gyrus. The superior and the inferior portions of the posteromedial surface of the uncus are related, respectively, to the crural and ambient cisterns. Posteriorly and superiorly to the uncus is the inferior choroidal point, where the choroid plexus of the temporal horn begins. The inferior choroidal point usually corresponds to the site where the AChA enters the

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A

B

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Figure 1-8. A, Medial view of the medial surface of the left hemisphere: 1 = central sulcus; 2 = paracentral lobule; 3 = marginal ramus of the cingulate sulcus; 4 = cingulate sulcus; 5 = medial frontal gyrus; 6 = cingulate gyrus; 7 = precuneus; 8 = subparietal sulcus; 9 = body of the corpus callosum; 10 = genu of the corpus callosum; 11 = parieto-occipital sulcus; 12 = rostrum of the corpus callosum; 13 = cuneus; 14 = isthmus of the cingulate gyrus; 15 = splenium of the corpus callosum; 16 = calcarine sulcus; 17 = lingual gyrus; 18 = anterior calcarine sulcus; 19 = uncus; 20 = parahippocampal gyrus; 21 = temporal pole. B, The functional mapping of the medial surface of the left hemisphere. C, Medial view of the medial surface of the left hemisphere: 1 = postcentral gyrus; 2 = central sulcus; 3 = precentral sulcus; 4 = marginal ramus of the cingulate sulcus; 5 = paracentral lobule; 6 = paracentral ramus of the cingulate sulcus; 7 = medial frontal gyrus; 8 = cingulate gyrus; 9 = fornix; 10 = straight sinus; 11 = hypothalamic sulcus; 12 = subcallosal area; 13 = medial frontal gyrus; 14 = vein of Galen; 15 = posterior perforated substance; 16 = rectus gyrus and the olfactory tract; 17 = tentorium edge; 18 = cerebellum; 19 = superior petrosal sinus; 20 = middle fossa; II = optic nerve; III = oculomotor nerve. Arrow, foramen of Monro; A2, A3, A4, and A5 = segments of the anterior cerebral artery. D, Vascularization of the basal ganglia and the thalamus: APS = anterior perforated substance A1; A2 = segments of the anterior cerebral artery; M1 = sphenoid segment of the middle cerebral artery; AchA = anterior choroidal artery; Pcom = posterior communicating artery; PPS = posterior perforated substance.

temporal horn through the choroidal fissure. The inferior surface is the superior lip of the uncal notch, and it is visible only from below when the parahippocampal gyrus is removed. The dentate gyrus bears this name because of its characteristic toothlike elevations. The dentate gyrus continues

anteriorly with the band of Giacomini, also called the tail of the dentate gyrus, and continues posteriorly with the fasciolar gyrus, a smooth grayish band that is located posteriorly to the splenium of the corpus callosum; the fasciolar gyrus continues above the corpus callosum as the indusium griseum to finally end as the paraterminal gyrus. The

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fimbrodentate and hippocampal sulci separate the dentate gyrus, respectively, from the fimbria superiorly and the parahippocampal gyrus inferiorly. The extraventricular and the intraventricular structures of the mesial temporal lobe are intimately related. The uncus is related medially to cisternal elements and laterally to intraventricular elements. The anterior segment is related to the proximal sylvian fissure, the lateral portion of the carotid cistern, and the amygdala. The apex is related to the oculomotor nerve medially, and to the uncal recess, and the amygdala laterally; the posterior segment is related to the head of the hippocampus and the amygdala laterally, to the P2A segment of PCA inferomedially, and to the AChA superomedially. The functional map of the mesial surface is shown in Figure 1-8B.

Medial Surface: Venous Relationships The medial surface of the frontal lobe is drained by the medial frontal veins. They can either empty superiorly into the superior sagittal sinus, or inferiorly either into the inferior sagittal sinus or into the veins that pass around the corpus callosum to drain into the anterior end of the basal vein. The medial surface of the parietal lobe is formed by part of the paracentral lobule located behind the central sulcus and the precuneus, and it is drained by the medial parietal veins. They can either empty superiorly into the superior sagittal sinus or course around the splenium of the corpus callosum (posterior pericallosal vein) and drain inferiorly into the vein of Galen or its tributaries. The occipital lobe is drained by the anterior and the posterior calcarine veins. The anterior calcarine, also called internal occipital vein, arises from tributaries that drain the anterior portion of the cuneus and lingual gyrus, and passes forward toward the vein of Galen. It frequently joins the posterior pericallosal vein near the splenium before terminating in either the internal cerebral vein or in the vein of Galen. The posterior calcarine vein arises from tributaries that drain the area bordering the posterior part of the calcarine fissure. The initial part of this vein may course posteriorly along the fissure, and then curve sharply upward on the cuneus to reach the superior sagittal sinus. The deep venous system of the mesial temporal region drains into the basal vein of Rosenthal. The cisternal group in the mesial temporal region comprises the basal vein; the anterior, middle, and the posterior temporal cortical veins; and the anterior longitudinal hippocampal, the anterior hippocampal, the lateral mesencephalic, the posterior mesencephalic, and the posterior longitudinal hippocampal veins. The ventricular group comprises those veins located in the temporal horn that ultimately drain into the second or peduncular segment of the basal vein of Rosenthal, usually via inferior ventricular vein. These include the amygdalar

vein, the transverse hippocampal veins, the inferior choroidal vein, and the inferior ventricular vein.

Medial Surface: Arterial Relationships The anterior cerebral artery (ACA) is classified according to Fisher into five segments:37 the A1 segment extends from the bifurcation of the internal carotid artery to the anterior communicating artery (ACom); the A2 segment extends from the ACom to the junction between the rostrum and the genu of the corpus callosum; the A3 segment extends from the genu of the corpus callosum to the point where the artery turns sharply and posteriorly above the genu of the corpus callosum (the A2 and A3 segments together are also called ascending segment); and the A4 and A5 segments extend above the corpus callosum, from the genu to the splenium. The combination of the A4 and A5 segments are also called horizontal segment. The separation between these two segments is the point bisected in the lateral view close behind the coronal suture. The segment of the ACA distal to the ACom (A2 to A5) has also been called the pericallosal artery. The A1 segment arises from the carotid bifurcation, in the carotid cistern and courses preferably above either the optic chiasm or the optic nerve to enter the lamina terminalis cistern. The medial lenticulostriate perforators, ranging from 1 to 11 branches (average of 6.4), arise from the superior, the posterior, or the posterior-superior aspect of the proximal half of A1 segment and pursue a direct posterior and superior course to the APS to supply the optic chiasm, the optic tract, the genu of the internal capsule, and the anterior part of the globus pallidus. They may extend to the adjacent part of the posterior limb of the internal capsule and, less commonly, to the thalamus. The ACom unites the paired anterior cerebral arteries in the lamina terminalis cistern to provide an anastomotic channel between the anterior circulation on both hemispheres. Embryologically the ACom develops from a multichanneled vascular network that coalesces to a variable degree by the time of birth. The ACom complex probably exists as a single channel in approximately 75% of the cases. In other cases, a spectrum of anomalies exists between the multichanneled network of the embryo and the single ACom, which include duplications and triplications, fenestrations, reticular patterns, and loops and bridges. The perforators from the ACom, ranging from 0 to 4 (average 1.6), usually arise from its postero-inferior aspect to supply the infundibulum, the APS, the optic chiasm, the subcallosal area, and the preoptic areas of the hypothalamus.38,39 The recurrent artery of Heubner of the ACA arises in 78% of the cases from the proximal A2 and it doubles back on its parent vessel, courses anterior to the A1 segment in 60% of the cases, and can be seen upon elevating the frontal lobe

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before the visualization of the A1 segment; it is the largest and longest branch directed to the APS. After its origin, it passes above the carotid bifurcation and accompanies the middle cerebral artery into the medial part of the sylvian fissure before entering the anterior and middle portions of the full mediolateral extent of the APS (from above the optic chiasm, close to the interhemispheric fissure, to the limen insulae) to supply the most anterior and inferior part of the head of the caudate nucleus and putamen, and the adjacent part of the anterior limb of the internal capsule.40 The A2 segment is also the source of the central or the basal perforating arteries, which pass posteriorly to enter the optic chiasm, the lamina terminalis, and the anterior forebrain, below the corpus callosum, to supply the anterior hypothalamus, the septum pellucidum, the medial portion of the anterior commissure, the columns of the fornix, and the anterior-inferior part of the striatum. The two first cortical branches of the anterior cerebral artery supplying the medial surface, the orbitofrontal and the frontopolar arteries, also usually arise from the A2 segment. The segments A3 to A5 give rise to other cortical branches to supply the medial surface of the hemisphere. The A3 segment is a frequent site of origin for the anterior and the middle internal frontal and the callosomarginal arteries. The A4 segment frequently gives rise to the paracentral artery. The A5 segment gives rise to the superior and the inferior parietal arteries. All the cortical branches arise more frequently from the pericallosal than from the callosomarginal artery (Fig. 1-8C). The anterior cerebral artery syndromes include:41 (1) paracentral lobule syndrome, (2) supplementary motor area (SMA) syndrome, (3) anterior cingulate syndrome, (4) callosal syndrome, (5) basal forebrain syndrome, and (6) total ACA territory infarction. Paracentral syndrome is characterized by weakness of the contralateral lower limb, most intense in the foot and ankle, with or without sensory loss. The transient or permanent incontinence of urine can also be present. The SMA occupies the mesial surface of the superior frontal gyrus immediately anterior to paracentral lobule. SMA syndrome can be characterized by dysphasia (when the dominant hemisphere is affected), akinesia in the contralateral limb, contralateral hand grasping or groping, contralateral alien hand signs (when dominant hemisphere is affected, the right hand consistently interrupts manual tasks performed by the left hand), and dyspraxia. Anterior cingulate syndrome is more evident when the cingulate cortex is bilaterally and extensively affected; this might cause akinetic mutism, complex behavioral changes, loss of sphincter control, and autonomic disfunctions (temperature, cardiac, and respiratory irregularities). The callosal syndromes can be characterized by “split brain” signs and symptoms: left hand apraxia (inability to perform actions with left hand on verbal command), alien hand syndrome (left hand behaving like a foreigner or an alien, and acts uncooperatively), and left

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hand agraphia. Basal forebrain syndrome occurs when the territories of the orbitofrontal and frontopolar arteries and the septal region are affected, and the signs and symptoms include amnesia, emotional disinhibition, inappropriate social conduct, and autonomic disturbances. Total ACA infarction syndrome is a combination of the previously mentioned syndromes. Vascularization of the Basal Ganglia and the Thalamus The “mass” that constitutes the core of the cerebrum comprises basal ganglia, internal capsule, and the thalamus. The vessels that supply this “mass” encircle it from below, behind, above, and from its lateral aspect. The external covering of this “mass” up to the claustrum, namely insula and extreme capsule, are supplied by the branches from M2 segment of the middle cerebral artery. The rest of the “mass” constituted by the basal ganglia is supplied by perforator branches from anterior cerebral, middle cerebral, internal carotid, and anterior choroidal arteries (Fig. 1-8D). The thalamus is supplied by four vascular groups that surround the thalamus: (1) anterior thalamoperforating arteries, coming from PCom artery, coming from inferior and anteriorly to supply the anterior thalamus; (2) posterior thalamoperforating arteries from P1 or basilar top, coming from inferiorly through the posterior perforated substance to supply the medial ventral part of the thalamus, which is related to alertness, memory, and emotion; (3) thalamogeniculate arteries arising from P2P segment of the PCA, coming from inferolaterally; and (4) medial and lateral posterior choroidal arteries from P2A or P2P segment of the PCA, coming from behind and above (Fig. 1-8D).42,43

Posterior Fossa The posterior fossa is the largest and deepest of the three cranial fossae. It comprises one eighth the intracranial space and contains the pathways regulating consciousness, vital autonomic functions, and motor activities, in addition to the centers for controlling balance and gait. Only two of the 12 pairs of cranial nerves are located entirely outside the posterior fossa. The posterior fossa extends from the tentorial incisura, through which it communicates with the supratentorial space, to the foramem magnum, through which it communicates with the spinal cord. The posterior fossa is separated from the supratentorial space by the tentorium cerebelli.44 The intracranial surface of the posterior fossa presents jugular foramen, internal acoustic meatus, hypoglossal canal, the vestibular and cochlear aqueducts, and several venous emissary foramina. The posterior fossa also presents neural (cerebellum, the brainstem, and the cranial nerves) and vascular elements (arteries and veins), which can be

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characterized by the “rule of three”: the brainstem presents three parts (midbrain, pons, and medulla), the cerebellum presents three surfaces (petrosal, tentorial, and suboccipital), three cerebellar peduncles (superior, middle, and inferior), three fissures (cerebellomesencephalic, cerebellopontine, and cerebellomedullary), three main arteries (superior cerebellar artery [SCA], anterior inferior cerebellar artery [AICA], and posterior inferior cerebellar artery [PICA]), and three main venous draining groups (petrosal, galenic, and tentorial).

Brainstem The brainstem cannot be considered simply a connecting structure between the diencephalon and the spinal cord. Through the long projection systems of its reticular formation, the brainstem modulates sensory and motor pathways, and modulates arousal and conscious states (ascending projections to the diencephalon and the cerebrum); the brainstem presents the nuclei of ten cranial nerves that supply the sensory and motor functions of the face and head and the autonomic functions of the body; the brainstem also coordinates reflexes and simple behaviors mediated by the cranial nerves. As a general rule, the descending motor system occupies the anterior portion of the brainstem, while the long ascending and descending sensory tracts (the medial lemniscus; spinothalamic tract; and auditory, vestibular, and visceral sensory pathways) run within the reticular formation, which is located at the core (tegmentum) of the brainstem. The brainstem is divided into three portions: midbrain, pons, and the medulla. The midbrain is the upper part of the brainstem, connecting the diencephalon superiorly to the pons inferiorly. The midbrain is separated superiorly from the diencephalon by the optic tract, lateral geniculate body, and the pulvinar of the thalamus. Inferiorly the midbrain is separated from the pons by the pontomesencephalic sulcus and by the emergence of the trochlear nerve, which is a mesencephalic structure (Fig. 1-9A). The midbrain is divided by a midline sagittal plane into two halves that are called cerebral peduncles. Each peduncle is further divided into three parts: an anterior part, crus cerebri or basis pedunculi; an intermediate part, the tegmentum; and a posterior part located behind the aqueduct that is the tectum. The substantia nigra and the lateral mesencephalic sulcus separate the crus cerebri from the tegmentum. The oculomotor nerves emerge from the medial side of the crura cerebri in the interpeduncular fossa (Fig. 1-9B). The pontomesencephalic sulcus, which separates the midbrain superiorly from the pons inferiorly, originates in the depth of the interpeduncular fossa and runs around the inferior margin of the crus cerebri to join the lateral mesencephalic sulcus behind the crus cerebri. The posterior or dorsal aspect of the midbrain is characterized by the

superior and inferior colliculi (quadrigeminal plate). The superior colliculi are connected to the lateral geniculate bodies via brachium of the superior colliculus, and the inferior colliculi are connected to the medial geniculate bodies via brachium of the inferior colliculus. The pons presents a prominent anterior surface that is considerably convex from side to side, and it consists of transverse fibers that cross the median plane and converge on each side to form the middle cerebellar peduncles. The basilar sulcus is a shallow median groove on the anterior surface of the pons and usually lodges the basilar artery; this sulcus is bounded on each side by an eminence caused by the descent of the corticospinal fibers through the substance of the pons. The middle cerebellar peduncle is separated from the belly of the pons by a vertical shallow groove, the lateral pontine sulcus. Just lateral to the lateral pontine sulcus is the emergence of the trigeminal nerve, with its smaller superomedial motor root and a larger inferolateral sensory root (Fig. 1-9A). Posteriorly the pons constitutes the upper portion of the floor of the fourth ventricle. The medulla presents at its anterior aspect three longitudinal fissures, one median and two paramedian; the median one is the anterior median fissure, which continues inferiorly as the anterior median fissure of the spinal cord. The paramedian sulci of the anterior aspect of the medulla are the anterolateral sulci. At the medulla, the anterolateral sulcus is located medially to the olive; because of that it is also called preolivary sulcus. The preolivary sulcus is the upper continuation of the anterolateral sulcus of the spinal cord. The rootlets of the hypoglossal nerve that exit from the preolivary sulcus are analogous to the ventral motor rootlets that exit from the anterolateral sulcus of the spinal cord. The anterior region, located between the anterior median fissure and the preolivary sulcus, is characterized by the pyramid. The olives are located laterally to the preolivary sulcus; behind the olive, the rootlets of the accessory, the vagus, and the glossopharyngeal nerves exit from the postolivary sulcus. The postolivary sulcus is the continuation of the posterolateral sulcus of the spinal cord in the medulla oblongata; therefore, these cranial nerve rootlets are analogous to the dorsal spinal rootlets. Those rootlets emerge from the brainstem and extend almost straight laterally to the jugular foramen. The pontomedullary sulcus separates the pons from the medulla, and its junction with the preolivary sulcus marks the apparent origin of the abducent nerve (Fig. 1-9A). When viewed obliquely, the brainstem presents a triangular depression located behind and above the olive, anteromedial to the flocculus, that corresponds to the junction among the pons, the medulla, the middle and the inferior cerebellar peduncles; this area is called supraolivary fossette and is limited superiorly by the inferior aspect of the pons and the middle cerebellar peduncle, and posteriorly by the inferior cerebellar peduncle. The fossette resembles a rightangled triangle with its right angle located between the supe-

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C D Figure 1-9. A, Frontal view: 1 = oculomotor nerve; 2 = crus cerebri; 3 = interpeduncular fossa; 4 = pontomesencephalic sulcus; 5 = pons; 6 = lateral pontine sulcus; 7 = pontomedullary sulcus; 8 = pyramid; 9 = flocculus; 10 = petrosal or great horizontal or cerebellopontine fissure; 11 = olive. V = trigeminal nerve; VI = abducent nerve; VII = facial nerve; VIII = vestibulocochlear nerve; IX = glossopharyngeal nerve; X = vagus nerve; XI = accessory nerve; XII = hypoglossal nerve. B, Basal view of the midbrain; the location of the fibers of the corticospinal tract in the crus cerebri is also shown. 1 = apex of the uncus; 2 = P2A (posterior cerebral artery); 3 = mamillary body; 4 = crus cerebri; 5 = substantia nigra; 6 = P2P (posterior cerebral artery); 7 = lateral mesencephalic sulcus; 8 = tegmentum of the midbrain; 9 = aqueduct; 10 = tectum of the midbrain; III = oculomotor nerve. C, Anterolateral view of the supraolivary fossette: 1 = pyramid; 2 = olive; * = supraolivary fossette. D, Midsagittal section of the posterior fossa: 1 = caudate nucleus; 2 = parieto-occipital sulcus; 3 = thalamus; 4 = fornix; 5 = anterior calcarine sulcus; 6 = massa intermedia and the hypothalamic sulcus; 7 = calcarine sulcus; 8 = superior colliculus; 9 = mamillary body; 10 = optic nerve; 11 = midbrain; 12 = lingual gyrus; 13 = pons; 14 = tentorium cerebelli; 15 = medulla; 4V = fourth ventricle. Ce = central lobule; Cu = culmen; De = declive; Fo = folium; Tu = tuber; Pi = pyramid; Uv = uvula; No = nodule; To = tonsil.

rior pole of the olive and the inferior aspect of the pons; the superior catheti corresponds to the inferior border of the pons and the middle cerebellar peduncle; the vertical catheti corresponds to the posterior border of the olive, and the hypotenuse corresponds to the inferior cerebellar peduncle. Cranial nerves VI, VII, and VIII exit from the brainstem at

the superior catheti of the supraolivary fossette; cranial nerves VII and VIII then pass above the flocculus to the internal acoustic meatus. Cranial nerves IX, X, and XI exit from the brainstem at the hypotenuse of the supraolivary fossette, and cranial nerves IX and X pass below the flocculus to the jugular foramen (Fig. 1-9C).

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Among all structures located in the brainstem, the reticular formation deserves special consideration. The reticular formation of the brainstem is located at the tegmentum (core) of the brainstem and it modulates sensation, movement, consciousness, reflexive behavior, and the activities of ten of the 12 cranial nerves. By convention, the reticular formation is defined only for the brainstem and it contains specific groups of cells extending from the upper pons to the hypothalamus that are responsable for “activating” the cerebral cortex and thalamus, increasing wakefulness, vigilance, and the responsiveness of cortical and thalamic neurons to sensory stimuli, a state known as arousal; those cell groups constitute the ascending reticular activating system. The ascending reticular activating system reaches the cerebral cortex through two major branches at the junction of the midbrain and diencephalon. One is through the thalamus, where it activates and modulates thalamic relay nuclei as well as intralaminar and related nuclei with extensive diffuse cortical projections. The second branch is through the lateral hypothalamic area and is joined by the ascending output from the hypothalamic and basal forebrain cell groups that diffusely innervate the cerebral cortex. Damage to either branch of the ascending reticular activating system and or its projections to the cerebral cortex or bilateral damage of the cerebral cortex can impair consciousness. The reticular formation also contains the cranial nerve nuclei that are organized in longitudinal columns. As a general rule, the sensory columns are located dorsal to the sulcus limitans, and the motor columns are located ventrally to the sulcus limitans. The sulcus limitans extends along the brainstem, through the cerebral aqueduct into the diencephalon as hypothalamic sulcus. The sulcus limitans can be easily identified on the surface of the floor of the fourth ventricle.

Cerebellum The cerebellum (from the Latin for little brain) is made up primarily of white matter covered with a thin layer of gray matter (cerebellar cortex), and three pairs of deep nuclei: the fastigial, the interposed (composed by two nuclei, the globose and emboliform), and the dentate. The cerebellum plays an important role in motor function by evaluating disparities between the intended movement and the actual action, and by adjusting the operation of motor centers in the cortex and brainstem while a movement is in progress, as well as during repetition of the same movement. The cerebellum is provided with extensive information about the goals, commands, and feedback signals associated with the programming and execution of movement. There are therefore 40 times more axons projecting into the cerebellum than exit from it.45 The cerebellum is also involved in the control of the balance, eye movements, and the movements of the body and the limb.

From a morphologic viewpoint, the cerebellum is composed of three parts: a small, median portion called the vermis; and two large, lateral cerebellar hemispheres. Both the vermis and the hemispheres are divided, by fissures and sulci, into lobules. The cerebellum is connected to the brainstem through the three cerebellar peduncles, and through the brainstem, the cerebellum establishes its connections with the cerebrum and the spinal cord. However, at its central portion, the cerebellum is separated from the brainstem by the fourth ventricle. From a functional viewpoint, the cerebellum presents three distinct regions: one is the vermis, and other two regions are located in the intermediate and in the lateral parts of the cerebellar hemispheres. These three regions and the flocculonodular lobe receive different afferent inputs, project to different parts of the motor systems, and represent distinct functional subdivisions. The flocculonodular lobule or vestibulocerebellum, also called the archicerebellum, is the most primitive part of the cerebellum. It receives input directly from the primary vestibular afferents and projects to the lateral vestibular nuclei through cranial nerve VIII, and it is related to controlling eye movements and balance. The vermis and the intermediate part of the cerebellar hemisphere constitute the spinocerebellum. Both superior and the inferior vermis receive vestibular input and somatic sensory inputs from the head and proximal parts of the body. It then projects through the fastigial nucleus to cortical and brainstem regions that give rise to the medial descending systems that control proximal muscles of the body and limbs. Some specific parts of the vermis (declive, folium, tuber, and pyramid) also receive visual and auditory inputs. The intermediate part of the cerebellar hemisphere also receives somatic sensory inputs from the limbs, and then projects through the interposed nucleus to lateral corticospinal and rubrospinal systems to control the more distal muscles of the limbs. The lateral part of the cerebellar hemisphere is called the cerebrocerebellum, as it receives input exclusively from the cerebral cortex. It projects via the dentate nucleus to motor, premotor, and prefrontal areas, and is involved in planning and mental rehersal of complex motor actions and in the conscious assessment of movement errors. All the cerebellar output comes from the deep nuclei (fastigial, globose, emboliform, and dentate) and from the flocculonodular lobule. The superior cerebellar peduncle contains most of the cerebellar efferent projections. The cerebellum presents three surfaces: petrosal, tentorial, and the suboccipital surfaces. The petrosal surface of cerebellum is related anteriorly to the petrous part of the temporal bone: the tentorial surface is related superiorly to the tentorium cerebelli and inferiorly to the upper part of the roof of the fourth ventricle; the suboccipital surface in its anatomic position is related inferiorly to the squamosal part of the occipital bone, and anteriorly to the inferior part of the roof of the fourth ventricle. Because the fourth

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ventricle and the cerebellum are intimately related, their anatomy will be considered together. The fourth ventricle is often described as a tent-shaped midline structure surrounded mainly by the vermian components of the cerebellum (Fig. 1-9D).46,47 A normal tent has a roof that is divided into two halves, a floor and two lateral walls; however, the actual overall shape of the fourth ventricle resembles that of a turned-over tent with its base facing forward and two open lateral walls (Fig. 1-10A): the floor is represented by the pons and medulla; the superior cerebellar peduncles, the superior medullary velum, and the adjacent lingula constitute the superior part of the roof of the fourth ventricle; the inferior part of the roof is composed by the inferior medullary velum, the tela choroidea, the choroid plexus, the uvula, and the nodule; the two open lateral walls of the fourth ventricle are open corridors represented by lateral recesses that communicate the fourth ventricle with the cerebellopontine angle.

Frontal View: Petrosal Surface of the Cerebellum and the Fourth Ventricle The two halves of the petrosal surface of the cerebellum are separated because of the interposition of the brainstem; each half of the petrosal surface is intersected by the great horizontal fissure that circumscribes the cerebellum; at the petrosal surface the great horizontal fissure is called the petrosal or cerebellopontine fissure. The petrosal fissure runs from lateral to medial and it presents, as its posterior wall, the white matter of the cerebellum. However, at the level of the flocculus, the petrosal fissure bifurcates into a larger superior portion and a smaller inferior portion. The superior portion or superior limb is the suprafloccular portion of the petrosal fissure. The inferior portion is the infrafloccular portion of the posterolateral fissure, which separates the flocculo-nodule lobule from the rest of the cerebellum, and communicates with the cerebellomedullary fissure at the cerebellopontine angle. The folia that constitute the upper half of the petrosal surface of the cerebellum are those folia of the tentorial surface that have folded over the middle cerebellar peduncle and over the core of the cerebellum. These folia are, respectively, the wing of the central lobule, the quadrangular, the simple, and the superior semilunar lobules. The folia that constitute the lower half of the petrosal surface of the cerebellum originate from the suboccipital surface of the cerebellum that have folded over the inferior cerebellar peduncle and over the core of the cerebellum, and correspond to the inferior semilunar and biventral lobules. The cerebellopontine (CP) angle is a triangular area on the petrosal surface of the cerebellum comprising the flocculus laterally, the supraflocular portion of the great horizontal fissure and the emergence of the trigeminal nerve superiorly, the infraflocular portion of the posterolateral

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fissure and the emergence of the glossopharyngeal nerve inferiorly, and the supraolivary fossette medially. When the brainstem, which is the floor of the fourth ventricle is removed from the cerebellum (by sectioning the three cerebellar peduncles), the cavity and the two parts of the roof of the fourth ventricle are exposed. The upper half of the roof of the fourth ventricle comprises neural elements: the superior cerebellar peduncles, the superior medullary velum, and the lingula. The lingula can be visualized through transparency behind the superior medullary velum. The lower half of the roof comprises nonneural elements, and presents a horizontal portion and a vertical portion. The horizontal portion is constituted by the inferior medullary velum, which covers the nodule at the midline and the superior pole of the tonsils laterally; the vertical portion is constituted by the tela choroidea and the choroid plexus, covering the anterior aspect of the nodule, uvula, and partly the tonsils. The two portions of the lower half of the roof of the fourth ventricle unite at the telovelar junction and continue laterally as the floor of the lateral recess. At the midline, the upper and the lower halves of the roof of the fourth ventricle converge at the fastigium (Fig. 1-10B). The cavity of the fourth ventricle communicates with the CP angle cistern through the lateral recess of the fourth ventricle. The lateral recess is the lateral extension of the fourth ventricle and connects the fourth ventricle to the CP angle.48 It is directed from medial to laterally, slightly from superior to inferior and from posterior to anterior, forming an angle of approximately 45 degrees with the sagittal plane. The lateral recess presents an anterior, superior, and posterior wall; and a floor. The anterior and superior walls are constituted by the inferior cerebellar peduncle as it runs upward and then turns backward toward the white matter of the cerebellum. The floor of the lateral recess is constituted by the tela choroidea anteriorly, the choroid plexus in the middle, and the inferior medullary velum posteriorly; at the foramen of Luschka, the inferior medullary velum becomes thicker and is called the peduncle of the flocculus. The peduncle of the flocculus constitutes the posterior wall of the foramen of Luschka, and connects the nodule to the flocculus (flocculonodular lobule). The morphology of the choroid plexus of the fourth ventricle resembles the letter “T” with two vertical bars. The horizontal part of the choroid plexus that starts from the fourth ventricle and protrudes into the CP angle resembles the horns of a bull. The vertical part and the proximal half of the horizontal part of the choroid plexus of the fourth ventricle is usually supplied by PICA; the lateral half of the horizontal part and the choroid plexus located at the cerebellopontine angle are generally supplied by the AICA (Fig. 1-10A and B).49 The inferior medullary velum separates the tonsil inferiorly from the superolateral recess superiorly. The tonsils are two riniform structures that are hemispheric components of the uvula and are attached to the cerebellum through the peduncles of the tonsil, located at the supero-

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D C Figure 1-10. A, A normal tent (left). The actual shape of the fourth ventricle resembles a turned over tent with its floor facing forward (right). F = floor. B, Frontal view: the pons and the medulla have been removed to display the roof of the fourth ventricle. 1 = culmen; 2 = central lobule; 3 = superior cerebellar peduncle; 4 = superior medullary velum; 5 = middle cerebellar peduncle; 6 = nodule; 7 = choroid plexus; 8 = tela choroidea. C, Right supero-anterolateral view of the fourth ventricle and the lateral recess. 1 = culmen; 2 = central lobule; 3 = superior cerebellar peduncle; 4 = superior medullary velum; 5 = middle cerebellar peduncle; 6 = nodule; 7 = superior pole of the tonsil (covered by the inferior medullary velum); 8 = peduncle of the flocculus; 9 = choroid plexus (exiting from the foramen of Luschka); 10 = choroid plexus; 11 = foramen of Magendie. D, Frontal view: the choroid plexus, the tela choroidea, and the right tonsil have been removed. 1 = superolateral recess; 2 = nodule; 3 = furrowed band of Reil; 4 = uvula; 5 = left tonsil; 6 = copula pyramidis; 7 = pyramid.

lateral aspect of each tonsil. The superior, the medial, the anterior, the posterior, and most of the lateral surfaces of the tonsils are free and can be separated easily from the adjacent structures. The tonsils, along with surrounding neural structures, determine important spaces: between its superior pole and the inferior medullary velum is the supratonsillar space; between the medial surfaces of the two tonsils is the vallecula; between the anterior surface of the tonsil and the medulla is the cerebellomedullary fissure; between the posterior surface of the tonsil and the adjacent vermis is the

retrotonsilar space where the inferior vermian veins originate (Fig. 1-10D).

Superior View: Tentorial Surface of the Cerebellum and the Fourth Ventricle The tentorial surface faces the tentorium and presents two cerebellar incisurae and three margins. The cerebellar

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incisurae are the anterior and posterior cerebellar incisurae; the brainstem fits into the anterior cerebellar incisura and the falx cerebelli fits into the posterior cerebellar incisura. The margins are the anterosuperior margin, which is the posterior wall of the cerebellomesencephalic fissure; the anterolateral margin, which separates the tentorial from the petrosal surfaces of the cerebellum; and the posterolateral margin, which separates the tentorial from the suboccipital surfaces. The folia of the tentorial surface are represented by the superior vermis and its hemispheric counterpart; from anterior to posterior: lingula (without hemispheric correspondent), central lobule (wing of the central lobule), culmen (quadrangular lobule), declive (simple lobule), and folium (part of the superior semilunar lobule), being the primary fissure located between the quadrangular and simple lobules, and the most prominent one, the postclival fissure located between the simple and the superior semilunar lobules. Most of the lobules of the cerebellum occupy more than one surface (except the lingula, the tonsil, and the nodule, which occupy one surface; and the superior semilunar lobule, which occupies three surfaces of the cerebellum). The tentorial surface presents the cerebelomesencephalic or the precentral cerebellar fissure. This fissure is located between the cerebellum posteriorly and the midbrain anteriorly. Posteriorly in the midline, the cerebellomesencephalic fissure is bounded by the anterior part of the culmen above and the central lobule below; posterolaterally, it is limited by the anterior surface of the quadrangular lobule above and the wing of the central lobule below. Anteriorly it is limited from the midline to laterally by the lingula, and the superior and the middle cerebellar peduncles. Among the cerebellar nuclei, the dentate nucleus is the most laterally located and the largest one. Because the majority of the fibers that constitute the superior cerebellar peduncle arise from the dentate nucleus, this nucleus is located at the posterior projection of the superior cerebellar peduncle. The lateral limit of the dentate nucleus extends from 0.5 to 2.0 cm from the midline,50 but the lateral limit of the dentate nucleus can be considered as the posterior continuation of the interpeduncular sulcus. Located between the postclival sulcus and the bottom of the cerebellomesencephalic fissure, the dentate nucleus can be considered as the roof of the superolateral recess of the fourth ventricle (the space in the fourth ventricle lateral to the nodule and above the superior pole of the tonsils) (Fig. 1-11A). The interpeduncular or interbrachial sulcus, which separates the superior from the middle cerebellar peduncles, ascends from the bottom of the cerebellomesencephalic fissure toward the lateral aspect of the pons, where it is joined by the ponto-mesencephalic sulcus to proceed superiorly as the lateral mesencephalic sulcus to the medial geniculate body; the lateral mesencephalic sulcus separates the crus cerebri anteriorly from the tegmentum posteriorly (Fig. 1-11B).

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Inferior View: Suboccipital Surface of the Cerebellum and the Fourth Ventricle This area of the cerebellum is located below the transverse and the sigmoid sinuses, and its surface faces inferiorly, almost parallel to the ground; therefore, for a better visualization of this surface either in surgery or for anatomic studies, the head or the cerebellum has to be bent forward; consequently, the cerebellum will not be in its anatomic position. The suboccipital surface presents the posterior cerebellar incisura, and the prominent vermohemispheric or paravermian fissure, which separates the inferior vermis from the cerebellar hemisphere. The components of the inferior vermis and its hemispheric correspondents are folium (superior semilunar lobule), tuber (inferior semilunar lobule), pyramid (biventral lobule), uvula (tonsil), and nodule (flocculus). In the anatomic position, the most inferior part of the inferior vermis is the pyramid. The most prominent fissure on the suboccipital surface is the great horizontal fissure, which is a circumferential fissure that begins in the posterior cerebellar notch between the folium and the tuber and runs forward and slightly downward on the suboccipital surface, between the superior and the inferior semilunar lobules, and then onto the petrosal surface. The secondary fissure is the one located between the tonsils and the biventral lobule (Fig. 1-11C). After the removal of the tonsils in the surgical position, the inferior portion of the roof of the fourth ventricle, namely tela choroidea and the inferior medullary velum, come to the view. After the removal of the inferior portion of the roof of the fourth ventricle, the floor of the fourth ventricle comes to the view (Fig. 1-11D). The floor of the fourth ventricle has a rhomboid shape and presents a strip between the lower margin of the cerebellar peduncles and the site of attachment of the tela choroidea; this strip is called the junctional part, and is characterized by the striae medullary that extends into the lateral recesses. The striae medullary are external arcuate fibers of the corticopontocerebellar afferents coming from the arcuate nuclei, located at the pyramid of the medulla that enter the cerebellum through the inferior cerebellar peduncle. The junctional part divides the floor of the fourth ventricle into two unequal triangles; the superior and larger one with its apex directed toward the aqueduct is the pontine part, and the inferior and smaller one with its apex directed toward the obex is the medullary part of the floor. These three parts of the floor are also divided longitudinally into two symmetrical halves by the median sulcus. The sulcus limitans, another longitudinal sulcus, divides each half of the floor into a raised median strip called the median eminence, and a lateral strip called area vestibular. The superior or pontine part is characterized by two rounded prominences called facial colliculi located on the median eminence, one on each side of the median sulcus. The facial colliculi are limited laterally by the

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C D Figure 1-11. A, Superior view of the cerebellum: 1 = quadrigeminal plate; 2 = wing of the central lobule; 3 = AICA and the internal acoustic meatus; 4 = superior petrosal sinus; 5 = quadrangular lobule; 6 = interpeduncular sulcus and the precentral branches of the superior cerebellar artery to the dentate nucleus; 7 = middle cerebellar peduncle; 8 = primary fissure; 9 = simple lobule; 10 = paramedian nuclei of the cerebellum; 11 = straight sinus; 12 = superior semilunar lobule; 13 = postclival fissure; 14 = transverse sinus; IV = trochlear nerve; 4V = fourth ventricle; DN = dentate nucleus. B, Posterosuperior view of the brainstem: 1 = right frontal horn; 2 = thalamus (floor of the body of the lateral ventricle); 3 = fornix; 4 = choroidal fissure; 5 = pineal gland; 6 = thalamus (anterior wall of the atrium); 7 = thalamus (roof of the wing of the ambient cistern); 8 = quadrigeminal plate; 9 = brachium of the superior and the inferior colliculi, and the lateral mesencephalic sulcus and the crus cerebri; 10 = branches of the superior cerebellar artery; 11 = superior cerebellar peduncle and the interpeduncular sulcus; 12 = middle cerebellar peduncle; 13 = floor of the fourth ventricle; 14 = superior pole of the left tonsil; 15 = nodule. C, Suboccipital view of the cerebellum: 1 = great horizontal fissure; 2 = inferior semilunar lobule; 3 = posterior cerebellar incisura; 4 = tuber; 5 = prepyramidal fissure; 6 = pyramid; 7 = biventral lobule; 8 = uvula; 9 = tonsil; 10 = flocculus; 4V = fourth ventricle. D, Suboccipital view: part of the biventral lobule and both tonsils have been removed to display the inferior portion of the roof of the fourth ventricle and the floor of the lateral recess. 1 = pyramid; 2 = peduncle of the tonsil; 3 = uvula; 4 = inferior medullary velum; 5 = tela choroidea; 6 = peduncle of the flocculus; 7 = rhomboid lip; 8 = flocculus; 9 = spinal cord; 4V = fourth ventricle.

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superior fovea, a dimple formed by the sulcus limitans. The inferior or medullary part presents the configuration of a feather, or pen nib, called calamus scriptorius, and it is characterized by three triangular areas overlying the hypoglossal and vagal nuclei (hypoglossal and vagal trigones), and the area postrema; just lateral to the hypoglossal trigone, the limitans sulcus presents another dimple called inferior fovea. At the junctional part, the sulcus limitans is discontinuous (Fig. 1-12A). As a general rule, the motor nuclei of the cranial nerves are located medially to the sulcus limitans, and the sensory nuclei are located laterally to the sulcus limitans. Their respective locations are shown in Figure 1-12B.

The Cranial Nerves Olfactory Nerve (Cranial Nerve I) The olfactory nerve is concerned with the sense of smell. The olfactory nerves are located in the olfactory epithelium, which covers most of the superior nasal conchae and the opposed surfaces of the nasal septum. The approximately 20 olfactory nerves traverse the ethmoidal cribriform plate to end in the “glomeruli”of the homolateral olfactory bulb. The input then goes along the olfactory tract up to the olfactory trigone, where the olfactory tract divides into two striae: medial and lateral olfactory striae. The medial olfactory striae terminate in the paraolfactory area, subcallosal gyrus, and in the inferior part of the cingulate gyrus. The lateral olfactory striae terminate in the uncus, anterior portion of the hippocampus, and the amygdaloid nucleus. The tertiary olfactory cortex occupies the posterior portion of the orbital gyri (medial orbital, posterior orbital, and the lateral orbital gyri). Optic Nerve (Cranial Nerve II) Two important aspects regarding the optic nerve are the vision and the pupillary light reflex. The central visual pathway is best summarized in Figure 1-12C. The main structures related to the vision and its pathways are lens, retina, optic nerve and chiasm, lateral geniculate body, pretectum area and the superior colliculi of the midbrain, optic radiation, and the primary visual cortex. The surface of the retina is divided in two parts with respect to the midline (where the fovea is located): the nasal and temporal hemiretinae. The former is responsible for the temporal side of the visual field, and the latter is responsible for the nasal visual field. The fovea is the area of the retina with the highest density of ganglion cells, and is responsible for the central region of the visual field. The superimposed area of the visual fields of both eyes is called the binocular zone, and the lateral part, or nonsuperimposed areas, of the visual field are called the monoc-

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ular zone. There is a normal blind spot in our visual field that corresponds to the optic disc, which is the exit site of the ganglion cell axons, and contains no photoreceptors; because the optic disc is located medially to the fovea, the natural blind spot of each eye is located in the temporal visual field of that eye. When an image passes through the eye to project onto the retina, the lens inverts the visual image: the upper half of the visual field projects onto the inferior half of the retina, while the lower half of the visual field projects onto the superior half of the retina. The visual information is then carried by the axons from the ganglion cells that exit the retina from the optic disc and, at the optic chiasm, the fibers from the nasal half of each retina cross to the opposite side of the brain. Therefore axons from the right half of each retina project in the right optic tract, which carries the complete representation of the left hemifield of vision. From the optic tract, the visual information will project to three subcortical regions: the lateral geniculate body (thalamus), the pretectum, and the superior colliculus (midbrain). Ninety percent of the retinal axons terminate in the lateral geniculate body. From the lateral geniculate body, the visual information is projected to the visual cortex via optic radiation. The optic radiation is a bundle of fibers that extends from the lateral geniculate body to the visual area in the occipital lobe. According to the direction of its fibers, the optic radiation may be divided in three parts: anterior, middle, and posterior. In the anterior part, the fibers initially take an anterior direction along the roof of the temporal horn, usually reaching as far anteriorly as the tip of the temporal horn and then loop backward in the lateral and inferior aspects of the atrium and occipital horn to end in the lower lip of the calcarine fissure; the anterior loop is called Meyer’s loop. The anterior part represents the upper quadrants of the visual field. In the middle part, the fibers take a lateral direction initially, coursing along the roof of the temporal horn, and then proceed posteriorly along the lateral wall of the atrium and the occipital horn; the middle part contains the macular fibers. The fibers of the posterior part course directly posteriorly along the lateral wall of the atrium and the occipital horn to end in the upper lip of the calcarine fissure; these fibers are responsible for the lower quadrants of the visual field (Fig. 1-12C).51–53 Each half of the visual field is represented in the contralateral primary visual cortex that is located along the lips of the posterior calcarine fissure, mainly at the medial surface. The visual cortex might extend into the lateral surface of the occipital lobe. The upper visual fields are mapped below the calcarine fissure, and the lower fields above it. Most of the visual cortex is devoted to representation of the fovea and region around the fovea. Pupillary Reflexes Light shining in one eye causes constriction of the pupil in that eye (the direct response) and in the other eye

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A

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Figure 1-12. A, Posterior view of the floor of the fourth ventricle: 1 = superior cerebellar peduncle; 2 = median sulcus and the median eminence; 3 = sulcus limitans; 4 = middle cerebellar peduncle; 5 = facial colliculus; 6 = superior fovea and the vestibular area; 7 = inferior cerebellar peduncle; 8 = striae medullary; 9 = hypoglossal trigone; 10 = inferior fovea; 11 = vagal trigone; 12 = area postrema; 13 = obex; IV = fourth nerve. B, Posterior view: the motor nuclei of the cranial nerves are located medially to the sulcus limitans and the sensory nuclei are located laterally to the sulcus limitans. C, Superior view of the visual pathways and the pupillary reflex: Cilliary gg = cilliary ganglion; III = oculomotor nerve; E.W. = Edinger-Westphal nucleus. D, Superolateral view of the right cavernous sinus: 1 = cerebellomesencephalic segment of the superior cerebellar artery; 2 = lower midbrain; 3 = basilar artery; 4 = pituitary stalk; 5 = anterior pontomesencephalic segment of the superior cerebellar artery; 6 = internal carotid artery; 7 = tentorium edge; 8 = lateral pontomesencephalic segment of the superior cerebellar artery; 9 = cerebellum; 10 = superior petrosal sinus; 11 = facial and the superior vestibular nerves; 12 = greater petrosal nerve; 13 = middle meningeal artery; 14 = geniculate ganglion and the superior semicircular canal; V1, V2, V3 = ophthalmic, maxillary, and the mandibular divisions of the trigeminal nerve; GG = gasserian ganglion.

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(consensual response). These reflexes are mediated by retinal ganglion cells that project from the optic tract to the pretectal area of the midbrain. The cells in the pretectal area project bilaterallly to preganglionic parasympathetic neurons in the Edinger-Westphal nucleus. From the Edinger-Westphal nuclei, the preganglionic parasympathetic fibers travel in the oculomotor nerve (inferior ramus) to the ciliary ganglion to innervate the pupillary sphincter that constricts the pupil (Fig. 1-12C). The retinal projection to the superior colliculus controls the saccadic (visually guided) eye movement. Oculomotor Nerve (Cranial Nerve III) The oculomotor nerve innervates striated muscles of the eyelid and all extraocular muscles except the superior oblique and lateral rectus muscles. Autonomic function mediates pupillary constriction and accommodation of the lens for near vision. The oculomotor nerve emerges from the interpeduncular fossa and constitutes the lateral limit of the interpeduncular cistern and passes between the posterior cerebral (above) and superior cerebellar (below) arteries; it then runs forward and laterally, below the apex of the uncus toward the cavernous sinus. During its subarachnoid course, the parasympathetic pupillary fibers lie peripherally in the dorsomedial part of the nerve. An uncal herniation will compress the oculomotor nerve from its lateral aspect, causing the dilation of the pupil. The nerve then perforates the posterior portion of the roof of the cavernous sinus, through the center of a triangular area called oculomotor trigone to course on the lateral wall of the cavernous sinus, where it lies above the trochlear nerve (Fig. 1-12D). It divides into superior and inferior rami, which enter the orbit by the superior orbital fissure within the annulus of Zinn (annulus tendineus communis), with the nasociliary and abducent nerves between them. The smaller superior ramus supplies the superior rectus and the levator palpebrae muscles; the inferior ramus divides into three branches: one passes under the optic nerve to the medial rectus muscle, another to the inferior rectus, the third and longest passes forward between the inferior rectus and lateral rectus muscles to the inferior oblique muscle. From the nerve to obliquus inferior muscle, a short branch passes to the lower part of the ciliary ganglion as its motor, parasympathetic root to innervate the sphincter pupillae and ciliaris muscles (Fig. 1-13A). The sympathetic and sensory fibers merely pass through the ciliary ganglion; however, the parasympathetic root, derived from the branch of the oculomotor nerve to the inferior oblique, consists of preganglionic fibers from the Edinger-Westphal nucleus, which relay in the ganglion, and have their postganglionic fibers traveling in the short ciliary nerves to the sphincter pupillae and ciliaris muscle. The sympathetic root consists of postganglionic fibers from the superior cervical ganglion, which traverse the ganglion without

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synapsing, to emerge into the short ciliary nerve. They are distributed to blood vessels of the eyeball but may include axons supplying the dilator pupillae when these do not follow their usual course in the ophthalmic, nasociliary, and long ciliary nerves. The sensory root is a ramus communicans of the nasociliary nerve, containing sensory fibers from the eyeball that reach the ganglion in short ciliary nerves and traverse it without synapsing. The ramus leaves the ganglion posteriorly and runs back to join the nasociliary nerve near its orbital entry.

Trochlear Nerve (Cranial Nerve IV) The trochlear nerve is the thinnest and the only cranial nerve to emerge dorsally from the brainstem. Its nucleus supplies the contralateral superior oblique muscle. The trochlear nucleus lies in the grey matter in the floor of the cerebral aqueduct, at the level of the upper part of the inferior colliculus. After leaving its nucleus, the trochlear nerve passes laterally through the tegmentum and then curves dorsocaudally around the aqueduct into the superior medullary velum; then it decussates with its mate, crossing the midline to emerge as one or more rootlets below the inferior colliculus. The nerve crosses to the lateral aspect of the superior cerebellar peduncle and winds around the cerebral peduncle just above the pons, between the posterior cerebral and superior cerebellar arteries. It pierces the dura below the free edge of the tentorium cerebelli, just behind the posterior clinoid process, and then passes forward in the lateral wall of the cavernous sinus, inferior to the oculomotor nerve and above cranial nerve V1. Near the anterior end of the cavernous sinus it crosses the oculomotor nerve, entering the orbit via superior orbital fissure, above the annulus of Zinn and medial to the frontal nerve. In the orbit it inclines medially, above the origin of the levator palpebrae muscle to enter the orbital surface of the superior oblique muscle (Figs. 1-12D; 1-13A and B). Trigeminal Nerve (Cranial Nerve V) The sensory function mediates sensation from the skin of the external ear canal and taste from the anterior two thirds of the tongue. The motor function innervates muscles of mastication, plus tensor tympani, tensor veli palatini, mylohyoid muscle, and anterior belly of digastric muscle (see Figs. 1-12D; 1-13A and B). Ophthalmic Nerve (Cranial Nerve V, Segment 1) The ophthalmic nerve is the smallest division of the trigeminal nerve. It is totally sensory supplying the eyeball, lacrimal gland and conjuntiva, part of the nasal mucosa and the skin of the nose, eyelids, forehead, and part of the scalp. It passes in the lateral wall of the cavernous sinus below the

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A

B

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Figure 1-13. A, Anterolateral view of the right orbit and the annulus of Zinn: 1 = basilar artery; 2 = nasociliary nerve; 3 = superior ophthalmic vein; 4 = ophthalmic artery and the ciliary ganglion; 5 = frontal nerve; SR = superior rectus muscle; Sup. div. = superior division; LP = levator palpebrae muscle; IR = inferior rectus muscle; LR = lateral rectus muscle; Inf. div. = inferior division; IO = inferior oblique muscle. B, Superior view of the right orbit: 1 = trochlea; 2 = supraorbital nerve; 3 = supratrochlear nerve; 4 = superior oblique muscle; 5 = anterior ethmoidal nerve and artery; 6 = frontal nerve; 7 = nasociliary; 8 = medial rectus muscle; 9 = superior rectus muscle; 10 = superior ophthalmic vein; II = optic nerve; III = oculomotor nerve; IV = trochlear nerve; V1 = ophthalmic division of the trigeminal nerve. C, Anterior view of the veins of the posterior fossa: 1 = crus cerebri; 2 = transverse pontine vein; 3 = vein of the cerebellopontine fissure; 4 = vein of the middle cerebellar peduncle; 5 = vein of the cerebellomedullary fissure or vein of the lateral recess of the fourth ventricle; FL = flocculus. D, Suboccipital view of the veins of the posterior fossa: 1 = inferior hemispheric vein; 2 = inferior vermian vein; 3 = inferior hemispheric vein; 4 = retrotonsillar veins; 5 = superior cerebellar peduncle; 6 = vein of the lateral recess of the fourth ventricle; 7 = tela choroidea; 8 = flocculus; VA = vertebral artery.

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oculomotor and trochlear nerves. Just before entering the orbit via the superior orbital fissure, it divides into lacrimal, frontal, and nasociliary branches. The lacrimal nerve is the smallest of the main ophthalmic branches, and enters the orbit through the lateral part of the superior orbital fissure and supplies the lacrimal gland and the adjoining conjunctiva. The frontal nerve is the largest branch of the ophthalmic division and enters the orbit via the superior orbital fissure above the annular tendon of Zinn to divide into a small supratrochlear and a large supraorbital branch. The nasociliary nerve is more deeply located in the orbit, which it enters through the annular tendon, lying between the two rami of the oculomotor nerve. It crosses the optic nerve with the ophthalmic artery and runs obliquely below the superior rectus and superior oblique muscles to the medial orbital wall. Here, as the anterior ethmoidal nerve, it traverses the anterior ethmoidal foramen to enter the cribriform plate and then into the nasal cavity. The nasociliary nerve connects with the ciliary ganglion and has long ciliary, infratrochlear, and posterior ethmoidal branches. The posterior ethmoidal nerve leaves the orbit via the posterior ethmoidal foramen and supplies the ethmoidal and sphenoidal sinuses.

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temporal region; part of the auricle, including the external meatus and tympanum; the lower lip; the lower part of the face; the muscles of mastication; the mucosa of the anterior two thirds of the tongue; and the mucosa of the floor of the oral cavity. Cranial nerve V3 has a large sensory and a small motor root. The sensory root exits from the trigeminal ganglion and leaves the skull base through the foramen ovale in the floor of the middle fossa. The small motor root passes under the ganglion and unites with the sensory root just outside the skull. The nerve immediately passes between the tensor veli palatini muscle and the lateral pterygoid muscle. Just beyond this junction, a meningeal branch and the nerve to the medial pterygoid muscle leaves the medial side of the nerve, which then divides into a small anterior and large posterior trunk. The anterior trunk presents the following branches: sensory (buccal nerve), and motor (masseteric, deep temporal, and nerve to lateral pterygoid). The posterior trunk presents the auriculotemporal, lingual, and the inferior alveolar nerves. Abducent Nerve (Cranial Nerve VI)

The maxillary nerve is totally sensory and, after leaving the trigeminal ganglion, it passes horizontally forward and medially in the lateral wall of the cavernous sinus to traverse the foramen rotundum. Through the foramen rotundum it courses directly into the posterior wall of the pterygopalatine fossa, where it sends off two large ganglionic branches containing fibers to the nose, palate, and pharynx. It then inclines laterally on the posterior surface of the orbital process of the palatine bone and on the upper part of the posterior surface of the maxilla in the inferior orbital fissure (which is continuous posteriorly with the pterygopalatine fossa) outside the orbital periosteum giving off its zygomatic branch, and then posterior superior alveolar branches. About halfway between the orbital apex and the orbital rim the nerve turns medially to enter the infraorbital canal as the infraorbital nerve through which it is conveyed progressively further below the orbital floor, in the roof of the maxillary antrum, until it emerges onto the face through the infraorbital foramen approximately 1 cm below the inferior orbital rim (in line with the pupil). The branches of the maxillary nerve are: in the cranial cavity, meningeal; in the pterygopalatine fossa, ganglionic, zygomatic, and posterior superior alveolar; in the infraorbital canal, middle superior alveolar and anterior superior alveolar; and on the face, palpebral, nasal, and superior labial.

This innervates the lateral rectus muscle (see Figs. 1-12D and 1-13A). The fibers arise from a small nucleus in the superior part of the floor of the fourth ventricle near the midline and beneath the facial colliculus. They descend ventrally through the pons, emerging in the junction of the pontomedullary sulcus and the anterolateral sulcus. After leaving the brainstem, the abducent nerve ascends anterolaterally through the prepontine cistern along the clivus, usually dorsal to the AICA. It pierces the dura mater lateral to the dorsum sellae and bends sharply forward over the superior border of the apex of the petrous temporal bone, medial to the trigeminal nerve. Here it enters a fibro-osseous canal (Dorello’s canal) formed by the apex of the petrous temporal bone and the petrosphenoidal ligament. The latter is a fibrous band connecting the lateral margin of the dorsum sellae to the upper border of the petrous temporal bone near its medial end. The nerve then traverses the cavernous sinus, lying laterally to the intracavernous internal carotid artery. Among those cranial nerves crossing through the cavernous sinus, the abducent nerve is the only one that traverses inside the cavernous sinus. All the rest course on the lateral wall of the cavernous sinus. Cranial nerve VI enters the orbital cavity via the medial end of the superior orbital fissure within the annulus of Zinn, between the superior and the inferior divisions of cranial nerve III and inferolateral to the nasociliary nerve, to finally enter the lateral rectus muscle through its ocular surface.

Mandibular Nerve (Cranial Nerve V, Segment 3)

Facial Nerve (Cranial Nerve VII)

The mandibular nerve is the largest trigeminal division. It supplies the teeth and gums of the mandible; the skin in the

The sensory function mediates sensation from the skin of the external ear canal and taste from the anterior two thirds of

Maxillary Nerve (Cranial Nerve V, Segment 2)

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the tongue. The motor function is responsible for innervating muscles of facial expression, plus stylohyoid, stapedius, and posterior belly of the digastric muscle. The autonomic function mediates all salivary glands except the parotid gland, as well as lacrimal glands and cerebral vasculare. The facial nerve has a motor root and a sensory root (nervus intermedius). The nervus intermedius gains its name from its position between the facial and vestibulocochlear nerves at the CP angle. The two roots arise from the pons at the superior catheti of the supraolivary fossette, slightly medial and anterior to the vestibulocochlear nerves. The facial nerve is divided into five segments: (1) cisternal, (2) labyrinthine, (3) tympanic or horizontal, (4) mastoid, and (5) extratemporal. The cisternal segment extends from its origin from the brainstem to the internal acoustic meatus. From their emergence from the brainstem, the two roots pass anterolaterally with the vestibulocochlear nerve toward the internal acoustic meatus; in this location, the motor root is in an anterosuperior groove on the vestibulocolchlear nerve, with the sensory root between them. At the lateral end of the internal acoustic meatus, the Bill’s bar and the transverse crest divide the meatus into quadrants: the facial nerve is located at the anterosuperior quadrant, the cochlear nerve at the anteroinferior quadrant, the superior vestibular nerve at the posterosuperior quandrant, and the inferior vestibular nerve at the posteroinferior quandrant. In its intratemporal course, its bony canal is narrowest at the meatal foramen. It is accompanied by the labyrinthine branch of the AICA or from the basilar artery. The labyrinthine segment of the nerve runs across the axis of the petrous pyramid to the geniculate ganglion. It is just medial to the tip of the cochleariform process. After the geniculate ganglion, the facial nerve turns 130 degrees and forms the tympanic segment, which is approximately 10 to 12 mm long, and passes lateral to the vestibule, above the oval window, and below the horizontal semicircular canal. In the medial wall of the middle ear, it slopes down from anterior to posterior forming an angle of approximately 10 degrees with the horizontal semicircular canal. It lies medial to the malleus head anteriorly, the incudomalleolar joint; incus and attic posteriorly. After the horizontal or tympanic segment, the facial nerve angles inferiorly within the mastoid to constitute the mastoid segment, and here it gives off the nerve to the stapedius muscle. Aproximately 5 mm before exiting from the stylomastoid foramen, the facial nerve gives off the corda tympani nerve. After exiting from the stylomastoid foramen, the nerve runs forward in the parotid gland, lateral to the styloid process, retromandibular vein, and external carotid artery and divides behind the neck of the mandible into branches that pierce the anteromedial surface of the parotid gland to innervate the face through five branches. The branches of the facial nerve are: from geniculate ganglion, greater petrosal

nerve; from facial canal, auricular branch to vagus, nerve to stapedius, and chorda tympani nerve; at the exit from the stylomastoid foramen, posterior auricular branch and branches to posterior belly of digastric and stylohyoid muscles; on the face, temporal, zygomatic, buccal, marginal mandibular, and cervical branches. Vestibulocochlear Nerve (Cranial Nerve VIII) This nerve is responsible for hearing and sense of motion (angular and linear acceleration). The vestibulocochlear nerve exits from the superior catheti of the supraolivary fossette and courses along with the facial and the intermedius nerves toward the internal acoustic meatus. At the fundus of the internal acoustic meatus, the vestibular part of the vestibulocochlear nerve expands to form the vestibular ganglion and then divides into superior vestibular and inferior vestibular nerves. The superior and inferior vestibular nerves are connected to the ampulle of the semicircular canals and the maculae of the saccule and utricle. Glossopharyngeal Nerve (Cranial Nerve IX) Cranial nerve IX is both motor and sensory, supplying motor fibers to the stylopharyngeus, parasympathetic secretomotor fibers to the parotid gland via the otic ganglion, and sensory fibers to the tympanic cavity, Eustachian tube, tonsils, nasopharynx, uvula, inferior surface of the soft palate and posterior third of the tongue; it is also the gustatory nerve for this part of the tongue. Cranial nerve IX is the uppermost single nerve that exits from the hypotenuse of the supraolivary fossette, anteriorly to the choroid plexus of the foramen of Luschka, and courses anterolaterally toward the jugular foramen. After exiting the jugular foramen, the glossopharyngeal nerve passes forward between the internal jugular vein and internal carotid to reach the posterior border of the stylopharyngeus. It curves forward on the stylopharyngeus and either pierces the lower fibers of the superior phryngeal constrictor or passes between it and the middle constrictor to be distributed to the tonsil, the mucosa of the pharynx, and the posterior part of the tongue. Vagus Nerve (Cranial Nerve X) The vagus nerve is also mixed in function. Its sensory function mediates sensation from the posterior pharynx, visceral sensation from pharynx, larynx, thoracic, and abdominal organs; and taste from posterior tongue and oral cavity. Its motor function innervates striated muscles of larynx and pharynx. The autonomic function innervates smooth muscle and glands of gastrointestinal, pulmonary, and cardiovascular systems in neck, thorax, and abdomen. The vagus nerve emerges as eight or ten rootlets from the hypotenuse of the supraolivary fossette, below cranial nerve

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IX. The vagal rootlets unite to form a flat cord that passes below the flocculus to the jugular foramen, where the vagus acompanies cranial nerve XI, sharing an arachnoid and dural sheath; both lie anteriorly to a fibrous septum that separates them from cranial nerve IX. The vagus has a more extensive course and distribution than any other cranial nerve, traversing the neck, thorax, and abdomen. Accessory Nerve (Cranial Nerve XI) The accessory nerve has two components: the cranial root, which joins the vagus, has been considered a special visceral efferent nerve. The spinal root is considered a motor nerve that innervates the trapezius and the sternocleidomastoid muscles. The cranial root is the smaller one, and emerges as four or five fine rootlets from the dorsolateral surface of the caudal medulla oblongata below cranial nerve X. It then runs laterally toward the jugular foramen, where it becomes separated from its spinal mate and joins cranial nerve X. These fibers are distributed in the pharyngeal branches of the vagus nerve. The spinal root arises from the lateral aspect of the ventral horn. However it does not exit either from the anterolateral nor from the posterolateral sulci; it exits anteriorly to the posterolateral sulcus and behind the dentate ligament. Its origin can extend from the junction of the spinal cord and medulla to the sixth cervical segment. It then ascends through the foramen magnum toward the jugular foramen. After exiting from the jugular foramen, the spinal root runs posterolaterally passing either medial or lateral to the internal jugular vein. The nerve then crosses the transverse process of the C1 and is itself crossed by the occipital artery. It descends obliquely, medial to the styloid process, stylohyoid, and the posterior belly of the digastric muscles. With the superior sternocleidomastoid branch of the occipital artery, it reaches the upper part of the sternocleidomastoid and enters its deep surface. It crosses the posterior triangle on the neck, on the levator scapulae muscle, and it is separated from that muscle by the prevertebral layer of deep cervical fascia and adipose tissue. Hypoglossal Nerve (Cranial Nerve XII) The hypoglossal nerve innervates intrinsic muscles of the tongue except the palatoglossus. Cranial nerve XII rootlets exit from the preolivary sulcus and run laterally behind the vertebral artery, then they are collected into two bundles that perforate the dura mater separately to enter the hypoglossal canal in the occipital condyle. The two bundles become united at the lateral end of the hypoglossal canal. This single bundle exits from the canal medially to the internal jugular vein, internal carotid artery, cranial nerves IX to XI, and passes inferolaterally behind the internal carotid artery and

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cranial nerves IX and X to the interval between the artery and the internal jugular vein. Here it makes a half-spiral turn around the inferior vagal ganglion, being united with it by connective tissue. The hypoglossal nerve then descends almost vertically between the vessels and anterior to cranial nerve X to a point level with the mandibular angle, becoming superficial below the posterior belly of the digastric and emerges between the internal jugular vein and internal carotid artery to supply the tongue. Veins of the Posterior Fossa The posterior fossa venous system can be divided into three groups: the anterior or petrosal group that drains into the superior and inferior petrosal sinuses, the superior or Galenic group that drains into the vein of Galen, and the posterior or tentorial group that drains into the sinuses near the torcula.54 There is a tendency for the veins to empty into the nearest draining system. The veins running on the petrosal surface of the cerebellum (anterior hemispheric veins, inferior and superior groups, vein of the great horizontal fissure) and the anterior surface of the brainstem tend to drain into the petrosal sinuses via superior petrosal veins, except those veins running on the surface of the midbrain that drain to the vein of Galen (Fig. 1-13C).55 The tentorial surface of the cerebellum and the posterior aspect of the brainstem are enclosed within the three draining systems; the midline portion of the cerebellomesencephalic fissure is closer to the vein of Galen. Therefore, the veins around the central lobule and culmen (superior vermian vein), and the veins draining the intermediate portion of the wing of the central lobule and the quadrangular lobule (superior hemipheric veins, anterior group) tend to drain into the vein of Galen. As the superior petrosal sinus runs along the anterolateral margin of the cerebellum, all the veins draining the lateral portion of the wing of the central lobule, quadrangular lobule, simple lobule, and tentorial part of the superior semilunar lobule (superior hemispheric veins, lateral group) tend to drain into the superior petrosal sinus. The tentorial surface of the cerebellum is enclosed posteriorly by the transverse sinuses and the torcula; therefore, the veins draining the declive, folium (declival vein), and the intermediate portion of the simple and the superior semilunar lobules (superior hemispheric veins, posterior group) tend to drain into those sinuses or into the tentorial sinus located in the tentorium cerebelli.56,57 The veins draining the suboccipital surface of the cerebellum tend to drain into the torcula or into the transverse sinus or into the sinuses located in the tentorium cerbelli. The cerebellar hemispheres are therefore drained by the posterior inferior hemipheric veins. The inferior vermis, comprising the tuber, pyramid, and uvula, is drained by the inferior vermian veins, which are formed by the junction of

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the superior and the inferior retrotonsilar veins that run in the retrotonsillar space.58,59 The inferior portion of the roof of the fourth ventricle and the lateral recess are drained by the vein of the lateral recess of the fourth ventricle, also called vein of the cerebellomedullary fissure. Although the vein of the lateral recess of the fourth ventricle is best seen from the suboccipital view, it courses laterally under the lateral recess toward the CP angle, then it passes above or below the flocculus and joins the vein of the middle cerebellar peduncle or joins the vein of the cerebellopontine fissure to finally empty into the superior petrosal sinus via the superior petrosal vein. The vein of the lateral recess of the fourth ventricle also can anastomose with the retrotonsilar veins at the retrotonsillar space, establishing therefore a communication between the petrosal and the tentorial groups of venous drainage (Fig. 1-13D). The brachial veins running in the cerebellomesencephalic fissure can also establish a communication between the petrosal and the galenic groups of venous drainage via the pontotrigeminal and precentral cerebellar veins, respectively (Fig. 1-14A). The veins of the posterior fossa can be summarized as follows: • The petrosal group may be divided into (1) veins related to the anterior aspect of the brain stem; (2) veins in the wing of the precentral cerebellar fissure (the brachial veins); (3) veins on the tentorial and mainly on the petrosal surfaces of the cerebellar hemispheres—superior and inferior hemispheric veins, including the veins of the great horizontal fissure; (4) veins on the cerebellar side (the medial tonsillar vein) and medullary side of the cerebellomedullary fissure (the retro-olivary vein and vein of the inferior cerebellar peduncle); and (5) the vein of the lateral recess of the fourth ventricle. • The superior or galenic group drains into the vein of Galen and includes (1) mesencephalic tributaries—the median anterior pontomesencephalic, the lateral anterior pontomesencephalic, the lateral pontomesencephalic, the lateral mesencephalic, the peduncular, the posterior mesencephalic, and the tectal veins; and (2) cerebellar tributaries—the precentral cerebellar vein and its variants and the superior vermian vein. • The posterior or tentorial group drains into the tentorial sinuses near the torcula and includes basically the veins that drain the suboccipital surface of the cerebellum: the inferior vermian vein and its superior and inferior retrotonsillar tributaries, and the superior and inferior hemispheric veins. Arteries of the Posterior Fossa The vertebral artery arises on each side from the subclavian artery, then enters the transverse foramen of the C6 and ascends through the transverse foramina of the upper cervi-

cal vertebrae up to the C2. After exiting from the transverse foramen of the C2, the vertebral artery deviates laterally to enter the laterally placed transverse foramen of C1. The vertebral artery then turns behind the lateral mass of the C1, above the posterior arch of the C1 to course medially and superiorly to pierce the dura at the foramen magnum. At this level, the vertebral artery usually gives off the posterior spinal and the posterior meningeal arteries. The intradural segment of the vertebral artery is divided into lateral medullary and anterior medullary segments before joining its contralateral mate to form the basilar artery. The lateral medullary segment of the vertebral artery extends from its entrance into the posterior fossa to the preolivary sulcus. From its entrance, the vertebral artery courses anterior, medial, and superiorly through the lower cranial nerve rootlets and laterally to the medulla to reach the preolivary sulcus. The anterior medullary segment begins at the preolivary sulcus, courses in front of, or between, the hypoglossal rootlets, and crosses the pyramid to join with the other vertebral artery at or near the pontomedullary sulcus to form the basilar artery. The main branches of the vertebral artery are the posterior spinal, anterior spinal, PICA, and anterior and posterior meningeal arteries. The vertebral artery also sends off branches to supply the lateral and anterior parts of the medulla along its way around the medulla (Fig. 1-14B). The PICA supplies the medulla, the inferior vermis, the inferior portion of the fourth ventricle, the tonsils, and the inferior aspect of the cerebellum.60–62 It is the most important branch of the vertebral artery, from which it usually arises at the anterolateral aspect of the brainstem near the inferior olive. It often has a tortuous course, and its area of supply is the most variable of the cerebellar arteries. The PICA gives off perforating, choroidal, and cortical arteries; when PICA is absent, the AICA usually supplies this area. The entire inferior cerebellar hemispheres may be supplied by the contralateral PICA. The “normal” PICA has the most complex and variable course of the cerebellar arteries, and is divided into five segments: 1. The anterior medullary segment, which lies on the front of the medulla and extends from the origin to the level of the inferior olive 2. The lateral medullary segment, which courses beside the medulla, and extends from the inferior olive to the origin of the glossopharyngeal, the vagus, and the accessory nerves 3. The tonsillomedullary or posterior medullary segment, which courses around the caudal half of the cerebellar tonsil and begins at the level of the nerves and loops below the inferior pole of the cerebellar tonsil and upward along the medial surface of the tonsil toward the inferior medullary velum (caudal loop) 4. The telovelotonsillar or supratonsillar segment, which courses in the cleft between the tela choroidea and the

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Figure 1-14. A, Superolateral view: 1 = transverse sinus; 2 = tentorial sinus; 3 = internal cerebral vein; 4 = anterior septal vein; 5 = declival veins; 6 = superior vermian vein; 7 = vein of Galen; 8 = pineal gland; 9 = precentral cerebellar vein; 10 = red nucleus; 11 = anterior cerebral vein; 12 = pontotrigeminal vein; 13 = posterior cerebral vein; 14 = internal carotid artery; 15 = superior petrosal vein; 16 = superior petrosal sinus. B, Posterior view: 1 = optic nerve; 2 = internal carotid artery; 3 = oculomotor nerve; 4 = posterior cerebral artery; 5 = trochlear nerve; 6 = superior cerebellar artery; 7 = trigeminal nerve; 8 = basilar artery; 9 = AICA; 10 = PICA; 11 = anterior spinal artery; 12 = first triangular process of the dentate ligament; 13 = second triangular process of the dentate nucleus. IAM, internal acoustic meatus; VA, vertebral artery; Jug. for., jugular foramen. C, Posterolateral view: 1 = thalamus; 2 = choroidal fissure; 3 = insula; 4 = fornix; 5 = thalamus; 6 = pineal gland; 7 = superior colliculus; 8 = inferior colliculus; 9 = branches from the superior cerebellar artery; 10 = middle cerebellar peduncle; 11 = anterior medullary segment of the PICA; 12 = lateral medullary segment of PICA; 13 = caudal loop of PICA; 14 = posterior medullary segment of PICA; 15 = supratonsillar segment of PICA; 16 = pyramidal loop of PICA; IAM = internal acoustic meatus; FL = flocculus; Jug. for. = jugular foramen; VA = vertebral artery. D, Frontal view: 1 = right posterior cerebral artery; 2 = left posterior cerebral artery; 3 = right superior cerebellar artery; 4 = left superior cerebellar artery; 5 = basilar artery; 6 = AICA; 7 = PICA; VA = vertebral artery.

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inferior medullary velum rostrally, and the superior pole of the cerebellar tonsil caudally, and begins below the fastigium, where the PICA turns posteriorly over the medial side of the superior pole of the tonsil. This segment forms the “cranial loop.” It sometimes passes posteriorly before reaching the superior pole of the tonsil, thus giving the cranial loop a variable relationship to the fastigium. The junction of the posterior medullary segment and the supratonsillar segment is called the choroidal point. 5. The cortical segment: after a short distance distal to the apex of the cranial loop, the PICA continues posteriorly downward in the retrotonsillar fissure where it usually bifurcates into two terminal trunks, the tonsillohemispheric and the inferior vermian branches. The inferior vermian branch lies on the lower aspect of the inferior vermis, and forms a loop convex around the copula pyramidis (pyramidal loop). The most anterior point of the curve of the pyramidal loop is also called the copular point. The terminal portion of the vermian branch curves around the tuber in the posterior cerebellar notch. The tonsillohemispheric branch runs inferiorly near the prepyramidal sulcus and gives off anterior or tonsillar branches and posterior or hemispheric branches that curve downward and backward around the biventral lobule to the under aspect of the cerebellar hemisphere (Fig. 1-14C). The AICA and PICA are defined according to their origin rather than by the portions of cerebellum that they supply. The AICA supplies the lateral pontine tegmentum and base, and the most anterior undersurface of the cerebellum.63,64 The AICA arises from the basilar artery and the PICA from the vertebral artery. The AICA arises more frequently from the lower third of the basilar artery and courses posteriorly, laterally, and usually downward on the belly of the pons, in contact with either the superior or inferior aspect of the abducent nerve. In this course, it supplies the lateral aspect of the lower two thirds of the pons and the upper medulla. Either immediately before or after crossing the roots of the facial, the intermedius, and the vestibulocochlear nerves within the cerebellopontine angle, the AICA bifurcates into its two major branches, the rostrolateral and the caudomedial arteries. The rostrolateral (RL) trunk has been divided into three segments—premeatal, meatal, and postmeatal—according to their relationship to cranial nerves VII and VIII. The premeatal segment begins at the basilar artery and courses around the brainstem to reach cranial nerves VII and VIII and the region of the meatus, usually anteroinferiorly to the nerves. Seventy-seven percent of the internal auditory arteries and 49% of the recurrent perforating arteries, which course medially from their origin to supply the brainstem, arise from this segment. The meatal segment is located in the vicinity of the internal auditory meatus, where the nerve-related vessels turn toward the brainstem. This segment often forms a later-

ally convex loop, the meatal loop, directed toward or through the meatus. It usually stays medial to the meatus, but sometimes it protrudes into the canal. The postmeatal segment begins distally to the nerves and courses medially to supply the brainstem and the cerebellum. The subarcuate artery to the subarcuate fossa usually arises from this segment. The caudomedial (CM) artery courses medially and downward toward the medial and anterior border of the cerebellum, supplying the biventral lobule and the middle cerebellar peduncle; the medial branch also has abundant anastomoses with branches of the PICA. From its origin on the lateral aspect of the pons in the vicinity of the sixth cranial nerve, the CM passes posterosuperiorly, toward the pontomedullary sulcus to describe its own caudal loop on the lateral aspect of the pons and medulla. This lateral loop can lie on the antero-inferolateral aspect of the flocculus, or on the petrosal aspect of the biventral lobule, or on the petrosal aspect of the undersurface of the biventral lobule. Multiple small arteries to the choroid plexus of the lateral recess often arise from the inner aspect of this lateral loop. Distal to the loop, the biventral segment turns postero-inferiorly on the lateral aspect of the biventral lobule, on the biventral ridge, or within the cerebellomedullary fissure to reach the posterior surface of the cerebellum. In a manner analogous to the descending branch of the RL, the CM may also anastomose with PICA or give rise to ascending hemispheric branches that supplement or replace the hemispheric branches of PICA (Figs. 1-14D and 1-15A). The superior cerebellar artery (SCA) is the most rostral of the infratentorial vessels, and it arises near the apex of the basilar artery and encircles the pons and the lower midbrain. It supplies the tentorial surface of the cerebellum, the midbrain tegmentum, the deep cerebellar nuclei, and the inferior colliculi.65–67 The SCA is divided in four segments: 1. The anterior pontomesencephalic segment extends from its origin to the anterolateral margin of the brainstem. It courses laterally on the anterior aspect of the upper pons, often in an arcuate curve convex inferiorly; at the anterolateral margin of the brainstem it lies inferior to the third nerve. 2. The lateral pontomesencephalic segment begins at the anterolateral margin of the brainstem and follows caudally onto the lateral side of the upper pons in the infratentorial portion of the ambient cistern to terminate at the anterior margin of the cerebellomesencephalic fissure. This segment is related medially to the brainstem, laterally to the wing of the central lobule, and to the middle cerebellar peduncle inferiorly. The anterior part of this segment is often visible above the free edge of the tentorium, whereas its caudal loop projects toward and often reaches the root entry zone of the trigeminal nerve. The bifurcation of the SCA into its rostral and caudal trunks often occurs in this segment, while the rostral trunk supplies the vermis and a

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D Figure 1-15. A, Frontal view: 1 = posterior cerebral artery; 2 = superior cerebellar artery; 3 = superior petrosal sinus; 4 = AICA; 5 = facial nerve and the meatal loop of AICA; 6 = origin of PICA; 7 = anterior spinal artery; 8 = vertebral artery between C1 and C2; VA = intradural vertebral artery. B, Posterior view: 1 = perforating branches from basilar tip and P1; 2 = medial posterior choroidal artery; 3 = superior cerebellar artery; 4 = perforating branches from midbasilar artery; 5 = PICA; BA = basilar artery; VA = vertebral artery. C, Midsagittal view of the interpeduncular region: 1 = thalamus; 2 = aqueduct; 3 = foramen of Monro; 4 = fornix; 5 = midbrain; 6 = hypothalamus; 7 = posterior perforated substance region; 8 = lamina terminalis; 9 = mamillary body; 10 = tuber cinereum; 11 = pituitary stalk; 12 = optic chiasm; 13 = pons and the posterior thalamoperforating artery; 14 = posterior communicating artery; 15 = P1; 16 = internal carotid artery; 17 = parahippocampal gyrus; III = oculomotor nerve. D, Coronal view: General pattern of the vascularization of the central nervous system (left); the approximate vascular territories of the major arteries (right).

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variable portion of the adjacent tentorial surface, the caudal trunk supplies the surface lateral to the area supplied by the rostral trunk. 3. The cerebellomesencephalic segment courses in the cerebellomesencephalic fissure through a series of hairpin-like curves; it then passes upward to reach the anterosuperior margin of the cerebellum. Inside the cerebellomesencephalic fissure, the cortical branches from the rostral and caudal trunks send off small arterial twig branches called precentral branches. Those precentral branches arising from the rostral trunk supply the inferior colliculi (the superior colliculi are supplied by PCA) and superior medullary velum, and those arising from the caudal trunk supply the deep cerebellar nuclei. 4. The cortical segment is represented by the hemispheric and the vermian branches to supply the tentorial surface of the cerebellum. Among these cortical branches, the marginal or lateral branch deserves a special attention: it was present in 62% of the cases; it is the first large cortical branch of the SCA, and arises from the lateral pontomesencephalic segment to course anteriorly and laterally to reach the anterolateral margin of the cerebellum, and then extends posterolaterally in the region of the petrosal fissure to supply the adjacent areas. Its area of supply is inversely related to the area supplied by AICA (Figs. 1-15A and B). The basilar artery averages approximately 3 cm and is formed at the level of the pontomedullary junction by the union of the two vertebral arteries. The basilar artery then courses superiorly in front of the pons toward the interpeduncular fossa to divide into the two posterior cerebral arteries. The main branches of the basilar artery are AICA, SCA, and short and long segment circumflex perforating arteries. These perforating arteries arise along the entire length of the basilar artery and supply the ventral pons and rostral brainstem. The branches arising from the top of the basilar artery have been discussed under the posterior cerebral artery (Fig. 1-15B and C).

The Brainstem Syndromes The general pattern of the vascularization of the central nervous system is applied for the whole central nervous system, from the telencephalon to the spinal cord. Following this pattern, the “tube-shaped” central nervous system is completely circumscribed by the major arteries of the cerebrum and the posterior fossa. These major arteries not only circumscribe the neural tube but also give off central perforators (paramedian arteries) to the central base region of the neural tube, lateral perforators to the lateral part of the neural tube, and finally perforators to the dorsal aspect of the neural tube. This pattern is still evident in the mature central nervous system (Fig. 1-15D and 1-16A).

The brainstem syndromes of vascular origin can be divided into midbrain, pontine, and medullary syndromes.68,69 Midbrain syndrome can be further divided into ventral midbrain, tegmental, and dorsal midbrain syndromes. Ventral midbrain syndrome, also called Weber’s syndrome, usually is characterized by diplopia, with homolateral dilated pupil (oculomotor nerve), occasional ataxia, and contralateral motor deficit, mainly upper limb and face (pyramidal tract) (Fig. 1-16B). Tegmental midbrain syndrome, also called Claude’s syndrome, is usually characterized by diplopia, with homolateral dilated pupil (oculomotor nerve), homolateral Horner’s syndrome, contralateral loss of pain and temperature sensation from trunk, limbs (spinothalamic tract), face (trigeminothalamic tract), contralateral loss of position sense in the limbs (medial lemniscus), contralateral resting tremor (red nucleus), contralateral ataxia (dentatothalamic tract after crossing), and contralateral motor deficit affecting mainly the leg (leg fibers from the pyramidal tract) (Fig. 1-16B). The combination of the ventral and the tegmental midbrain syndromes is called Benedikt’s syndrome. Tectal midbrain syndrome, also called Parinaud syndrome, is characterized by deficit of upward conjugate gaze (type 1) or deficit of downward conjugate gaze (type 2) (Fig. 1-16B). Pontine syndrome can be divided in medial and lateral pontine syndromes. The medial pontine syndrome, also called Millard-Gubler syndrome, is characterized by homolateral abducent nerve palsy, homolateral facial paralysis, homolateral ataxia (transverse fibers of pons), and contralateral loss of pain and temperature sensation from the face (trigeminothalamic tract), contralateral loss of position sense of limbs (medial lemniscus), and contralateral motor deficit (pyramidal tract) (Fig. 1-16C). Lateral pontine syndrome, also called Foville’s syndrome, is characterized by homolateral tinnitus or deafness (cochlear nerve), homolateral ataxia (inferior cerebellar peduncle), paralysis of homolateral conjugate gaze (paraabducent nucleus), vomiting, nystagmus, vertigo (vestibular nerve), homolateral Horner’s syndrome, homolateral anesthesia of the face (sensory root of the trigeminal nerve), weakness of jaw muscles (motor root of trigeminal nerve), homolateral facial paralysis, and contralateral loss of pain and temperature sensation from trunk and limbs (spinothalamic tract) (Fig. 1-16C). Medullary syndromes can be divided into medial and lateral medullary syndromes. Medial medullary syndrome is characterized by weakness of tongue (hypoglossal nerve), contralateral loss of position sense in limbs (medial lemniscus), and contralateral motor deficit sparing the face (pyramid) (Fig. 1-16D). Lateral medullary syndrome, also called Wallenberg’s syndrome, is characterized by vertigo, vomiting, nystagmus (vestibular nucleus), homolateral ataxia of limbs (inferior cerebellar peduncle), homolateral loss of pain and temperature sensation from face (spinal tract of trigeminal nerve), homolateral Horner’s syndrome, dysphagia, hoarseness (nucleus ambiguus),

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Figure 1-16. A, Axial view: the approximate vascular territories of the major arteries (right). B, The midbrain syndromes: 1 = ventral midbrain syndrome; 2 = tegmental midbrain syndrome; 3 = tectal midbrain syndrome. C, The pontine syndromes: 1 = medial pontine syndrome; 2 = lateral pontine syndrome. D, The medial and lateral medullary syndromes (shaded areas).

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Figure 1-17. A, The location of the pyramidal and the lateral spinothalamic tracts in the spinal cord. B, Frontal view of the dermatomes.

and contralateral loss of pain and temperature sensation from trunk and limbs (lateral spinothalamic tract) (Fig. 1-16D).

The Spinal Cord For a quick and concise neurologic examination of the spinal cord in an intensive care unit, two basic aspects of spinal cord

organization should be kept in mind: (1) the topographical organization of the main fiber tract in the spinal cord (the motor and the superficial sensory tracts; Fig. 1-17A), and (2) the distribution of the dermatomes—the strips of skin supplied by the posterior nerve roots. The clinical importance of the dermatomes is evident in determining the level of the spinal cord lesion (for instance in spinal cord injuries; Fig. 1-17B).

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P earls 1. The cerebrum is arbitrarily divided into five lobes: frontal, parietal, temporal, occipital, and the hidden insula. 2. From the neurosurgical viewpoint, the sylvian fissure can be considered as the gateway connecting the surface of the anterior part of the brain to its depth with all the neural and vascular components along the way. 3. The corpus callosum is the largest transverse commissure connecting the cerebral hemispheres. 4. The basal ganglia play a major role in voluntary motor movement; however, they do not have direct input or output with the spinal cord. 5. The disturbance of the basal ganglia is usually characterized by (1) tremor and other involuntary movements, (2) changes in posture and muscle tone, and (3) poverty and slowness of movement without paralysis. 6. The thalamus is not a relay station where information is simply passed on to the neocortex; the thalamus acts as a gatekeeper for information to the cerebral cortex, preventing or enhancing the passage of specific information depending on the behavioral state of the person. 7. The choroidal fissure is one of the most important landmarks in microneurosurgeries involving the tem-

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poral lobe; it separates those structures located laterally that can be removed (temporal structures) from those structures located medially that should be preserved (thalamic structures). The internal carotid artery is divided into five parts: cervical, petrous, cavernous, clinoid, and supraclinoid portions. Paracentral syndrome can be characterized by weakness of the contralateral lower limb, most intense in the foot and ankle, with or without sensory loss. The transient or permanent incontinence of urine can also be present. SMA syndrome can be characterized by dysphasia (when the dominant hemisphere is affected), akinesia in the contralateral limb, contralateral hand grasping or groping, contralateral alien hand signs (when dominant hemisphere is affected, the right hand consistently interrupts manual tasks performed by the left hand), and dyspraxia. Anterior cingulate syndrome is more evident when the cingulate cortex is bilaterally and extensively affected; this might cause akinetic mutism, complex behavioral changes, loss of sphincter control, and autonomic dysfunctions (temperature; cardiac and respiratory irregularities).

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22. Ture U, Yasargil MG, Al-Mefty O, et al: Arteries of the insula. J Neurosurg 2000;92:676. 23. Taveras JM, Wood EH: Diagnotic Neuroradiology. Baltimore, Williams & Wilkins, 1964. 24. Rosner SS, Rhoton AL Jr, Ono M, et al: Microsurgical anatomy of the anterior perforating arteries. J Neurosurg 1984;61:468. 25. Huang YP, Wolf BS: The basal cerebral vein and its tributaries. In Newton TH, Potts DG (eds): Radiology of the Skull and Brain, vol 2, book 3. St. Louis, CV Mosby, 1974, pp 2111–2154. 26. Seoane E, Rhoton AL Jr, de Oliveira E: Microsurgical anatomy of the dural collar (carotid collar) and rings around the clinoid segment of the internal carotid artery. Neurosurgery 1998;42:869. 27. Gibo H, Lenkey C, Rhoton AL Jr: Microsurgical anatomy of the supraclinoid portion of the internal carotid artery. J Neurosurg 1981;55:560. 28. Hayreh SS: The ophthalmic artery. In Newton TH and Potts DG (eds): Radiology of the Skull and Brain. Angiography, vol 2, book 2. St. Louis, CV Mosby, 1974, pp 1333–1350. 29. Rhoton AL Jr, Fujii K, Fradd B: Microsurgical anatomy of the anterior choroidal artery. Surg Neurol 1979;12:171. 30. Theron J, Newton TH: Anterior choroidal artery: 1—Anatomic and radiographic study. J Neuroradiol 1976;3:5. 31. Hayman LA, Berman SA, Hinck VC: Correlation of CT cerebral vascular territories with function: II. Posterior cerebral artery. AJR 1981;137:13–19. 32. Margolis MT, Newton TP, Hoyt WF: The posterior cerebral artery II. Gross and roentgenographic anatomy. In Newton TH, Potts DG (eds): Radiology of the Skull and Brain, vol 2, book 2. St. Louis, CV Mosby, 1974, pp 1551–1576. 33. Saeki N, Rhoton AL Jr: Microsurgical anatomy of the upper basilar artery and the posterior circle of Willis. J Neurosurg 1977;46:563. 34. Yasargil MG: Microneurosurgery: Microsurgical Anatomy of the Basal Cisterns and Vessels of the Brain. Stuttgart, Georg Thieme Verlag, 1984, vol I. 35. Zeal AA, Rhoton AL Jr: Microsurgical anatomy of the posterior cerebral artery. J Neurosurg 1978;48:534. 36. George AE, Raybaud CH, Salamon G, et al: Anatomy of the thalamoperforating arteries with special emphasis on arteriography of the third ventricle: Part 1. AJR 1975;124:220–230. 37. Perlmutter D, Rhoton AL Jr: Microsurgical anatomy of the distal anterior cerebral artery. J Neurosurg 1978;49:204. 38. Dunker RO, Harris B: Surgical anatomy of the proximal anterior cerebral artery. J Neurosurg 1976;44:359. 39. Perlmutter D, Rhoton AL Jr: Microsurgical anatomy of the anterior cerebral-anterior communicating-recurrent artery complex. J Neurosurg 1976;45:259. 40. Gomes F, Dunovny M, Umansky F, et al: Microsurgical anatomy of the recurrent artery of Heubner. J Neurosurg 1984;60:130. 41. Hung TP, Ryu SJ: Anterior cerebral artery syndromes. In Vinken PJ, Bruyn GW, Klawans HL (eds): Handbook of Clinical Neurology, vol 53, part 1. Amsterdam, Elsevier Science, 1988, pp 339–352. 42. Salamon G, Lazorthes G: Tumours of the basal ganglia: An angiographic study. Neuroradiology 1971;2:80–89. 43. Westberg G: Arteries of the basal ganglia. Acta Radiol Diagn 1966;N.S.5:581–596. 44. Rhoton AL Jr: The Posterior Cranial Fossa: Microsurgical Anatomy and Surgical Approaches. Neurosurgery 2000;47:S1. 45. Ghez C, Thach WT: The cerebellum. In Kandel ER, Schwartz JH, Jessel TM (eds): Principles of Neuroscience, 4th ed. New York, McGraw Hill, 2000, pp 832–852.

46. Matsushima T, Rhoton AL Jr, Lenkey C: Microsurgery of the fourth ventricle: Part 1: Microsurgical anatomy. Neurosurgery 1982;11:631. 47. Corrales M, Greitz T: Fourth ventricle: I. A morphologic and radiologic investigation of the normal anatomy. Acta Radiol 1972;12:113. 48. Bentson JR, Alberti JB: Lateral recess of the fourth ventricle. Radiology 1972;104:593. 49. Fujii K, Lenkey C, Rhoton AL Jr: Microsurgical anatomy of the choroidal arteries: fourth ventricle and cerebellopontine angles. J Neurosurg 1980;52:504. 50. Gortvai P, Teruchkin S: The position and extent of the human dentate nucleus. Acta Neurochir 1974;21:101. 51. Buren van JM, Baldwin M: The architecture of the optic radiation in the temporal lobe of man. Brain 1958;81:2. 52. Ebeling U, Reulen HJ: Neurosurgical topography of the optic radiation in the temporal lobe. Acta Neurochir 1988;92:29. 53. Rasmussen AT: The extent of recurrent geniculo-calcarine fibers (loop of Archambault and Meyer) as demonstrated by gross brain dissection. Anat Rec 1943;85:277. 54. Matsushima T, Rhoton AL Jr, de Oliveira E: Microsurgical anatomy of the veins of the posterior fossa. J Neurosurg 1983;59:63. 55. Huang YP, Wolf BS, Antin SP, et al: The veins of the posterior fossaanterior or petrosal draining group. AJR 1968;104:36. 56. Huang YP, Wolf BS: The veins of the posterior fossa-superior or galenic draining group. AJR 1965;95:808. 57. Huang YP, Wolf BS: Precentral cerebellar vein in angiography. Acta Radiol 1966;5:250. 58. Huang YP, Wolf BS, Okudera T: Angiographic anatomy of the inferior vermian vein of the cerebellum. Acta Radiol 1969;9:327. 59. Huang YP, Wolf BS: Veins of the posterior fossa. In Newton TH, Potts DG (eds): Radiology of the Skull and Brain, vol II, book 3. St Louis: CV Mosby, 1974, pp 2155–2216. 60. Lister JR, Rhoton AL Jr, Matsushima T, et al: Microsurgical anatomy of the posterior inferior cerebellar artery. Neurosurgery 1982; 10:170. 61. Takahashi M, Okudera T, Fukui M, et al: The choroidal and nodular branches of the posterior inferior cerebellar artery. Radiology 1972;103:347. 62. Wolf BS, Newman CM, Khilnani MT: The posterior inferior cerebellar artery on vertebral angiography. AJR 1962;87:322. 63. Martin RG, Grant JL, Peace D, et al: Microsurgical relationships of the anterior inferior cerebellar artery and the facial-vestibulocochlear nerve complex. Neurosurgery 1980;6:483. 64. Naidich TP, Kricheff II, George AE, et al: The normal anterior inferior cerebellar artery. Anatomic-radiographic correlation with emphasis on the lateral projection. Radiology 1976;119:355. 65. Hardy DG, Peace D, Rhoton AL Jr: Microsurgical anatomy of the superior cerebellar artery. Neurosurgery 1980;6:10. 66. Hoffman HB, Margolis MT, Newton TH: The superior cerebellar artery: I. Normal gross and radiographic anatomy. In Newton TH, Potts DG (eds): Radiology of the Skull and Brain, vol 2, book 2. St. Louis, CV Mosby, 1974, pp 1809–1830. 67. Mani RL, Newton TH, Glickman MG: The superior cerebellar artery: An anatomic-roentgenographic correlation. Radiology 1968;91:1102. 68. Brust JCM: Circulation of the brain. In Kandell ER, Schwartz JH, Gessell TM (eds): Principles of Neuroscience, 4th ed. New York, McGraw-Hill, 2000, pp 1302–1316. 69. Fitzgerald MJT: Brain stem. In Fitzgerald MJT (ed): Neuroanatomy Basic and Applied. London, Bailliére Tindall, 1985, pp 84–93.

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Chapter 2 Neuroradiologic Imaging Ronald G. Quisling, MD and Lorna Sohn-Williams, MD

Understanding Magnetic Resonance Imaging The Physical Basis for Magnetic Resonance Imaging Diagnostic imaging is often critical in the treatment of patients undergoing acute neurological decline. Brain imaging in this context typically relies on magnetic resonance imaging (MRI) and computed tomography (CT) studies, although occasionally angiography and nuclear medicine testing is also valuable. However, only brain MRI and CT modalities will be discussed in this chapter. Fundamental to providing adequate sectional imaging is access to sufficient clinical information to appropriately protocol the examination. No single test fits all, and not all patients can undergo all varieties of imaging studies. When an especially complex diagnostic dilemma arises, direct discussion with the neuroradiologist is necessary to (1) select all areas of clinical interest, (2) choose the most appropriate imaging modality, (3) optimize the imaging parameters, and (4) exclude patients unsuitable for imaging, especially with MRI. There is a wide array of technical choices for how an imaging procedure(s) can be performed, but usually only a finite time in which to acquire the data. Imaging protocols must include the most appropriate imaging sequences, the best plane of section to achieve true longitudinal or transverse sectional anatomy (unplanned obliquity often causes ambiguity or worse), and a decision on whether to use contrast medium. The delivery of the contrast material then requires decisions on the type and amount of contrast material, and how to

time the injection relative to image acquisition. Choices must also be made concerning physical factors related to section thickness, region of interest, magnification, postprocessing algorithms, and actual CT energy or MRI parameter settings. Each procedure must be tailored to individual patient requirements; it is rare that unfocused imaging will substantially contribute to treatment decisions. The primary objective for any diagnostic MRI or CT study is to distinguish between normality and abnormality (“lesion detection”). Establishing normality is typically more difficult than recognizing obvious pathology. To declare that an imaging procedure reveals either “no apparent and/or no significant disease” requires the examination to have been performed appropriately with the most sensitive imaging modality and scanned in the right location using parameters capable of providing the optimum spatial and contrast resolution. Once a lesion is observed the role of imaging shifts toward more specialized tasks, including predicting the type of lesion, establishing the spatial relationship between the lesion and eloquent areas, and judging the acuteness of the changes (“time course”). These tasks require sophisticated imaging and experienced interpretation. In essence, the neuroradiologic imager should be provided with the presenting symptom complex and the main clinical considerations before the examination to enable the imaging to guide an appropriate treatment plan. The following discussion will provide an overview of the basic principles of MRI and CT; a summary of the strengths, weaknesses, and restrictions of special imaging for both MRI and CT, and to provide examples of key neuropathology for the neurointensivist. 47

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Understanding the Standard Magnetic Resonance Imaging Sequences Magnetic resonance imaging compares the relative intensity differences between anatomic subunits of tissue that are exposed to both a constant main magnetic field, and intermittently to a changing set of secondary gradients (to give spatial resolution) and to an external radiofrequency (RF) pulse(s) to energize the nuclear spin systems.1–4 Proton MR, in essence, is a map of hydrogen nuclei bound to oxygen, as water, or to carbon, as organic compounds. It is obvious that protons must be present for any signal to be detected at all. Hence, air generates no signal. Signal intensity is a measure of how all protons within any small block of tissue (volume element or “voxel”) respond to the RF signal. This signal is then compared to its neighbors and represented as a shade on a gray scale. What is critical in generation of MR signal is that all the tissue within a voxel responds more or less similarly magnetically; all the tissue in the voxel need not be organically the same, but all needs to be of similar magnetic susceptibility. If tissue within a voxel behaves discordantly, then the overall signal of that voxel is diminished or lost (i.e., “susceptibility artifact”). These susceptibility artifacts can actually be emphasized with certain sequence to detect, for example, hemosiderin. It is also imperative that tissue remain stationary during the standard MR experiment; otherwise, “flow-related artifacts” occur. These flow effects can actually be emphasized and stationary brain de-emphasized in the process of acquiring MR angiography (MRA). The process of deriving signal from the magnetic response of most stationary brain tissue placed under the conditions of the MR experiment is referred to as “relaxivity.” The actual measurable response time is called the “relaxation rate.” Types of tissue are referenced by their relative relaxation rates; some are faster and some are slower. These differences are portrayed on MR images as differences in shade-of-gray. Although technically complex and beyond the scope of this chapter, all MR experiments require a refocusing of signal before the read-out (signal detection phase). This refocusing is obtained either by using a second RF pulse (i.e., the spin-echo experiment), or by using magnet gradients (i.e., gradient-echo experiment or GRE). The former have better contrast resolution; the latter are substantially faster. Both are described in the following sections along with a general overview of basic MR signal characteristics. Standard Spin-Echo Sequence with T1 Weighting The T1 experiment evaluates a progressively increasing signal over time (i.e., a constructive effect), while the T2 experiment measures a declining signal over time (i.e., a destructive effect). In essence, the tissue with quicker recovery (i.e., more rapid T1 relaxation rates) will appear relatively brighter than their slower neighbors on a T1-weighted

MR sequence. The terms, signal hyperintensity and hypointensity, are descriptive and based on the signal characteristics of the object in question compared to normal brain, which is assigned the term isointensity. Thus, inherent T1 hyperintensity (compared to isointense normal brain) will appear “brighter” (approaching a shade toward white) and implies the presence of substances that naturally exhibit rapid proton relaxation (a more rapid return to baseline), such as structures with high lipid content. Other substances with faster T1 relaxivity include methemoglobin (subacute residua of hemorrhage), melanin, dilute amounts of intracellular calcium, and hyperconcentrated proteins (as might occur in a colloid containing mass or very hypercellular tumors). Inherent T1 hypointensity (compared to normal brain signal) is displayed as a darker shade of gray, and indicates that tissue in these voxels are not like fat but is either rigidly bound (an anisotrophic effect), as seen in fibrosis or matrix calcification, or virtually unbound (an isotropic effect), as seen in edema, necrosis, or cyst formation. T1 hypointensity reflects both extremes of hydrogen states: too tightly bound or too loosely bound compared to lipid or lipid-like protons. T1 weighting assigns a bright signal (tending toward white) to tissues containing higher inherent lipid concentration but also to those affected by substances that cause proton relaxation enhancement. As mentioned, compounds that quickly return to baseline (and appear hyperintense to brain), include methemoglobin, melanin, concentrated protein, and increased intracellular calcium ions, and intravenous gadolinium injected at the correct concentration. Gadolinium will normally cause proton relaxation “enhancement” in tissues that lack endothelial tight junctions and an intact blood-brain barrier (pineal gland, pituitary gland, choroid plexus) normally. Gadolinium causes abnormal enhancement in the context of an altered bloodbrain barrier or an increased regional capillary blood volume (Fig. 2-1). Standard Spin-Echo Sequence with T2 Weighting T2-weighted sequences provide different information than T1-weighted data. In physical terms T2 rate reflects the time required for the signal to degrade or to lose signal intensity. It is a measure of loss of phase coherence of the precessing magnetic vectors, which had been refocused by either the second RF pulse for spin-echo sequences or by the secondary gradients in gradient echo (GRE) imaging. Tissue with more rapid T2 relaxation rates (T2 hypointensity) destroy signal more quickly and appear darker than their neighbors. Abnormal T2 hypointensity implies a more restricted bulk water pool. The latter occurs in fibrosis, ossification, and dehydrated tissues. Tissues that possess more unbound water molecules (like cerebrospinal fluid [CSF] or tissue edema) will preserve phase coherence longer, which translates into a slower T2 rate, and a brighter signal or T2 hyperintensity (Fig. 2-2).

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Figure 2-1. Arachnoid cyst on T1 sequence. An axial, nonenhanced, T1-weighted MR image through the posterior fossa demonstrates the features of a large arachnoid cyst residing in the right cerebellopontine angle cistern. The fluid within the cyst matches cerebrospinal fluid (hypointense to normal brain) consistent with either an arachnoid cyst or an epidermoid cyst. Differentiation between these entities requires additional information, which is provided in Figures 2-2, 2-6, and 2-7.

Magnetic Resonance Imaging Contrast Medium and Abnormal Contrast Enhancement Up to this point, discussion has focused on the inherent relaxivity effects of tissue. But the MRI T1 signal can also be altered by certain compounds containing heavy metals, which can artificially accelerate the return to baseline of tissue if such compounds can be retained in voxels throughout the data acquisition period. The basis for abnormal contrast enhancement is similar for both CT (using iodinated contrast medium) and MRI (using gadolinium-diethylenetriamine pentaacetic acid [DTPA]). Abnormal contrast enhancement is related either to an expanded intravascular pool or to an increased endothelial permeability and diffusion of the gadolinium into the brain substance. An expanded vascular pool can occur in areas of brain that have lost autoregulation and increased the capacity of a regional capillary bed. This most commonly is observed in patients with recent head trauma, or a recent seizure. A second cause of an expanded blood pool occurs in vascular malformations where there is an increase in size and number of capillary vessels within the lesion nidus. A third cause for expansion of a vascular pool occurs in neoplastic lesions that generate angioneogenesis. Thus, lesions with an expanded vascular

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Figure 2-2. Arachnoid cyst on T2 sequence. An axial, T2weighted, spin-echo, MR image (through the same posterior fossa cyst in Figure 2-1) illustrates how cystic lesions exhibit bright (hyperintense to normal brain) MR signal. The internal cyst intensity is even greater than that of other cerebrospinal fluid–containing spaces, due to reduced normal pulsatile effects during the cardiac cycle; this limitation is created by the wall of the cyst. Figures 2-1 and 2-2 provide standard T1 and T2 information about the cyst nature of this lesion; however, to differentiate between epidermoid cyst and arachnoid cyst requires FLAIR or diffusion imaging, both of which are provided for illustration of their method in Figures 2-6 and 2-7, respectively.

pool, created by either an increased size of and/or increased number of vessels, can also enhance, because the additional vessel capacity physically can accumulate more contrast material than adjacent tissue. A second major cause for abnormal enhancement occurs when the vessels within a region either lack tight endothelial junctions or now leak because of a pathologic process. Enhancement on this basis occurs because of actual extravasation of contrast material out of the vessels and into the interstitium. This form of enhancement occurs normally in the pituitary gland (and stalk), the choroid plexus, and dural structures. However, brain structures whose vessels normally have tight endothelial junctions, and thus an intact bloodbrain barrier, do not normally enhance on this basis. Abnormal contrast enhancement occurs as the result of lost endothelial integrity, increased capillary permeability, and escape of contrast material into the interstitium. It may take the shape of a variety of forms including nodular (or mass like), gyriform (conforming to the cortex), superficial (conforming to the Virchow-Robin spaces), or just be

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A Figure 2-4. Cerebral infarction with regional hyperemia. An axial, gadolinium-enhanced, T1-weighted MR image through the high convexity demonstrates abnormal enhancement within otherwise normal regional vessels (arrows) in the area surrounding the left frontal stroke illustrated in Figure 2-3A. In this instance, the increased enhancement represents dilated collateral arteries with expanded intravascular space rather than disruption of the blood-brain barrier. This is a second mechanism of abnormal contrast enhancement.

nonspecific. The anatomic configuration of the enhancement pattern can provide significant clues to the underlying pathologic entity (Figs. 2-3 and 2-4).

B Figure 2-3. A, Cerebral infarction. An axial, nonenhanced, T1weighted MR image through the high convexity of brain demonstrates a hypointense area of edema (arrow) consistent with brain infarction in the left frontal cortex. There is no spontaneous hyperintense signal in the area of infarction to suggest a hemorrhagic component. B, Cerebral infarction with focal enhancement. An axial, gadolinium-enhanced, T1-weighted MR image through the high convexity of brain demonstrates a focal area of abnormally increased signal (arrow) following gadolinium injection within the caudal aspect of the ischemic region consistent with altered blood-brain barrier and abnormal contrast enhancement. Disruption of the blood-brain barrier is a common mechanism for abnormal contrast enhancement.

Fast Spin-Echo (or RARE) Techniques The inherently slow relaxation process in standard spin-echo MR makes such imaging particularly susceptible to patient motion artifact. This potential for motion-related image degradation has spawned attempts to shorten the data acquisition process. Unfortunately, this is by necessity at the expense of tissue contrast resolution. In spin-echo sequences, the raw data acquisition must fill a matrix (called K-space) so a mathematical process can be applied that converts electrical signals from a time dimension into an intensity dimension, which provides image contrast resolution. It turns out that some of the data can be predicted rather than measured. This occurs in the commonly used “fast” T2 (or RARE) spin-echo sequences. By acquiring more lines of Kspace within each TR (repetition time) interval, the image acquisition speed of the examination is substantially shortened. The advantage is clearly to improve spatial resolution

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obtained by reducing patient motion–related image degradation. The trade-off is a reduced sensitivity to T2 tissue changes and reduced sensitivity to magnetic susceptibility artifacts. In our experience neither shortcoming appears to significantly lessen the acquisition of essential T2-weighted images as long as the “effective TE (echo time)” exceeds 100 msec.

Gradient-Recalled Echo Sequences All MRI sequences must refocus the inherent signal (of stationary tissue) before the data read-out. This refocusing is obtained with an RF pulse in spin-echo images, but is done with an applied secondary gradient in the GRE examination. For spin-echo image formation, the second 180degree RF pulse reverses most unwanted extrinsic phase shifts, which have occurred up to that point, but does not (by design) reverse the inherent relaxivity that has occurred. The GRE method of refocusing does not reverse extrinsic susceptibility phase effects, and therefore is subject to greater susceptibility artifacts than spin-echo sequences. However, we can use this apparent shortcoming to our advantage to identify one of the prime causes of extrinsic phase artifacts, hemosiderin. The presence of substances such as hemosiderin alters the local magnetic field producing magnetic inhomogeneity and signal loss within the affected voxels. Such intravoxel inhomogeneity creates a signal loss referred to as magnetic susceptibility artifact. Evidence of hemosiderin-related susceptibility artifact provides important diagnostic data because it is easily detected and implies previous hemorrhage. Selection of these GRE parameters must be specifically included in protocols whenever previous hemorrhage is being investigated, as in the diagnosis of cavernous angiomata and other occult vascular malformations. Gradient-recalled imaging has an additional role in volumetric analysis. Three-dimensional (3D) GRE imaging techniques provide contiguous sections without interval section gaps, which are necessary in standard spin-echo imaging. Volumetric data are used commonly in assessment of tumor analysis before radiation surgery, in hippocampal volume assessment in patients with partial complex seizures being considered for seizure surgery. The most effective GRE sequence for postprocessing of brain tumor data is generally a magnetization-prepared GRE. These in conjunction with gadolinium infusion provide excellent T1-weighted background to display the enhancement of the tumor (Fig. 2-5).

Fluid Attenuating Inversion Recovery Imaging with Strong T2 Weighting An innovative technique has been developed that uses a preliminary 180-degree RF pulse to invert the overall signal.5–9 By empiric methods it was possible to suppress the signal of CSF at the same time allowing tissue edema to appear hyper-

Figure 2-5. Example of gradient-recalled echo (GRE) type of T1 sequence. An axial, nonenhanced, T1-weighted GRE image through the mid-convexity of brain demonstrates anatomic detail similar to that of a standard spin-echo T1 sequence, but with some differences. Because this image has been obtained more rapidly than spin-echo image, there is less time to saturate the intravascular blood flow, and, as a result, larger vessels often exhibit spontaneously increased signal, as seen within the middle cerebral arteries and the internal cerebral veins in this example.

intense (bright by comparison to normal brain) on T2weighted images. The advantage of this technique is in the ability to detect tissue edema (T2 brightness) when the pathologic tissue is adjacent to CSF within cisterns or sulci or ventricles. In standard T2 sequences tissue edema is hyperintense but so is CSF, which makes distinction between the two very difficult (“lost conspicuity”). In fluid attenuating inversion recovery imaging with strong T2 weighting (FLAIR) imaging, which is a strongly T2-weighted sequence, CSF remains hypointense (or dark) while the pathology (containing edema) will be hyperintense (or bright), substantially improving conspicuity and lesion. FLAIR imaging is also very sensitive to blood in the subarachnoid and subdural spaces. Again the blood products provide a hyperintense signal relative to brain. FLAIR imaging has the disadvantage of taking longer to perform and therefore is more susceptible to patient motion. This disadvantage has been obviated in part by using the fast (RARE) scanning techniques in conjunction with the FLAIR parameters to achieve a scan time of less than 4 minutes (Fig. 2-6).

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Figure 2-6. Arachnoid cyst on T2-weighted FLAIR sequence. An axial, T2-weighted FLAIR image through the mid-posterior fossa demonstrates the appearance of the same cyst shown in Figures 2-1 and 2-2. FLAIR images are heavily T2 weighted, but additionally, are performed is such a way that cerebrospinal fluid (CSF) generates a dark signal, while tissue edema generates a brighter signal. In this case the cyst fluid is homogeneous and matches CSF indicating that this mass is an arachnoid cyst.

Special Magnetic Resonance Imaging Techniques Newer technologic developments are constantly unfolding. Some provide new information and some improve contrast or spatial resolution. In this section we will provide an overview of these techniques and the clinical setting in which they are most likely to be used. Magnetic Resonance Diffusion Imaging This form of physiologic imaging relies on the presence of axoplasmic motion of bulk water during the interval between two applied, but opposing, field gradients.10–18 Normal motion of water (protons) within axons limits refocusing of the signal (the protons do not remain stationary during the intrascan interval). As a consequence, less signal output is observed and the background intensity diminishes. The term which describes the rate of diffusion during the time between the gradient pulses is called the apparent diffusion coefficient (ADC). A sequence that is generated from these coefficients is called an ADC map. A map of the consequence of the variability of such motion can also be generated. This is referred to as the diffusion map and it will have a value applied to it that indicates mainly the interval between the first and second diffusion gradient (the “b

value”). Motion of molecules in the brain is not uniform but is affected by the orientation of the white matter bundles. The diffusion gradients are first applied in all three directions (phase, frequency, and major field). The intensity data from the three individual sequences are summed and presented as a single trace image. Diffusion images suffer in one respect from being a T2-weighted sequence. When edema is present on the initial b = 0 sequence (performed without applying the diffusion gradients), the underlying T2 hyperintensity will “shine through” into the diffusion images and simulate abnormal restriction of water motion, which is also detected by a brighter than normal signal. The main, but certainly not the only, use for diffusion imaging is in acute stroke, especially in the hyperacute time frame when standard MRI and CT demonstrate no abnormality. Acute brain infarction axoplasmic motion is reduced, leaving the water protons in virtually the same position during the period between the applied diffusion gradients. Because no motion occurs, less image degradation occurs and the signal within the infarcted area is relatively stronger, which translates into a brighter shade of gray on diffusion images and reduced signal on the ADC (see Fig. 2-32). If pathology has greater motion, as in a cystic lesion, the reverse effect will be observed, as presented in Figure 2-7. Relative Brain Perfusion Imaging Relative brain perfusion can be performed with CT or MRI using a measure of time-concentration graphs following injection of a contrast agent and then monitoring the intensity change in the region of interest during the first pass of the contrast material.19,20 This is especially useful in delineating areas of reduced flow as in acute ischemia, but also in focally increased flow in hypervascular masses as hemangioblastoma and hypervascular metastases, as melanoma or choriocarcinoma. Evidence of increased intratumoral blood volume compared to uninvolved gray matter supports the diagnosis of a higher grade tumor (anaplastic and glioblastoma categories). These methods are qualitative and not quantitative at present but this will be resolved as new applications evolve. We typically standardized our cerebral perfusion to the perfusion of the rostral cerebellum and vermis. Vermic perfusion is seldom restricted with the exception of intercurrent basilar or superior cerebellar artery thrombosis, and hence provides a benchmark to compare areas of altered cerebral perfusion. Magnetic Resonance Angiography and Magnetic Resonance Venography20–22 Arterial and venous MR angiography can be obtained by using the natural magnetic properties of flowing blood, referred to as time-of-flight (TOF) MR angiography (MRA) or magnetic resonance venography (MRV). In standard imaging, the inherent signal of flowing blood in the carotid arteries and superior sagittal sinus is suppressed by a presaturation RF pulse, applied outside the area of interest but in

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A B Figure 2-7. A, Arachnoid cyst on diffusion sequence. An axial, trace (b = 1000) diffusion map through the low convexity of brain demonstrates the appearance of this same arachnoid cyst, as seen in Figures 2-1, 2-2, and 2-6. The cyst is hypodense (implying completely unrestricted water motion) and relatively homogeneous indicating no septation within the cyst. This response is mirrored on the ADC map of B. B, Arachnoid cyst on apparent diffusion coefficient (ADC) sequence. An axial, ADC image through the posterior fossa demonstrates bright signal (*). This implies that the coefficient of motion is high; the water motion is unrestricted. We would expect just the opposite effect in a brain stroke where the apparent diffusion coefficient would be low because tissue water motion is lost. An example of stroke is presented for comparative purposes in Figure 2-32.

the range of antegrade blood flow. Most commonly the presaturation pulse is applied over the neck and vertex of the head in standard head imaging to reduce flow-related signals in the brachiocephalic arteries flowing superiorly and the sagittal sinus blood flowing inferiorly. These presaturation pulses are routinely used to obviate confusing vascularrelated phase shift signal artifacts. In MRA and MRV, a reciprocal process is used. Instead of suppressing flowing blood, suppression of stationary tissue in the brain is allowed, making the inflowing blood appear relatively brighter. The procedure can be altered to emphasize inflowing arterial blood, MRA, or out-flowing venous sinus blood, MRV. Background suppression is further improved using magnetization transfer techniques. Water molecules can exist freely (“unbound water”), as in a fluid compartment, or they may be trapped within the interstices of larger, complex molecules even though they are not chemically attached. This state is described as “bound water.” However, there is a constant exchange of water molecules between the bound and unbound compartments. As it turns out, bound water precesses at a slightly different rate than unbound water. By applying an appropriate off-resonant RF pulse immediately before the imaging sequence, it is possi-

ble to saturate only the bound water molecules thereby obliterating their MR signal. When an exchange of water molecules occurs between the saturated, bound, and unbound molecules, a net reduction in overall background signal is observed for either T1 or T2 sequences. This has been reported to be approximately a 37% reduction in background signal. The percentage drop in signal intensity is less than that in pathologic tissue presumably related to increased regional free water either within the neuropil or within cells. MRA can also be performed using two-dimensional GRE images obtained sequentially while injecting gadolinium intravenously. This works for imaging of the aortic arch and the cervicobrachial arteries, because the examination can be performed with most sections obtained during the first pass arterial opacification phase. After a few more seconds, vein opacification occurs, which obscures arterial detail. This form of MRA is more anatomically correct and suffers fewer artifacts than time-of-flight MRA. Its value is providing high quality noninvasive (other than the intravenous contrast injection) evaluation of the carotid and vertebral arteries in the context of transient ischemic attacks and stroke (Fig. 2-8).

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Figure 2-8. Time-of-flight (TOF) MRA. This TOF angiographic image demonstrates the normal appearance of both the proximal carotid and vertebrobasilar arteries. TOF imaging depends on the fast inflow of arterial blood to generate adequate signal. Slower flowing blood is saturated during the MR acquisition and will not generate sufficient signal to be visualized.

Magnetic Resonance Venography Examination of intracranial veins and dural sinuses is possible using the same techniques as discussed previously under time-of-flight MRA. The difference is only where the presaturation pulse is applied. In MRV, arterial flow is, by necessity, suppressed by applying a presaturation pulse over the neck. This saturates (essentially eliminates) the flow signal from the carotid and vertebral arteries. The only flowing blood is from the dural sinuses and internal cerebral veins and some major cortical veins. This forms the basis of the MR venogram. It, like MRA, is entirely noninvasive. The only limitation is that where dural sinuses parallel the plane of imaging acquisition some saturation can occur; this most often occurs in the superior sagittal sinus just before the torcula. The other limitation is related to interpretation of the widely disparate variations of normal cerebral venous drainage (Fig. 2-9). Functional Magnetic Resonance Imaging Functional MRI (FMRI) requires rapid acquisition of whole brain MR data in the same time frame that the physiologic alterations are occurring, generally in the range of subsecond brain sections.23–28 The physical basis for current FMRI methods relies on regional changes in blood flow occurring in response to a particular external stimulus. By applying specific neurophysiologic testing while concurrently imaging with rapid MR acquisitions, alterations in regional vascularity can be detected based on the concentration of deoxyhemoglobin in the blood. The stimulus alters neuronal activity affecting regional metabolism, which in turn increases

Figure 2-9. Time-of-flight (TOF) MRV. This TOF venograph demonstrates normal dural sinuses and normal deep venous drainage pathways. Venography requires intentionally saturating the fast inflowing arterial circulation, which by default emphasizes the slower flowing venous efferent circulation.

regional blood flow. Increased local perfusion rates expand local blood volume, while maintaining the same, or even less, oxygen extraction fraction. The net effect is reduced concentration of deoxyhemoglobin. Because deoxyhemoglobin is paramagnetic and normally reduces tissue signal, then obviously less of it in the activated area would contribute to relatively more signal. This is in fact what happens. The clinical challenge is detected by a localized reduction in deoxyhemoglobin compared to the proportion of oxyhemoglobin. This process is called blood oxygen level–dependent imaging. Current use in oncology remains limited but the technique is finding early utilization for motor strip localization before tumor resection when the mass is located near this portion of eloquent cortex. Magnetic Resonance Spectroscopy MR proton spectroscopy is obtained in much the same way routine MR but does not emphasize the proton water peak and is not used to define anatomic data.29–41 However, two differences exist. The applied gradients, which normally establish anatomic location in space, are limited to only a single area or multiple areas in the same axial region. Then the large water peak within the spectra is suppressed, because water is not of interest. Once the large water peak is suppressed, the smaller peaks of organic compounds can be visualized. These include peaks for N-acetyl aspartate, lactate, creatine, and choline to name a few. The heights of these peaks provide insight into the biologic state of the

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tissue being studied. In this way differences in spectra related to pathology emerge. Tumor appears different from radiation necrosis, for instance. Currently, spectroscopy can be used to differentiate the location of tumor versus radiation

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effects when there is imaging discordance between the tumor site and other areas of abnormal signal in the treatment field. Many other nontumor assessment uses are being explored (Fig. 2-10).

Figure 2-10. A, Brain tumor spectroscopy. An axial, gadolinium-enhanced, T1-weighted MR section through the mid-convexity of brain demonstrates a focal tumor mass (arrow) in the major forceps of the right spleniumcorpus callosum. The central portion of the mass exhibits typical abnormal contrast enhancement produced by the retained proton-relaxing effects of the gadolinium. B, Single voxel proton spectroscopy. Proton spectroscopy provided through the same lesion (illustrated in A) demonstrates the typical spectroscopic features of an anaplastic, nonnecrotic brain tumor. In this instance, there is less-than-normal amount of N-acetyl-aspartate (the “N” peak) and elevation of the choline concentration (the “C” peak). A

B

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A

B Figure 2-11. A, Pre–fat suppression in optic neuritis. This coronal, enhanced, T1-weighted MR image through the retroglobal orbital area demonstrates a posterior orbital structure, including the rectus muscle sheath and the optic nerve complex on both sides. The intensity of the right optic nerve (arrow) appears symmetric with the left nerve; no apparent abnormal enhancement. No fat suppression has been applied to this image. B, Fat suppression in optic neuritis. This coronal, enhanced, T1-weighted MR image with fat suppression through the same retroglobal orbital area as illustrated in (A), but now including a fat-suppressive prepulse. The study now demonstrates evidence of optic nerve enhancement in the right optic nerve (arrow). The fat suppression allows this subtle abnormal contrast enhancement to become diagnostic of optic neuritis in this case.

Fat Suppression Techniques Fat suppression is possible on MRI by using a RF presaturation pulse before the data acquisition that is directed at the spin frequency of lipids.42 In doing so, the normally bright fat signal on T1 sequences is substantially reduced. This is a necessary process when trying to detect gadolinium contrast enhancement in a structure (like the optic nerve) that is surrounded by retroglobal fat. By using fat suppression, the conspicuity of the enhancement is substantially improved. Several other fat suppression methods are also available (Fig. 2-11). Cerebrospinal Fluid Flow Studies The pulsatile movement of CSF can be detected using phasesensitive imaging where the direction of the CSF movement affects whether the CSF is portrayed as a positive signal (hyperintense to background) or negative (hypointense to background).43 MR CSF flow studies have value in selective instances. These include determination of blockage or restriction of CSF passage in the ventricles, or in cisterns, especially at the foramen magnum. A common use in our institution is assessment of CSF block at the foramen magnum in the context of Chiari 1 malformations, assessing whether there is a significant foramen magnum impaction

syndrome. Other intracranial uses include determining ventricular blockage at other levels and whether a third ventriculostomy (performed endoscopically) is patent (Fig. 2-12).

Restrictions to the Use of Magnetic Resonance Imaging Pregnancy The current policy for MR examinations during pregnancy states “patients suspected of being pregnant will not be scanned unless the risk/benefit has been evaluated by an attending Radiologist” “If the MR is indicated, an informed consent will be obtained by a Radiologist.”44–51 This policy is based on a recent review of the literature, in which some animal studies report teratogenic effects following MRI exposure performed during the first and second trimester. It should be emphasized to the patient that the MR effects on the human fetus are unknown. Our policy includes the following: “If a patient is known to be pregnant, the MR examination should only be performed if there is clear medical benefit to the patient or fetus, and the examination is deemed medically necessary despite

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B

Figure 2-12. A, Cerebrospinal fluid (CSF) MR flow study: positive phase. Phase-contrast CSF flow studies are dependent on the direction of the CSF pulsation during imaging acquisition, which in this circumstance is in a positive direction (bright signal) indicating a cephalad direction. B, CSF MR flow study: negative phase. The flow out of the fourth ventricle is highlighted in this and the following image (arrows) to demonstrate the cyclical change of pulsatile flow, but CSF flow in the prepontine cistern is also apparent. This phase-contrast CSF flow study illustrates the CSF pulsing in a negative direction (dark signal). Observation of the CSF pulsations reflected in the change between positive and negative signal on a video loop allows for a reasonable assessment of the movement of CSF. This type of study is usually used in ventricular or cisternal CSF flow restrictions.

the pregnancy.” For example, the MRI examination would provide information that potentially would be used to change the treatment of the mother or fetus during the pregnancy. This risk-benefit assessment should be discussed with the referring clinician and a radiologist from the service that will be interpreting the examination. It should be emphasized to the referring clinician that there is insufficient data to support, or refute, the safety of MRI during pregnancy, particularly in the first and second trimester. Once the radiologist from the service that will be interpreting the examination agrees that MRI is medically necessary, then that person will: 1. Inform the MR technologist/center that the study has been approved. 2. Give the MR technologist/center the reason for the medical necessity of the case and the name of the referring clinician with which the case was discussed. This information will be recorded by the MR technologist. 3. When the patient undergoes MRI, this information will be written on the consult sheet by the MR technologist so that it may be included in the official dictation by the radiologist interpreting the study. This information will allow the radiologist interpreting the study to defend the medical necessity of the examination at a future date if

an unexpected fetal or postnatal event occurs after the MR examination. Gadolinium contrast administration can be administered only under certain circumstances at the discretion of the radiologist supervising the examination. A conservative approach to the use of contrast administration during pregnancy is recommended. Because gadolinium readily crosses the placenta and is excreted by the fetal kidneys, it ultimately passes through the bladder and into the amnion where it circulates and is swallowed and reabsorbed repeating the process over and over. Thus, the clearance rate of MR contrast agent from the amniotic fluid and fetal circulation is prolonged during which the chelation of the gadolinium can disassociate. The effects of elemental gadolinium on an embryo or fetus are unknown. The manufacturers of contrast material do not support the use of MR contrast agents in pregnant women. Obesity Obesity or a large body habitus presents a problem in MRI. The patients’ body cannot touch the inner surface of the MR scanning gantry or substantial image distortion will result from magnetic interference. To combat this problem, manufacturers have developed large, open bore solid magnets

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that are capable of handling larger patients. The trade-off is that these are typically permanent magnets running at lower Tesla strength, usually 0.3 T. This limits both the spatial and contrast resolution of the images. Newer, short bore cryomagnets are now being introduced with a shorter area of confined space allowing a larger patient to be imaged.

An Uncooperative Patient MRI suffers significantly from patient motion, because data are acquired sequentially over time and accumulated in a matrix, called K-space. Once the K-space per single phase is filled, the machine then acquires data from the second and so on for 128 or 256 or more phase shifts per slice. Only after the full K-space data set is filled out does mathematical manipulation occur to generate anatomic and intensity information for the image. Any intervening motion of the patient during the image acquisition process actually changes the phase data, which ultimately misrepresents the data when the final mathematical transform is applied. This can create both anatomic and intensity misregistration. Data misregistration means anatomic structures will be placed where they do not exist and intensity misinformation will appear abnormally (spurious pathology). MRI is not like CT scanning where the consequence of motion is merely an unsharp or fuzzy image. Because patient motion artifact has such adverse consequences, any patient likely to be uncooperative (pediatric patients, patients with reduced level of conscience, etc.) should be controlled, monitored and sedated, either with intravenous (IV) medication or with intubation and general anesthesia. The latter presents additional challenges and is not a trivial matter, because the magnetic field precludes the use of all routine anesthesia and intravenous injectors, and monitoring equipment. MRI-compatible anesthesia and monitoring equipment must be purchased to deal with this issue. In our experience general anesthesia should be considered early and not delayed to see whether routine sedation fails.

A Claustrophobic Patient The scanning gantry of most MR scanners used currently are fairly long and tubular in shape. Virtually every patient experiences some degree of claustrophobic response when they are first placed within the gantry. Most patients are able to tolerate such an experience, but not all. Sedatives and antianxiety drugs, such as the benzodiazepines, can be used to limit such claustrophobic effects. However, a certain proportion of patients will be intolerant to MRI because of claustrophobia. The possible solutions for this include scanning within an open bore magnet (widely available), scanning within a newer short bore magnet (currently less available), or use of anesthesiology.

Restriction of Gadolinium Usage Gadolinium is a relatively strong paramagnetic rare earth element, with seven unpaired electrons, which contribute to its effect of proton relaxation enhancement on T1 sequences. Gadolinium is a heavy metal that is toxic. However, the manufacturers of the contrast medium have attached it to a variety of chelating agents, which bind the gadolinium molecule, making it quite safe in most patients. There are reported idiosyncratic reactions to all drugs, including gadolinium compounds, but these are very rare with an incidence in the neighborhood of one per million patients injected. Minor reactions are reported, but for the most part are far less than those of IV iodinated contrast medium. The major current restriction to gadolinium use is in pregnant women, where the gadolinium crosses the placenta, is ingested by the fetus, absorbed then excreted back into the amniotic fluid, where the process repeats itself. Ultimately, disconjugation of the heavy metal can occur from the chelating agent. At this point, the gadolinium becomes a potential hazard. Effect of Corticosteroids on Contrast Enhancement One of the mechanisms for abnormal contrast enhancement is disruption of the blood-brain barrier and extravasation of contrast medium into the neuropil. This mechanism occurs similarly for both intravenous iodinated contrast material in CT and for paramagnetic contrast material in MRI. Corticosteroids, often given to stabilize inflammatory processes, have the ability to stabilize the blood-brain barrier and close the altered endothelial tight junctions. This has an impact on imaging where the presence of abnormal contrast enhancement is often a critical feature in detection of abnormal pathologic conditions. Hence, it is necessary to alert the imager who intends to interpret MRI or CT scans that therapeutic levels of steroids have been given, and that this might prevent or at least alter the appearance of the contrasted portion of the imaging study. This effect of corticosteroids has been reported with a wide variety of lesions but especially lymphoma and inflammatory processes (Fig. 2-13). Patients with Implanted Metal Any metal that has magnetic susceptibility (especially iron) will create a problem for MRI. Several factors require discussion. The high magnetic susceptibility of any ironcontaining metal object means that it is affected by the main magnetic field and can torque. If the metal is securely fastened, such motion effects would be insignificant. If, on the other hand, the object is moveable, as it might be with an aneursym clip, then the torque effect might be disastrous. The second consideration is the effect of heating of the metal. The RF pulses used to activate the spin system are, in many respects, similar to those of a microwave oven. Just as no metal should be put into a microwave because of severe heating effects, the same is true for metal in a MR scanner.

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A B Figure 2-13. A, Effect of steroid therapy in radiation therapy—related contrast enhancement (before treatment). An axial, gadolinium-enhanced, T1-weighted MR image through the posterior fossa demonstrates multicentric areas of abnormal contrast enhancement (arrows). This represents areas of altered blood-brain barrier inferior secondary to cranial radiation therapy. B, Effect of steroid therapy in radiation therapy—related contrast enhancement (following corticosteroid treatment). An axial, gadolinium-enhanced, T1-weighted MR image through the posterior fossa demonstrates no residual abnormal enhancement in the areas seen previously to enhance (see A). The difference in the enhancement pattern is related to stabilization of the blood-brain barrier following corticosteroid therapy.

Heating of the object can be rapid and cause burning of the surrounding tissue. The third effect of the metal would be to alter the local magnetic field. This causes the scanner to misregister anatomic data because the overall magnetic field within the scanning zone is not uniform and hence not predictable. Metal, therefore, typically causes a severe susceptibility artifact, usually rendering the image unreadable. Not all metal has susceptibility properties. Newer metals, like titanium, have little magnetic susceptibility and, hence, create little MR artifact. However, even with these metals, there is a question of whether repeated sterilization, as occurs when aneurysm trays are resterilized between cases, may change the magnetic properties of the clips. The final verdict in this issue remains to be determined.

lists many devices and their MR safety qualifications. In addition to problems related to the metallic content of internal devices, there are issues related to function of the devices. For instance, cardiac pacemakers can malfunction in a strong magnetic field. Therefore, the presence of a cardiac pacemaker is a contraindication to MRI. Morphine pumps for chronic pain therapy can be emptied (to be safe) and then the patient can undergo MRI. The third safety issue is whether the torque effects on the implanted device would cause injury. For instance, ossicular stents can be dislodged, so patients with these devices cannot be studied with MRI.

Pacemakers and Implanted Devices Do not assume any implanted metallic device can be safely scanned. The number of potential devices is endless. Manufacturers of a device for the most part, provide MR compatibility information and usually this information can be accessed from the company directly by telephone or website. There is a noncommercial website, www.mrisafety.com/, that

Introduction

Understanding Computed Tomography

Computed tomography (CT) is a commonly used means of intracranial evaluation.52 But as with MRI, the imaging protocol must match the indication. Imaging protocols are designed to focus on a specific clinical issue and to achieve the most diagnostic information possible during a

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“one patient” sitting. CT has the advantage of rapid imaging time. The newer scanners have substantially improved heat loading capacities to allow continuous (spiral or helical format) imaging. The principles of CT are similar to those of standard radiography, except that the former uses stationary detectors rather than radiographic film to capture the image. CT uses an x-ray beam and counter-balanced x-ray detector bank situated within the outer ring of the scan gantry. As with traditional radiographs, the degree to which the incident beam is absorbed or scattered determines the radiographic density of the structure. When an x-ray beam enters two separate but contiguous structures, the structure that is composed of the densest material (i.e., has the highest electron density) will absorb more of the beam than its neighbor allowing fewer x-ray photons to reach the detectors. A diminished detector signal is translated into a lighter shade of gray on the image gray scale than that of its less dense neighbor. Such differential x-ray absorptive capacity provides a means of tissue differentiation based on contrast resolution. Once tissue can be resolved on the basis of inherent tissue density then anatomic detail, or anatomic resolution, can be added to the diagnostic capability. The opposite is also true. Insignificant density differences between contiguous structures preclude anatomic delineation. When two larger structures are separated by a smaller intervening structure of different density, the larger structures can be distinguished only if the resolving capacity of the scanner is adequate to detect the smaller of them. Resolution on this basis is referred to as spatial discrimination, and is based mainly on slice thickness. If the resolving ability of the scanner is inadequate, tissues are blended together in a process called partial volume averaging. Spatial resolution, or the ability to distinguish small adjacent structures, is affected by the quality of the x-ray beam collimation, the number and size of the detectors, and the thinness of the beam itself. The thinner the slice, the greater the detail. However, the negative trade-off for thin sectioning is an increased radiation dose (approximately 3 rad per slice for routine imaging). The increased imaging time and x-ray tube heating requirements for more slices has substantially improved with the latest generation of CT scanners. However, there still is a finite limit determined, in part, by x-ray tube limits and, in part, by the time required for the patient to remain still within the scanner.

Filters, Image Segmentation, and Postprocessing CT can be performed with a variety of post-acquisition electronic filters. Filters selectively add or remove various frequencies from the raw data and change the limits of the gray scale, producing either a smoothing or an accentuation of the edges (or borders) of structures, as needed. Filters

are applied to the raw data during post-acquisition manipulation. Postprocessing allows the same set of image data to emphasize either bone or soft tissue contrast. The raw data can be adjusted through image segmentation to deal with the effects of patient motion. Not all the data are needed to produce an adequate image. When motion occurs in only a portion (i.e., a segment) of the tube swing, the data from that portion can be deleted. Segmentation significantly improves the final images in patients who cannot, or will not, lie still.

Computed Tomography Contrast Medium Both ionic and nonionic forms of contrast media are available. The differences between them in terms of contrast enhancement of lesions are minimal. However, other differences between them are distinct and important. Ionic contrast agents are much less costly than are the nonionic forms. While the incidence of severe idiosyncratic complications (i.e., shock or death) is minimal with either type of contrast agent, the nonionic contrast agents have substantially fewer secondary effects. Structurally, the monomeric types of ionic contrast media link a sodium or meglumine cation with an iodine-containing (benzene-ring) anion. A dimeric form of ionic contrast agent links two (iodine-containing) anion molecules together with only one cation. The dimeric contrast medium, thereby, achieves a higher concentration of iodine for the same degree of osmolality, making it less irritating on IV injection. Nonionic forms of contrast agents have the benefit of lower osmolality and yet deliver the same number of grams of iodine per unit volume as the monomeric ionic contrast agents. These attributes result in fewer contrast material– related symptoms. The drawback of nonionic contrast agents is in the area of viscosity. At body temperature, they are nearly twice as viscous as ionic contrast media. Idiosyncratic reactions, although reduced in frequency, still occur with nonionic contrast medium, nonionic contrast agents have significantly fewer or, possibly, no significant anticoagulation effects on blood compared with the ionic contrast agents. This difference has relevance during arterial injections during angiography but has little relevance to intravenous administration during CT. The major advantage of using a nonionic contrast medium is that it causes less tissue injury if it is inadvertently extravasated during an intravenous injection. Most enhanced studies are performed with power injectors to achieve the correct timing and volume of contrast. Thus, the protection of tissues surrounding the injection site is an important consideration in the selection of a contrast medium. Several techniques can be used to achieve contrast enhancement. The standard technique administers the contrast medium slowly, as an infusion for roughly 15 minutes before initiation of the actual CT scanning. This allows time

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Figure 2-14. Abnormal CT enhancement in metastatic tumor. An axial, nonionic, contrast-enhanced, CT scan through the high convexity of brain illustrates the features of abnormal CT contrast enhancement within a metastatic lesion (arrow). The basis of abnormal contrast enhancement on CT is similar to abnormal gadolinium enhancement on MRI. Both are the result of either blood-brain barrier disruption or expanded intravascular spaces.

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intravenous contrast whether they have previously received a contrast medium and whether they experienced any untoward reaction to it. If there has been a severe reaction, as described previously, then contrast material should not be given unless absolutely necessary. If critical, a pretreatment regimen (see following discussion) plus anesthesiology stand-by is suggested. Despite severe reactions to intravenous contrast material, the same contrast medium injected intraarterially may not produce the same reaction. There are many less dramatic contrast reactions and effects. These usually include urticaria (especially around the mouth) and mild bronchospasm with wheezing. These types of reaction can be the harbinger of a more severe reaction. Hence, they are important and intravenous contrast material should not be given without pretreatment. The current accepted pretreatment for contrast material reactions, excluding patients with severe reactions, is prednisone 50 mg given at 13, 7, and 1 hour before the procedure plus diphenhydramine hydrochloride (Benadryl) 50 mg given 1 hour before contrast material injection. If a patient is currently taking metformin hydrochloride (Glucophage) for control of diabetes, then IV iodinated contrast material should not be given unless the drug has been stopped at least 24 hours before the study. If metformin has not been stopped on the day of examination, it must be discontinued for 48 hours after the contrast material has been given. A renal laboratory screen should be obtained before reinstituting the drug. Non-immune–Mediated Contrast Effects. While idiosyncratic

for the contrast agent to recirculate and diffuse into the interstices of the pathologic region. This routine injectionto-scan interval is optimal for most tumors, subacute strokes, and inflammatory disease. It is not optimal for lesions that leak contrast material very slowly or those with rapid arteriovenous shunting. These lesions require a different timing sequence that could include either delayed imaging or first pass dynamic imaging (Fig. 2-14). Restrictions for Use of Iodinated Contrast Medium There are restrictions on the use of all IV contrast agents, but these are particularly important for CT contrast medium. Several issues become relevant based on the types of potential contrast effects. Idiosyncratic Reactions: Major and Minor. The most severe reactions that occur with intravenous contrast include an idiosyncratic anaphylactic event, major upper airway edema, and direct cardiac toxicity effects. All can result in major cardiopulmonary complications. Hence, it is always important to ask patients undergoing CT procedures performed with

responses are uncommon, physiologic contrast effects are not. All contrast effects are diminished with the use of nonionic contrast media. Contrast effects are, in part, related to the osmolality or concentration of the agent and, in part, to the contrast or to its carrier directly. As a result, some reactions that are related to the direct effects of the contrast agent can be severe. These mainly affect cardiac rhythm and function. Hence, cardiac arrest can occur with IV contrast medium injections that are not idiosyncratic (immunemediated) but are related to direct drug toxicity. These are very unusual and occur with a very low incidence. Renal Toxicity. Because CT contrast agents are excreted by the kidneys and, when concentrated, have renal toxicity, the status of renal function is important. Relative contraindication to IV contrast agents include borderline renal insufficiency, diabetic patients, or patients with one kidney plus borderline renal insufficiency, and patients younger than 6 years of age. Absolute contraindication for IV contrast agent is evidence of overt renal failure (creatinine serum level > 2) and no plans for dialysis within the next day or two. If dialysis is available within 24 to 48 hours, contrast material may be given. Contrast Material Extravasation. One of the difficulties in

the administration of contrast material is the necessity

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of obtaining and maintaining venous access. Most contrast agent injections are made at rates of approximately 1 cc/sec. Dynamic scanning requires 3 to 4 mL/sec. The bolus of contrast material is delivered most effectively by mechanical contrast injectors. The problem with this is obvious: if the contrast agent extravasates during the injection, the process cannot be stopped immediately. The effects of extravasated contrast agent depend on the type of contrast medium being used. Ionic contrast is capable of causing severe local pain and possibly local tissue necrosis. Nonionic contrast may cause some regional pain, but has the major advantage of not causing tissue necrosis when extravasated. Use of Computed Tomography and Intravenous Contrast in Pregnant Women. CT is used judiciously in pregnant women

or potentially pregnant women. There should be a clear and pressing need for such imaging. Scanning with CT is not contraindicated in pregnant women, including the pelvis, provided there are no other means of addressing the clinical problem. Head CT is performed routinely with use of pelvic shielding. Intravenous contrast administration, likewise, is

not contraindicated by pregnancy. Again, there ought to be a compelling clinical need for such data, and the total contrast load should be minimized. We do not routinely obtain an “informed consent” for pre- and postcontrast CT examinations of head.

Specialty Computed Tomography Sequences Helical Computed Tomography Scanning The most recent advance in CT technology uses continuous spiral or helical image acquisition.53,54 Helical CT uses a constantly revolving x-ray tube during which the table is indexed, or incremented, in the desired direction. The raw data are later subdivided to produce sections as thin as submillimeters in size, if necessary. This is possible because advances in x-ray tube and detector design allow for substantially improved heat-loading capacity. The advantage of helical scanning is markedly improved image acquisition speed, now producing anatomic submillimeter slices in 1 second or less. Furthermore, there is an isotrophic dataset that allows for excellent multiplanar (MPR), maximum

A B Figure 2-15. A, Multiplanar reformation (MPR) for anterior communicating artery aneurysm. An axial, gradient-recalled echo (high-speed gradient acquisition) single section representative of one of many contiguous images demonstrates the presence of an aneurysm. By using the whole block of images, the MPR software can reformat the data into multiple thin section in other planes (as in B) without actually having to repeat the scan process. These MPR reformations have the advantage of being capable of being performed in oblique projections, which is useful in “straightening” curving objects, especially arteries. B, MPR in sagittal plane for anterior communicating artery aneurysm. This sagittally reformatted MPR is able to delineate the features of the aneurysm (arrow) in sagittal plane. By combining several MPR projections, all aspects of the aneurysm and its relationship to its parent artery can be appreciated.

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intensity projection (MIP), and 3D surface–rendered image reconstruction. The drawback of this procedure is less image data acquired per slice. In standard 2D image acquisition, the CT tube acquires data throughout its entire arc, which we place at 360 degrees for discussion purposes. All the 360-degree tube arc data goes into producing that one section. With helical scanning the table moves during this acquisition process. Thus, less than 360 degrees of data contributes to each slice, and some image detail is necessarily lost. The trade-off becomes one of lessened image detail versus improved image acquisition speed, which translates into less patient motion artifact per slice. As it turns out, this advantage of speed combined with thinner slice thickness, in most instances, outweighs the effect of lost detail. At comparable slice thickness, standard 2D images have more information per slice than helical sections of the same thickness. When submillimeter pathology is sought, especially for instance in the temporal bones, standard imaging should be requested. In most other circumstances, helical scanning will be advantageous. Image Reformations and Computed Tomography Angiography Thin CT sections obtained with helical scanning and performed during a rapid infusion of contrast material produces a dataset that contains vascular information which can be reformatted using several methods, MPR (multiplanar single slice reformation), MIP (maximum intensity projection into a 2D combined image), and 3D surface rendering. To the less sophisticated angiographer, the vascular detail on the 3D and 2D MIP images are the most easily appreciated. However, the most anatomic detail is evident on the MPR images. MPR reformations do not sum the data, but rather allow for reformatting of single sections. The true advantage to MPR is its ability to reformat into any oblique plane necessary to accurately displace the long axis of a vessel, even when it is tortuous. MIP, or maximum intensity projection, image reformatting sums the axial section data and reformats the data into a 2D look at the vascular tree. It also allows for subtraction of background. Having been summed in this manner, the entire 2D image can then be rotated into other planes for interpretation. This is a reasonably good way to portray the data providing accurate background subtraction can be performed. This process requires that anatomic judgements be made and is very labor-intensive. The background subtraction process is subject to error created by attempting to remove bone and calcified structures when they are contiguous to opacified vessels of the same CT density. The same error is created in subtracting the background for 3D surface–rendered images. This method exploits surface-rendering software to create a 3D version of the vascularity in question. It loses internal detail and also loses information from the subtraction of background.

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These limitations and the need for labor intensive postprocessing to create the image make both MIP and 3D rendering less practical, especially in acute care situations (Fig. 2-15). Computed Tomography Brain Perfusion CT perfusion can be a useful means of evaluating the presence of regional brain oligemia. Helical scanning combined with dynamic contrast infusion can be exploited to produce a time-concentration data set. By comparing the CT density curves over time in similar regions of brain, a graph of the contrast medium concentration can be created, which in turn, reflects intravascular perfusion. By comparing similar areas in one hemisphere with comparable regions in the opposite hemisphere, a relative brain perfusion analysis can be obtained. Reduction of greater than 20% is considered oligemic. It is uncommon to simultaneously have oligemia in both cerebral hemispheres and in the cerebellum. Thus, the reliability of the CT perfusion is increased by normalizing the cerebral blood flow to the cerebellar blood flow and vice versa. This is much the same method used to define relative brain perfusion using IV technetium-99m and gamma camera analysis. CT perfusion in the next software update is expected ultimately to provide actual brain perfusion analysis in milliliters per 100 g of tissue per minute as can be achieved with Xenon-CT. The clear advantage of CT perfusion and CT angiography is the speed of data acquisition. The primary area of use currently is in the evaluation of hyperacute stroke. Thrombolytic therapy has a window of opportunity of roughly 6 hours after onset of symptoms. Intra-arterial thrombolysis is currently valuable in treating acute proximal middle cerebral artery and acute basilar artery occlusions. The presence of either of these can be easily determined from CT angiography, and detection of significant arterial zone oligemia can be determined by the CT perfusion. Thus, the critical branch points in the thrombolytic treatment scheme can now be obtained on a helical CT scanner within 10 minutes, including all postprocessing. CT perfusion evaluates relative brain flow. It does not provide actual flow values and does not appreciate the full extent of actual brain infarction because of its focused nature. If intra-arterial clot lysis is not being considered and proof of the extent of injury for IV clot lysis is sought, then the drug can be started and diffusion MRI can be performed. This whole treatment scheme is in flux and this method should be viewed in the same manner (Fig. 2-16).

Which Modality to Use? This discussion will be mostly subject to change as old techniques evolve and newer techniques appear. However, for the present, the strengths and weakness of a variety of widely available techniques for MRI and then CT are presented.

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Figure 2-16. CT perfusion. This technique is performed by repeating CT sections at subsecond speeds through a predetermined slab of brain and then comparing the first pass timeconcentration curves of intravenously injected contrast in symmetric portions of brain. This study can be obtained in less than 2 minutes and provides qualitative information about cerebral blood flow. New software will soon be available for quantitative CT perfusion.

Figure 2-17. STIR imaging in cortical dysplasia. High detail inversion recovery (STIR) image with strong T1 weighting demonstrates abnormal gray matter signal and abnormal gray matter thickness in the left occipital lobe (arrows). These are features of the cortical dysplasia. Such features are often hard to detect on standard spinecho imaging. This inversion recovery technique allows for thinner sections and accentuation of the gray and white matter T1-weighted contrast differences.

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Available Magnetic Resonance Imaging Sequences Standard T1-Weighted and T2-Weighted Sequences T1- and T2-weighted information is necessary for evaluation of virtually every abnormality. Spin-echo techniques provide the most spatially resolved information. However, other imaging sequences provide special information. While spin-echo proton density sequences have been largely supplanted by FLAIR imaging, proton density gradient–recalled imaging is especially sensitive to the presence of hemosiderin and is used routinely in our vascular malformation workup to detect cavernous angiomata. Standard Magnetic Resonance Imaging Plus Intravenous Gadolinium The addition of intravenous gadolinium is warranted in many circumstances. This is true especially for the detection and staging of tumors, both primary and secondary. Enhanced scanning is important for both inflammatory and infectious etiologies. Generally, however, enhanced scanning is unnecessary for screening of developmental lesions or for follow-up of patients with partial complex epilepsy or ventriculomegaly. These workups should have included contrast material to exclude tumors on their initial MR study. Screening patients for first-onset seizures usually necessitates the use of IV contrast material as part of their initial evaluation. Dynamic MR studies with power-injected intravenous gadolinium have occasional use. This is most commonly used in our protocols for evaluation of pituitary microadenomas. The differential enhancement rates between the normal pituitary gland versus the microadenoma, can in many cases, provide the only clue to the presence of the microadenoma on imaging. Dynamic imaging is the basis for MR perfusion studies, as well. Fat-Suppressed T1-Weighted Magnetic Resonance Imaging with or Without Gadolinium There are circumstances and locations when it is necessary to rid the image of fat-related hyperintensity of T1-weighted images, for example, when it is necessary to differentiate between subacute hematoma (hyperintense because of methemoglobin) and lipoma (hyperintense because of lipid content). Another instance occurs when trying to visualize abnormal gadolinium enhancement in the orbit, as might occur in radiation-induced optic neuritis, optic nerve ischemia, and multiple sclerosis (acute phase). The periorbital fat makes such enhancement difficult to detect without fat-suppression techniques (see Fig. 2-11). High Detail Inversion Recovery (STIR) T1-Weighted Inversion recovery imaging uses a preparatory RF pulse that emphasizes T1-weighting. This creates hyperintense white matter and a relatively hypointense gray matter. The result is excellent gray matter to white matter differentiation. This,

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combined with thin sections, is very helpful in detecting subtle migrational abnormalities affecting the cortex. This process is time intensive. Therefore, it is not a screening exam and necessarily must be used in conjunction with electroencephalograph data to pick the site of interest (Fig. 2-17). Gradient-Recalled Imaging with T1 Weighting and/or with and Without Flow Compensation The GRE allow nearly isotropic evaluation of tissue and thin section capability without gaps between sections. These suffer from less signal quality, but provide better spatial resolution. The most common use of such images is for radiation surgery planning and for volumetric analyses, for instance, for hippocampal volumes in patients with partial complex epilepsy. A variation of GRE imaging, which performs the examination with and without flow compensation gradients, is useful in detecting low flow states, especially in radiation therapy–treated arteriovenous malformations. Low-flow vessels can exhibit signal characteristics similar to thrombosed vessels. Scanning the site without flow compensation followed by rescanning with flow compensation gradients allows differentiation of thrombosis from slow flow. This sequence is a routine part of our post-radiation surgery assessment of the arteriovenous malformation nidus (Fig. 2-18).

Figure 2-18. Gradient-recalled echo (GRE) imaging of hemosiderin in multifocal cavernous angiomata. GRE image through the low convexity of brain demonstrates focally reduced signal in the left lateral mesencephalic and left occipital areas (arrows) representing hemosiderin found within cavernous angiomata. Susceptibility artifacts produced by the presence of hemosiderin are more conspicuous with a gradient type image sequence, as illustrated in this examination.

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Magnetic Resonance Angiography (Time of Flight) MRA is acquired using the intrinsic signal of fast-flowing arterial blood. The process uses a presaturation pulse over the top of the head to obviate dural sinus venous blood flow signal. The process of imaging the brain plus the use of magnetic transfer prepulses causes dampening of stationary brain signal. The unsaturated inflowing arterial blood in the carotid and vertebral arteries provide the tissue contrast nec-

A

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essary to generate the MRA signal. Postprocessing, back-projection, computer manipulation creates the arterial images. The limitation of this method is that saturation occurs in distal intracranial vessels, precluding their opacification. The other significant limitation is patient motion during data acquisition resulting in misregistration of vessel segments. Time-of-flight MRA remains the mainstay of intracranial MR arterial evaluation (Fig. 2-19).

Figure 2-19. A, Time-of-flight (TOF) MRA in carotid occlusion. Threedimensional TOF MRA in dark-contrast mode demonstrates abnormally reduced flow in the left intracranial carotid distribution (arrow). Because some left cerebral circulation is present, this does not represent a complete occlusion of the middle cerebral circulation, but rather, a slow flow state with collateral vessels derived through the circle of Willis. The collateralized circulation is less apparent because its slower flow is subject to additional saturation of the inherent signal (less available signal than faster flowing blood). B, TOF MRA in segmental basilar artery occlusion. Three-dimensional TOF MRA with contrast in white-contrast mode demonstrates an absent signal (thrombosis) in the mid-portion of the basilar artery (arrow). Both the remaining antegrade flow from the vertebral arteries and the retrograde flow through the posterior communicating arteries can be appreciated on MRA.

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Magnetic Resonance Angiography (Two-Dimensional with Gadolinium) MRA of the brachiocephalic vessels can be performed using a simultaneous intravenous infusion of gadolinium and acquiring 2D coronal sections. Postprocessing provides a high-quality MRA that rivals digital angiography. The limitation is timing the contrast material bolus. If filming occurs too soon there is insufficient arterial detail. If image acquisition is too late then the cervical veins flood the image and obscure arteries. Nevertheless, when performed correctly in a cooperative patient, infusion MRA can accurately image the aortic arch and cervicobrachial vessels. This method is less suitable for intracranial arterial studies (Fig. 2-20). Magnetic Resonance Venography MRV can be performed to evaluate patency of the major dural sinuses and the internal cerebral vein/vein of Galen/straight sinus complex. The difference between MRA and MRV relates to where the presaturation pulse is placed. In cranial MRV, the saturation bands are placed over the cervical arterial vessels obviating any arterial inflow signal. No presaturation RF pulse is used over the top of the head,

Figure 2-21. Dural sinus thrombosis on MRV. Three-dimensional time-of-flight MRV demonstrates very little signal within the superior sagittal sinus. Some cortical veins are visualized. These findings are indicative of sagittal sinus thrombosis. For comparison, review the normal cranial MRV in Figure 2-9.

allowing signal from efferent flow in dural sinuses to generate the vascular signal. Hence, this study, for the most part, images veins and not arteries. The cavernous sinus is imaged only fairly reliably. MRV is used, in large measure, for evaluation of superior and transverse dural sinus thrombosis. It is occasionally used for deep vein thromboses. It is seldom used for cavernous sinus thrombosis. The features of the latter are usually apparent on standard imaging sequences (Fig. 2-21).

Figure 2-20. Gadolinium-enhanced MRA of the aorta and brachiocerebral arteries. Two-dimensional gradient-recalled echo images with gadolinium being actively injected (early in the infusion to emphasize arteries) demonstrate opacification of the thoracic aorta and the brachiocephalic arteries to the level of the skull base. The good visualization of vessels in this instance depends not on the inflow effects but rather on the physical presence of gadolinium within the vessels to create the image. This makes artifacts related to turbulence substantially less of a problem, which translates into greater lesion conspicuity.

Magnetic Resonance Diffusion The most common current use of diffusion MR is for the diagnosis of hyperacute cerebral infarct. It has the advantage of delineating the area of central ischemia before being detectable by routine CT or MR sequences. It has other uses, for instance, distinguishing between epidermoid cysts and arachnoid cysts where both exhibit CSF features on standard imaging. Examples of both of these issues are presented in Figures 2-7 (arachnoid cyst) and 2-33 (stroke). Magnetic Resonance Cerebrospinal Fluid Flow Study CSF flow studies can detect abnormal CSF pulsation dynamics. This becomes relevant in cases of possible hydrocephalus when minimal ventriculomegaly is present. Differentiation of arrested or low-grade hydrocephalus and mild atrophy is often a problem. In most cases, the intracranial CSF flow studies evaluate CSF dynamics within the cerebral aqueduct,

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the outlet of the fourth ventricles and within the foramen magnum. The latter is especially relevant when there is downward tonsillar ectopia (Chiari 1 malformations; see Fig. 2-12 for example). Magnetic Resonance Spectroscopy MR proton spectroscopy is used currently in brain tumor staging as mentioned previously. In this capacity, it is used to help distinguish between radiation necrosis and persistent tumor. It is helpful in identifying gliomatosis cerebri and in distinguishing sequestered stroke or organized abscess from tumor. It has other nontumor uses as well, including assessment of leukodystrophy. Spectroscopy is not limited to proton spectroscopy alone. Phosphorus imaging is also possible. This can be used to map adenosine triphosphate and brain metabolism. While not in common use today, phosphorus imaging likely will be in time. Phosphorus spectroscopy is likely to be valuable in assessment of metabolic abnormalities and dementia (Fig. 2-22).

Available Computed Tomography Imaging Sequences Computed Tomography with or Without Intravenous Contrast Medium CT performed without contrast material is used as the standard screening examination for the brain in patients being evaluated for both spontaneous intracranial hemorrhage and posttraumatic brain imaging. Combined with sections through the maxillofacial regions, this provides a screen for uncomplicated sinusitis and headache. Bone windows allow diagnosis of skull and maxillofacial fractures. CT performed with and without contrast material is commonly used for screening of most infectious entities, inflammatory lesions (including vasculitis), and tumors. It is occasionally helpful in stroke. CT perfusion is likely to replace precontrast and postcontrast CT for stroke evaluation. Ventricular assessment seldom needs the postcontrast examination unless the cause of the ventriculomegaly is

B A Figure 2-22. A, Brain tumor spectroscopy. An axial, FLAIR image (strongly T2 weighted) demonstrates signal abnormalities evident in the right cerebral hemisphere in two locations. Review of Figure 2-10A, which is the same case, demonstrates that the more medial lesion is contrast enhancing and represents the primary tumor (single arrow). The more lateral lesion (double arrows) is a problem and could represent either radiation therapy effect or a satellite tumor implant. Mulitvoxel spectroscopy was applied in this case to differentiate these two possibilities. B, Multivoxel spectroscopy scout film. Mulitvoxel MR proton spectroscopy can be applied to assess the presence of tumor versus radiation change in both of the suspected areas. This scout image demonstrates how the spectroscopy is positioned to include both lesions and intervening brain. Spectroscopy revealed that the more lateral lesion exhibited features of radiation change and not tumor. Differentiation of tumor from radiation effects when multicentric abnormalities are evident represents one current role for proton spectroscopy.

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unknown or if infectious-based shunt malfunction is suspected. Routine sinusitis evaluation seldom requires contrast material, whereas the complication of acute sinusitis may require a postcontrast examination. Computed Tomography Brain Perfusion CT perfusion is currently being used in the evaluation of hyperacute stroke. A preceding noncontrast examination should be acquired to evaluate the presence of blood products before the contrasted study. CT angiography is added if evidence of stroke or vascular thrombosis is suspected (see Fig. 2-16). Computed Tomography Angiography CT angiography is now available as a screen for extracranial or intracranial vascular thromboses. The detail is excellent. It also provides assessment of both mural thickness and residual lumen size. It can be used for diagnosis of arterial

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dissections as well as stenosis or thrombosis. Because of the ease and speed of providing appropriate data, the combination of CT perfusion and CT angiography will likely become the standard for pretreatment assessment in the context of acute brain attack (Fig. 2-23).

Relevant Radiologic-Clinical Issues The following discussion focuses on radiologic-clinical issues often affecting treatment decisions for the neurointensivist. In order of presentation, these issues include understanding the changes of brain herniations, imaging of hyperacute stroke/hypoxia/metabolic abnormalities, MR and CT manifestations of hemorrhage, early changes in hydrocephalus and intracranial hypotension, and finally, exclusion of tumefactive lesions from intrinsic brain tumor. Each of these subjects requires common understanding between the neuroradiologist and the neurointensivist because each has important clinical consequences and may affect outcome. Brain Herniations

Figure 2-23. Maximum intensity projection reconstruction (MIP). Individual, contiguous, thin, CT sections can be post processed in a number of ways. They can, as in Figure 2-15, be reformatted as individual sections in another plane (multiplanar reconstruction), or as in this instance, the entire data set can be combined to make a two-dimensional MIP image that can be rotated in any projection. Or, the data can be put into a three-dimensional mode using surface rendering. Both the MIP image and the three-dimensional surface rendering subtract out the bone. The MIP form of reconstruction with subtraction is presented in this case, and demonstrates the same anterior communicating aneurysm (arrow) as presented in Figure 2-15. The process of subtracting bone is subject to interpretive error, which limits the usefulness of both two-dimensional MIP and three-dimensional surface modeling techniques.

One of the common indications for CT imaging is “change in mental status” and, as a corollary, answering whether it is “safe” to perform lumbar puncture on a patient for CSF analysis.55–59 What is being asked, in essence, is whether there is a space-occupying lesion of any type and whether it is producing a brain herniation syndrome. This discussion will review the topographic arrangement of structures adjacent to the tentorial incisura and at the foramen magnum. It will present both simulated and actual imaging data to illustrate both pertinent normal relationships and abnormal consequences of the major herniation syndromes. Certain elements need to be present for herniation to occur. For supratentorial masses to cause herniation they must exist anatomically in reasonable proximity to the falx (for subfalcine herniation) or to the tentorial incisura (for downward transtentorial herniation). The size of the mass must be large enough to displace pertinent anatomic structures into specific cisternal spaces. In other words, herniations occur in the context of a mass exerting pressure in a direction, or “a vector.” It is the direction of the vector that defines the type of herniation. Herniation syndromes, as discussed in this chapter, include subfalcine herniation (produced by a mesial mid-convexity vector), downward transtentorial uncal herniation (produced by a mesial, lowconvexity, mid-temporal vector), downward transtentorial parahippocampal herniation (produced by a mesial, lowconvexity, posterior-temporal vector), upward herniation (produced by a superior cerebellar-region vector), and downward cerebellar tonsillar herniation (produced by a mid to inferior, cerebellar-region vector). Larger, nonfocal brain swellings can produce herniations, but these seldom

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Figure 2-24. Subfalcine herniation. An axial, nonenhanced, CT section through the mid-convexity of brain demonstrates displacement of brain structures from left-to-right related to a large left cerebral infarction affecting the ipsilateral middle and posterior cerebral artery territories. In addition to the midline shift, there is also dilatation of the contralateral right-sided ventricle related to distortion of the foramina of Monro. These findings are typical of subfalcine type of brain herniation.

exert a single vector, but rather combine multiple types of herniation. For instance, global unilateral brain swelling might produce uncal herniation, parahippocampal herniation, and subfalcine herniation simultaneously. Subfalcine Herniation Subfalcine herniation implies a shift of midconvexity brain structures into the aperture formed beneath the falx cerebri. Generally, it is produced by an asymmetrical hemispheric mass, which displaces brain structures (cingulate gyrus and corpus callosum) across the midline and compresses them against the free margin of the falx cerebri. Injury to midline brain structures occurs more readily from acute shifts than from chronic or more slowly evolving masses. In the orbitofrontal region, the falx is small and midline shift does not result in focal tissue compression, but merely a midline shift. Masses in the midconvexity of the brain, usually in the frontoparietal area, the basal ganglia and the sylvian region most commonly account for subfalcine shifts. Lesions in the cerebral high convexity and those in the occipital polar region usually produce little shift of midline because they exist in proximity to the solid portions of the falx where no aperture is available through which to herniate brain. Similarly, anterior temporal lesions that reside in the temporal

fossa produce no shift until they expand into the midtemporal or lateral orbitofrontal regions (Fig. 2-24). Downward Transtentorial Herniation of the Uncus Downward transtentorial herniation of the uncus results from an asymmetric supratentorial mass of the midtemporal region that shifts the uncal portion of the parahippocampal gyrus medially into the suprasellar space (a medial vector) and then downward into the crural cistern (an inferior vector). The medial uncal shift produces an asymmetry of the suprasellar cistern initially, but obliterates the cistern as herniation becomes more severe. The downward vector results in compression of the crural portion of the circummesencephalic cistern initially, but, as it becomes more severe, results in displacement of the mesencephalon, ultimately compressing it upon the free margin of the opposite tentorial edge. Ipsilateral cisterns below the tentorium, as the cerebellopontine angle cistern, progressively enlarge as the brainstem is shifted to the contralateral side (Fig. 2-25). Downward Transtentorial Herniation of the Parahippocampal Gyrus Downward transtentorial herniation of the parahippocampal gyrus results from an asymmetric supratentorial mass of

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Figure 2-25. A, Downward transtentorial herniation: axial plane. Simulated MR image through the low convexity of brain demonstrating normal incisural anatomy and relationships. Cisterns surrounding the mesencephalon include the interpeduncular fossa and suprasellar cisterns anteriorly, the crural cisterns outlining the cerebral peduncles anterolaterally, the ambient cisterns outline the lateral aspect of the mesencephalon, and the quadrigeminal plate cistern outlines the tectal surface of the mesencephalon. The uncus (the uncal portion [u] of the parahippocampal gyrus) is also delineated by the crural cistern and contiguous to the cerebral peduncle. Brain adjacent to the ambient cistern is the parahippocampal gyrus (p). Brain adjacent to the quadrigeminal plate cistern is the superior vermis. All these cisterns combine to comprise the circummesencephalic cisterns which, along with the mesencephalon, fill the tentorial hiatus (or incisura). B, Downward transtentorial herniation (uncal herniation). The first stage of downward tentorial herniation is related to both medial and downward displacement of the uncal portion of the parahippocampal gyrus creating deformity of the suprasellar space, effacement of the crural cistern and early deformity of the ipsilateral cerebral peduncle. This simulated MR image with an apparent temporal lesion illustrates the findings of early downward transtentorial herniation with mesial shift of uncus and secondary compression of the crural cistern and ipsilateral cerebral peduncle (arrow). C, Downward transtentorial herniation (parahippocampal gyrus and uncal herniation). As downward incisural herniation worsens, there is further mesial displacement of the remaining parahippocampal gyrus into the incisura with further compression and contralateral midbrain displacement and loss of both the crural cistern and the ambient cistern. This simulated MR image through the tentorial hiatus illustrates these changes with substantial mesial shift of the parahippocampal gyrus including both the uncus (arrow) and the more posterior portions (arrow) with further contralateral displacement of the mesencephalon and effacement of the ipsilateral crural and ambient cisterns. D, Downward transtentorial herniation (prior to herniation). An axial, nonenhanced, CT section through the tentorial hiatus (incisura) demonstrates the normal anatomic relationships of the hippocampal gyrus in the mesencephalon surrounded by the circummesencephalic cisterns.

Figure continues

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Figure 2-25 continued. E, Downward transtentorial herniation (early stage). An axial, nonenhanced, CT section through the tentorial hiatus (incisura) demonstrates features of early uncal herniation. The crural cistern is compressed, while the ambient cistern is preserved. There is also minimal deformity of the left cerebral peduncle. F, Downward transtentorial herniation (advancing stage). An axial, nonenhanced, CT section through the tentorial hiatus (incisura) demonstrates features of progressive downward transtentorial herniation. There is now obliteration of the suprasellar, crural, and ambient cisterns. There is early obstructive hydrocephalus with dilatation of the left temporal horn. The herniated brain is edematous (low CT density; arrows). Notice that the quadrigeminal plate cistern is preserved and even accentuated in the case of downward herniation. This effect should be compared and contrasted to the effects of upward transtentorial herniation illustrated in Figure 2-26. G, Downward transtentorial herniation (advanced stage). Three-dimensional TOF MRA image demonstrates preservation of the basilar (b) arterial flow, but virtual elimination of the intracranial carotid circulation. These are MRA features of severe brain swelling with incisural compression and obstructed carotid circulation, but with preservation of the posterior fossa circulation. H, Downward transtentorial herniation (advanced stage). An axial, proton-density MR image through the occipital lobes demonstrates evidence of focally reduced signal (edema) in the left posterior cerebral artery territory (arrow). Downward herniation has occluded the parietal-occipital branch of the left posterior cerebral artery at the point where it crossed over the free edges of the left tentorium as it passes between the infra and supratentorial compartments.

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Figure 2-26. Upward transtentorial herniation. An axial, nonenhanced, CT scan through incisura demonstrates features of upward transtentorial herniation. Upward displacement of the superior vermis secondary to cerebellar swelling results in first compression and then complete effacement of the quadrigeminal plate cistern (arrow).

the posterior temporal region that shifts the mid and caudal portions of the parahippocampal gyrus medially into the ambient cistern. The first evidence of herniation is obliteration of the ambient cistern followed by displacement of the mesencephalon, ultimately compressing it upon the free margin of the contralateral tentorial edge. Parahippocampal gyrus herniation has another important consequence. The parietal occipital branch of the posterior cerebral artery (PCA) crosses from an infratentorial position to a supratentorial position in its post tectal portion. Antegrade blood flow in this portion of the PCA may be compromised when the parahippocampal herniation becomes significant. Characteristically, this results in brain infarction in the mesial portion of the ipsilateral occipital lobe. Upward Transtentorial Herniation Upward transtentorial herniation occurs as the result of a mass within the upper half of the posterior fossa, either intra-axial or extra-axial types. The upward vector displaces the superior vermis and the contiguous portion of the rostral cerebellum into the tentorial notch, while displacing the rostral brainstem against the clivus. The presenting feature of upward transtentorial shift is obliteration of the quadrigeminal plate cistern and deformity of the inferior colliculi. As mass effects worsen, there will be obliteration of the prepontine cistern and deformity of the interpeduncular fossa. It is important to recognize the differences between

upward and downward herniation. Upward herniation seldom affects the crural and ambient portions of the circummesencephalic cisterns, and downward herniation seldom affects the quadrigeminal plate cistern. When both vectors are present, it is likely that a global brain insult has occurred affecting both supratentorial and infratentorial brain (Fig. 2-26). Downward Cerebellar Tonsillar Herniation Caudal-half posterior fossa masses produce a downward vector which shifts the cerebellar tonsils inferiorly into the cistern of the cisterna magna. If the mass effect is lateralized, an asymmetric tonsillar herniation is produced. A generalized or midline oriented mass will produce a symmetric tonsillar herniation. A mass arising within the fourth ventricle will separate the tonsils as they are downwardly displaced. The two cisterns, which must be identified to exclude tonsillar herniation, include the vallecula, a midline extension of the cisterna magna that separates the mesial surfaces of the cerebellar tonsils, and the circummedullary cisterns located in the plane of the foramen magnum. If either of these cisterns is obliterated, tonsillar herniation is imminent. If it is visualized but compressed and displaced away from its normal midline position, then there is an asymmetric mass in the posterior fossa. Low tonsillar position by itself is not abnormal. Three conditions exist where low tonsillar position is not related to

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Figure 2-27. A, Downward tonsillar herniation. Simulated MR image through the low posterior fossa illustrating the normal relationships between the medulla, the cerebellar tonsils (T), and cerebrospinal fluid within the cisterna magna, the vallecular extension of the cisterna magna (called the vallecula), and the remaining circummedullary cisterns. The vallecula is the midline postmedullary cistern that separates the mesial surfaces of the cerebellar tonsils. This cistern is used to delineate the midline structures in the lower posterior fossa, and therefore, must be visualized in all normal head scans to exclude tonsillar shifts. B, Downward tonsillar herniation. Simulated MR image through the low posterior fossa illustrating left-to-right shift of the cerebellar tonsils compressing and displacing the vallecula to the opposite side (arrow). Lower sections would show displacement of the inferior pole of the left cerebellar tonsils below the plane of the foramen magnum. The plane of the foramen magnum is defined by the imaginary line interconnecting the anterior and posterior margins of the foramen magnum. The anterior margin is delineated by the anatomic points of reference which include the basion (or caudal tip of the clivus) and the opisthion (or posterior margin of the occipital bone as it forms the foramen magnum). The caudal poles of the tonsils lie above this line, as shown in Figure 2-28. C, Downward tonsillar herniation. An axial, T2-weighted, spin-echo MR image through the plane of the foramen magnum demonstrates early bilateral downward tonsillar herniation. The caudal tonsillar poles (arrows) are positioned at or slightly below the plane of the foramen magnum. D, Downward tonsillar herniation (same patient as in C). An axial, T2-weighted, spin-echo MR image through the plane of the cisterna magna demonstrates substantial downward tonsillar herniation with obliteration of the circummedullary cisterns, obliteration of the vallecula, and anterior displacement of the medulla against the clivus. The caudal tonsillar poles are displaced well below the plane of the foramen magnum.

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Figure 2-28. Downward tonsillar herniation; sagittal plane. This sagittal, nonenhanced, T1weighted MR image through the tonsillar region demonstrates features of downward tonsillar herniation. The caudal poles of the tonsils project below the plane of the foramen magnum (dotted line). Normally, the caudal tonsillar poles lie above this line. In this case, the tonsillar herniation was related to hyponatremia and generalized brain swelling. Once corrected, the tonsillar herniation improved over a very short time without clinical sequelae.

mass effect. Two are developmental and the last is the consequence of a suboccipital craniotomy. It is not uncommon for the caudal poles of the cerebellar tonsils to be positioned normally a little below the plane of the foramen magnum. In this instance, the foramen magnum tends to be large and the tonsils are more laterally placed. Significantly, the vallecula is unusually large and remains in a midline position. The second developmental variation is that of a Chiari malformation. In this instance, the cervicomedullary portion of the brain stem is also displaced inferiorly and there is no mass evident. The tonsils are frequently both ectopic and dysmorphic, appearing elongated and ending in a pointed shape. It may, however, be difficult to differentiate between the effects of intracranial hypotension and a mild Chiari-1 malformation without clinical history (Figs. 2-27, 2-28). Evaluation of Oligemia, Stroke, and Dural Sinus Thrombosis Brain perfusion is normally autoregulated maintaining perfusion in the range of 40 to 80 mL per 100 gm of tissue per minute.60–67 Oligemia results when perfusion falls beneath 20 mL/100 gm of tissue, placing the brain at risk of infarc-

tion. Perfusion exceeding 80 mL/100 gm of tissue per minute is considered hyperemic and usually implies a loss of autoregulation; it takes the appearance of luxury perfusion on angiographic images. Clinical function is typically affected by ischemia earlier than most of our radiologic methods can detect, but the gap is rapidly closing with diffusion MRI and both perfusion CT and MRI. Most brain perfusion modalities (other than Xenon-CT studies) provide relative measures of perfusion comparing abnormal to more normal areas of circulation, and not actual values, although this is changing as well. When oligemia becomes symptomatic, it implies that some portion of brain is at imminent risk of infarction. This area at risk has two components: the central ischemic core, which is likely to infarct, and the surrounding, oligemic zone, or penumbra, which is potentially at risk for infarction. The extent of the penumbra depends on collateralization by adjacent brain circulation. Diffusion MRI can facilitate assessment of the extent of the ischemic core, and either CT or MRI perfusion estimates the overall area of ischemia penumbra. Superimposing these studies determines the likely ischemic core and the likely oligemic penumbra. Arterial patency can be determined using either CT or MRA. Routine CT is used to evaluate for acute clot in

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A B Figure 2-29. A, Early brain stroke on CT. An axial, nonenhanced CT scan through the mid-convexity of brain demonstrates features of early brain swelling (*). In this case, the findings are subtle, but there is effacement of the gray matter-white matter junction along the right insula. The follow-up CT study, performed 24 hours later, is illustrated in B. The earliest stage (hyperacute) of cytogenic edema is often difficult to detect on CT without reviewing the images in a high-contrast mode. B, Early brain stroke diagnosis on CT. An axial, nonenhanced CT scan through the mid-convexity of brain demonstrates features of acute stroke with focal cytogenic changes in the subinsular centrum semiovale regions on the right side. Once focal edema is present, the site of the ischemic area is relatively easy to detect with CT. However, this usually requires more than 12 hours postictus, which is most likely beyond the time frame for intra-arterial clot lysis therapy.

a proximal cerebral artery and/or parenchymal cerebral hemorrhage (Figs. 2-29 to 2-31). The first component of a stroke workup requires documentation that brain injury has actually occurred. Time is of the essence if either intravenous or intra-arterial treatments are to be effective. Currently, MR diffusion has become the current means of early stroke diagnosis, although with time it may be supplanted by perfusion CT. MR diffusion methods are very sensitive and can detect an ischemic event, usually within minutes to hours. The limitation of this method is spatial discrimination. Several cubic centimeters of tissue need to be affected to confidently make a radiologic diagnosis of stroke in progress. The features that characterize an acute infarct on MR diffusion imaging include a reduced diffusion coefficient (low ADC values implying

restricted tissue water movement) and increased signal on the trace diffusion images (high values implying failure of the molecular motion to reduce the overall signal as it occurs in normal brain). The limitation of the trace images is “T2 shine through.” This means that increased tissue water (cytogenic edema) also creates increased signal on the diffusion images, because diffusion is a T2-sensitive sequence. In practical terms, cerebral infarction diagnosis is most secure when the ADC map has a negative defect (dark area) and the trace images have a bright area. These changes are detectable before cytogenic edema produces an abnormality on the standard MR sequences. The perfusion portion of the study, which is an estimate of the signal change following a first pass method after an intravenous gadolinium injection, will estimate the total area of regional oligemia. Comparing the

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Figure 2-30. A, Hyperdense artery sign in stroke. An axial, nonenhanced, CT scan through the low convexity of brain near the base of the sylvian fissure demonstrates a hyperdense segment of the middle cerebral artery (M2 segment). The hyperdensity of the vessel is related intravascular clot. B, Basilar artery thrombosis. Sagittal, nonenhanced, T1weighted MR scan through the posterior fossa demonstrates acute thrombus (arrows) within the basilar artery in its mid-portion. The flowing portion of blood is hypointense, while the mid-portion of the basilar artery contains isodensity material consistent with intraluminal clot.

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Figure 2-31. Laminar necrosis. An axial T1-weighted MR scan through the mid-convexity of brain demonstrates features of a large zone infarct but also gyriform blood products collecting in the cortex (arrows). This gyriform type of blood distribution is indicative of thrombosis at a capillary level and corresponds pathologically to laminar necrosis. The spontaneous hyperintensity indicates the presence of methemoglobin.

perfusion study with the diffusion study allows differentiation of the ischemic core versus the oligemic penumbra versus the remaining normal brain volume. The second component of a stroke includes evaluation of actual cervical and intracranial arterial patency. Both MRA and CT angiography can provide these data. However, TOF MRA (which is used intracranially) suffers in two respects. First, it is motion sensitive and requires a cooperative patient. Second, acute thrombus containing methemoglobin can generate signal similar to blood flow on TOF sequences. Thus, MR can provide spurious information if care is not used to correlate the standard MRI sequences with the MRA. Gadolinium-enhanced MRA is more accurate than TOF sequences, but is only suitable in the neck. Our standard stroke MRA sequences include a gadolinium-enhanced MRA for the neck vessels, a TOF MRA for the intracranial vessels, and thin section T1 sequences through the skull base and upper cervical region to assess for intraluminal thrombus and to detect concomitant dissection, when it is present.

The latter study is, in our experience, the most sensitive method of delineating mural dissection. Both direct angiography and MRA only image the status of the lumen and not the vessel wall. CT angiography obtained with newer generation helical scanners produces vascular patency data that are very accurate. CT will likely replace MRI in our institution for acute stroke evaluation when the patient is imaged in a period that does not preclude intraarterial clot lysis (less than 6 hours post ictus) (Fig. 2-32). The diagnosis of arterial dissection is sometimes a problem. Although the features of dissections are well known on angiography, this procedure only evaluates the lumen of the affected vessel. What is needed is evaluation of the lumen as well as the vessel wall (i.e., mural and extramural thickening). Hence, direct transfemoral arteriography is used only in indeterminate cases and thin section T1-weighted MRI or thin section spiral CT with contrast material are used as initial procedures. In most cases, these studies are diagnostic without being invasive (Fig. 2-33).

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Figure 2-32. A, Early stroke diagnosis on MRI. An axial, nonenhanced, T1-weighted MR image through the low convexity of brain in a patient with acute neurologic deficit demonstrates no abnormality. An asterisk (*) indicates the region of actual ischemia presented in the following images. B, Early stroke diagnosis on MRI. An axial, trace (b = 1000), diffusion image through the low convexity of brain demonstrates features of a hyperacute infarct with a focal (hyperintense) diffusion abnormality in the mesial right occipital lobe (*). Diffusion MR imaging can detect hyperacute stroke, when routine MRI and CT typically fail in the absence of hemorrhage. C, Early stroke diagnosis on MRI. An axial, apparent diffusion coefficient (ADC) image through the same low convexity brain demonstrates reduced apparent diffusion (hypointensity) on the ADC map. This indicates less inherent motion in this portion of brain compared to the remainder of brain.

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Venous obstruction is a less common form of vascular disease producing global or focal symptoms. Imaging is helpful in delineating this problem, especially in the major dural sinuses and in the cavernous sinus. Individual cortical vein thrombosis can also be diagnosed occasionally. The imaging features of dural sinus thrombosis include evidence of clot within the lumen of the dural sinus

on nonenhanced images and abnormal enhancement of the wall of the dural sinus. Brain edema is often bilateral, straddling the dural sinus. Blood products within cortical veins or extravasated into the brain parenchyma are common. MRI and MRV are often the noninvasive diagnostic modalities of choice in venous occlusive disease of the head (Fig. 2-34).

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Figure 2-33. A, Thrombosis of the cervical carotid in acute stroke. An axial, nonenhanced, CT scan through the mid-convexity of brain demonstrates the presence of a focal zone of edema (arrow) in the anterior sylvian region on the right side consistent with an acute ischemic event (stroke in progress). B, Thrombosis of the cervical carotid in acute stroke. An axial, T2-weighted section through the high cervical region in the same patient demonstrates asymmetric intensity within the high cervical carotid arteries. There is a normal flow void on the left side (arrow), but not on the right (double arrows). The usual hypointense lumen of the right carotid is replaced with nearly isodense clot. These findings are indicative of lumenal thrombosis in the high cervical portion of the right carotid artery.

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Figure 2-34. A, Dural sinus thrombosis (superior sagittal sinus). An axial, nonenhanced, CT section through the low convexity of brain demonstrates spontaneous hyperdensity within the central lumen of the posterior portion of the superior sagittal sinus (arrow), representing acute clot within its lumen (“delta sign”). B, Dural sinus thrombosis. An axial, gadolinium-enhanced, T1-weighted MR image through the low convexity of brain demonstrates abnormal enhancement of the wall of the superior sagittal sinus (arrow) with little or no enhancement within the central lumen (“empty delta sign”). Spontaneous, hyperdensity within the lumen of the vein of Galen and proximal straight sinus (double arrows) represents acute intravascular clot, as well. C, Acute dural sinus thrombosis. Sagittal, nonenhanced, T1-weighted MR image through the superior sagittal sinus (*) demonstrates spontaneous hyperintensity consistent with clot already in a methemoglobin phase. Similar changes are also evident in the deep venous system (arrow). These are features of acute dural sinus thrombosis on MRI.

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Evaluation of Hypoxia and Metabolic Insufficiency This is a diverse group of abnormalities.68–72 The basic physiologic defect common to most hypoxic/metabolic (excluding storage diseases and dysmyelination) diseases is a failure to produce adequate energy to maintain cell function and/or integrity. Global hypoxia, carbon monoxide poisoning, and genetic defects in aerobic metabolism typically develop brain

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changes affecting regions of highest adenosine triphosphate (energy) demands. These include, in order of susceptibility, mesial globus pallidus, periaqueductal gray matter, dorsal pontine nuclei, dentate cerebellar nuclei, hippocampi, cerebellar cortex, and cerebral cortex. We refer to these regions as areas of high adenosine triphosphate demand and when abnormalities are evident in these zones, effects of global hypoxia, diabetes (global glucose loads), or mitochondrial

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dysfunction become prominent in the differential diagnosis (Figs. 2-35 to 2-37). Evaluation of Intracranial Hemorrhage Intracranial hemorrhage is a common cause of mental status change.73–76 The source of the hemorrhage is always a problem. Extra-axial blood products typically arise from

B

Figure 2-35. A, Diffuse cytogenic brain edema-global insult. An axial, nonenhanced, CT section through the mid-convexity of brain demonstrates abnormal CT density characterized by virtual homogenization of the gray and white matter tissue density. Such change is indicative of a global insult with either a hypoxic or a hypoperfusion basis. Generalized cytogenic (or cytoxic) edema in its early stage often produces little mass effect other than effacement of superficial sulci. The global injury in this patient is seen to progress in B and C. B, Diffuse cytogenic brain edema-global insult. An axial, nonenhanced, CT scan through the low convexity of brain demonstrates evidence of severe cytogenic edema affecting both hemispheres. The degree of cytogenic edema is often underappreciated unless the cerebellar density (*) is used for comparison. In this instance, the cytogenic temporal edema stands out because it can be contrasted with the more normal cerebellar density. C, Diffuse cytogenic brain edema-global insult. An axial, nonenhanced, CT scan through the low convexity of brain demonstrates features of diffuse brain swelling with compression of the ventricular spaces, loss of gray-white junction differentiation, effacement of the superficial sulci, and compression of the incisural cisterns.

trauma or vasculopathy, and especially chronic anticoagulation. Aneurysm and arteriovenous malformations figure prominently when subarachnoid blood is present. These lesions figure prominently in discussions by other authors and, hence, will not be further discussed. Intra-axial hemorrhage, on the other hand, occurs in a wide assortment of lesions and often requires specialized imaging to resolve the basic lesion. Discussion in this section will deal with the fea-

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Figure 2-36. Central nuclear injury in diabetic ketoacidosis. An axial, T2-weighted FLAIR image through the basal ganglia region demonstrates features of metabolic brain injury. In this instance, the patient has been treated for diabetic ketoacidosis. But, despite usually appropriate therapy, the patient had a negative clinical outcome. The changes of a metabolic insult to brain tend to affect areas of higher adenosine triphosphate utilization. These regions include the mesial basal ganglia, the periaqueductal gray matter, the dentate nuclei, thalamic, and hippocampi. Injury to these regions (as in this case) results in abnormal T2 hyperintensity (arrows) distributed in the structures mentioned previously. Abnormalities of this type are based on a metabolic insult and are usually related either to hypoxia, carbon monoxide poisoning, or underlying abnormalities of aerobic metabolism as occurs in patients with cytochrome oxidase enzymatic and/or mitochondrial deficiencies.

tures of resolving blood on MRI and CT in general and then examine some of the underlying causes. CT and FLAIR MRI sequences are both sensitive to subarachnoid and other acute extra-axial blood products. CT, because of its easy accessibility, is typically used in the acute state. The location and likely cause of the hemorrhage depends on its location. Subarachnoid blood collects in basilar (suprasellar space, cerebellopontine angle, and interpeduncular fossa) cisterns and in communicating (sylvian and interhemispheric) cisterns. Subarachnoid or subpial blood, over the convexities of brain, takes on a “gyriform” appearance. If the gyriform appearance is well delineated, the blood is likely within the sulci adjacent to the cortex; if less well delineated, the blood is likely intraparenchymal. Blood collections delimited by a margin in brain are likely within lesions of the brain and

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Figure 2-37. Progressive necrotizing leukoencephalopathy (PNL). Coronal, enhanced, CT scan through the posterior frontal region demonstrates features of acquired small vessel vascular disease associated with combination chemotherapy and radiation resulting in PNL. The imaging features typically include bilateral (although often asymmetric) distribution, abnormal marginal contrast-enhancement (arrows), and leukomalacic changes.

not the brain per se. These include thrombus within lesions as cavernous angioma, metastatic deposits, or within the fundus of a giant aneurysm. The following sections will review the appearance of blood as it evolves toward ultimate resorption. This evolution of blood, where pertinent, can help with the dating of the time of onset of the hemorrhage. Hemorrhage and the Evolution of Blood Products on Computed Tomography In the acute phase of clot evolution, which generally lasts 1 to 3 days, acute blood on CT is hyperdense relative to brain and CSF alike. Over the next few days, the blood passes into an isodense phase and then over 2 weeks into a hypodense phase. This entire process of clot evolution is accelerated for subarachnoid blood and slowed for extra-axial (epidural and subdural) hematomas. The intermediate, isodense stage is sometimes a problem because differentiation between isodense blood and intra-axial swelling may be difficult. This is less of a problem on current generation CT scanners than in the past. It may at times, however, be necessary to administer IV contrast material to increase the background brain density to exclude an extra-axial subacute hematoma. Intra-

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ventricular blood usually clears readily while subependymal hematomas do not (Fig. 2-38).

Hemorrhage and the Evolution of Blood Products on Magnetic Resonance The appearance of hemorrhage on MRI is more complex than that on CT. CT density varies in proportion to the density of the hematoma. In MRI, the signal is affected by both the physical and chemical status of the clot and of

hemoglobin. The hemoglobin effects are related mainly to changes in the magnetic properties of the iron contained in the hemoglobin molecule and are directly influenced by the iron’s oxidation state and biochemical form. These changes in the products of blood-iron breakdown are influenced by local oxygen saturation, age of the hematoma, size of the hematoma, degree of clot retraction, and status of the local circulation, as well as by other factors. Despite knowledge of the evolution of blood clot, dating the time of the hemorrhage exactly is somewhat of a problem after the hyperacute phase.

A B Figure 2-38. A, Evolution of blood on CT; subdural hematoma (acute phase on CT). An axial, nonenhanced, CT scan through the mid-convexity of brain demonstrates acute extra-axial hematoma on CT. There is hyperdense blood (arrow) layered along the lateral aspect of the right brain margin separating brain from the inner table of the skull consistent with an acute subdural hematoma. There is a concomitant right-to-left subfalcine shift. B, Evolution of blood on CT; subdural hematoma (subacute phase on CT). An axial, nonenhanced, CT scan through the mid-convexity of brain (as in A) but approximately 1 week later. The subdural hematoma density has changed from acute clot to a subacute hematoma (arrow). The hyperdense clot evident on A has now become nearly isodense to brain with only a minimal hyperdense component. Intracranial hemorrhages pass through an intermediate phase when they become virtually isodense to brain. If the hematomas happen to be bilateral, their mass effect can be missed. This error has been partially eliminated with recent vintage CT scanners. However, if an isodense subdural is suspected, but remains unconfirmed, contrastenhanced CT should be performed to increase brain density, making the subdural hematoma become apparent.

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The first stage in hematoma evolution is termed the hyperacute stage. This stage lasts only a few hours and is therefore encountered less frequently in routine imaging. During this hyperacute period, red blood cell integrity is preserved, as is the oxygenation of hemoglobin. The blood does not have paramagnetic properties during this time, and the appearance of the blood is related mainly to its proton density. The clot at this time is isointense or slightly hypointense on T1-weighted images and slightly hyperintense on T2-weighted sequences. The clot, during this stage, may not be distinguishable from other pathologic processes on the basis of its intrinsic signal intensity. The hematoma then passes into the acute stage, which lasts for approximately 1 week. The first dramatic change that occurs is that the oxyhemoglobin is converted to deoxyhemoglobin. This deoxyhemoglobin within the red blood cells has little effect on the signal intensity of the blood on T1-weighted images but produces a susceptibility artifact on T2-weighted images with reduced signal in the clot. This effect is more clearly seen in magnets of higher field strength. In the next stage of hematoma evolution, the subacute stage, the hematoma undergoes two changes: a conversion of hemoglobin to methemoglobin through oxidation of the iron, and a break down of red cell membranes with influx of tissue water. The methemoglobin transformation may be seen as early as 2 days after the hemorrhage, but depending on the location of the hematoma, may not be very noticeable until about a week has passed. Methemoglobin results in T1 shortening (proton relaxation enhancement) resulting in a high signal intensity on T1-weighted scans. This high signal intensity first appears at the outer margin of the hematoma, then progresses inward. Initially, the area containing methemoglobin remains hypointense on T2-weighted images. When red blood cell membranes burst and the methemoglobin is released, the extracellular methemoglobin combined with increased water content produces high signal on T2-weighted scans (hyperintensity on T2 sequences). The hyperintense T1 signal of methemoglobin persists well into the chronic phase of the hematoma and may remain visible for months or perhaps years. The last phase is the chronic stage of hematoma evolution. The principal feature of the chronic hematoma is the appearance of hypointensivity evident on T2-weighted sequences in or around the hematoma and the adjacent tissue. This signal change is related to susceptibility artifacts produced by accumulation of iron in the form of ferritin and hemosiderin within macrophages. The zone of hypointensity on T2-weighted images appears to remain indefinitely at the border of a hemorrhage, even after the high signal intensity of methemoglobin may have disappeared and the hematoma cavity has been converted to a thin, slit-like

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space. The preceding description of the changes within hematomas applies mainly to bleeds into neural tissue. Hemorrhages into other anatomic compartments may have different characteristics. For example, subarachnoid blood is notoriously difficult to detect by magnetic resonance imaging, except on FLAIR imaging. This difficulty is probably related to the relatively high oxygen content of cerebrospinal fluid, which does not promote the formation of deoxyhemoglobin. The signal intensity of a chronic subdural hematoma is dictated primarily by methemoglobin, which remains for a very long time. Hemosiderin does not appear to form at the margins of subdural hematomas. Hemorrhagic malignant tumors in the brain may demonstrate a slower evolution of blood product changes. Deoxyhemoglobin may persist longer in tumors than in parenchymal hematomas, a delay in methemoglobin may also be apparent, and a clear hemosiderin-ferritin ring may never develop (Fig. 2-39).

Evaluation of Ventricular Size Ventriculomegaly is readily defined with either MRI or CT. The grading scheme we use for estimation of ventricular enlargement is based on a scale of four steps beyond normal. Determination of normal ventricular size requires experience because it varies by chronologic age. Once the ventricular size is estimated to exceed normal limits for age, then a grading scheme is useful. We use a method that examines the mid-convexity images where the bodies of the lateral ventricles are best seen. Grade 2 (of 4) is defined as having bodies of the lateral ventricles taking up roughly half the hemibrain volume and the cerebral mantle the remaining half. Grade 1/4 ventriculomegaly exceeds normal-for-age, but has not reached the level of grade 2/4. Grade 3/4 is moderately severe ventriculomegaly but leaving at least 1.5 cm of cerebral mantle, and grade 4/4 reduces the cerebral mantle to under 1 cm. Signs of elevated CSF pressure include acute expansion of ventricle size and developing transependymal fluid migration. Acute changes in ventricular size in either direction become important from the perspective of critical care. Symptoms can be produced by ventricular size, which is too small from overshunting or from intracranial hypotension, as well as acutely increased ventricular volume. The ventriculomegaly can be generalized or occur in an asymmetric fashion in cases of sequestered ventricular components. Acute change in ventricular size is best assessed by comparing temporal horn size. It is difficult to appreciate a 10% change in the lateral ventricular size. However, the same change is usually easily seen in temporal horn volume. Other signs of increasing ventricular size are effacement of high convexity sulci and evidence of transependymal fluid migration. Any acute change in ventricular size can be symptom

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Figure 2-39. A, Evolution of blood on MR; subdural hematoma in an acute phase on MRI. An axial, T2-weighted FLAIR, MR image through the high convexity of brain demonstrates features of mixed age subdural hematomas. The blood products on the right are very hyperintense indicating completed transition to a fluid state. On the left side the hematoma (*) is relatively less bright indicating that the clot is relatively more solid and, hence, younger. B, Evolution of blood on MR: subdural hematoma (subacute phase on MR). An axial, T1-weighted, spin echo, MR scan through the high convexity of brain demonstrates that both the right and left (*) subdural hematomas contain methemoglobin, but there is more on the right indicating a slightly older age. The methemoglobin does not require being within cells to be hyperintense on a T1weighted sequence. C, Evolution of blood on MR; methemoglobin within cavernous angioma of the mesencephalon. Sagittal, T1-weighted, spin-echo MR image through the mesencephalon demonstrates spontaneous hyperintensity within a well-delineated mass (*) within the mesencephalon. This hyperintensity is related to methemoglobin within the clot, which remains confined within the borders of the lesion. The outer margin of the mass is hypointense, indicating the presence of hemosiderin. These are the features of the intra-axial mesencephalic cavernous angioma.

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producing. Thus, these early signs of hydrocephalus become important (Figs. 2-40 to 2-42).

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tures that discriminate between aggressive and nonaggressive intracranial tumors.

Screening patients with a depressed level of consciousness includes evaluation for intracranial mass lesions.77–93 Focused imaging protocols tailored to the clinical setting are the most suitable means of establishing an initial diagnosis, excluding nontumoral conditions, and answering questions related to staging. The first step in this diagnostic algorithm is to determine whether the scan is normal or not. Assuming a significant lesion has been detected, then an attempt must be made to distinguish between tumor and tumor mimics (“tumefactive lesions”). In adults, stereotactic biopsies of mass lesions (all thought to be tumors before biopsy) reveal an 8% to 12% incidence of nontumoral, tumefactive lesions. Thus, a 10% incidence of tumefactive lesions becomes a useful number to remember when evaluating mass lesions on imaging procedures. A corollary to the tumefactive issue (nontumors masquerading as tumors) is the reverse scenario where tumors masquerade as nontumoral conditions, most notably strokes. Both of these issues are considered in the following section, along with the fea-

Inflammatory or Infectious Tumefactive Lesions The more common inflammatory tumefactive lesions include “tumefactive MS” (multiple sclerosis or Schilder’s disease in children), myelin basic protein hypersensitivity disorders (i.e., acute disseminated leukoencephalopathy), adrenoleukodystrophy, sequestered cerebral infarction, herpes encephalitis, and resolving sequelae of occult trauma or hemorrhage. Each of these entities has features that aid in their diagnosis, but full analysis is beyond the scope of this discussion; references are, however, included in the bibliography. Infectious lesions can occasionally simulate tumors as well. Notable among this group are chronic empyema or brain abscess, neurocystercercosis, tuberculoma, and cryptococcoma. Chronic empyema is usually associated with adjacent paranasal sinusitis or otomastoid inflammatory disease. Patients undergoing immune therapy and bone marrow transplantation as part of their tumor treatment plan are subject to the opportunistic superinfections. Infections that might simulate persistent tumor include progressive multifocal leukoencephalopathy associated with papova viral encephalitis and cryptococcus (forming cryptococcomas).

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Evaluation of Brain Masses and Tumor Mimics

Figure 2-40. A, An axial, nonenhanced, CT scan through the mid-convexity of brain demonstrates small ventricular size in a patient with a right frontal ventriculo-peritoneal shunt in place. Although slightly small for age, the ventricles are still well delineated. B, An axial, nonenhanced CT scan through the mid-convexity of brain demonstrates features of overshunting. This patient has become symptomatic in the interim from the first scan (A). Ventricle size has become slitlike, indicating overdrainage.

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Figure 2-41. A, Ventriculomegaly. An axial, nonenhanced, CT scan through the mid-convexity of brain demonstrates lateral ventricular size that is at the upper limits of normal but not clearly enlarged for chronologic age. Subtle change in lateral ventricular size is often difficult to appreciate when examining the bodies of the lateral ventricles. But examination of the temporal horn size is often more revealing for early ventricular enlargement (B). B, Ventriculomegaly. An axial, nonenhanced, CT scan through the temporal horns in the low convexity of brain demonstrates unequivocal enlargement of the temporal horn size compared to anticipated normal size for age. Temporal horn size increases are more easily appreciated when detecting early hydrocephalus in middle age and younger patients. It is less effective in elderly patients where temporal atrophy may coexist. The ventriculomegaly in this case is related to a previous subarachnoid hemorrhage and secondary external hydrocephalus. C, Ventriculomegaly. An axial, nonenhanced, CT scan through the high convexity of brain demonstrates the additional feature of early hydrocephalus of sulcal.

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Figure 2-42. Intracranial hypotension. This midline, sagittal, nonenhanced, T1-weighted MR image demonstrates tonsillar herniation (arrow) related to intracranial hypotension produced by over drainage through an implanted lumboperitoneal subarachnoid shunt. Low tonsillar position combined with dural enhancement are the main features of intracranial hypotension.

Abnormalities related to surgical intervention also create tumor mimics. Surgical resection commonly produces a thin rim of enhancement in the tumor bed and regional dural structures; occasionally this may appear somewhat nodular. The distinguishing feature of the surgically altered tumor bed is the presence of a thin rim of hemosiderin evident on the T2-weighted images. We call these findings “bovey tracks” (from the name of the commonly used electrocautery unit). Occasionally, patients exhibit reactive ventricular marginal changes to the catheters inserted for chemotherapy (i.e., an idiopathic reactive ventriculitis). These changes are quite dramatic. Ventricular shunting produces a generalized dural thickening with abnormal enhancement that can mimic dural implantation by tumor. This is probably related to chronic intracranial hypotension created by the ventricular drainage. It is contrasted to the more nodular dural thickening found in dural tumor implants. Delayed effects of radiation surgery or stereotactic radiation therapy add additional considerations to the tumefactive list including subacute radiation effects, chronic radiation-induced necrosis (see Fig. 2-13A), and rarely telangiectasis or radiation-induced tumor formation. Radiation necrosis can be distinguished by the presence of focal enhancement confined to the zone of radiation and hemosiderin deposition. Radiation necrosis typically reveals reduced uptake on both thallium-enhanced single-photon

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emission CT (SPECT) and positron emission tomography imaging, while persistent tumor generally exhibits increased uptake. Radiation-induced telangiectasia results in multicentric deposition of hemosiderin (evident on MRI) and simulates cryptic vascular lesions. In patients who have received both intrathecal chemotherapy and radiotherapy, the possibility of progressive necrotizing leukoencephalopathy also exists. This necrotizing vasculopathy causes destructive, multicentric necrosis of the brain, mainly in the white matter. It is generally associated with whole brain irradiation. Other less common events can occur associated with some chemotherapeutic agents (i.e., tacrolimus and cyclosporin). These patients exhibit capillary zone infarctions, usually in the parietal-occipital artery territories, which are probably related to elaboration of thromboxane associated with a regional vasculopathy (“capillary leak”). Additional imaging observations essential for distinguishing a nontumoral mass from a recurrent tumor include lack of progression or improvement following in the absence of radiation therapy or chemotherapy on serial studies. MRI has the advantage of distinguishing blood products from other substances thus obviating the confusion with occult trauma, and hemorrhagic infarction. This is important because hemorrhagic cerebral metastases, or hemorrhage within primary tumors, are uncommon in children and the presence of a hemorrhage would therefore suggest other histologically benign etiologies such as arteriovenous malformation. CT plays an important role in defining and distinguishing extra-axial disease, especially those entities involving the skull base, orbits, and cranial nerves. Thin section CT adds imaging value whenever evidence of bone (skull or skull base) destruction is being considered. Direct extension of a primary tumor to bone is rare. The presence of a mass with both brain and bone involvement widens the differential diagnosis to include lesions metastatic to bone and dura, as neuroblastoma, histiocytosis, or hemangiopericytoma. CT is also helpful in confirming the presence of paranasal sinus or otomastoid inflammatory disease, and thereby supports a diagnosis of chronic empyema. Neither CT nor MRI has been particularly reliable in distinguishing intra-axial inflammatory lesions from tumors. This has prompted the adjunctive use of thallium-SPECT imaging. Providing that the intravascular thallium can find access to the brain (usually through sites of blood-brain barrier disruption or areas of gadolinium enhancement), it can then be metabolized by tumors but not by inflammatory processes. Thallium positivity is consistent with the presence of residual tumor, or the onset of immune-suppression– related tumors, such as primary cerebral lymphoma. Thallium negativity is generally indicative of radiation necrosis or inflammatory lesions of the brain (i.e., progressive multifocal leukodystrophy) (Fig. 2-43).

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C D Figure 2-43. A, Tumefactive lesion (focal multiple sclerosis). An axial, gadolinium-enhanced, T1weighted MR section through the posterior fossa demonstrates a focal nodular enhancing mass (arrow) in the low part of the right cerebellar hemisphere. Whenever masses are identified both tumor and tumefactive (nonneoplastic) masses must be considered, which, in this case, proved to be an active plaque of multiple sclerosis with marginal enhancement. B, Tumefactive lesion (pontine myelinolysis). Sagittal, nonenhanced, T1-weighted MR image through the pons demonstrates a hypodense lesion (*) simulating a pontine glioma. Etiology, however, is that of acute pontine myelinolysis. C, Tumefactive lesion (cortical heterotopia). An axial, nonenhanced, CT scan through the high convexity of brain demonstrates an additional tumefactive lesion. There is a focal gray matter hypodensity (arrow) on the left side, which, on biopsy, was found to be an area of cortical heterotopia. D, Tumefactive lesion (resolving intra axial hematoma). An axial, nonenhanced, CT scan through the mid-convexity of brain demonstrates a mass lesion in the right frontal region (arrow) that has the appearance of a metastatic focus, because of its ring enhancement. Ring enhancement, however, is nonspecific and in this instance is related to reaction surrounding a resolving intra-axial hematoma.

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Dyshistiogenesis Certain lesions, especially the neurocutaneous syndromes, are associated with what can be described as, for lack of a better term, dyshistiogenesis. These changes take two forms. The first is an increased T2 signal occurring mainly within the basal ganglia, pons, and deep cerebellar nuclei, and are most evident in neurofibromatosis type 1 (NF-1). They do not exhibit evidence of mass effect. There are other lesions in NF-1 commonly seen in the medulla, which have mass effect but little signal alteration. Their cause remains unknown. The T2-hyperintense lesions are most evident in childhood and diminish or resolve later in childhood or adolescence. The other form of dyshistiogenesis is associated with neurocutaneous syndromes involving melanin concentrations (or neurocutaneous melanosis). These syndromes cause signal changes in the brain (mainly T1 hyperintensity), but are significantly more rare. The presence of dyshistiogenetic changes is useful in confirming the presence of a genetic based disease as NF-1. Focal masses in patients with neurocutaneous syndromes are likely to represent specific cell types that exhibit reasonably predictable biologic behavior (Fig. 2-44).

Figure 2-44. Dyshistiogenesis in neurofibromatosis type 1 (NF1). An axial, T2-weighted, spin-echo, MR image through the mid convexity of brain demonstrates multicentric areas of abnormality consisting of bright signal (arrows) seen on T2weighted images in the basal ganglia in the context of NF1. This abnormality is consistent with the intracellular cystic changes seen in NF1. This process is self-limited and usually resolves by the age of 12. It is a common MR finding in NF1 and does not evolve or represent infiltrative tumor.

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Tumefactive Lesions of Vascular Nature The most common vascular masses simulating tumors include venous and cavernous angiomata and giant aneuryms, especially when they are partially thrombosed. Cavernous and venous angiomas are separate and distinct entities but often occur in conjunction with each other. Venous angiomas are misnamed and in fact represent anomalies of venous drainage rather than actual masses. They seldom cause significant clinical deficit. Cavernous angiomata, however, are vascular malformations of capillary formation that lack vessels with muscular walls as well as arterial or venous components. They may be multicentric or unicentric. When they present clinically, symptoms are usually the result of internal thrombosis and expansion. They have a hemosiderin-containing pseudocapsule that is evident on MRI and represents a major diagnostic feature. Occasionally, these lesions actually hemorrhage outside the pseudocapsule into the adjacent neuropil. Although occurring infrequently, giant aneurysms occur spontaneously in both adults and children. Large saccular aneurysms are most commonly seen arising from the ophthalmic, cavernous, or internal carotid artery bifurcation region of the carotid arteries. Most giant aneurysms in the posterior fossa arise from the basilar tip. Large fusiform aneurysms are likely to be the result of dissection of the parent artery, occurring spontaneously or following a known traumatic event. Not all aneurysms are arterial; some are associated with arteriovenous malformations (AVMs), most often of dural type with aneurysms forming in the venous system. Brain AVMs that drain into the deep venous system, most notably the vein of Galen, can also form large venous aneurysms. The preoperative exclusion of a giant aneurysm is important to avoid biopsy of such a lesion. Aneurysms cause variable degrees of turbulence and distortions of flow. This can create a variety of appearances on imaging, especially on MRI, where flow-related enhancement and turbulence-related signal dropout can simulate masses with heterogeneous signals. In these circumstances, the actual diagnosis can usually be confirmed with either MRA, or CT angiography. The advent of spiral image techniques has substantially improved the reliability and clarity of CT angiography. Both are essentially noninvasive procedures capable of excluding vascular causes of mass lesions (Fig. 2-45).

Tumors Masquerading as Other Lesions Most brain tumors are centered in white matter and grow along white matter tracts. In adults, some gliomas, mainly oligodendrogliomas, have a gray matter epicenter with secondary white matter involvement. When such lesions lack nodular enhancement, they can easily mimic strokes on standard imaging. We expect that spectroscopy will make

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Figure 2-45. A–C, Tumefactive lesion (giant intrasellar carotid aneurysm). A, An axial, nonenhanced, CT scan through the low convexity of brain and sellar area demonstrates abnormal enhancement within the sella (*). Pituitary adenoma is included in the differential diagnosis but intrasellar giant aneurysm must always be excluded. B, An axial, gadolinium-enhanced, T1weighted MR scan through the sella demonstrates MR features of a hypodense mass within the sella, plus pulsation artifact creating the bright linear densities (arrows) overlying the mesencephalon and vermis. This pulsation artifact is a clue that the mass is indeed vascular in nature. C, Digital, cerebral angiography in this case demonstrates a large aneurysm (arrow) arising from the left carotid artery projecting medially into the sella. Exclusion of aneurysm is essential in evaluation of any enhancing sellar or parasellar masses.

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B Figure 2-46. A, Tumor simulating a stroke. An axial, nonenhanced, T1-weighted MR scan through the mid-convexity of brain demonstrates an area of subtle hypodensity (arrow) in the caudal aspect of the insula, which corresponds to the posterior division of the right middle cerebral artery. These findings are consistent with stroke. However, with every stroke there always remains a possibility of an underlying brain tumor simulating a stroke, as in this case. Those tumors most likely to be confused with strokes include primary cerebral lymphoma, angiocentric lymphoma, and oligodendroglioma. All of these tumors can primarily involve the gray matter rather than an underlying white matter, which accounts for the confusion. Patients with apparent stroke often present with seizures rather than typical stroke symptoms and, if the diagnosis is not clear, the patient needs to be rescanned after 6 to 8 weeks. Persistence of the abnormality at that time may indicate biopsy. B, Tumor simulating a stroke. An axial, T2-weighted, spin-echo MR scan through the mid convexity of brain on a follow-up examination after 6 weeks demonstrates that the lesion has both persisted and minimally increased in size rather than evolve to a post-infarct status. This course is indicative of a brain tumor (arrow).

inroads in this delineation, but experience is limited (Figs. 2-46, 2-47). Predicting the Biologic Behavior of Tumors Once the biopsy provides evidence of an underlying tumor, imaging features can then be combined with pathologic features to predict biologic activity. Pathology may be limited if selection-sampling bias of the biopsy-sampled tissue results in it not being reflective of the most aggressive cell line. Additionally, many tumors demonstrate poor to limited correlation between their respective cytologic appearance and their biologic or clinical behavior. The following section addresses those imaging features that help predict likely clinical aggressiveness of a tumor. Features Suggesting a Less Aggressive Neoplasm. Low-grade,

true neoplasms tend to occur in children and adolescents rather than in infants. These are true neoplasms and can

exhibit malignant behavior. Lesions that are somewhat unique to children include mixed ganglion-glial cell gangliogliomas, pilocytic astrocytomas, desmoplastic astrocytomas, and pleomorphic xanthoastrocytomas. Geneticbased neoplasia also begins to occur in children and adolescents. These are lesions associated with neurocutaneous syndromes, especially tuberous sclerosis, von HippelLindau, and neurofibromatosis types 1 and 2. The features typical of lower grade neoplasms include slow growth potential on serial imaging; masses containing nonenhancing cysts often with a mural nodule; and no tumoral necrosis or tumor growth away from the epicenter. Importantly, there is concordance between the tumor size on both T1 and T2 images (Fig. 2-48). Features Suggesting a More Aggressive Neoplasm. Higher grade primary neoplasms tend to occur primarily in infants, younger children, and then later in life. In older children they

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B B Figure 2-47. A, Tumor presenting as hypertensive hemorrhage (melanoma metastasis). An axial, nonenhanced, CT scan through the mid-convexity of brain demonstrates a focal parenchymal hematoma within the left thalamus and a small amount of intraventricular blood. In older patients, as indicated by the agerelated brain atrophy, most intra-axial hemorrhages away from the circle of Willis are seldom related to aneurysm or vascular malformation but more often small vessel vasculopathy of amyloid angiopathy or hypertension. Again, as with brain stroke, tumor must also be considered in cases of focal hematoma. B, Tumor presenting as hypertensive hemorrhage (melanoma metastasis). Follow-up axial, contrast-enhanced CT scan through the mid-convexity of brain demonstrates how the solid hematoma has evolved to mass with a peripheral enhancing ring and a mural nodule (arrow) consistent with a metastatic tumor focus. These findings were related to metastatic melanoma, a common tumor presenting with brain hemorrhage.

Figure 2-48. A, Low-grade brain tumor. An axial, gadoliniumenhanced, MR image through the high convexity of brain demonstrates features of a relatively noninvasive low-grade brain neoplasm. There is no abnormal contrast enhancement within the microcystic (low intensity) mass (arrow) seen in this right, high convexity, lateral cortex. Most importantly, there is concordance between the margins of the mass on the T1 images compared with the T2 images. B, Low-grade brain tumor. An axial, T2-weighted, spin-echo MR image through the high convexity of brain demonstrates features of a low-grade, low-aggressive type of tumor. Findings illustrated include hyperintense T2 changes that closely match the margins on T1 imaging, with no evidence of subependymal or subpial extension of tumor and with no intratumoral necrosis. Lack of enhancement is also evident and supportive of a low-grade lesion, but intratumoral enhancement is not a reliable indicator of tumor aggressiveness.

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usually occur as anaplastic transformation of lower grade tumors. Metastatic tumor occurs in all age groups, but tends to be seen in older patients. The features that suggest a higher grade tumor include growth on serial imaging, tumor necrosis, T1 and T2 spatial discordance, evidence of subpial or subependymal extension, and increased efferent venous drainage away from the epicenter of the tumor (related to angioneogenesis). There are proposed anatomic reasons why aggressive tumors extend into the subependymal and subpial spaces. Tumor extension in most cases is oriented along fiber pathways; nodular tumor growth occurs in areas of high dendritic concentration. It is suggested that the dendritic concentration is lower in the subpial zone beneath the basement membrane of the pia. Similar reasons for growth are suggested for the subependymal region. Subependymal growth along the third ventricle is common

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in germinoma and lymphoma. Other features of aggressive tumors include invasion of dura, satellitosis, and the most obvious are “drop metastases” with seeding of distant portions of intracranial or intrathecal CSF-filled spaces. Additional risk factors for brain tumor formation include immunosuppression (with resultant lymphoma) and prior cranial radiation. Patients with a history of cranial radiation for any reason have a substantial increased likelihood of development of another intracranial tumor, often brain sarcoma (Figs. 2-49, 2-50). Post-treatment Imaging. Post-treatment imaging is critical to correctly determine follow-up therapy and to correctly assess patients enrolled in treatment protocols.94,95 The success, or relative success, of the therapeutic regimen is monitored in part by MRI or occasionally by CT. The greatest problem

B A Figure 2-49. High-grade (primary) brain tumor. A, Coronal, gadolinium-enhanced, T1-weighted MR image through the parietal occipital junction region of brain demonstrates features of a high-grade, highly infiltrative brain tumor. There is dense contrast enhancement in the epicenter (*) of the mass but also enhancement in brain adjacent to the apparent mass (arrow) and in the subpial region (arrows) well away from the primary lesion. Subependymal spread was seen on other images. There is obvious discordance between the T1 image (this image) and the T2 image (B), indicating tumor infiltration. B, An axial, T2-weighted, FLAIR scan through the mid-convexity of brain demonstrates discordance between the enhancing mass (seen in A) and the overall zone of peritumoral edema.

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B A Figure 2-50. A, Metastatic brain tumor. Coronal, gadolinium-enhanced, T1-weighted MR image through the occipital polar region of brain demonstrates an intra-axial neoplasm with marginal enhancement, central necrosis and dural involvement. These are always features of a high-grade neoplasm, either of primary or secondary type. B, Highly aggressive (metastatic) brain tumor. An axial, T2-weighted, spin-echo MR image through the low convexity of brain demonstrates unusual hypodensity within the mass itself. There is hyperintense peritumoral edema. Hypodensity within the mass is suggestive of a metastatic lesion of colon (as occurred in this patient) because of intratumoral mucin production, which reduces the T2 signal.

arises because of insufficient baseline information. Thus, as a routine, we obtain a postoperative MRI with contrast enhancement as soon as the patient is able to tolerate the procedure, generally within the first postoperative week. In doing so, we establish a functional baseline with which we can compare later developments. The goal of subsequent imaging is to define the presence or absence of residual disease; establish which changes are related to surgery, including those associated with ventricular shunting; and to identify recurrent tumor when and if it occurs. The following discussion focuses on the usual and the untoward consequences of therapy. Postoperative Changes. Following brain resection, a variety

of changes are commonly observed.96,97 The most obvious of these is an encephalomalacic defect. The second is evidence of the surgical excision and bipolar coagulation of bleeding sites within the tumor bed. Postoperative findings include linear, non-nodular contrast enhancement conforming to the margins of the encephalomalacic cavity in the same areas as hypodense susceptibility artifact related to hemosiderin

deposition on T2-weighted images. Persistent tumor generally appears more nodular and appears hyperintense on T2-weighted sequences. Occasionally, persistent operative material, such as Gelfoam, may be intentionally left in the operative site. In some cases, this can be misconstrued on repeat imaging as a persistent mass or herniation. The next surgically related abnormality is dural thickening and enhancement associated with the presence of an indwelling ventricular-peritoneal (VP) shunt catheter. The dural changes may be regional, near the entrance of the shunt, but more often are widespread. Benign dural thickening is not nodular and generally measures in the 1- to 3mm range of thickness. VP shunts also alter ventricular size. The shunt typically will reduce the volume of the ipsilateral lateral ventricle more so than the contralateral side. This ventricular asymmetry can cause diagnostic concern at times. VP shunts can infrequently induce an untoward reaction within the ventricular cavity, presumably thought to be a hypersensitivity response to the catheter material. This hypersensitivity response produces an inflammatory ventriculitis that can easily be confused with tumor seeding.

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Loculation (or sequestration) produced by ventricular inflammation and cicatrix formation can create cystic appearing spaces also simulating tumor. A third postoperative change that can occur is unexpected postoperative hemorrhage occurring away from the site of surgical intervention. This, in our experience, often occurs in the cerebellum. In all likelihood, it is related to transient hypertension sometime in the perioperative period. This is an uncommon occurrence, but must be considered when any neurosurgical patient fails to wake in the anticipated period (Fig. 2-51). Postradiation Effects. Radiation therapy is commonly used

to control brain tumors. The imaging manifestations vary according to time and dose. The most common anticipated manifestations include mucositis within the paranasal sinuses and mastoid air cells, and fat-replaced marrow space. There are subacute changes in the neuroaxis, which often occur following stereotactic radiation therapy or radiation

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surgery. In the vicinity near these areas of concentrated radiation doses, T2 hyperintensity commonly occurs. These changes generally resolve over 1 to 2 years. Full neuroaxis radiation, on the other hand, elicits little acute or subacute change. Mild diffuse brain atrophy and chronic ischemic demyelination similar to that of arteriosclerosis may develop in patients receiving whole brain or whole neuroaxis irradiation (usually longer than 6 months). Radiation dosage that exceeds neural tolerance can produce other untoward effects including radiation necrosis, progressive necrotizing leukoencephalopathy (usually seen in conjunction with chemotherapy), and radiationinduced second primary tumor formation (usually brain/dural sarcoma). The appearance of radiation necrosis on MRI and CT studies can closely mimic a residual or recurrent tumor. As a consequence, we have resorted to thallium-SPECT studies to help differentiate the two. Radiation necrosis is thallium-negative, while recurrent tumor is generally thallium-positive. As the technology evolves, it is

B Figure 2-51. A, Postoperative changes simulating pathology. Sagittal, nonenhanced, T1-weighted MR image through the foramen magnum region demonstrates pseudotonsillar herniation. During a suboccipital craniotomy, Gelfoam was applied over the dural closure. This material can, as in this instance, take on the appearance of cerebellar tonsils, which have been downwardly displaced (arrow). Closer inspection reveals a normal tonsillar position (*). The craniotomy in this instance was performed to remove a mesencephalic cavernous angioma. B, Postoperative unexpected cerebellar hemorrhage. An axial, nonenhanced CT scan through the posterior fossa demonstrates evidence of a spontaneous hemorrhage into the left cerebellar hemisphere (*) following a recent anterior temporal lobectomy. Exact etiology for such a cerebellar hemorrhage is not clear, but presumably is related to transient acute hypertension.

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Figure 2-52. Radiation necrosis. Coronal, gadolinium-enhanced, T1-weighted MR image through the posterior temporal lobe region demonstrates nodular-appearing enhancement mesial aspect of the temporal lobe (*). Despite its mass-like appearance, which simulates residual tumor, this mass corresponds to a previous radiation field and represents the MR changes of radiation necrosis. In cases where treatment was originally performed for anaplastic tumor, it is likely that residual tumor cells will remain on repeat biopsy, even when most of the changes are related to radiation necrosis. MR spectroscopy and thallium-SPECT help differentiate whether such findings are dominantly related to recurrent tumor or predominantly to radiation necrosis.

likely that MR perfusion imaging will play a role in this diagnosis as well (Fig. 2-52). Postchemotherapeutic Complications. The onset of progres-

sive necrotizing leukoencephalopathy is characterized on MRI and CT as multicentric areas of contrast enhancement that are scattered throughout cerebral white matter in a somewhat random manner. They do not necessarily correspond anatomically with the site of the primary tumor or the region of maximal radiation therapy. The findings may be more intense along the tract of the Omaya reservoir catheter, presumably because of a higher concentration of the chemotherapeutic agent.

Recently, there have been brain changes associated with the use of particular chemotherapeutic agents that have been delivered not by an intrathecal route but intravenously. These agents can infrequently produce a zone of infarction in deep capillary beds. For the most part, these have occurred in the parieto-occipital regions and produced visual loss. The mechanism is presumed to be related to a regional vasculopathy causing elaboration of intrinsic thromboxane. The thromboxane results in localized vasospasm and accelerated clotting, hence the capillary zone infarctions (Fig. 2-53).

Figure 2-53. Reversible neurotoxicity (immune-suppression drug effect). An axial, T2-weighted FLAIR scan through the low convexity of brain demonstrates bilateral occipital region cerebral edema (arrows). The posterior distribution, the mainly white matter involvement, and the bilaterality are typical of reversible vasogenic edema associated with acute hypertension or (as in this case) exposure to immunosuppressive drugs.

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P earls 1. Fundamental to providing adequate sectional imaging is access to sufficient clinical information to appropriately protocol the examination. No single test fits all, and not all patients can undergo all varieties of imaging studies. 2. T1 hyperintensity (compared to isointense normal brain) will appear “brighter” (approaching a shade toward white) and implies the presence of substances that naturally exhibit rapid proton relaxation (a more rapid return to baseline), such as structures with high lipid content. 3. T1 hypointensity (compared to normal brain signal), is displayed as a darker shade of gray, and indicates that tissue in these voxels are not like fat but are either rigidly bound (an anisotrophic effect), as seen in fibrosis or matrix calcification, or are virtually unbound (an isotropic effect), as seen in edema, necrosis, or cyst formation. 4. Tissues that possess more unbound water molecules (like CSF or tissue edema) will preserve phase coherence longer, which translates into slower T2 rate, and a brighter signal or T2 hyperintensity. 5. Any intervening motion of the patient during the image acquisition process actually changes the phase data, which ultimately misrepresents the data when the final mathematical transform is applied. This can create both anatomic and intensity misregistration. Data misregistration means anatomic structures will be placed where they do not exist and intensity misinformation will appear abnormally (spurious pathology). MRI is not like CT scanning where the consequence of motion is merely an unsharp or fuzzy image.

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6. The high magnetic susceptibility of any iron containing metal object means that it is affected by the main magnetic field and can torque. If the metal were securely fastened, such motion effects would be insignificant. If, on the other hand, the object is moveable, as it might be with an aneurysm clip, then the torque effect might be disastrous. 7. The major advantage of using a nonionic contrast medium is that it causes less tissue injury if it is inadvertently extravasated during IV injection. 8. Helical scanning combined with dynamic contrast infusion can be exploited to produce a timeconcentration data set. By comparing the CT density curves over time in similar regions of brain, a graph of the contrast medium concentration can be created, which in turn reflects intravascular perfusion. By comparing like-areas in the one hemisphere with comparable regions in the opposite hemisphere, a relative brain perfusion analysis can be obtained. 9. The features typical of lower grade neoplasms include slow growth potential on serial imaging; masses containing nonenhancing cysts often with a mural nodule; and no tumoral necrosis or tumor growth away from the epicenter. Importantly, there is concordance between the tumor size on both T1 and T2 images. 10. The features that suggest a higher grade tumor include growth on serial imaging, tumor necrosis, T1 and T2 spatial discordance, evidence of subpial or subependymal extension, and increase efferent venous drainage away from the epicenter of the tumor (related to angioneogenesis).

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32. Coo D, Van De Kerckhove T, De Reuck J, Caemaert J, Kunnen M: Singlevoxel proton MR spectroscopy and positron emission tomography for lateralization of refractory temporal lobe epilepsy. Am J Neuroradiol 1998;19:1–8. 33. DeLano MC, Cooper TG, Siebert JT, Potchen MJ, Kuppusamy K: High-b-value diffusion-weighted MR imaging of adult brain—Image contrast and apparent diffusion coefficient map features. Am J Neuroradiol 2000;21:1830–1836. 34. Filippi CG, Ulu AM, Ryan E, Ferrando SJ, van Gorp W: Diffusion tensor imaging of patients with HIV and normal-appearing white matter on MR images of the brain. Am J Neuroradiol 2001;22:277– 283. 35. Haseler LJ, Sibbitt WL, Mojtahedzadeh HN Jr, Reddy S, Agarwal VP, McCarthy DM: Proton MR spectroscopic measurement of neurometabolites in hepatic encephalopathy during oral lactulose therapy. Am J Neuroradiol 1998;19:1681–1686. 36. Itoh R, Melhem ER, Folkers PJM: Diffusion-tensor MR imaging of the human brain with gradient- and spin-echo readout—Technical note. Am J Neuroradiol 2000;21:1591–1595. 37. Kadota T, Horinouchi T, Kuroda C: Development and aging of the cerebrum—Assessment with proton MR spectroscopy, Am J Neuroradiol 2001;22:128–135. 38. Krouwer HG, Kim TA, Rand SD, et al: Single-voxel proton MR spectroscopy of nonneoplastic brain lesions suggestive of a neoplasm. Am J Neuroradiol 1998;19:1695–1703. 39. Melhem ER, Itoh R, Jones L, Barker PB: Diffusion tensor mr imaging of the brain—Effect of diffusion weighting on trace and anisotropy measurements. Am J Neuroradiol 2000;21:1813–1820. 40. Pavlakis SG, Lu D, Frank Y, Wiznia A, Eidelberg D, Barnett T, Hyman RA: Brain lactate and N-acetylaspartate in pediatric AIDS encephalopathy. Am J Neuroradiol 1998;19:383–385. 41. Sinson G, Bagley LJ, Cecil KM, et al: Magnetization transfer imaging and proton MR spectroscopy in the evaluation of axonal injury—Correlation with clinical outcome after traumatic brain injury. Am J Neuroradiol 2001;22:143–151. 42. Amano Y, Amano M, Kumazaki T: Normal contrast enhancement of the extraocular muscles—Fat-suppressed MR findings. Am J Neuroradiol 1997;18:161–164. 43. Bhadelia RA, Bogdan AR, Wolpert SM: Analysis of cerebrospinal fluid flow waveforms with gated phase–contrast MR velocity measurements. Am J Neuroradiol 1995;16:389–400. 44. Beer GJ: Biological effects of weak electromagnetic fields from 0 hz to 200 mhz—A survey of the literature with special emphasis on possible magnetic resonance effects. Magn Reson Imaging 1989;7: 309–331. 45. Colletti PM, Sylvestre PB: Magnetic resonance imaging in pregnancy. Magn Reson Imaging Clin North Am 1994;2:291–307. 46. Heinrichs WL, Fong F, Flannery M, et al: Midgestational exposure of pregnant BALBIC mice to magnetic resonance imaging conditions. Magn Reson Imaging 1988;6:305–313. 47. Kanal E: An overview of electromagnetic safety considerations associated with magnetic resonance imaging. Ann NY Acad Sci 1992; 649:20424. 48. Kanal E: Pregnancy and the safety of magnetic resonance imaging. Magn Reson Imaging Clin North Am 1994;2:309–317. 49. Shellock FG, Kanal F: Magnetic Resonance Bioeffects, Safety, and Patient Management. Philadelphia, Lippincott Williams & Wilkins, 1996. 50. Salvolini U, Provinciali L, Signorino M: Functional effects of contrast media on the brain. Am J Neuroradiol 2001;22:229. 51. Shehock PG: Biological effects and safety aspects of magnetic resonance imaging. Magn Reson Imaging 1989;5:243–261. 52. Quisling RG, Peters K: Computed tomography. In Youmans, ed: Neurological Surgery, 2nd ed, part 2. Philadelphia, Saunders, 1996, pp. 93–147.

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Chapter 2  53. Alberaico RA, Patel M, Casey S, Jacobs B, Maguire W, Decker R: Evaluation of the circle of Willis with three-dimensional CT angiography in patients with suspected intracranial aneurysms. Am J Neuroradiol 1995;16:216–217. 54. Brink JA, Heiken JP, Wang G, McEnery KW, Schlueter FJ, Vannier MW: Helical CT: Principles and technical considerations. Radiographics 1994:887–893. 55. Dillon WP, Fishman RA: Some lessons learned about the diagnosis and treatment of spontaneous intracranial hypotension. Am J Neuroradiol 1998;19:1001b–1002b. 56. Laine FJ, Shedden AI, Dunn MM, Ghataki NR: Acquired intracranial herniations—MR imaging findings. AJR 1995;165:967–973. 57. Messori A, Polonara G, Salvolini U: Dilation of cervical epidural veins in intracranial hypotension. Am J Neuroradiol 2001;22:224–225. 58. Rabin BM, Roychowdhury S, Meyer JR, Cohen BA, LaPat KD, Russell EJ: Spontaneous intracranial hypotension—Spinal MR findings. Am J Neuroradiol 1998;19:1034–1039. 59. Quisling RG, Lotz P: Correlative Neuroradiology. Baltimore, Williams and Wilkins, 1985. 60. Augustin M, Bammer R, Simbrunner J, Stollberger R, Hartung HP, Fazekas F: Diffusion-weighted imaging of patients with subacute cerebral ischemia—Comparison with conventional and contrast-enhanced MR imaging. Am J Neuroradiol 2000;21:1596–1602. 61. Bryan RN: Diffusion-weighted imaging of stroke—A brief follow-up. Am J Neuroradiol 1998;19:1003–1004. 62. Chong J, Lu D, Aragao F, et al: Diffusion-weighted MR of acute cerebral infarction—Comparison of data processing methods. Am J Neuroradiol 1998;19:1733–1739. 63. Ducreux D, Oppenheim C, Vandamme X, et al: Diffusion-weighted imaging patterns of brain damage associated with cerebral venous thrombosis. Am J Neuroradiol 2001;22:261–268. 64. Karonen JO, Partanen PLK, Vanninen R, Vainio PA, Aronen HJ: Evolution of MR contrast enhancement patterns during the first week after acute ischemic stroke. Am J Neuroradiol 2001;22:103–111. 65. Lovblad KO, Jakob PM, Chen Q, et al: Turbo spin-echo diffusionweighted MR of ischemic stroke. Am J Neuroradiol 1998;19:201–208. 66. Meyer JR, Gutierrez A, Mock B, et al: High-b-value diffusion-weighted MR imaging of suspected brain infarction. Am J Neuroradiol 2000;21:1821–1829. 67. Rumpel H, Ferrini B, Martin E: Lasting cytotoxic edema as an indicator of irreversible brain damage—A case of neonatal stroke. Am J Neuroradiol 1998;19:1636–1638. 68. Coskun A, Lequin M, Segal M, Vigneron DB, Ferriero DM, Barkovich AJ: Quantitative analysis of MR images in asphyxiated neonates—Correlation with neurodevelopmental outcome. Am J Neuroradiol 2001;22:400–405. 69. Barkovich AJ, Ali FA, Rowley HA, Bass N: Imaging patterns of neonatal hypoglycemia. Am J Neuroradiol 1998;19:523–528. 70. Bryan RN: Diffusion-weighted imaging—To treat or not to treat? That is the question. Am J Neuroradiol 1998;19:396–397. 71. Dubowitz DJ, Blum S, Arcinue E, Dietrich RB: MR of hypoxic encephalopathy in children after near drowning—Correlation with quantitative proton MR spectroscopy and clinical outcome. Am J Neuroradiol 1998;19:1617–1627. 72. Falini A, Barkovich AJ, Calabrese G, Origgi D, Triulzi F, Scotti G: Progressive brain failure after diffuse hypoxic ischemic brain injury—A serial MR and proton MR spectroscopic study. Am J Neuroradiol 1998;19:648–652. 73. Atlas SW, Thulborn KR: MR detection of hyperacute parenchymal hemorrhage of the brain. Am J Neuroradiol 1998;19:1471–1477. 74. Horowitz M, Kondziolka D: Multiple familial cavernous malformations evaluated over three generations with MR. Am J Neuroradiol 1995;16:1353–1355. 75. Levy RA, Allen R, McKeever P: Pleomorphic xanthoastrocytoma presenting with massive intracranial hemorrhage. Am J Neuroradiol 1996;17:154 –156.

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76. Offenbacher H, Fazekas F, Schmidt R, Koch M, Fazekas G, Kapeller P: MR of cerebral abnormalities concomitant with primary intracerebral hematomas. Am J Neuroradiol 1996;17:573–578. 77. Berry I, Osaki L, Brasch R, et al: Gd-DTPA in clinical MR of the brain— Intra-axial lesions. Am J Radiol 1986;147:1223–1230. 78. Bowen BC: Proton MR spectroscopy and the ring-enhancing lesion. Am J Neuroradiol 1998;19:589–590. 79. Brant-Zawadzki M, Badami P, Mills CM, Norman D, Newton TH: Primary intracranial tumor imaging: A comparison of magnetic resonance and CT. Radiology 1984;150:435–440. 80. Brown MS, Stemmer SM, Simon JH, et al: White matter disease induced by high-dose chemotherapy—Longitudinal study with MR imaging and proton spectroscopy. Am J Neuroradiol 1998;19:217–221. 81. Castillo M, Smith JK, Kwock L, Wilber K: Apparent diffusion coefficients in the evaluation of high-grade cerebral gliomas. Am J Neuroradiol 2001;22:60–64. 82. Castillo M, Smith JK, Kwock L: Correlation of myo-inositol levels and grading of cerebral astrocytomas. Am J Neuroradiol 2000;21:1645– 1649. 83. Dean B, Drayer B, Bird C, et al: Gliomas—Classification with MR imaging. Radiology 1990;174:411– 415. 84. Gideon P, Sorensen PS, Thomsen C, Stahlberg F, Gjerris F, Henriksen O: Increased brain water self-diffusion in patients with idiopathic intracranial hypertension. Am J Neuroradiol 1995;16:381–387. 85. Hwang JH, Egnaczyk GF, Ballard E, Dunn RS, Holland SK, Ball WS Jr: Proton MR spectroscopic characteristics of pediatric pilocytic astrocytomas. Am J Neuroradiol 1998;19:535–540. 86. Iwana T, Yamada H, Era S, et al: Proton nuclear magnetic resonance studies on water structure in peritumoral edematous brain tissue. Magn Reson Med 1992;24:53–63. 87. Krouwer HG, Kim TA, Rand SD, et al: Single-voxel proton MR spectroscopy of nonneoplastic brain lesions suggestive of a neoplasm. Am J Neuroradiol 1998;19:1695–1703. 88. Maheshwari SR, Mukherji SK, Neelon B, et al: The choline/creatine ratio in five benign neoplasms—Comparison with squamous cell carcinoma by use of in vitro MR spectroscopy. Am J Neuroradiol 2000;21:1930–1935. 89. Medina LS, Zurakowski D, Strife KR, Robertson RL, Poussaint TY, Barnes PD: Efficacy of fast screening MR in children and adolescents with suspected intracranial tumors. Am J Neuroradiol 1998;19: 529–534. 90. Poptani RK, Gupta, RR, R Pandey, Jain VK, Chhabra DK: Characterization of intracranial mass lesions with in vivo proton MR spectroscopy. Am J Neuroradiol 1995;16:1593–1603. 91. Roberts HC, Dillon WP: MR imaging of brain tumors—Toward physiologic imaging. Am J Neuroradiol 2000; 21:1570–1571. 92. Tovi M, Lilja A, Bergstrom M, et al: Delineation of gliomas with magnetic resonance imaging using Gd-DTPA in comparison with computed tomography and positron emission tomography. Acta Radiol 1990;31:417– 429. 93. Waldrop SM, Davis PC, Padgett CA, Shapiro MB, Morris R: Treatment of brain tumors in children is associated with abnormal MR spectroscopic ratios in brain tissue remote from the tumor site. Am J Neuroradiol 1998;19:963–970. 94. Cloft HJ, Matsumoto JA, Lanzino G, Cail WS: Posterior fossa hemorrhage after supratentorial surgery. Am J Neuroradiol 1997;18: 1573–1580. 95. Poussaint TY, Siffert J, Barnes PD, et al: Hemorrhagic vasculopathy after treatment of central nervous system neoplasia in childhood—Diagnosis and follow-up. Am J Neuroradiol 1995;16:693–699. 96. Gaensler EHL, Dillon WP, Edwards MSB, Larson DA, Rosenau W, Wilson CB: Radiation-induced telangiectasia in the brain simulates cryptic vscular malformation at MR imaging. Radiology 1994;193: 629–636. 97. Valk PE, Dillon WP: Radiation injury of the brain. Am J Neuroradiol 1991;12:45–62.

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Chapter 3 Introduction to Neurophysiology Dean Lin, MD, PhD, Ehud Mendel, MD, and Bernard H. Guiot, MD, FRCSC

Introduction The neuron (Fig. 3-1), embryologically derived from epithelial precursor cells, is charged with the highly specialized function of signal transmission. It contains the basic cellular organelles required to carry out cellular metabolism and maintenance. These include a cytoskeleton, a nucleus, an endoplasmic reticulum, a Golgi apparatus, mitochondria, and liposomes. The neuronal membrane is however, unique in that it contains a very high concentration of proteins embedded into its phospholipid bilayer. The proteins form specialized pores that function as either ion-specific pumps or channels. These allow for the passage of ions through the impermeable plasma membrane (Fig. 3-2). All ionic species, if allowed to pass freely through open channels, would flow across the neuronal membrane until the electrical and the chemical driving forces equilibrate. An electrical potential, specific for every ion, exists at this state of equilibrium and can be calculated using the Nernst equation.1 The net equilibrium potential for a given neuron depends on the state of the various ionic channels. Each ion channel, when open, will shift the membrane potential toward the equilibrium potential of that particular ion (ENa = +55 mV, ECl = -60 mV, and EK = -75 mV). At rest, the neuron is relatively impermeable to the passage of all ions except potassium. The charge imbalance that arises therefore produces a resting membrane potential (RMP) that approximates the equilibrium potential for potassium (RMP = -65 mV).2 When the membrane depolarizes, the sodium channels open, thereby shifting the equilibrium potential closer to that of sodium.

Most ion channels are composed of multiple protein subunits, which form a central pore. Ion channels permit the nearly instantaneous translocation of thousands of charged ions from one side of the plasma membrane to the other. A single channel can gate up to one billion ions in a second.2 Channels are generally very specific with regard to the ionic species they gate. Thus sodium channels are 10 to 20 times more specific for sodium than for potassium, despite the fact that both are monovalent cations.3 Only two broad classes of channels will be considered in this chapter, namely voltage-gated channels and ligand-gated channels. Voltagegated channels (Fig. 3-3, p. 106) are activated by a change in the transmembrane potential, which triggers a conformational change in the channel’s tertiary structure. This conformational change opens the channel’s central pore, thereby permitting a flux of ions. Common examples include voltage-gated sodium- and calcium-channels (Fig. 3-4, p. 106), which allow ions into the cell, and voltage-gated potassium channels, which cause a potassium efflux. Ligandgated channels undergo a conformational change when activated by agonist binding to the channel’s extracellular domain. These specialized channels are receptors. Their activation may be excitatory or inhibitory onto the postsynaptic neuron. The receptors play a vital role in maintaining homeostasis between the excitatory and inhibitory tone in the central nervous system (CNS); therefore, derangements in their function can lead to a number of pathologic states. Receptors can be grouped into two main categories based on the mechanism by which they implement their effects. 103

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Figure 3-1. Anatomy of a neuron. Although there are numerous neuronal morphologies, all neurons have several basic features in common that allow signal transmission. Incoming signals are received at the postsynaptic terminals of dendrites. These signals subsequently travel along dendritic trees until they arrive at the cell body. Action potentials may be formed at the axon hillock and subsequently propagate along the axons with or without the assistance of a myelin sheath, until the signal reaches the presynaptic terminal. Arrival of an action potential at the presynaptic terminal induces release of neurotransmitter into the synaptic cleft, thereby propagating the signal to another neuron.

Ionotropic Receptors

Glutamate Receptors

Activation of ligand-gated ionotropic receptors produces a conformation change, which causes the ion channel to open. Immediately, a large ionic flux occurs resulting in a small, transient alteration in the membrane potential. The direction of this change determines whether an excitatory or an inhibitory signal is conveyed. As ligand unbinds from the receptor, thereby reversing the initial opening conformational change and closing the central pore, the flow of ions ceases just as rapidly as it began. Some examples of ligandgated channels include the ionotropic glutamate receptors (N-methyl-D-aspartate [NMDA], a-amino-3-hydroxyl-5methyl-4-isoxazolepropionic acid [AMPA], and kainate), the gamma-aminobutyric acid (GABAA) receptor, glycine receptors, and nicotinic acetylcholine receptors.

AMPA and kainate receptors (Fig. 3-5) are rapidly activated by ligand binding, and thus are involved in the rapid upstroke of an excitatory postsynaptic potential. These channels primarily gate sodium and potassium, but a small percentage of AMPA receptors also gate calcium, depending on the presence or absence of the glu-R2 subunit. If this subunit is present, as it is in the vast majority of AMPA receptors, the channel is impermeable to calcium ions.4 In the receptor subset lacking the glu-R2 subunit, however, calcium is able to flow through the pore, although to a much lesser degree than is gated by NMDA receptors. NMDA receptor channels are much slower to open and close than the AMPA and kainate receptors. They are therefore responsible for the latter phases of the excitatory poten-

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Figure 3-2. Electrochemical gradients determine the flow of ions across open ion channels. Channel opening results in an ionic flux either into or out of the neuron, depending on the driving forces. The intracellular concentration of potassium ions, for example, is significantly higher than the extracellular concentration. The neuronal interior, however, is negatively charged, and subsequently the electrical potential tends to drive cations into a neuron. Opening of a potassium channel results in an efflux of potassium ions because the concentration gradient generates an electromotive force much greater than the force generated by the opposing electrical gradient. As long as the channel remains open, ions will flow until electrochemical equilibrium is achieved.

tial. Their major role is in determining intracellular calcium levels. Indeed, under physiologic conditions, NMDA receptor activation and the subsequent increase in intracellular calcium may be vital to the formation of long-term memory.2 Hyperstimulation of NMDA receptors and pathologically elevated levels of intracellular calcium, however, are believed to be key in various CNS pathologies, such as stroke and traumatic brain injury.5,6 There are several features unique to the NMDA receptor. First, binding of glutamate alone is insufficient to open the NMDA channel; the cofactor glycine must also be present and bind to the receptor concurrently to affect channel opening. Typically, the ambient glycine in the extracellular space is sufficient to activate the receptor. Another unique property of the NMDA receptor is the magnesium blockade. Even after both glutamate and glycine have bound, the NMDA receptor will remain shut at resting membrane potential because extracellular magnesium ions obstruct the pore in a voltagedependent manner. Only after the membrane has been depolarized to between -40 mV and -20 mV by AMPA and kainate receptors is the electrostatic repulsion sufficient to

expel magnesium, relieving the blockade and permitting sodium and calcium influx.4 Gamma-aminobutyric Acid and Glycine Receptors Activation of inhibitory ionotropic receptors such as GABAA and glycine receptors generates an inhibitory postsynaptic potential. GABA mainly localizes to the brain, where it serves as the primary inhibitory neurotransmitter, whereas glycine is the primary inhibitory neurotransmitter in the spinal cord. These channels gate chloride into neurons. The open chloride channels can be inhibitory in two different ways. First, a depolarized membrane is repolarized toward the chloride equilibrium potential (ECl = -60 mV) by the anion flux. Second, when a membrane is at resting potential, opening chloride channels would not hyperpolarize the membrane any further because the ECl and the resting potential are nearly equal. Instead, open chloride channels essentially short-circuit incoming excitatory postsynaptic potentials (EPSPs) by gating anions and clamping the membrane at ECl as an excitatory influx of cations attempts to

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Figure 3-3. Selectivity of voltage-gated channels. Many of the channels lining the polarized neuronal membrane are voltagesensitive, ion-specific channels. This figure shows a channel specific for potassium ions. The basis for the selectivity filter is not size alone; although sodium is a smaller monovalent cation than potassium, potassium-selective channels are many times more selective for potassium ions. A change in the membrane voltage potential induces a conformational change that causes voltage-sensitive potassium channels to open, thereby selectively gating potassium down its electrochemical gradients.

B

Metabotropic Receptors These receptors act quite slowly through intracellular second messengers. As such, they do not convey fast, discrete signals. Rather, they serve a modulatory role in neurons, regulating basal levels of excitation that last much longer than the brief inhibitory postsynaptic potentials (IPSPs) or EPSPs. Activation of metabotropic receptors rarely generates enough depolarization to result in an action potential. Although they do facilitate opening and closing of

Figure 3-4. Selectivity filter of voltage-gated channels. Cations are surrounded by a sphere of water molecules. Theoretically, the basis of the selectivity filter is active sites within the channel pore. Sodium ions traversing bind weakly to active sites within the channel pore. As a sodium ion passes through the sodium-selective channel, the sodium ion fleetingly binds to a negatively charged amino acid residue lining the channel pore while an adjacent water molecule is stabilized by a negatively charged residue on the opposite wall. Within a sodium-selective channel, active site binding is specific for the sodium’s unique cationic charge and hydration sphere. Subsequently, other cations are excluded.

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B

Figure 3-5. Glutamate receptors. There are three basic ionotropic glutamate receptors, each with numerous binding sites for a number of ligands. A, NMDA receptors require both binding of glutamate and glycine, and membrane depolarization to initiate the conformation change that results in the gating of sodium, potassium, and calcium. Membrane depolarization must occur in order to relieve the magnesium pore blockade. The NMDA receptor also has binding sites to which modulators such as zinc and PCP bind. B, Non-NMDA receptors such as kainate and AMPA gate sodium and potassium ions. These receptors also have numerous binding sites for modulators.

ion channels, binding of ligand to metabotropic receptors may have more profound effects on resting membrane potential, action potential duration, passive membrane properties, and presynaptic neurotransmitter release.1 Furthermore, metabotropic receptors may be excitatory or inhibitory. Onset of action may be delayed several seconds after ligand binding because metabotropic receptor activation typically initiates a cascade of events with multiple intracellular players. In turn, their modulatory effects can last for minutes or longer. Metabotropic receptors initiate reaction cascades, which may activate transcription factors. They may also generate numerous second messengers, which results in signal amplification. For example, norepinephrine binding to a catecholamine receptor may activate a G-protein.2 Each stimulatory G-protein then induces activation of multiple adenyl cyclase enzymes, which subsequently generate copious amounts of cyclic adenosine monophosphate (cAMP) from adenosine triphosphate (ATP). Each cAMP molecule can then proceed to activate numerous protein kinase A molecules. In this manner, a relatively small number of metabotropic receptors can cause widespread and longlasting effects in postsynaptic neurons. Some examples of metabotropic receptors include catecholamine receptors, neuropeptide receptors, metabotropic glutamate receptors, the GABAB receptor, and muscarinic receptors.

Signal Transmission Neurons communicate using both electrical and chemical forms of signaling. The fundamental unit by which a neuron conducts information is the action potential, a localized, ephemeral, self-regenerating membrane depolarization that typically forms at a trigger zone, which is anatomically correlated to the initial segment of the axon. The process begins with the localized influx of sodium into the neuron, producing a zone of focal membrane depolarization. If the resulting membrane potential reaches a threshold, then an action potential is generated. This threshold, known as the action potential threshold, is -55 to -35 mV.3 At the onset of the action potential, a large number of sodium channels are suddenly opened, resulting in an almost instantaneous and massive regional depolarization of the plasma membrane. The rapid influx of sodium, known as the upstroke or rising phase of the action potential, produces membrane potential changes of 70 to 90 mV. These potential changes can, in turn, depolarize the membrane in adjacent segments. If the action potential threshold is reached in these neighboring regions, then the action potential is spread to contiguous membrane segments. The process may repeat itself along the entire length of the neuron. Membrane depolarization does not continue unchecked. Two voltage-dependent mechanisms work to halt the action potential upstroke.

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1. Voltage-sensitive sodium channels open and gate sodium when the membrane becomes slightly depolarized. Further depolarization, however, causes these channels to close.3 Less than a millisecond after they open, the sodium channels rapidly transition into an inactive, closed state. The influx of sodium ceases and the depolarizing drive stops. 2. Depolarization of the membrane also causes voltagesensitive potassium channels to open. Potassium flows down its electrochemical gradient out into the extracellular space, causing the membrane to repolarize, and counteracting the sodium channel-mediated depolarization. Potassium channels cycle from closed to open to closed states more slowly than their sodium-channel counterparts and, subsequently, the potassium efflux does not peak until the majority of sodium channels transition to their closed and inactive states.1,3 The membrane subsequently repolarizes as the membrane is driven back toward potassium’s equilibrium potential (EK = -75 mV). Because potassium’s equilibrium potential is more polar than the cell’s resting membrane potential (-65 mV), the membrane is transiently hyperpolarized before returning to its resting potential. These depolarization-mediated mechanisms repolarize the cell membrane relatively quickly. As a result, action potentials last only a few milliseconds. If action potential propagation were to occur by simply depolarizing adjacent axonal segments, signal transmission would be quite slow. Indeed, a signal originating in the brain and transmitted to one’s foot, for example, could take up to 2 seconds to reach its destination. This delay is incompatible with survival. Rather, signal transduction occurs by saltatory conduction. The basis for this rapid form of conduction is the myelin sheath.3 Most axons are invested by myelin, a phospholipid extension of a glial cell membrane. In the CNS, the glial cells responsible for myelinating axons are oligodendrocytes. In the peripheral nervous system, Schwann cells provide the myelination. Each oligodendrocyte projects myelin appendages to the axons of several neurons. These appendages form concentric lipid layers around the axon, with each extension covering 1 to 2 mm of axonal membrane. The insulated regions of the axon, or internodes, are interrupted by 2-mm segments of bare membrane known as nodes of Ranvier. These nodes are specialized portions of membrane that contain a high density (1000 to 2000 channels/mm2) of sodium channels.2 These nodal regions are therefore extremely sensitive to membrane depolarization. The myelin sheath functionally increases the membrane thickness 100-fold, thereby decreasing the membrane’s electrical capacitance and increasing membrane resistance. The increased resistance precludes sodium influx in an internodal segment.3 Rather, current flow is forced down the longitudinal axis of the axon to the next node of Ranvier, where

there are exposed sodium channels. In this way, the action potential effectively skips from node to node and is regenerated one internode away from its original location. This skipping action, known as saltatory conduction, increases action potential velocity up to 100-fold, so that signals can propagate as briskly as 120 m/sec.2 This velocity is clearly more suitable for transmitting signals. At the axon terminal, the action potential initiates a cascade of events, which results in the transmission of a signal from one neuron to another. The interneuronal site of communication is called a synapse. The presynaptic terminal is separated from the postsynaptic terminal by a synaptic cleft. Two basic kinds of synapses exist, namely electrical and chemical. Electrical Synapse The neurons in this type of synapse are linked by gap junctions. These form narrow (3.5 nm) bridges through which cytoplasm and small intracellular metabolites can pass.2 The cytoplasm is essentially continuous between neurons, so that current is conducted from one neuronal membrane to the next with negligible delay. Chemical Synapse These account for the vast majority of synapses in the central nervous system. In contrast to electrical synapses, neurons in a chemical synapse are not in physical contact. The synaptic clefts are large, typically measuring between 20 and 40 nm.2,8 The action potential is not able to span this distance. Rather, depolarization at the presynaptic terminal results in the release of neurotransmitters into the synaptic cleft.

Neurotransmitters and Synaptic Transmission Neurotransmitters are broadly divided into two classes: small-molecule transmitters and neuroactive peptides (Table 3-1). Both are stored within vesicles at the axon terminal and are released into the synapse through exocytosis.8 Neurotransmitters are packaged into membrane-bound vesicles, concentrated at the axon terminal. At rest, the vesicles are anchored to presynaptic cytoskeletal elements by a class of proteins known as synapsins. The vesicles are attached just proximal to the active zone. There are four known members of the synapsin family: Ia, Ib, IIa, and IIb. In their basal, unphosphorylated states, the synapsins form a bridge between the cytoskeleton and the vesicles. When an action potential arrives at the presynaptic terminal, these protein bridges break down, permitting vesicular fusion with the presynaptic plasma membrane and subsequent release of neurotransmitter into the synaptic cleft. They are released at a synapse, resulting in changes in a postsynaptic cell.

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Table 3-1  Two Major Classes of Neurotransmitters Small-Molecule Transmitters

Neuroactive Peptides

Acetylcholine Dopamine Norepinephrine Epinephrine Serotonin Histamine Gamma-aminobutyric acid Glycine Glutamate

Hypothalamic-releasing hormones Neurohypophyseal hormones Pituitary peptides Gastrointestinal peptides Others

Transmitter release begins with presynaptic depolarization (Fig. 3-6). The depolarization, caused by a shift of sodium ions, results in the activation of voltage-gated calcium channels. Although these channels are sparsely dis-

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tributed through most of the axon, they are concentrated at the active zone, which is the site of neurotransmitter release. Activation of the calcium channels results in an influx of calcium into the cell, in keeping with the large gradient at the axon terminal. The abrupt increase in intracellular calcium levels leads to the rapid activation of calcium/calmodulin protein kinases, which phosphorylate the synapsins.2,8 This phosphorylation triggers a conformational change that extricates the synaptic vesicles from cytoskeletal incarceration. The vesicles then proceed to the active zone with the assistance of the guanosine triphosphate (GTP)—bound proteins, Rab3A and Rab3C. The Rab3vesicle complex is diverted toward the active zone, and on arrival, GTP is hydrolyzed to guanosine diphosphate (GDP) and an inorganic phosphate as the vesicle dissociates from the Rab3 molecule near the active zone. The Rab3 protein then exchanges the GDP for a GTP molecule in priming itself to ferry another vesicle to the active zone. The vesicle then

Figure 3-6. Release of neurotransmitter vesicles at the presynaptic terminal. Numerous steps are involved in the fusion of a vesicle with the presynaptic membrane. (1) Mobilization: As local calcium concentrations skyrocket, synapsins that normally tether vesicles to the neuronal cytoskeleton release the vesicles. (2) Targeting: Rab3 proteins subsequently hydrolyze bound GTP molecules and guide the vesicle toward its release site. (3) Docking-priming: v-SNARE proteins such as synaptobrevin then dock the vesicles with t-SNARES (syntaxin and SNAP-25) and prime the vesicles for membrane fusion. (4) Fusion pore: Through mechanisms not entirely elucidated, a slender pore subsequently forms between the vesicle and the plasma membrane, initiating the release of neurotransmitter molecules into the synaptic cleft.

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must dock in the active zone.2 In docking a vesicle, proteins bound to the vesicular membrane (vesicular-SNAREs or vSNAREs) interact with proteins bound to the plasma membrane (target-SNAREs or t-SNAREs). In neurons, the only v-SNARE identified thus far is VAMP (otherwise known as synaptobrevin). Linkage of VAMP with the t-SNAREs, syntaxin and SNAP-25, forms a stable protein complex, and this complex serves to secure the vesicle in position for impending fusion with the plasma membrane. This protein complex is later disassembled by N-ethylmaleimide-sensitive fusion (NSF) protein and soluble NSF attachment protein (SNAP) as the vesicle is recycled. Synaptotagmin is another protein that plays an integral role in neurotransmitter release. Although its exact functions have yet to be elucidated, possible actions, among others, include regulation of neurotransmitter release, a role as a v-SNARE, and facilitation of vesicular recycling.2,8 Soon after the vesicle is properly positioned, a narrow fusion pore (1 to 2 nm in diameter) temporarily forms, joining the vesicular membrane with the plasma membrane. Formation of the pore is the first step in fusion of the vesicle with membrane. After the pore has been established, the pore promptly dilates, dumping the vesicle’s contents into the cleft, thereby completing fusion of the vesicle with the presynaptic membrane.2 The neurotransmitter molecules then rapidly diffuse into and across the synaptic cleft to interact with postsynaptic receptors. Neurotransmitter is cleared from the synaptic cleft within milliseconds. The mechanisms vary from neurotransmitter to neurotransmitter, but three basic mechanisms exist. Reuptake The most common means of terminating a signal is reuptake. High-affinity transporter proteins embedded in neuronal and glial membranes rapidly convey neurotransmitter molecules from within the cleft back to the intracellular compartment shortly after neurotransmitter is released. The neurotransmitter may be repackaged into vesicles and then re-released with subsequent depolarizations. Numerous medications antagonize neurotransmitter reuptake. These agents effectively permit continued and protracted postsynaptic neurotransmitter-receptor interaction, thereby amplifying the postsynaptic signal. The selective serotonin reuptake inhibitors, as well as cocaine and other sympathomimetics, are examples of agents that use this mechanism of action.1 Enzymatic Degradation Neurotransmitters may be enzymatically degraded within the synaptic cleft. The classic example of degradation is the breakdown of acetylcholine by acetylcholinesterases near the postsynaptic acetylcholine receptors at the neuromuscular junction. The choline generated by acetylcholine hydrolysis

then is rapidly taken up to be recycled. Other neurotransmitters that are broken down enzymatically include GABA and some of the neuropeptide neurotransmitters.1,2 Diffusion Diffusion plays a role in clearance of every neurotransmitter. After achieving high synaptic cleft concentrations, neurotransmitter rapidly diffuses away from its site of action into the extracellular space.

Postsynaptic Signal Transduction When synaptic vesicles fuse with presynaptic membranes, neurotransmitter concentrations in the synaptic cleft increase exponentially in less than a millisecond. The neurotransmitter molecules rapidly diffuse to the postsynaptic membrane and saturate, or fully occupy, the postsynaptic receptors. Binding of neurotransmitter to a receptor induces conformational changes that initiate a signal cascade originating at the postsynaptic membrane.8 In this manner, the neurotransmitters carry a message from a presynaptic membrane, across the void of the synaptic cleft, to a postsynaptic neuron. Activation of postsynaptic receptors generates a postsynaptic potential. A postsynaptic potential is a sudden, brief alteration in the local membrane potential followed by a gradual return to baseline potential over a few hundred milliseconds. There are two kinds of postsynaptic potentials; an EPSP is generated by activation of excitatory receptors, whereas an IPSP results from inhibitory receptor activation. Similar to an action potential, a postsynaptic potential propagates along neurites; however, a postsynaptic potential is neither an all-or-none nor a self-regenerating phenomenon. Rather, it is a graded response the amplitude of which is dependent on the number of activated receptors and which propagates electrotonically, or passively, independent of sodium channel activation. Therefore, a postsynaptic potential degenerates rapidly, unlike a self-regenerating action potential that travels by saltatory conduction. All three ionotropic glutamate receptors are involved in an EPSP. AMPA and kainate receptors are rapidly activated by ligand binding, and thus are involved in the rapid upstroke of an excitatory postsynaptic potential. As the NMDA receptor is slow to open and close, its activation produces the tail of an excitatory potential. IPSPs, although usually mediated by a single kind of receptor, may also be mediated by a mixed population of receptors.9 CNS neurons are constantly bombarded by excitatory and inhibitory inputs from other neurons. Tens of thousands of synapses, in fact, may grace a single motor neuron, and part of the neuron’s function is to integrate these signals into the all-or-none response of an action potential. How, then, does a neuron know when to fire an action potential? To begin with, it is important to realize that a single EPSP is typically

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insufficient to generate an action potential. Even without input from inhibitory synapses, tens or even hundreds of EPSPs in proximity both temporally and spatially may be necessary to produce enough depolarization to reach action potential threshold.2 At the same time, IPSPs are also arriving and counteracting the EPSPs. A neuron integrates these opposing inputs into a coherent signal to pass along the information that it is receiving. Charles Sherrington termed the summation of inputs the “integrative action of the nervous system.”10 With the highest density of voltage-sensitive sodium channels, the axon hillock is the usual site of synaptic integration. At the hillock, depolarization has the highest probability of opening the most sodium channels, thereby bringing the membrane closer to threshold potential. Only a 10-mV depolarization from resting potential is necessary to fire an action potential at the hillock. This relatively small depolarization is in sharp contrast to the 30-mV depolarization typically required elsewhere along the neuron. Thus, if an action potential is to fire from anywhere on a neuron, it is most likely to fire from the hillock.2 How does the hillock summate the synaptic inputs? First, it is important to understand two passive properties of neuronal membranes, the length constant and the time constant. The length constant determines the degree to which a potential degrades over a fixed distance. The amount of degradation is crucial because most excitatory synapses are axo-dendritic and thus lie a long distance from the axon hillock. The result is that the depolarization generated by a single EPSP is typically too weak to fire an action potential because it is but a fraction of its initial amplitude by the time it reaches the hillock. How much signal remains is dictated by the membrane’s length constant; a large length constant indicates that a potential will degrade only slightly over a long distance whereas a small length constant indicates that the potential will decay completely over a short distance.2 In contrast, the time constant is another passive membrane property that influences summation. As the name implies, the time constant determines how rapidly a postsynaptic potential decays over time. A large time constant implies that a postsynaptic potential will decay very little over a given period whereas a small time constant indicates that a potential will decay rapidly.11 Although the length and time constants determine the degree to which postsynaptic potentials have decayed before they reach the hillock, it is rare that a single potential will arrive without having encountered another potential during its journey. Postsynaptic potentials, when they interact with one another, have a tendency to combine to form a single potential. This property is especially important for EPSPs because individual EPSPs are usually too small to generate an action potential. When two EPSPs merge, however, they summate and form a larger-amplitude EPSP,11 one more capable of reaching action potential threshold. Thus, summation is critical to synaptic communication because

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without summation, very few action potentials would be fired. There are two kinds of summation, spatial summation and temporal summation. The first is heavily influenced by the length constant whereas the time constant largely determines the latter. With spatial summation, two inputs, traveling along different dendrites from distal synapses, encounter each other at a common branch point and merge to form a single potential. Because the length constants of individual dendrites dictate the extent to which these disparate signals degrade, the length constant influences the fraction of signal remaining from each distal dendrite. With dendrites that have small length constants, spatial summation will occur more infrequently or be rather inconsequential, because most potentials will degenerate completely before they summate. In this manner, the magnitude of the length constant impacts the integration of multiple synaptic inputs; a neuron with a larger length constant is more likely to summate potentials. Thus, this neuron will fire more action potentials when it receives a constant number of EPSPs than another neuron with smaller length constants.2 On the other hand, temporal summation occurs when multiple inputs arrive at a single point in rapid succession. In this situation, the second potential may ride the coattails of the first potential and summate with the initial potential if it has not yet decayed completely. Therefore, temporal summation is governed by the time constant because this passive membrane property determines the fraction of signal remaining after a given period.2 Thus, the magnitude of the time constant can have a significant effect on the integrative properties of a neuronal membrane. Similar to spatial summation, a neuron with larger time constants will tend to integrate more potentials than those with smaller time constants and may thus fire more action potentials. As a neuron receives input from other neurons, the multitudes of excitatory signals arriving on distal dendritic branches propagate toward the soma, converging on the axon hillock. As previously discussed, action potentials typically do not originate along these dendrites because of the low concentration of sodium channels. By the time these EPSPs reach the soma, however, they may have undergone enough summation that they are of sufficient amplitude to generate an action potential at the hillock. Before an EPSP can reach the axon hillock, however, it must propagate through the soma. Most inhibitory neurons synapse at the soma and hillock, and the soma functions as a gatekeeper and filter.2 In traveling along dendrites, most interpotential interactions have been excitatory up to this point and therefore additive in nature, resulting a large EPSP. Interactions between EPSPs and IPSPs at the soma, however, have a negating effect, as one would expect, and the opposite potentials short-circuit one another. Because most GABA-ergic synapses occur at the soma, the incipient EPSPs reaching the soma on their way to the hillock are heavily curtailed. In this manner, IPSPs increase the size of the EPSPs necessary to

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reach and depolarize the axon hillock. Should the EPSPs surviving the expedition still be of sufficient amplitude, the axon hillock, loaded with its high density of sodium channels, will fire an action potential. The cycle is then complete; this action potential, like the presynaptic action potentials that resulted in the EPSPs that ultimately depolarized this neuron’s hillock, will travel down this neuron’s axon, acting as the combined expression of numerous signals arriving at this central neuron. As with other action potentials, this one will eventually result in the release of neurotransmitter onto other postsynaptic receptors, thereby continuing to propagate information.

Pathophysiology Under normal efficiently and however, the described may function. Two

circumstances, neurotransmission proceeds effectively. In some situations (Fig. 3-7), well-tuned neurophysiologic mechanisms fail, leading to significant neurologic dystypical injuries that disrupt physiologic

neurotransmission are traumatic CNS injury and ischemic cerebrovascular accidents, or stroke. CNS trauma is a result of mechanical injury to the brain or spinal cord, whether it be by motor vehicle accident, gunshot wound, or any mechanism that physically disrupts CNS tissue. Strokes, on the other hand, occur as a result of ischemia. The CNS receives the greatest blood flow given its volume of any organ in the body, and it is exquisitely sensitive to decreases in its supply of oxygen and glucose. Classically, both trauma and ischemia cause two stages of CNS damage. The initial insult is the instantaneous damage that occurs at the time of the trauma or ischemia. The primary insult results in irreversible neuronal dysfunction and is typically characterized pathologically by necrosis at the primary site of injury, in which membrane failure and local inflammation lead to swelling of the neuron and its organelles.12 The lack of oxygen and glucose results in the depletion of cellular energy stores. The deficiency of ATP causes the energy-dependent ion pumps to fail, so that ionic homeostasis fails and neurons depolarize. This phenomenon, known as anoxic depolarization, has serious repercus-

Figure 3-7. Pathophysiologic states. Synaptic transmission may be hindered or arrested at multiple sites along a neuron. For example, numerous medications augment postsynaptic receptor function by inhibiting neurotransmitter re-uptake (selective serotonin release inhibitors, tricyclic antidepressant drugs) or augmenting neurotransmitter binding (benzodiazepines). Far too often, however, a pathophysiologic state is present that is pernicious to normal signal transduction (tetrodotoxin). For example, demyelinating diseases such as Guillain-Barré syndrome or multiple sclerosis hinders action potential propagation, thereby precluding effective signal transduction.

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sions at axonal terminals.6,13 Depolarization results in a large influx of sodium and calcium into neurons and glia, both at and around the primary injury site; chloride ions and water soon follow. A large efflux of potassium ions also occurs. The overall cellular energy failure prevents ion pumps from correcting the derangements in ionic homeostasis, and cellular edema rapidly ensues.13 At the axon terminals, depolarization opens voltage-gated calcium channels, which then results in the massive release of vesicular glutamate, thereby increasing the extracellular glutamate concentration. Extracellular concentrations of other neurotransmitters such as GABA and adenosine also increase at this time.14,15 The increased glutamate levels, however, are believed to result in excitotoxicity, a pathologic state characterized by the hyperstimulation of glutamate receptors, which may inevitably lead to neuronal degeneration and death. The glutamate level peaks at 5 minutes after injury, before returning to basal concentrations. Studies have demonstrated that the magnitude and duration of the increased glutamate levels are directly correlated with the severity of injury.14,15 Although the initial step in a neuron’s downward spiral is the dramatic increase in glutamate levels, it is the resultant increase in intracellular calcium that directly causes cellular damage. One must keep in mind that cytoplasmic calcium concentrations are approximately 100 nM, and the extracellular concentrations are typically greater than 1 mM. Thus, there is a powerful driving force for calcium ions to enter neurons. There are many means by which calcium can enter neurons. Entry occurs through the various glutamate receptors, as well as via voltage-gated calcium channels, opened as a result of membrane depolarization.5,16,17 In addition, calcium enters through the sodium-calcium antiporter, which, under normal circumstances, transports calcium out of cells. After injury, however, the antiporter operates in reverse, moving calcium into the neuron while pumping sodium into the extracellular space. Finally, metabotropic glutamate receptors are activated and induce secondmessenger cascades that increase cytoplasmic inositol 1,4,5triphosphate concentrations, thereby releasing calcium from intracellular stores. The calcium buffering mechanisms are rapidly overloaded, and free calcium ion concentrations increase rapidly, setting into motion a number of potentially pernicious chain reactions.14,15 How does calcium wreak havoc within cells? Under physiologic circumstances, calcium serves a number of roles. Many cytosolic proteins are calcium-dependent and become activated when calcium is bound. These include kinases, phospholipases, and proteases. When intracellular calcium levels go unchecked, these proteins are activated with devastating consequences. Activated phospholipases such as phospholipase A2 and phospholipase C begin to digest cellular phospholipids such as the plasma membrane and membranes lining organelles. Calcium-activated intracellular proteases such as the calpains chew up structural and regulatory proteins such as actin and spectrin, while nucleases

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induce deoxyribonucleic acid (DNA) strand breaks.13,18,19 Some of these DNA breaks may set off a chain of events that irrevocably leads to cellular apoptosis. High intracellular calcium concentrations also stimulate the arachidonic acid cascade, activating 5-lipoxygenase, prostaglandin synthase, and neuronal nitric oxide synthase, which in turn stimulate free radical generation. These free radicals are mostly reactive oxygen species that are potentiated by iron liberated from hemoglobin, transferrin, and ferritin secondary to increased environmental acidity.6 Iron serves as a catalyst for free radical reactions, such as lipid peroxidation and protein destruction. The resultant damage takes a toll as membranes begin to leak and transmembrane ion pumps and other membrane proteins begin to fail. Consequently, derangements in ionic homeostasis worsen. Similar damage is dealt to the mitochondrial membrane, resulting in mitochondrial swelling and loss of cellular energy stores as the electron transport system is disrupted. Furthermore, the mitochondrial permeability transition pore is affected, liberating cytochrome C from its intramembranous home in the mitochondria into the cytoplasm. Cytochrome C sets off a cascade of events that ultimately activates caspases, which are aspartate-specific cysteine proteases. The activation of caspases, especially caspase-3, has been shown in a number of studies to be a late-stage event in apoptosis.13,20 The connection between free radical generation and neuronal damage is corroborated by in vitro studies demonstrating that free radical scavengers and antioxidants substantially curtail the damage incurred by neurons after trauma or ischemia.21,22 In addition, cyclosporin A, an immunosuppressant that has been shown to preclude the translocation of cytochrome C into the cytoplasm, appears to decrease tissue damage following both stroke and trauma in animal models.23,24 The secondary insult is the damage that occurs several hours to weeks after the primary insult and affects regions neighboring the initial injury site—known as the penumbra—where damage is initially insufficient to kill. In this region, cell death may occur as a result of apoptosis, or programmed cell death, a process in which a cell actively undergoes an orderly characteristic pattern of degenerative changes, such as chromatin condensation, cell shrinkage, internucleosomal DNA fragmentation, and the appearance of membrane-bound apoptotic bodies.15 Because disparate processes may result in cell death at different times following CNS damage, distinct interventional strategies may be more effective in halting apoptosis than in saving cells dying by necrosis. Apoptosis versus Necrosis As discussed previously, several of the reactions initiated by excitotoxicity lead to cellular necrosis while others tend to induce cellular apoptosis. What, then, are the factors that lead a dying neuron toward one and not the other? Certainly, activation of some genes have clearly been shown to be pro-

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apoptotic (bax, bad, bcl-xS) while others are anti-apoptotic (bcl-2, bcl-xL),5 but what events activate or inhibit these gene products? First of all, the boundaries dividing necrosis and apoptosis are not as clear-cut as they were once thought to be. Recently, it has been shown that some of the classic pathologic features of apoptosis, namely DNA laddering and a positive TUNEL reactivity, may also be observed during necrosis. In addition, it appears that the two processes are not mutually exclusive of one another; a dying neuron may not follow a specific pathway but rather exhibit a mixture of morphologic features from both processes. Nevertheless, some researchers have proposed that several factors may be crucial to determining which path a cell takes: (1) the nature and severity of the insult, (2) the kind of cell damaged, (3) the cell’s stage of maturation, and (4) the complexity of the neuron’s dendritic tree. In addition, some investigators have proposed that intracellular calcium concentration may play a large role in determining the neuron’s fate, with lower calcium levels, perhaps, resulting in a propensity toward apoptosis.5 Such a premise, if it were shown to be true, would go a long way toward explaining why glutamate receptor antagonists have been such a disappointment after stroke or traumatic CNS injury. It is possible that the well-intentioned efforts to block excitotoxicity cause calcium concentrations to dip too low, thereby encouraging cellular apoptosis. This hypothesis still lacks a preponderance of evidence, however, and a great deal of debate remains. Other Mechanisms—Zinc, Inflammation, and Microvascular Changes There are other mechanisms, some of which are only peripherally related to excitotoxicity, that may be actively contributing to CNS injury. These mechanisms include zinc translocation, regional inflammation, and vascular changes in the CNS. The heavy metal zinc is a divalent cation found in all cells and is typically bound to metalloproteins. In the CNS, zinc’s physiologic role is unclear, although recent studies have shown that it may play a significant role as a modulator of neurotransmission.25–27 This heavy metal has been shown to be co-localized with glutamate in a number of excitatory pathways.28,29 Typically, zinc is only released with glutamate under conditions of high neuronal stimulation, and excess zinc liberation has been shown to be associated with a number of pathologic states such as epilepsy, stroke, and traumatic brain injury. In models of stroke, zinc translocates from nerve terminals into postsynaptic neurons. Zinc ions are believed to gain entry into neurons by the same routes by which calcium ions enter during states of membrane depolarization, namely voltage-gated calcium channels, NMDA channels, calcium-permeable AMPA channels, and sodium/calcium antiporters.30–33 In support of its possible role in neuronal damage, zinc has been shown to be present in neurons in concentrations up to 0.5 mM just before neu-

ronal degeneration.33 Additionally, the administration of a zinc chelator, calcium-ethylenediamine tetraacetic acid, administrated intracerebroventricularly blocks the translocation of zinc into postsynaptic cells and greatly attenuates cellular damage after an acute event.18 Again, a great deal of research remains to be performed with regard to this mysterious ion before a definitive causal relationship between zinc and neuronal damage is uncovered. Inflammatory processes may also play a role in exacerbating CNS damage. In some models of stroke, messenger ribonucleic acid transcripts for tumor necrosis factor-a and interleukin-1b have been increased as early as 1 hour after ischemia. These cytokines have been shown to increase brain water content, as well as exacerbate blood-brain barrier breakdown and increase production of free radicals. In addition, cellular adhesion molecules such as intracellular adhesion molecule–1, P-selectins, and E-selectins are upregulated on the surface of vascular endothelial cells in and around ischemic regions. These factors increase the inflammatory cells’ adhesion to the vessel walls, and augment vessel permeability to these cells. Neutrophils are the first cells to arrive at the scene after ischemia, followed shortly thereafter by macrophages and monocytes. The presence of these inflammatory cells not only leads to microvascular obstruction, further contributing to ischemia, but also to the release of toxic mediators onto wounded neurons. Corroborating the relationship between the inflammation and brain damage, numerous investigators have shown that blockade of the inflammatory response has been shown to decrease infarct volume substantially.5,34,35 Thus, antiinflammatory measures, such as corticosteroids, have been used with some success in traumatic injury. Microvasculature changes have also been demonstrated following traumatic brain injury. Under physiologic conditions, CNS arteries have a remarkable ability to autoregulate cerebral blood flow, maintaining an adequate supply of oxygen and glucose despite drastic changes in perfusion pressure. Several investigators have shown that, after traumatic brain injury, the microvasculature no longer responds appropriately to physiologic challenges. For example, acetylcholine application to microvasculature normally causes vasodilation; after trauma, however, acetylcholine causes vasoconstriction. Changes such as this may reduce blood flow to damaged brain tissue, exacerbating injury. Similarly, under hypocapnic conditions, vessels vasoconstrict under physiologic conditions; after traumatic injury, however, vessels vasodilate.12,36,37 In general, there is loss of normal vascular autoregulation, which may decrease brain tissue perfusion, resulting in more severe injury.

Conclusions The process of signal transmission within the central nervous system is complex. Membrane characteristics

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P earls 1. Most ion channels are composed of multiple protein subunits, which form a central pore. 2. Activation of ligand-gated ionotropic receptors produces a conformation change, which causes the ion channel to open. 3. Metabotropic receptors act quite slowly through intracellular second messengers. 4. This skipping action, known as saltatory conduction, increases action potential velocity up to 100-fold, so that signals can propagate as briskly as 120 m/sec. 5. . . . a large length constant indicates that a potential will degrade only slightly over a long distance whereas a small length constant indicates that the potential will decay completely over a short distance. 6. A large time constant implies that a postsynaptic potential will decay very little over a given period, whereas a small time constant indicates that a potential will decay rapidly.

underlie the separation of ionic species, required for the maintenance of a membrane potential. The action potential is propagated along the axon by saltatory conduction and reaches the axon terminal where neurotransmitters, bundled in vesicles, are released into the synapse. The postsynaptic receptor sites in turn give rise to excitatory or inhibitory potentials, which are integrated with the inputs from thousands of other neurons at the soma. These processes are disrupted in trauma and ischemia, leading to cell death through necrosis and apoptosis.

References 1. Nicholls JG, Martin AR, Wallace BG, Fuchs PA: From Neuron to Brain. Sunderland, England, Sinauer Associates, 2001. 2. Kandel ER, Schwartz JH, Jessell TM: Principles of Neural Science. New York, McGraw-Hill, 2000. 3. Waxmann SG, Kocsys JD, Stys PK: The Axon. Oxford, Oxford University Press, 1995. 4. Hollmann M, Heinemann S: Cloned glutamate receptors. Annu Rev Neurosci 1994;17:31–108. 5. Lee JM, Zipfel GJ, Choi DW: The changing landscape of ischaemic brain injury mechanisms. Nature 1999;399:A7–14. 6. Narayan RK, Wilberger JE, Povlishock JT: Neurotrauma. New York, McGraw-Hill, 1996. 7. Gibbs JW III, Shumate MD, Coulter DA: Differential epilepsyassociated alterations in postsynaptic GABA(A) receptor function in dentate granule and CA1 neurons. J Neurophysiol 1997;77:1924–1938. 8. Cowan WM, Sudhof TC, Stevens CF: Synapses. Baltimore, Johns Hopkins University Press, 2001. 9. Jonas P, Bischofberger J, Sandkuhler J: Corelease of two fast neurotransmitters at a central synapse. Science 1998;281:419–424.

7. The lack of oxygen and glucose results in the depletion of cellular energy stores. The deficiency of ATP causes the energy-dependent ion pumps to fail, so that ionic homeostasis fails and neurons depolarize. This phenomenon, known as anoxic depolarization, has serious repercussions at axonal terminals. 8. Although the initial step in a neuron’s downward spiral is the dramatic increase in glutamate levels, it is the resultant increase in intracellular calcium that directly causes cellular damage. 9. High intracellular calcium concentrations also stimulate the arachidonic acid cascade, activating 5-lipoxygenase, prostaglandin synthase, and neuronal nitric oxide synthase, which in turn stimulate free radical generation. 10. The activation of caspases, especially caspase-3, is shown in a number of studies to be a late-stage event in apoptosis.

10. Sherrington C: Integrative Action of the Nervous System. New Haven, Yale University Press, 1947. 11. Stuart G, Spruston N, Hausser M: Dendrites. Oxford, Oxford University Press, 1999. 12. Povlishock JT: Pathophysiology of neural injury: Therapeutic opportunities and challenges. Clin Neurosurg 2000;46:113–126. 13. Dirnagl U, Iadecola C, Moskowitz MA: Pathobiology of ischaemic stroke: An integrated view. Trends Neurosci 1999;22:391–397. 14. Obrenovitch TP, Urenjak J: Is high extracellular glutamate the key to excitotoxicity in traumatic brain injury? J Neurotrauma 1997;14: 677–698. 15. Zipfel GJ, Babcock DJ, Lee JM, Choi DW: Neuronal apoptosis after CNS injury: The roles of glutamate and calcium. J Neurotrauma 2000;17:857–869. 16. Choi DW: Calcium-mediated neurotoxicity: Relationship to specific channel types and role in ischemic damage. Trends Neurosci 1988;11:465–469. 17. Choi DW: Calcium: Still center-stage in hypoxic-ischemic neuronal death. Trends Neurosci 1995;18:58–60. 18. Lee JM, Grabb MC, Zipfel GJ, Choi DW: Brain tissue responses to ischemia. J Clin Invest 2000;106:723–731. 19. Zipfel GJ, Lee JM, Choi DW: Reducing calcium overload in the ischemic brain. N Engl J Med 1999;341:1543–1544. 20. Green DR, Reed JC: Mitochondria and apoptosis. Science 1998;281:1309–1312. 21. Hall ED, Braughler JM: Free radicals in CNS injury. Res Publ Assoc Res Nerv Ment Dis 1993;71:81–105. 22. Kontos HA, Povlishock JT: Oxygen radicals in brain injury. Cent Nerv Syst Trauma 1986;3:257–263. 23. Okonkwo DO, Buki A, Siman R, Povlishock JT: Cyclosporin A limits calcium-induced axonal damage following traumatic brain injury. Neuroreport 1999;10:353–358. 24. Uchino H, Elmer E, Uchino K, Lindvall O, Siesjo BK: Cyclosporin A dramatically ameliorates CA1 hippocampal damage following transient forebrain ischaemia in the rat. Acta Physiol Scand 1995;155:469–471.

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25. Barberis A, Cherubini E, Mozrzymas JW: Zinc inhibits miniature GABAergic currents by allosteric modulation of GABAA receptor gating. J Neurosci 2000;20:8618–8627. 26. Lin DD, Cohen AS, Coulter DA: Zinc-induced augmentation of excitatory synaptic currents and glutamate receptor responses in hippocampal CA3 neurons. J Neurophysiol 2001;85:1185–1196. 27. Mozrzymas JW, Barberis A, Michalak K, Cherubini E: Chlorpromazine inhibits miniature GABAergic currents by reducing the binding and by increasing the unbinding rate of GABAA receptors. J Neurosci 1999;19:2474–2488. 28. Assaf SY, Chung SH: Release of endogenous Zn2+ from brain tissue during activity. Nature 1984;308:734–736. 29. Howell GA, Welch MG, Frederickson CJ: Stimulation-induced uptake and release of zinc in hippocampal slices. Nature 1984;308: 736–738. 30. Choi DW, Yokoyama M, Koh J: Zinc neurotoxicity in cortical cell culture. Neuroscience 1988;24:67–79. 31. Choi DW, Weiss JH, Koh JY, Christine CW, Kurth MC: Glutamate neurotoxicity, calcium, and zinc. Ann NY Acad Sci 1989;568:219–224.

32. Kerchner GA, Canzoniero LM, Yu SP, Ling C, Choi DW: Zn2+ current is mediated by voltage-gated Ca2+ channels and enhanced by extracellular acidity in mouse cortical neurones. J Physiol 2000; 528:39–52. 33. Sensi SL, Canzoniero LM, Yu SP, et al: Measurement of intracellular free zinc in living cortical neurons: Routes of entry. J Neurosci 1997;17: 9554–9564. 34. Becker KJ: Inflammation and acute stroke. Curr Opin Neurol 1998;11:45–49. 35. Zhang RL, Chopp M, Li Y, et al: Anti-ICAM-1 antibody reduces ischemic cell damage after transient middle cerebral artery occlusion in the rat. Neurology 1994;44:1747–1751. 36. Ellison MD, Erb DE, Kontos HA, Povlishock JT: Recovery of impaired endothelium-dependent relaxation after fluid-percussion brain injury in cats. Stroke 1989;20:911–917. 37. Wei EP, Dietrich WD, Povlishock JT, Navari RM, Kontos HA: Functional, morphological, and metabolic abnormalities of the cerebral microcirculation after concussive brain injury in cats. Circ Res 1980;46:37–47.

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Chapter 4 Neurologic Disease: An Overview William A. Friedman, MD, Kelly D. Foote, MD, and David Peace

Introduction Central and peripheral nervous diseases are different from most other medical problems in one fascinating and important way: The precise site of the neurologic disorder can almost always be determined from a careful history and neurologic examination. Once the site of disease is elucidated, a differential diagnosis, drawing from the basic categories of neurologic illness can be constructed. The history is particularly valuable in ordering the differential diagnosis from most to least probable. When this intellectual process is finished, appropriate diagnostic tests can be ordered. Hopefully, the precise diagnosis will then be established.

The Neurologic Examination The neurologic examination is generally divided into the following parts: mental status, cranial nerves, motor examination (including cerebellar function), reflexes, and sensory examination. As in other parts of the physical examination, adhering to a strict order helps the physician avoid errors of omission. Mental Status Examination of mental status focuses on level of consciousness, orientation, memory, emotional state, and higher cortical functions (including language). Orientation is typically tested to person, place, and time. Patients are frequently described as “oriented times three.” Typically recent memory

is tested by asking the patient to remember three objects and then testing them 2 and 5 minutes later for recall. Long-term memory may be tested by asking for their address, telephone number, or the names of presidents, capitals, and so forth. Altered states of consciousness are described by a variety of terms including, in order of severity, clouded, lethargic, obtunded, stuporous, and comatose. Clouding of consciousness refers to a mildly depressed level of awareness and slowing of mentation. A “lethargic” patient will lie quietly or sleep in the absence of stimulation but can interact fairly well when prompted. An “obtunded” patient will sleep in the absence of stimulation, can be aroused with some difficulty, and has generally depressed intellectual function. A “stuporous” patient requires vigorous stimulation to provoke any arousal and is incapable of meaningful verbal exchange. A “comatose” patient fits the following precise definition: “incapable of following commands, does not speak, and does not open eyes to pain.” Dementia, unlike the previous descriptors, refers only to a loss of intellectual function and does not imply any alteration of consciousness. Unfortunately, these terms are rather imprecise. To eliminate interobserver variability in describing decreased levels of consciousness, the Glasgow coma scale (GCS) was developed. It relies on three simple tests: best eye opening response, best verbal response, and best motor response (Fig. 4-1). The worst score is 3 and the best score is 15. The definition of coma cited previously corresponds to a GCS score of 8 or less. The differential diagnosis of coma is broad and includes toxic/metabolic disorders such as electrolyte imbalance, endocrine dysfunction, toxin ingestion, infection, nutri117

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Eye Opening Spontaneous To Speech To Pain None

4 3 2 1

Best Verbal Response Oriented Confused speech Inappropriate Incomprehensible None

5 4 3 2 1

Best Motor Response Obeys commands Localizes pain Withdraws Abnormal flexion Extension None

6 5 4 3 2 1

Figure 4-1. The Glasgow coma scale.

tional deficiency, organ failure, and epilepsy. A variety of structural disorders can also cause coma, including hemorrhage, ischemic stroke, brain abscess, brain tumor, and trauma. A variety of disorders of higher cortical function can occur without alteration of consciousness. The most important are those which disturb language function. Disorders affecting the ability to use speech are called aphasias. Broca’s aphasia refers to a disorder affecting the posterior inferior left frontal lobe (Brodmann’s area 45). It produces difficulty with speech output, but has little effect on speech understanding. Wernicke’s aphasia involves the posterior superior left temporal lobe (Brodmann’s area 22). It causes loss of ability to understand spoken or written language but speech output remains fluent (although nonsensical). A rarer disorder, called conduction aphasia, refers to a condition in which understanding spontaneous speech is relatively preserved, with loss of the ability to repeat. This condition results from lesions in the pathways that connect Broca’s and Wernicke’s areas (Figs. 4-2, 4-3). In general, peri-Sylvian

Figure 4-2. Brodmann’s cytoarchitectonic map. Most cerebral cortex consists of six layers. The anatomy of each layer may vary depending on whether that area is more sensory, motor, or associative in function. Brodmann sliced the brain horizontally, starting from the top, and assigned numbers to each new area of cortex. These “Brodmann’s numbers” are still used to refer to different anatomic areas of the brain.

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Figure 4-3. A functional map of the brain shows the expected deficit from focal lesions. Lesions in Wernicke’s area (Brodmann 22) tend to produce an aphasia where comprehension is lost but speech is fluent. Lesions in Broca’s area (Brodmann 45) produce aphasia with relatively preserved comprehension, but lack of speech output.

lesions are associated with loss of the ability to repeat, while deeper lesions produce the transcortical aphasias, which are associated with preserved repetition. Gerstmann’s syndrome refers to a constellation of four neurologic findings: finger agnosia, alexia, acalculia, and agraphia. It is usually found with lesions of the left inferior parietal lobe. Alexia without agraphia is seen with lesions of the dominant occipital lobe, when they extend into the splenium of the corpus callosum. A detailed discussion of the fascinating varieties of higher cortical dysfunction and their localization is beyond the scope of this chapter.

nerve will produce funduscopically visible optic pallor (optic atrophy). The most valuable localizing test of visual pathway function involves visual fields. Visual fields are tested in the clinic by having the patient occlude one eye. The examiner then directs the patient to look straight ahead and tests his ability to count fingers in the four quadrants of that eye’s visual field. Formal visual fields can be performed by an ophthalmologist if this test is abnormal. A variety of visual field abnormalities are described, unilateral visual loss, junctional scotoma, bitemporal hemianopia, homonymous hemianopia, which very accurately localize the site of the lesion within the nervous system (Fig. 4-6). CN III. The oculomotor nerve innervates the levator palpe-

Cranial Nerves Cranial Nerve (CN) I. The olfactory nerve mediates the sense

of smell (Fig. 4-4). This can be tested by asking the patient to identify vials containing common substances (coffee, orange extract, etc.) by smell alone, while alternately occluding each nostril. The olfactory nerve is the most frequently injured by head trauma. It can also be affected by neoplasms growing near the olfactory groove area intracranially, including meningiomas and esthesioneuroblastomas. CN II. The optic nerve connects the retina to the optic chiasm and, hence, to the posterior visual pathways (Fig. 4-5). Unlike other cranial nerves, it can be directly viewed via the funduscopic examination. Increased intracranial pressure will often be manifest as papilledema of the optic nerve head. Longstanding pressure or inflammation of the optic

brae, the medial rectus, the superior rectus, and inferior oblique, the inferior rectus, the pupilloconstrictor muscle, and the muscle that controls accommodation of the lens within the eye (Fig. 4-7). Lesions of CN III result in movement of the globe into a “down-and-out” position, ptosis, and pupillary dilatation. Temporal lobe herniation can produce a unilateral injury of CN III with, usually, contralateral hemiplegia. Direct compression of CN III by an aneurysm or tumor can produce these findings, as can diabetes or stroke. CN IV. The trochlear nerve innervates the superior oblique muscle (Fig. 4-8). Lesions of this nerve result in vertical diplopia, with the affected eye elevated and externally rotated. The patient will attempt to correct the condition by tilting the head away from the affected side (to internally rotate the eye). The trochlear nerve is rarely affected in

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Figure 4-4. Anterior inferior view of the brain shows the 12 paired cranial nerves.

Figure 4-5. The optic nerves meet at the optic chiasm. The optic tracts run from the chiasm to the lateral geniculate nuclei of the thalamus. The optic radiations run from these nuclei to the primary visual cortex in the occipital lobe. The nasal retinal fibers cross in the chiasm, so a lesion there tends to produce the characteristic bitemporal visual field cut. Lesions of the tract, radiations, or occipital lobe tend to produce complete loss of vision on the opposite side (a homonymous hemianopia).

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isolation, but frequently affected in combination with cranial nerves III and VI by lesions of the cavernous sinus area. CN V. The trigeminal nerve provides sensation to the face

(Fig. 4-9). It has three divisions: the ophthalmic division innervates the forehead and eye; the maxillary division innervates the upper jaw and side of nose; and the mandibular division innervates the lower jaw, teeth, and tongue. The trigeminal nerve also innervates the muscles of mastication. Injuries to this nerve will result in ipsilateral loss of facial sensation and atrophy and weakness of the masseter muscle. This most frequently results from tumors (acoustic schwannoma, trigeminal schwannoma, nasopharyngeal carcinoma, etc.). The trigeminal nerve is also involved in a severe, lancinating pain disorder, called trigeminal neuralgia, which is frequently treated with surgery. CN VI. The abducens nerve innervates the lateral rectus Figure 4-6. Lesions in various parts of the visual pathways lead to very characteristic and localizing visual field defects: A, Optic nerve; B, Optic chiasm; C, Optic tract; D, Temporal optic radiations; E, Parietal optic radiations; F, Primary visual cortex.

muscle, which moves the globe laterally (Fig. 4-10). Lesions of this nerve will produce inward deviation of the eye. Because of its long subarachnoid course, CN VI is commonly affected by increased intracranial pressure, which can produce unilateral or bilateral palsy (a false localizing sign).

Figure 4-7. The oculomotor nerve exits the brainstem between the mesencephalon and pons and travels to the cavernous sinus and on to the orbit. The motor nucleus innervates multiple extraocular muscles. The Edinger-Westphal nucleus provides parasympathetic innervation to the pupil and the lens of the eye.

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Figure 4-8. Cranial nerve IV is the only one that decussates (crosses midline). It exits just below the collicular plate and travels along the tentorium to the cavernous sinus. It enters the orbit and innervates one extraocular muscle— the superior oblique.

CN VII. The facial nerve innervates the muscles of facial expression (Fig. 4-11). It is also responsible for salivary gland activity, lacrimation, and taste over the anterior two thirds of the tongue. Peripheral lesions of the nerve (such as trauma or Bell’s palsy) cause weakness of the upper and lower face. Lesions of the upper motor neuron pathways from the motor cortex innervating the facial nerve nucleus in the brainstem cause weakness of the contralateral lower face only. The upper face receives bilateral cortical innervation and remains normal. This type of facial paralysis is called a central seventh. CN VIII. The vestibulocochlear nerve innervates the cochlea

(the organ of hearing) and the vestibular complex (the organ of balance). Lesions of this nerve are seen after basilar skull fractures and with tumors of the cerebellopontine angle (usually acoustic schwannomas). Hearing is usually tested in the clinic by determining whether a patient can hear fingers rubbing together outside the external ear canal. Formal audiometry is performed if this test result is abnormal.

Lesions of CN IX rarely occur in isolation and sectioning of the nerve usually does not result in any significant deficit. CN X. The vagus nerve innervates most of the muscles responsible for swallowing and supplies sensory input to the pharynx as well (Fig. 4-13). Lesions of the nerve result in asymmetry of palatal movement. Of course, the vagus nerve also supplies parasympathetic input to the heart and gastrointestinal tract. Cranial nerves IX, X, and XI exit through the jugular foramen, where they can be jointly affected by tumors (especially jugular foramen schwannomas and meningiomas). CN XI. The spinal accessory nerve innervates the trapezius and sternocleidomastoid muscles (Fig. 4-14). These muscles are tested by shoulder shrug and head turning. Trauma is the most frequent cause of an isolated injury of CN XI. CN XII. The hypoglossal nerve innervates the muscles of the

CN IX. The glossopharyngeal nerve innervates the stylopha-

ryngeus muscle, which is involved in swallowing (Fig. 4-12). This nerve supplies taste sensation to the posterior tongue.

tongue. Dysfunction leads to protrusion of the tongue toward the affected side. This nerve may be affected by tumor, trauma, or stroke.

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Figure 4-9. The trigeminal nerve exits the brainstem at the pontine level. The trigeminal (Gasserian) ganglion is just lateral to the cavernous sinus. Three branches enter the cavernous sinus and innervate the face: the ophthalmic branch (V1), the maxillary branch (V2), and the mandibular branch (V3). The trigeminal nerve also mediates motor function (the muscles of mastication and the tensor tympani).

Figure 4-10. The CN VI nucleus is in the floor of the fourth ventricle. The nerve exits the midline at the junction of the pons and medullar. It travels along the clivus and through Dorello’s canal to reach the cavernous sinus. This nerve innervates one extraocular muscle—the lateral rectus.

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Figure 4-11. Cranial nerve VII exits laterally to cranial nerve VI, in the pontomedullary groove. It innervates the muscles of facial expression through multiple branches after exiting the stylomastoid foramen. This nerve also provides parasympathetic innervation to the geniculate and sphenopalatine ganglia, and hence, to the lacrimal and salivary glands. The chorda tympani branch provides taste sensation to the anterior two thirds of the tongue.

Figure 4-12. The glossopharyngeal nerve provides motor innervation to the stylopharyngeus muscle, and parasympathetic innervation to the parotid gland and carotid body.

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Figure 4-13. The vagus nerve provides motor innervation to the pharyngeal muscles and parasympathetic innervation to the heart and gut.

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Figure 4-14. The spinal accessory nerve has branches from the brainstem (nucleus ambiguus) and the upper cervical spinal cord. It provides motor innervation to the trapezius and sternocleidomastoid muscles.

Motor Examination Motor function involves motor cortex of the brain, the corticospinal (and other descending) tracts, the motor pathways within the spinal cord, the motor neurons within the brainstem and spinal cord, the nerve roots, peripheral nerves, neuromuscular junction, and muscles. In addition, normal motor function is heavily dependent on complex circuitry within the basal ganglia and the cerebellum. Disease at any of these sites will lead to alterations during the motor examination and, in many cases, will clearly localize to a specific part of the nervous system (Fig. 4-15). Diseases of the motor cortex and descending motor pathways are called upper motor neuron disorders and are characterized by weakness, lack of atrophy, spasticity, and increased reflexes (Fig. 4-16). Diseases of the motor neurons in the brainstem and spinal cord, as well as the peripheral and cranial nerves, are called lower motor neuron disorders (Fig. 4-17). They are characterized by weakness, atrophy, decreased tone, and decreased reflexes. Diseases of the neuromuscular junction (such as myasthenia gravis) result in

fluctuating weakness affecting cranial and limb muscles, normal tone and reflexes, and no atrophy. Diseases affecting the muscle (like polymyositis) result in atrophy, weakness, decreased reflexes and tone. Diseases affecting the basal ganglia and its related pathways (like Parkinson’s disease) are called extrapyramidal disorders. They are frequently associated with normal strength, increased tone, unchanged reflexes, and tremor. Diseases of the cerebellar pathways can result in decreased tone and reflexes, normal strength, limb incoordination, and gait ataxia. Examination of the motor systems should include evaluation for atrophy and changes in tone, strength, and coordination. Strength is usually tabulated on a 0 to 5 scale: 0 is total paralysis; 1 is a visible flicker of movement only; 2 is movement weaker than antigravity; 3 is full movement against gravity; 4 is full movement overcome by resistance; and 5 is normal strength. Coordination is tested by having the patient touch fingertip to nose and by observing gait. Lateral cerebellar lesions tend to affect extremity coordination; vermian lesions tend to produce ataxic gait. In Parkinson’s disease and

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Figure 4-15. Coronal section through the primary motor strip of the brain, illustrating the motor homunculus. The parts of the body that are innervated by different motor strip areas are shown.

other extrapyramidal disorders, gait tends to be stooped and shuffling. A hemiparesis will typically cause a spastic gait. Waddling gait is associated with muscular dystrophy affecting the hips. Reflexes The reflex examination centers on determination of the deep tendon reflex responses at the elbows, knees, and ankles. This reflex arc requires integrity of sensory neurons, motor neurons, and muscle. The rating is 0 to 4, with 0 signifying absence, 2+ being normal, and 4+ being very hyperactive. Hyperactive reflexes may be seen with upper motor neuron disease. Hypoactive reflexes may be seen with diseases of the peripheral nerve (e.g., polyneuritis), sensory root (e.g., tabes dorsalis), anterior horn cell (e.g., polio), proximal nerve root (e.g., lumbar disk herniation), peripheral motor nerve (e.g., trauma), and muscle (myopathy). Various superficial (cutaneous) reflexes are released in upper motor neuron disease. The most commonly tested are the Babinski (Fig. 4-18), a dorsiflexion of the toes to plantar stimulation, and the Hoffman, twitching of the distal thumb in response to flicking the distal fingers (Fig. 4-19).

Sensation Examination Pain and temperature sensation are mediated via the spinothalamic tracts, which cross in the spinal cord and ascend to the opposite side of the brainstem and cortex (Figs. 4-20, 4-21). Touch and proprioception are mediated by the dorsal columns of the spinal cord. These pathways remain ipsilateral until they reach the sensory decussation in the lower brainstem. Consequently, lesions of the hemispinal cord will result in loss of pain and temperature on the opposite side of the body and loss of touch and proprioception on the ipsilateral side of the body. The sensory examination should include tests of pain fibers (pin), light touch (fingers), proprioception (checking that the patient can tell whether toes or fingers are being moved up or down), and vibration (tuning fork). Various patterns of sensory loss can localize to specific areas of the nervous system and/or to certain well-known disease processes (Figs. 4-22, 4-23). For example, loss of all sensory modalities in the distribution of one peripheral or cranial nerve clearly localizes to that nerve. Loss of all modalities below a given spinal level localizes to the spinal cord. Loss of sensation on one side of the face and the opposite side of the Text continued on page 134

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Figure 4-18. The Babinski sign.

Figure 4-16. The upper motor neuron fibers descend through the internal capsule into the ventral mesencephalon to the pyramids of the medulla. There the pathways decussate and form the corticospinal tracts in the posterolateral spinal cord.

Figure 4-17. The corticospinal (and other) axons synapse with the motor neurons of the ventral spinal gray matter. The lower motor neuron axons exit through the ventral root and travel through the spinal roots and peripheral nerves to reach the neuromuscular junction. The basic spinal reflex arc, whereby stretch of the muscle spindle leads to synaptic connections with the motor neurons leading to the muscle involved in the reflex, is also shown.

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Figure 4-19. The Hoffman (A) and Tromner (B) reflexes produce flexion of the distal thumb if upper motor neuron disease is present.

Figure 4-20. All sensory neurons reside in the dorsal root or brainstem ganglia. Sensory fibers enter the spinal cord through the dorsal root. Those mediating proprioception, vibration, and fine touch enter the dorsal columns and ascend ipsilaterally. Those mediating pain and temperature sensation cross the midline and ascend in the spinothalamic tracts.

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Figure 4-21. The spinothalamic tracts ascend to the sensory thalamic nuclei and on to the sensory cortex. The dorsal column fibers synapse in the dorsal column nuclei of the medulla, decussate, ascend to the thalamus, and then to the cortex.

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Figure 4-22. Each spinal sensory root, from C2 to coccygeal 5, innervates a specific skin area called a dermatome.

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Figure 4-23. Spinal nerves combine to form a multiple of peripheral nerves. Each peripheral nerve also has a known sensory skin representation. Careful attention to the sensory examination can localize the nervous system lesion to a peripheral nerve, a spinal nerve, the spinal cord, the brainstem, or the cerebrum.

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Figure 4-23. continued.

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body localizes to the brainstem. Loss of sensation of one side of the body and face localizes to the opposite cerebrum. Loss of dorsal column modalities only usually indicates a metabolic disease such as vitamin B12 deficiency.

Clinical-Anatomic Correlation in Neurologic Disease In this section of the chapter we will briefly review the neurologic functions that commonly localize to the major anatomic divisions of the nervous system. Brain Frontal Lobe The frontal lobes of the brain subserve many important neurologic functions. First, the frontal association areas are responsible for personality and level of energy. Frontal lobe lesions can result in apathy, inactivity, depression, changes in personality, inappropriate actions, and so forth. Severe bilateral frontal lobe injury leads to a condition called akinetic mutism. Alternatively, some frontal lesions lead to a sense of euphoria accompanied by inappropriate jocularity (witzelsucht). The frontal eye fields (Brodmann’s area 8) direct both eyes to the opposite side of the body. Damage to this area of the brain will frequently result in head and eye turning toward the side of injury. This is seen after trauma and stroke. The posterior portion of the frontal lobes contains the primary motor cortex (Brodmann’s area 4). This strip is organized in a somatotopic pattern, with face most inferior, then hand, then arm. Hip and shoulder are near the top of the strip. Leg function is localized to the mesial hemisphere. Injury to this area will result in paralysis of an upper motor neuron variety. The inferior posterior surface of the dominant (usually left) frontal lobe is called Broca’s area (Brodmann’s area 45). This area of the brain mediates speech output. Injury to this area results in Broca’s aphasia, which is characterized by loss of spontaneous speech, inability to write, and inability to repeat, but with relatively preserved speech comprehension and reading ability. Temporal Lobe The temporal lobes, especially the mesial limbic structures (including the hippocampus) are an important part of the neurologic circuits involved in memory. Disease of the temporal lobes, especially when bilateral, can lead to profound recent memory loss. The dominant temporal lobe is involved in language function. The posterior superior temporal gyrus is called Wernicke’s area (Brodmann’s area 22). Lesions of this area cause Wernicke’s aphasia, which is characterized by inability

to understand spoken or written speech. Speech output is fluent, but nonsensical. Lesions of both temporal tips can produce a condition called Klûver-Bucy syndrome, which is characterized by oral automatisms and hypersexuality. This condition is rare and is most commonly seen with head trauma. Parietal Lobe The anterior parietal lobes contain the primary somatosensory cortex (Brodmann’s areas 3, 1, 2). Like the motor strip, this area is organized somatotopically. Lesions of the primary sensory cortex cause loss of all sensory modalities in the corresponding opposite body parts. Posterior to the primary sensory cortex, in the superior parietal lobules, are the sensory association areas. Lesions of this area produce agnosias wherein objects cannot be recognized by sensory input even though the primary sensory modalities are intact. Parietal lesions can produce neglect of the opposite hemibody, wherein the patient tends to ignore stimuli on that side. Severe neglect can lead to autotopagnosia, the inability to recognize one’s own body. Anosognosia refers to ignorance of the existence of disease and has been specifically applied to denial of hemiplegia. A more subtle test for parietal lobe dysfunction involves simultaneous stimulation of bilateral body parts. With parietal lesions, the sensation over the opposite body frequently will not be perceived. The left inferior parietal lobe integrates many sensory modalities. Lesions in this area can produce Gerstmann’s syndrome, which is characterized by finger agnosia, acalculia, left-right confusion (allochiria), and agraphia. Lesions in the angular gyrus area of the inferior parietal lobe are particularly likely to cause anomia, the inability to remember the names of objects. The right parietal lobe is implicated in higher sensory processing as well. Lesions in this area can produce dressing apraxia, wherein a patient cannot figure out how to properly put on clothing because of inability to integrate sensory information.

Occipital Lobe The occipital lobes contain primary visual cortex. Lesions of the occipital lobe tend to produce loss of vision in the opposite visual fields of both eyes (homonymous hemianopia). The macular (central) fields may be spared. More anterior occipital areas contain visual association cortex. Lesions here will produce a variety of visual agnosias. The inability to recognize faces is called prosopagnosia. Brainstem The brainstem is usually divided into three parts: mesencephalon, pons, and medulla. The brainstem connects the cerebral hemispheres and deep structures to the spinal cord, so it contains the long motor and sensory tracts that connect

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these structures, as well as all of the cranial nerve nuclei. Because so many important structures are crowded into such small areas, even minor injuries to the brainstem produce highly localizable deficits. Large brainstem insults frequently produce coma or death. Ventral mesencephalic lesions tend to produce an ipsilateral third nerve palsy and contralateral hemiplegia. This symptom complex, called Weber’s syndrome, may be seen with stroke and tumors. Dorsal mesencephalic lesions often are associated with Parinaud’s syndrome. Parinaud’s syndrome is characterized by decreased pupillary light reflex, preserved pupillary constriction to accommodation, paralysis of upgaze, retraction-convergence nystagmus, and other anomalies. Parinaud’s is most often seen with pineal region tumors but can also be seen with severe hydrocephalus. Ventral pontine lesions produce an ipsilateral sixth nerve palsy and contralateral weakness (Millard-Gubler syndrome) that is most often seen with stroke. More dorsolateral lesions are associated with hearing loss, vertigo, facial weakness, and ataxia. Ventral medullary lesions produced an ipsilateral CN XII palsy and contralateral hemiplegia (Hughlings-Jackson syndrome). Dorsolateral lesions produce Wallenberg’s syndrome, which is usually associated with vertebral artery occlusion and characterized by dysphonia, Horner’s syndrome, dysphagia, ataxia, ipsilateral facial numbness, and contralateral body numbness. Many other brainstem syndromes have been described— a comprehensive review is beyond the scope of this chapter. Spinal Cord The spinal cord may be injured by trauma, tumor, degenerative disease, infection, and metabolic disorders. A complete spinal cord injury results in loss of all motor and sensory function below the level of the lesion. If the thoracic cord is involved, this results in paraplegia. If the cervical cord is involved, quadriplegia is seen. In the acute phase of an injury—spinal shock—all reflexes are lost. Because sympathetic outflow to the body is interrupted, hypotension associated with bradycardia is often seen. Gradually, reflexes return and, because of the upper motor neuron nature of the injury, become hyperactive. A variety of partial spinal cord injury syndromes are commonly described. Brown-Sequard syndrome refers to a hemispinal cord injury, which can be produced by trauma or by neoplasm. This is characterized by loss of ipsilateral motor function, as well as proprioception and vibratory sensation below the lesion. Contralateral pain and temperature sensation are lost. The anterior spinal artery syndrome is usually associated with trauma, but can be caused by vascular disease of the aorta. It is characterized by bilateral paralysis and loss of pain and temperature sensation, with preservation of dorsal column function (touch and proprioception).

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The dorsal column syndrome refers to isolated injury of the dorsal columns, most commonly associated with metabolic disease. This results in loss of touch and proprioception below the lesion, with preservation of other function. The motor neurons of the spinal cord can be selectively injured in certain diseases, including poliomyelitis, and some forms of amyotrophic lateral sclerosis. This results in weakness and atrophy of the associated muscles, without sensory loss.

Peripheral Nerve The peripheral nerves contain motor and sensory axons. The cell bodies of origin of the sensory axons are found in the dorsal root ganglia. The cell bodies of origin of the motor axons are found in the ventral horn of the spinal cord. The sensory axons subserve the many peripheral sensory organs, which convey pain, temperature, touch, special sensory function, and so forth. The motor axons conduct impulses from the lower motor neurons to the muscles. Hundreds of disorders can affect the peripheral nerves. Peripheral nerve disease typically leads to weakness and atrophy of the involved muscles. Disease of a specific nerve will lead to sensory loss in the known distribution of that nerve. Generalized peripheral neuropathy tends to cause loss of sensation in a “stocking-glove” distribution, although there are many exceptions. The reader is referred to several excellent texts for a detailed discussion of peripheral neuropathy.1–6

Neuromuscular Junction The synapse between the motor axon and the muscle is called the neuromuscular junction. It is probably the best studied and understood synapse in the body. Diseases of the neuromuscular junction (like myasthenia gravis) tend to produce fluctuating weakness, no signs of atrophy, and involvement of cranial and peripheral muscles. These disorders respond to anticholinesterase inhibitors.

Muscle Diseases of muscle are called myopathies. Myopathy can be congenital, metabolic, inflammatory, infectious, or can present as a remote effect of carcinoma. Myopathies are characterized by weakness, most frequently affecting the proximal more than the distal musculature. Often atrophy is present and reflexes are reduced. Muscle pain may be present and muscle enzyme concentrations may be elevated.

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Major Categories of Neurologic Disease Once the history and neurologic examination are completed, the neurologic specialist should, in most cases, be able to localize the disease to a specific nervous system area, based on the principles discussed previously. Then, one draws from the extensive lists of neurologic disorders that are most likely to cause a lesion in that location based on historical details.

Subsequent laboratory investigations, including radiographs, cerebrospinal fluid analysis, electroencephalography, electromyography, biopsy, will help to narrow the differential to a specific diagnosis for appropriate treatment. The major categories of neurologic disease, and the most common diseases in each category, are outlined in Table 4-1. A detailed discussion of all of these disease categories is the topic of many excellent textbooks of neurology.

Table 4-1  Major Categories of Neurologic Disease Disturbances of cerebrospinal fluid circulation Hydrocephalus Congenital Acquired Normal pressure hydrocephalus Pseudotumor cerebri Intracranial neoplasms Gliomas Glioblastoma Astrocytoma Oligodendroglioma Ependymoma Medulloblastoma/peripheral neuroectodermal tumor Meningioma Pituitary adenoma Schwannoma Metastatic tumor Craniopharyngioma, dermoid, epidermoid, etc. Infections of the nervous system Bacterial meningitis Subdural empyema Epidural abscess Brain abscess Tuberculous meningitis Neurosyphilis Fungal infections of the brain Acquired immunodeficiency syndrome (AIDS) and AIDS-related infections Viral syndromes Poliomyelitis Herpes zoster Viral meningitis/encephalitis Cerebrovascular diseases Transient ischemic attacks Thrombotic stroke Embolic stroke Aneurysm or arteriovenous malformation Arteritis Intracerebral hemorrhage Trauma Basilar skull fracture Concussion Cerebral contusion Epidural hematoma

Subdural hematoma Intracerebral hematoma Diseases of the spinal cord Spinal cord trauma Myelitis Infectious Inflammatory/demyelinating Spinal vascular malformations Spinal neoplasms Arnold-Chiari malformation/hydromyelia Multiple sclerosis and other demyelinating diseases Inherited metabolic disorders (Too numerous to list here) Diseases due to nutritional deficiency Wernicke’s disease and Korsakoff psychosis Beriberi Pellagra Subacute combined system disease (vitamin B12) deficiency Acquired metabolic disorders Hypoxia Hypo/hyperglycemia Hepatic failure Uremia Disturbances in sodium metabolism Alcohol intoxication or withdrawal Degenerative diseases of the nervous system Dementia Huntington’s disease Parkinson’s disease Progressive ataxias Amyotrophic lateral sclerosis Hereditary sensory neuropathies Developmental disorders of the nervous system Hydrocephalus Craniosynostosis Myelodysplasia Arnold-Chiari malformation Phakomatoses (e.g., neurofibromatosis) Cerebral palsy Idiopathic epilepsy Mental retardation

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P earls 1. The precise site of the neurologic disorder can almost always be determined from a careful history and neurologic examination. 2. The neurologic examination is generally divided into the following parts: mental status, cranial nerves, motor examination (including cerebellar function), reflexes, and sensory examination. As in other parts of the physical examination, adhering to a strict order helps the physician avoid errors of omission. 3. In general, peri-Sylvian lesions are associated with loss of the ability to repeat, while deeper lesions produce transcortical aphasias, which are associated with preserved repetition. 4. Diseases of the motor cortex and descending motor pathways are called upper motor neuron disorders, and are characterized by weakness, lack of atrophy, spasticity, and increased reflexes. 5. Lower motor neuron disorders are characterized by weakness, atrophy, decreased tone, and decreased reflexes. 6. The right parietal lobe is implicated in higher sensory processing as well. Lesions in this area can produce

References 1. Aronson AE, et al: Clinical Examination in Neurology, 4th ed. Philadelphia, WB Saunders, 1977, pp 1–235. 2. Heilman KM, Watson RT, Greer M: Differential Diagnosis of Neurologic Signs and Symptoms. London, Appleton-Century-Crofts, 1977, pp 1– 231. 3. Newman NJ: Practical neuro-ophthalmology. In Tindall GT, Cooper PR, Barrow DL (eds): The Practice of Neurosurgery. Baltimore, Williams and Wilkins, 1996, pp 159–185.

7.

8.

9.

10.

dressing apraxia, wherein a patient cannot figure out how to properly put on clothing because of inability to integrate sensory information. Parinaud’s syndrome is characterized by decreased pupillary light reflex, preserved pupillary constriction to accommodation, paralysis of upgaze, retractionconvergence nystagmus, and other anomalies. Parinaud’s is most often seen with pineal region tumors but can also be seen with severe hydrocephalus. The anterior spinal artery syndrome is usually associated with trauma, but can be caused by vascular disease of the aorta. It is characterized by bilateral paralysis and loss of pain and temperature sensation, with preservation of dorsal column function (touch and proprioception). Diseases of the neuromuscular junction (such as myasthenia gravis) tend to produce fluctuating weakness, no signs of atrophy, involvement of cranial and peripheral muscles, and respond to anticholinesterase inhibitors. Myopathies are characterized by weakness, most frequently affecting the proximal more than the distal musculature.

4. Rengachary SS: Cranial nerve examination. In Wilkins RH, Rengachary SS (eds): Neurosurgery. New York, McGraw-Hill, 1985, pp 50–70. 5. Victor M, Ropper AH: Adams and Victor’s Principles of Neurology. New York, McGraw-Hill, 2001, pp 1–1644. 6. Youmans JR: Neurological Surgery, 4th ed., vol. I. Philadelphia, WB Saunders, 1996.

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Chapter 5 Central Nervous System Neoplasia William A. Friedman, MD

Epidemiology of Central Nervous System Tumors According to Rubinstein, central nervous system tumors account for less than 2% of all autopsied deaths and for approximately 9% of all primary tumors.1 However, the central nervous system (CNS) is the second most common site of primary tumor formation in children. Notably, 70% of CNS tumors in children are infratentorial and 70% of CNS tumors in adults are supratentorial. The American Cancer Society estimates that 16,800 new intracranial tumors were diagnosed in 1999, more than double the number of diagnosed cases of Hodgkin’s disease.2 The incidence of symptomatic intracranial tumors is approximately 12 per 100,000 persons per year. Additional information about brain tumor epidemiology is shown in Tables 5-1 to 5-3. Gliomas tend to be more common in males, whereas schwannomas are slightly more common in females. Intracranial meningiomas are twice as likely to develop and intraspinal meningiomas are four times more likely to develop in females. Certain diseases, called phakomatoses, present as a neurocutaneous syndrome wherein characteristic skin changes are coupled with CNS tumors. The most common is Von Recklinghausen’s disease, associated with CNS meningiomas, bilateral acoustic schwannomas, as well as gliomas. Von Hippel-Lindau disease presents with retinal lesions, as well as multiple hemangioblastomas of the brain and spinal cord. Tuberous sclerosis classically presents with the triad of adenoma sebaceum, mental retardation, and

seizures. Cortical tubers and subependymal giant cell tumors tend to develop in these patients.

Symptoms and Signs of Central Nervous System Tumors The symptoms and signs of CNS tumors can generally be divided into three groups: those due to increased intracranial pressure, those due to focal irritative effects on the brain, and those due to focal destructive effects on the brain.3 Increased Intracranial Pressure Tumors produce increased intracranial pressure (ICP) by local mass effect, surrounding edema and, sometimes, by accompanying hydrocephalus, either obstructive or communicating. Increased ICP usually causes progressively increasing headache. This type of headache is usually pancephalic and is frequently worse in the morning, after prolonged supine posture. With time, this headache is frequently accompanied by nausea and vomiting. Further increases in pressure produce a decreased level of consciousness. Patients with increased ICP often have papilledema on funduscopic examination. Occasionally, increased ICP will produce unilateral or bilateral palsy of cranial nerve VI as well. The symptoms and signs of increased ICP are generally regarded as urgent indications for therapy. Frequently, steroids will provide dramatic, although transient, relief. 139

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Table 5-1  The Percentage Incidence of Primary Brain Tumors, All Ages

Table 5-3  The Percentage Incidence of Intracranial Gliomas in Children

Glioma Meningoma Pituitary adenoma Schwannoma Other

Astrocytomas Medulloblastomas Ependymomas

50% 20% 15% 10% 15%

Tumors presenting in this fashion will frequently require surgical debulking and/or shunting. Focal Irritative Symptoms The incidence of epilepsy associated with brain tumors is approximately 35% overall. Tumor is an important cause of a first seizure in adults (Table 5-4). Seizures may be partial, indicating no alteration of consciousness. Partial seizures can involve focal motor activity, focal sensory effects (paresthesiae), or focal visual phenomena. Complex partial seizures involve a short alteration of consciousness, with inattention to the surrounding environment. They are typically associated with unusual smells, or unusual emotions, such as fear, anxiety, or a déjà vu sensation. Complex partial seizures usually originate in the temporal lobe. Grand mal seizures involve a loss of consciousness, with tonic-clonic activity of the arms and legs. Urinary and bowel control are usually lost as well. Grand mal seizures result when focal seizures propagate throughout the brain. All types of seizures can usually be controlled well with medication. The most commonly used medications are Dilantin (phenytoin, fosphenytoin) and Tegretol (carbamazepine). Focal Destructive Symptoms Tumors can usually be distinguished from strokes, because tumor symptoms develop relatively slowly and are clearly progressive. The exceptions occur when tumors present with a hemorrhage or a seizure (sudden symptoms). These slowly progressive symptoms are dependent almost entirely on the location of the tumor and provide valuable clues as to where

Table 5-2  The Percentage Incidence of Intracranial Gliomas, Regardless of Age Glioblastomas Astrocytomas Ependymomas Medulloblastomas Oligodendrogliomas Choroid plexus papillomas Colloid cysts

55% 20.5% 6% 6% 5% 2% 2%

48% 44% 8%

the tumor might be, even before radiographic imaging is performed. Tumors with weakness generally involve the frontal motor cortex. Those with sensory changes frequently involve the parietal, sensory cortex. Speech problems usually involve the left inferior frontal area (Broca’s area) or the left temporal lobe (Wernicke’s area). Visual changes are particularly valuable in localization. Optic nerve compression affects the vision in one eye only. Optic chiasm compression typically produces a bitemporal field cut. Optic tract, radiation, or occipital lobe lesions usually cause a homonymous hemianopia (loss of the visual field on the same side in each eye). Tumors in certain locations may produce a characteristic constellation of symptoms, called a syndrome. Pineal region tumors, regardless of histologic findings, often produce Parinaud’s syndrome, which is characterized by loss of upgaze, loss of light reflex, and preservation of papillary constriction with near gaze (accommodation). Suprasellar neoplasms frequently produce a bitemporal field cut and endocrine disturbances. Intra-axial brainstem lesions often produce a hemiplegia alternans syndrome, characterized by cranial nerve findings on one side, and motor or sensory findings involving the opposite side of the body.

Radiographic Evaluation of Central Nervous System Tumors Tumors can produce radiographic changes on plain skull or spine radiographs, computed tomography (CT) scan, bone scan, ventriculography, or pneumoencephalography. Magnetic resonance imaging (MRI), however, produces superior diagnosis of almost all CNS tumors, so this section will be confined to that modality alone. The interpretation of MR images is a complex undertaking, requiring many years of training to refine. Nonetheless, a small number of characTable 5-4  Incidence of Cause of First Seizure in Adults Idiopathic Stroke Alcohol withdrawal Tumor Central nervous system infection Vascular malformation Trauma Drug toxicity

28% 24% 11% 8% 8% 6% 4% 2%

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teristic changes are helpful in narrowing down the differential diagnosis of CNS neoplasms. These characteristics include multiplicity, enhancement, surrounding edema, dural attachment, and location. Multiplicity Metastatic brain tumors are frequently multiple. However, approximately 40% of these lesions will present with a solitary lesion. Conversely, malignant gliomas are usually solitary, but at least 10% are radiographically multicentric, even involving different lobes or hemispheres of the brain. Infectious and inflammatory lesions of the brain are also frequently multiple. Enhancement Most CNS tumors enhance with the administration of gadolinium. Benign lesions, such as meningiomas and acoustic schwannomas, tend to be homogeneously enhancing. Malignant lesions, such as glioblastoma and metastasis, tend to have less regular enhancement because of their necrotic centers (ring enhancement is common). Low-grade gliomas, especially those that are not pilocytic, rarely enhance. Surrounding Edema Malignant tumors are usually associated with surrounding edema. Metastatic tumors tend to have more associated edema than gliomas. Benign lesions usually do not have surrounding edema, although there are certainly exceptions. Infectious lesions, such as abscesses, are frequently associated with edema.

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Treatment of Central Nervous System Tumors The most commonly used methods of treating CNS tumors are surgery, radiation therapy, radiosurgery, and chemotherapy. The evolving field of molecular biology promises to offer sophisticated immunotherapy and/or gene therapy alternatives in the near future. Surgery Stereotactic Biopsy Surgical procedures on the brain fall into two general categories: stereotactic biopsy and craniotomy. A typical stereotactic biopsy procedure is as follows: The patient presents in the morning to preoperative holding. After the injection of local anesthetic, a stereotactic head ring is applied (Fig. 5-1). The patient is then transported to the CT scanner. There, a series of 1-mm-thick CT scan slices are taken from the top to the bottom of the head. These images are transferred, via Internet, to the stereotactic computer system, where each slice is quickly converted to a set of pixels, each of which has a defined anteroposterior, lateral, and vertical coordinate relative to the fixed head ring. Usually, a nonstereotactic MRI, performed the day before the procedure, is then fused, with special software, to the stereotactic CT scan. The patient is then transported to the operating room. In the operating room, the stereotactic MRI is viewed on computer. The desired target points and a precise trajectory, designed to avoid blood vessels and other danger spots, are computed. The target point is set up on a device called a phantom. The stereotactic frame is set to the desired coor-

Dural Attachment Meningiomas, one of the more common primary CNS neoplasms, almost always have a clear dural attachment, as well as enhancement running away from the attached area (“a dural tail”). Occasionally, metastatic tumors or gliomas will arise from or secondarily attach to the dura. Location Certain neoplasms have very characteristic locations within the brain. Lesions commonly encountered in the suprasellar space include pituitary adenoma, craniopharyngiomas, meningioma, and germinomas. Lesions that occur in the cerebellopontine angle are usually acoustic schwannomas or meningiomas. Common pineal region tumors are germinomas, pineocytoma, and meningioma. Meningiomas tend to occur in the following locations: parasagittal, falcine, sphenoid wing, tentorial, foramen magnum, and cavernous sinus.

Figure 5-1. The stereotactic head ring is applied under local anesthesia. No shaving or prepping is required. This head ring becomes the platform upon which subsequent imaging and instrument guidance is performed. It allows the entire imaged brain to be redrawn in a Cartesian coordinate system. Each pixel on a CT scan or MR image has an anteroposterior, lateral, and vertical coordinate in relation to the fixed head ring.

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Introduction This complication may necessitate rapid conversion of the procedure to a general anesthetic and open craniotomy. Other reported complications are seizure (rare), focal deficit without hemorrhage, infection, and lack of diagnostic tissue. Craniotomy Craniotomy is the most commonly performed procedure for all types of brain tumors. Craniotomy not only provides tissue diagnosis (usually via frozen section neuropathologic examination during surgery), but it provides the means for relieving symptoms of increased ICP and, sometimes, focal irritation or destruction of brain tissue. The myriad details of the craniotomy procedure are beyond the scope of this text. In general, the following steps are used.

Figure 5-2. A variety of computer systems are used to determine the stereotactic coordinate target coordinates. A stereotactic frame is then attached to the top of the ring. A burr hole or twist drill hole is placed at the desired entry point. The stereotactic frame is then used to direct a biopsy needle directly to the target point.

dinates and connected to the phantom to verify that no errors of setup have occurred. The skin is shaved and prepped over a small scalp area where the entry point is anticipated. The stereotactic frame is attached to the head ring. At the point where the biopsy probe touches the scalp, local anesthetic is injected and an incision made. A single burr hole is then placed (Fig. 5-2). The dura is coagulated and opened. A biopsy needle is advanced through the burr hole to the target point and several biopsy specimens are taken. A neuropathologist examines the tissue. Once a pathologic diagnosis is confirmed, the needle is withdrawn and the scalp wound closed in layers. The stereotactic frame is removed and the patient returned to the recovery room and, later, the floor. The following morning the patient is discharged. Anesthetic Considerations. These procedures are almost

always “local-standby” in adults. A small amount of sedation and pain control is frequently helpful. However, if the patient’s mental status is already altered, one should be careful not to render them uncooperative with too much medication. Complications. The most feared complication of stereotactic biopsy is arterial hemorrhage. Fortunately this occurs in less than 2% of cases.4,5 Hemorrhage will usually be manifest in surgery, with arterial blood in the biopsy needle and, sometimes, with the onset of new neurologic deficit.

1. Induction of anesthesia: The type of anesthesia may be influenced by the perceived intracranial pressure or coexistent medical problems. Rarely, brain tumor excision may be performed under local anesthesia, to allow electrical stimulation of the brain and mapping of function (typically speech, memory, and motor function), during brain tumor excision. 2. Positioning: The majority of craniotomies for frontal lesions are performed with the patient in the supine position, perhaps slightly rolled to one side (Fig. 5-3). Many parietal tumors are removed with the patient in the lateral position. Most occipital and suboccipital (posterior fossa) tumors are removed with the patient in the three-quarter prone position (Fig. 5-4). The most important surgical consideration in this position is to get the shoulder out of the way of surgery. This is accomplished by rolling the shoulder away from the head, flexing the head away from the shoulder, and turning the head away from the shoulder. Rarely, neurosurgical tumor procedures are performed with the patient in the semi-sitting position. This facilitates drainage of blood and CSF out of the field, but increases the risk of air embolism. 3. Skin incision: The skin flap is designed to encompass the involved area of the brain while preserving blood supply to the flap. The incision is made sharply and clips are applied to the skin edges to control bleeding. Often, the underlying muscle is separated from the skull and elevated with the skin flap. Occasionally, a separate muscle flap (such as the Yasargil flap) will be elevated to facilitate skull exposure (Fig. 5-5). 4. Skull flap: The skull overlying the tumor is removed by placing one or more burr holes around its periphery with a high-speed drill. The burr holes are connected with a power saw and the skull is lifted away from the dura. When skull flaps cross venous sinuses in the dura (like the sagittal sinus), there is a risk of significant hemorrhage (Fig. 5-6).

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Figure 5-3. Artist’s depiction of a typical supine position craniotomy. The standard positions of patient, surgeon, microscope, anesthesiologist are shown.

Figure 5-4. A, “Bird’s-eye” view of patient in “park-bench” or three-quarter prone position, as would typically be used for a posterior fossa tumor. B, Side view of three-quarter prone position.

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Introduction 6. Tumor excision: A variety of instruments, including microdissectors, ultrasonic dissectors, lasers, and so forth, are used to remove brain tumors. Probably, the most important technical development over the past several decades has been the routine use of the operating microscope, which allows the surgeon to identify and preserve normal neural and vascular structures. 7. Closure: Once the tumor is removed and hemostasis is obtained, the wound is closed in layers, including the dura, skull, muscle, galea, and skin. Anesthetic Considerations. Craniotomy for tumor is most

Figure 5-5. The skin is incised. Clips are applied to the skin edges to control bleeding. The temporalis muscle is elevated separately (this is a called a Yasargil flap) to provide better exposure of the anterior skull base. Burr holes are placed as indicated. A saw is used to incise the skull as indicated by the dotted line.

5. Dural opening: The dura, which covers the entire brain, is incised and opened. Usually, the dura is left attached to a pedicle and remains viable. Occasionally, the dura is involved with the tumor (i.e., meningioma) and must be removed. In this case, a dural substitute is often sewn in place at closure.

Figure 5-6. Once the skull is removed, the dura is incised and retracted. The arachnoid overlying the Sylvian fissure is incised with a knife and dissection proceeds under the operating microscope.

frequently performed under general anesthesia. If ICP is elevated, induction may need to be modified to avoid transient exacerbations of this problem. If facial nerve or motorevoked potential monitoring is used, muscular paralytic agents must be minimized. If somatosensory-evoked potentials are used, halogenated agents should be minimized. If the surgical procedure has the potential to traumatize lower cranial nerves or the brainstem, consideration should be given toward leaving the endotracheal tube in place until neurologic function (such as gag reflex) can be fully assessed. Finally, most neurosurgeons will be interested in a rapid emergence from anesthesia, so that they can assess the patient’s neurologic function and detect and correct any surgical complications (see following discussion). Complications. A variety of complications can occur during and after brain tumor surgery. The most common are listed following.

1. Intracranial hemorrhage: Any tumor case may be complicated by immediate or delayed intracerebral, subdural, or epidural hematoma. If the neurologic examination is abnormal at any time postoperatively, a noncontrast CT scan is urgently needed to rule out intracranial hemorrhage. 2. Hydrocephalus: Residual mass effect from tumor may cause obstructive hydrocephalus. Subarachnoid blood or infection may cause communicating hydrocephalus. Neurologic abnormalities should prompt an urgent CT scan, which may lead to the detection and treatment of hydrocephalus. 3. Seizures: Surgery of the posterior fossa is rarely complicated by seizure activity. However, all supratentorial surgery may be followed by postoperative seizures. Although focal motor or grand mal seizure activity is obvious, subclinical seizures may cloud consciousness and are sometimes only detected by bedside electroencephalography (EEG). Any patient with an unexplained decreased level of consciousness should be considered for EEG. 4. Meningitis: Acute bacterial meningitis may complicate any surgical procedures. Altered mental status, meningismus, and fever should prompt an early lumbar

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puncture (if not otherwise contraindicated) and antibiotic coverage while culture results are pending. 5. Hyponatremia: The syndrome of inappropriate antidiuretic hormone secretion, as well as cerebral salt wasting, may lead to hyponatremia. When the sodium concentration is less than 130 mmol/L, alterations in consciousness and/or seizure activity may occur. See Chapter 18 for more information. Radiation Therapy Radiation therapy is of value in the treatment of many types of tumors, once tissue diagnosis is established. Radiation therapy involved the administration of high-energy photon beams to a well-defined target area including the tumor and a variable degree of surrounding normal tissue. The most commonly used device for manufacturing and focusing these radiation beams is the linear accelerator (LINAC) (Fig. 5-7). LINACs accelerate electrons very close to the speed of light. These highly energetic electrons then collide with a heavy metal. The collision produces mainly heat, but a small percentage of the energy is converted to braking radiation, whereby high-energy photons are electronically produced. These photon beams are focused by a series of shaping devices called collimators onto the tumor. To take advantage of the increased sensitivity of tumors versus normal brain to the effects of radiation, the treat-

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ments are typically delivered in small daily doses (measured in centiGray), Monday through Friday, for approximately 6 weeks. There are many variations in dosing schedules, dose per daily fraction, and total dose delivered, depending on tumor type and treatment philosophy. Radiation ultimately produces its effects by damaging the deoxyribonucleic acid (DNA) strands in tumor cells. Double strand breaks eliminate the ability of the tumor cell to further reproduce. Cells that are not normally dividing (like normal neurons) are much more resistant to the effects of radiation. However, the blood vessels and glial cells may be damaged by radiation, leading to either short-term or longterm side effects. The following brain tumors are routinely irradiated in most institutions: • • • • • • •

Anaplastic astrocytoma Glioblastoma Medulloblastoma Pineal germinomas Metastatic brain tumor Pituitary adenoma (when not curable with surgery alone) Craniopharyngioma (when not curable with surgery alone) • Meningiomas (when not curable with surgery alone and/or radiosurgery) Expected Outcomes Conventional radiation therapy produces long-term tumor control rates of at least 75% for medulloblastoma, germinoma, pituitary adenoma, craniopharyngioma, and meningioma. Fewer than 50% of metastatic tumors will be cured by radiation therapy alone. Median survival after radiation therapy for anaplastic astrocytoma is approximately 18 months, and for glioblastoma less than 1 year. Complications Radiation therapy may be associated with acute complications, including nausea, vomiting, malaise, hair loss and, rarely, neurologic deficit. Radiation necrosis of the brain may develop years after treatment but is quite uncommon. The delayed onset of cognitive deficit, including severe memory loss, is commonly seen after large fields of radiation are used in the treatment of brain tumors. Radiosurgery

Figure 5-7. A linear accelerator accelerates electrons, which collide with a heavy metal. A small percentage of the energy from this collision generates highly energetic photons, called x-rays. The x-rays are focused on the patient’s tumor.

Stereotactic radiosurgery (SRS) is a minimally invasive treatment modality that delivers a large single dose of radiation to a specific intracranial target while sparing surrounding tissue. SRS treatments are administered using special devices. The gamma knife is one such device that uses 201 fixed cobalt sources, all focused on one spot within the head. LINAC radiosurgical systems use the linear accelerator as the source of radiation. Particle beam devices use cyclotrons.

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Following is a description of the SRS protocol at the University of Florida that, with minor changes, could apply to most SRS centers.6,7 Almost all SRS procedures in adults are performed on an outpatient basis. The patient reports to the neurosurgical clinic the day before treatment for a detailed history and physical examination, as well as an in-depth review of the treatment options. If SRS is deemed appropriate, the patient is sent to the radiology department for a volumetric MRI scan. The next morning, the patient arrives at 7:00 am. A stereotactic head ring is applied under local anesthesia. No skin shaving or preparation is required. Subsequently, stereotactic CT scanning is performed. One-millimeter slices are obtained throughout the entire head. The patient is then transported to an outpatient holding area where he and his family have breakfast and relax until the treatment planning process is complete. The stereotactic CT scan and the nonstereotactic volumetric MR image are transferred via Internet to the treatment-planning computer. The CT scans are quickly processed so that each pixel has an anteroposterior, lateral, and vertical stereotactic coordinate, all related to the head

ring previously applied to the patient’s head. Using image fusion software, the nonstereotactic MRI is fused, pixel for pixel, with the stereotactic CT. Dosimetry then begins and continues until the neurosurgeon, radiation therapist, and radiation physicist are satisfied that an optimal dose plan has been developed. A variety of options are available for optimizing the dosimetry. The fundamental goal is to deliver a radiation field that is precisely conformal to the tumor shape (Fig. 5-8), while delivering a minimal dose of radiation to all surrounding neural structures. Dosimetric options include arc elimination, arc weighting, arc tilting, and the use of multiple isocenters. A detailed review of dosimetry is beyond the scope of this chapter. When dose planning is complete, the radiosurgery device is attached to the LINAC. The patient then is attached to the device and treated (Fig. 5-9). The head ring is removed and, after a short observation period, the patient is discharged. The radiosurgery device is disconnected from the LINAC, which is then ready for conventional usage. Close clinical and radiologic follow-up is arranged at appropriate intervals depending on the pathology treated and the condition of the patient.

Figure 5-8. In SRS, the goal is to create a very high radiation application that conforms to the shape of the tumor. Many hundreds of small beams of radiation are aimed at multiple target points. The computer snapshot shows the treatment isodose, one half the treatment isodose, and 20% of the treatment isodose displayed around a cavernous sinus area meningioma in the axial, sagittal, and coronal MRI views.

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apy is complicated by the blood-brain barrier, which limits the penetration of many chemotherapeutics to the central nervous system and, hence, reduces their potential efficacy. Nonetheless, chemotherapy has a well-established role in the treatment of a variety of brain tumors, especially when they are recurrent after surgery and radiation treatment. The following sections classify the most commonly used brain tumor drugs. Alkylating Agents Most alkylating agents form positively charged carbonium ions that attack nucleophilic sites on nucleic acids, proteins, and amino acids. The result of DNA base alkylations can be cross-linking of DNA, single-strand and double-strand breaks, with subsequent misreading of the DNA code and cell death.

Figure 5-9. Depiction of procedure once the computer plan is completed. The patient’s head ring is clamped to the modified linear accelerator. Multiple arcs of radiation are delivered, always focused on the target. The end result is a very high dose of radiation delivered to the target.

SRS is commonly used to the treat the following brain tumors (surgery and conventional radiation therapy are often used as part of the treatment of these patients, as well): • • • • •

Acoustic schwannoma Meningioma Pituitary microadenoma, endocrine active Metastatic tumor Small malignant gliomas

Expected Outcomes SRS can cure as many as 90% of treated acoustic schwannomas and meningiomas. Approximately two thirds of endocrine active pituitary microadenomas will normalize within 18 months of treatment. Approximately 70% of metastatic brain tumors can be cured with SRS. It is only palliative in the treatment of malignant gliomas. Complications SRS may lead to delayed (3 to 18 months after treatment) radiation necrosis in a small percentage of cases. Neurologic symptoms will depend on the precise area of the brain involved. A course of oral steroids will often lead to resolution. In severe cases, surgical resection of the necrotic area may be required. Chemotherapy As is the case with most cancers, chemotherapy for brain tumors is palliative, not curative. Brain tumor chemother-

1. Nitrosoureas: These are generally considered to be the most active CNS drugs, especially for malignant gliomas. 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) is given intravenously and N-(2-chloroethyl)-N’cyclo-hexyl-N-nitrosourea (CCNU) is given orally. Dose-limiting adverse effects are myelosuppression and pulmonary fibrosis. 2. Procarbazine: This oral agent has been used as a single agent or in combination with others in the treatment of malignant gliomas. Limiting adverse effects are myelosuppression and gastrointestinal complications. 3. Platinum compounds: Cis-platinum is a water-soluble intravenous agent that primarily acts on the guanine bases. It is active against medulloblastoma, primitive neuroectodermal tumors (PNET), lymphoma, and germ cell tumors. Limiting toxicities are myelosuppression, nephrotoxicity, ototoxicity, and peripheral neuropathy. Plant Alkaloids 1. Vinca alkaloids: Vincristine is a water-soluble, intravenously administered alkaloid that acts as a spindle toxin. In combination with CCNU and procarbazine, it is used for the treatment of anaplastic oligodendrogliomas and medulloblastomas. Its main toxicity is peripheral neuropathy. 2. Podophyllotoxins: VM-26 (tenoposide) and VP-16 (etoposide) are lipophilic, intravenously administered drugs that arrest cells in the G2 phase by binding to topoisomerase II. VP-16 is used in combination chemotherapy of pediatric brain tumors, including medulloblastoma and germ cell tumors. 3. Methotrexate: This drug is an antifolate antimetabolite. It is active only on cells in the S phase. It is used in the treatment of lymphoma, medulloblastoma, and PNET. It is administered intravenously or intrathecally.

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Future directions for brain tumor chemotherapy include blood-brain barrier disruption, and intratumoral chemotherapy (e.g., Gliadel wafers). More importantly, new molecular biologic methods may enable the profiling of individual brain tumors to determine which drugs would be most effective, either singly or in combination.

Common Brain Tumors Gliomas Low-Grade Gliomas Approximately 25% of all gliomas are low-grade astrocytomas or oligodendrogliomas. Low-grade gliomas tend to occur in children and younger adults. The pediatric tumors frequently have pilocytic morphology on pathologic examination and are considered truly benign in that curative surgical excision is often possible. Pilocytic tumors tend to occur in the cerebellum, optic nerve/hypothalamic region, and thalamus. Adult low-grade tumors have a propensity for the convexity of the brain, in relative proportion to the size of the various lobes. Thus frontal locations are most common. Pilocytic tumors often have homogenous enhancement on MRI, with no surrounding edema. Adult low-grade gliomas

A

typically have no enhancement on MRI and are best seen on T2-weighted or FLAIR (fluid attenuated inversion recovery) sequences (Fig. 5-10). As with all brain tumors, low-grade gliomas may present with symptoms referable to increased ICP, focal brain irritation (seizures), or focal destruction (neurologic deficit). Those presenting with mass effect and ICP increase are typically treated with craniotomy. Most, however, present with focal symptoms and the best treatment is controversial. Recent guidelines for the management of presumed lowgrade tumors call for attempted resection when locations are lobar and complete resection can be accomplished without high risk of neurologic deficit. In other tumors, stereotactic biopsy is recommended to confirm diagnosis. Conservative follow-up, with serial MRI scanning, is then pursued because there is no evidence that radiation therapy or chemotherapy alter the natural history of the disease. In practice, many presumed low-grade tumors presenting with seizure are followed without biopsy until evidence of growth occurs. Adult low-grade gliomas should not be regarded as benign tumors. If unresectable, most will eventually undergo malignant degeneration. Average life expectancy with lowgrade astrocytoma is between 5 and 10 years from the time of diagnosis. Oligodendrogliomas have a better prognosis, with longer than 10 year survival commonly seen.

B Figure 5-10. A, T1-weighted, enhanced, axial MRI shows a typical low-grade glioma. The lesion does not enhance and it has no surrounding edema. B, T2-weighted axial MR image shows hyperintensity characteristic of a low-grade glioma.

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B

Figure 5-11. A, T1-weighted, enhanced axial MR image shows ring enhancement and surrounding edema characteristic of a malignant glioma. B, T2-weighted axial MR image reveals a pattern of hyperintensity characteristically caused by the vasogenic edema around a malignant glioma.

Malignant Gliomas Malignant gliomas account for about 40% of the approximately 17,000 new cases of CNS malignancy in the United States every year, and an exceptionally high fatality rate makes their clinical impact dramatic. Glioblastoma multiforme (GBM) accounts for roughly 80% of malignant gliomas and has an annual incidence of over 5000 cases. The natural history of untreated GBM results in a median survival of 3 months. With current standard therapy (resection plus conventional fractionated radiation therapy), median survival is typically 9 to 10 months with a 5-year survival rate of approximately 5%. Five-year survival rate for anaplastic astrocytoma (AA) is typically less than 20%. AAs are pathologically defined by the presence of mitoses, endothelial proliferation, and nuclear pleomorphism. Glioblastomas have the added pathologic characteristic of necrosis. The anaplastic lesions have a peak incidence in the sixth decade of life, with glioblastomas tending to occur later than the sixth decade. Because of their rapid growth, ICP symptoms are more frequent than those in low-grade gliomas. Malignant gliomas characteristically have irregularly enhancing areas and surrounding edema on MRI (Fig. 5-11). Most studies support the concept that cytoreductive surgery (craniotomy) is beneficial in terms of patient survival and quality of life.8 For those lesions that cannot be resected safely, stereotactic biopsy is performed for diagno-

sis. Radiation therapy, typically to a dose of 6000 cGy, is routinely administered because it clearly increases survival. A variety of chemotherapy protocols are used, both as upfront and salvage treatments, with generally low response rates. The observation that local control and median survival can be extended through dose escalation is the basis for the application of brachytherapy and radiosurgery to malignant gliomas.9 While achievable radiation doses with conventional external beam irradiation are limited by induced toxicity to around 70 Gy, the addition of a stereotactically focused boost of radiation allows total cumulative doses in excess of 100 Gy to be delivered to residual focal tumor. Ependymoma Intracranial ependymomas are relatively uncommon tumors; at least one half occur in the first two decades of life. Tumors of the posterior fossa predominate, although supratentorial ependymomas are also seen, especially in older patients. In the posterior fossa, the most common presenting symptoms are headache, nausea, vomiting, and imbalance, related to obstructive hydrocephalus. Small ependymomas, because of their typical origin from the floor of the fourth ventricle, near the area postrema, may present with insidiously progressive nausea in the absence of clear neurologic symptoms. Typically, these tumors are noncystic,

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Introduction of at least 3000 cGy will produce a 50% to 70% 5-year eventfree survival. Chemotherapy has a treatment role in two situations: the high risk patient, with large invasive tumors and/or metastatic disease; and the very young patient in whom chemotherapy has been used in an attempt to avoid the harmful effects of radiation therapy on the immature nervous system. Cisplatin, CCNU, vincristine, and other agents have demonstrated efficacy in these situations. Vestibular Schwannomas

Figure 5-12. Noncontrast MR image shows mass filling fourth ventricle. This has caused severe obstructive hydrocephalus.

relatively homogenously enhancing masses, within the lower fourth ventricle area on MRI (Fig. 5-12). The treatment of choice for ependymoma is surgery. Surgery has three goals: tissue diagnostic confirmation, tumor resection, and relief of obstructive hydrocephalus. The most important prognostic factor is the extent of surgical resection—gross total resection confirmed by postoperative scan correlates with a high cure rate. Resection is so important that residual disease on postoperative MRI frequently leads to “second-look” surgery. When complete resection is deemed impossible secondary to brainstem invasion, adjuvant radiation therapy and chemotherapy protocols have been followed, with low response rates.

These common tumors (representing approximately 10% of all primary brain tumors) are a benign proliferation of Schwann cells arising from the myelin sheath of the vestibular branch of cranial nerve VIII. These tumors are slightly more common in women, present at an average age of 50 years, and occur bilaterally in patients with neurofibromatosis type II. The most common presenting symptoms are hearing loss, tinnitus, and ataxia. MRI typically shows an enhancing, well-defined mass in the cerebellopontine angle, extending into the internal auditory meatus (Fig. 5-13). The mainstay of treatment for vestibular schwannoma has long been surgical resection, which has been significantly refined during the past 20 years.10,11 Results have been improved by use of the operating microscope, improved understanding of the involved microsurgical anatomy, modifications of the various approaches to access the tumor site, and intraoperative neurophysiologic monitoring of the facial and cochlear nerves. Recent reports from centers that have extensive experience with surgical management of vestibu-

Medulloblastoma Medulloblastomas account for 7% to 8% of all primary CNS tumors and nearly one third of all childhood brain tumors. They are also called infratentorial PNETs. In children, the tumors are almost always within the fourth ventricle whereas in adults a more lateral, cerebellar hemispheric location may be found. The overwhelming majority of children present with symptoms of increased ICP due to obstructive hydrocephalus. MRI usually reveals an enhancing, sharply delineated fourth ventricle mass. Much like ependymoma, the role of surgery is to relieve the hydrocephalus and to attempt a radical tumor resection. Extent of tumor resection is thought to correlate with survival. Unlike ependymomas, these are clearly malignant tumors, with a propensity to metastasize throughout the cerebrospinal fluid. Adjuvant radiation therapy, with posterior fossa doses of at least 5000 cGy, and craniospinal doses

Figure 5-13. T1-weighted enhanced axial MR image shows enhancing lesion in the right cerebellopontine angle. Note that the lesion extends into the internal auditory canal, in a manner characteristic of vestibular schwannoma.

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lar schwannomas confirm the efficacy and relatively low morbidity of this mode of treatment.12 Many institutions have also documented their successful experience with radiation surgery for small acoustic tumors. For tumors less than 3 cm in diameter, radiosurgery offers a one-time outpatient alternative to surgery. Success rates of greater than 90% are routinely reported. Modern dosimetry methods have reduced the complication rate to less than 5% facial or trigeminal neuropathy, which compares favorably with most surgical series.

Meningiomas Meningiomas are common tumors that result from proliferation of meningothelial cells. They account for approximately 20% of primary brain tumors, affect predominantly middle-aged patients, and have a 2 : 1 predilection for females. Like vestibular schwannomas, they are generally noninvasive, pathologically benign, and tend to behave indolently, but the natural history of any particular case is unpredictable. Clinical presentation is variable, includes seizures, hemiparesis, visual field loss, aphasia, and other focal findings, and is determined in large part by the location of the tumor. MRI typically shows a homogeneously enhancing, well-defined mass, with a dural attachment (Fig. 5-14). Surgical resection is the long-standing treatment of choice for all operative candidates.13 In Black’s 1993 review of the contemporary management of meningiomas, overall surgical mortality rates ranged from 7% to 14% in modern published series.14 Common surgical complications include hemorrhage, significant blood loss, and cortical deficits. Cranial nerve deficits may occur in skull base meningiomas, and these deficits, especially in the posterior fossa, may be very disabling. Like clinical presentation, surgical outcomes are largely dependent on the location of the tumor. Convexity, parasagittal and lateral sphenoid wing meningiomas are the most accessible and resectable. Cavernous sinus, petroclival, and foramen magnum locations present considerably greater technical challenges. The rate of postoperative recurrence of meningiomas is clearly dependent on extent of resection. In a classic paper from 1957, Simpson defined five classes of resection:15 grade I, complete removal, including resection of dural attachment and any abnormal bone; grade II, complete tumor removal with coagulation of dural attachment; grade III, complete tumor removal without resection or coagulation of dural attachments; grade IV, subtotal removal; and grade V, decompression only. Simpson reported 10-year recurrence rates of 9%, 19%, 29%, and 40% for grade I through grade IV resections, respectively. This trend has been confirmed in more recent series, and the higher recurrence rates associated with meningiomas in certain locations correlate with a

Figure 5-14. T1-weighted, contrast-enhanced axial MR image shows a homogenously enhancing lesion arising from the falx—a characteristic location and MRI pattern for a meningioma.

high frequency of subtotal resection due to poor accessibility or involvement of critical structures (e.g., sagittal sinus, cranial nerves, carotid artery). Radiation for meningiomas has been somewhat controversial given its implication as an etiologic factor in some meningiomas. However, most reports have demonstrated a beneficial effect.16 Several reports have demonstrated the efficacy of radiation therapy in preventing recurrence after subtotal resection. For example, Condra and associates reported 15-year local control rates of 76% after total excision, 87% after subtotal excision plus radiation therapy, and 30% after subtotal excision alone.17 Survival rates at 15 years were 51% for subtotal excision alone versus 88% and 86% for total excision and subtotal excision plus radiation, respectively. Because local recurrence was associated with lower survival rates, prompt postoperative radiation therapy was recommended after subtotal resection, rather than waiting until regrowth. Goldsmith and colleagues16 reported similar findings after a retrospective analysis of 140 patients at the University of California at San Francisco who received postoperative external beam radiation therapy after subtotal resection from 1967 to 1990. For patients with benign lesions, the

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overall 10-year progression-free survival rate was 77%. Results improved significantly with the advent of CT and MRI. After 1980, the 5-year progression-free survival rate for benign meningiomas thus treated improved to 98% from a pre-1980 rate of 77%. No secondary neoplasms occurred. These findings strongly suggest that postoperative radiation is beneficial if complete resection cannot be achieved. Successful outcomes from radiosurgery treatment of vestibular schwannomas and the encouraging results of conventional radiation therapy for meningiomas have led to enthusiasm about radiosurgery as a possible alternative treatment for meningiomas. A large number of reports now document the efficacy and safety of radiosurgery in the treatment of small meningiomas. Cure rates of greater than 90% are commonly reported.13,18 Radiosurgery is regarded by some as the treatment of choice for meningiomas that are high risk for surgery (e.g., cavernous sinus). Pituitary Adenomas Pituitary adenomas account for as many as 15% of all primary intracranial neoplasms. Symptoms are caused by pituitary hypersecretion, pituitary hyposecretion, or mass effects in the sellar areas.19 The most common hypersecretion syndromes are amenorrhea-galactorrhea (from prolactin hypersecretion), acromegaly (from growth hormone hypersecretion), and Cushing’s disease (from adrenocorticotropin hormone hypersecretion). Nonsecreting tumors are much more common and are often accompanied by pituitary hypofunction. Low levels of luteinizing hormone and follicle-stimulating hormone lead to amenorrhea in women and impotence in men. Additional hyposecretion symptoms include fatigue (hypocorticalism) and hypothyroidism (low thyroid-stimulating hormone secretion). An enlarging mass in the sella most commonly impinges on the optic chiasm, producing a bitemporal field cut. A sudden hemorrhage into a large pituitary tumor, called pituitary apoplexy, can produce sudden visual loss, endocrine failure (Addisonian crisis), and extraocular muscle dysfunction secondary to cavernous sinus compression. Pituitary tumors present at all ages. MRI typically shows an enhancing mass within the pituitary fossa (sella turcica) (Fig. 5-15). The treatment of choice for pituitary adenoma is complete surgical excision. This is most commonly accomplished through a transnasal, transphenoidal approach. For the majority of hypersecreting microadenomas, and many macroadenomas, surgery is curative. Complications of surgical treatment include cerebrospinal fluid leakage, visual dysfunction, hypopituitarism, and, rarely, carotid injury. If complete resection is not possible, multiple studies have demonstrated a greater than 90% 10-year tumor control rate with conventional radiation therapy.20–22 Microadenomas are also treatable with radiosurgery.

Figure 5-15. Coronal contrast-enhanced MR image shows pituitary tumor with impingement on the optic chiasm.

Figure 5-16. Contrast-enhanced axial MR image shows multiple enhancing lesions, most at gray-white junction locations, characteristic of metastatic brain tumors.

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Cerebral Metastases Metastatic brain tumors outnumber all other brain tumors combined. Each year, 75,000 to 140,000 new cases of brain metastases are diagnosed. Half are solitary. The incidence of metastatic tumors is increasing as cancer therapy leads to longer control of systemic disease. The most common primary tumors to metastasize to the brain are lung, breast, and renal carcinoma. Although less common tumors, melanomas have a very high propensity for spreading to the brain. Metastases can present with seizures (20%), focal neurologic deficit, or symptoms of increased ICP. Although gradually progressive symptoms are most common, sudden neurologic deficit may result from hemorrhage into a metastatic tumor. This is especially common with melanoma and choriocarcinoma. Contrast-enhanced MRI typically shows multiple lesions that enhance and are surrounded by significant edema (Fig. 5-16). Metastases tend to occur at the gray-white junction areas of the brain, where the blood vessels narrow to the point that metastatic deposits lodge and grow.

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The medical therapy of metastatic brain tumors includes the administration of anticonvulsant medications and the use of high-dose steroids (usually dexamethasone, 4 mg four times daily). Steroids usually produce rapid and dramatic relief of mass-effect symptoms by reducing the edema surrounding these tumors. Unfortunately the effect of steroids is short-lived (weeks at most) and steroids do have significant adverse effects when used for longer periods. Surgical treatment of a metastatic brain tumor is clearly indicated when it presents with significant mass effect.23,24 In addition, when there is no known primary cancer, surgical resection or stereotactic biopsy may be needed to establish a diagnosis. Conventional radiation therapy usually involves whole brain treatment to a dose of 3000 cGy. There is serious debate over the value of such therapy, because it is rarely curative and may cause significant neurocognitive side effects in long-term survivors. Radiosurgery has become an attractive alternative to whole-brain radiation therapy because it produces a higher local control rate and does not expose the whole brain to potential injury.25 The relative roles of surgery, radiation therapy, and radiosurgery are currently under investigation and are controversial.

P earls 1. The incidence of symptomatic intracranial tumors is approximately 12 per 100,000 persons per year. 2. The symptoms and signs of CNS tumors can generally be divided into three groups: those due to increased intracranial pressure, those due to focal irritative effects on the brain, and those due to focal destructive effects on the brain.3 3. Malignant tumors are usually associated with surrounding edema. Metastatic tumors tend to have more associated edema than gliomas.

References 1. Rubinstein LJ: Tumors of the Central Nervous System. Washington DC, Armed Forces Institute of Pathology, 1972. 2. DeAngelis LM: Brain tumors. N Engl J Med 2001;344:114–123. 3. Kaye AH, Laws ER: Brain Tumors: An Encyclopedic Approach. Edinburgh, Churchill Livingstone, 1995. 4. Apuzzo MLJ, Chandrasoma PT, Cohen D, Zee CS, Zelman V: Computed imaging stereotaxy: Experience and perspective related to 500 procedures applied to brain masses. Neurosurgery 1987;20:930–937. 5. Ostertag CB, Mennel HD, Kiessling M: Stereotactic biopsy of brain tumors. Surg Neurol 1980;14:275–283. 6. Friedman WA, Bova FJ: The University of Florida radiosurgery system. Surg Neurol 1989;32:334–342.

4. Conventional radiation therapy produces long-term tumor control rates of at least 75% for medulloblastoma, germinoma, pituitary adenoma, craniopharyngioma, and meningioma. Fewer than 50% of metastatic tumors will be cured by radiation therapy alone. 5. Radiosurgery can cure as many as 90% of treated acoustic schwannomas and meningiomas.

7. Friedman WA, Buatti JM, Bova FJ, et al: LINAC Radiosurgery—A Practical Guide. Berlin, Springer-Verlag, 1998. 8. Salcman M: Survival in glioblastoma: Historical perspective. Neurosurgery 1980;7:435–439. 9. Kondziolka D, Flickinger JC, Bissonette DJ, et al: Survival benefit of stereotactic radiosurgery for patients with malignant glial neoplasms. Neurosurgery 1997;41:776–785. 10. Ebersold MJ, Harner SG, Beatty CW, et al: Current results of the retrosigmoid approach to acoustic neurinoma. J Neurosurg 1992;76:901– 909. 11. Gormley WB, Sekhar LN, Wright DC, et al: Acoustic neuromas: Results of current surgical management. Neurosurgery 1997;41:50–60. 12. Samii M, Matthies C: Management of 1000 vestibular schwannomas (acoustic neuromas): Surgical management and results with an empha-

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13.

14. 15. 16.

17.

18.

19.

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sis on complications and how to avoid them. Neurosurgery 1997;40: 11–23. Hakim R, Alexander III E, Loeffler JS, et al: Results of linear accelerator-based radiosurgery for intracranial meningiomas. Neurosurgery 1998;42:446–454. Black PM: Meningiomas. Neurosurgery 1993;32:643–657. Simpson D: The recurrence of intracranial meningiomas after surgical treatment. J Neurol Neurosurg Psychiatry 1957;20:22–39. Goldsmith BJ, Wara WM, Wilson CB, et al: Postoperative irradiation for subtotally resected meningiomas: A retrospective analysis of 140 patients treated from 1967 to 1990. J Neurosurg 1994;80:195–201. Condra KS, Buatti JM, Mendenhall WM, et al: Benign meningiomas: Primary treatment selection affects survival. Int J Radiat Oncol Biol Phys 1997;39:427–436. Shafron DH, Friedman WA, Buatti JM, et al: LINAC radiosurgery for benign meningiomas. Int J Radiation Oncology Biol Phys 1999; 43:321–327. Kramer S: Diagnosis and Treatment of Pituitary Tumors. Amsterdam, Exerpta Medica, 1973, pp 217–229.

20. Grigsby PW, Stokes S, Marks JE, et al: Prognostic factors and results of radiotherapy alone in the management of pituitary adenomas. Int J Radiat Oncol Biol Phys 1988;15:1103–1110. 21. McCollough WM, Marcus RB, Rhoton AL, et al: Long-term follow-up of radiotherapy for pituitary adenoma: The absence of late recurrence after greater than or equal to 4500 centigray. Int J Radiat Oncol Biol Phys 1991;21:607–614. 22. Sheline GE, Tyrrell B: Pituitary adenomas. New York, Raven Press, 1984, pp 1–35. 23. Noordijk EM, Vecht CJ, Haaxma-Reiche H, et al: The choice of treatment of single brain metastasis should be made based on extracranial tumor activity and age. Int J Radiat Oncol Biol Phys 1994;29:711– 717. 24. Patchell RA, Tibbs PA, Walsh JW, et al: A randomized trial of surgery in the treatment of single metastases to the brain. N Engl J Med 1990;322:494–500. 25. Flickinger JC, Kondziolka D, Lunsford LD, et al: A multi-institutional experience with stereotactic radiosurgery for solitary brain metastasis. Int J Radiat Oncol Biol Phys 1994;28:797–802.

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Chapter 6 Hemorrhagic Cerebrovascular Disease Pascal M. Jabbour, MD, Issam A. Awad, MD, MSc, FACS, and Daniel Huddle, DO

General Principles of Critical Care of Hemorrhagic Stroke

stroke. In this chapter we review the general principles of critical care for hemorrhagic stroke and specific interventions in the setting of various etiologies.

Epidemiology and Significance Hemorrhagic stroke, including intracerebral hemorrhage (ICH) and subarachnoid hemorrhage (SAH), constitutes 23% to 25% of all stroke cases.1,2 It is a catastrophic event, occurring when a cerebral vessel ruptures spontaneously and causes brain damage. Hemorrhagic stroke kills or disables most of its victims, and accounts for more than half of stroke-related deaths, disabilities, and costs.3 Hemorrhagic stroke typically refers to a spontaneous hemorrhage, as opposed to bleeding caused by trauma. The age-adjusted incidence of ICH is 10 to 15 per 100,000 per year, with a mean age of 65, and its incidence doubles with each decade of life above age 45.1,4,5 Most ICHs in younger patients are caused by a vascular malformation, coagulopathy, or drug use, while the vast majority of intracerebral bleeds affecting the elderly are caused by hypertensive or amyloid angiopathy. The incidence of SAH has been estimated at 6 to 30 per 100,000 per year, with a mean age of 50 years.6,7 Most nontraumatic SAHs are caused by a ruptured intracranial aneurysm affecting the circle of Willis or its branches. It has been estimated that up to 30% of SAH cases die from initial effects of hemorrhage, with half of the survivors dying or being disabled from rebleeding or other sequelae. The prompt recognition, acute resuscitation, and early diagnostic evaluation and therapeutic intervention have vastly improved the outcome of patients with hemorrhagic

Recognition, Transport, and Acute Resuscitation Acute Evaluation The hallmark characteristics of the clinical presentation of hemorrhagic stroke are the sudden onset of headache, loss of consciousness, and focal neurologic symptoms. A careful history from prehospital witnesses or family can identify some features of onset of the symptoms (e.g., headache preceding loss of consciousness), or other risk factors (e.g., use of anticoagulation, other drugs, untreated hypertension, or known preexisting vascular anomaly) raising suspicion about a hemorrhagic stroke. Regardless, the possibility of hemorrhagic stroke must be raised in any case of unexplained loss of consciousness or severe headache, with or without other neurologic symptoms.8 Whenever hemorrhagic stroke is suspected, and after stabilization of vital signs (airway, respiratory support, and blood pressure), urgent referral to a center where diagnostic evaluation can be carried out and subsequent treatment can be instituted must be considered. Coagulation parameters are tested and a toxic screen performed for possible drug use. During transport, patients must be kept comfortable, with good control of pain, anxiety, and agitation. The airway must be secured in all but fully conscious patients; blood pressure is closely controlled; anticonvulsant prophylaxis is administered; and reversal of coagulopathy is initiated. 155

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Diagnosis and Etiology of Hemorrhagic Stroke A computed tomography (CT) scan of the brain is the imaging of choice when a hemorrhagic stroke is suspected, with near absolute sensitivity and specificity. It will differentiate between an ischemic stroke and hemorrhagic one, and between an SAH and an ICH (Figs. 6-1 and 6-2).8 The localization of the hemorrhage combined with the characteristics of the onset of symptoms, and the patient’s risk factors will help determine a possible etiology and the need for further diagnostic studies. The mere diagnosis of hemorrhagic stroke, its broad type (ICH versus SAH), and any associated hydrocephalus can allow the institution of early management interventions to minimize neurologic and systemic sequelae. In ICH, a search for etiology is often undertaken more electively, when the patient is otherwise stabilized, or if urgent surgical intervention is being entertained for hematoma evacuation. Administration of contrast material can often highlight suspected vascular abnormalities on CT scan (Fig. 6-3), and a CT angiogram (Fig. 6-4) can be useful when the patient is not stable enough for formal catheter angiography. For cases in which the clinical presentation is typical of SAH urgent definition of the etiology is indicated, because early rebleeding from ruptured aneurysm is common and potentially catastrophic. If the CT scan is negative or questionable in a case where there remains clinical suspicion of SAH, a lumbar puncture should be performed and CSF should be examined for xanthochromia and for red blood cell count. Lumbar puncture is not indicated, and may be harmful, if the CT scan already confirms the diagnosis of hemorrhagic stroke.

Figure 6-1. CT scan showing polycisternal subarachnoid hemorrhage. The cause is most likely aneurysmal.

Figure 6-2. CT scan showing lobar intracerebral hemorrhage. In older patients, the most likely etiology is amyloid angiopathy. In younger patients, an underlying tumor or vascular malformation is likely. Coagulopathy may cause such a bleed at any age.

Four-vessel cerebral angiography remains the gold standard for detecting aneurysms and for planning their most optimal therapy (Fig. 6-5). It should be performed as soon as possible in patients with SAH. Angiographic techniques have recently been enhanced by three-dimensional rotational angiography, allowing a dramatic spatial rendition of the vascular anatomy (Fig. 6-6). Magnetic resonance angiography (MRA) and computed tomographic angiography (CTA) may detect intracranial aneurysms but with lesser sensitivity and spacial resolution than angiography (Figs. 6-4 and 6-7). These tests may be performed urgently if a catheter angiogram is not promptly available. They are also quite useful in highlighting the anatomy of giant aneurysms, especially thrombosed portions not filling on angiography (Fig. 6-8). Magnetic resonance imaging (MRI) is more sensitive than CT scan for detecting structural abnormalities such as tumors and vascular malformations9 and is used when these etiologies are suspected, as in ICH in younger patients (Fig. 6-9). Catheter angiography remains the most sensitive study for detecting arteriovenous malformations and should be performed in younger patients with ICH to exclude this

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Figure 6-5. Angiogram revealing basilar summit region aneurysm.

Management Strategy

Figure 6-3. Contrast-enhanced CT scan showing middle cerebral artery aneurysm.

etiology (Fig. 6-10). It also should be performed, urgently, as in cases of SAH, whenever an ICH communicates with the circle of Willis or its branches (Fig. 6-11), or if contrast CT or MRI/MRA suggest a possible cerebral aneurysm (see Figs. 6-3 and 6-7).

Figure 6-4. CT angiogram performed by computer reconstruction of thin-cut high-resolution CT scan with contrast material reveals an aneurysmal dilation at the middle cerebral artery.

ABCs of Multisystem Support The acute resuscitation of hemorrhagic stroke follows the general guidelines of the “ABC” rules of airway, blood pressure, and cerebral perfusion. The airway should be cleared, and any patient with a Glascow coma scale (GCS) score of 8 or less, or unable to protect the airway, should be intubated. A good oxygen saturation is not sufficient and does not reflect the arterial partial pressure of carbon dioxide (PaCO2), so even if the saturation is normal, one should make sure that the patient is not hypercapnic because this may worsen

Figure 6-6. Three-dimensional (3D) rotational angiogram in the same case depicted in Figure 6-5, revealing much more spacial resolution than in the conventional angiogram images. The information in 3D angiography can help guide therapeutic decisions regarding endovascular versus surgical intervention.

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Figure 6-7. MRA revealing a carotid summit berry aneurysm. This is an excellent modality for screening patients for aneurysms. A negative MRA is insufficient to exclude aneurysm in a patient with subarachnoid hemorrhage.

Figure 6-9. Magnetic resonance image of intracranial arteriovenous malformation showing nidus of abnormal vessels as flow voids in the brain.

intracranial hypertension. A central line and an arterial line should be inserted. Blood pressure should be controlled aggressively (Table 6-1); hypertension and hypotension should be avoided.

A

Intracranial Pressure and Cerebral Perfusion The cerebral perfusion pressure (CPP) is the pressure gradient responsible for cerebral blood flow and its compromise results in cerebral ischemia. The CPP is defined as mean arterial pressure minus intracranial pressure (MAP - ICP). Monitoring of ICP can be used to guide CPP management1,10 whenever intracranial hypertension is suspected or is potentially compromising cerebral perfusion. Elevated ICP is defined as intracranial pressure exceeding 20 mm Hg for longer than 5 minutes. The goal of treatment for elevated ICP is less than 20 mm Hg and CPP greater than 60 to

B Figure 6-8. Magnetic resonance imaging of partially thrombosed giant aneurysm. A, T1-weighted imaging. B, T2weighted imaging.

Figure 6-10. Angiogram revealing arteriovenous malformation nidus.

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Table 6-1  Blood Pressure Management in Hemorrhagic Stroke

Figure 6-11. CT scan in a comatose patient with massive subarachnoid hemorrhage and intracerebral hemorrhage (plus subdural hemorrhage). Such a patient is taken emergently for surgical evacuation of hematoma with or without contrastenhanced CT scan, but without taking additional time for conventional angiography.

70 mm Hg.11 An ICP monitor should be placed in all patients with a GCS score of 8 or less or who could be suffering elevated ICP and cannot be followed by a neurologic examination. Intraparenchymal fiberoptic ICP monitors and intraventricular monitors are commonly used, with the former being more accurate and less vulnerable to obstruction, while the latter allows simultaneous drainage of cerebrospinal fluid to treat elevated ICP. Intracranial hypertension can be treated by draining cerebrospinal fluid, by decreasing brain tissue bulk or cerebral blood volume, or by sedation and decreasing brain metabolic demands. External ventricular drainage allows diversion of cerebrospinal fluid in cases of hydrocephalus (Fig. 6-12), or whenever ICP exceeds a certain level. This may be performed continuously (by titrating the level of the drip chamber) or intermittently depending on intracranial pressure. External ventricular drainage is ineffective if the ventricles are “slit-like” from brain edema, overdrained, or if the catheter is obstructed by clotted blood. Brain bulk may be treated to lower ICP with osmotherapy using mannitol (0.25 to 0.5 g/kg every 4 hours) and furosemide (10 mg every 2 to 8 hours), and these are administered alternately or simultaneously as needed for ICP waves. Serum osmolarity and sodium concentrations should

From Broderick JP, Adams HP, Barsan W, et al: Guidelines for the management of spontaneous intracerebral hemorrhage. A statement of healthcare professionals from a special writing group of the stroke council, American Heart Association. Stroke 1999;30:905, with permission.

be measured at least twice a day to target an osmolarity less than 310 mOsm/L,8 and fluid administration should aim to maintain euvolemia and normonatremia. Osmotherapy

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cannot be used to treat ICP if extremes of hypovolemia and hypernatremia are allowed to develop. Hypocarbia (PaCO2 25 to 35 mm Hg) decreases the ICP by causing a cerebral vasoconstriction, and this can be very effective in acute crises with waves of elevated ICP. Extreme hyperventilation (PaCO2 < 20 mm Hg) can exacerbate brain ischemia by decreasing cerebral blood flow. Hyperventilation should also not be used for a long time because it can become ineffective with metabolic adjustment to respiratory alkalosis. Further response to life-threatening ICP waves becomes ineffective after chronic hyperventilation, and the patient becomes vulnerable to rebound increased ICP when restoring normocapnea.8 Sedation (propofol, benzodiazepine, or morphine) with neuromuscular paralysis can reduce elevated ICP, and it does so by preventing agitation and straining, and by decreasing brain metabolic demands. If the ICP is still high despite maximizing all the previous medical treatments, induced barbiturate coma may be instituted with continuous electroencephalographic (EEG) monitoring. Central and arterial lines are used, and even a pulmonary artery catheter and pressors, if needed, to maintain hemodynamic support during barbiturate-induced coma.8 Barbiturates can decrease ICP in proportion to the level of sedation, down to EEG burst suppression. Further administration of barbiturates beyond effective EEG burst suppression offers no additional benefits of ICP control, while increasing toxic complications. Decompressive craniotomy allows control of ICP by opening the cranial vault and dura, allowing therapeutic herniation of cerebral tissue. It is used in cases of diffuse hemispheric cerebral edema from ischemic or hemorrhagic stroke, and is discussed elsewhere in this book (see Chap. 25).

Anticipation and Treatment of Delayed Sequelae In patients with SAH, the major cause of early death during the first 24 hours is rebleeding from an unsecured aneurysm.6,12 Controlling blood pressure helps to prevent rebleeding after aneurysmal rupture and may minimize the risk of hematoma expansion in ICH.8 The coagulation parameters should also be checked and corrected if needed to avoid rebleeding. In the case of SAH and intraventricular hemorrhage, or any hemorrhage compromising the CSF circulation pathways, acute hydrocephalus should be suspected and treated with a ventriculostomy, performed as a quick bedside procedure (see Fig. 6-12). Subsequent lumbar punctures or permanent ventriculoperitoneal shunting may be performed for subacute and chronic hydrocephalus. The breakdown products of subarachnoid blood are probably responsible for spasm in cerebral arteries following SAH.6,13 Vasospasm begins 3 to 5 days after the SAH and may last for 2 to 3 weeks, during which time the brain is vulner-

able to further ischemic insults. Nimodipine at 60 mg orally every 4 hours for 21 days should be started on the day of admission as it has been shown to decrease neurologic sequelae from vasospasm and/or reperfusion injuries.6,14,15 Noninvasive monitoring for vasospasm should be instituted during this vulnerable period, with other treatments instituted (hypertensive, hyperdynamic, hemodilution [HHH] therapy and endovascular interventions) if there is evidence of progression or neurologic symptoms. All patients with hemorrhagic stroke should be loaded with anticonvulsant to prevent early seizures,1 which can increase rebleeding and elevate ICP. Patients who experience acute seizures and those with cortical parenchymal hemorrhages may benefit from longer-term anticonvulsant prophylaxis. The breakdown of the blood-brain barrier in ICH will cause edema in the brain around the hematoma. This edema can be managed by fluid intake restriction, diuretics, and osmotherapy.

Systemic Complications of Hemorrhagic Stroke Hemorrhagic stroke has been shown to induce subendocardial ischemia, proportional to the severity of neurologic insult. Electrocardiographic changes, elevation of myocardiac enzymes, ventricular wall motion abnormalities, cardiogenic pulmonary edema, and life-threatening arrhythmias can occur in patients with hemorrhagic stroke especially in the acute phase.16,17 These do not typically alter the course of the illness, and should not generally prevent timely interventions for diagnosis or therapy. Cardiac complications can be life threatening in the setting of preexisting cardiac disease, or after multisystem complications of illness or therapies (i.e., myocardiac depression by barbiturates). These complications should be monitored and treated prophylactically. Pulmonary complications may develop for a variety of reasons. The patients with poor neurologic grade are at increased risk of aspiration, atelectasis, pneumonia, and pulmonary embolism.18 Neurogenic pulmonary edema is a complication that occurs after significant neurologic insult, and consists of leakage of protein-rich fluid into the pulmonary alveoli. It is believed to be due to the disruption of the endothelial barrier in response to massive sympathetic discharge.19 Volume overload during HHH therapy for vasospasm can cause or exacerbate pulmonary edema; for this reason pulmonary artery catheter-optimized hemodynamics are often used with this therapeutic modality. Hyponatremia is common in patients with hemorrhagic stroke.7 It may result from two mechanisms, the syndrome of inappropriate antidiuretic hormone (SIADH) with free water retention, or inappropriate natriuresis (also known as cerebral salt wasting) mediated by the atrial natriuretic

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A B Figure 6-12. Patient with subarachnoid hemorrhage and severe hydrocephalus. Before (A) and after (B) placement of ventriculostomy catheter.

factor (ANF) and brain natriuretic peptide (BNP).20,21 Determining the likely cause is important because the two syndromes are managed differently. Hyponatremia is treated with fluid restriction in the setting of SIADH, as is common after ICH. Hyponatremia is treated with hypertonic fluid and salt replacement in natriuresis syndrome, common after SAH. The fluid balance (intake versus output), urine sodium concentrations, urine and sodium osmolality, and the clinical setting assist in differentiating the two syndromes. Patients who suffer SAH have been shown to be predominantly fluid contracted from inappropriate natriuresis. Especially during periods of vulnerability to vasospasm, these patients can suffer irreversible brain infarctions if they are further fluid restricted. Volume and salt maintenance are the mainstay of therapy during vasospasm after SAH. Hypernatremia may be caused by diabetes insipidus (DI) and should be treated with free water replacement and vasopressin.6 Gastroduodenal erosions may develop in patients with sustained cerebral injuries (Cushing ulcers). Prophylaxis against this complication is instituted using gastric ulcer

pharmacotherapy, stomach pH management, and early enteric feeding. Patients’ hematocrit and stool guaiac status should be determined daily, and any decrease in the hematocrit should be investigated. Gastrointestinal motility is often compromised in acute neurologic illness, or as a result of pharmacologic sedation, especially with barbiturates and opiates. Monitoring of gastric emptying should be ongoing via nasogastric tube in unconscious patients, and early enteric feeding encouraged whenever possible. Early percutaneous gastrojejunostomy may prevent aspiration complications in patients with decreased level of consciousness or impaired swallowing, and allow removal of nasal tubes with enhanced comfort, ease of care and rehabilitation, and prevention of nasal septomucosal erosion and sinusitis. Patients with diarrhea should be investigated for treatable causes, including alteration of feeds and possible intoxication from Clostridium difficile. Fever can be caused by noninfectious sources such as medications, deep venous thrombosis, or neurogenic causes. Nevertheless close monitoring of patients for any source of infection is important, keeping in mind the vascular catheter

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insertion sites, ventriculostomies, pneumonitis, and urinary tract infections. Early tracheotomy in patients with impaired level of consciousness can minimize pulmonary complications and allow earlier mobilization and rehabilitation. Pneumonia should be treated aggressively with antibiotics, mobilization of secretions, and bronchoscopy, if necessary. Timing and Management of Underlying Cause The timing and management of the underlying cause of hemorrhagic stroke depend on the patient’s neurologic status, the type of hemorrhagic stroke, and the underlying etiology. This subject will be addressed in detail later in this chapter. Any accessible hematoma with serious mass effect and impending herniation should be evacuated emergently regardless of the cause (see Fig. 6-11). In SAH, securing the aneurysm should be done early to prevent rebleeding. In arteriovenous malformations (AVMs), treating the etiology is generally deferred until the patient is stable and until the brain edema decreases because risk of early rebleeding from most AVMs is not high. Psychosocial Support, Mobilization, and Rehabilitation Hemorrhagic stroke is a catastrophic illness, with lifealtering consequences to patients and families. Aggressive care and invasive interventions should be tempered by the patient’s advanced directives, his or her expressed wishes communicated through the family, and evidence-based assessment of realistic prognosis. Survival in severely disabled or vegetative states has been described by families as “worse than death.” This is particularly true if there is evidence of catastrophic brain damage or if the patient’s quality of life or life expectancy is already significantly compromised by advanced age or previous illness. Otherwise, outcome predictions remain less than certain, and patients with apparently dire illnesses can still achieve dramatic recoveries. This is especially true in younger patients.3 An ongoing evaluation of response to treatments, reassessment of prognosis, and open lines of communication with family are essential throughout the illness, with frequent revision of therapeutic stance. Counseling and spiritual support services can be very helpful during every phase of the illness. Decisions on withdrawal of care and determination of brain death are handled with the utmost sensitivity and a sense of patient advocacy (see Chap. 30). Organ donation options are best presented by a separate team uninvolved in the patient’s acute critical care, so there is never the remotest perception of conflict of interest or compromise of advocacy. On recovery from the acute and most critical and dangerous phases of the illness, there must be ongoing education about expectations during recovery and rehabilitation, and about expected quality of life and the risks and benefits of various interventions, including treatment of residual lesions which might cause recurrent hemorrhagic stroke. All

management considerations are guided by considerations of quality of life3 integrated over the patient’s remaining life expectancy.22 Options of rehabilitation are reviewed in detail, considering the availability of ongoing neurologic and medical care, and also the proximity of services to patients’ home and family (see Chap. 29). Special rehabilitation needs are considered, such as higher executive functions in relation to prior occupation. Advocacy is maintained in negotiations with insurance carriers and managed care plans. Early evaluation for rehabilitation and the coordination and overlap between acute care interventions and rehabilitation services are encouraged, to hasten recovery. Communication is maintained with the patient’s primary care providers and local physicians to ensure optimization of long-term prophylaxis, therapies, and follow-up.

Subarachnoid Hemorrhage Etiology Intracranial Aneurysm The prevalence of cerebral aneurysms in the population is estimated to range between 0.2% and 7.9%, with greater prevalence in older patients.23 This etiology is considered to be responsible for 70% to 80% of spontaneous SAHs. Aneurysms are known to develop at vessel bifurcations, points of maximum hemodynamic stress. The ones associated with infection or trauma tend to occur more distally in the circulation. Eighty percent to 90% of aneurysms affect the anterior (or carotid) circulation, at the anterior communicating artery, posterior communicating artery, middle cerebral artery, and other locations. Ten percent to 20% of aneurysms affect the posterior (or vertebrobasilar) circulation, most likely at the basilar summit and at the posterior inferior cerebellar arteries, and other locations. Aneurysms can be classified by shape, with the great majority of aneurysms saccular or berry shaped, involving an eccentric pathology of the arterial wall, usually at a branching point. A small fraction of aneurysms are fusiform, with or without saccular protrusions, reflecting more diffuse vessel wall pathology, including arteriopathy, dissection, or infection. Saccular aneurysms are classified by size; small, if less than 10 mm in diameter (78%); large, from 10 to 24 mm in diameter (20%); and giant, if more than 24 mm in diameter (2%). The pathogenesis of saccular aneurysms is not fully understood, although their risk factors appear to be both congenital and acquired. Some systemic conditions are associated with the presence of cerebral aneurysms. These include connective tissue disorders (including EhlersDanlos syndrome, Marfan syndrome), autosomal dominant polycystic kidney disease, fibromuscular dysplasia, and atherosclerosis, but these account for only a small fraction of all aneurysms. Approximately 20% of patients with

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aneurysms have a family history of aneurysm affecting a first-degree blood relative.24 Hypertension and smoking appear to contribute to the risk of aneurysm formation, and also the risk of hemorrhage.6 Risk of hemorrhage increases with larger aneurysm size.7 The annual risk of hemorrhage for unruptured aneurysms varies between 0.1% and 5% to 10% per year, with highest risks in giant aneurysms. Higher bleed risk also occurs in patients who have bled from another aneurysm, and in aneurysms at certain locations (basilar summit and anterior communicating arteries).25,26 Twenty percent of patients harbor multiple aneurysms.

Vascular Malformations Vascular malformations are a heterogeneous group of lesions categorized as proposed by McCormick in 1966,27 including the AVMs, cerebral cavernous malformations (CCMs), capillary malformations or telangiectasia, and venous malformations or angiomas (also known as venous developmental anomalies). Less than 10% of patients with SAH are found to have an AVM as etiology for the bleeding,28 and this usually occurs in association with a parenchymal ICH or intraventricular hemorrhage. The prevalence of AVMs is 14 per 10,000 population.29 Patients diagnosed with AVMs have an average age 10 years younger than those diagnosed with aneurysms.30 The average risk of hemorrhage from an AVM varies between 2% and 4% per year.31 Seven percent to 10% of the AVMs have an aneurysm enclosed in the malformation, located on the feeding arteries or in the nidus, and when present, this is more often the source of hemorrhage than the nidus proper.32 The CCMs are uncommonly the cause of SAH, when adjacent to a pial or ependymal surface, and these are often associated with an adjacent venous angioma. The venous angioma is rarely the sole source of hemorrhage. Another vascular anomaly that can cause SAH or ICH is the dural arteriovenous malformation or fistula (Fig. 6-13), an indirect communication between a meningeal artery and a vein.33 Dural fistulae are usually acquired and frequently associated with thrombosis of a major venous sinus. They are composed of a network of dilated dural meningeal arterial capillaries, usually within the wall of a dural sinus, that shunt in a retrograde fashion into a leptomeningeal vein, or antegrade into the dural sinus itself. They are classified according to the lesion location and pattern of venous drainage.33,34 The cardinal feature affecting risk of aggressive clinical behavior of dural arteriovenous malformations, including hemorrhage, is the presence of leptomeningeal venous drainage. Spinal vascular malformations35 can rarely cause subarachnoid hemorrhage, and they should be sought and excluded in cases with associated myelopathy, or if the symptoms of SAH include severe neck or back pain.

Figure 6-13. Angiogram of external carotid injection showing a dural arteriovenous fistula with cortical venous drainage. Such a lesion commonly presents with intracerebral or subarachnoid hemorrhage.

Arterial Dissection Arterial dissection is the extravasation of blood from the true lumen of a vessel through the arterial wall and it can affect extracranial or intracranial vessels. Yamaura36 suggested three types: (1) dissection between the intima and the media with luminal compromise; (2) dissection between the media and the adventitia with aneurysm formation (Fig. 6-14); and (3) artery rupture and encapsulation of the hematoma causing a pseudoaneurysm (Fig. 6-15). When the dissected artery involves an intracranial segment within the subarachnoid space, there is a risk of subarachnoid hemorrhage due to the second or third mechanisms described by Yamaura. Arterial dissection can be spontaneous, associated with collagen vascular disease or fibromuscular dysplasia, or other arteriopathies. It can be post-traumatic following blunt or penetrating injury, or iatrogenic due to angiography catheters. Arterial dissection occurs in young adults.37 A large series of 260 cases36 found that the vertebral artery was the most common intracranial site, and the most common source of SAH from dissection. Arterial dissections account for less than 5% of SAH. Idiopathic Subarachnoid Hemorrhage and Benign Perimesencephalic Bleeds Other SAHs are idiopathic. The incidence of angiogramnegative SAH is estimated to be between 10% and 15%.38,39 A small fraction of these include an occult aneurysm, with

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Figure 6-16. Perimesencephalic SAH. Cerebral angiogram did not reveal an aneurysm. A perimesencephalic SAH may also be attributed to basilar aneurysm or other causes. Figure 6-14. Angiogram of patient with severe subarachnoid hemorrhage, revealing dissection of the vertebral artery, with double lumen and small aneurysmal dilatation.

incomplete or misread angiogram, poor filling of aneurysm due to flow patterns or thrombosis, or parent vessel vasospasm. A second or third angiogram may reveal occult aneurysm. The pretruncal nonaneurysmal SAH is a benign entity.40,41 It includes primary SAH in perimesencephalic

Figure 6-15. Angiogram showing traumatic pseudoaneurysm arising from disruption of the internal carotid artery by basilar skull fracture.

cisterns without involvement of other cisterns (Fig. 6-16). Schwartz and Solomon presented follow-up data on 169 patients with perianeurysmal SAH and negative angiogram for 8 to 51 months, and did not document any instance of rebleeding. The cases also were found to have lower risk of vasospasm and better overall outcome than aneurysmal SAH.42 It is thought that the cause of hemorrhage in such cases may be a small perimesencephalic vein.43 It must be emphasized that perimesencephalic SAH may also be caused by ruptured basilar or superior cerebellar or posterior cerebral artery aneurysms, so it remains a diagnosis of exclusion after a negative, good quality cerebral angiogram. An SAH involving other cisterns reflects a higher risk of missed or occult aneurysm or dissection. This can be revealed on repeat angiograms or with MRI or CTA scans. Some experts have recommended surgical exploration of SAH with negative angiograms, involving the interhemispheric or Sylvian cisterns, likely revealing occult anterior communicating or middle cerebral artery aneurysms, respectively.44 Other Causes Other causes of SAH include unrecognized trauma, coagulation disorder, vasculitis, tumor,45 pituitary apoplexy,46 cocaine use,47 sickle cell disease, and infection (endarteritis or septic embolism). Hemorrhagic stroke including SAH has been reported at higher incidence in women using certain vasoactive drugs including decongestant cold remedies and diet pills containing phenylpropranolamine.48

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Clinical Presentation The typical presentation of SAH is a sudden onset of severe headache, “thunderclap,” or the worst headache the patient has ever experienced.1 The presentation could also be a seizure, loss of consciousness, or altered level of consciousness. Some circumstances may precipitate the rupture of an aneurysm like physical efforts, postural modification, or intense emotions. Other associated symptoms in the wake patient may include photophobia, nausea, double vision, or neck stiffness. Clinical signs may include hypertension, meningismus, cranial neuropathy, altered level of consciousness, focal neurologic deficit, and ocular hemorrhage. Subarachnoid hemorrhage is frequently misdiagnosed, with dire clinical consequences and a poorer outcome among misdiagnosed cases.49 Hence a concerted level of clinical suspicion should always accompany any clinical presentation suggestive of possible SAH. Among chronic headache sufferers, the headache of SAH is typically different and more severe than other previous headaches, and may be associated with a sense of impending doom.50 The patient’s level of consciousness is a cardinal determinant of outcome after subarachnoid hemorrhage, and it can affect treatment decisions as well as prognostication. It can be assessed using the Hunt and Hess grade (Table 6-2), or the World Federation of Neurological Surgeons scoring system (Table 6-3). The former is quite simple and widely used, while the latter grade has been shown to have better positive and negative predictive power in relation to outcome, especially among high-grade patients.6,51–54 Cases with cranial neuropathy may represent elevated ICP (abducens or oculomotor palsies), or aneurysmal compression on the cranial nerve (posterior communicating artery or superior cerebellar artery aneurysm compression on the oculomotor nerve). Other focal neurologic deficits likely imply an ICH in addition to the SAH, as is common with middle cerebral artery aneurysms, associated ischemic event, or mass effect from giant aneurysm. Vascular malformations and fistulae are more likely to cause ICH than SAH, but could result in both. Aneurysmal bleeds from anterior

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Table 6-3  World Federation of Neurologic Surgeons (WFNS) Subarachnoid Hemorrhage Grade WFNS Grade

Glasgow Coma Scale Score

Major Focal Deficit

0 (intact aneurysm) 1 2 3 4 5

— 15 13–14 13–14 7–12 3–6

— Absent Absent Present Present or absent Present or absent

From Drake CG: Report of World Federation of Neurological Surgeons Committee on a Universal subarachnoid hemorrhage grading scale. J Neurosurg 1988;68:985, with permission.

communicating artery and basilar summit, or from posterior inferior cerebellar artery aneurysms may cause intraventricular hemorrhage (Fig. 6-17), and this in turn may cause ventricular obstruction and account for decreased level of consciousness.

Table 6-2  Hunt and Hess Classification Scale Grade I II III IV V

Neurologic Status Asymptomatic; or minimal headache and slight nuchal rigidity Moderate to severe headache; nuchal rigidity; no neurologic deficit except cranial nerve palsy Drowsy; minimal neurologic deficit Stuporous; moderate-to-severe hemiparesis; possibly early decerebrate rigidity and vegetative disturbances Deep coma; decerebrate rigidity; moribund appearance

From Hunt WE, Hess RM: Surgical risk as related to time of intervention in the repair of intracranial aneurysms. J Neurosurg 1968;28:14, with permission.

Figure 6-17. Severe intraventricular hemorrhage from rupture of anterior communicating artery aneurysm. Note bilateral intraventricular catheters used to drain the ventricles pending endovascular treatment of the aneurysm. Subsequent clotting of the catheters required intraventricular tissue plasminogen activator administration for clot lysis and restoration of ventricular drainage (this treatment is contraindicated if aneurysm is not secured).

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Diagnostic Evaluation The diagnosis of an SAH must be executed rapidly because of dire consequences of rebleed or misdiagnosis. It is usually done with a simple nonenhanced brain CT scan, which can detect the SAH in as many as 95% of the cases (see Fig. 6-1).55 The amount of SAH is evaluated by the Fischer grading system, which has a prognostic value in predicting the risk of vasospasm and overall patient outcome (Table 6-4).56 In the cases where the presentation is typical and the CT scan is negative or questionable, a lumbar puncture should be done and CSF should be examined for xanthochromia and for red blood cell count. The latter should not drop between the first and the last tube because this would more likely reflect a traumatic tap rather than SAH. Once the diagnosis of SAH has been made, a four-vessel cerebral angiogram will typically reveal the etiology of the bleed. In the cases where the angiogram fails to show the etiology, MRI should be performed to rule out any angiographically occult lesion. The angiogram should be repeated 1 to 2 weeks after the first study if the source of the SAH is still indeterminate. In arterial dissection the cerebral angiogram may reveal one of the following findings: luminal stenosis, complete occlusion, double lumen sign (see Fig. 6-14), fusiform dilation (see Fig. 6-14), frank extravasation of dye, or pseudoaneurysm (see Fig. 6-15). An arterial dissection may be associated with normal luminal filling on angiography, and is not excluded by negative results on angiography. The MRI image with axial T1 sequences and MRA source images are more sensitive than catheter angiography (and the reconstructed MRA) for the diagnosis of an arterial dissection. They reveal a crescent sign, which is the hematoma in the vessel wall, as a bright signal surrounding the signal void of the carotid or vertebrobasilar arteries on axial T1-weighted or source images. If angiography does not reveal the source of SAH, a systematic search of other causes is undertaken, including an MRI of the brain and spine, performed with and without contrast and with dissection detection protocol. This would reveal occult vascular malformations, dissections, or tumors. If none is found, a repeat cerebral angiogram is performed, Table 6-4  Fischer Grading System of Severity of Subarachnoid Hemorrhage

From Fisher CM, Kistler JP, Davis JM: Relation of cerebral vasospasm to subarachnoid hemorrhage visualized by CT scanning. Neurosurgery 1980;6:1, with permission.

1 week or more later, this time with external carotid selective injections in addition to traditional four-vessel views, to exclude dural fistula (see Fig. 6-13). A second angiogram is not performed if another definite etiology of SAH is found or if the bleed was solely limited to perimesencephalic cisterns and if the first angiogram was of excellent quality. Critical Care Management The acute resuscitation of SAH follows the general guidelines discussed previously for hemorrhagic stroke in general. • Any patient with a GCS score of 8 or less or unable to protect the airway should be intubated, especially for planned transport. • Anticonvulsant prophylaxis should be administered as soon as possible because seizures can increase morbidity and brain edema. A central venous line and an arterial line should be inserted to assist with acute management. • Blood pressure should be controlled aggressively, and both hypertension and hypotension should be avoided (see Table 6-1). Hypertension should be avoided because of the presumed presence of an unsecured vascular lesion. Hypotension should be avoided because it could compromise cerebral perfusion, especially in the setting of elevated ICP in an unconscious patient. • Coagulation parameters should be examined and corrected promptly. • The patient should be given stool softeners to avoid any physical effort that could cause rebleeding of the cerebral aneurysm. • Pain management should be optimized, and the patient should be transferred as soon as possible to a critical care environment where these measures are maintained along with other multisystem homeostasis, as further diagnostic and therapeutic interventions are planned. Timing of Intervention The major cause of death in patients who survive an initial aneurysmal SAH is rebleeding. The timing of intervention should consider this risk, and there is a general consensus that good-grade patients should have early intervention to eliminate the aneurysm from the circulation within the first 48 hours.12 In experienced neurovascular centers, early treatment of aneurysm is also performed on poor-grade patients if they are hemodynamically stable.57 Arterial dissection that has caused an SAH also mandates early therapeutic intervention aimed typically at excluding the dissected segment from the circulation. Other causes may require urgent treatment, such as correction of coagulopathy. Rebleeding from tumors and vascular malformations is not common in the early phase, and treatment of these lesions is typically deferred until the patient is stabilized and optimal plans for lesion therapy are made.

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Specific Treatment of Underlying Cause of Subarachnoid Hemorrhage: Endovascular Endosaccular aneurysm occlusion with platinum coils has been shown to be a safe and effective treatment option when performed by an experienced team. The goal of treatment is to obliterate and promote thrombosis of the aneurysm sac (see Chap. 7). This technique appear to be most effective in nongiant aneurysms with narrow necks and in poor surgical candidates.1 The recently published International Subarachnoid Aneurysm Trial (ISAT)58 is the only prospective randomized trial that compared endosaccular coiling to surgical clipping in ruptured aneurysms suitable for both treatments and observed for 1 year; this study concluded that coiling is significantly more likely to result in survival free of disability 1 year after SAH than surgical treatment.58 Yet fewer than 25% of eligible patients (1% to 40% at the various centers) in ISAT were randomized, while the others received treatment thought best by their physicians. Hence the results of this study cannot be generalized to patients with aneurysmal SAH, but rather are applicable to cases where a well-thoughtout discussion between endovascular and surgical experts does not favor one treatment over another. Aneurysms were more likely to rebleed after coiling than surgery, and to require retreatment, especially aneurysms with broader neck and at certain locations.58 Morbidity rate after coiling was close to 4% with 1% of mortality in a systemic review.59 One series of 75 patients treated with coiling found a 5% incidence of rebleeding within 6 months of treatment, complete obliteration was achieved in 40%, 37% had residual necks, and angiographic recurrences occurred in 24%.60 While coiling may be favored in certain cohorts such as in the ISAT, or in aneurysms at certain locations, such as the basilar summit,61,62 and in older or sicker patients,63 there is no evidence that the introduction of coiling has improved overall outcome of aneurysm treatment at large neurovascular centers.64 Other endovascular interventions have an important role in the management of SAH. Parent vessel occlusion, performed with endovascular coils or glue, can be used for occlusion of distal vessels harboring aneurysm, as in mycotic or traumatic aneurysms, and aneurysms on feeding vessels of AVMs. More proximal parent vessel occlusion, using endovascular balloons or coils, is performed in cases of fusiform aneurysm or dissection.65 This is preceded by balloon test occlusion under full anticoagulation and clinical monitoring, and is often deferred until patient is stabilized and awakened to tolerate test occlusion, and also until vasospasm has subsided because occlusion of a major artery poses a significant ischemic risk during vasospasm. Newer endovascular treatments include stents and balloon-assisted coiling of aneurysms with broad neck. Endovascular adjuncts, including proximal control, suction

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decompression, and intraoperative angiography have enhanced surgical treatment of certain aneurysms such as giant lesions and those at paraclinoid locations.66 Endovascular coiling may be used in cases where surgery has failed to completely clip an aneurysm, and the residual neck is narrow. Specific Treatment of Underlying Cause of Subarachnoid Hemorrhage: Surgical Microsurgical clipping remains the definitive method for exclusion of an aneurysm and prevention of rebleeding.1 Surgery is not favored if the patient is unstable, in poor medical condition, or in the setting of intractable elevated ICP. Surgery is specifically indicated and should be performed emergently for cerebral aneurysm whenever there is an associated ICH causing or threatening herniation syndrome (see Fig. 6-11), as is common with middle cerebral aneurysms with temporal clots and anterior communicating or carotid aneurysms with deep frontal clots. Surgery for hematoma and aneurysm clipping should be perfomed emergently, and if necessary without cerebral angiography. An emergent enhanced CT scan should follow a regular CT scan before surgical intervention whenever there is a blood clot with a suspicion of aneurysm or vascular malformation rupture. This will often show the suspected lesion and avoid unexpected findings at surgery, such as more complex lesion than anticipated. An aneurysm should always be sought and clipped at the time of hematoma evacuation, but an AVM does not require excision at the same setting unless the patient is stable and the lesion is simple and well defined. Intraoperative or immediate postoperative angiography (before awakening) may be considered if there is any question about adequacy of treatment of aneurysm, especially if angiography was not performed preoperatively. Complications of Therapy A range of potential complications are associated with endovascular or surgical therapy. Aneurysm rupture may occur during attempted coiling or surgical clipping. This is typically handled with emergent technical maneuvers, but may result in untoward sequelae. Coils or clips may compromise parent vessels, their branches, or perforating vessels, and thromboembolism may occur during endovascular or surgical manipulation of blood vessels—all causing a spectrum of ischemic complications. These are prevented by judicious anticoagulation during endovascular interventions, and by verification of vessel patency by micro-Doppler insonation or intraoperative angiography. They are treated according to the specific clinical scenario, as with interventions for brain ischemia discussed elsewhere in this text.

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Hydrocephalus Hydrocephalus is documented in 15% to 20% of patients with SAH.67,68 It is explained by blood interfering with CSF circulation in the ventricles, sylvian aqueduct, or the basal cisterns.69 A ventriculostomy should be performed whenever there is ventriculomegaly on the CT scan, especially if associated with altered mental status or with intraventricular hemorrhage (see Figs. 6-12 and 6-17). It is a bedside procedure, using a sterile technique and compact cranial access kits for twist drill or burr hole. In one study there was an improvement in 80% of the patients in whom this was used.67 Overdrainage should be avoided because it can provoke aneurysmal rebleeding67,70,71 by rapid modification of the transmural pressure. Overdrainage may also precipitate slit ventricles and prevent further cerebrospinal fluid drainage for treatment of elevated ICP. Optimal ventricular drainage aims to keep ICP below 10 to 15 mm Hg. Ventriculostomy is also performed in conjunction with aneurysm surgery to enhance brain relaxation for access to the aneurysm, and in cases of decreased level of consciousness, regardless of ventricular size, to monitor and assist in ICP management. Infection occurs in 5% to 10% of cases undergoing ventriculostomy.1,72,73 This is minimized by optimizing sterile technique at catheter insertion, by tunneling and carefully caring for the catheter exit site, by avoiding unsterile breach of the draining system, and by prophylactic intravenous antibiotics. Ventricular infections are best detected before fulminant ventriculitis and meningitis, by frequent (every 1 or 2 days) cerebrospinal fluid sampling for gram stain, cell counts, glucose, protein, and cultures. These infections are treated by optimizing intravenous antibiotic coverage, intrathecal antibiotics, and by changing the infected catheter. More than half of patients who undergo ventriculostomy are weaned from cerebrospinal fluid drainage in the first 2 weeks after SAH. This is assisted by a gradual increase of drainage threshold, intermittent clamping of ventriculostomy, or by intermittent lumbar punctures. Ventriculoperitoneal shunting, or the permanent implantation of a ventricular diversion system, is performed in cases where external ventricular drainage cannot be weaned, and symptomatic ventriculomegaly persists 1 to 2 weeks after SAH.74

infarctions in up to one third of patients with SAH. The risk of vasospasm increases with the severity of SAH as assessed on Fisher grade. Delayed neurologic deterioration after SAH is presumed due to ischemic sequelae of vasospasm unless proven otherwise, or attributed to other causes. The diagnosis of symptomatic vasospasm is supported by clinical evidence of spasm by transcranial Doppler (TCD) or angiography (see later discussion), and/or evidence of ischemia on diagnostic tests of cerebral blood flow (although such tests are not widely available, and are by themselves nonspecific to vasospasm). Symptomatic vasospasm is exacerbated by dehydration (hypovolemia) and by hypotension. The precise pathogenesis of vasospasm is not yet totally understood. The breakdown products of subarachnoid blood are probably responsible for initiating the vasospasm response in arteries of the circle of Willis and its branches.13 Vasospasm may be monitored noninvasively by insonating the circle of Willis vessels and its branches using TCD (Fig. 6-18). This bedside procedure has a high sensitivity

A

Vasospasm Monitoring, Prophylaxis, and Therapy Monitoring and Prophylaxis of Vasospasm Several days after SAH, there is an inflammatory reaction in blood vessels bathed in subarachnoid blood, resulting in luminal narrowing. The phenomenon, known as vasospasm, affects 60% to 70% of patients after SAH, and results in symptomatic ischemia in approximately half those cases. It reaches its maximal severity in the second week after SAH, and typically resolves spontaneously in the third or fourth weeks. Vasospasm causes death or serious disability from

B Figure 6-18. Transcranial Doppler insonation of intracranial artery. A, Normal tracing with mean velocity below 100 cm/sec and peak systolic velocity below 140 cm/sec. B, Severe vasospasm tracing with mean velocity exceeding 150 cm/sec and peak systolic velocity exceeding 240 cm/sec.

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and specificity for vasospasm, but requires technical expertise and experience.75 The course of TCD documented vasospasm correlates closely with the course and clinical sequelae of vasospasm detected on angiography, and its severity closely reflects clinical sequelae of brain ischemia. Angiography may be used to confirm vasospasm in clinical situations in which the cause of delayed neurologic deterioration is questionable, TCD findings are nonconcordant with clinical progress, or endovascular therapy for vasospasm is being contemplated. Otherwise, TCD has largely replaced catheter angiography for the mere diagnosis of vasospasm, as catheter angiography carries definite risks, and the contrast dye load may exacerbate hypovolemia and precipitate or worsen clinical manifestations of spasm. Additionally, the dye load may impair renal function. Vasospasm prophylaxis includes pharmacologic therapy, judicious hydration, and volume and blood pressure support. Nimodipine, 60 mg orally or by nasogastric tube administered every 4 hours, for 21 days after SAH has been shown to significantly decrease the clinical sequelae of symptomatic vasospasm. Curiously, orally administered calcium channel blockers have not been shown to decrease the incidence of angiographic or TCD vasospasm. It has also been suggested that early surgery, with washing of the subarachnoid cistern, may help prevent vasospasm by clearing blood breakdown products. The same has been suggested for external ventricular drainage after SAH. Intravascular volume and blood pressure are judiciously maintained during the period of vulnerability to vasospasm, commencing 2 to 3 days after SAH. By then, risk of aneurysm rebleeding ought to have been eliminated by surgery or endovascular treatment, as the “spasm watch” phase of the illness is entered. During this phase, TCD is monitored every day or every other day. Close attention is given to monitoring of fluid balance, electrolytes, and central venous pressure, as indices of adequate hydration. Hyponatremia is treated with hypertonic saline rather than dehydration. Blood pressure parameters are liberalized, by withholding antihypertensives. Nimodipine is given more frequently in divided doses (30 mg every 2 hours) or held altogether if blood pressure is low. Any hint of neurologic deterioration is closely correlated with TCD findings to diagnose symptomatic vasospasm. Volume maintenance is gradually tapered following the period of vulnerability to vasospasm, and confirmed by resolving TCD velocities. Hypertensive, Hyperdynamic, Hemodilution Therapy Hypervolemia and induced hypertension are instituted in cases of TCD velocities indicating severe vasospasm (mean TCD velocities exceeding 150 cm/sec or peak systolic velocities exceeding 200 cm/sec in the anterior circulation vessels), or if there is any hint of neurologic deterioration attributed to vasospasm.76 Central venous pressure monitoring is mandatory in these cases, with a low threshold for

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introducing a pulmonary artery catheter for optimizing volume resuscitation. Pressors are used to induce hypertension, titrated in proportion to TCD velocities, or to reverse ischemic neurologic deficits. Typically, volume status is aimed at a CVP value between 8 and 10 mm Hg. If the step to a pulmonary artery catheter is made, pulmonary artery wedge pressure (PAWP) or end diastolic volume indices (EDVI) are titrated through the creation of a pressure-volume (Starling) curve. This curve details the lowest PAWP or EDVI with the highest cardiac index. The fluid loads used for the generation of this relationship may be either isotonic crystalloid or 5% albumin solution. Simply pushing fluids to make the PAWP an arbitrary number is not an acceptable manner of handling hemodynamics, as one may either overshoot the optimal cardiac filling volume (or pressure) or keep the patient volume “underloaded.” Systolic blood pressure is maintained at blood pressure greater than 160 to 180 mm Hg. True hemodilution is no longer advocated as the goal of HHH therapy, for fear of inducing anemia and limiting oxygen carrying capacity to the brain. In fact, a hematocrit less than 30% is treated with red blood cell transfusion, while a hematocrit of between 40% and 45% is generally treated with volume expansion and iatrogenic hemodilution in the ICU setting. Alternated crystalloids and colloids are used for volume resuscitation, and dopamine or neosynephrine infusions are used for induced hypertension, after withholding all antihypertensive agents.6 Endovascular Therapy Cases of worsening vasospasm despite hyperdynamic therapy are considered for endovascular treatment.77–80 The precise threshold for endovascular interventions remains controversial, with some centers advocating early and frequent endovascular treatment of spasm, while other centers reserve endovascular intervention for cases where symptomatic vasospasm does not respond to hyperdynamic therapy. It is clear that not all cases of severe TCD spasm will require endovascular intervention, and such therapy introduces an added risk that must be considered and weighed. Conversely, endovascular treatment of spasm should not be delayed until actual infarction has developed. Endovascular treatment of spasm consists of balloon angioplasty, best used for large-vessel spasm (Fig. 6-19), or intra-arterial vasodilator infusions, papaverine or verapamil, best used for more distal branch vasospasm (Fig. 6-20). Angioplasty is associated with greater risk of arterial rupture or dissection, especially if applied to more distal vessels, but its effect is more durable than intra-arterial pharmacologic infusions.81–83 The latter may need to be repeated daily, driven by clinical response and monitoring of TCD velocities. With aggressive monitoring, prophylaxis, HHH therapy, and judicious use of interventional techniques, morbidity from vasospasm can be minimized to less than 5% of SAH patients.84

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A

Figure 6-19. Angiogram of severe basilar artery vasospasm. Before (A) and after (B) balloon angioplasty.

Outcome after Subarachnoid Hemorrhage Subarachnoid hemorrhage is associated with significant morbidity and mortality. Despite affecting patients in the middle years of their lives, often without other preexisting or associated diseases, it is estimated that 25% to 50% of all SAH patients will die as a result of their bleed. A common cause of death is neurologic damage from the initial bleed, with 10% of patients estimated to die before reaching a medical facility, while others reach medical attention in poor condition. Many survivors are left with persistent physical, cognitive, behavioral, and emotional changes that affect their day-to-day lives. The most common predictor of death or major disability after SAH is the patient’s clinical condition at presentation.50,53,54 Age, medical morbidities, severity of hemorrhage on CT, and aneurysm type (giant or posterior circulation) are also correlated with poorer outcome.85–90 Other patients are initially in good condition, and deteriorate in the setting of misdiagnosis, from rebleed, as a result of therapeutic complications, or from vasospasm or other medical or neurologic sequelae of the disease.

Much of what is discussed in this chapter and elsewhere in this book, as well as ongoing advances in surgical and endovascular therapy will further reduce mortality and morbidity from SAH. Those who survive will benefit from early rehabilitation.91 Some studies showed an improvement in the Functional Independence Measure (FIM) after an inpatient rehabilitation stay.91,92 The quality of life of those who apparently recover with minimal disability may still be impaired by cognitive, psychological, and emotional sequelae. Recognition and intervention for these higher functional deficits may further improve the quality of life of patients inflicted by this disease. The clinical outcome after SAH cannot be addressed at a single point in time, without regard to whether the aneurysm has been treated effectively. It is essential to note whether the aneurysm may still pose a risk of future rupture, and what additional follow-up and retreatments may be indicated. These questions of long-term durability of treatment, and the impact on quality of life and future risks, are essential when addressing relative benefits of endovascular versus surgical interventions.

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B A Figure 6-20. Angiogram of severe middle cerebral artery vasospasm. Before (A) and after (B) intraarterial verapamil infusion.

Intracerebral Hemorrhage Etiology Hypertensive Small Vessel Disease The major risk factors for primary ICH are age, hypertension, and alcohol abuse.1,93,94 The most frequent sites of hypertensive ICH are the putamen (50%) (Fig. 6-21), thalamus (15%), pons (10% to 15%), and cerebellum (10%).2 The relative risk of ICH with hypertension is increased 3.9- to 5.4-fold.93 Hypertensive arteriopathy includes arterial and arteriolar sclerosis, dilated perivascular Virchow-Robin spaces (“état criblé”), and deep brain matter ischemic degeneration (“leukoaraoisis”), all likely predisposing to hemorrhage. Deep ganglionic hypertensive bleeds are often caused by miliary aneurysms,95 also known as microaneurysms of Charcot-Bouchard. They occur at bifurcation of small perforators of lenticulostriate arteries mainly in hypertensive patients.96 Deep ganglionic hemorrhages occur at any age in the setting of uncontrolled hypertension, but their prevalence increases exponentially with each decade above age 60.

Outcome of hypertensive bleeds is mostly determined by the volume of hemorrhage, patient age, neurologic condition at presentation, and clot location (anterior ganglionic bleeds of caudate and putamen have a better outcome than thalamic or pontine bleeds). Amyloid Angiopathy Amyloid angiopathy, also known as congophilic angiopathy, is associated with degeneration of lobar parenchymal vessels in advancing age. It is found at autopsy in the brains of one third of patients older than 60 years of age.97 It consists of the deposition of beta amyloid protein within the media of small meningeal and cortical vessels.98 Fibrinoid necrosis of the vessel wall is also present in some vessels.99,100 This arteriopathy is thought to predispose to lobar ICH (see Fig. 6-2), mostly in subcortical white matter.101 It is thought to account for 10% to 32% of nontraumatic ICH.102 It has a better prognosis than deep basal ganglia bleed.102 Coagulopathy The risk of ICH is increased in patients on warfarin, estimated at 0.3% per year and increasing with advancing age

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Figure 6-21. Deep (ganglionic ICH). Most common cause is hypertension, although an underlying vascular anomaly must be sought if patient is young or has no history of hypertension. A, At presentation. B, After placement of catheters in the ventricle for treatment of hydrocephalus, and in the clot for thrombolytic drainage of ICH. C, After five doses of intra-clot ICH performed twice daily, with serial aspiration of ICH.

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and with uncontrolled hypertension.103 The risk of hemorrhage is the highest during the first 3 months of anticoagulation104 and with extremes of anticoagulation. In one series, the only fatal bleeding complication related to warfarin therapy was ICH.104 Thrombolytic therapy for ischemic stroke and acute MI is also associated with increased risk of ICH.105–107 Aspirin treatment is associated with a risk of ICH at a rate of 0.2% to 0.8% per year.103,108 Patients with amyloid angiopathy are also at increased risk of ICH with anticoagulant therapy.109 Vascular Malformations The average risk of hemorrhage from an AVM varies between 2% and 4% per year, typically causing an ICH (Fig. 6-22), and less commonly intraventricular hemorrhage and SAH.31 Hemorrhage is frequently associated with arterial feeder aneurysm, nidal aneurysm, venous varices, and venous outflow obstruction of AVM nidus.32 An AVM hemorrhage is associated with 10% mortality and 30% to 50% morbidity.110

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Angiographically occult vascular malformations, including cavernous malformation, can cause ICH and yet be occult on angiography. These also are difficult to detect on MRI when obscured by overlying hematoma. It is important to suspect such lesions as the cause of ICH, especially in younger patients. If surgical evacuation and exploration of hematoma is not undertaken, a follow-up MRI is mandatory, after resolution of ICH, to detect underlying lesions. Intracranial Aneurysm ICH is an uncommon presentation of an aneurysm rupture (see Fig. 6-11). When ICH is present, it is almost always associated with an SAH or IVH component, or the hematoma is contiguous with a major subarachnoid artery. The middle cerebral artery aneurysm is most frequently associated with ICH, although aneurysms at all locations can also do it.111 Venous Occlusive Disease Many conditions have been incriminated in cerebral venous thrombosis including birth control pills,112 otitis media,113,114 pregnancy and puerperium,115 dehydration, closed head injury, hypercoagulable state, and postcraniotomy. Venous occlusion results in hyperemic brain edema and extravasation of blood into the surrounding brain parenchyma, predisposing to SAH or ICH.116 Postoperative Hemorrhage The frequency of clinically significant postoperative intracerebral hemorrhage varies between 0.8%117 and 3.9%.118 Other minor contusional changes are quite common after craniotomy. Usually the hemorrhage occurs at the site of surgery, but cases are also reported remote from the surgical bed.119,120 Blood pressure and coagulation parameters have been implicated in the majority of these bleeds.117 ICH can also occur after carotid endarterectomy or stenting, and is known as cerebral hyperperfusion syndrome.121

Figure 6-22. CT scan with contrast in a young patient revealing a frontal ICH and an adjacent AVM. The location of AVM would not have been expected from CT scan without contrast. Contrast-enhanced CT scan should always be performed before surgical evacuation of ICH to avoid unexpected findings and complications at surgery. The hematoma was evacuated emergently at primary procedure, without disrupting the AVM. Following recovery from acute event, the AVM was embolized and excised surgically.

Drug Use Hemorrhagic stroke and ICH in particular have been associated with the use or abuse of a variety of drugs including cocaine,122,123 amphetamines,124 cannabis,125 and nasal decongestant and diet drugs containing phenylpropranolamine.126,127 Women are more predisposed to the latter etiology.127 The mechanisms of hemorrhage are thought to include drug-induced vasculopathies, hemodynamic effects of drug use (notably hypertension), and bleeding from an associated brain pathology (vascular malformation or aneurysm). Other Causes There are other known etiologies of ICH, including hemorrhagic transformation of an ischemic stroke,128 primary vasculitis of the central nervous system, endarteritis from septic emboli, and primary and metastatic brain tumors. In the latter category, the most important etiology is glioblastoma

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multiforme and metastases from melanoma, renal cell carcinoma, and choriocarcinoma.129–131 Tumors often exhibit contrast enhancement on MRI, and may be detectable within or adjacent to ICH. Multiple metastases may also be seen on MRI. Otherwise, a late MRI is indicated, as with occult vascular malformations, to exclude underlying lesions after resolution of ICH. Presentation and Diagnosis Clinical Presentation The classic presentation of ICH is sudden onset of headache, decreased consciousness, a focal neurologic deficit slowly progressing over hours, nausea, vomiting, and elevated blood pressure.1,8 The acute onset of thunderclap headache is typical of aneurysm rupture and is not documented classically with other etiologies. The neurologic examination including hemiparesis, ataxia, sensory disturbances, gaze syndromes, and cranial neuropathies can often suggest the ICH location.1 The level of consciousness at clinical presentation often deteriorates in the first hours after ICH, correlating with expansion of hematoma volume. Diagnostic Evaluation It is important to obtain a detailed history about the onset of symptoms, medical risk factors, anticoagulation, drug abuse, and head trauma. The history by itself can orient toward a possible etiology, as with drug use or uncontrolled hypertension. Preliminary laboratory testing should include coagulation parameters, blood cell counts, electrolytes, drug screen, and liver function tests.1 A CT scan is the best initial imaging modality for the diagnosis of acute ICH. An enhanced brain CT scan should typically be performed before any invasive interventions, to highlight suspected vascular abnormalities or underlying structural lesions as etiology of ICH. The CT scan also assists in determining the volume of the ICH in cubic centimeters by a simple equation, based on ellipsoid volume: volume = (A ¥ B ¥ C)/2, where A is the maximal diameter of hematoma in centimeters on its largest axial cut, B is its diameter in centimeters in the dimension perpendicular to A on the same axial cut, and C is the height of the hematoma. C is calculated by multiplying the number of slices on which the hematoma is visible (excluding the first and last cuts just showing its extremes) by the slice thickness of the CT scans in centimeters.132,133 The estimated hematoma volume in cubic centimeters is an important prognostic indicator, and may influence surgical indications. The MRI/MRA can be useful in identifying ICH etiologies including AVMs, cavernomas, tumors, and aneurysms. Although MRI may miss small aneurysms and vascular malformations, it is superior to CT and angiography in detecting cavernous malformations. Lesions may often be

obscured by overlying blood on early imaging after ICH. A delayed MRI will often reveal underlying structural lesions that may have been obscured by overlying ICH in the acute state. Cerebral four-vessel angiography remains the gold standard for the diagnosis of aneurysms and AVMs, and should be performed in younger patients where the etiology of ICH is not known. An angiogram should be performed urgently when ICH extends into a subarachnoid cistern, and could represent intracranial aneurysm. A contrast-enhanced CT or a CT angiogram can be performed in lieu of four-vessel angiography in unstable patients, or in patients taken for urgent surgery because of impending herniation from ICH. For the evaluation of AVM, the angiogram may be delayed until the patient is stable, because early rebleeding is not common from AVMs. An AVM may be compressed by mass effect on early angiography after ICH, and may fill more readily on delayed angiograms. Critical Care Management Acute Resuscitation The principles of airway management are as considered previously in this chapter for hemorrhagic stroke in general and for SAH. Blood pressure should be controlled closely8,134 because hypertension may contribute to rebleeding within the first hours after ICH.135 However, excessive reduction of blood pressure should be avoided so as not to compromise the cerebral perfusion pressure. In patients with a history of hypertension, the mean arterial pressure should be maintained below 130 mm Hg.11 Vasopressors, albumin, and crystalloid boluses can be used to treat hypotension. The American Heart Association evidence-based guidelines for blood pressure control in ICH are summarized in Table 6-1.8 Patients with ICH should be kept euvolemic or relatively dry to avoid exacerbations of brain edema. Hyponatremia should be monitored and treated as appropriate for SIADH because it can exacerbate brain edema and lower seizure threshold. Seizures can contribute to neuronal injury and systemic instability, especially in the acute state after ICH, so anticonvulsant prophylaxis is administered acutely (phenytoin 17 mg/kg as a loading dose, then 100 mg every 8 hours) and tapered after 1 month if the patient is seizure free.8 Intracranial Pressure Intracranial hypertension is the main cause of death in ICH. Elevated ICP is defined as intracranial pressure greater than or equal to 20 mm Hg for greater than 5 minutes. The goal of treatment is ICP less than 20 mm Hg and cerebral perfusion pressure greater than 60 to 70 mm Hg (see Chap. 25).136 Patients with ICH and GCS score less than 9, or who cannot be followed up by neurologic examination are considered for hematoma evacuation or ICP monitoring. The type of device

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depends on availability and experience. Intraventricular ICP monitors and intraparenchymal fiberoptic ICP devices are two commonly used methods of monitoring ICP.8 Ventriculosomy is favored in cases without slit ventricles because it allows cerebrospinal fluid drainage for treatment of elevated ICP, and is essential in cases of hydrocephalus or intraventricular hemorrhage associated with ICH. Cerebral compartment herniation can occur from ICH in the setting of low or moderate ICP, especially with ICH in the frontal or temporal lobes, and in cases of cerebellar or brainstem hematomas. Direct destructive effects of expanding ICH may cause much neurologic damage without elevated ICP. Intracranial pressure monitoring and management are not considered as substitutes for hematoma evacuation if ICH volume and the clinical situation warrant it (see later discussion). Medical Therapy Therapeutic measures for blood pressure control, correction of coagulopathy, and seizure prophylaxis are continued after the acute resuscitation. Measures for ICP control are instituted as discussed previously, but these should never be considered in lieu of hematoma evacuation as appropriate.8 Fluid management is aimed at minimizing brain edema, and hence judicious fluid restriction is instituted with close follow-up of electrolytes. There is no evidence that steroids are generally beneficial in the treatment of ICH, and they may increase systemic complications. Attention to multisystem homeostasis is maintained, including judicious prevention and treatment of pneumonia and other sepsis, and the use of tracheotomy and percutaneous feeding tube if long-term impairment of consciousness is anticipated. Surgical Therapy Ventricular Drainage and Intraventricular Thrombolysis Obstructive hydrocephalus may require ventriculostomy placement and external cerebrospinal fluid drainage. This can be a lifesaving maneuver, and has contributed to many dramatic recoveries after intraventricular hemorrhage. Ventricular catheters often occlude from clot (see Fig. 6-17), which limits their effectiveness. This drawback has recently been effectively and safely managed with intraventricular instillation of thrombolytic agent (1 to 2 mg of tissue plasminogen activator, administered through the catheter every 8 to 12 hours as needed to maintain patency). This intervention is only considered if a structural cause (tumor, AVM, or unsecured aneurysm) or coagulopathy have been excluded as causes of ICH. Ventricular catheters are managed as discussed previously for SAH, with gradual weaning and consideration of ven-

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triculoperitoneal shunting if hydrocephalus persists after the acute stage. Hematoma Evacuation The patient’s clinical condition, co-morbidities and life expectancy, the size and location of the hematoma, and the presence of an underlying etiology are all primary factors in the decision whether to evacuate an ICH. Aggressive interventions should be avoided in patients in poor neurologic state, those with premorbid conditions limiting life quality or expectancy, or with specific advance directives. Hematoma evacuation is also avoided when ICH affects the brainstem or diencephalon and the patient is elderly or deeply comatose. Patients with favorable life expectancy, especially younger patients, who are deteriorating rapidly from large lobar ICH should undergo emergent hematoma evacuation regardless of the underlying etiology and without waiting for further elaborated imaging. Cerebellar or temporal lobe ICH causing any mass effect or neurologic impairment should be evacuated urgently because of high risk of dire complications from subsequent herniation.8,137 A contrast-enhanced CT scan may be helpful at revealing unexpected etiology, and may avoid unexpected findings and complications at surgery. Associated aneurysm is clipped at the time of hematoma evacuation if at all possible. In younger patients, clot evacuation is performed with a thorough microsurgical exploration of the cavity because of high likelihood of underlying structural lesion as etiology of ICH. If a simple vascular malformation or tumor is associated with ICH, it is dealt with during the same procedure. Otherwise, the blood clot is removed and thorough hemostasis and brain relaxation are ensured. The patient is allowed to recover and any underlying lesion is further investigated and tackled at a subsequent stage when brain edema has subsided and under the most optimal conditions and preparations for addressing a complex lesion.137 This may include subsequent preparatory embolization, or a modified surgical approach (see Fig. 6-22). If the brain is swollen or anticipated to likely swell, the dural layer is not closed, and the bone flap is left out (frozen or implanted in the patient’s preperitoneal fat) for subsequent autogenous cranioplasty after brain swelling has subsided. In certain situations, imaging cannot exclude an underlying occult lesion as the cause of ICH in a young patient with favorable life expectancy. Even if the patient is neurologically stable or the ICH is not particularly large, ICH evacuation may be performed if it can be accomplished at very low risk, as in young patients with superficial bleeds, along with microsurgical exploration for underlying etiology (see Fig. 6-2). Often, such patients recover faster because of evacuation of clot, and earlier surgery provides a more generous cavity for exploring and resecting underlying lesion that may have required surgery anyway at a later time. Early surgery also avoids any risk, however small, of rebleeding while

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waiting for hematoma to resolve. If early surgery is not performed in a young patient with ICH, delayed follow-up is always planned, with subsequent imaging for underlying lesion after ICH has resolved. When underlying structural lesion is not suspected, as in elderly or severely hypertensive patients with a negative contrast-enhanced CT scan, the role of hematoma evacuation is controversial.1 Lobar ICH in a patient neurologically stable and with a volume less then 20 cc should be treated conservatively, with close clinical and radiographic follow-up,1,8 while surgery is recommended in deteriorating young patients with large lobar hematomas.138,139 Cerebellar hemorrhage is usually a surgical emergency because of the risk of brainstem compression and sudden death, and some nonrandomized studies have favored the evacuation of every cerebellar hematoma greater than 3 cm in diameter.136,138–140 The management of deep thalamic and ganglionic hematomas is complex. A large Japanese prospective registry concluded that medical therapy was superior to surgery in patients with minimal neurologic impairment or clots smaller than 15 cc. In comatose patients there was an apparent reduction in mortality in the surgical group but very poor functional recovery.141 Randomized studies reported to date on surgical removal of ICH have not shown a clear benefit of open surgical evacuation (most of these studies did not randomize younger patients with active neurologic deterioration who were most likely to benefit from surgery). Several studies have indicated a potential benefit of ICH evacuation when performed using minimally invasive techniques (endoscopic or stereotactic aspiration rather than open surgery).142–145 The American Heart Association has published recommendations for surgical evacuation of ICH and these are summarized in Table 6-5.8 It may be that the benefits of ICH volume reduction are obviated by the morbidity of open surgery in older patients, while hematoma reduction may be beneficial if it can be performed noninvasively. One such technique of noninvasive evacuation is the thrombolysis of ICH using tissue plasminogen activator (tPA) or urokinase, and aspiration of hematoma through a catheter (see Fig. 6-21).146–150 One commonly proposed protocol advocates tPA infusion in the catheter in doses of 1 to 2 mg at 12-hour intervals, with open catheter drainage between instillation for deep or lobar ICH with volume greater than 15 to 20 cc.146 Early results are very encouraging regarding the safety and effectiveness of this ICH volume reduction technique in cases without underlying structural lesion and/or coagulopathy.146–148 The optimization of this technique, dose escalation studies, thorough assessment of clinical efficacy, and quality of life among survivors awaits more rigorous trials.

Table 6-5  Recommendations for Surgical Treatment of Intracerebral Hemorrhage

From Broderick JP, Adams HP, Barsan W, et al: Guidelines for the management of spontaneous intracerebral hemorrhage. A statement of healthcare professionals from a special writing group of the stroke council, American Heart Association. Stroke 1999;30:905, with permission.

cerebral herniation occurring mainly during the first week after ICH.152 Mortality rate is related to the size, location, and underlying etiology of the hematoma, and age of the patient. The 30-day mortality rate is approximately 44%.153 The subgroup of patients with lobar hemorrhage fares significantly better, with a mortality rate estimated at 11%.101 The most consistent predictor of a poor outcome, described in various studies are large ICH, with clots less than 15 cc in volume commonly resulting in good outcome, and those larger than 60 cc almost always resulting in death or serious disability.132,154–157 Patient age, in particular those older than 60 to 70 years, is an independent predictor of mortality and poor outcome. Other co-dependent factors influencing outcome include neurologic condition at presentation (poorer outcome in comatose patients), and clot location (poorer outcome in deep compared to lobar bleeds, in posterior compared to anterior ganglionic bleeds, and in brainstem hemorrhage). Survival is not uncommon in younger patients who are often disabled and their lives and careers permanently altered by sequelae of ICH. Even patients with apparently good outcomes by gross criteria suffer cognitive, emotional, or other more subtle limitations affecting their quality of life.

Summary and Conclusions Outcome after Intracerebral Hemorrhage ICH accounts for 10% to 13% of strokes,151 but is associated with a case fatality rate of 50%.2 The main cause of death is

Hemorrhagic stroke is a catastrophic disease with numerous factors that have an impact on clinical outcome and secondary sequelae. A thorough understanding of every facet of

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this illness and its potential complications has allowed a rational approach to its critical care management. Common aims are to minimize neurologic injury, prevent and treat systemic complications, enhance recovery, and prevent delayed recurrence and complications. Numerous interventions have been accredited by firm scientific evidence, while others depend on our best interpretation of current modalities and interventions. Much future research and rigorous documentation of outcome with various interventions will allow further refinements of the broad strategies outlined in this chapter. Current outcome predictions in hemorrhagic stroke, and the basis for clinical decisions, continue to be derived from

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group or cohort statistical associations, while we lack good models for absolute outcome prediction in individual patients based on all factors known to affect the outcome of this disease. Such absolute outcome prediction modeling should be possible in the near future with emerging megadatabases and advanced statistical techniques. These would ideally include confidence intervals (measures of uncertainty) of outcome predictions, and modifiable and unmodifiable variables in a given clinical situation, to help guide treatment decisions and prognostic judgments in individual patients.

P earls 1. Hemorrhagic stroke, including intracerebral hemorrhage (ICH) and subarachnoid hemorrhage (SAH) constitutes 23% to 25% of all stroke cases. 2. The age-adjusted incidence of ICH is 10 to 15 per 100,000 per year, with a mean age of 65, and its incidence doubles with each decade of life above age 45. 3. The incidence of SAH has been estimated at 6 to 30 per 100,000 per year, with a mean age of 50 years. 4. Magnetic resonance imaging (MRI) is more sensitive than CT scan for detecting structural abnormalities such as tumors and vascular malformations, and it is used when these etiologies are suspected, as in ICH in younger patients. 5. The acute resuscitation of hemorrhagic stroke follows the modified “ABC” guidelines of airway, blood pressure, and cerebral perfusion. The airway should be cleared, and any patient with a Glasgow Coma Scale (GCS) score of 8 or less or unable to protect the airway should be intubated. 6. Hyponatremia is common in patients with hemorrhagic stroke. It may result from two mechanisms, the syndrome of inappropriate antidiuretic hormone (SIADH) with free water retention or inappropriate natriuresis (also known as cerebral salt wasting) mediated by the atrial natriuretic factor (ANF) and brain natriuretic peptide (BNP). Determining the likely cause is important because the two syndromes are managed differently. 7. The incidence of angiogram-negative SAH is estimated to be between 10% and 15%. A small fraction of these include an occult aneurysm with incomplete or misread angiogram, poor filling of aneurysm due to flow pattems or thrombosis, or parent vessel vasospasm. A second or third angiogram may reveal occult aneurysm. 8. The typical presentation of SAH is a sudden onset of severe headache, “thunderclap,” or the worst

9.

10.

11.

12.

13.

14. 15.

16.

headache the patient has ever experienced. The presentation could also be a seizure, loss of consciousness, or altered level of consciousness. Subarachnoid hemorrhage is frequently misdiagnosed with dire clinical consequences and a poorer outcome among misdiagnosed cases. Hence a concerted level of clinical suspicion should always accompany any clinical presentation suggestive of possible SAH. Among chronic headache sufferers, the headache of SAH is typically different and more severe than other previous headaches and may be associated with a sense of impending doom. The major cause of death in patients who survive an initial aneurysmal SAH is rebleeding. The timing of intervention should consider this risk, and there is a general consensus that good-grade patients should have early intervention to eliminate the aneurysm from circulation within the first 48 hours. While coiling may be favored in certain cohorts such as in the ISAT, or in aneurysms at certain locations, such as the basilar summit, and in older or sicker patients, there is no evidence that the introduction of coiling has improved overall outcome of aneurysm treatment at large neurovascular centers. Many survivors of SAH are left with persistent physical, cognitive, behavioral, and emotional changes that affect their day-to-day lives. The most common predictor of death or major disability after SAH is the patient’s clinical condition at presentation. The major risk factors for primary ICH are age, hypertension, and alcohol abuse. The most frequent sites of hypertensive ICH are the putamen (50%), thalamus (15%), pons (10% to 15%), and cerebellum (10%). The classic presentation of ICH is sudden onset of headache, decreased consciousness, a focal neuroContinued

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logic deficit slowly progressing over hours, nausea, vomiting, and elevated blood pressure. The acute onset of thunderclap headache is typical of aneurysm rupture and is not documented classically with other etiologies. 17. The MRI/MRA can be useful in identifying ICH etiologies including AVMs, cavernomas, tumors, and aneurysms. Although MRI may miss small aneurysms and vascular malformations, it is superior to CT and angiography in detecting cavernous malformations. 18. Obstructive hydrocephalus may require ventriculostomy placement and external cerebrospinal fluid drainage. This can be a lifesaving maneuver and has contributed to many dramatic recoveries after intraventricular hemorrhage. 19. Lobar ICH in a patient neurologically stable and with a volume less than 20 cc should be treated conservatively with close clinical and radiographic follow-up,

while surgery is recommended in deteriorating young patients with large lobar hematomas. 20. Cerebellar hemorrhage is usually a surgical emergency because of the risk of brainstem compression and sudden death, and some nonrandomized studies have favored the evacuation of every cerebellar hematoma greater than 3 cm in diameter. 21. The most consistent predictor of a poor outcome, described in various studies, are large ICH, with clots less than 15 cc in volume commonly resulting in good outcome, and those larger than 60 cc almost always resulting in death or serious disability. 22. Survival is not uncommon in younger patients who are often disabled and their lives and careers permanently altered by sequelae of ICH. Even patients with apparently good outcomes by gross criteria suffer cognitive, emotional, or other more subtle limitations affecting their quality of life.

References 15. 1. Abdulrauf SI, Furlan AJ, Awad IA: Primary intracerebral hemorrhage and subarachnoid hemorrhage. J Stroke Cerebrovasc Dis 1999;8: 146. 2. Foulkes MA, Wolf PA, Price TR, et al: The stroke data bank: Design, methods and baseline characteristics. Stroke 1988;19:547. 3. Hamedani AG, Wells CK, Brass LM, et al: A quality-of-life instrument for young hemorrhagic stroke patients. Stroke 2001;32:687. 4. Furlan AJ, Whisnant JP, Elveback LR: The decreasing incidence of primary intracerebral hemorrhage: A population study. Ann Neurol 1979;5:367. 5. Sacco RL, Wolf PA, Bharucha NE, et al: Subarachnoid and intracerebral hemorrhage: Natural history, prognosis, and precursive factors in the Framingham study. Neurology 1984;34:847. 6. Wecht DA, Awad IA: Subarachnoid hemorrhage. In Grossman RG, Loftus CM (eds): Principles of Neurosurgery, 2nd ed. Philadelphia, Lippincott-Raven, 1999:297–309. 7. Mayberg MR, Batjer HH, Dacey R, et al: Guidelines for the management of aneurysmal subarachnoid hemorrhage. A statement of healthcare professionals from a special writing group of the stroke council, American Heart Association. Stroke 1994;25:2315. 8. Broderick JP, Adams HP, Barsan W, et al: Guidelines for the management of spontaneous intracerebral hemorrhage. A statement of healthcare professionals from a special writing group of the stroke council, American Heart Association. Stroke 1999;30:905. 9. Dul K, Drayer B: CT and MR imaging of intracerebral hemorrhage. In Kase CS, Caplan LR (eds): Intracerebral Hemorrhage, vol 5. Boston, Butterworth-Heinemann, 1994:73–93. 10. Ropper AH, King RB: Intracranial pressure monitoring in comatose patients with cerebral hemorrhage. Arch Neurol 1984;41:725. 11. Diringer MN: Intracerebral hemorrhage: Pathophysiology and management. Crit Care Med 1993;21:1591. 12. Broderick JP, Brott TG, Duldner JE, et al: Initial and recurrent bleeding are the major causes of death following subarachnoid hemorrhage. Stroke 1994;25:1342. 13. Inagawa T: Cerebral vasospasm in elderly patients treated by early operation for ruptured intracranial aneurysms. Acta Neurochir (Wien) 1992;115:79. 14. Haley EJ, Kassel NF, Torner JC: A randomized controlled trial of high dose intravenous nicardipine in aneurysmal subarachnoid hemor-

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53. Hunt WE, Hess RM: Surgical risk as related to time of intervention in the repair of intracranial aneurysms. J Neurosurg 1968;28:14. 54. Drake CG: Report of World Federation of Neurological Surgeons Committee on a Universal subarachnoid hemorrhage grading scale. J Neurosurg 1988;68:985. 55. Van Gijn J, Bromberg JE, Lindsay KW, et al: Definition of initial grading, specific events, and overall outcome, in patients with aneurysmal. subarachnoid hemorrhage. A survey. Stroke 1994;25: 1623. 56. Fisher CM, Kistler JP, Davis JM: Relation of cerebral vasospasm to subarachnoid hemorrhage visualized by CT scanning. Neurosurgery 1980;6:1. 57. Crowell RM, Ogilvy CS, Gress DR, et al: General management of aneurysmal subarachnoid hemorrhage. In Ojemann RG, Heros RC, Crowell RM, Ogilvy CS (eds): Surgical Management of Neurovascular Disease, 3rd ed. Baltimore, William and Wilkins, 1996:111– 122. 58. International Subarachnoid Aneurysm Trial (ISAT) Collaborative Group: International subarachnoid aneurysm trial (ISAT) of neurosurgical clipping versus endovascular coiling in 2143 patients with ruptured intracranial aneurysms: A randomised trial. Lancet 2002;360:1267. 59. Brilstra EH, Rinkel GJE, van Der Graaf Y, et al: Treatment of intracranial aneurysms by embolization with coils: A systemic review. Stroke 1999;30:470. 60. Raymond J, Roy D: Safety and efficacy of endovascular treatment of acutely ruptured aneurysms. Neurosurgery 1997;41:1235. 61. Raymond J, Roy D, Bojanowski M, et al: Endovascular treatment of acutely ruptured and unruptured aneurysms of the basilar bifurcation. J Neurosurg 1997;86:211. 62. Nichols DA, Brown RD Jr, Thielen KR, et al: Endovascular treatment of ruptured posterior circulation aneurysms using electrolytically detachable coils. J Neurosurg 1997;87:374. 63. Anonymous: Guiglielmi Detachable Coil (GDC) U.S. Clinical Study Summary. Fremont, CA, Target Therapeutics, 1995. 64. Sturaitis MK, Rinne J, Chaloupka JC, et al: Impact of Guglielmi detachable coils on outcomes of patients with intracranial aneurysms treated by a multidisciplinary team at a single institution. J Neurosurg 2000;93:569. 65. Lee S, Huddle D, Awad IA: Which aneurysms should be referred for endovascular therapy? In Howard M, Elliot P (eds): Clinical Neurosurgery, vol. 47. Philadelphia, Lippincott, Williams and Wilkins, 2000:188–220. 66. Ng PY, Huddle D, Gunel M, et al: Intraoperative endovascular adjuncts in the microsurgical treatment of paraclinoid aneurysms of the internal carotid artery. J Neurosurg 2000;93:554. 67. Hassan D, Vermeulen M, Wijdicks EFM, et al: Management problems in acute hydrocephalus after subarachnoid hemorrhage. Stroke 1989;20:747. 68. Graff-Radford N, Torner J, Adams HP, et al: Factors associated with hydrocephalus after subarachnoid hemorrhage. Arch Neurol 1989;46:744. 69. Vermeij FH, Hasan D, Vermeulen M, et al: Predictive factors for deterioration from hydrocephalus after subarachnoid hemorrhage. Neurology 1994;44:1851. 70. Kusske JA, Turner PT, Ojemann GA, et al: Ventriculostomy for the treatment of acute hydrocephalus following subarachnoid hemorrhage. J Neurosurg 1973;38:591. 71. Van Gijn J, Hijdra A, Wijdicks EFM, et al: Acute hydrocephalus after aneurysmal subarachnoid hemorrhage. J Neurosurg 1985;63:355. 72. Bogdahn U, Lau W, Hassel W, et al: Continuous-pressure controlled, external ventricular drainage for treatment of acute hydrocephalusevaluation of risk factors. Neurosurgery 1992;31:898. 73. Rajshekhar V, Harbaugh RE: Results of routine ventriculostomy with external ventricular drainage for acute hydrocephalus following subarachnoid hemorrhage. Acta Neurochir (Wien) 1992;115:8.

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74. Auer LM, Mokry M: Disturbed cerebrospinal fluid circulation after subarachnoid hemorrhage and acute aneurysm surgery. Neurosurgery 1990;26:804. 75. Proust F, Debono B, Gerardin E, et al: Angiographic cerebral vasospasm and delayed ischemic deficit on anterior part of the circle of Willis. Usefulness of transcranial Doppler. Neurochirurgie 2002;48:489. 76. Awad IA, Barnett GH: Acute management of subarachnoid hemorrhage. Neurosurgical Emergencies. Park Ridge, IL, American Association of Neurological Surgeons, 1994:137–149. 77. Barnwell SL, Higashida RT, Halbach VV, et al: Transluminal angioplasty of intracerebral vessels for cerebral arterial spasm: Reversal of neurological deficits after delayed treatment. Neurosurgery 1989;25:424. 78. Eskridge JM, Newell DW, Pendleton GA: Transluminal angioplasty for treatment of vasospasm. Neurosurg Clin North Am 1990;1:387. 79. Higashida RT, Halbach VV, Cahan LD, et al: Transluminal angioplasty for treatment of intracranial arterial vasospasm. J Neurosurg 1989;71:648. 80. Newell DW, Eskridge JM, Mayberg MR, et al: Angioplasty for the treatment of symptomatic vasospasm following subarachnoid hemorrhage. J Neurosurg 1989;71:654. 81. Kassell NF, Helm G, Simmons N, et al: Treatment of cerebral vasospasm with intra-arterial papaverine. J Neurosurg 1992;77:848. 82. Newell DW, Eskridge JM, Mayberg MR, et al: Angioplasty for the treatment of symptomatic vasospasm following subarachnoid hemorrhage. J Neurosurg 1989;71:654. 83. Linskey ME, Horton JA, Rao GR, et al: Fatal rupture of the intracranial carotid artery during transluminal angioplasty for vasospasm induced by subarachnoid hemorrhage. J Neurosurg 1991;74:985. 84. Fandino J, Schuknecht B, Yüksel C, et al: Clinical, angiographic, and sonographic findings after structured treatment of cerebral vasospasm and their relation to final outcomes. Acta Neurochir (Wien) 1999;141:677. 85. Ferch R, Pasqualin A, Barone G, et al: Surgical management of ruptured aneurysms in the eighth and ninth decades. Acta Neurochir (Wien) 2003;145:439. 86. Pinsker MO, Gerstner W, Wolf S, et al: Surgery and outcome for aneurysmal subarachnoid hemorrhage in elderly patients. Acta Neurochir Suppl 2002;82:61. 87. Lagares A, Gomez PA, Lobato RD, et al: Prognostic factors on hospital admission after spontaneous subarachnoid haemorrhage. Acta Neurochir (Wien) 2001;143(7):665. 88. Seifert V, Raabe A, Stolke D, et al: Management-related morbidity and mortality in unselected aneurysms of the basilar trunk and vertebrobasilar junction. Acta Neurochir (Wien) 2001;143(4):343–348; discussion 348. 89. Hijdra A, van Gijn J, Nagelkerke NJ, et al: Prediction of delayed cerebral ischemia, rebleeding, and outcome after aneurysmal subarachnoid hemorrhage. Stroke 1988;19:1250. 90. Lanzino G, Kassell NF, Germanson TP, et al: Age and outcome after aneurysmal subarachnoid hemorrhage: Why do older patients fare worse? J Neurosurg 1996;85(3):410. 91. B M Saciri BM, Kos N: Aneurysmal subarachnoid haemorrhage: Outcomes of early rehabilitation after surgical repair of ruptured intracranial aneurysms. J Neurol Neurosurg Psychiatry 2002;72:334. 92. O’Dell MW, Watanabe TK, De Roos ST, et al: Functional outcome after inpatient rehabilitation in persons with subarachnoid hemorrhage. Arch Phys Med Rehabil 2002;83:678. 93. Brott T, Thalinger K, Hertzberg V: Hypertension as a risk factor for spontaneous intracerebral hemorrhage. Stroke 1986;17:1078. 94. Juvela S, Hillbom M, Palomäki H: Risk factors for spontaneous intracerebral hemorrhage. Stroke 1995;26:1558. 95. Wakai S, Nagai M: Histological verification of microaneurysms as a cause of cerebral hemorrhage in surgical specimens. J Neurol Neurosurg Psychiatry 1989;52:595.

96. Newton TH, Potts DG, eds: Radiology of the skull and brain. St. Louis, Mosby, 1971. 97. Kaufman HH: Spontaneous intracerebral hematoma. In Grossman R (ed): Clinical Neurosciences, 2nd ed. New York, Raven, 1990. 98. Gilles C, Brucher JM, Khoubesserian P, et al: Cerebral amyloid angiopathy as a cause of multiple intracerebral hemorrhages. Neurology 1984;34:730. 99. Mandybur TI: Cerebral amyloid angiopathy: The vascular pathology and complications. J Neuropathol Exp Neurol 1986;45:79. 100. Vonsattel JP, Myers RH, Hedley-White ET, et al: Cerebral amyloid angiopathy without and with cerebral hemorrhages: A comparative histological study. Ann Neurol 1991;30:637. 101. Ropper AH, Davis KR: Lobar cerebral hemorrhages: Acute clinical syndromes in 26 cases. Ann Neurol 1980;8:141. 102. Gorelick PB, Kelly MA: Ethanol. In Feldman E (ed): Intracerebral Hemorrhage. Armork, NY, Futura, 1994:195–208. 103. Blackshear JL, Kopecky SL, Litin SC, et al: Management of atrial fibrillation in adults: Prevention of thromboembolism and symptomatic treatment. Mayo Clin Proc 1996;71:150. 104. Fihn SD, McDonell M, Martin D, et al: Risk factors for complications of chronic anticoagulation: A multicenter study. Ann Intern Med 1993;118:511. 105. The National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group: Tissue plasminogen activator for acute ischemic stroke. N Engl J Med 1995;333:1581. 106. Aldrich MS, Sherman SA, Greenberg HS: Cerebrovascular complications of streptokinase infusion. JAMA 1985;253:1777. 107. Grines CL, Browne KF, Marco J, et al: A comparison of immediate angioplasty with thrombolytic therapy for acute myocardial infarction. N Engl J Med 1993;328:673. 108. The Steering Committee of the Physician’s Health Study Group: Preliminary report: Findings from the aspirin component of the ongoing physician’s health study. N Engl J Med 1988;318:262. 109. Greenberg SM, Edgar MA: Hemorrhage in a 69-year old woman receiving warfarin. Case records of the Massachusetts General Hospital. N Engl J Med 1996;335:189. 110. Hartmann A, Mast H, Mohr JP, et al: Morbidity of intracranial hemorrhage in patients with cerebral arteriovenous malformation. Stroke 1998;29:931. 111. Nowak G, Schwachenwald D, Schwachenwald R, et al: Intracerebral hematomas caused by aneurysm rupture. Experience with 67 cases. Neurosurg Rev 1998;21:5. 112. Shende MC, Lourie H: Sagittal sinus thrombosis related to oral contraceptives: Case report. J Neurosurg 1970;33:714. 113. Symonds CP: Otitic hydrocephalus. Brain 1931;54:55. 114. Garcia RDJ, Baker AS, Cunningham MJ, et al: Lateral sinus thrombosis associated with otitis media and mastoiditis in children. Pediatr Infect Dis J 1995;14:617. 115. Estanol B, Rodriguez A, Conte G, et al: Intracranial venous thrombosis in young women. Stroke 1979;10:680. 116. Singh T, Chakera T: Dural sinus thrombosis presenting as unilateral lobar haematomas with mass effect: An easily misdiagnosed cause of cerebral haemorrhage. Australas Radiol 2002;46:351. 117. Kalfas IH, Little JR: Postoperative hemorrhage: A survey of 4992 intracranial procedures. Neurosurgery 1988;23:343. 118. Fukamachi A, Koizumi H, Nukui H: Postoperative intracerebral hemorrhages: A survey of computed tomographic findings after 1074 intracranial operations. Surg Neurol 1985;23:575. 119. Haines SJ, Maroon JC, Jannetta PJ: Supratentorial intracerebral hemorrhage following posterior fossa surgery. J Neurosurg 1978;49:881. 120. Harders A, Gilsbach J, Weigel K: Supratentorial space-occupying lesions following infratentorial surgery: Early diagnosis and treatment. Acta Neurochir (Wien) 1985;74:57. 121. Caplan LR, Skillman J, Ojemann R, et al: Intracerebral hemorrhage following carotid endarterectomy: A hypertensive complication. Stroke 1979;9:457.

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Chapter 6  122. Lowenstein DH, Collins SD, Massa SM, et al: The neurologic complications of cocaine abuse. Neurology 1987;37S1:195. 123. Levine S: Cocaine and stroke. Current concepts of cerebrovascular disease. Stroke 1987;22:25. 124. Harrington H, Heller A, Dawson D, et al: Intracerebral hemorrhage and oral amphetamines. Arch Neurol 1983;40:503. 125. Freeze TE, Miotto K, Reback CJ: The effects and consequences of selected club drugs. J Substance Abuse Treat 2002;23:151. 126. Levine SR, Brust JCM, Futrell N, et al: Cerebrovascular complications of the use of the crack form of alkaloid cocaine. N Engl J Med 1990;323:699. 127. Kernan WN, Viscoli CM, Brass LM: Phenylpropanolamine and the risk of hemorrhagic stroke. N Engl J Med 2000;343:1826. 128. Hornig CR, Dorndorf W, Agnoli AL: Hemorrhagic cerebral infarction: A prospective study. Stroke 1986;17:179. 129. Scott M: Spontaneous intracerebral hematoma caused by cerebral neoplasm. J Neurosurg 1975;42:338. 130. Dublin AB, Norman D: Fluid-fluid level in cystic cerebral metastatic melanoma. J Comput Assist Tomogr 1979;3:650. 131. Weir B, MacDonald N, Mielke B: Intracranial vascular complications of choriocarcinoma. Neurosurgery 1978;2:138. 132. Broderick JP, Brott TG, Duldner JE, et al: Volume of intracerebral hemorrhage: A powerful and easy-to-use predictor of 30-day mortality. Stroke 1993;24:987. 133. Kothari RU, Brott TG, Broderick JP, et al: The ABCs of measuring intracerebral hematoma volumes. Stroke 1996;27:1304. 134. Adams HP Jr, Brott TG, Furlan AJ, et al: Guidelines for thrombolytic therapy for acute stroke: A supplement to the guidelines for the management of patients with acute ischemic stroke: A statement for healthcare professionals from a special writing group of the Stroke Council, American Heart Association. Circulation 1996;94:1167. 135. Broderick JP, Brott TG, Tomsick T, et al: Ultraearly evaluation of intracerebral hemorrhage. J Neurosurg 1990;72:195. 136. Waidhauser E, Hamburger C, Marguth F: Neurosurgical management of cerebellar hemorrhage. Neurosurg Rev 1990;13:211. 137. Ogilvy CS, Stieg PE, Awad IA: Recommendation for the management of intracranial arteriovenous malformations. A Statement for Healthcare Professionals From a Special Writing Group of the Stroke Council, American Stroke Association. Stroke 2001;32:1458. 138. Kase C, Mohr J, Caplan R, et al: Intracerebral hemorrhage. In Barnett H, Mohr J, Stein B, Yatsu F (eds): Stroke: Pathophysiology, Diagnosis, and Management. New York, Churchill Livingstone, 1992:561–616. 139. Broderick J, Brott T, Zuccarello M: Management of intracerebral hemorrhage. In Batjer H (ed): Cerebrovascular Disease. Philadelphia, Lipincott-Raven, 1996:1–18. 140. Auer LM, Auer T, Sayama I: Indications for surgical treatment of cerebellar hemorrhage and infarction. Acta Neurochir 1986;79:74. 141. Kanaya H: All Japan cooperative study on the treatment of hypertensive intracerebral hemorrhage. Jpn J Stroke 1990;12:509.

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142. Batjer HH, Reisch JS, Allen BC, et al: Failure of surgery to improve outcome in hypertensive putaminal hemorrhage: A prospective randomized trial. Arch Neurol 1990;47:1103. 143. Auer L, Deinsberger W, Niederkorn K, et al: Endoscopic surgery versus medical treatment for spontaneous intracerebral hematoma: A randomized study. J Neurosurg 1989;70:530. 144. McKissock W, Richardson A, Taylor J: Primary intracerebral hemorrhage: A controlled trial of surgical and conservative treatment in 180 unselected cases. Lancet 1961;2:222. 145. Fayad PB, Awad IA: Surgery for intracerebral hemorrhage. Neurology 1998;51S:69. 146. Montes JM, Wong JH, Fayad PB, et al: Stereotactic computed tomographic-guided aspiration and thrombolysis of intracerebral hematoma: Protocol and preliminary experience. Stroke 2000;31:834. 147. Miller DW, Barnett GH, Kormos DW, et al: Stereotactically guided thrombolysis of deep cerebral hemorrhage: Preliminary results. Cleve Clin J Med 1993;60:321. 148. Schaller C, Rhode V, Meyer B, et al: Stereotactic puncture and lysis of spontaneous intracerebral hemorrhage using recombinant tissueplasminogen activator. Neurosurgery 1995;36:328. 149. Tzaan WC, Lee ST, Lui TN: Combined use of stereotactic aspiration and intracerebral streptokinase infusion in the surgical treatment of hypertensive intracerebral hemorrhage. J Formos Med Assoc 1997;96:962. 150. Lippitz BE, Mayfrank L, Spetzger U, et al: Lysis of basal ganglia hematoma with recombinant tissue plasminogen activator (rTPA) after stereotactic aspiration: Initial results. Acta Neurochir (Wien) 1994;127:157. 151. Ojemann RG, Heros RC: Spontaneous brain hemorrhage. Stroke 1983;14:468. 152. Poungvarin N, Bhoopat W, Viriyavejakul A, et al: Effect of dexamethasone in primary supratentorial intracerebral hemorrhage. N Engl J Med 1987;316:1229. 153. Broderick JP, Brott TG, Tomsick T, et al: Intracerebral hemorrhage more than twice as common as subarachnoid hemorrhage. J Neurosurg 1993;78:188. 154. Hallevy C, Ifergane G, Kordysh E: Spontaneous supratentorial intracerebral hemorrhage. Criteria for short-term functional outcome prediction. J Neurol 2002;249:1704. 155. Daverat P, Castel JP, Dartigues JF, et al: Death and functional outcome after spontaneous intracerebral hemorrhage. A prospective study of 166 cases using multivariate analysis. Stroke 1991;22:1. 156. Poungvarin N, Viriyavejakul A: Spontaneous supratentorial intracerebral hemorrhage: A prognostic study. J Med Assoc Thai 1990;73:206. 157. Tuhrim S, Dambrosia JM, Price TR, et al: Prediction of intracerebral hemorrhage survival. Ann Neurol 1988;24:258.

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Chapter 7 Basic Endovascular Neurosurgery and Neuroradiology Matthew V. Burry, MD and Robert A. Mericle, MD

Introduction The endovascular approach to cerebrovascular lesions is becoming an increasingly attractive treatment option. Endovascular techniques and technologies continue to evolve and improve rapidly, pushing the capabilities of the neuroendovascular surgeon further. Today, endovascular neurosurgery is an essential component of any comprehensive neurosurgical service and an exciting area for subspecialization. It is essential that neuro-critical care physicians understand the specific risks, complications, and other postoperative issues of patients treated by a neuroendovascular approach. In this chapter, the current state of endovascular neurosurgery is reviewed with particular emphasis on the details most pertinent for critical care physicians who may care for these patients postoperatively. The chapter is organized by disease and covers the nine diseases most commonly treated by endovascular neurosurgeons. Each disease section is divided into three parts. The first part broadly reviews the natural history of the condition and discusses the indications for the endovascular procedures. The second part describes some of the pertinent detail of the endovascular approaches for each disease. Finally, each section ends with a discussion of the possible intraoperative and postoperative complications from the endovascular procedures. Because this field is rapidly evolving, with many new technologies and approaches every year, a completely current review is difficult to accomplish. Every effort was made to include the most current information and references.

A team approach is optimal for providing the best health care for these challenging patients. Neurocritical care physicians are an essential component of the neurosurgical team. This chapter details the most commonly treated neurovascular diseases in the depth and breadth necessary for a neuro-critical care physician to increase his or her understanding of the disease process, endovascular indications, approaches, and to anticipate and manage most complications that can occur when treating these difficult diseases.

Endovascular Surgery for Acute Thromboembolic Stroke Review Stroke is the second most common cause of mortality worldwide, causing an estimated 5.1 million deaths annually.1 At least 80% of ischemic strokes are caused by acute thromboembolic cerebral artery occlusion.2 The arterial distribution and duration of local cerebral ischemia determine how large an infarct will become.3 The goal of acute stroke treatment is to preserve tissue affected by potentially reversible ischemia.4 Currently, the only U.S. Food and Drug Administration (FDA)-approved treatment for stroke is the emergent administration of intravenous (IV) recombinant tissue plasminogen activator (r-tPA) for thrombolysis of clots that have been symptomatic for less than 3 hours. Effective therapeutic alternatives and longer treatment windows are needed. Morbidity and mortality from 183

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“routine” treatment of acute middle cerebral artery (MCA) occlusion are extremely high. This mortality can be approximated by the placebo groups of two of the recent randomized clinical trials on stroke treatment.5,6 The National Institute of Neurological Disorders and Stroke (NINDS) study group and the Intra-arterial prourokinase for acute ischemic stroke (PROACT II) study demonstrated that the mortality rate at 3 months after MCA occlusion without thrombolytic therapy was 21% and 27%, respectively.5,6 Initially, IV r-tPA seemed to hold great promise. The NINDS trial showed clinical benefit at 90 days when intravenous r-tPA was administered less than 3 hours after symptom onset. The fact that there was no significant benefit seen at 24 hours suggests that the large MCA clot did not dissolve immediately, but rather there was an improvement in smaller, nearby occluded arteries that saved some of the penumbra of the evolving stroke. Unfortunately, the efficacy of intravenous r-tPA was found to be very time-dependent. Six other randomized clinical trials using intravenous thrombolytic therapy on patients after 3 hours of symptom onset demonstrated an increased rate of symptomatic intracerebral hemorrhage (ICH), and subsequently, no benefit from the intravenous treatment.7–12 There has not yet been a randomized clinical trial demonstrating IV r-tPA to be beneficial in patients with large vessel occlusions. Secondary analysis of data from the NINDS randomized clinical trial showed that patients with a dense MCA sign on computed tomography (CT), which is indicative of thrombus within this vessel, have an extremely poor response after IV thrombolysis, with only one of 18 demonstrating a positive outcome.13 Other studies have shown IV r-tPA alone does not open major arterial occlusion during the first few hours.14 Because IV r-tPA has a limited therapeutic window and limited efficacy in treating MCA trunk occlusions, there have been investigations into local, intra-arterial infusion of thrombolytic agents at the site of the cerebral arterial occlusion.15,16 Local intra-arterial thrombolysis fully or partially recanalizes occluded cerebral arteries in approximately 50% to 85% of patients.5,15,16 The rate of symptomatic intracerebral hemorrhage after intra-arterial thrombolysis has been acceptable in these studies. The two largest randomized clinical trials of intra-arterial thrombolysis are the PROACT I and PROACT II studies, which compared intra-arterial recombinant pro-urokinase plus IV heparin to placebo treatment plus IV heparin.5,15 These studies doubled the effective treatment window for thrombolysis from 3 to 6 hours, when the thrombolytic is given intra-arterially by a catheter embedded in the clot. Despite inclusion of patients with more severe and disabling strokes, the PROACT I showed a recanalization rate of 58% after 2 hours of infusion of pro-urokinase and heparin compared with 14% after an infusion of placebo and heparin. PROACT II had recanalization rates in the pro-urokinasetreated group of 66% compared to 18% in the control group.

Excellent neurologic outcomes were more common after intra-arterial thrombolysis. In PROACT II, 40% of the experimental group achieved a modified Rankin score of two or less (excellent neurologic outcome). This was significantly higher than the control group, where only 25% of the patients achieved that outcome. The rates of symptomatic ICH and mortality were not significantly different between the experimental and control groups.5 Intra-arterial thrombolysis appears to achieve higher rates of recanalization than IV r-tPA, with hemorrhage rates that are similar to those in the NINDS stroke trial. It has been suggested by many experts that mechanical clot disruption may increase the recanalization rate and improve neurologic outcome compared to thrombolysis alone.17–19 Randomized controlled trials testing mechanical clot disruption should begin in the near future. Other ongoing clinical trials are testing new thrombolytic drugs. The most promising of these is the Fab antibody fragment Abciximab (ReoPro, Eli Lilly, Indianapolis, IN).20 Endovascular Approaches An important principle affecting the outcome of stroke patients is emergent detection and treatment. All physicians and lay people should know both the signs of acute stroke and that early intervention can save lives. All critical care physicians should know the specific risk factors for thromboembolic stroke in all their patients. Some of the most significant risk factors for stroke are smoking, hypertension, coronary artery disease, hypercholesterolemia, diabetes mellitus, and obesity. Additionally, any patient undergoing any cerebrovascular or neuroendovascular procedure is at increased risk for stroke perioperatively. The physician taking care of neuro-critical care patients should be aware of specific periprocedural risk factors in their patients. Recently placed aneurysm clips can cause thrombotic stroke. Any recent endovascular procedure can cause stroke in the early postoperative period. This is especially true if detachable coils, embolic agents, or stents were used. With any neurologic change in a patient, the possibility of thromboembolic stroke must be considered, and this event should be treated emergently. A CT scan and neurologic/neurosurgical consultation should be obtained; if a thromboembolic stroke seems likely, computed tomographic angiography (CTA), magnetic resonance angiography (MRA), or catheter cerebral angiography is necessary for an accurate anatomic diagnosis of acute thromboembolism. If the patient is considered a good candidate for intra-arterial thrombolysis, catheter cerebral angiography is performed emergently after the initial noncontrast CT scan. If an acute clot is found on catheter angiography, various endovascular interventions are possible. As mentioned previously, the most thoroughly studied technique is to place the tip of a microcatheter into the proximal clot and inject

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thrombolytics through the catheter and directly into the clot (Fig. 7-1) Although pro-urokinase is the most carefully studied thrombolytic agent for intra-arterial use, it is not currently commercially available. Therefore, we currently use r-tPA for this procedure. At our institution, we slowly inject 2 mg over 10 to 20 minutes. This dose may be repeated every 20 minutes if the major arterial occlusion persists until a maximum of 20 mg or until the patient has exceeded the

6-hour limit after the onset of symptoms. We also commonly use abciximab (ReoPro) as an adjunct to thrombolysis. Our protocol for abciximab is an intra-arterial bolus of 0.25 mg/kg followed by an intravenous infusion of 0.125 mcg/kg/min for a total of 12 hours. If recanalization is not achieved with pharmacologic agents, we frequently use mechanical disruption of the clot with wires, catheters, balloons, or saline injection devices (Fig. 7-2).

A

B

Figure 7-1. Digital subtraction angiography in the anteroposterior view of a patient who presented with left-sided hemiplegia. A, Initial angiographic imaging revealed complete occlusion of the right middle cerebral artery (MCA) and the right anterior cerebral artery (ACA). B, A microcatheter was implanted into the occluding clot of the MCA and intra-arterial thrombolytics were infused, resulting in excellent MCA recanalization. Note the persistent ACA occlusion. C, The microcatheter was moved to the ACA and intra-arterial thrombolysis was performed with an excellent result. The patient’s neurologic examination improved almost immediately and was intact to gross neurologic examination several days later.

C

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B A Figure 7-2. Oblique view super-selective digital subtraction angiography of a patient who suffered a thromboembolic stroke. A, Selective middle cerebral artery (MCA) injection angiography showing an occlusion of two branches in the distal MCA territory. A microwire is in place in preparation for mechanical thrombolysis. B, After mechanical thrombolysis, partial recanalization of the anterior M3 branch and improvement in the posterior M3 branch was achieved.

Complications The most dreaded complication from endovascular treatment of acute stroke is an ICH, either from a hemorrhagic transformation of an infarct or vessel rupture during the procedure. Symptomatic ICHs occurred in 15% of PROACT patients and 10% of PROACT II patients who received intra-arterial pro-urokinase.5,15 To properly care for patients suspected of having an ICH, it is imperative that the critical care physician knows the technical and pharmacologic details of the procedure. The treating physician must have a clear sense of the patient’s current thrombolytic and coagulative state to effectively treat any possible hemorrhagic complications. The timing of the onset of the stroke, the onset of therapy, and any neurologic improvement or deterioration should be noted.

Endovascular Surgery for Intracranial Aneurysms Review Tremendous advances have been made during the past two decades in the endovascular treatment of intracranial aneurysms. With the introduction of electrolytically detachable platinum coils in 1991, an effective and safe method of endovascular aneurysm embolization became available. The

coils, Guglielmi detachable coil (GDC) (Target Therapeutics [Boston Scientific], Fremont, CA), are FDA approved and have rapidly spread to worldwide use.21–23 The endovascular placement of GDC is by far the most popular endovascular treatment of intracranial aneurysms. GDC placement is now the primary alternative for patients with intracranial aneurysms who are not good candidates for craniotomy and microsurgical clipping. Surgical clipping is still the gold standard for many intracranial aneurysms, but with further refinement of endovascular materials and techniques, the number of aneurysms treated with the minimally invasive endovascular approaches will continue to increase. Several other companies now have released their own version of endovascular detachable coils approved for embolization of intracranial aneurysms. It is essential for critical care physicians to understand coiling techniques, effectiveness, and potential complications. GDCs are thin platinum microcoils that are attached to a stainless steel introducing wire. They are advanced through a microcatheter that has been previously placed in the aneurysm. The coil is advanced into the aneurysm and it assumes a shape that is dependent both on the shape of the lumen of the aneurysm and the intrinsic shape of the coil. Several coil shapes are available, including standard, twodimensional and three-dimensional designs. While the coil is being placed into the aneurysm, it remains attached to the stainless steel introducing wire. Once placed to the satisfac-

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tion of the endovascular surgeon, the coil can be electrolytically detached by placing a low voltage current (1 to 2 mA) that dissolves the attachment site of the coil to the wire introducer. This occurs because the attachment site undergoes electrolysis, but the stainless steel introducing wire and the platinum coil resist electrolysis. Multiple coils of varying size, stiffness, and shape can be sequentially placed in the aneurysm. The aneurysm is gradually filled from the outside in. Ideally, the entire aneurysm lumen can be occluded with the coils and associated thrombus (Fig. 7-3). The use of intra-operative anticoagulation is at the physician’s discretion. At our institution, all patients with unruptured aneurysms are given a 100 U/kg bolus of heparin before the placement of the first coil. In ruptured aneurysms, we administer heparin at the same dose only after the successful placement of the first coil. This may reduce the risk of aneurysm rupture, which is more common during the first coil placement. Also, the first coil can help improve the initiation of thrombosis in the aneurysms, if it is placed before systemic anticoagulation. Unfortunately, GDC placement does not achieve complete, durable occlusion of all intracranial aneurysms. One recent study has shown a 20% rate of incomplete occlusion and an 8.6% rate of delayed recanalization at 3 years’ follow-

Figure 7-3. Digital subtraction angiography in the anteroposterior view of a patient who has had two ophthalmic aneurysms treated with Guglielmi detachable coils (GDCs). The patient’s aneurysms were discovered secondary to visual loss. One aneurysm is occluded with GDCs, with no contrast entering the aneurysm lumen (right). The other aneurysm is not yet completely occluded with the GDCs. Notice the contrast entering the aneurysm lumen between the coils and at the dome of the aneurysm (left).

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up.22 Despite these incomplete aneurysm embolizations, there is likely a protective effect from the incomplete coiling. Although this has not been proven in a clinical trial, few incompletely occluded aneurysms have hemorrhaged after coiling.23 Endovascular Approaches The decision to treat an aneurysm with either microsurgical clipping or endovascular coiling is complex and controversial. A complete discussion is beyond the scope of this chapter, but a few critical points are important for critical care physicians to understand. The decision to coil or clip an aneurysm is based primarily on four factors: 1. Aneurysm Geometry. Often, the decision to coil or clip an aneurysm is made on the basis of aneurysm geometry. The endovascular placement of coils favors an aneurysm shape that has a high fundus-to-neck ratio. The fundus is defined as the widest part of the body of the aneurysm. Most coils prefer a spherical shape and thus, the more closely an aneurysm approximates a spherical shape, the more natural fit for most coils. Aneurysms with complex shapes or wide necks are more difficult to manage, and once placed, the coils are less stable. Loops of coils can extrude out of the aneurysm into the parent vessel. This is highly undesirable and can lead to thromboembolic complications.24 Endovascular techniques have been developed to improve the coiling of difficult aneurysms. These include balloon assisted and stent assisted coiling.25,26 Briefly, these techniques involve the temporary placement of a balloon or permanent placement of a stent into the parent artery during coiling to keep the coil mass stable in the aneurysm lumen. These additional procedures add to the complexity and risk of the operation. 2. Aneurysm Size. Size decreases the safety and efficacy of coil embolization at both of the extremes of measurement. Very small aneurysms (< 3 mm) and giant aneurysms (≥ 25 mm) are much more difficult to occlude with endovascular coiling. Very small aneurysms are dangerous to catheterize, because there is an extremely limited safety margin for placement of the intraluminal catheter and the coils. Giant aneurysms are difficult to treat with endovascular coiling because of the very large intraluminal volume and frequent association with intraluminal thrombus. Many coils are required, and often it is not possible to fill the entire aneurysm. Also, long-term follow-up has not been as favorable for giant aneurysms. Late recanalization of the aneurysmal dome is more common in giant aneurysms and late re-bleeding rates are higher.27 3. Aneurysm Location. The risk of endovascular coiling versus microsurgical clipping varies with aneurysm location. Currently at our institution, most basilar tip

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aneurysms, small paraclinoid internal carotid artery aneurysms, and other posterior circulation aneurysms are treated with coiling. These locations are generally believed to have increased risk associated with microsurgical clipping. Conversely, there are other anatomical regions where coiling is more difficult. Aneurysms that are particularly difficult for endovascular coils are most middle cerebral artery aneurysms and some anterior communicating artery aneurysms. 4. Clinical Status of Patient. In deciding on the appropriate therapy for aneurysm patients, it is essential to consider the overall neurologic status and the general health of the patient. Several grading systems have been developed to standardize the clinical classification of patients after subarachnoid hemorrhage. The commonly used grading systems are the Hunt and Hess grading system and the World Health Organization (WHO) system. These are covered more fully in the chapter of this text on subarachnoid hemorrhage. The general assumption is that in patients with a poor clinical grade, endovascular surgery is preferred over craniotomy with microsurgical clipping. There is considerable variation from institution to institution concerning the importance of these four factors in the choice of treatment depending on the particular expertise and experience of the treating physicians. In all institutions, the decision should be made by an interdisciplinary neurovascular team with expertise in endovascular and microsurgical aneurysm treatment. Complications The most dreaded intraoperative complication with endovascular surgery is aneurysmal rupture. This complication is far more likely to occur in previously ruptured aneurysms than in an unruptured aneurysm. Intraprocedural rupture can be either a spontaneous rupture unassociated with aneurysmal manipulation or it can be secondary to perforation of the aneurysm with a microwire, microcatheter, or coil. Aneurysmal rupture should be suspected with any sudden increase in systolic blood pressure, decrease in heart rate, increase or decrease in respirations, or deterioration in neurologic status. In patients with external ventricular drainage, the cerebrospinal fluid will often change to bright red. Conscious patients will complain of the worst headache of their life and possibly deteriorate neurologically. Angiographically, contrast material extravasation from the aneurysm lumen is seen (Fig. 7-4A). If the rupture is caused by perforation from one of the endovascular instruments, the offending microwire or microcatheter should not be withdrawn until the aneurysm is secured with either further coil deployment or rapid injection of N-butyl cyanoacrylate glue (NBCA) (Cordis, Miami Lakes, FL) or other embolic agent (Fig. 7-4B).

An intraoperative rupture is an immediate, lifethreatening emergency. If heparin has been administered, it should be immediately and completely reversed with protamine sulfate (Eli Lilly, Indianapolis, IN). At least 1 mg of protamine sulfate should be given for each 100 units of heparin for reversal. Next, the hemorrhage must be controlled by emergently embolizing blood flow to the aneurysms. This is usually most quickly performed by emergently placing two or three more coils (Fig. 7-4A and B) In cases of neurologic deterioration without external ventricular drainage, an emergent CT scan and ventriculostomy should be performed as soon as the bleeding has been controlled. Thromboembolism is a risk both during coil placement and in the postoperative period. This is the most frequent complication, occurring in 2.5% to 5% of GDC procedures.22,23,28 Thromboembolism can occur at any time during the endovascular procedure, but is especially likely while manipulating the coil or while withdrawing a misplaced coil (Fig. 7-5) It is important to remember that there is a small risk of thromboembolism from the coil mass for several weeks after the procedure. This is very uncommon, however, unless coils have herniated into the parent artery.24 If thromboembolism has occurred, intra-arterial thrombolysis should be performed as described in the section of this chapter on the endovascular treatment of acute stroke. The clot may be treated with r-tPA, ReoPro, or mechanical clot disruption with microwires, catheters, balloons, or saline injection devices (Fig. 7-6). Extreme care should be taken in the setting of a thromboembolus with a still unsecured ruptured aneurysm, because the thrombolytic agents could lead to a severe repeat hemorrhage. In this case, the aneurysm should be quickly secured with coils until it is adequately protected for the emergent thrombolytic procedure. Although a complete discussion of endovascular coil placement strategies and complications is beyond the scope of this chapter, knowledge of a few key points is important for critical care physicians treating postoperative coiling patients. First, coils may sometimes break or migrate from the coil mass. Broken or migrated coils can cause potentially serious ischemic events. Coils that have broken or migrated from the aneurysm body may be retrieved with endovascular snares, surgical removal, or stenting the coil against the artery wall. After being stented against the vessel wall, these coils presumably will become endothelialized to the wall.29 Sometimes a significant portion of the coil mass can protrude into the parent vessel. Attempts can be made to push this mass back into the aneurysm with angioplasty or stent placement, but success varies. Often with these complications, despite salvage efforts, one is left with a less than ideal situation in which some part of a coil is exposed in the parent artery. Most experts initiate long-term anticoagulant or antiplatelet therapy in this situation. All physicians managing the postoperative care of these patients should be aware of the details of the procedure and any complications, and the efforts to correct them.

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B A Figure 7-4. Towne’s view digital subtraction angiography (DSA) of a patient who presented with a subarachnoid hemorrhage from a basilar tip aneurysm. During the coiling procedure, acute severe hypertension developed with sudden bright red blood from the ventriculostomy. A, DSA confirmed extravasation outside of the aneurysm lumen. B, After emergently packing two more coils in the aneurysm lumen, repeat DSA shows no further contrast extravasation. Notice the difference between these two figures to appreciate the extraluminal contrast.

B A Figure 7-5. Lateral view digital subtraction angiograpyh of a patient with an MCA aneurysm who suffered an embolic complication after the removal of a coil during Guglielmi detachable coil (GDC) treatment. A, Note the clot in an inferior and posterior M3 branch of the MCA. B, The clot was treated by mechanical thrombolysis with a microwire. Notice improved blood flow to the area that previously was occluded.

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B

A

C

Figure 7-6. Anteroposterior view digital subtraction angiography (DSA) of a patient with a giant internal carotid artery bifurcation aneurysm. A, During Guglielmi detachable coil treatment, the patient had a middle cerebral artery (MCA) occlusion secondary to an extruded intraluminal thrombus from the coil mass. B, The occlusion was treated with microwire mechanical thrombolysis. C, DSA after MCA angioplasty. Notice the improved flow to the M1 segment, but still no distal MCA filling. The two markers in the MCA represent the ends of a compliant angioplasty balloon and excellent distal flow.

Endovascular Surgery for Cerebral Vasospasm Review Cerebral vasospasm is a frequent and devastating condition following subarachnoid hemorrhage (SAH). Delayed ischemic neurologic deficits secondary to cerebral vasospasm will develop in as many as one third of patients who survive the initial hemorrhage.30 Cerebral vasospasm

has been shown to lead to a 1.5- to threefold increase in mortality at 2 weeks following SAH.31 Cerebral vasospasm occurs most often between 4 and 12 days after the initial hemorrhage.32 During this period, vasospasm often presents with focal neurologic deficits, decreased level of consciousness, confusion, headache, and meningismus. In patients with secured aneurysms, after the initial subarachnoid hemorrhage, cerebral vasospasm is the leading cause of death and disability.33 Recent MRI studies have shown that vasospasm might also be the cause of many strokes that do not cause

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gross neurologic dysfunction detectable during the patient’s initial stay in the intensive care unit, but are a cause of the more subtle memory and personality changes frequently seen in these patients.34 Vasospasm is the narrowing of the cerebral arteries in delayed response to blood products in the subarachnoid space. The primary arteries affected are usually the large conductive arteries at the skull base: the supraclinoid segments of the internal carotid arteries, the proximal MCAs, anterior cerebral arteries, posterior cerebral arteries, the basilar artery, and the intradural vertebral arteries. Additionally, there has been a reported 10% incidence of focal distal vasospasm.35 The stenosis from cerebral vasospasm leads to decreased focal cerebral blood flow. This effect is predicted by the Hagen-Poiseuille equation: Q=

DPpr 4 8Lh

In this equation, Q is blood flow, P is the pressure in the artery, r is the radius or the artery, L is the length of the artery, and h is the viscosity of the blood. Blood flow varies with the fourth power of the radius; hence, even modest changes in vessel diameter can have profound effects on cerebral blood flow. Cerebral vasospasm has been shown in several randomized clinical studies to lead to cerebral infarction causing increased morbidity and mortality.36 Intensive basic and clinical research over the past 50 years has led to many advances in the detection and treatment of cerebral vasospasm. The diagnosis of vasospasm and the numerous medical therapies, including nimodipine, socalled triple H therapy (hypertension, hypervolemia, and hemodilution) and their complications, are beyond the scope of this chapter and are covered elsewhere in this book. Instead, the remainder of this chapter will cover the endovascular treatment of cerebral vasospasm, endovascular complications, and postoperative care. The two most important endovascular therapies will be discussed: pharmacologic and mechanical balloon angioplasty. Endovascular Approaches Two endovascular procedures for cerebral vasospasm are currently used: local intra-arterial infusion of a vasodilating drug and intracranial transluminal angioplasty. Both procedures aim to improve blood flow to areas of the brain that are suffering decreased blood flow secondary to severe vasospasm. These procedures are usually reserved for patients who have symptoms with neurologic deficits; therefore, these procedures are usually considered emergent. This factor of emergency timing cannot be overemphasized. Patients who have symptomatic vasospasm are in danger of irreversible cerebral infarction. The quicker blood flow is improved, the better the outcome. This has been demonstrated by a recent study showing a 2-hour window for blood

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flow restoration for maximum improvement in clinical outcome.37 In a patient thought to be symptomatic from vasospasm, maximal medical therapy is instituted. If the patient’s deficit is refractory, the patient should be taken emergently to the endovascular suite for digital subtraction angiography and possible endovascular therapy. Pharmacologic vasodilation is performed by the local, intra-arterial infusion of a vasodilating drug. The vasodilating drug most frequently used is papaverine. Papaverine is a cyclic nucleotide phosphodiesterase inhibitor that increases cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) and leads to smooth muscle relaxation and arterial vasodilation. The reported half-life of papaverine is 45 to 60 minutes, although some sources think that it is closer to 24 hours.38 Following diagnostic angiography confirmation of vasospasm, a microcatheter is placed in the affected artery. Papaverine is usually injected in 60-mg increments up to 300 mg per major artery distribution, including the MCA, anterior cerebral artery, and posterior cerebral artery distributions. The medication given is usually diluted to 300 mg/100 cc administered over 30 to 60 minutes. This protocol has been shown to consistently dilate proximal and distal cerebral arteries.39 There are numerous difficulties with the intra-arterial administration of papaverine. When mixed with blood, both a 3% and a 0.3% papaverine solution sometimes precipitate out of solution. This nearly always occurs when the papaverine is mixed with heparinized saline. If any significant precipitation occurs, the papaverine crystals could lodge in the distal arteries being treated and an iatrogenic ischemic stroke could result. Thus, papaverine must be kept away from solution containing heparin and it must be infused very slowly to keep its concentration low enough to prevent crystallization.40 The side effects of papaverine are numerous. Dosedependent hypotension and bradycardia have been reported. Papaverine-induced thrombocytopenia has also been reported. Mydriasis is also a frequent side effect secondary to the smooth muscle dilation of the iris. Because of this, most operators ensure that the microcatheter is distal to the origin of the ophthalmic artery, the principal arterial supply to the globe. Numerous side effects of treatment are thought to be secondary to microemboli from papaverine that has precipitated out of solution. Transient focal deficits have been reported in up to 7% of patients, probably secondary to microemboli. Additionally, in cases involving treatment of the vertebrobasilar system, several cases of respiratory depression have been reported.36 Despite the frequent robust vasodilation seen after the infusion of papaverine (Fig. 7-7), the clinical efficacy of papaverine is unproven. One report showed immediate improvement in the neurologic examination and transcranial Doppler (TCD) readings following intra-arterial papaverine infusion, but no difference in the 3-month clinical outcome when compared to controls.41 Other reports

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A

B

Figure 7-7. A, Digital subtraction angiography: lateral view showing severe distal spasm of the anterior cerebral artery in a patient with a subarachnoid hemorrhage. B, After treatment with intra-arterial papaverine, the vessel diameter is much improved.

have shown the frequent need for re-treatment after an apparently successful papaverine treatment.39 The reason for the lack of long-term efficacy is likely the short half-life of papaverine, leading to poor durability of vessel dilation. The future role of intra-arterial papaverine for cerebral vasospasm is unclear. The current indications at our institution are (1) extreme distal vasospasm not suitable for balloon angioplasty, and (2) temporary vasodilation of proximal vessels to facilitate the placement of a micro-balloon for more definitive intracranial transluminal angioplasty. Intracranial transluminal balloon angioplasty involves the placement of a micro-balloon into stenotic proximal cerebral arteries either through flow directed or “over the wire” techniques. The micro-balloons are gently inflated with a mixture of saline and angiographic contrast material to allow direct fluoroscopic visualization of the balloon inflation. Predictable angiographic dilations with consistent blood flow increases have been reported.42 Clinical studies have shown that up to 70% of patients treated demonstrated clinical benefit.32 The angiographic results with balloon angioplasty are more durable than the results from intraarterial papaverine infusion. It is extremely rare to see further vasospasm in an artery that has been treated with intracranial transluminal angioplasty (Fig. 7-8).40,43 The ease of balloon angioplasty continues to improve with each new generation micro-balloon. Complications The most serious complication with intracranial balloon angioplasty is arterial rupture secondary to inadvertent overinflation of the balloon. The currently available compliant balloons suitable for vasospasm angioplasty have maximum

inflation diameters of 3.5 to 4 mm, greater than vessels to be angioplastied (usually 2 to 3 mm). Great care must be taken to slowly inflate the balloons under good fluoroscopic visualization to prevent accidental overinflation. Vessel dissection or rupture from balloon angioplasty usually has devastating consequences. In one large series, 4% of patients undergoing balloon angioplasty died as a result of intraoperative vessel rupture.43 The routine use of systemic heparinization during balloon angioplasty has potential complications. Many of the patients treated for cerebral vasospasm will only be a few days postcraniotomy if their aneurysm was clipped. Physicians treating these patients after the procedure should monitor for signs of intracranial mass effect and ICH. Patients should be monitored for signs of ischemic neurologic events, which can occur from clots forming on the various endovascular instruments and from emboli or thrombus that can form from iatrogenic vessel injury and dissection.

Endovascular Surgery for Arteriovenous Malformations Review Arteriovenous malformations (AVMs) are congenital vascular lesions of the brain, which are rare, but with an unclear prevalence.44 These malformations consist of a dysplastic nidus that contains vascular channels connecting arteries and veins without intervening capillaries. This low resistance mass of vessels acts as a high flow shunt from the arterial feeders to the draining veins. The combined high flow and

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Figure 7-8. Digital subtraction angiography (DSA) of a patient who became aphasic and developed a right hemiplegia several days after subarachnoid hemorrhage. A, DSA of the left internal carotid artery (ICA) shows severe vasospasm of the supraclinoidal ICA, proximal middle cerebral artery, and anterior cerebral artery. B, After balloon angioplasty, all vessels had improved diameters. The patient’s neurologic condition markedly improved.

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high pressure leads to dilation of the vascular channels of the nidus as well as the afferent arteries and efferent veins. The combination of high-pressure arterialized blood and thinned, dilated vessel walls can lead to hemorrhage. Fifty percent of symptomatic AVMs present with an intracranial hemorrhage.45 The next most common symptoms at presentation are seizures and focal neurologic deficits. Seizures and focal deficits are thought to be more likely related to cerebral steal phenomena secondary to the low-pressure, high-flow arteriovenous shunt through the nidus, which can decrease the perfusion of the brain parenchyma surrounding the AVM. Reports have shown that up to 7% of cerebral arteriovenous malformations have at least one associated aneurysm.46 These aneurysms often occur on large feeding arteries and are likely formed by the pathologic high flow through artery feeding the nidus, and are referred to as “flow-related” arterial aneurysms. AVM-associated aneurysms have a greatly increased rate of subarachnoid hemorrhage. Studies show that the hemorrhage rate of an AVM is 2% to 4% per year and that the mortality rate of each of these hemorrhages is 10% to 15%.47 Historically, AVMs have been extremely difficult to treat. Early surgical experience to remove the nidus had a high mortality rate from intraoperative hemorrhage. To better predict the surgical risks according to the angiographic features of the AVM, a grading system was developed by Spetzler and Martin (Table 7-1).48 This grading system stratified the surgical risk of removing AVMs according to size, proximity to eloquent brain tissue, and the pattern of venous

193

B

drainage. The points are totaled, giving a score range of 1 to 5. The higher the grade, the higher the perioperative major morbidity and mortality. This grading system has been shown to adequately predict surgical morbidity and mortality in a prospective study.49 This study reported no major or minor neurologic deficits in patients who had a grade 1 AVM removed, while in patients having grade 5 lesions removed, 19% had a minor deficit and 12% had a major deficit. Other therapies have emerged to address this difficult pathology. Stereotactic radiation surgery has been extremely successful in treating many AVMs. During stereotactic radiation surgery, a single fraction, high-dose, finely targeted dose of radiation is given to the AVM. Secondary to dangers

Table 7-1  Spetzler Martin Grading of AVMs Feature

Point Assigned

Size of AVM Small (<3 cm) Medium (3–6 cm) Large (>6 cm)

1 2 3

Eloquence of surrounding brain Noneloquent Eloquent

0 1

Pattern of venous drainage Superficial only Deep

0 1

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of increasingly large irradiated volumes, the maximum diameter of AVM able to be safely treated is generally considered to be less than 3.5 cm.50 The radiation-induced injury that occurs during radiation surgery causes a gradual occlusion of the AVM over 2 to 3 years. AVM cure rates at centers treating large numbers of these malformations exceed 80% at 3 years.51 Unfortunately, the AVMs for which radiation surgery are efficacious are often the same, small AVMs that could safely be removed with microsurgery. Endovascular techniques were developed to serve as either a primary or adjuvant therapy for AVMs. It was hoped that particle or glue embolization would cure many large or deep AVMs. However, a cure using endovascular surgery exclusively is uncommon. In a recent analysis by Wikholm and Lundqvist of long-term follow-up of 150 patients with embolized AVMs, only 19 (13%) of the AVMs were totally obliterated with glue embolization.52 Thus, endovascular embolization is more often performed as an adjunct with a goal of making either microsurgery or radiation surgery more safe and efficacious. This goal is usually achieved by making the AVM smaller with much less abnormal blood flow (Fig. 7-9). Partial embolization has also been performed as a sole therapy by other investigators with the theory that a smaller AVM has a safer natural history. The Wikholm and Lundqvist long-term study found that protective effects of partial embolization only occurred if greater than 90% of the AVM was embolized.52 The goal of preoperative endovascular embolization is to make the dangerous, inoperable AVM into a safer, technically less difficult lesion (Fig. 7-10). This usually requires multiple endovascular procedures. Embolization is directed at reducing the flow through the nidus, eliminating deep arterial feeders that would be difficult to access surgically, and decreasing the overall size of the nidus. After serial embolizations, the patient has microsurgical removal of a lower flow, less dangerous lesion. The goals of pre-radiation surgery embolization are slightly different from those of preoperative embolization. The principal goal is to make a large AVM small enough to be safely and adequately treated with radiation surgery. This generally requires a volume of less than 25 cm3. Instead of attempting to remove large central feeders as in the preoperative embolizations, it is instead important to occlude peripheral feeders and nidus. Also, any dural component is also targeted with embolization because these respond less well to radiation surgery.53 The utility of pre-radiation surgery embolization has not yet been firmly established. Also, the glue casts left after embolization sometimes make the necessary stereotactic imaging and localization for radiation surgery more difficult. Further research is needed to investigate improvements for pre-radiation surgery embolization. Endovascular Approaches The two most common categories of materials used to embolize AVMs are particles and glue.54 Currently, the wide-

spread particulate material used is polyvinyl alcohol particles (PVA). These particles are available in a variety of size ranges. The particles are released into the AVM and become lodged into the nidus where they cause blood to clot and cause an inflammatory reaction. Unfortunately, this material is associated with frequent recanalization of the nidus and the effect of embolization is not durable. PVA is most effective as an embolic agent if the AVM is resected within a few days after embolization to decrease the amount of AVM recanalization. Glue embolic agents were developed because of the lack of permanent occlusion with particulate materials. A number of glues have been used. Recent FDA approval of NBCA has led to its widespread use. NBCA is a liquid polymer, which begins to polymerize on contact with an ionic environment, including blood. The rate of polymerization can be controlled through various dilutions with Ethiodol—an oil-based, radiopaque material. By appropriately diluting the glue and carefully controlling the rate of injection, NBCA can reliably be placed into the nidus of the AVM, causing permanent occlusion of the embolized section. A recent randomized trial has shown NBCA to be safer and at least as effective as PVA in the immediate embolization. There is also considerable data confirming NBCA has a more durable effect than PVA.54 To increase the safety of endovascular embolization, preembolization provocative testing can be performed. This testing involves the injection of a short-acting barbiturate drug (i.e., methohexital [Jones Medical Industries, St. Louis MO]) through the microcatheter before embolization. A neurologic examination is performed before and after the barbiturate injection to ascertain if the artery feeds a portion of normal brain, which would cause a deficit if embolized. All relevant higher cortical function is tested, including alertness, orientation, language production and comprehension, in addition to visual field examination, and a four-extremity motor and sensory examination. If there is a possibility that the arterial supply of a cranial nerve could also be embolized from the arterial pedicle, then it is mandatory that provocative testing also be performed with lidocaine because of differences in cellular neurophysiology between central and peripheral neurons. After confirming that no apparent neurologic deficit will occur with the occlusion of the artery, embolization proceeds. Sometimes, depending on surgeon preference, systemic heparinization is administered before the injection of glue. Usually, multiple vascular pedicles can be embolized during a single procedure. Complications The most dreaded complication from AVM embolization is intracerebral hemorrhage. This complication occurs most often secondary to the complex hemodynamic changes in and around the AVM that occur during and after embolization. Knowledge of these hemodynamic changes is essential for physicians taking care of these patients postoperatively.

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D C Figure 7-9. A 22-year-old man presented with left hemiparesis and seizures. He was subsequently diagnosed with a very large arteriovenous malformation (AVM). A, Contrast-enhanced magnetic resonance imaging shows part of the right cerebral AVM. B, Digital subtraction angiography (DSA) of the right internal carotid artery shows the large AVM. Notice the absence of visualized distal middle cerebral artery and anterior cerebral artery (ACA) because of the high arteriovenous shunting. C, DSA after several glue embolizations showing markedly decreased AVM size and flow. Notice the wellvisualized normal ACA branches that were previously not visualized. D, Unsubtracted fluoroscopic view of glue cast after several glue embolizations. All of this glue material is lodged within the nidus of the AVM, preventing flow through their respective channels.

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As each vascular pedicle is embolized, abrupt changes in the flow patterns and filling pressures of the AVM occur. With embolization of part of the nidus, redirected flow through other parts of the nidus causing a sudden change in filling pressure in the nidus of the AVM can lead to vessel rupture and intracerebral hemorrhage. Hemorrhage can also occur secondary to venous thrombosis. Thus, it is extremely important to understand and monitor the venous drainage of the AVM during the embolization procedure. The venous drainage of cerebral

Figure 7-10. Patient with arteriovenous malformation (AVM) that was embolized in two sessions. A, Digital subtraction angiography (DSA) anteroposterior view of the left carotid artery showing the AVM. B, DSA lateral view of the AVM. C, DSA lateral view after two glue embolizations. Notice the AVM was dramatically reduced in size.

AVMs is often characterized by large venous varices dilated from the pathologically high flow. Sometimes, after a large amount of the afferent arterial blood flow to the nidus is removed, either through embolization or surgery, the flow in these enlarged draining veins will become stagnant and the veins are at high risk to thrombose. Sudden thrombosis of the venous drainage system leads to on outflow restriction and resultant passive hyperemia.55 This vascular congestion places the patient at extremely high risk for infarction and intracerebral hemorrhage in the peri-procedural period.

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Changes in the venous flow pattern are monitored during the procedure and the presence of venous stagnation during the procedure should be an indication for procedure termination and the consideration of anticoagulation therapy to prevent thrombosis or urgent surgical removal of the AVM. In a patient thought to be at high risk for postprocedural vascular thrombosis, it is recommended to maintain good hydration and ensure good cerebral perfusion pressure.56 Another cause of intracerebral hemorrhage following AVM embolization is the phenomenon of normal perfusion pressure breakthrough. This phenomenon is controversial but is commonly believed to occur from the sudden redistribution of blood that would normally transit through the AVM into the arteries of the nearby brain parenchyma.57 This brain tissue has chronically been exposed to low flow secondary to the nearby AVM and the resultant cerebral steal from its high flow shunt. The sudden, large increase in local blood flow that occurs when the nearby AVM is embolized can cause vessel rupture and intracerebral hemorrhage. The fundamental principle in decreasing risk of all of the preceding causes of intra- or postembolization intracerebral hemorrhage is a gradual, staged treatment of these lesions with multiple embolizations. Care must be taken not to decrease the blood flow too much and too quickly during a single embolization procedure because this can have a disastrous result on the hemodynamics of these lesions. Staging the procedures ensures that the hemodynamic changes the AVM is exposed to are as gradual as possible. Thus, it is commonly recommended that less than one third of an AVM be embolized during any single procedure. If patients are thought to be at high risk for an intracerebral hemorrhage from having greater than one third of their AVM removed during a single procedure, the risk of hemorrhage can be minimized with strict postoperative blood pressure control. This blood pressure can be slowly normalized over the next 3 days as the brain around the AVM gradually becomes accustomed to the increased flow. Ischemic stroke is another serious complication of AVM embolization. Ischemic stroke is a constant threat during all endovascular procedures where intravascular manipulations occur. In embolization procedures, there is further risk from the particles or glue used during the procedure. Preembolization provocative testing, as described previously, is helpful in predicting the safety of embolizing a specific artery, but accidental reflux of embolic agents can occur. All embolizations should proceed slowly and under fluoroscopic guidance. As an embolization proceeds and part of the nidus is occluded, the local hemodynamics can change and the embolic agents can take unexpected vascular routes. Sometimes these inadvertent arterial occlusions involve arteries that were not tested during provocative testing. Unexpected neurologic deficits can occur.

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Endovascular Surgery for Dural Arteriovenous Fistulas Review Dural arteriovenous fistulas (DAVFs) are abnormal, acquired arteriovenous shunts that occur in the dura of the central nervous system. These uncommon lesions account for 10% to 15% of intracranial vascular malformations.58 These fistulae are usually multiple with tens or hundreds of branching arterial feeders all terminating on a major dural venous sinus. Any dural sinus can be involved, and DAVFs are classified according to the dural venous sinus that forms the primary outflow of the fistula. These lesions have an association with precedent venous thrombosis. The venous congestion caused by a venous sinus thrombosis could lead to the enlargement of normally microscopic arteriovenous shunts. The causes of the antecedent intracranial venous thrombosis leading to DAVF formation are numerous. Venous sinus thrombosis secondary to trauma, infection, surgical intervention, or a hypercoagulable state have all been shown to be associated with the DAVFs.59 Classification of DAVFs by anatomy is extremely important in understanding the symptoms, natural history of disease, and treatment. Several classification systems exist. The most frequently used is the system proposed by Cognard and colleagues.60 This system, like most systems, classifies these lesions according to the pattern of the venous outflow (Table 7-2). It is the pattern of venous outflow that has been shown to be most predictive of patient outcome. The symptoms, natural history and treatments vary significantly according to draining venous anatomy. Type I lesions, with normal antegrade venous drainage, have a benign course and pose little risk of future serious neuro-

Table 7-2  Classification of Dural Arteriovenous Fistulas Grade

Pattern of Venous Flow

I

Venous drainage into a sinus, normal antegrade flow Venous drainage into a sinus, with insufficient antegrade flow and reflux Retrograde venous drainage into a sinus only Retrograde venous drainage into a cortical vein only Retrograde venous drainage into a sinus and cortical veins Venous drainage into a cortical vein with ectasia Venous drainage directly into a cortical vein with venous ectasia larger than 5 mm diameter and three times larger than the diameter of the draining vein

II A B A+B III IV

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logic events such as infarction or hemorrhage. These lesions often present with headaches or bruits. Sometimes the presenting symptoms are dependent on the anatomic location, for example, pulsatile tinnitus caused by highflow transverse sinus DAVFs, or retrobulbar pain and ocular motility disorders caused by high flow and venous congestion of a cavernous sinus DAVF. Numerous studies have shown that these lesions do not pose a serious neurologic risk.61–64 Treatment for these lesions is generally only performed if the symptoms are particularly bothersome to the patient. Patients with a type IIA lesion, sinus stenosis without cortical venous drainage, have a slightly more dangerous natural history.60 These patients have higher flow fistulas, and symptoms are likely to develop secondary to intracranial hypertension. This intracranial hypertension can lead to bilateral papilledema, loss of vision, and diplopia. Because these lesions do not have venous drainage that refluxes into the cortical venous system, they do not cause intracerebral hemorrhage. The goal of treatment for these lesions is to decrease flow to control symptoms and normalize intracranial pressure. Complete obliteration of the fistula is not usually necessary. Patients with venous drainage reflux into the cortical veins, types IIb, a + b, III-IV, do have significant risk for intracerebral hemorrhage. In a large series, it was reported that 10% of type IIB, 40% of type III, and 65% of type IV lesions presented with intracranial hemorrhage.60 A recent study that followed a subset of untreated DAVFs with cortical venous drainage found an annual mortality rate of 10.4%, with an annual rate of intracranial hemorrhage of 8.1%, and rate of nonhemorrhagic neurologic deficit of 6.9%. Unlike patients with type I and IIa, the treatment of these patients is not only to alleviate symptoms but to protect the patient from significant future risk of ICH and progressive neurologic deficits. The goal of endovascular or surgical treatment of these lesions is the elimination of the cortical venous reflux. Endovascular Approaches Several treatment approaches exist for DAVFs. The specific treatment performed depends on the lesion anatomy and goals of therapy. Carotid artery-jugular vein compression is a potential therapy for motivated patients with low-flow DAVFs. It is appropriate for DAVFs with primary flow from the meningeal branches of the internal carotid artery or dural branches of the external carotid artery. Theoretically, the flow stagnation produced by this compression of the carotid artery and jugular vein could lead to thrombosis of the fistula. Patients are instructed to compress the ipsilateral carotid artery in the neck with the contralateral hand for 30-minute sessions. This therapy enables a complete cure in 22% of cases, with clinical improvement in 33% of

patients.65 This technique is only appropriate for patients with small, low-flow fistulas. Arterial compression of the carotid artery is contraindicated in patients with ipsilateral atherosclerotic disease secondary to risk of embolic complications. Transarterial embolization with either PVA particles or NBCA glue can also be effective in the treatment of DAVFs. Please see the section of this chapter on embolization of intracerebral AVMs for a brief description of the various available embolic agents. It is important to understand that as with AVMs, transarterial embolization is rarely curative for DAVFs. These lesions are often extremely complex with numerous small arterial feeders too small to be selectively embolized. Instead, the goals of therapy are either reduction of flow for symptomatic relief or reduction of flow in anticipation of a curative procedure (microsurgical removal or transvenous embolization; Fig. 7-11). The procedure involves the super-selective catheterization of a DAVF feeder, usually an external carotid artery branch. Before embolization with PVA or glue, the super-selective angiogram is analyzed to assess for potential dangerous external carotid to internal carotid or vertebral artery anastomoses. Potential anastomoses to the ophthalmic artery or cranial nerves must also be assessed. Transvenous embolization is the most definitive endovascular procedure for DAVFs. The exact site of the fistula must be eliminated to cure these lesions. Because the fistula is frequently in multiple locations along the dural venous sinus, curing the fistula generally requires a venous approach. This can be accomplished by a transvenous embolization procedure, or by an open microsurgical skeletonization of the dural venous sinus. The transvenous approach can be via a transfemoral, transfacial, transjugular, or trans-superior ophthalmic vein. Transvenous embolization involves the endovascular occlusion of the venous sinus draining the fistula (Fig. 7-12). Careful analysis of the preoperative angiogram is important in establishing if the patient can tolerate the occlusion of the draining sinus. Occlusion of a transverse or sigmoid sinus is especially dangerous if the contralateral transverse and sigmoid sinus are absent or not robust. The adequacy of collateral venous drainage is important to note. This drainage can be tested during the procedure with temporary sinus occlusion with a nondetachable compliant balloon. In performing transvenous embolization, a microcatheter is placed in the venous sinus and the occlusion can be performed with glue or coils. As the sinus is packed with embolic materials, the embolization is monitored with intermittent angiograms from a catheter placed in a feeding artery. Embolization proceeds until no flow exists through the DAVF. This usually requires complete occlusion of the involved dural sinus. Often, to ensure the remaining sinuses and venous outflow are maintained during the transition to the new flow pattern, systemic anticoagulation is maintained for 24 hours after the procedure.

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Figure 7-11. Digital subtraction angiography of a patient with a dural arteriovenous fistula (DAVF) that presented with an audible bruit. A, Lateral view selective internal carotid artery (ICA) injection demonstrates that the DAVF is fed by dural branches of the meningohypophyseal trunk from the cavernous segment of the ICA. B, Lateral view selective external carotid artery (ECA) injection shows several dural branches that feed the fistula. Note there is cortical venous reflux at the left inferior part of the image. C, After N-butyl cyanoacrylate glue embolization of the ECA feeders. Notice a dramatic decrease in flow to the fistula. There were residual feeders from the meningohypophyseal trunk that could not be embolized safely. These will require either surgical or radiosurgical obliteration, or transvenous embolization.

C

Complications Because of potential anastomoses between dural arteries and the arteries supplying the cranial nerves and retina, loss of cranial nerve function and vision is a potential complication. The use of large PVA particles (>150 mm) can decrease the likelihood of this complication, because these are less likely to cause capillary level occlusion. Another potential complication of transarterial embolization is the inadvertent placement of glue past the fistula and into the venous drainage. Sudden venous occlusion can shift the venous drainage through new pathways. Sudden increased flow into a supe-

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rior ophthalmic vein or cortical vein can lead to visual loss, intracranial hemorrhage, and neurologic deficit. Sometimes a relatively safe lesion with normal, antegrade venous drainage can be made into a more dangerous lesion with retrograde venous reflux into cortical veins. The most dangerous complications occur secondary to venous occlusions. With shifting of the venous drainage secondary to the loss of the treated sinus, symptoms of venous congestion with occasional intracerebral hemorrhage are possible. Postoperatively, patients should be monitored for the development of focal deficits. Venous congestion can affect various parts of the brain including

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Figure 7-12. Lateral view digital subtraction angiography (DSA) of a patient with a preembolization DAVF who presented with proptosis, chemosis, and diplopia. A, Preembolization DSA showing a DAVF of the ophthalmic artery draining via the superior ophthalmic vein. B, Postembolization DSA of the same internal carotid artery injection. The glue embolization was delivered through a transvenous approach, and the lesion was cured.

cranial nerves, the cerebral cortex, and structures of the posterior fossa. It is imperative for all critical care physicians who take care of post-embolization patients to understand various special complications that can occur with these patients.

can include direct or indirect connections with the internal carotid artery (ICA) and/or external carotid artery (ECA) and the cavernous sinus. In understanding the etiology, natural history, and treatment of these lesions, it is important to classify them by their arterial anatomy and supply. The most common classification system used is the one proposed by Barrow and associates:66

Endovascular Surgery for CarotidCavernous Fistulas

A. Direct intracavernous ICA to cavernous sinus. B. Indirect dural ICA branches (i.e., meningohypophyseal trunk) to cavernous sinus. C. Indirect dural ECA branches to cavernous sinus. D. Indirect dural ICA and ECA branches to cavernous sinus.

Review Carotid cavernous fistulas (CCFs) are abnormal arteriovenous shunts between the carotid artery and the cavernous sinus. These lesions can occur spontaneously or they can be acquired secondary to trauma or venous thrombosis. A CCF

Type A fistulas are also called direct fistulas because they involve a direct connection between the ICA and the cav-

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ernous sinus without intervening dural branches. The other three types (types B to D) are also called indirect fistulas because the arterial supply to the fistula involves dural branches (Fig. 7-13). Indirect CCFs are similar to other DAVFs in their pathogenesis and treatment and are considered a subset of DAVF based on their location at the cavernous sinus (see Figs. 7-11 to 7-13). Therefore, this section will only focus on Barrow type A direct CCFs, because they represent a unique pathologic entity with special treatment options. The reader is referred to the section in this chapter on the endovascular treatment of dural AVF for further information on the natural history and treatment of indirect carotid cavernous fistulas. Type A CCFs are most frequently traumatic in nature. The most common cause is motor vehicle accidents, followed by falls and penetrating injuries.67 The incidence of CCF is increased in patients with basilar skull fractures. In all of these cases, a rent forms in the cavernous segment of the ICA allowing direct, high-flow arteriovenous shunting into the cavernous sinus. Spontaneous CCFs also occur. This situation can occur following the rupture of an intracavernous ICA aneurysm. Collagen deficiency syndromes, such as Ehlers-Danlos syndrome and pseudoxanthoma elasticum, can predispose patients to spontaneous CCF.68,69 As with DAVFs, the venous drainage pattern of the CCF is extremely important in the clinical presentation and the natural history of the patient. The cavernous sinus normally

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receives venous inflow from the orbit via the superior ophthalmic vein and from the brain via the superficial middle cerebral veins and the sphenoparietal sinus. Venous outflow from the cavernous sinus is to the transverse and sigmoid sinuses via the superior and inferior petrosal sinuses and basilar plexus. There is also an anteroinferior venous outflow via emissary veins to the pterygoid plexus. The route that the pulsatile, high flow blood takes from the arterialized cavernous sinus is variable and can change. Studies with large series of patients have shown a higher risk of intracranial hemorrhage in patients who present with retrograde cortical outflow through the sphenoparietal sinus into the cortical veins.70 The clinical presentations of CCFs are varied. The increased venous pressure through the superior ophthalmic vein leads to tissue congestion through the orbit. The affected eye is usually proptotic and chemotic. Diplopia can result from cranial nerve dysfunction or a restrictive ophthalmoplegia secondary to the swollen proptotic orbital contents. Patients often show evidence of decreased visual acuity and optic nerve dysfunction if the lesion is not promptly treated. The visual loss can be secondary to retinal ischemia from arterial steal and venous congestion, from glaucoma secondary to increased intraocular pressure secondary to venous congestion, and from exposure keratitis if the eye is too proptotic for proper lid closure or if the eye is anesthetic secondary to trigeminal dysfunction.

B Figure 7-13. A young boy presented after an all-terrain vehicle accident with proptosis, chemosis, and diplopia. The patient was found to have a Barrow type D carotid cavernous fistula (CCF). The CCF had fistulous filling of the cavernous sinus by very small, indirect dural branches of the internal carotid artery (A), and large, high-flow, indirect dural branches of the external carotid artery (B).

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Patients often complain of unilateral, pulsatile tinnitus or bruit, or retro-orbital headache at presentation. This pain is likely secondary to distention of the dural and orbital content from venous congestion. Symptoms from cerebral ischemia secondary to steal are quite rare, but can occur if there is a combination of inadequate flow past the CCF into the distal supraclinoid carotid artery and inadequate collateral flow from the circle of Willis (isolated hemisphere). It is important to note that the affected eye is not always ipsilateral to the CCF. Intracavernous sinus flow through the circular sinus can lead to a bilateral presentation of ocular symptoms, or rarely a contralateral ocular presentation. The clinical indications for urgent treatment include increased intraocular pressure, progressive visual field loss, exposure keratitis, rapidly progressive proptosis, cerebral ischemia, and cortical venous outflow. Endovascular Approaches Carotid compression therapy, as described in the section on DAVFs, is rarely effective with high-flow type A CCFs. Although uncommon, occasional cures with few complications have been reported with this approach.71 It is very important that only the patient perform this maneuver, not family members, and that only the patient’s contralateral hand is used. This would automatically stop the occlusion if a hemiparesis occurs secondary to cerebral ischemia. Also, it is important to exclude severe atherosclerosis in the ipsilateral cervical carotid to prevent iatrogenic embolic events occurring from manual compression and disruption of plaque. The most common and most effective treatment is transarterial occlusion of the fistula with detachable balloons. This procedure entails passing a flow-directed detachable balloon into the affected carotid artery. The partially inflated balloon is allowed to pass through the fistula and into the cavernous sinus. The balloon is then pulled back into the fistula (i.e., the rent in the carotid artery wall) and inflated. Repeat angiography is performed. If the fistula is closed and the ICA is patent, the balloon can be detached. Sometimes the fistula is slowed but not occluded (Fig. 7-14). This is usually due to the hole in the artery being larger than the inflated diameter of the balloon. In this case, multiple balloons can be positioned into the fistula. These additional balloons are more difficult to place because the previous balloon or balloons are partially blocking the fistula. In a large study, 88% of traumatic type A fistulas were successfully treated with detachable balloons with preservation of the parent artery.72 Sometimes using detachable balloons alone in the occlusion of the fistula is not possible. In this case, transarterial placement of endovascular detachable coils into the fistula can be attempted either alone or in conjunction with detachable balloons. Transvenous placement of coils or other embolic agents into the cavernous sinus can also be attempted. If all of these therapies fail, it is sometimes

necessary to occlude the parent ICA both proximally and distally to the fistula with detachable balloons. Adequate collateral blood flow is essential (Fig. 7-14C). A temporary balloon occlusion test can be performed distal to the fistula to test the patient’s tolerance of an ICA occlusion. A balloon occlusion test is unnecessary if the pretreatment angiogram shows steal from the intracranial circulation down into the fistula. In this case, the patient has already tolerated having no cerebral flow from the affected artery and the flow will actually increase because there will no longer be cerebral steal after the artery is occluded. Most operators perform this procedure with the patient under systemic heparinization. Complications Complications following endovascular therapy for CCF are relatively uncommon. Most are minor in nature. Often following a successful balloon occlusion of the fistula, the patient will complain of worsening chemosis, proptosis, or headache. This is probably secondary to acute cavernous sinus thrombosis. These symptoms are usually limited and short-lived. It is also possible to develop a palsy or worsening function of cranial nerves III, IV, V, or VI (the intracavernous cranial nerves) secondary to mass effect, balloon compression, or cavernous sinus thrombosis. One very serious complication that can occur is balloon migration. This can occur during the procedure or can be a delayed complication. Detachable balloons can be difficult to place and control. They are mechanically detached and at times can detach inadvertently or can move inappropriately by the detaching process. These balloons can also deflate gradually and cause late ischemic complications or reestablishment of the fistula. Any misplaced detached balloon can move into the cerebral circulation and cause ischemic sequelae. Delayed, gradual balloon deflation can be a problem because of osmotically driven diffusion across the balloon, which is a semipermeable membrane. This phenomenon can be essentially eliminated if the balloons are inflated with an isosmotic, isotonic contrast agent. Another important complication is an extension of the flow dynamics discussed previously. In attempting to occlude the CCF, the venous flow can sometimes be changed to a much more dangerous pattern. During an attempt to treat a patient with predominant venous flow anteriorly through the superior ophthalmic vein, it is possible to inadvertently change the arterialized venous outflow posteriorly through the sphenoparietal sinus and superior and inferior petrosal sinuses. This can cause acute venous hypertension of the brain with the associated risks of cerebral edema or intracranial hemorrhage. In an article by Higashida, 4.9% of patients undergoing treatment for direct type A fistulas had major complications. Half of these patients had transient ischemic symptoms and the other half had thromboembolic strokes.72 It is important for all physicians treating these patients postoperatively to

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A

Figure 7-14. Digital subtraction angiography (DSA) of a patient who presented after a motor vehicle accident with proptosis and chemosis of the right eye. A, Lateral view of the right internal carotid artery (ICA) showing a type A carotid cavernous fistula (CCF) with enlargement of the superior ophthalmic vein and significant cortical venous reflux. This fistula was treated with balloon packing. B, Lateral DSA view of the CCF with a single balloon in the fistula. Note that there is less fistulous flow. Because of this, now the middle cerebral artery and anterior cerebral artery are filling intracranially, which were not previously visualized. Also notice that there is no further intracranial retrograde cortical venous flow as seen previously and increased arterial cerebral filling. To cure this lesion, the ICA had to be sacrificed. C, Anteroposterior view of the contralateral (left) ICA, which demonstrates excellent collateral flow through the anterior communicating artery of the circle of Willis.

understand the procedural details and any adverse technical events to understand better the postoperative risks to the patients.

Endovascular Surgery for Extracranial Stenosis Review Angioplasty and stenting can be safely performed on a variety of brachiocephalic atherosclerotic lesions. The vast majority of brachiocephalic lesions are atherosclerotic

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lesions of the cervical carotid bifurcation. Additional vessels routinely treated are the origins of the innominate, subclavian, carotid, and vertebral arteries. Carotid bifurcation revascularization will be discussed first, followed by a discussion of angioplasty and stenting of the other brachiocephalic vessels. Atherosclerotic disease at the carotid bifurcation has been studied extensively. The natural history of the disease and treatments have been well delineated in several large randomized clinical trials. Carotid bifurcation atherosclerosis causes 20% of all ischemic strokes and transient ischemic attacks (TIAs).73 The natural history of the lesion is most dependent on the degree of luminal stenosis and on whether it is associated with symptoms of TIAs.

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Asymptomatic carotid stenosis is a risk factor for ipsilateral cerebral infarction; and with a stenosis of greater than 50%, a 2.4% annual stroke risk exists.74 The asymptomatic lesion with a 60% to 99% stenosis has been shown to have a 3.2% annual risk of ipsilateral stroke.75 The proper treatment for asymptomatic carotid stenosis is an area of debate. The largest study examining the role of carotid endarterectomy (CEA) in these lesions is the Asymptomatic Carotid Atherosclerosis Study (ACAS). This randomized study of patients with lesions of at least 60% stenosis found a significant benefit from surgery. The 5-year risk of stroke or death was 5% in patients who had a CEA versus 11% in the population treated with medical therapy only. Of note, the benefit of CEA was only significant in men and when the total perioperative complications were less than 3%. The benefit of CEA in asymptomatic lesions is modest and is dependent on keeping the surgical complication rates low. Symptomatic carotid stenosis is defined as a stenotic lesion associated with an ipsilateral stroke, ipsilateral hemispheric TIA, or ipsilateral amaurosis fugax (i.e., transient monocular blindness). These lesions have a much worse natural history, and therefore patients with symptomatic lesions receive a more substantial benefit from CEA.76 In the North American Symptomatic Carotid Endarterectomy Trial (NASCET), patients with symptomatic stenosis greater than 70% were found to have an ipsilateral stroke risk of 26% when treated with medical therapy versus 9% when treated with CEA. Patients with moderate carotid stenoses (50% to 69%) also benefit from CEA compared to medical treatment, but the difference was less dramatic. Those treated with CEA had a 5-year stroke rate of 15.7% while the medically treated group had a 5-year stroke rate of 22.2%.77 Based on these studies, CEA is now the recommended treatment for symptomatic lesions with a stenosis greater than 70% and for selected asymptomatic lesions with a stenosis greater than 60% and symptomatic patients with stenosis greater than 50%. The perioperative surgical risks of major stroke and death must be less than 3% in asymptomatic patients, and less than 6% in symptomatic patients, for many of the benefits from CEA to be realized.76 Endovascular carotid revascularization with angioplasty and stenting has become increasingly common as an alternative to CEA (Fig. 7-15). Originally, the procedure was developed as an alternative therapy for patients who did not fit the inclusion criteria of the study populations in the previously mentioned trials, and those patients for whom the risks of CEA are deemed excessive. Endovascular revascularization held the promise of treating these high-risk patients with a potentially lower risk procedure, requiring no anesthesia, less operative time, and less systemic stress. With increased experience, the indications for endovascular therapy are expanding at many centers. Many neurosurgeons will recommend endovascular revascularization for patients if they have certain factors that increase the technical difficulty of the CEA. These include but are not limited to bifur-

cation disease in patients with an unusually high cervical bifurcation, patients with recurrent stenosis who have undergone ipsilateral CEA, patients with radiation-induced stenosis, patients with occlusions of the contralateral carotid artery, or patients with one or more vertebral artery occlusions. The efficacy of endovascular therapy for cervical carotid stenosis as a therapy for all patients including those who do fulfill the NASCET criteria is very controversial and is currently being studied in several randomized clinical studies.73,78 One of these trials, Carotid and Vertebral Artery Transluminal Angioplasty Study (CAVATAS), was recently published.73 This trial randomized patients with symptomatic or asymptomatic cervical carotid stenosis to either CEA or endovascular therapy. This study found that the overall morbidity and mortality at 30 days was the same in each group. The perioperative stroke and death rate was similar between the two groups (surgery 9.9% vs. angioplasty and stenting 10%). Although the morbidity and mortality for the two groups were the same in this study, these rates were considerably higher than the NASCET study, which had a rate of 5.8%.73,79 Another important finding in the CAVATAS study was a significantly higher rate of restenosis at 1 year in the endovascular group. This was not, however, associated with increase in clinical symptoms at 1 year. Most of the patients in CAVATAS treated by endovascular means underwent angioplasty alone without stenting. Most carotid atherosclerotic lesions are now treated with stenting in addition to angioplasty. It is thought that the stent will decrease emboli during the procedure, decrease symptomatic plaque dissections, and improve long-term restenosis rates. Until further large, randomized trials with large numbers of stented patients are published, endovascular therapy for carotid atherosclerosis cannot be recommended for patients who are candidates for carotid endarterectomy. Balloon angioplasty and stenting are currently reserved for patients who are poor candidates for surgery secondary to comorbidities, complex anatomy, or a history of CEA or radiation-induced stenosis. Other brachiocephalic vascular lesions frequently treated with endovascular surgery are stenoses of the origins of the carotid and vertebral arteries, innominate artery stenosis, and subclavian stenosis. The indications for these procedures typically include intermittent neurologic symptoms referable to the area of the brain supplied by the diseased artery. Although these spells can be embolic in nature, similar to stenosis of the carotid bifurcation, symptoms in the proximal vertebral, carotid, innominate, and subclavian arteries are usually secondary to hypoperfusion caused by the stenotic blockage (Fig. 7-16). One notable symptom complex occurs in the case of subclavian steal. These patients often experience posterior fossa ischemic symptoms, including dizziness, diplopia, visual disturbances, and unilateral and bilateral weakness when they use one of their arms. The anatomic substrate is a subclavian stenosis or occlusion that

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Figure 7-15. Digital subtraction angiography (DSA) of a patient with transient ischemic attacks of the right cerebral hemisphere. A, View of right cervical internal carotid artery showing severe stenosis. The patient was treated with angioplasty and stenting. B, DSA showing the crossing of the lesion with the undeployed stent after preliminary angioplasty. C, DSA showing deployed stent. Notice that the diameter of the carotid artery lumen has dramatically increased.

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A B Figure 7-16. Digital subtraction angiography (DSA) of a patient who presented with posterior fossa transient ischemic attacks. A, Anteroposterior view of the left subclavian artery showing severe stenosis of the left vertebral artery origin. Angioplasty and stenting were performed. B, After angioplasty and stent placement, DSA shows much improved vessel diameter.

is proximal to the origin of the ipsilateral vertebral artery. The perfusion demand of the arm causes a reversal of flow through the vertebral artery and steals blood flow from the intracranial circulation. Sometimes the patient will only experience symptoms when the ipsilateral arm is active (Fig. 7-17).80

Endovascular Approaches The goal of endovascular therapy for the preceding lesions is to reduce the level of stenosis and restore normal anatomy. This goal will increase cerebral blood flow and decrease sludging and turbulence of flow, thereby reducing embolic events. During balloon angioplasty, the atherosclerotic plaque is stretched and cracked and the three layers of the vessel are dilated. To decrease the distal embolization of plaque, vessel dissection, and long-term restenosis, a metallic stent is placed at the site of the stenosis. The stent is placed before angioplasty if the lesion can be safely crossed without preceding angioplasty. This, of course, is not possible in

extremely tight lesions where the remaining lumen is no bigger than the undeployed stent. These lesions require angioplasty before crossing the lesion with the stent. Endovascular therapy of these lesions is almost always done with the patient receiving systemic anticoagulants. Some operators pretreat the stenotic lesion with abciximab or r-tPA to clear any thrombus from the lesion. The lesion is crossed with a wire over which the angioplasty balloon or stent will be passed. If the stenosis is not extremely tight, then primary stenting is performed. The stent is deployed over the area of greatest stenosis with some overlap of normal artery to prevent stent migration. Balloon angioplasty can be performed after stenting if there is a “waist” in the stent, indicating residual stenosis. This is often referred to as “poststent remodeling,” performed after stent deployment with slow dilation of the balloon up to a predetermined diameter. The result is checked with an angiogram. The angioplasty can be repeated until there is no residual stenosis identifiable. The patient’s vital signs are constantly monitored during balloon inflation for bradycardia or hypotension. Following the procedure, the patient is gener-

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D Figure 7-17. Digital subtraction angiography (DSA) of a patient who presented with subclavian steal syndrome. A, Anteroposterior DSA showing severe stenosis of the innominate artery. B, A left vertebral artery injection shows retrograde flow “steal” down the right vertebral artery. C, Angioplasty and stenting DSA showing an excellent angiographic result. D, A left vertebral artery injection after the innominate artery was angioplastied and stented shows normal antegrade flow into the basilar artery system, and therefore an angiographic cure of the “subclavian steal.”

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ally maintained on heparin drip for 24 hours, clopidrogel for 3 months, and lifelong enteric-coated aspirin.

Endovascular Surgery for Intracranial Stenosis

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Review

Major intraoperative complications of extracranial angioplasty and stenting include bradycardia and asystole, stroke, and perfusion breakthrough. During the balloon dilation of the atherosclerotic lesion, the carotid bulb is stretched. Stretch receptor afferents in the carotid bulb travel to the brainstem via cranial nerve IX. These signals can lead to a profound bradycardia or asystole during the carotid bulb manipulation. The operator should monitor the patient’s vital signs continuously during the dilation process. Early in our experience, prophylactic transvenous pacing, external pacing, or atropine were used. We discovered that these are rarely necessary unless the bradycardic response is severe and sustained, which is exceedingly rare. The bradycardia induced by angioplasty resolves after prompt balloon deflation, especially if the balloon is deflated at the first sign of decreased heart rate, before brachycardia occurs. If symptomatic bradycardia occurs, atropine can be given. Ischemic stroke occurs as a peri-procedural complication of endovascular cervical carotid revascularization in up to 10% of patients, according to the recently published CAVATAS trial.73 The causes of these strokes are embolic material dislodged during the balloon angioplasty or from emboli from iatrogenic carotid dissection. Numerous techniques and devices are used to help protect the distal circulation from embolic materials. Some operators balloon occlude the internal carotid artery distal to the stenosis, flush out debris produced during the angioplasty, and then remove the distal balloon.81 New, investigational distal protection devices, which catch the embolic debris with a filter, are currently being studied in clinical trials with early promising results.82,83 Patients who have a severe stenosis with poor distal perfusion of the ipsilateral hemisphere are at risk for ICH related to the phenomenon of normal perfusion pressure breakthrough, caused by the sudden increase in the transmitted blood pressure normally blocked by the stenosis.84,85 This brain tissue, which has been accustomed to very low flow, has arterioles and capillaries that maximally dilate to increase blood flow to the parenchyma. The sudden hyperemia following treatment of the stenosis can lead to headache, seizures, focal deficits, vessel rupture, and resultant ICH. The incidence of this complication has been reported to be as high as 5%.86 This complication can be minimized by strict postoperative blood pressure control, sometimes to 70% of the preoperative systolic blood pressure. The blood pressure is then slowly normalized over the next several days, as the normally dilated vessels gradually acquire autoregulatory capacity and regain the ability to constrict in response to the increased flow.

Stroke secondary to thromboembolic events from intracranial stenoses has been underestimated. Studies have shown that approximately 8% of transient ischemic attacks are secondary to intracranial stenosis.87 Autopsy studies have shown an incidence of these atherosclerotic lesions of 6.5%.88 The natural history of these atherosclerotic lesions is poorly understood. Various studies have suggested that intracranial stenosis carries a risk of stroke of greater than 8% in 1 year.89,90 One reason the natural history of intracranial stenosis has been difficult to define is that it varies according to the anatomic location of the stenosis. For example, while MCA stenosis may have an annual stroke rate of 7.8%, stenosis of the basilar artery has an annual stroke rate of 11%.91,92 There has not been convincing data in the literature correlating the natural history of intracranial stenosis with the degree and severity of stenosis. There is general consensus that hemodynamic significance, and therefore a possible dangerous natural history, begins to increase with stenosis greater than 50%.89 The clinical presentation of patients with intracranial stenosis is variable, depending on the anatomic location. Description of the various ischemic syndromes is beyond the scope of this chapter. Recurrent TIAs, although much more common in extracranial disease, can indicate intracranial disease. Recurring, fluctuating symptoms might indicate the low-flow hemodynamics that occur as a result of these lesions versus the sudden, maximal deficit associated with thromboembolism. This low-flow state is important in assessing these patients. Patients with clinically asymptomatic lesions are sometimes considered at higher risk if brain blood flow imaging, including single photon emission computed tomography, positron emission tomography, and other radiographic diagnostic testing show poor perfusion in the territory of the involved artery. Previous treatments for these lesions include antiplatelet medications, anticoagulation, and extracranial-tointracranial bypass. The best medical therapy is not yet clear. Currently, a large, randomized clinical trial is underway comparing warfarin and aspirin in patients with symptomatic intracranial stenosis.89 A large randomized study of extracranial-to-intracranial arterial bypass was performed in 1985 to assess efficacy in preventing stroke in patients with extracranial carotid occlusion, distal carotid occlusive disease, and MCA stenosis.93 Subgroup analysis showed no benefit in the prevention of future strokes in patients with carotid siphon or MCA stenoses when compared with medical therapy. Patients with severe (>70%) stenosis of the MCA actually did worse in the extracranial-to-intracranial bypass study group.

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With the rapid advances in endovascular technology, new therapies are available. Micro-balloons are now available that are small and flexible enough to be maneuvered into the intracranial circulation. Many intracranial stenoses are now treated with angioplasty with or without stenting. To date, no randomized controlled trial has been completed, although several are underway. The best treatment for these lesions is under intense study but at this time remains unclear.

Endovascular Approaches Endovascular treatment of intracranial stenosis is most often attempted after the patient has failed maximal medical therapy. This includes patients who are symptomatic despite appropriate antiplatelet therapy and anticoagulation, or have unacceptable side effects from these medications. Endovascular treatment originally involved balloon angioplasty alone. With the recent introduction of coronary microballoons with improved flexibility, intracranial stenting has been performed along with the angioplasty (Fig. 7-18). Currently, these stents are metallic mesh, deployed by balloon inflation. In the near future, biodegradable, self-expanding stents and covered micro-stents will be available for the intracranial circulation.

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In angioplasty or stenting, the balloon or balloondeployed stent are placed across the lesion in an over-thewire manner. Systemic heparinization with a bolus is usually administered immediately before the placement of the balloon or balloon stent. After satisfactory placement of the device, the balloon is inflated to a predetermined pressure depending on the desired balloon diameter using a balloon compliance chart supplied by the manufacturer. Once the desired inflation is performed, the balloon is deflated and removed from the lesion to a more proximal location. If a stent was used, it should remain in the lesion. An angiogram is obtained to assess vessel patency and distal arterial filling (Fig. 7-19). The patient’s vital signs and neurologic examination, if general anesthesia is not used, are continuously monitored during this critical portion of the procedure. Depending on the preference of the operator and the final anatomic result, systemic anticoagulation can be continued after the procedure. Many operators are using perioperative abciximab (ReoPro) instead of heparin when performing intracranial angioplasty and stenting. Complications One complication from the endovascular treatment of intracranial stenosis is ischemic stroke. These strokes can be secondary to occlusion or thrombosis of the treated vessel or

A B Figure 7-18. Digital subtraction angiography (DSA) of a patient with posterior fossa transient ischemic attacks who was found to have a severe, symptomatic basilar artery stenosis. The patient also had a large basilar artery aneurysmal dissection that was asymptomatic. A, Lateral view DSA showing severe basilar artery stenosis with a large fusiform basilar aneurysm. The stenosis was treated with angioplasty and stenting. B, Same lateral view DSA after angioplasty and stenting of the stenosis with an excellent angiographic result.

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B A Figure 7-19. Digital subtraction angiography (DSA) of a patient having recurrent transient ischemic attacks secondary to severe carotid siphon stenosis. A, Lateral view DSA showing severe stenosis of the carotid siphon. This lesion was treated with angioplasty and stenting. B, Same lateral view after angioplasty and stenting of the carotid siphon with increased vessel diameter. The patient was no longer symptomatic after treatment.

perforating branches, or from embolic occlusion of distal branches. This complication has been reported to occur in 8% to 11% of patients during the procedure.94–96 More recent, but smaller studies have reported a 0% rate for intraprocedural ischemic stroke.97,98 Patients with acute thromboembolic events should be treated with intra-arterial thrombolysis and clot disruption as described in the section of this chapter on the endovascular treatment of acute stroke. The physician treating these patients postoperatively should understand that these patients are at risk for hemorrhage or further ischemic injury in the territory of the treated vessel and should be closely monitored, because postoperative hemorrhage, TIAs, stroke, and restenosis have been reported in most studies. Intracranial hemorrhage is another devastating complication that uncommonly occurs during or after intracranial angioplasty or stenting, especially in the basilar artery (Fig. 7-20). The vessels being treated are small, severely atherosclerotic, and fragile. Any manipulation from

the various wires, catheters, or balloon can cause a vessel perforation or hemorrhagic dissection. The most dangerous portions of the procedure are balloon inflation and stent deployment. Careful angiographic analysis is performed to determine the vessel diameter. These determinations can be difficult in diseased vessels, and the margin for error is small. Especially in the context of systemic anticoagulation, hemorrhages are extremely dangerous and mortality is high. Rapid reversal of anticoagulation is mandatory with the appropriate agent. Sometimes dissections can occur during the procedure, which then hemorrhage in the postoperative period. Because of this, as with all procedures, the critical care physicians treating these patients should always know the anticoagulation and antiplatelet medications that have been given to the patient, along with the dosages and the time the medication was given. Patient lives can be saved by rapid reversal of anticoagulation. Therefore, constant monitoring for possible hemorrhagic complications is imperative.

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Figure 7-20. Digital subtraction angiography (DSA) of an elderly patient with a severe basilar artery stenosis who presented with posterior fossa transient ischemic attacks that were refractory to medical therapy. A, Anteroposterior (AP) view showing the severe basilar stenosis. The lesion was treated with angioplasty and stenting. B, Same AP view showing the vessel after angioplasty and stenting with an improvement in the stenosis. During the procedure the patient complained of a sudden headache. The patient was found to have a subarachnoid hemorrhage immediately after the procedure. C, Noncontrastenhanced head computed tomography after the angioplasty and stenting procedure shows subarachnoid hemorrhage and contrast material extravasation. The patient had immediate reversal of his anticoagulation and an external ventricular drain placed. Several hours later, the patient experienced another episode of hemorrhage and died.

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P earls 1. The NINDS trial showed clinical benefit at 90 days when intravenous r-tPA was administered less than 3 hours after symptom onset. The fact that there was no significant benefit seen at 24 hours suggests that the large MCA clot did not dissolve immediately. 2. The two largest randomized clinical trials of intraarterial thrombolysis are the PROACT I and PROACT II studies, which compared intra-arterial recombinant pro-urokinase plus intravenous heparin to placebo treatment plus intravenous heparin.5,15 These studies doubled the effective treatment window for thrombolysis from 3 to 6 hours, when the thrombolytic agent is given intra-arterially by a catheter embedded in the clot. 3. Symptomatic intracerebral hemorrhages occurred in 15% of PROACT patients and 10% of PROACT II patients who received intra-arterial pro-urokinase. 4. Unfortunately, GDC placement does not achieve complete, durable occlusion of all intracranial aneurysms. One recent study has shown a 20% rate of incomplete occlusion and an 8.6% rate of delayed recanalization at 3 years follow-up. 5. The most dreaded intraoperative complication with endovascular surgery is aneurysmal rupture. This complication is far more likely to occur in previously ruptured aneurysms than in an unruptured aneurysm. 6. Thromboembolism is a risk both during coil placement and in the postoperative period. This is the most frequent complication, occurring in 2.5% to 5% of GDC procedures.

7. Delayed ischemic neurologic deficits secondary to cerebral vasospasm will develop in as many as one third of patients who survive the initial hemorrhage.30 Cerebral vasospasm has been shown to lead to a 1.5to threefold increase in mortality at 2 weeks following SAH. 8. Recent MRI studies have shown that vasospasm might also be the cause of many strokes that do not cause gross neurologic dysfunction detectable during the patient’s initial stay in the intensive care unit, but are a cause of the more subtle memory and personality changes frequently seen in these patients. 9. Patients who have symptomatic vasospasm are in danger of irreversible cerebral infarction. The quicker blood flow is improved, the better the outcome. This has been demonstrated by a recent study showing a 2-hour window for blood flow restoration for maximum improvement in clinical outcome. 10. Vessel dissection or rupture from balloon angioplasty usually has devastating consequences. In one large series, 4% of patients undergoing balloon angioplasty died as a result of intraoperative vessel rupture. 11. Fifty percent of symptomatic AVMs present with an intracranial hemorrhage.45 The next most common symptoms at presentation are seizures and focal neurologic deficits. 12. Type A CCFs are most frequently traumatic in nature. The most common cause is motor vehicle accidents, followed by falls and penetrating injuries.

References 1. Gorelick PB: Stroke prevention therapy beyond antithrombotics: Unifying mechanisms in ischemic stroke pathogenesis and implications for therapy: An invited review. Stroke 2002;33:862–875. 2. del Zoppo GJ, Poeck K, Pessin MS, et al: Recombinant tissue plasminogen activator in acute thrombotic and embolic stroke. Ann Neurol 1992;32:78–86. 3. Rosner G, Heiss W: Survival of cortical neurons as a function of residual flow and duration of ischemia. J Cereb Blood Flow Metab 1983;3:s393–s394. 4. Overgaard K: Thrombolytic therapy in experimental embolic stroke. Cerebrovasc Brain Metab Rev 1994;6:257–286. 5. Furlan A, Higashida R, Wechsler L, et al: Intra-arterial prourokinase for acute ischemic stroke. The PROACT II study: A randomized clinical trial. Prolyse in Acute Cerebral Thromboembolism. JAMA 1999;282:2003–2011. 6. The National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group: Tissue plasminogen activator for acute ischemic stroke. N Engl J Med 1995;333:1581–1587. 7. Clark WM, Wissman S, Albers GW, Jhamanadas JH, Madden KP, Hamilton S: Recombinant tissue-type plasminogen activator (Alteplase) for ischemic stroke 3 to 5 hours after symptom onset. The

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Chapter 7  14. Wolpert SM, Bruckmann H, Greenlee R, Wechsler L, Pessin MS, del Zoppo GJ: Neuroradiologic evaluation of patients with acute stroke treated with recombinant tissue plasminogen activator. The rt-PA Acute Stroke Study Group. Am J Neuroradiol 1993;14:3–13. 15. del Zoppo GJ, Higashida RT, Furlan AJ, Pessin MS, Rowley HA, Gent M: PROACT: A phase II randomized trial of recombinant prourokinase by direct arterial delivery in acute middle cerebral artery stroke. Stroke 1998;29:4 –11. 16. Gönner F, Remonda L, Mattle H, et al: Local intra-arterial thrombolysis in acute ischemic stroke. Stroke 1998;29:1894–1900. 17. Ueda T, Sakaki S, Nochide I, Kumon Y, Kohno K, Ohta S: Angioplasty after intra-arterial thrombolysis for acute occlusion of intracranial arteries. Stroke 1998;29:2568–2574. 18. Ringer AJ, Qureshi AI, Fessler RD, et al: Angioplasty of intracranial occlusion resistant to thrombolysis in acute ischemic stroke. Neurosurgery 2001;48:1282–1288. 19. Becker KJ, Monsein LH, Ulatowski J, et al: Intraarterial thrombolysis in vertebrobasilar occlusion. Am J Neuroradiol 1996;17:255–262. 20. The Abciximab in Ischemic Stroke Investigators: Abciximab in acute ischemic stroke: A randomized, double-blind, placebo- controlled, dose-escalation study. Stroke 2000;31:601–609. 21. Guglielmi G, Vinuela F, Sepetka I, Macellari V: Electrothrombosis of saccular aneurysms via endovascular approach. Part 1: Electrochemical basis, technique, and experimental results. J Neurosurg 1991;75:1–7. 22. Thomas JE, Armonda RA, Rosenwasser RH: Endosaccular thrombosis of cerebral aneurysms: Strategy, indications, and technique. Neurosurg Clin North Am 2000;11:101–121. 23. Connors JJ, Wojak JC: Intracranial aneurysms: General considerations. In Connors JJ, Wojak JC (eds): Interventional Neuroradiology. Philadelphia, WB Saunders, 1999. 24. Derdeyn CP, Cross DT 3rd, Moran CJ, et al: Postprocedure ischemic events after treatment of intracranial aneurysms with Guglielmi detachable coils. J Neurosurg 2002;96:837–843. 25. Mericle RA, Lanzino G, Wakhloo AK, Guterman LR, Hopkins LN: Stenting and secondary coiling of intracranial internal carotid artery aneurysm: Technical case report. Neurosurgery 1998;43:1229–1234. 26. Mericle RA, Wakhloo AK, Rodriguez R, Guterman LR, Hopkins L: Temporary balloon protection as an adjunct to endosaccular coiling of wide-necked cerebral aneurysms: Technical note. Neurosurgery 1997;41:975–978. 27. Hayakawa M, Murayama Y, Duckwiler GR: Natural history of the neck remnant of a cerebral aneurysm treated with the Guglielmi detachable coil system. J Neurosurg 2000;93:561–568. 28. Lempert TE, Malek AM, Halbach VV, et al: Endovascular treatment of ruptured posterior circulation cerebral aneurysms. Stroke 2000;31: 100–110. 29. Fessler RD, Ringer AJ, Qureshi AI, Guterman LR, Hopkins LN: Intracranial stent placement to trap an extruded coil during endovascular aneurysm treatment: Technical note. Neurosurgery 2000;46:248–251. 30. Kassel NF, Torner JC, Haley EC, Jane JA, Adams HP, Kongable GL: The International Cooperative Study on the Timing of Aneurysm Surgery. Part 1: Overall management results. J Neurosurg 1990;73:18–36. 31. Biller J, Godersky JC, Adams HP Jr: Management of aneurysmal subarachnoid hemorrhage. Stroke 1998;19:1300–1305. 32. Treggiari-Venzi MM, Suter PM, Romand JA: Review of medical prevention of vasospasm after aneurysmal subarachnoid hemorrhage: A problem of neurointensive care. Neurosurgery 2001;48:249–261. 33. Yalamanchili K, Rosenwasser RH, Thomas JE, Liebman K, McMorrow C, Gannon P: Frequency of cerebral vasospasm in patients treated with endovascular occlusion of intracranial aneurysm. Am J Neuroradiol 1998;19:553–558. 34. Shimoda M, Takeuchi M, Tominaga J, et al: Asymptomatic vs. symptomatic infarcts from vasospasm in patients with subarachnoid hemorrhage: Serial magnetic resonance imaging. Neurosurgery 2001;49: 1341–1348. 35. Song JK, Eskridge JM: Intracranial angioplasty and thrombolysis. Neurosurg Clin North Am 2000;11:49–65.

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36. Macdonald RL, Weir B: Medical aspects of vasospasm, cerebral vasospasm. San Diego, Academic Press, 2001. 37. Rosenwasser RH, Armonda RA, Thomas JE, Benitez RP, Gannon PM, Harrop J: Therapeutic modalities for the management of cerebral vasospasm: Timing of endovascular options. Neurosurgery 1999;44:975–980. 38. Cook P, James I: Drug therapy: Cerebral vasodilators (first of two parts). N Engl J Med 1981;305:1508–1513. 39. Milburn JM, Moran CJ, Cross DT 3rd, Diringer MN, Pilgram TK, Dacey RG Jr: Increase in diameters of vasospastic intracranial arteries by intraarterial papaverine. J Neurosurg 1998;88:38–42. 40. Connors JJ, Wojak JC: Endovascular therapy of postsubarachnoid hemorrhage vasospasm. In Connors JJ, Wojak JC (eds): Interventional Neuroradiology. Philadelphia, WB Saunders, 1999. 41. Polin RS, Hansen CA, German P, Chadduck JB, Kassel NF: Intraarterially administered papaverine for the treatment of symptomatic cerebral vasospasm. Neurosurgery 1998;42:1256–1267. 42. Firlik AD, Kaufmann AM, Jungreis CA, Yonas H: Effect of transluminal angioplasty on cerebral blood flow in the management of symptomatic vasospasm following aneurysmal subarachnoid hemorrhage. J Neurosurg 1997;86:830–839. 43. Eskridge JM, McAuliffe W, Song JK, et al: Balloon angioplasty for the treatment of vasospasm: Results of first 50 cases. Neurosurgery 1998;42:510–516. 44. Berenstein A, Lasjaunias P: Surgical Neuroangiography. Berlin, Springer, 1991. 45. Drake CG: Cerebral arteriovenous malformations: Considerations for and experience with surgical treatment in 166 cases. Clin Neurosurg 1979;26:145–208. 46. Crawford PM, West CR, Chadwick DW, et al: Arteriovenous malformations of the brain: Natural history in unoperated patients. J Neurol Neurosurg Psychiatry 1986;49:1–10. 47. Brown RD, Wiebers DO, Forbes G, et al: The natural history of unruptured intracranial arteriovenous malformations. J Neurosurg 1988;68:352–357. 48. Spetzler RF, Martin NA: A proposed grading system for arteriovenous malformations. J Neurosurg 1986;65:476–483. 49. Hamilton MG, Spetzler RF: The prospective application of a grading system for arteriovenous malformations. Neurosurgery 1994;34:2–6. 50. Friedman WA, Bova FJ: Linear accelerator radiosurgery for arteriovenous malformations. J Neurosurg 1992;77:832–841. 51. Pollock BE, Lunsford LD, Kondziolka D, Maitz A, Flickinger JC: Patient outcomes after stereotactic radiosurgery for “operable” arteriovenous malformations. Neurosurgery 1994;35:1–8. 52. Wikholm G, Lundqvist C, Svendsen P: The Göteborg cohort of embolized cerebral arteriovenous malformations: A 6-year follow-up. Neurosurgery 2001;49:799–806. 53. Pan DH, Chung WY, Guo WY, Wu H, Liu KD, Shiau CY, Wang LW: Stereotactic radiosurgery for the treatment of dural arteriovenous fistulas involving the transverse-sigmoid sinus. J Neurosurg 2002;96: 823–829. 54. The n-BCA Trial Investigators: N-butyl cyanoacrylate embolization of cerebral arteriovenous malformations: Results of a prospective, randomized, multi-center trial. Am J Neuroradiol 2002;23:748–755. 55. al Rodhan NR, Sundt TM Jr, Piepgras DG, et al: Occlusive hyperemia: A theory for the hemodynamic complications following resection of intracerebral arteriovenous malformations. J Neurosurg 1993;78: 167–175. 56. Wilson CB, Hieshima G: Occlusive hyperemia: A new way to think about an old problem. J Neurosurg 1993;78:165–166. 57. Spetzler RF, Wilson CB, Weinstein P, et al: Normal perfusion pressure breakthrough theory. Clin Neurosurg 1978;25:651–672. 58. Newton TH, Cronqvist S: Involvement of dural arteries in intracranial arteriovenous malformations. Radiology 1969;93:1071–1078. 59. Sundt TM, Jr., Piepgras DG: The surgical approach to arteriovenous malformations of the lateral and sigmoid dural sinuses. J Neurosurg 1983;59:32–39.

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60. Cognard C, Gobin YP, Pierot L, et al: Cerebral dural arteriovenous fistulas: Clinical and angiographic correlation with a revised classification of venous drainage. Radiology 1995;194:671–680. 61. Awad IA, Little JR, Akarawi WP, Ahl J: Intracranial dural arteriovenous malformations: Factors predisposing to an aggressive neurological course. J Neurosurg 1990;72:839–850. 62. van Dijk JM, terBrugge KG, Willinsky RA, Wallace MC: Clinical course of cranial dural arteriovenous fistulas with long-term persistent cortical venous reflux. Stroke 2002;33:1233–1236. 63. Lasjaunias P, Chiu M, ter Brugge K, Tolia A., Hurth M, Bernstein M: Neurological manifestations of intracranial dural arteriovenous malformations. J Neurosurg 1986;64:724–730. 64. Vinuela F, Fox AJ, Pelz DM, Drake CG: Unusual clinical manifestations of dural arteriovenous malformations. J Neurosurg 1986;64:554–558. 65. Halbach VV, Higashida R, Hieshima GB, Goto K, Norman D, Newton TH: Dural fistulas involving the transverse and sigmoid sinuses: Results of treatment in 28 patients. Radiology 1987;163:443–447. 66. Barrow DL, Spector RH, Braun IF, Landman JA, Tindall SC, Tindall GT: Classification and treatment of spontaneous carotid-cavernous sinus fistulas. J Neurosurg 1985;62:248–256. 67. Larsen D, Higashida R, Connors JJ: Treatment of carotid-cavernous sinus fistulae. In Connors JJ, Wojak JC (eds): Interventional Neuroradiology. Philadelphia, WB Saunders, 1999. 68. Farley MK, Clark RD, Fallor MK, Geggel HS, Heckenlively JR: Spontaneous carotid-cavernous fistula and the Ehlers-Danlos syndrome. Ophthalmology 1983;90:1337–1342. 69. Koo AH, Newton TH: Pseudoxanthoma elasticum associated with carotid rete mirabile. Am J Roentgenol Radium Ther Nucl Med 1972;116:16 –22. 70. Halbach VV, Hieshima GB, Higashida RT, Reicher M: Carotid cavernous fistulae: Indications for urgent treatment. AJR 1987;149: 587–593. 71. Higashida RT, Hieshima GB, Halbach VV, Bentson JR, Goto K: Closure of carotid cavernous sinus fistulae by external compression of the carotid artery and jugular vein. Acta Radiol Suppl 1986;369:580–583. 72. Higashida R, Halbach VV, Tsai FY, et al: Interventional neurovascular treatment of traumatic carotid and vertebral artery lesions: Results in 234 cases. AJR 1989;153:577–582. 73. CAVATAS Investigators: Endovascular vs. surgical treatment in patients with carotid stenosis in the Carotid and Vertebral Artery Transluminal Angioplasty Study (CAVATAS): A randomised trial. Lancet 2001; 357:1729–1737. 74. Hobson RW, Weiss DG, Fields WS, et al: Efficacy of carotid endarterectomy for asymptomatic carotid stenosis. The Veterans Affairs Cooperative Study Group 5. N Engl J Med 1993;328:221–227. 75. Inzitari D, Eliasziw M, Gates P, Sharpe BL, Chan RK, Meldrum HE, Barnett HJ: The causes and risk of stroke in patients with asymptomatic internal-carotid artery stenosis. North American Symptomatic Carotid Endarterectomy Trial Collaborators. N Engl J Med 2000;342:1693–1700. 76. Sacco RL: Clinical practice. Extracranial carotid stenosis. N Engl J Med 2001;345:1113–1118. 77. Barnett HJ, Taylor DW, Eliasziw M, et al: Benefit of carotid endarterectomy in patients with symptomatic moderate or severe stenosis. North American Symptomatic Carotid Endarterectomy Trial Collaborators. N Engl J Med 1998;339:1415–1425. 78. Hobson RW: Update on the Carotid Revascularization Endarterectomy versus Stent Trial (CREST) protocol. J Am Coll Surg 2002;194:S9–14.

79. North American Symptomatic Carotid Endarterectomy Trial Collaborators: Beneficial effect of carotid endarterectomy in symptomatic patients with high-grade carotid stenosis. N Engl J Med 1991;325: 445–453. 80. Eisenhauer AC: Subclavian and innominate revascularization: Surgical therapy versus catheter-based intervention. Curr Intervent Cardiol Rep 2000;2:101–110. 81. Theron JG, Payelle GG, Coskun O, Huet HF, Guimaraens L: Carotid artery stenosis: Treatment with protected balloon angioplasty and stent placement. Radiology 1996;201:627–636. 82. Henry M, Amor M, Henry I, et al: Carotid stenting with cerebral protection: First clinical experience using the PercuSurge GuardWire system. J Endovasc Surg 1999;6:321–331. 83. Parodi JC, La Mura R, Ferreira LM, et al: Initial evaluation of carotid angioplasty and stenting with three different cerebral protection devices. J Vasc Surg 2000;32:1127–1136. 84. Schoser BG, Heesen C, Eckert B, et al: Cerebral hyperperfusion injury after percutaneous transluminal angioplasty of extracranial arteries. J Neurol 1997;244:101–104. 85. McCabe DJ, Brown MM, Clifton A: Fatal cerebral reperfusion hemorrhage after carotid stenting. Stroke 1999;30:2483–2486. 86. Meyers PM, Higashida RT, Phatouros CC, et al: Cerebral hyperperfusion syndrome after percutaneous transluminal stenting of the craniocervical arteries. Neurosurgery 2000;47:335–343. 87. Gorelick PB, Caplan LR, Langenberg P, et al: Clinical and angiographic comparison of asymptomatic occlusive cerebrovascular disease. Neurology 1988;38:852–858. 88. Borozan PC, Schuller JJ, LaRosa MP, et al: The natural history of isolated carotid siphon stenosis. J Vasc Surg 1984;1:744. 89. The Warfarin-Aspirin Symptomatic Intracranial Disease (WASID) Study Group: Prognosis of patients with symptomatic vertebral or basilar artery stenosis. Stroke 1998;29:1389–1392. 90. Bogousslavsky J, Barnett HJM, et al: Atherosclerotic diseases of the middle cerebral artery. Stroke 1986;17:1112–1120. 91. Craig DR, Meguro K, Watridge C, Robertson JT, Barnett HJ, Fox AJ: Intracranial internal carotid artery stenosis. Stroke 1982;13:825– 828. 92. Chimowitz MI, Kokkinos J, Strong J, et al: The Warfarin-Aspirin Symptomatic Intracranial Disease Study. Neurology 1995;45:1488–1493. 93. EC/IC Bypass Study Group: Failure of extracranial-intracranial arterial bypass to reduce the risk of ischemic stroke: Results of an international randomized trial. N Engl J Med 1985;313:1191–2000. 94. Hyodo A, Matsumaru Y, Anno I, et al: Percutaneous transluminal angioplasty for atherosclerotic stenosis of the intracranial cerebral arteries: Results with more than one year follow-up (abstract). Intervent Neuroradiol 1997;3:38. 95. Clark WM, Barnwell SL, Nesbit G, O’Neill OR, Wynn ML, Coull BM: Safety and efficacy of percutaneous transluminal angioplasty for intracranial atherosclerotic stenosis. Stroke 1995;26:1200–1204. 96. Connors JJ, III, Wojak JC: Percutaneous transluminal angioplasty for intracranial atherosclerotic lesions: Evolution of technique and shortterm results. J Neurosurg 1999;91:415–423. 97. Mori T, Kazita K, Chokyu K, et al: Short-term arteriographic and clinical outcome after cerebral angioplasty and stenting for intracranial vertebrobasilar and carotid atherosclerotic occlusive disease. Am J Neuroradiol 2000;21:249–254. 98. Marks MP, Marcellus M, Norbash AM, et al: Outcome of angioplasty for atherosclerotic intracranial stenosis. Stroke 1999;30:1065–1069.

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Chapter 8 Multiple Organ System Injuries Resulting from and Critical Care of Isolated Severe Central Nervous System Trauma John L. D. Atkinson, MD, FACS and Jack E. Wilberger, Jr., MD

Introduction

Pathophysiology of Head Injury

Head injury remains a serious public health problem, occurring at a rate of 150 per 100,000 population per year in the United States. The most current data indicate that head injury accounts for more than 20,000 deaths and 50,000 permanent disabilities each year.1,2 With an understanding of the mechanisms of secondary injury and the development of appropriate critical care treatment strategies, there has been a significant decline in head injury mortality over the past two decades. Indeed, contemporary multicenter studies are reporting mortality rates as low as 17%.3 In this regard, two important questions remain unanswered: Can such favorable outcomes be achieved outside rigorous scientific studies in routine clinical practice? Can critical care treatment strategies be developed to further improve outcomes? It is likely that adherence to the management principles enumerated in the Guidelines for the Management of Severe Head Injury coupled with the concept of targeted therapy and improved brain monitoring will result in a sustained lowering of mortality after head injury. Such principles and technologies can now be readily applied in most current neurointensive care practice settings. For the future, however, improved outcomes may require refocusing attention on neuro-protective agents and identification of the genetic factors resulting in repair and recovery after head injury.

Patients with severe traumatic central nervous system injury may experience immediate alterations in cerebral and systemic physiology within the first 10 minutes of the postinjury period. These alterations not only determine life or death at the scene of injury, but set into motion critical physiologic and biochemical cascades that influence medical care and determine outcome. This critical phase of injury encompasses the pathophysiologic sequelae of apnea and catecholamine surge responsible for multiple organ injuries early post–central nervous system trauma. The following sections discuss the pathophysiology and treatment along with potential future therapeutic options. Critical Phase of Head Injury Apnea and Catecholamine Surge The critical phase of head injury is arbitrarily defined in this manuscript as the first 10 minutes after the onset of severe head injury, as patients will live or die at the scene based on the pathophysiology that occurs during this period. The phases of severe head injury outlined in Figure 8-1 and Table 8-1 are extrapolated from JD Miller’s review of head injury4 and Overgaard and Tweed’s5 summary comments. These authors note that significant ischemic and hypoxic brain injury occurs before hospital admission, and they emphasize the importance of this critical phase in patient outcome. 215

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Figure 8-1. Outline of the phases of head injury. The first 10 minutes are aptly termed the “critical phase” because if respirations do not resume (spontaneously or otherwise), death will ensue due to hypoxic cardiovascular collapse.

Other phases in addition to this “critical phase” are depicted as well, and listings of various other mechanisms of injury during severe head injury management are outlined. There are two immediate pathophysiologic events occurring with the onset of severe head injury that markedly affect subsequent outcome: head injury–induced apnea, and a stress-related massive sympathetic discharge (Fig. 8-2). In combination, the effects of hypoxia, hypercarbia, acidosis, and blood pressure surge, as well as the direct effects of catecholamines on tissue, all lead to a synergistic injury effect in the host. The extent of the catecholamine surge and apnea occurring after severe head injury is directly related to the amount

Table 8-1  Phases of Head Injury Critical phase Apnea: Always occurs with concussive head injury; the more energy delivered to the brain, the longer the subsequent apnea, and the poorer the respiratory recovery. • No respiratory recovery; dead at the scene unless resuscitate early. • Long apnea and poor respiratory recovery fosters hypoxia and hypercarbia leading to early, massive brain swelling from increased cerebral blood volume due to vasodilatation from hypercarbia; profound hypoxia may take minutes to occur but markedly effects the neuronal environment. • Early intervention may dramatically alter course. Catecholamine surge: Markedly elevated blood pressure occurs immediately due to massive sympathetic discharge; this augments hypercarbia-induced cerebrovascular dilatation and promotes early vasogenic edema, endothelial injury, BBB disruption, and progressively increased ICP occurs depending on the magnitude of epinephrine release and CO2 retention. Intense vasoconstriction of other susceptible vascular beds produces ischemic gastric mucosal ulceration (stress ulcers, previously known as Cushing’s ulcers), and neurogenic pulmonary edema, along with catecholamine tissue injury such as myocardial necrosis. Primary brain injury: Fracture or tearing of bones, meninges, brain parenchyma, and blood vessels occurs to varying degrees as forces converge through various vectors. Secondary brain injury mechanisms initiated: Vasogenic edema; astrocytic swelling with altered EAA uptake and K+ alterations, etc.; hemorrhage; neuronal and oligodendroglial ischemia; thromboplastin release with altered coagulation; SAH and progressive ICP, various molecular cascades, etc. Exponential phase Respiratory recovery frequently leads to hyperventilatory drive; any respiratory recovery may prolong life; early ventilation intervention may alter outcome. • Catecholamine surge abates and blood pressure falls to mid- or high-normal levels. However, brain may be massively swollen due to hypercarbic-induced vasodilatation and subsequent BP surge, and any hemorrhage may have been augmented; ischemic injury to gastric mucosa, myocardium, and neurogenic pulmonary edema may present complications. • Molecular cascades continue to progress such as buildup of excess excitatory amino acids, lipid peroxidation, possible apoptosis of select cell populations, etc. • Hemorrhage progresses or injured vessels thrombose; ICP may continue to increase from progressive edema, mass effect, SAH; nonviable or ischemic brain undergoes cellular swelling; marginally compensated parenchymal cells live or die depending on cellular milieu; diffuse axonal injury matures; seizures may augment cerebral blood volume and ischemic cascade. Plateau phase ICP stabilizes or may increase due to gradual transition from vasogenic edema to cellular edema; delayed intracerebral hematoma may develop from dead or injured brain and blood vessels; dead parenchyma promotes edema; SAH and RBC lysis may precipitate vascular injury which may lead to vasospasm; molecular cascades may slow or stop; 75% of deaths occur in the first 48 to 72 hours. Resolution phase Collagen and glial repairs progress; SAH-induced vasospasm may evoke ischemia and infarction; previously infarcted parenchyma maximally swells and resolves; continued risk for 1 to 2 weeks of delayed intracerebral hematoma; cellular edema becomes greater component of swelling vs. vasogenic edema and may slowly subside; post-traumatic hydrocephalus may evolve short or long term. BP, blood pressure; EAA, excitatory amino acid; ICP, intracranial pressure; RBC, red blood cell; SAH, subarachnoid hemorrhage. Data from Miller JD: Head injury and brain ischaemia—Implications for therapy. Br J Anaesth 1985;57:120–129; and Overgaard J, Tweed WA: Cerebral circulation after head injury. Part 4: Functional anatomy and boundary-zone flow deprivation in the first week of traumatic coma. J Neurosurg 1983;59:439– 446.

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Figure 8-2. Severe head injury sequelae of disturbance in medullary-driven diaphragmatic ventilation and massive sympathetic stimulation. The magnitude and severity of both events are directly proportional to the magnitude of energy transmitted to the brainstem.

of energy transmitted to the brainstem. As a result, a significant number of severely head-injured patients live or die at the scene based on whether or not there is resumption of breathing. Prolonged apnea-induced hypoxic brain and cardiac injury, augmented by markedly elevated stress catecholamines, will increase mortality and, in survivors, morbidity. Therefore, the substrate from which medical and surgical therapy must begin is determined at the scene before hospital-based medical assistance is rendered. The modern aggressive care delivered in hospital and directed at optimizing cerebral perfusion, while scientifically grounded, may in many cases be too little, too late. The clear implication here is that the prehospital care provided by the emergency medical services system, as well as bystander witnesses to the injury, will significantly influence outcome for better or worse (see Chapter 14, Prehospital Care of the CNS Injured Patient). The following sections will critically examine apnea and catecholamine surge induced in the critical phase of head injury. From this analysis, conclusions for clinical management will be drawn. Apnea. Apnea resulting from head concussive injury has been recognized experimentally for longer than a century. Koch and Filehne6 reported in 1874 that repeated small

blows to the head of animals led to death by respiratory paralysis without any visible structural abnormality in the brain. Polis7 showed in 1894 that concussive head injury in the cat, dog, and rabbit were followed by respiratory arrest and a significant increase in mean arterial blood pressure. If respirations did not recover, the animal died, even though there were no gross anatomic lesions in the brains. In 1896, Kramer8 also reported that animals receiving a blow to the head experienced respiratory paralysis. In 1927 Miller9 repeated Polis’ work with identical findings. However, it was Denny-Brown10 in 1941 who clearly revealed that immediate death from most severe experimental head injuries was due to respiratory failure. Using respirometric methods, he demonstrated that increasing degrees of energy delivered to the brain produced increasing duration of apnea. A light blow produced a respiratory gasp, a moderate blow produced varying degrees of apnea with respiratory recovery, and heavy blows produced respiratory arrest and subsequent death due to hypoxic cardiovascular collapse. There were no observable lesions in the brains when sectioned. DennyBrown concluded that the response was brainstemmediated, as it was noted to occur in decerebrate preparations of animals. He also thought that it was energydependent, based on the force and rate of change (acceleration) transmitted to the brainstem, and had nothing to do

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with physical disruption of the brain or development of space-occupying hematomata. In 1944, Walker11 followed Denny-Brown’s work with a classic report on the physiologic basis of concussion in a number of different animal species. Using hammer, weight drop, and projectile techniques, he confirmed that the respiratory response was energydependent and characterized by a respiratory gasp at low energy, and apnea of long duration with higher energy. Walker also demonstrated that this response was brainstemmediated, and not related to elevated intracranial pressure. Sullivan and Becker12 showed that animals subjected to fluid percussion injuries exceeding the lethal threshold for apnea could recover normal function by both clinical and electroencephalographic (EEG) parameters if they added respiratory support. Gennarelli13 developed a headaccelerating machine and found that in primates, increasing the magnitude of acceleration caused apneustic changes in respiration, and at higher forces, the animals died without ventilatory support. In short, the more energy delivered to the brainstem, the more likely the animal was to die. Carey14 concluded the same with a projectile mechanism of brain injury in cats. Respiratory arrest was a constant physiologic response, even though the missile did not injure the brainstem directly. The duration of apnea was directly proportional to the energy transmitted to the brain. He concluded that the integrity of the medullary respiratory center after head injury determines, very early, whether the animal will live or die, regardless of the degree of other parenchymal injury. Carey further noted that if respiratory support were delayed, secondary hypoxic brain and cardiac damage ensued, resulting in marked morbidity or death. Anderson and associates15 combined mechanical brain injury with controlled postinjury hypoventilation followed by resumption of normal respiratory parameters in an attempt to simulate a more realistic model of head injury. These investigators found marked alterations in cerebral blood flow, cerebral metabolic rate of glucose, and brain ischemia not seen with either head injury or hypoxic injury alone. This was further delineated by Ito and associates,16 showing that weight drop brain injury–induced hypoventilation and hypotension in laboratory animals produced marked brain ischemia. Diffusion weighted magnetic resonance imaging (MRI) identified aberrations that were not visualized if only head injury, without hypoventilation or hypotension, occurred. Kim and associates17 and Levasseur and associates18 produced graded respiratory responses to fluid percussion head injury, and showed a marked increase in fatalities in ethanol pretreated animals who were subjected to this model of injury. They postulated that increased alcohol-related traumatic fatalities were due to synergistic respiratory depression as a result of head injury combined with the well-known depressant effect of ethanol. Others have also substantiated the increased morbidity and mortality resulting from head injury when combined with

ethanol.19–21 Both Kim and associates17 and Levasseur and colleagues18 verified that mechanical ventilation after head injury is essential in reducing acute mortality after experimental head injury. To date, irrespective of the methods used, all experimental head injury in a spontaneously breathing model has consistently produced apnea.22 The degree of respiratory paralysis and recovery has repeatedly been shown to be directly related to the amount of energy delivered to the brain (Fig. 8-3).22 In fact, the lethality of the respiratory response after head injury is used as a benchmark for the evaluation of new techniques in experimental brain injury model.23 Despite overwhelming experimental evidence of apnea and dysfunctional respiration immediately after head injury, there is less corroborating evidence derived from clinical studies. Johnson and associates24 examined nonaccidental closed head injury (i.e., child abuse) in 28 children. These investigators found 57% had a verifiable history of apnea before hospitalization. They concluded that trauma-induced apnea causes cerebral hypoxia and ischemia, which proves to be more fundamental to outcome in these patients than the mechanism of primary brain injury itself (i.e., subdural hematoma, subarachnoid hemorrhage, diffuse axonal injury, or contusions). Severe closed head injury–associated hypoxia (19%), hypotension (24%), or both (7%) were reported in the Traumatic Coma Data Bank as strong predictors of morbidity and mortality.25–27 These percentages are certainly under-representative, as they were recorded on admission to the emergency department (ED) following ambulanceassisted resuscitation, and do not reflect changes that might have been noted at the scene of head injury. However, the most powerful testimony to the association of apnea with clinical head injury results from eyewitness accounts recorded by physicians who were at the scene of injury.28 In two separate patients with head injury, both were rescued at the scene by early ventilation. Both patients initially had Glasgow Coma Scale scores of 3, with fixed dilated pupils, no corneal reflexes, and no respirations or pulse. Both patients made uneventful recoveries. The authors summarized that without early ventilatory assistance, these two patients would almost certainly have died or suffered serious brain damage due to respiratory failure as a result of their nonlethal head injuries. Catecholamine Surge. It is irrefutable that catecholamine surge is a “stress response” to head injury, and as such represents an important and neglected contribution to head injury morbidity and mortality. Marked elevations in blood pressure and heart rate are universal responses to head injury and have been documented for longer than a century. For example, Polis, in 1894,7 described marked elevation in blood pressure and heart rate with experimental head injury. Furthermore, blood pressure and heart rate elevation is discussed as a concomitant response of all previously discussed studies regarding head injury–associated apnea.7,10–23

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Figure 8-3. Rat model of fluid percussion head injury with increasing magnitudes of energy delivered to the brain and corresponding responses of blood pressure, spirometry measured tidal volume, and intracranial pressure. A, 1.15 atm pressure delivered to the brain with 45 seconds of apnea followed by rapid resumption of normal respiratory pattern and no significant change in the mean arterial blood pressure or ICP. B, 2.2 atm pressure delivered to the brain with 45 seconds of apnea followed by very slow resumption of normal respiratory pattern with immediate marked elevation in blood pressure and rapid (1–3 minutes) elevation in ICP to 10x baseline level. C, 3.5 atm pressure delivered to the brain with immediate apnea never followed by any organized respiratory effort with immediate and marked elevation in blood pressure and ICP. Animals in this group will die from hypoxic cardiovascular collapse, but can be salvaged if mechanically ventilated. There were no space-occupying hematomas identified in any of the groups. (From Atkinson JLD, Anderson RE, Murray MJ: The early critical phase of severe head injury: Importance of apnea and dysfunctional respiration. J Trauma 1998;45:941–945, with permission.)

The blood pressure and dynamic response of the heart to head injury was labeled early in the past century as the “Cushing response”29 because of Cushing’s early work with experimentally induced intracranial mass lesions, itself a continuation of Spencer and Horsely’s previously performed work.30 However, the Cushing response, although mediated by a catecholamine surge, is a response to increased intracranial pressure and the diminution of cerebral perfusion. Subsequent early studies concentrated on this sympathetic discharge resulting from acutely elevated intracranial pressure (ICP). Grimson and asscociates31 reported in 1937 that the increase in blood pressure from increasing intracranial pressure could be abolished by total sympathectomy.

Freeman and Jeffers32 repeated this experiment by creating sudden increased intracranial pressure by injection of saline under pressure into the cisterna magna of dogs. They discovered that the systemic blood pressure response was prevented by sympathectomy.32 Roozerkrans and Van Zwieten33 were able to block the “Cushing response” by adrenergic blockade using phentolamine in a manner similar to Cushing’s blockade of the splanchnic response of the intestines to blood pressure surge by cocainization of the medullary centers.29 The previous studies demonstrate that elevated ICP results in activation of the sympathetic nervous system with subsequent marked catecholamine release. However, it has

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become clear that massive catecholamine surge is an immediate brainstem mediated response to severe head injury in the absence of elevated ICP, as vividly described by Walker11 in brainstem preparation animals. Massive sympathetic discharge and subsequent marked elevation in mean arterial blood pressure and heart rate has proven to be a consistent immediate response in any experimental severe head injury model, such as fluid percussion injury,12 acceleration,13 projectile,14 or weight drop techniques.22 The benchmark experimental study conducted by Rosner in Becker’s laboratory at Medical College of Virginia34 confirmed what Beckman and Iams had concluded earlier.35 They documented as much as a 500-fold increase in plasma epinephrine and 100fold increase in plasma norepinephrine with severe head injury. The conclusion was that both epinephrine and norepinephrine plasma levels increased in direct response to the amounts of energy delivered to the brain and paralleled injury severity. The systolic arterial blood pressure directly correlated with the level of circulating catecholamines, was an instantaneous sequela to all but the most lethal of head injuries sequelae, and did not correlate with elevated ICP. In the clinical setting, patients often continue to have increased circulating catecholamines for many days after isolated head injury. Hörtnagl and associates36 found elevated plasma epinephrine and norepinephrine levels in 15 severely head-injured patients, and suggested that longstanding overactivity of the sympathetic nervous system was a characteristic feature in the clinical course of head injury. Sculte Am Esch and associates37 also found a hyperdynamic state after head injury due to over-activity of the sympathetic nervous system. Clifton and colleagues38 reported that, in patients with head injury alone, circulating catecholamine concentrations were significantly elevated, and blood pressure was directly proportional to the plasma concentration of norepinephrine. Subsequent clinical work from the same institution has shown that increased circulating catecholamines were common in head-injured patients, but did not correlate with either the GCS score or increased intracranial pressure.39,40 The investigators suggested that rational treatment in head-injured patients would include beta-blockade both to decrease hypertension as well as the catabolic effects of this hyperdynamic state.41 Increased circulating catecholamines have been confirmed in other stress conditions as well, such as subarachnoid hemorrhage,42,43 shock,44 or severe thermal injury,45 in addition to having been reconfirmed in clinical head injury.46,47 Serum catecholamine levels have even been used as a marker to assess the severity of head injury in the setting of alcohol-intoxicated patients in the ED.48 Recommended treatment of this hyperdynamic, sympathetically mediated response to head injury46,47 is betablockade.49–51 Many studies suggest that the early elevated ICP seen after severe head injury, in the absence of a space occupying mass, is due to a marked increase in cerebrovascular volume and

breakdown of the blood-brain barrier.52–56 It is logical to suggest that an apneic patient with profound hypercarbic and hypoxic cerebrovascular dilatation, in the setting of probable impaired autoregulation, and subjected to massive blood pressure elevation, would experience a rapid increase in cerebral blood volume, with resultant increased intracranial pressure. It may well be that in many patients without space-occupying hematomata, elevated ICP noted on admission to the ED has been fostered and augmented by these immediate post–head injury conditions. Figure 8-3 reveals that increasing energy transmitted to the brain yields different physiologic results. In Figure 8-3B, 2.2 atm of pressure is delivered with immediate marked elevation of blood pressure. However, the ICP elevation closely parallels hypoventilation-induced CO2 elevation and subsequent gradual cerebrovasodilatation with increased cerebrovascular volume. Figure 8-3C represents a rapid elevation of and significant elevation in ICP that is graphically representative of absent autoregulation in the setting of a massive blood pressure surge with a resultant marked increase in cerebral blood volume. There were no space-occupying hematomata in any of the experimental animals.22 In summary, head injury induces an instantaneous stress response via massive sympathetic discharge. The response depends on the “energy dose” applied to the brain, and clinically this hyperdynamic state may last for hours or even days in many patients with severe head injury. Negative ramifications of this catecholamine surge include stressinduced hyperglycemia, and injuries to the gastroduodenum, heart, and lungs, as will be discussed in the following sections. Anatomic Abnormalities Primary Neural Injury. Primary neural injury of the brain occurs at impact, resulting in the shearing and destruction of neurons, glial, and vascular structures by the mechanical forces imposed by the impact. This injury is irreversible and the neurologic deficits created by the primary injury have little potential for recovery. When epidural or subdural hematomata or brain contusions occur, the significance of primary neural injury may be unclear. Prompt and appropriate surgical and medical therapy can frequently improve the patient’s condition in these settings. Primary neural injury rarely results in immediate mortality, thus providing the opportunity for affecting survival through postinjury management. The degree and extent of primary neural injury are fixed at the time of the accident, and depend partially on the mechanism of injury. The only defense against the occurrence of primary neural injury is prevention. Extensive efforts at injury prevention have occurred in recent years. However, the success of programs such as decreased speed limits, mandatory seat belt laws, and passive restraints (air bags) have yet to be confirmed. In Pennsylvania, which has an extensive trauma registry program, there was a 30%

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decrease in severe traumatic brain injury in 1996 as compared to 1995 (unpublished data). The reason(s) for the significant decrease have not yet been analyzed. Ongoing educational programs such as Think First, are aimed at increasing the awareness of the association of risk-taking behaviors and the potential occurrence of trauma brain injury and its consequences. Secondary Neural Injury. Singular advancements in the crit-

ical care management of head injury have been based on the understanding of the concept that a large number of patients die not because of the initial injury to the brain but entirely because of additional secondary insults that occur following injury.3,25,57 Several clinical and multiple biochemical events occur following primary neural injury. These events cause secondary neural injuries that can convert a potentially recoverable traumatic brain injury into one resulting in either mortality or significant long-term disability. Hypotension and hypoxia are the most consistent predictors of poor outcome in head injury, presumably because of their role in facilitating the processes that lead to secondary neural injury. More than 30% of patients with severe traumatic brain injury present to the ED with significant hypotension (systolic blood pressure < 90 mm Hg) or hypoxia (PaO2 < 60 mm Hg). The occurrence of hypotension or hypoxia alone increases morbidity and mortality of traumatic brain injury by up to 50%.25,57 When hypoxia and hypotension occur together, the risk of a poor outcome increases to more than 60%. Adequate prehospital and ED resuscitation is of critical importance. Concern over the effects of hypotension underlies one of the cornerstones of head injury management: adequate volume resuscitation and maintenance of positive fluid balance. Given the concern that currently used intravenous fluids can potentially exacerbate cerebral edema especially in areas of blood-brain barrier breakdown, other resuscitative and maintenance fluids are under active investigation. Because of the small volumes required (approximately 8 mL/kg) to maintain an adequate blood pressure, hypertonic saline solution has been used as a resuscitative fluid in experimental studies.58 The biomechanical substrates of secondary injury have been extensively investigated. A cascade of events is triggered shortly after injury, having a variable time course and effect. This cascade is multifactorial, interrelated, and, to some extent, time dependent.59–62 More recently, investigators have focused on the genetic response to head injury. The research so far has been primarily descriptive in nature, however, a number of genes have been found to be up or down regulated following ischemia and trauma.3,63,64 While the concept of secondary injury is valid and generally applicable in a given head injury patient, it must be borne in mind that head injury is structurally, physiologically, metabolically, and biochemically heterogeneous. Additionally, the factors that may be operative in any individual patient may vary from one time to another. For example,

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autoregulation may be present, absent, or altered in the same head-injured patient at various intervals of assessment.65 Such information is vitally important as some forms of current critical care treatment take advantage of the presence—i.e., cerebral perfusion pressure management—or absence—i.e., barbiturates—of autoregulation. Thus, the heterogeneity of head injury and the patient-dependent features of secondary injury provide a further challenge to develop more sophisticated monitoring systems and to be able to modify treatments based on patient specific parameters. Central Nervous System Trauma–Associated Pathologies Hyperglycemia and Brain Injury. It is known that the head injury–induced “stress response” results in a marked hyperglycemia mediated both by catecholamine surge and, likely, stress-induced cortisol release.34,66 It is also known that hyperglycemia existing before ischemic brain injury significantly worsens outcome.67–69 Serum glucose levels correlate directly with the magnitude of head injury and can rise to as high as 400 mg/dL by 1 hour postinjury in experimental animals.34 This relatively slow rise in glucose levels may be too late to adversely effect immediate postinjury brain hypoxic ischemia, but may significantly worsen any secondary brain injury ischemic damage, such as focal ischemia derived from evolving space-occupying lesions. In an animal model, Cherian and associates70,71 have convincingly demonstrated that cortical impact injury followed by ischemic insult in the presence of hyperglycemia significantly increases brain ischemic volume, contusion volume, and mortality, and decreases functional outcome in survivors. Hyperglycemia remains to be adequately assessed in the clinical head-injury setting. Based on the preceding conclusions, elevated glucose levels (>200 mg/dL) in patients at risk for central nervous system ischemia, due to oligemic blood flow or elevated ICP, may warrant insulin management. Maintenance of serum glucose between 80 and 150 mg/dL (“normal range”) should be strongly considered. Avoidance of glucose solutions would be prudent.69 Gastric Mucosal Ulceration. Gastroduodenal mucosal injury

frequently develops after severe head injury, and frank ulceration is common as well. Esophageal gastroduodenoscopy in patients soon after severe head injury reveals these lesions in as many as 90% of patients.72–74 These ulcerations occur very early after head injury, and are similar to catecholamine stress ulcers produced experimentally,72,75,76 or by other systemic stress injuries such as burns or sepsis.77,78 The mechanism may be a combination of factors, such as increased vagal activity resulting in increased gastric acidity or slowed gastric emptying, or increased circulating pancreatic polypeptide levels.79,80 However, the predominant theory of

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gastric ulcerogenesis in head-injured patients is that catecholamine-induced vasoconstriction causes decreased splanchnic blood flow with resultant ischemic mucosal injury.81,82 Regardless of the mechanism, pharmacologic prophylaxis of further mucosal erosion should be considered in these patients.72–74 Prophylaxis of further mucosal erosions differs from the small percentage of these patients who actually suffer active gastrointestinal bleeding. Fortunately, most hemorrhages are minor. The first line of treatment is volume replacement. H2blockers, proton-pump inhibitors, or sucralfate should be used prophylactically. If significant blood loss occurs, or if bleeding continues despite therapy, then general surgery or gastroenterology specialists should be consulted early for endoscopic assessment and management.72 Myocardial Injury. Isolated head trauma-induced cardiac

injury is well documented in the pathology literature, and may be found at autopsy in up to two thirds of patients dying from acute head injury alone.83–85 The catecholamine surge accompanying head injury,86–88 spinal cord injury,89 or subarachnoid hemorrhage90–93 can precipitate these cardiac lesions. The injuries vary from disorganization, clumping, and necrosis of myocardial cells, to extensive areas of necrosis with hemorrhage, particularly in the ventricular septal region.84,85,94 The most common clinical manifestations are electrocardiographic abnormalities such as S-T segment depression or elevation, Q-T interval prolongation, and inversion of T waves.90,92,94,95 The lesions, if sufficiently extensive in their acute form, can contribute to, or cause, death.84,95,96 There is evidence that pretreatment with catecholamine blocking agents will markedly reduce the cardiac injury induced by stress catecholamine surge and help prevent further extension of myocardial damage.97,98 Any posttraumatic ECG changes warrant serial electrocardiographs, myocardial enzymes, and troponin-I evaluation. Transthoracic or transesophageal echocardiography is helpful in delineating wall motion abnormalities. Most cardiac arrhythmias are transient, and often do not require therapeutic intervention. However, enzyme elevation suggesting myocardial death or persistent arrhythmias should be assessed by an intensivist or cardiologist. Use of betareceptor blocking agents in patients at risk will diminish the extent of cardiac injury.91,97 Neurogenic Pulmonary Edema. A retrospective review of

the Traumatic Coma Data Bank suggests that pulmonary lesions, resulting from factors other than direct pulmonary trauma, are common.99,100 Although neurogenic pulmonary edema (NPE) may be mediated by a variety of mechanisms, the prevailing theory is that it is caused by a massive catecholamine surge.101 Marked pulmonary congestion and edema have been noted in other head injury autopsy series102 (Fig. 8-4) and are known to be a response in animals to massive autonomic discharge.103 This theory

Figure 8-4. Anteroposterior chest radiograph of a 46-year-old woman with severe head injury 2 hours after a single car rollover ejection from the vehicle. The radiograph shows marked neurogenic pulmonary edema.

suggests acute cardiac failure results from a catecholamineinduced increase in cardiac preload due to venoconstriction, and increased cardiac afterload by massive arterial constriction. In conjunction with catecholamine-induced cardiac injury, these mechanisms combine to produce edema in the lungs by increasing pulmonary capillary pressures. Early experiments showed that pulmonary edema could be prevented by adrenergic blocking agents or cordotomy, and that vagotomy by itself had little, if any, effect.103–106 The conclusions of the classic Vietnam war-era head injury series were that acute pulmonary edema after severe head injury occurred rapidly, resulted from a massive sympathetic discharge that produced a fluid shift from the periphery to the lungs, and was augmented by transient left ventricular failure and loss of left ventricular compliance from catecholamine-induced myocardial injury.101 Since that landmark article,101 evidence has grown in support of catecholamine surge as the major pathway in neurogenic pulmonary edema. Any cause of massive stressinduced autonomic discharge such as seizures, head injury, subarachnoid hemorrhage, or major stroke can produce NPE.107–109 Experimental models of head injury or subarachnoid hemorrhage continue to show massive sympathetic discharge as the primary mediator of neurogenic pulmonary edema,110–114 and this etiology permeates the literature in clinical and summary articles as well.113,115–117 Fulminant neurogenic pulmonary edema after severe head injury is uncommon. The most common cause of hypoxemia in the intensive care unit management of these patients is ventilation-perfusion mismatch due to atelectasis or aspiration. The diagnosis of NPE is supported by marked hypoxemia, appropriate chest radiograph findings (see Fig. 8-4), and exclusion of a cardiogenic cause for pulmonary

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edema. Maximizing oxygen delivery at the lowest inspired fraction of oxygen (FiO2) setting with the addition of positive end-expiratory pressure (PEEP; 10 to 15 cm H2O) if tolerated, and augmented by dobutamine (5 to 15 mg/kg/min), may help in refractory cases.107,108,115

Therapeutic Options for Postinjury Apnea MacIver and associates118 pleaded 40 years ago that the staggering morbidity and mortality of severe head injury could be markedly reduced simply by ventilating these patients at the accident scene. When this simple measure was undertaken, the 90% mortality in these patients was dramatically decreased to 40%. It can be seriously argued that the most significant reduction of trauma morbidity and mortality in this country came about with the 1966 publication of “Accidental Death and Disability: The Neglected Disease of Modern Society,” and the subsequent legislative development and continued refinement of emergency medical services (EMS).119 It comes as no surprise, when isolated head injury is reviewed within trauma resuscitation systems, that morbidity and mortality have continued to decline over the past decade almost exclusively due to improvement in the rapid response of EMS which, in turn, facilitates timely medical and surgical intervention.120 Even when comparing neurosurgical trauma care and patient outcome in countries as medically diverse as the United States and India, it again should come as no surprise that it is timely care in the field and expeditious transport to trauma centers that are the most important criteria separating the two countries’ head injury morbidity and mortality statistics.121 Brain ischemia remains a major focus of brain injury research. This investigative work has been stimulated by the neuropathologic findings reported by Graham and colleagues,122,123 who discovered that ischemic brain lesions were a common autopsy finding in humans who died following traumatic brain injury. Over half of the ischemic brain lesions found in head injury fatalities were of the arterial boundary zone type. Such lesions are most often seen in patients with a known clinical episode of hypoxemia or hypotension due to hypoxic cardiac failure. The explanation proposed by the investigators for this type of ischemic brain injury was that the pathophysiologic events likely occurred immediately after head injury, but before arrival of medical personnel to the scene of trauma. Other autopsy series have clearly documented the same ischemic brain injury findings, substantiating the proposition that factors occurring during the critical phase of head injury are the initiating events.83,124 These same pathologic cascades are believed to initiate injury to the gastrointestinal tract, heart, and lungs.83 It is evident that clinical and laboratory research should be directed toward lowering patient morbidity and mortality, and improving outcome of traumatic head injury.

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However, the vast majority of this care is directed toward patients who survive long enough to arrive in the emergency department, while the “critical phase” has essentially been ignored in the current spectrum of treatment.125 This is exemplified by the fact that 21 clinical head-injury trials targeting therapies directed toward patients on their arrival to hospital have all failed to statistically improve outcome (Ross Bullock, MD, PhD; personal communication).126 The purpose of this chapter is to draw attention to the critical phase of head injury and emphasize the importance of immediate post–head-injury events in determining patient outcome. Apnea and catecholamine surge clearly dictate the patient substrate from which medical or surgical intervention must begin. Therefore, it is imperative that treatment options be directed toward traumatic headinjured patients in the prehospital setting. Treatment Strategies The treatment principles of the 1980s were based on a concept of preventing and minimizing cerebral edema through fluid restriction, neural protection using prophylactic hyperventilation and steroids, and minimizing secondary injury by monitoring and treating elevated ICP. A better understanding of the elements of secondary injury has led to a virtually complete revolution in basic treatment tenets: adequate fluid resuscitation to prevent hypotension, ICP monitoring as a means of maximizing cerebral perfusion pressure (CPP), and avoidance of hyperventilation are now first-line treatment strategies. Nevertheless, it is critical to continually reevaluate our treatment approaches as recent articles have questioned the effectiveness of CPP management at the levels currently recommended. Alternative resuscitative fluid such as hypertonic saline and mannitol solutions are being aggressively studied, and the reportedly deleterious effects of hyperventilation are being re-examined.127–129 A codification of current treatment principles can be found in the Guidelines for the Management of Severe Head Injury. Guidelines for the Management of Severe Head Injury The Guidelines for the Management of Severe Head Injury were developed using an evidence-based approach.130 All pertinent clinical literature for the past 20 years was assessed, reviewed, and classified based on the following methods: class I evidence—prospective randomized controlled clinical trials; class II evidence—clinical studies with prospective data collections such as case control studies, cohort studies, or retrospective analyses based on reliable data; and class III evidence—retrospective data collections such as clinical series, databases, case reviews, and expert opinion. Each article assessed in this process was then carefully studied with respect to design and method to ascertain the

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reliability of its findings. This evidence was then weighted to determine the level of certainty that could be determined that a particular treatment or intervention in question would positively affect patient outcome. This level of certainty was then expressed as a standard, guideline, or option with respect to patient management strategies: standard— accepted principles of patient management that reflect a high degree of clinical certainty; guideline—recommendations that reflect a particular strategy or range of management strategies with a moderate degree of clinical certainty; option—all remaining strategies for patient management for which there is unclear clinical certainty. Generally, standards can only be supported by high-quality class I evidence. The lack of such studies in current neurotrauma literature is reflected in the fact that the guidelines propagate only three standards in the entire document. The guidelines have attempted to comprehensively address the clinical management of adult closed-head injury from initial resuscitation to the critical care phase of management. Fifteen separate sections address individual treatment considerations and pertinent examples are provided for each. Each recommendation is supported by detailed explanation of the available scientific evidence, evidentiary tables, and recommendations for future research. The guidelines were revised in 2000 to reflect new scientific literature that had become available since their publication in 1996. Additional chapters that are in the process of

being added include pediatric head injury, penetrating head injury, and surgical management of head injury. Prehospital Care Improved Emergency Medical Services Response A faster response of EMS would be extremely beneficial for any traumatically injured patient. Specifically, unwitnessed motor vehicle accidents (i.e., single car) or accidents in rural areas would all benefit from immediate notification and response of EMS to the exact location of injury. Endeavors such as the Mayday experiment at the Mayo Clinic and other areas are such an attempt to improve response time (Fig. 8-5), but other ideas need to be generated as well. In an effort to refine EMS care during the critical phase of head injury, there must be efforts to gather information at the scene of injury. Such field measurement might include analysis of arterial blood, including PaO2, PaCO2, pH, and level of circulating catecholamines, in an effort to determine the magnitude of energy the brain has received as well as the presence of hypoxic injury before arrival at the hospital. This information will give the treating neurosurgeon and trauma surgeon in the emergency department valuable information as to the severity of injury during the critical phase, and how best to manage and target therapy to the brain and other organs when the patient arrives. Data gathered at the scene might also spur laboratory development of treatments that

Figure 8-5. The Mayday trial uses a motor vehicle mounted sensor detecting collision events strongly suggestive of occupant injury and sends an immediate notification to the nearest EMS for rapid response deployment of service to the exact satellite depicted location of the accident.

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could be expeditiously initiated in the field rather than on arrival to the trauma care facility. Treatment of apnea in the field will be difficult to address. Patients who recover ventilation early after head injury are not at significant apneic hypoxic risk, but may have contributing aspiration or other pulmonary injury risks. The patient who is apneic for some period followed by a dysfunctional but poorly coordinated respiratory effort may sustain life on their own for a longer period of time awaiting EMS arrival. Patients who do not resume any respirations after the initial apnea will die unless ventilated early in the course of their head injury. These patients may benefit most from first responder delivered cardiopulmonary resuscitation (CPR). Continued education that CPR at the scene may be lifesaving in head-injured patients should be emphasized. For the patient with prolonged apnea, it is doubtful whether EMS response, regardless of how rapid, will make a significant difference in outcome. Ventilatory support must be provided early by the first responders at the scene of injury or multisystem hypoxic injury will occur. Target Therapy There is significant evidence that early generalized increased intracranial pressure and marked brain swelling on initial CT scans of head injured patients reflect an increased cerebral blood volume. In many cases, head injury may be characterized as a pathological state in which the cerebrovasculature is maximally vasodilated by hypercarbia and hypoxia, in the setting of head injury–induced dysfunctional vascular autoregulation. Thus, when a catecholamineinduced blood pressure surge occurs, the already increased cerebral blood volume of the brain will markedly increase. As the pressure surge enters a maximally dilated, unresponsive cerebrovascular bed, the result may lead to markedly elevated ICP with or without blood-brain barrier disruption.52–56 Better methods of triaging injured patients, based on information gathered at the scene regarding the critical phase of head injury, should help to select patients who merit maximal resuscitation efforts versus those with little or no likelihood of survival. There is no question that imaging is a powerful tool in determining prognosis, and newer MRI techniques may improve our diagnostic and prognostic capability.131,132 Target therapy could then be directed to foster recovery in predicted survivors, and as clinical information of the pathophysiology during this phase of head injury accumulates, potentially redirect future therapy to be rendered at the scene of head injury. The Critical Care of Head Injury Monitoring Modalities As noted previously, head injury has heterogeneous clinical manifestations and, more importantly, the pathophysiology in any given patient may change from one time epoch to the

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next.129,133 Thus, it is vitally important to establish appropriate monitoring of these patients to react to pathophysiologyinduced changes. At the most fundamental level, continuous arterial blood pressure monitoring is essential to rapidly react to episodes of hypotension. While there is still some controversy over the utilization of intracranial pressure monitoring with regard to its direct impact on patient outcome, it is clear that prolonged periods of intracranial hypertension increase head injury mortality. It has been clearly shown that if intracranial pressure is greater than 20 mm Hg and cannot be controlled by any measure, head injury mortality approaches 100%.134 Thus, it is important to consider intracranial pressure monitoring in any comatose patient with head injury or in patients who meet the criteria described by Narayan and associates,135 that is, normal head CT, older than 40 years of age, episode(s) of hypotension, brainstem dysfunction as evidenced by posturing. The exact method of ICP monitoring is, perhaps, not as important as the information obtained therefrom. Many prefer intraventricular monitoring because of the simultaneous ability to use cerebrospinal fluid drainage as a therapeutic modality. Nevertheless, there is reasonable and appropriate concern about the incidence of infection with these types of monitors. Various parenchymal monitors have proven useful; however, one must be aware of the limitations associated with drift of the monitors that can be as high as 2 mm Hg per day. Most authors consider subdural or epidural monitors to be relatively insensitive to levels of increased intracranial pressure in the setting of severe head injury (see Chapter 25, Elevated ICP). Monitoring of hemodynamic function by central venous pressure or pulmonary artery (PAC) lines are generally recommended to guide fluid resuscitation and to minimize the occurrence of hypotensive episodes. If intensive therapy, such as barbiturates, is used in the treatment of patients, then pulmonary artery catheter monitoring is mandatory because of the potential deleterious effects of these medications on cardiac function, even in young patients. Recently, critical care interest in the treatment of head injury has focused on more specific monitors of the perfusion and metabolic requirements of the injured brain. Perhaps the best known of these are the oximetric jugular venous oxygen saturation monitors. When the brain is ischemic, it will extract more oxygen and, thus, less is present in the jugular venous outflow. Robertson and associates136 have made great use of these types of monitors in the clinical treatment of severe head injury and have established clear correlation between jugular venous blood desaturation and outcome. Nevertheless, jugular venous oximetry has not been widely used because of its propensity for falsepositive readings and the need to frequently cross check the accuracy and reliability of the device. The use of cerebral perfusion pressure (mean arterial pressure minus intracranial pressure) has been advocated as an important parameter to not only monitor, but also aggressively treat to prevent

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cerebral ischemia occurring after severe head injury. Rosner and colleagues have been the most outspoken proponents of this monitoring (and treatment) modality.137,138 A CPP of greater than 70 mm Hg has been thought to be necessary to insure adequate brain perfusion. Obviously, to determine the CPP, one must have in place an appropriate blood pressure monitoring device as well as an intracranial pressure monitor. More recently, commercial monitors of focal cerebral oxygenation, glucose levels, pH and CO2 levels have become available. While several studies have indicated that brain PO2 levels correlate with outcome, there is no reliable information on how to specifically treat brain PO2 levels or how to use brain glucose, pH, and CO2 levels in the overall management strategy for patients with head injury.139–141 A critique of these monitors is that they only monitor tissue of several cubic millimeters in size and, thus, may have no correlation whatsoever with the overall perfusion and metabolic situation of the injured brain, unless the injury is diffuse. While microdialysis in head-injured patients has been studied, and clear and significant elevations in a number of different compounds—most prominently, the excitatory neurotransmitter glutamine—found, these technologies are available only experimentally. Critical Care Treatment Guidelines Once appropriate monitoring of the head-injured patient has been accomplished, it is then possible to use this information in conjunction with careful repeated clinical examination to establish treatment guidelines based on the principles enumerated in the Guidelines for the Management of Severe Head Injury. As noted previously, a number of secondary insults can potentially occur throughout the patient’s initial hospitalization—especially in the critical care phase—that require immediate attention. The first and foremost of these are the prevention and/ or early recognition and aggressive treatment of hypotension or hypoxia. There are multiple sources for hypotension in the severely head-injured patient. The least likely source is a terminal event associated with cerebral herniation and bilateral pupillary dilatation. Thus, it is often possible to intervene appropriately to maintain an adequate systolic and mean arterial blood pressure. Initially, the intravascular volume is best assessed utilizing a central venous pressure monitor or a pulmonary artery catheter. Hypovolemia can be effectively treated with infusions of crystalloid, colloids or, when appropriate, blood. If adequate volume replacement does not provide for sufficient maintenance or restoration of blood pressure, then inotropic or pressor agents should be used. In head-injured patients, a well-tolerated inotropic agent is dobutamine, while norepinephrine provides optimal peripheral vasoconstriction. It should always be borne in mind, however, that when fluid or pressors are being used to restore or maintain blood pressure, the source

of the underlying hypotension must be determined and treated. Blood loss from chest or abdominal injuries, cardiac contusion or tamponade, or tension pneumothorax must always be considered and investigated. Spinal shock from spinal cord injury should also be considered in individuals who are difficult to evaluate from a clinical neurologic standpoint. Hypoxia is another dangerous secondary insult to the brain and is generally treated by adequate artificial ventilation. In most patients, increasing the FiO2 improves oxygenation. However, many of these patients suffer from pulmonary contusions or develop acute respiratory distress syndrome (ARDS) and may require the addition of positive end-expiratory pressure (PEEP). Concerns, however, have arisen over the effects of PEEP on intracranial pressure. Levels of PEEP in excess of 8 cm H2O may be associated with a rise in intracranial pressure and a decrease in cerebral perfusion pressure. Usually, however, simply elevating the patient’s head reduced the effects of PEEP on ICP. Further, in noncompliant lungs, airway pressure is minimally transmitted, so no increase in ICP would be seen. Thus, if PEEP is required to maintain adequate oxygenation, there should be little concern over the use of this therapy. The primary focus of critical care management to this point in time has been maintenance of normal or near normal intracranial pressure. There are a number of general measures that can be undertaken to affect some degree of ICP control. These include utilization of sedatives and analgesics. However, one must remember that the use of these medications may result in a drop in blood pressure and their use must be titrated appropriately and monitored on a continuous basis. The primary agents currently utilized include midazolam at a dose of 0.025 to 0.35 mg/kg or through a continuous infusion at 0.05 to 5 mg/kg/min. The primary narcotics include morphine at a dose of 2 to 5 mg/hour or fentanyl at a dose of 50 to 100 mg/hour. Other agents such as a propofol and etomidate have been studied. Propofol does provide for smooth sedation and can be reversed quickly; however, the expense of the agent may limit its use. Infusions of Etomidate are inappropriate because the drug blocks 11-betahydroxylase and may lead to adrenal insufficiency. When these general measures fail to maintain an appropriate ICP, pharmacologic paralysis is often instituted. Such drug therapy prevents agitation, posturing, or coughing that can increase ICP to excessive levels. Unfortunately, when these agents are used, the neurologic examination is lost and consideration needs to be given to more frequent CT scan monitoring. In addition, prolonged use of pharmacologic paralysis can increase pulmonary complications, prolong stay in the ICU, and lead to iatrogenic neuromuscular disorders. The use of neuromuscular blocking agents should be limited to the shortest time possible. One popular agent in use at this time is the nondepolarizing agent vecuronium. It is given as a bolus at a dose of 0.1 to 0.2 mg/kg ideal body

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weight, and then run at a maintenance infusion of 1 to 10 mg/hour, titrated to one to two twitches of a train of four, stimulated by supramaximal electrical impulses at the ulnar nerve. The depolarizing agent succinylcholine is not recommended, except in an emergency, after the first several days of severe head injury because of its potential potassium elevating effect. Cerebrospinal fluid drainage is the simplest and most direct route to lowering intracranial pressure. This, however, requires ventriculostomy placement and as discussed in the previous section, it is not always possible to accomplish in patients with extremely small ventricles secondary to elevated intracranial pressure. Additionally, when there is intraventricular blood, the catheter may intermittently malfunction. Finally, when large amounts of cerebrospinal fluid are withdrawn, the ventricles normally collapse, thus limiting the utilization of this approach. Osmotic diuretics have long been utilized in the treatment of elevated intracranial pressure. Mannitol is typically given in a bolus dose of 0.25 to 1 g/kg and will maximally reduce the ICP within 15 minutes. This reduction generally lasts for 3 to 4 hours. Additional doses can be given as needed so long as there is careful monitoring of serum sodium and osmolality to prevent a hyperosmolar state. Oftentimes, mannitol is combined with furosemide at a dose of 20 mg given several times a day. The combination of these medications has been felt to be synergistic, although there are no definitive studies to indicate that such is indeed the case. Certainly, if mannitol and furosemide are to be used concomitantly, then even greater vigilance must be maintained for the development of a hyperosmolar state. A subsequent step available in controlling intracranial pressure when other measures have failed is the use of optimized hyperventilation. As noted previously, discussion related to the use of hyperventilation has significantly changed over the past several decades. Prolonged prophylactic hyperventilation, not being used to control intracranial pressure, is contraindicated because of the potentially significant decrease in cerebral blood flow associated with vasoconstriction. It is well known that for each 1 mm Hg drop in the PaCO2, there is a 3% decrease in cerebral blood flow and in the first 24 hours after severe head injury, the cerebral blood flow may be as low as 50% of normal. Nevertheless, when intracranial pressure is refractory to other modes of treatment, hyperventilation may be very effective. When hyperventilation is utilized, it is generally recommended that the PaCO2 be kept above 25 mm Hg. If more extreme levels of hyperventilation are required, then alternative monitoring is undertaken in order to document whether or not the brain is being made ischemic by the degree and extent of vasoconstriction associated with the hyperventilation. Such methods include xenon cerebral blood flow studies, jugular venous oxygen saturation monitoring, and the new technology of brain PO2 sensors.

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If the preceding measures have failed, the use of barbiturates is generally considered. Barbiturates suppress cerebral metabolism and, thus, decrease the demand for glucose and oxygen to theoretically tide the brain through periods of inadequate perfusion. When barbiturates are utilized, however, there must be exceedingly careful hemodynamic monitoring, including the placement of a pulmonary artery catheter. Barbiturates are associated with hypotensive complications and in many cases, have been the source of a patient’s demise in this setting. The most frequently used barbiturate is pentobarbital. The typical loading dose is 5 to 10 mg/kg given over 30 minutes with the subsequent administration of 5 mg/kg to obtain therapeutic levels. A maintenance infusion is then established at 1 to 2 mg/kg/hour. Various authors have suggested that following the levels of barbiturates to ensure that they are “therapeutic” provides the best information as to the establishment of appropriate treatment with this modality. However, therapeutic levels are sometimes difficult to obtain and may take many hours to return. Thus, the use of continuous electroencephalography (EEG) monitoring is real time and exceedingly sensitive to “therapeutic” levels of barbiturates. The end-point of treatment with barbiturates is 90% burst suppression on the two-channel EEG. There are other important management issues in the critical care of these patients, which include avoidance or correction of electrolyte disturbances and of hyperthermic states. It should be borne in mind that severe head-injured patients may be susceptible to cerebral vasospasm because of associated traumatic subarachnoid hemorrhage; this possibility should be considered in patients who are otherwise not responding to treatment. This occurrence can be documented either by the use of transcranial Doppler or, if necessary, angiography. Corticosteroids, which have been used extensively in the treatment of severe head injury in the past, are not indicated for the treatment of intracranial pressure or to improve the outcome after severe head injury. Extensive studies including meta-analysis of various studies have shown that corticosteroids have no effect whatsoever in this regard and are associated with a level of complications that are not acceptable. Targeted Therapy A logical extension of the Guidelines for the Treatment of Severe Head Injury is the concept of targeted therapy— treating a specific patient’s specific pathophysiology. Such an approach requires pertinent and contemporaneous information based on systemic and cerebral monitoring. An excellent example of this approach is directed management to maintain a CPP greater than 70 mm Hg. Such a goal requires ICP and systolic blood pressure monitoring. However, once established, a variety of targeted approaches can be brought into play. Various studies suggest that this approach improves head-injury outcome and it is, indeed,

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one of the most widely used strategies for the treatment of head injury today.137,138 However, this treatment strategy has frequently been taken to extremes in raising the CPP above 90 or 100 mm Hg to counteract extremely elevated ICPs. A recent randomized controlled clinical trial was reported by Robertson and associates136 in which they studied patients who were treated based on CPP alone versus those who were treated based on ICP alone. This study found no significant difference between neurologic outcomes in either group of patients. The authors, however, did find statistically significant increases in medical complications—particularly those related to pulmonary dysfunction (i.e., ARDS) in patients who were treated with large volumes of fluid and pressers in order to maintain elevated CPPs.136 Another example of targeted therapy is the avoidance of impaired cerebral oxygenation either due to a decrease in oxygen delivery or an increase in oxygen consumption. This approach currently requires jugular venous oxygen saturation monitoring in addition to a variety of other systemic variables. There are, however, now available commercial surface PO2 sensors, the reliability of which is currently being validated. The identification of oxygen desaturation allows for targeted therapy, depending on its source. Several studies have indicated that optimization of blood flow and metabolism through monitoring and normalization of cerebral oxygenation influences outcome.133,140–143 Fluid Management On a more fundamental level of targeted therapy, recent attention has been focused on the type of resuscitation and maintenance fluids used in head-injured patients. As noted previously, the concepts of fluid management in headinjured patients have been revolutionized over the past several decades. Nevertheless, aggressive fluid management may have its drawbacks as was discussed in relationship to CPP management. With these concerns in mind, a number of investigators have studied the use of hypertonic saline solution in traumatic brain injuries, both as a resuscitative and a maintenance fluid. It has been suggested that hypertonic saline solution not only improves hemodynamic parameters and modulation of intracranial hypertension after head injury, but also may possess osmotic, vascular, neurochemical, and immunologic effects. Numerous animal models support the use of hypertonic saline solution in the presence of traumatic brain injury, especially in the presence of hypotension. Worthley and associates144 reported two patients with traumatic injury and intractable intracranial hypertension successfully treated with 20 mL of 29.2% hypertonic saline solution. Einhaus and associates145 reported a similar experience with a patient with traumatic brain injury (TBI) who had intracranial hypertension refractory to mannitol. Simma and colleagues146 were the first to prospectively evaluate hypertonic saline solution, randomizing severely

head-injured pediatric patients to receive either 1.7% hypertonic saline or lactated Ringers solution as maintenance fluid for the first 72 hours following admission. They observed that patients receiving hypertonic saline solution had lower ICP values and required fewer interventions to manage ICP elevations. Qureshi and associates147 evaluated the effects of a continuous infusion of hypertonic saline solution in eight patients with intracranial hypertension of various causes. Patients were given 3% saline solution to raise their serum sodium to 145 to 155 mEq/L. An inverse relationship between serum sodium and ICP was observed in patients with TBI or postoperative edema but not with subarachnoid hemorrhage or ischemia. Patients receiving hypertonic saline solution also had less edema and mass effect on serial CT scans. Neuroprotection Considerable effort has been expended in the past decade to identify and organize clinical trials of pharmacologic agents which potentially hold great promise in blocking or ameliorating various components of the secondary injury biochemical cascade.148 In spite of extremely encouraging experimental animal studies to date, no human trial has proven successful. 149–151 Currently there is an ongoing trial at the Medical College of Virginia and the University of Florida evaluating the use of cyclosporin A to prevent secondary injury in TBI. A recent trial of a selective NMDAsubunit antagonist has been completed but results were not available at the time of this writing. There is speculation as to the reasons for the failure to identify a clinically active compound. The most pertinent concerns are an inability to appropriately target the population of patients most likely to benefit from such an intervention and the unrealistic projections of the magnitude of benefit that these agents might provide. Nevertheless, if a patient could be identified who clearly had a specific biochemical alteration associated with the head-injury pathophysiology—that is, excess glutamate release in association with a cerebral contusion—he or she could then be targeted for treatment with the appropriate pharmacologic agent in the appropriate time frame. Unless such strategies become clinically practical, however, it is unlikely that the field of neuroprotection will advance significantly beyond its present state. Gene Therapy The ultimate substrate of the CNS response to injury and repair is genetically mediated152 (see Chapters 31 and 32). There are ongoing discoveries related to the CNS genetic response to trauma and ischemia. While most studies have been descriptive in nature and their relevance to recovery, if any, unknown, increasing efforts are being expended not only to quantify this response but to manipulate it as well. Teasdale and associates153 recently reported preliminary data suggesting a relationship between apolipoprotein E and the brain’s response to injury. Individuals with a specific allele of

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this gene appear to have an increased vulnerability to head injury. Similarly, Sorbi and colleagues154 have suggested a possible association between another allele of the apolipoprotein E gene and poor outcome after severe head injury. The ultimate treatment strategy, therefore, would be to downregulate those genes responsible for the harmful biochemical cascade occurring after injury and to upregulate those genes responsible for repair and recovery. Given current research, such seems an obtainable goal within the next decade.

Strategies for the Millennium Marked improvements have occurred in the recognition and management of severe head injury with concomitant

improvements in outcome. The majority of these accomplishments have evolved through greater attention to the details of critical care management of this patient population. More sophisticated monitoring technology has further enhanced the timely identification and reaction to evolving pathophysiology and metabolic derangements. These advancements have been codified in the Guidelines for the Management of Severe Head Injury. The concept of targeted therapy is a logical extension of the guidelines to provide for more patient specific intervention. Ultimately, identification of a patient’s specific biochemical and genetic responses to injury will allow for complete understanding of the secondary injury process with a concomitant opportunity to provide the ultimate form of neuroprotection from head injury.

P earls 1. Head injury remains a serious public health problem, occurring at a rate of 150 per 100,000 population per year in the United States. The most current data indicate that head injury accounts for over 20,000 deaths and 50,000 permanent disabilities each year. 2. This critical phase of injury encompasses the pathophysiologic sequelae of apnea and catecholamine surge responsible for multiple organ injuries in the early period after central nervous system trauma. 3. There are two immediate pathophysiologic events that occur with severe head injury onset that markedly effect subsequent outcome: head injury–induced apnea, and a stress-related massive sympathetic discharge. In combination, the effects of hypoxia, hypercarbia, acidosis, and blood pressure surge, as well as the direct effects of catecholamines on tissue, all lead to a synergistic injury effect in the host. 4. To date, irrespective of the method used, all experimental head injury in a spontaneously breathing model has produced apnea as a consistent response. 5. . . . trauma-induced apnea causes cerebral hypoxia and ischemia which proves to be more fundamental to outcome in these patients than the mechanism of primary brain injury itself (i.e., subdural hematoma, subarachnoid hemorrhage, diffuse axonal injury, or contusions). 6. Massive sympathetic discharge and subsequent marked elevation in mean arterial blood pressure and heart rate has proven to be a consistent immediate response in any experimental severe head injury

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7.

8.

9.

10.

11.

model, such as fluid percussion injury, acceleration, projectile, or weight drop techniques. The degree and extent of primary neural injury is fixed at the time of the accident, and depends partially on the mechanism of injury. The only defense against the occurrence of primary neural injury is prevention. Singular advancements in the critical care management of head injury have been based on the understanding of the concept that a large number of patients die not because of the initial injury to the brain but entirely because of additional secondary insults that occur following injury. The occurrence of hypotension or hypoxia alone increases morbidity and mortality of traumatic brain injury by up to 50%. When hypoxia and hypotension occur together, the risk of a poor outcome increases to more than 60%. Given the concern that currently used intravenous fluids can potentially exacerbate cerebral edema especially in areas of blood brain barrier breakdown, other resuscitative and maintenance fluids are under active investigation. Because of the small volumes required (approximately 8 mL/kg) to maintain an adequate blood pressure, hypertonic saline solution has been used as a resuscitative fluid in experimental studies. Gastroduodenal mucosal injury frequently develops after severe head injury, and frank ulceration is common as well. Esophageal gastroduodenoscopy in patients soon after severe head injury reveals these lesions in as many as 90% of patients. These Continued

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ulcerations occur very early after head injury, and are similar to catecholamine stress ulcers produced experimentally, or by other systemic stress injuries such as burns or sepsis. 12. Isolated head trauma–induced cardiac injury is well documented in the pathology literature, and may be found at autopsy in up to two thirds of patients dying from acute head injury alone. 13. There is evidence that pretreatment with catecholamine blocking agents will markedly reduce the cardiac injury induced by stress catecholamine surge and help prevent further extension of myocardial damage. 14. . . . cardiac failure results from a catecholamineinduced increase in cardiac preload due to venoconstriction, and increased cardiac afterload by massive

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81. Kincaid EH, Miller PR, Meredith JW, et al: Enalaprilat improves gut perfusion in critically injured patients. Shock 1998;9:79–83. 82. Pastores SM, Katz DP, Kvetan V: Splanchnic ischemia and gut mucosal injury in sepsis and the multiple organ dysfunction syndrome. Am J Gastroenterol 1996;91:1697–1710. 83. Clifton GL, McCormick WF, Grossman RG: Neuropathology of early and late deaths after head injury. Neurosurgery 1981;8:309–314. 84. Connor RCR: Myocardial damage secondary to brain lesions. Am Heart J 1969;78:145–148. 85. McCormick WF: Trauma. In: Schochet SS Jr (ed). Clinical Neurosciences, vol 3. New York: Churchill-Livingstone, 1983, pp 241–283. 86. Burch GE, Sun SC, Colcolough HL, et al: Acute myocardial lesions following experimentally-induced intracranial hemorrhage in mice: A histological and histochemical study. Arch Pathol 1967;84:517–521. 87. Hawkins WE, Clower BR: Myocardial damage after head trauma and simulated intracranial hemorrhage in mice: The role of the autonomic nervous system. Cardiovasc Res 1971;5:524–529. 88. Heinrich D, Müller W: Focal myocardial necrosis in cases of increased intracranial pressure. Eur Neurol 1974;12:369–376. 89. Guha A, Tator CH: Acute cardiovascular effects of experimental spinal cord injury. J Trauma 1988;28:481–490. 90. Greenhoot JH, Reichenbach DD: Cardiac injury and subarachnoid hemorrhage. A clinical, pathological, and physiological correlation. J Neurosurg 1969;30:521–531. 91. Marion DW, Segal R, Thompson ME: Subarachnoid hemorrhage and the heart. Neurosurgery 1986;18:101–106. 92. Offerhaus J, Van Gool J: Electrocardiographic changes and tissue catecholamines in experimental subarachnoid hemorrhage. Cardiovasc Res 1969;3:433–440. 93. Yuki K, Kodama Y, Onda J, et al: Coronary vasospasm following subarachnoid hemorrhage as a case of stunned myocardium. Case report. J Neurosurg 1991;75:308–311. 94. Prichard BN, Owens CW, Smith CC, et al: Heart and catecholamines. Acta Cardiol 1991;46:309–322. 95. Reichenbach DD, Benditt EP: Catecholamines and cardiomyopathy: The pathogenesis and potential importance of myofibrillar degeneration. Human Pathol 1970;1:125–150. 96. Jiang JP, Downing SE: Catecholamine cardiomyopathy: Review and analysis of pathogenic mechanisms. Yale J Biol Med 1990;63:581–591. 97. Cruickshank JM, Neil-Dwyer G, Degaute JP, et al: Reduction of stress/catecholamine-induced cardiac necrosis by Beta-1-Selective blockade. Lancet 1987;2:585–589. 98. McNair JL, Clower BR, Sanford RA: The effect of reserpine pretreatment on myocardial damage associated with simulated intracranial hemorrhage in mice. Eur J Pharmacol 1970;8:1–6. 99. Atkinson JLD: Acute lung injury in isolated traumatic brain injury [letter]. Neurosurgery 1997;41:1214–1215. 100. Bratton SL, Davis RL: Acute lung injury in isolated traumatic brain injury. Neurosurgery 1997;40:707–712. 101. Simmons RL, Martin AM, Heisterkamp CA, et al: Respiratory insufficiency in combat casualties: II. Pulmonary edema following head injury. Ann Surg 1969;170:39–44. 102. Agar JM: The medical complications of the early management of head injury in the adolescent. Med J Aust 1966;2:1182–1183. 103. Ducker TB, Simmons RL: Increased intracranial pressure and pulmonary edema. II. The hemodynamic response of dogs and monkeys to increased intracranial pressure. J Neurosurg 1968;28:118–123. 104. Berman IR, Ducker TB: Changes in pulmonary, somatic, and splanchnic perfusion with increased intracranial pressure. Surg Gynecol Obstet 1969;128:8–14. 105. Berman IR, Ducker TB: Pulmonary, somatic and splanchnic circulatory response to increased intracranial pressure. Ann Surg 1969;169:210–216. 106. MacKay EM: Experimental pulmonary edema. IV. Pulmonary edema accompanying trauma to the brain. Proc Soc Exp Biol Med 1950;74:695–697.

107. Chen HI: Hemodynamic mechanisms of neurogenic pulmonary edema. Biol Signals 1995;4:186–192. 108. Pender ES, Pollack CV Jr: Neurogenic pulmonary edema: case reports and review. J Emerg Med 1992;10:45–51. 109. Theodore J, Robin ED: Pathogenesis of neurogenic pulmonary oedema. Lancet 1975;2(7938):749–751. 110. Hoff JT, Nishimura M, Garcia-Uria J, et al: Experimental neurogenic pulmonary edema. Part 1: The role of systemic hypertension. J Neurosurg 1981;54:627–631. 111. Lang SA, Maron MB: Oxygen consumption after massive sympathetic nervous system discharge. Am J Physiol 1989;256:E345–E351. 112. Maron MB: Pulmonary vasoconstriction in a canine model of neurogenic pulmonary edema. J Appl Physiol 1990;68:912–918. 113. Maron MB, Holcomb PH, Dawson CA, et al: Edema development and recovery in neurogenic pulmonary edema. J Appl Physiol 1994;77:1155–1163. 114. Millen JE, Glauser FL: Low levels of concussive brain trauma and pulmonary edema. J Appl Physiol 1983;54:666–670. 115. Deehan SC, Grant IS: Haemodynamic changes in neurogenic pulmonary oedema—effect of dobutamine. Intensive Care Med 1996;22:672–676. 116. Mayer SA, Fink ME, Homma S, et al: Cardiac injury associated with neurogenic pulmonary edema following subarachnoid hemorrhage. Neurology 1994;44:815–820. 117. Weir BK: Pulmonary edema following fatal aneurysm rupture. J Neurosurg 1978;49:502–507. 118. MacIver IN, Frew IJC, Matheson JG: The role of respiratory insufficiency in the mortality of severe head injuries. Lancet 1958;1:390–393. 119. National Academy of Sciences—National Research Council: Accidental Death and Disability: The Neglected Disease of Modern Society. Washington, National Academy of Sciences—National Research Council, 1966. 120. Klauber MR, Marshall LF, Toole BM, et al: Cause of decline in headinjury mortality rate in San Diego County, California. J Neurosurg 1985;62:528–531. 121. Colohan ART, Alves WM, Gross CR, et al: Head injury mortality in two centers with different emergency medical services and intensive care. J Neurosurg 1989;71:202–207. 122. Graham DI, Adams JH, Doyle D: Ischemic brain damage in fatal non-missile head injuries. J Neurol Sci 1978;39:213–234. 123. Graham DI, Ford I, Adams JH, et al: Ischemic brain damage is still common in fatal non-missile head injury. J Neurol Neurosurg Psychiatry 1989;52:346–350. 124. Freytag E: Autopsy findings in head injuries from blunt forces. Statistical evaluation of 1,367 cases. Arch Pathol 1963;75:402–413. 125. Marshall LF, Marshall SB, Klauber MR, et al: A new classification of head injury based on computerized tomography. Report on the Traumatic Coma Data Bank. J Neurosurg 1991;75(Suppl):S14–S20. 126. Doppenberg EM, Bullock R: Clinical neuroprotection in traumatic brain injury: Lessons from previous studies. J Neurotrauma 1997;14:71–80. 127. Battistella F, Wisner D: Combined hemorrhagic shock and head injury: effects of hypertonic saline (7.5%) resuscitation. J Trauma 1991;31:182–188. 128. Freshman S, Battistella F, Matteumli M, Wisner D: Hypertonic saline (7.5%) vs. mannitol: A comparison for treatment of acute head injuries. J Trauma 1993;35:344–348. 129. Jones PA, Andrews PJD, Midgely S, et al: Measuring the burden of secondary insults in head injured patients during intensive care. J Neurosurg Anesthesiol 1994;6:4–14. 130. Bullock RM, Chestnut RM, Clifton GL, et al: Management and prognosis of severe traumatic brain injury—Guidelines for the management of severe head injury. J Neurotrauma 2000;17:449–553. 131. Firsching R, Woischneck D, Diedrich M, et al: Early magnetic imaging of brainstem lesions after severe head injury. J Neurosurg 1998;89:707–712.

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132. Tomida M, Muraki M, Uemura K, et al: Postcontrast magnetic resonance imaging to predict progression of traumatic epidural and subdural hematomas in the acute stage. Neurosurgery 1998;43:66–71. 133. Messeter K, Nordstrom CH, Sundbarg G, et al: Cerebral hemodynamics in patients with acute severe head trauma. J Neurosurg 1986;64:231–237. 134. Chestnut RM, Marshall LF, Marshall SB: Medical management of intracranial pressure. In Cooper PR (ed): Head Injury. Baltimore: Williams & Wilkins, 1993, pp 225–246. 135. Narayan RK, Greenberg RP, Miller JD, et al: Improved confidence of outcome prediction in severe head injury. A comparative analysis of the clinical examination, multimodality evoked potentials, CT scanning and intracranial pressure. J Neurosurg 1981;54:751–762. 136. Robertson CS, Valadka AB, Hannay HJ, et al: Prevention of secondary ischemic insults after severe head injury. Crit Care Med 1999;27:2086– 2095. 137. Rosner M: Cerebral perfusion pressure: Link between intracranial pressure and systemic circulation. In Wood JH (ed): Cerebral Blood Flow. New York: McGraw-Hill, 1987, pp 425–448. 138. Rosner MJ, Coley IB: Cerebral perfusion pressure, intracranial pressure, and head elevation. J Neurosurg 1986;65:636–641. 139. Chan KH, Dearden NM, Miller JD, et al: Multimodality monitoring as a guide to treatment of intracranial hypertension after severe brain injury. Neurosurgery 1993;32:547–553. 140. Cruz J, Miner ME, Allen J, et al: Continuous monitoring of cerebral oxygenation in acute brain injury: Assessment of hemodynamic reserve. Neurosurgery 1991;29:743–749. 141. Unterberg AW, Klening KL, Hartl R, et al: Multimodal monitoring in patients with head injury: evaluation of the effects of treatment on cerebral oxygenation. J Trauma 1997;42:532–537. 142. Gopanath SP, Robertson CS, Contant CF, et al: Jugular venous desaturation and outcome after head injury. J Neurol Neurosurg Psychiatry 1994;57:717–723. 143. Obrist WD, Langfitt T, Yaggi J, et al: Cerebral blood flow and metab-

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olism in comatose patients with acute head injury. Relationship to intracranial hypertension. J Neurosurg 1984;61:241–253. Worthley LI, Cooper DJ, Jones N: Treatment of resistant intracranial hypertension with hypertonic saline—Report of two cases. J Neurosurg 1988;68:478–481. Einhaus S, Croce M, Watridge C, et al: The use of hypertonic saline for the treatment of increased intracranial pressure. J Tennessee Med Assoc 1996;89:381–382. Simma B, Burger R, Falk M, et al: A prospective randomized controlled study of fluid management in children with severe head injury: Lactated ringer solution vs. hypertonic saline. Crit Care Med 1998;26:1265–1270. Qureshi A, Surez J, Bhardwaj A, et al: The use of hypertonic (3%) saline/acetate infusion in the treatment of cerebral edema: Effective control of intracranial pressure and lateral displacement of the brain. Crit Care Med 1998;26:440–446. McIntosh TK: Novel pharmacologic therapies in the treatment of experimental traumatic brain injury—a review. J Neurotrauma 1993;10:215–222. Marshall LF, Maas AIR, Marshall SB, et al: A multi-centered trial on the efficacy of using tirilazad mesylate in cases of head injury. J Neurosurg 1998;89:519–525. Murray GD, Teasdale GM, Schmitz H: Nimodipine in traumatic subarachnoid hemorrhage: A reanalysis of the HIT1 and HIT2 trials. Acta Neurochir 1996;138:1163–1167. Young B, Runge JW, Wilberger JE, et al: Effect of pegorgotein on neurological outcome of patients with severe injury. A multi-centered randomized control trial. JAMA 1996;276:538–543. Yakolev AG, Faden AI: Molecular biology of CNS injury. J Neurotrauma 1995;12:767–777. Teasdale GM, Nicoll JAR, Murray G, et al: Association of apolipoprotein E polymorphism with outcome after head injury. Lancet 1997;350:1069–1071. Sorbi S, Nacimias B, Piacenti S, et al: Apo E as a prognostic factor for post traumatic coma. Natl Med 1995;1:852.

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Chapter 9 Spinal Neurosurgery Trent L. Tredway, MD, Lorenzo F. R. Muñoz, MD, Robin L. Wellington, PhD, and Richard G. Fessler, MD, PhD

The spine, through its various segments, serves to protect the neural structures it encloses while at the same time providing flexibility of movement. As a result, this bony structure is prone to degenerative changes that result from the dynamic forces of “wear and tear” to which it is constantly exposed. Moreover, the spinal column is also the end target of trauma, degenerative disorders, systemic disease, congenital malformations, and primary or metastatic tumors. Diseases of the spine can manifest as neurologic deficits, pain, and cosmetic deformities. Once identified, surgical clinical judgment defines the operation that is suitable for the pathologic process. As a result of the complexity of spinal anatomy, there are a myriad of procedures, approaches, and types of instrumentation that can be used. Subsequently, there are also a number of complications that can occur. Detailed management of these complications is beyond the scope of this chapter. However, a comprehensive review of the epidemiology and natural history of the most common disease processes will be addressed in conjunction with common complications.

Cervical Spine Cervical Spine Trauma According to the National Spinal Cord Injury Registry, when spine trauma occurs the cervical segment is the most often affected location. Approximately 50% of these injuries are caused by motor vehicle accidents and approximately 25% are the result of falls. Additionally, sports and recreation–

related events account for 10% of these injuries with pool diving being the most common recreational cause. The incidence of traumatic spinal cord injury is five times greater in males than in females.1 The cervical spine is the region most frequently injured in car accidents. National studies have found a one in 300 incidence of severe neck injury in those vehicular accidents severe enough to have the vehicle towed from the scene. That incidence increases to one in 14 for cases in which the patient has been ejected from the car.2 The C2 vertebral level is the most frequently injured with fractures of C5 and C6 being the next most frequently injured levels. These injuries are most common in the third decade of life and decrease with advancing age.

Atlas Fractures (C1) The incidence of atlas fractures peaks in the second decade of life, with men being affected almost twice as often as women. Atlas fractures account for 4% to 15% of all cervical fractures. The most common mechanism of injury is motor vehicle accidents. When isolated, the incidence of neurologic deficits is between 4% and 17%. Atlas fractures occur in association with axis fractures in approximately half of the cases.3–5 Atlas fractures can be classified as: (1) anterior arch fractures, (2) posterior arch fractures, (3) simple lateral mass fractures, (4) comminuted lateral mass fractures, (5) multiple ring burst (Jefferson) fractures, and (6) anteroposterior ring fractures (Fig. 9-1).6 235

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C1 burst fractures carry the eponym of “Jefferson fracture” after Sir Geoffrey Jefferson’s first systematic description of this injury in 1920.7 A “pure” Jefferson fracture is a fourpart ring fracture as a result of the lateral displacement of the lateral masses secondary to compression by the occipital condyles. The eponym is often used to describe most types of C1 fractures regardless of the specific fracture anatomy involved. The biomechanics of axial loading are thought to be the most common factor in the genesis of atlas fractures. The injury can occur with different neck positions so that multiple force vectors come into play. Therefore, it is imperative for the pathology of the fracture to be properly identified to assess if there has been an injury to the transverse ligament. When assessing the integrity of the transverse ligament, an open mouth or anteroposterior radiograph may be obtained. If the sum total of the overhang of both C1 lateral masses on C2 is greater than or equal to 7 mm, then the transverse ligament is probably disrupted. This measurement is commonly known as the “Rule of Spence.”8 This injury requires

B

Figure 9-1. Atlas fracture. A, Anterior arch fracture; B, Posterior ring fracture; C, Jefferson fracture.

immediate rigid immobilization and eventual surgical fusion. Management of Atlas Fractures Nondisplaced atlas fractures can be treated with semirigid external orthoses such as the Philadelphia collar or sternooccipital-mandibular immobilizer brace. More complex fractures, such as comminuted, or fractures with widely displaced fragments, must be treated with a Halo brace. In fact, more than 95% of isolated atlas fractures and 75% of C1-C2 combination fractures can be treated with an orthosis.6 There are two types of atlas fractures that are considered unstable. These types occur when the transverse liagment has become disrupted or when its insertion into the bony tubercle has been fractured. In either case, surgery is indicated because external immobilization will not promote healing of these structures. The goal of surgery is fixation of the unstable segment with preservation of normal motion. When the posterior arch of C1 is intact, posterior cervical wiring may be a rea-

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sonable option.9 If the posterior arch is incompetent to sustain such wiring, then posterior atlantoaxial facet screws may be indicated. However, this procedure can only be perfomed if intact C2 pedicles and intact C1 lateral masses are present.10 If C1 cannot be directly fixated, an occipitocervical fusion may become necessary. When assessing the treatment for C1 and C2 combination fractures, there are essentially two instances in which internal fixation is warranted: (1) when there is a disruption of the transverse liagment, and (2) when the associated odontoid type II fracture has greater than 6 mm of displacement between the dens fragments.

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Axis Fractures (C2) There are essentially three types of axis fractures: (1) odontoid, the most common (55%); (2) “hangman’s” fracture (23%); and (3) those classified as “other” (22%) but most commonly being fractures of the body of C2 (Fig. 9-2).11 In 1974, Anderson and D’Alonzo described subtypes of odontoid fractures.12 Type I fractures (0% to 5%) consist of a fracture through the tip of the dens. This occurs secondary to avulsion of the apical ligament. Although long considered to be a stable injury, they may not occur as an isolated fracture and may be a manifestation of atlanto-occipital disloca-

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Figure 9-2. Axis fracture. A, Odontoid fracture; B, Hangman’s fracture.

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tion.13 Type II fractures, the most common (37% to 80%), consist of a fracture through the base of the dens where it attaches to the body of C2. Type II fractures are considered unstable; however, controversy exists on whether rigid immobilization or operative fusion is the treatment of choice. The degree of displacement and the age of the patient are important factors in predicting nonunion and should be considered when treating this type of odontoid fracture. Type III fractures extend into the cancellous portion of the body of C2 and are usually considered stable fractures. Approximately 90% heal with external immobilization if adequately maintained for 8 to 14 weeks.14 A hangman’s fracture is a bilateral fracture through the pars interarticularis (the bridge of bone between the superior and inferior facets) or through the pedicles of the axis. Hangman’s fractures typically are the result of hyperextension-axial loading injuries. These fractures have been classified into three types based on the amount of subluxation, angulation, and disruption of the facet capsules. Type I fractures have a subluxation of C2 on C3 of less than 3 mm, whereas type II fractures have a greater subluxation with angulation of greater than 11 degrees. Type III fractures involve disruption of the facet capsules with significant subluxation and spinal canal compromise (Fig. 9-3). Closed reduction of this injury may lead to further deterioration in the neurologic examination.15–17 Open reduction with internal fixation is recommended in this highly unstable type of C2 fracture. The fractures characterized as “other” are mostly fractures of the body of C2. Benzel and co-workers have classified these fractures mostly based on the orientation of the fracture (e.g., coronally, sagittal).18 Management of Axis Fractures Almost 100% of type I odontoid fractures heal without treatment as long as there has been no C1 ligamentous injury. Type II odontoid fractures are a management challenge because of their high rate for nonunion. Hadley and colleagues described a 67% nonunion rate for those fractures displaced 6 mm or more and a 26% union rate for those less than 6 mm.14 These nonunion rates are applicable even with adequate Halo brace external immobilization. The Halo brace remains the mainstay of treatment for these fractures in the initial stages. When deciding whether an open fixation is needed, other factors such as age, ligamentous injuries, systemic disease, and so on, must be taken into consideration. Type II odontoid fractures can be addressed with either an anterior or posterior approach. The anterior approach involves the standard exposure for the anterior cervical spine. Then, with the assistance of biplanar fluoroscopy, a lag screw is inserted through the body of C2 into the fractured odontoid segments (Fig. 9-4A). This procedures allows for instant fixation of the odontoid while preserving the rotational axis of the C1/C2 complex. The posterior approach deals mostly with wiring or screw fixation and fusion (arth-

Figure 9-3. Hangman’s fracture types I, II, and III.

odesis) of the posterior arch of C1 with C2 (Fig. 9-4B). However, the preservation of rotation that is seen with odontoid screws is eliminated with posterior stabilization techniques. For wiring to be feasible, the posterior arch of C1 needs to be intact. If the posterior arch is not intact, then C1C2 transarticular screws can be placed. Alternatively, the occiput could be incorporated into the fusion using lateral mass plates or rods (Fig. 4C and D). Type III odontoid fractures have a higher union rate then Type II. The nonunion rate varies from 0% to 17%.19 External immobilization is the treatment of choice with fusion rates near 100%.11 An internal fixation might be required in those more complex fractures were there are comminuted fragments or severe ligamentous injuries. In these cases, a C1/C2 wiring with arthrodesis is recommended. Complications of Axis Fractures The complications of anterior odontoid screw fixation are similar to other anterior cervical approaches. The main difference pertains to the actual screw placement. It is imperative that biplanar fluoroscopy guide the experienced surgeon in the screw trajectory. Malposition of the screw can result

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Figure 9-4. A, Odontoid screw fixation; B, Transarticular screw fixation; C, C1/C2 lateral mass screw fixation; D, Occipitocervical fusion.

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in dural penetration with cerebrospinal fluid (CSF) leak, catastrophic neurologic deficits, or vertebral artery injury. As with other instrumentation, screw migration or screw fractures can occur over time. For this reason frequent followup cervical spine radiographs are recommended. Another complication of odontoid screw fixation is nonunion. Apfelbaum describes a nearly 100% rate of union in those fractures nonunited less than 6 months.20 In contrast, the rate of succesful bony union was just 27% in those chronically nonunited fractures (more than 6 months). However, successful stabilization, defined as bony plus fibrous union, was approximately 60% in nonunited fractures. Posterior atlantoaxial wiring and arthrodesis provides excellent translational and rotational stability. Several techniques for wiring and bone graft have been proposed. The interspinous method for atlantoaxial arthrodesis, as proposed by Sonntag, has a fusion rate of 86%.21 Extreme caution must be used when making the sublaminar wire passes in order to avoid dural tears or damage to the underlying cervical spinal cord. The bone grafts can migrate and the wires can break or erode through the bone increasing that rate of nonunions. Often, this is a function of the health of the bone undergoing fusion. For this reason, many surgeons will use a halo brace for several months after surgery. Cervical Subaxial Fractures Trauma also affects the subaxial (C3-C7) spine. Injuries to this region of the spine most commonly occur as a result of flexion-rotation or hyperflexion injuries. Ligamentous injuries may occur that allow for subluxation of vertebrae. Cadaveric studies have been performed, and demonstrate that a horizontal subluxation of greater than 3.5 mm of one vertebral body on another, or greater than 11 degrees angulation of one vertebral body relative to the next indicates ligamentous instability.22 Severe ligamentous injuries caused by hyperflexion may result in “locked-facets” (Fig. 9-5A). Patients with unilateral locked facets may present with subluxation greater than 3.5 mm and are generally neurologically intact. Bilateral lockedfacets occur less frequently and are associated with severe hyperflexion injuries. These patients present with subluxation of greater than 50% and also demonstrate signs of spinal cord or nerve root injury. Locked-facets require reduction that may be attempted through a closed technique using incremental traction or by open surgical reduction. In either case, surgical intervention with instrumentation and arthrodesis is required for definitive treatment. Teardrop fractures, as originally described by Schneider, are unstable fractures resulting from hyperflexion.23 These injuries are so named because of the chip of bone just beyond the anterior inferior edge of the vertebral body seen on a lateral cervical spine radiograph (Fig. 9-5B). This injury should be differentiated from a simple avulsion fracture. With teardrop fractures, a fracture through the sagittal plane of the vertebral body may be observed. Patients with

teardrop fractures are often quadriplegic, although some may be intact. True teardrop fractures are unstable and require surgical stabilization. The extent of injury usually requires a combined anterior and posterior surgical procedure. A more common and less threatening injury seen in the subaxial spine is the Clayshoveler’s fracture that was first described in Australia (Fig. 9-5C). In this injury, the spinous process, usually C7, is avulsed. The fracture is stable and does not require surgical intervention. Flexion-extension radiographs should be performed to assess if any occult fractures have made this segment of the spine unstable. Congenital Abnormalities of the Craniovertebral Junction Congenital abnormalities of the craniovertebral junction are rare conditions that are often latent until late childhood or early adulthood. Many of these conditions are recognized secondary to traumatic or degenerative processes. These conditions often require surgical intervention to halt the progression of neurologic deficits, decrease intractable pain, or stabilize the occipital-C1-C2 complex. Basilar invagination is the most common congenital anomaly of the atlanto-occipital junction. The anomaly results from malformation of all three parts of the occipital bone (basiocciput, exocciput, and squamous occipital bone) (Fig. 9-6).24 This anomaly may compromise the space available within the foramen magnum. Patients with symptomatic basilar invagination often complain of paresthesias and weakness in the limbs. Vertebral artery anomalies may accompany basilar invagination; therefore, symptoms of vertebral artery insufficiency can occur.25 The diagnosis of basilar invagination is based on radiographic imaging. A series of reference lines have been described to help define this anomaly. McRaes’ line is an imaginary line across the foramen magnum connecting the basion with the opisthion. The length of this line should exceed 19 mm and no part of the odontoid should be above this line. If any part of the odontoid is above this line, then basilar invagination is present.26 A second reference line, Chamberlain’s line, connects the hard palate to the opisthion. Less than 3 mm of the dens should be above this line.27 A third line, McGregor’s baseline, connects the posterior margin of the hard palate to the most caudal point of the occiput. No more than 4.5 mm of the dens should be above this line.28 A fourth reference line, Wackenheim’s clivus-canal line, joins the dorsum sellae to the tip of the clivus. The odontoid should be tangential to or below this line. A fifth reference line, Fishgold’s digastric line, connects the digastric notches on an anteroposterior radiograph. The odontoid should lie below this imaginary line.29 Basilar impression is often associated with basilar invagination; however, the former describes the acquired form of basilar invagination secondary to softening of the occipital bone. This condition is prevalent in rheumatoid arthritis,

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Figure 9-5. Subaxial fracture. A, Bilateral locked facets; B, Teardrop fracture; C, Clayshoveler’s fracture.

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as well as in Paget’s disease, hyperparathyroidism, achondroplasia, and osteogenesis imperfecta.24 These patients often require surgical intervention consisting of decompression and stabilization. Another commonly seen congenital anomaly of the craniovertebral junction is assimilation of the atlas. In this condition, a failure of segmentation between the fourth occipital and the first spinal sclerotomes occurs. It occurs in approximately 0.25% of the population, and is often associated with other anomalies such as cleft palate, basilar invagination, and Klippel-Feil syndrome.30–33

The onset of symptoms usually occurs between the ages of 20 to 40 years. Symptoms include weakness, spasticity, gait disturbances, and occasionally cranial nerve dysfunction.34 Furthermore, evidence of cerebellar dysfunction may also be present. Surgical stabilization and fusion may be necessary in these patients. Degenerative Disorders Degenerative processes of the cervical spine most frequently present as spondylosis, osteophytic compression, and disk

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Figure 9-6. Basilar invagination.

herniation.35 Cervical radiculopathy is a common occurrence. It has been reported that individuals who lift heavy objects as well as those who smoke are predisposed to acute cervical disk disease. Operators of vibrating equipment and individuals riding in cars for extended periods also have an increased frequency of disk herniations.36 Repetitive subclinical trauma probably influences the onset and rate of progression of cervical spondylosis.37 There appear to be no gender differences in the occurrence of spondylosis; however, women are less severely affected. The incidence of cervical disk herniations peaks in the fourth decade. This peak incidence in disk herniations appears to be the result of the combination of the maximum expansile strength of the disk (i.e., when the disk is the most hydrated) and the peak incidence of annular tears. Thus, after the age of 50, the dehydrated disks are less prone to herniate even when the incidence of annular tears increases. Studies revealed 61% to 68% of patients exhibit preoperative motor weakness with disk herniation.38 However, the recovery of motor function after decompressive surgery is excellent. Cervical spondylosis as defined by Clarke and Robinson in 1956 refers to “chronic degenerative changes due primarily to intervertebral disc decay, which are probably universally present in elderly persons” (Fig. 9-7).39 Some authors extend Clarke and Robinson’s definition to include degenerative changes in the facet joints, longitudinal ligaments, and ligamentum flavum. The osteophytes of spondylosis are associated with degeneration of the intervertebral disk.40 The genesis of the spondylotic ridge lies in the bulging annulus fibrosus, which in turn elevates the periosteum triggering subperiosteal bone formation (osteophytes). The deterioration of the disk actually starts in childhood when children begin to walk. This has been associated with a loss of blood supply, which might be secondary to the increased axial loading pressures of upward posture.41

Although disk herniations may cause significant pain, the etiology of the pain is rather elusive. For one, there seems to be no uniform explanation as to why some patients with clear evidence of disk herniation do not have the typical radicular pain distribution.42,43 Moreover, there also is no universal explanation for the sharp pain experienced as a result of the nerve root compression caused by the extruded fragment. For instance, usually paresthesias and numbness are all that is felt with entrapment neuropathies such as carpal tunnel syndrome. The difference may be due to traction on the nerve root instead of compression from the disk fragment.44 Other theories postulate that the extruded disk fragments elicit reactions in the epidural space that cause a cascade of enzymatic reactions that in turn hydrolyze the extruded material.45 This breakdown of products may produce the nerve root irritation. The most common sites of herniation in the cervical spine are at C5-C6 and C6-C7, causing compression of the C6 and C7 root, respectively. Involvement of the C5 nerve root is perhaps the most disabling. The deltoid muscle weakness that ensues makes it difficult to adduct the arm over 20 degrees. The C6 radicular pain radiates down the lateral aspect of the forearm to include the first two fingers. The biceps muscle is affected with loss of its reflex and motor weakness. The C7 radicular pain radiates down the posterolateral aspect of the arm going on to the middle finger. Its characteristic motor involvement is the triceps muscle. Early loss of the triceps reflex and weakness are commonly seen.

Figure 9-7. Degenerative cervical spine/spondylosis.

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Cervical spondylotic changes are often the cause for cervical myelopathy. Classic signs in cervical spondylotic myelopathy (CSM) include Lhermitte’s sign (electrical shock sensation associated with neck flexion), hand clumsiness, distal weakness, generalized hyperreflexia, Hoffman’s sign (contraction of the thumb and index finger upon flickering of middle finger), and spastic gait.46,47 Most cases of cervical radiculopathy will resolve with conservative management.48 In fact, almost 80% of those patients with cervical radiculopathy who are treated conservatively will have partial or total relief of their symptoms.49 However, much less is known about the natural history of spondylotic cervical myelopathy. Onset is typically in the sixth decade of life with males more commonly affected. CSM has a slow onset, and once present, complete reversal is rare.50 The treatment options for cervical spine disease are divided between nonoperative and operative management. It is reasonable to attempt nonoperative treatment if there is improvement in pain relief without deterioration in motor function. Surgery is recommended when there has been neurologic deterioration or nonoperative treatment has failed. Nonsurgical Management Immobilization of the cervical spine is a primary goal in nonoperative management. With this in mind, numerous braces have been designed. Most soft collars do not limit cervical motion.51 These collars serve as a reminder for the patient to protect the neck against excessive motion. The more rigid orthoses (Philadelphia collar, sternooccipital-mandibular immobilizer brace, etc.) provide reasonable immobilization of the mid-cervical segments for flexion and extension but fail to immobilize against lateral flexion. Other orthoses, such as the Minerva body vest, can provide significant immobilization. One of the most significant limitations in the use of orthoses is patient compliance and tolerance. Bed rest and cervical traction can often be used in the nonoperative management of cervical spine disease while a combination of muscle relaxants, nonsteroidal anti-inflammatory drugs, steroids, and analgesics can provide reasonable relief to many patients. Antidepressants can be used in some patients with chronic pain.48 Following pain control, physical therapy becomes a key component to return the patient to full activities. Surgical Management There are many approaches and operations in the treatment of cervical spine disease. The best approach is the one that allows the most direct and safe decompression of the offending pathology. Each patient’s individual (Fig. 9-8) pathology must be scrutinized so that the operative plan can be tailored to the specific disease process. As with any other surgical

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interventions, there are complications associated with these different procedures that vary with the anatomy. Anterior Cervical Diskectomy with Interbody Fusion The anterior approach allows direct visualization of the intervertebral interspace. Thus, it allows direct access for decompression of the anterior aspect of the cervical spinal cord. This approach does not only enable the surgeon to effectively treat soft disks, but it also allows for the resection of osteophytes. In the anterior approach to the cervical spine, thorough knowledge of the anatomic landmarks of the neck is important in planning the incision. The hyoid bone is approximately at the level of C3, the thyroid cartilage corresponds to the level of C4-C5, and the cricoid cartilage corresponds to the C5-C6 interspace. A transverse incision is often chosen over a vertical one because it is cosmetically more acceptable. Once the platysma muscle is opened and undermined for further access, the plane medial to the sternocleidomastoid muscle is bluntly dissected. The carotid sheath is displaced laterally with gentle retraction and the prevertebral fascia is opened until the longus colli muscles are found attached to the anterior aspect of the vertebral bodies. A combination of monopolar and bipolar coagulation is used to separate the muscles from the vertebral bodies along their medial borders. The longus colli muscles are retracted laterally with self-retaining retractors. The disk level is then checked with the help of a spinal needle and a cross table radiograph. Once the level is confirmed, the anterior longitudinal ligament and the annulus are incised and the anterior aspect of the disc is removed. A high-speed hand drill can be used to remove bone from the two adjacent vertebral bodies to better decompress the spinal canal and gain access to the posterior longitudinal ligament. Osteophytic processes may also be carefully removed with the drill or with rongeurs. Next, the posterior longitudinal ligament is opened and the epidural space is inspected for loose fragments. After an adequate decompression has been confirmed, a bone graft is placed in the interspace with the help of gentle interbody retraction (Fig. 9-8C). Instrumentation may also be used in this approach with little complication.52 Complications. The incidence of increased neurologic deficits after surgery is less than 1%.53 The most common neurologic complication following anterior cervical diskectomy is persistence of neurologic signs and symptoms. Persistent or worsening symptoms have a 5% incidence and are most likely secondary to the incomplete removal of the bony osteophytes compressing the neural elements.54 The possible complications associated with this approach start from the time the patient is intubated and positioned. Excess flexion or extension can produce neurologic damage in the congenitally or degeneratively narrowed canal. In patients with narrowed canals, fiberoptic intubation is often

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Figure 9-8. Cervical herniated nucleus pulposus. A, Sagittal MRI; B, Axial MRI; C, Anterior cervical diskectomy with fusion radiograph.

chosen when placing these patients under anesthesia. Once anesthetized, that patient’s neck should be carefully protected from extreme positioning. The patient may be placed in gentle traction to help avoid this problem. Transient dysphagia secondary to tissue swelling is common. Direct esophageal injury has also been reported.55 This complication can be decreased when the esophagus is identified intraoperatively after insertion of a nasogastric tube. Pneumothorax is a possible complication when a low anterior approach (C7-T1) is performed. At this level, the dome of the parietal pleura is at risk for injury.56

Hoarseness, secondary to anterior cervical spine surgery, as reported by Riley and colleagues, has a 4% incidence.57 Permanent recurrent laryngeal nerve injury and CSF leak complications have a 1% incidence. Horner’s syndrome may result from manipulation of the sympathetic ganglia located on the lateral surface of the longus colli. Injury to the spinal cord and nerve roots may lead to devastating consequences. Graft extrusion is seen in 2% to 8% of cases.58 Patients could very well be asymptomatic after graft extrusion; however, a retropulsed graft can cause neurologic problems

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Complications. The complications of corpectomies are not different from those associated with the anterior diskectomy approach insofar as the anterior neck anatomy is at risk for injury. Specifically, the esophagus, cranial nerves X and XII, the vertebral arteries, the trachea and the vessels of the carotid sheath are at risk. Corpectomies tend to be lengthy procedures that, even in the best of hands, usually take a few hours. Injuries to the vascular structures may be caused by the sharp surfaces of the retractor blades. These lesions, if identified intraoperatively, can often be repaired primarily.63 Postoperative paratracheal soft tissue swelling can compromise the airway and thus require prolonged intubation.64 Postoperative hoarseness is often present. However, it is most commonly related to the endotracheal intubation or soft tissue dissection. The incidence of voice changes secondary to recurrent laryngeal nerve injury is less than 1%.65 However, because a true transection of the nerve is rare, phonation improves within weeks to months. Injury to the cervical sympathetic chain causing Horner’s syndrome can occur with excessive lateral retraction on the longus colli.66 Esophageal injuries can have disastrous consequences. If undetected, they can result in prevertebral abscesses and even mediastinitis. Again, the insertion of a nasogastric tube can help the surgeon palpate the esophagus when positioning the retractor blades to avoid undue retraction pressure. CSF leaks, when present, usually occur during removal of the Figure 9-9. Postoperative complication: failed instrumentation with broken screw.

as it impinges on the spinal cord. Usually, surgery is necessary to realign the malpositioned graft. Complications associated with the iliac bone graft harvest are infection, hemorrhage, and pain.59 For this reason, many surgeons prefer the use of allograft to eliminate these postoperative complications. Instrumentation failures may also occur (Fig. 9-9). Corpectomy for Cervical Spondylotic Myelopathy The advent of magnetic resonance imaging (MRI) (see Fig. 9-8) has enabled the sagittal visualization of the cervical spinal cord as well as provided another pathway to the treatment algorithm of CSM. Most neurosurgeons will agree that the approach to cervical spine disease (i.e., anterior vs. posterior) is largely dependent on two aspects: the anatomic location of the pathology and the prevalent curvature of the spine. When a diskectomy will not adequately decompress the spinal cord from in front, then a corpectomy may be indicated (Fig. 9-10). Laminectomy may be indicated if the cervical lordosis is well preserved.60 Saunders and associates found that 85% of those patients in the series had significant improvement of their CSM with the central corpectomy approach.61 In contrast with another series, a 70% improvement was reported with laminectomy or diskectomy.62

Figure 9-10. Anterior cervical corpectomy.

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posterior longitudinal ligament. Given the very narrow surgical corridor, primary repair is virtually impossible. Many surgeons use a lumbar drain to reduce pressure and divert CSF during the acute healing phase. Posterior Approach for Cervical Disk Disease The posterior approach in the treatment of cervical disk disease may be indicated where the cervical nerve root compression is in a posterolateral location. In this approach, the medial aspect of the cervical facet is usually approached through a midline incision. Once the lamina/articular process complex has been exposed, the bony dissection proceeds. The next phase involves removing bone over the junction between the lamina and the articular process of the level in question. The ligamentum flavum and the venous plexus associated with the nerve root sheath will be seen. The bone removal is then carried out into the facet joint laterally and dorsal to the nerve root. To avoid instability, it is important to avoid drilling of more than half of the facet joint.67 Complications. Careful dissection should be performed to delineate the ligamentum flavum from the exiting nerve root. Furthermore, incomplete bony decompression will most certainly result in the persistence of the radiculopathy. Removal of a disk through a limited posterior approach can also result in spinal cord injury. Finally, as in most spinal procedures, it is imperative that the appropriate level of pathology be properly selected. Therefore, intraoperative radiographs are recommended to confirm the correct surgical level.

Posterior Lateral Mass Plate Fixation of the Subaxial Cervical Spine These systems, which have evolved from spinous process wire fixation into today’s titanium alloy lateral mass plates/screws, are used for the management of posterior cervical instability. The rigid internal fixation of the posterior cervical spine is most often performed with lateral mass plates. One of the greatest advantages of lateral mass plates is that they provide immediate stability to the treated segments of the posterior cervical spine (Fig. 9-11). However, given the persistent loading forces of the cervical spine, all instrumentation is destined to “fail.” For that reason, for the construct to be successful, a solid bony fusion is needed. The necessity for arthrodesis in conjunction with lateral mass plates is nevertheless a controversial issue because some authors report good results with plating alone. When performed, the facet joints are denuded of their cartilage in order to facilitate apposition of their bony surfaces. It is at this point that some surgeons choose to add some cancellous bone to the denuded joint. Generally, there are four indications for spinal stabilization: (1) to restore clinical stability to a spine in which the structural integrity has been compromised, (2) to maintain alignment after a deformity correction has been performed,

Figure 9-11. Posterior lateral mass plates with anterior cervical plating and fusion.

(3) to prevent progression of a deformity, and (4) to alleviate pain.68 Trauma is one of the most common indications for lateral mass plating.69 However, external fixation usually is adequate in treating those injuries in which there are no ligamentous injuries. Moreover, when extensive tumor resection mandates wide laminectomies with involvement of the facet joints or pedicles, lateral mass plating is also useful in the stabilization of the posterior cervical spine. This technique might suffice as long as the tumor does not involve the anterior and middle spinal column. Once the patient has been carefully positioned and intubated, proper reduction of the cervical spine is achieved and confirmed with a cross table radiograph. Reduction and proper alignment are often achieved with axial traction. However, internal reduction may be required. Once subperiosteal exposure as far laterally as the facet joints has been achieved, the field is then prepared for the bony fusion and for the lateral mass plate implantation. Complications. Sawin and Traynelis70 subdivide the compli-

cations associated with lateral mass plating into three categories: (1) wound complications, (2) neurovascular injuries, and (3) spinal/biomechanical complications. Problems such as hematomas, CSF leak, and infections were identified as causes for wound breakdown. Sizable hematomas can cause compression of the neighboring neural structures with catastrophic results. Even small

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hematomas that do not cause neurologic problems can hinder wound healing and even promote infection. CSF leaks, as previously mentioned, should be repaired intraoperatively. Usually these leaks are not a result of the instrumentation per se but rather are caused from a combination of the pathology at hand and the surgical technique. Persistent pseudomeningoceles can contribute to wound breakdown and even persistent infections. Surgical reexploration and lumbar CSF drainage are at times required to address this problem. When infection occurs, surgical debridement of the site may be warranted. At first, the instrumentation should be spared from removal with aggressive antibiotic treatment. However, if the infection persists, then the instrumentation should be removed. When placing lateral mass screws, the spinal cord and the vertebral artery are at risk for injury. However, the incidence of injury to these structures is low. Acute neural compromise may occur as a result of misguided drilling and screw placement. Immediate deficits would be recognized in this setting. It is possible that late onset deficits could occur in situations where the cervical spine alignment is altered. Cadaveric studies indicate that neither the spinal cord nor the vertebral artery is in real danger when lateral mass screws are placed along the standard trajectories.71 A less than 1% to a 3.6% incidence of inadvertent nerve root involvement with screw placement has been reported.71,72 In a review of 490 cases, Traynelis reports only one case of vertebral artery trauma as a result of this technique.72 Postoperative spinal complications resulting from hardware misplacement can occur. Suboptimal screw placement may lead to further deformities over time. Loosening of screws can occur even months after the procedure. Although otherwise rare, these complications are more commonly encountered with osteoporotic bone. Heller and colleagues reported a 1.3% incidence of plate breakage over an average follow-up of 1.5 years. A 0.1% incidence of screw fracture and 0.9% incidence of screw loosening were also reported during this period.73 Laminectomy for Cervical Spondylotic Myelopathy Laminectomy has been performed for years for the treatment of cervical spondylotic myelopathy. It is generally indicated for patients with a compressive myelopathy and an associated lordosis. Benzel has reported an increased effectiveness with sectioning of the dentate ligament in those patients with progressive or more severe myelopathy symptoms.62 If the laminectomy extends far laterally past the medial one fourth or one third of the facet joint, instability may ensue. In these cases, fusion and instrumentation may be indicated. Ossification of the Posterior Longitudinal Ligament Ossification of the posterior longitudinal ligament (Fig. 9-12) appears in approximately 2% of the cervical spine

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Figure 9-12. Ossification of posterior longitudinal ligament.

radiographs in the Japanese population. Autopsy studies from Japan demonstrate an incidence of 20% in subjects older than 60 years of age.74 The pathogenesis for this disease remains unclear. Patients with this rare disease usually present with myelopathic findings. Because the process is usually a long, progressive disease, many patients remain asymptomatic. However, patients may deteriorate and require surgical intervention in the form of decompression to enlarge the spinal canal. Paget’s Disease Paget’s disease is a metabolic bone disorder that commonly affects the spinal column. The cause of this disease is unknown, but a viral origin has been postulated. Areas of bone resorption and new bone deposition with the cumulative effect of a net positive bone balance characterize the disease. Patients with Paget’s disease may present with pain, paresthesias, or neurologic deficits secondary to neural compromise. The overgrowth of bone may exacerbate foraminal and canal stenosis. Surgical decompression may be necessary in some individuals; however, surgery does not halt the disease process.

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Rheumatoid Arthritis Rheumatoid arthritis is a systemic disease of unknown etiology that primarily affects the synovium of the feet, hands, and spine. This disease is more commonly observed in women and may result in severe neurologic problems. The cervical spine is frequently involved and may result in atlantoaxial subluxation, subaxial subluxation, and vertical basilar impression of the odontoid process. The cervical spine abnormalities are a result of destruction in the joints, ligaments, and bone by synovitis.75 Atlantoaxial subluxation represents the most common manifestation of rheumatoid involvement of the cervical spine.76 The most common clinical finding in these patients with atlantoaxial involvement is severe and persistent pain. The pain may be exacerbated with neck movement and may not respond to conservative management. Furthermore, as the disease progresses, patients may demonstrate signs and symptoms of myelopathy. The degree of myelopathy may not correspond to the degree of bony impingement, as often the culprit is a large pannus formation (Fig. 9-13). Indications for surgery include worsening of neurologic examination findings, progressive myelopathy, and intractable pain. Neural decompression with fusion of C1-C2 or occipitocervical fusion is usually performed. Subaxial subluxation of the cervical spine secondary to the rheumatoid process may lead to myelopathic findings as well. These patients often are osteoporotic and therefore,

Figure 9-14. Ankylosing spondylitis with pathologic fracture.

surgical intervention with instrumentation may lead to a higher complication rate when compared to the nonrheumatoid patient. Basilar impression secondary to pannus formation may cause myelopathy as well as lower cranial nerve palsies. The vertebral artery may also be compromised from the disease process and patients can present with signs and symptoms of vertebrobasilar insufficiency.77 Ankylosing Spondylitis Ankylosing spondylitis is an inflammatory disorder that affects synovial and cartilaginous joints, especially the joints of the spinal column. The etiology of this disorder remains unknown; however, individuals possessing the HLA-B27 histocompatibility subtype are at higher risk.78 Furthermore, there is a 3 : 1 to 8 : 1 male predominance.79 The age of onset is between 15 and 30 years, with less than 5% presenting after age 50.80 The prevalence in the U. S. population is approximately 0.1%.81 Inflammation of the ligamentous attachments, enthesopathy, occurs along the spinal ligaments. Intervertebral disks and vertebrae erode with new bone formation contributing to ankylosis. The bone is stiffer and more prone to fracture (Fig. 9-14) and subluxation after trivial trauma.82 In plain radiographs, the classic appearance of a “bamboo spine” may be observed. Patients with ankylosing spondylitis may require surgical intervention in the form of decompression and fusion or correction of severe kyphosis with osteotomy and fusion.

The Thoracic Spine Anatomic Considerations Figure 9-13. Rheumatoid arthritis with C1 pannus.

The thoracic spine is protected from injury by the paraspinal muscles and the thoracic cage; however, the spinal canal

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diameter is narrow throughout the thoracic spine and may lead to neurologic deficits with further narrowing of the canal. Furthermore, the lower cervical/upper thoracic region has a tenuous blood supply that may complicate injuries to this region. The blood supply to the upper thoracic cord relies on an anastomotic supply from the thyrocervical and costocervical trunks as well as the radicular arteries. In the middle region, T4-T8, a single thoracic radicular artery supplies this vulnerable area. In trauma cases or when hypotension occurs, this region of the spinal cord is the first to be affected. The middle and lower thoracic region has a more robust blood supply that relies on the great radicular artery of Adamkiewicz. This artery usually arises on the left at the T10 to T12 levels in 75% of patients. The anatomy of this region needs to be taken into consideration when performing thoracic spinal surgery. In addition, general and vascular surgeons should keep this anatomic relationship in mind when performing surgery on abdominal aortic aneurysms because cross-clamping of the aorta proximal to the great radicular artery takeoff may leave patients with postoperative paraplegia if the collateral blood flow is insufficient during the procedure. Congenital: Scoliosis and Kyphosis Congenital lesions of the thoracic spine include congenital scoliosis and congenital kyphosis (Fig. 9-15). In the former, abnormal curvature in the coronal plane develops secondary to anomalous vertebrae present at birth. Individuals with these hemivertebrae anomalies do not present until childhood or early adulthood. Clinical presentation of these lesions encompasses a wide spectrum. Many present as an

Figure 9-15. Thoracic spine scoliosis.

Figure 9-16. Scheuermann’s disease.

asymptomatic finding during a routine physical examination; however, some patients present with pain, neurologic deficits, and occasionally rapidly progressive scoliosis resulting in severe morbidity. In general, 25% of congenital scoliosis patients do not progress, 50% progress slowly, and 25% progress rapidly.83 Congenital kyphosis is an uncommon sagittal plane deformity that is caused by formation segmentation failure. Both congenital scoliosis and kyphosis may require combined anterior and posterior instrumentation procedures. Scheuermann first described progressive dorsal kyphosis of adolescent children in 1920.84 The deformity is a fixed thoracic kyphosis that does not correct with hyperextension, thus differentiating it from a postural kyphosis. Typically, Scheuermann’s disease involves the midthoracic spine, most commonly the T7 and T8 vertebrae.85 A mild scoliosis is present in 20% to 30% of patients.86 The characteristic features of this disease of ventral wedging of 5 degrees or more of at least three adjacent vertebrae were described by Sorenson.87 Other characteristics include kyphosis of greater than 40 degrees, vertebral body end plate irregularity, and disk space narrowing (Fig. 9-16).88 The prevalence of the disease ranges from 0.4% to 8% and occurs predominantly in males.87 Initial treatment consists of rigid bracing, exercise, and regular clinical and radiographic examination. Surgical treatment of patients with Scheuermann’s disease is contro-

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versial and reserved for patients exhibiting advanced kyphosis, failure of conservative bracing, or neurologic deficits.89 Degenerative or Herniated Nucleus Pulposus Thoracic disk herniation (Fig. 9-17) accounts for 0.25% to 0.57% of all symptomatic disk herniations of the spine.90 The symptoms from herniated disks usually present as localized back pain; however, the pain may be represented as a bandlike radiculopathy in the region of the particular dermatome level. Motor deficits, sensory deficits, and bowel or bladder dysfunction may also occur. The surgical approaches to thoracic disks vary. Traditionally, dorsal decompression via laminectomy was performed with poor results as reviewed by Logue in 1952.91 Many of the patients undergoing laminectomy were paraplegic after the surgery. This complication was a stimulus for safer surgical approaches to the thoracic spine. Transpedicular, lateral extracavitary, lateral parascapular extrapleural, and costotransversectomy approaches have reduced the complication rate of paraplegia. Furthermore, ventral approaches including transthoracic thoracotomy, transthoracic thorascopy, and retropleural thoracotomy approaches have allowed the neurosurgeon access to the ventral thoracic spine to address ventral pathology more safely. Pathologic Processes of the Thoracic Spine Although disk herniation is quite rare, pathologic processes involving the thoracic spine are common. These processes include traumatic vertebral fractures, spinal metastases, bacterial and tuberculous infections, primary bone tumors, meningeal tumors, vascular malformations, primary bone disease, and connective tissue or skeletal disorders. These disorders commonly cause a compressive myelopathy or radiculopathy. Many of these disorders require decompres-

sion of the neural elements with spinal reconstructive stabilization for treatment of the symptoms. Trauma Thoracic fractures and thoracolumbar fractures are usually associated with high-speed motor vehicle accidents or traumatic falls. The thoracolumbar region (T10-L5) has greater mobility than that of the thoracic spine (T1-T9) and is, therefore, more commonly associated with traumatic injury. Thoracic fractures may be divided into three categories: (1) compression or wedge fractures, (2) burst fractures, and (3) fracture-dislocation (Fig. 9-18).92 Wedge fractures result from severe flexion and are generally stable. If contiguous vertebral levels are involved, then severe kyphosis can occur and stabilization may be necessary. Burst fractures result from axial compression with varying degrees of flexion. The result is compression and failure of both anterior and posterior cortices of the vertebral body. These fractures may be associated with spinal canal compromise secondary to retropulsion of the bony elements. Fracture-dislocation injuries are the most severe of the fracture types and usually occur as a result of lap belt injuries. In this fracture type, fractures occur and then distraction occurs resulting in severe ligamentous injury. This type of fracture requires surgical stabilization. The three-column model as described by Denis (Fig. 9-19) may aid in determining the instability of fractures.93 In this widely acknowledged system, the vertebral body and the posterior elements are classified into columns: anterior, middle, and posterior. The anterior column consists of the anterior longitudinal ligament and the anterior half of the vertebral body and disk. The middle column consists of the posterior half of the vertebral body and disk as well as the posterior longitudinal ligament. The posterior column consists of the posterior arch with facets, supraspinous and interspinous ligaments as well as the ligamentum flavum. In the Denis model, if two or more columns are disrupted instability exists. Indications for surgical treatment of thoracolumbar fractures include progressive neurologic deficit, spinal cord compression, dural laceration, and instability. Instability may include fracture-dislocation injuries; anteroposterior or lateral translocation; and severe wedge or burst fractures with canal compromise, and progressive angulation as assessed on serial radiologic examinations. Spinal Metastases

Figure 9-17. Thoracic disk herniation.

Cancer is the second leading cause of death in the United States with approximately 1.3 million new cases per year.94,95 The spinal column, especially the thoracic region, is the most frequent site of bony metastasis.96 Most patients with metastases report a history of back pain; however, epidural compression has been reported to be the presenting symptom in approximately 8% to 10% of patients with metastatic

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Figure 9-18. Traumatic fracture of the spine. A, Compression/wedge; B, Burst; C, Fracture/dislocation; D, Chance.

disease.97 At diagnosis, more than 50% will have a paraparesis or bowel/bladder disturbance.98 Surgical intervention for metastatic disease to the spine remains controversial. Experience with different surgical approaches has allowed for easier decompression and stabilization. Indications for surgical intervention include biopsy for histopathologic analysis, decompression for progressing neurologic deficit, and stabilization. It is important to assess the prognosis of the systemic disease before undertaking a long and laborious operation. Generally, a life expectancy of less than 6 months may help guide intervention. Furthermore, many of the metastatic tumors are radiation-sensitive and chemosensitive and these treatment options should be considered before any surgical intervention. Prognostic

factors and individual differences influence outcome, although, in general, extended survival may be commonly observed in patients with breast, prostate gland, thyroid gland, or renal carcinomas. Patients with other types of tumors, such as adenocarcinoma of the lung, are associated with relatively short survival times. Primary Tumors of the Spine Multiple myeloma (Fig. 9-20) accounts for 45% of all malignant bone tumors.99 It is primarily a disease of the sixth and seventh decades with a predilection for the thoracic spine, followed by the lumbar and rarely the cervical spine.100 The 5-year survival rate is 18%.101 On occasion, isolated plasma-

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ISL LF C

Figure 9-19. Three-column model, as per Denis.

cytomas may occur and have a better prognosis when compared to multiple myeloma. Other malignant bone tumors include chondrosarcomas, chordomas, and lymphomas. Chondrosarcomas affects the spine in only 6% of cases.102 Chondrosarcomas frequently occur between the second and third decades of life. Histologically, the appearance of these tumors lies between a benign chondroma and a malignant sarcoma thus making them difficult to diagnose. Chordomas are thought to originate from the notochord remnant and are locally invasive tumors most commonly found in the sacrum or clivus. Age of onset can vary, but is most common between the third and fifth decades of life. Treatment of chordomas usually consists of surgical resection; however, these tumors have a high recurrence rate.103 Chordomas do not respond well to traditional radiation therapy, but recent studies suggest that these lesions may respond to stereotactic radiation surgery and proton beam therapy. Lymphomas involve the spine in approximately 10% of extranodal lymphoma and usually respond well to steroids and radiation therapy.94 Benign tumors of the spinal column include osteochondromas (the most common benign bone tumor), giant cell tumors, osteomas, osteoblastomas, aneurysmal bone cysts, hemangiomas, and eosinophilic granulomas. Often, these tumors require surgical intervention with removal, decompression of the neural elements, and spinal reconstruction as the mainstay of therapy. Spinal Cord Tumors Spinal cord tumors may present with varied symptoms. Back pain is the most common initial complaint, which is usually diffuse and unrelated to mechanical activity. Patients may also present with myelopathic findings, motor deficits, paresthesias, and even bowel or bladder problems. Radiologic imaging with MRI and computed tomography (CT) may

suggest the location of the tumor; however, CT myelography often will demonstrate whether the lesion is intradural or extradural. Tumors may be intramedullary, intradural extramedullary, or extradural. Intramedullary spine neoplasms represent 2% to 4% of all central nervous system tumors.104 The intramedullary tumors include astrocytomas, ependymomas, and hemangioblastomas. Often the spinal cord is enlarged with edema present on T2-weighted MR images. Cysts or syrinxes may be also be observed. Astrocytomas (Fig. 9-21) of the spinal cord portend a poor prognosis; however, compared to the brain astrocytomas, these lesions usually are of lower grade. Ependymomas of the spinal cord are the second most common type of intramedullary tumor and are often seen in the conus. In this region, a variant known as a myxopapillary ependymoma is the most common and is seen in the adolescent/young adult population. Surgical removal of these lesions provides a more favorable prognosis. Hemangioblastomas are the third most common intramedullary tumor and are often associated with von Hippel-Lindau disease. Complete resection of these tumors is often curative; however, if remnants of these tumors are inadvertently missed, recurrence is likely. Intradural extramedullary tumors may be best imaged with CT myelography. With this technique, a meniscus may be seen with a paucity of dye in the region of the mass. Schwannomas and meningiomas (Fig. 9-22) are the most common types of intradural extramedullary lesions. Neurofibromas may also be found in the intradural extramedullary space and are more often associated with the phacomatoses (neurofibromatosis type 1). Many patients present with pain secondary to nerve root irritation, but some may present with myelopathy from spinal cord compression. Treatment consists of exploration and excision of tumor as well as radiation therapy for lesions that recur. Extradural lesions are usually secondary to metastases. However, meningiomas, schwannomas, and neurofibromas may consist of only extradural involvement. These lesions are usually readily resectable. Lipomatous masses causing spinal cord compression may also occur in patients with Cushing’s disease. Infection Infections of the spine include intramedullary abscesses, subdural and epidural abscesses, and osteomyelitis. Intramedullary spinal cord abscesses are uncommon. The pathogenesis of this type of abscess is thought to be secondary to infection in an area of infarction or septic emobolization. Treatment usually includes surgical exploration and drainage combined with long-term antibiotic therapy. Spinal epidural abscesses usually present with severe neck or back pain and progressive neurologic deficit that may occur rapidly. Approximately one half of epidural abscesses result from hematogenous spread to the epidural space. This type of abscess is more common in intravenous drug abusers. The

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Figure 9-20. Multiple myeloma. A, Sagittal MRI; B, Sagittal CT; C, Axial CT.

C

treatment usually consists of surgical debridement and evacuation followed with antibiotic therapy. The neurologic sequelae may be secondary to direct compression from the abscess or may be due to infarction and necrosis of the spinal cord.105 Spinal subdural abscesses are extremely rare, but are treated in a similar fashion with evacuation and antibiotic therapy as the mainstay of treatment. The thoracic and lumbar regions are common sites of osteomyelitis of the spine. More than half of the patients presenting with vertebral osteomyelitis are older than 50 years and the time from initial presentation to diagnosis ranges from 2 weeks to 5 months with a mean of 6 to 8 weeks.106,107 Patients may present with pain and muscle spasm, paresthesias, or neurologic deficits.

Evidence of pyogenic osteomyelitis of the spine has been found in Egyptian mummies and was described by Hippocrates. Although physicians knew of this problem for many years, antibiotic therapy finally facilitated adequate treatment of this disease. The most frequent route of osteomyelitis is via hematogenous spread. The most common infections of the spinal column include pyogenic organisms (Staphylococcus aureus and coliform bacilli), infections caused by fungi (Actinomycetes and Blastomycetes), and Pott’s disease (Mycobacterium tuberculosis).108 In the adult, the vertebral body is a site favorable for seeding due to its rich vascular supply. The infection involves the body, but commonly does not respect the vertebral body/disk interface. This is an important clue when differ-

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Figure 9-21. Spinal cord astrocytoma.

A

entiating infection from tumor when reviewing radiographs and CT/MRI examinations (Fig. 9-23). These infections usually present with subacute back pain and commonly intense paraspinal muscle spasms. Treatment may consist of biopsy with antibiotic therapy. Often, thoracolumbosacral orthoses are used to decrease the rate of kyphotic and scoliotic deformities. If severe bony destruction is present, spinal stabilization above and below the involved vertebral levels may need to be performed. Pott’s disease, a tuberculous infection of the spinal column, is a common problem in economically underdeveloped countries; however, epidemiology suggests resurgence in more wealthy countries. Extrathoracic involvement increased from 8% to 18% with an estimated 20,000 cases per year in the United States with the thoracolumbar spine as the most commonly affected site (Fig. 9-24).109 Patients may present with radiculopathy, cauda equina, or chronic back pain and muscle spasm secondary to paraspinal muscle involvement. Purified protein derivative testing should be performed on suspected cases; however, some patients may exhibit anergy secondary to the infectious process. Open surgical exploration and evacuation of the granulomatous tissue is often required and allows for specimens to be obtained and sent for microbiologic analysis. Dorsal decompression is usually sufficient, but many cases may require instrumentation and stabilization if the bone has been destroyed.

B

Vascular Malformations Vascular malformations of the spine are rare entities but have been classified into four types. The most common type of spinal arteriovenous malformation (AVM) is the dural, or type I, AVM. Most patients with type I dural AVMs are between 40 and 70 years of age; 80% are male and no familial tendency has been identified.110,111 The most common symptom associated with dural AVMs is pain, which may be

Figure 9-22. Nerve sheath tumor. A, Schwannoma; B, Meningioma.

local, radicular, or nonspecific. Most patients will also complain of lower extremity weakness and sensory changes by the time of diagnosis. Because of the gradual clinical course, many patients go undiagnosed until the appropriate studies are performed, namely MRI and selective angiography (Fig. 9-25). These lesions may be treated surgically; however, with advancing technology in endovascular procedures, options other than surgery may exist. Type II, or glomus, spinal AVMs are intramedullary AVMs with a true compact nidus.112 Type III spinal AVMs, also known as juvenile AVMs, are less common. These lesions are usually more extensive and involve both intramedullary and extramedullary spaces over more than one spinal level.112 The final type is type IV and consists of intradural extramedullary AV fistulas as classified by Heros.113 Type IV lesions are fed from the anterior spinal artery or, less commonly, from the posterior spinal

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B Figure 9-23. Osteomyelitis/diskitis. A, MRI; B, CT sagittal reconstruction.

artery. These lesions lie outside of the spinal cord and its pia mater and vary in size and flow.114

The Lumbosacral Spine Congenital Disorders and Spondylolisthesis Excluding spinal dysraphism (myelomeningoceles), congenital lesions of the lumbar spine are rare. Congenital

Figure 9-24. MRI of Pott’s disease.

spinal stenosis occurs in a very small number of patients who present with spinal stenosis. Congenital or dysplastic spondylolisthesis is a more common entity. Spondylolisthesis refers to the slippage of all or part of one vertebra onto another. Wiltse and colleagues have proposed the most widely accepted classification of spondylolisthesis.115 They divided spondylolisthesis into five types: type I, dysplastic or congenital; type II, isthmic; type III, degenerative; type IV, traumatic; and type V, pathologic. Congenital spondylolisthesis accounts for 14% to 21% of the cases of spondylolisthesis with a 2 : 1 female-to-male ratio.116,117 This type of spondylolisthesis is characterized by structural anomalies of the lumbosacral junction including dysplasia of the lamina and facet joints. The defects allow for slippage to occur, compromising the neural foramina. Individuals may present with hamstring spasm, back or leg pain, or neurologic deficits. Spondylolisthesis may be graded regardless of the etiology. In this system, grade I (Fig. 9-26) refers to subluxation of the superior vertebral body on the inferior vertebral body of less than 25% its anteroposterior diameter. Grade II refers to slippage of 25% to 50%. Grade III refers to slippage of 50% to 75%. Grade IV refers to slippage greater than 75%. Grade V, or spondyloptosis, refers to complete subluxation of a vertebral body on another. Grade I spondylolisthesis may be followed with serial radiographs; however, many patients will have significant pain unrelieved by

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B Figure 9-25. Spinal cord AVM. A, MRI; B, Angiogram.

conservative therapy. Many patients with higher grade spondylolisthesis will require decompressive surgery with fusion. Degenerative changes in the disk and vertebral column occur over time and may be accelerated due to increased loading forces, vascular compromise, and anatomic changes. The result of these ongoing processes leads to disk herniation, spondylosis, and compression of the neural elements, which ultimately result in radiculopathy. The intervertebral disk is comprised of an annulus fibrosus, the nucleus pulposus, and the cartilaginous endplates (Fig. 9-27). The nucleus pulposus is a remnant of the notochord and is contained within the tough outer annulus. Radial tears in the annulus will allow the nucleus pulposus to extrude into the spinal canal or into the neural foramen, leading to radicular symptoms. The cartilaginous endplates are also affected by the degenerative changes and may allow for herniation into adjacent vertebral bodies. The disk is composed of proteoglycans and has high water content. During the aging process, the disks lose their water content and may appear as blackened disks on MRI. With the loss of water and the changes that occur within the disks, the elastic properties of the disk change. The changes in the disks can also lead to changes in the facet joints in the form of hypertrophy. The combination of disk disease and

facet hypertrophy may also contribute to instability of the spine. Epidemiology of Low Back Pain Low back pain (LBP) is extremely prevalent; it is the second most common reason for people to seek medical attention.118 LBP accounts for approximately 15% of all sick leaves, and is the most common cause of disability for persons younger than 45 years of age.119 The estimated lifetime prevalence is 60% to 90% with an annual incidence of approximately 5%.120 Because of its prevalence and demand on health care, back pain is one of the most expensive medical problems. The natural history of back pain is very favorable; most episodes resolve in 10 to 30 days.121 Of the patients seeking medical attention, only 1% of patients will have nerve root symptoms and only 1% to 3% will have lumbar disk herniations. More than 50% of patients who have an acute episode of low back pain will have another episode within 1 year.121 Occupational factors associated with increased risk of low back pain include heavy physical work, frequent bending and twisting, lifting, pushing, pulling, repetitive work, static work postures, vibrations, and psychologic and psychosocial

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factors.123 Individual factors associated with low back pain include age and gender, with men having a higher risk. The highest prevalence rate for back pain occurs in the 35- to 55year age range for men, whereas women have a somewhat higher prevalence rate later in life. Surgery is seldom necessary for low back pain. The lifetime incidence of surgery ranges from 1% to 3%.121 Back pain is initially treated with nonsurgical conservative therapy. This therapy usually consists of analgesics, muscle relaxants, physical therapy, education, and occasionally epidural injections. A course of this type of therapy should be continued for approximately 4 to 6 weeks. Most individuals (85%) will demonstrate an improvement in pain relief and do not require surgical intervention. However, some individuals may experience progression and require surgery. Indications for surgery in the lumbar region include failure of conservative management, cauda equina syndrome, progressive motor deficits, and intolerable pain. Imaging of the lumbosacral spine includes plain radiographs of the lumbosacral spine, CT, or MRI. The correlation between images and clinical findings improves outcome. Because there are a number of pathologic processes that could contribute to low back pain, the surgery performed should address the demonstrated pathology.

Figure 9-27. Intervertebral disk anatomy.

Lumbar Herniated Disks

Figure 9-26. Grade I spondylolisthesis.

A herniated disk in the lumbosacral spine (Fig. 9-28) is a very common finding among healthy individuals. When the disks protrude and cause neural compression or irritation, radiculopathies occur. Patients harboring a herniated nucleus pulposus may complain of back pain, radicular pain, weakness, paresthesias, and occasionally bowel and bladder problems. These symptoms are typically managed with conservative therapy; however, some patients may require surgical intervention in the form of a diskectomy (see Fig. 9-28). The L5-S1 disk is the most common region of disk herniation in the lumbar spine followed by L4-L5 (40%) and then L3-L4 (3% to 10%). An L5-S1 disk herniation with compression of the S1 nerve root usually causes pain in the buttock with radiation to the posterior leg and often to the ankle. Weakness may be observed on plantar flexion, which

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Figure 9-28. Lumbar herniated nucleus pulposus. A, Sagittal MRI; B, Axial MRI; C, Free fragment.

C

tests the strength of the gastrocnemius muscle. Furthermore, an ankle jerk reflex may be diminished or absent and decreased sensation may be assessed over the lateral malleolus and lateral foot. The L4-L5 disk usually compresses the L5 nerve root and may cause pain in the posterolateral leg with decreased sensation in the web space of the large toe and dorsum of the foot. Weakness may be assessed in the extensor hallucis longus (EHL) and tibialis anterior. A foot drop may be the presenting sign. There is no reliable reflex to assess an L5 nerve root compression. The L3-L4 disk usually compresses the L4 nerve root and may manifest as pain in the anterior thigh with radiation to the medial malleolus and medial foot. Decreased sensation may also be observed in this particular distribution. The quadriceps muscle is commonly affected causing weakness in knee extension and a decreased patellar reflex.

Lumbar laminectomy with microdiskectomy is one of the most common procedures performed by the spinal surgeon. The overall risk of mortality in large series is 0.06%.122 During this procedure, partial removal of the lamina is necessary to obtain exposure to the disk space and neural foramina. Removal of the ligamentum flavum and medial retraction of the thecal sac is necessary to expose the nerve root and the protruding disk. The disk space is then entered and its contents removed. During this procedure, numerous complications can occur. Dural tears may occur during the removal of the bony elements or when removing the disk. The risk of a CSF fistula requiring operative repair is approximately 10 in 10,000.122 Nerve root injury may occur in the form of retraction injury as well as direct trauma from the instruments used during the procedure. Worsened motor deficits are seen in approximately 1% to 8% of cases.123 When entering the disk space,

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special attention to the depth of the instruments is important because deep penetration past the anterior vertebral body can lead to retroperitoneal injury. Many surgeons mark the instruments at 3 cm distal to the tip to ensure that the instrument does not penetrate through the anterior longitudinal ligament. Hemorrhage during and after diskectomy is very rare; however; if significant hypotension and hypovolemia occur intraoperatively, a vascular injury should be suspected. The mortality of a vascular injury during a lumbar diskectomy can be as high as 50%.124 Lumbar Stenosis Lumbar stenosis refers to a degenerative disease with associated osteophyte formation, hypertrophied ligamentum flavum, and hypertrophied facet joints. In lumbar stenosis, narrowing of the anteroposterior diameter of the spinal canal occurs. This narrowing causes compromise of the neural elements and/or blood supply to the spinal cord and nerve roots. Lumbar stenosis is found on plain radiographs in 95% of men and 80% of women older than 65.125 It is more common in the lumbar region where the majority of the load share is transmitted (Fig. 9-29). Patients with lumbar stenosis often present with back pain and radicular complaints. A syndrome known as neurogenic claudication is common. In this syndrome, unilateral or bilateral buttock, hip, thigh, or leg pain that is precipitated by standing or walking and characteristically relieved by a change in posture to sitting, squatting, or recumbency is observed. Once again, this syndrome is thought to arise from ischemia of the lumbosacral roots secondary to an increased metabolic demand during exercise. Surgical treatment for lumbar stenosis includes dorsal decompression of the neural elements via laminectomies

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and foraminotomies. Complications of decompressive lumbar spinal surgery include dural tears, neurologic injuries, and worsening pain syndromes. Cauda Equina Syndrome Cauda equina syndrome (CES) is a complex of symptoms and signs including low back pain, sciatica, motor weakness, sensory changes, and bowel or bladder incontinence. The nerve root compression may be due to trauma, metastatic tumors of the spine, spinal infections, and severe spinal stenosis. However, acute CES most commonly presents secondary to intervertebral disk prolapse. The incidence of CES has been estimated to range from 1.2% to 6%.126–128 CES is an indication for urgent surgical intervention. The onset of bladder paralysis is an important indicator for urgent surgery. Although the prognosis for CES is good, there is a significant difference in the outcome of cases operated on within 24 hours of bladder paralysis compared to those operated on after this period.129 Thus, if CES occurs postoperatively, it is usually reversible if recognized early. These early postoperative causes may be secondary to hematoma or improper graft placement. A delayed cause may be secondary to abscess. Fractures of the Lumbosacral Spine Fractures of the lower lumbar spine and lumbosacral junction are encountered infrequently.130 These fractures usually result from severe flexion and compression and occasionally rotation. In these injuries, CES may result. These injuries are usually treated with decompression of the neural elements and stabilization with transpedicular screw systems or rod systems combined with posterolateral bone grafting.

B Figure 9-29. Lumbar stenosis. A, MRI sagittal; B, MRI axial.

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Spinal Fusion Procedures Posterior Lumbar Interbody Fusion Procedures Ralph Cloward, a neurosurgeon living in Hawaii during World War II, pioneered and popularized posterior lumbar interbody fusions (PLIF). In this procedure, a subtotal diskectomy is performed along with decompression of the neural elements (Fig. 9-30). The interbody space is then fused with autologous bone. The indications for a PLIF procedure include persistent low back pain, recurrent disk disease, spondylolisthesis, and symptomatic spinal stenosis with or without degenerative scoliosis or spondylolisthesis.131 Patient selection remains the most critical factor for surgical success.132 Results of the PLIF procedure are usually determined by clinical improvement and by fusion rate. Cloward reported a clinical success rate of 87% to 92% and a fusion success rate of 92% in his 40-year experience performing the operation.133 Others including Gill and Blumenthal, Stefee and Brantigan, and Ray have subsequently supported these findings.134–136 The procedure is technically demanding and tragic mishaps may occur in the hands of inexperienced surgeons. The surgical complications observed in the dorsal decompression of the lumbar spine are inherent in this procedure; however, PLIF-related complications may also be observed.

A

In the immediate postoperative period, complications secondary to technical error may occur. New or increased neurologic deficits occur postoperatively in 0.5% to 4.0% of the patients after a PLIF.131,134,137–140 These injuries may be a result of excessive traction placed on the nerve roots while performing the procedure. Retraction of the sacral nerve roots may also lead to postoperative urinary retention.133,134 Increased bleeding may occur secondary to bleeding from epidural veins or the vertebral bodies. Infection rates after PLIF range from 0.2% to 7%.131,134,138,141,142 The infections may be superficial in nature or may lead to osteomyelitis. Delayed complications, usually 3 to 6 months postoperatively, occur secondary to instability and strain problems. Delayed complications include disease at adjacent levels and pseudoarthrosis. A motion segment adjacent to the fused spine may undergo accelerated degeneration and lead to new-onset symptoms. Spondylosis and spondylolisthesis has also been reported after PLIF procedures.143 These complications may present with new-onset pain or neurologic deficit. Finally, pseudoarthrosis after a PLIF procedure may lead to failed back syndrome. Anterior Lumbar Interbody Fusion Procedures Anterior lumbar interbody fusions (ALIFs) (see Fig. 9-30) reconstruct the anterior column of the spine and improve

B

Figure 9-30. Posterior lumbar interbody fusion and anterior lumbar interbody fusion. A, Lateral radiograph; B, Anteroposterior radiograph.

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sagittal plane alignment. Operative indications for this procedure include degenerative disk disease with chronic back pain as well as degenerative spondylolistheses. A failure of a previous dorsal lumbar surgery may be an indication for ALIF. Chronic low back pain with failure of conservative therapy may also be an indication for ALIF. In this procedure, a transabdominal or retroperitoneal approach is performed to allow access to the ventral lumbar spine. With these approaches, the neural elements are avoided. However, risk of injury to the peritoneal structures may occur. Injuries to the bowel may occur and should be detected and treated with direct repair. Injuries to the major blood vessels are rare; however, injuries to the iliac arteries or veins, the inferior vena cava, and the aorta can occur. These injuries should be addressed quickly and may require the experience of a general or vascular surgeon. Postoperative hernias may also be present if meticulous attention to fascial closure is not adhered. A serious complication of ALIF procedures in male patients is retrograde ejaculation. This occurs when the autonomic nerves are injured, usually at the L5-S1 level. This problem occurs in 0.5% to 2.0% of all ALIF procedures performed on males.144–147 Urinary retention may also result from ALIF surgery, but it is usually temporary. Endoscopic Procedures With advancing technology, the endoscope has allowed many standard spinal surgical procedures to be performed with minimal invasiveness (Fig. 9-31). This burgeoning field is advantageous for numerous reasons. First, with the use of dilators, tissue damage while approaching the spine can be

Figure 9-31. Minimally invasive surgery diagram.

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reduced. This technique can result in less postoperative pain. Second, these procedures may be performed on an outpatient surgery format with decreased hospitalization stay. Also, blood loss is usually less when compared to that with open surgery. Although minimally invasive surgery may be a useful technique in the spinal surgeon’s armamentarium, there is a steep learning curve. In inexperienced hands, complications can arise because surgical procedures are being performed with a two-dimensional image. Neural element damage, CSF leaks, and hemorrhage can occur and may require an open surgical procedure to address the complications. Medical Complications of Spinal Surgery In spinal surgery, medical complications in the postoperative period can lead to significant morbidity and mortality. Many of the complex spinal cases are routinely observed in the intensive care unit to limit these complications. Moreover, preventative measures may also be taken to lessen the amount of morbidity in these patients. Thromboembolic disease is a serious complication in the spinal surgery patient. Rates of acute deep venous thrombosis (DVT) may be as high as 14%.148 The incidence is significantly higher in spinal cord–injured patients. DVTs may lead to pulmonary embolism, which has been reported in up to 8% of spinal surgery patients.149 Recommendations for DVT prophylaxis vary; however, gradient pressure stockings, intermittent pneumatic compression devices, mini-dose heparin, low-molecular-weight heparin, and low-dose warfarin may be used. Another alternative to prevent pulmonary embolism is placement of an inferior vena cava filter.

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The cardiovascular system may be adversely affected by spinal cord injury. With cervical and high thoracic injuries, the sympathetic outflow may be completely or partially compromised. Initially, the patient may experience what has been labeled as spinal cord shock. A block in the sympathetic outflow with an unopposed parasympathetic stimulus below the level of the injury leads to spinal cord shock. The effect leads to vascular pooling of blood, hypotension, and bradycardia. It is important to recognize spinal shock because overaggressive fluid resuscitation may cause the patient to become fluid-overloaded and pulmonary edema may ensue. Therefore, evaluation of central venous pressure, blood pressure, and heart rate are extremely important for proper management. Intravenous crystalloid fluids as well as colloid fluids may be used initially for resuscitation; however, dopamine and dobutamine may be required to help maintain adequate blood pressure and heart rate. Another effect of spinal cord injury on the cardiovascular system includes dysrhythmias that may occur in the absence of prior cardiac disease. A careful cardiac history should be ascertained and an echocardiogram should be obtained on admission. A third well-described phenomenon observed in spinal cord–injured patients is autonomic dysreflexia. In patients with injuries above T6, uncontrolled sympathetic reflex response to noxious stimuli may cause intense headache, flushing, excessive diaphoresis, and episodes of extreme hypertension. The stimuli may include distention of the bowel or bladder and aggressive movement of the patient. The treatment for autonomic dysreflexia involves removal of the inciting stimuli. The hypertension associated with this phenomenon may require acute treatment with nitroprusside and/or hydralazine. Patients with spinal cord injuries often have serious, lifethreatening pulmonary complications. The major causes of death in the acute phase in spinal cord–injured patients are pulmonary failure and shock.150 Approximately 35% of spinal cord–injured patients will have a major pulmonary complication.151 The diaphragm is innervated by the ventral roots of C3, C4, and C5 and therefore, patients with spinal cord lesions of C4 or higher will need immediate intubation and mechanical ventilation. Patients with lower cervical/high thoracic cord injuries may initially have normal respiration, but may progress to require mechanical ventilation. In patients with impaired external intercostal muscle function as seen with thoracic cord injuries, the activity of the diaphragm combined with the inactivity of the external intercostal muscles causes a decrease in the anteroposterior diameter of the chest. This type of breathing has been referred to as paradoxical breathing. If this type of breathing is observed in a patient, close monitoring is critical because these patients often succumb to respiratory collapse. The position of the patient is also an important concept concerning the respiratory status of a spinal cord–injured patient. The upright position allows for gravity to affect the

abdominal viscera, which allows for better respiratory performance. The upright position may also aid in pulmonary toileting and thus decrease the incidence of respiratory complications and infections. Gastrointestinal complications may also be prevalent in the spinal cord–injured patient. Stress ulcerations may result from a complicated surgery, the use of high-dose steroids, or a concomitant brain injury. Prophylaxis with H-2 blockers and gastric mucosal protective agents should be used. Adynamic ileus is a well-known complication of spinal surgery and also occurs in patients with acute spinal cord injury. An ileus may lead to increased abdominal distention with compromise of diaphragmatic excursion. This may further complicate pulmonary function. The treatment of an ileus should include decreasing oral intake, and the use of laxatives, bowel stimulants, and enemas. Occasionally, a nasogastric tube may be fed into the small bowel to help decompress the distended bowel. Neostigmine, at a dose of 0.5 to 2 mg, has been used successfully for treatment of this complication. Olgivie’s syndrome, or pseudo-obstruction of the colon, has been reported in patients after lumbar spinal surgery.152 This syndrome is characterized by abdominal distention with an enlarged cecum (>9 cm). Nausea, vomiting, constipation, and diarrhea may be present in patients suffering from this syndrome. Initial treatment consists of nasogastric tubes, insertion of rectal tubes, and decreasing oral intake. If patients do not respond to initial therapeutic intervention, then laparotomy and placement of a cecostomy tube may be required. The mortality rate for patients treated conservatively with colonoscopy is 13%; however, in patients undergoing laparotomy with cecostomy tube placement, the mortality rate is approximately 30%.153 Genitourinary complications after spinal cord injury may lead to significant morbidity. Initially, spinal cord–injured patients may exhibit detrusor muscle inactivity, decreased bladder sensation, and compromised sphincter activity. Uninhibited reflex activity of the detrusor and sphincter gradually returns and during this time, the patient may exhibit varying dysfunction. Distention of the bladder or bowel can lead to autonomic dysreflexia in patients with spinal cord injuries above T6 as previously described. Therefore, it is important that a catheter regimen be enforced in these patients to limit morbidity. Frequent bladder catheterizations as well as aggressive bowel programs should be implemented. Patients with injuries to the lower thoracic spinal cord usually have impairment of bladder sensation, detrusor hyperreflexia, and sphincteric dyssynergia. These impairments lead to incomplete bladder emptying and elevated bladder pressures. Renal damage may ensue due to hydroureteronephrosis. In-dwelling catheters may be used for genitourinary problems associated with spinal cord injury; however, these catheters are subject to infection. Therefore, scheduled bladder catheterizations may be associated with less morbidity when compared to indwelling catheters.

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Summary With the advancing age of our society, the number of patients seeking surgical intervention for spinal disease will increase. This increased demand will place added pressure on hospitals, doctors, nurses, and ancillary medical services. Therefore, a sound understanding of the epidemiology, natural history, and various treatment modalities will be necessary to facilitate this shift in workforce. A multidisciplinary approach consisting of primary care physicians, neurologists, neurosurgeons, internists, anesthe-

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siologists, and rehabilitation specialists may be required to provide comprehensive care for the patient with a spinal disorder. Perhaps the most challenging problem we will be faced with in the new millennium is not how to maintain the quality of care for the patient with a spinal disorder, but how to advance our understanding of the disease processes and develop novel treatment modalities. The exciting and rapidly shifting disciplines of molecular biology, biomedical engineering, and minimally invasive surgery may offer some answers to these perplexing problems.

P earls 1. National studies have found a 1 in 300 incidence of severe neck injury in vehicular accidents severe enough to have the vehicle towed from the scene. That incidence increases to 1 in 14 for cases in which the patient has been ejected from the car. 2. When assessing the integrity of the transverse ligament, an open mouth or anteroposterior radiograph may be used. If the sum total of the overhang of both C1 lateral masses on C2 is greater than or equal to 7 mm, then the transverse ligament is probably disrupted. This measurement is commonly known as the “Rule of Spence.” 3. The complications of anterior odontoid screw fixation are similar to other anterior cervical approaches. The main difference pertains to the actual screw placement. It is imperative that biplanar fluoroscopy guide the experienced surgeon in the screw trajectory. Malposition of the screw can result in dural penetration with CSF leak, catastrophic neurologic deficits, or vertebral artery injury. 4. Trauma also affects the subaxial (C3-C7) spine. Injuries to this region of the spine most commonly occur as a result of flexion-rotation or hyperflexion injuries. Ligamentous injuries may occur that allow for subluxation of vertebrae. 5. Degenerative processes of the cervical spine most frequently present as spondylosis, osteophytic compression, and disk herniation.35 Cervical radiculopathy is a common occurrence. Individuals who lift heavy objects as well as those who smoke are predisposed to acute cervical disk disease. 6. The incidence of cervical disk herniation peaks in the fourth decade. This peak incidence in disk herniation appears to be the result of the combination of the maximum expansile strength of the disk (i.e., when the disk is the most hydrated) and the peak incidence of annular tears. Thus, after the age of 50, the dehydrated disks are less prone to herniate even when the incidence of annular tears increases.

7. Although disk herniation may cause significant pain, the etiology of the pain is rather elusive. 8. The most common sites of herniation in the cervical spine are at C5-C6 and C6-C7, causing compression of the C6 and C7 root, respectively. Involvement of the C5 nerve root is perhaps the most disabling. 9. Cervical spondylotic changes are often the cause for cervical myelopathy. Classic signs in CSM include Lhermitte’s sign (electrical shock sensation associated with neck flexion), hand clumsiness, distal weakness, generalized hyperreflexia, Hoffman’s sign (contraction of the thumb and index finger upon flickering of middle finger), and spastic gait.46,48 10. Corpectomies tend to be lengthy procedures that, even in the best of hands, usually take a few hours. Injuries to the vascular structures may be caused by the sharp surfaces of the retractor blades. These lesions, if identified intraoperatively, can often be repaired primarily.63 Postoperative paratracheal soft tissue swelling can compromise the airway and thus requires prolonged intubation.64 11. Given the persistent loading forces of the cervical spine, all instrumentation is destined to “fail.” For that reason, for the construct to be successful, a solid bony fusion is needed. 12. The blood supply to the upper thoracic cord relies on an anastomotic supply from the thyrocervical and costocervical trunks as well as the radicular arteries. In the middle region, T4-T8, a single thoracic radicular artery supplies this vulnerable area. In trauma cases or when hypotension occurs, this region of the spinal cord is the first to be affected. 13. The symptoms from herniated disks usually present as localized back pain; however, the pain may be represented as a band-like radiculopathy in the region of the particular dermatome level. Motor deficits, sensory deficits, and bowel or bladder dysfunction may also occur. Continued

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14. Cancer is the second leading cause of death in the United States, with approximately 1.3 million new cases per year.94,95 The spinal column, especially the thoracic region, is the most frequent site of bony metastasis.96 15. Multiple myeloma accounts for 45% of all malignant bone tumors.99 It is primarily a disease of the sixth and seventh decades with a predilection for the thoracic spine, followed by the lumbar and rarely the cervical spine.100 The 5-year survival rate is 18%.101 16. Spinal epidural abscesses usually present with severe neck or back pain and progressive neurologic deficit that may be rapid. Approximately one half of epidural abscesses result from hematogenous spread to the epidural space. This type of abscess is more common in intravenous drug abusers. 17. The most common infections of the spinal column include pyogenic organisms (Staphylococcus aureus and coliform bacilli), infections caused by fungi (Actinomycetes and Blastomycetes), and Pott’s disease (Mycobacterium tuberculosis).108 18. Spondylolisthesis refers to the slippage of all or part of one vertebra onto another.

References 1. Yashon D: Spinal Injury. Norwalk, Conn., Appleton-Century-Crofts, 1986, pp 7–11. 2. Huelke DF, O’Day J, Mendlesohn RA: Cervical injuries suffered in automobile crashes. J Neurosurg 1981;54:316–322. 3. Hadley MN, Dickman CA, Browner CM, et al: Acute traumatic atlas fractures: Management and long term outcome. Neurosurgery 1988;23:31–35. 4. Landells CD, Van Peteghem PK: Fractures of the atlas: Classification, treatment, and morbidity. Spine 1988;13:450–452. 5. Fowler JL, Sandhu A, Fraser RD: A review of fractures of the atlas vertebra. J Spinal Dis 1990;3:19–24. 6. Dickman CA, Greene KA: Treatment of atlas fractures. In Menezes AH, Sonntag VK (eds): Principles of Spinal Surgery. New York,. McGraw-Hill, 1996, pp 855–866. 7. Jefferson G: Fracture of the atlas vertebra: Report of four cases, and a review of those previously recorded. Br J Surg 1920;7:407– 422. 8. Spence KF, Decker S, Sell KW: Bursting atlantal fracture associated with rupture of the transverse ligament. J Bone Joint Surg 1970;52A: 543–549. 9. Dickman CA, Papadopolous SM, Sonntag VKH, et al: The interspinous method of posterior atlantoaxial arthrodesis. J Neursosurg 1991;74:190–198. 10. Marcotte P, Dickman CA, Sonntag VKH, et al: Posterior atlantoaxial facet screw fixation. J Neurosurg 1993;79:234–237. 11. Hadley MN, Browner C, Sonntag VKH: Axis fractures: A comprehensive review of management and treatment in 107 cases. Neurosurgery 1985;17:281–290. 12. Anderson LD, D’Alonzo RT: Fractures of the odonoid process of the axis. J Bone Joint Surg 1974;56A:1663–1674.

19. Hemorrhage during and after diskectomy is very rare; however; if significant hypotension and hypovolemia occur intraoperatively, a vascular injury should be suspected. The mortality of a vascular injury during a lumbar diskectomy can be as high as 50%.124 20. CES is an indication for urgent surgical intervention. The onset of bladder paralysis is an important indicator for urgent surgery. Although the prognosis for CES is good, there is a significant difference in the outcome of cases operated on within 24 hours of bladder paralysis compared to those operated on after this period.129 21. Although minimally invasive surgery may be a useful technique in the spinal surgeon’s armamentarium, there is a profound learning curve. In inexperienced hands, complications can arise because surgical procedures are being performed with a two-dimensional image. 22. The major causes of death in the acute phase in spinal cord–injured patients are pulmonary failure and shock.150 Approximately 35% of spinal cord–injured patients will have a major pulmonary complication.151

13. Scott EW, Haid RW, Peace D: Type I fractures of the odontoid process: Implications for atlanto-occipital instability: Case report. J Neurosurg 1990;72:488–492. 14. Sonntag VKH, Hadley MN: Nonoperative management of cervical spine injuries. Clin Neurosurg 1988;34:630–649. 15. Levine AM, Edwards CC: The management of traumatic spondylolisthesis of the axis. J Bone Joint Surg 1985;67A:217–226. 16. Effendi B, Roy D, Cornish B, et al.: Fractures of the ring of the axis: A classification based on the analysis of 131 cases. J Bone Joint Surg 1981;63B:319–327. 17. Sonntag VKH, Dickman CA: Treatment of upper cervical spine injuries. In Rea GL, Miller CA (eds): Spinal Trauma: Current Evaluation and Management.Neurosurgical Topics. Park Ridge, Ill, American Association of Neurological Surgeons, 1993, pp 25–74. 18. Benzel EC, Hart BL, Ball PA, et al: Fractures of the C-2 vertebral body. J Neurosurg 1994;81:206–212. 19. Clark CT, Apuzzo MLJ: The evaluation and management of trauma to the odontoid process. In Cooper PR (ed): Management of Posttraumatic Spinal Instability. Park Ridge, Ill, American Association of Neurological Surgeons, 1990, pp 77–97. 20. Apfelbaum RI: Screw fixation of odontoid fractures. In Rengachary SS, Wilkins RH (eds): Neurosurgery, vol 2. New York, McGraw-Hill, 1996, pp 2965–2972. 21. Sonntag VKH, Dickman CA: Occipitocervical and high cervical stabilization. In Rengachary S, Wilkins R (eds): Neurosurgical Operative Atlas. Baltimore, Williams and Wilkins, 1991, pp 327–339. 22. White AA, Johnson R M, Panjabi MM, et al,: Biomechanical analysis of clinical stability in the cervical spine. Clin Orthop 1975;109: 85–96. 23. Schneider RC, Kahn EA, Arbor A: Chronic neurological sequelae of acute trauma to the spine and spinal cord. The significance of acute flexion or teardrop cervical fracture-dislocation of the cervical spine. J Bone Joint Surg 1956;38A.

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Chapter 9  24. Menezes AH: Developmental and acquired abnormalities of the craniovertebral junction.In Van-Gilder JC, Menezes AH, Dolan KD (eds): The Craniovertebral Junction and Its Abnormalities. New York, Karger, 1987, pp 109–158. 25. Bernini F, Elefante R, Smaltino F, et al: Angiographic study on the vertebral artery in cases of deformities of the occipitocervical joint, abstracted. Am J Roentgenol Radium Ther Nucl Med 1969;107: 526. 26. McRae DL: The significance of abnormalities of the cervical spine. AJR 1960;70:23–46. 27. Chamberlain WE: Basilar impression (platybasia): Bizarre developmental anomaly of occipital bone and upper cervical spine with striking and misleading neurologic manifestations. Yale J Biol Med 1939;11:487–496. 28. McGregor J: The significance of certain measurements of the skull in the diagnosis of basilar impression. Br J Radiol 1948;21:171–181. 29. Hinck VC, Hopkins CE, Savara BS: Diagnostic criteria for basilar impression. Radiology 1961;76:579. 30. VonTorkus D, Gehle W: The upper cervical spine. Regional anatomy, pathology and traumatology. In Georg, Thieme, Verlag (eds): A Systemic Radiological Atlas and Textbook. New York, Grune & Stratton, 1972, pp 2–77. 31. Bharucha EP, Dastur HM: Craniovertebral abnormalities (a report of 40 cases). Brain 1964;97:469–480. 32. McRae DL, Barnum AS: Occipitalization of the atlas. Am J Roentgenol 1953;70:23–46. 33. Spillane JD, Pallis C, Jones AM: Developmental abnormalities in the region of the foramen magnum. Brain 1957;80:11–48. 34. Hensinger RN: Congenital anomalies of the cervical spine—atlantooccipital fusion. In Rothman RH, Simeone FA (eds): The Spine. Philadelphia, WB Saunders, 1992, pp. 288–289. 35. Ball P, Benzel E: Pathology of Disk degeneration. In: Principles of Spinal Surgery. New York, McGraw-Hill, 1996, p 517. 36. Kelsey J, Githenss P, Walter S, et al: An epidemiological study of acute prolapse cervical intervertebral discs. J Bone Joint Surg 1984; 66A:907. 37. Braakman R: Cervical Spondylotic Myelopathy: Advances and Technical Standards in Neurosurgery. New York, Springer-Verlag, 1979, pp 137–170. 38. Henderson C, Henessy R: Posterolateral foraminotomy as an exclusive operative technique for cervical radiculopathy: A review of 846 consecutively operated cases. Neurosurgery 1983;13:504. 39. Clarke E, Robinson PK: Cervical myelopathy: A complication of cervical spondylosis. Brain 1956;79:483–510. 40. Parke WW: Correlative anatomy of cervical spondylotic myelopathy. Spine 1988;13:831–837. 41. Kramer J: Intervertebral Disc Disease. Causes, Diagnosis, Treatment, and Prophylaxis, 2nd ed. New York, Thieme, 1990. 42. Jensen MC, Brandt-Zawadski MN, Obuchowski N: Magnetic resonance imaging of the lumbar spine in people without back pain. N Engl J Med 1994;331:69–73 43. Boden SD, McCowin PR, Davis DO: Abnormal magnetic resonance scans of the cervical spine in asymptomatic subjects: A prospective investigation. J Bone Joint Surg 1990;72A:1178. 44. Smyth MJ, Wright V: Sciatica and the intervertebral disc: An experimental study. J Bone Joint Surg 1958;40A:1401–1418. 45. Brown M: Pathophysiology of disc disease. Orthop Clin North Am 1971;2:359–370. 46. Montgomery DM, Brower RS: Cervical spondylotic myelopathy. Orthop Clin North Am 1992;23:487–493. 47. Clark CR: Cervical spondylotic myelopathy. Spine 1988;13:347– 349. 48. Beck DW: Cervical spondylosis: Clinical findings and treatment. Contemp Neurosurg 1991;13:1–6. 49. Simeone FA, Rothman RH: Cervical Disc Disease: The Spine, 2nd ed. Philadelphia, Saunders, 1988, pp 440–499.

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50. Zeidman SM, Ducker TB: Cervical disc diseases: Part I. Treatment options and outcomes. Neurosurg Q 1992;2:116–143. 51. Johnson RM, Hart DL, Simmons EF, et al: Cervical orthoses. J Bone Joint Surg 1977;59A:332–339. 52. Kaiser MG, Haid RW, Subach BR, et al: Anterior cervical plating enhances arthorodesis after discectomy and fusion with cortical allograft. Neurosurgery 2002;50:229–236. 53. Wilson DH, Campbell DD: Anterior cervical discectomy without bone graft. J Neurosurg 1977;47:551–555. 54. Jeffries RV: The surgical treatment of cervical myelopathy due to spondylosis and disc degeneration. J Neurol Neurosurg Psychiatry 1986;49:353–361. 55. Connolly E, Seymour R, Adams J: Clinical evaluation of anterior cervical fusion for degenerative cervical disc disease. J Neurosurg 1965;23:431–437. 56. Fielding W: Complications of anterior cervical disc removal and fusion. Clin Orthop Rel Res 1992;284:10–13. 57. Riley L, Robinson R, Johnson K, et al: The results of anterior interbody fusion of the cervical spine. J Neurosurg 1969;30:127–133. 58. Gore D, Sepic S: Anterior cervical fusion for degenerated of protruded discs. Spine 1984;9:667. 59. Bishop RC, Moore KA, Hadley MN: Anterior cervical interbody fusion using autogeneic and allogeneic bone graft substrate: A prospective comparative analysis. J Neurosurg 1996;85:206–210. 60. Maravilla KR, Hartling RP:Imaging decisions in degenerative spinal disease: A practical approach. MRI Decisions 1988;2:2–15. 61. Saunders RL, Bernini PM, Shirrefs TG: Central corpectomy for cervical spondylotic myelopathy: A consecutive series with long term follow up evaluation. J Neurosurg 1991;74:163–170. 62. Benzel EC, Lacon J, Kesterson L, Hadden T. Cervical laminectomy and dentate ligament section for cervical spondylotic myelopathy. J. Spinal Disord 1991;4:286–295. 63. Whitecloud TS II: Cervical spondylosis: The anterior approach. In Frymoyer JW,ed.: The Adult Spine: Principles and Practice. New York, Raven Press, 1978, pp 1165–1186. 64. Emery SE, Smith MD, Bohllman HH: Upper airway obstruction after multilevel cervical corpectomy for myelopathy. J Bone Joint Surg 1991;73A:544–551. 65. Bulger RF, Rejowski JE, Beatty RA: Vocal cord paralysis associated with anterior cervical fusion: Consideration for prevention and treatment. J Neurosurg 1985;62:657–661. 66. Tew JM, Mayfield FH: Complications of surgery of the anterior cervical spine. Clin Neurosurg 1976;23:424–434. 67. Raynor RB, Pugh J, Shapiro I: Cervical facetectomy and its effects on spine strength. J Neurosurg 1985;63:278. 68. White AA, Panjabi MM: Biomechanical considerations in the surgical management of the spine. In Wite AA, Panjabi MM (eds): Clinical Biomechanics of the Spine, 2nd ed. Philadelphia, Lippincott, 1990, pp 511–634. 69. Nazarian SM, Louis RP: Posterior internal fixation with screw plates in traumatic lesions of the cervical spine. Spine 1987;16S:64. 70. Sawin PD, Traynelis VC: Posterior articular mass plate fixation of the subaxial cervical spine. In Menezes AH, Sonntag VK (eds): Principles of Spinal Surgery. New York, McGraw Hill, 1996, pp 1099–1100. 71. Heller JG, Carlson GD, Abitbol JJ, Garfin SR: Anatomic comparison of the Roy-Camille and Magerl technique for screw placement in the lower cervical spine. Spine 1991;16S:552. 72. Traynelis VC: Anterior and posterior plate stabilization of the cervical spine. Neurosurg Q 1992;2:59. 73. Heller JG, Silcox H, Sutterlin CE: Complications of posterior cervical plating. Presented at the 22nd annual meeting of the cervical spine research society, Baltimore, December, 1994. 74. Tsuyama N: Ossification of the posterior longitudinal ligament of the spine. Clin Orthop Relat Res 1984;184:71–84. 75. Lipson SJ: Rheumatoid arthritis in the cervical spine. Clin Orthop 1989;239:121–127.

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76. Simpson JM, An HS, Balderston RA: Complications of surgery of the spine in rheumatoid arthritis and ankylosing spondylitis. In Balderston RA, An HS (eds): Complications of Spinal Surgery. Philadelphia, WB Saunders, 1991, pp 169–175. 77. Grantham SA: Rheumatoid arthritis and other noninfectious inflammatory diseases: Atlantoaxial instability. In The Cervical Spine Research Society: The Cervical Spine. Philadelphia, Lippincott-Raven, 1983. 78. Moller P, Vinje O, Dale K, et al: Family studies in Bechterew’s syndrome (ankylosing spondylitis) I. Prevalences of symptoms and signs in relatives of HLAB27 positive proband. Scand J Rheumatol 1984;13:1–10. 79. Gran JT: The epidemiology of rheumatoid arthritis. Monogr Allergy 1987;21:162–196. 80. Blumberg B. Ragan C: The natural history of rheumatoid spondylitis. Medicine 1956;35:1. 81. Cardenosa G, Deluca SA: Ankylosing spondylosis. Am Fam Phys 1990;42:147–150. 82. Murray GC, Persellin RH: Cervical fracture complicating ankylosing spondylitis: A report of eight cases and review of the literature, review. Am J Med 1981;70:1033–1041. 83. Winter RB, Moe JH, Eilers VE: Congenital scoliosis: a study of 234 patients treated and untreated. J Bone Joint Surg 1968;50A:1–47. 84. Scheuermann H: Kyphosis dorsalis juvenilis. Ugeskr Laeger 1920;82: 385–393. 85. Rothman RH, Simeone FA: Scheuermann’s juvenile kyphosis. In The Spine, 3rd ed., Vol 1. Philadelphia, WB Saunders, 1980, pp 2380–2388. 86. Bradford DS, Moe JH, Montalvo FJ, Winter RB: Scheuermann’s kyphosis and roundback deformity: Results of Milwaukee brace treatment. J Bone Joint Surg 1974;56A:749. 87. Sorenson KH: Scheuermann’s Juvenile Kyphosis. Clinical Appearances, Radiography, Aetiology, and Prognosis. Copenhagen, Munksgaard, 1964. 88. Bradford DS: Juvenile kyphosis. Clin Orthop Relat Res 1977;128:45– 55. 89. Sturm PF, Dobson JC, Armstrong GWD: The surgical management of Scheuermann’s disease. Spine 1993;18:685–691. 90. Kumar R, Dunsker SB: Surgical management of thoracic disk herniations. In Schmidek, ed: Operative Neurosurgical Techniques, 4th ed. Vol 2. Philadelphia, WB Saunders, 2000, pp 2122–2131. 91. Logue V: Thoracic intervertebral disc prolapse with spinal cord compression. J Neurol Neurosurg Psych 1952;15:227–241. 92. Jelsma RK, Kirsch PT, Rice JF, Jelsma LF. The radiographic description of thoracolumbar fractures. Surgl Neurol 1982;18:230–236. 93. Denis F. The three column spine and its significance in the classification of acute thoracolumbar spinal injuries. Spine 1983;8:817–831. 94. Masaryk TJ: Neoplastic disease of the spine. Radiol Clin North Am 1991;29:829–843. 95. O’Conner MI CB: Metastatic disease of the spine. Orthopedics 1992;15:611–620. 96. Malawer MM, Delaney TF: Treatment of metastatic cancer to bone. In DeVita VT, Hellman S, Rosenberg SA (eds): Cancer: Principles and Practice of Oncology, 4th ed. Philadelphia, Lippincott-Raven, 1993, p 2225. 97. Boogerd W JV: Diagnosis and treatment of spinal cord compression in malignant disease. Cancer Treat Rev 1993;19:129–150. 98. Gilbert RW, Kim JH, Posner JB: Epidural spinal cord compression from metastatic tumour: Diagnosis and treatment. Ann Neurol 1978;3:40–51. 99. Ansari A YD, Seymour JL: Acute pyogenic spondylodiscitis with epidural phlegmon. Diagnosis and management by MRI and multidisciplinary approach. Minn Med 1993;76:21–24. 100. Wolcott WP, Malik JM, Shaffrey CI, Shaffrey ME, Jane JA: Differential diagnosis of surgical disorders of the spine. In Benzel (ed): Spine Surgery: Techniques, Complication Avoidance, and Management. Philadelphia, Churchill Livingstone, 1999, pp 25–51.

101. Masaryk TJ: Neoplastic disease of the spine. Radiol Clin North Am 1991;29:829–843. 102. Abdelwahab IF Casden AM, Klein MJ, Spollman A: Chondrosarcoma of a thoracic vertebra. Bull Hosp J Dis Orthop Inst 1991;55:34–39. 103. Saeger W, Ludecke DK, Muller S, et al: Chordome des clivus: Histologie, Ultrastruktur und Klinik. Tumor Diagnostik Therapie 1983;4:74– 79. 104. Stein BM MP: Intramedullary neoplasms and vascular malformations. Clin Neurosurg 1992;39:361–387. 105. Hanley EN, Phillips ED: Profiles of patients who get spine infections and the type of infections that have a predilection for the spine. Semin Spine Surg 1990;2:257–267. 106. Sapico FL MJ: Vertebral osteomyelitis, review. Infect Dis Clin North Am 1990;4:539–550. 107. Correa AG EM, Baker CJ: Vertebral osteomyelitis in children, review. Pediatr Infect Dis J 1993;12:228–233. 108. Siddiqi SN, Fehlings MG: Ventral and ventrolateral spine decompression and fusion. In Benzel (ed): Spine Surgery: Techniques, Complication Avoidance, and Management. Philadelphia, Churchill Livingstone, 1999, pp 267–284. 109. Bloch AB SD: The epidemiology of tuberculosis in the United States. Clin Chest Med 1989;10:297–313. 110. Rosenblum B, Oldfield EH, Doppman JL, et al: Spinal arteriovenous malformations: A comparison of dural arteriovenous fistulas and intradural AVMs in 81 patients. J Neurosurg 1987;67:795–802. 111. Symon L, Kuyama H, Kendall B: Dural arteriovenous malformations of the spine: Clinical features and surgical results in 55 cases. J Neurosurg 1984;60:238–247. 112. Malis LI: Arteriovenous malformations of the spinal cord.In Youmans JR (ed): Neurological Surgery: A Comprehensive Reference Guide to the Diagnosis and Management of Neurosurgical Problems, 2nd ed. Philadelphia, WB Saunders, 1982, pp 1850–1874. 113. Heros RC, Debrun GM, Ojemann RG, et al: Direct spinal arteriovenous fistula: A new type of spinal AVM: Case report. J Neurosurg 1986;64:134–139. 114. Barrow DL, Colohan AR, Dawson R: Intradural perimedullary arteriovenous fistulas (type IV spinal cord arteriovenous malformations). J Neurosurg 1994;81:221–229. 115. Wiltse LL, Newman PH, Macnab I: Classification of spondylolysis and spondylolisthesis. Clin Orthop 1976;117:23–39. 116. Boxall D, Bradford DS, Winter RB et al: Management of severe spondylolisthesis in children and adolescents. J Bone Jt Surg 1979;61A:479–495. 117. Newman PH: Stenosis of the lumbar spine in spondylolisthesis. Clin Orthop 1976;115:116–121. 118. Cypress BK: Characteristics of physician visits for back symptoms: A national perspective. Am J Public Health 1983;73:389–395. 119. Cunningham LS, Kelsey JL: Epidemiology of musculoskeletal impairments and associated disability. Am J Public Health 1984;74:574–579. 120. Frymoyer JW: Back pain and sciatica. N Engl J Med 1988;318:291–300. 121. Anderson GB: Epidemiology. In Weinstein, Rydevik, and Sonntag (eds): Essentials of the Spine. New York, Raven Press, 1995, pp 1–10. 122. Ramirez LF, Thisted R: Complications and demographic characteristics of patients undergoing lumbar discectomy in community hospitals. Neurosurgery 1981;25:226–231. 123. Davis RA: A long-term outcome analysis of 984 surgically treated herniated lumbar discs. J Neurosurg 1994;80:415–421. 124. Smith DA, Cahill DW: Vascular and soft-tissue complications. In Benzel (ed): Spine Surgery: Techniques, Complication Avoidance, and Management. Philadelphia, Churchill Livingstone, 1999, pp 1407–1417. 125. Lawrence JS: Disc degeneration. Its frequency and relationship to symptoms. Ann Rheum Dis 1969;28:121. 126. Raaf J: Removal of protruded lumbar intervertebral discs. J Neurosurg 1970;32:604–611. 127. Spangfort EV: The lumbar disc herniation: A computer-aided analysis of 2,504 operations. Acta Orthop Scand Suppl 1972;142:1–95.

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Chapter 9  128. Gleave JR, MacFarlane R: Prognosis for recovery of bladder function following lumbar central disc prolapse. Br J Neurosurg 1990;4:205– 209. 129. Dinning TA, Schaeffer HR: Discogenic compression of the cauda equina: A surgical emergency. Aust NZ J Surg 1993;63:927–934. 130. Das De S, McCreath SW. Lumbosacral fracture-dislocations: A report of four cases. J Bone Joint Surg (Br) 1981;63B:58–60. 131. Hutter CG: Spinal stenosis and posterior lumbar interbody fusion. Clin Orthop 1985;193:103–114. 132. Gill K: Clinical indications for lumbar interbody fusion. In Lin PM, Gill K (eds): Lumbar Interbody Fusion. Rockville, Md, Aspen Publishers, 1989, pp 35–53. 133. Cloward RB: Posterior lumbar interbody fusion updated. Clin Orthop 1985;193:16–19. 134. Gill K, Blumenthal SL: Posterior lumbar interbody fusion. A 2 year follow-up of 238 patients. Acta Orthop Scand 1993;64[suppl 251]:108–110. 135. Steffee AD, Brantigan WJ: The VSP spinal fixation system. Report of a prospective study of 250 patients enrolled in FDA clinical trials. Proceedings of the North American Spine Society, 7th Annual Meeting, Boston, MA, 1992 (July 8–11). 136. Ray CD: Spinal interbody fusions: A review, featuring new generation techniques. Neurosurg Q 1997;7:135–156. 137. Blume HG: Unilateral posterior lumbar interbody fusion: Simplified dowel technique. Clin Orthop 1985;193:75–84. 138. Collins JS: Total disc replacement: A modified lumbar interbody fusion. Report of 750 cases. Clin Orthop 1985;193:64–67. 139. Lin PM: Posterior lumbar interbody fusion technique: Complications and pitfalls. Clin Orthop 1985;193:2–4. 140. Rish BL: A critique of posterior lumbar interbody fusion: 12 years’ experience with 250 patients. Surg Neurol 1989;31:281–289.

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141. Branch CL, Branch CL Jr: Posterior lumbar interbody fusion with the keystone graft: Technique and results. Surg Neurol 1987;27:449–454. 142. Schechter NA, France MP, Lee CK: Painful internal disc derangements of the lumbosacral spine: Discographic diagnosis and treatment by posterior lumbar interbody fusion. Orthopedics 1991;14:447–451. 143. Brunet JA, Wiley JJ: Acquired spondylolysis after spinal fusion. J Bone Joint Surg 1984;66:720–724. 144. Gill K: Technique and complications of anterior lumbar interbody fusion.In Lin P, Gill K (eds.): Lumbar Interbody Fusion. Rockville, Md, Aspen Publishers, 1989, pp 95–106. 145. Goldner JL, Urbaniak JR, McCollum DE: Anterior disc excision and interbody spinal fusion for chronic low back pain. Orthop Clin North Am 1971;2:543–568. 146. Johnson RM, McGuire EJ: Urogenital complications of anterior approaches to the lumbar spine. Clin Orthop 1981;154:114–118. 147. Sacks S: Anterior interbody fusion of the lumbar spine. J Bone Joint Surg Br 1965;47B:211–223. 148. Rokito SE, Schwartz MC, Neuwirth MG: Deep vein thrombosis after major reconstructive spinal surgery. Spine 1996;21:853–859. 149. Ferree BA: Deep venous thrombosis following lumbar laminectomy. Orthopedics 1994;17:35–38. 150. Soden RJ, Walsh J, Middleton JW, et al: Causes of death after spinal cord injury. Spinal Cord 2000;38:604–610. 151. Reines HD, Harris RC: Pulmonary complications of acute spinal cord injuries. Neurosurg 1987;21:193–196. 152. Feldman RA, Karl RC: Diagnosis and treatment of Ogilvie’s syndrome after lumbar spinal surgery. Report of three cases. J Neurosurg 1992; 76:1012–1016. 153. Vanek VW, Al-Salti M: Acute pseudo-obstruction of the colon (Olgivie’s syndrome). An analysis of 400 cases. Dis Colon Rectum 1986;29:203–210.

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Chapter 10 Stereotactic and Functional Neurosurgery William A. Friedman, MD

Introduction The present state of stereotactic surgery is the consequence of more than 100 years of evolution in experimental neurology, neuroimaging modalities, engineering and, most recently, computer technology.1 The need for a method of exact intracranial localization and reproducible targeting was recognized long ago but, aside from the creation of several craniometric systems that intended to relate different brain structures to visible or palpable cranial reference points, little progress was made until early in this century. While doing basic research on anatomic networks, Sir Victor Horsley became disappointed with his ability to hit the deep cerebellar nuclei using a free-hand directed electrode. More often than not, his lesions fell far from the desired target. He recruited Robert H. Clarke, a young engineer with little previous background in experimental neurology, to help him find “a means of producing lesions of the cerebellar nuclei which should be accurate in position, limited . . . in extent, and involving as little injury as possible to other structures.”2 Clarke’s solution to the problem was simple, original, and enduring. He transformed the brain into a regular geometric body, dividing it with three imaginary intersecting spatial planes, orthogonal to each other: horizontal, frontal, and sagittal (Fig. 10-1). In this manner, each hemisphere was split into four segments, each having three deep planar walls and one curved wall corresponding to the brain surface. Any point within the brain could be specified by measuring its distance along the three intersecting planes (Fig. 10-2).

This concept, the brain as a geometric volume, is central to stereotaxis. The two other basic elements of stereotactic surgery involve the definition of suitable reference points in this geometric volume, and the construction of appropriate surgical instruments for operating on the targets thus identified. In this chapter, we will show how these three basic principles: geometry, reference points, and surgical instruments, have evolved, with the aforementioned developments in experimental neurology, imaging modalities, and computer technology, to produce the field of modern stereotactic and functional neurosurgery.

The Three Basic Elements of Stereotaxis The Brain in a Geometric (Cartesian) Coordinate System The place an object occupies in space is determined by its relative position with respect to a given point, which is arbitrarily defined as the reference. The addition of three orthogonal planes intersecting at the given reference point (defined as zero), establishes a system of axes. The location of any other point within the system requires the measurement of its distance from zero in the three planes of space, that is, x centimeters anterior, y centimeters to the left, z centimeters up. This concept, introduced by the French mathematician Rene Descartes in the 17th century, is intrinsic to modern geometry. However, its full application to intracranial 269

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Figure 10-1. Clarke’s solution: Divide the brain along three orthogonal planes to generate a Cartesian coordinate system.

Figure 10-2. The stereotactic map is made by cutting brain slices parallel to the three planes of the selected Cartesian reference system. The slices are stained to enhance either gray nuclei or white fibers. They are photographed along with millimetric scales zeroed at the intersection of the reference planes.

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localization had to await the seminal intervention of Robert Clarke. He based the new concept of stereotactic localization on the application of a Cartesian system of axes to the brain. This system requires the selection of suitable reference points within the skull or brain. The Reference Points There are two ways of defining the position of a given target in relation to the selected Cartesian reference system; the obvious one is to directly measure its distance from the zero point of the axes. This ideal method is feasible today with the interfacing of stereotactic frames and computed tomography (CT) or magnetic resonance imaging (MRI), as long as the target is visible (e.g., a tumor). For targets invisible even to these modern imaging modalities (e.g., the ventrolateral nucleus of the thalamus), an indirect localization method—the stereotactic map—has to be adopted. For its construction, fixed brain specimens are cut in regular spaced slices, parallel to the reference planes (sagittal, axial, frontal). The slices are stained to enhance either nuclei or fiber pathways. Then, each slice is photographed along with a millimetric ruler, and its relevant structures are identified and labeled. Each slice is numbered according to its distance from the corresponding zero reference plane. The reference planes must relate the invisible targets to structures that are visible on the imaging modality used (see the following discussion). All measurements are standardized from a large number of specimens, and the coordinates are depicted on a specimen representing a statistical average for normal subjects. It follows that map coordinates are only a good approximation to target localization in practice because the patient may not correspond to the standard. With these limitations in mind, map stereotactic coordinates are used to hit a target in clinical practice, once the reference points used in the map have been identified in the patient. Stereotaxis was born as a technical aid in experimental neurology. Clarke selected external skeletal points to define the planes of section in laboratory animals: a line through the auditory canals and the inferior margin of the orbits constituted the basal plane (actually, a parallel plane 1 cm above the former was used, bringing the basal plane closer to the center of the brain). A section passing through both external auditory meati and orthogonal to the basal plane (the interaural line), was selected as the frontal plane. The midline of the skull represented the sagittal plane. Skeletal points were the only reasonable reference available at that time and they were practical for use in the laboratory. Because the skull shape is remarkably constant in many animals, their external skull points were also reliable. Multiple animal stereotactic atlases developed since then, applying the previously mentioned reference points (starting with Horsley and Clarke’s study on the Macacus Rhesus brain), have proven their reproducibility.

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Spiegel and Wycis introduced stereotaxis to clinical practice in 1947. They recognized that, given the wide variability in skull shape characteristic of the human being, external skeletal points would be useless as a reference frame for intracerebral targets. Consequently, they determined the need for intrinsic brain reference points. As the likelihood of statistical error increases with the distance between any two points (already noted by Horsley and Clarke), Spiegel and Wycis looked for intracerebral landmarks as close as possible to their potential targets. The first stereotactic applications were envisioned for the interruption of neural pathways in the thalamus to “reduce emotional reactivity,” mesencephalotomy for “interruption of the spinothalamic tract in certain types of pain” and “. . . production of pallidal lesions for involuntary movements.” Thus, most of the potential targets were anatomic structures surrounding the third ventricle. Consequently, the reference points selected by Spiegel and Wycis were periventricular structures (the pineal body when calcified, or the posterior commissure [PC]) consistently depicted by ventriculography or pneumoencephalography, the fundamental neuroimaging modalities at the time. Reids’ base line (a skeletal landmark), was relied on to define the angulation of the basal plane. The first human stereotactic map was published by Spiegel and Wycis in 1952,3–5 using the PC as the only intracerebral reference point. This system of axes had certain imperfections that prompted its abandonment a few years later. The calcified pineal body was acknowledged by Spiegel and Wycis as unreliable, because its inconstant calcification may lie at any point within its mass of 12 ¥ 8 ¥ 4 mm. The angulation of Reids’ line (or any other line based on cranial landmarks) has an unpredictable variability that also made it unsuitable to define the angulation of the cerebral basal plane. Talairach recognized the need for a completely intracerebral reference framework and introduced the anterior commissure/posterior commissure (AC/PC) system in his stereotactic atlas of the human brain.6 The line joining both commissures represented the basal plane, and two orthogonal lines at each commissure became the reference frontal planes. The sagittal plane corresponded with the midline. Two years later, Schaltenbrand and Bailey7 published their atlas based on a simplified AC/PC line reference system: the frontal plane was defined by a single line orthogonal to the basal plane, erected at the midpoint of the AC/PC (Fig. 10-3). Although other atlases were published later, with improvements in anatomical definition of certain structures, this reference system has endured until the present day. The Stereotactic Frame Although some exceptions exist, most stereotactic systems consist of two elements: the coordinate frame and the aiming

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Figure 10-3. Because external skull landmarks are unreliable for determining intracerebral stereotactic coordinates in the human, a mapping system related to purely intracranial coordinates was devised. Modern systems rely on the mapped position of functional target relative to the anterior commissure and posterior commissure. These commissures were originally identified on ventriculography, then CT scans and, now, on MR images. The basal plane is defined by the AC-PC line. The coronal planes are perpendicular slices anterior and posterior to the midpoint of that line.

device. The frame is a rigid, metallic platform, which can be secured to the skull in such a way that no displacement is possible. This rigid attachment is in general achieved with three or four screws that tightly abut the outer table of the skull. The frame now becomes a foundation upon which a localizing system can be elaborated, or the aiming device can be attached. The latter is a rigid system of precision moving parts, bearing a probe holder. This can be moved in either

multiple angular or linear directions, so that it can be set to direct a probe to any target within the skull. Diverse geometric systems could potentially be used for construction of stereotactic guidance instruments. Due to practical constraints, however, only three of them have been actually selected for most of the frames currently available. These systems are polar coordinate, arc-radius, and focal point.8 The most popular stereotactic frames in use today are the Leksell frame9 and the Cosman-Roberts-Wells (CRW) frame, both of the arc-radius type. With this kind of system, once the target coordinates are set, the probe holder and arc can be moved to any entry point (Fig. 10-4).

Modern Stereotaxis

Figure 10-4. In arc-radius frames (the Leksell frame is shown here), the aiming arc can be moved along the three spatial planes (AP, lateral, and vertical), according to the obtained target coordinates. After this is completed, the focal point of the arc corresponds with the target. A probe equal in length to the arc’s radius will then hit the target regardless of its position along the arc, or the elevation of the arc from the horizontal plane, allowing the selection of virtually infinite trajectories for any target.

Before the revolution in neuroimaging brought about by the introduction of CT scanning in 1973 and MRI in the 1980s, stereotactic localization required conventional radiographs of the skull, supplemented with gas or dye ventriculography. Aside from being time-consuming and painful, exact orthogonal radiologic pairs and precise frame application were critical to avoid parallax and simplify the already cumbersome calculations needed to eliminate radiologic magnification. When CT became available, displaying normal and abnormal cerebral anatomy in undistorted, scaled axial slices, the scenario was set for a revolution in stereotactic localization. The Vertical Coordinate Problem Once stereotactic frames were constructed with low-artifact materials, it became possible to obtain undistorted CT scans with the frame secured to the patient’s head. For

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the first time, the brain and the geometric system of reference could be seen together, in linear scale, without parallax or differential magnification. All that was needed was to mark the center of the frame on a CT slice and, considering it the zero point, anteroposterior (AP) and lateral coordinates for any visible intracranial target became directly obtainable. Determination of the vertical coordinate for the target was still a problem. Several years would elapse and many short lived methods would be proposed before effective solutions were worked out. In 1979, a medical student at the University of Utah applied a simple geometric principle and computerized trigonometric algorithms to derive a solution to the problem.10 His Lucite prototype became, with modifications, the first stereotactic system entirely designed to interface with CT: the Brown-Roberts-Wells frame. Three Nshaped arrays of carbon fiber rods are attached to the stereotactic base ring for CT localization. Each N produces three fiducial artifacts (for a total of nine) in any CT slice. The distance of the diagonal rod from the vertical rods allows calculation of the slice height (Fig. 10-5). Determination of the height at three points defines the spatial orientation of a plane through the frame and the patient’s skull, obviating a fixed relation between the frame and the CT gantry. This last feature is especially helpful in functional procedures: the CT gantry may be tilted as needed to include the anterior and posterior commissures in the same CT slice, substantially simplifying the data acquisition process. Magnetic Resonance Imaging Localization The introduction of MRI in the 1980s prompted the adoption of nonferromagnetic alloys for construction of stereotactic frames. The ability of MRI to directly image in the sagittal and coronal planes demanded the addition of localizing rods in proper planes, to specially designed localizer frames. Although MRI provides superior imaging quality for most brain lesions, especially in the posterior fossa, spatial distortion can be a problem. Nonlinear distortion of scanned structures increases in the vicinity of the magnet. As a consequence, central intracranial structures are less likely to be distorted but the stereotactic localizer itself, near the periphery of the lesion, is more likely to be distorted. Most importantly, MRI allows easy identification of the AC/PC plane, rendering it very useful as a functional surgical imaging modality. Currently two approaches are taken in the use of MRI in stereotactic surgery. First are systems that use MRIcompatible, nonferromagnetic frames. These systems allow the direct acquisition of MR images for use in stereotaxis but do not necessarily detect or correct for image distortion. Second are systems that acquire the MR images in a nonstereotactic format, some time before the actual procedure. On the day of surgery, a stereotactic CT scan is obtained and software is used to fuse the previously acquired MR images

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to the CT scans. This approach has the advantage of reducing imaging time on the day of the procedure and detecting spatial distortion when MR images are warped compared to CT scans. This approach has the disadvantage of introducing another source of error: the fusion process itself (Fig. 10-6). Visible and Invisible Targets A visible target is any structure (normal or abnormal) falling within the resolution of a given imaging technique. As such, its coordinates may be obtained directly, without referring to a stereotactic map. High-field MRI is pushing the boundaries of visibility; more stable magnetic fields, changes in coil design, and different signal recovery techniques are constantly improving the spatial and tissue resolution of this modality so that, more than ever, the concept of visible target is a dynamic one. As previously noted, coordinates for visible targets are obtained directly from the scan, and referred exclusively to the Cartesian system represented by the stereotactic frame. For the invisible targets, such as specific thalamic nuclei, reliance on a stereotactic map is still necessary. A stereotactic procedure requiring the use of a map involves the use of two unrelated Cartesian systems: the stereotactic anatomic atlas and the stereotactic frame system. The two systems are tied together through the identification of common reference points such as the AC-PC line. When map coordinates for an invisible target are marked on the stereotactic scan, the target becomes visible (Figs. 10-7, 10-8). Its coordinates can then be identified as stereotactic frame coordinates. The identification of an invisible target, using a stereotactic map, is only an approximation for any individual patient, given normal variability in anatomy.11 However, it enables the design of an operative plan, the selection of an entry point, and a probe trajectory. Once the probe has been advanced to the tentative target as obtained by map coordinates, physiologic confirmation of its positioning is mandatory. This may be carried out by two methods, both of which are performed under local anesthesia: recording of spontaneous or evoked electrical activity; and/or electrical stimulation with either microelectrodes or macroelectrodes. The final position of the probe depends on the results of this physiologic testing.12 From Point to Volume The amazing progress of computer technology has turned three-dimensional reconstruction of CT scans and MR images into a real-time process. Constant reduction in hardware costs is making this technology cost-efficient for wider use as an aid in stereotactic surgery. Images generated by CT, MRI, angiography, and MR angiography, may be superimposed and reconstructed in different planes in stereotactic space, presenting the lesion geometry (and the surrounding anatomy) as it will be seen from the surgical trajectory.13

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Figure 10-5. A, The BRW CT localizer has three N-shaped carbon fiber rods. In each N, the distance between the vertical rods is fixed and known. The distance of the diagonal rod from the posterior rod varies with the height of the CT slice. Its measurement allows the determination of the height above the base ring at which the rods have been imaged. B, The nine fiducial rods are visible on each CT slice as nine points. This computer screen shot is from a program called “CT process,” which automatically identifies the nine points and computes the vertical coordinate relative to the stereotactic head ring. In this manner the entire CT database, which may contain over 100 slices, can be quickly converted to a coherent stereotactic database wherein each CT pixel has an assigned anteroposterior, lateral, and vertical coordinate.

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Figure 10-6. Using image fusion software, a nonstereotactic MR image is fused to a stereotactic CT scan. This computer screen is used to evaluate the alignment of the MR images and CT scans. The cursor slides across each screen, to dynamically change from CT (left) to MRI (right). The alignment of the ventricular surfaces, tumor edges, sulci, and vessels can be quickly determined.

Controlled changes in depth of the surgical field may be instantly correlated with concomitant modifications of the computer display. Current image-guided stereotactic programs are capable of directly porting stereotactic images to computer workstations in the operating room. Standard orthogonal, oblique, and probe’s-eye views are readily available. Any point on the scan is instantaneously converted to stereotactic coordinates. A trajectory for a biopsy or lesioning probe can be adjusted to produce the safest pathway to the target. Frameless Stereotaxis Although frame-based stereotaxis remains the most accurate and most popular method for performing stereotactic biopsy and most functional stereotactic procedures, frameless stereotaxis has become increasingly popular as a com-

puterized guidance method to facilitate craniotomy. Many commercial systems are now available. The basic method is as follows: First, markers are attached to the patient’s scalp (usually with glue). Then CT or MRI is performed. In surgery, the positions of the markers are registered by using a stereotactic device such as a mechanical wand or infrared probe. All of the acquired CT scans or MRI images are displayed on a computer in the operating room. After the registration process is complete, the wand or probe can then be used to display its position, in real time, on the imaging database. Thus, a linear skin incision can be made directly over a tumor, or a deep lesion can be found through a minimally invasive brain pathway. As computer technology and registration methods become faster and more transparent to the user, a greater percentage of neurosurgical procedures will undoubtedly be performed with this type of guidance.

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Figure 10-7. This is the Shaltenbrand atlas axial plate, 2 mm above the AC-PC plane. The midline is on the right edge of the image. The grid displays 10-mm boxes running from PC (bottom) to AC (top). Vim is the desired target for thalamotomy and for thalamic stimulation. Its Cartesian coordinates relative to AC and PC are read from this map and then superimposed onto the stereotactic MR image for surgical targeting.

Common Stereotactic Procedures Stereotactic Biopsy A typical stereotactic biopsy procedure is as follows: The patient presents in the morning to preoperative holding. After the injection of local anesthetic, a stereotactic head ring is applied (Fig. 10-9). The patient is then transported to the CT scanner. There, a series of 1-mm-thick CT scan slices are taken from the top to the bottom of the head. These images are transferred, via Internet, to the stereotactic computer system, where each slice is quickly converted to a set of pixels, each of which has a defined AP, lateral, and vertical coordinate relative to the fixed head ring. A nonstereotactic MR image, obtained the day before the procedure, is then fused, with special software, to the stereotactic CT scan. Alternatively, many systems allow for the direct acquisition of stereotactic MR images while in an MRI-compatible head frame. The patient is then transported to the operating room. In the operating room, the stereotactic MRI is viewed on com-

puter. The desired target points and a precise trajectory, designed to avoid blood vessels and other danger spots, are computed. The target point is set up on a device called a “phantom.” The stereotactic frame is set to the desired coordinates and connected to the phantom to verify that no errors of setup have occurred. The skin is shaved and prepped over the small scalp area where the entry point is anticipated. The stereotactic frame is attached to the head ring. At the point where the biopsy probe touches the scalp, local anesthetic is injected and an incision made. A single burr hole is then placed (some prefer a smaller twist drill hole.). The dura is coagulated and opened. A biopsy needle is advanced through the burr hole to the target point and several biopsies taken (Fig. 10-10). A neuropathologist examines the tissue14; once a pathologic diagnosis is confirmed, the needle is withdrawn and the scalp wound closed in layers. The stereotactic frame is removed and the patient returned to the recovery room and, later, the hospital patient ward. The following morning the patient is discharged.

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A

Figure 10-8. A, Axial T1-weighted MR image shows anterior commissure (cursor). This structure is seen clearly as a white matter pathway crossing from one hemisphere to the other. It is found several slices below the foramen of Monroe. B, Axial T1-weighted MR image shows posterior commissure (behind cursor). This white matter structure is less obvious and is found below the pineal gland. C, The computer has taken the indicated positions of the anterior and posterior commissures and has determined the Shaltenbrand atlas location of the posteromedial globus pallidus (cursor). The target position actually appears to be within the internal capsule, probably because the width of the third ventricle is relatively small. This reflects the anatomic variation commonly seen and the reason why final adjustment of the lesion position is done with reference to the actual MR image and with reference to intraoperative physiologic confirmation of correct target location.

Complications The most feared complication of stereotactic biopsy is hemorrhage. Fortunately symptomatic hemorrhage occurs in less than 2% of cases.15–17 Hemorrhage will usually be manifest in surgery, with blood out the biopsy needle and, sometimes, with the onset of new neurologic deficit. Usually such bleeding will stop spontaneously, with no deficit. If a deficit develops, however, rapid conversion of the procedure to a general anesthetic and open craniotomy may be necessary. Other re-

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ported complications are seizure (rare), focal deficit without hemorrhage, infection, and lack of diagnostic tissue. Functional Stereotactic Lesions A variety of brain lesioning procedures have been used to control pain, psychiatric diseases, and movement disorders. By far the most commonly performed modern lesioning procedures are stereotactic thalamotomy and stereotactic

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Figure 10-9. The stereotactic head ring is applied. After the injection of local anesthetic, metal-tipped pins are screwed into place. They rest tightly against the outer table of the skull, producing a rigid platform on which subsequent imaging and treatment can be performed.

pallidotomy. Thalamotomy is used primarily for the treatment of “intention” tremor disorders, which can be familial or secondary to trauma or multiple sclerosis. Intention tremors are usually mild or absent at rest, but become much more severe when the patient attempts to use that extremity. Severe intention tremor can interfere with eating and grooming, as well as all other fine motor activities. When

Figure 10-10. After computer planning, a stereotactic frame is attached to the head ring. This figure shows the BrownRoberts-Wells frame. In the BRW system, four angular coordinates and a depth are computed and the frame assembled. At the point where the drill touches the scalp, local anesthetic is injected. A twist drill hole or burr hole is placed. The biopsy needle is then inserted to the target point and a specimen of the lesion obtained. After frozen section confirmation of pathology, the small skin wound is sutured and the frame removed.

unresponsive to medication (primidone is best), the patient may be a candidate for thalamotomy. The thalamotomy procedure starts in an identical way to stereotactic biopsy, with ring application and data acquisition. The thalamic target is a so-called invisible target on MRI, so its location must be inferred from the position of the anterior commissure and posterior commissure, using a stereotactic atlas. Once identified on the computer, a probe is inserted to the target point. Under local anesthesia, the patient’s response to electrical stimulation is monitored. A good response is disappearance of tremor, with minimal sensory or motor effect. A radiofrequency heat lesion is then made to make the effect permanent. Some surgeons also perform microelectrode recording of the potential target to further refine its selection. Thalamotomy is a tried-and-true procedure. It carries a small risk of hemorrhage, paralysis, language problems, and memory disturbance. Bilateral thalamotomy is generally regarded as unsafe because of the risk of pseudobulbar side effects (drooling, difficulty speaking and swallowing, etc.). Pallidotomy is used to treat Parkinson’s disease. Parkinson’s disease is a degenerative disorder of the brain, which causes loss of dopamine-secreting neurons in the substantia nigra. This leads to resting tremor (not intention tremor), bradykinesia, and rigidity. Parkinson’s disease is usually effectively treated with medication. After 5 to 10 years of medical treatment, severe adverse effects to medications occur, the most common of which is the on-off effect. When “on,” patients have severe dyskinetic movements; when “off,” they are frozen. Such patients are regarded as candidates for surgical intervention, including pallidotomy. The pallidotomy procedure is very similar to thalamotomy except the target is the posteromedial globus pallidus (Fig. 10-11). The procedure has a remarkable effect on dyskinesias, with additional reduction of tremor, rigidity, and akinesia. Adverse effects can include hemorrhage, paralysis, partial visual loss, and so forth.18–20 Bilateral pallidotomies have been performed in large numbers of patients but are also thought to carry a risk of pseudobulbar complications. A recent review article looked at 1959 patients undergoing pallidotomy for Parkinson’s disease at 40 centers worldwide.21 There was a consensus on the benefits of pallidotomy for off period motor function and on period, drug-induced, dyskinesias. The overall mortality rate was 0.4% and persistent neurologic morbidity was estimated at 14%. Major adverse events, including intracerebral hemorrhage, hemiparesis, and visual field cut, occurred in 5% of cases. Limited data are available on the long-term outcome of this procedure. Deep Brain Stimulation The observation that electrical stimulation during pallidotomy leads to transient relief of tremor has given rise to the use of implanted stimulators for functional disorders, as opposed to heat lesions. An implantable stimulator can, at

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Figure 10-11. Motor cortex activates the putamen, which then interacts with the globus pallidus via indirect and direct pathways. The globus pallidus output inhibits the thalamus, which then exerts inhibitory control on motor cortex. The object of pallidotomy and deep brain stimulation of the globus pallidus and subthalamic nucleus is to ultimately reduce the inhibitory feedback to motor cortex.

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Figure 10-12. This lateral skull radiograph was taken postoperatively, after installation of a deep brain stimulator. The stimulating electrode is inserted stereotactically to the desired target point (such as the ventrolateral thalamus, for tremor). The final electrode position is adjusted to produce the desired clinical result (like tremor relief), then secured in place. The patient is then repositioned for insertion of the battery/ computer system in a subcutaneous pocket under the clavicle.

Radiosurgery least in theory, be turned off if the effect is undesirable, whereas a lesion’s effects are permanent. Deep brain stimulation (DBS) has primarily been used for chronic pain, with marginal success. Now DBS is increasingly used for movement disorders, especially in Europe. The deep brain stimulation equivalent of thalamotomy involves an identical targeting procedure. Instead of a lesioning probe, a stimulating electrode is introduced to the target point and tested under local anesthesia. The electrode is implanted under the skin and connected to a computer/ battery combination, which is installed under the clavicle (Fig. 10-12). The stimulator can be interrogated and adjusted through the skin with a special programmer. The patient can turn the stimulator on and off as desired. Unlike thalamotomy, bilateral stimulators appear both safe and effective, so severe bilateral tremor can be effectively treated. DBS has the same risks as lesioning procedures during the electrode insertion process, and also has the risk of equipment breakage or malfunction. Bilateral DBS of the globus pallidus and subthalamic nuclei has proven successful for Parkinson’s disease. If preliminary results are borne out by further studies, DBS may replace lesioning procedures in the treatment of Parkinson’s disease and other movement disorders.22

In 1951, Lars Leksell extended stereotactic techniques to the delivery of radiation to circumscribed targets in the brain.23 He described the concept of focusing multiple nonparallel beams of external radiation on a stereotactically defined intracranial target. The averaging of these crossfiring beams resulted in very high doses of radiation to the target volume, but much lower doses to nontarget tissues along the path of any given beam. Leksell coined the term “radiosurgery” to emphasize the precise destruction of a defined intracranial target—the focused radiation replacing the surgeon’s blade or probe by destroying a well-circumscribed volume of tissue while sparing surrounding structures. His research culminated in the development of the gamma knife, a system (described in the next section) that uses concentrically focused gamma rays from radioactive cobalt sources fixed in a hemispherical array (Fig. 10-13). All radiosurgery systems use this fundamental principle of intersecting beams to produce focal high-dose radiation and a steep dose gradient that spares nontarget structures. The development of radiosurgery presented the attractive prospect of administering a single, heavy dose of radiation to destroy any deep brain structure without the morbidity associated with open techniques. Radiosurgery was initially intended for use in functional neurosurgery for the section of deep fiber tracts or nuclei. This application has been

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Introduction be a limiting factor in certain cases. Recently developed techniques for the delivery of fractionated stereotactic radiation give up the convenience of single dose therapy, but combine the advantages of a well-circumscribed target volume with traditional exploitation of the differential radiation sensitivity between neoplastic lesions and healthy brain tissue. Three main systems have been developed for the stereotactic delivery of radiation to the brain. Their descriptions follow. The Gamma Knife System

Figure 10-13. The gamma knife is a hemispherical array containing 201 fixed cobalt sources. All sources are focused on one spot, producing a highly focused radiation treatment with very steep falloff.

limited by the inability to verify proper localization by stimulating or recording from a site before its destruction, as routinely practiced in open stereotactic lesioning methods. Over time, however, radiosurgery has proven effective for the treatment of selective vascular malformations, acoustic neuromas, meningiomas, pituitary adenomas, and other lesions not amenable to surgical resection. The noninvasive nature of radiosurgery is its obvious advantage. Disadvantages include the delay between treatment and therapeutic effect, and efficacy for only a limited size and spectrum of lesions. In comparison to conventional radiation therapy, radiosurgery does not rely on, or exploit, the higher radiation sensitivity of neoplastic lesions relative to normal brain (therapeutic ratio). Its selective destruction is dependent only on sharply focused high-dose radiation and a steep dose gradient away from the defined target. This allows treatment to be administered in a single dose and eliminates the inclusion of large amounts of healthy brain tissue in the field of radiation. A therapeutic ratio is not required, so traditionally radiation-resistant lesions can be treated. Because destructive doses are used, however, any normal structure included in the target volume is subject to damage. Advances in neuroimaging and the precise contouring of target volumes have minimized this problem, but in the case of pituitary tumors abutting the optic chiasm, this continues to

The gamma knife is the culmination of the design efforts of Leksell and associates. The modern gamma knife contains 201 cobalt-60 sources fixed in a hemispherical array. As the Co60 nuclei decay, they emit photons with an average energy of 1.25 MeV (gamma radiation). The radiation from each source is collimated initially so that all 201 beams are focused on a single point. Secondary collimation is achieved through the use of one of four collimator helmets (4, 8, 14, or 18 mm). The different sized collimator openings are used to vary the diameter of the dose distribution. The Leksell stereotactic frame is used to position the patient relative to the isocenter. The stereotactic head ring is fixed to the patient’s skull and attached to an adjustable assembly. The assembly is then set to the proper coordinates and the patient is slid into the gamma knife. The positioning assembly locks into a mechanical mount that accurately locates the frame relative to the dose isocenter. The dose delivered is determined by the duration of the irradiation (10 minutes per isocenter on average). Multiple isocenter treatments are performed by withdrawing the patient, repositioning the head ring assembly, choosing the appropriate collimator helmet, and administering the desired dose of radiation to that isocenter. Particle Accelerator Systems At a few institutions, mainly where high-energy physics research is conducted, charged particle irradiation is used as an alternative to standard photon radiation for radiosurgery.24 These systems use a synchrocyclotron to generate beams of energetic (100 to 200 MeV) nuclei of lowmolecular-weight atoms such as protons, or helium nuclei. Particle beam radiation has some advantages for application to radiosurgery, such as less beam scatter than x-rays or gamma rays, increased biologic effectiveness over photon radiation, and a favorable depth-dose distribution called the “Bragg peak.” Particle beams lose energy uniformly (“plateau”) until the particle nears the end of its range. At this point, the particle decelerates rapidly, depositing a well-defined maximum dose two to four times greater than the path dose. This region of increased dose at the end of the beam is the Bragg peak. The depth at which the Bragg peak occurs can be varied by interposing extracranial absorbers to change the entrance energy of the particle beam. Absorbers are also used to tailor the

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width of the Bragg peak to match the target width. Because there is little exit dose of radiation beyond the target and the entry path dose is low, exploitation of the Bragg peak allows for very steep dose gradients with relatively few convergent beams. The primary limitation of this system is that a synchrocyclotron is required as the radiation source. In the United States, these facilities are currently available at only two sites: Harvard and Loma Linda universities.

Linear Accelerator Systems Linear accelerators (LINACs) are devices that use microwave power to accelerate electrons to high energies. These electrons, traveling at nearly the speed of light, are focused onto a heavy metal target. When the electrons collide with the target, their kinetic energy is converted into heat and photon radiation called x-rays. The x-ray beam thus generated has an effective energy equal to approximately one third of the maximum energy of the LINAC, so a 6-MeV LINAC produces an x-ray beam with an average energy of approximately 2 MeV. This 2-MeV x-ray beam is comparable to the 1.25-MeV gamma ray beam generated by the decay of radioactive cobalt in the gamma knife. Both beams are photon radiation and they differ only in their sources. The LINAC was developed in the 1950s and over the ensuing decades LINACs have become the favored treatment device for conventional radiation therapy. In 1984, Betti and colleagues described a radiosurgery system using a LINAC as the radiation source.25 Colombo and associates described such a system in 1985, and LINACs have subsequently been modified in various ways to achieve the precision and accuracy required for radiosurgery applications.26 In 1986, a team composed of neurosurgeons, radiation physicists and computer programmers began development of the University of Florida radiation surgery system.27 All LINAC radiosurgery systems rely on the following basic paradigm (Fig. 10-14): A collimated x-ray beam is focused on a stereotactically identified intracranial target. The gantry of the LINAC rotates around the patient, producing an arc of radiation focused on the target. The patient couch is then rotated in the horizontal plane and another arc performed. In this manner, multiple noncoplanar arcs of radiation intersect at the target volume and produce a high target dose, with minimal radiation to surrounding brain. This dose concentration method is exactly analogous to the multiple intersecting beams of cobalt radiation in the gamma knife.

Radiosurgical Paradigm Although the details of radiosurgery treatment techniques differ somewhat from system to system, the basic paradigm is quite similar everywhere. Following is a detailed description of a typical radiosurgery treatment at the University of Florida.

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Almost all radiosurgery procedures in adults are performed on an outpatient basis. The patient reports to the neurosurgical clinic the day before treatment for a detailed history and physical examination, as well as an in-depth review of the treatment options. If radiosurgery is deemed appropriate, the patient is sent to the radiology department for volumetric MRI. The next morning, the patient arrives at 7:00 am. A stereotactic head ring is applied under local anesthesia. No skin shaving or preparation is required. Subsequently, stereotactic CT scanning is performed. One-millimeter slices are obtained throughout the entire head. The patient is then transported to an outpatient holding area for breakfast and relaxation until the treatment-planning process is complete. The stereotactic CT scan, as well as the nonstereotactic volumetric MR image are transferred via Internet to the treatment-planning computer. The CT scans are quickly processed so that each pixel has an anteroposterior, lateral, and vertical stereotactic coordinate, all related to the head ring previously applied to the patient’s head. Using image fusion software, the nonstereotactic MR image is fused, pixel for pixel, with the stereotactic CT scan. Dosimetry then begins and continues until the neurosurgeon, radiation therapist, and radiation physicist are satisfied that an optimal dose plan has been developed (Fig. 10-15). A variety of options are available for optimizing the dosimetry. The basic goal is to deliver a radiation field that is precisely conformal to the tumor shape, while delivering a minimal dose of radiation to all surrounding neural structures. The dosimetric options include arc-weighting, arc-tilting, and multiple isocenters. A detailed review of dosimetry is beyond the scope of this chapter. As soon as dosimetry is complete, the radiosurgery device is attached to the LINAC. The patient then is attached to the device and treated. Radiosurgery has high success rates in the treatment of arteriovenous malformations,28 meningiomas, acoustic schwannomas, and metastatic brain tumors.29

Stereotaxis: Past and Future Stereotaxis has come a long way since its origin as an elaborate, tedious method to locate a point within the brain. Present day technology enables real-time definition and visualization of the whole intracranial volume in stereotactic space. Still incorporating the three basic principles: geometry, reference points, and surgical instruments, stereotaxis today guides, with equal precision, a probe, the surgeon’s microscope, or a radiation beam, pushing the boundaries of what is considered surgically treatable intracranial disease. What was yesterday the realm of exclusive, high-tech, highbudget medical facilities, is now part of general neurosurgical practice.

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Figure 10-14. In LINAC-based radiosurgery, a beam of x-rays is focused on the target point as the LINAC rotates around the patient. The patient is moved to another table position and another arc of focused radiation is executed. This results in multiple, noncoplanar arcs of radiation that intersect only at the target point.

Figure 10-15. This computer screen shot shows the treatment isodose line, one half of the treatment dose, and one fourth of the treatment dose to a left cavernous sinus meningioma. Axial, sagittal, and coronal views are displayed.

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P earls 1. Stereotaxis was born as a technical aid in experimental neurology. 2. As previously noted, coordinates for visible targets are obtained directly from the scan, and referred exclusively to the Cartesian system represented by the stereotactic frame. 3. Once the probe has been advanced to the tentative target as obtained by map coordinates, physiologic confirmation of its positioning is mandatory. This may be accomplished by two methods, both of which are performed under local anesthesia: recording of spontaneous or evoked electrical activity; and/or electrical stimulation with either microelectrodes or macroelectrodes. The final position of the probe depends on the results of this physiologic testing.25

4. The most feared complication of stereotactic biopsy is hemorrhage. Fortunately symptomatic hemorrhage occurs in less than 2% of cases.15-17 5. Bilateral DBS of the globus pallidus and subthalamic nuclei has proven successful for Parkinson’s disease. If preliminary results are borne out by further studies, DBS may replace lesioning procedures in the treatment of Parkinson’s disease and other movement disorders.22 6. Radiosurgery has high success rates in the treatment of arteriovenous malformations,28 meningiomas, acoustic schwannomas, and metastatic brain tumors.29

References 16. 1. Spiegelmann R, Friedman WA: Principles of stereotaxis. In Crockard A, Hayward R, Hoff JT (eds): Neurosurgery: The Scientific Basis of Clinical Practice, 3rd ed. Oxford. Blackwell Scientific, 2000, pp 877–898. 2. Horsley V, Clarke RH: The structure and functions of the cerebellum examined by a new method. Brain 1908;31:45–124. 3. Spiegel EA, Wycis HT: Stereoencephalotomy. Thalamotomy and related procedures. JAMA 1952;148:446–451. 4. Spiegel EA, Wycis HT: Stereoencephalotomy. New York, Grune & Stratton, 1952. 5. Spiegel EA, Wycis HT, Marks M, Lee AJ: Stereotaxic apparatus for operations on the human brain. Science 1947;106:349–350. 6. Talairach J, David M, Tournoux P, Corredor H, Kasina T: Atlas D’anatomie Stereotaxique. Paris, Masson et Cie, 1957. 7. Schaltenbrand G, Bailey P: Introduction to stereotaxis with an atlas of the human brain. Stuttgart, George Thieme Verlag, 1959. 8. Friedman WA, Coffey RJ: Stereotaxic surgical instrumentation. In Heilbrun MP (ed): Concepts in Neurological Surgery, vol 2. Philadelphia, Williams and Wilkins, 1988, pp 55–72. 9. Leksell L: A stereotaxic apparatus for intracerebral surgery. Acta Chir Scandinava 1949;99:229–233. 10. Brown RA: A computerized tomography-computer graphics approach to stereotaxic localization. J Neurosurg 1979;50:715–720. 11. Spiegelmann R, Friedman WA: Rapid determination of thalamic CTstereotactic coordinates: A method. Acta Neurochir 1991;110:77–81. 12. Tasker RR, Organ LW, Hawrylyshyn PA: The Thalamus and Midbrain of Man: A Physiological Atlas Using Electrical Stimulation. Springfield, Ill, Charles Thomas, 1982. 13. Kelly PJ, Kall B, Goerss S: Transposition of volumetric information derived from computed tomography scanning into stereotactic space. Surg Neurol 1984;21:465–471. 14. Friedman WA, Sceats DJ, Nestok BR, Ballinger WE: A comparison of preoperative and pathologic diagnosis of intracranial lesions. A review of 100 consecutive stereotactic biopsies. Neurosurgery 1989;25:180– 184. 15. Apuzzo MLJ, Chandrasoma PT, Cohen D, Zee CS, Zelman V: Computed imaging stereotaxy: experience and perspective related to

17. 18.

19.

20.

21. 22.

23. 24.

25. 26. 27. 28.

29.

500 procedures applied to brain masses. Neurosurgery 1987;20:930– 937. Kaye AH, Laws ER: Brain Tumors: An Encyclopedic Approach. Edinburgh, Churchill Livingstone, 1995. Ostertag CB, Mennel HD, Kiessling M: Stereotactic biopsy of brain tumors. Surg Neurol 1980;14:275–283. Laitinen LV, Bergenheim AT, Hariz MI: Leksell’s posteroventral pallidotomy in the treatment of Parkinson’s disease. J Neurosurg 1992;76:53–61. Lang AE, Lozano AM, Montgomery E, Duff J, Tasker R, Hutchinson W: Posteroventral medial pallidotomy in advanced Parkinson’s disease. N Engl J Med 1997;337:1036–1042. Vitek JL, Baksy RAE, Hashimoto T, et al: Microelectrode—guided pallidotomy: Technical approach and its application in medically intractable Parkinson’s disease. J Neurosurg 1998;88:1027–1043. Alkhani A, Lozano AM: Pallidotomy for Parkinson disease: A review of contemporary literature. J Neurosurg 2001;94:43–49. Ghika J, Villemure JG, Fankhauser H, Favre J, Assal G, Ghika-Schmid F: Efficiency and safety of bilateral contemporaneous pallidal stimulation (deep brain stimulation) in levodopa-responsive patients with Parkinson’s disease with severe motor fluctuations: A 2-year follow-up review. J Neurosurg 1998;89:713–718. Leksell L: The stereotaxic method and radiosurgery of the brain. Acta Chir Scand 1951;102:316–319. Kjellberg RN, Koehler AM, Preston WM, Sweet WH: Intracranial lesions made by the Bragg peak of a proton beam. In Haley TJ, Snider RS (eds): Response of the Nervous System to Ionizing Radiation (Second International Symposium). Boston, Little, Brown, 1964, pp 36–53. Betti OO, Derechinsky VE: Hyperselective encephalic irradiation with linear accelerator. Acta Neurochir Suppl 1984;33:385–390. Colombo F, Benedetti A, Pozza F, et al: stereotactic irradiation by linear accelerator. Neurosurgery 1985;16:154–160. Friedman WA, Bova FJ: The University of Florida radiosurgery system. Surg Neurol 1989;32:334–342. Friedman WA, Bova FJ, Mendenhall WM: LINAC radiosurgery for arteriovenous malformations: Outcome versus size. J Neurosurg 1995;82:180–189. Friedman WA, Buatti JM, Bova FJ, Mendenhall WM: LINAC Radiosurgery—A Practical Guide. Berlin, Springer-Verlag, 1998.

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Chapter 11 Pediatric Neurosurgery David H. Shafron, MD

Introduction Pediatric neurosurgery involves the diagnosis and treatment of disorders of the developing and mature nervous system. With improvements in diagnostic and multimodality therapeutic techniques, patients treated in infancy and early childhood may have normal life expectancies, although they often require long-term, if not indefinite, follow-up care. As our understanding of the pathogenesis and treatment of nervous system disorders grows at an exceptional rate, so does our appreciation for the many unresolved controversies inherent in the field. For most of the disorders seen on a daily basis, the optimal method of management remains unresolved. Our success with, and enthusiasm for, a particular intervention often overshadow the lack of stringent scientific proof of its superiority over other techniques. The literature is rife with controversy, dogma, and bias. As more evidence-based data accumulate, the answers to our most basic questions may emerge, either validating or dispelling long-held beliefs. Many treatment strategies may not be amenable to prospective, randomized study, due to ethical issues or other constraints. For certain disease processes, intervention must be individualized, taking into account not only a sick child, but often a frightened and confused family. The goal of this chapter is to provide a broad overview of some of the more common disorders encountered by the pediatric neurosurgeon; special emphasis will be given to hydrocephalus, by far the most prevalent pediatric neurosurgical disorder. For the most part, the remainder of this chapter presents issues relevant to the treatment of adults with brain and spinal cord pathologies; although there may

be some overlap, an attempt is made to highlight, when appropriate, the differences in presentation and treatment for these disorders in children.

Neurologic Evaluation The cornerstone to a successful neurologic evaluation in a child is observation. Watching the spontaneous movements of an infant, the play habits of a toddler, and the gait of a child provides valuable information before any formal testing. The first step of any assessment begins with a detailed history, searching for the earliest onset of symptoms, and the progression of complaints. As the patient matures through and beyond infancy, developmental assessment plays a paramount role in the evaluation of neurologic well-being. The Denver Developmental Standard Test measures social, motor, and language development as a function of age1 and can indicate the presence of subtle or gross neurologic insults. There is tremendous variability in skill acquisition for an individual child; of greatest importance are the continued gain of sequential milestones, or the loss of a previously acquired skill. Likewise, changes in scholastic performance may be an early sign of neurologic dysfunction. As will be discussed, the hereditary nature of certain disorders mandates a detailed family history, including both immediate and extended family members. Finally, the patient’s social situation must be explored because issues of parental understanding, compliance, and (sadly) resources may play a role in determining an optimal management plan. 285

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A focused general physical examination must also be conducted to seek manifestations of nervous system disease. The evaluation of an infant or child must include the rate of head growth, presence and character of the fontanelle and cranial sutures, and a careful search for anomalies involving the appendicular and axial spine, such as syndactyly and scoliosis. The integument must be examined for the cutaneous stigmata of occult spinal dysraphism or the phakomatoses. The neurologic assessment of a preterm infant may be confounded by the need for mechanical ventilation and sedation, as well as their enormous sleep requirement. Primitive reflexes, including the grasp, suck, rooting, and Moro responses should be present in some form by 28 weeks’ gestation, and complete by full term.2 Healthy premature and term infants arouse with eye openings. After approximately 30 weeks’ gestation, infants will display pupillary constriction to light, and blink in response to a bright light. Extraocular movement in the neonate may be gauged by the vestibulo-ocular reflex, while older infants will track objects in space. Disorders of oculomotility, such as nystagmus, may be present in primary position but often are evident only with gaze, and may indicate chiasmal, diencephalic, brainstem, cerebellar, or craniovertebral junction pathology. Facial sensation can be evaluated with the corneal reflex, as well as the expected grimace or cry in response to a noxious stimulus. Facial movements are observed both while the infant is quiet, as well as during crying spells. Asymmetry can result from facial nerve injury, but may also be secondary to congenital hypoplasia of facial muscualture. Absence of the depressor anguli oris, causing a characteristic “asymmetric crying facies,” can be associated with major congenital anomalies.3 Hearing may be evaluated by observing an infant’s response to a loud stimulus, although more sophisticated electrophysiologic analyses can be performed if indicated. The gag response is present after 30 weeks’ gestation.2 Infancy precludes formal manual muscle testing, so the examiner must rely on observing the symmetry, velocity, and fluidity of spontaneous and induced movements to assess motor function. Hypotonia is an important sign of brain dysfunction, but is a nonspecific finding. The hypotonic infant displays little spontaneous movement, and occipital flattening (plagiocephaly) may develop early. The more common indicator of motor-tract dysfunction, spasticity, may not manifest until after the first year of life because of continued postnatal myelination. The dystonic posturing indicative of basal ganglia pathology may be seen early in life, although it often worsens later in childhood. Persistence of posturing or abnormal reflexes, such as the asymmetric tonic reflex, may indicate severe cortical or subcortical insult. Strength testing becomes more reliable as a child begins to follow commands. Changes in handedness, which normally develops after 2 years of age, can signify brain, spinal cord, or peripheral nerve pathology. Deep tendon reflexes can be

elicited at 33 weeks’ gestation and thereafter; the presence of an extensor4 response to plantar stimulation may be normal during the first 2 years of life.2,4 The sensory examination may be confined to the reaction to noxious stimuli in an infant or young toddler. Indirect cues to sensory disturbance must be sought, such as skin ulcerations or burns in asensate areas, or gait dysfunction secondary to proprioceptive problems. As the child matures and is able to provide verbal feedback, direct dermatomal and proprioceptive testing can be carried out. For the older child and adolescent with a nervous system complaint, an evaluation similar to that of an adult may be appropriate. These patients have a mature (or nearly so) nervous system, and a neurologic examination that takes into account mental status, and cranial nerve, motor, sensory, cerebellar, and reflex function is often sufficient. The examination must be tailored to a patient’s age and level of sophistication and development.

Hydrocephalus No treatment in the history of neurosurgery has had as important an impact in reducing morbidity and mortality than the use of cerebrospinal fluid (CSF) shunts. The treatment of hydrocephalus with CSF diversion was revolutionized in the 1950s, with the advent of the first valve-regulated shunting system by Nulsen and Spitz, at Case Western Reserve University in Cleveland, Ohio.5 Before this landmark development, there was no consistently safe or effective technique for the management of hydrocephalus. Despite nearly a half-century of innovation and modification, neurosurgery remains vexed by problems in attempting to redirect CSF flow, with the imperfections of modern shunting systems brought to light throughout the interim, most recently in a multicenter, randomized trial.6 The scope of hydrocephalus is enormous. The prevalence of CSF shunts in the United States was conservatively estimated to be greater than 127,000 based on data for 19887; this figure has no doubt increased substantially in the past 15 years. This study estimated nearly 70,000 admissions for hydrocephalus, and more than 36,000 shunting procedures annually, with approximately 40% of these for shunt revision. The evaluation and treatment of hydrocephalus dominates the pediatric neurosurgeon’s practice, but despite 50 years of progress, decisions regarding whom to shunt, when to shunt, and how to shunt are often cloudy. Hydrocephalus occurs whenever there is a disparity between CSF production and absorption; with the rare exception of CSF-producing tumors, hydrocephalus is due to an obstruction, either anatomic or functional, between the ventricular system and the arachnoid villi, the primary site of absorption. Hydrocephalus usually presents during the first decade, although it may arise later in life, when it occurs secondary to tumor or vascular disorders. Overwhelmingly,

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Table 11-1  Etiology of Pediatric Hydrocephalus

From Drake JM, Kestle JR, Milner R, et al: Randomized trial of cerebrospinal fluid shunt valve design in pediatric hydrocephalus. Neurosurg 1998;43: 294, 303.

hydrocephalus in association with myelomeningocele and hemorrhage of prematurity are the most common etiologies in pediatric neurosurgical practice (Table 11-1), although in many cases the etiology cannot be determined. Clinical and Radiographic Features The clinical features of hydrocephalus in children depend on the age of presentation, the rapidity with which the CSF obstruction occurs, and the underlying cause. The compliant skull of an infant often allows mechanical distension to occur before the onset of overt signs of increased intracranial pressure (ICP), whereas the older child typically becomes symptomatic as ventricular distension and increased ICP develop. It is not uncommon to encounter hydrocephalus on prenatal ultrasound examination; in this situation, head size and ventricular distension may be monitored on serial imaging studies before confinement. Decisions regarding timing and method of delivery are then made with regard to ventricular and head size, respectively (see following discussion). The child diagnosed prenatally may be born with a head circumference greater than the 95th percentile, a full or bulging fontanelle, and spilt sutures; in this situation, the diagnosis is straightforward. However, quite often ventricular enlargement noted on prenatal studies is not clinically evident at delivery, and treatment decisions depend on continued observation of the infant. Ventriculomegaly in the preterm infant secondary to periventricular-intraventricular hemorrhage (PIVH) is often an “incidental” finding on surveillance ultrasound evaluation, and may be asymptomatic. In this population, the impairment in CSF absorption may be mild at first, and can increase, stabilize, or normalize in the ensuing weeks. Daily occipital-frontal circumference is monitored, in conjunction with serial ultrasound studies. Signs of hydrocephalus in this group include accelerated head growth, progressive widening of sutures, and increased fullness of the fontanelle. Lethargy, apneic and bradycardic spells, and poor feeding may ensue, indicating a process of decompensation. These patients often present a considerable challenge in management decisions, as will be discussed.

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Infantile hydrocephalus from causes other than PIVH typically presents with accelerated head growth, full fontanelle, and sutural widening. Percussion of the head can result in a hollow timbre if the ventricles are sufficiently dilated, and transillumination examination may be revealing. As venous outflow is impeded by an elevated ICP, scalp veins become dilated and more prominent. Paresis of upward gaze, the presence of ocular “sun-setting,” feeding intolerance, vomiting, and lethargy may occur in advancing cases. As the process continues, other ocular disturbances such as sixth nerve paresis, nystagmus, and optic atrophy may ensue, although true papilledema in the presence of open sutures is uncommon. In less acute cases, however, these signs may be absent, because the accommodating nature of the infant skull can permit significant ventricular distension. Other than an enlarged head, the only clues may be the failure to develop age-expected milestones, or the loss of those previously attained. Extremity tone may be decreased, normal, or increased. In the older child, features of hydrocephalus again depend on the etiology and development over time. If due to a slowly progressive congenital cause, head size may be at the upper limits of normal or slightly enlarged. Young children will often not voice complaints, but may exhibit behavioral changes, such as increased napping, diminished play activity, or enuresis (after toilet-training). The older child may readily complain of headache, usually worse with recumbancy. Vomiting may accompany, and briefly relieve the headache, possibly due to the hyperventilation or positional changes accompanying bouts of emesis. Parents or teachers may note a change in school performance. In the absence of obvious associated signs, patients may be misdiagnosed as harboring migraine headache or gastrointestinal motility disorders. In late childhood and adolescence, central nervous system neoplasms are the primary cause of hydrocephalus, and symptoms of increased ICP are often the initial, or only, manifestations of tumor progression. Lethargy, papilledema, oculomotor dysfunction, and hyperreflexia may be noted before the development of focal deficits. The use of radiographic imaging complements the clinical evaluation in the diagnosis of hydrocephalus. In the neonatal period, ultrasonography is often the initial study obtained; magnetic resonance imaging (MRI) or computed tomography (CT) may provide the necessary detail to determine a specific etiology, and to facilitate decision-making. In the older child or adolescent, CT or MRI studies are obtained, often by primary care personnel. Management decisions for children with hydrocephalus may be straightforward when they present with obviously symptomatic disease, and studies reveal significant ventriculomegaly. Often, however, neurosurgical consultation is obtained when clinical manifestations are mild or absent, and radiographic imaging results equivocal. Decisions regarding treatment options may be made over days to months.

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The prenatal diagnosis of hydrocephalus presents important questions to parents, obstetricians, and neurosurgeons: “Can the child attain normal intelligence?” “Should pregnancy continue?” “When and how should the child be delivered?” The answers are often elusive. If massive and progressive ventriculomegaly is detected within the first trimester, intellect is usually significantly impaired.8 When ventricular size is normal or mildly enlarged on initial studies, and progresses during the latter stages of gestation, intervention may succeed in preserving intelligence. Progressive ventricular enlargement in utero is variable—absent in one study of 40 patients,9 present in 4% of 47 patients,10 and present in 45% of 20 patients11 in yet another series. A general guideline, although by no means absolute, suggests that a cortical mantle less than 1-cm thick is indicative of significant cognitive impairment, and delivery should be entertained after 32 to 34 weeks’ gestation as the mantle approaches this cut-off measurement, as detected on serial ultrasound studies. Amniocentesis can be performed at approximately 32 weeks, and delivery is carried out if the biophysical profile indicates lung maturity. In the absence of lung maturity, maternal steroid therapy is initiated, with subsequent delivery. Route of delivery depends on the fetal head size, and other associated anomalies; ventriculomegaly alone does not preclude vaginal delivery, although in most series cesarean sections predominate. The most common cause of ventriculomegaly diagnosed in utero is myelomeningocele.9,10,12 In a minority of cases, increased ventricular size is found as an isolated phenomenon, without an apparent underlying cause, and in these children the condition may stabilize or resolve.9,13 Among patients diagnosed with hydrocephalus in utero who survive, approximately 50% to 70% ultimately require CSF diversion.9,10 Associated brain or other systemic anomalies are common, and are associated with deficits in cognitive development.10,13–15 As an isolated finding, however, approximately 50% to 60% of patients with fetal ventriculomegaly can attain normal intelligence.13,15 Most patients diagnosed in utero with isolated ventriculomegaly that ultimately stabilized or resolved without requiring shunting demonstrated satisfactory cognitive outcome.9,13 Post-hemorrhagic Hydrocephalus As noted previously, hydrocephalus secondary to germinal matrix-intraventricular hemorrhage is among the most common indications for CSF diversion in most modern series. In the past several decades, the incidence of PIVH of prematurity has decreased,16 while the survival of very low birth-weight infants has improved dramatically as a result of advances in critical care medicine. The greater survival rates have resulted in a possible increase in the prevalence of post-hemorrhagic hydrocephalus (PHHC),17 estimated at approximately 1.7% overall for infants less than 32 weeks’ gestation.18 The true incidence of PIVH and resultant

Table 11-2  Grading Scale for PeriventricularIntraventricular Hemorrhage • Grade I • Grade II • Grade III • Grade IV

germinal matrix hemorrhage germinal matrix and intraventricular hemorrhage; ventricles normal in size germinal matrix and intraventricular hemorrhage; ventricles dilated germinal matrix and intraventricular hemorrhage, with parenchymal extension

Papile LA, Burstein J, Burstein R, et al: Incidence and evolution of subependymal and intraventricular hemorrhage: A study of infants with birth weights less than 1500 gm. J Pediatr 1978;92:529–534.

PHHC, however, is difficult to elucidate, as reports have varied in inclusion criteria (such as birth weight), and grade of bleeding severity. The most commonly accepted classification of PIVH is shown in Table 11-2.19 Grades I and II hemorrhage pose little risk of subsequent PHHC or neurologic injury, while grades III and IV bleeding harbor an increased risk of PHHC, as well as subsequent cognitive impairment.20–22 Risk of bleeding severity and PHHC is strongly correlated with lower birth weight and degree of prematurity20,23–26; grade II to IV PIVH is uncommon in infants older than 29 weeks’ gestation.27 Other risk factors for PIVH in the premature population, apparently independent of birth weight and age, include the need for intubation, transport to another facility,24 and respiratory distress syndrome.26 Fluctuations in blood pressure, low cerebral blood flow,28 and amniotic sac inflammatory changes29,30 have also been associated with development of PIVH. In a large-scale recent series, grade II to IV PIVH developed in 22% of infants less than 1000 g surviving more than 12 hours 26; another modern series demonstrated severe PIVH in 11.4% of infants less than 1000 g, and in 5% of those between 1000 and 1250 g.25 The etiology of PIVH is uncertain and probably multifactorial.31 Advances in perinatal care and neonatal cardiorespiratory support have undoubtedly contributed to the overall decline in the incidence in the past 20 years. Multiple class I (prospective, randomized) studies32 have shown that the use of indomethacin in low birth weight infants reduced the risk and severity of PIVH.33–36 Most infants with PIVH do not develop PHHC; of those that do, issues regarding the necessity, timing, and type of neurosurgical intervention are not well established, because most patients with post-hemorrhagic ventriculomegaly stabilize and do not require shunting.17,37–39 Even those who demonstrate progressive ventricular enlargement over the first month of life may not ultimately require treatment.40 The subset of infants with PIVH who do finally require CSF diversion manifests with progressive ventriculomegaly, enlarging head size, and perhaps signs of increased ICP. Given the possibility of stabilization and resolution of symptoms, however, the optimal time for surgical intervention is unknown. Rekate8 suggested a goal of achieving a cortical mantle size of 3.5 cm by

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age of 5 months to optimize intellectual outcome. The neurosurgeon is faced with a dilemma: balancing the possibility of injury to the developing brain from progressive ventricular expansion against the risks of surgery for a potentially reversible situation.In this regard,several forms of intervention are advocated to allow the decision regarding shunt placement to evolve over weeks or months. Removal of (bloody) CSF in an intermittent or continuous fashion is a logical “middleground”in this controversy, and studies have evaluated the efficacy of intermittent lumbar puncture,41,42 ventricular-access reservoirs or subgaleal shunts,39,43–48 and external ventricular drainage.49–51 These strategies may in theory protect the cortical mantle during periods of ventricular enlargement, and reduce signs of elevated ICP, but there is no clear evidence for their efficacy in reducing the likelihood of shunt placement, or future cognitive disability.41,52 Based on experimental models developed in canines by Pang and colleagues,53 the use of intraventricular fibrinolytic therapy as a means of preventing PHHC and shunt requirement has been explored in several studies. Despite the apparent benefit seen in several pilot studies and uncontrolled trials,54–57 others failed to show a benefit.58,59 There is currently no class 1 or 2 evidence supporting the use of fibrinolytic therapy for the treatment of PIVH,60,61 and larger, randomized, and well-controlled protocols are needed to establish its safety and efficacy. Similarly, the use of diuretic therapy to prevent PHHC in patients with PIVH62,63 was recently examined in a large, randomized, multicenter study. The use of diuretic agents plus standard therapy, such as CSF removal, was found not only to be less effective, but more harmful than standard therapy alone.64 At this time, CSF removal may be the only acceptable option for the symptomatic child too small to undergo shunt placement. Myelomeningocele and Hydrocephalus Myelomeningocele (MMC), the most common associated anomaly noted in patients with fetal ventriculomegaly, will be discussed in greater detail later in this chapter. Approximately 80% to 90% of children born with MMC have hydrocephalus, and most require shunt placement. The cause of hydrocephalus in these patients is unknown and is probably multifactorial. Hindbrain anomalies predispose to fourth ventricular outlet obstruction, and there may be obstruction of the aqueduct from cephalad herniation of the cerebellum. For unknown reasons, the level of the MMC is associated with the risk of hydrocephalus, being greatest for those with higher lesions, and lowest for sacral MMC.65 For infants with overt symptoms of increased ICP, clearly enlarged ventricles, or those with symptoms from hindbrain herniation, simultaneous repair and shunting can be performed safely,66,67 and may reduce wound complications or CSF leak. In patients without symptoms or radiographic evidence of hydrocephalus, an expectant approach can be used after primary repair, observing the patient with serial neurologic exami-

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nation, head circumference measurement, and ultrasound imaging. The need for shunt placement typically manifests within days to weeks of the repair; if there is no indication for shunting before hospital discharge, careful follow-up evaluation will determine those requiring diversion. The use of endoscopic third ventriculostomy (see following discussion) for the initial treatment of hydrocephalus in the MMC population is controversial. The enlarged massa intermedia, thickened ventricular floor, and other associated anomalies often preclude safe passage of the scope,68 and the low success rates in neonates69 do not warrant its use. Treatment and Complications Ventriculoperitoneal shunt placement is the standard treatment for patients with hydrocephalus. The principal shunt complications, malfunction and infection, have been the objects of considerable study, and attempts to examine the multiple factors predisposing to shunt complications have largely been single-institutional reviews.70 Variables such as type of shunt, site of entry, cause of hydrocephalus, age of patient, length of operation, antibiotic regimen, and others have all been scrutinized, often with variable conclusions. There is significant disparity in shunt insertion practices among different institutions,71 and no technique has proven superior to others. Although systematic retrospective reviews can provide valuable information, the most effective method to examine factors predisposing to shunt failure is with a prospective, randomized study. Proximal ventricular catheter obstruction is usually, although not always,72 the most common cause of shunt failure, and the theory of reducing this risk with the use of anti-siphoning technology spurred the development of several modern shunt systems. The recent Shunt Design Trial6 found no differences in complication or shunt survival rates among standard differential-pressure, anti-siphon, or flow-limiting valve systems in 344 children randomized at first shunt insertion. The overall rates of shunt obstruction (31.4%) and infection (8.1%) were not significantly different between the systems. Kaplan-Meyer analysis showed shunt survival rates of 61% and 47%, at 1 and 2 years, respectively. Extended follow-up evaluation from this study continued to show no difference between the systems, with a 41% shunt survival at 4 years,73 and revealed that the rate of decrease in ventricular size after shunt placement was no different among the different designs.74 Another multi-institutional, randomized, prospective series involving 377 patients found no overall difference in failure rates between nonprogrammable and programmable valves (although it did not attempt to identify subsets of patients who may benefit from the programmable feature).75 For each group, the 2-year actuarial survival was identical, 48%, mirroring the rates seen in the 1998 Shunt Design Trial. Obstruction was the leading cause of failure, and the infection rate was approximately 10%. A prospective, nonran-

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domized, single-institution series of 50 patients, comparing differential pressure and anti-siphon valves, showed no difference in shunt survival between the groups at 5 years (59%).76 Infections were seen in 11%, all in the siphoncontrol group. These recent prospective series highlight the continued high rates of shunt malfunction and infection in the modern era. The lack of apparent differences between the shunt systems underscores the need for continued innovations in shunt technology. In addition to choosing from among the scores of commercially available shunt systems, surgeons are faced with technical issues regarding shunt placement, often with little consensus. Previous series had shown efficacy for both the frontal77 and posterior78 approaches. A prospective, randomized study of 121 patients requiring a first shunt examined anterior versus posterior burr-hole placement. The posteriorly placed systems had longer survival, prompting the author79 to conclude that anteriorly placed shunts conferred no advantage. Follow-up analysis of the shunt-design trial revealed that catheter tips completely surrounded by CSF on follow-up imaging, in either the frontal or occipital horn, had the longest survival.80 These studies were not designed to identify reasons for shunt failure, so few conclusions regarding risk factors could be drawn from them. A single-institution retrospective analysis of 727 shunt procedures identified several variables associated with failure, including patient age less than 2 years, previous failure within 6 months, and placement for perinatal hemorrhage.81 Neither shunt system nor location had an effect on survival. Tuli and colleagues80 examined risk factors for recurrent shunt failure and also found that variables such as shunt location, type of shunt, and length of surgery, all factors within the surgeons’ control, were not significant. Patients younger than 1 year, and especially those who underwent a shunt procedure before 40 weeks’ gestation, had significantly higher failure rates than older children, and shunt revision in the previous 6 months was also found to confer a significant risk of future failure. Additionally, IVH, meningitis, and tumor-related hydrocephalus were associated with increased risk of failure in this series. The signs and symptoms of shunt malfunction are similar to those of hydrocephalus and increased ICP described previously, and are a reflection of the age, acuity of dysfunction, and degree of shunt dependency. Infants may display asymptomatic fluid accumulation in the subgaleal plane and along the tubing. Although uncommon, seizures may also occur de novo, or increase in frequency.6,72 Patients with Chiari II malformations can present with neck pain, lower cranial neuropathy, and symptoms related to syrinx.72 The diagnosis of shunt malfunction typically begins with concern on the part of a parent, with the ensuing workup involving clinical and radiographic examination. Overwhelmingly, diagnosis of shunt malfunction can be made on

clinical grounds, based on complaints and findings on examination. The time-honored technique of pumping a shunt to evaluate proximal or distal obstruction has no clear predictive value.81 Radiographic demonstration of ventricular enlargement is seen in the majority of documented malfunctions, but may be absent or equivocal in up to one third of cases82; normal or small ventricles cannot provide assurance in the face of clinical evidence to the contrary. Overall, the finding of discontinuity on shunt series radiographs is not common, but its use in planning a revision warrant its use as part of the evaluation. Tapping a shunt can provide supplemental information when clinical and radiographic evaluation is equivocal,83,84 and may be particularly valuable for the infant, in whom a viral syndrome can mimic symptoms often indistinguishable from those of shunt dysfunction or infection. Other ancillary tests, such as radionuclide studies, may be helpful in certain cases.85 After mechanical obstruction, shunt infection is the most common complication associated with CSF diversion. The causes of shunt infections are multifactorial, and the sources of contamination are often unknown.86 In addition to necessitating shunt replacement, which confers morbidity, central nervous system infections may have a profound effect on future cognitive development. Most shunt infections occur within several months of insertion, with Staphylococcus epidermidis and Staphylococcus aureus the most common organisms isolated.87 Fever, irritability, signs of shunt malfunction, and erythema around the incision site are the most common findings. Uncommonly, infection can present in a delayed fashion88; these cases are notable for the frequent association with abdominal pseudocyst, and the variety of organisms isolated, including enteric flora. The discovery of a remote infection should always prompt a workup for pseudocyst.88–90 The treatment of shunt infection usually mandates removal of all hardware, external ventricular drainage, intravenous (and rarely, intrathecal) antibiotics, and shunt replacement after approximately 1 week of sterile CSF culture results. Pseudocysts generally resolve upon removal of the peritoneal catheter, although aspiration may be required in select cases. The infection rates noted in the prospective randomized trials described previously, roughly 8% to 10%, are not unusual for large centers, although single institutional reviews have described significantly lower rates,91 even less than 1%.92 Retrospective analyses of risk factors for infection have yielded widely disparate findings. A prospective evaluation of risk factors for 299 patients undergoing shunt placement was recently reported.93 The rate of infection was 10.1%, with Staphylococcus species the most common isolated pathogens. Univariate analysis revealed that only postoperative CSF leak, contamination of implant by a breached glove, and patient age (less than 40 weeks’ gestation) were significant factors for infection. Other factors, such as cause

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of hydrocephalus, duration of surgery, or previous shunt operation, were not associated with increased risk. An earlier study from the same institution94 described a significant decrease in shunt infection (from 12.9% to 3.8%) after instituting a protocol for shunt surgery that included early start times, minimal operating room personnel, and perioperative antibiotics. Further analysis in this report showed that antibiotic use and shorter duration of surgery were associated with lower infection rates, findings not noted in the recent, prospective analysis.93 Antibiotic prophylaxis is used in most, if not all, centers regularly performing shunt surgery, although there is no agreement regarding the most efficacious agent, nor the timing of perioperative antibiotic administration. A metaanalysis of randomized, controlled trials95 did confer a benefit to the use antibiotic prophylaxis in decreasing infection rates, with the strongest effect noted when baseline (control) rates were high. Endoscopic procedures are gaining popularity for the management of hydrocephalus in select pediatric patients. In patients with multiloculated hydrocephalus, the use of endoscopic cyst fenestration can be an effective means for reducing the number of shunt revisions, and simplifying existing shunt systems.96 Endoscopic third ventriculostomy (E3V) can obviate shunt placement, most commonly in patients with noncommunicating hydrocephalus. The best candidates are patients with aqueductal stenosis, or mass lesions obstructing flow into or through the fourth ventricle (triventriculomegaly). As an initial procedure for the treatment of hydrocephalus secondary to aqueductal stenosis in children, Tuli et al.97 reported nearly identical failure rates between E3V and shunts (44% and 45%, respectively) using survival analyses. In general, success rates are 50% to 90% for children with triventricular hydrocephalus.98–102 The use of E3V for hydrocephalus secondary to myelomeningocele and hemorrhage is not as well established,68,69,98,101 with variable success rates reported. Its use in infancy is also unclear; efficacy is generally, although not universally,98 lower in this group, presumably due to immature subarachoid pathways and inefficient absorption at the arachnoid villi.69,101,103 In experienced hands, complications of E3V are not common, usually less than 10%; reported complications include perforation of the basilar artery or its branches, injury to hypothalamic structures, and infection.69,99,101,102,104 Uncommonly, the ostomy can become occluded months or years after the procedure, and patients may present with chronic or acute symptoms of increased ICP, similar to shunt failure. As with every technical development, there is a steep learning curve, not only for the technical aspects involved in neuroendoscopy, but perhaps more importantly, for proper patient selection.98,101 As more long-term results are reported, greater insight into the best indications for its use should be clarified.

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Myelomeningocele Epidemiology and Etiology Myelomeningocele is the most common congenital defect of the nervous system compatible with life. It occurs as a result of nonclosure of the posterior neuropore, at approximately 26 days’ gestation (failure of primary neurulation), although the mechanism of this failure is unknown. The incidence is changing, with a distinct decrease over the past 50 years or more.105 Currently, the incidence in the United States is one per 2000 live births,106,107 although it may be higher in some U.S. populations.108 Rates in the United Kingdom are also falling, but are still more than double the U.S. incidence.109 The reasons for the worldwide decline are multifactorial, but are primarily due to an increase in elective abortion rates,107,110 and the use of periconceptual folic acid. The link between folate metabolism and neural tube defects was suspected more than 30 years ago. Despite earlier studies that cast doubt on a protective effect of maternal folate intake,111 such an effect is now firmly established109,112–117; in 1996, the U.S. Food and Drug Administration mandated folate fortification of all enriched grain products. Folate supplementation may reduce the risk of concurrent and recurrent neural tube defects by up to 60% and 72%, respectively.115 The current recommendation for women of childbearing potential is 0.4 mg/day, and 4 mg/day for those with a previously affected offspring.109 Increased maternal homocysteine levels have been linked to the development of neural tube defects, and the protection afforded by folate is likely due to its effects in homocysteine metabolism. Mutations in the gene for methylene tetrahydrofolate reductase (MTHFR), a folate-dependent enzyme in the homosysteine remethylation cycle, are associated with increased risk of neural tube defects.109,118 Deficient MTHFR activity results in increased serum homocysteine levels, which can be corrected by exogenous folate supplementation. Folatedependent enzymes, including MTHFR, are involved in amino acid methylation, as well as nucleotide (DNA and RNA) synthesis; the association of these processes and neural tube formation during embryogenesis remains to be fully elucidated. In additional to folic acid deficiency, other environmental factors have been linked to neural tube defects, such as maternal use of carbemazapine and valproic acid,119 and pre-pregnancy maternal obesity.120 Diagnosis and Management The diagnosis of myelomeningocele is often made during prenatal ultrasound screening.14 Prenatal management of MMC is usually dictated by the degree of hydrocephalus noted on sonography. Although studies regarding vaginal versus cesarean delivery (as well as timing of delivery) have

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led to conflicting conclusions,121,122 most obstetricians favor the latter, soon after lung maturity has been ensured. There is continued debate regarding the potential for injury that labor and vaginal delivery may impart upon spinal cord function. Similarly, there is controversy as to the possible damaging effect of the intrauterine environment on the dysraphic and exposed spinal cord.123 MMC is immediately apparent at birth as an open spinal defect, usually at the lumbar or sacral level; thoracic lesions account for approximately 20% of lesions, and cervical MMC is rare. A fluid-filled, epithelialized sac is typically present, although it is often flattened or ruptured by intrauterine or perinatal trauma. The dorsal spinal elements are absent or atretic. When the roof of the sac is opened, the neural placode is seen, often herniated ventrally out of the confines of the spinal canal. The placode is composed of a dysraphic spinal cord, flayed open in the dorsal midline so that the normally dorsal aspect of the cord faces ventrally. The dura is also deficient over the lesion, similarly open in such a matter that its lateral margins end in a juctional zone at the margins of the defect. Immediately after birth, the defect should be covered in saline-moistened gauze, and prophylactic antibiotics initiated. Neurosurgical assessment includes evaluation of the head circumference, and character of the fontanelle and sutures; most infants will not exhibit gross manifestations of hydrocephalus at birth, particularly if there is CSF leakage from the sac. The location and size of the defect is noted. Spinal cord function is diminished, usually absent, below the level of the dysraphic cord. Motor and sensory levels are tested by observing both spontaneous movement, as well as response to noxious stimuli. The presence of joint deformity or contracture can assist in the assessment of motor level. The anus is typically patulous due to sacral involvement. Chiari II malformation (caudal herniation of vermis and brainstem) can lead to quadriparesis, often in association with lower cranial neuropathy, although these lesions are uncommonly symptomatic at birth. Repair of the MMC is usually carried out within 48 hours of birth, and shunting can be performed concurrent with closure if signs or symptoms of hydrocephalus, or ventricular enlargement, are present.124,125 The repair consists of a multilayer closure, beginning with the restoration of the placode to a cylindrical configuration by suturing together the pial margins. Dural edges are freed from the junctional zone, undermined, and approximated around the placode. Fascial flaps are then elevated and closed, followed by subcutaneous layer and skin closure. Some authors doubt that placode closure is beneficial, although it may reduce the risk of subsequent spinal cord tethering.126 Nearly all patients with MMC have anatomic evidence of Chiari II malformation, consisting of herniation of the cerebellar vermis (and often the tonsils), caudal brainstem, and fourth ventricle through an enlarged foramen magnum, often with kinking of the medulla. The calvaria, brains,

meninges, and spines of these patients display additional abnormalities, including a small posterior fossa, dysplasia of the falx and associated interdigitation of the septum pellucidum, hypoplasia of the tentorium (often in association with cephalad displacement of the cerebellum through a widened incisura), lacunar skull (lukenschadel), and enlarged massa intermedia; the ventricles may display a colpocephalic appearance, with disproportionately enlarged occipital horns. Cervical spinal fusion or segmentation anomalies may be present. The causes of the Chiari II and other MMCassociated abnormalities are unknown, but McLone and Knepper127 theorized that CSF leakage from the MMC leads to decompression of the developing ventricular system. This disturbance removes the distension forces that normally provide impetus for brain and calvarial development. Despite its nearly universal presence in MMC, Chiari II malformations become symptomatic in only a minority of patients, approximately 10% to 20%,128–130 resulting in potentially life-threatening lower cranial nerve dysfunction (stridor, nasopharyngeal regurgitation, aspiration, apnea), quadriparesis, and cerebellar signs. In selected patients, such symptoms and signs may in part be due to dysplasia or absence of brainstem nuclei,131 but because symptoms are not typically present at birth, in most cases they are thought to be due to acquired neural compression at the foramen magnum. Before ascribing such symptoms to the Chiari malformation, it is imperative to ensure a functional shunt, because even modest ventricular or brain distension may lead to identical symptoms. The majority of malformations become symptomatic in childhood,128,130 although they can manifest later.132 Abnormal CSF flow at the foramen magnum contributes to the formation of syringomyelia and syringobulbia (discussed later in this chapter). Once symptoms of hindbrain herniation develop (and shunt function is ensured), decompression should be carried out on an urgent basis, especially in infants. This involves bony removal of the rim of the foramen magnum, and cervical laminectomies along the entire descent of the herniated hindbrain. The dura is then opened, and dissection of cerebellar tissues is carried out to identify outflow from the fourth ventricle. Due to the low position of the transverse sinuses, as well as the presence of large venous lacunes, even the dural opening can be daunting. The abnormal anatomy of the herniated structures, as well as the presence of dense adhesions between cerebellum and brainstem, can complicate the procedure. If the decompression is performed in a timely fashion after the onset of symptoms, they can be reversed, although persistent brainstem dysfunction may occur, necessitating gastrostomy and tracheostomy.128,129 The outlook for patients with MMC has improved dramatically in the past several decades. Overall long-term survival data are limited,133 although at least 75% of patients survive to adulthood.134 As a group, children with MMC are below average, but within normal limits, on many facets of intelligence testing; however, cognitive problems (especially

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performance intelligence quotient, visual-spatial function, and mathematical ability)135–137 are not uncommon. Sixty percent to 80% of children can attend normal classes, at a grade appropriate for age.135,137 Children without shunts may have superior intellectual development compared to those with shunts,137–139 although others have noted no difference between the groups. Previous shunt infections have been reported to negatively impact intelligence,138 although others have not seen such an effect.135 Patients with MMC are usually followed in a multidisciplinary fashion, with neurosurgical, urologic, orthopedic, and rehabilitation specialists. During childhood, scarring and tethering of the placode can lead to progressive pain and functional deterioration. Increased weakness, gait changes, and scoliosis, alone or in combination, may be seen in approximately half of children with symptomatic tethering, and back or lower extremity pain occurs in approximately one third of patients.140 Progressive foot deformity and worsening bowel or bladder function may accompany these symptoms. MRI typically confirms tethering of the placode to the dorsal aspect of the thecal sac. If operative untethering is accomplished during the early onset of symptoms, improvement can be seen in most cases, especially with respect to pain. Scoliosis tends to stabilize if untethering is performed before the curvature has progressed past approximately 40 to 50 degrees.140,141 In patients with MMC and progressive scoliosis, a syrinx related to Chiari II must be ruled out as a cause; tethering can also lead to syrinx formation, although these are usually low-level cysts. Many children will require a subsequent untethering procedure due to recurrent symptoms.142 Between 1997 and 1999, two centers in the United States began reporting initial experience with in utero closure of MMC defects.143–147 The rationale for this bold undertaking was based on experimental evidence that amniotic fluid and other aspects of the intrauterine milleau exert a toxic effect on the already injured spinal cord.123,148,149 These early series suggest that in utero closure may decrease the extent of

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subsequent hindbrain herniation,146 as well as reduce the risk of shunt dependence150; the evidence for improvement in motor function has been extremely limited.146,150,151 The ultimate effect of this procedure on hydrocephalus, symptomatic Chiari II, and neurologic function will require careful analysis in the coming decade.

Occult Spinal Dysraphism Occult spinal dysraphism (OSD), also known as spina bifida occulta, refers to a group of lesions characterized by abnormal embryogenesis of the distal spinal cord and associated midline structures. The spectrum of OSD is vast (Table 11-3), and includes disorders of primary neurulation (dermal sinus tract and associated inclusion cyst), secondary neurulation (terminal myelocystocele, tight filum terminale), and notochord development (split cord malformations, neurenteric cyst). Primary neurulation, discussed previously in relation to MMC, is the process through which the neural tube is formed by closure of the anterior and posterior neuropore, giving rise to the upper lumbar cord and segments cephalad to this. Secondary neurulation refers to the formation of the caudal-most segments of the spinal cord and filum terminale, and occurs after 26 days’ gestation through processes of canalization and retrogressive differentiation.152 The stage at which lipomyelomeningocele, the most common occult defect, develops is unclear.153 Despite their heterogenous etiology, they are grouped together because of their skin-covered (hence occult) appearance. The presence of anorectal abnormalities is not uncommon in these patients.154 Many of these lesions may be suspected in a neonate harboring cutaneous stigmata on the back, including hemangiomas, dermal appendage (“tail”), dimple or sinus tract above the gluteal fold; or a hairy patch. Lipomatous lesions often manifest with a visible subcutaneous lump above the gluteal fold, often asymmetric in location. The presence of

Table 11-3  Occult Spinal Dysraphism Lesion

Features

• Lipomyelomeningocele

• Subcutaneous fat, extending through bifid posterior elements and dura, attaching to low-lying distal cord • Midline, epithelialized tract extending intradurally from a lumbosacral dimple; may be associated with intradural (epi)dermoid cyst • Cystic dilatation of distal spinal cord, usually with intradural lipoma; often associated with cloacal exstrophy • Thickened filum terminale, often with fatty infiltration of filum; conus usually below inferior portion of L2 • Spinal cord or conus split along the parasagittal plane; may be in a single or duplicated dural canal; usually associated with cutaneous hairy patch • Extension of endodermally derived tissue, lined with alimentary tract mucosa, into spinal canal or cord; often at cervico-thoracic junction

• Dermal sinus tract • Terminal myelocystocele • Tight filum terminale • Split cord malformation • Neurenteric cyst

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any of these markers, or the discovery of anorectal malformation, mandates further imaging; sonography can depict the level of the conus and overt anomalies, while MRI depicts detailed anatomy of the distal spinal cord and surrounding structures. These lesions may be otherwise asymptomatic, especially in the neonatal period, with no abnormalities of neurologic function. If not detected on the basis of cutaneous findings, they usually come to attention as the child grows, producing symptoms and signs of spinal cord tethering, including back and leg pain, weakness, gait changes, bladder and bowel dysfunction, orthopedic foot changes, and progressive scoliosis.155–159 Meningitis can occur when dermal sinus tracts communicate with the intradural compartment. Lipomatous lesions of the distal spinal cord are the most common of the occult defects, and the one for which the natural history is best established. The incidence is approximately one tenth of that for MMC, and there appears to be a female preponderance in most series. Terminology for these lesions remains confusing and inconsistent in the literature. Lipomyelomeningocele is characterized by a lipomatous mass that extends from the subcutaneous plane through dysraphic posterior elements and dura, and inserts into the caudally displaced distal spinal cord. The diffentiation between lipomyelomeningocele and lipomeningocele may be a matter of semantics; the former describes such a lesion in which neural elements herniate outside the confines of the canal, and is the term most commonly used, although some think that the elements are almost never found dorsal to the canal.160 Subclassifications of lipomyelomeningocele depend on where the lipoma enters the spinal cord, and include dorsal, caudal, and transitional variants. Additionally, many lipomas are confined to the filum terminale, and may appear as a mass, or simply a thickened filum. These classification schemes, however, are inadequate to explain many of the diverse lesions described in large series.161 Lipomyelomeningoceles are often associated with normal neurologic function at birth, but because of the tethering of the spinal cord, almost invariably become symptomatic with time and growth. In a recent series, 41% of infants less than 1 year old were symptomatic at presentation; neurologic signs, urologic dysfunction on formal assessment, and orthopedic deformity were each present in approximately 60% of these symptomatic patients.157 In a series of 177 patients from two institutions, two thirds were asymptomatic when evaluated at younger than 6 months, whereas most had incurred deficits by age 4.162 Because of the near universal development and progression of deficits with time, most authors advocate surgery at diagnosis to prevent or stabilize neurologic dysfunction. Bladder dysfunction is unlikely to recover completely after it is lost, and motor signs may not improve significantly once progressive weakness occurs. Surgery involves debulking the lipomatous mass to its interface with the neural elements, thereby untethering the spinal cord, followed by a multilayered closure. In the

case of a fatty filum, the thickened filum is simply divided to release the tethering. The results of untethering procedures vary among series, and are often difficult to compare due to differences in methods and terminology. Lesions of the filum result in almost no surgical morbidity, and delayed deterioration is extremely rare; surgery for both asymptomatic and symptomatic lesions is warranted.161,163,164 For symptomatic conus lesions, surgical untethering is accepted by almost all authors to prevent progressive deficit.161,163,164 Controversy remains in regard to asymptomatic conus lesions, which can be a more formidable surgical undertaking. LaMarca and colleagues163 reported postoperative neurologic morbidity in none of 71 asymptomatic patients and in two of 87 symptomatic patients following untethering of conus lesions. Delayed worsening occurred in 12.7% of asymptomatic patients and in 41.4% of symptomatic patients following initial repair. Actuarial analysis showed that delayed worsening occurs in less than 20% of asymptomatic patients following initial repair, while 60% of those initially with symptoms deteriorate after repair; they concluded that prophylactic untethering was warranted, as have numerous other authors.164–166 In a review of 94 patients with lipomyelomeningocele, delayed retethering occurred in 20% of patients after mean followup of nearly 6 years, and was most common in transitional lesions; actuarial analysis revealed approximately 40% delayed worsening due to retethering at 8 years.167 Prophylactic surgery for conus lipomas in asymptomatic patients has recently been questioned in a detailed review and personal series of 253 conus lesions, many with extensive longterm follow-up.161 In this series, long-term deficits developed in almost half of asymptomatic patients after primary repair, not all of which could be explained by recurrent tethering. These authors and others168 could not conclude that prophylactic surgery provided an outcome superior to the natural history of the disease.

Chiari I Malformations and Syringomyelia The Chiari I malformation (CM1) is a poorly understood disorder, characterized by cerebellar tonsillar descent below the foramen magnum, in the setting of an underdeveloped posterior cranial fossa.169 The disorder is distinct from the Chiari II malformation associated with myelomeningocele, and the Chiari III malformation, which is characterized by cerebellar herniation into a cervical encephalocele. The Chiari IV malformation refers to congenital absence of the cerebellum, and is not a type of hindbrain herniation. Although the disorder usually presents in young adults, MRI has facilitated the understanding of the CM1, and the disorder is diagnosed earlier. It is now clear that CM1 is not a disease of adults, but rather a congenital disorder that may present at any time of life, with an enormous variety of

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symptoms and signs, and an array of associated radiographic findings, including syringomyelia, scoliosis, and craniocervical anomalies. Although the incidence of CM1 in children is unknown, an MRI database search found the abnormality in 0.9% of more than 8000 pediatric patients, 43% of whom were symptomatic170; similar searches in the general population (adults and children) found rates of 0.56%171 to 0.77%,172 with 69% and 86% of patients symptomatic, respectively. Most series report a female predominance among symptomatic adults with CM1, although pediatric reports do not demonstrate this proclivity.170,173 A minority of cases are associated with familial inheritance.169 Symptoms and signs of CM1 are caused by a variety of mechanisms, including direct compression of the cervicomedullary junction and cerebellum, and abnormal CSF dynamics, the latter responsible for syrinx development and many nonspecific symptoms. Although CM1 is the result of an anatomic anomaly, the pathophysiologic mechanisms responsible for the development of neurologic dysfunction may take years or decades to manifest clinically; this may explain the large percentage of asymptomatic pediatric patients. Headache, typically suboccipital and increased with Valsalva maneuver, and often with associated neck pain, is present in the majority of adults, although it may be less frequent in younger children.174,175 Varying degrees of weakness, numbness, coordination deficits, ocular, and otoneurologic disturbances are common, although the frequency varies significantly among both adult169,176,177 and pediatric series.170,173–175,178 Presentation is uncommon within the first few years of life, although motor delay178 and disturbances of lower cranial nerve function, usually in the form of breathing disturbances, may occur.175 Unexplained crying179 and paroxysmal rage behavior180 are uncommon as the sole manifestation of CM1 in young children. Chiari malformation has been discovered in patients with SCIWORA (spinal cord injury without radiographic abnormality) injuries of the cervical spine181,182 and in cases of sudden, unexplained death. In older children and teenagers, CM1 is often discovered during workup for unexplained scoliosis175,183 and is the only reason for referral in as many as 73% of pediatric patients184; scoliosis is usually, although not always, associated with syrinx in these patients. The degree to which CM1 and scoliosis occur in patients with “idiopathic scoliosis” is unknown, and there is mixed consensus as to whether all children with this condition should undergo MRI evaluation.185–188 The traditional hallmark of CM1 is tonsillar descent below the plane of the foramen magnum. Although acquired tonsillar herniation may occur after placement of lumboperitoneal shunts189–191 or in the setting of hydrocephalus or mass lesions, these comprise only a small minority of cases. Several reports have demonstrated small posterior cranial fossa volumes in patients with the condition,169,192–194 suggesting a primary mesodermal disorder resulting in underdevelopment of occipital somites194 and subsequent

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overcrowding of posterior fossa contents. The pathogenesis of syrinx formation is also unknown; recent reports analyzing CSF flow and subarachnoid pressures in both CM1 patients and unaffected controls revealed that tonsillar impaction at the foramen magnum results in elevation of the cervical subarachnoid pressure, forcing CSF transmurally into the spinal cord from the subarachnoid space.195,196 Milhorat and colleagues169 theorize that abnormal CSF dynamics due to crowding at the foramen magnum not only cause syrinx formation, but may lead to the headaches and otoneurologic disturbances seen in many patients. The radiographic findings in CM1 reflect the proposed pathophysiologic mechanisms described previously. Although the classic definition of the syndrome includes tonsillar descent below the foramen magnum, usually 5 mm or more, or 3 to 5 mm in association with syrinx (present in ≥50% pediatric cases) or brainstem kinking,197 this may be too restrictive, because 9% of the 364 patients evaluated by Milhorat et al.169 with MRI did not have significant tonsillar herniation. All patients in this series, however, had an MRI appearance of hindbrain overcrowding, and all patients evaluated with cine-MRI showed decreased CSF flow at the foramen magnum. Similarly, a small series of children with syringomyelia in the absence of tonsillar herniation was recently described, in whom the posterior fossa contents were compromised.198 In these patients with the so-called Chiari 0 malformation, syrinx resolution was seen following posterior fossa decompression.199 Other cranio-cervical anomalies may be present in CM1, including Klippel-Feil anomaly and basilar invagination.169,200 The treatment options for Chiari malformation include observation, posterior fossa decompression, and shunting of syringomyelia, if present. If hydrocephalus is present, placement of a ventriculoperitoneal shunt should be performed before considering these other options. Surgery is generally recommended for children with clear and persistent symptoms related to hindbrain compression and those with neurologic deficits. Asymptomatic patients may be observed conservatively, although they (or their parents) must be counseled about symptom development, and the potential risks of contact sports. The definitive treatment for symptomatic CM1 is suboccipital craniectomy, often combined with upper cervical laminectomy, to enlarge the crowded posterior fossa. The goal of surgery is re-establishment of normal CSF flow at the foramen magnum, although the mechanisms by which this is best accomplished are controversial.201 Most surgeons open the dura, often inspecting the intradural contents to ensure CSF flow from the fourth ventricle, and close the dura with a patch graft. Alternative techniques include bony decompression, opening only the outer dural layer,202 coagulation or resection of the cerebellar tonsils,183,203 and leaving the durotomy open.184 In patients with significant ventral compression at the foramen magnum, transoral decompression may be indicated.200,204 In patients with large syrinxes, some physicians favor primary shunting of the

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syrinx over posterior fossa decompression.205 In general, all of these procedures are successful in reducing the signs and symptoms associated with hindbrain compression and syringomyelia in most children, although no technique has proven superior to the others. Patients with the least favorable results after surgery are typically those with advanced disease at presentation. Outcomes in children may be more favorable than those in adults, possibly due to the shorter disease duration and resiliency of the pediatric nervous system.183 Progressive scoliosis, seen in a large percentage of affected children, tends to stabilize or improve after treatment.

Craniosynostosis and Abnormal Head Shape Craniosynostosis is a term used to describe a vast spectrum of malformations resulting from premature closure of a cranial suture or sutures, and the resultant abnormalities of head growth and shape. Growth of the skull is a complex phenomenon, and though our understanding of this process at the genetic and molecular level has grown appreciably in the past few decades, the process is not fully understood. In simplest terms, calvarial growth is driven by development of the underlying brain. After approximately 2 months’ gestation, centers of ossification develop within the ectomenix, a rudimentary fibrous covering of the brain. Ultimately, these centers develop into the frontal, parietal, and occipital bones, and osteogenic fronts appear at the bony margins, the site of the calvarial sutures.206–208 At a suture, bone is deposited in a spicule configuration, and a subsequent microfracture and redeposition of bone continues during brain growth to allow calvarial expansion.209 With the exception of the metopic suture, the cranial sutures never fully fuse, even through adulthood, remaining separated by a microscopic layer of fibrous tissue.207 The reasons for premature suture fusion are unknown.210 Mutations in the various subtypes of the fibroblast growth factor receptors genes are well described in some of the familial (syndromic) and in isolated forms of synostosis.211–214 Other mutations, involving the TWIST, MSX2, and other genes have been described.213,215 The site of suture formation

is in large part influenced by dura; in tissue culture, sutures transplanted in the absence of their underlying dura undergo fusion, while transplantation with dura allows continued patency.216,217 These influences have also been demonstrated in animals.218 Mechanical influences can lead to suture closure in experimental animals. The ultimate causes are likely a multifactorial response to genetic predisposition, with a complex set of physical and biochemical interactions involving the dura, calvarium, and skull base. No matter the cause, the pathogenesis of the resultant abnormal skull shape is the result not only of the fused suture, but also the compensatory growth that occurs in patent sutures.219 When growth is restricted at a suture, the adjacent plates functionally become a single bone. Compensatory bone growth occurs in a symmetric fashion at sutures in line with the fused suture, and asymmetrically at sutures along the margins of the fused segment. The compensatory growth is greatest at sutures closest to the abnormally fused suture.207,219 This expansion of Virchow’s observations of 150 years ago can explain the head shape in the various forms of synostosis. More than 90 syndromes are associated with craniosynostosis and facial dysostosis,220 although the majority of cases occur in isolation. These nonsyndromic varieties result in characteristic head shape, reflecting the suture(s) that have fused prematurely (Table 11-4). Sagittal synostosis, the most common form, accounts for nearly half of all cases,221,222 and for unclear reasons, is at least three times more prevalent in males. Growth is resticted in the lateral plane, giving rise to a long, narrowed head (scaphocephaly or dolochocephaly), with prominent frontal and occipital bossing. Intelligence is usually normal, although increased intracranial pressure rarely occurs.223 Unilateral coronal synostosis is the second most common syndrome and results in frontal plagiocephaly. The ipsilateral forehead is flattened, with contralateral frontal bossing. Because of skull base shortening of the involved side, the sphenoid wing is displaced superiorly and anteriorly, and the brow is recessed; the resultant orbital involvement leads to the “harlequin eye” seen on skull radiographs. The ipsilateral ear is displaced anteriorly, and the nasal root deviates toward the affected suture. In bicoronal synostosis (turribrachycephaly), the head has a shortened anterior-posterior dimen-

Table 11-4  Craniosynostosis Affected Suture

Findings

• Sagittal • Unilateral coronal

• Long, narrow head; occipital and frontal bossing; midline “saddle” • Ipsilateral forehead flattened with recessed brow; harlequin eye; ipsilateral ear displaced anteriorly; nasal root deviated ipsilaterally; contralateral frontal bossing • Shortened anterior-posterior distance; widened and towered head; orbital rims recessed and hypoplastic • Triangulated appearance, with palpable or visible vertical ridge over forehead; bitemporal narrowing; hypotelorism common • Rare; ipsilateral occipital flattening; ipsilateral ear displaced posteriorly; contralateral parietal bossing

• Bicoronal • Metopic • Lambdoid

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sion, a widened mediolateral distance, and is elongated vertically, with recession and hypoplasia of the superior orbital rims. Although it commonly occurs as an isolated phenomenon, bicoronal synostosis is the most typical pattern seen in the syndromic craniofacial dysostoses, in which there is significant deformity of the midface. Metopic synostosis leads to a characteristic triangular shape to the head when viewed from above or on axial CT images (trigononcephaly). The bitemporal width is narrowed, and there is a visible or palpable ridge along the suture on the pointed forehead. Hypotelorism is seen in most cases. The most common abnormality of head shape seen in pediatric neurosurgical practice is occipital plagiocephaly, nearly always due to positional molding. The incidence has dramatically increased recently, due to recommendations of the American Academy of Pediatrics that a prone sleeping position for infants be avoided to reduce sudden infant death syndrome.224 The condition can also result from neonatal torticollis. In occipital plagiocephaly, the ipsilateral occiput is flattened, with foreward displacement of the ear and ipsilateral frontal bossing, resulting in a parallelogram head configuration. More severe cases result in anterior midface displacement on the ipsilateral side. For unknown reasons, most affected infants prefer to lie on the right occiput. Benign extra-axial fluid collections are quite common in patients with positional molding, and this may render the skull more vulnerable to compressive forces.225 The deformation usually peaks by 5 to 6 months, when most infants are rolling over, and in general spending less time in the supine position. Unilateral lambdoid synostosis is quite rare, accounting for approximately 3% of craniosynostosis; in contrast to positional molding, the ipsilateal ear in true synostosis is displaced posteriorly and somewhat inferiorly, and bossing occurs most prominently in the contralateral parietal region, although ipsilateral frontal bossing can be seen. Crouzon’s syndrome is the most common craniofacial syndrome, occurring in approximately one in 25,000 births.226 It is familial in one half to two thirds of patients, with autosomal dominant inheritance.227 The disorder is characterized by bicoronal synostosis and resultant turribrachycephaly, proptosis and orbital hypoplasia, and midface anomalies characterized by hypoplasia and retrusion of the maxilla. Progressive sutural fusion at the skull base can occur during the first several years of life.228 Apert’s syndrome is less common, with a prevalence of one in 55,000 to 65,000 births,227,229 and is usually sporadic, although an autosomal dominant inheritance has been noted. The craniofacial features of Apert’s syndrome are quite complex, and involve bicoronal synostosis, as well as aberrant metopic, sagittal, anterior skull base sutures, and mid-face hypoplasia. In infancy, there is a large defect of the midline calvarium, extending from the nasion to the posterior fontanelle, which gradually fills with bone during the first several

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years.230 Syndactyly of the hands and feet are part of the syndrome, and multiple apendicular joints can be affected.227 The majority of these children are of subnormal intelligence.231 The relationship between craniosynostosis and hydrocephalus is not well understood. In nonsyndromic, singlesuture involvement, increased ICP is seen in a minority of patients, and is not clinically evident in most cases.223 In syndromic patients, abnormal CSF dynamics can result from calvarial vault restriction, veno-occlusive skull base involvement, or a combination of these. In a retrospective review of 1727 cases of craniosynostosis, nearly 30% of patients with Crouzan’s syndrome and 12% of patients with Apert’s syndrome required CSF diversion; in the latter group, asymptomatic ventricular dilation was seen in half of the cases.228 In a series of 22 syndromic patients observed prospectively from diagnosis, five patients required diversion before or just after initial reconstruction for papilledema or macrocephaly associated with ventriculomegaly; in all cases, papilledema resolved after reconstruction and shunting.232 Increased ICP developed in eight patients 12 to 37 months after primary repair, requiring either shunt, or if head size was less than the 25th percentile, re-expansion. In this report, asymptomatic papilledema was the only sign of delayed ICP elevation in four cases. The treatment of craniosynotosis depends on the involved suture(s) and the severity of the deformity. Patients with metopic or coronal synostosis typically undergo calvarial and orbital reconstruction within the first 6 to 12 months of life; those with syndromic involvement also require cranio-orbital reconstruction, and may require subsequent re-expansions, as well as delayed midface reconstructive procedures. Significant controversy remains concerning the optimal treatment for the most common entity, isolated sagittal synostosis. The dozens of published procedures can be categorized into three basic groups: strip craniectomy (without or with interposition material), extended strip craniectomy, and calvarial vault remodeling. The extended strip craniectomy techniques usually involve removal of the sagittal suture, combined with wedge, barrelstave, or other types of parietal and occipital osteotomy. These procedures typically minimize blood loss, are relatively fast and technically simple, minimize hospital stay, and provide a satisfactory outcome in the vast majority of cases.233,234 Proponents of primary calvarial reconstruction argue that remodeling procedures optimize rapid correction of head shape, do not depend on continued skull growth to achieve adequate cosmesis, minimize risk of premature restenosis and the need for subsequent procedures, and provide outcomes superior to those with strip or extended strip procedures based on anthropomorphic measurements.235–237 Recently, a technique of endoscopic-assisted strip craniectomy, combined with subsequent cranial remodeling orthosis, was described for sagittal synostosis.238,239 The authors demonstrated satisfactory early results

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for head shape, less blood loss, shorter operating time, and greatly reduced length of hospitalization compared to more invasive procedures. Until prospective studies are performed comparing the various techniques, controlling for patient age and preoperative cranial shape, the procedure of choice is unknown.

Encephalocele Encephalocele (cephalocele) refers to a skin-covered defect in which there is herniation of brain and meninges through a defect in the calvarium or skull base. The term meningocele is used when there is no evidence of parenchyma within the defect. These lesions are classified according to the site of the defect and are broadly categorized into basal, anterior (sincipital), posterior, and convexity encephaloceles,240 although basal herniations may be categorized as a subtype of anterior lesions.241 Basal lesions primarily arise through defects in the sphenoid or ethmoid bones at the skull base.240 Sincipital encephaloceles, which arise in the region of the foramen cecum, can be further subdivided into frontoethmoidal (nasofrontal, naso-ethmoidal, and naso-orbital subtypes), and the uncommon interfrontal and craniofacial cleft subtypes.242 Posterior encephaloceles result from herniation through an occipital defect, and may be above or below the torcula.243 Convexity encephaloceles arise from herniations along the vertex.240 The overall incidence of these lesions is approximately 1 in 5000 live births,240,244 but this may be an underestimate due to fetal loss.245 In North America and Western cultures, occipital encephaloceles are by far the most common entity, accounting for approximately 90% of cases,243 with a female predominance.246 Anterior encephaloceles are the predominant lesions in Southeast Asia, with an incidence of approximately one in 5000 live births.247 Encephaloceles in other locations are less common. The embryologic bases of these lesions is unknown, and given the diversity of locations in which they occur, is likely multifactorial. A disorder of primary neurulation (akin to myelomeningocele defects) is unlikely, given the skin-covered nature of these lesions. It is more tenable that they are due to a disruption in the mesenchymal structures overlying the brain, with resultant herniation through the affected area.244,245 Encephaloceles typically occur in isolation, but may be associated with a variety of nervous system and systemic abnormalities.240 If large enough, encephaloceles can be documented on prenatal sonography, and maternal alpha-fetoprotein levels may be increased. The diagnosis is usually straightforward upon delivery, however, with an outpouching noted over the occipital or suboccipital region for posterior lesions. Anterior encephaloceles are characterized by a midline or paramedian mass near the nasion and can cause proptosis and hypertelorism. Naso-ethmoidal lesions may not be readily apparent at birth, but may present later with symptoms

of nasopharyngeal obstruction or CSF rhinorrhea. Basal encephaloceles may present with a midline mass, or in a delayed fashion, with obstructive symptoms or CSF leak. MRI is the most accurate means of delineating the contents of the sac and assessing the presence of associated anomalies, while CT is useful for characterizing the relationship of the herniation to skull base structures in anterior encephaloceles. Occipital lesions are often associated with anomalous venous sinus anatomy, and rarely these veins may be part of the sac contents; magnetic resonance venography can be used to examine the relationship of the herniation with respect to the venous system.248,249 The principles of treatment for encephaloceles include exploration of sac contents, with preservation of the normal brain present within the sac, if technically feasible. Anterior and basilar lesions may involve craniofacial reconstruction concurrent with or after the primary repair; the sac is typically explored both intradurally and extradurally to delineate clearly its anatomy and contents. Anterior defects usually contain atretic and nonfunctional frontal lobe tissue, which can be resected, while hypothalamic or chiasmal elements may be present in basal lesions. The goal for anterior and basal repairs is resection of the sac, and a watertight dural closure. For occipital and other convexity defects, the sac is explored and amputated, followed by dural closure. Cranioplasty is usually not needed for lesions with small necks. Because of the venting of CSF into the sac during development, hydrocephalus develops in a significant number of patients after closure of large occipital encephaloceles, which ultimately may require shunt placement. The long-term outcome is more favorable for patients with lesions containing very little or no brain tissue, and for anterior versus occipital defects. Those with underlying associated brain anomalies, significant amounts of brain herniation, or critical structures within the sac, generally have significant deficits. Most patients with anterior encephaloceles have normal or near-normal intelligence,241 while the majority of those with occipital lesions have persistent deficits, often secondary to seizures, hydrocephalus, or visual impairment.240,250

Intracranial Arachnoid Cysts Intracranial arachnoid cysts are thought to be congenital lesions that arise from anomalous splitting of the arachnoid membrane during embryogenesis.251 They typically present during early childhood, with signs and symptoms depending on their location, size, and age of the patient. In modern series, the most common location is the middle fossa (sylvian fissure), representing nearly one half 252 to two thirds253 of cases, followed by posterior fossa and supracellar locations, approximately 25% and 10%, respectively. The prevalence of these lesions is unknown because they often remain asymptomatic, but there is no question

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Figure 11-1. T2-weighted axial MR images of type I and type II arachnoid cysts. A, Type I cysts are small lesions located behind the sphenoid wing. B, Type II cysts are larger, splaying apart the sylvian fissure.

that the reported prevalence has increased with use of CT and MRI. Arachnoid cysts may be incidental findings, especially in adults, but are usually discovered during childhood for specific complaints. In 95 children presenting in the era of modern imaging, the average age at the time of surgery was 4.9 years254; the median age of 2.2 years noted in another series of 40 patients suggest that most come to attention at an earlier age.255 More than one half of patients presented during their first year of life in a report of 67 pediatric cases.256 A male predominance of approximately 65% has been noted in large series.254,257 Overall, the most common symptoms and signs are related to increased ICP or abnormal head growth, seen in more than one half of all cases.254,256,257 In series of middle fossa cysts, seizures were present in approximately 30% to 40% of patients.253,258 Posterior fossa lesions most commonly present with headache and vomiting; cerebellar and cranial nerve dysfunction are less common.259 Suprasellar lesions can produce ventricular obstruction, visual dysfunction, and endocrine disturbances, including growth disturbance and precocious puberty.255,260 Based upon CT appearance, Galassi261 divided middle fossa cysts into types I through III, depending on size and morphology. Type I cysts are small and spindle-shaped, located just behind the sphenoid at the temporal pole, and without mass effect on the ventricles or midline. Type II cysts

are moderate in size and have a triangular or quadrangular appearance, occupying the anterior and middle part of the fossa. These cysts splay apart the sylvian fissure, and may cause shift. Type III cysts are large, round or oval lesions occupying the entire fossa, causing significant compression of frontal and parietal lobes and pronounced midline shift. MRI is now the diagnostic study of choice for characterizing cyst location and size, and for preoperative planning (Fig. 11-1). The management options for arachnoid cysts in children include observation (no treatment), open resection and fenestration, cystoperitoneal shunt, ventriculoperitoneal shunt, and endoscopic fenestration. The optimal strategy is not known, because there have been no randomized analyses comparing the two most common techniques (fenestration and cystoperitoneal shunt), and most series have been weighted heavily toward one procedure. Treatment decisions are based on the presentation, cyst location, the presence of hydrocephalus, and the surgeon’s preference or experience. The natural history of arachnoid cysts is not well understood; the mechanisms by which they can grow include a “slit-valve” mechanism, in which CSF can enter but not readily escape,262 cyst wall production of fluid, and osmotic gradients favoring fluid uptake.240,263 There is no question that cysts can enlarge with time, although they often remain quiescent throughout life, and can, uncommonly, resolve without treatment.263–265 Observation and nonoperative

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treatment are the initial management for small, incidentally discovered cysts. To ensure stability, repeat imaging should be undertaken within the first 6 to 12 months following diagnosis, and then on a regular schedule for at least several years, while monitoring for the development of symptoms or signs. For any lesion other than a very small type 1 cyst, contact sports should be avoided, due to the known risk of subdural hemorrhage or bleeding into the cyst.266–269 Patients presenting with atypical headaches, in whom a small arachnoid cyst is discovered during a workup, may be treated conservatively initially; if symptoms progress, or if there is any change in cyst size, treatment is probably warranted. Surgery is recommended for patients harboring clearly symptomatic cysts, especially related to mass effect or increased ICP. In young children with asymptomatic cysts causing pronounced mass effect, treatment is indicated to reduce the possibility of deleterious effects with development. Proponents of fenestration into the basal cisterns as a primary treatment option note not only the high success rates reported in the literature, but also the avoidance of shunt complication and dependence. The success rate for alleviating symptoms and obviating future procedures was 79% in a recent series of 44 patients with middle fossa cysts treated by fenestration.253 Fewel and colleagues254 noted a 73% success rate with fenestration alone among patients without hydrocephalus, although one half of all patients in the series treated with fenestration required subsequent shunt placement. Conversely, in a series of 77 middle fossa cysts, all were effectively treated with cystoperitoneal shunts, although shunt malfunctions developed in eight patients during the 7.7-year mean follow-up period.258 In a report of 40 pediatric patients, fenestration was efficacious in only 20% of 15 patients so treated, while cystoperitoneal shunting was successful in all 20 patients in whom it was attempted, with six patients (none with middle fossa cysts) requiring subsequent shunt revision.255 For cysts located in the cerebellopontine angle, open excision and fenestration is probably the most consistently effective treatment,259 and obviates shunt placement near critical neural and vascular structures. The use of neuroendoscopy for cyst exploration and fenestration has been described in a limited number of cases. This technique offers the advantages described for open craniotomy, and avoids the potential morbidity associated with shunt placement. Choi and colleagues270 reported successful outcomes in all 36 patients (31 children) undergoing endoscopic fenestration, with minimal morbidity. A smaller series, comprised mostly of adults, showed favorable outcomes in six of seven cases.271

Dandy-Walker Complex The Dandy-Walker complex refers to a spectrum of anomalies typified by varying degrees of cerebellar hypoplasia and cystic dilatation of the fourth ventricle.272 Limitations in

imaging in the pre-MRI era led to difficulty in making distinctions among patients with posterior fossa cystic fluid collections, and a variety of terms were used to categorize the variations seen, often creating confusion. Barkovitch and colleagues272 studied patients with multiplanar MRI, and concluded that what had historically been referred to as mega cisterna magna, Dandy-Walker malformation, and Dandy-Walker variant were actually similar disorders along a continuum, manifested by posterior fossa fluid collections directly communicating with the fourth ventricle, and no evidence of cerebellar atrophy. They suggested the term Dandy-Walker complex (DWC), and divided patients into DWC type A (vermis absent on axial views at the level of the fourth ventricle, and varying degrees of vermian aplasia or hypoplasia or vermian rotation seen on sagittal views), and DWC type B (vermis present on axial views, with little or no hypoplasia on sagittal views, with clear communication between cyst and fourth ventricle)272; the term “prominent cisterna magna” was used to describe patients with enlagement of the cistern due to cerebellar atrophy. In their analysis, patients with DWC type A were those who would have classically been referred to as having DandyWalker malformation or variant, and nearly all patients (11/12) had hydrocephalus. Enlargement of the posterior fossa and elevation of the tentorium and transverse sinuses was seen in most patients with DWC type A, and other brain anomalies, such as dysgenesis of the corpus callosum, were seen in more than one half (Fig. 11-2). Patients with DWC type B, who likely would have been categorized in the past as having mega-cisterna magna, also had hydrocephalus and associated anomalies, but less frequently. This classification scheme is useful in that it unifies radiologic criteria for the evaluation of treatment of these patients,273 although others have separated cystic malformations of the posterior fossa based on variations in cerebellar development.274 The cause of DWC is unknown; theories had focused on atresia of the fourth ventricular outflow foramina, although a subsequent study has shown these foramina to be patent in some patients with DWC. The etiology is likely more complex and multifactorial, and due to development anomalies of the anterior membranous area occurring during formation of the cerebellum and fourth ventricle.272,274 In addition to brain anomalies, such as callosal dysgenesis and occipital meningocele, DWC has also been associated with widespread malformations, especially cardiac defects.275–277 The true incidence of DWC is unknown.278 Patients with DWC typically present in childhood because of signs and symptoms of increased ICP, either due to mass effect from the cyst itself, or from the frequent associated hydrocephalus (pan-ventricular); it is now being diagnosed earlier, and at greater frequency, because of prenatal imaging.276,279 Patients with DWC type A usually present in infancy (mean, 0.4 years), while DWC type B manifests later (mean, 4.2 years).273 In cases in which hydrocephalus is absent, the

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Figure 11-2. T2-weighted MR images of Dandy-Walker complex, type A. A, Sagittal. There is complete absence of the cerebellar vermis, and hydrocephalus is present. B, Axial. Dysgenesis of the corpus callosum is depicted.

malformation may be discovered during workup for motor delay, intellectual impairment, or seizures. Surgery, in the form of CSF diversion, is indicated for patients who present with hydrocephalus, increased ICP, or symptoms or signs related to the mass effect from the posterior fossa cyst. Ventriculoperitoneal, cystoperitoneal, and ventriculocystoperitoneal shunts can all be used, and there is no concensus as to the preferred method; patency of the aqueduct should be assessed on the initial MRI studies to help in preoperative planning. Domingo and Peter273 found that cystoperitoneal shunts had lower rates of obstruction, and both ventricular and cyst size were reduced more effectively compared to ventriculoperitoneal shunts, although cystoperitoneal shunts had a high likelihood of poor shunt position; overall complication rates were high for both groups, with no statistical difference. Asai and colleagues280 noted that an isolated fourth ventricle developed in more than 40% of patients treated with a primary ventriculoperitoneal shunt; this was thought to be secondary to acquired aqueductal stenosis, necessitating additional cyst shunting, compared to only 10% of those treated initially with a cystoperitoneal shunt; cases of upward herniation of the cyst after ventriculoperitoneal shunting alone have been

reported.281 Bindal and colleagues277 noted conversion rates from single to double shunt systems in 42% of primary cystoperitoneal shunts and 30% of ventriculoperitoneal shunts, implying that each method is fraught with the problem of malcommunication between supratentorial and infratentorial compartments; primary shunting of both compartments is advocated in an effort to minimize this risk, and to avoid pressure differentials across the tentorium.282,283 The outlook for DWC is now improving, with advances in imaging and better understanding of the shunt requirements necessary for these patients. Approximately one half of patients are normal or mildly delayed intellectually,284,285 and one half have normal cerebellar function. There is no association between cerebellar appearance on imaging studies and ultimate functional outcome.284

Head and Spinal Injuries Head Injury The physiologic and clinical aspects of severe traumatic brain injury (TBI) are covered elsewhere in this text, and will

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not be detailed in this section. Nonetheless, some important differences in etiology, pathophysiology, management, and outcome have been noted for the pediatric age group, and will be highlighted in the present section. In the United States, TBI is the leading cause of death in children, and is the major factor impacting outcome in the injured child.286 Each year, there are at approximately 100,000 to 150,000 hospital admissions related to head injury in the United States for children younger than 15,287,288 with the vast majority of these admissions being mild in nature. After the first year of life, injury kills more children than all diseases combined.289 At least 7000 children die each year as a result of head injury, representing 30% of all accidental deaths in children.288 For all ages, with the possible exception of infancy, motor vehicle accidents are the most common cause of serious brain injury and mortality.288 In children younger than 5, falls are the most prevalent overall cause of head injury, while recreation-type injuries (including bicycle accidents) are the most common cause in the 10- to 14-year-old age group; after age 15, motor vehicle accidents are the primary source of injury.288 After age 5, males are far more likely than females to suffer TBI.288 Nonaccidental trauma (NAT) is becoming recognized with greater frequency as a major cause of brain injury in children, and NAT-related brain injury may be the most common cause of trauma-related death in infancy.290,291 The evaluation of older children and adolescents with head injury is relatively straightforward, encompassing a routine general physical and neurologic examination, and assessment of level of consciousness; the most widely used index for this population is the Glascow Coma Scale (GCS), which evaluates eye opening, verbal response, and motor response.292 For the young child, this scale is not reproducible and often impractical, given their limited communications skills, and a variety of pediatric coma scales have been developed to circumvent shortcomings inherent in the GCS.293–295 CT should be routine in any child with alteration of consciousness, significant mechanism (e.g., patient ejected from vehicle, crash at speed >40 miles per hour, death in the passenger compartment), external signs of head trauma, or skull fracture noted on plain radiographs. The incidence of specific clinical and radiographic findings after head injury is difficult to ascertain because reported series vary widely with respect to definition of head or brain injury, inclusion criteria, and population base. In a series of more than 9000 consecutive children evaluated in an emergency department after any type of head injury, most (86%) did not suffer loss of consciousness, although symptoms and signs of brain injury (such as vomiting or alteration of consciousness) were common, seen on greater than one third of patients requiring admission after injury.296 In children younger than 2 years, skull fractures were present in 45% of those admitted following head injury, while only 11% of those 2 years and older had such fractures.296 Depressed skull fractures account for up to one fourth of

pediatric skull fractures,297 and are far more prevalent in children than adults after head injury. The presence of significant mass lesions such as epidural hematoma, subdural hematoma, and intracranial clot is less common in children compared to adults. In a series of 1906 consecutive children with injury resulting in skull fracture, loss of consciousness, or amnesia, the incidence of subdural and epidural hematoma was 2% and 1%, respectively,298 although other series have shown rates of pediatric subdural and epidural hematomata as high as 18% each after mild head injury (GCS 13–15).299 Severe head injury—defined at GCS £ 8—represents a minority of cases, but is the greatest source of mortality and acquired long-term morbidity in children. The brain sustains insult not only at the moment of impact (primary injury), but also as the result of secondary regenerative cascades mediated by ischemia, cellular energy failure, excitatory amino acid release, calcium fluxes, free radical formation, and resultant cellular death, a process termed excitotoxicity.300 Programmed cell death (apoptosis), also induced by trauma, is characterized by condensation of nuclear and cytoplasmic components, cell shrinkage, fragmentation, and degradation301; this process is ultrastructurally distinct from excitotoxic death. Secondary injury may progress in the hours and days following trauma, and contribute to brain swelling and delayed deterioration.302–304 Systemic insults after the initial trauma, such as shock and hypoxia, deprive the brain of substrates necessary for normal oxidative metabolism, further aggravating these cyclic cascades, and contributing to neuronal death. Injury to the developing brain differs from that of adults, although the specific reasons are unknown.305 In immature rat models of brain injury, apoptotic cell death occurs in a delayed fashion, with the most significant damage occurring in the youngest pups; mature rats did not demonstrate apoptotic death after identical injury, suggesting a particular age-dependent vulnerability to injury.301 An understanding of the effects of brain injury on cerebral perfusion and ICP, autoregulation, compliance, and metabolism is important when devising effective treatment strategies; these parameters are discussed elsewhere in this text and in several excellent recent reviews.306,307 In landmark reports on pediatric brain injury by Bruce and colleagues, in which the GCS was first used to assess children,308,309 several points were demonstrated, including the overall low incidence of mortality in children following traumatic brain injury, and the relatively high incidence of diffuse brain edema. In the relatively short time since that publication, there have been numerous series in the literature highlighting the pathophysiologic differences between children and adults after severe brain injury, and the implication of these differences with respect to management and outcome; these reports have resulted in significant controversy, and many questions remain unanswered.310–314 Head-injured children do appear to be more prone to diffuse cerebral swelling than

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adults,315–317 although the mechanisms by which this occurs and the ultimate consequences are unknown. The assumption that hyperemic cerebral blood flow was responsible for this swelling, with hyperventilation advocated for its treatment315 is being reconsidered. Recent studies of cerebral perfusion in normal children313,318 and in children with brain injury319,320 have shown a tremendous variation in cerebral blood flow in both normal and injured children, and further work is necessary to clarify the issue. In light of our lack of understanding of the age-related differences in pathophysiologic response to TBI, “there is no reason to treat children differently from adults.”313 Treatment of severe brain injury is in large part that of ICP control, to preserve cerebral perfusion and the metabolic demands of the injured brain. The tenets of aggressive resuscitation, avoidance of systemic hypotension and hypoxia, and control of ICP and maintenance of adequate cerebral perfusion are applicable to all age groups and are discussed in another chapter of this text. For children with refractory intracranial hypertension, several “nonstandard” treatment methods have been advocated. Lumbar cistern CSF drainage has been advocated as a means of ICP control in the refractory patient,321,322 although its efficacy has not been demonstrated in large retrospective or prospective studies. Decompressive craniectomy as a means of controlling refractory ICP remains controversial, and is not routinely performed; several retrospective reports323–326 as well as small prospective trials327,328 have suggested its efficacy in children and younger patients, if performed before the onset of irreversible cerebral ischemia. The largest series on severe pediatric brain injury have differed with respect to patient age, timing of assessments, and definitions regarding severity of injury.312 In a prospective study involving analysis of over 8000 head-injured patients of all severity, the mortality rate for children with GCS 3 to 8 was 28.4%, significantly better than the adult rate of 47.7%.298 Within the pediatric population, mortality was highest in infants and toddlers, with declining rates throughout the remainder of childhood until mid-adolescence.298 Most large series have shown similar mortality rates in severely injured children, approximately 25% to 35%.312,329–332 Not surprisingly, multiple risk factors such as low initial GCS (particularly motor score)289; diffuse cerebral swelling, especially when combined with hemorrhage333,334; and low mean cerebral perfusion pressure332 have all been associated with poor outcome. The reasons for the improved survival in children compared to adults, and the seemingly worse outlook for critically injured infants, remain unknown. In addition to mortality, sustained neurologic deficits, especially cognitive impairment, are exceedingly common in children after severe brain injury.333–338 Intentionally inflicted trauma is a common cause of pediatric brain injury. In one series, at least 24% of such injuries in 100 consecutive patients younger than 2 years old were the result of child abuse.339 In some centers, nonaccidental brain

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injury is the most common cause of pediatric traumatic death,290 and an estimated one in 4000 children may suffer nonaccidental head injury during the first year of life.340 Such injuries are the result of forceful shaking, often, but not invariable, in conjunction with blunt trauma, in a patient whose body habitus renders him or her particularly vulnerable.341–345 The average victim age in a series of 48 patients was 7.85 months, with none older than 3 years of age.343 The term “shaken impact syndrome” was coined by Bruce and Zimmerman to describe the constellation of clinical and radiographic findings in abused infants.345 Because of vague circumstances surrounding shaken impact syndrome, abuse is typically inferred from examination and findings on cranial and skeletal imaging. The diagnosis has no strict criteria, but is usually made in the presence of extra-axial hemorrhage, retinal hemorrhage, external signs of trauma, and a vague or incompatible mechanism of injury. Typical scenarios provided by parents usually involve a fall or other minor trauma that is not compatible with the patient’s injury. Although level of consciousness may be normal in the most mild cases, the patient is often significantly depressed, with coma or posturing present in approximately one half of cases.346 Apneic events, inconsolability and irritability, and seizures are frequent, with a tense fontanelle present in severe cases. External evidence of head trauma, such as bruising or soft tissue swelling, is present in less than one half of patients.343,344 Retinal hemorrhages, often with preretinal and subretinal components, are present in the majority of patients,347 and are extremely rare after accidental trauma339 or cardiopulmonary rescuscitation348; retinal folds may be found in more severe cases.349 Radiographic findings, typically on CT, may rarely be the sole manifestation of intentional trauma. Acute subdural hemorrhage is the most common finding, seen in more than 80% of cases,350 often interhemispheric in location.351 Chronic subdural collections, with or without an acute component, as well as subarachnoid blood may be present. Diffuse edema on initial imaging is present in a significant percentage of patients, and may indicate prolonged apnea,352 or a prolonged delay in presentation after injury. Skull fractures may be present in one fourth of cases,343 while long bone and rib fractures are less prevalent.344 Treatment of inflicted brain injury is no different than that of accidental trauma. Outcome after nontraumatic brain injury depends on severity, but is associated with mortality rates as high as 27% to 37%.343,344 At autopsy, diffuse brain injury is universal, and there is often concomitant damage to the cervical spinal cord,341,353 which may contribute to hypoxic brain injury. Long-term dysfunction is common in survivors.354 Injuries of the Spine Spinal column and cord trauma in children differs from that sustained by adults with respect to frequency, mechanism,

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levels involved, radiographic findings, and outcome. Pediatric spine and spinal cord injuries are approximately 20 times less common than severe head trauma.355 In large referral centers, pediatric spinal cord and spinal column injuries, including fracture, fracture and subluxation, subluxation only, and spinal cord injury without radiographic abnormalities (SCIWORA)356 are approximately 20 times less frequent than such injuries in adults,357,358 although the incidence rises throughout childhood and abruptly beyond the teenage years. The reasons for the rarity of spine trauma in children relate both to causative and anatomic factors. Young children are less likely to participate in many of the activities associated with spinal injury, and are more likely to be restrained and in the rear seat of vehicles, rendering them less vulnerable to severe impact injury than adults. The ligamentous structures of children are more elastic than those of adults, and their facets are oriented in a more horizontal configuration, allowing greater deformity without resultant fracture or dislocation.359 Their disproportionately larger head results in different inertial forces dissipated to the neck during deceleration.360 Such anatomic differences may also explain the predisposition for relatively unique pediatric injuries, such as atlantoaxial rotatory subluxation361 and occipito-atlantal dislocation. In young children, the most common causes of spinal injury are falls and pedestrian versus car accidents,358,360 although motor vehicle accidents are the primary cause in some series.362,363 The injuries sustained by older children and teenagers are due to motor vehicle accidents, followed by sports-related mishaps, with the former assuming greater importance with increasing age.357,358,362 Except in the youngest age groups, there is a strong male predominance. Half of pediatric patients with spinal column injuries are neurologically normal (by definition, none with SCIWORA are normal); among patients with deficit, incomplete injury is slightly more common than complete impairment.357,358,362 The cervical region is by far the most frequently affected level in children, with no significant difference between the thoracic, thoracolumbar, and lumbar regions.358,364 Associated head injury is present in approximately one third to one half of cervical spine injuries, especially those involving the upper cervical region.365 Noncontiguous injuries are present in approximately 10% to 15% of children. In young children, the upper cervical spine (occiput to C3) is disproportionately affected,357,360,362,363,365 with lower cervical levels increasingly affected throughout later childhood and beyond. SCIWORA is most common in younger patients (birth to 9 years), representing more than one third of spinal injuries in this group, and becomes less prevalent with advancing age.356–358,362 SCIWORA is associated with greater neurologic deficit in young patients, while older children and teenagers with SCIWORA suffer less severe impairment.366–368 Fractures (with or without subluxation) are common at all ages, but assume greater predominance in older children and

teenagers. Because of the frequency of SCIWORA in young patients, this population is more prone to neurologic deficit, while patients with fracture only, who tend to be older, are at lowest risk for neurologic injury. Interestingly, delayed neurologic deficit may develop in approximately one fourth358,360,367 of patients with SCIWORA, with onset of signs and symptoms hours to several days after injury, although others have not seen this phenomenon.357 The signs and symptoms of spine and spinal cord injuries are variable, and primarily depend on the age and level of consciousness of the patient. In an awake, cooperative patient, pain and spasm at the level of injury is nearly universal; in cervical injury, neck movement is voluntarily restricted, and the head may assume an abnormal posture in cases of subluxation. Neurologic findings range from no deficit to complete loss of sensory, motor, and autonomic function, and may change early in the course, as noted previously. Severe spinal cord injury, especially in the cervical region, may be associated with unexplained hypotension without compensatory tachycardia. Standard radiography remains invaluable in the evaluation of pediatric spine injury, and should be performed in any child with neck or back pain following injury, and in all patients with neurologic deficit or depressed mental status. In the cervical region, anatomic variants in children include pseudosubluxation of the upper cervical vertebrae, increased atlantodental interval, bifid arch of C1, and the anteriorly “wedged” vertebral bodies.369 Normal synchondroses, especially at C1 and C2, appear lucent and may be misdiagnosed as fractures. Flexion and extension cervical views may be obtained under supervision if pain does not prohibit active range of motion, and can indicate areas of hypermobility. CT imaging, often with coronal and sagittal reconstruction, is useful for evaluating areas not well visualized on plain radiographs, and is essential for further depicting osseous injury and subluxation. MRI is necessary in all children with suspected spinal cord or root injury, and in patients with any unexplained neurologic deficit. SCIWORA was defined before the advent of MRI; such imaging may reveal areas of ligamentous disruption, spinal cord edema, hemorrhage, or transection.369 The principles of treatment for children with spinal cord or column injuries do not differ in theory from adults: prevention of further injury by immediate immobilization of unstable segments, decompression of neural elements if necessary, and maintenance of long-term stability. All children with suspected spinal injuries must be immobilized with a hard collar during transport and evaluation. Because of their relatively large head, young children placed directly on a rigid transport board will be forced into a relatively flexed position; their back and shoulders must be “built up” to avoid this posture.370,371 Obviously, attention must be given to airway management and hemodynamic stability in the acute setting, especially in cases of cervical cord injury. Highdose methylprednisolone is usually initiated when neuro-

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logic deficit is present, although its efficacy in the pediatric population is not known; the recent National Spinal Cord Injury Studies372,373 did not include children younger than 13 years, and results for older children were not separately analyzed. Problems inherent in the management of pediatric spine injuries, including skeletal immaturity, future growth potential, and relative difficulty with both internal and external fixation techniques, complicate treatment decisions in children. In several ways, however, young children with spinal column injuries are at a relative advantage compared to adults. Both ligamentous and bony injuries may experience degrees of healing not seen in adults and the presence of such injuries does not always mandate surgical fusion; less than one third of spinal column injuries in children require surgical stabilization,357,358,365 with the majority managed successfully with prolonged external immobilization. Indications for operative intervention include significant instability, irreducible subluxation, spinal cord compression with persistent or worsening deficit, and failure of external immobilization. The overall rarity of such cases mandates an individualized approach in the formulation of a surgical plan, taking into account the patient’s age, level and type of injury, degree of deficit, and other injuries. The outcome of children with spinal column and cord injuries is variable. Hamilton and Myles358 reported a mortality rate of 28% among children with spinal injury, more than double that of adults; 45% of cord-injured children in their report died, usually at the scene. Although death could not be definitively attributed to spinal column or cord injuries in many of these patients, the incidence of cervical spine injury, particularly occipital to C2, was significantly overrepresented in the group of children who died. The prognosis for children surviving spinal injury is generally favorable, and is directly related to the severity of the initial injury. Because of the tremendous healing capacity of the pediatric spine, long-term failure of either operative or nonoperative spinal stabilization is the exception. In all large series, the vast majority of patients with complete neurological deficit remain significantly impaired at long-term follow-up, while most patients with partial impairment recover useful function.357,358,362 In a recent report of 102 pediatric cervical injuries, 83% of the 46 patients with incomplete injury returned to normal.365

Neoplasms Brain tumors are the most common solid neoplasms affecting children, second only to leukemia when all tumor types are considered. The annual incidence of pediatric brain tumors is approximately 32.5 cases per million children.374 A recent survey revealed that despite the declining mortality rates for pediatric brain tumors, they now represent the most common cause of tumor-related death in children.375 The incidence of brain tumors in children appears to have

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increased over the past several decades, a jump which cannot be fully explained by advances in imaging.376 Overall, the difference in incidence between supratentorial and infratentorial lesions in children is not profound377; when children younger than 15 years of age are considered, there is a slight predominance of infratentorial (53.5%) versus supratentorial (46.5%) lesions,374 although in infancy the latter are far more common.378,379 Tumors of glial origin are the most common histologic type overall, and although several subtypes exist, the majority are benign lesions, unlike those of the adult population. Medulloblastoma is the most common malignant pediatric brain tumor,374,380 and is exceedingly rare in adults. Brain tumors are discussed elsewhere in this text, and a detailed survey of pediatric neoplasms is beyond the scope of this chapter. Rather, several of the more common brain tumors in children will be described. Medulloblastoma Medulloblastoma, or posterior fossa primitive neuroectodermal tumor, accounts for approximately 20% to 25% of pediatric brain tumors,374,377 and represents slightly less than one third of posterior fossa tumors. There is a distinct male predominance,381 and the median age at diagnosis is approximately 5 years old; there is a second peak during adulthood. Although the vast majority of these lesions occur sporadically, several syndromes are associated with medulloblstoma, including Turcot’s syndrome,382 Gorlin’s syndrome,383 and Li-Fraumeni syndrome.380 The clinical presentation of medulloblastoma relates to its location, typically arising from the medullary velum, and growing within the fourth ventricle. Most patients present with symptoms of hydrocephalus, including headache (usually early morning), vomiting, and progressive lethargy.381 In infancy, excessive fussiness and vomiting are found in conjunction with accelerated head growth. Because of its relatively fast growth, symptoms are usually present for less than 3 months in more than three fourths of patients.381 Lesions with more lateral growth may present with cerebellar symptoms, rather than those due to ventricular obstruction. On examination, papilledema is present in most patients, and truncal more so than limb ataxia may be seen. Sixth nerve paresis occurs due to hydrocephalus, and the presence of other cranial neuropathies is typically associated with brainstem involvement. MRI is now the standard imaging procedure for medulloblastoma (Fig. 11-3). They usually appear as midline posterior fossa lesions filling the fourth ventricle, and are typically hypointense on T1-weighted images and hyperintense on T2-weighted images. There is usually moderate to robust enhancement with gadolinium, although this may be heterogeneous. Even in experienced hands, the radiographic distinction between medulloblastoma and other posterior fossa tumors may be difficult.384 Because there is a 31% likelihood of visible metastatic disease at diagnosis, nearly

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Figure 11-3. Axial (A) and sagittal (B) T1-weighted, postcontrast MR image of a medulloblastoma. The lesion fills the enlarged fourth ventricle, and there is moderate, heterogeneous contrast enhancement. The temporal horns are minimally enlarged, representing early hydrocephalus.

always within the spinal or intracranial subarachnoid space,385 both brain and spinal MRI should be obtained. Staging is based on tumor size and growth pattern, and the presence of metastatic disease.386 Neither the cause nor cell of origin of medulloblastoma is known, although the tumors are believed to represent malignant transformation of primitive cells in the external granule cell layer of the cerebellum. Deletions or alterations of multiple chromosomes, especially chromosome 17, have been noted, and amplification of the oncogene n-myc has been observed.387,388 Alterations in proto-oncogenes, such as Smoothened, and the Patched tumor-suppressor gene, have been linked to medulloblastoma.389 The initial treatment of medulloblastoma involves control of hydrocephalus and surgical resection. Because there is no difference in outcome between total and neartotal resection, critical structures (brainstem) should not be violated in an attempt to remove all visible tumor.390 Hydrocephalus is managed initially with external drainage, because only one third of patients or fewer require long-term diversion.391 Following resection, chemotherapy and (if age permits) radiation therapy are usually used, although optimal regimens are still unknown.392 Prognosis, as well as treatment strategies, are based on risk stratification; patients are considered high risk of they are less than three years of age, have greater than 1.5 cm2 residual tumor after resection, or have cytologic or radiographic evidence of tumoral dis-

semination. Survival may be as high as 85% at 5 years with aggressive adjunctive treatment,393,394 although typical overall survival rates are approximately 40% to 70%, for high- and low-risk patients, respectively.380,395 Cerebellar Astrocytoma Cerebellar astrocytoma represents approximately 25% to 35% of all posterior fossa tumors in the pediatric population,380,396 but occurs only rarely in adults. The average age at presentation is 7 years,397,398 and a slight male predominance may exist,397,399 although this is not universally accepted.398,400 Because of the benign nature of most of these lesions, symptoms are more insidious, with an average duration of 5 months before diagnosis.399,401 Headache and vomiting, secondary to hydrocephalus, and ataxia are present in the majority of patients.397,399–401 Papilledema is present in 55% to 85%,397,399–401 and cerebellar signs are more pronounced with this lesion as compared to medulloblastoma, with truncal ataxia more common than appendicular disturbance (74% to 88% vs. 39% to 58%).399,400 Head tilt and nystagmus are present in fewer than 20% of patients. Radiographically, these lesions may be cystic, often with a densely enhancing mural nodule, although this “classic” appearance is seen in a minority of cases400; when present in

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Figure 11-4. A and B, Axial T1-weighted postcontrast MR images of cerebellar astrocytoma. Unlike the classic cystic lesions, this lesion is solid, with irregular contrast uptake. The lesion arose from the superior vermis, and caused significant hydrocephalus.

children this appearance is almost pathognomonic for astrocytoma.396 Solid tumors, often with a microcystic component, are probably more common, and a “false” cystic pattern, in which the cyst wall shows enhancement, may be found occasionally.396,399 Astrocytomas are located more commonly within the cerebellar hemisphere in which case the cystic pattern is more often seen than in the vermis, where the solid lesions predominate.380,401 Hydrocephalus is present in most cases (Fig. 11-4). Histologically, most cerebellar astrocytomas are benign; the pilocytic variant is seen in approximately 70% to 80%400,401 of cases, while the fibrillary (diffuse) pattern is present in most of the remainder; mixed and anaplastic or malignant subtypes, similar to supratentorial astrocytomas of adults, are rare. The treatment of these lesions involves alleviation of the hydrocephalus, usually by temporary external drainage, and gross surgical resection. In the classical cystic tumor with mural nodule, only the solid portion requires resection; in cases in which there is diffuse enhancement of the wall (false cyst), the cyst wall may be resected. Brainstem invasion, which may occur in 8% to 40% of cases,399–401 usually precludes total removal. Overall, the survival at 10 years approaches 90%.377 Most recurrences occur in those with known postoperative residual disease, and are quite rare when postoperative imaging reveals total resection.400 Small residual tumor may involute spontaneously, but this is the

exception; the residual may either be re-resected or followed with serial imaging. Recurrent disease may be treated with resection if technically feasible. The role for radiation therapy for the treatment of these lesions is not clear; some reports have described a protective effect,402–404 while others have shown no benefit.400 Ependymoma Ependymomas account for 5% to 10% of pediatric brain tumors overall, and in young children, the most common group affected, the majority of these occur in the posterior fossa, arising from the floor of the fourth ventricle. Overall, approximately 60% to 70% of ependymomas in children arise in this location; when they occur supratentorially, half occur in a periventricular location.380 Approximately one third of cases occur in children younger than 2 years of age, and two thirds occur before age 7405; there is a male predominance.406 Symptoms and signs relate to tumor location. Because most infratentorial lesions arise from the floor of the fourth ventricle, most patients usually present with headache and vomiting, secondary to ventricular obstruction. As ependymomas may arise from or extend through the fourth ventricular apertures, symptoms may include those related to cranial nerve deficit, torticollis, or cerebellar distur-

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bance.406,407 Because of their site of origin near the area postrema, unexplained vomiting may predate the development of other symptoms, and can prompt workup for gastrointestinal disease. Younger children and infants typically have a slightly more protracted duration of symptoms before diagnosis than older children, due to the often nonspecific nature of complaints.408 Supratentorial lesions may present with symptoms of hydrocephalus, focal deficits, or seizures. On imaging studies, fourth ventricular ependymomas may be difficult to distinguish from medulloblastoma, but several characteristics are more common in the former, including the presence of calcification (best seen on CT), and extension through the fourth ventricular foramina, into the cerebellopontine angle or cisterna magna. The signal characteristics are often variable, and most enhance in a heterogeneous manner409 (Fig. 11-5). Complete brain and spinal MRI should be obtained perioperatively, because dissemination may occur in approximately 20% of patients,377 although usually the spread is detected only on CSF analysis and not on imaging studies. Histologically, intracranial ependymomas may be subdivided broadly into benign and anaplastic variants, the former occurring in about 62% to 75% of cases,380,410,411 although the criteria regarding classification has been subject to debate.412 Chromosomal analysis has revealed multiple abnormalities in tumor karyotype, most commonly involving chromosome 22.413

The primary treatment of ependymoma remains surgical resection and control of hydrocephalus, as described previously. Because of their common origin from the fourth ventricular floor, and growth through the posterior fossa subarachnoid space, gross total resections are often impossible,411,414 and are impractical in the event of known dissemination, because the risk of deficit related to brainstem or cranial nerve injury is high. Supratentorial lesions are usually more amenable to total removal. Tumor progression is inevitable when residual tumor remains, however, and the benefits of aggressive resection must be balanced against quality-of-life issues.407 After complete resection, the value of adjuvant therapy is unknown,415 but radiation may be advised, given the risk of recurrence even after a documented gross removal.414 After incomplete resection, radiation therapy has been shown to prolong survival and delay disease progression.411,416–418 Prolonged chemotherapy may benefit infants in whom radiation is delayed,411 but its effectiveness in older children is not known, nor is the most efficacious regimen.419 There is little question that young age at diagnosis and incomplete resection are each associated with shorter survival,414,420 although intensive adjuvant therapy appears to provide some benefit for young children.411 Overall, the 5-year survival rate for patients following incomplete resection is approximately 22%, while total resection improves the rate to 80%.414

Figure 11-5. A and B, Axial T1-weighted postcontrast MR images of an anaplastic ependymoma. There is invasion of the brainstem and right cerebellar peduncles, and extension toward the right cerebellopontine angle.

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Cerebellar Mutism Neurologic deficits related to resection of the posterior fossa tumors described previously typically depend on the degree to which the lesions infiltrate or involve critical neural or vascular structures, and the aggressiveness of the resection; such deficits are often manifest immediately after surgery. A syndrome nearly exclusive to the pediatric population, characterized by the delayed onset of transient mutism and oropharyngeal dysfunction after surgery, is seen in approximately 8% of patients undergoing such resections,421–423 with a higher incidence noted for vermian lesions. The onset of mutism usually occurs after a brief period of normal speech (1 to 3 days), and can last for weeks to months.421,422,424,425 Most affected patients have some degree of swallowing difficulty, emotional lability, or decreased volitional limb movement, which tend to improve prior to the mutism.421,423 Gradually, the mutism is replaced by dysarthric speech, which continues to improve with time. The cause of this syndrome is not known, but damage incurred during resection cannot explain the latent nature of onset. Most cases are associated with splitting of portions of the inferior vermis,421,423 but can occur after opening the superior vermis.426 The anatomic substrate for the mutism and pseudobulbar signs, and the role of cerebellar structures in the initiation and modulation of speech, attention, movement, and cognition in general, are unknown.427,428 Pollack and colleagues421 blindly evaluated postoperative MRI studies of affected and non-affected patients undergoing similar resections, and found that bilateral edema within the middle cerebellar peduncles was strongly correlated with development of the syndrome, although this finding was not absolute; such edema could explain the delayed onset and ultimate recovery of function. They hypothesized that interruption of dentate nuclei efferent and afferent tracts could compromise the volitional input necessary for initiating speech, swallowing, and kinesis.

Brainstem Gliomas Primary brainstem gliomas comprise approximately 25% to 30% of posterior fossa tumors in children.380,429 Before the routine use of MRI, the classification of these lesions, and therefore their treatment, was a problem because the extent of involvement was difficult to ascertain.430,431 Approximately 60% of gliomas are diffuse astrocytomas, and nearly 80% of these diffuse lesions primarily involve the pons, although most extend above or below the pons.431 Diffuse pontine tumors are nearly exclusive to the pediatric population, with median age at diagnosis approximately 7 to 8 years.432,433 Symptoms and signs are usually of short duration, with a median onset less than 1 month before diagnosis. Cranial neuropathies, often bilateral, and cerebellar dysfunction are present in most patients at initial presentation, and long

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tract signs are seen in about half 433; hydrocephalus is generally a late finding, and is rare with diffuse pontine tumors.431 Focal brainstem tumors are less common than diffuse lesions, and symptoms are usually more insidious. Symptoms and signs depend on the level affected, and the presence or absence of hydrocephalus. Lesions within the midbrain commonly present with oculomotor abnormality or pyramidal involvement429,434; tectal tumors often cause aqueductal obstruction, leading to symptoms of hydrocephalus.419, 435 Lesions confined to the lower brainstem or cervico-medullary junction lead to a combination of long tract signs and lower cranial neuropathy. A subclass of tumors that primarily grow into the fourth ventricle in an exophytic manner cause symptoms secondary to ventricular obstruction.436 MRI has revolutionized the understanding of brainstem tumors. Diffuse pontine tumors appear as an enlarged pons, typically with extension into the midbrain or medulla; approximately one third to one half of tumors show areas of enhancement with gadolinium.431,433 The infiltrative aspects are best appreciated on T2 imaging. Focal lesions show variable patterns of enhancement on MRI.431,434 For diffuse pontine tumors, biopsy is usually unnecessary, and may be hampered by sampling error; the majority are malignant astrocytomas on pathologic examination.437,438 In a series of 12 patients, all focal midbrain lesions, both tectal and tegmental, were nonpilocytic, low-grade astrocytomas.434 Focal lesions at the cervico-medullary junction are most often low-grade gliomas, most commonly astrocytoma.439 Treatment and prognosis depend on the type of brainstem tumor. For diffuse pontine gliomas, steroids and radiation therapy may temporarily improve symptoms, but progression is inevitable. Even with aggressive hyperfractionated radiation, approximately one third survive for 1 year, and 10% are alive at 3 years.432 Outlook for patients with tectal tumors is far better; when patients present with aqueductal obstruction, CSF diversion alone is the primary treatment, using shunting, and more recently, third ventriculostomy. Of 16 such patients treated with shunts,419 progressive symptoms developed in only four at a mean of nearly 8 years after diversion. Biopsy specimens of these lesions revealed three benign gliomas, and one anaplastic astrocytoma; all patients were treated with radiation and remained stable more than 4 years after treatment.419 For tumors at the cervico-medullary junction, resection is usually indicated, and can result in long-term survival for nearly all patients, although cranial nerve dysfunction and long tract deficits may remain after resection.440,441 Dorsally exophytic tumors are also treated with resection of the ventricular component, with no attempt to excise tumor infiltrating the brainstem. Of 18 patients treated in this manner, only four showed progression at a mean follow-up of 9 years.436 Radiation may be beneficial for patients with residual tumors after resection, although this component often

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remains quiescent for long periods. Chemotherapy has not shown effectiveness for any type of brainstem glioma.406,430 Craniopharyngioma Craniopharyngiomas are the most common non-glial brain tumor in children, and account for approximately 5% to 9% of pediatric brain tumors.374,442 Although they can arise at any age, there are two fairly distinct peaks of occurrence, the earlier typically occurring in the first or second decades, and a later onset after age 50.443 In children, the mean age at diagnosis is approximately 7 to 9 years.444–446 There do not appear to be racial or gender differences,447 although several series have demonstrated a small male predominance.444,448 Because of their slow growth, and proclivity for the sellar region, presentation is usually due to hydrocephalus, endocrine dysfunction, or visual impairment, with symptoms present an average of 10 months before diagnosis.445 Headache, often with vomiting, is present in more than 75%,446 and visual disturbance due to optic nerve or chiasm compression is present in approximately 60%.444,446 Papilledema is seen at presentation in approximately 30% to 40%.445,446 Although endocrine dysfunction is rarely the sole manifestation of craniopharyngioma, more than 80% of children have abnormal hormonal function at presentation. Growth hormone deficiency can be detected in 75% of affected children; small stature is seen in at least half of patients, and decreased rate of growth occurs in more than 75%.449 Decreased levels of leutinizing or follicle-stimulating hormone occurs in approximately 40%, and disturbances of cortisol and thyroid function each occur in one-fourth of patients.449 Abnormal posterior pituitary function is less common at presentation.449,450 Radiographically, craniopharygiomas can be identified on plain radiographs due to calcification and expansion of the sella, although these studies are now uncommonly performed. These lesions are usually intrasellar and suprasellar in location, although they rarely may be entirely within the sella.451 CT imaging typically reveals a combination of cystic and solid components, with the latter usually showing contrast enhancement; the majority of tumors are at least 50% cystic.452 Calcifications are seen on CT in more than 90% of pediatric craniopharyngiomas.380 MRI is valuable in revealing the tumoral relation to vital structures, such as the anterior cerebral arterial branches, the visual apparatus, and the pituitary stalk and tuber cinerum. In the suprasellar region, tumor growth may be broadly classified as prechiasmatic, subchiasmatic, or retrochiasmatic.380 Prechiasmatic tumors cause posterior displacement of the chiasm and elevation of the anterior cerebral artery branches, while subchiasmatic lesions elevate the optic apparatus. Retrochiasmatic tumors displace the chiasm anteriorly, and involute or grow within the third ventricle. Prechiasmatic tumors have a greater tendency to cause early visual dysfunction, while retrochias-

matic growth may result in signs and symptoms of ventricular obstruction.442,453 Histologically, craniopharyngiomas are benign cystic epithelial lesions, of unknown embryologic origin.454 They are thought to arise from cell rests along Rathke’s pouch, the precursor of the infidibulum and anterior lobe of the pituitary gland. The cystic component typically contains a dark, “crank-case” fluid, often harboring cholesterol crystals. In children, the epithelial component is usually of the adamantinomatous variety, similar in appearance to primitive tooth-forming tissues, while tumors in adults typically harbor a papillary pathology. Keratin nodules are found within the epithelial component of most lesions; this “wet” keratin appearance is nearly unique to craniopharyngiomas. Although the tumors are largely extra-axial in location, adamantinomatous tumors often have foci of brain invasion, usually into adjacent hypothalamic tissue.455,456 The management of craniopharyngiomas includes a thorough preoperative endocrine workup, and correction of hormonal (usually cortisol and thyroid) deficiencies that could impact anesthesia and surgery. Ophthalmologic evaluation is important in identifying evidence of optic nerve or chiasmatic impairment, and for obtaining baseline acuity and visual fields. If time permits, baseline neuropsychological testing may be obtained preoperatively. Hydrocephalus, if present, is usually managed via temporary external ventricular drainage at the time of surgery. The optimal treatment for craniopharyngiomas in children is unknown because the excellent long-term survival seen with most forms of therapy allows more intense focus on quality-of-life issues. These tumors may be managed with surgery alone, limited resection followed by radiation therapy, or intracavitary approaches. Several management algorithms have been advocated, based on factors including patient age, size and location of tumor, presence of hydrocephalus, and hypothalamic function,442,457 suggesting the importance of multiple patient- and tumor-related variables in formulating a treatment plan. Surgery is usually carried out via subfrontal or pterional approach, although subdiaphragmatic lesions can be removed from a transphenoidal approach.443,458 Surgery may be curative, but aggressive resection may be at the expense of permanent endocrine or neurologic deficit. Gross total resection can be obtained in most cases,444,453,459 although adherence to optic or vascular structures, poor visualization, hypothalamic invasion, and dense calcification may preclude total removal.443 Most patients will have permanent pituitary dysfunction, primarily diabetes insipidus, after gross resection,453,459 and depend on lifelong replacement therapy, although sparing the infundibulum reduces the risk of anterior pituitary dysfunction.450 Although visual function often improves after resection, worsened acuity and new field deficits are not uncommon.453,459 Major neurologic deficits, usually related to vascular injury or vasospasm, are relatively uncommon in experienced centers. After documented total

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resection, recurrence is uncommon,442,459 usually less than 20% of cases, and long-term survival is seen in greater than 90%. Limited resection alone usually results in tumor regrowth; the addition of adjuvant radiation offers similar control rates compared to radical resection, and carries a significantly lower risk of major morbidity, especially diabetes insipidus.445,446,460–465 Long-term sequellae after radiation therapy, including endocrine dysfunction, visual impairment, and cognitive difficulty, are not uncommon, however, and usually occur in a delayed fashion.466 Stereotactic radiosurgery may provide tumor control without the morbidity of conventional external beam therapy, although proximity to visual structures may limit its use for tumors in this region467,468; stereotactic radiation therapy may allow equivalent dose delivery without risking long-term visual injury.469 For lesions with a proportionally large cystic component, intracavitary therapy, using bleomycin470,471 or radioactive agents (usually phosphorus or yttrium)472,473 may provide excellent long-term tumor control; worsening of visual function after such treatment is common, occurring in as many as half of patients, while new onset endocrine dysfunction is relatively rare.472 Neurofibromatosis Type I A small subset of pediatric brain tumors occurs in the setting of the phakomatoses. The most common of these neurocutaneous disorders is neurofibromatosis type 1 (NF1), which affects approximately one in 3000 people.474 It is transmitted in an autosomal dominant pattern and is eventually fully penetrant, although with a wide variety of clinical features that tend to become more frequent and severe with age; half of all cases are sporadic mutations.475 The cause of NF1 is due to a mutation on chromosome 17q11.2. The NF1 gene is a tumor-suppressor gene whose protein product, neurofibromin, is a GTPase activator protein (GAP) involved in cell growth regulation.476–478 The mechanism through which loss of neurofibromin activity results in tumorigenesis is unknown. With the advent of modern imaging, greater insight into the neoplastic and non-neoplastic processes affecting the brain of NF1 patients is being uncovered, although it is diffucult to correlate clinical, radiographic, and histologic findings. The most common findings on MRI are areas of increased T2 signal in the white matter of the supratentorial or infratentorial compartment, nearly always without mass effect or contrast enhancement. These unidentified bright objects, present in approximately 60% to 80% of patients, may increase in size and frequency throughout childhood.479–481 The etiology of these foci is uncertain, but given their tendency toward resolution by adulthood,482 and the lack of associated focal deficits, they are thought to be non-neoplastic in nature,480,483 and do not require biopsy or treatment. Gliomas involving the optic nerves, chiasm, or hypothalamus (optic pathway gliomas) are found in approx-

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imately 15% of children with NF1,479,484 although approximately half of these patients have visual or endocrinologic disturbance at the time of diagnosis. Optic pathway gliomas in patients with NF1 may involve only the optic nerve (unilaterally or bilaterally), a pattern that is distinctively rare in non-NF1 patients.485,486 Involvement of the chiasm, seen in nearly all non-NF1 optic pathway gliomas,486 is seen in 70% of NF1 gliomas.485 The clinical manifestations of symptomatic optic pathway gliomas differ significantly between children with and without NF1. Though decreased visual acuity is common in both groups of patients, sporadic cases typically present with symptoms and signs related to increased intracranial pressure or nystagmus, which is extremely rare in NF1. Conversely, symptomatic children with NF1 commonly have precocious puberty or proptosis, which is quite uncommon in sporadic cases.485 The natural history of optic pathway gliomas in these two groups is also vastly different. Whereas most non-NF1 patients experience tumor growth and progression of symptoms if not treated, this occurs in less than 20% of symptomatic NF1 cases followed for more than 3 years.485 Progression is even less common among asymptomatic or minimally symptomatic patients.487 The reasons for the relatively indolent nature of optic pathway tumors in NF1 patients are unknown, because low grade astrocytoma is seen pathologically in all NF1 and nearly all non-NF1 tumors.485 Because of the quiescent nature of these lesions in NF1, they do not require therapy unless significant symptoms develop, and in this event, options for treatment are controversial. Tumors anterior to the chiasm associated with significant proptosis or visual loss may be safely resected. For lesions involving the chiasm, chemotherapy may be preferred, because radiation therapy, the traditional therapy for these unresectable lesions, can lead to cognitive disturbance, endocrine dysfunction, or moyamoya disease.488,489 Gliomas, usually low-grade astrocytomas, occur less commonly in other locations in NF1 patients, such as the cerebellum or cerebral hemispheres. In contrast to the unidentified bright objects described previously, these tumors are associated with mass effect, changes on T1weighted images, and often enhance with contrast material.489 Aggressive resection is usually recommended for these tumors, with adjuvant treatment reserved for unresectable or recurrent lesions, or those with aggressive histologic findings.489 Fewer than 10% of NF1 patients have brainstem tumors associated with mass effect or changes on both T1and T2-weighted images (distinguishing them from unidentified bright objects), and only half of these patients are symptomatic. In a series of 21 such patients, Pollack and colleagues490 subdivided these lesions into diffuse, infiltrating tumors (causing brainstem enlargement), focally enhancing lesions, tectal tumors, and focal, non-enhancing masses. In general, the behavior of most of these lesions was indolent, and therapy was reserved for those tumors exhibiting progressive growth or neurologic deficit, although hydro-

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cephalus was treated if present. Although they were the most common type of tumor in this series, none of the diffuse, infiltrating tumors, so aggressive in patients without NF1, progressed during the course of follow-up, raising the possibility that these lesions may represent a hamartomatous process. The focally enhancing tumors were the most likely to exhibit growth; histologic studies of these lesions showed low-grade, non-pilocytic astrocytoma.490 Neurofibromas are seen in most patients with NF1; they usually come to the attention of neurosurgeons when they are associated with deficit or pain due to spinal or major peripheral nerve involvement. In most instances, these are histologically benign, although malignant degeneration may occur in up to 15% of cases.491 Neurofibromas tend to involve a significant portion of fascicles of the affected nerve, making functional resection difficult, although not unfeasible, for fusiform tumors.491 The less common plexiform neurofibromas, however, involve nearly all fascicles along a significant length of the affected nerve or plexus, and complete resection is always associated with sacrifice of the nerve.491,492 Their behavior may be more aggressive in younger NF1 patients. Neurofibromas causing spinal cord compression are relatively infrequent; when necessary, canal decompression can be performed safely to preserve neurologic function.493 Spinal Cord Tumors Intramedullary spinal cord tumors are uncommon, compromising between 2% to 4% of central nervous glial neoplasms; among intraspinal tumors, intramedullary tumors account for over 35% of pediatric cases, a significantly higher percentage than is seen in adults.494,495 Pediatric spinal cord tumors tend to be evenly distributed throughout childhood, and there is no gender predominance. As opposed to adults, in whom ependymomas are the most common lesion, lowgrade astrocytomas are the most common pediatric tumor, accounting for nearly half of cases.494 In many reports, ependymomas are second in frequency,496,497 and are more common in older children, although in the largest pediatric series to date,494 gangliogliomas were the second most common tumor, accounting for more than one fourth of 164 cases, followed by ependymoma. The reasons for this discrepancy are unknown, and may be related to historical inaccuracy in diagnosing ganglioglioma. Malignant lesions are uncommon in all series. Tumors occur in a relatively even distribution along the spinal cord, and span an average of more than five bony levels.494 Symptoms of benign intramedullary tumors in children are usually insidious, with an average duration of approximately 1 year before diagnosis.494 Loss of function or delay in attaining motor milestones is the most common complaint of parents, seen in approximately two thirds of patients, followed by axial pain, often worse at night. Slowly progressive scoliosis and urinary complaints are each present

in approximately one third of children.494 Cervical tumors commonly present with head tilt, and less commonly, with arm weakness. Hydrocephalus is seen in more than half of those with malignant spinal cord tumors, usually due to meningeal infiltration, and in a small percentage of benign tumors, secondary to rostral extension of tumor or associated cyst toward the obex.498 Because of the slow growth of these tumors, most children have only mild deficits at presentation, with overt plegia being uncommon. Histologically aggressive tumors have a shorter duration of symptoms, and ependymomas, more so than other tumors, often present with bilaterally symmetric dysesthesia.495 While MRI is the procedure of choice for intramedullary tumors, children often undergo plain radiography as an initial procedure, particularly if pain or scoliosis are present before the development of overt neurologic signs. In addition to demonstrating mild curvature, these studies often show a widened canal and increased interpedicular distance, which, if subtle, may be overlooked initially. MRI is of enormous value in operative planning, as the rostral-caudal extent of the tumor may not be apparent on CT scan or myelography. Intrinsic tumors are typically hypointense on T-1 weighted images, and bright on T-2 sequences. Cysts may be present either at the poles or within the tumor itself. Ependymomas tend to be centrally located and usually enhance intensely and homogeneously with gadolinium, while astrocytomas may be eccentric, and show patchy enhancement.499 The optimal management of intramedullary spinal cord tumors in children is controversial.500,501 Although historical as well as recent series496 have noted long-term relapse-free survival in the majority of children treated with radiation therapy without resection, aggressive resection is considered the most effective treatment for low-grade pediatric spinal cord tumors,500,501 and carries a relatively low risk of serious neurologic deficit in experienced centers.494 Gross total resection of ependymomas, which often have a distinct cleavage plane, is associated with 5- and 10-year, progression-free survival rates of 100% and 86%, respectively; corresponding rates for ganglioglioma are 67% and 47%.494 Low-grade astrocytomas, typically more infiltrative into the surrounding cord, are nonetheless associated with long-term, progression-free survival after total or subtotal resection alone.494,500 High-grade neoplasms are associated with the highest rates of recurrance, even after aggressive resection and adjuvant therapy, although long-term survival may be seen in a minority of patients with anaplastic astrocytoma; cord glioblastomas are uniformly fatal within several years. For recurrent, low-grade tumors, resection may again result in long survival, and may be preferred over radiation therapy.494,501 The role of radiation therapy in the treatment of low-grade spinal cord tumors is unclear, because no series has carefully compared this modality against surgery for primary or recurrent tumors. After gross resection, radiation should not be given, as the potential deleterious effects on

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the cord as well as the pediatric spine may outweigh its potential benefit.501 Chemotherapy has no role in the management of low-grade tumors, but may play a palliative role in the treatment of malignant cord tumors in children.502

Vascular Malformations and Disease Cerebrovascular diseases are uncommon in pediatric patients because atherosclerosis, and most vascular malformations and aneurysms, usually become symptomatic during adulthood. Nonetheless, diseases of the cerebral circulation in children remain an important cause of long-term morbidity, and their potential for cumulative damage mandates careful scrutiny and understanding of both their natural history and management. Arteriovenous Malformations Pial arteriovenous malformations (AVMs) usually present during young adulthood, with intraparenchymal, subarachnoid, or intraventricular hemorrhage, new onset seizure, progressive deficit, or headache as the most common symptoms. Most pediatric AVMs manifest with hemorrhage, seen in 80% of cases.503 Sudden headache, neurologic deficit, seizures, or lethargy may occur, depending on the location and extent of hemorrhage. Only 15% to 20% of childhood AVMs present with seizures.503,504 In infancy, congestive heart failure leads to diagnosis in more than half of patients, while approximately one third present with seizures; only 15% of infants present with acute hemorrhage.505 As in adults, most AVMs in children are hemispheric in location (two thirds among a series of 160 patients), while cerebellar and brainstem lesions occur in something less than one fourth of cases.503 The diagnosis of AVM can be suggested on CT scan or MRI, in which acute hemorrhage may be detected. Nidal calcifications are seen in a minority of cases in children; contrasted images may reveal dilated vessels feeding and draining the malformation. While MR angiography can be useful in displaying the nidus, angiography remains the gold standard for depicting the anatomy of the AVM, and should be performed expeditiously in a child presenting with hemorrhage, if the patient is clinically stable. The “classic” appearance is that of an inverted wedge-shaped nidus, with the apex approaching the ventricle, although small, globular niduses or indistinct fistulae can occur. In children, the appearance of an AVM may reflect an immature or developing arterialvenous communication; a “fluffy,” or diffuse-appearing nidus may be indicative of an evolving process.506,507 In a small subset of patients, especially those with large, compressive clots, the presence of a small nidus may be obscured due to mass effect; rarely, an AVM may spontaneously thrombose before hemorrhage. In these situations, consid-

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Table 11-5  Spetzler-Martin Grading Scale for Arteriovenous Malformations Feature • AVM (nidus) size <3 cm 3–6 cm >6 cm • Eloquence Noneloquent Eloquent • Venous Drainage Superficial Deep

Points 1 2 3 0 1 0 1

Grade = total points (1–5); Grade 6 AVM implies large, diffuse, inoperable lesion. Spetzler RF, Martin NA: A proposed grading system for arteriovenous malformations. J Neurosurg 1986;65:476–483.

eration must also be given to the presence of a cavernous malformation as the cause of an occult bleed. Upon the completion of imaging evaluations, AVMs in children can be assigned a Spetzler-Martin grade508 (Table 11-5) based on size, pattern of venous drainage, and involvement of eloquent cortex; smaller AVMs are thought to be more likely than large lesions to present with hemorrhage in children,503 similar to those seen in adults. Historically, AVMs have been presumed to be congenital lesions arising from anomalous formation of capillary and arteriolar channels, although the causes remain elusive. Mullan and colleagues509 believe that AVMs develop due to errors in the formation and subsequent absorption of cortical surface veins, usually after 9 to 10 weeks’ gestation. AVMs most commonly present during adulthood, and growth or enlargement of these lesions is well known to occur after birth, suggesting that other mechanisms, such as hemodynamic vascular recruitment or humoral factors, may be involved in the development of clinically relevant AVMs. Recent work has shown increased expression of vascular endothelial growth factors in recurrent AVMs, which lends credence to postnatal factors in their genesis.510 The majority of AVMs occur as isolated phenomena, although multifocal lesions have been reported511; AVMs may also be associated with familial disorders, such as hereditary hemorrhagic telangiectasia.512 The natural history of AVMs in children is unknown, because most children present with hemorrhage and are therefore not managed expectantly. AVMs presenting in childhood may have a higher frequency of eloquent brain involvement, especially thalamic, basal ganglia, or posterior fossa structures,503,504 compared to adult patients. The annual risk of bleeding of a newly discovered AVM is probably not different between children and adults, but the lifetime risk in children is obviously much higher; if one assumes an annual bleed risk of 3%, the chance of eventual hemorrhage equals 1-0.97x, where x equals the remaining years of expected life.513

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The optimal treatment strategies for children harboring AVMs is unknown, because the largest reported series have been biased toward a single mode of treatment, either surgical503 or endovascular,514 and the options available for treatment are constantly improving. The goals of intervention are elimination of lifetime bleeding risk and preservation of function. For small and accessible lesions (Spezler-Martin I and II), surgery alone can achieve cure in the majority of patients.503,515 Endovascular procedures alone historically result in cures in approximately 5% of patients,516 and are usually a prelude to other forms of treatment. Multimodality therapy, including surgery, embolization techniques, and radiation surgery, is becoming increasingly common for the management of large or poorly accessible lesions. A recent series of 40 pediatric patients treated with multimodality therapy demonstrated anatomic cure in more than 90% of patients completing treatment.504 Radiosurgery is particularly successful for smaller pediatric AVMs, with obliteration rates of 80% for lesions less than 3 mL in volume, although the reported overall cure rate of less than 60% at a mean of 3 years follow-up implies a continued risk of hemorrhage in a significant number of patients.517 The ultimate outcome of children with AVMs is strongly related to condition at time of presentation, as well as the resultant morbidity associated with future hemorrhages in incompletely obliterated cases.503,515 Most patients presenting in good condition after hemorrhage remain so after treatment,503,504 with new deficits relatively uncommon in current practice. In patients with unresected or incompletely obliterated AVMs, nearly 40% suffered recurrent hemorrhage.503 Seizures are typically reduced after treatment; 11 of 15 patients were seizure-free after radiosurgery,518 and nearly 60% remained so after resection.503 Even after complete obliteration, children are at risk, albeit low, for delayed recurrence or regrowth. Kader and associates519 reported five such recurrences, from 1 to 9 years after angiographically confirmed resection, and none in more than 650 adults from the same institutions. Although they postulated that spasm or mass effect could have led to a false-negative postoperative angiography result, the absence of recurrent lesions in adults implied an inherent difference in pediatric AVMs, suggesting that AVMs in children may be in a dynamic state of development. Subsequent analysis by this group confirmed higher rates of astrocytic endothelial growth factor in the original specimens of the recurrent patients compared to controls.510 The authors indicated that children may benefit from delayed angiography to assure continued obliteration.

tures. In general, the manner of presentation depends on age. Neonates usually have high-output cardiac failure; hydrocephalus or seizures develop in infants; and older children and adults present with hydrocephalus, hemorrhage, seizures, or neurologic deterioration; most cases present within the first several years.520–522 In neonates and infants, cranial bruits are often present, and the diagnosis must be suspected in patients with unexplained cardiac failure that is usually unresponsive to medical management. Imaging studies reveal a midline mass in the area of the vein of Galen, often in association with hydrocephalus; CT scan may reveal diffuse calcifications secondary to prolonged ischemia. Angiography remains essential in evaluating the architecture of these malformations. Yasargil523 described four types of malformations: type I malformations have one or several feeders, usually from the pericollosal or choriodal arteries; type II malformations are fed primarily from posterior cerebral or thalamoperforator branches; type III lesions are a combination of types I and II. Types I to III are true subarachnoid fistulas, while type IV malformations are parenchymal AVMs with secondary dilatation of the vein of Galen. The causes of anomalous communication between primitive deep arterial feeders and the vein of Galen, or its precursor, the median prosencephalic vein of Markowski, are unknown.522,524 The ultimate endpoint of therapy for true vein of Galen malformations is elimination of the anomalous fistula, although the immediate goal of treatment is often a reduction of abnormal flow to a point where patients are rendered clinically stable. Before the advent of modern endovascular techniques, the treatment for vein of Galen malformations was surgical interruption of the fistulae,520,521,525 often complicated by high rates of permanent morbidity or death; most untreated patients, especially neonates, succumbed to complications secondary to cardiac failure. Surgery is now generally reserved for treatment of hydrocephalus and to provide access for transtorcular embolization.522,526 Most modern series describe transarterial or transvenous endovascular approaches, alone or in combination, occasionally using transtorcular embolization. While less than half of malformations are completely obliterated in this manner, symptoms secondary to shunting are reduced in the majority of patients.522,527–530 The majority of patients now survive, usually with no or minor neurologic deficits, with the highest mortality rates in neonates with cardiac failure.522,527–529 Patients with residual lesions can undergo staged endovascular procedures if symptoms persist, whereas asymptomatic patients can be observed expectantly.

Vein of Galen Malformations

Cavernous Malformations

Vein of Galen malformations are a rare subclass of pediatric vascular malformations, characterized by high flow arterial shunting through the galenic system, usually in association with aneurysmal dilation of the midline deep venous struc-

Cavernous malformations are angiographically occult vascular lesions that can present at any age, though they are relatively rare in the elderly. In large series, most patients become symptomatic by the fourth decade of life, with pedi-

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atric patients comprising approximately one fourth of patients531,532; the average age in a series of 40 pediatric patients was approximately 10 years.533 A bimodal distribution within children may exist, with one peak during the first several years, and a later peak in the early teens.534,535 As with pial AVMs, children most commonly present with focal deficits related to hemorrhage; seizures, headache, and irritability are less prevalent,533,536 although in early reports, seizures were the most frequent symptom.534 Increasingly, incidentally discovered lesions have been noted, especially with MRI screening of family members of affected patients. The deficits incurred by hemorrhage are generally less severe than those associated with AVM. Cavernous malformations are multiple in up to 25% of children.533,537 Familial clustering of cavernous malformations are noted in up to 30% of patients, most notably in the Hispanic population, and has usually been linked to chromosome 7q,538–541 although other foci exist.542 Imaging studies are usually successful in revealing areas of hemorrhage, although the malformation may be obscured by blood products. CT is excellent for depicting acute blood and calcifications, although MRI is the more sensitive study, and often reveals a lesion of mixed intensity, indicating areas of both recent hemorrhage as well as hemosiderin deposition. MRI is often superior to CT in depicting multiple lesions, especially those that have not bled.537 Cavernous malformations may occur anywhere along the central nervous system, including the spinal cord; they are most common within the hemispheres, but brainstem lesions are present in approximately one fourth to one third of patients.533,543 Pathologically, cavernous malformations are composed of thin-walled, dilated vascular channels, often filled with clot, and with little or no intervening brain; on an ultrastructural level, these channels lack a collagen support matrix, and the endothelial cells lining the malformation often lack tight junctions.544 Associated venous angiomas are often seen in proximity to cavernous malformations, especially in the posterior fossa.545,546 The natural history of cavernous malformations in adults is becoming better characterized, with annual risk of hemorrhage less than 1% in patients presenting without a bleed, and 4.5% for those presenting with hemorrhage.543 In children, however, the natural history is not well known; as with AVMs, children presumably have a greater overall risk of future bleeds. These malformations can arise de novo after exposure to ionizing radiation,547,548 and new lesions may occur in more than one fourth of patients with familial malformations,549,550 and less commonly in non-familial cases. Lesions can also exhibit significant growth over time in children, likely secondary to microhemorrhage and subsequent angiogenesis.533 Surgery remains the mainstay of treatment for symptomatic malformations in children. It is recommended for all symptomatic patients with surgically accessible lesions, because complete resection eliminates the potential for hem-

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orrhage, and eliminates or reduces seizure frequency in most patients533,551; incomplete removal is not protective. For children with incidentally discovered lesions, treatment options include observation, with resection only after documented radiographic change or onset of symptoms, or prophylactic resection. For patients with multiple lesions, only the symptomatic lesion should be addressed surgically, although resection of clinically silent lesions may be considered if accessible through the same approach. Brainstem malformations are usually resected only when the lesion or clot extends to a pial surface, or in cases of progressive neurologic deterioration533,552; these lesions are the most technically challenging, but can be managed safely in experienced centers.553,554 Radiosurgery has been described for patients with inaccessible lesions, and may reduce the annual hemorrhage rate in those with frequent bleeds,555,556 but the results have been largely disappointing557,558; its effect in pediatric cases is unknown. Moyamoya Disease Moyamoya disease is a disease of unknown etiology characterized by cerebral ischemia or hemorrhage, secondary to progressive occlusion of the distal carotid arteries and anterior circle of Willis, and the development of compensatory collateral circulation. The disease is relatively rare in the Western hemisphere, and is most prevalent in Japan, and less so in other Asian cultures.559,560 The disease is most prevalent in children, with a second peak in the third and fourth decades.561 Nearly all affected children present with transient or permanent deficits secondary to ischemia, often precipitated by bouts of hyperventilation, and often associated with headache; seizures or hemorrhage may uncommonly be the initial manifestation.559,560,562 The long-term consequences depend on the ishemic damage incurred prior to the development of sufficient collateralization, but a gradual worsening of cognitive function has been noted in untreated patients.563 Approximately 10% of Japanese cases are familial,561 although this tendency is not present in Western cultures. CT or MRI may show areas of ischemia or infarction, but angiography remains central to the diagnosis. Angiographic changes include progressive stenosis or occlusion of the anterior circle of Willis, and the subsequent development of enlarging collateral vessels, initially from the basal perforators off the circle of Willis (which appear similar to a puff of smoke, “moyamoya” in Japanese), and later from the extracranial circulation, which gradually fill the middle cerebral territory.564,565 The process is nearly always bilateral. Nuclear blood flow studies usually show reduced perfusion at baseline, and more commonly, diminished reserve.560 The cause of moyamoya disease is unknown, and by strict definition is an idiopathic process, without associated syndrome or illness; similar vascular changes can be seen in children after whole brain radiation, and in children with neurofi-

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bromatosis type 1 (NF 1); interestingly, linkage analysis in Japanese families has shown a focus on chromosome 17q, the site of the gene responsible for NF 1.566 The treatment for moyamoya involves surgical augmentation of collateral flow to areas at risk for permanent ischemia. More than 40 procedures have been described, and can be broadly categorized into direct and indirect anastomoses559; it is uncertain whether any technique is superior. The direct procedures involve a surgical bypass, usually from superficial temporal artery to middle cerebral artery, while indirect procedures usually involve placement of inverted dura, scalp vessels (usually superior temporal artery), temporalis muscle, or a combination of these directly on the brain surface. Some series combine direct and indirect anastomoses, and procedures are commonly performed on both hemispheres. In general, most current procedures result in long-term clinical stabilization and elimination of ischemic symptoms in the majority of patients, and delayed angiography usually reveals robust extracranial-to-intracranial collateral vessel development. Indirect procedures are increasing in popularity,559 and reports have shown favorable clinical and radiographic outcome in most patients.562,567 Three fourths of patients have no further ischemic symptoms after the first year, which is far faster than the natural course of the disease,568 although postoperative infarction may occur in up to 10% of patients.569 Indirect procedures may be most suitable for children, in whom the small vessels make direct anastomosis difficult. Because most children stabilize after surgery, the long-term outcome is usually related to the presence of a fixed deficit before the development of collateral circulation. Young children (younger than 3 years) are more likely to suffer a significant preoperative stroke than older children, and thus have a poorer prognosis.570

Infectious Disorders Bacterial infection may occur within any intracranial compartment, including the subdural and epidural spaces, or within the brain parenchyma or cerebrospinal fluid pathways. With the exception of shunt infection, the incidence of these processes in children is low in Western societies, where better access to health care and the availability of antibiotics have resulted in effective treatment for many of the conditions predisposing to such infections. The potential for significant morbidity, if improperly diagnosed or treated, and the common occurrence among certain populations, mandate a thorough understanding of the causes and management of intracranial bacterial infections. Subdural Infection (Empyema) Causes of subdural suppuration are typically a reflection of patient age, and may also vary with respect to geographical

location or patient population. Subdural empyema is primarily a disease of children and young adults, and for unknown reasons, there is a strong male predominance.571,572 More than 85% of 699 recent (CT era) cases from a native South African population occurred in patients less than 20 years old, with 32% of the total occurring in children 10 years or younger, and 54% occurring in the 11- to 20-yearold age group.571 More than 70% of 102 cases in children ages 5 years and younger were associated with meningitis, while 86% of infections in older children and teenagers were the result of paranasal sinus disease; only 8% of pediatric cases were secondary to an otogenic source, although chronic middle ear infection was the most common etiology in an Indian patient population.573 In the United States, sinusitis remains the most common condition predisposing to subdural infection in children, and is seen primarily in the second decade,572,574,575 after development of the paranasal sinuses; otogenic sources are a less common cause.576 A recent study of intracranial infection highlighted the relative rarity of pediatric cases, 7%, in a United States tertiary care setting; two thirds of the 41 cases were of postoperative origin, and the mean age was 50 years.577 Infection usually spreads from thrombophlebitis of valveless extracranial and intracranial veins, although direct extension may uncommonly occur. In infantile meningitis, a significant percentage of patients develop subdural effusions in response to the infection; although these collections are usually sterile, empyema may result from inoculation of the fluid.578 Less common causes of subdural infection in children include trauma, scalp infection, or iatrogenic inoculation, in which staphylococcal species predominate. Overall, streptococcal species are the most frequently isolated organisms, although mixed flora and negative culture results are also common.571,579 In infants, Hemophilus has been the most common pathogen, followed by aerobic Streptococcus,578,580 although immunization against the type B may lower the prevalence of Hemophilus. The symptoms and signs associated with subdural empyema depend on the age of the patient, the underlying cause, and the site and severity of infection. Infantile infections, usually due to associated meningitis, typically present with fever (refractory to or recrudescent after antibiotics), bulging fontanelle, and lethargy; seizures are not uncommon.581 Older children and teenagers usually have a history of recent or chronic otorhinologic symptoms, although purulent discharge may be absent571; fever, headache, lethargy, and seizures are the most common complaints. A significant number of patients have a depressed level of consciousness and focal deficits, including hemiparesis and cranial neuropathy, and facial swelling may be present.571,572,579 Infratentorial empyema, usually the result of mastoid or middle ear disease, typically presents with depressed level of consciousness, fever, and ear drainage. Meningismus and signs of increased ICP are common, while focal signs are less prevalent.581

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The diagnosis of subdural empyema may be suspected on clinical grounds. Ancillary test results such as from white blood cell count and sedimentation rate are usually abnormal, but are nonspecific, and blood culture specimens are frequently sterile. CT reveals the presence of a hypodense or isodense subdural fluid collection, usually with rim enhancement and associated mass effect, although MRI is more sensitive582; associated paranasal or mastoid disease is detected on most studies. Associated osteomyelitis, epidural infection, and parenchymal abscess may be present, and venous thrombosis is an unusual but potentially devastating occurrence. Empyemas are usually seen overlying the convexity, with frontal and panhemispheric collections most common, although interhemispheric collections are frequently seen.571,579 Treatment involves the use of prolonged intravenous antibiotics and surgical drainage; an attempt should be made to obtain culture specimens before antibiotic administration, and associated sinus or middle ear collections should be evacuated. Anticonvulsants are initiated if seizures have occurred, and are often given prophylactically. Subdural pus may be drained via burr-hole or open craniotomy; although the former approach can be adequate in select cases,579 an open procedure may allow a more aggressive and thorough drainage,580,581,583 and may reduce the need for subsequent procedures. Infants can be treated successfully with percutaneous subdural taps or catheter drainage.578,584 Serial imaging is required during treatment to ensure that no reaccumulation has occurred. In the modern era, mortality is usually less than 15%, and is usually seen only in those with advanced cases at the time of presentation.579,585 Detailed large-scale outcome data specific to children are lacking; in the South African study of 699 patients, most of whom were children or teenagers, seizures, focal deficit, or other permanent morbidity were noted in one fourth of survivors.571 Bok and Peter579 reported excellent outcome for 70% of 70 patients 20 years or younger. Mortality in this group was 9%, and 6%, all age 5 or younger, were left with severe handicaps. Epidural Infection Isolated epidural abscesses are significantly less frequent than subdural infections; in areas where intracranial suppuration remains common, subdural empyema is nine times more frequent,585 and epidural abscess associated with subdural empyema is more frequent than isolated epidural infection. Like subdural infection, epidural abscess usually affects older children and teenagers, with more than 80% of cases reported during the first two decades.585 Paranasal sinus disease remains the culprit in three fourths of young patients, with middle ear infection responsible for most of the remaining cases. Because meningitis does not predispose to epidural infection, the process is rare in the first 5 years.585,586 In the United States, epidural abscess may be a

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more frequent complication of otorhinologic disease than subdural empyema.587,588 The bacterial profile and pathophysiology is similar to that seen in subdural empyema, although the reasons for confinement within the epidural compartment are not clear. Fever, headache, and facial swelling are common, although symptoms are more insidious than in subdural infection, and focal signs and lethargy are exceedingly rare; seizures occur in approximately 10%.585 Subgaleal abscess (Pott’s puffy tumor) is seen in slightly less than half of patients (Fig. 11-6). CT imaging, and especially MRI, reveal the presence of a rim-enhancing extradural process, and the distinction between intradural and extradural infection is usually apparent.582 Treatment principles are the same as those for subdural empyema, although burr-hole drainage may be more successful in the setting of epidural infection. Nearly all patients have excellent outcomes. Brain Abscess Parenchymal brain abscess is the most serious of the intracranial suppurative processes; despite advances in diagnostic and treatment modalities over the past 30 years, and improved survival, there remains a significant potential for long-term sequelae in affected children. Like other forms of intracranial infection, brain abscess is strikingly common in the pediatric population,589 although the conditions with which it is associated are more diverse than those in extra-axial infection, and again depend on the population examined. Cyanotic congenital heart disease, especially tetralogy of Fallot, and other conditions with right-to-left cardiac shunting are among the most common associated conditions in children with brain abscesses in many recent series.589–593 Of 149 patients with brain abscesses, 103 were associated with cardiac shunting; more than half of these were seen in children 10 and younger, and three fourths occurred in the first two decades of life.592 Meningitis is the most common antecedent in neonates and young infants, but can lead to abscess formation at any age.589,590,593–595 Otorhinologic sources are responsible for a significant percentage of brain abscess, although they were found to be the cause in less than 15% of recent cases in the United States,587 and in only 6% in a large Chinese report593; otitis and mastoid infection appear to be far more important than paranasal sinusitis.591,595 Trauma is an important cause in most pediatric series, usually seen in teenagers, although it remains more common among adults. Interestingly, no known antecedent is noted in up to 40% of cases,591 although this figure is significantly lower, approximately 5% to 15%, in most large pediatric series.589,590,593 These cases are usually presumed to be the result of bacteremic spread from an occult source, such as lung or soft tissue. The presentation of intraparenchymal abscesses reflects the infectious and space-occupying nature of these lesions. Combining four pediatric series totaling 346 patients,589–591,593

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Figure 11-6. Noncontrast CT scan of an epidural abscess, presumably from sinus disease. A, The extensive subgaleal involvement over the forehead (Pott’s puffy tumor) is demonstrated. B, The epidural abscess causes mild mass effect on the frontal lobes.

headache was the most common sign or symptom (62%), followed by vomiting (53%), papilledema (53%), fever (46%), seizures (31%), and hemiparesis (32%). Patients who were alert and neurologically normal were exceedingly rare, as were deeply comatose patients (each seen in less than 10%); approximately one third were alert and with minor or moderate deficts.589 Another one third were obtunded, with moderate deficit, and approximately 15% were stuporous, with severe deficit.589 The pathogenesis of abscess formation is complex, and varies according to the primary cause, as does the responsible pathogen. Patients with cyanotic cardiac disease are at risk for several reasons, including the lack of normal pulmonary filtration, low oxygen tension, and polycythemia and elevated blood viscosity; this scenario sets the stage for bacterial deposition from septic emboli within abnormally perfused and oxygenated brain. Abscesses are multiple in approximately one third of these patients, and are classically found in the middle cerebral distribution at the grey-white interface; a wide variety of pathogens is seen, most commonly Peptostreptococcus, Staphylococcus, and Streptococcus species, although negative culture results are quite common.591,592 Infection from the middle ear, mastoid, and paranasal sinuses gains access to the brain via a similar

thrombophlebitic process seen in other forms of intracranial suppuration, and are usually solitary. Temporal or cerebellar abscesses generally result from an otogenic or mastoid focus, whereas paranasal sinus disease, more common in older children and teens, usually results in frontal abscess formation. The organisms cover a wide spectrum, and are often mixed. Abscesses due to neonatal sepsis and meningitis occur in any location, and are often multiple; their occurrence may result from an infectious vasculitis.596 The most frequent organisms are those seen in neonatal sepsis and meningitis, including group B Streptococcus, Escherichia coli, and Proteus species. Citrobacter diversus abscesses may complicate meningitis in more than 75% of affected patients.597 Direct focal bacterial deposition may occur as a result of open fracture, surgical procedure, or other penetrating injury, and are due to Staphylococcus or mixed flora. After bacterial inoculation, the infected brain responds with a characteristic pattern of inflammatory changes, initially with a focal area of cerebritis, progressing over several weeks into an encapsulated mass containing necrotic, purulent brain.598 These changes are reflected on CT and MRI, which may not show the classical rim-enhancing necrotic mass early in the course of abscess development. MRI is more sensitive in demonstrating small areas of infection,

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particularly in the case of multiple abscesses, and more clearly demonstrates the relationship of the abscess wall to the ventricular system, which has important implications for management and outcome. The treatment strategy for intracranial abscess in children is no different than that of adult infection; goals are eradication of any primary source, bacterial identification, longterm antibiotic therapy, and, in most cases, drainage or excision. Very small lesions, or those in the earliest stages of cerebritis may be cured with antibiotic therapy alone,599 but in the absence of organism identification (blood culture, sinus aspiration), some form of drainage is necessary. Modern imaging has revolutionized the treatment of bacterial abscesses, and increasingly, aspiration techniques are being used for management,589,591,600,601 often coupled with image guidance. Such techniques are often more practical and less morbid than open excision, especially in cases of multiple abscesses, and may be preferable in children.591,602 In the pre-CT era, mortality rates for brain abscess ranged from 25% to 50%, while recent pediatric series generally report rates below 15%589,591; severely affected neonates remain at higher risk than older children. Intraventricular rupture is associated with a significant risk of death and disability,592 as is an initial moribund presentation. Long-term morbidity, especially intellectual impairment, remains high, especially among infants and young children.594,603,604 Pediatric Movement Disorders In the past 15 years, the pediatric neurosurgeon has assumed a greater role in the treatment of pediatric movement disorders. The two most common disorders, spasticity and dystonia, are usually seen in the setting of cerebral palsy, a condition occurring in approximately two per 1000 live births,605 although any cause of brain injury, including trauma, tumor, cerebral ischemia, or infection, as well as hereditary and metabolic disorders, may result in spasticity, dystonia, or a mixed disorder. The treatment of children with movement disorders has traditionally involved a multidisciplinary approach, using oral medications, rehabilitative therapy, orthopedic intervention, and neurosurgical procedures, including intramuscular botulinum injection, dorsal rhizotomy, and intrathecal baclofen delivery. Spasticity is defined as a velocity-dependent increase in muscle tone, often associated with hyperactive deep-tendon reflexes, weakness, and a breakdown in isolated movements and coordination. Affected patients may also have pain associated with tonic muscle contraction, and long-standing spasticity can result in contracture development and joint deformity. Any insult to the descending inhibitory tracts within the brain or spinal cord may interfere with segmental reflex circuitry, and result in a disorder characterized by spasticity, but the exact pathophysiologic mechanisms responsible for increased tone are unknown.606 Spasticity may be manifest in the lower extremities (spastic diplegia),

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all extremities (spastic quadriplegia), or may be unilateral. Dystonia, which often co-exists with spasticity in braininjured patients, is characterized by involuntary and sustained muscular contraction, resulting in abnormal twisting and repetitive movements, or abnormal postures607; such abnormal movements may increase in severity with attempted voluntary activity, or during periods of excitement or startle. Primary dystonias are hereditary disorders, many which have known genetic loci and patterns of inheritance,608 while secondary dystonias are due to an acquired insult to the developing or mature brain, usually within the basal ganglia. Heredo-degenerative dystonias are seen in the context of progressive neurologic or systemic conditions, such as Huntington’s disease or HallervordenSpatz disease.608,609 Dystonia can be focal or segmental in nature, or can involve only one side of the body (hemidystonia). Generalized dystonia, involving both axial and appendicular muscle groups, is the pattern most commonly seen in the context of cerebral palsy and the degenerative conditions. The specific pathways involved in the genesis of dystonia are unknown. Lesions affecting the feedback loop between the motor cortices and basal ganglia, causing impaired inhibition of the motor cortex, may lead to dystonic movement,610–612 although the exact pathophysiologic disturbances are an area of controversy. The evaluation of a child with a movement disorder requires a detailed perinatal history and evolution of the disability over time. If the cause of the disorder is in doubt (absence of prematurity, hypoxia, or other known insult), a careful family history must be obtained, and genetic or metabolic testing may be required if such a disorder is suspected. Brain MRI may not be necessary in cases which are clearly due to perinatal insult, but is needed to search for structural lesions that can impact motor function in questionable cases; imaging may be helpful to assess ventricular size, as well as basal ganglia or white matter lesions in patients with cerebral palsy. Input from a multidisciplinary team requires a thorough assessment of the type and severity of the movement disorder, addressing not only the abnormal motor pattern, but also the degree to which this affects strength, coordination, and function. Spasticity is usually assessed utilizing the Ashworth scale, a five-point grading system based upon resistance to passive range of motion, in which a score of 1 is normal tone, and 5 is a rigid, immobile limb.613 Dystonia is assessed by observing the patient’s pattern of involuntary movement at rest, and often during volitional activity. A variety of scales have been used to grade dystonia; the recently described Barry-Albright dystonia scale assesses the severity and distribution of dystonia, as well as its impact on function.614 Input from patients and parents regarding goals of treatment is a vital part of the evaluation process, and has important implications for decisions regarding therapeutic intervention. The optimal treatment of a patient with spasticity depends on the age of the patient and the severity of the dis-

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ability. Mild spasticity may not require any treatment, particularly in cases of spastic diplegia associated with cerebral palsy, as some children are only minimally incapacitated, and may actually improve with time.615 For most children with spasticity, oral agents, alone or in combination, are the initial form of therapy. Baclofen, a GABAB agonist, reduces spasticity by causing hyperpolarization of neurons in the spinal cord, resulting in enhanced presynaptic inhibition. In a double-blind study, baclofen was found to be effective in reducing tone in children with spasticity due to cerebral palsy.616 Benzodiazepines also increase postsynaptic inhibition by enhancing the affinity of GABA to the GABAA receptor, and are effective at reducing tone in children with cerebral palsy.617 The beneficial effects of both baclofen and the benzodiazepines may be limited by sedation, and cessation of either of these drugs may be associated with withdrawal. Alpha-2 adrenergic agonists, such as tizanadine, decrease spasticity by interfering with excitatory amino acid release618 and inhibition of spinal cord interneuronal activity.619 Multiple double-blind, randomized studies have demonstrated efficacy in tone reduction similar to baclofen and benzodiazepines in adults with spasticity from various causes,620,621 although tizanidine’s effect in children has not been similarly evaluated. Dantrolene inhibits calcium release from the sarcoplasmic reticulum, inhibiting excitationcontraction coupling within skeletal muscle. Although it has been shown effective in treating spasticity in children with cerebral palsy,617 its use has been supplanted by newer, centrally acting agents. Botulinum toxin type A (Botox) is a purified form of one of the seven serotypes of toxins produced by Clostridia botulinum, and causes muscle weakness by binding to presynaptic cholinergic nerve terminals at the neuromuscular junction, inhibiting release of acetylcholine into the synaptic cleft.622 In patients with spasticity, botulinum toxin type A is injected directly into spastic muscles, resulting in temporary weakness, to equilibrate agonist-antagonist forces across the affected joints. The clinical response begins within several days, peaks within a few weeks, and lasts for several months, as vesicle turnover at the motor end-plate restores cholinergic transmission. Botulinum toxin type A therapy for children with spasticity is usually combined with oral agents and aggressive physiotherapy; because it only works on a temporary basis, serial injections are usually used in younger children until more definitive forms of therapy, if necessary, are used. Multiple double-blind, randomized studies have demonstrated functional improvement in children with cerebral palsy and other forms of spasticity,623–626 with a paucity of side effects. By directly causing muscular relaxation, botulinum toxin type A therapy may reduce the development of contracture formation, delaying or potentially obviating orthopedic intervention.627 The sectioning of dorsal rootlets involved in the spastic reflex response was described in the early 1900s, although the popularity of selective dorsal rhizotomy for the treatment of

spasticity escalated after Peacock’s reports in the 1980s demonstrated its efficacy for children with spastic cerebral palsy.628,629 The ideal candidates for the procedure are children with spastic diplegia, approximately 4 to 8 years old, who are independent or partially dependent ambulators; relative contraindications include the presence of significant dystonia or upper extremity involvement. The procedure performed in most centers involves a multilevel osteoplastic laminotomy, intradural stimulation of individual dorsal rootlets between L2 and S2, and the sectioning of those with abnormal electrophysiologic or clinical responses, although the validity of the electrophysiological parameters used to “selectively” cut individual rootlets has been questioned.630 Outcomes after selective dorsal rhizotomy have been the subject of multiple reports that were recently analyzed by Steinbok.631 In this evidence-based review of 63 articles, the procedure was deemed effective in reducing lower extremity tone, increasing range of motion, and improving lower extremity function. Additionally, there was weaker evidence that rhizotomy may improve upper extremity function via suprasegmental interneuronal effects in some patients, and may reduce the need for subsequent orthopedic procedures.631 Intrathecal baclofen (ITB) has become an increasingly popular treatment for children with spasticity due to its ability to concentrate the drug at its site of action within the spinal cord, while minimizing the side effects associated with systemic delivery. Candidates for ITB include patients with spasticity or a mixed movement disorder, if they are of sufficient size to accommodate a pump. Response to ITB is usually gauged via instillation of a test dose via lumbar puncture, with subsequent implantation of an externally programmable pump and intrathecal catheter in those with clear improvement in lower extremity tone. The use of ITB has been shown to be beneficial in children with spasticity due to CP and other insults.632–634 Unlike rhizotomy, ITB may be used in patients with spastic quadriplegia or dystonia. Additionally, ITB is not a destructive procedure, and the dose can be titrated to effect. Its main disadvantages include the need for serial pump refills and eventual replacement, and the risks of pump or catheter dysfunction, and less commonly, infection.633 ITB has not been subject to the same level of scrutiny as rhizotomy, and there have been no reports prospectively comparing the efficacy of these procedures, although the cost of ITB therapy is significantly higher than that of rhizotomy.635 The treatment of dystonia in children is often more challenging than that for spasticity. Generalized dystonia, the pattern most prevalent in cerebral palsy, may be modestly improved with oral baclofen, but the doses necessary to impart significant benefit are often associated with unacceptable sedation. The anticholinergic agent trihexyphenidyl may be used alone or in combination with baclofen in cases of generalized dystonia, and appears to be more effective in younger patients, with a lower side-effect profile.636,637 One

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P earls 1. The recent Shunt Design Trial6 found no differences in complication or shunt survival rates among standard differential-pressure, anti-siphon (Delta), or flow-limiting (Orbis-Sigma) valve systems in 344 children randomized at first shunt insertion. The overall rates of shunt obstruction (31.4%) and infection (8.1%) were not significantly different between the systems. Kaplan-Meyer analysis showed shunt survival rates of 61% and 47%, at 1 and 2 years, respectively. 2. Most shunt infections occur within several months of insertion, with Staphylococcus epidermidis and Staphylococcus aureus the most common organisms isolated.87 Fever, irritability, signs of shunt malfunction, and erythema around the incision site are the most common findings. Uncommonly, infection can present in a delayed fashion88; these cases are notable for the frequent association with abdominal pseudocyst, and the variety of organisms isolated, including enteric flora. 3. A prospective evaluation of risk factors for infection in 299 patients undergoing shunt placement was recently reported.93 The rate of infection was 10.1%, with Staphylococcus species the most common isolated pathogens. Postoperative CSF leak, contamination of implant by a breached glove, and patient age less than 40 weeks’ gestation were found to be significant risk factors. 4. MMC is immediately apparent at birth, as an open spinal defect, usually at the lumbar or sacral level; thoracic lesions account for approximately 20% of lesions, and cervical MMC is rare. 5. Despite its nearly universal presence in MMC, Chiari II malformations become symptomatic in only a minority of patients, approximately 10% to 20%,128–130 resulting in lower cranial nerve dysfunction (stridor, nasopharyngeal regurgitation, aspiration, apnea), quadriparesis, and cerebellar signs. Symptoms secondary to lower cranial neuropathy may be life-threatening.

of the primary dystonias is characterized by dramatic response to l-dopa therapy,638 although this agent is not effective for the secondary dystonias. Botulinum toxin type A can reduce dystonia by its effect on the neuromuscular junction, and is most practical for patients with nongeneralized involvement639,640; intramuscular injection may secondarily affect cortical excitatory and inhibitory circuitry, as measured by response to transcranial magnetic stimulation.641 The use of intrathecal baclofen for generalized dystonia in children has recently been shown to be effective

6. In spina bifida patients with symptomatic spinal cord tethering, stabilization or improvement can be seen in many cases, especially with respect to pain, if detethering is performed during the early onset of symptoms. Scoliosis tends to stabilize if untethering is performed before the curvature has progressed past approximately 40 to 50 degrees.140,141 7. Because of the near universal development and progression of deficits in patients with tethered cord due to lipomyelomeningocele or fatty filum, most authors advocate surgery at the time of diagnosis, to prevent or stabilize neurological dysfunction. Bladder dysfunction is unlikely to recover completely after it is lost, and motor signs may not improve significantly once progressive weakness occurs. 8. The pathogenesis of syrinx formation in Chiari malformation (CM1) is unknown; recent reports analyzing CSF flow and subarachnoid pressures in both CM1 patients and unaffected controls revealed that tonsillar impaction at the foramen magnum results in elevation of the cervical subarachnoid pressure, forcing CSF transmurally into the cord from the subarachnoid space.195,196 9. Because of vague circumstances surrounding shaken baby (impact) syndrome, abuse is typically inferred from examination and findings on cranial and skeletal imaging. The diagnosis has no strict criteria, but is usually made in the presence of extra-axial hemorrhage, retinal hemorrhage, external signs of trauma, and a vague or incompatible mechanism of injury. 10. Severe spinal cord injury, especially in the cervical region, may be associated with unexplained hypotension without compensatory tachycardia. 11. Because of their relatively large head size, young children placed directly upon a rigid transport board will be forced into a relatively flexed position; their back and shoulders must be “built up” to avoid this posture.370,371

not only in reducing dystonia scores, but in improving quality of life.642,643 In these reports, the doses necessary to control dystonia were significantly higher than those used for pure spasticity. The use of thalamotomy and pallidotomy for dystonia in children is limited, and has shown modest success.644 As experience with deep brain stimulation expands, as it has for the treatment of parkinsonian symptoms, this nondestructive modality may find utility in the treatment of children with refractory hyperkinetic movement disorders.

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526. Mickle JP, Quisling RG: The transtorcular embolization of vein of Galen aneurysms. J Neurosurg 1986;64:731–735. 527. Lasjaunias P, Garcia-Monaco R, Rodesch G, et al: Vein of Galen malformation. Endovascular management of 43 cases. Childs Nerv Syst 1991;7:360–367. 528. Lasjaunias P, Hui F, Zerah M, et al: Cerebral arteriovenous malformations in children. Management of 179 consecutive cases and review of the literature. Childs Nerv Syst 1995;11:66–79. 529. Lylyk P, Vinuela F, Dion JE, et al: Therapeutic alternatives for vein of Galen vascular malformations. J Neurosurg 1993;78:438–445. 530. Horowitz MB, Jungreis CA, Quisling RG, Pollack I: Vein of Galen aneurysms: A review and current perspective. AJNR 1994;15:1486– 1496. 531. Maraire JN, Awad IA: Intracranial cavernous malformations: Lesion behavior and management strategies. Neurosurgery 1995;37:591–605. 532. Herter T, Brandt M, Szuwart U: Cavernous hemangiomas in children. Childs Nerv Syst 1988;4:123–127. 533. Frim DM, Scott RM: Management of cavernous malformations in the pediatric population. Neurosurg Clin North Am 1999;10: 513–518. 534. Fortuna A, Ferrante L, Mastronardi L, Acqui M, d’Addetta R: Cerebral cavernous angioma in children. Childs Nerv Syst 1989;5:201–207. 535. Edwards M, Baumgartner J, Wilson C: Cavernous and other cryptic vascular malformations of the pediatric age group. In Awad IA, Barrow DL (eds): Cavernous Malformations. Park Ridge, IL, American Association of Neurological Surgeons, 1993;163. 536. Mazza C, Scienza R, Beltramello A, Da Pian R: Cerebral cavernous malformations (cavernomas) in the pediatric age-group. Childs Nerv Syst 1991;7:139–146. 537. Scott RM, Barnes P, Kupsky W, Adelman LS: Cavernous angiomas of the central nervous system in children. J Neurosurg 1992;76:38–46. 538. Gunel M, Awad IA, Anson J, Lifton RP: Mapping a gene causing cerebral cavernous malformation to 7q11.2-q21. Proc Natl Acad Sci USA 1995;92:6620–6624. 539. Gunel M, Awad IA, Finberg K, et al: A founder mutation as a cause of cerebral cavernous malformation in Hispanic Americans. N Engl J Med 1996;334:946–951. 540. Notelet L, Chapon F, Khoury S, et al: Familial cavernous malformations in a large French kindred: Mapping of the gene to the CCM1 locus on chromosome 7q. J Neurol Neurosurg Psychiatry 1997;63:40– 45. 541. Dubovsky J, Zabramski JM, Kurth J, et al: A gene responsible for cavernous malformations of the brain maps to chromosome 7q. Hum Mol Genet 1995;4:453–458. 542. Gunel M, Awad IA, Finberg K, et al: Genetic heterogeneity of inherited cerebral cavernous malformation. Neurosurgery 1996;38:1265– 1271. 543. Kondziolka D, Lunsford LD, Kestle JR: The natural history of cerebral cavernous malformations. J Neurosurg 1995;83:820–824. 544. Wong JH, Awad IA, Kim JH: Ultrastructural pathological features of cerebrovascular malformations: A preliminary report. Neurosurgery 2000;46:1454–1459. 545. Maraire JN, Awad IA: Intracranial cavernous malformations: Lesion behavior and management strategies. Neurosurgery 1995;37:591–605. 546. Abe T, Singer RJ, Marks MP, Norbash AM, Crowley RS, Steinberg GK: Coexistence of occult vascular malformations and developmental venous anomalies in the central nervous system: MR evaluation. AJNR 1998;19:51–57. 547. Chang SD, Vanefsky MA, Havton LA, Silverberg GD: Bilateral cavernous malformations resulting from cranial irradiation of a choroid plexus papilloma. Neurol Res 1998;20:529–532. 548. Maeder P, Gudinchet F, Meuli R, de Tribolet N: Development of a cavernous malformation of the brain. AJNR 1998;19:1141–1143. 549. Zabramski JM, Wascher TM, Spetzler RF, et al: The natural history of familial cavernous malformations: Results of an ongoing study. J Neurosurg 1994;80:422–432.

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550. Labauge P, Brunereau L, Levy C, Laberge S, Houtteville JP: The natural history of familial cerebral cavernomas: A retrospective MRI study of 40 patients. Neuroradiology 2000;42:327–332. 551. Zevgaridis D, van Velthoven V, Ebeling U, Reulen HJ: Seizure control following surgery in supratentorial cavernous malformations: A retrospective study in 77 patients. Acta Neurochir (Wien) 1996;138:672– 677. 552. Scott RM: Brain stem cavernous angiomas in children. Pediatr Neurosurg 1990;16:281–286. 553. Fritschi JA, Reulen HJ, Spetzler RF, Zabramski JM: Cavernous malformations of the brain stem. A review of 139 cases. Acta Neurochir (Wien) 1994;130:35–46. 554. Morcos JJ, Heros RC, Frank DE: Microsurgical treatment of infratentorial malformations. Neurosurg Clin North Am 1999;10:441–474. 555. Maesawa S, Kondziolka D, Lunsford LD: Stereotactic radiosurgery for management of deep brain cavernous malformations. Neurosurg Clin North Am 1999;10:503–511. 556. Kondziolka D, Lunsford LD, Flickinger JC, Kestle JR: Reduction of hemorrhage risk after stereotactic radiosurgery for cavernous malformations. J Neurosurg 1995;83:825–831. 557. Pollock BE, Garces YI, Stafford SL, Foote RL, Schomberg PJ, Link MJ: Stereotactic radiosurgery for cavernous malformations. J Neurosurg 2000;93:987–991. 558. Karlsson B, Kihlstrom L, Lindquist C, Ericson K, Steiner L: Radiosurgery for cavernous malformations. J Neurosurg 1998;88: 293–297. 559. Matsushima Y: Moyamoya disease. In Albright AL, Pollack IF, Adelson PD (eds): Principles and Practice of Pediatric Neurosurgery. New York, Thieme, 1999:1053–1069. 560. Kim SK, Wang KC, Kim DG, et al: Clinical feature and outcome of pediatric cerebrovascular disease: A neurosurgical series. Childs Nerv Syst 2000;16:421–428. 561. Fukui M: Current state of study on moyamoya disease in Japan. Surg Neurol 1997;47:138–143. 562. Scott RM: Moyamoya syndrome: A surgically treatable cause of stroke in the pediatric patient. Clin Neurosurg 2000;47:378–384. 563. Matsushima Y, Aoyagi M, Nariai T, Takada Y, Hirakawa K: Long–term intelligence outcome of post-encephalo-duro-arterio-synangiosis childhood moyamoya patients. Clin Neurol Neurosurg 1997;99(suppl 2):S147–S150. 564. Suzuki J, Kodama N: Moyamoya disease—a review. Stroke 1983;14:104–109. 565. Matsushima T, Inoue T, Suzuki SO, Fujii K, Fukui M, Hasuo K: Surgical treatment of moyamoya disease in pediatric patients— Comparison between the results of indirect and direct revascularization procedures. Neurosurgery 1992;31:401–405. 566. Yamauchi T, Tada M, Houkin K, et al: Linkage of familial moyamoya disease (spontaneous occlusion of the circle of Willis) to chromosome 17q25. Stroke 2000;31:930–935. 567. Adelson PD, Scott RM: Pial synangiosis for moyamoya syndrome in children. Pediatr Neurosurg 1995;23:26–33. 568. Matsushima Y, Aoyagi M, Suzuki R, Tabata H, Ohno K: Perioperative complications of encephalo-duro-arterio-synangiosis: Prevention and treatment. Surg Neurol 1991;36:343–353. 569. Kim SK, Wang KC, Kim DG, et al: Clinical feature and outcome of pediatric cerebrovascular disease: A neurosurgical series. Childs Nerv Syst 2000;16:421–428. 570. Karasawa J, Touho H, Ohnishi H, Miyamoto S, Kikuchi H: Long-term follow-up study after extracranial–intracranial bypass surgery for anterior circulation ischemia in childhood moyamoya disease. J Neurosurg 1992;77:84–89. 571. Nathoo N, Nadvi SS, van Dellen JR, Gouws E: Intracranial subdural empyemas in the era of computed tomography: A review of 699 cases. Neurosurgery 1999;44:529–535. 572. Dill SR, Cobbs CG, McDonald CK: Subdural empyema: Analysis of 32 cases and review. Clin Infect Dis 1995;20:372–386.

573. Pathak A, Sharma BS, Mathuriya SN, Khosla VK, Khandelwal N, Kaak VK: Controversies in the management of subdural empyema. A study of 41 cases with review of literature. Acta Neurochir (Wien) 1990;102:25–32. 574. Lerner DN, Choi SS, Zalzal GH, Johnson DL: Intracranial complications of sinusitis in childhood. Ann Otol Rhinol Laryngol 1995;104:288–293. 575. Maniglia AJ, Goodwin WJ, Arnold JE, Ganz E: Intracranial abscesses secondary to nasal, sinus, and orbital infections in adults and children. Arch Otolaryngol Head Neck Surg 1989;115:1424–1429. 576. Gower DJ, McGuirt WF, Kelly DL Jr: Intracranial complications of ear disease in a pediatric population with special emphasis on subdural effusion and empyema. South Med J 1985;78:429–434. 577. Hlavin ML, Kaminski HJ, Fenstermaker RA, White RJ: Intracranial suppuration: A modern decade of postoperative subdural empyema and epidural abscess. Neurosurgery 1994;34:974–980. 578. Curless RG: Subdural empyema in infant meningitis: Diagnosis, therapy, and prognosis. Childs Nerv Syst 1985;1:211–214. 579. Bok AP, Peter JC: Subdural empyema: Burr holes or craniotomy? A retrospective computerized tomography-era analysis of treatment in 90 cases. J Neurosurg 1993;78:574–578. 580. Feuerman T, Wackym PA, Gade GF, Dubrow T: Craniotomy improves outcome in subdural empyema. Surg Neurol 1989;32:105–110. 581. Nathoo N, Nadvi SS, van Dellen JR: Infratentorial empyema: Analysis of 22 cases. Neurosurgery 1997;41:1263–1268. 582. Weingarten K, Zimmerman RD, Becker RD, Heier LA, Haimes AB, Deck MD: Subdural and epidural empyemas: MR imaging. AJR 1989;152:615–621. 583. Nathoo N, Nadvi SS, Gouws E, van Dellen JR: Craniotomy improves outcomes for cranial subdural empyemas: Computed tomography–era experience with 699 patients. Neurosurgery 2001;49:872–877. 584. Pattisapu JV, Parent AD: Subdural empyemas in children. Pediatr Neurosci 1987;13:251–254. 585. Nathoo N, Nadvi SS, van Dellen JR: Cranial extradural empyema in the era of computed tomography: A review of 82 cases. Neurosurgery 1999;44:748–753. 586. Smith HP, Hendrick EB: Subdural empyema and epidural abscess in children. J Neurosurg 1983;58:392–397. 587. Giannoni C, Sulek M, Friedman EM: Intracranial complications of sinusitis: a pediatric series. Am J Rhinol 1998;12:173–178. 588. Go C, Bernstein JM, de Jong AL, Sulek M, Friedman EM: Intracranial complications of acute mastoiditis. Int J Pediatr Otorhinolaryngol 2000;52:143–148. 589. Ciurea AV, Stoica F, Vasilescu G, Nuteanu L: Neurosurgical management of brain abscesses in children. Childs Nerv Syst 1999;15:309–317. 590. Jadavji T, Humphreys RP, Prober CG: Brain abscesses in infants and children. Pediatr Infect Dis 1985;4:394–398. 591. Tekkok IH, Erbengi A: Management of brain abscess in children: Review of 130 cases over a period of 21 years. Childs Nerv Syst 1992;8:411–416. 592. Takeshita M, Kagawa M, Yato S, et al: Current treatment of brain abscess in patients with congenital cyanotic heart disease. Neurosurgery 1997;41:1270–1278. 593. Wong TT, Lee LS, Wang HS, et al: Brain abscesses in children—a cooperative study of 83 cases. Childs Nerv Syst 1989;5:19–24. 594. Renier D, Flandin C, Hirsch E, Hirsch JF: Brain abscesses in neonates. A study of 30 cases. J Neurosurg 1988;69:877–882. 595. Ersahin Y, Mutluer S, Guzelbag E: Brain abscess in infants and children. Childs Nerv Syst 1994;10:185–189. 596. Boop FA, Jacobs RF, Young RF: Brain abscesses and encephalitis in children. In Albright AL, Pollack IF, Adelson PD (eds): Principles and Practice of Pediatric Neurosurgery. New York, Thieme, 1999:1203– 1226. 597. Graham DR, Band JD: Citrobacter diversus brain abscess and meningitis in neonates. JAMA 1981;245:1923–1925.

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Chapter 11  598. Britt RH, Enzmann DR, Placone RC Jr, Obana WG, Yeager AS: Experimental anaerobic brain abscess. Computerized tomographic and neuropathological correlations. J Neurosurg 1984;60:1148–1159. 599. Rosenblum ML, Mampalam TJ, Pons VG: Controversies in the management of brain abscesses. Clin Neurosurg 1986;33:603–632. 600. Barlas O, Sencer A, Erkan K, Eraksoy H, Sencer S, Bayindir C: Stereotactic surgery in the management of brain abscess. Surg Neurol 1999;52:404–410. 601. Mamelak AN, Mampalam TJ, Obana WG, Rosenblum ML: Improved management of multiple brain abscesses: A combined surgical and medical approach. Neurosurgery 1995;36:76–85. 602. Hirsch JF, Roux FX, Sainte-Rose C, Renier D, Pierre-Kahn A: Brain abscess in childhood. A study of 34 cases treated by puncture and antibiotics. Childs Brain 1983;10:251–265. 603. Buonaguro A, Colangelo M, Daniele B, Cantone G, Ambrosio A: Neurological and behavioral sequelae in children operated on for brain abscess. Childs Nerv Syst 1989;5:153–155. 604. Carey ME, Chou SN, French LA: Long–term neurological residua in patients surviving brain abscess with surgery. J Neurosurg 1971;34:652–656. 605. Albright AL: Spasticity and movement disorders. In Albright AL, Pollack IF, Adelson PD (eds): Principles and Practice of Pediatric Neurosurgery. New York, Thieme, 1999:1157–1173. 606. Thompson FJ, Parmer R, Reier PJ, Wang DC, Bose P: Scientific basis of spasticity: Insights from a laboratory model. J Child Neurol 2001;16:2–9. 607. Fahn S: Concept and classification of dystonia. Adv Neurol 1988;50: 1–8. 608. Jarman PR, Warner TT: The dystonias. J Med Genet 1998;35:314–318. 609. Fahn S, Bressman SB, Marsden CD: Classification of dystonia. Adv Neurol 1998;78:1–10. 610. Hallett M: The neurophysiology of dystonia. Arch Neurol 1998;55:601–603. 611. DeLong MR: Primate models of movement disorders of basal ganglia origin. Trends Neurosci 1990;13:281–285. 612. Parent A, Cicchetti F: The current model of basal ganglia organization under scrutiny. Mov Disord 1998;13:199–202. 613. Ashworth B: Preliminary trial of carisoprodol in multiple sclerosis. Practitioner 1964;192:540–542. 614. Barry MJ, VanSwearingen JM, Albright AL: Reliability and responsiveness of the Barry-Albright dystonia scale. Dev Med Child Neurol 1999;41:404–411. 615. Nelson KB, Ellenberg JH: Children who “outgrew’ cerebral palsy. Pediatrics 1982;69:529–536. 616. Milla PJ, Jackson AD: A controlled trial of baclofen in children with cerebral palsy. J Int Med Res 1977;5:398–404. 617. Krach LE: Pharmacotherapy of spasticity: Oral medications and intrathecal baclofen. J Child Neurol 2001;16:31–36. 618. Lapierre Y, Bouchard S, Tansey C, Gendron D, Barkas WJ, Francis GS: Treatment of spasticity with tizanidine in multiple sclerosis. Can J Neurol Sci 1987;14:513–517. 619. Coward DM: Tizanidine: Neuropharmacology and mechanism of action. Neurology 1994;44(suppl 9):S6–S10. 620. Groves L, Shellenberger MK, Davis CS: Tizanidine treatment of spasticity: A meta-analysis of controlled, double-blind, comparative studies with baclofen and diazepam. Adv Ther 1998;15:241–251. 621. Wallace JD: Summary of combined clinical analysis of controlled clinical trials with tizanidine. Neurology 1994;44:S60–68. 622. Edgar TS: Clinical utility of botulinum toxin in the treatment of cerebral palsy: Comprehensive review. J Child Neurol 2001;16:37–46. 623. Ubhi T, Bhakta BB, Ives HL, Allgar V, Roussounis SH: Randomised double blind placebo controlled trial of the effect of botulinum toxin on walking in cerebral palsy. Arch Dis Child 2000;83:481–487.

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624. Fehlings D, Rang M, Glazier J, Steele C: An evaluation of botulinumA toxin injections to improve upper extremity function in children with hemiplegic cerebral palsy. J Pediatr 2000;137:331–337. 625. Koman LA, Mooney JF 3rd, Smith BP, Walker F, Leon JM: Botulinum toxin type A neuromuscular blockade in the treatment of lower extremity spasticity in cerebral palsy: A randomized, double-blind, placebo-controlled trial. BOTOX Study Group. J Pediatr Orthop 2000;20:108–115. 626. Sutherland DH, Kaufman KR, Wyatt MP, Chambers HG, Mubarak SJ: Double-blind study of botulinum A toxin injections into the gastrocnemius muscle in patients with cerebral palsy. Gait Posture 1999;10:1– 9. 627. Eames NW, Baker R, Hill N, Graham K, Taylor T, Cosgrove A: The effect of botulinum toxin A on gastrocnemius length: Magnitude and duration of response. Dev Med Child Neuro 1999;41:226–232. 628. Peacock WJ, Arens LJ: Selective posterior rhizotomy for the relief of spasticity in cerebral palsy. S Afr Med J 1982;62:119–124. 629. Peacock WJ, Arens LJ, Berman B: Cerebral palsy spasticity. Selective posterior rhizotomy. Pediatr Neurosci 1987;13:61–66. 630. Steinbok P, Keyes R, Langill L, Cochrane DD: The validity of electrophysiological criteria used in selective functional posterior rhizotomy for treatment of spastic cerebral palsy. J Neurosurg 1994;81:354–361. 631. Steinbok P: Outcomes after selective dorsal rhizotomy for spastic cerebral palsy. Childs Nerv Syst 2001;17:1–18. 632. Albright AL, Barron WB, Fasick MP, Polinko P, Janosky J: Continuous intrathecal baclofen infusion for spasticity of cerebral origin. JAMA 1993;270:2475–2477. 633. Albright AL: Baclofen in the treatment of cerebral palsy. J Child Neurol 1996;11:77–83. 634. Armstrong RW, Steinbok P, Cochrane DD, Kube SD, Fife SE, Farrell K: Intrathecally administered baclofen for treatment of children with spasticity of cerebral origin. J Neurosurg 1997;87:409–414. 635. Steinbok P, Daneshvar H, Evans D, Kestle JR: Cost analysis of continuous intrathecal baclofen versus selective functional posterior rhizotomy in the treatment of spastic quadriplegia associated with cerebral palsy. Pediatr Neurosurg 1995;22:255–264. 636. Fahn S: High-dosage anticholinergic therapy in dystonia. Adv Neurol 1983;37:177–188. 637. Hoon AH Jr, Freese PO, Reinhardt EM, et al: Age-dependent effects of trihexyphenidyl in extrapyramidal cerebral palsy. Pediatr Neurol 2001;25:55–58. 638. Nygaard TG, Marsden CD, Fahn S: Dopa–responsive dystonia: Long–term treatment response and prognosis. Neurology 1991;41: 174–181. 639. Quirk JA, Sheehan GL, Marsden CD, Lees AJ: Treatment of nonoccupational limb and trunk dystonia with botulinum toxin. Mov Disord 1996;11:377–383. 640. Arens LJ, Leary PM, Goldschmidt RB: Experience with botulinum toxin in the treatment of cerebral palsy. S Afr Med J 1997;87:1001– 1003. 641. Gilio F, Curra A, Lorenzano C, Modugno N, Manfredi M, Berardelli A: Effects of botulinum toxin type A on intracortical inhibition in patients with dystonia. Ann Neurol 2000;48:20–26. 642. Albright AL, Barry MJ, Painter MJ, Shultz B: Infusion of intrathecal baclofen for generalized dystonia in cerebral palsy. J Neurosurg 1998;88:73–76. 643. Albright AL, Barry MJ, Shafron DH, Ferson SS: Intrathecal baclofen for generalized dystonia. Dev Med Child Neurol 2001;43:652–657. 644. Speelman D, van Manen J: Cerebral palsy and stereotactic neurosurgery: Long term results. J Neurol Neurosurg Psychiatry 1989;52:23–30.

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Chapter 12 Central Nervous System Infections Kenneth H. Rand, MD, with a contribution on Vertebral Osteomyelitis, Epidural Abscess, and External Ventricular Drain Infections, Arthur J. Ulm, MD and David W. Pincus, MD, PhD

Acute Bacterial Meningitis Definition Bacterial meningitis can be defined as a pyogenic inflammatory response to bacterial invasion of the pia arachnoid membranes surrounding the central nervous system. This infection typically involves the entire length of the neuraxis including the brain, spinal cord, and optic nerves because the subarachnoid space is continuous. Clinically, one sees the acute onset of headache, fever, and stiff neck with or without focal neurological signs over hours to a few days. Epidemiology The most common bacterial causes of bacterial meningitis in the United States include Streptococcus pneumoniae, Neisseria meningitidis, Haemophilus influenzae, Listeria monocytogenes, and group B streptococcus. Collectively, these agents account for over 95% of cases. Table 12-1 summarizes the age distribution, predisposing conditions and fatality rates for the most common agents. Streptococcus pneumoniae S. pneumoniae is the most common cause of bacterial meningitis in the United States today in all age groups, except infants in the immediate neonatal period. The risk of pneumococcal meningitis varies with age, being significantly higher in infants than in young children and adults. When patients are older than 70 years of age, the incidence increases again to approximately double the average

for young and middle-aged adults. In children the most common predisposing conditions are sinus or middle ear infection, which lead to transient bacteremia and hematogenous seeding of the central nervous system.1 In adults, the major risk factors include alcoholism, splenectomy, human immunodeficiency virus (HIV), diabetes, sinusitis, spontaneous bacterial peritonitis, and acquired immunodeficiencies. Pneumococcal meningitis is the most common form of recurrent meningitis in patients who have cerebrospinal fluid (CSF) leaks. S. pneumonia is spread by respiratory transmission in the general population and results in colonization of the nasopharynx with rates commonly in the range of 5% to 10% of healthy adults. During the winter, carriage rates can increase to 20% to 30% in certain populations. Overcrowded environments such as day care centers, barracks, and prisons may serve as foci for spreading of these organisms. Neisseria meningitidis The incidence of meningitis due to N. meningitidis in the United States has been estimated at 0.6 per 100,000 population per year.2 The incidence of meningococcal meningitis is at least tenfold higher in third world countries. Strains of N. meningitidis are classified according to serologic recognition of epitopes on their capsule and outer membrane. N. meningitidis is classified into serogroups A, B, C, Y, W135 and other less common types based on polysaccharide capsule antigens. In the United States, strains from sera groups B and C cause the majority of infections, whereas in underdeveloped countries sera groups A and C predominate. Over the past 30 years in industrialized nations, clonal outbreaks of strains 337

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Table 12-1  Age, Proportion of Cases, Predisposing Factors, and Approximate Fatality Rates for the Most Common Agents of Acute Bacterial Meningitis Microorganism

Age

Haemophilus influenzae

ª 4 mo–3 y

Streptococcus pneumoniae

All

Neisseria meningitidis

Percentage of Cases <5

Predisposing Conditions

Fatality Rate (%)

Lack of antibody to polysaccharride capsule, Preceding otitis media

ª 4–8

40–50

Otitis media, sinusitis, Alcoholism, cirrhosis, Pneumococcal pneumonia, Immunocompromise, Skull fracture, CSF leak, Myeloma, Sickle cell disease

ª 20

All

20–30

“Closed” institutional setting, Lack of specific antibody, Complement deficiencies

ª 3–5

Streptococcus agalactiae (Group B Strep)

< 3 mo

10–15

Newborn period, Immunocompromise

ª 5–9

Listeria monocytogenes

< 1 mo > 50 yr

5–10

Newborn period, Immunocompromise, Age, Alcoholism/cirrhosis

ª 15

CSF, cerebrospinal fluid.

belonging to the sera group B have predominated. For example, in Northern Europe a pattern of hyperendemic infection with attack rates between 4 and 50 per 100,000 population has been observed since the mid 1970s. Most of these isolates have been identified as belonging to the ET5, lineage 3 serologic subgroup. Strains of this serotype have been observed to slowly circulate through the population and periodically result in isolated outbreaks. Such strains have been observed in the United States and in almost all parts of the world. Some clonal complexes such as ET-37 can nonetheless express the group C polysaccharide capsule type, but also sera group B, W135, and Y. Thus, epidemiologic studies using modern molecular typing methods show a low-level endemic background of cases punctuated by school dormitory–based or other epidemiologically linked local outbreaks of meningitis. Haemophilus influenzae Until the introduction of the H. influenzae type b, polysaccharide capsular vaccine, H. influenzae was the most common etiology of acute bacterial meningitis in children younger than 5 years of age. Before the introduction of the H. influenzae type b vaccination in 1986 it was estimated that there were approximately 12,920 cases of meningitis in the United States, compared with 5,755 in 1995, a reduction of 55%.2 Before the availability of this vaccine, it was estimated that invasive Haemophilus infection developed in as many as one in 200 children and included epiglottitis, septicemia, arthritis, and soft tissue infections in addition to meningitis. In a study in Washington state (King County), from 1977 to

1986, the incidence of H. influenzae meningitis in the age group younger than 5 months old was 63.5 per 100,000 population and increased to 128.2 per 100,000 in the 6- to 11month age group, decreasing to fewer than 8.5 per 100,000 after the age of 5 years.3 The occurrence of H. influenzae meningitis is directly related to the development of type specific anticapsular antibodies.4 The development of antibodies to polyribosylribitol phosphate, whether vaccine induced or occurring naturally, is directly related to protection from invasive Haemophilus infection. These antibodies have been shown to be opsonic and bactericidal against H. influenzae in vitro, and are protective in vivo as shown by numerous clinical studies. H. influenzae can be classified into six serologically distinct antigenic types based on capsular polysaccharides A-F. Of these, only type b is pathogenic. In the prevaccine era, colonization with nontypable strains of H. influenzae led to the development of cross-reacting antibodies, which were protective against infection due to type b. Following the introduction of the H. influenzae type b vaccine, there has been a profound reduction in the number of invasive infections due to H. influenzae in the United States. For example, Murphy and colleagues5 found a reduction of 85% to 92% in the incidence of invasive H. influenzae type b disease between 1983 to 1984 and 1991 after widespread use of the vaccine. Listeria monocytogenes L. monocytogenes is a significant cause of neonatal meningitis. This arises from a generally asymptomatic colonization of the genital or gastrointestinal tract in the mother before

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delivery of an infant with transmission at the time of birth. L. monocytogenes causes meningitis most often in adults who are immunocompromised because of steroids, drugs for transplantation, diabetes, alcoholism, or who are extremely elderly. The organism is widespread in the animal population, both domestic and wild. Transmission to humans occurs through fecal-oral transmission from the animal reservoirs. Outbreaks in the United States and elsewhere have involved milk products such as Swiss cheese, undercooked chicken, hot dogs, seafood, vegetables, and a variety of other items. Stool carriage of this organism among asymptomatic adults has been documented in the range of 1%; thus the human reservoir of this agent is substantial. However, healthy adults exposed to the organism will generally not become ill unless exposed, in an outbreak type setting, to high levels of infectious organisms. Under normal circumstances, a significant degree of susceptibility of the host such as neonatal age group or the elderly, as indicated previously, is required for infection. Gram-Negative Bacilli Escherichia coli with the K1 capsular polysaccharide antigen accounts for a majority of the cases of gram-negative meningitis in the newborn.6 Carriage rates of the E. coli K1 serotypes vary in different populations, but range from 7% to 38% in women of child-bearing age and may be as high as 50% in nursing personnel.5,7–9 In a 15-year study of bacterial meningitis in a children’s hospital in Seattle, Washington, there was a total of 28 cases of E. coli meningitis comprising 3% of the total meningitis cases. However, 13 of these were in the neonatal group and accounted for 15% of neonatal meningitis.10 Other gram-negative organisms such as Klebsiella, Enterobacter, Pseudomonas, Citrobacter, and Salmonella may also cause meningitis in the neonatal period, with an epidemiology similar to that of the E. coli K1 sera type. Beyond the neonatal period, gram-negative meningitis is rare. However, gram-negative meningitis is highly significant in hospital acquired cases of meningitis. The vast majority of these cases are seen following neurocranial surgery, spinal surgery, and in patients who have suffered head trauma. Group B Streptococcus Streptococcus agalactiae (group B streptococcus) is the single most frequent cause of neonatal meningitis. This organism has been cultured from vaginal secretions in 30% to 35% of women before delivery, and transmission to the infant during delivery can result in neonatal meningitis within the first week of life. Alternatively, the organism may be acquired within the first few days after birth from adult contacts, either relatives or hospital personnel, and meningitis may develop during the first 1 to 2 months after birth. Group B streptococci are divided into six main serotypes: Ia, Ib/c, Ia/c, II, III, IV, based on capsular polysaccharide antigens. The vast majority of neonatal meningitis is caused by the type III

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group and virulence factors such as production of higher levels of neuraminidase have been described as an explanation for this. A recent analysis of 128 isolates suggested the clonality of certain invasive strain types.11 Other Etiologic Agents Acute meningitis can be produced by almost every organism known to medicine, including such organisms as group A streptococci, nonpneumococcal alpha hemolytic streptococci, Neisseria gonorrhea, Salmonella species, Flavobacterium meningosepticum, non–H. influenzae species, and even anthrax. Organisms such as Staphylococcus aureus and Staphylococcus epidermidis are extremely unusual as causes of primary bacterial meningitis. However, following trauma, the placement of CSF shunts, and neurosurgical procedures, these organisms are quite common causes of bacterial meningitis. Many other species such as mycobacteria, nocardia, fungi, spirochetes, brucella, and leptospira can also produce meningitis. However, with the exception of leptospira, the presentation of these illnesses tends to be more chronic and generally these would not be considered agents of acute bacterial meningitis. Pathogenesis of Meningeal Invasion Colonization of the respiratory tract is the critical first step, which precedes infection by the three major bacterial species causing meningitis. Biologically, colonization is mediated by attachment of these organisms to cell surface receptors and/or affinity for nasopharyngeal mucosa, which permits the organism to replicate in the upper airway for prolonged periods of time. All three major pathogens typically colonize the upper airway without producing symptoms. Both hostand pathogen-specific factors are critical in the development of invasive disease; many of these have been identified but are not fully understood. For example, splenectomy definitely predisposes to invasive disease by S. pneumoniae while having very little effect on the incidence of invasion by N. meningitidis, despite the fact that both are encapsulated organisms. The first step in colonization of the upper airway is attachment of the bacteria to the surface of the host mucosal epithelial cells. This adherence is mediated by fimbriae or pili in the case of gram-negative organisms. The pili of meningococcus are filamentous glycoproteins that are attached to the bacterial surface, traverse the polysaccharide capsule, and extend beyond the surface of the bacterium where they can bind to specific receptors on nasopharyngeal cells, in this instance the CD46 receptor.12,13 After receptor binding, further interaction with the host cell is established by certain outer membrane proteins on the meningococcus, designated Opa and Opc.14 Binding of the outer membrane proteins to specific receptors promotes engulfment of the meningococci by the epithelial cells and allows transportation of the meningococci across the cell. Meningococci also possess other outer membrane proteins that function as IgA pro-

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teases, which can specifically degrade surface IgA, further enhancing the probability of invasive disease.15,16 Once the mucosal barrier has been penetrated, the development of meningococcal disease depends on the survival of the organism in the bloodstream. Here the most important virulence factor for survival of meningococci is the polysaccharide capsule, which protects against complement mediated phagocytosis by neutrophils in the reticular endothelial system.17 Host defense is clearly determined by the existing humoral antibody to specific polysaccharide capsular types and the cellular responses of the innate immune system. Protective antibody for meningococcal disease is acquired through maternal transmission and is protective for the first several months after birth. Colonization by nonpathogenic Neisseria, and a possibly cross-reacting gram-negative organism such as E. coli K1, induces protective antibodies. The protective effect of antibodies is to promote optimization of phagocytosis through opsonization and specific lysis via complement activation. For this reason, patients who are deficient in complement factor C5 are susceptible to repeated invasive infections by N. meningitidis. In fact, individuals with an inherited deficiency of any of the terminal components of complement C5, C6, C7, C8 have approximately 6000-fold greater risk of invasive disease.18–20 Interestingly, the overall mortality rate in these patients is only about 2%, less than that of patients whose complement system is normal. In two European studies of a total of 127 patients with fulminant meningococcal infection, there was only one case of complement deficiency.21,22 Colonization of the upper airway by H. influenzae is apparently also mediated by fimbrial attachment to epithelial cells. Alpha fimbriae enhance the binding to the anterior nasopharynx and b fimbriae facilitate binding to the posterior ciliated nasopharyngeal cells.23 H. influenzae type b lacking fimbriae appear not to colonize the nasopharynx and, interestingly, H. influenzae type b isolates from spinal fluid do not express fimbria, suggesting that although their presence is important in colonization and attachment, it is not necessary to cause meningitis.24,25 Virulence factors for the invasion of S. pneumoniae seem to be primarily a function of the capsular polysaccharide type. There are 90 known sera types, 18 of which are responsible for approximately 87% of bacteremic pneumococcal disease.26,27 The factors involved in invasion of the subarachnoid space have been extensively studied by Kim and colleagues28 using E. coli as a model system. However, while the specific details of the mechanisms described may or may not relate directly to invasion by meningococci and S. pneumoniae, the general principles probably do. Using human brain microvascular endothelial cells (BMEC), Prasadarao and co-workers29 were able to show that E. coli expressing the outer membrane protein A (OmpA) gene exhibited a 25- to 50-fold greater ability to attach and invade these vascular endothelial cells than E. coli not expressing the (OmpA) gene. The ability of E. coli to invade these cells in vitro was specific for the brain-derived endothelial cells and

was not found in endothelial cells obtained from human umbilical vein. On electron microscopy, invasive strains of E. coli were shown to migrate through the BMEC in enclosed vacuoles, which were dependent on recruitment of F-actin. Thus, transport through the cell appears to be dependent on cytoskeletal rearrangement involving both microfilaments and microtubules. Using a bacteremic neonatal rat model, these workers were also able to show that mutations of E. coli that affect expression of surface proteins, specifically OmpA as well as others, significantly affect the ability of these strains to actually invade the central nervous system in vivo.28 Thus the factors that appear to be important for the attachment and transport across brain endothelial cells in vitro affect the in vivo outcome of infection. On entering into the subarachnoid space, bacterial replication proceeds virtually unchecked by host defense mechanisms. By virtue of the blood-brain barrier, both immunoglobulin and complement levels are far lower in CSF than in serum and interstitial fluid. In addition, leukocyte proteases derived from an initial influx of leukocytes have actually been shown to degrade complement components in CSF from patients with meningitis.30 The major host response to the invasion of the subarachnoid space by pathogenic microorganisms is a rapid influx of polymorphonuclear leukocytes. The influx of neutrophils can be produced experimentally by the intracisternal injection of either encapsulated or nonencapsulated S. pneumoniae, heat-killed unencapsulated S. pneumoniae, and even pneumococcal cell walls.31 Purified lipopolysaccharide (LPS) from gram-negative bacteria is known to be extremely potent in the development of inflammation, and intracisternal injection of purified LPS from H. influenzae also elicits a strong inflammatory response.32,33 The mechanism by which LPS and presumably other bacterial cell wall components act to stimulate inflammation is probably through the induction of inflammatory cytokines such as interleukin 1 (IL-1) or tumor necrosis factor (TNF).34,35 In vitro studies with LPS, and with IL-1 and TNF show that incubation with endothelial cell monolayers leads to a rapid transient increased expression of the intercellular adhesion molecules (ICAM-1 and ICAM-2) as well as the selectin molecules such as ELAM-1. As a result, neutrophils are able to bind to central nervous system vascular endothelial cells at vastly increased rates and then subsequently migrate by diapedesis into the subarachnoid space. The pathophysiologic consequences of this intense neutrophil response in the subarachnoid space accounts for most, if not all, of the serious clinical and pathologic consequences of meningitis, such as a decrease in the blood-brain barrier and increased intracranial pressure (ICP). The increase in ICP occurs through several mechanisms. Vasogenic cerebral edema is caused by the increased permeability of the blood-brain barrier, which is a direct result of inflammatory bacterial products or the inflammatory cytokines released in response to these materials. The alterations in brain cellular membranes lead to cytotoxic cerebral

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edema, that is, increased intracellular water content, potassium leakage, and a shift in brain metabolism to anaerobic glycolysis with increased lactate production. Also as a result of the inflammation in the subarachnoid space (SAS), there is decreased ability to reabsorb CSF, which leads to interstitial edema in brain parenchyma. All three of these mechanisms contribute to the risk of increased intracranial pressure and brain herniation. Clinical Manifestations The typical clinical presentation of meningitis in adults consists of fever, headache, and stiff neck, and varying degrees of altered consciousness. The majority of bacterial meningitis in adults is caused by S. pneumoniae, and the nature of the presentation of meningitis may depend on the underlying initial infection by the pneumococcus. For example, in pneumococcal pneumonia and sepsis, the onset of fever and hypotension may present with an acute shaking chill, which may evolve into a picture of meningitis in some patients. Alternatively, the disease may present with a more gradual onset consisting of symptoms of upper respiratory infection with or without symptoms of bronchitis and pneumonia for several days before the onset of meningitic symptoms. In the classic series by Carpenter and Petersdorf 36 approximately 27% of the patients had a sudden onset of headache, confusion, lethargy, and alteration of consciousness in the 24 hours before hospitalization. In contrast, 53% presented with a more slowly progressive course over 1 to 7 days. In a review of 493 episodes, Durand and associates37 found that 95% of the patients with bacterial meningitis had fever greater than 37.7°C on admission; neck stiffness was present in 88% of patients. Only 22% were alert while 51% were confused or lethargic and 22% were responsive only to pain. Within the first 24 to 48 hours of onset, 29% had focal seizures and/or focal neurologic findings. The most common predisposing factors were pneumonia, sinusitis, otitis media, alcoholism, diabetes, and some form of immunosuppression. A variety of other predisposing conditions have been identified such as malignancy, sickle cell disease, organ transplantation, splenectomy, dialysis, and steroid or other immunosuppressive therapy. In many of these settings, the presentation of meningitis may not be classic because of alteration of the immune response and the diagnosis only made upon investigation of altered sensorium, persistent headache, or newonset seizures. The presentation of meningococcal meningitis as such is quite similar to that of pneumococcal meningitis, and clinically one cannot distinguish between the two. However, meningococcal meningitis is part of the spectrum of meningococcal sepsis and the manifestations of meningococcal septicemia may precede the meningitis by 12 to 24 hours. Depending on their severity, signs of sepsis may dominate the clinical presentation. The initial presentation in meningococcemia may be completely nonspecific, with the patient simply complaining of not feeling well, but not

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having any clinical signs or symptoms of meningitis. Such patients may progress to irreversible shock and die before the development of meningitis. Early in meningococcemia a subtle petechial rash may develop that precedes the development into fulminant disseminated intravascular coagulation (DIC) and development of a massive purpuric rash. Indeed the purpura may be so severe that in some cases actual necrosis of the digits of the fingers and toes results. Purpura fulminans in the patient with meningococcemia is classically associated with hemorrhagic necrosis of the adrenal gland, commonly called Waterhouse-Friderichsen syndrome. Thus, the clinical manifestation of meningitis in patients with meningococcemia depends on the balance of factors between sepsis and shock and those of meningitis. It is important to recognize that in the elderly the presentation of meningitis may be subtler than that in young adults and children. For example, in a review of 54 cases, Gorse and colleagues found that confusion was a predominating symptom in presentation of disease in the elderly and was statistically more common than in that of the younger age group. In addition, pneumonia was much more often likely to be present in the older age group as well.38 There may also be alteration of physical signs in the elderly because there is very commonly cervical rigidity due to osteoarthritis and cervical spondylolysis in this age group and true nuchal rigidity has to be distinguished by careful physical examination. In addition, there may be hypertonicity of the neck muscles for diseaserelated reasons such as Parkinsonism or nonspecific conditions. The meningitis itself may progress more rapidly in the elderly, and elderly patients are more likely to present in coma than are younger patients. With the development of coma, nuchal rigidity may be markedly less pronounced. In children, the presentation of meningitis is fundamentally similar to that in young and middle-aged adults. There is a tendency for fever to be higher in children, and nonspecific symptoms such as irritability, nausea and vomiting, respiratory symptoms and photophobia are probably more common in children as well. In addition to nuchal rigidity, the classic physical signs of meningeal inflammation are Kernig’s and Brudzinski’s signs.39,40 Although Brudzinski originally described several signs of inflammation of the meninges, the best known of these is the “nape of the neck” sign which is now known as Brudzinski’s sign. This sign is elicited when flexion of the neck results in flexion of the hips and knees. Kernig’s sign is elicited with the patient in the supine position and the thigh flexed on the abdomen with the knee flexed. Upon passive extension of the leg in the presence of meningeal irritation the patient resists extension. Kernig’s and Brudzinski’s signs can only be elicited in approximately 50% of children with acute bacterial meningitis. Diagnosis Bacterial meningitis has to be differentiated from aseptic meningitis, encephalitis, brain abscess, subdural empyema,

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and noninfectious conditions affecting the CNS. The differentiation from encephalitis can be difficult and initially is made on clinical grounds. In meningitis, meningeal signs such as stiff neck, photophobia, and so on tend to be more prominent, whereas in encephalitis the altered state of consciousness, confusion, and degree of obtundation are the predominant symptoms. As the level of consciousness declines, in both meningitis and encephalitis, differentiation between the two may only be possible with laboratory and radiologic findings. Because acute bacterial meningitis is a medical emergency, treatment should be implemented on clinical grounds without waiting for proof by laboratory or radiographic studies. In the case of brain abscess, the presentation generally is one of intracranial mass lesion with focal neurologic deficits, headache and a subacute onset. Fever may be present only in up to 50% of cases. In general, nuchal rigidity is not prominent in patients with brain abscess. Patients with subdural empyema similarly seem to present with a more localized headache and focal neurologic symptoms as well as an altered level of consciousness. Depending on the location of the lesion, fever and stiff neck may be present. However, the frequent occurrence of focal neurologic symptoms should suggest the possibility of a mass lesion. Fever and altered mental status with or without meningismus may occur in a variety of systemic infections as well as noninfectious conditions. For example, Rocky Mountain spotted fever can present with fever, shock, and a petechial rash, which must be differentiated from early meningococcemia. Meningococcal disease may initially present simply as meningococcemia with shock and skin rash; meningeal signs may not be prominent. Likewise, staphylococcal sepsis typically presents with high fever, with or without localizing signs, which may include encephalopathy. Noninfectious conditions, such as subarachnoid hemorrhage, can present precipitously with severe headache, loss of consciousness, and even fever and nuchal rigidity. The neuroleptic malignant syndrome, usually related to drugs, typically presents with very high fever, generalized rigidity, fluctuating levels of consciousness, and autonomic instability with blood pressures ranging from hypertensive to hypotensive levels along with arrhythmias and diaphoresis. Laboratory abnormalities in the neuroleptic malignant syndrome include increases of liver function enzyme concentrations and a striking increase of creatine kinase to levels exceeding 10,000 IU/L. Cerebrospinal Fluid Analysis Laboratory confirmation of the diagnosis of meningitis can almost always be made by the analysis of the spinal fluid. However, the decision to perform a lumbar puncture emergently upon presentation of the patient is not straightforward. Because of the presence of increased ICP, there is a significant increased risk of uncal or tonsillar herniation, which can lead to serious neurologic consequences and/or death.

For example, Renick and co-workers carried out a study of 445 children with meningitis. There were 19 episodes of herniation, which occurred in 17 children who had lumbar puncture. Twelve of these episodes occurred in the first 12 hours after the procedure and the remainder over the subsequent 12-hour period. Computed tomography (CT) scans were normal in five of the 14 episodes at the time of the procedure. Most of the patients with impending herniation are clinically identifiable based on coma, marked obtundation (Glasgow Coma Score <8), prolonged seizures, decorticate posturing, pupillary changes, absent oculocephalic reflexes, or papilledema. Lumbar puncture should be delayed in such patients even with a normal CT scan, until preventive measures can be implemented to decrease ICP (see following section).41 If the patient is critically ill, intravenous antibiotics may be started while these procedures are carried out without fear of altering the CSF results within the first few hours. If the patient is not critically ill, one is certainly justified in withholding antibiotic treatment until radiographic studies and lumbar puncture can be performed. Blood cultures and routine laboratory investigations should be performed immediately. If increased ICP is suspected and no focal lesions are defined by radiographic studies, one can infuse a bolus dose of 1 g/kg body weight of mannitol intravenously to acutely reduce cerebral edema and perform the lumbar puncture approximately 20 minutes after that. In addition, one can intubate the patient electively and hyperventilate him or her in addition to mannitol infusion. Under these conditions, it is very likely that with a 22-gauge needle lumbar puncture can be performed without a significantly increased risk of herniation. Analysis of the CSF is one of the most important aspects of the diagnosis of bacterial meningitis and all other conditions affecting the central nervous system. After insertion of the needle, the opening pressure should be measured with the patient, in the supine position first. In adults the normal range is between 50 and 195 mm H2O or 3.8 and 15 mm Hg. The level should fluctuate with respiration and can be increased by a Valsalva maneuver. If the pressure is measured again at the end of the procedure after appropriate volumes of CSF have been obtained, and have dropped to 0 mm H2O (or 0 mm Hg), the possibility of a complete CSF block must be entertained. CSF is normally clear and colorless. A minimum of 200 white blood cells or 400 red blood cells/mm3 is necessary to impart turbidity to the fluid. CSF will appear reddish if more than 6000 red blood cells per cubic millimeter are present.42,43 Xanthochromia or a yellowish color of the CSF can be due to either the breakdown of red blood cells or to increased protein. In cases of subarachnoid hemorrhage, as little as 2 to 4 hours after the bleed occurs is enough time to impart xanthochromia to the CSF and xanthochromia may develop in vitro if the spinal fluid contains sufficient red blood cells and is not centrifuged right away. When xan-

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thochromia occurs because of increased protein concentrations, it requires a level above 150 mg/dL. In adults and children beyond the neonatal age group, CSF normally contains less than 5 white blood cells/mm3, generally small lymphocytes. In neonates, CSF may contain up to 25 to 30 white cells/mm3 up to 60% of which may be neutrophils, but this decreases after a few days to the range of 8 to 9 white cells/mm3.8 Because red blood cells may be present in spinal fluid as a result of subarachnoid hemorrhage or through a traumatic tap, it is important to note whether red-tinged or bloody CSF clears as subsequent tubes of CSF are obtained. Such clearing suggests a traumatic tap. This can be documented in the laboratory by counting the red blood cells in successive tubes. CSF cells should be counted in the laboratory within 1 to 2 hours of collection. Delays beyond that period of time may result in a falsely low cell count because of cell lysis and/or adherence of cells to the walls of the tube. Glucose enters the cerebrospinal fluid by transport through the choroid plexus and endothelium of the capillaries in the subarachnoid space. CSF levels of glucose are thus a function of active transport of glucose and the rate of glucose consumption within the CNS. The level of CSF

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glucose under normal conditions in normal subjects is 60% to 70% of the blood glucose level. However, a study by Skipper and Davis44 showed this CSF/serum ratio was only accurate when the serum glucose concentration was between 89 and 115 mg/dL. For blood glucose levels greater than 125 mg/dL, the ratio was under 60%, and when the blood glucose level was elevated above 192 mg/dL the ratio fell to 50%, even among normal patients with no evidence of meningitis. CSF protein levels are generally less than 40 mg/dL due to the exclusion of larger proteins by the blood-brain barrier. When this breaks down during meningitis, protein tends to increase and increases with duration of disease before treatment. Levels in newborn infants are significantly higher than those of older children and adults, with an average of 90 mg/dL and a normal level up to 170 mg/dL. Extremely high levels of CSF protein above 1 g/dL are suggestive of a CSF spinal block. Elevation of the protein in the spinal fluid is not specific for any particular kind of meningitis. Table 12-2 shows the range and differential cell count in different types of meningitis. In general, the highest CSF cell counts are found in bacterial meningitis where levels may reach greater than 10,000 cells/mm3 with 95% polymor-

Table 12-2  CSF Findings in Acute and Chronic Meningitis, and Other CNS Infectious Conditions Type of Infection (common examples) Bacterial S. pneumoniae N. meningitidis L. monocytogenes

Viral Enteroviruses Herpes simplex Arboviral encephalitis

Fungal Cryptococcus Histoplasmosis Coccidioidomycosis

Tuberculous

Parameningeal Sinusitis Epidural abscess Paraspinous abscess

WBC* (% PMN)

Protein (mg/dL)

Glucose (mg/dL)

100–500

<40

>200 (>80 %) Usual range: 500–3000 typically >90% PMNs Can be normal in meningococcemia <200 (<50%)

<200

Normal

100–900

<40

100–900

<40

<100

Normal

May have PMN predominance early in the course of infection, converts to lymphocytic predominance within 12–24 h >100 (<50%) Usual range 100–400, usually lymphocytic predominance May be normal in Cryptococcal meningitis >100 (<50%) Usual range 100–400, usually lymphocytic predominance <100 (<50%) Occasionally PMN predominance If rupture into CSF, like acute meningitis

*Per mm3. CSF, cerebrospinal fluid; PMNs, polymorphonuclear neutrophils.

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phonuclear leukocytes (PMNs). Typically, the cell count in bacterial meningitis is between 500 and 5000 cells, and the CSF glucose is generally less than 40 mg/dL. Protein is typically in the 100 to 500 mg/dL range. It is important to recognize that a predominance of PMNs may occur early in viral meningitis, within the first 24 to 48 hours,45 but this gradually shifts to a mononuclear predominance over the next eight hours if the LP is repeated.46 In meningitis due to L. monocytogenes in infants, there may also be a monocytic predominance. CSF Gram stain should be performed immediately in patients with suspected bacterial meningitis. In general, the Gram stain requires the presence of at least 103 organisms/mL for organisms to be seen with staining. Below that level there are simply too few to detect by direct visualization. Approximately 75% of patients with acute bacterial meningitis will have a positive Gram stain result; this percentage may drop to about 50% among patients who have received significant doses of antibiotic treatment. Gram stain results are generally positive in 90% of untreated patients with pneumococcal meningitis, 86% of patients with meningitis due to H. influenzae and approximately 75% of cases due to N. meningitidis.42 CSF should be centrifuged by the laboratory and the pellet submitted for culture and Gram stain to improve the yield on both culture and Gram stain. In addition to Gram stain, a number of other rapid diagnostic tests have been developed over the past 20 years for diagnosis of acute bacterial meningitis. In the 1970s, counterimmunoelectrophoresis was used as a means of directly detecting bacterial polysaccharide antigens. However, this test is quite insensitive and is no longer in use.47 Agglutination tests are commercially available for H. influenza, S. pneumoniae, and five serotypes of N. meningitidis. However, the sensitivity and specificity of these tests are not better than those of the Gram stain.48 Several studies have been published showing that they provide no additional diagnostic yield above and beyond the Gram stain and the clinical picture and would almost never influence treatment.49,50 Therefore, they are not currently recommended in the diagnosis of acute bacterial meningitis upon initial presentation. The underlying problem with these tests is that the results are not sensitive and specific enough to affect treatment parameters by themselves. In other words, if a patient is sick enough to be admitted to the hospital, and/or has a low CSF glucose level and increased CSF white blood cells, one cannot stop empiric treatment if the agglutination test results are negative. Conversely, if a patient is considered well enough to send home with a negative CSF Gram stain result and normal glucose level, there is almost no possibility that one of these tests will yield a true positive result. Miscellaneous Cerebrospinal Fluid Tests C-reactive protein can be measured in CSF and, when present in concentrations greater than 100 mg/mL, may be useful in differentiating between bacterial and viral menin-

gitis.51 Several studies have also reported the use of the polymerase chain reaction in the detection of bacterial deoxyribonucleic acid (DNA) in spinal fluid in patients with bacterial meningitis. However, this technique is expensive and not readily available in most hospital laboratories. Radiologic Studies Neuroimaging plays little role in the diagnosis of acute bacterial meningitis except as indicated previously to rule out the presence of mass lesions and increased ICP, which might increase the risk of herniation when lumbar puncture is performed. The major value of CT and magnetic resonance imaging (MRI) in patients with acute bacterial meningitis is in the investigation of complications. In patients with prolonged fever, up to 10 days or longer, as many as 25% may have a subdural effusion (Fig. 12-1). In some cases this may become subdural empyema and account for the prolonged fever. Cortical infarction is a not uncommon complication of bacterial meningitis and is due to vasospasm or vasculitis of vessels. MRI is probably more useful in the detection of cortical infarction, as well in delineating areas of cerebritis, than is the CT scan (Fig. 12-2). Imaging studies are also useful in the diagnosis of hydrocephalus.

Figure 12-1. Axial contrast-enhanced CT scan demonstrates features of both active and secondary meningitis and subdural effusion associated with H. influenzae meningitis. There is increased ventricular enlargement compatible with external hydrocephalus, and abnormal pial surface enhancement most evident along the mesial surface of the frontal lobes and along the right lateral brain convexity. The left-sided effusion shows no sign of accumulated abnormal or dural enhancement. These effusions are typically sterile. (Courtesy of Ronald Quisling, MD, University of Florida.)

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Figure 12-2. Axial mid-convexity, contrast-enhanced T1-weighted MR image demonstrates diffuse pial and dural enhancement along the left side of brain. There is cytogenic edema distributed to both the anterior cerebral and middle cerebral arterial territories as well as mild ventricular enlargement. There is also enhancement along the ependymal surface of the left trigone indicative of ependymitis. These findings represent a combination of pial inflammation and vascular territory edema consistent with infarction or cerebritis. Bacterial meningitis often causes vasculitis, which in turn, as in this instance, causes secondary cerebral infarction. Thus, cytogenic edema conforming to a vascular pattern is more likely a reflection of secondary stroke than cerebritis leading to brain abscess formation. (Courtesy of Ronald Quisling, MD, University of Florida.)

Treatment The pathophysiology of the blood-brain barrier is of critical importance in determining the choice of antibiotics for the treatment of acute bacterial meningitis. The penetration of the blood-brain barrier is a function of the lipid solubility, molecular size, and structure of the antibiotic, as well as the degree of the inflammation of the meninges. Thus, for example, chloramphenicol, which is highly lipid-soluble, will significantly penetrate uninflamed meninges. Fortunately, in inflamed meninges concentrations of penicillins, cephalosporins, and vancomycin can be achieved for treatment of the vast majority of cases. A critical variable in the penetration of the blood-brain barrier is protein binding of antibiotics in serum, because only the free, unbound portion of the drug is capable of passing through the blood-brain barrier. Thus, the gradient will be very low for drugs that are highly protein-bound. Furthermore, with increased concentrations of protein in the spinal fluid itself, protein binding

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can once again become a significant factor in the effectiveness of those antibiotics that are highly protein-bound. The penetration of aminoglycosides is generally so poor that they are of no value in the treatment of acute meningitis when given intravenously, although they may be useful intrathecally. Among the cephalosporins, the penetration of the third-generation cephalosporins, ceftriaxone and cefotaxime, is significantly better than that of the first- and second-generation cephalosporins. Thus for example, CSF concentrations of these antibiotics average between 8.7 and 11.0 mg/mL with concentrations recorded as high as 27 mg/mL. However, there is a great deal of variability in the achievement of these concentrations and at the present time some organisms, for example, S. pneumoniae, may be resistant to lower levels of these drugs. In general, quinolones, tetracyclines, and macrolides do not penetrate the central nervous systems sufficiently to be useful first-line agents in the treatment of meningitis. Sulfa drugs and vancomycin in the presence of inflamed meninges, however, do reach sufficient concentrations to be of therapeutic utility. Treatment regimens for acute bacterial meningitis in children older than 3 months and in adults up to the age of 50 are geared toward treating the most common pathogens, which include meningococcus and S. pneumoniae together with only rare cases of H. influenzae. The prevalence of penicillin-resistant S. pneumoniae has increased, so that more than 50% of strains may be resistant or intermediately resistant to penicillin in some parts of the United States and other countries. By definition, fully susceptible pneumococci are susceptible to penicillin at <0.1 mg/mL. Those that are intermediate are susceptible to £2 mg/mL and fully resistant S. pneumoniae are resistant to ≥4 mg/mL. Among penicillinresistant strains, resistance to the third-generation cephalosporins, cefotaxime and ceftriaxone, has risen to levels as high as 10% to 20% in some areas. Thus, based on the clinical diagnosis of acute meningitis, children between 3 months and 15 years of age should receive cefotaxime 225 to 300 mg/kg intravenously (IV) every 8 hours.52 The adult dose is 8 to 12 g per day divided into four to six doses. Ceftriaxone is considered to be therapeutically equivalent and should be administered at 100 mg/kg/day in one or two doses for children younger than 15 years of age and 2 g every 12 hours for patients older than 15 years. Because of the problem of resistance among S. pneumoniae, vancomycin in a dose of 2 to 3 g per day given every 8 to 12 hours in adults and at 60 mg/kg for children in four divided doses should also be administered.53,54 For patients with a history of severe penicillin allergy, chloramphenicol at a dose of 75 to 100 mg/kg in four divided doses for children52 and at a dose of 4 g per day in four divided doses for adults should be given in place of the third-generation cephalosporin together with vancomycin. In adults older than 50 years of age, patients with chronic alcoholism, other debilitating conditions, or immunosuppression the possibility of Listeria should be considered. L. monocytogenes infection should be treated

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with ampicillin 2 g IV every 4 hours in addition to thirdgeneration cephalosporins and vancomycin. For patients with penicillin allergy the use of chloramphenicol, imipenem, or trimethoprim/sulfamethoxazole can be considered as an alternative to cover for Listeria until culture results are available. Therapy may need to be broadened depending on the results of the Gram stain. For example, if gram-negative rods are seen and bacterial antigen test results for Haemophilus are negative or not available, it is probably wise to add at least systemic treatment with an aminoglycoside if not intrathecal treatment. In cases where gram negative diplococci are seen it is probably prudent to wait until culture results confirm N. meningitidis before narrowing the bacterial coverage to penicillin because of the possibility that the Gram stain may have been misinterpreted. Treatment of the most common etiologic agents of acute bacterial meningitis is summarized in Table 12-3. The use of dexamethasone as an adjunct to therapy in acute bacterial meningitis is complex. It has been shown clearly in animal models and in patient studies that dexamethasone reduces the level of inflammation and reduces the levels of the inflammatory cytokines IL-1b and tumor necrosis factor-a.55 However, in an animal model, administration of dexamethasone together with vancomycin reduced the penetration of vancomycin into the CSF by 29% and lowered the rate of bacterial clearance during the first 6 hours in animals who received an intermediate dose of vancomycin. Animals who received a higher dose had therapeutic peaks maintained despite steroid use, suggesting that the antiinflammatory effect of the steroids that reduces entry of antibiotics into the CSF may be overcome to some extent by increasing the dose.56 Human studies of the use of dexamethasone have clearly shown that there is a reduction in severe hearing loss in patients who have H. influenzae type b meningitis and there is a similar reduction in overall neurologic complications, although perhaps not as significant. In children with meningitis due to S. pneumoniae, there also appears to be a significant reduction in long-term hearing loss.57 Major side effects from dexamethasone include secondary fever and a small incidence of gastrointestinal bleeding, which is probably negligible if treatment is limited to 2 days, but increases up to 3% in patients who received 4 or more days of treatment. Based on recent studies, dexamethasone should be used as an adjunct in children and adults at a dose of 0.4 mg/kg IV every 12 hours for 2 to 3 days and should be given just before, or at the time of, the first antibiotic dose to block any increase in any inflammatory cytokine production following initial bacterial lysis.58,59 The duration of treatment is based on empiric observation and has not been subject to clinical trials. In general, the minimum duration treatment is 7 days as long as the patient is afebrile for the last 4 to 5 days. Treatment of S. pneumoniae generally takes longer than H. influenzae and N. meningitidis, and probably should be extended to 10 to 14 days,

depending on the patient’s response. Meningitis following trauma and neurosurgical procedures is discussed elsewhere. Complications Increased ICP is to be expected in acute bacterial meningitis and should be anticipated. Some of the signs of increased ICP include altered consciousness as manifested by drowsiness, obtundation, and coma. Ocular abnormalities include unilateral or bilateral dilated, poorly reactive or nonreactive pupils. Other signs include abnormalities of ocular movement and a combination of bradycardia and hypertension. Papilledema may be unreliable as an early sign because it takes several hours to develop after the ICP has increased. Signs of herniation may supersede those of increased pressure and include nonreactive pupils which are unequal or dilated, dysconjugate eye movements, decorticate and decerebrate posturing, and bradycardia with abnormal respiratory patterns. Patients who are awake and alert can probably just be monitored closely. Patients who are obtunded and/or comatose or who show other signs of increased ICP may benefit from ICP monitoring. Pressures exceeding 20 mm Hg should be treated, and some studies suggest that pressures greater than 15 mm Hg may benefit from treatment.60,61 The reason for treating at lower pressure levels is the phenomenon of “plateau waves,” which are large elevations in pressure that may occur spontaneously or due to small shifts in intracranial blood volume from hypoxia, fever, or otherwise innocuous events such as tracheal suctioning. When these waves develop on a background of relatively increased ICP, herniation and irreversible brainstem injury may result.61 The treatment of increased ICP includes elevation of the head of the bed to 30 degrees, hyperventilation to decrease the arterial PaCO2 concentration pressure between 27 and 30 mm Hg, and the use of mannitol and phenobarbital. Caution is advised in the use of hyperventilation to lower arterial PaCO2 concentrations because overly vigorous treatment may lower these values below 25 mm Hg with the risk of producing cerebral ischemia. The dose of mannitol in children is 0.5 to 2.0 g/kg infused over 30 minutes and repeated as necessary; in adults, the usual dose is 1 g/kg bolus injection and 0.25 g/kg every 2 to 3 hours as needed.53 Mannitol acts as a hyperosmolar agent because it remains almost entirely within the intravascular space, producing an osmotic gradient that results in the reduction of intracranial fluid. Serum osmolality should be frequently checked and kept between 315 and 320 mOsm/L (see Chapter 25).61 Dexamethasone has been used to reduce intracranial swelling in other settings primarily because of its effectiveness in vasogenic cerebral edema. However, its effectiveness in reducing cerebral edema in patients with acute bacterial meningitis is not well established and its use is complex, as discussed previously. High-dose barbiturates may be helpful when other methods have failed to control increased ICP.

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Table 12-3  Treatment of the Most Common Agents of Acute Bacterial Meningitis Microorganism Streptococcus pneumoniae Empiric, before culture results

For clinically significant penicillin allergy Known penicillin susceptible (£0.1 mg/mL) Known penicillin intermediate (0.1–2 mg/mL) or resistant (≥4 mg/ml)

Treatment

Cefotaxime 2 g IV q 4–6 h or ceftriaxone 2 g IV q 12 h plus vancomycin 15 mg/kg q 6 h Plus: consider dexamethasone 0.4 mg/kg IV q 12 h for 2–3 d In adults: >50, add ampicillin 2 g IV q 4 h, until culture results are known Substitute chloramphenicol 75–100 mg/kg/d in four divided doses for the cephalosporin In adults: penicillin G 4 million units IV q 4 h In children: penicillin G 250,000–400,000 U/kg IV q 4–6 h As above for empiric treatment

Neisseria meningitidis

In adults: penicillin G 4 million units IV q 4 h Penicillin allergic—as for S. pneumoniae above In children: penicillin G 250,000–400,000 U/kg IV q 4–6 h For penicillin allergy, chloramphenicol as above Dexamethasone use not studied

Haemophilus influenzae

Chloramphenicol 75–100 mg/kg in four divided doses, plus Plus any of: Ampicillin 200–400 mg/kg IV q 6 h Cefotaxime 225–300 mg/kg IV q 8 h Ceftriaxone 100 mg/kg once or twice daily Plus: dexamethasone 0.4 mg/kg IV q 12 h for 2 d Do not use ampicillin alone

Streptococcus agalactiae (Group B streptococcus) Suspected/empiric Infants £ 7 d

Infants > 7 d

Known Infants £7 d Infants >7 d Listeria monocytogenes Newborn (documented or suspected infection) Infants £7 d

Infants ≥7 d

Adults >50, alcoholism, or other risk factors (documented or suspected infection)

Ampicillin 200–300 mg/kg/d IV in three divided doses Plus an aminoglycoside, adjusted for age and birth weight (BW) e.g., gentamicin 2.5 mg/kg IV q 12 h for infants < 1 wk 2.5 mg/kg IV q 8–12 h > 1 wk if BW <2000 g 2.5 mg/kg IV q 8 h if BW > 2000 g Ampicillin 300 mg/kg/d IV in 4–6 doses/d Plus an aminoglycoside, adjusted for age and birth weight (BW) e.g., gentamicin 2.5 mg/kg IV q 12 h for infants < 1 wk 2.5 mg/kg IV q 8–12 h > 1 wk if BW < 2000 g, 2.5 mg/kg IV q 8 h if BW > 2000 g Penicillin G 250,000–450,000 U/Kg/d IV in three divided doses Penicillin G 450,000 U/kg/d IV

Ampicillin 200–300 mg/kg/d IV in three divided doses Plus an aminoglycoside, adjusted for age and BW e.g., gentamicin 2.5 mg/kg IV q 12 h for infants <1 wk 2.5 mg/kg IV q 8–12 h > 1 wk if BW < 2000 g 2.5 mg/kg IV q 8 h if BW > 2000 g Ampicillin 300 mg/kg/d IV in 4–6 doses/d Plus an aminoglycoside, adjusted for age and birth weight e.g., gentamicin 2.5 mg/kg IV q 12 h for infants <1 wk 2.5 mg/kg IV q 8–12 h > 1 wk if BW < 2000 g 2.5 mg/kg IV q 8 h if BW > 2000 g Penicillin allergic: trimethoprim/sulfamethoxazole 15–20 mg/kg/d trimethoprim, 75–100 mg/kg/d sulfamethoxazole in 3 to 4 doses Ampicillin 2 g IV q 4 h plus ceftriaxone 2 g IV q 12 h or cefotaxime 2 g IV q 6 h, plus gentamicin 2 mg IV loading dose, then 1.7 mg/kg q 8 h Plus dexamethasone 0.4 mg/kg IV q 12 h ¥ 2 d For penicillin allergy: trimethoprim/sulfamethoxazole

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Barbiturates decrease the CNS metabolic demand for oxygen and thus decrease cerebral blood flow with a resulting decrease in ICP. Phenobarbital is given at an initial dose of 5 to 10 mg/kg, at a rate of 1 mg/kg per minute followed by 1 to 3 mg/kg per hour.48 Such treatment requires an ICP monitoring device and/or an electroencephalogram (EEG) to monitor cerebral electrical activity. Phenobarbital is given until the ICP is reduced below 20 mm Hg or until approximately 90% burst suppression on the EEG (nine of the ten screens of the EEG are flat) has been achieved. It is recommended that serum phenobarbital concentrations be kept within the range of 20 to 40 mg/mL, although obtaining levels in “real-time” may be impossible. The clinical examination and monitoring may have to suffice. Pentobarbital is preferred because of its relatively short half-life of 24 hours compared with significantly longer half-life agents such as phenobarbital. It is important to recognize that there may be significant cardiac depression with arrhythmias and even hypotension from the use of high dose barbiturate treatment.

tis and septicemia) among college freshmen living in dormitories is 4.6 cases/105 population, compared with rates of 0.6 to 0.7/105 among college students as a whole, and 1.5/105 among noncollege students, aged 18 to 23.64 Similar figures were found in the United Kingdom. The vaccine contains immunogenic polysaccharide capsular material from serogroups A, C, Y, and W-135. The capsular material from serogroup B, which accounts for approximately 30% of cases in the United States, is unfortunately nonimmunogenic. The vaccine has not been tested in controlled clinical trials but produces protective antibody levels in over 90% of young adults, and has been used by the military since 1971.65 The vaccine has few side effects and is believed to be protective for at least 3 to 5 years. Vaccination for S. pneumoniae is recommended for immunocompromised and splenectomized patients to prevent fulminant sepsis and pneumonia, but is not thought to be cost effective for the general public.

Viral Meningitis and Encephalitis Seizures Seizures occur in approximately 30% to 40% of both children and adults with acute bacterial meningitis within the first few days of illness.62 If not treated, these seizures may progress to status epilepticus, which in turn can result in anoxic damage to the temporal lobe, cerebellum, and thalamus.61,63 The main principles of therapy are to control seizure activity quickly and definitively. Initially, short-acting anticonvulsants such as lorazepam or diazepam are given, followed by the long-acting agent, phenytoin. Lorazepam is given IV in doses of 1 to 4 mg in adults, and 0.05 mg/kg in children. Phenytoin is given IV at a dose of 18 to 20 mg/kg and at a rate of no more than 50 mg/min. The rate should be decreased if signs of toxicity such as hypotension or a prolonged QT interval develop. If phenytoin is not successful in controlling seizure activity, intubation and treatment with IV phenobarbital may be necessary. Patients must be watched carefully for signs of toxicity such as hypotension and respiratory depression. Phenobarbital should be given IV at a rate of 100 mg/min until seizure activity stops, up to an initial dose of 20 mg/kg. In children, the rate should be decreased to 30 mg/min. If these measures fail to control seizures, general anesthesia and additional phenobarbital may be necessary. Vaccination for Meningitis Following the widespread use of the conjugated H. influenzae capsular vaccines in the late 1980s and early 1990s, the incidence of Haemophilus meningitis has dramatically declined.10 Recently, the U.S. Public Health Service Advisory Committee on Immunization Practices has recommended that college students be targeted for meningococcal vaccination. The reasoning behind this approach is the observation that the incidence of meningococcal disease (both meningi-

Viral infections of the CNS occur as part of the spectrum of systemic viral infections. Viruses are obligate intracellular parasites that can only replicate within a cell. By definition they contain only one nucleic acid, either DNA or ribonucleic acid (RNA), which is surrounded by a protein coat called the capsid. This nucleocapsid is in turn surrounded by surface proteins called capsomers. In addition, some viruses, such as the herpes viruses, retroviruses, and most of the respiratory viruses, have lipid envelopes. Once inside the cell, viruses may replicate their nucleic acids within the cell’s nucleus or cytoplasm. Following replication of the nucleic acid, viral structural proteins are produced that either self-assemble or are actively assembled, generally at the cell membrane, where the completed viral particles are released. For every viral particle that infects a cell, several thousand viral particles are produced in a productive infection. The outcome of viral infection of a given cell may be lytic, as just described, or may lead to latent infection. In the latter case, the virus does not kill the host cell; rather, the viral DNA may be carried as an episome, as in the case of herpes viruses, or a DNA copy of its RNA genome may be integrated into the host chromosome, as in the case of the retroviruses. Virus infections of the CNS may be classified as exogenous due to infection with a viral agent acquired outside the host. Alternatively, CNS infections may be produced by reactivation of viruses that remain latent in the host. The majority of viral CNS infections are due to exogenously acquired enteroviruses, arborviruses, and less commonly, herpes viruses, respiratory viruses or lymphocytic choriomeningitis virus. Herpes simplex encephalitis is unique in that it may occur as part of the primary infection or be seen in patients in whom the infection has been latent for many years. CNS infections due to the other herpes viruses, such as Epstein-

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Barr virus, varicella, or cytomegalovirus may occasionally be seen as part of the primary infection and may also occur as reactivated infections in patients also infected with human immunodeficiency virus (HIV). Epidemiology Aseptic meningitis and meningoencephalitis are the most common viral CNS infections encountered in the United States. The overwhelming majority of these cases are caused by enteroviruses, which produce disease in outbreaks occurring during the summer months, generally July and August, but occurring from May to October in warmer parts of the United States. While virtually all of the different serotypes of echovirus and coxsackievirus can produce meningitis and meningoencephalitis, in addition to other syndromes, the most prevalent serotype in the United States during the years 1997 and 1999 reported by the Centers for Disease Control (CDC) was echovirus 30, which accounted for 37.5% of all isolates, followed by echovirus 11 with 13.8%, and echovirus 9 with 8.7%. Of the more than 75 known enterovirus serotypes, the 15 most common of these account for 90% to 95% of all isolates each year. Thus, the pattern is one in which certain strains, such as echovirus 30, cause disease endemically while other strains occur in scattered outbreaks varying from year to year in different locations. Enteroviruses are transmitted from person to person by the fecal-oral route and their activity tends to be increased in areas of overcrowding, poverty, and poor hygienic conditions. Arboviruses account for the majority of epidemic cases of encephalitis. Their occurrence follows an identical seasonal distribution to that of aseptic meningitis and meningoencephalitis due to the enteroviruses. However, the mode of transmission is completely different. Arboviruses are spread by the bite of infected mosquitos, which are part of a complex cycle of enzootic transmission between birds, mosquitos and small mammals. Horses and human beings get infected incidentally to this natural cycle. From 1996 to 1997, a total of 252 cases of La Crosse encephalitis were reported to the CDC in patients ranging in age from 5 months to 70 years. Onset ranged between late June and early November. One hundred thirty-nine of these cases were reported from West Virginia and only one fatality was recorded.66 In contrast, during the same period there were only 15 cases of St. Louis encephalitis, and 19 cases of Eastern equine encephalitis five of which were fatal, illustrating the differences in frequency and severity between the different types of encephalitis viruses. The distribution of cases of equine encephalitis across the United States differs depending on the particular virus. For example, St. Louis encephalitis is found throughout the Midwest and South, as far north as New York and Michigan, with cases even reported on the West Coast. Eastern equine encephalitis, however, is essentially confined to the Southeast, and California encephalitis

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and La Crosse encephalitis tend to be seen primarily in the northern Midwest. The epidemiology of these diseases may be affected in part by prevention efforts from the public health authorities. For example, many states maintain surveillance systems, which include testing of mosquitoes for the presence of virus, as well as sentinel chicken flocks to determine arbovirus activity. Such efforts lead to early recognition of an outbreak and warnings by public health authorities for the population to take precautions such as insect repellants, wearing long sleeve shirts, and avoiding outdoor activity in the early evening hours when transmission is most likely to occur. In addition, mosquito control activities may be undertaken and diminish the infection as well. In August of 1999, an outbreak of encephalitis was detected in New York City, focused on the borough of Queens, where 62 patients were confirmed infected, seven of whom died with infection due to an agent identified as West Nile virus. This followed a massive die off among birds, particularly crows, that had been noticed in the month before the outbreak. Most of those affected with serious illness were elderly, although one patient was 29 years old.67,68 Initially, there was some question as to whether this virus would be able to survive winter conditions in the Northeast. However, surveillance data from the CDC found West Nile virus in 237 mosquito pools from 15 counties in the states of New York, New Jersey, Connecticut, and Massachusetts in the summer of 2000.69 Fourteen thousand seventy-one West Nile virus–infected bird carcasses from 79 counties in a total of six states were also noted. At least 12 persons were hospitalized with confirmed West Nile virus infection in the summer of 2000, most of them in New York City. In 2001, 42 human cases were reported to the CDC in Florida (ten cases), New York (ten cases), Connecticut (six cases), Maryland (six cases), New Jersey (six cases), Pennsylvania (three cases), and Georgia (one case). Overall, the median age was 70.5 with a range of 36 to 90 years, and two persons (4.8%) died. At least 26 states, mostly east of the Mississippi River, reported infections in birds and horses.70 A total of 4156 cases of West Nile virus infection, with 284 (approx. 7%) fatalities, were reported in 2002 from almost all states east of the Rocky Mountains. Thus, it seems likely that this virus will become endemic in the United States. It is interesting that this virus has been well known in Africa and the Middle East for many years. However, it was recently recognized as the cause of a large urban outbreak in Bucharest, Romania, and thus its epidemiology may be changing on a worldwide basis for unknown reasons. Although rabies is rare among humans in the United States, potential exposures to rabid animals lead to between 16,000 and 39,000 persons receiving post–rabies exposure prophylaxis each year. Since the 1950s, the incidence of rabies in domestic animals has declined dramatically because of immunization of dogs and other domestic animals. However, there has been a dramatic increase in the level of

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endemic rabies in wild animals such as raccoons, skunks and bats, particularly on the East Coast.71 Pathogenesis Viral infection of the central nervous system occurs via two distinct routes: hematogenous and neuronal. In the case of the enteroviruses and arboviruses, CNS infection occurs as part of a systemic infection with the virus carried to the central nervous system via the bloodstream. In the case of herpes simplex and rabies encephalitis, the virus is carried to the CNS via nerve cells themselves. Because viruses must replicate intracellularly, the ability to cause disease is largely determined by whether viral surface proteins can attach to specific receptors on specific cells in affected tissues. One of the most well-documented examples of this phenomenon comes from animal model studies of reovirus type 1. In neonatal mice inoculated orally, type 1 reovirus grows to very high titers in intestinal tissue, whereas type 3 reovirus replicates minimally there. Genetic studies showed that ability to replicate was determined by the M2 gene segment, which codes for an outer capsid polypeptide of the virus. However, if reovirus type 3 is injected directed intravenously, it causes fatal encephalitis whereas reovirus virus type 1 does not. When an S-1 gene from type 3 reovirus is recombined with type 1 reovirus, neural entry is conferred and the ability to infect the central nervous system occurs. Another example of viral tropism being determined by the combination of viral surface proteins and specific tissue receptors is that of the binding of the HIV GP120 to the CD4+ receptor on T4 lymphocytes. The distribution of HIV also includes macrophages, dendritic cells and certain neural cells, all of which express the CD4+ receptor. Cells that do not express this receptor generally do not become infected with HIV.72 So important are these surface binding sites for their respective cellular receptors that several viruses such as rhinovirus, influenza virus, and poliovirus have evolved sophisticated molecular mechanisms to protect these sites from the host immune response. For example, receptors embedded in a molecular “canyon” may be so small that antibodies cannot bind to it, or the sequence of the attachment site is highly conserved while surrounded topologically by a hypervariable region so that the host’s humoral immune response cannot keep up with the number of variations.73,74 Like poliovirus, enteroviruses spread in the population through fecal-oral transmission. These viruses survive stomach acid, replicate in the intestine, and an initial viremia leads to infection of multiple organs within the body. A secondary viremia from these sources can infect the CNS. The prompt production of antibody disrupts this second viremia and prevents invasion of the CNS. In the case of the arboviruses the natural host defense mechanisms of the skin and mucous membrane are bypassed by the direct injection of the skin through the infected mosquito. Once again, local

replication is followed by viremia and infection of the brain is probably determined by viral tropism and the rapidity of the host immune response. In the case of viremic infections of the CNS, invasion of the brain involves attachment to the endothelial cells, presumably via specific receptors. Following invasion, an acute inflammatory reaction is generally seen with a perivascular distribution within the brain parenchyma and varying degrees of infection in the meninges depending on the particular agent involved. The perivascular inflammatory response is predominantly mononuclear although polymorphonuclear leukocytes may be seen. Infection of neural cells results in degenerative changes and phagocytosis by tissue macrophages or microglial cells. Some pathologic features are unique to certain viruses such as the production of multinucleated giant cells in the case of HIV infection of the brain, and the characteristic inclusions seen in herpes simplex infections, namely, the Cowdry type A intranuclear inclusion body, and the characteristic Negri bodies in the case of rabies.75,76 Some viral infections, most notably herpes simplex and rabies, spread to the CNS via a neuronal route. In the case of herpes simplex virus, the distribution involves the medial part of the temporal lobe bilaterally with one temporal lobe generally much more involved than the other. Autopsy studies on patients who died during active HSV encephalitis show the presence of virus in the olfactory bulbs, olfactory tracts, and the tracts of the limbic system that end in the hippocampus, amygdala, insula, cingulate gyrus, and olfactory cortex.77 Thus, the virus appears to gain access to the CNS from the nasal mucosa to the olfactory bulbs and olfactory tracts, although the mechanism by which the virus does this is unknown. About two thirds of cases of herpes simplex encephalitis in adults and older children occur in patients who have antibody to the virus at the time the infection begins. Many of these patients have a history of cold sores dating back 20 to 30 years. In the other one third of patients, antibody to herpes simplex is lacking at the time of onset of symptoms, indicating that the encephalitis is part of the primary infection. Approximately 90% to 95% of the cases of herpes simplex encephalitis in older children and adults are due to herpes simplex type I, with the remaining 5% to 10% due to herpes simplex type II. Neonatal herpes appears to be different, in that 90% to 95% of these cases are due to herpes simplex type II acquired from maternal or other sources at the time of birth. Infection of the CNS in neonates is part of a systemic viremic spread and there is no temporal lobe localization. Neuronal spread also accounts for the invasion of the central nervous system by rabies. Rabies infection may result from contact with saliva or other secretions from infected animals as well as the animal bite itself. Rabies replicates initially at the local site of inoculation and for this reason emergency preventive measures such as thorough cleansing of the wound and infiltration with human rabies immunoglobulin can be effective in preventing infection with this agent. In

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the process of local replication, the virus gets into the nerve sheaths and is transported via infection of the nerve cells to the central nervous system. The rapidity of this process in reaching the CNS is a function of the distance of the nerve endings from the central nervous system. Thus bites on the lower extremities may take months to produce symptoms in the CNS, whereas bites in the face may reach the CNS in weeks. It is also important to recognize that the initial incident may be forgotten because of the time of the onset of the CNS symptoms and also because the inoculation may be inapparent as has been reported for bats.78 Therefore, one must always have a high index of suspicion for rabies for any unknown encephalitis, especially in patients who exhibit signs of hyperirritability. Clinical Manifestations The clinical presentation of viral meningitis includes fever, stiff neck, photophobia, and varying degrees of nonspecific symptoms such as malaise, myalgias, nausea, vomiting, abdominal pain, or diarrhea. The presence of impairment of consciousness, such as obtundation, disorientation, seizures, or localized neurologic signs or symptoms, should suggest brain parenchymal involvement and a diagnosis of encephalitis or meningoencephalitis. Stiff neck, while prominent, is generally less intense than that in bacterial meningitis. When the patient presents with meningitis, the most important consideration is to rule out bacterial meningitis as discussed previously. Because patients with viral meningitis tend to be less clinically ill, there is generally less need to obtain radiologic studies before performing lumbar puncture. In viral meningitis, the CSF typically shows an elevated white blood cell count, which may be predominantly polymorphonuclear leukocytes within the first 24 to 48 hours, although this number rarely exceeds 80% of total CSF white cells. The protein level is generally mildly elevated, and the glucose concentration is normal with the occasional exception of approximately 10% to 20% of patients with mumps and much less often in patients with enterovirus or herpes simplex virus. When the initial spinal fluid shows over 50% polymorphonuclear leukocytes, it is not uncommon for clinicians to repeat the lumbar puncture over the next 12 to 24 hours to determine whether there is a shift toward a lymphocytic predominance as one would expect in viral meningitis. In viral meningitis, the CSF Gram stain result will be negative and routine bacterial cultures will show no growth. For this reason, the term viral meningitis is often used interchangeably with the term aseptic meningitis. It is important to recognize that a wide range of nonviral illnesses can present similarly to meningitis and that, in addition to the enteroviruses, certain other viral agents can present with meningitis as well (Table 12-4). A parameningeal infectious focus will characteristically be associated with a CSF pleocytosis, somewhat elevated protein concentration, and a normal glucose concentration. Thus, a

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patient with an epidural or brain abscess could present with mild headache, fever, and a CSF picture identical to that of viral meningitis if radiologic studies were not done. Some cases of severe sinusitis, such as sphenoid sinusitis or frontal sinusitis may be associated with CSF pleocytosis. Patients with fungal and tuberculous meningitis will also present with headache, fever, and stiff neck, but in general the clinical course is much longer than in acute viral meningitis, usually at least 1 to 3 weeks before the patient seeks medical attention. Spinal fluid in these cases should show a low glucose, almost always less than 40 mg/dL. It is important to recognize that cryptococcal meningitis may present with completely normal spinal fluid analysis. Fever, headache, and nonspecific CSF findings can also be seen in such bacterial infections as syphilis, ehrlichiosis, and noninfectious conditions such as sarcoidosis, Behçet’s disease, and uveoparotitis. Viruses other than enteroviruses can also produce aseptic meningitis. The classic example is that of herpes simplex type II, which produces typical aseptic meningitis with low-grade fever, headache, stiff neck, and photophobia as part of primary genital herpes infection. It is, therefore, very important to question any potentially sexually active patient about the possibility of genital herpetic lesions, and in women perform a pelvic examination if indicated. Aseptic meningitis can also be seen as part of the syndrome of primary HIV infection. Certain strains of leptospirosis will typically present with aseptic meningitis. However, most cases present in conjunction with systemic disease and severe involvement of other organs such as lung, liver, and kidney. Lymphocytic choriomeningitis virus does occur with some frequency, particularly in patients with exposure to rodents such as house mice and pet hamsters. The laboratory diagnosis of viral meningitis is generally one of exclusion, as described previously. Viral cultures that grow enteroviruses from the spinal fluid are diagnostic. However, these results are positive in at most 30% to 50% of cases. Polymerase chain reaction (PCR) has become available for the diagnosis of enteroviral meningitis and this technique correlates very well with the results of viral culture. Unfortunately, this test is only available through reference laboratories or highly specialized research laboratories, and is costly. In the case of herpes simplex meningitis, the diagnosis is confirmed if herpes simplex is cultured from the spinal fluid or detected by PCR. In the case of aseptic meningitis associated with systemic infections such as leptospirosis, syphilis, or Ehrlichia, standard serologic tests generally available at state public health laboratories or reference laboratories would be diagnostic. Finally, certain drugs such as sulfa and nonsteroidal anti-inflammatory agents can produce acute syndromes of aseptic meningitis. Other agents that have been associated with aseptic meningitis include intravenous immunoglobulin, certain vaccines, and the intrathecal administration of drugs.79

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Table 12-4  Laboratory Diagnosis of Selected Viral Diseases Virus Herpes viruses Herpes simplex

CNS Disease

Serologic Results

Viral Culture Results

Direct Antigen and PCR Results

Temporal lobe encephalitis

Almost always negative in CSF, throat, etc

Varicella

Encephalitis in HIV patients

About two thirds seropositive on admission, not helpful in diagnosis Not helpful diagnostically

Cytomegalovirus

Encephalitis in HIV patients

Almost always positive, not helpful diagnostically

Urine, throat, blood may be positive—consistent with, but not proof of, encephalitis

Epstein-Barr virus

Rare encephalitis in mononucleosis

Not available

Human herpes virus 6 and 7 (HHV 6 and 7)

Seizures, encephalitis in 1–3 year olds

MonoSpot test good presumptive test, may be negative in up to 20% in 1st wk VCA-IgG and IgM, positive IgM virtually diagnostic Reference laboratories only

CSF–PCR diagnostic FA can be done on brain biopsy No antigen test, PCR available (CSF) FA can be done on brain biopsy Antigenemia test on blood, positive test consistent with, but not proof of encephalitis Not available

Reference laboratories only

Not available

Respiratory viruses Influenza A and B Parainfluenza 1–3 Adenovirus Respiratory Syncytial virus (RSV)

Usually negative in CSF, throat, etc

Parainfluenza occasionally, others rarely cause encephalitis

Not useful

Nasopharyngeal swabs Throat washings, Cultures via bronchoscopy—excellent sensitivity, diagnostic if positive

Direct antigen ELISA available for RSV (excellent sensitivity), and Influenza (moderately sensitivity)

Summertime outbreaks of meningitis, meningoencephalitis

Not useful, too many serotypes, too much cross-reactivity

Send stool, throat, CSF If throat or CSF culture positive, diagnostically definitive If stool culture positive, presumptive (enteroviruses may be shed in stool for weeks)

None for direct antigen, CSF–PCR diagnostic

Summertime outbreaks of encephalitis

Diagnostic, if positive Send serum and CSF—done in reference laboratories and state public health laboratories

Generally not available

Direct antigen not available but PCR for West Nile virus diagnostic

HIV

Encephalopathy

ELISA, confirm with Western Blot

Research laboratories only

Use PCR in CSF or serum

Lymphocytic chorimeningitis virus

Meningitis

Reference laboratory

Not available

Not available

JC virus

Progressive Multifocal leukoencephalopathy, mostly in HIV, other immunocompromised patients

Reference laboratory

Not available

Direct antigen not available; PCR available in reference laboratory

Rabies

Encephalitis

Reference or state public health laboratories, antibody is generally undetectable before day 6, 50% by day 8, and 100% by day 15

Research laboratories only

Direct FA staining of hair follicles in skin biopsy from nape of neck above the hairline—50% positive in 1st wk, higher later

Enterovirus Coxsackie Echovirus

Arboviruses St. Louis encephalitis California encephalitis Western equine Eastern equine La Crosse West Nile virus

CSF, cerebrospinal fluid; ELISA, enzyme-linked immunosorbent assay; FA, fluorescent antibody; HIV, human immunodeficiency virus; PCR, polymerase chain reaction.

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Serologic studies for the diagnosis of enterovirus infections are not recommended. Because there are over 75 different enterovirus serotypes, testing is only possible for a subset of these. In addition there is tremendous overlap in the serologic response between the different serotypes such that a diagnostic seroconversion to more than one enterovirus serotype may be found. Moreover, because there is no effective treatment, there is no need for expensive laboratory testing that cannot affect patient outcome. Another common diagnostic misconception is the usefulness of CSF antibodies. With the exception of the Venereal Diseases Research Laboratories (VDRL), which indicate active CNS syphilis, CSF IgM for West Nile virus and the ratio of measles antibodies in the spinal fluid to those in serum in extremely rare cases of subacute sclerosing panencephalitis, there is no useful diagnostic value in CSF antibody testing. In essence, all agents that are diagnosable can be diagnosed from serum studies rather than the use of spinal fluid. A list of common viral infections and preferred diagnostic methods is provided in Table 12-4. The hallmark of the presentation of viral encephalitis is the prominence of an altered level of consciousness with or without focal neurologic signs and symptoms in the setting of an acute febrile illness. The differential diagnosis is essentially the same as that for acute bacterial meningitis and acute viral meningitis as discussed previously. Varying degrees of nuchal rigidity can be present in patients with encephalitis due to the enteroviruses that in effect produce combined disease, for example, meningoencephalitis. Lumbar puncture reveals spinal fluid with a similar picture to that of viral meningitis. Radiologic studies, particularly MRI, are critical in arriving at a definitive or provisional diagnosis in cases of encephalitis. It is important to recognize that in some cases arbovirus encephalitis, particularly Eastern equine encephalitis, very commonly have focal lesions on MRI. However, their distribution is not consistent and differs from that of herpes simplex encephalitis (Figs. 12-3 and 12-4). Diagnosis of arbovirus encephalitis can almost always be made with serologic studies because antibody titers to all of the common arboviruses are generally present at the time the patient presents with the illness. Because there is only a very low background frequency of these antibodies in the general healthy population, a positive arbovirus serology can be accepted as clinically definitive. Arbovirus isolation is only possible in specialized research laboratories, as is PCR for West Nile virus. The diagnosis of herpes simplex encephalitis is of critical importance because of the ability of antiviral agents to treat this infection and improve the outcome. Unfortunately, almost nothing in the clinical presentation of patients with herpes encephalitis is of any value in diagnosing this condition. As part of an antiviral trial in the early 1980s, Whitley and colleagues obtained biopsy specimens from a total of 202 patients with signs and symptoms of encephalitis.80 Of these 202 patients, 113 had herpes simplex virus isolated

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Figure 12-3. Axial low convexity FLAIR image through the central nuclear structures demonstrates cytogenic edema within the basal ganglia and thalami bilaterally. In addition there is vasogenic edema in the subinsular white matter tracts, especially on the right, and in the posterior limb of the internal capsule on the right. Such findings would be consistent with either acute encephalitis versus acute disseminated postinfectious encephalomyelitis. In this instance, elevated titers for eastern equine encephalitis virus were observed. (Courtesy Kenneth H. Rand, MD, University of Florida.)

from brain tissue, only four of the remaining patients were thought to have herpes simplex encephalitis based on serology and other data. Subsequent studies confirmed these numbers using PCR. When the patients with positive brain biopsy results and those with negative brain biopsy results were compared statistically for the presence of findings such as alteration of consciousness, fever, headache, CSF pleocytosis, personality change, seizures, vomiting, hemiparesis, and memory loss, there were no differences between the two groups. In general, herpes encephalitis presents with a 3- to 5-day history of fever, and headache with or without systemic signs that progresses to obtundation and coma; the latter may appear abruptly with the onset of seizures. Herpes encephalitis can occur in any age group from childhood through old age, and occurs with equal frequency at all times of the year. The incidence is estimated at one in 250,000 to one in 500,000 people per year and is thought to account for approximately 10% to 20% of viral encephalitides in the United States. A diagnosis of herpes encephalitis is made highly likely from MRI findings that show bilateral temporal lobe involvement, which is generally asymmetrical (see Fig. 12-4). In untreated patients, this may progress to hemor-

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Figure 12-4. Axial, low convexity, proton-density MR image demonstrating cytogenic edema (increased signal intensity represented as increased regional brightness) within the cortical and immediate subcortical portions of mainly the right temporal lobe. Similar, but less extensive, changes are seen in the lower portion of the left insula and in the right basifrontal cortex. Since this distribution of the edema does not conform to any specific vascular territory, an inflammatory process more likely. A frontotemporal distribution of mainly cortical edema is most consistent with herpes simplex encephalitis in an acute phase. (Courtesy of Ronald Quisling, MD, University of Florida.)

rhagic lesions with mass effect and herniation. PCR for herpes simplex virus in the spinal fluid is almost uniformly positive in patients with herpes encephalitis, despite the fact that one cannot grow the virus from spinal fluid or other peripheral sites in more than 1% to 4% of patients.81–83 Serologic diagnosis is not particularly helpful early on, although in general all patients with herpes encephalitis will show a significant increase in herpes simplex titer both in the spinal fluid and serum, and will show seroconversion in the case of those undergoing primary infection. Conditions that mimic herpes simplex encephalitis, and viral encephalitis in general, were well described by Whitley and associates84 and include brain abscess, subdural empyema, cerebritis due to Listeria, Mycoplasma, and infections with fungi, tuberculosis, cryptococcus, rickettsia, toxoplasmosis, mucor, and even routine bacterial meningitis caused by agents such as pneumococcus and meningococcus. Tumors, subdural hematomata, CNS lupus, and adrenal leukodystrophy may also mimic the signs and symptoms of encephalitis. It is important to recognize that strokes may present with fever as well, and toxic encephalopathy such as neuroleptic malignant syndrome or Reye’s syndrome can also mimic encephalitis.

Encephalitis can sometimes occur as part of systemic infection with common viruses that do not normally produce encephalitis. For example, Epstein-Barr virus can, on occasion, present with seizures and even coma that fortunately, in general, resolve with complete recovery from the disease. CNS involvement with toxoplasmosis, lymphoma, varicella, and cytomegalovirus in patients with HIV can mimic the presentation of the patients with encephalitis. Table 12-5 lists nonviral infections that may present as encephalitis. Although rare, it is important to be alert to the possibility that a patient with encephalitis, in fact, has rabies. Rabies generally presents with a prodrome of 1 to 4 days consisting of fever, headache, malaise, myalgias, fatigue, anorexia, nausea, vomiting, sore throat, and a cough. The patient may complain in particular of paresthesias or fasciculations at the site of the original animal bite due to viral replication at the site of inoculation and/or in the dorsal ganglia of the sensory nerve supplying that area. Between 50% and 80% of patients with rabies will have some manifestations of this sort. The disease quickly progresses to an encephalitic phase consisting of agitation, excitation, and excessive motor activity. Patients may experience hallucinations, become combative, and develop muscle spasms with opisthotonus. Seizures are not infrequent. Periods of hallucinations and aberrant men-

Table 12-5  Common Nonviral Causes of Encephalomyelitis Infectious Ehrlichia Rocky Mountain spotted fever Bacterial endocarditis Brain abscess/cerebritis Staphylococcus aureus sepsis Syphilis (primarily meningovascular) Lyme disease Leptospirosis Mycoplasma Listeria (rhomboid encephalitis) Typhus Legionella Cat-scratch disease Nocardia Tuberculosis Cryptococcus Histoplasmosis Coccidioidomycosis Amebae Malaria Trypanosomiasis Noninfectious Drugs Carcinoma Lymphoma Vasculitis Behçet’s disease

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tation may alternate with lucid periods that get progressively shorter as the disease progresses. Hyperesthesias with excessive reactivity to normal stimulation of light, sound, and touch are very common; autonomic nervous system changes such as dilated pupils, increased salivation, lacrimation, perspiration, and postural hypotension occur. Ultimately brainstem function is affected with cranial nerve palsies, optic neuritis, and the characteristic hydrophobia due to the painful, violent involuntary contractions of the muscles of respiration, the pharynx, and the larynx initiated by attempts to swallow. Eventually the disease progresses to cardiorespiratory depression, coma, and death. Occasionally, rabies may present as an ascending paralysis clinically similar to the Guillain-Barré syndrome and in fact corneal transplants from two patients presumed to have died from GuillainBarré syndrome actually transmitted clinical rabies, resulting in the death of the recipients. The laboratory diagnosis of rabies requires viral isolation, positive serologic study results (assuming the patient has not been immunized) or demonstration of the characteristic Negri bodies in brain tissue. Viral antigen can also be demonstrated by immunofluorescent antibody in infected tissue including corneal scrapings, or skin biopsy or brain biopsy specimens. The yield from skin biopsy of the nape of the neck above the hairline is apparently significantly better than that of corneal scrapings.85 In patients who have traveled overseas, a large number of infectious diseases may present with encephalitis either as a primary entity or as part of a systemic disease, including agents such as Japanese B encephalitis, Murray Valley encephalitis, Omsk hemorrhagic fever, Kyasanur forest disease complex, Powassan virus, louping ill, Russian springsummer encephalitis, Rift Valley fever, yellow fever, dengue, chikungunya, Hantaan virus, Puumala virus, and the highly fatal hemorrhagic fevers, Marburg, Ebola, and Lassa. Following the bite of several species of monkeys, encephalitis may develop due to Monkey B virus, a herpes virus. This virus is related to human herpes simplex but humans have little native ability to contain it, in contrast to its natural host in whom it produces “cold sores.” It is transmitted to humans from saliva in monkeys and reaches the brain via nerves at the site of the monkey bite. Since 1932 about 40 cases have been described, with fatal outcome in approximately 70%. Treatment with ganciclovir or acyclovir may be useful. Consultations with the CDC or the Southwest Foundation for Biomedical Research in San Antonio TX (210-674-1410) is advised for the management of monkey bites or suspected cases due to Monkey B virus. Treatment No specific drug or serologic therapy is currently available for enterovirus or arbovirus infections. In general, viral meningitis due to enteroviruses is clinically mild and most patients can be treated without admission to the hospital

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unless there is a serious differential diagnostic question about bacterial meningitis. In patients with any suggestion of encephalitic symptoms or brain parenchymal involvement, assuming that appropriate radiologic studies have ruled out conditions such as brain abscess and subdural empyema, most physicians empirically treat the patient with acyclovir intravenously in doses appropriate for herpes encephalitis. Because of the rarity of complications from acyclovir it is difficult to argue with this practice and brain biopsy certainly is not justified to prove the presence of herpes encephalitis before treatment. Before the availability of antiviral agents for the treatment of herpes encephalitis, the disease was fatal in approximately 70% of patients, with an additional 20% to 25% surviving with severe disabilities. A National Institutes of Health– sponsored trial in the 1980s proved conclusively that acyclovir was superior to vidarabine, which had been shown to be superior to a placebo in earlier studies. Patients who received acyclovir had a 19% mortality at 6 months compared with a mortality of 55% for those who received the vidarabine. Furthermore, the outcome of surviving patients was significantly better for patients who received acyclovir, with 38% having only minor impairment or returning to baseline compared with only 13% among the vidarabine recipients. The most important host factors in determining the outcome of treatment are age and level of consciousness at the time that treatment is begun. Thus, those patients treated with acyclovir who had a Glasgow coma score greater than 10 had 100% survival, whereas those with a Glasgow coma score less than 6 had only a 50% survival; survival was significantly better for patients under the age of 30 than those above 30.84 The dosage of acyclovir is 10 mg/kg IV every 8 hours for 14 to 21 days.

Brain Abscess Brain abscesses have been recognized from the days of Hippocrates in 460 bc, but did not enter the realm of medical consciousness until William Macewen developed surgical procedures in the 1890s for the management of this entity. By definition, a brain abscess is a localized suppurative infection of the brain parenchyma.86 Brain abscess is fundamentally an uncommon disease. For example, during a 9-year period from 1990 to 1999, 57 intracranial complications developed among 2890 cases of chronic otitis media, an incidence of 1.97% in a highly selected susceptible population.87,88 The incidence in the general population has been estimated at 1.3 to 100,000 person years, with the rates slightly higher in children between 5 and 9 years of age and in adults older than 60 years of age. Most series document a male preponderance of between 2 : 1 and 3 : 1 and the age distribution is somewhat dependent on the associated underlying etiologies.89–91 Thus, some series have shown a bimodal age distribution with a peak in the pediatric age group and

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after the age of 40.92,93 While the etiology and distribution of associated diseases has remained essentially unchanged over the years for pyogenic brain abscesses, the AIDS epidemic has led to the emergence of a large group of patients with brain abscess due to toxoplasmosis. Pathogenesis Brain abscess develops as a localized area of cerebritis initially consisting of bacteria in the brain parenchyma together with inflammation and edema. Over the next several days, this area of infection becomes more localized with the development of necrosis in the middle and a ring-enhancing capsule. Ultimately, host defenses lead to the development of a well-formed capsule. The most common predisposing conditions for the development of a brain abscess are infections in the middle ear, paranasal sinuses, mastoids, and teeth. It is believed that bacteria reach the brain through valveless emissary veins, which traverse the cranium into the venous drainage system of the brain. Alternatively, direct extension through an area of osteitis or osteomyelitis adjacent to the sinus or middle ear infection could provide access to the CNS. The other major mechanism for seeding the brain parenchyma is metastatic transmission from an extracranial focus of infection. Hematogenous brain abscesses tend to be multiple, to be located at the gray-to-white matter junction, and to follow a vascular distribution within the brain. Pyogenic lung abscess and bronchiectasis are frequently noted as underlying associated conditions.92,94,95 Hematogenous dissemination from a contiguous focus of infection has been described. Other distant foci that have been associated with brain abscess include wound infections, osteomyelitis, pelvic infection, cholecystitis and other intra-abdominal foci. Any procedure that results in a transient bacteremia can on occasion be associated with the subsequent development of a brain abscess. Despite its chronicity and high level of bacteremia endocarditis accounts for only 1% to 5% of cases of brain abscess.96 A significant number of brain abscesses are associated with penetrating trauma such as gunshot wounds, depressed skull fractures with retained bone fragments, cranial penetration from objects such as pencils, animal bites, or even as a complication of cervical traction associated with pin site infection. In approximately 25% of cases, no underlying etiology can be found. Microbiology The bacterial etiology of brain abscess is to a great extent dependent on the location of the abscess and the predisposing factors. Thus, aerobic, anaerobic, and microaerophilic streptococci are the most frequently isolated bacterial species. S. aureus makes up 10% to 25% of the isolates in most series. However, its occurrence is most likely secondary to trauma, infection following neurological surgery, and

endocarditis.96 In addition to streptococci, brain abscess associated with paranasal sinus or chronic otitis media infection may be caused by Haemophilus species, Bacteroides species, other anaerobes, and P. aeruginosa in the case of chronic otitis media. The bacteria found in intracranial abscesses from patients with hematogenous spread depend on the underlying source, for example, S. aureus and viridans streptococci associated with endocarditis. If the source of bacteremia is intraabdominal, Enterobacteriaceae, enterococci, and anaerobes may be found, while a urinary tract origin is likely to lead to infection with Pseudomonas and/or Enterobacteriaceae, but not anaerobes. Anaerobes, including actinomyces, may be associated with spread from a lung abscess. Although S. aureus is the most common organism complicating penetrating trauma, Clostridium species and Enterobacteriaceae must be considered. The nature of the trauma is important too, because if it occurs in water, associated organisms such as Pseudomonas and Aeromonas would also have to be considered. The organisms associated with postoperative infections include S. aureus, S. epidermidis, Enterobacteriaceae, and Pseudomonas. On occasion, unusual organisms such as nocardia can produce brain abscesses. In a series of 11 cases and review of 120 cases of nocardial brain abscess in the literature, concomitant pulmonary disease was present in 34%. Most of the brain abscesses were single but approximately one third were multiple and overall 38% of the cases occurred in patients who were immunocompromised by virtue of HIV or iatrogenic causes.97 Rarely, Mycobacterium tuberculosis may produce a space-occupying lesion (tuberculoma). While uncommon in the United States, tuberculoma is the most common cause of brain abscess in some developing countries. Yeast and fungal infections are quite rare as causes of brain abscess, but it is important to recognize that they do occur. Candida albicans almost never causes isolated brain abscesses, but may cause microabscesses in association with disseminated candidiasis. Cryptococcus usually produces meningitis but cryptococcomas are frequently seen if sensitive radiographic techniques are used. Agents of Phaeohyphomycosis, such as Cladosporium, Bipolaris, Curvularia, and Wangiella, as well as the agents of Chromoblastomycosis have all been reported to cause brain abscess. Aspergillosis is well known to cause brain abscess but is almost always limited to the immunocompromised population particularly the transplant patients. Zygomycoses such as Mucor rhizopus, and Rhizomucor produce brain infection by direct extension from the paranasal sinuses in poorly controlled diabetics. Even protozoa and other parasites may cause brain abscess. As mentioned previously, toxoplasmosis is probably the most frequent protozoal cause of brain abscess observed in the United States and is almost entirely associated with HIV infection. Strongyloides, Entamoeba, Echinococcus, Paragonimus, Trichinosis, Sparganosis, and Angiostrongylus have all been reported, particularly in developing nations.

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Rarely, brain abscess due to Naegleria and Acanthamoeba occurs in this country.

Clinical Manifestations Headache of varying degree is the most consistent symptom among patients with brain abscess. The headache is generally not well localized and may be mild and difficult to differentiate from ordinary headaches. In many series, fever is present in only 50% or less of cases, and focal neurologic signs and symptoms such as hemiparesis, aphasia, ataxia, and sensory deficits may only be present in one third to one half of cases. Papilledema as a reflection of increased ICP is present in a minority of cases.98,99 Likewise, seizures are observed in approximately 25% to 45% of patients by the time they present. The seizures are most often generalized and most commonly associated with frontal lobe lesions. To some extent, the presenting signs and symptoms are dependent on the location of the abscess. For example, cerebellar abscesses often present with nystagmus, ataxia, vomiting, and dysmetria.100 Frontal lobe abscesses generally present with headache, drowsiness, and deterioration of mental status together with hemiparesis and unilateral motor signs. Temporal lobe abscesses may present with or without asphasia or dysphasia, depending on whether the abscess is in the dominant hemisphere. Pituitary abscesses may simulate a tumor and can present with visual field defects and endocrine abnormalities. Brainstem abscesses typically exhibit facial weakness, fever, headache, hemiparesis, dysphasia, and vomiting. The differential diagnosis includes a wide range of other infections such as meningitis, subdural empyema, epidural abscess, and viral encephalitis; noninfectious causes include migraine, intracerebral and subarachnoid hemorrhage, venous sinus thrombosis, and malignancies.

Diagnosis The introduction of CT scanning in the 1970s revolutionized the diagnosis of mass lesions in the CNS. For brain abscess, CT scans are 95% to 99% sensitive, and provide information on the size, location, and stage of the abscess together with the extent of surrounding edema and the presence or absence of mass effect such as midline shift, hydrocephalus, and impending herniation. Characteristic findings are a ring-enhancing lesion in the contrast-enhanced CT scan or MR image with a hypodense center reflecting the necrotic center of the abscess surrounded by a variable zone of edema (Fig. 12-5). The major problem in radiographic diagnosis is the differentiation from tumors including neuroblastomas as well as metastatic lesions. In one study, eight of 26 patients with a brain abscess were initially diagnosed as having a tumor.101 Another study noted that in 18% of CT scans from 100 patients with confirmed brain abscess, the

Figure 12-5. Axial, mid-convexity, T1-weighted, post– gadolinium-enhanced, MR image demonstrates a cavitary lesion in the right frontal region. There is abnormal enhancement surrounding the margin of this centrally necrotic mass. The deepest, innermost portion of the enhancement appears thinner, typical of a brain abscess. There is extensive edema surrounding the abscess cavity producing a right-to-left subfalcine shift. In addition to the abnormal enhancement of the cavity, there is also enhancement of the adjacent pial surface of brain consistent with meningeal inflammation. These are features of a subacute organized brain abscess with central suppuration. (Courtesy of Ronald Quisling, MD, University of Florida.)

initial findings could not be radiographically distinguished from that of a malignancy.102 MRI provides soft tissue resolution and detail that is superior to that achieved with CT. In addition, there is no exposure to ionizing radiation; the cost, however, is substantially greater. On T1-weighted images, brain abscesses appear hypointense and show ring enhancement following administration of the contrast agent gadolinium. On T2-weighted sequences, the central area of necrosis appears hyperintense and is surrounded by a well-defined hypointense capsule and readily discernible surrounding edema. One of the advantages of MRIs is that they can detect the cerebritis stage before the formation of the abscess with a fully developed capsule and, thus, can diagnose pyogenic brain infection earlier and with greater accuracy than CT scan. Newer methods such as MR spectroscopy, which can detect products of bacterial metabolism such as lactate, acetate, or pyruvate, should improve our ability to differentiate brain abscess from malignancy as these methods become more widely available in clinical practice.103 Use of radionuclide brain scans with agents such as indium-

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111–labeled leukocytes probably does not provide any advantage over conventional radiographic techniques. Thallium 201 single-photon emission computed tomography is a promising new technique, but its use in differentiating toxoplasma encephalitis from intracerebral lymphoma in patients with AIDS has to be regarded as preliminary at this time. Routine laboratory studies are not particularly useful in the diagnosis of brain abscess. Patients should have routine laboratory tests such as CBC, differential cell count, erythrocyte sedimentation rate, and standard chemistries performed. If the sedimentation rate is elevated, it may be useful to observe the rate to document a therapeutic response. Lumbar puncture in a patient with a space-occupying lesion is to some extent contra-indicated and probably should not be done unless there is a clear clinical suspicion of meningitis or meningeal carcinomatosis to justify the risk of herniation. The CSF in patients with brain abscesses generally shows findings similar to any other parameningeal focus of infection, in that the cell count and protein show mild elevations and the glucose is normal. Cultures are generally sterile, unless there is some anatomic connection between the abscess and the spinal fluid as may occur in cases in which the brain abscess is secondary to trauma or to a postoperative complication. While reasonable empiric treatment can be devised for most common brain abscesses, culture of the material and transport to the laboratory under strictly anaerobic conditions is essential for optimal identification of the causative agent(s). In addition, a biopsy can be obtained or material sent for pathologic examination to rule out malignancy as well as for stains for unusual microorganisms, if needed. The choice of antibiotics is to be determined both by the spectrum of microbiologic agents known to cause brain abscess and the degree to which individual antibiotics penetrate the blood-brain barrier and enter into the abscess cavity itself. Treatment Treatment for brain abscess represents expert consensus based on empiric treatment, rather than randomized controlled trials. Brain abscesses that develop in contiguity with frontal sinus infection may be assumed to contain mixed aerobic and anaerobic flora. In this situation, even if anaerobic bacteria are not recovered, treatment should be given with high-dose penicillin ranging from 10 to 20 million units per day together with metronidazole 7.5 mg/kg IV every 6 hours or 15 mg/kg IV every 12 hours. If there is any suspicion that the abscess may have arisen from a dental focus, anaerobic culture should be held for 7 to 14 days to detect the growth of Actinomycosis. However, Actinomycosis should respond to standard therapy with penicillin. Brain abscesses that are related to chronic otitis media and mastoiditis should be treated with a combination of antibiotics that will cover anaerobes as well as Enterobacteriaceae and

Pseudomonas. A combination of cefotaxime, ceftazidime, or ceftriaxone plus metronidazole would work well in this particular setting. Although culture specimens may not always grow anaerobes, particularly if they are fastidious, the absence of growth of Enterobacteriaceae or Pseudomonas from abscess material from a patient who has not received IV antibiotics can be relied on to exclude these particular organisms. Similarly, the absence of a culture showing S. aureus would also be very good evidence that this agent is not involved in the particular process. In general, S. aureus is much more likely to be a pathogen in the setting of endocarditis, metastatic infection to the CNS, and in the setting of trauma or postoperative infection. If a brain abscess is associated with a neurosurgical procedure, vancomycin should be included in the regimen to cover both methicillinresistant S. aureus and coagulase-negative staphylococci. The dosage of third-generation cephalosporins is 2 g IV every 4 hours for ceftazidime and 2 g IV every 12 hours for ceftriaxone. Patients with a Nocardia brain abscess should be treated with higher doses of trimethoprim-sulfamethoxazole, 15 mg/kg/day of the trimethoprim component in three to five divided doses until the disease is under control; thereafter, the dose can be lowered to one double-strength trimethoprim-sulfamethoxazole tablet orally twice daily for 3 to 6 months in nonimmunocompromised patients and up to 1 year in the immunocompromised. Patients with severe immunocompromise due to advanced AIDS probably need lifelong treatment for this disease.

Tuberculous Meningitis Tuberculosis has been known to humankind since antiquity, having been demonstrated recently by molecular methods in mummies from both the new and the old world dating to 1000 to 1500 years bc.104,105 Tuberculosis was recognized on clinical grounds in the 18th century and with the isolation of the organism by Robert Koch in 1882, its ability to produce CNS disease was quickly recognized. Epidemiology Tuberculosis is a truly worldwide disease, with between one and two billion people infected. It is estimated that approximately 8 to 10 million new cases occur each year and two to three million people die from tuberculosis worldwide every year. In the United States and Western Europe, the number of cases of tuberculosis has declined dramatically during the past 100 years. For example, in the early 1950s there were approximately 84,000 cases per year in the United States; this declined to 20,000 to 25,000 cases per year in the mid 1980s. This downward trend abruptly changed in 1984 and by the early 1990s there was actually an increase in the number of cases to approximately 27,000 new infections per year in the United States. Investigations by the CDC showed

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that much of the increase could be explained by the occurrence of HIV infections leading to an increasing pool of highly susceptible individuals and a resultant increase in urban outbreaks.106 Fortunately, increased surveillance and treatment efforts nationwide resulted in a resumption of the downtrend in the number of tuberculosis cases. The development of effective antiretroviral therapy in the mid to late 1990s further hastened this decline; approximately 13,000 new cases were reported for the year 2000 in the United States. On a worldwide basis, however, the uncontrolled HIV epidemic, particularly in sub-Saharan Africa and parts of Asia, will unfortunately lead to an increasing disease burden from tuberculosis in those areas for the foreseeable future. Pathogenesis Transmission of tuberculosis occurs by airborne droplet nuclei, which directly reach the alveolar spaces. During replication in the aveoli and within alveolar macrophages, the tubercle bacilli are transported via lymphatics to the pleural surface of the lung and thence to the hilar and mediastinal lymph nodes. During the 3 to 4 weeks of this infection there is virtually no immune response and the tubercle bacilli readily disseminate via the bloodstream and seed all organs in the body including bone marrow, liver, spleen, kidney, meninges, genitourinary tract and brain parenchyma itself. The overwhelming majority of these primary infections occurs in children and are asymptomatic, or nearly so. With healing, the only residue are a few calcified lymph nodes in the hilar region, characteristically designated a “Ghon” complex, and a lifelong positive skin test result. Lifelong persistence of tuberculosis DNA has been demonstrated in macrophages and nonphagocyte cells in histologically normal lung tissue from individuals dying of unrelated causes (e.g., trauma) by in situ PCR.107 In children with normal immunity, the primary infection rarely progresses to symptomatic pulmonary disease. However, in immunosuppressed patients of any age and in patients with HIV infection depending on the degree of immunosuppression, progression to active cavitary tuberculosis is much more common. The immunologic processes involved in controlling tuberculosis are almost entirely dependent on intact cell-mediated immunity. T lymphocytes are stimulated to produce lymphokines, which in turn attract and activate mononuclear macrophages. Macrophages may successfully kill the tubercle bacilli. However, very commonly they are killed by the organisms in the process. A focus of macrophages and lymphocytes develop with central necrosis, which is termed caseation. The tubercle thus is the pathologic hallmark of the caseating granuloma seen microscopically in mycobacterial disease. Tuberculous meningitis occurs as a reactivation of metastatic foci in the meninges and brain parenchyma, which have been present asymptomatically for months to

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years following primary infection. Pathologically, tuberculous meningitis exhibits a thick exudate at the base of the brain, particularly involving the optic nerves at the optic chiasm, the pons, and cerebellum. The histologic appearance depends on the stage of the disease. Initially it consists of polymorphonuclear leukocytes, macrophages, and lymphocytes. But later, after a phase of lymphocytic proliferation, granulomas with caseous centers become a prominent feature. Another feature of tuberculous infection of the meninges is involvement of the blood vessels traversing the meninges. Small- and medium-sized arteries are most often involved, although capillaries and veins may be similarly affected. The changes involve granuloma formation and inflammation of the adventitia, which causes a reactive cellular proliferation of the intima, which in turn may lead to occlusion of the vessel and infarction of the areas supplied by the vessel. Clinically, this phenomenon is most often found in the distribution of the middle cerebral artery due to its location in relation to disease at the base of the brain. Hydrocephalus is one of the most frequent complications of tuberculous meningitis, commonly accompanying symptomatic primary infection in children. Hydrocephalus occurs either by mechanical blockage of the spinal aqueduct or the foramina of Luschka due to the exudate at the base of the brain, or to edema of the surrounding brain parenchyma with the same result. Hydrocephalus may also be caused by blockage of CSF reabsorption at the base of the brain due to the intense infiltrate. The former mechanism leads to noncommunicating hydroencephalus and the latter mechanism to communicating hydrocephalus. Clinical Presentation The classical clinical presentation of tuberculous meningitis in adults is fever and headache, together with meningismus that becomes progressively more severe over a period of 2 to 3 weeks. However, the duration of prodromal symptoms can be quite variable and some patients have been reported with symptoms for several months before seeking medical attention. None of these signs or symptoms is universally present in all patients with tuberculous meningitis. Several recent studies have documented that fever is present in approximately 60% to 80% of patients. Stiff neck and meningismus are reported approximately as frequently as is headache among adult patients.108–110 Other signs that are commonly observed in these patients include lethargy and other behavioral changes in 30% to 70%, seizures in 10% to 15%, and cranial nerve palsies in up to 20% to 30% of adults. Occasionally, abnormal movements such as chorea, hemiballismus, athetosis, myoclonus, and cerebellar signs and symptoms are observed. Localizing neurologic symptoms due to tuberculomas depend on the size and location of the mass lesion. Strokes due to tuberculous vasculitis usually involve the distribution of the middle cerebral artery and produce symptoms related to that distribution. The most

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common cranial nerve abnormalities involve the sixth cranial nerve followed by the third, fourth, and seventh cranial nerves, but may even involve the second, eighth, tenth, eleventh, and twelfth cranial nerves.111 Higher degrees of mental obtundation, such as coma, are present or develop in approximately 30% of adults and children. In some series as many as 50% of children have a history of tuberculosis, whereas only 8% to 12% of adults have such a history. Hydrocephalus is a serious and potentially devastating complication that may develop in as many as 40% of children and be associated with a variety of focal neurologic signs including hemiparesis and blindness. Predisposing conditions in adults include alcohol abuse, intravenous drug abuse, immunosuppression due to steroid and other immunosuppressive treatments, HIV, and an assortment of underlying chronic illnesses. The differential diagnosis is quite wide and includes bacterial, viral, and fungal infections of the CNS as well as malignancies and noninfectious conditions such as CNS lupus (Table 12-6). Diagnosis Routine laboratory tests are not particularly helpful. The sedimentation rate varies considerably in series of patients with proven tuberculous meningitis, ranging from normal to as high as 90 mm/hr. Similarly, a syndrome of inappropriate antidiuretic hormone, manifested by hyponatremia and hypochloremia, has been observed in some cases, but this is by no means diagnostic and is affected by a variety of other symptoms such as vomiting and anorexia, which may accompany the disease. The chest radiograph is likewise nondiagnostic; however, 25% to 50% of adults may show evidence consistent with current or remote tuberculous infection. In children where tuberculous meningitis quite commonly follows on the heels of primary infection, chest radiographic evidence of tuberculosis has been observed in 50% to 80% of cases. Miliary disease was fairly commonly associated with tuberculous meningitis in the preantibiotic era. However, it is relatively rare at present. Skin testing is notoriously unreliable, ranging from 40% to 65% positive skin test results in adult series. Skin testing is more helpful among children, with positive results in the neighborhood of 85% to 90%.112 Perhaps the single most useful diagnostic procedure is examination of the CSF. Here the classic findings of elevated protein level, depressed glucose level, and elevated white blood cell count with a lymphocytic predominance, together with a chronic history, that is, weeks of illness as opposed to days as in acute bacterial meningitis, is strongly suggestive of a tuberculous or fungal etiology. Median CSF protein levels are generally 100 to 400 mg/dL with occasional levels as high as 1 to 2 g/dL, although levels that high usually suggest CSF block. The median white blood cell count generally runs between 100 to 200 WBC/mm3. The CSF glucose is less than

Table 12-6  Common Noninfectious Causes of Aseptic Meningitis Syndrome Drugs Nonsteroidal anti-inflammatory agents (ibuprofen, naproxen, tolmetin, diclofenac) Antibiotics (trimethoprim/sulfamethoxizole, trimethoprim, cephalosporins, penicillin, amoxicillin, isoniazid, ciprofloxacin, metronidazole) Intravenous immunoglobulin Muromonab-CD3 (OKT3) Azathioprine Carbamazepime Ranitidine Famotidine Indinivir Sulfasalazine Vaccines Measles, mumps, rubella (MMR), alone or in combination (pertussis—acute encephalopathy, not aseptic meningitis) Other conditions Intrathecal injections Neurosurgery-related procedures CNS tumors and cysts Carcinomatous meningitis Lymphoma Leukemia Systemic lupus erythematosus Sjögren’s syndrome Behçet’s disease Vogt-Koyanagi-Harada syndrome Mollaret’s meningitis* Sarcoidosis Vasculitis Kikuchi’s disease Relapsing polychondritis and aseptic meningitis Still’s disease Hypophysitis Uveomeningoencephalitis Steroid-responsive meningitis *Has been associated with herpes simplex virus.

45 mg/dL in 70% to 80% of patients. The glucose level tends to become progressively lower and the protein progressively higher as the duration of illness continues without treatment; when treatment is successful, the glucose level tends to return toward normal. Any one of these tests in spinal fluid may be completely normal, but it is extremely unusual for all three parameters to be completely normal in a patient with true tuberculous meningitis. If a patient has a completely normal spinal fluid and M. tuberculous is reported by the laboratory, the report should be considered suspect until proven otherwise. The spinal fluid acid-fast smear is positive in less than 25% of patients who ultimately have cultureproven tuberculous meningitis. It is also important to recognize that the culture itself is significantly less than 100% sensitive; in most series, the culture positivity ranges from 40% to 70%.108,113–117

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Figure 12-6. Axial, low convexity, T1-weighted, post– gadolinium-enhanced, MR image demonstrates abnormal contrast enhancement involving the superficial ventral surface of the mesencephalon and also along the surface of the optic chiasm. Less pronounced changes are seen along the mesial surface of the left uncus. The enhancement appears thick as well. In addition, there is evidence of significant ventriculomegaly indicating concurrent external hydrocephalus. These findings are consistent with a more chronic type of granulomatous meningitis, most often seen in CNS tuberculosis or fungal infections of the meninges. (Courtesy of Ronald Quisling, MD, University of Florida.)

Newer diagnostic methods include measurements of mycobacterial antigens, tuberculostearic acid, and antibody to mycobacteria in spinal fluid. Although initial reports with all of these show up to 100% sensitivity and specificity, it is extremely unlikely that these spectacular results will withstand the test of time. PCR has likewise been applied to the diagnosis of tuberculosis meningitis, but it is probably even less sensitive than culture. Modern radiographic techniques such as CT, MRI with gadolinium enhancement, and MR angiography are extremely sensitive in delineating CNS involvement, readily demonstrating meningeal inflammation and entrapment of cranial nerves in the basilar tuberculous exudate (Fig. 12-6). In addition, MR angiography can detect characteristic vascular narrowing that accompanies tuberculous meningitis but is less common in other entities. Treatment Treatment of tuberculous meningitis consists of at least three, and usually four, drugs until the susceptibilities are

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established: isoniazid (INH), rifampin, ethambutol, and pyrazinamide are the standard, together with pyridoxine at a dose of 25 to 50 mg daily to prevent depletion by INH; many authors recommend dexamethasone for the first month to improve outcome. Treatment must be continued at least 1 year. INH is generally used at a dose of 300 mg/day in adults and 10 mg/kg/day in children. The most serious side effect is hepatitis, which ranges from asymptomatic enzyme elevations to fulminant hepatitic necrosis. This complication historically was observed in 0.5% to 2.0% of patients receiving INH, but recent data from over 11,000 persons suggest the true risk is approximately 0.1% among those receiving INH alone for prophylaxis and approximately 1% for those receiving INH as part of a treatment regimen for tuberculosis.118 The incidence of hepatotoxicity is higher in persons older than 35 years of age, as well as those with other conditions affecting liver function such as alcoholism and viral hepatitis. The dose of rifampin is 600 mg/day and is only infrequently associated with side effects such as a flu-like syndrome and a hypersensitivity reaction with renal, hepatic, and hematologic toxicity. Pyrazinamide is given in at a dosage of 25 mg/kg/day and has a relatively low incidence of side effects; there is little added toxicity when combined with INH and rifampin. The CSF penetration of pyrazinamide is excellent. Ethambutol is generally administered at a dose of 25 mg/kg for the first 1 to 2 months of treatment, with a reduction in dose to approximately 15 mg/kg/day because of the risk of optic neuritis that is seen in approximately 25% of patients. The first clue to the development of this complication is loss of red-green vision or diminished visual acuity; ophthalmologic consultation is suggested in these situations. Streptomycin was one of the first drugs found to be active against tuberculosis, and is commonly administered in a dose of 20 to 40 mg/kg/day for children and 1 g/day for adults. Unfortunately, the irreversible ototoxicity is so frequent that it is not advisable to use this agent unless absolutely necessary. Second-line antituberculous drugs such as para-aminosalicylic, cycloserine, ethionamide, kanamycin, and amikacin should only be used based on treatment failure with primary agents and antibiotic susceptibility studies. Of these agents, ethionamide and cycloserine penetrate well into the CNS. Because one cannot rule out tuberculosis based on all of the immediately available diagnostic modalities, empiric treatment may often have to be given while awaiting the results of cultures. Cryptococcal meningitis can be readily ruled out by a negative cryptococcal antigen, negative India ink, and no growth within the 10 to 14 days of culture. However, other fungal meningitides cannot be totally ruled out, and some patients may have to be placed empirically on treatment with both antituberculous medications and amphotericin B. Occasionally, patients treated in this fashion turn out to have noninfectious causes for their CNS symptomatology and careful radiographic studies or invasive diagnostic studies may be needed. In patients who show no

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signs of improvement within the first week or so and particularly in the setting where the patient is known to have a malignancy, the spinal fluid should be reexamined for the possibility of meningeal carcinomatosis. Despite voluminous literature over the past 40 years, the place of steroids in the treatment of tuberculous meningitis remains unclear. Case reports and many numerous series demonstrate the often dramatic and immediate effects of steroids in terms of defervescence and clearing of the sensorium, even after a few doses. While there seems to be general agreement that survival from tuberculous meningitis is improved with the use of steroids, many of the survivors do so with severe sequelae. Therefore, most authorities currently recommend using steroids only for patients in certain specific situations such as extreme neurologic compromise, elevated ICP, impending herniation, or spinal block. The dose of prednisone is 60 mg/day or 1 mg/kg/day; dexamethasone may also be used at a dose of 8 to 16 mg/day in divided doses. Steroids are given for 3 to 6 weeks and then tapered over a 2- to 4-week period.112 Prognosis and Sequelae Before the availability of antibiotic treatment, survival from tuberculous meningitis was exceedingly rare. Survival rates are 70% to 80% in most recent series. Probably the most significant prognostic factor for survival is how advanced the disease is at the time of presentation. Other factors correlating with poor response to treatment are extremes of age and co-existent miliary disease. The earliest sign of response to therapy in most cases is reduction in peak daily temperatures within the first 1 to 2 weeks and subjective improvement in fatigue and malaise over the same time. However, early studies pointed out that it was not uncommon for some markers of disease, such as the presence of bacilli in a smear of the CSF or an increase in CSF protein, to occur shortly after the initiation of treatment. In general the glucose level in the CSF rises with successful treatment while the protein returns to normal more slowly, a process that may take as long as 6 months. In some series, up to 50% of survivors have a variety of neurologic deficits. As with survival itself, the more seriously ill the patient is on presentation, the more likely complications or sequelae are to occur. Among children, the most common of these complications are seizure disorders, ataxia, incoordination, persistent cranial nerve abnormalities, and spastic hemiparesis. Adults are most frequently left with chronic organic brain syndrome, with or without cranial nerve palsies, paraplegia, and hemiparesis. Optic atrophy can lead to varying degrees of visual impairment or blindness in both children and adults. Eighth cranial nerve abnormalities frequently reported in early series are probably the result of the use of streptomycin, which has largely been replaced.

Tuberculoma Tuberculomas are space-occupying mass lesions within the brain parenchyma ranging in size from less than 1 to more than 10 cm. Pathogenically, they arise by a similar mechanism to that of tuberculous meningitis in that a tubercle seeded during the time of primary infection breaks down but because of its location within the brain parenchyma, produces a mass lesion rather than meningitis. Clinically these lesions present with fever, headache, seizures, and other neurologic signs and symptoms that are related to their anatomic location. Generally, patients have a single lesion on presentation; however, autopsy series and sophisticated radiologic studies have shown that in up to 70% of patients, multiple lesions are present. The duration of symptoms prior to presentation is somewhat longer than in tuberculous meningitis, averaging weeks to months with occasional patients having symptoms for years prior to diagnosis. CT scanning and MRI have a virtually 100% diagnostic sensitivity; however, tissue confirmation is essential to rule out malignancies or other space-occupying lesions. Approximately 60% of the specimens from tuberculomas stain positive for acid fast on smear and approximately the same number ultimately grow in culture. Caseating granulomas are almost invariably seen histologically. Treatment is essentially the same as that for tuberculous meningitis. Spinal Tuberculosis Tuberculous spinal meningitis may accompany tuberculous meningitis or may occur as an isolated entity. The pathogenesis and pathologic findings consist of characteristic exudate surrounding many parts of the spinal cord with symptoms due to compression and vasculitic changes, as would be expected. Symptoms of transverse myelitis and spinal block, as well as nerve root pain, paresthesia, and motor weakness may be seen. The onset can be sudden or present as a slow ascending paralysis over several months to years. Fever and systemic symptoms occur in less than 50% of patients, but a sensory level was demonstrable in twothirds of patients with thoracic involvement in one series.119 Less commonly, intramedullary tumors of the spinal cord can present as a Brown-Sequard lesion. MRI is generally required for accurate diagnosis of spinal tuberculosis. However, biopsy is required to establish etiology. Treatment for these lesions may require surgical intervention to relieve compressive symptoms. Antibiotic therapy is based on that for tuberculous meningitis.

Fungal Meningitis The most common fungal pathogens of the central nervous system include the yeast Cryptococcus and the dimorphic fungi Histoplasma, Coccidioides, and Blastomyces. In

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immunocompromised patients, Aspergillosis, Candida, and the Mucorales may be important pathogens as well. Cryptococcal Meningitis Cryptococcus neoformans is perhaps the most common fungal pathogen of the CNS. Cryptococcus has a worldwide distribution and is particularly associated with soil that has become contaminated with bird droppings. There are two varieties of C. neoformans: C. neoformans var neoformans and C. neoformans var gatti, which have a somewhat different distribution in nature. C. neoformans var neoformans is found worldwide and produces most of the infections in patients in the United States, while C. neoformans var gatti is a more common pathogen in Southeast Asia, Africa, Australia, and parts of Southern California. The most important determinant of CNS infection by Cryptococcus is the immune status of the host. This can be most easily demonstrated by the marked increase in the number of cases associated with HIV infection and the fact that as the CD4+ count decreases the incidence of cryptococcal infection increases markedly, particularly at CD4+ counts less than 200 cells/mm3. Although a variety of virulence factors have been described in Cryptococcus, such as the production of the pigment melanin, it is probably the production of the thick polysaccharide capsule that protects the fungus from phagocytosis by the host which is the most important parasiteassociated virulence factor. The initial infection with Cryptococcus is due to inhalation and the production of a pneumonitis, which is generally asymptomatic even in immunosuppressed patients. Symptomatic patients usually present with fever and cough, and a variety of chest radiographic findings, such as nodular, pleural-based lesions and lobar infiltrates. The initial pneumonia generally clears without treatment, even in immunosuppressed patients. Dissemination from the pneumonitis seeds many organs in the body particularly the central nervous system. The organism may remain latent in the lung and at other sites indefinitely. Thus, most patients presenting with cryptococcal meningitis have no evidence of a concurrent pulmonary disease. Clinically, the presentation of cryptococcal meningitis is indistinguishable from that of any other chronic meningitis due to pathogens such as Coccidioidomycosis, Histoplasmosis, or from tuberculous meningitis. Patients generally describe a history of 2 to 3 weeks of headache, fever, and stiff neck together with a variety of nonspecific symptoms, such as lethargy, confusion, nausea, vomiting, and relatively rarely, focal neurologic deficits. As the disease advances in untreated patients, evidence of increased ICP develops, cranial nerve palsies and seizures may be observed, and the disease progresses to obtundation and death. Papilledema may be seen in up to one third of cases and cranial nerve palsies may develop in approximately 20%. Occasionally, total visual loss develops secondary to fungal

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involvement of the optic tracts, as well as from adhesive arachnoiditis, chorioretinitis, or elevated ICP. Hydrocephalus frequently develops even in successfully treated patients. The diagnosis of cryptococcal meningitis is usually not difficult. The classic and time-honored method for diagnosis is demonstration of the yeast in spinal fluid by India ink stain. Microscopically, the India ink particles serve to outline the very large clear polysaccharide capsule surrounding the yeast. The test is positive in over 90% of patients with HIV, but in only 50% of patients with normal immunity. In the past 20 years, several latex agglutination tests have been developed that detect the excess polysaccharide capsule produced in the spinal fluid of patients with cryptococcal meningitis. This test result is positive in more than 95% of patients with the disorder. While the test is highly reliable, it is important to recognize that there can be both false-negative and false-positive reactions. For example, patients with HIV who have an overwhelming cryptococcal meningitis may have so much polysaccharide capsule in their CSF that a “prozone” effect occurs, resulting in the finding that undiluted CSF or CSF tested at a 1 : 2 dilution may appear negative. Generally, on dilution of the spinal fluid to 1 : 10 or greater, a positive reaction will be observed. Laboratories must be aware of this prozone effect and physicians who suspect cryptococcal meningitis in patients with patients should alert the laboratory to ensure that this possibility is not overlooked. In addition, cross-reactions with Trichosporon beigelii or Capnocytophaga may occasionally produce false-positive latex agglutination test results. The latex agglutination should be confirmed by growth of cryptococci in culture. If a positive cryptococcal antigen titer result is found in the spinal fluid from a patient whose CSF does not grow cryptococcus, the test cannot be assumed to be a false-positive result. A large volume of spinal fluid, 10 to 20 mL, should be obtained and recultured for cryptococci as well as used for repeating the cryptococcal antigen test. The higher the cryptococcal antigen titer, the less likely it is to be a false-positive result. Spinal fluid changes in cryptococcal meningitis generally parallel those of chronic tuberculous meningitis and other chronic meningitides (see Table 12-2). The CSF glucose level is generally below 40 mg/dL and the CSF protein elevated in the large majority of patients. CSF white blood cell count is also elevated with a lymphocytic predominance. Treatment of cryptococcal meningitis depends in part on the host susceptibility factors. In patients with no underlying chronic illness or HIV infection, amphotericin B at a dosage of 0.5 to 0.8 mg/kg/day IV together with flucytosine 37.5 mg/kg orally every 8 hours should be administered until the patient has become afebrile and culture negative; this takes approximately 6 weeks. This should probably be followed with treatment of fluconazole at a dose of 400 mg/day for an additional 2 to 3 months. Flucytosine may cause

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severe leukopenia and thrombocytopenia, particularly in patients with impaired renal function that in turn may develop as a result of amphotericin therapy. Therefore, patients need to be watched extremely carefully for these particular toxic developments. Some authorities recommend measuring flucytosine levels and adjusting the dose to give a peak of 70 to 80 mg/L and a trough of 30 to 40 mg/L. However, these levels may not be readily available at many hospitals. Alternative treatments include the substitution of various lipid soluble amphotericin B preparations, which may be used for patients in whom nephrotoxicity develops. Additionally, if the patient is intolerant to flucytosine, treatment with amphotericin at a higher dose of 0.7 to 1 mg/kg/day for 6 to 8 weeks may be substituted. Fluconazole at a dose of 400 mg/day orally for 8 to 10 weeks may be curative, particularly in nonimmunocompromised patients who are less ill. However, it should be recognized that fluconazole alone is less effective than the combination of amphotericin B plus flucytosine, in that the duration of positive culture results of spinal fluid is longer and a higher rate of treatment failures have been associated with fluconazole regimens. Histoplasmosis Although found worldwide, histoplasmosis has a very distinct geographic distribution in the United States. Most cases occur in the Ohio and Mississippi River valleys in the Central Midwestern part of the United States, with extension as far east as Maryland, Delaware, and some parts of Georgia and Florida. The disease is rarely seen west of Texas, Oklahoma, and Kansas. Histoplasmosis belongs to a group of fungi known as the dimorphic fungi because they change their characteristic morphology depending on temperature. Along with Coccidioides immitis and Blastomyces dermatitidis, H. capsulatum exists as a mold at room temperature (approximately 23°C) and converts to a yeast form at a body temperature of 37°C. The organism is widely disseminated in nature in the soil and may reach high levels in areas where birds roost and in caves inhabited by large numbers of bats. In vitro, the mold phase is characterized by both macroconidia and microconidia. The microconidia are small, smooth oval bodies ranging in diameter from 2 to 5 microns and are believed to be the infective phase because their small size is such that they are readily carried down to the terminal bronchioles and alveoli. Once inhaled, the microconidia are ingested by alveolar macrophages and rapidly undergo conversion to the yeast phase. From the initial pulmonary foci, the yeast rapidly migrates to hilar lymph nodes from which they can disseminate to multiple foci in the body. As is the case with Cryptococcus and tuberculosis, an asymptomatic pulmonary infection frequently develops approximately 2 to 3 weeks after exposure. The development of the cellular immune response limits the spread of the organism and generally

clears the initial, early, pulmonary focus, leaving minimal to no calcifications in hilar lymph nodes and lung tissue. The disseminated lesions are most commonly manifest by widespread calcific lesions in the spleen and liver after they heal. Although the vast majority of primary infections in immunologically normal hosts resolve spontaneously, leaving the patient with a positive histoplasma skin test result, there are a number of unfavorable outcomes. Pulmonary disease may go on to produce chronic cavitary histoplasmosis that is radiographically identical to pulmonary tuberculosis. The initial pulmonary infection may result in an acute progressive disseminated infection that characteristically presents with fever, chills, weight loss, hepatosplenomegaly, and pancytopenia from bone marrow involvement. This form of disseminated histoplasmosis most often affects those who are highly immunosuppressed due to AIDS, lymphoma, or iatrogenic therapy. CNS involvement in this syndrome includes encephalitis, acute meningitis, and encephalopathy. Occasionally, histoplasmomas or mass lesions in the CNS are observed.120 A syndrome of disseminated histoplasmosis may also be observed in patients with normal immunity, which presents as a much lower grade chronic illness, rather than the acute presentation of disseminated histoplasmosis in immunosuppressed patients. CNS involvement manifests itself, therefore, as symptomatic intracranial mass lesions; isolated chronic meningitis, with or without other manifestations of disseminated histoplasmosis; and meningitis occurring in the presence of disseminated infection. Some patients may have CNS disease secondary to emboli from histoplasma endocarditis. In what is likely the most comprehensive series in the literature, Wheat and colleagues found that approximately 40% of patients with histoplasma meningitis had chronic meningitis as part of their disseminated disease.120 Approximately 25% to 30% had isolated chronic meningitis and the remainder presented with various forms of mass lesions and encephalitis. In general, the duration of symptoms of meningitis before diagnosis tends to be somewhat longer than for cryptococcal or tuberculous meningitis. In Wheat and coworkers’ series, approximately 30% of patients had duration of symptoms of less than a month, 44% a duration between 2 and 6 months, and another 27% had symptoms lasting for more than 6 months before the diagnosis was made. The diagnosis of histoplasma infection in the central nervous system is, to some extent, dependent on the presentation of the patient. Those who present with localizing CNS signs and symptoms should undergo CT and MRI to rule out mass lesions. Those with systemic manifestations may have the diagnosis made by culture or biopsy of an enlarged lymph node, liver, or bone marrow. CSF findings are typical for chronic fungal and tuberculous meningitis, with 90% of patients having abnormal leukocyte count in the CSF with lymphocytic predominance (see Table 12-2). At least 80% of patients will have an elevated protein level and a glucose level of less than 40 mg/dL. Serologic testing results for antibod-

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ies to H. capsulatum in blood are generally positive in 60% to 90% of patients with CNS histoplasmosis. However, in an endemic area, serology is difficult to interpret because patients may have antibodies from prior exposure rather active infection. Likewise, skin testing in an endemic area is probably of no diagnostic value. In Wheat and associates’ series,120 CSF cultures were only positive in 26.7% of cases. A recently described histoplasma antigen test that detects the histoplasma polysaccharide capsular antigen is reported to have positive results in the urine in 90% of patients with disseminated histoplasmosis,120 but, positive results in the spinal fluid of only 40% of patients with CNS histoplasmosis.121 Treatment Amphotericin B at a dose of 0.7 to 1.0 mg/kg should be used to treat patients with histoplasma meningitis.120 After the first seven to ten days, this dose can be lowered to 0.8 mg/kg every other day; the lipid amphotericin formulation may be substituted if renal toxicity occurs. Therapy can be assessed with serial weekly or biweekly lumbar punctures, which will show a rise in the CSF glucose and fall in the CSF cell count and protein with successful treatment. The published data suggest that although approximately 80% of patients will respond to amphotericin, at least half of those initial responders will relapse and approximately 20% will die from the disease. Itraconazole and fluconazole are not useful in the treatment of CNS histoplasmosis, as they do not cross the blood-brain barrier particularly well. In non-CNS disease, treatment with amphotericin B should be continued for at least 8 to 12 weeks, to a total dose of approximately 30 to 35 mg/kg, in view of poor outcome among patients receiving less than this total dose.120 In patients with HIV, suppressive treatment with itraconazole, 200 mg orally every day, should begin after the initial course of amphotericin. Coccidioides immitis Infections with C. immitis have been recognized for longer than 100 years and were originally believed to be a nearly uniformly fatal infection. However, a widely publicized laboratory acquired infection in a young medical student in 1929 resulted only in pulmonary disease that spontaneously healed. This led to the recognition that this agent was capable of producing both fatal disseminated infection as well as the self-limited, well-recognized “Valley Fever” that was frequently observed in residents of the San Joaquin Valley in California. Like the other dimorphic fungi, H. capsulatum and B. dermatitidis, the natural habitat of C. immitis is soil. But unlike the other fungi, C. immitis is not distributed worldwide but limited to the lower Sonoran life zone, found primarily in the desert southwest of the United States, Mexico, and parts of South and Central America. The characteristics of this particular zone are an arid climate with a yearly rainfall of 5 to 20 inches, hot summers, warm winters,

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and an alkaline soil. In the mold phase of the fungus, which is the form found in soil and other environmental sources, the hyphae fragment into specific structures known as arthrospores, which are highly infectious and readily aerosolized when dust is produced. Thus, on occasion, dust storms have blown infectious spores of C. immitis as far north as Sacramento and beyond to produce outbreaks well outside the endemic area of the San Joaquin Valley. Transmission of the organism on fomites as far as the East Coast has produced occasional cases as well. The narrow environmental requirements of this fungus account for its endemic distribution within the United States. Epidemiologic studies of people who migrate into the Central Valley of California suggest that the annual risk of infection is approximately 15%. For example, Smith and co-workers showed that between 25% and 50% of military personnel stationed in the San Joaquin Valley had conversion of their skin test results within the first year of moving to that region.122 Pathogenesis As is the case with the other dimorphic fungi, the initial route of infection is inhalation with an early focus of infection in lung tissue. The arthrospores convert, through unknown mechanisms, into a structure called the spherule, which enlarges to approximately to 50 to 70 microns in diameter and subdivides into an extremely large number of locally invasive and infectious spores that are released upon spherule rupture. The outcome of this infection is highly variable. Approximately one-half to two-thirds of patients who are demonstrated to be infected with this agent show absolutely no, or very mild, initial pulmonary infection. The majority of patients who become symptomatic develop a mild selflimited respiratory infection manifested by fever, cough, malaise, arthralgias, weight loss, and in some patients, a striking clinical syndrome of erythema nodosum and erythema multiforme. The vast majority of these symptomatic cases resolve within 2 to 4 weeks, occasionally taking up to several months, without treatment. Complications occur in no more than about 10% of all patients with clinically symptomatic primary infections. Occasionally, patients will present with fulminant pneumonia and shock-like syndrome, possibly resulting from a particularly high inoculum or perhaps as a result of fungemia and miliary dissemination of the disease. Such a presentation is not uncommon among patients with HIV and severe depression of the CD4+ count. Other manifestations include pulmonary nodules, cavities, and chronic lung disease indistinguishable from chronic tuberculosis. The most common site of disseminated lesions is the skin where maculopapular lesions may progress to keratotic and verrucous ulcers with subcutaneous fluctuant abscesses. The most serious form of disseminated coccidioidal infection is coccidioidal meningitis. Without treatment it is nearly uniformly fatal within 2 years of diagnosis.123 Obser-

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vational studies suggest about 80% of patients in whom meningitis develops become symptomatic within 6 months of the initial infection.124,125 The signs and symptoms of coccidioidal meningitis are very similar to those of other chronic fungal and tuberculous meningitides. Patients have headache, may or may not have fever, varying degrees of nuchal rigidity, nausea, vomiting, and altered mental status.123,124 A number of factors including pregnancy, immunosuppression due to HIV infection, steroids or other immunosuppressive drugs, and nonwhite race predispose to dissemination of C. immitis and the development of meningitis. Diagnosis of coccidioidal meningitis is based on analysis of the CSF, which shows typical findings of elevated white count, predominantly lymphocytic in nature, elevated protein, and depressed glucose (see Table 12-2). Occasionally, patients with this entity are found to have a striking CSF eosinophilia, which in one series, was seen in 70% of cases.126 Thus, in a patient who presents with a chronic meningitis together with typical CSF findings, a history of travel to or having lived in an endemic area must be carefully sought. Complications such as meningitis may occur as late as 2 years after the exposure, and the exposure may be exceedingly brief, as minimal as a drive through the California’s Central Valley.127 Although C. immitis grows well on typical fungal media, culture is often negative in spinal fluid. The most reliable method of diagnosis is the detection of complement-fixing antibodies in the spinal fluid. Although these results may be negative in a few patients early in the disease, after several months they are virtually 100% positive. In patients with pulmonary disease or extrapulmonary manifestations, biopsy with culture and histopathologic examination of involved tissue may give positive results. The demonstration of a spherule in tissue or a positive culture is diagnostically definitive. Treatment There is considerable disagreement among experts in regard to treatment of uncomplicated pulmonary disease in otherwise healthy patients, with some experts recommending amphotericin B for all patients while others reserve it for patients with risk factors such as HIV infection, immunosuppression, or non-white race. Fluconazole at a dose of 400 to 800 mg/day is currently recommended as the treatment of choice for coccidioidal meningitis because the response rate of approximately 70% is very close to that achieved with intrathecal amphotericin B, which was used previously. In patients who do not respond to the 400 mg/day dose of fluconazole, higher doses may be used. If there is no response to azole therapy, amphotericin B at a dose of 0.1 to 0.3 mg/day may be given intrathecally, optimally through an Omaya reservoir. With the demonstration of increasing CSF glucose, and decreasing cell count and protein, this schedule of amphotericin B administration may be decreased to three

times a week after 2 to 3 weeks of daily treatment, and maintenance may be achieved with once- or twice-weekly injections. Treatment with either oral fluconazole or intrathecal amphotericin B must be prolonged for at least 2 years after the spinal fluid becomes completely normal. In patients with HIV, treatment is lifelong. Patients who have disseminated extra-pulmonary disease in addition to meningitis should also receive systemic amphotericin at a dose of 0.6 to 1.0 mg/kg/day for 7 days followed by 0.8 mg/kg dose every other day, to a total dose of 2.5 to 3 g. The amphotericin should then be followed by a dosage of oral fluconazole at 400 mg/day for up to a year after the course of amphotericin. It should be noted that the response rate is by no means 100% in either meningitis or disseminated disease, and that relapses are not uncommon, even in patients who respond initially. As is the case with other fungi and tuberculosis, patients have presented occasionally with mass lesions in brain parenchyma due to C. immitis, which may require surgical drainage or excision. In addition, hydrocephalus is relatively common in patients with C. immitis meningitis, particularly in children, and must be managed with ventricular shunting. It should be pointed out that, on occasion, C. immitis may actually grow in the shunt and cause obstruction. In patients who have a ventricular shunt in place, intrathecal amphotericin B cannot be given into an Omaya reservoir, but rather must be administered intrathecally via intracisternal puncture or lateral neck injection under radiographic guidance. Although intrathecal therapy can be given via the lumbar route this inevitably leads to varying degrees of potentially severe and debilitating arachnoiditis after several weeks in most patients. Blastomyces dermatitidis B. dermatitidis is a dimorphic fungus that grows as a yeast form at 37°C and in a hyphal form at room temperature. It is believed that B. dermatitidis exists in nature in warm moist soils of wooded areas rich in organic debris, such as decaying vegetation. However, the reports of isolation of the organism in nature have been relatively few and somewhat inconsistent. Epidemiologically, the distribution appears to follow the distribution of the Mississippi River, and is most commonly reported in Louisiana, western Alabama, central Arkansas, Missouri, Kentucky, western Tennessee, and as far north as Minneapolis, Minnesota. However, the distribution also includes outbreaks along the St. Lawrence River in Canada and in many parts of North and South Carolina. Pathogenesis Pulmonary infection occurs by the inhalation of conidia, which convert to the yeast phase in the lung. From there, dissemination to skin and other organs may occur. Pulmonary manifestations vary from asymptomatic to multilobar over-

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whelming infection. Chronic pulmonary infection resembling tuberculosis or other chronic fungal disease may develop. Dissemination to the skin produces a variety of manifestations such as chronic verrucous, giant keratoacanthoma, and even lesions mimicking pyoderma gangrenosa or squamous cell carcinoma. Pathologically, the histologic response is that of neutrophils and noncaseating granulomas with epithelioid and giant cells. Because of a vigorous proliferative response, the pseudoepitheliomatous changes seen on skin and mucosal surfaces in response to B. dermatitidis may resemble squamous cell carcinoma. Clinical Manifestations The vast majority of patients present with symptoms of pneumonia after an incubation period of 30 to 45 days. Symptoms are nonspecific, and include fever, cough, myalgias, arthralgias, and pleuritic chest pain. Chest examination may reveal lobar or segmental consolidation, including mass lesions mimicking carcinoma with hilar adenopathy. Suppurative granulomatous lesions of the skin and bone may develop and become chronic. CNS involvement occurs in between 6% and 33% of disseminated cases.128,129 Although CNS blastomycosis may develop in patients without evidence of disseminated disease, most cases do have evidence of systemic infection at the time of CNS involvement. In addition to meningitis, patients with blastomycosis may present more frequently with blastomycomas or mass lesions in the CNS than are seen with other fungal CNS infections. While steroids and immunosuppressive treatment do not predispose to meningitis per se, they may predispose to dissemination of pulmonary blastomycosis and, hence, increase the probability neurologic involvement. Diagnosis Because there is no highly specific serologic or diagnostic skin test material available, the diagnosis rests on culture of the organism from pulmonary secretions, skin biopsy material, or demonstration of the organism in biopsy tissue. Probably the best and the most widely available serologic diagnostic test is immunodiffusion, which has a sensitivity of 80%.130 Treatment Before the availability of amphotericin B and itraconazole, the disease was progressive and had a mortality rate greater than 60%. In view of this historical perspective, and the recognition that some patients with pulmonary disease have a self-limited infection, it is currently unclear whether the initial primary pulmonary infection should be treated. However, because of our inherent limited ability to predict which cases will disseminate, it certainly seems reasonable to treat most cases of pulmonary infection due to Blastomyces. In mild cases, the treatment of choice is itraconazole at a dose of 200 to 400 mg/day orally. In more serious cases, a

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dose of amphotericin B at 0.7 to 1.0 mg/kg/day should be used. Treatment should continue for 6 months with itraconazale, and up to a total dose of 1.5 to 2 grams with amphotericin B. If disease persists, itraconazole may be given as a follow-up to amphotericin B therapy. If the patient is immunosuppressed or has HIV infection, this follow-up treatment is certainly indicated. In those patients with lifethreatening disease, the total dose of amphotericin B must be increased. CNS disease should be treated with high dose amphotericin B and followed with longer term itraconazole suppression in patients with HIV. Candida Candida species are a part of the normal human mucosal flora and only rarely produce CNS disease. In general, CNS disease due to Candida species occurs as part of disseminated infection in hospitalized patients who have predisposing factors such prematurity, intravenous hyperalimentation, indwelling catheters, treatment with corticosteroids, neutropenia, diabetes, and/or broad spectrum antibiotic use. Typically, CNS microabscesses result from disseminated infections in these settings. Meningitis is rare except as an operative complication or complication of ventricular shunts. Neonates and premature infants seem to be at higher risk than are adults. Although C. albicans accounts for a majority of the infections, non-albicans species such as tropicalis, pseudotropicalis, guillermondii, krusei, and lusitaniae have been reported. Zygomycosis The genuses Rhizopus, Mucor, and Rhizomucor may invade the CNS by direct extension or from hematogenous spread. In patients with diabetes, this disease typically presents as rhinocerebral mucor (Figs. 12-7A and B). Patients are generally predisposed to this complication if their blood glucose has remained uncontrolled and they are acidotic for several weeks. Initial symptoms usually include sinus pain, headache, fever, and nasal stuffiness and discharge, which quickly progress to facial cellulitis, swelling, proptosis, cavernous sinus thrombosis and, if not treated, death. In addition to diabetics, patients who remain neutropenic for longer than 2 to 3 weeks are also subject to this particular infection. Disseminated disease occurring via the hematogenous route may also produce CNS mucormycosis resulting in infarction and abscess formation. Treatment requires amphotericin B in a dose of at least 1 mg/kg/day, together with vigorous surgical debridement of all involved tissue. Aspergillus Species Aspergillus fumigatus and Aspergillus flavus may also produce CNS disease, which is very similar to that described for

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Figure 12-7. A, Coronal, T1-weighted post–gadolinium-enhanced MR image through the frontal temporal region demonstrates abnormal contrast enhancement affecting not only the meningeal surface above the fovea ethmoidalis and tuberculum sella but also affecting the pial surface of brain and portions of the brain parenchyma. This has an aggressive appearance. The parenchymal enhancement follows a distribution along the Virchow-Robin spaces representing either cerebritis or ischemic effects of perivascular infection. This appearance of multicompartment disease is consistent with invasive aspergillus or mucormycosis derived from associated frontal and/or ethmoid sinus disease. B, Oblique projection, right carotid arteriogram demonstrates fusiform aneurysmal dilatation of the mid portion of the first portion (A1 segment) of the right anterior cerebral artery. The parent artery both proximal and distal to the aneurysm is abnormal and displays inflammatory changes (regional vasculitis). This combination of fusiform aneurysm and regional vasculitis confirms the diagnosis of either an inflammatory or, as in this instance, an infectious (mycotic) aneurysm. Both aspergillosis and mucormycosis are known to cause such aneurysms. (Courtesy of Ronald Quisling, MD, University of Florida.)

mucormycosis. The majority of these cases occur in immunosuppressed transplant patients in the hospital who develop systemic disease, or who develop pulmonary disease and systemic spread to the brain via hematogenous dissemination. Direct extension from maxillary and ethmoid sinuses does occur with the production of cavernous sinus thrombosis, as seen with mucormycosis. However, Aspergillus sinus infection and extension to cavernous sinus thrombosis is generally seen in patients with prolonged neutropenia rather than in diabetes where mucor is the more common cause. Treatment requires surgical debridement of all involved tissue, plus voriconazole, caspofungin, or highdose amphotericin.

Central Nervous System Infections in Human Immunodeficiency Virus Infection Despite the marked improvement in and outlook for patients with HIV due to the introduction of highly active antiretroviral therapy (HAART) in 1995, there are approxi-

mately 40,000 new cases of HIV infection per year in the United States. Neurologic involvement in patients with HIV ranges from the traditional “big three” of Cryptococcus, toxoplasmosis, and primary B-cell lymphoma, to viral infections such as cytomegalovirus or progressive multifocal leukoencephalopathy (PML), as well as a variety of neuropathologic manifestations of HIV itself. Toxoplasma gondii T. gondii has a worldwide distribution, and infects numerous wild and domestic animals. Human infection generally occurs through the ingestion of raw or undercooked meat that contains cysts or through the ingestion of food or water contaminated by the oocysts shed in the stool of infected animals. In the United States, the major reservoir for this infection is the domestic cat. Infection in the cat results in the formation of oocysts in the intestine for approximately 3 weeks after initial infection; during this time, as many as 10 million oocysts may be shed daily. Oocysts require 1 to 5 days to become infectious after being shed by the cat, a process that depends on temperature and availability of

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lethargy, obtundation, and focal neurologic signs developing over 1 to 3 weeks. In some patients, the presentation can be abrupt, with seizures or cerebral hemorrhage. Hemiparesis and abnormalities of speech are quite common. Less commonly, brainstem involvement may result in cranial nerve deficits, while dyskinesias such as parkinsonism, dystonia, tremor, and hemiballismus may also accompany the presenting syndromes. Patients occasionally present with endocrine abnormalities due to involvement of the pituitary axis as well as psychiatric manifestations, such as psychoses and dementia.

Figure 12-8. Cyst of Toxoplasma gondii in brain tissue, original magnification approximately x1200, hematoxylin and eosin. (Courtesy of Anthony Yachnis, MD, University of Florida.)

oxygen.131 During intestinal infection, the tachyzoite form of the organism, a 2- to 4-micron wide by 4- to 8-micron long crescent-like structure, is produced and disseminates to many different areas in the host. In humans, as in many domestic and wild animals, this dissemination is asymptomatic and results in the formation of cysts in brain parenchyma as well as muscle and numerous other organs (Fig. 12-8). Transmission to humans is thus a result of exposure to excreta from cats, as well as ingested meat, particularly pork, that has not been fully cooked. In humans, primary infection with toxoplasma may, on occasion, produce a mononucleosis-like illness characterized by lymphadenopathy, fever, malaise, liver function abnormalities, and occasionally, myocarditis. However, in the large majority of cases, primary infection is asymptomatic and only becomes recognized under conditions of extreme immunosuppression, such as occurs in patients with HIV with CD4+ counts less than 100 cells/mm3 when the cysts break down and initiate symptomatic infection. Serologic surveys in the United States show that approximately 10% of the general population has been infected with toxoplasmosis at some time, with figures ranging from 3% to 35%, depending on the study.131,132 The prevalence is higher in less developed countries and, in certain parts of western Europe such as France, may range as high as 70% to 80% of the population. Although reactivation of toxoplasmosis in the brain generally leads to local replication with the production of single or multiple abscesses, hematogenous dissemination and infection in the lung and in other parts of the body has been documented.120 Clinical Manifestations Toxoplasma encephalitis generally presents with a syndrome of fever; headache; and varying degrees of confusion,

Diagnosis In a patient with HIV, the finding of single or multiple ringenhancing lesions on CT or MRI strongly suggests Toxoplasma encephalitis (Fig. 12-9). If the patient is also known to be, or is found to be, serologically positive for antibodies to toxoplasma, the combination is virtually diagnostic. The sensitivity of the CT scan in patients with HIV and multiple ring-enhancing lesions is estimated at 70% to 80%.131,132 The sensitivity is probably significantly higher with the use of MRI with gadolinium enhancement. In patients with a single

Figure 12-9. Axial, mid-convexity, T1-weighted post–gadoliniumenhanced MR image demonstrates multicentric, enhancing nodules with marginal enhancement and central necrosis. In addition to the nodules, there is further enhancement of the ependymal surface of the trigone of the right lateral indicating active ventriculitis. Cavitary multicentric lesions distributed mainly in the territories of end-arteries are indicative of a hematogenously disseminated process, in this case, toxoplasmosis. (Courtesy of Ronald Quisling, MD, University of Florida.)

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lesion, the major differential diagnostic possibility is lymphoma, and a brain biopsy may be required to make a definitive diagnosis. A variety of newer imaging techniques, such as positron emission tomography and thallium 201 scanning,133–135 have been developed and appear promising in their ability to improve specificity of radiographic diagnosis of toxoplasmosis encephalitis. Examination of the spinal fluid shows nonspecific abnormalities such as increased white blood cell count and protein. Attempts to improve the sensitivity by the detection of toxoplasma oligoclonal antibody bands have been reported, but do not add any more diagnostic value than a positive serum antibody test. PCR for toxoplasmosis in CSF has been reported to have a sensitivity of 81% in untreated patients.136 Although a wide variety of antibody tests are available, including the original Sabin Feldman Dye Test, current commercial enzyme-linked immunosorbent assay, IgG and IgM tests, along with the indirect fluorescent antibody test, should be readily available and highly specific. Because the disease in patients with HIV is almost always due to reactivation of an old focus, the IgG test result should be positive and the IgM test result should be negative in these individuals. Treatment Treatment should be instituted empirically based upon the clinical setting of a patient with HIV and compatible clinical and radiographic findings. The standard drug regimens include pyrimethamine, 200 mg as a loading dose, followed by 75 to 100 mg/daily, together with a dose of either sulfadiazine at 1 to 1.5 g every 6 hours or clindamycin at 600 to 1200 mg IV every 6 hours. A dose of folinic acid (leucovorin) at 10 to 20 mg/day is given to reduce bone marrow toxicity. Alternative regimens include trimethoprimsulfamethoxazole, given either orally or IV, at a dose of 3 to 5 mg of the trimethoprim component per kg every 6 hours. In addition to pyrimethamine and folinic acid, if the patient is intolerant of sulfadiazine or clindamycin, doses of clarithromycin at 1 g orally every 12 hours, atovaquone at 700 mg orally every 6 hours, azithromycin at 1200 to 1500 mg/day orally, or dapsone at 100 mg/day may be substituted. Signs of improvement are generally seen in the level of consciousness and in a decrease of fever within 5 to 7 days, with over 90% generally responding by day 14.137 If there is no clinical or radiographic response within 10 days, alternative diagnoses and brain biopsy must be considered. Patients should be treated with the initial regimen for 3 to 6 weeks, depending upon the degree and rapidity of improvement, and then receive lifelong suppression with sulfadiazine at a dosage of 500 to 1000 mg orally four times daily, and with pyrimethamine at 25 to 75 mg and folinic acid at 10 to 20 mg, both by mouth daily. Relapse rates with pyrimethamine alone range from 10% to 28% at 50 mg/day, but decrease to 5% at 100 mg/day.138,139

Lymphoma As discussed previously, the major differential diagnostic consideration in toxoplasma encephalitis is CNS lymphoma. It has been estimated that systemic lymphoma will develop in as many of 5% of patients with HIV, and approximately one-third will present with neurologic disease.140 The isolated CNS lymphoma is almost always due to the Epstein-Barr virus–associated B cell type. Patients generally present with confusion, lethargy, memory loss, hemipareisis, speech and language disorders, seizures, and cranial nerve palsies.141 Involvement of the meninges is common and may be seen both in primary CNS lymphoma as well as spread to the meninges from systemic lymphoma. To date, there is nothing in the presentation or in the radiographic appearance that can distinguish CNS lymphoma from cerebral toxoplasmosis with complete certainty. Thus, patients who do not respond to empiric therapy for Toxoplasma encephalitis will need to undergo brain biopsy, in many cases, to establish a definite diagnosis. In patients with known systemic lymphoma and/or in patients who are known to be seronegative for toxoplasma, biopsy of the CNS lesion should be undertaken without waiting for an empiric response to treatment for Toxoplasma encephalitis. Primary CNS lymphoma does respond to therapy with whole brain irradiation and chemotherapy, but survival is generally less than 4 months.142,143

Cytomegalovirus In adults with HIV, serologic evidence of previous infection by cytomegalovirus (CMV) is present in over 90%. Serologic surveys in the general adult population show a range of CMV infection between 50% and 80%, depending on the socioeconomic status and the particular group studied. The seroprevalence of CMV increases with age. Approximately 10% of all infants born in the United States either have CMV infection at birth or acquire it within the neonatal period. The vast majority of these infections are asymptomatic and result from exposure to reactivated virus in seropositive mothers. Subsequently, both children and adults may become infected through exposure to infected urine, often from infants in day care; the virus may also be acquired from sexual contact, generally during the late teens and twenties. In nonimmunocompromised adults, primary CMV infection is clinically identical to that of infectious mononucleosis and runs a self-limited course of 2 to 3 weeks characterized by fever, fatigue, malaise, adenopathy, sore throat, and increased liver enzyme levels, together with atypical lymphocytes in the blood smear. In individuals with HIV, as long as cell-mediated immunity remains relatively intact, symptomatic reactivation of cytomegalovirus is not generally seen. However, as the disease progresses and the CD4+ count decreases to less than

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50 cells/mm3, reactivation of CMV becomes particularly frequent. CMV retinitis is the most common form recognized clinically and in the pre-HAART era, up to 30% of patients wtih HIV showed evidence of CMV retinitis. The diagnosis of CMV retinitis is a based on the puffy white retinal infiltrates seen together with retinal hemorrhage. It may or may not be associated with systemic or other manifestations of cytomegalovirus. Either one or both eyes may be involved at a given time. CMV may also produce ulcerations at any level of the gastrointestinal tract, from the esophagus to the colon, and is probably the most frequent cause of gastrointestinal hemorrhage in patients with HIV. The diagnosis has to be made by colonoscopy or endoscopy with biopsy and demonstration of typical cytopathology, or culture of the virus. There are several forms of CNS involvement with CMV. The pathogenesis of CNS involvement with CMV appears to follow two different routes, first, via the ependymal cells in the ventricles, and second via the blood through capillary endothelial cells. Infection via the ependymal cells and CSF is manifest pathologically as necrotizing encephalitis limited to the periventricular areas, with numerous cytomegalic inclusions in and around the lesions. In contrast, infection acquired via hematogenous dissemination results in microglial nodular encephalitis, which is manifest pathologically as glial nodules formed by rod cells, few lymphocytes and macrophages. Very little tissue damage is associated with these lesions.144 The microglial nodular disease may involve multiple parts of the brain including the periventricular areas. As with CMV retinitis, these CNS complications of CMV occur very late in HIV infection, almost always in patients with CD4+ counts less than 50 cells/mm3. In the series reported by Grassi and colleagues, the mean CD4+ count for patients with microglial nodular encephalitis was 21 cells/mm3 and the average CD4+ count of patients with ventriculoencephalitis was 11 cells/mm3. Although there is considerable overlap of symptomatology between these two pathologic conditions, microglial nodular encephalitis is characterized by the onset of acute confusion associated with delirium and psychomotor agitation, whereas the onset of ventriculoencephalitis is insidious and generally characterized by cognitive disturbances, memory deficits, and mental sluggishness. Patients with either type of encephalopathy may complain of headaches and have seizures. CSF examination in these conditions reveals a slightly elevated protein, which tends to be lower in microglial nodular encephalitis, averaging approximately 60 mg/dL as compared with 171.5 mg/dL in ventriculoencephalitis. Glucose levels are normal and cells are generally, although not always, absent. Although MRI is more sensitive than CT in the diagnosis of these conditions, the MRI may be normal or show nonspecific changes.145 In patients with ventriculoencephalitis, typical MRI findings include a hyperintense ventricular rim on T2-weighted imaging or enhancements with gadolinium.

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Almost all cases show nonspecific cerebral atrophy. Systemic involvement with cytomegalovirus is more frequently associated with microglial nodular encephalitis, which may be documented with CMV antigenemia, PCR, or viral culture. Patients with ventriculoencephalitis are more likely to have the clinical syndrome of CMV radiculopathy, which is described next. CMV infection in patients with HIV may also involve the spinal cord. A syndrome characterized by ascending weakness of the lower extremities associated with loss of deep tendon reflexes progressing to loss of bowel and bladder control has been described.146 The syndrome may begin with low back pain with radiation down to the legs or into the groin or anal area, followed over 1 to 3 weeks by the development of progressive weakness. Pathologically, the CMV radiculopathy is characterized by mononuclear infiltration of the cauda equina and lumbar sacral nerve roots together with CMV inclusions seen in the Schwann’s cells and epithelial cells, leading to axonal destruction. Untreated, this condition generally progresses to irreversible paralysis. Analysis of spinal fluid in patients with this syndrome characteristically shows elevation of neutrophils in the spinal fluid, sometimes as high as 3000 to 5000 cells/mm3. Although the protein is only mildly elevated and the glucose generally normal, some patients may have marked hypoglycorrhachia with glucose levels as low as 5 to 10 mg/dL. Treatment Ganciclovir at a dose of 5 mg/kg IV every 12 hours should be given for 14 to 21 days, followed by maintenance or lower dose IV ganciclovir. Alternatively, a dose of foscarnet at 90 mg/kg, adjusted for renal function, can be given IV twice daily for 2 to 3 weeks. Following induction with either ganciclovir or foscarnet, HAART therapy can then be given in the hope of sustained improvement in CD4+ count and maintenance of a response to treatment. In the pre-HAART era, CMV encephalitis responded relatively poorly to ganciclovir, with general survival rates of only 3 to 4 months.

Human Immunodeficiency Virus Encephalopathy HIV encephalopathy has been observed in up to 7.3% of the 144,184 persons reported with AIDS to the CDC between 1987 and 1991. Only 2% to 4% of adult patients will manifest signs of HIV encephalopathy at diagnosis. However, this number increases as the disease progresses, so it is estimated that between 7% and 14% of patients per year will manifest signs of HIV encephalopathy. It has been estimated that approximately one-third of patients with AIDS will exhibit dementia at the time of death.147 This figure is well corroborated in a large autopsy series of 450 cases spanning the years 1984 to 1999, in which pathologic evidence of HIV

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Figure 12-10. A, Axial, mid-convexity, T1-weighted, nonenhanced MR image demonstrating both ventriculomegaly and sulcal dilatation (indicating cortical brain atrophy). There is no transependymal fluid to suggest elevated CSF pressure. These findings are indicative of both central and cortical brain atrophy which, in this case, is out of proportion to chronological age. Generalized atrophy is one of the features of primary HIV involvement of brain. B, Axial T2-weighted high convexity MR image through the centrum semiovale demonstrates evidence of increased T2 signal. These changes are relatively symmetric and are consistent with nonfocal white matter, which is one of the main imaging features of primary brain HIV. (Courtesy of Ronald Quisling, MD, University of Florida.)

encephalopathy was found in 28.7% to 38%, depending on the year of diagnosis. Interestingly, no change in the incidence of HIV encephalopathy was seen between 1996 and 1999, during the era of HAART treatment.148 Pathologically, the most frequent findings are brain atrophy characterized by sulcal widening and ventricular dilatation together with varying degrees of meningeal fibrosis. The most distinctive histologic feature of this condition is white matter pallor, chiefly seen in a periventricular distribution together with microglial nodules, diffuse astrocytosis, and perivascular mononuclear inflammation. HIV can be readily demonstrated in these nodules by immunohistochemical techniques. Clinically, HIV encephalopathy presents with altered mental status characterized by mental slowing frequently accompanied by evidence of subcortical dementia such as bradykinesia, postural instability, slow and clumsy gait, and altered muscle tone. Radiographically, the most common features are generalized cerebral atrophy together with widespread relatively symmetric hyperintense white matter abnormalities seen on T2 imaging that generally have a periventricular distribution. Examples are shown in Figures

12-10A and B. CSF studies are nondiagnostic. A mononuclear pleocytosis is seen in approximately 20% of patients with cell counts generally less than 50 cells/mm3.149 Approximately two-thirds of patients will have an elevated protein, generally to levels less than 200 mg/dL. HIV may be detected by a variety of techniques in the spinal fluid, but is not diagnostic for HIV encephalopathy. HIV encephalopathy is treated by standard HAART therapy. Patients with are also at increased risk of CNS infection due to a variety of other microorganisms such as M. tuberculosis, atypical mycobacteria, syphilis, and Listeria, and are at higher risk for infection with common communityacquired agents such S. pneumoniae.

Parasitic Infections Malaria Despite its eradication from North America and Europe, it is estimated that malaria infects over 2.5 billion people worldwide and causes between one and three million deaths each year. The disease is caused by one of four different

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species of Plasmodium: P. vivax, P. ovale, P. malariae, and P. falciparum. Essentially all deaths and all serious infections, especially those with CNS involvement, are caused by P. falciparum. Malaria sporozoites are transmitted from the female Anopheles mosquito to the patient at the time the mosquito bites. Sporozoites are carried rapidly to the liver where they multiply in approximately 1 week to become tissue schizonts or the dormant hypnozoites. Infected liver cells then burst, releasing thousands of merozoites, each of which in turn infects red blood cells in the bloodstream. Continued asexual replication in the bloodstream through repeated cycles of maturation and rupture of red blood cells with release of merozoites eventually results in symptomatic infection. During this process, some of the parasites develop into sexual forms called gametocytes that produce no symptoms themselves but that may circulate for a prolonged period. It is the ingestion of these gametocytes that leads to the sexual reproduction cycle in the Anopheles mosquito, resulting in the motile sporozoites that invade the mosquito salivary glands and can be transmitted back to humans at the time of the next feeding. Malaria is widely distributed in developing countries, particularly Central America, South America, Africa, the Middle East, the Far East, and Indonesia. The reader is strongly urged to access the CDC’s website for the most up to date availability on the distribution and drug resistance of malaria, especially P. falciparum, on a country-by-country basis. Pathogenesis Essentially, all serious infections and CNS involvement with malaria, as mentioned previously, are attributable to P. falciparum. As the P. falciparum trophozoites mature in the red blood cells, they induce changes in the surface of the cell and in the flexibility of the cell membrane so that red blood cells tend to stick to capillary endothelium, and because of their increased rigidity, tend to become trapped in capillaries. As a result, in severe cases of malaria in which the parasitemia level is high, capillary vascular obstruction ensues, preventing delivery of oxygen and nutrients to the tissues. In the CNS, this process results in impaired consciousness and tendency toward seizures. Systemic manifestations of severe falciparum malaria include anemia, lactic acidosis, hypoglycemia, pulmonary edema, and even disseminated intravascular coagulation. In a series of 158 cases of falciparum malaria, 83% had fever and chills, altered sensorium was seen in 48%, jaundice in 27%, anemia in 75%, cerebral malaria in 45%, thrombocytopenia in 40.5%, and renal failure in 25%. Overall mortality was 20%, most of which resulted from a delay in diagnosis and treatment. Adult respiratory distress syndrome was also a significant complication.150 The diagnosis of malaria is made from examination of the blood smear, provided that the diagnosis is considered as a differential diagnostic possibility in a patient with altered

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consciousness and fever. Examination of the blood smear is highly accurate. Because the level of parasitemia in falciparum malaria tends to be high, generally greater than 5%, it is not hard to find the ring forms characteristic of the disease. A travel history is critically important to elicit, as is the history of whether the patient took prophylaxis for malaria. The location of the travel is particularly critical because P. falciparum malaria is typically resistant to chloroquine, and resistance to trimethoprim-sulfamethoxazole, mefloquine, and other agents have been observed in many parts of the world, particularly Southeast Asia. Because there is no latent form of P. falciparum in the liver, as there is for P. vivax and P. ovale, all cases of P. falciparum malaria should become clinically evident within a month after leaving an endemic area. However, hypnozoites of P. vivax and P. ovale may survive in the liver for 6 to 11 months, particularly if the patient did not take a full course of prophylaxis on returning from overseas. It should be kept in mind that cases of malaria have been transmitted by transfusion and IV drug abuse. Finally, one must never to rule out the possibility of endemic transmission within the United States despite “eradication” of the disease. Treatment In cases of severe malaria with CNS involvement, the patient must be treated as though he or she has falciparum malaria, regardless of the preliminary interpretation of the blood smear. Standard treatment for adults is a dose of quinine sulfate at 650 mg orally every 8 hours for 3 to 7 days plus doxycycline 100 mg twice a day orally for 7 days. If the patient is intolerant of doxycycline, the quinine may be followed with pyrimethamine sulfadiazine, three tablets on the last day of quinine treatment. Alternatives include quinine followed by clindamycin at a dose of 900 mg three times daily for 5 days or followed by mefloquine 1250 mg as a single dose; quinine followed by halofantrine at 500 mg every 6 hours for three doses, repeated 1 week later, or followed by atovaquone at a dose of 1000 mg daily for 3 days plus proguanil 400 mg daily for 3 days after quinine treatment. If parenteral treatment is required, quinidine gluconate at a 10 mg salt/kg loading dose up to a maximum of 600 mg in normal saline is infused slowly over 1 to 2 hours, followed by a continuous infusion of 0.02 mg/kg/min until the patient is able to begin oral treatment.151 For P. vivax and P. malariae, a dose of 1000 mg chloroquine phosphate orally (600 mg base), followed by an additional 500 mg (300 mg base) dose 6 hours later and again on days 2 and 3 should result in a prompt therapeutic response. In the case of P. vivax and P. ovale, the treatment with chloroquine must be followed by primaquine phosphate 15.3 mg base (26.5 mg) phosphate salt (per day orally for 14 days) to clear the hepatic forms of the organism. With treatment, almost all patients with CNS malaria recover completely if they survive the acute episode. However, approximately 12% may have lasting neurologic complications.

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Cysticercosis Neurocysticercosis in adults results from infection of the brain with the larval cysts of the cestode, T. solium, the pork tapeworm. Human infection occurs by two different mechanisms. Ingestion of the eggs leads to embryonization of the eggs and penetration of the intestinal wall with hematogenous transport of cysticerci to many different tissues, primarily muscle and brain, where they encyst and remain potentially infectious for long periods. Alternatively, ingestion of undercooked pork can result in ingestion of the cysticerci by humans. In this instance the cysticerci mature into the typical tapeworm, which attaches to the intestine and may grow to lengths of up to 3 m and live for as long as 25 years. During this time it produces egg-filled segments, called proglottids, which are excreted in the feces. It is ingestion of the eggs from these proglottids that leads to neurocysticercosis, occasionally even by autoinfection from the patient’s own intestinal tapeworm. Cysticercosis is widespread in areas such as Mexico, Central America, South America, Africa, Southeast Asia, India, the Philippines, and Southern Europe. Symptomatic neurocysticercosis results from the enlargement of the cysticercal cysts in the brain parenchyma over months to years. Patients in the United States may present with seizures due to neurocysticercosis after having left endemic areas for up to 30 years. Symptoms of disease depend on the location and size of cysts and most frequently include seizures and headaches. If the cysts block the flow of cerebrospinal fluid, signs of increased ICP, such as headache, nausea, vomiting, changes in vision, dizziness, ataxia, and confusion may result. When the cysts are located in the meninges, chronic meningitis may be seen. An unusual form called “racemose” cysticercosis due to the proliferation of cysts at the base of the brain can result in severe disease including mental deterioration and death. Intraspinal cysts are often found as well and may produce symptoms of spinal cord compression depending on their location and size. The disease is readily diagnosed with either CT or MRI, in which multiple cysts of varying sizes and stages are demonstrated. Serology is available with sensitivity as high as 94% in patients with multiple cysts, but significantly lower in those with single cysts or old calcified lesions. Serologic studies are generally available only through the CDC or at some national commercial laboratories. Treatment Based on MRI, CNS lesions can be classified into active and inactive neurocysticercosis (Fig. 12-11). Patients with inactive parenchymal neurocysticercosis have no evidence of viable or degenerating parasites and, thus, antiparasitic drugs have no useful role. However, these patients are at high risk of seizures, and standard anticonvulsive therapy with phenytoin, phenobarbital, or carbamazepine is indicated.

Figure 12-11. Axial, contrast-enhanced, mid-convexity CT scan demonstrates multicentric areas of focal brain abnormalities. Some of the lesions have lucent centers where an intracystic hyperdense object is evident. These areas represent neurocysticercosis in its early phase. The visualized objects are the scolices and indicate that organism is still viable. In the left anterior basal ganglia there is a calcified lesion which represents the chronic, nonviable state of neurocysticercosis. Other lesions of similar age are seen in other portions of brain. There is no hydrocephalus. The combination of both new and old lesions is typical of neurocysticercosis. (Courtesy of Ronald Quisling, MD, University of Florida.)

Patients in whom hydrocephalus develops need to be treated with ventricular peritoneal shunting. Virtually all patients with active neurocysticercosis have seizures that must be treated with anticonvulsants. Probably the majority of these patients can be treated symptomatically and observed with MRI because the cysticerci typically undergo complete degeneration over a 1- to 2-year period. This process results in either calcified inactive cysticerci, which will continue to require anticonvulsants or, in a majority, a normal MRI in which case anticonvulsants may be tapered as long as the patients remain seizure free. Antiparasitic treatment can be given with praziquantel at doses of 50 to 100 mg/kg/day for 15 to 30 days or albendazole at 10 to 15 mg/kg/day for 8 days. Although these agents apparently kill the cysticerci, their controlled trials have not shown any clinical benefit over symptomatic treatment alone.152–154 The main adverse side effect of praziquantel is worsening neurologic function, for example, headaches, dizziness, seizures, and increased ICP, probably as a result of an increase in the host inflammatory response to the dying parasites. Standard treatment of ventricular neurocysticer-

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cosis has been the surgical removal of cysts, which block the flow of CSF. Recent studies have found fewer shunt failures when such patients are treated with antiparasitic drugs.155,156 Cysticercosis involving the basilar cisterns is associated with a prominent inflammatory arachnoiditis and can be complicated by both vasculitis, resulting in lacunar infarctions, and invasion of the cysticerci into larger vessels, resulting in strokes. Thus, some authors have recommended the addition of corticosteroids in the treatment of patients with cisternal cysticercosis.157 As with parenchymal disease, there is no definite clinical evidence that the addition of antiparasitic drugs improves the outcome compared with treatment of symptoms alone.

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develop as the parasite invades tissue. These structures also contain numerous protoscoleces. Because of the risk of spilling the contents in the cysts, which will result in potentially fatal local proliferation of the disease and possible dissemination, it is critical to remove the echinococcal cyst intact. Many surgeons use hypertonic saline or formalin injection to kill the protoscoleces prior to removal of the cyst. Although this technique is definitely safer for the patient, it literally destroys the morphology of the scoleces and renders histologic diagnosis impossible. Drug treatment with albendazole has been reported to show some activity both in animals and in humans.161,162 Strongyloidiasis

Echinococcus Echinococcal disease is caused by tapeworms, which commonly infect dogs, cats, wolves, and other carnivores. It is found worldwide but is particularly common in countries surrounding the Mediterranean, parts of East Africa, Russia, and South America. There is very little echinococcal disease in the United States, but it is important to recognize that bears, foxes, and wolves in Canada and Alaska are commonly infected with this parasite. Disease is produced when an egg from an infected animal is ingested and the oncosphere within it is activated, penetrates the gut wall, and travels via veins or lymphatics to various tissues in the body where cysts form. The most commonly involved areas are the liver in 50% to 70% of cases and the lungs in 20% to 30% of cases. The CNS is only involved in approximately 2% of cases.158 Four species infect humans; however, Echinococcus granulosus and E. multilocularis account for the vast majority of cases. The disease presents most frequently as solitary cysts of the liver and, in the case of CNS involvement, as a solitary cyst that slowly enlarges. Depending on the size and location of the cyst, the patient may be asymptomatic. However, as the CNS lesion enlarges, symptoms arise from the local effects of the lesion itself or secondary to increased ICP. Patients thus present with headache, papilledema, nausea and vomiting, seizures, hemiparesis, dysarthria, and cranial nerve palsies. The diagnosis may be suspected from the radiographic appearance of the cyst itself seen on CT or MRI. Classic radiographic features include a sharp, spherical border lacking a rim of enhancement or surrounding edema. Serologic testing is available from the CDC. Sensitivity of these tests varies from 60% to 90% so a negative test result does not absolutely rule out the disease.159,160 History of travel to or living in an endemic area, especially with exposure to sheep, also increases the likelihood of the diagnosis of echinococcus. In the case of E. granulosus, protoscoleces develop slowly on the inside of the capsule wall by budding while E. multilocularis forms aggregates of small grapelike cysts that

Strongyloides stercoralis is a small nematode with free-living forms found in soil, while parasitic forms, for example, the adult female, live within intestinal crypts in the duodenum and the jejunum. The eggs released from these organisms normally mature in the soil to produce more larvae that can directly penetrate the skins of humans and other mammals. Burrowing through the skin, the larvae enter lymphatics and, ultimately, the venous system where they are carried to the pulmonary capillaries. Here, they migrate out of the blood vessels into alveoli, up the airways and then down through the esophagus to reach the small bowel. Normally, the adult worms bore into the mucosa and produce eggs that pass out with the feces. For reasons not fully understood, in some patients the eggs hatch before being excreted and the larvae burrow through the intestinal wall and perianal skin to reinfect the patient. The phenomenon has been observed in World War II veterans who were in POW camps on the pacific front up to 30 years after their return to the United States. However, in immunosuppressed patients or patients on high-dose corticosteroids or with HIV, a cycle of autoinfection can reach such proportions that life-threatening pulmonary disease can develop, which is characterized by pulmonary infiltrates and adult respiratory distress syndrome. As part of this hyperinfection syndrome in immunocompromised patients, CNS involvement may be manifested by headache, altered mentation, meningismus, focal or generalized seizures, and motor weakness. The unique aspect of this process is that meningitis due to E. coli and other gram-negative enteric organisms may be observed. It is believed that enteric organisms are carried either on the larvae or within the gut of the larvae as they migrate through the tissues and thus causing meningitis when the CNS is invaded. Despite involvement by large numbers of migrating parasitic organisms, eosinophilia is almost never seen because of the setting of immunosuppression, (usually corticosteroids). The diagnosis can be readily made by a parasite examination of the stool. Treatment with thiabendazole at a dose of 25 mg/kg twice daily for 10 days has been effective for the treatment of this condition.

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Toxocariasis Toxocara canis and T. cati are nematodes that infect the intestines of dogs and cats respectively. As a result of this infection in domestic animals, the eggs of these organisms are distributed widely in the soil to which humans may be exposed. Human infection occurs when eggs are ingested and hatch in the small intestine. Larvae then migrate through the intestinal wall and into various tissues into the body and most often manifest as visceral larvae migrans (VLM). Symptoms include abdominal pain, hepatomegaly, anorexia, nausea, vomiting, lethargy, behavioral changes, pneumonia, cough, wheezing, lymphadenopathy, and even fever. The hallmark of the disease is striking eosinophilia. When eosinophilia is seen in small children between the ages of 2 and 4 years, it readily suggests this diagnosis. Serologic surveys in the United States in the early 1970s showed that between 4.6% and 7.3% of children in varying parts of the United States have been infected with T. canis.163 A similar survey in New York in the 1980s showed a prevalence of 5.1% of female and 5.7% of male school children seropositive for T. canis.164 More recent serologic data from Ohio showed a seroprevalence of T. canis antibodies in 12% of children aged 4 to 10 years. No adverse outcome, as measured by intelligence testing, were noted once baseline differences in intelligence were taken into account.165 CNS involvement may occur in patients with VLM most commonly presenting as encephalopathy with seizures.166 Other manifestations include meningoencephalitis, transverse myelitis, and psychiatric disturbances. Treatment is diethylcarbamazine 2 mg/kg orally three times daily for 10 days or albendazole 400 mg orally twice a day for 5 days. Steroids are indicated for ocular disease and may be necessary for severe lung, heart, or CNS involvement. Differential diagnosis includes other migratory eosinophilia associated diseases such as Ancylostoma, Gnathostoma, or Spirometra.

Syphilis Syphilis is caused by the spirochete Treponema pallidum, belonging to the family Spirochaetaceae. The organisms are thin, tightly coiled bacteria that exhibit a characteristic undulating movement under direct dark-field observation. The clinical manifestations of the different stages of disease caused by T. pallidum have been recognized since the 1500s and controversy persists to this day as to whether it was transported de novo to Europe from contact with the indigenous population of South and Central America or whether it originated from closely related species of Treponemes found in the Near East. When serologic surveys first became available at the end of the 19th and the beginning of the 20th centuries between 8% and 14% of adults in major cities such as Paris, Berlin, and New York had positive test results.167 Before the availability of penicillin, cases of the primary and

secondary syphilis reached a high of approximately 100,000 per year in the 1940s, and fell rapidly with the introduction of antibiotics after World War II. Perhaps coincident with the introduction of oral contraceptives and the “sexual revolution,” the incidence of primary and secondary syphilis increased from the range of approximately 20,000 cases per year with a gradual rise to as high as 40,000 cases a year in the late 1980s during the early stages of the HIV epidemic. Since 1990, new cases of primary and secondary syphilis have dramatically declined to 6000 to 7000 cases per year between 1999 and 2000.168 Although syphilis can be transmitted from any skin or mucous membrane lesion containing infectious spirochetes, the vast majority of cases are transmitted through genital sexual contact. The initial manifestation is the chancre, which begins at the site of inoculation as a painless papule and rapidly ulcerates into a relatively painless ulcer that is dark-field positive. Regional lymphadenopathy frequently accompanies primary chancre, and the chancre generally heals spontaneously in 3 to 6 weeks. For a period of two to eight weeks following the chancre, a systemic illness known as secondary syphilis may develop in as many as 25% of untreated patients. The classic manifestations are macular papular, papular, or pustular skin lesions, which are distributed over the entire body and include the palms and soles, characteristic findings seen in very few other conditions. Genital ulcerations develop in between 20% to 35% of those with clinically evident secondary syphilis. Approximately two-thirds of patients will develop systemic manifestations including fever, malaise, pharyngitis, anorexia, weight loss, arthralgias. Some evidence of CNS infection develops in 8% to 40% of patients, including meningitis, headache, decreased vision, tinnitus, vertigo, and even cranial nerve involvement. Direct dark-field examination of the CSF in these patients rarely reveals spirochetes. Using rabbit inoculation, Lukehart found that 12 of 40 patients (30%) with primary and secondary syphilis had viable treponemes in CSF.169 Like the primary chancre, secondary syphilis resolves spontaneously without antibiotic therapy. After secondary syphilis, the patient is once again is asymptomatic until manifestations of tertiary syphilis appear 5 years to longer than 40 years after the primary infection. Without treatment, at least 25% of infected patients will develop some manifestations of tertiary syphilis. Clinically, tertiary syphilis is divided into three general types: neurosyphilis, cardiovascular, and gummatous syphilis. The classical manifestation of cardiovascular syphilis is an aneurysm of the ascending aorta, which may dissect down into the aortic valve ring with distortion of the valve cusps and resultant aortic insufficiency. Pathogenically, this is due to syphilitic inflammatory involvement of the vasa vasorum which leads to destruction of the elastic tissue and saccular dilatation of the aortic route. Cardiovascular syphilis will develop in approximately 10% of untreated patients.

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Syphilitic gummas are progressive granulomatous tumorlike lesions primarily involving skin, mucous membranes, and bone but which can develop in any organ in the body including the brain. Localized findings range from small superficial nodules to large radiating lesions. Symptoms depend on the location of the lesions. Neurosyphilis is generally divided into four syndromes. Syphilitic meningitis most often occurs within the first two years after infection and results from small vessel arteritis in the meninges, which leads to typical symptoms of headache, nausea, and vomiting seen in approximately 90% of patients. In addition, up to 45% of patients with syphilitic meningitis may have cranial nerve palsies. Seizures have been reported in 17% and fever occurs in less than 50%.170 This condition tends to occur as part of secondary syphilis and, therefore, may resolve even without treatment, with the exception of cranial nerve abnormalities that may not fully recover, particularly eighth cranial nerve lesions. The CSF white blood cell count is almost invariably abnormal, but there is only a mild decrease in CSF glucose. Although there is some overlap in terms of symptoms, meningovascular syphilis presents with findings of meningitis together with focal neurologic findings due to syphilitic arteritis. The peak incidence of this condition is approximately seven years after acquisition of syphilis and accounts for approximately 10% to 12% of patients with CNS involvement.171–173 Patients with meningovascular syphilis generally present with several weeks to months of prodromal signs and symptoms such as headache, vertigo, personality changes, behavioral changes, insomnia or seizures, and stroke-like neurologic deficits most frequently involving the distribution of vessels in the territory of the middle cerebral artery followed by that of the basilar artery. Thus, while the distribution of strokes in such patients may be similar to that of the patient with atherosclerotic disease, the occlusive symptoms develop gradually over a period of time in meningeal vascular syphilis as opposed to suddenly in patients with atherosclerotic strokes.131,170,174 The majority of neurologic manifestations of tertiary syphilis are known as parenchymatous neurosyphilis and include the two classical syndromes, tabes dorsalis and general paresis. In contrast to the pathogenesis of meningovascular syphilis or syphilitic meningitis, these syndromes result from progressive neuronal destruction rather than ischemic damage from vasculitis. General paresis, also known as general paralysis of the insane, is a chronic progressive meningoencephalitis with a peak incidence 10 to 20 years after acquisition of syphilis. It generally presents with a gradual deterioration of mental functioning characterized by difficulties in concentration, irritability, and deficits of higher cognitive function. As the condition progresses, these manifestations become more obvious and symptoms may mimic psychiatric disease. Difficulties with motor control then develop with a loss of facial muscle and extremity tone, loss of fine motor control, and the development of tremors

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and dysarthria. Subsequently, patients may have seizures, loss of bowel and bladder control, and paralysis. Untreated, the disease follows a progressive or subacute course over 3 to 4 years. Pathologically there is diffuse cortical atrophy, dilatation of the ventricles, and neuronal dropout with accompanying glioses. Spirochetes can be demonstrated in 25% to 40% of patients with silver stain. The diagnosis is established with a combination of the clinical presentation, positive serologic test results, and elevated CSF white count and protein. Tabes dorsalis, like general paresis, results from progressive neuronal degeneration. It has a peak incidence that is slightly later than that of paresis, approximately 15 to 20 years after infection, and the progression of this condition is somewhat slower than that of paresis. The classical early symptom is “lightning pains” in the distribution of nerve roots.170 These pains are described as lancinating, lasting for minutes to hours, and most often involve the lower extremities. In 10% to 20% of cases, patients with tabes may also present with episodic attacks of abdominal pain. In addition to pain, some patients experience parethesias, which also occur episodically. Ultimately, patients experience progressive loss of sensation and proprioception, particularly in the lower extremities. As a result, the patients exhibit a characteristic broad-based shuffling gait and Charcot joints may develop. Muscular atrophy develops in approximately 20% of patients. The Argyll Robertson pupil is one in which one or both pupils constrict with accommodation, but do not react directly to light; this is a characteristic feature of tabes dorsalis. Pathologically there is atrophy of the posterior columns of the spinal cord with inflammatory infiltrates and loss of neurons. In contrast to paresis, it is unusual to be able to stain the spirochete in nerve tissue. The diagnosis is readily made from the characteristic neurologic findings together with positive serologic test results. However, CSF leukocytosis is observed in only 50% of patients, and protein elevation is seen in approximately 53% of patients, as well.170 Finally, gummas may arise in almost any part of the CNS, most often associated with the pia mater and consisting of rubbery masses varying in size from several millimeters to centimeters.175 Serologic Testing Laboratory diagnosis of syphilis depends on the stage of the disease and clinical manifestations. Patients with lesions on moist skin or mucous membranes during either primary or secondary syphilis can usually be diagnosed by the demonstration of treponemes on dark-field microscopy. While treponemes can be demonstrated in dry lesions or lymph nodes by biopsy or saline aspiration, the yield is considerably lower. Serologic tests for syphilis are generally divided into two different types: treponemal tests and nontreponemal tests. The nontreponemal tests are IgG or IgM antibodies that are

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directed at lipid antigens, which were originally extracts of cardiolipin from beef heart or liver. Currently, a standardized mixture of cardiolipin, cholesterol, and lecithin, which has fewer false-positive test reactions, is used and forms the basis of today’s standardized tests. The most common of these are the classic VDRL, in which agglutination of the cardiolipin, cholesterol, and lecithin antigen is done on a slide using heated serum, the rapid plasma reagin (RPR) card test, the automated reagin test, or the toluidine red unheated test. Because of the stringency of the technical requirements for the test, the VDRL is generally performed only on CSF and serum screening tests are generally done with the RPR and its variants. Specific treponemal tests for syphilis include the fluorescent treponemal antibody absorption (FTA-ABS), Treponema pallidum immobilization, microhemagglutination Treponema pallidum, hemagglutination treponemal test for syphilis (HATTS), as well as newer tests such as the Serodia Treponema pallidum particle agglutination (TP-PA) and the Captia Syphilis-G-enzyme immunoassay. These tests use treponemal antigens as the target antigen and use either indirect immunofluorescence, ELISA, or hemagglutination formats. It is important to understand that the serologic response to syphilis increases gradually over the course of the primary infection, so that when the chancre is first observed no more than 10% to 20% of patients may be seropositive by any method. However, this will increase with the duration of the chancre during primary infection to approximately 70% for both the treponemal and nontreponemal tests by the time the chancre heals. During secondary syphilis serologic test results, whether treponemal or nontreponemal, are positive in almost 100% of patients. Early treatment of the primary infection should render the patient seronegative within a year. Treatment of syphilis during the secondary and latent stages will generally result in a significant decrease in the titer of the nontreponemal tests. These test results should be negative within 1 year in a patient treated for primary syphilis or within 2 years for a patient treated for secondary syphilis. Patients who remain seropositive by nontreponemal tests after treatment probably have either persistent infection or the so-called biologic “false-positive” result sometimes seen with HIV infection.176,177 In general, once the treponemal test results become positive they remain so for life, even if the patient has been successfully treated. Serologic tests can be used to diagnose neurosyphilis during the latent and late, latent stages by testing the spinal fluid for VDRL antibodies. With the exception of rare false-positive results, possibly resulting from blood contamination, a positive CSF VDRL is diagnostic of neurosyphilis. Unfortunately, the CSF VDRL has been reported to be negative in up 30% of patients with neurosyphilis, thus a negative test result does not exclude the diagnosis. Unfortunately, one cannot use the more sensitive treponemal antibody tests with CSF to diagnosis neurosyphilis because these antibodies cross the blood-brain barrier and are present essentially in all patients who are seropositive for

treponemal tests for syphilis. Thus, they do not provide any more information than testing serum alone. For example, in one study the CSF-FTA-ABS test result was positive in 48 patients, 15 of whom had clinical neurosyphilis.178 While one can resort to sophisticated methods of CSF analysis, such as levels of CSF treponemal antibody compared with serum levels adjusted for changes in the blood-brain barrier by using serum/CSF albumin ratios, and demonstrating a significantly higher than expected CSF level of specific treponemal antibody, it is probably safer to treat patients who have a positive serum test result if they have any clinical signs of neurosyphilis. If the patient has no clinical manifestations of neurosyphilis and preventive treatment for latent neurosyphilis is being considered, treatment should be based on the presence of an abnormal number of white blood cells in the spinal fluid rather than trying to fine tune the serologic diagnosis. Recent studies have been published using PCR showing that DNA from T. pallidum can be detected in CSF. However, it is unclear whether a positive test result means that the patient has to be treated for latent neurosyphilis or that a negative test result excludes the diagnosis.169,179–183 Treatment The preferred treatment for all manifestations of neurosyphilis is intravenous aqueous crystalline penicillin G 12 to 24 million units per day given in six divided doses for 10 to 14 days. Alternatively, 2.4 million units of procaine penicillin G can be given intramuscularly (IM) together with 500 mg per day of probenecid four times a day for 10 to 14 days. In penicillin-allergic patients, a dose of doxycycline 200 mg orally each day for 21 days, or ceftriaxone 1 g IM or IV for 14 days has been recommended. However, treatment failures have been documented with ceftriaxone, especially in patients with HIV. Treatment of syphilitic meningitis or meningovascular syphilis is generally very good with the exception of focal cranial nerve abnormalities sometimes associated with syphilitic meningitis and larger ischemic defects associated with meningovascular syphilis. For patients with tabes dorsalis or paresis, improvement approaching cure is relatively uncommon and, in fact, a majority of patients actually continue to progress despite “adequate” penicillin treatment.184 Patients with asymptomatic neurosyphilis, that is, positive syphilis serologic test results together with CSF abnormalities, appear to respond very well to treatment. In one study, 89% of 454 patients who initially had a minimum of 10 leukocytes/mm3 of CSF had normalized their cell counts at a one year follow-up, as had 69% of those with abnormal protein before treatment.185 Because patients with primary and secondary syphilis are curable with standard treatment of benzathine penicillin G 2.4 million units IM weekly for three weekly doses, the question of proper treatment always arises when an asymptomatic patient is found to have a positive VDRL result, RPR

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test result, or other screening test for syphilis. The problem is that this regimen does not reliably provide CSF levels in excess of 0.018 mg/mL of CSF in all patients, which is believed to be necessary to kill spirochetes within the CNS.186–188 To rule out neurosyphilis in an asymptomatic patient, examination of the spinal fluid is required and if no abnormalities of protein or cells are found, weekly treatment can be safely administered. It is also recommended that all patients found to have serologic evidence of syphilis, assuming that false-positive test results such as those due to pregnancy and other intercurrent illness can be ruled out, should have serologic testing for HIV because the ability to eradicate syphilis is considerably lower in patients with HIV and retreatment may be necessary.

Lyme Disease Lyme disease was first recognized in the United States in the early 1970s when Dr. Allen Steere at Yale University investigated an outbreak of juvenile rheumatoid arthritis in the small towns of Lyme, Old Lyme, and East Haddum, Connecticut. In the initial report, they found 39 children and 12 adults who had a classic, characteristic, remitting, relapsing oligoarticular arthritis generally with onset in the summer or early fall. All of these patients lived in rural areas and half of the patients lived on two adjacent country roads. In addition, 13 of these patients had noted an unusual skin lesion an average of 4 months before the onset of the arthritis.189 Subsequent prospective studies then defined neurologic abnormalities such as Bell’s palsy, sensory radiculoneuritis, lymphocytic meningitis, and cardiac conduction abnormalities also associated with Lyme disease. These studies showed that at least a quarter of the patients remembered a tick bite at the site of the initial skin lesion, and based on examination of the actual tick from one of these patients, the vector was identified as a tick from the Ixodes family.190–192 The agent of Lyme disease was finally isolated by Dr. Willie Burgdorfer, from the Rocky Mountain Laboratory in Hamilton, Montana, when he was searching for evidence of Rocky Mountain spotted fever in ticks isolated from New York State. No rickettsia were found; however, spirochetes were seen in stains of the insect’s digestive tract.193 The earliest manifestations of Lyme disease occur at the site of the tick bite, beginning as a red macule or papule that then expands to an area as large as 10 to 15 cm with red outer borders and partial central clearing. The lesion develops as early as 3 days and as late as 30 days following the bite and generally lasts 3 to 4 weeks. It is most commonly located on the thigh or groin and develops in approximately 80% of patients.194–198 Dissemination of the spirochete occurs during the development of this initial lesion, and many patients will have multiple secondary annular lesions that are similar to the primary site. Systemic symptoms of fatigue, lethargy, and malaise along with generalized lymphadenopathy, meningis-

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mus, encephalopathy, migratory musculoskeletal pain, splenomegaly, sore throat, and cough may develop in varying degrees during this early disseminated phase.195 For the most part, the systemic manifestations as well the erythema chronicum migrans lesions themselves usually resolve without treatment in 3 to 4 weeks. Untreated, however, the Lyme disease spirochete becomes sequestered and persists in certain tissues such as the nervous system, joints, heart, and even the skin. In some patients with meningitis, particularly in Europe where the disease is caused by a different species of spirochete, significant neurologic abnormalities develop including cranial neuritis that can present as a isolated facial palsy (motor and sensory), radicular mononeuritis multiplex, or myelitis alone or in varying combinations. Although these patients may have some neck stiffness on extreme flexion, typical Kernig’s and Brudzinski’s signs are not present. Patients may complain of excruciating headache as well as severe musculoskeletal pain. Early on, examination of the spinal fluid may be normal but patients generally develop a lymphocytic pleocytosis of approximately 100 cells/mm3 with a normal glucose level. It is during this early dissemination stage that cardiac manifestations are generally seen, usually consisting of atrial-ventricular block with varying degrees of other forms occasionally noted including complete heart block, which rarely persists for more than a week and generally does not require the insertion of a pacemaker.199–201 Occasional patients have been described with osteomyelitis, myositis, panniculitis, eosinophilic fasciitis, conjunctivitis, or even deeper involvement of the orbital structures including panophthalmitis and choroid retinitis with exudative retinal detachment or interstitial keratitis. The third stage of Lyme disease is characterized by arthritis, which develops in approximately 60% of untreated patients. Symptoms include intermittent attacks of pain particularly involving the large joints, such as the knee, in an asymmetric pattern. Attacks generally last weeks to months followed by periods of remission. Joint fluid counts range from 500 to 100,000 cells/mm3 with a high percentage of polymorphonuclear leukocytes. Even untreated, this condition resolves gradually over a period of years. The late manifestations of CNS involvement of Lyme disease generally develop a year or more after the onset of illness and generally do not improve spontaneously. In both North American and European forms of this disease, persistence of the Borrelia burgdorferi spirochete has been demonstrated in CSF and in brain parenchyma up to 9 years after the onset of illness.202–204 Symptoms of late progressive Lyme encephalomyelitis may develop either acutely or gradually, and once started they worsen progressively over months to years. Progression may be gradual or stepwise characterized by sudden deterioration and only partial improvement between episodes. The most common neurologic symptoms are speech abnormalities, limb weakness,

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gait difficulties, ataxia, bladder dysfunction, visual changes, hearing loss, and poor memory and concentration.203,205–216 Headaches, nausea, vomiting, and neck stiffness are reported but occur less often, while mental deficits such as behavioral changes and poor memory and concentration are common. More severe changes including confusion, disorientation, dementia, delirium, and somnolence can occur. Symptoms such as apraxia, monoclonus, hemiparesthesia, and visual field abnormalities have been reported. Spinal cord involvement is common, and myelitis may present as progressive paraparesis or quadriparesis that can be quite severe. Approximately 45% of patients have cranial nerve palsies, most frequently unilateral facial nerve involvement and bilateral hearing loss. Optic nerve involvement is also common and abnormalities of the ocular motor nerves as well as cranial nerves and have all been reported.193,217–219 Peripheral radiculoneuritis occurs in less than 10% of patients. Cerebrospinal fluid is abnormal in almost all cases. Generally, there is CSF pleocytosis, predominantly monocytic in the range of 100 to 200 cells/mm3, although levels as high as 2300 cells/mm3 have been reported. Protein concentrations are usually in the range of 100 to 200 mg/dL, but concentrations levels as high as 1800 mg/dL have been reported. The glucose concentration is generally normal to low. Oligoclonal bands specific for B. burgdorferi have been reported. Both EEG and CT abnormalities including infarcts in the internal capsule, thalamus, and lentiform nucleus, and hydrocephalus and cerebral atrophy have been reported.205,207,214–216,220,221 MRI shows additional lesions such as multifocal white matter abnormalities, infarcts, periventricular and subinsular cavities, and atrophy of the pons and medulla.207,214,216,220 MRI in patients with myelitis have shown diffuse or focal signal abnormalities in relevant parts of the spinal cord.207,220 In contrast to the dramatic and objectively documented neurologic abnormalities and syndromes seen in a small number of patients with Lyme encephalopathy, a certain number of North American patients have reported the development of a less dramatic, but nonetheless disabling CNS symptom complex. These patients complain of overwhelming fatigue, accompanied by loss of memory and concentration, and almost always without physical neurologic abnormalities. Psychological testing shows abnormalities of immediate and delayed memory, ability to learn information, attention span, concentration, problem solving, perceptual motor performance, and verbal fluency. Depression and irritability are frequently reported, but in general fatigue is the most overriding complaint. Many of these patients fit the definition of the chronic fatigue syndrome as defined by the CDC. Objective laboratory and radiographic signs of infection are generally absent. CSF pleocytosis is present in less than 5% of the cases, and CSF protein is elevated in only a minority of patients. Oligoclonal bands for Borrelia are

absent and patients with these complaints may or may not have antibodies to Lyme disease in the serum. Some of these patients have been reported to have MRI abnormalities such as focal areas of increased signal in deep cerebral white matter.215,222,223 In general, symptoms in these patients do not improve spontaneously and a variable number apparently do respond to antibiotic treatment, although it may require 6 months or more.215,224 In addition, a number of North American patients have developed a mild multifocal polyneuropathy distinct from the meningopolyneuritis of early disseminated Lyme disease as a manifestation of late Lyme disease. Intermittent tingling and paresthesias of the extremities are the most common symptoms, occurring in approximately 50% of patients with this form of late Lyme disease. The onset is generally eight months to several years after the initial infection. The symptoms are usually distal, may be symmetric or asymmetric, and can involve both arms and legs. About one-quarter of patients present with carpal tunnel syndrome or develop it at some point. Radicular pain occurs in 25% to 50% of those with this syndrome and is intermittent, asymmetric, and multifocal, typically radiating from the spine into the limbs or trunk.73,215,224–226 Sensory changes such as mild stocking and glove distal sensory loss, as well as distal asymmetrical or truncal sensory loss also occur. 73,215,224–226 Objective evidence of organic disease is much more common in these patients than in those reporting symptoms of chronic fatigue, with up to 83% of patients having electromyographic abnormalities demonstrable particularly among those with distal paresthesias. In addition, CSF abnormalities, mostly in the form of increased CSF protein concentration and intrathecal antibody synthesis specific for B. burgdorferi, are found in up to 70% of patients with these symptoms.215,225 Treatment with antibiotics does improve the paresthesias and electrophysiologic conduction abnormalities, but may require 3 to 7 months.75,215,224–226 Improvement among patients with radicular pain is less frequent and is only seen in about 50%.227 The diagnosis of Lyme disease can be made with reasonable assurance by observation of typical skin lesions of erythema chronicum migrans together with a well-documented history of a tick bite. However, during this early stage of the disease, only 30% to 40% of patients will have a positive serologic test result for Lyme disease in an acute serum specimen, and only 60% to 70% of these patients will have positive results in the convalescent sera 2 to 4 weeks later. In general, serologic testing is done using an ELISA to screen for the presence of antibody, together with confirmation by Western blot assay. Both IgG and IgM antibodies are formed. However, persistence of the IgM antibody alone in the absence of an IgG response after the first month of illness may represent a false-positive reaction. After the first 1 to 2 months of infection, over 90% of patients will have a specific IgG antibody response to the spirochete. It has been

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noted that patients treated effectively early in the course of erythema chronicum migrans may never develop a humoral immune response, although cellular immunity may be demonstrated and may persist for years. Treatment of early dissemination and localized erythema chronicum migrans consists of doxycycline at a dose of 100 mg twice a day for 20 to 30 days or amoxicillin at 500 mg three times daily for 20 to 30 days, with some experts recommending the addition of probenecid at 500 mg three times daily to the amoxicillin regimen. Cefuroxime axetil at a dose of 500 mg orally three times daily for 2 to 3 weeks has also been recommended, as has erythromycin at 400 kg/mg/day in four divided doses for 2 to 4 weeks in children. For patients with arthritis, treatment with doxycycline or amoxicillin is extended to 1 to 2 months, and IV ceftriaxone at 2 g/day for 14 to 30 days is also recommended. For patients with early or late neurologic abnormalities, ceftriaxone at 2 g/day IV for 2 to 4 weeks is generally recommended. Alternatives include doses of penicillin G at 20 million units IV in four divided doses daily for up to 30 days, as well as doxycycline at 100 mg orally three times per day for 14 to 30 days. Treatment failures have been reported for all of these regimens and treatment may need to be repeated. Cardiac abnormalities are treated as for early infection in those patients with first-degree atrioventricular (AV) block; intravenous ceftriaxone or penicillin is used for higher degrees of AV block. In patients with neurologic manifestations of early disseminated Lyme disease, intravenous treatment with penicillin or ceftriaxone can lead to a mild Herxheimer-like reaction with worsening of pain and fever during the first 18 to 20 hours199,220,228 However, in general, meningismus, radicular pain, and systemic symptoms improve within days although residual fatigue, arthralgias, and muscular skeletal pain can persist for some time thereafter. Motor deficits improve more slowly, over 2 to 3 months, and sometimes never fully recover. Central nervous system abnormalities usually stop progressing and begin to improve slowly, but residual deficits may remain.220,228–232 CSF cell counts respond over the course of treatment but may not return to normal for several months, and the protein concentration falls even more slowly, remaining elevated for as long as a year in some patients. If the patient does not respond by the end of the second week, treatment should be extended for at least another 2 weeks. The severe abnormalities of late Lyme disease generally respond well to high dose penicillin, doxycycline or ceftriaxone.205,207,216,220,221,229,233 Altogether 80% to 90% of patients improve with IV cephalosporins, but recovery is slow and often incomplete, with little change occurring during the treatment itself and only developing over the subsequent weeks after treatment has stopped. At this point, use of steroids is not recommended because a controlled trial showed that patients responded as well to antibiotic treat-

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ment alone as to the combination of antibiotic with steroids.234

Miscellaneous Infectious Agents Rickettsia and Ehrlichia A wide variety of infectious agents invade the CNS and produce symptoms there as part of their systemic infection. For example, symptoms such as severe headache, photophobia, stiff neck, confusion, lethargy, restlessness, insomnia, and vertigo are relatively common, nonspecific symptoms seen in Rocky Mountain spotted fever and in patients with human monocytic or granulocytic ehrlichiosis. Rickettsia and Ehrlichia are small gram-negative, obligate intracellular organisms transmitted by tick bites. Despite the name, most infections with Rocky Mountain spotted fever occur in the inland parts of North Carolina, Virginia, and other southeastern States. As the name implies, the disease is also seen in the Rocky Mountain states such as Colorado and Wyoming. Infections generally follow the distribution of the main vectors Dermacentor andersoni in the west and Dermacentor variabilis in the east. Infections are limited to warmer months. The primary pathogenesis of rickettsial infection, particularly that of Rocky Mountain spotted fever, is a vasculitis characterized by endothelial swelling, necrosis, and mononuclear cell infiltrate. This is in contrast to the infiltrate of polymorphonuclear leukocytes seen in typical immunocomplex vasculitis. As a result of the variability of the vessels involved in the central nervous system, a wide range of neurologic findings are occasionally seen in Rocky Mountain spotted fever such as seizures, deafness, facial diplegia, gaze palsies, nystagmus, ataxia, dysphasia, transverse myelitis, neurogenic bladder, hemiplegia, and paraplegia, or quadriplegia. Approximately 25% of cases have significant alteration of consciousness and thus present as encephalitis. The diagnosis of Rocky Mountain spotted fever is fundamentally a clinical diagnosis, and depends on the history of a tick bite together with a compatible systemic illness with or without a rash. Although serologic diagnosis is highly accurate, it is not readily available in most institutions and therefore treatment must be started empirically. In adults and children older than 8 years of age, recommended treatment is a dose of doxycycline at 100 mg twice daily. For children younger than 8 years of age, chloramphenicol at 50 mg/kg/day in four divided doses is recommended because of the tooth discoloration associated with tetracyclines. Most patients show improvement within 2 days, but may require up 7 to 10 days in severe cases. Despite the use of modern antibiotic treatment the fatality rate is still in the range of 2% to 6%.235,236 Even after recovery, CNS abnormalities may persist in a significant number of patients with Rocky Mountain spotted fever, including intellectual defects, impaired fine motor skills, aphasia, and EEG changes.237

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Human granulocytic ehrlichiosis and human monocytic ehrlichiosis are caused by two recently described rickettsia of the genus Ehrlichia: E. chaffeensis, which causes human monocytic ehrlichiosis (HME); and an unnamed Ehrlichia species associated with infection of granulocytes (HGE). Both diseases are spread by tick bites and HME is relatively common in the South and Southeast, while most cases of human HGE so far have been recorded from the upper Midwest. DNA studies of the agent of HGE show that it is mostly closely related to E. canis, but probably represents a different subspecies. Symptoms of ehrlichiosis include high fever, chills, severe headache, and myalgias, and may include confusion, disorientation, obtundation, and ataxia in some patients.238,239 CSF and laboratory studies are nondiagnostic, and as with Rocky Mountain spotted fever, treatment with doxycycline or chloramphenicol must be given empirically. Serologic confirmation of illness is highly accurate, but available only from state and other reference laboratories. Cat Scratch Disease The agent of cat scratch disease, Bartonella henselae, may on occasion involve the CNS. While the typical case develops impressive fluctuant localized adenopathy 1 to 7 weeks after inoculation of the infectious agent, systemic symptoms, such as fever and malaise, will develop in approximately one third of patients; 10% may actually have a variety of CNS symptoms including encephalopathy, retinitis, or Parinaud’s ocular glandular syndrome.240,241 Although most cases of cat scratch disease in the normal host are self-limited and resolve over 3 to 8 weeks, treatment is recommended and azithromycin is probably the treatment of choice since macrolides as well tetracyclines and rifampin appear to significantly reduce the levels of infectious organisms in tissue.242 Whipple’s Disease Whipple’s disease is a slowly progressive infection, which primarily involves the gastrointestinal tract of middle-aged men and presents with arthralgias, abdominal pain, fever, diarrhea, malabsorption, and weight loss. The disease is caused by Tropheryma whippleii. CNS involvement is one of the more frequent complications of this disease and can, on occasion, occur in the absence of recognized gastrointestinal or systemic involvement. The disease is most often diagnosed through biopsy of intestine or a mesenteric lymph node revealing the presence of PAS-positive material, with occasional bacilliform organisms being stainable. Pathologically, involvement of the brain is most often manifested by chalky, yellowish white, 1- to 2-mm nodules distributed diffusely throughout the cortical and subcortical gray matter of both the cerebrum and the cerebellum. The most frequently involved sites are the temporal, periventricular, and periaqueductal grey matter as well as the hippocampus, hypo-

thalamus, and basal ganglia. Histologically, the nodules are made up of microglia that stain strongly positive with PAS. The most frequent neurologic manifestations of Whipple’s disease are dementia, ophthalmoplegia, myoclonus, and hypothalamic dysfunction. The dementia progresses slowly and is characterized by memory impairment, confusion, personality change, paranoia, emotional instability, and depression.243–249 An unusual syndrome of synchronized eye movements and contractions of the jaw, known as oculomasticatory myorrhythmia, is sometimes seen and may be unique to Whipple’s disease.250,251 Although PCR diagnosis of Whipple’s disease is possible, it is available only on a research basis and, because of the wide range in the differential diagnosis of degenerative CNS diseases, tissue biopsy is generally required for diagnosis. CNS radiographic studies consistent with Whipple’s disease occurring in the setting of biopsy proven systemic Whipple’s disease are also sufficiently diagnostic. The initial treatment of CNS Whipple’s disease is ceftriaxone at a dose of 2 g IV twice daily, with streptomycin at 1 gram IM daily for 14 days, followed by trimethoprim/ sulfamethoxazole at 160 mg to 800 mg orally two to three times daily for at least 1 year.252,253 Intravenous trimethoprim/sulfamethoxazole at a dose of 960 mg twice daily for 2 weeks can be used in place of ceftriaxone.197 Two weeks of daily IM procaine penicillin G, one to two million units, together with streptomycin at 1 g IM daily has also been recommended,254 but the superior CNS penetration of ceftriaxone and trimethoprim/sulfamethoxazole would seem critical. Some clinicians continue treatment for 2 years to life. Unfortunately, the overall prognosis of CNS Whipple’s disease is not good. With antibiotic therapy progression can usually be stopped, but significant clinical improvement is limited 255 and relapses are frequent. Amebic Encephalitis A dramatic and almost uniformly fatal primary meningoencephalitis can be seen with infection caused by the free-living ameba Naegleria fowleri. These free-living amebae are widespread in nature, particularly in the upper surface layers of lakes in warm climates. In animal models it can be shown that the amebae are capable of invading through the nasal cavity along the blood vessels associated with the olfactory nerves and reach the frontal lobes and the surrounding meninges where they rapidly produce a highly necrotizing destructive encephalitis. Clinically, patients present with sudden onset of high fever, photophobia, headaches, with progression to obtundation relatively quickly. There is classically a history of swimming in warm, freshwater lakes. Because of the olfactory involvement, there may be alterations of smell or taste. Otherwise nonspecific symptoms such as confusion, irritability, restlessness, and seizures with rapid progression to delirium, stupor, and coma unfortunately are the rule. Examination of the spinal fluid shows leukocytosis with neutrophil predominance, low glucose

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levels, and elevated protein. However, Gram stain and culture results are negative, but if the diagnosis is suspected one can examine the CSF unstained with a slide warmer to look for the typical, mobile, ameboid motion of the trophozoites. Radiographically the frontal lobe involvement is readily seen on MRI but the diagnosis is unfortunately often delayed because of the rarity of the condition and paucity of immediately diagnostic signs. Only a small number of patients have been reported to have survived and all received amphotericin B to which the Naegleria are susceptible in vitro.256–258 The optimal treatment regimen is not known for this condition and some authors recommend maximal systemic doses of amphotericin B with intracisternal amphotericin B and concomitant rifampin or tetracycline.255 Progressive Multifocal Leukoencephalopathy Progressive multifocal leukoencephalopathy (PML) is a progressive, severe, usually fatal demyelinating disease that is primarily seen in highly immunosuppressed patients. Before the HIV epidemic, the reported incidence was 1.5 cases per 10 million people. By 1987, with the HIV epidemic, the incidence had increased to 6.1 cases per 10 million persons259 and the risk of PML in HIV infected persons was estimated to be 80- to 100-fold higher than that of the general population.260 PML is caused by JC virus, a small nonenveloped DNA virus, closely related to two other polyomavirus, BK virus and the simian virus SV40. Both BK and JC were isolated in the early 1970s, JC from a patient with PML and BK from the urine of renal transplant patients.261,262 These viruses share approximately 75% DNA homology and 70% homology with SV40.263,264 Based on serologic studies, it appears that approximately 60% to 80% of adults in the United States have been infected with one or both and that infection with BK virus occurs in early childhood at approximately age 3 to 4 years while infection with JC virus occurs in the age range of 10 to 14 years.53,265,266 It is believed that both viruses remain clinically latent in renal tissue and other tissues in normal persons following primary infection. Approximately 30% to 50% of normal persons have detectable BK or JC virus sequences demonstrable by PCR and other methods in renal tissue obtained at surgery or autopsy.267–269 Asymptomatic viruria with BK virus has been detected in up to 3% of pregnant woman and increases significantly in immunosuppressed patient populations. JC virus has been detected in the blood of up to 22% of immunosuppressed patients in the absence of PML.270,271 Even normal brain tissue from immunologically normal patients with no evidence of PML has been found to contain JC virus DNA by sensitive PCR methods.272–275 Thus, it is believed that under conditions of immunosuppression, replication of JC virus in the CNS increases and depending on factors not understood at this time, may ultimately result in clinical disease.

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PML characteristically presents with progressive focal neurologic defects, primarily hemiparesis, visual field defects, and cognitive deterioration.276–288 As the disease progresses, aphasia, ataxia, and cranial nerve defects may occur, ultimately resulting in cortical blindness, quadriparesis, profound dementia, and coma. The average duration of survival is approximately 4 months, although a subset of 5% to 10% of patients, even with HIV, lives for a year or more. The diagnosis is made from a combination of the clinical picture with characteristic findings on CT or MRI (Figs. 12-12A and B) Definitive diagnosis requires brain biopsy and histologic examination, which should demonstrate characteristic cytopathic changes in the oligodendrocytes. These cells typically contain a homogeneous basophilic nuclear inclusion and virus can be demonstrated by in situ hybridization. Involvement of the oligodendrocytes ultimately leads to widespread, but patchy, multifocal demyelination which correlates with the patients clinical status. Virus particles can be demonstrated in the inclusions by electronmicroscopy.289,290 Not surprisingly, many studies have attempted to use PCR diagnostically to detect JC virus DNA by less invasive means, using CSF rather than brain biopsy. JC virus can be detected in the CSF of most patients with PML, whether immunosuppressed or not.271,291–293 Caution must be observed in interpreting these results. For example, McGuire and colleagues291 found that CSF of 24 of 26 patients with HIV-1 and PML had JC virus sequences present, but so did ten of 114 patients with HIV-1 without evidence of neurologic disease. In general, patients with PML are highly likely to have JC virus DNA in their CSF as compared with normal or immunosuppressed patients without PML.294–296 However, one recent study found JC virus DNA in the CSF of 12 of 12 patients with HIV-1 and no evidence of PML, but zero of 11 patients with multiple sclerosis (MS), if the test was made sufficiently sensitive.297 Despite the sensitivity of PCR testing for JC virus, occasional cases of PML have been observed in which no JC virus can be found even in brain tissue at autopsy.297 It is possible these cases may be due to the closely related polyoma virus, SV40.298 A relatively new agent for the treatment of CMV infection, cidofovir, does have activity against polyoma viruses in vitro and in animal models, and may be of benefit in the treatment of PML.299 There is no proven effective therapy for PML at this time. Initial reports of success with cytosine arabinoside (ara-C) were not supported by a recent clinical trial.300 In fact, a recent nonblinded, multicenter trial showed that one year survival with PML was 61% in patients with HIV-1 who received HAART with cidofovir, compared with 29% in those who received HAART without cidofovir.301 Thus although blinded studies are needed to confirm this observation, cidofovir should be strongly considered in the empiric treatment of PML, keeping in mind its significant renal toxicity. Other agents such as camptothecin and analogs, which inhibit topoisomerase I, are currently under consideration.

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A B Figure 12-12. A, Axial, high convexity, T2-weighted FLAIR image demonstrates focally increased T2signal within the deep white matter bilaterally. The effects are confined predominantly to white matter with minimal cortical involvement and, as seen in (B), little or no enhancement. There is little or no mass effect. B, Axial, high-convexity, gadolinium-enhanced MR image demonstrates low-density changes (cystic leukomalacia) within the white matter of the frontal regions bilaterally. There is no significant enhancement of the lesion or the margins surrounding the lesion. These two findings are indicative of a white matter destructive process, which in this case, is related to progressive multifocal leukoencephalopathy associated with a JC (papova) virus encephalitis in an immunosuppressed host. (Courtesy of Ronald Quisling, MD, University of Florida.)

Spinal Epidural Abscess Epidemiology Spinal epidural abscess (SEA) is a rare clinical entity with a prevalence of between 0.2 and 2.0 per 10,000 hospital admissions.302–305 SEA is more common in the elderly, with a peak incidence during the 6th and 7th decades.302,303 The disease is rare among children and typically affects patients whose comorbid conditions predispose them to immunocompromised states.302–304,306 A recent increase in the incidence of SEA has been noted and is thought to be secondary to the aging population, increased numbers of IV drug abusers, the prevalence of AIDS, and the increased number of spinal surgical procedures.303,304 Risk Factors The majority of patients who develop an SEA have a recognizable risk factor.305,307 In one large review of the literature, encompassing 254 cases, the following frequencies of comorbid conditions were observed: osteomyelitis/diskitis 18%;

diabetes 16%; degenerative joint disease of the spine 11%; IV drug abuse 7%; alcoholism 4%, and cancer 4%.305 The spectrum of risk factors is fairly consistent between reports of other large case series.302–304,307 Certain comorbid states such as diabetes, chronic renal failure, and alcoholism result in an immunodeficient state that predisposes a patient to the development of a spinal abscess.304,308 Other risk factors have a more direct role in the development of SEAs. Diskitis and the bacteremia associated with IV drug abuse directly seed the epidural space with pathogens and result in the epidural infection.302 Pathophysiology The formation of SEAs can be spontaneous or secondary to direct inoculation of pathogen. The most common cause of the spontaneous variety is hematogenous spread from infections of the skin, respiratory tract, urinary tract, or oral cavity.302 Other causes of spontaneous abscess formation include extension from pre-existing diskitis/vertebral osteomyelitis or extension of a paraspinal abscess.302 Secondary causes include postoperative infections (16% of all

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SEAs) and infections associated with epidural anesthesia catheters.302 Some series suggest that blunt spinal trauma precedes the development of SEA formation in 15% to 35% of cases.302,309 The authors propose that the trauma results in an epidural hematoma that then becomes secondarily infected.302 A relationship exists between the underlying cause of the epidural abscess and its location within the spinal canal.302–304 The majority of spontaneous epidural abscesses are the result of hematogenously spread bacteria and the resultant SEA is usually located posteriorly within the spinal canal.302–304 Conversely, epidural abscesses secondary to preexisting vertebral osteomyelitis are confined to the anterior spinal canal.302–304 The segregation and isolation of abscesses to the anterior or posterior spinal canal is thought to be secondary to septations within the epidural fat.303 These septations not only divide the epidural space into an anterior and posterior compartment but also divide the space longitudinally.303 The longitudinal septations usually limit the extent of epidural abscess formation to 3 to 4 vertebral levels.303 Postsurgical SEAs often involve multiple compartments, extending several levels and circumferentially around the spinal cord, secondary to disruption of the epidural septations.304 The neurologic compromise caused by epidural abscess formation can be slowly progressive or dramatically acute in nature with complete paralysis in a matter of hours.303,304,308,309 The underlying cause of neurologic injury is thought to be secondary to both compression of the neural elements and vascular thrombosis.303,304,308–310 Animal studies suggest that early neurologic dysfunction is the result of neural compression, with irreversible vascular compromise occurring later.310 Clinical Features and Diagnostic Considerations The classic clinical presentation of an SEA is back pain and fever associated with nerve root symptoms followed by limb weakness.302 In reality, the presentation is highly variable and most patients are initially misdiagnosed.305 The most common symptom associated with an SEA is back pain, present in 90% of patients.302,304,305,307,308 Other common findings include fever (61%), paresis (53%), bowel or bladder dysfunction (36%), sepsis (17%), radiculopathy (12%) and plegia (14%).307 Point tenderness over the involved vertebral levels is present in about one quarter of patients and is associated with underlying bony involvement.305 The most common location of SEA formation is in the lumbar region, but thoracic and cervical involvement is not uncommon.302 Time between symptom onset and presentation is highly variable and does not correlate well with intra-operative findings.311 Neurologic deficits are present in the majority of patients at the time of presentation.302,305 Neurologic decline can occur chronically over months or precipitously over a few hours.302,304,305

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The most consistent laboratory abnormality is an elevated erythrocyte sedimentation rate, which is present virtually 100% of the time.304,305,311 Leukocytosis is found in roughly 75% of patients.305 Results of cerebrospinal fluid analysis are variable, ranging from normal to frank pus.304 Blood cultures have been reported to be positive in up to 60% of cases.303 When the diagnosis of SEA is suspected, an imaging study of the spine should be performed.302 The imaging study of choice is a contrast enhanced MRI scan, which gives superior soft tissue resolution when compared to CT myelography and is noninvasive.302,309 After radiologic diagnosis, consultation with a neurosurgeon should be undertaken.304 Microbiology The spectrum of microbial pathogens capable of causing SEA formation is wide.302 However, Staph. aureus is responsible for the overwhelming majority of cases, with a reported incidence of 60% to 70% of culture positive abscesses.302,304,305,307,309 In one large review of pyogenic infections, Staph. aureus accounted for 62%, other gram-positive cocci 10%, gram-negative species 18%, and anaerobes 2% of culture positive spinal abscesses.302 Mycobacterium has been reported as the cause in up to 25% of infections in some series.302 Other less common causes include Brucella, Actinomyces, and fungal etiologies such as Cryptococcus and Aspergillus.302 Treatment Most authorities consider the treatment of SEAs to be surgical evacuation followed by prolonged parenteral antibiotics.302–304,307,308 SEA carries with it a high mortality rate and a significant long-term neurologic morbidity rate.305,307 The mortality rate is estimated to be 14%, and 35% to 40% of patients will have residual neurologic deficits.302,303,305 Prognosis depends on the clinical and neurologic condition of the patient at the time of presentation.302 Patients presenting with sepsis or plegia have higher mortality and long-term morbidity rates.302,305 Some authors have reported success treating SEAs with medical therapy alone.309 The majority of these patients fell into one of three categories: (1) panspinal infections not amenable to drainage, (2) poor operative candidates secondary to poor health, or (3) complete paralysis for greater than 24 hours.308 In order to treat patients nonoperatively, the clinician must obtain the organism by another means such as blood culture or needle aspirate, be willing to perform serial neurologic exams, or monitor the response to therapy with serial MRI scans.308 Caution is warranted in treating spinal epidural abscesses nonoperatively.309 Culture specific antibiotic therapy failed to protect 9 of 39 patients in one series from developing an acute irreversible neurologic deficit.304

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Vertebral Osteomyelitis Epidemiology Vertebral osteomyelitis (VO) is another relatively uncommon clinical entity with an estimated population incidence of 1/250,000.312 Pyogenic spinal infections account for approximately 2% to 4% of all cases of osteomyelitis, ranking third behind infections of the femur and tibia in adults.313,314 VO is the most common hematogenously acquired osteomyelitis.313,314 The incidence of VO appears to have increased in proportion to the increase in the number of immunocompromised patients over the past decade.313,315,316 VO is characteristically a disease of older men, occurring with a two-fold higher incidence in men, with 50% of cases occurring in patients older than fifty years.314,315,317 VO occurring in conjunction with IV drug abuse accounts for the majority of cases in younger patients.314,315 There are a number of known risk factors for the development of spontaneous VO, which include diabetes mellitus, systemic steroid use, history of a genitourinary infection or procedure, bacteremia, protein calorie malnutrition, IV drug abuse, and malignancy.313,314,317–319 Advanced age may be an independent risk factor for the development of the disorder.320 The common denominator in each of these predisposing conditions appears to be a deficiency in some aspect of cellular or humoral immunity.319 Postsurgical VO accounts for approximately 2.5% of all spinal osteomyelitis and has been shown to have an increased incidence in malnourished patients, diabetics, and patients on steroid therapy.317,318,321 The overall incidence of diabetes in patients with VO is between 18% and 25%.313 As the prevalence of AIDS has increased, there has been resurgence in the incidence of spinal tuberculosis and the emergence of other fungal causes of VO.319 IV drug abusers have accounted for over half the cases of pyogenic spinal osteomyelitis in some large series of patients.315 Prolonged steroid use is a risk factor not only for the more common bacterial VO, but is also a risk factor for atypical mycobacterium causes.319,322 In summary, patients at risk for VO are typically of advanced age, diabetic (18% to 25%), have other immunodeficient states, have a history of a recent bacteremic state (50%), or urinary tract infection or procedure (30%).313,314 An exception to the typical presentation is the young male IV drug abuser.315 Pathogenesis Spontaneous VO results from hematogenous spread of organisms through the segmental spinal arteries to the subchondral plate region of the vertebral body adjacent to the disk space.318,320 In adults, the nidus of infection begins in the vertebral bodies at the level of the end arteriolar arcades and, after endplate destruction, spreads secondarily

into the avascular disk space.313,320 In children, the disk space contains vascular channels that allow primary seeding of the intervertebral disk.313,320 Segmental spinal arteries typically bifurcate to supply adjacent vertebral segments; this bifurcation is thought to account for the fact that VO typically involves two adjacent vertebrae and the intervening disk space.320 Postoperative VO results from direct inoculation at the time of surgery.313,318 Surgical teams and the patient’s skin flora are the principal sources of wound contamination.318 Unlike spontaneous VO, the nidus of infection in postoperative patients is often the disk space.313,318 Other forms of direct inoculation can result in VO and include decubitus ulcers and trauma.317 Clinical Presentation and Diagnostic Considerations The most common presentation of VO is pain, occurring in more than 90% of patients.314,319 The pain is localized, continuous, and classically unrelated to movement or position.314 Nearly all spinal infections are associated with tenderness to palpation over the involved level.314,319 The pain is most commonly over the lumbar spine due to the fact that nearly 50% of VO cases are localized to the lumbar vertebrae.313,314 There is an increased incidence of cervical VO in IV drug abusers and thoracic disease in tuberculous osteomyelitis.313 The presence of radiculopathy, positive straight leg raise, and neurologic deficit (4% to 16%), are less reliable and often indicate the presence of epidural involvement.314,319 Fever is found in approximately half of patients with pyogenic spinal osteomyelitis.318 Constitutional symptoms, including malaise, night sweats, and anorexia have been reported.314 VO has an insidious onset and has proven to be a diagnostic challenge.320 In several large patient series, the delay between the onset of symptoms and eventual diagnosis has ranged from 3 weeks to 3 months.314,315,320,323 These delays in diagnosis have resulted in significant neurologic morbidity.320 When VO is suspected, a diagnostic work-up should proceed in a logical manner. Basic laboratory work-up should include a complete cell count, ESR, and blood cultures. A leukocytosis is found in less than half of patients with VO.314 The most common laboratory abnormality is an elevated ESR, with 90% of cases being between 20 and 100 mm/hr.314 Blood cultures are positive in 25% of cases and when positive may mitigate the need for an invasive diagnostic biopsy.314,317 The principal diagnostic modality in VO is spinal imaging. Plain radiologic findings include disk space narrowing and vertebral endplate changes that usually become apparent 2 to 4 weeks after symptom onset in approximately 80% of patients.313,314,318 Technetium99m bone scanning combined with gallium scanning has a 90% sensitivity and specificity for VO.324 MRI imaging is the most sensitive and

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specific imaging modality for VO and has the added benefit of providing detail regarding the presence of an epidural abscess, paraspinal abscess, or other sources of neural compromise.313,325 Characteristic MRI changes include decreased T1 signal and increased T2 signal of the involved vertebral endplates and disk space.325 Once a radiographic diagnosis of VO has been made, optimal pharmacologic treatment requires that the infecting microbe be identified and antibiotic susceptibilities be determined.314 A positive blood culture is present 25% of the time, correlates strongly with the responsible spinal pathogen, and can direct antibiotic therapy without the need for invasive procedures.314,315 When blood cultures are negative, biopsy of the infected vertebra is mandatory.313,314,318 A CT-guided needle biopsy can be used to make a definitive microbiologic diagnosis in most cases and this technique is successful 60% to 90% of the time.314 An open biopsy should be considered when both blood cultures and CT aspirates are negative.318 A skin test for tuberculosis should be undertaken in all patients and CT aspirates or biopsy material should be sent for routine fungal stains and cultures.318,323

Microbiology There exists in the literature an enormous array of bacterial and nonbacterial pathogens that have been reported to cause VO.316,317,319,323,326,327 The most common pathogen is Staph. aureus, found in up to 60% of cases.313,317 In one large review of the literature, the etiology of culture positive pyogenic VO was found to be due to gram-positive aerobic cocci 68% of the time, gram-negative aerobic bacilli in 29% of the patients, and the remaining 3% were due to anaerobic bacteria.317 Tuberculous osteomyelitis is often indistinguishable on a radiologic basis from bacterial infection and must be in the differential of spinalosteomyelitis.316 Coccidioides immitis, Blastomyces dermatiditis, Cryptococcus neoformans, Aspergillus species, and other less common fungi have all been associated with VO.317 Stratification of patients by known risk factors has revealed some interesting correlations between predisposing conditions and the microbiology of VO.319 Pseudomonas and Staph. aureus are the most prevalent pathogens in IV drug abusers and occur at roughly equal rates.317 In elderly males with urinary tract infections or following invasive urological procedures, the most common pathogens are E. coli and Proteus species317; postoperative spinal infections are usually caused by Staph. aureus.317 There is a high prevalence of mycobacterial infections in countries where tuberculosis is endemic and in the growing AIDS population.317,319 Patients on long term steroid treatment are susceptible to infections caused by atypical mycobacterium and Aspergillus.319,322,326,327 VO is overwhelmingly caused by a single organism; however, decubitus ulceration leading to direct spread of infection is often polymicrobial in nature.317,319

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Treatment Focused antibiotic therapy, spinal immobilization, and when necessary surgical interventions are the mainstays of treatment for VO.313,314,317 Seventy-five percent of patients with spinal osteomyelitis can be managed without surgical intervention.313 Prolonged courses of parental antibiotics directed by specific culture results and antibiotic susceptibilities are the rule.317 One large review of the literature has shown that four weeks of high dose IV antibiotics is sufficient to treat pyogenic spinal osteomyelitis as long as the following criteria are met: (1) there are no undrained abscesses; (2) the patient is clinically stable; and (3) the ESR has decreased to one half its original value.317 Tuberculous VO requires an average of 12 months treatment with a combination of isoniazid, rifampin, ethambutol, and pyrazinamide depending on regional susceptibility.313 Treatment of other less common bacterial and fungal causes of VO should be tailored to the individual pathogen and to regional susceptibilities. The indications for surgical intervention in spinal osteomyelitis are the presence of a neurologic deficit, spinal instability, unresponsiveness to medical therapy, or a nondiagnostic CT-guided biopsy.315 In addition, surgery is recommended for the drainage of epidural or paraspinal abscesses that often accompany VO.317 The goals of surgery are decompression of the neural elements, correction of spinal deformity, debridement of necrotic tissue, and the promotion of long term stability.313,315,320,323 A variety of surgical approaches have been described in the literature, each with its own advantages and disadvantages.313,315,323 Most recent surgical reviews recommend early instrumentation and fusion at the time of the initial operation to facilitate ambulation and avoid the complications of prolonged bedrest.313,315,323

External Ventricular Drainage Infectious Considerations External ventricular drainage (ventriculostomy) devices are an integral aspect of the intensive care management of neurosurgical patients. Common indications for their use include management of hydrocephalus, elevated intracranial pressure, intracranial hemorrhage, and the administration of intrathecal medications.328–330 External ventricular drains (EVDs) provide diagnostic information as well as providing therapeutic cerebrospinal fluid drainage.328–330 The most common complication involving the use of EVDs is infection. The reported infection rate is 0% to 27%.328,329 Risk factors for the development of an EVD– associated infection include hemorrhage, neurosurgical operation, and irrigation or manipulation of the drainage system.328,330 Conflicting data exist regarding the association between the duration of ventricular drainage and the rate of

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EVD–associated infections.328,329,331 Some clinical series have shown a linear relationship between infection and duration of ventricular drainage.332,333 Several of these authors have advocated the routine changing of ventricular catheters after day five in order to lower the risk of infection.333 Other studies have suggested that the duration of monitoring is not a risk factor associated with infection. In contrast, these later studies have shown a constant daily rate of infection that actually decreases after day 10 or 11 of drainage.334 The role of perioperative and prophylactic antibiotics in the prevention of EVD–associated infections has been extensively debated. Alleyne and colleagues reviewed over 300 patients who received either daily prophylactic antibiotics or perioperative antibiotics alone and found no significant difference in the infection rate between the two groups.328

Low infection rates associated with prolonged EVD placement have been reported.328,329,331 Factors thought to be important in preventing infection include perioperative antibiotic administration prior to skin incision, tunneling of the ventricular catheter, surgical skin prep, closed ventricular drainage system, and meticulous sterile nursing care.328–331,335 Perioperative antibiotics should be chosen for their efficacy against skin flora, keeping in mind that Staph. epidermidis is the most frequent cause of EVD–associated infections.330,335 Recently, antibiotic impregnated catheters have been manufactured for a variety of applications.336 Preliminary use of ventriculostomy catheters has been promising but further study is needed to validate the efficacy of this emerging technology.

P earls 1. S. pneumoniae is the most common cause of bacterial meningitis in the United States today in all age groups except infants in the immediate neonatal period. 2. Pneumococcal meningitis is the most common form of recurrent meningitis in patients who have CSF leaks. 3. Following the introduction of the H. influenzae type b vaccine there has been a profound reduction in the number of invasive infections due to H. influenzae in the United States. For example, Murphy and colleagues5 found a reduction of 85% to 92% in the incidence of invasive H. influenzae type b disease between 1983 to 1984 and 1991 after widespread use of the vaccine. 4. . . . . gram-negative meningitis is highly significant in hospital acquired cases of meningitis. The vast majority of these cases are seen following neurocranial surgery, spinal surgery, and in patients who have suffered head trauma. 5. On entering into the subarachnoid space, bacterial replication proceeds virtually unchecked by host defense mechanisms. By virtue of the blood-brain barrier, both immunoglobulin and complement levels are far lower in CSF than in serum and interstitial fluid. In addition, leukocyte proteases derived from an initial influx of leukocytes have actually been shown to degrade complement components in CSF from patients with meningitis. 6. In a review of 493 episodes, Durand and associates37 found that 95% of the patients with bacterial meningitis had fever greater than 37.7°C on admission; neck stiffness was present in 88% of patients. Only 22% were alert, while 51% were confused or lethargic and 22% were responsive only to pain. Within the

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first 24 to 48 hours of onset, 29% had focal seizures and/or focal neurologic findings. Glucose enters the cerebrospinal fluid by transport through the choroid plexus and endothelium of the capillaries in the subarachnoid space. CSF levels of glucose are thus a function of active transport of glucose and the rate of glucose consumption within the CNS. The level of CSF glucose under normal conditions in normal subjects is 60% to 70% of the blood glucose level. However, a study by Skipper and Davis44 showed this CSF/serum ratio was only accurate when the serum glucose was between 89 and 115 mg/dL. St. Louis encephalitis is found throughout the Midwest and South, as far north as New York and Michigan with cases even reported on the West Coast. Eastern equine encephalitis, however, is essentially confined to the Southeast, and California encephalitis and La Crosse encephalitis tend to be seen primarily in the northern Midwest. At least 12 persons were hospitalized with confirmed West Nile virus infection in the summer of 2000, most of them in New York City. The clinical presentation of viral meningitis includes fever, stiff neck, photophobia, and varying degrees of nonspecific symptoms such as malaise, myalgias, nausea, vomiting, abdominal pain, or diarrhea. The presence of impairment of consciousness such as obtundation, disorientation, seizures or localized neurologic signs or symptoms should suggest brain parenchymal involvement and a diagnosis of encephalitis or meningoencephalitis. Because of the rarity of complications from acyclovir it is difficult to argue with presumptive treatment and brain biopsy certainly is not justified to prove the presence of herpes encephalitis before treatment.

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12. Despite its chronicity and high level of bacteremia, endocarditis accounts for only 1% to 5% of cases of brain abscess.96 A significant number of brain abscesses are associated with penetrating trauma such as gunshot wounds, depressed skull fractures with retained bone fragments, cranial penetration from objects such as pencils, animal bites, or even as a complication of cervical traction associated with pin site infection. In approximately 25% of cases no underlying etiology can be found. 13. The most common fungal pathogens of the central nervous system include the yeast Cryptococcus and the dimorphic fungi Histoplasma, Coccidioides, and Blastomyces. In immunocompromised patients, Aspergillosis, Candida, and the Mucorales may be important pathogens as well. 14. The diagnosis of cryptococcal meningitis is usually not difficult. The classic and time-honored method for diagnosis is demonstration of the yeast in spinal fluid by India ink stain. Microscopically, the India ink particles serve to outline the very large clear polysaccharide capsule surrounding the yeast. The test result is positive in over 90% of patients with HIV, but in only 50% of patients with normal immunity. 15. The most serious form of disseminated coccidioidal infection is coccidioidal meningitis. Without treatment it is nearly uniformly fatal within 2 years of diagnosis.123 Observational studies suggest about 80% of patients in whom meningitis develops become symptomatic within 6 months of the initial infection. 16. The genuses Rhizopus, Mucor, and Rhizomucor may invade the CNS by direct extension or from hematogenous spread. In patients with diabetes, this disease typically presents as rhinocerebral mucor.

References 1. Ryan MW, Antonelli PJ: Pneumococcal antibiotic resistance and rates of meningitis in children. Laryngoscope 2000;110(6):961–964. 2. Schuchat A, Robinson K, Wenger JD, et al: Bacterial meningitis in the United States in 1995. Active surveillance team. N Engl J Med 1997;337(14):970–976. 3. Sherry B, Emanuel I, Kronmal RA, et al: Interannual variation of the incidence of haemophilus influenzae type b meningitis. JAMA 1989;261(13):1924–1929. 4. Fothergill LD, Wright J. Influenzal meningitis: Relation of age incidence to bacterial power of blood against causal organism. J Immunol 1933;24:273–284. 5. Murphy TV, White KE, Pastor P, et al: Declining incidence of haemophilus influenzae type b disease since introduction of vaccination [see comments]. JAMA 1993;269(2):246–248. 6. Unhanand M, Mustafa MM, McCracken GH Jr, Nelson JD: Gramnegative enteric bacillary meningitis: A twenty-one-year experience. J Pediatr 1993;122(1):15–21. 7. Sarff LD, McCracken GH, Schiffer MS, et al: Epidemiology of escherichia coli K1 in healthy and diseased newborns. Lancet 1975;1(7916):1099–1104.

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Patients are generally predisposed to this complication if their serum glucose has remained uncontrolled, and they are acidotic for several weeks. Initial symptoms usually include sinus pain, headache, fever, and nasal stuffiness and discharge, which quickly progresses to facial cellulitis, swelling, proptosis, cavernous sinus thrombosis and, if not treated, death. Interestingly, no change in the incidence of HIV encephalopathy was seen between 1996 and 1999, during the era of HAART treatment. The diagnosis of malaria is made from examination of the blood smear, provided that the diagnosis is considered as a differential diagnostic possibility in a patient with altered consciousness and fever. Examination of the blood smear is highly accurate. Because the level of parasitemia in falciparum malaria tends to be high, generally greater than 5%, it is not hard to find the ring forms characteristic of the disease. Serologic tests for syphilis are generally divided into two different types: treponemal tests and nontreponemal tests. The nontreponemal tests are IgG or IgM antibodies that are directed at lipid antigens, which were originally extracts of cardiolipin from beef heart or liver. If left untreated, the Lyme disease spirochete becomes sequestered and persists in certain tissues such as the nervous system, joints, heart, and even the skin. In some patients with meningitis, particularly in Europe where the disease is caused by a different species of spirochete, significant neurologic abnormalities develop including cranial neuritis, which can present as a isolated facial palsy (motor and sensory), radicular mononeuritis multiplex, or myelitis alone or in varying combinations.

8. Sarff LD, Platt LH, McCracken GH Jr: Cerebrospinal fluid evaluation in neonates: Comparison of high-risk infants with and without meningitis. J Pediatr 1976;88(3):473–477. 9. Smith AL: Neonatal bacterial meningitis. In Scheld WM, Whitley RJ, Durack DT (eds): Infections of the Central Nervous System, 2nd ed. Philadelphia, Lippincott-Raven, 1997, pp 313–334. 10. Dawson KG, Emerson JC, Burns JL: Fifteen years of experience with bacterial meningitis. Pediatr Infect Dis J 1999;18(9):816–822. 11. Musser JM, Mattingly SJ, Quentin R, Goudeau A, Selander RK: Identification of a high-virulence clone of type iii streptococcus agalactiae (group b streptococcus) causing invasive neonatal disease. Proc Natl Acad Sci USA 1989;86(12):4731–4735. 12. Kallstrom H, Liszewski MK, Atkinson JP, Jonsson AB: Membrane cofactor protein (MCP or CD46) is a cellular pilus receptor for pathogenic neisseria. Mol Microbiol 1997;25(4):639–647. 13. Virji M, Alexandrescu C, Ferguson DJ, Saunders JR, Moxon ER: Variations in the expression of pili: The effect on adherence of neisseria meningitidis to human epithelial and endothelial cells. Mol Microbiol 1992;6(10):1271–1279. 14. Virji M, Watt SM, Barker S, Makepeace K, Doyonnas R: The Ndomain of the human CD66a adhesion molecule is a target for opa proteins of neisseria meningitidis and neisseria gonorrhoeae. Mol Microbiol 1996;22:929–939.

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270. Dubois V, Dutronc H, Lafon ME, et al: Latency and reactivation of JC virus in peripheral blood of human immunodeficiency virus type 1infected patients. J Clin Microbiol 1997;35(9):2288–2292. 271. Koralnik IJ, Boden D, Mai VX, Lord CI, Letvin NL: JC virus DNA load in patients with and without progressive multifocal leukoencephalopathy. Neurology 1999;52(2):253–260. 272. Elsner C, Dorries K: Evidence of human polyomavirus BK and JC infection in normal brain tissue. Virology 1992;191(1):72–80. 273. Quinlivan EB, Norris M, Bouldin TW, et al: Subclinical central nervous system infection with JC virus in patients with AIDS. J Infect Dis 1992;166(1):80–85. 274. Ferrante P, Caldarelli-Stefano R, Omodeo-Zorini E, Vago L, Boldorini R, Costanzi G: PCR detection of JC virus DNA in brain tissue from patients with and without progressive multifocal leukoencephalopathy. J Med Virol 1995;47(3):219–225. 275. White FA III, Ishaq M, Stoner GL, Frisque RJ: JC virus DNA is present in many human brain samples from patients without progressive multifocal leukoencephalopathy. J Virol 1992;66(10):5726–5734. 276. Astrom K-E, Mancall EL, Richardson EP Jr: Progressive multifocal leukoencephalopathy: A hitherto unrecognized complication of chronic lymphatic leukemia and Hodgkin’s disease. Brain 1958;(81): 93–110. 277. Richardson EP Jr: Progressive multifocal leukoencephalopathy. N Engl J Med 1961;(265):815–823. 278. Newton P, Aldridge RD, Lessells AM, Best PV: Progressive multifocal leukoencephalopathy complicating systemic lupus erythematosus. Arthritis Rheum 1986;29(3):337–343. 279. Rockwell D, Ruben FL, Winkelstein A, Mendelow H: Absence of immune deficiencies in a case of progressive multifocal leukoencephalopathy. Am J Med 1976;61(3):433–436. 280. Bolton CF, Rozdilsky B: Primary progressive multifocal leukoencephalopathy. A case report. Neurology 1971;21(1):72–77. 281. Fermaglich J, Hardman JM, Earle KM: Spontaneous progressive multifocal leukoencephalopathy. Neurology 1970;20(5):479–484. 282. Holman RC, Janssen RS, Buehler JW, Zelasky MT, Hooper WC: Epidemiology of progressive multifocal leukoencephalopathy in the United States: Analysis of national mortality and AIDS surveillance data [see comments]. Neurology 1991;41(11):1733–1736. 283. Berger JR, Kaszovitz B, Post MJ, Dickinson G: Progressive multifocal leukoencephalopathy associated with human immunodeficiency virus infection. A review of the literature with a report of sixteen cases. Ann Intern Med 1987;107(1):78–87. 284. Brooks BR, Walker DL: Progressive multifocal leukoencephalopathy. Neurol Clin 1984;2(2):299–313. 285. Gillespie SM, Chang Y, Lemp G, et al: Progressive multifocal leukoencephalopathy in persons infected with human immunodeficiency virus, San Francisco, 1981–1989. Ann Neurol 1991;30(4):597–604. 286. von Einsiedel RW, Fife TD, Aksamit AJ, et al: Progressive multifocal leukoencephalopathy in AIDS: A clinicopathologic study and review of the literature. J Neurol 1993;240(7):391–406. 287. Hair LS, Nuovo G, Powers JM, Sisti MB, Britton CB, Miller JR: Progressive multifocal leukoencephalopathy in patients with human immunodeficiency virus. Hum Pathol 1992;23(6):663–667. 288. Krupp LB, Lipton RB, Swerdlow ML, Leeds NE, Llena J: Progressive multifocal leukoencephalopathy: Clinical and radiographic features. Ann Neurol 1985;17(4):344–349. 289. Silverman L, Rubinstein LJ: Electron microscopic observations on a case of progressive multifocal leukoencephalopathy. Acta Neuropathol (Berl) 1965;5(2):215–224. 290. ZuRhein GM, Chou S-M: Particles resembling papova viruses in human cerebral demyelinating disease. Science 1965;(148):1477– 1479. 291. McGuire D, Barhite S, Hollander H, Miles M: JC virus DNA in cerebrospinal fluid of human immunodeficiency virus-infected patients: predictive value for progressive multifocal leukoencephalopathy. Ann Neurol 1995;37(3):395–399.

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292. Vago L, Cinque P, Sala E, et al: JCV-DNA and BKV-DNA in the CNS tissue and CSF of AIDS patients and normal subjects. Study of 41 cases and review of the literature. J Acquir Immune Defic Syndr Hum Retrovirol 1996;12(2):139–146. 293. Hammarin AL, Bogdanovic G, Svedhem V, Pirskanen R, Morfeldt L, Grandien M: Analysis of PCR as a tool for detection of JC virus DNA in cerebrospinal fluid for diagnosis of progressive multifocal leukoencephalopathy. J Clin Microbiol 1996;34(12):2929–2932. 294. Cinque P, Vago L, Dahl H, et al: Polymerase chain reaction on cerebrospinal fluid for diagnosis of virus-associated opportunistic diseases of the central nervous system in HIV-infected patients. AIDS 1996;10(9):951–958. 295. De Luca A, Cingolani A, Linzalone A, et al: Improved detection of JC virus DNA in cerebrospinal fluid for diagnosis of AIDS-related progressive multifocal leukoencephalopathy. J Clin Microbiol 1996;34(5):1343–1346. 296. Fong IW, Britton CB, Luinstra KE, Toma E, Mahony JB: Diagnostic value of detecting JC virus DNA in cerebrospinal fluid of patients with progressive multifocal leukoencephalopathy. J Clin Microbiol 1995;33(2):484–486. 297. Dorries K, Arendt G, Eggers C, Roggendorf W, Dorries R: Nucleic acid detection as a diagnostic tool in polyomavirus JC induced progressive multifocal leukoencephalopathy. J Med Virol 1998;54(3):196– 203. 298. Tognon M, Martini F, Iaccheri L, Cultrera R, Contini C: Investigation of the simian polyomavirus SV40 as a potential causative agent of human neurological disorders in AIDS patients. J Med Microbiol 2001;50(2):165–172. 299. Dodge P: A case study: The use cidofovir for management of progressive multifocal leukoencephalopathy. J Assoc Nurses AIDS Care 1999;10(4):70–74. 300. Hall CD, Dafni U, Simpson D, et al: Failure of cytarabine in progressive multifocal leukoencephalopathy associated with human immunodeficiency virus infection. AIDS clinical trials group 243 team [see comments]. N Engl J Med 1998;338(19):1345–1351. 301. De Luca A, Giancola ML, Ammassari A, et al: Potent anti-retroviral therapy with or without cidofovir for AIDS-associated progressive multifocal leukoencephalopathy: Extended follow-up of an observational study. J Neurovirol 2001;7(4):364–368. 302. Mackenzie AR, Laing RBS, Smith CC, Kaar GF, Smith FW: Spinal epidural abscess: The importance of early diagnosis and treatment. J Neurol Neurosurg Psychiatry 1998;65:209–212. 303. Martin RJ, Yuan HA: Neurosurgical care of spinal epidural, subdural, and intramedullary abscesses and arachnoiditis. Spinal Infections 1996;27:25–136. 304. Hlavin ML, Kaminski HJ, Ross JS, Ganz E: Spinal epidural abscess: A ten year perspective. Neurosurgery 1990;27:177–184. 305. Maslen DR, Jones SR, Crislip MA, Bracis R, Dworkin RJ, Flemming JE: Spinal epidural abscess: Optimizing patient care. Arch Intern Med 1993;153:1713–1721. 306. Auletta JJ, Chandy JC: Spinal epidural abscesses in children: A 15-year experience and review of the literature. Clin Infect Dis 2001;32:9–16. 307. Khanna RK, Ghaus MM, Rock JP, Rosenblum ML: Spinal epidural abscess: Evaluation of 5 factors influencing outcome. Neurosurgery 1996;39:958–964. 308. Obrador GT, Levenson DJ: Spinal epidural abscess in hemodialysis patients: Report of three cases and review of the literature. Am J Kidney Dis 1996;27:75–83. 309. Wheeler D, Keiser P, Rigamonti D, Keay S: Medical management of spinal epidural abscesses: Case report and review. Clin Infect Dis 1992;15:22–27. 310. Feldenzer JA, McKeever PE, Schaberg DR, Campbell JA, Hoff JT: The pathogenesis of spinal epidural abscess: Microangiopathic studies in an experimental model. J Neurosurg 1998;69:110–114. 311. Curling OD, Gower DJ, McWhorter JM: Changing concepts in spinal epidural abscess: A report of 29 cases. Neurosurgery 1990;27:185–192.

312. Digby JM, Kersley JB: Pyogenic non-tuberculous spinal infection: an analysis of thirty cases. J Bone Joint Surg [Br] 1979;61:47–55. 313. Khan IA, Vaccaro AR, Zlotolow DA: Management of vertebral diskitis and osteomyelitis. Orthopedics 1999;22:758–765. 314. Strausbaugh LJ: Vertebral osteomyelitis: How to differentiate it from other causes of back and neck pain. Postgrad Med J 1995;97:147– 154. 315. Rezai AR, Woo HH, Errico TJ, Cooper PR: Contemporary management of spinal osteomyelitis. Neurosurgery 1999;44:1018–1025. 316. Nussbaum ES, Rockswold GL, Bergman TA, Erickson DL, Seljeskog EL: Spinal tuberculosis: A diagnostic and management challenge. J Neurosurg 1995:83:243–247. 317. Sapico FL: Microbiology and antimicrobial therapy of spinal infections. Orthopedic Clinics of North America 1996;27:9–13. 318. Ozuna RM, Delamarter RB: Pyogenic vertebral osteomyelitis and postsurgical disc space infections. Orthopedic Clinics of North America 1996;27:87–94. 319. Broner FA, Garland DE, Zigler JE: Spinal infections in the immunocompromised host. Orthopedic Clinics of North America 1996;27:37–46. 320. Cahill DW, Love LC, Rechtine GR: Pyogenic osteomyelitis of the spine in the elderly. J Neurosurg 1991;74:878–886. 321. Klein JD, Garfin SR: Nutritional status in the patient with spinal infection. Orthopedic Clinics of North America 1996;27:33–36. 322. Sarria JC, Chutkan NB, Figueroa JE, Hull A: Atypical mycobacterial vertebral osteomyelitis: Case report and review. Clin Infect Dis 1998:26:503–505. 323. Rath SA, Neff U, Schneider O, Richter H: Neurosurgical management of thoracic and lumbar vertebral osteomyelitis and discitis in adults: A review of 43 consecutive surgically treated patients. Neurosurgery 1996;38:926–933. 324. Turpin S, Lambert R: Role of scintigraphy in musculoskeletal and spinal infections. Radiologic Clinics of North America 2001;39:169–189. 325. Vaccaro AR, Shah SH, Schweiter ME, Rosenfeld JF, Cotler JM: MRI description of vertebral osteomyelitis, neoplasm, and compression fracture. Orthopedics 1999;22:67–73. 326. Martinez M, Lee AS, Hellinger WC, Kaplan J: Vertebral Aspergillus osteomyelitis and acute diskitis in patients with chronic obstructive pulmonary disease. Mayo Clin Proc 1999;74:579–583. 327. Vinas FC, King PK, Diaz FG: Spinal Aspergillus osteomyelitis. Clin Infect Dis 1999;28:1223–1229. 328. Alleyne CH, Hassan M, Zambramski JM: The efficacy and cost of prophylactic and periprocedural antibiotics in patients with external ventricular drains. Neurosurgery 2000;47:1124–1127. 329. Khanna RK, Rosenblum ML, Rock JP, Malik GM: Prolonged external ventricular drainage with percutaneous long-tunnel ventriculostomies. J Neurosurg 1995;83:791–794. 330. Cummings R: Understanding external ventricular drainage. J Neurosci Nurs 1992;24:84–87. 331. Chan K, Mann KS: Prolonged therapeutic external ventricular drainage: A prospective study. Neurosurgery 1988;23:436–438. 332. Narayan RK, Kishore PRS, Becker DP, et al: Intracranial pressure: To monitor or not to monitor? A review of our experience with severe head injury. J Neurosurg 1982;56:650–659. 333. Mayhill CG, Archer NH, Lamb VA, et al: Ventriculostomy-related infections: A prospective epidemiologic study. N Engl J Med 1984;310:553–559. 334. Winfield JA, Rosenthal P, Kanter RK, Casella G: Duration of intracranial pressure monitoring does not predict daily risk of infectious complications. Neurosurgery 1993;33:424–431. 335. Rodvold KA: Therapeutic considerations for infections caused by Staphylococcus Epidermidis. Pharmacotherapy 1988(Suppl 8):14S–18S. 336. Darouiche RO, Raad II, Heard SO, et al: A comparison of two antimicrobial-impregnated central venous catheters. Catheter Study Group. N Engl J Med 1999;340:1–8.

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Chapter 13 Acute Stroke and Other Neurologic Emergencies David M. Greer, MD, MA

Intensive Care Management of Cerebrovascular Disorders Introduction The focus of this section will be cerebrovascular disorders necessitating intensive care unit (ICU) level of care, including a discussion of ischemic stroke pathophysiology and subtypes, relative outcomes, and potential treatment modalities. Consideration will be given to current therapies in ischemic stroke, including intravenous and intra-arterial thrombolysis, blood pressure management, and anticoagulation. Next will be a review of the clinical features, diagnosis, and treatment of primary intracerebral hemorrhage, including deep, lobar, and primary intraventricular hemorrhage. Finally, the current diagnosis and treatment options for cerebral venous thrombosis will be discussed. Hemorrhagic cerebrovascular disease is reviewed elsewhere (see Chapter 6). Ischemic Stroke Pathophysiology Ischemic stroke can be separated into three broad categories (Fig. 13-1; Table 13-1): large vessel atherothrombosis, small vessel or lacunar infarction, and cerebral embolism, up to two thirds of which may have an unknown clinical source (cryptogenic embolus) (Fig. 13-2). The determination of the etiology in the acute setting is imperative, because progression of stroke and clinical worsening can occur within minutes to hours of presentation, depending on the cause. For example, a patient presenting with subtle speech changes

and right hand weakness due to a small left middle cerebral artery (MCA) infarct may experience a subsequent severe aphasia and dense right hemiparesis if the underlying lesion is a critical stenosis of the left internal carotid artery (ICA) with recurrent embolism or progressive hemispheric hypoperfusion. On the other hand, if the infarct is secondary to a small cardiogenic embolus to the hand motor cortex region, the symptoms will likely be maximal at the onset, with a relatively low probability for progression. Large vessel atherothrombosis encompasses approximately 15% of all strokes; 9% are of extracranial ICA origin, and 6% are due to intracranial atheromatous disease.1 The typical clinical presentation is a sudden onset of focal neurologic deficits, with potential stepwise progression of symptoms referable to the same arterial distribution. Events in the anterior circulation present with cortical surface symptoms (aphasia, apraxia, neglect) and/or deep white matter or basal ganglia symptoms (weakness, sensory changes, movement disorders). Posterior circulation events present with brainstem (cranial nerve, motor), cerebellar (ataxia), thalamic (sensory, aphasia), or occipital symptoms (vision changes, personality changes, memory disturbance). In stroke secondary to large vessel disease, the pathophysiology is secondary to atherosclerosis in a major extracranial or intracranial artery, with subsequent ulcer formation and thrombosis. This leads to recurrent thromboemboli, as well as arterial stenosis or occlusion.2 Stroke occurs secondarily either by artery-to-artery embolism or by hypoperfusion causing a low flow state, in which there may be blood pressure–sensitive fluctuations in the clinical examination, causing progressing or regressing stereotyped symp397

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Figure 13-1. Classification of stroke by mechanism, with frequency estimates of the abnormalities. Note that about 30% of stroke is cryptogenic. (From Albers GW, et al: Chest 2001;119:300S, with permission.)

toms. The most common site of extracranial stenosis is the origin of the ICA, followed by the origin of the great vessels, with the vertebral artery origin more common than the common carotid origin.3,4 In the intracranial circulation, the most common sites for atherosclerotic lesions are the distal vertebral artery, the proximal to midbasilar artery, the siphon portion of the ICA, and the MCA stem. Small vessel or lacunar infarction encompasses approximately 25% of all ischemic strokes. Patients present with focal neurologic deficits in the territory of a single penetrating artery arising from the distal vertebral artery, basilar artery, MCA stem, or the arteries of the circle of Willis. The mechanism of vascular compromise in this subtype is thought to be progressive lipohyalinosis, in which the midportion of the penetrating artery is concentrically occluded.5 Hypertension is a leading factor in the development of lacunae, with possible contributions from diabetes mellitus, dyslipidemia, and smoking. The infarcts are by definition

less than 1.5 cm in horizontal diameter. Classic lacunar syndromes include pure motor hemiparesis (caused by infarction in the internal capsule or basis pontis), pure hemisensory symptoms (caused by infarction in the ventroposterolateral [VPL] thalamic nucleus), dysarthria-clumsy hand syndrome (with pontine or internal capsule infarcts), and ataxia-hemiparesis (pontine infarct).

Table 13-1  Broad Categorization of Stroke Types* Type of Stroke Large-vessel atherothrombotic Due to internal carotid artery stenosis Small-vessel (lacunar) Embolic Due to atrial fibrillation Other (Due to dissection or other causes)

Proportion of Strokes (%) 15 9 25 60 15 3

*The data are from the Stroke Data Bank of the National Institute of Neurological and Communicative Disorders and Stroke and the Framingham Study. The percentages do not total 100 because of a modification of the categories of stroke used. From Kistler JP, Furie KL: N Engl J Med 2000;342:1743, with permission.

Figure 13-2. Common sites of arterial and cardiac lesions causing ischemic stroke. (From Albers GW, et al: Chest 2001;119:300S, with permission.)

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An important consideration in the stroke patient presenting with a lacunar syndrome is the possibility of atherothrombotic disease in the parent vessel, causing occlusion of the penetrator vessel by thrombotic occlusion at the origin of the penetrator artery. These patients merit early evaluation of their intracranial circulation to exonerate the parent vessel in question. In addition, lacunar infarction may be the initial presentation of an embolic event, and a search for an embolic source should be undertaken. In a study by Ay and associates,6 patients with acute stroke presenting with a classic lacunar syndrome were studied with diffusionweighted magnetic resonance imaging (MRI), and 16% (10 of 62) were found to have evidence of multiple emboli in addition to the suspected syndrome-causing lacune, or “index lesion.” As a general rule, patients with small vessel infarcts have a relatively better clinical outcome than those with strokes secondary to large vessel atherothrombosis. However, in some cases, depending on the location of the stroke, patients may be left with pronounced motor and/or cranial nerve deficits. The mainstay of prevention is the control of risk factors, such as hypertension and smoking, as well as use of antiplatelet agents. Studies evaluating the use of oral anticoagulant therapy in lacunar infarction failed to show any benefit.7 Approximately 60% of all ischemic strokes are caused by cerebral embolism, only one third of which have known clinical sources.8 Cerebral emboli present with sudden, focal neurologic deficits in the territory of an extracerebral artery. They may present with cortical and/or subcortical symptoms, as well as cerebellar hemispheric or diencephalic symptoms. By definition, there is a lack of intrinsic pathology in the parent artery or arteries, allowing a direct conduit from a more proximal source, such as the heart or aortic arch. The clinical outcome depends on the size and location of the infarct, and cerebral emboli are thought to have a higher rate of hemorrhagic conversion in comparison to ischemic stroke caused by other subtypes.9 Cerebral emboli may originate from multiple sources,10 including atrial fibrillation, intrinsic or mechanical valvular disease, intracardiac thrombus (atrial or ventricular), atrial myxoma, dilated cardiomyopathy, patent foramen ovale and/or atrial septal aneurysm, aortic arch athromatous disease, and marantic or bacterial endocarditis. It is important to seek out the definitive source, because it may have a profound impact on the management of secondary stroke prevention. For example, most sources of cardiogenic emboli are treated with oral anticoagulation; however, this may be contraindicated in a number of conditions such as with bacterial endocarditis,11 atrial myxoma,12 and potentially aortic arch atheromatous disease, because these conditions may have a higher rate of hemorrhagic conversion. Despite the number of potential mechanisms by which a cerebral embolus can arise, approximately two thirds of embolic infarcts remain cryptogenic. The optimal treatment of cryptogenic emboli has been a controversial subject for

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years. Although the recent Warfarin vs. Aspirin in Recurrent Stroke Study (WARSS)7 showed no significant benefit for warfarin over aspirin for the primary endpoint, it provided some suggestion of potential benefit in favor of oral anticoagulant therapy over aspirin in the selected subpopulation of patients with cryptogenic emboli and a cortical element to their infarct. However, due to the relatively small number of patients with this stroke subtype, as well as the design of this study, this finding did not reach statistical significance in the WARSS study, and further studies of this subgroup are needed. Several other etiologies of ischemic stroke bear mentioning. Arterial dissection is an important consideration, especially in young patients or following a traumatic head or neck injury.13 Dissections typically arise at the petrous portion of the ICA, or at the C1 to C2 level in the vertebral artery. Dissections in the petrous carotid artery can give rise to pain involving the ipsilateral eye and posterior pharynx, as well as a Horner’s syndrome. Vertebral artery dissections cause posterior cervical and auricular pain, and may present with a stroke in the distribution of the posterior inferior cerebellar artery, also at times causing a Horner’s syndrome. Thrombus may form at the site of an intimal tear, extending into the media, with subsequent artery-to-artery embolism. Low-flow or “watershed” infarction can also occur with severe vessel narrowing or occlusion. Dissection may also lead to subarachnoid hemorrhage when a pseudoaneurysm forms after the artery passes intradurally.14 Cerebral angiitis is another rare cause of stroke, and may cause lesions that are ischemic, hemorrhagic, or both.15 The etiology may be as part of a systemic angiitis (e.g., with SLE), as a drug-induced phenomenon (e.g., with cocaine or marijuana), or as a manifestation of primary cerebral angiitis. Consideration should also be given for a hypercoagulable state, especially in a young patient, or one with a known or occult carcinoma. Multiple prothrombotic conditions may currently be detected, including protein C and S deficiency, antithrombin III deficiency, activated protein C resistance, antiphospholipid antibodies, prothrombin G20210A gene mutation, and factor V Leiden mutation.16 Evaluation The most crucial step in the evaluation of a patient presenting with an acute neurological change suggestive of ischemic stroke is to exclude an intracerebral hemorrhage. This is usually most easily done with computed tomography (CT), which is the safest, most convenient and readily available modality.17 MRI is also useful to evaluate for hemorrhage, but is not as readily available or convenient, and is more cumbersome for monitoring patients with acute stroke, many of whom may be unstable from a respiratory or hemodynamic standpoint.18–20 Based on the findings on a noncontrast-enhanced CT scan, consideration may be given for possible thrombolytic therapies. Exclusion criteria for thrombolysis based on

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the CT scan include the presence of hemorrhage, a wellestablished acute infarct, a brain tumor (other than small meningiomas), a cerebral abscess, or a vascular malformation. Further CT evaluation in the acute stroke setting may include CT angiography (CTA; Fig. 13-3), involving an intravenous bolus of iodinated contrast, which may give additional information regarding the extracranial and intracranial circulation.21 This may be especially important for patients in whom intra-arterial thrombolysis is considered. This modality is currently available mostly in specialized care centers, and must be used with caution in patients with renal insufficiency (due to nephrotoxicity) or with known hypersensitivity to contrast material. The initial evaluation of a patient with acute stroke must allow for the exclusion of other conditions that can mimic a stroke presentation. These include seizure (with subsequent Todd’s paresis or other postictal syndromes), cerebral neoplasm, encephalitis, complex migraine, and hypoglycemia. Clinicians must also be vigilant for stroke as a presentation of bacterial endocarditis. Exclusion of these stroke mimics may save patients from unnecessary and potentially harmful therapies. MRI may be useful in the evaluation of the patient with acute stroke, especially when trying to determine if a patient has the potential to benefit from intra-arterial thrombolysis or hypertensive therapy. Diffusion-weighted imaging gives useful information regarding tissue that is reversibly or irreversibly ischemic.22 Perfusion-weighted imaging, using a timed bolus of intravenous gadolinium contrast material, gives further insight to tissue destined for

infarction, as well as tissue at risk for ischemic injury, the so-called ischemic penumbra.23 Furthermore, MRA can provide useful anatomic information regarding the extraand intracranial vasculature, and the sensitivity of this modality may be enhanced by the use of gadolinium contrast material.24 Other noninvasive measures may be used in the acute and subacute settings to evaluate stroke patients. Duplex carotid ultrasound provides information regarding the status of the extracranial circulation, including the carotid system as well as the extracranial vertebral arteries. Carotid duplex can evaluate the degree of stenosis, the presence of turbulent flow, and plaque morphology. Furthermore, transcranial Doppler (TCD) can be used to evaluate the intracranial circulation, including the vessels of the Circle of Willis as well as the distal vertebral and basilar system. TCD can be used continuously in the acute stroke setting to evaluate the efficacy of thrombolysis.25 The benefit of conventional cerebral angiography has diminished with the introduction of less invasive diagnostic modalities.26 However, it is still used in some circumstances, including during the performance of intra-arterial thrombolysis, in defining a questionable area of carotid stenosis, in diagnosing cerebral angiitis, and for exclusion of mycotic aneurysms in the setting of bacterial endocarditis. It is still considered the “gold standard” for diagnosing arterial dissection, but advances in MRI and CT angiography have diminished its necessity. In particular, MRI of the head and neck vessels using fat-saturated axial T1 images has emerged as a sensitive noninvasive means of evaluating for dissection.14

Figure 13-3. Contrast-enhanced CT and MR scans of the head showing the effects of a right internal carotid occlusion.

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Other modalities may be used in the subacute evaluation of stroke patients. Cardiac monitoring (24- to 48-hour Holter monitoring) can detect paroxysmal atrial or ventricular dysrhythmias. Transthoracic echocardiography helps to delineate cardiac valvular abnormalities, wall dyskinesis, atrial or ventricular aneurysms, and patent foramen ovale (PFO) or atrial septal defect with the use of agitated saline contrast. Trans-esophageal echocardiography provides greater detail to these abnormalities, and is better suited to look for intracardiac thrombi and aortic atheromatous disease. However, it is a more invasive and expensive modality, and at present is only used in the minority of cases. Management Patients with acute stroke should be evaluated initially as potentially medically unstable. Therefore, the first priority should be to assess cardiovascular and respiratory function. An electrocardiograph (ECG) should be obtained shortly after admission to the emergency department, as stroke can commonly accompany an acute myocardial infarction.27 In addition, a secure airway should be established for patients with a depressed level of consciousness, as seen in patients with intracerebral hemorrhage or major strokes involving the vertebrobasilar system. An extensive and rapid laboratory evaluation should be undertaken, including a complete blood cell count with platelet count, basic metabolic and hepatic panel, glucose, prothrombin time (PT) and partial thromboplastin time (PTT), fibrinogen, erythrocyte sedimentation rate, urine human chorionic gonadotropin concentration in women of childbearing age, type and cross match, and in specific settings, a toxicology screen and hypercoagulability panel. Furthermore, prompt grading of the stroke severity is vital to choosing appropriate therapy, and standard stroke scales, such as the National Institutes of Health Stroke Scale (NIHSS) (Table 13-2)28 or the Scandinavian Stroke Scale (SSS) (Table 13-3),29 can help to exclude a patient from a potentially harmful therapy on the basis of the stroke being too small or too severe. Equally crucial for therapy is the proper determination of the exact time of onset of the stroke. The patient must be witnessed to have had an abrupt change in neurologic status by a reliable observer; otherwise the time of onset, by default, must be the last time the patient was seen at his or her baseline level of neurologic function. At this point, only the United States and Canada have regulatory approval for recombinant tissue plasminogen activator (rt-PA) use in stroke. Tissue-PA is endogenously synthesized and secreted by endothelial cells in physiologic concentrations. It specifically targets fibrin clots, with minimal consumption of circulating coagulation factors. It has a serum half-life of four to six minutes and a rapid onset of action.30,31 Free rt-PA is rapidly inactivated by plasminogen activator inhibitor type-1 (PAI-1) in circulation, but fibrin-bound rt-PA is only slowly inhibited by PAI-1. Given the mechanism of rt-PA thrombolysis, it is not surprising that platelet-rich clots can be resistant to rt-PA therapy.32–34

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To date, four large trials of intravenous rt-PA have been performed: the NINDS (National Institute of Neurologic Disorders and Stroke) recombinant tPA study,35–37 the European Cooperative Acute Stroke Study (ECASS)-I,38 ECASS-II,39 and the ATLANTIS (Alteplase Thrombolysis for Acute Noninterventional Therapy in Ischemic Stroke) rt-PA (Alteplase) Acute Stroke Trial (parts A and B).40,41 The NINDS rt-PA Acute Stroke Study was a randomized, doubleblind, placebo-controlled study of rt-PA given within 3 hours of clearly defined symptom onset. The study enrolled 624 patients and the NIHSS, modified Rankin score (mRS), Barthel Index (BI) and Glasgow Outcome Scale (GOS) were measured at 24 hours and 3 months. The results of this study were positive in favor of rt-PA. The global odds ratio (OR) for favorable outcome in the rt-PA–treated group was 1.7 (95% CI, 1.2 to 2.6) (Table 13-4). Patients treated with rt-PA were at least 30% more likely to have minimal or no disability at 3 months compared to patients treated with placebo (Fig. 13-4). The rt-PA treatment group had an 11% to 13% absolute increase in the number of patients with good outcomes, defined as a mRS score of 0 or 1. A similar degree of benefit was seen for all stroke subtypes. The two groups had no statistical difference in mortality rates at 3 months (17% in the rt-PA–treated group vs. 21% in the placebotreated group, P = .30), but symptomatic hemorrhage occurred more often in the rt-PA–treated group (6.4% vs. 0.6% in the placebo-treated group, P < .001). The benefit seen by the rt-PA–treated group existed regardless of patient age, stroke location, or stroke subtype. Severity of stroke and brain edema or mass effect on the pretreatment CT scan were associated with an increased risk of intracerebral hemorrhage in the rt-PA–treated group, although both groups still were more likely to have favorable outcomes if treated with rt-PA (although the difference was not statistically significant for the group with brain edema or mass effect). The benefits of rt-PA were durable over 1 year, with an odds ratio for favorable outcome of 1.7 (95% CI, 1.2 to 2.3), and the rt-PA–treated patients were at least 30% more likely to have minimal or no disability than the placebo-treated patients.42 The results of the other major trials of rt-PA in acute ischemic stroke (ECASS-I, ECASS-II, and ATLANTIS) all showed a similar benefit for the rt-PA treated group when treated within three hours of symptom onset. However, this benefit was not sustained in patients treated within three to six hours (ECASS-I and II), or 3 to 5 hours (ATLANTIS). At present, intravenous rt-PA cannot be recommended beyond the three-hour time window, although some suggest it may be useful in a carefully selected patient population within 3 to 6 hours.43 Additionally, in patients beyond the 3-hour time window, consideration may be given for intra-arterial thrombolysis in certain instances (see following section on Intra-arterial Thrombolysis). The NINDS study helped to establish strict inclusion criteria for the administration of thrombolytic therapy in acute stroke patients: (1) symptoms consistent with acute brain

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Table 13-2  NIH Stroke Scale: “Quick and Easy” Version Category

Description

1a. Level of consciousness (LOC) (Alert, drowsy, etc)

Alert Drowsy Stuporous Coma Answers both correctly Answers 1 correctly Incorrect Obeys both correctly Obeys 1 correctly Incorrect Normal Partial gaze palsy Forced deviation No visual loss Partial hemianopsia Complete hemianopsia Bilateral hemianopsia Normal Minor Partial Complete No drift Drift Can’t resist gravity No effort against gravity No movement Amputation, joint fusion (explain) No drift Drift Can’t resist gravity No effort against gravity No movement Amputation, joint fusion (explain) No drift Drift Can’t resist gravity No effort against gravity No movement Amputation, joint fusion (explain) No drift Drift Can’t resist gravity No effort against gravity No movement Amputation, joint fusion (explain) Absent Present in 1 limb Present in 2 limbs Normal Partial loss Severe loss No aphasia Mild to moderate aphasia Severe aphasia Mute Normal articulation Mild to moderate dysarthria Near to indecipherable or worse Intubated or other physical barrier No neglect Partial neglect Complete neglect

1b. LOC questions (Month, age) 1c. LOC commands (Open, close eyes, make fist, let go) 2. Best gaze (Eyes open—patient fallows examiner’s finger or face) 3. Visual (Introduce visual stimulus/threat to patient’s visual field quadrants) 4. Facial palsy (Show teeth, raise eyebrows, and squeeze eye lids) 5a. Motor arm–left (Elevate extremity to 90° and score drift/movement)

5b. Motor arm–right (Elevate extremity to 30° and score drift/movement)

6a. Motor leg–right (Elevate extremity to 30° and score drift/movement)

6b. Motor leg–right (Elevate extremity to 30° and score drift/movement)

7. Limb ataxia (Finger-nose, heel to shin) 8. Sensory (pin prick to face, arm, trunk, and leg—compare side to side) 9. Best language (Names items, describe a picture, and read sentences) 10. Dysarthria (Evaluate speech clarity by patient repeating listed words) 11. Extinction and inattention (Use information from prior testing to identify neglect or double simultaneous stimuli testing)

From NNDS rt-PA Stroke Study Group: N Engl J Med 1995;333:1581, with permission.

Score 0 1 2 3 0 1 2 0 1 2 0 1 2 0 1 2 3 0 1 2 3 0 1 2 3 4 9 0 1 2 3 4 9 0 1 2 3 4 9 0 1 2 3 4 9 0 1 2 0 1 2 0 1 2 3 0 1 2 9 0 1 2

Baseline Date/Time

Date/Time

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Table 13-3  Scandinavian Stroke Scale Individual Administering Scale 1. Consciousness Fully conscious Somnolent, can be awakened to full consciousnes Reacts to verbal command but is not fully conscious Stupor (reacts to pain only) Coma 2. Orientation Correct for time, place, and person Two of these (time, place, person) One of these Completely disoriented 3. Speech No aphasia Impairment of comprehension or expression disability More than yes/no or less 4. Eye movement No gaze palsy Gaze palsy present Forced lateral gaze 5. Facial palsy None/dubious/slight Present 6. Gait Walks at least 5 m without aids Walks with aids Walks with help of another person Sits without support Bedridden/wheelchair 7. Arm, motor power (assessed only on affected side) Raises arm with normal strength Raises arm with reduced strength Raises arm with flexion in elbow Can move but not against gravity Paralysis 8. Hand, motor power (assessed only on affected side) Normal strength Reduced strength in full range Some movement, fingertips do not reach palm Paralysis 9. Leg, motor power (assessed only on one side) Normal strength Raises straight leg against resistance with reduced strength Raises leg with flexion of knee against gravity Can move but not against gravity Paralysis 10. Foot paresis None Present

Score 6 4 2 0 0 6 4 2 0 10 6 0 4 2 0 2 0 12 9 6 3 0 6 5 4 2 0 6 4 2 0 6 5 4 2 0 2 0

From Scandinavian Stroke Study Group: Stroke 1985;16:885, with permission.

infarction, with a clearly defined onset of less than 3 hours before rt-PA will be given (if the onset was not witnessed, the ictus is measured from the time the patient was last seen to be at baseline); (2) a significant neurologic deficit expected to result in long-term disability; and (3) a noncontrast-enhanced CT with no evidence of hemorrhage or well-established infarction.

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Absolute exclusion criteria have been established as well. These include (1) mild or rapidly improving deficits; (2) hemorrhage on CT, well-established acute infarct on CT, or any other CT diagnosis that contraindicates treatment, including abscess or tumor, excluding small meningiomas; (3) a known CNS vascular malformation or tumor; and (4) bacterial endocarditis. The rationale for excluding patients with improving symptoms is to not give potentially harmful treatments to patients with postictal presentations or with arterial occlusions secondary to clot that is already dissolving on its own. In addition, there is a long list of relative contraindications to thrombolytic therapy, including • significant trauma within 3 months, including cardiopulmonary resuscitation with chest compressions within 10 days • ischemic stroke within 3 months • history of intracranial hemorrhage, or symptoms suggestive of subarachnoid hemorrhage • major surgery within 14 days • minor surgery within 10 days, including liver and kidney biopsy, thoracentesis, and lumbar puncture • arterial puncture at a noncompressible site within 14 days • pregnancy, and up to 10 days postpartum • gastrointestinal, urologic, or respiratory hemorrhage within 21 days • known bleeding diathesis, including renal or hepatic insufficiency • peritoneal dialysis or hemodialysis • PTT greater than 40 seconds • INR > 1.7 • platelet count less than 100,000/mm3 • seizure at onset of stroke (this relative contraindication is intended to prevent treatment of patients with a deficit due to postictal Todd’s paralysis or with seizure due to some other CNS lesion that precludes thrombolytic therapy—if rapid diagnosis of vascular occlusion can be made, treatment may be given) • glucose concentration less than 50 or greater than 400 mg/dL (this relative contraindication is intended to prevent treatment of patients with focal deficits due to hypoglycemia or hyperglycemia; if the deficit persists after correction of the serum glucose, or if rapid diagnosis of vascular occlusion can be made, treatment may be given) • systolic blood pressure greater than 180 mm Hg or diastolic blood pressure greater than 110 mm Hg, despite basic measures to lower it acutely. • Consideration should be given to the increased risk of hemorrhage in patients with severe deficits (NIHSS >20), older than 75 years, or early edema with mass effect on CT. The dose of rt-PA is 0.9 mg/kg, with a maximum dose of 90 mg. Ten percent is given as a bolus over 1 minute. This is

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Table 13-4  Final Multivariate Model for Predicting Benefit from rt-PA*

From NINDS rt-PA Stroke Trial: Stroke 1997;28:2119, with permission.

followed by a continuous infusion of the remaining 90% over 60 minutes. Following treatment, patients should be monitored in an ICU for at least 24 hours. Vital signs should be checked every 15 minutes for the first 2 hours, then every 30 minutes for 6 hours, then every hour for 16 hours. Blood pressure should be strictly controlled for 24 hours, keeping the systolic blood pressure less than 180 mm Hg and the diastolic blood pressure less than 110 mm Hg. Labetolol is recommended for control of hypertension; 10 mg should be given intravenously over 1 to 2 minutes, and then the dose repeated or doubled every 5 to 15 minutes, up to a total of 150 mg. If the blood pressure remains refractory despite these measures, consideration can be given to a continuous infusion of sodium nitroprusside. With refractory hyperten-

sion, the risk of hemorrhage increases, and withholding therapy might be in the patient’s best interest. Neurologic evaluations should be performed every hour. Oxygenation should be checked by continuous pulse oxymetry. An oxygen cannula or mask should be used to keep oxygen saturation greater than 95%. Acetaminophen, 650 mg every 4 hours orally or rectally, should be given for any temperature greater than 37.4°C, and a cooling blanket used for temperatures greater than 38.9°C. Antiplatelet or anticoagulant therapies should be avoided for the first 24 hours. No Foley catheter, nasogastric tube, arterial catheter, or central venous catheter should be placed for 24 hours unless absolutely necessary, due to hemorrhage risk. Emergent head CT should be performed for any neurologic worsening.

Figure 13-4. Graph showing an odds ratio estimate model for favorable outcome at 3 months in rtPA–treated patients as compared to placebo-treated patients, from time of stroke onset to time of treatment. An OR greater than 1 (solid line) suggests there are greater odds that a rt-PA–treated patient will have a favorable outcome, compared to patients receiving placebo, at 3 months. With 95% confidence intervals (dotted lines). (From Marler, et al: Neurology 2000;55:1649, with permission.)

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If an intracerebral hemorrhage develops following thrombolysis, several steps must be taken emergently. Neurosurgery should be contacted for possible hematoma evacuation. Blood should be sent immediately for complete blood cell count, PT, PTT, platelets, fibrinogen, and D-dimer (this should be repeated every 2 hours until bleeding is controlled). Two units of fresh frozen plasma should be given every 6 hours for 24 hours after the thrombolytic agent was given. Cryoprecipitate (20 U) should be given; if the fibrinogen level is less than 200 mg/dL at 1 hour, repeat the cryoprecipitate dose. Four units of platelets should be given. Protamine sulfate (1 mg per 100 U of heparin given in the past 3 hours) should be given; a test dose of 10 mg slow IV push over 10 minutes should be given while observing for anaphylaxis, and then the remaining dose by slow IV push, up to a maximum dose of 50 mg. Institute frequent neurologic checks, as well as management of increased intracranial pressure, as needed. Aminocaproic acid (Amicar) can be given as a last resort, in a dose of 5 g in 250 cc normal saline IV over 1 hour. Intra-Arterial Thrombolysis The use of thrombolytic interventions outside of the 3-hour time window is controversial. Trials that have extended the therapeutic window beyond 3 hours for intravenous therapy have failed to show convincing benefit, including the ECASS I and II studies and the ATLANTIS trial. However, there have been several attempts to prove the benefit of catheterdirected therapy via an intra-arterial approach for focal clot lysis. Theoretically, there are several potential benefits to treatment of stroke via an intra-arterial approach. First, with angiographic confirmation of vessel occlusion, patients can be protected from receiving an unnecessary and potentially harmful therapy. Second, high concentrations of thrombolytic agents can be given directly at the site of thrombosis, thus minimizing systemic concentrations. Third, the response to lysis can be monitored by direct visualization, and thus discontinued if quickly successful. Fourth, mechanical disruption of the clot (e.g., via balloon angioplasty) may aid in clot disruption and thrombolysis. To date, there have been two randomized trials using recombinant pro-urokinase (r-pro-UK) in catheter-directed clot lysis of the middle cerebral artery stem. PROACT I (Prolyse in Acute Cerebral Thromboembolism) compared rpro-UK versus placebo.44 Patients displaying TIMI grade 0 or 1 occlusion of the M1 or an M2 branch of the MCA were randomized 2 : 1 to receive either r-pro-UK 6 mg or placebo over 120 minutes into the proximal end of the thrombus. At 24 hours, the researchers assessed recanalization efficacy and symptomatic intracerebral hemorrhage. In total, 40 patients were treated, 26 of whom received r-pro-UK. The median time to treatment from symptom onset was 5.5 hours. Recanalization occurred at a significantly higher rate in the r-pro-UK-treated group (P = .0085). However, intracerebral hemorrhage occurred in 15.4% of the r-pro-UK–treated

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patients vs. 7.1% of the placebo-treated patients, although this did not reach statistical significance. In patients who also received adjuvant higher-dose heparin, the recanalization rate was 81.8%, vs. 40% in the low-dose heparin group (the dose was lowered due to concerns raised during the study by the safety committee). The mortality rate appeared to be lower in the r-pro-UK–treated group, but this result was not statistically significant. Based on the suggestion of possible benefit from the PROACT I study, a second study was designed to address the efficacy of intra-arterial thrombolysis, PROACT II.45 In PROACT II, 180 patients were randomized 2 : 1 to receive either treatment with 9 mg r-pro-UK over 2 hours plus the PROACT I lower dose of heparin (2000 IU bolus followed by a 500 IU/hour continuous infusion for 4 hours) vs. heparin alone. Again, the inclusion criteria mandated new neurologic signs attributable to a MCA stem occlusion within 6 hours (i.e., allowing initiation of treatment by 6 hours). Mechanical clot disruption (e.g., with balloon angioplasty) was not permitted in this study. The primary outcome was the modified Rankin Scale (mRS) of 2 or less at 90 days. Secondary outcomes included recanalization rates (TIMI 2 and 3), symptomatic ICH, and overall mortality. Forty percent of the r-pro-UK–treated patients and 25% of the heparin-only patients had a mRS of 2 or less, translating into an absolute benefit of 15%, relative benefit of 58%, and a number needed to treat (NNT) of 7 (P = .04) (Fig. 13-5). The recanalization rate was 66% in the r-pro-UK group vs. 18% in the control group (P < .001), and the TIMI 3 recanalization rate in the r-pro-UK group was 19% vs. 2% in the control group (P < .003). Overall mortality was 25% in the r-pro-UK group and 27% in the control group (P = NS). Early symptomatic ICH occurred only in patients with NIHSS scores greater than 11 within 24 hours; these

Figure 13-5. Modified Rankin Scale Score in patients treated with either recombinant pro-urokinase or as controls. There was a significant outcome difference between treated and control subjects. (From Furlan, et al: JAMA 1999;282:2003, with permission.)

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A B Figure 13-6. A, Pretreatment angiogram showing absence of middle cerebral artery (MCA) flow. B, Post-treatment angiogram, showing significant improvement in flow.

occurred in 10.2% of the r-pro-UK patients vs. 2% of the control patients. Based on the currently available clinical trials, the U.S. Food and Drug Administration (FDA) has not approved intra-arterial thrombolysis as a therapeutic modality for acute stroke, except in experimental conditions. Given the increased risk of intracerebral hemorrhage, informed consent must always be obtained prior to intra-arterial therapy. The increased hemorrhage rate is at least partially explained by the severity of the strokes admitted to the trials. The average baseline NIHSS in PROACT II was 17 vs. 11 in ECASS II and ATLANTIS and 14 in NINDS. Furthermore, in the PROACT II study, patients were given a fixed dose of 4.5 mg r-pro-UK per hour in 2 sequential hours, regardless of whether recanalization was seen between doses. Additionally, no mechanical disruption of clot was allowed, perhaps hindering the abilities of the interventional neuroradiologist to achieve clot lysis, further predisposing the patient to either hemorrhage or poor outcome. The protocol for patient management prior to performing intra-arterial thrombolysis is similar to that for IV thrombolysis, with notable exceptions. The inclusion criteria for IA thrombolysis mandate that there be a proximally occlusive clot involving the internal carotid artery, the middle cerebral artery stem, or the basilar artery. If there is

clearly going to be a delay prior to initiation of therapy, many clinicians advocate the interim use of intravenous heparin, although this remains quite controversial. Hypertension is permitted to preserve penumbral tissue perfused via collateral circulation; at our institution, we allow for a blood pressure up 220/110 mm Hg. If angiographic recanalization (Fig. 13-6) is achieved (TIMI 2 or 3 flow), the patient’s blood pressure is then lowered, because this will minimize the risk of hemorrhagic conversion of the infarct. The treatment of patients following IA thrombolysis is also controversial. We adopted a general practice of discontinuing all anticoagulation in patients in whom there is complete recanalization of the vessel, with no evidence of intimal injury or disruption. Frequently, however, complete recanalization is not achieved, and guidelines for the use of heparin, intravenous glycoprotein IIb/IIIa inhibitors, or oral antiplatelet agents in patients with only partial recanalization have not been established. If a stent is placed during the procedure, antiplatelet agents are typically used to prevent thrombosis. A third project, PROACT III, has been planned, with an attempt to implement magnetic resonance imaging to aid with proper patient selection.46 Unfortunately, r-pro-UK was removed from the market in 1999 due to concerns with its preparation, and as a result rt-PA is the thrombolytic agent

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Table 13-5  Time to Treatment of Various Stroke Studies

From Ernst, et al: Stroke 2000;31:2552, with permission.

currently under investigation. In our experience at the Massachusetts General Hospital, rt-PA has been less satisfactory than r-pro-UK had been in terms of recanalization results as well as clinical outcomes. One possible explanation is that rt-PA may actually be prothrombotic at the site of intra-arterial infusion, due to platelet aggregation. With this in mind, we evaluated the efficacy of adding a glycoprotein IIb/IIIa inhibitor (eptifibatide), 90 mcg/kg bolus followed by 0.5 to 2.0 mcg/kg/min infusion, in the background of applying rt-PA intra-arterially.47 In a series of 37 patients, 13 of whom were treated with intra-arterial (IA) rt-PA and 24 of whom were treated with combination therapy, we found a trend toward better revascularization (TIMI 2 or 3 flow) in the combination therapy group (58% vs. 31%). However, this trend disappeared when balloon angioplasty was performed in cases resistant to thrombolytics alone. There was one symptomatic hemorrhage in the combination therapy group, and two in the rt-PA-alone group. Thirty-eight percent of patients in the combination therapy group had a good outcome (mRS 0-2) vs. 27% in the rt-PA-alone group. This study is promising, but prospective data on larger numbers of patients will be necessary to convincingly advocate this approach. Eckert and colleagues recently reported three cases of acute basilar artery occlusion treated successfully by a similar combination of IA rt-PA and a glycoprotein IIb/IIIa receptor inhibitor.48 The Emergency Management of Stroke Bridging Trial49 was a multicenter trial designed to evaluate the safety and potential efficacy of combined IV and IA rt-PA when initiated within 3 hours of stroke onset. Thirty-five patients were randomized to receive either placebo or an adjusted IV rtPA dose (0.6 mg/kg, up to a maximum of 60 mg; 15% given as a bolus, followed by the remainder over 30 minutes). All patients subsequently underwent angiography, where, if an appropriate clot was seen (correlating to the patient’s symptoms), 2 mg of rt-PA was injected directly into the clot, followed by continuous direct infusion of IA rt-PA at 10 mg/hour for up to 2 hours. This study had remarkably quick treatment times: the mean time to IV treatment from stroke onset was 2 hours and 30 minutes (±32 minutes), and to IA treatment was 4 hours and 10 minutes. In total, there were nine patients who received IV + IA therapy, with a baseline NIHSS of 17.2. Of these, six patients (66%) achieved a modified Rankin Score of 0 to 2 at 3 months. Of the six patients treated with only IA rt-PA (with an average NIHSS of 11.6),

5 (83%) achieved an mRS of 0 to 2 at 3 months. Although the numbers of patients in this study were too small to reach statistical significance, the authors postulated that the surprisingly high number of favorable outcomes could be at least partially attributable to the rapid time to treatment. Based on the safety and the positive trend in the Emergency Management of Stroke Bridging Trial (EMS) study, Ernst and co-workers50 studied an additional 20 patients with combination therapy, using a similar protocol. The median NIHSS for the patients in this study was higher than in EMS, at 21 (range, 11 to 31). Again, a distinguishing feature of this study was the rapidity of treatment (Table 13-5): IV therapy was started at a median of 2 hours and 2 minutes, and IA therapy was initiated at a median of 3 hours and 30 minutes. Of the 20 patients, 13 (65%) recovered to a mRS of 0 to 2 at 2 months. Of the remainder, five patients had a mRS of 4 or 5, a symptomatic intracerebral hemorrhage (thought to be secondary to labile blood pressure postprocedure) developed in one patient who eventually died, and another patient died of complications from the stroke (Fig. 13-7). Although the data from these studies are encouraging, improved efficacy of combined IV-IA therapy over IV

Figure 13-7. Percentage of patients from various stroke studies recovering to a modified Rankin Scale Score of 0 to 2 (favorable outcome with slight or limited disability). Controls are from the PROACT II study treated only with intravenous heparin. (From Ernst, et al: Stroke 2000;31:2552, with permission.)

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therapy alone will need to be proven in a larger randomized prospective study. Additional Techniques and Future Directions Newer agents for chemical and mechanical treatment of acute stroke have recently been implemented in small studies. Alteplase, which is the wild-type recombinant t-PA, consists of a fibronectin finger-like domain, which binds to fibrin. It also contains the kringle-1 domain with receptor binding, the kringle-2 domain with low affinity fibrin binding, and a protease domain with specific binding to plasminogen. In addition, it has an epidermal growth factor domain, which is thought to be responsible for hepatic binding, and thus accelerated hepatic clearance, with a halflife of 3 to 5 minutes.51 Retavase is a more fibrin-specific molecule, in which the finger domain, epidermal growth factor domain, and the kringle-1 region of the wild-type t-PA have been deleted. The retention of the kringle-2 domain allows the molecule to keep its fibrin specificity. It is produced in Escherichia coli, and thus does not contain carbohydrate side chains. Its halflife is 18 minutes. Pro-urokinase (Prolyse) is a glycosylated 411 amino acid single-chain pro-enzyme precursor of urokinase. It is derived from murine hybridoma cells. Single chain prourokinase is activated by fibrin-bound plasmin at the thrombus surface to form two-chain urokinase. The half-life of pro-urokinase is approximately 20 minutes. In comparison, 5 mg of Alteplase is equivalent to one unit of Retavase and 9 mg of pro-urokinase. Despite the success seen in the PROACT II study and other trials of IA thrombolysis using chemical methods, a large proportion of occlusive cerebrovascular disease is refractory to these measures, and 25% to 40% of attempts using chemical methods alone are unsuccessful. In refractory cases, the angiographer must be prepared to consider additional techniques to achieve clot lysis. Mechanical disruption of the clot may aid in clot lysis by means of increasing surface area on which chemical thrombolytic agents can act, or by fragmenting the clot itself.52,53 Certain risks accompany these techniques, including distal embolization of clot, vessel rupture or dissection, or failure of disruption. The approach is limited by the ability of the angiographer to navigate toward the target vessel. Perhaps the most commonly used tool for mechanical disruption of clots is angioplasty. The angioplasty balloons currently in use are either polytetrafluoroethylene- or silicone-based, and are intended for atheromatous plaque or vasospasm, respectively. Stent placement has traditionally been reserved for the internal carotid artery, but more recently the distal circulation has become experimentally amenable to stenting with the advent of super-flexible balloon-mounted stents. Newer techniques are rapidly being introduced into the angiography suite in an attempt to safely mechanically

disrupt clots, but to date all of these techniques remain unproven and experimental. With laser-induced microcavitation, a low energy laser is used as a transducer, creating an ultra short-lived microbubble that collapses and induces a series of waves that act to gently agitate the clot surface. The goal is to create clot disruption, but with such low energy that surrounding tissues are not harmed. Endovascular photoacoustic recanalization (EPAR) creates a microcavitation effect by using a neodymium yttrium-argon-garnet laser with similarly low energy levels. In vivo studies with this technique have demonstrated a primary fragment peak at the 3-mm particle size, which is considerably smaller than the diameter of capillaries. Furthermore, ultrasonic cavitation of clots has been investigated, and this technique similarly creates a cavitation phenomenon through the use of ultrasonic energy. Ultrasonic energy may be generated using either a piezoelectric driver (Ekos) or with acoustic horn technology (ACS/Guidant). All of these techniques are limited by the ability of the fiberoptic assembly to navigate to the target vessel safely. Other techniques have aimed at mechanical extraction or physical removal of the offending clot from the vessel, without creating distal emboli. These include a “flowering” type catheter with distal enclosures designed to openly approach the clot face, following which an extraction compartment is intended to surround and entrap the clot (Interventional Innovations); a “corkscrew” device that screws into a clot, and then may be removed into a protective guiding catheter (MIS); and a “snare” that has been employed much like a lasso, encircling and withdrawing a clot into a protective guiding catheter (Wikholm). Additional techniques include the Possis Angiojet, which uses a high-pressure microstream to create a distal Venturi suction, so that the approached clot face is gently agitated and the fragments are sucked into the catheter (Fig. 13-8). Future acute stroke therapies that may move from the laboratory to the emergency room include hyperoxygenation, aimed at increasing the oxygen carrying capacity in the circulation to penumbral tissue; retroperfusion, in which the venous system is used to temporarily provide oxygenated blood into an ischemic capillary bed; hypothermia, which is also being tested in other forms of brain injury, including traumatic brain injury, subarachnoid hemorrhage, and cardiac arrest; neuroprotective agents; and growth factors aimed at angiogenesis and neurogenesis. Presently, all of these techniques remain experimental. Therapies in Patients not Eligible for Thrombolysis For patients who are not eligible for IV or IA thrombolysis, there is considerable debate regarding the use of heparin and antiplatelet agents (Table 13-6). Patients are considered at risk for neurological worsening during the acute stroke period, either from extension of thrombosis or from recurrent embolism. Large artery atherosclerotic lesions may be at the highest risk of worsening in the acute period, with risk

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Figure 13-8. The AngioJet catheter. (From Chow, et al: Stroke 2000;31:1420, with permission.)

of deterioration approaching 30% during the initial hospitalization.54 Neurologic worsening may occur by several mechanisms, including progressive hypoperfusion secondary to inadequate collateral circulation, progression of an existing thrombus, or recurrent thromboembolism. With this in mind, anticoagulation with heparin is often undertaken, but with inadequate supportive data.55 The data to

support the use of heparin in atrial fibrillation are even less convincing.56,57 The International Stroke Trial (IST) evaluated the possibility of benefit of subcutaneous heparin in two different doses (5000 U or 12,500 U twice daily), with or without aspirin, versus aspirin alone.58 This trial included a placebo arm as well. The results of this study suggested that the

Table 13-6  Agents Used in Patients for Whom IV or IA Thrombolysis Is Inappropriate

From Coull et al: Neurology 2002;59:13, with permission.

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higher dose of heparin was accompanied by excessive bleeding risk, but that the lower dose may have been effective in preventing recurrent stroke or PE. The Trial of ORG 10172 in Acute Stroke Treatment (TOAST) compared a lowmolecular-weight heparin with placebo in acute stroke, and failed to demonstrate a statistical difference in the primary endpoint of favorable outcome at 3 months.59 A subgroup analysis, however, suggested a benefit in favor of the danaparoid group for the subset of patients with stroke caused by larger artery atherosclerosis. A second study, evaluating dalteparin in acute ischemic stroke patients with atrial fibrillation, failed to show a benefit in favor of heparin over aspirin (160 mg/day).60 Currently in progress, the Rapid Anticoagulation Preventing Ischemic Damage (RAPID) study is a randomized, multicenter trial comparing the safety and efficacy of IV unfractionated heparin with aspirin. They are enrolling patients with acute, nonlacunar ischemic strokes within 12 hours of symptom onset. Aspirin therapy in acute stroke has been evaluated in two large randomized trials. In the International Stroke Trial,58 the patients who were randomized to aspirin had significantly fewer recurrent ischemic strokes vs. placebo (2.8% vs. 3.9%), had no increase in hemorrhagic strokes (0.9% vs. 0.8%), and had a nonsignificant trend toward a reduction in death or dependence at 6 months (61.2% vs. 63.5%). The Chinese Acute Stroke Trial (CAST)61 randomized 21,106 patients to receive either aspirin (160 mg/day) or placebo within 48 hours of symptom onset. Significant reductions were found in the aspirin-treated group for both recurrent ischemic strokes (1.6% vs. 2.1%) and for early mortality (3.3% vs. 3.9%). There was a nonsignificant trend toward

decreased death or dependence in the aspirin-treated group as well (30.5% vs. 31.6%). Management of Specific Stroke Emergencies The neurointensivist must be aware of at least two additional ischemic stroke emergencies beyond thrombolytic therapies: large cerebellar infarcts and large cerebral hemispheric infarcts. Larger cerebellar hemispheric infarctions present with lethargy, confusion, decreased spontaneous activity, and profound ipsilateral ataxia. The cerebellopontine angle can become compromised, leading to reduced ipsilateral corneal reflex and ipsilateral seventh cranial nerve palsy. As a general rule, infarct volumes of greater than one third of a cerebellar hemisphere carry a more ominous prognosis, and more readily progress to an edematous state, causing mass effect and fourth ventricular compression, leading to hydrocephalus (Figs. 13-9, 13-10).62 The lower brainstem tegmentum can be directly compressed by the expanding mass, and the cerebellar tonsils may be forced into the foramen magnum. Upward herniation can also occur, with distortion of the midbrain and cerebral aqueduct, as well as buckling of the quadrigeminal plate.63 Given the insensitivity of CT for detecting early infarction in the posterior fossa, we recommend using MRI with diffusion-weighted imaging to outline the volume of injury. If the volume is greater than one third of a cerebellar hemisphere, early surgical decompression should be strongly considered. Medical measures that may be used before surgery include hyperosmotic therapy with mannitol, glycerol, or hypertonic saline; however, these patients can acutely decompensate due to rapidly progressive edema causing

Figure 13-9. Noncontrast CT of brain showing right cerebellar hemispheric infarction with edema and compression of the fourth ventricle.

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Figure 13-10. MR and CT images of the brain showing multiple bilateral cerebellar and occipital lobe infarctions, with incipient hydrocephalus due to fourth ventricular compression.

acute hydrocephalus, and thus these medical measures are considered only temporizing prior to definitive surgical decompression. Postoperatively, patients may have continued edema and fourth ventricular compromise, and many advocate the use of a ventriculostomy in the management, even in patients in whom there is not yet evidence of hydrocephalus. In addition to frequent serial clinical examinations, serial CT scans may be checked every one to two days in the early postoperative period to evaluate the degree of edema, fourth ventricular compression, and hydrocephalus. The patient should be observed in the ICU until it is clear that the edema is abating, and that close neurologic monitoring is no longer necessary. The data to support hemicraniectomy in large hemispheric ischemic lesions are less robust. To date, there have been no prospective, controlled trials of hemicraniectomy in large hemispheric ischemic stroke patients. The idea behind hemicraniectomy is to limit secondary ischemic injury that can occur due to either increased ICP or secondary infarction due to compression of the anterior cerebral or posterior cerebral arteries as they are impinged upon by the expanding MCA lesion. As a general rule, younger patients are at the greatest risk of secondary injury given the relatively preserved baseline brain volume, in contrast to older patients in whom generalized cerebral atrophy decreases their risk of herniation from a mass lesion. Hemicraniectomy prior to secondary injury and/or herniation can be a life-saving procedure, but selecting the correct patient population remains problematic. The largest series in the evaluation of early hemicraniectomy in large hemispheric ischemic strokes was performed

by Schwab and colleagues.64 Sixty-three patients prospectively underwent hemicraniectomy with acute complete middle cerebral artery infarction. Seventy-three percent survived, and none of the survivors had residual complete hemiplegia or were permanently wheelchair bound. In patients with dominant hemispheric strokes (n = 11), their degree of aphasia was graded as only “mild to moderate.” The authors postulated that one of the reasons for the exceptionally good outcomes in their study might have been that the patients were operated on early, before the onset of secondary injury. Common pitfalls with this approach include (1) the inability to recognize which patients will fail medical therapy alone and (2) the creation of an inadequate hemicraniectomy window to allow sufficient room for brain expansion and relief from edema. Studies are ongoing using bilateral ICP monitors to predict which patients will necessitate hemicraniectomy, using standardized surgical technique to ensure adequate windows for expansion. Intracerebral Hemorrhage Approximately 10% of all primary cerebrovascular events are spontaneous intracerebral hemorrhages (ICH). They can impact neurologic functioning based on dissection of brain tissue, the development of a mass lesion, the formation of edema, or by causing hydrocephalus. An intracerebral hemorrhage can occur in the setting of trauma (see Chapter 8), illicit drug use (e.g., marijuana- or cocaine-induced vasculitis, heroin-associated embolus/bacterial endocarditis), or over-the-counter medications (e.g., phenylpropanolamine),65 excessive alcohol consumption,66,67 due to an underlying vascular abnormality (e.g., arteriovenous mal-

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Table 13-7  Risk Factors for Intracerebral Hemorrhage

From Monforte, et al: Stroke 1990;21:1529, with permission.

formation, cerebral aneurysm), secondary to an underlying brain tumor (primary or secondary), or with a bleeding diathesis (Table 13-7). In addition, primary intracerebral hemorrhages can occur in the absence of pre-existing intracranial pathology. The location of the hemorrhage (Fig. 13-11) and the age of the patient can give clues regarding the etiology of the ICH. Spontaneous intracerebral hemorrhages that occur in the basal ganglia (Fig. 13-12), thalamus, cerebellum, and pons are typically attributed to hypertension, and are less commonly seen in the elderly population. A theoretical explanation for why hypertensive hemorrhages occur in these locations is that they arise in the distribution of the lenticulostriate and paramedian vessels, which have thinner walls in comparison to cortical vessels, and are exposed to higher intravascular pressures due to their proximity to main vascular trunks.68,69

Figure 13-11. Location of lobar hemorrhage on initial CT scan of the head. (From Flemming, et al: J Neurol Neurosurg Psych 1999;66:600, with permission.)

In contrast, lobar intracerebral hemorrhages occur more commonly in the elderly population (Fig. 13-13), and are often associated with cerebral amyloid angiopathy. They occur in patients without documented hypertension, and recur in 10% of cases.70,71 Diagnosis is confirmed only with biopsy or postmortem examination, but probable diagnosis can be made in an elderly patient in whom there are multiple recurrent lobar hemorrhages without an underlying cause.72 MRI with susceptibility-weighted imaging may be helpful in looking for evidence of previous, perhaps silent, lobar microhemorrhages.73 More rarely, hemorrhage can occur directly into the ventricular system, sparing the brain parenchyma. Primary intraventricular hemorrhage (PIVH) accounts for approximately 3% of all intracerebral hemorrhages (Fig. 13-14). The acute form of this disease can have a very high mortality rate, especially if signs of brainstem dysfunction are present on the initial examination. There are a variety of purported causes, the most common of which are likely hypertensivetype hemorrhages arising from tissues adjacent to the ventricular system (caudate nucleus, thalamus, cerebellar vermis). MRI can help to distinguish in these patients whether an intraparenchymal component is present. Additional causes include arteriovenous malformations (AVMs), especially in younger, nonhypertensive patients; systemic bleeding disorders; intracranial aneurysms; brain tumors; and venous thrombosis. PIVH is historically associated with a high mortality rate, and ventriculostomy is often of little benefit unless performed very early after onset to relieve the sudden, massive increase in ICP.74 If patients survive the initial insult, control of hypertension is an additional early necessary step to minimize ongoing bleeding. More recent studies have suggested that prognosis for survival may be improving.75,76 Recent studies have suggested that the use of intraventricular urokinase and hematoma drainage may be helpful, but this needs to be studied in a larger, more controlled fashion.77

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Figure 13-12. CT scan of the head showing hemorrhage of the left basal ganglia.

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Figure 13-14. MR image of a primary intraventricular hemorrhage in an infant.

Outcomes in intracerebral hemorrhage are dependent on a number of factors, including the location and size of the hemorrhage (Fig. 13-15),78 the age of the patient, the Glasgow Coma Score (GCS)79 and the etiology of the hemorrhage. Furthermore, the presence of intraventricular blood greatly influences outcome,80 as does the volume of blood within the ventricular system.81 Hydrocephalus can also portend a poor outcome in ICH patients82 (Table 13-8), and the placement of an extraventricular drain alone has had little impact on outcome.83 Several small studies have evaluated the use of intraventricular hemorrhage with thrombolytic medications, with promising results,84 but this has yet

to be studied in randomized, controlled fashion. Other factors associated with a poor outcome include hyperglycemia,85 anemia or hypoxia,86 midline shift,85 active bleeding,87 and marked hypertension.85 Patients with lobar hemorrhage may have an additional set of factors that portend deterioration, including a decreased level of consciousness on presentation and the presence of shift on CT (Table 13-9).88 Interestingly, some propose that the poor outcomes associated with ICH may be a “self-fulfilling prophesy,” in that patients may have care withdrawn when the outcome is presumed to be poor, and thus long-term clinical data about the

Figure 13-13. Graph showing age-specific incidence rates of intracerebral hemorrhage by location. (From Broderick, et al: Stroke 1993;24:49, with permission.)

Figure 13-15. Volume of hemorrhage on initial CT scan of the head. The y-axis is number of patients. (From Flemming, et al: J Neurol Neurosurg Psych 1999;66:600, with permission.)

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Table 13-8  Impact of Hydrocephalus on Hospital Outcome in ICH

From Diringer, et al: Stroke 1998;29:1352, with permission.

true course of the illness and possible recovery may be lacking.89 The initial steps in the treatment of patients with an intracerebral hemorrhage must always include a rapid assessment of the level of consciousness, the security of the airway, the blood pressure, and the detection of any cardiac dysrhythmias. A quick assessment of the neurologic examination should be performed. If intubation is necessary, it should be performed carefully, with mindful attention to

Table 13-9  CT Characteristics

From Diringer, et al: Stroke 1998;29:1352, with permission.

provide maximal pre-oxygenation, and to avoid administering drugs that might cause reflex arrhythmias or major blood pressure fluctuations, including atropine, thiopental, midazolam, propofol, or succinylcholine. Once the patient is stabilized, a noncontrast-enhanced head CT should be performed urgently to verify brain hemorrhage. CT may also be helpful in detecting aneurysms, AVMs, underlying tumors or abscesses, especially when contrast is administered to suspected abnormalities. Becker and colleagues found that contrast extravasation into the hematoma correlated with poor outcome in ICH patients, and that the risk of contrast material extravasation increased with extreme hypertension, depressed level of consciousness, and larger hemorrhages.89 This study provides more evidence for aggressive blood pressure control in the acute treatment of ICH to limit ongoing bleeding and edema formation. MRI is also sensitive in the evaluation of hemorrhage, but is more cumbersome to perform and is potentially risky for an acutely ill patient, given the limitations of monitoring ability in the MRI suite. MRI may be especially useful in dating the time course of the hemorrhage, in detecting areas of prior hemorrhage (with the use of gradient-echo imaging),90 and in diagnosing cavernous malformations. We recommend a follow up MRI at approximately three months after the hemorrhage if the cause remains unclear. This should include the use of intravenous gadolinium to evaluate for an underlying mass lesion, MRA to evaluate for an underlying vascular malformation or aneurysm, and gradient-echo sequencing to evaluate for evidence of hemorrhage, if not done previously. Angiography should be considered in a young patient with an intracerebral hemorrhage with no history of hypertension, as this may reveal an underlying AVM or aneurysm not readily appreciated on CT. Halpin and associates91 performed angiography on 38 patients with suspicious CT findings, including the presence of subarachnoid or intraventricular hemorrhage, abnormal intracranial calcifications, prominent vascular structures, or an abnormal site

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of hemorrhage. Eighty-four percent of the cases were positive for an underlying abnormality, either an AVM or aneurysm. The timing of angiography should take into account the patient’s clinical state and the urgency of surgery, if surgery is anticipated.92 The patient’s coagulation status, in particular the platelet count, PT, and PTT, should be checked immediately, and corrected if abnormal. If the patient recently received heparin, 1 mg protamine sulfate per 100 units of heparin should be administered with caution, given that protamine can cause hypotension. Patients taking coumadin who have an elevated INR on admission should be reversed with vitamin K (10 mg subcutaneously for three doses), as well as fresh-frozen plasma to control the PT to less than 14.5 during the time it takes for vitamin K to take effect. The mainstays of medical treatment of acute intracerebral hemorrhage are correction of any coagulopathy and avoidance of severe hypertension, although no studies of medical (or surgical) therapy have shown definitive benefit.92 Most data suggest that the bulk of hematoma expansion occurs within the first several hours of onset, and that this is the crucial time in which to control any elevations of blood pressure that may be present (Table 13-10).93,94 Beyond the first 4 to 6 hours, lowering the blood pressure is of questionable benefit. Careful consideration should also be given to the patient’s baseline blood pressure, possible raised intracranial pressure, the presumed etiology of the hemorrhage, and any vascular stenoses that may be present, so as not to incur additional injury by hypoperfusion. In patients with large intracerebral hemorrhages, ICP may be such an issue that overly aggressive lowering of blood pressure theoretically may cause a decrease in cerebral perfusion pressure (CPP) below an acceptable level. Qureshi and colleagues found a possible correlation between rapid blood pressure decline within the first 24 hours of ICH patients and mortality, suggesting that the rate of blood pressure control may influence secondary injury by possible hypoperfusion due to inadequate cerebral perfusion pressure.95 Several studies have evaluated PET and CT perfusion to document an ischemic penumbra around a hematoma, but these have been unconvincing to date. Qureshi and coworkers used a dog model of ICH to determine whether blood pressure reduction caused regional hypoperfusion or significant ICP reductions, and found no adverse effect.96 Subsequently, Powers and colleagues performed positron emission tomography studies in humans with spontaneous ICH at an average of 15 hours from symptom onset, before and after pharmacologic lowering of blood pressure.97 They found no significant impairment in cerebral autoregulation in the peri-hematoma region with blood pressure lowering. The major limitation of this study was that the hematoma sizes were small, and may not have had as significant an influence as a larger mass lesion.98 Furthermore, Rosand and colleagues, using dynamic single-section CT perfusion (CTP) imaging found a rim of decreased cerebral blood flow

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Table 13-10  Blood Pressure Management in ICH

Modified from Broderick, et al: Stroke 1999;30:905, with permission.

in the immediate perihematoma region, but it was unclear whether this area was critically ischemic.99 The guidelines for management of intracerebral hemorrhage set forth by Broderick and associates recommend that “blood pressure levels be maintained below a mean arterial pressure of 130 mm Hg in persons with a history of hypertension,”and that “in patients with elevated ICP who have an ICP monitor, cerebral perfusion pressure (= MAP - ICP) should be kept >70 mm Hg.”92 The first-line intravenous agents to be used in control of hypertension should be the alpha- and beta-blocker labetalol or the beta-blocker esmolol, given the theoretical risk of increased ICP with the use of nitroprusside or nitroglycerine, which are potent vasodilators. This potential risk has not been proven in a clinical study. In addition to the initial cerebral insult caused by the hemorrhage, secondary injury can occur by a number of means, including seizures, hydrocephalus, and edema, all of which can lead to a further increase in ICP. Prophylactic anti-

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convulsant medications may be considered for patients with lobar or superficial subcortical bleeding, especially if they have had a seizure. Phenytoin remains the preferred agent, given that it may be administered intravenously and its relative lack of impact on level of consciousness. We recommend a loading dose of 15 to 18 mg/kg. The duration of therapy with anticonvulsants is unclear, but if the patient remains seizure-free, and has never had a seizure, antiepileptic medications are typically withdrawn after 4 to 6 weeks of therapy. The role for prophylactic anticonvulsant therapy in patients with a deeper hemorrhage, with or without an intraventricular component, is more controversial, and not generally recommended. Another potentially catastrophic secondary complication of ICH, especially in the right hemisphere or insula region, is the higher propensity for causing abnormal cardiac electrical activity, and “cerebrogenic sudden death.”100 These patients should be monitored closely in the intensive care unit during their first several days after hemorrhage. ICP monitors should be considered for patients with larger hematomas with suspected increases in ICP, or in patients with a deteriorating neurological examination, especially with a declining level of consciousness. An intraventricular drain should be placed in patients in whom hydrocephalus is present, or who are considered to be at high risk for developing hydrocephalus. ICP monitoring was studied in a systematic fashion by Fernandes and associates101 and was thought to play a significant role in predicting delayed deterioration, death, and Glasgow Outcome Scale (GOS) at discharge. The study went on to suggest that ICP monitoring may be a useful guide to determining which patients would eventually require surgical evacuation of their hematomas. The principles for control of ICP are discussed in detail in Chapter 25, but the initial mainstays of treatment include hyperventilation in the acutely decompensating patient (as a temporizing measure), followed by hyperosmotic therapy (using mannitol, hypertonic saline, or glycerol), and perhaps barbiturate coma, although this has never proven definitively to be of benefit in this patient population. In a study by Poungvarin and co-workers102 there was no benefit to ICH patients who received steroids vs. placebo in terms of outcome, and there was a higher rate of infectious complications in the steroid-treated group. We do not recommend the use of corticosteroids in the setting of ICH, other than for the treatment of unrelated disorders as needed. Further medical measures that are commonly implemented in the care of ICH patients include head of bed elevation, cautious sedation to avoid agitation with associated elevations in ICP, avoidance of hyponatremia and hyperthermia, and maintenance of a euvolemic or slightly hypovolemic state. Patients with ICH and immobility are at high risk for developing deep venous thromboses (DVT) and subsequent pulmonary embolism. In a small study by Boeer and colleagues,103 22 ICH patients were treated with subcutaneous heparin (5000 U three times a day), starting day 2 after

Table 13-11  Recommendations for Surgical Treatment of ICH

From Broderick, et al: Stroke 1999;30:905, with permission.

ICH. This significantly lowered the incidence of PE compared with initiation of heparin at a later time (day 4 or day 10), with no increase in the number of patients with increased hematoma size. To date, no larger randomized study has been performed, but these results suggest that early anticoagulation may be safe and effective in this patient population. Patients with ICH may require neurosurgical consultation (Table 13-11). This is especially true in the case of cerebellar hemorrhages, in which mortality is high due to a rapidly expanding mass lesion with edema in the smaller posterior fossa. Patients with a cerebellar hemorrhage greater than 3 cm in diameter should be considered for emergency decompression, especially if there are signs of brainstem compression, hydrocephalus, or neurologic deterioration.93 There is a relatively low morbidity associated with the procedure. The data to support surgical evacuation of hemorrhages in the anterior fossa are less convincing. Patients are typically treated medically with anterior fossa hemorrhages, unless they are showing clear signs of clinical deterioration despite maximal medical therapy. In addition, there may be significant postoperative morbidity associated with hematoma evacuation in the dominant hemisphere, and most clinicians are hesitant to push for surgery in these instances. Furthermore, patients with lobar hemorrhages secondary to amyloid

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angiopathy have exceptionally friable cortical blood vessels, and control of bleeding around the hematoma can be quite difficult. In general, patients with a GCS of 4 or less have a uniformly poor outcome (either death or severely disabled) regardless of whether or not surgery is performed, and thus these patients should be treated medically. The Surgical Trial in Intracerebral Hemorrhage (STICH) is underway to assess whether early surgical evacuation of ICH is superior to conservative medical management in improving patient outcome. The STICH study pilot trial104 was a single-center, randomized trial comparing standard craniotomy performed within 12 hours of symptoms onset vs. best medical therapy. Although the results did not reach statistical significance, the mortality in the surgical group was 17.6% vs. 23.5% in the medically treated group. The study was criticized for having unequal numbers of lobar hemorrhage in each group, as well as the small numbers of patients. The current STICH study is a multicenter randomized trial, with the goal of enrolling 1000 patients.105 Other surgical approaches have been studied as well. Auer and associates105 randomized 100 patients to either best medical therapy or burr hole with endoscopic drainage. In this procedure, the hematoma was continuously irrigated with artificial CSF at a pressure of 10 to 15 mm Hg, followed by suction removal of fluid and clot at regular intervals. Continued bleeding within the hematoma cavity was laser coagulated under direct visual control. The 6-month mortality in the surgical group was 42%, compared with 70% in the medical group (P < .01). In this study, the patients with larger hematoma volumes had a significantly lowered mortality rate, but without an improvement in quality of life. The benefits seen were primarily in patients with smaller hemorrhages (which were lobar) and in the younger patients in the study. Other methods that have been employed to aid in hematoma evacuation include an Archimedes screw inside a cannula,106 an ultrasonic aspirator,107 a modified nucleotome,107,108 a double track aspiration,109 and direct instillation of chemical thrombolytics into a partially evacuated hematoma.108 At this time, there have been no surgical techniques that have been studied adequately enough to provide definitive recommendations.92 Cerebral Venous Thrombosis Cerebral venous thrombosis (CVT) is a disease state in which there is thrombotic occlusion of one or several cerebral veins. This leads to a process of venous backflow or congestion, with associated increase in intracranial pressure and occasionally venous infarction, which commonly has a hemorrhagic component. The most common conditions that lead to CVT are disorders of hypercoagulability (Table 13-12). Numerous studies have suggested that the Factor V Leiden and the Prothrombin 20210A gene mutations are

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Table 13-12  Causal Factors in the Pathogenesis of Cerebral Venous Thrombosis in Adults Prothrombotic states Pregnancy; puerperium Hereditary coagulopathies Protein S deficiency Antithrombin III deficiency Factor II (prothrombin) gene mutations (20210 G Æ A) Factor V gene mutations (factor V Leiden) Von Willebrand’s disease 5, 10 methylene tetrahydrofolate reductase mutation (677C Æ T) Homocystinuria Familial thrombophilia of unknown nature Coagulopathies secondary to blood dyscrasia Thrombocythaemia Primary polycythaemia Paroxysmal nocturnal haemoglobinuria Iron deficiency anaemia Sickle cell disease Disseminated intravascular coagulation After bone marrow transplantation Coagulopathies secondary to systemic disease Behçet’s disease Carcinoma (breast, prostate) Lymphoma Systemic lupus erythematosus Nephrotic syndrome Vasculitis Ulcerative colitis, Crohn’s disease Antiphospholipid antibodies Coagulopathies caused by drugs Oral contraceptives (3rd generation >2nd) Corticosteroids Dihydroergotamine Androgens “Ecstasy” (3,4-methylenedioxymethamphetamine) Coagulopathies secondary to local infection or infiltration Otitis Sinusitis Dental abscess Tonsillitis Obstruction by tumour Coagulopathies secondary to general infections or infiltration Uveomeningitis Sarcoidosis Chronic meningitis Subdural empyema Carcinomatous meningitis Dural puncture Epidural anaesthesia Metrizamide myelography Diagnostic tap Trauma Unknown (20%) From Van Gijn, et al: J Royal Soc Med 2000;93:230, with permission.

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associated with CVT.110-113 Other combinations of hypercoagulable states have been implicated: peripartum mothers with protein S deficiency,114 Behçet’s disease while pregnant,115 and oral contraceptive use with the presence of factor V Leiden mutation.116 Other than hypercoagulable states, several other conditions can lead to CVT, including infection (e.g., adjacent bacterial meningitis), infiltration of the venous system by a neoplastic process, direct trauma to the venous system, and dehydration. The etiology remains idiopathic in 20% of patients. The clinical presentation of patients with CVT includes progressive generalized headache, vision changes, and occasionally seizures, lethargy, and focal deficits. Patients frequently are found to have papilledema, and in a young, obese person it may be difficult to distinguish between CVT and benign intracranial hypertension, or “pseudotumor cerebri.” Patients with CVT may have sixth cranial nerve palsy or other cranial nerve palsies, secondary to increased ICP. Venous infarctions develop in the areas adjacent to the venous thrombosis (e.g., parasagittally with superior sagittal sinus thrombosis), and the focal deficits are consistent with the location of the infarction. They are frequently hemorrhagic, and commonly lead to seizures. Seizures or focal deficits may be the presenting feature in 10% to 15% of patients.117 Prognosis depends on the extent of venous thrombosis, the amount of parenchymal damage, and the response to therapy. Additionally, Stolz and colleagues found that intracranial venous hemodynamics, as measured by transcranial duplex sonography, may aid in prognostication.118 The mortality rate is from 5% to 30% in different studies.119-121 The main causes of death include herniation due to increased ICP with a hemorrhagic mass lesion, status epilepticus, and medical complications.117) Features associated with a poor outcome in CVT include rapid onset of symptoms, early low GCS, focal neurologic signs, seizures, and a concomitant infection.122

Neuroimaging used in the diagnosis of CVT includes CT and MRI. With CT, there are two signs that are thought to be pathognomonic for the disease. The first is the “empty delta sign” (Fig. 13-16), with a naturally enhancing dura surrounding a nonenhancing thrombus in the sagittal sinus.123 The second sign is the “cord” or “dense triangle” sign (Fig. 13-17), which signifies an acute thrombus within a vein or sinus, respectively.124 With the use of helical scanning and high-dose intravenous contrast material, CT venography can greatly add to the ability to detect thrombus in the venous system.125 MRI with MR venography may also be used in the diagnosis of CVT, but may be limited in the detection in the acute phase.126 MRI, in comparison to CT, may be more sensitive for detecting early parenchymal changes (including microhemorrhages) that may accompany CVT, especially with the use of susceptibility-weighted127,128 and diffusionweighted imaging.129 The appropriate therapy for CVT remains controversial. Numerous retrospective studies have evaluated anticoagulation therapy130,131 and, although suggestive of a benefit in favor of anticoagulation, were for the most part inconclusive. One small prospective randomized trial was published in 1991.130 This trial was stopped early after 20 patients were enrolled to either intravenous heparin therapy or placebo, as the heparin-treated group appeared to have a significantly lower morbidity and mortality rate (zero deaths versus three in the placebo group), but this trial drew abundant criticism132 due to its small numbers, unclear clinical criteria, and late entry into the trial (over 1 month for the heparin-treated group). A larger prospective study of anticoagulation was performed by De Bruijn and colleagues.133 In all, 59 patients were randomized to either low-molecular-weight heparin (approximately 180 anti-factor-Xa U/kg per 24 hours, divided into twice daily dosing) or placebo. After three weeks, the heparin-treated group received oral coumadin

Figure 13-16. CT scan of head showing empty delta sign in cerebral venous thrombosis.

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Figure 13-17. CT venography showing the dense triangle sign that signifies acute cerebral venous thrombosis.

anticoagulation, and the placebo group received nothing. The outcome measures suggested a benefit in favor of the heparin-treated group, but this did not reach statistical significance. In spite of inconclusive studies thus far, heparin anticoagulation is generally regarded as safe and effective therapy of patients with CVT, even with associated intracerebral hemorrhage.134–136 Intravenous thrombolytic therapy has been attempted, but has been unconvincing as a successful therapy thus far.137,138 Only small numbers of patients have been evaluated, with great concern regarding expansion of hematoma volumes.139 Catheter-directed local thrombolysis may be used in selected cases. Many patients are maintained on heparin, and thus one indication for proceeding to the more invasive procedure could be progression of disease, either clinically or radiographically, despite adequate anticoagulation. Other considerations include the clinical state (coma or obtundation) and the degree of clot burden. The data to support the use of local thrombolytic agents are sparse140,141 and studies are limited to small numbers of patients. Additionally, mechanical disruption of clot, as with intra-arterial thrombolysis, may aid in recanalization efforts, and two case reports have illustrated the efficacy of a rheolytic catheter device.142–144 At present, the use of catheter-directed local thrombolysis is limited to specialized care centers and is still considered experimental.

Intensive Care Management of Neuromuscular Weakness Introduction This section first discusses Guillain-Barré syndrome (GBS) and its various subtypes, reviewing etiology, presentation, and management implications, especially from an intensive care standpoint. Second, it presents the modern approaches to and management of myasthenia gravis (MG). Third, guidelines to the approach for the patient who develops neuromuscular weakness in the intensive care unit are provided. Finally, there is a brief discussion of neuroleptic malignant syndrome. Guillain-Barré Syndrome Presentation and Diagnosis GBS encompasses a collection of related illnesses that manifest as a self-limited, acute-to-subacute onset of an inflammatory demyelinating polyneuropathy. New diagnostic and classification criteria were set forth in 2001, delineating specific subsets as acute inflammatory demyelinating polyneuropathy (AIDP) or motor-sensory GBS, pure motor GBS, the Miller-Fisher variant (MFS), bulbar variant, and primary axonal GBS.145 The heterogeneity of presentations, as well as the numerous specific autoantibodies that have been con-

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nected with specific syndromes, led to the subclassification system. The incidence of GBS is approximately 1 to 2 per 100,000, with speculation that the rising incidence may simply be a reflection of improvements in diagnosis. It is frequently precipitated by an illness, including Campylobacter jejuni,146 cytomegalovirus (CMV),147 herpes simplex virus, and upper respiratory infections and immunizations (Table 13-13).148 However, in up to one third of patients no precipitating cause is found. The underlying pathophysiology is thought to be complement activation triggering myelin destruction in the peripheral nervous system. An infecting organism may induce a cellular and humoral immune response, leading to cross-reactivity with ganglioside surface components of peripheral nerves with similar epitopes (molecular mimicry).149 The complement cascade is triggered by the binding of antibodies to Schwann cells, leading to vesicular myelin degeneration. The axon may also be involved in up to 15% of cases, most typically secondary to Campylobacter infection. The clinical presentation (Table 13-14) commonly consists of the subacute onset of migratory weakness, sensory dysesthesias, and hyporeflexia. A nonspecific but frequently accompanying symptom is back pain.150 The necessary criteria for the clinical diagnosis of GBS were set forth by Van der Meché and colleagues:145 (1) subacutely developing flaccid paralysis; (2) weakness starts on both sides of the body, with a strong tendency to do so symmetrically; (3) deep tendon reflexes decrease and usually disappear altoTable 13-13  Events That May Precede Onset of GBS Infection Campylobacter jejuni Mycoplasma pneumoniae Cytomegalovirus Epstein-Barr virus Human immunodeficiency virus Lyme disease Neoplasia Hodgkin’s disease Other lymphoma Vaccination Rabies vaccine Flu vaccine Tetanus vaccine Drug Zimelidine Penicillamine Streptokinase Captopril Danazol Heroin GBS, Guillain-Barré syndrome. From Fulgham, Wijdicks, et al: Crit Care Clin 1997;13:1, with permission.

Table 13-14  Clinical Presentation of GBS Motor power Upper limb weakness Lower limb weakness Asymmetry in the minority Reflexes Complete areflexia Partial areflexia/hyporeflexia Cranial nerves Ophthalmoplegia, complete or partial Ptosis Facial weakness Bulbar dysfunction Decreased or absent gag reflex Dysarthria Palatal weakness Tongue weakness Dysphagia Weak cough Sensory impairment Light touch Pin prick Vibratory sensation Proprioception GBS, Guillain-Barré syndrome. From Fulgham, Wijdicks, et al: Crit Care Clin 1997;13:1, with permission.

gether transiently; and (4) other causes for a rapidly developing flaccid paralysis are ruled out based on the clinical history and additional tests, as needed. Clinical variants include MFS, in which the cardinal features are ataxia, ophthalmoplegia, and hyporeflexia without appendicular weakness.151 Of significant note, GBS can present with rapidly progressive symptoms, to the point at which patients can appear brain dead.152 In its most severe form, patients can appear comatose, with completely flaccid extremities and absent brainstem reflexes. GBS should be considered in patients who appear comatose or even brain dead, but in whom there is no immediately apparent cause for their clinical state. The differential diagnosis (Table 13-15) for the patient presenting with an acute-to-subacute flaccid paralysis should include: myasthenia gravis and other myasthenia-like syndromes (e.g., Lambert-Eaton syndrome), polymyositis, botulism, tick paralysis, organophosphate poisoning, snake or spider bites, porphyria, glue sniffing, and poisoning by ingestion of puffer fish or fruit of the buckthorn shrub in places where these species are endemic. The evaluation of GBS primarily comprises the clinical examination with supportive ancillary tests, including CSF evaluation and electromyography/nerve conduction studies (EMG/NCS). Neuroimaging is of little use, as the MRI is typically normal. There have been reports of pronounced gadolinium enhancement of the spinal nerve roots and cauda equina153,154 as well as multifocal white matter lesions

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Table 13-15  Differential Diagnosis in GBS Brainstem (pontine) infarction Acute myelopathy/skull base lesions Polymyositis Defects at the neuromuscular junction (myasthenia gravis, Lambert-Eaton myasthenic syndrome, black widow spider venom) Tick paralysis Acute porphyria Critical illness polyneuropathy Polyradiculoneuropathy (Lyme disease, Epstein-Barr virus, hepatitis) GBS, Guillain-Barré syndrome. From Fulgham, Wijdicks, et al: Crit Care Clin 1997;13:1, with permission.

in the periventricular area and brainstem in chronic inflammatory demyelinating inflammatory polyneuropathy,155 but these are of uncertain significance. Typical CSF findings include an elevated protein early in the course of the illness with normal cell counts (albumino-cytologic dissociation), but the protein may be normal in the first week of the illness.156 In clinical variants of GBS, the CSF protein tends to be normal. If a marked pleocytosis (>20 cells) is present, an evaluation for human immunodeficiency virus157 and Lyme disease158 should be undertaken. EMG/NCS tend to be the most useful tests in the evaluation of GBS. Characteristic findings include motor nerve conduction block, prolonged distal conduction, and slowing of nerve conduction. An important early finding is prolongation, dispersion, or absence of F waves, suggesting root demyelination.159 In more severely affected patients, early extensive fibrillations, multifocal conduction block, or inexcitable motor responses suggest a more protracted course.160 Phrenic nerve conduction studies can help to establish the diagnosis, but are of little predictive value for the need for mechanical ventilation.161 Grand’Maison eloquently outlined the usefulness, as well as the pitfalls, of EMG/NCS testing in the intensive care unit.162 Antiganglioside antibody testing has become more frequently employed in the past several years. Antibodies that can be investigated in GBS include GQ1b Ab (associated with MFS),163,164 GM1 Ab, GM2 Ab, GD1a (associated with axonal forms)165 and antibodies to C. jejuni and CMV. The prognosis for patients with GBS is generally good, with 65% achieving a complete or almost complete cure at the end of 1 year, to the point at which they can perform manual work. Of the remainder, up to 8% may die in the acute phase from medical complications, including cardiac arrhythmias and pulmonary emboli.166 Furthermore, Lawn and Wijdicks167 retrospectively analyzed 320 patients with GBS, 14 of whom died. The patients who died were older (mean age 75 years in the fatal group, 55 in the nonfatal group, P = .006), and were more likely to have underlying pulmonary disease (six, or 43% in the fatal group; ten, or 10% in the nonfatal group, P = .004). This study may have

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been subject to a referral bias, being performed at a tertiary care center where more severely affected and elderly patients were treated. Clearly, intensive physical therapy is essential in the recovery process, and guidelines have been set forth regarding specific physical therapy methods and concerns.168 Management The initial steps in the management should include the assessment of respiratory function, including the patients’ ability to protect their own airway from secretions; management of volume status; and detection of autonomic instability. Indeed, for as much attention as has been paid to the specific therapies for the underlying illness, it is clear that troubleshooting the medical complications is perhaps equally important as a focus of care, if not more so.169 Indications for intubation (Table 13-16) should include vital capacity less than 15 mL/kg and maximum negative inspiratory pressure of less than or equal to 25 mm Hg.170 Patients who do not meet these criteria should undergo incentive spirometry every hour to prevent atelectasis. Other clinical markers that may be used include restlessness, tachycardia, tachypnea, staccato speech, use of accessory muscles, paradoxical breathing, and sweating. Patients who are rapidly developing symptoms and signs of respiratory distress should be electively intubated, rather than waiting for the crisis of respiratory decompensation. Lawn and associates171 retrospectively analyzed 114 patients, measuring the clinical and electrophysiologic features in 60 patients with GBS who received mechanical ventilation, and 54 who did not. They found that the clinical features that were associated with a high likelihood of need for mechanical ventilation included rapid disease progression, bulbar dysfunction, bilateral facial weakness, and dysautonomia. Respiratory parameters included a vital capacity less than 10 mL/kg, maximal inspiratory pressure of less than 30 cm H2O, maximal expiratory pressure less than 40 cm H2O, or a reduction of more than Table 13-16  Clinical and Laboratory Criteria for Mechanical Ventilation in Patients with GBS Clinical

Restlessness, anxiety Tachycardia Tachypnea Staccato speech Inability to count to 20 on one breath Use of accessory muscles (heightened activity of sternocleidomastoid muscles) Parodoxic breathing

Laboratory

VC £15 mL/kg* Pi max £ -25 mm Hg Hypoxemia Respiratory acidosis on arterial blood gases (late)

*Or 50% decline from baseline. GBS, Guillain-Barré syndrome; VC, vital capacity. From Fulgham, Wijdicks, et al: Crit Care Clin 1997;13:1, with permission.

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30% in any of those three parameters. The presence of a chest radiograph abnormality, upper limb paresis, age, and preexisting pulmonary disease all showed trends for intubation, but did not reach statistical significance. It is important to stress the precarious situation of the patient with bulbar weakness with GBS, with or without appendicular weakness. These patients are particularly susceptible to aspiration, and need close monitoring for the need for mechanical ventilation. Respiratory rate, adequacy of coughing, the ability to count to 20 on one breath, and other methods of measuring bulbar function should be employed.170 Patients are typically placed on an SIMV setting of six to ten breaths per minute, with tidal volumes of 10 to 12 mL/kg and 5 cm H2O CPAP to prevent atelectasis. Patients with adequate triggering may perform well on pressure support ventilation (PSV), and this is the more comfortable setting. Early tracheostomy can be considered in patients with an expected protracted course, such as those with a rapidly progressive quadriplegia; those with EMG evidence of widespread fibrillations, low amplitudes or absent responses; and those with no response after a course of IVIG or plasma exchange. Aggressive pulmonary toilet with frequent suctioning is paramount in these patients to prevent atelectasis and pneumonia. Diaphragmatic weakness can improve significantly earlier than weakness in the extremities, and thus respiratory parameters should be observed as the indication for extubation. Extubation should be delayed in patients with ongoing dysautonomia, as the stress of weaning can cause dramatic fluctuations in blood pressure, as well as cardiac arrhythmias. Weaning typically occurs 20 to 30 days after intubation, and tracheostomy should be delayed during this time to await the potential effectiveness of specific therapy. Weaning entails reducing the IMV and switching to PSV. When the vital capacity has reached 15 mL/kg, the patient can produce tidal volumes of 10 to 12 mL/kg, and the pressure support has been reduced to 5 cm H2O or a level at which imposed work of breathing is zeroed out, extubation can be attempted. It is important to institute rest periods during the weaning period, especially when nearing the time of extubation. Some clinicians prefer weaning with a T-piece and humidified oxygen, but this may place additional stress on the patient. Dysautonomia is one of the most significant causes of morbidity and mortality in patients with GBS. The autonomic nervous system can be involved in patients with varying degrees of weakness, but is most typically seen in patients with rapidly progressive symptoms/signs, bulbar weakness, and ophthalmoplegia, as well as those with severe motor weakness and respiratory failure.172,173 The cardinal manifestations of dysautonomia are blood pressure fluctuations and cardiac dysrhythmias. Hypotension in patients with GBS can be caused by sepsis, pulmonary embolus, venous pooling or severe electrolyte disturbances, but wide fluctuations of blood pressure over minutes is suggestive of dysautonomia. The presumed cause is impaired barorecep-

tor buffering.174 Hypotension may also follow the administration of vasoactive medications by the mechanism of denervation hypersensitivity175 with vagal stimulation during tracheal suctioning or ocular pressure. Most patients will show some spontaneous fluctuations of blood pressure that quickly self-correct, and these are best left untreated. Persistent hypotension is treated by placing the patient in the Trendelenburg position and administering a fluid bolus. Alpha-agonists, such as phenylephrine, can be used, but can cause hypertension by overcompensation. Hypertension can also be present, even without the use of vasopressor medications, because increased sympathetic outflow and activity are common in patients with GBS.176,177 Persistent hypertension may lead to congestive heart failure and/or cardiac ischemia in patients with underlying coronary artery disease or systolic dysfunction, and can be treated with a morphine bolus, or with careful administration of intravenous antihypertensive medications with a short half-life, such as sodium nitroprusside. Beta-blockers should be avoided, as their use has been linked with cardiac arrest in patients with dysautonomia and profound bradycardia. The short-acting (T1/2 ~9 minutes) beta-blocker esmolol has been used successfully in a pediatric patient with GBS.178 Careful attention to volume status may aid in treating hypotension, and a pulmonary artery catheter may be helpful in selected cases. Cardiac dysrhythmias are most often insignificant, primarily manifesting as sinus bradycardia or sinus tachycardia. Sinus bradycardia, sinus arrest, and atrioventricular block typically occur in the setting of intubation and with tracheal suctioning. A frequently reported cause of sudden death in patients with GBS who experience dysautonomia is complete heart block. This is emergently treated with a temporary pacemaker. Few patients ultimately require permanent pacing.179 Untreated vagal activity can progress to profound bradycardia and asystole.180,181 On the other hand, insufficient vagal tone can lead to tachyarrhythmias, including sinus tachycardia, atrial fibrillation, atrial flutter, and ventricular tachycardia.182,183 Identifying patients with GBS at risk of developing dysrhythmias is of paramount importance.184 Other consequences of the dysautonomic state include gastroparesis and bladder paralysis. All patients should be given stool softeners, and many will require bowel motility agents. Ileus develops in 3% to 5% of patients, and is treated with continuous suctioning, intravenous hydration, and placement of a flatus tube. If ileus persists beyond three days, assuming normal nutritional status at disease onset, parenteral nutrition should be considered. For patients with bladder paralysis, intermitted catheterization can be attempted, but most will require indwelling catheter placement. Patients should continue to take in enteral nutrition for as long as possible. For those with bulbar weakness and swallowing difficulties, a nasogastric tube should be placed, and enteral feeding begun. Attention must be paid to the devel-

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opment of ileus, and parenteral nutrition, either peripheral or central, should be instituted as noted previously. General medical measures should also be instituted in the care of GBS, as with other prone patients. This should include DVT prophylaxis with subcutaneous heparin (5000 U twice daily) or low-molecular-weight heparin, as well as intermittent pneumatic compression devices. Patients should be turned frequently to prevent pressure sores. Proper positioning is important to prevent pressure palsies at peripheral nerves, including the ulnar nerve at the elbow, and the peroneal nerve at the fibular head. Psychological support is needed, with reassurance that many patients with GBS have a full recovery. Pain is a common component of the disease, but tricyclic antidepressant medications, with their anticholinergic side effects, must be used with great caution in this patient population prone to autonomic dysfunction. Other agents that may be used in pain control, especially that of a neuropathic quality, include antiepileptic medications, such as valproic acid and gabapentin. Nonsteroidal anti-inflammatory drugs are also useful, but many patients may require narcotic medications, such as morphine and its longer acting forms. Specific Therapy Given the underlying pathophysiology of an autoimmune reaction, directed treatment approaches in GBS have focused on immunomodulatory actions, including plasma exchange, intravenous immunoglobulin (IVIG), and steroids. Recently, a review was performed for all three modalities in the treatment of GBS, using the Cochrane Neuromuscular Trial Register.185–187 It concluded that plasma exchange is the “first and only treatment that has been proven to be superior to supportive treatment alone in Guillain-Barré syndrome.” The benefit was seen for mild, moderate, and severe forms of the disease. Furthermore, continuous flow plasma exchanges were thought to be superior to intermittent treatments, and albumin was felt to be safer as the replacement fluid than fresh-frozen plasma. Plasma exchange was felt to be most beneficial when started within the first seven days of presentation, but could still be beneficial in patients treated up to 30 days. Plasma exchange is considered the “gold standard” against which all other treatments are compared. Relative contraindications to treatment with plasma exchange include sepsis, myocardial infarction within 6 months, marked dysautonomia, and active bleeding. Side effects from the treatment may include vasovagal reactions, hypovolemia, anaphylaxis, hemolysis, air embolism, hematoma formation, hypocalcemia, thrombocytopenia, hypothermia, hypokalemia, and postpheresis infection. The Cochrane Review did not find sufficient evidence based on adequate clinical trials in the past to determine a benefit for IVIG over placebo (supportive therapy). They did find that IVIG had a similar ability to plasma exchange in speeding the recovery from GBS, but that IVIG following plasma exchange was not significantly better than plasma

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exchange alone. It is unclear from the trials thus far performed whether IVIG is helpful in milder forms of the disease, or when the symptoms have lasted more than two weeks. Two small studies have suggested a higher relapse rate with IVIG than plasma exchange188,189 but this has yet to be demonstrated in a larger trial. IVIG is typically less expensive than plasma exchange, and does not require the placement of a central venous catheter. The standard dose is 0.4 g/kg/day for 5 days. Side effects include aseptic meningitis, anaphylaxis, acute renal failure, and thromboembolic events (including ischemic stroke).190 Patients who relapse with either therapy will typically respond favorably to a second course with the same therapy.191 Of note, a randomized, multicenter study comparing IVIG, plasma exchange, and immune adsorption was attempted.192 In total, 67 patients were randomized to the three groups, and there were no statistical differences between the groups in either outcomes or adverse events. Unfortunately, the study was discontinued prematurely, secondary to a declining referral base in Europe in the late 1990s with the publication of favorable results with the use of IVIG, as small hospitals were subsequently treating their patients locally with the less invasive therapy. The Cochrane Review also evaluated six randomized or quasi-randomized clinical trials of corticosteroids in GBS, and found it to be of no benefit over controls. They concluded that it does not have a primary role in the treatment of GBS, but if the patient with GBS required corticosteroid treatment for some other reason it would probably not be harmful to their recovery. On the other hand, corticosteroids have been well established to be effective in the treatment of chronic inflammatory demyelinating polyneuropathy,193 but these patients rarely require an ICU level of care. Myasthenia Gravis Presentation and Diagnosis Myasthenia gravis (MG) is an autoimmune disease characterized by an autoantibody reaction at the antigen epitopes of the acetylcholine receptor, leading to destruction and simplification of the junctional fold, with subsequent widening of the synaptic cleft. The prevalence of the disease is 50 to 125 cases per million.194 It occurs at all ages, with a peak in women in the second and third decades, and a peak in men in the sixth and seventh decades. The most common reason for ICU admission is myasthenic crisis, in which respiratory decompensation is the most threatening complication. Triggers for a myasthenic crisis include recent upper respiratory infection, surgery, delivery, and use of an exacerbating medication. In most patients, symptoms become most severe within the first 3 years of onset. The natural history is of spontaneous, typically short remissions. There are some reports of spontaneous remissions lasting more than 10 years. Patients

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typically present with weakness and easy fatigability of the skeletal muscles, primarily affecting the proximal musculature more than the distal. The weakness characteristically is exacerbated by repeated activity, and alleviated by rest. Ptosis and ophthalmoparesis occur commonly early in the course of the disease, and the weakness can remain localized to the extraocular and levator palpebrae muscles in 15% of patients.195 When the facial musculature is prominently involved, there is a tendency for other elements of bulbar weakness, including hypophonic or nasal speech, as well as difficulty with chewing and swallowing. Generalized weakness develops in approximately 85% of patients,195 often affecting the diaphragm. If the weakness affecting respiration is severe enough to require mechanical ventilation, the patient is in myasthenic crisis by definition. It is important to objectively quantify the degree of weakness to establish the clinical course, as well as the response to treatment. In particular, bulbar function must be assessed early in order to determine the necessity for elective intubation. The degree of ptosis is established by having the patient maintain an upward gaze for three minutes. Jaw opening is typically stronger than jaw closure, and forceful biting on a tongue depressor for 20 seconds can establish the degree of closure weakness. Nasopharyngeal weakness can be determined by listening to the voice for slurring or nasal tone. Dysphagia is assessed by having the patient attempt to take a few sips of water. Respiratory failure can present with staccato-type speech, restlessness, diaphoresis, tachycardia and tachypnea. The tachypnea typically allows the patient to have a normal pCO2 despite low tidal volumes. The degree of respiratory weakness can be measured at the bedside by having the patient count to 20 on one breath, or by performing sequential vital capacity measurements. Isolated respiratory failure has been reported as the presenting symptom in a myasthenic patient.196 In patients with a known diagnosis of myasthenia who present with a respiratory decompensation, it is important to evaluate for cholinergic crisis as the cause, which can occur when patients are overmedicating. Clues are excessive salivation, thick bronchial secretions, and diarrhea. The diagnosis of MG is typically made on clinical grounds. The edrophonium test is helpful in establishing the diagnosis, but should only be performed in a well-monitored setting, such as the emergency room or ICU. Markers for improvement can include improvement in upward gaze, ptosis, and dynamometry of a muscle or muscle group in the extremity. The dose is 1 mL of edrophonium in a 10 mg/mL solution. One-tenth of a milliliter (1 mg) is given as a test dose, waiting 30 seconds for excessive muscarinic effects. The remainder (9 mg) is given over 1 minute. Edrophonium has a rapid onset (30 seconds) and a short duration of action (2 to 20 minutes). The test result is considered positive if there is unequivocal improvement in an objectively tested weak

muscle.197 Atropine at a dose of 0.5 mg IV bolus should be given if abdominal cramps, bronchospasm, vomiting or bradycardia occurs. If the bradycardia persists and is accompanied by hypotension, an additional 1 mg dose of atropine should be given. Edrophonium can also be given when cholinergic crisis is considered, but in a smaller dose (1 mg). EMG/NCS are useful in establishing the diagnosis of MG as well. The patient should be without anticholinesterase medications for 12 hours before testing. Any significant improvement with plasmapheresis or IVIG is delayed by 2 to 3 days, and thus testing during this period is valid. Surface electrodes are used for repetitive stimulation at a rate of 2 to 5 Hz before and after maximal voluntary contraction of the tested muscle. An abnormal result is defined as a 15% or greater reduction of the compound muscle action potential (CMAP) amplitude between the first and fourth responses with supramaximal stimulation.198 Single-fiber EMG shows increased jitter and blocking. In more severe disease, needle EMG can show fibrillations, indicating functional denervation of the muscle fibers.199 Several autoantibodies have been shown to be useful in the diagnosis. Acetylcholine-receptor antibodies are positive in approximately 85% of all patients with MG, but in a lower proportion (approximately 50%) in patients with isolated ophthalmoparesis or bulbar weakness.200–202 Straitional antibodies are present in 80% of patients with thymoma. In seronegative patients, antibodies against thyroid or gastric parietal cells can support the diagnosis.203 All patients with MG should have a chest CT or MRI performed to detect the presence of a thymoma or enlargement of the thymus gland.204 If a thymoma is detected, it is an absolute indication for removal unless the patient is a poor operative candidate, or if the tumor is significantly involving the mediastinum. For tumors that cannot be completely resected at the time of surgery, focused radiation can be carried out postoperatively. Patients between the ages of puberty and 60 should have a surgical thymectomy,205 because removal of the thymus can induce remission in a significant proportion of patients.206 However, patients may be weaker following their thymectomy, either from the stress of surgery or from the loss of a suppressive effect from the thymoma,207 and may require further immunosuppressive therapy. The differential diagnosis for MG should include Lambert-Eaton myasthenic syndrome, which may be the initial presentation of an occult malignancy208,209; congenital myasthenic syndromes210; Graves disease; botulism; progressive external ophthalmoplegia211 and intracranial mass lesions.212 Lambert-Eaton syndrome is distinguished from MG on the basis of the clinical presentation, in which there are commonly seen autonomic and sensory symptoms, as well as with EMG/NCS, in which there is an improvement in response to repetitive stimulation.

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Another highly important consideration in the differential diagnosis is drug-induced or exacerbated MG.213–215 The medications that can aggravate MG include certain antibiotics, cardiovascular agents, anti-epileptic medications, and psychotropic agents. The prognosis with MG has dramatically improved, with a mortality rate of essentially zero.206 Some patients are able to achieve a complete remission with thymectomy or induction with immunosuppressive agents, but the majority of patients must take immunosuppressive medications indefinitely. There are reports of spontaneous remissions lasting more than 10 years.216 Management The cause for ICU admission for patients with MG is usually myasthenic crisis with respiratory decompensation. This can be precipitated by a recent infection (especially an upper respiratory tract infection), new insulting medication, initial administration of a large dose of corticosteroids, recent tapering of steroids, hyperthyroidism or hypothyroidism, surgery, or postpartum state. Patients with early signs of respiratory distress should be admitted to the ICU for close observation, with consideration for early intubation before decompensation. Although many find it useful to perform serial bedside measures of pulmonary function, including negative inspiratory force and vital capacity, these measures have recurrently failed to be adequate predictors of the need for mechanical ventilation in these patients.217,218 Normally, when the vital capacity has fallen to less than 15 mL/kg, or is less than 25% of the predicted value, ventilatory failure is considered imminent.219 However, the performance on these respiratory tests may be hampered by the myasthenic patient’s inability to form a tight seal on the mouthpiece due to weakened facial musculature, giving misleading measurements. Further complicating factors for respiration in myasthenics include difficulty with controlling airway secretions due to bulbar weakness, a situation exacerbated at times by anticholinesterase medications that can increase secretions. Aggressive pulmonary toilet and frequent suctioning may aid in the prevention of aspiration and subsequent pneumonia. Hypoxemia precedes hypercarbia, and is the harbinger for the incipient need for mechanical ventilation. Once intubated, patients are most comfortable when on pressure support ventilation, provided that they have adequate triggering of the ventilator. Often, SIMV may be used at night to provide additional rest. The patient is continued on mechanical ventilation until it is clear that their respiratory mechanics are improving, they are medically stable, and they have completed several days of definitive therapy for their disease. Again, patients may often worsen shortly after the institution of corticosteroid therapy, and some suggest starting therapy at lower levels or on alternating dosing schedules.220

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Specific therapy of MG includes immunomodulation and enhancement of neuromuscular transmission with anticholinesterase agents. Plasma exchange is thought by many to be more effective than IVIG, but the treatment must be tailored to the individual patient.221 The typical course is removal of 2 to 3 L of plasma three times a week, with replacement with albumin to preserve oncotic pressure. This is repeated until improvement plateaus, which is usually after five to six exchanges. Improvement typically begins within the first 48 hours of the first exchange, and can last for weeks to months.222 IVIG has also been shown to be effective in the treatment of myasthenia, and the typical protocol is 0.4 g/kg/day for 5 days.223 There may be a role for IVIG following plasma exchange in the future as a means of prophylaxis against relapse, but no clinical trial has been conducted to date. Additional agents used in the treatment of MG include anticholinesterase medications and corticosteroids, but their use in the acute setting is a matter of continued debate. A recent retrospective study by Berrouschot and co-workers224 compared the use of pyridostigmine alone, pyridostigmine plus prednisolone, and plasma exchange, and suggested that none demonstrated a significant superiority in outcome. This study had numerous limitations, however, with variable treatments used, as well as an unusually high mortality rate of 17%. The concern raised by using anticholinesterase medications in the acute setting pertains to the increased secretions caused, which may lead to respiratory worsening with atelectasis and pneumonia. Previous reports suggested a benefit in favor of a continuous infusion of pyridostigmine in patients with myasthenic crisis.225 Corticosteroids are typically continued for 1 month, and there is general consensus that they aid in keeping patients in remission. Other modes of therapy are considered second line, and are reserved for patients who have poor tolerance or contraindications to corticosteroid therapy. These include azathioprine,226 cyclosporine,227 and immunoadsorption therapy. In known myasthenic patients with a new respiratory decompensation, it is important to distinguish whether they are having an exacerbation of their underlying illness (myasthenic crisis) or are overdosing on their anticholinesterase medication (cholinergic crisis). Patients with progressive weakness may incrementally increase their anticholinesterase medication in an effort to avoid a myasthenic crisis, but this may lead to progressive respiratory difficulties due to the increased secretions. Other signs that help to distinguish cholinergic crisis include miosis (patients with myasthenic crisis typically have mydriasis), muscle fasciculations, abdominal cramping, diarrhea, and excessive sweating and tearing. The edrophonium test may be helpful in distinguishing the two as well, as there may be worsening in the patient with cholinergic crisis, versus possible improvement in the patient with myasthenic crisis.220 Treatment consists

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of withholding or weaning the anticholinesterase medication, being mindful of potential rapid worsening of weakness and respiratory distress.228 Thymectomy is recommended for most patients with MG, but perioperative management is complicated, as clinical worsening is common.207 Approximately 50% of patients show clinical improvement with thymectomy, with the prospect of achieving a complete remission.229 Strong indications for surgery include severe generalized MG, age less than 60 years, patients with a progressively decreasing response to medication, and patients with repeated episodes of myasthenic crisis.205 Transcervical or transsternal thymectomy may be performed. Transcervical thymectomy may be associated with damage to the phrenic nerve, parathyroid gland, or recurrent laryngeal nerve, as well as pneumothorax and hemothorax.230 Extended thymectomy via transsternal approach is recommended for patients with presumed thymoma, especially if considered invasive.231 Anticholinergic medications are discontinued on the morning of surgery. Atropine or glycopyrrolate is used to decrease secretions. In patients on corticosteroid maintenance, stress dose steroids are given (typically hydrocortisone 125 mg IV every 8 hours for 3 days postoperatively). Some also advocate the use of plasma exchange before surgery. D’Empaire and associates232 retrospectively evaluated 37 patients with myasthenia who underwent thymectomy. For the 11 patients who underwent prethymectomy plasma exchange, they found a significantly decreased time on mechanical ventilation and a shorter stay in the ICU, compared with the 26 patients who did not receive plasma exchange. Intensive Care Unit Weakness A common challenge in the surgical or medical ICU is determining the cause of weakness in critically ill patients. Although GBS and MG can occur in the ICU setting and should be considered as potential etiologies, other conditions are more common, including critical illness polyneuropathy (CIP), critical illness myopathy, and deconditioning syndrome. Other less common entities include acute rhabdomyolysis and central pontine myelinolysis. Often there are multiple causes at play, and it may be erroneous to try to label a patient with a particular syndrome when overlap is so common.233 Critical illness polyneuropathy typically appears in elderly, severely ill patients, often with sepsis syndrome.234,235 It is a self-limited process, and recovery is often quite good, if the underlying critical condition can be adequately treated. In some studies it has been found to develop in 70% to 80% of patients with severe sepsis and multiple organ failure.236,237 The exact cause is unknown, but some have postulated the role of systemic inflammatory factors involving the peripheral nerves.238 Additional risk factors that have been postulated include duration of mechanical ventilation,

hyperosmolality, parenteral nutrition, nondepolarizing neuromuscular blockers and neurologic failure,239 as well as the APACHE III score.240 Examination in CIP reveals that both motor and sensory systems are affected, with flaccid tetraparesis and muscle atrophy. Deep tendon reflexes are typically reduced or absent, although they may be preserved in up to one third of patients.241 EMG/NCS reveal a distal axonal sensorimotor polyneuropathy, with fibrillation and positive sharp waves in the proximal and distal muscles, and with relative sparing of the facial muscles.242 Spinal cord injuries must also be ruled out if the patient has undergone a significant traumatic injury. Nerve biopsy reveals predominantly axonal degeneration,243 as well as denervation atrophy of both proximal and distal muscles, chromatolysis of anterior horn cells, and loss of dorsal root ganglia in more severe cases.244 Suxamethonium should not be given to patients with CIP given their risk of developing hyperkalemic cardiac arrest.245 Outcome is guarded, and closely tied in with the underlying critical illness. The course of recovery is protracted, often with a less than favorable ultimate functional status.246,247 Patients with slowing of nerve conduction may have a particularly poor prognosis. Some argue that use of intermitted bolus pancuronium may be less prone to inciting the syndrome than a continuous infusion, but this has yet to be proven definitively.248 Critical illness myopathy is often difficult to distinguish from CIP, and there is commonly an overlap of the two. In fact, some have proposed the term critical illness polyneuromyopathy, or CIPNM.249 Some argue that myopathy is even more common than polyneuropathy in critical illness.250 A proposed mechanism for injury is the generalized catabolic state induced by the systemic inflammatory response syndrome, with a coincident catabolic state.251 Corticosteroids are thought to play a vital role in the development or exacerbation of the syndrome, as is the use of neuromuscular blocking agents.252,253 Pathologic changes include abnormal fiber size, atrophy, angulated fibers, internalized nuclei, rimmed vacuoles, fatty degeneration, fibrosis, and single fiber necrosis.253 All patients with neuromuscular weakness being evaluated for possible myopathy should undergo repetitive stimulation testing during EMG to rule out an underlying neuromuscular junction process (MG), which could be unmasked due to the use of neuromuscular blocking agents. Thick filament myopathy is a variant that is often seen in patients who have received corticosteroids for acute severe asthma or for organ transplantation, with or without concomitant neuromuscular blocking agents.234 Its appearance may be potentiated by disuse.254 Still another variant is necrotizing myopathy, which is distinguished by often highly elevated serum creatine kinase. No specific therapies for these different myopathies has been found to be helpful, other than minimizing offending agents, such as neuromuscular blockade, sepsis, and corticosteroids, as well as proper

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supportive care of patients, including positioning to avoid damage due to pressure. There are ongoing arguments as to whether patients with suspected critical illness myopathy should undergo muscle biopsy, as it rarely impacts treatment. The case has been made that muscle biopsy should be reserved for patients in whom an inflammatory myopathy might be present, as this would clearly impact therapy.255 Some advocate the use of EMG/NCS early in the ICU course, to predict which patients are likely to develop CIP or CIM, so that potentially offending agents may be minimized or withheld.256 Deconditioning syndrome occurs in immobile, poorly nourished patients, who reach a highly catabolic state. It is exacerbated by prolonged, dense neuromuscular blockade. On examination, patients have diffuse weakness as well as atrophy. EMG/NCS are often normal. Muscle biopsy reveals predominantly type II fiber atrophy. If the underlying cause of immobility can be corrected, the clinical course is often favorable, with intensive physical therapy. Acute rhabdomyolysis occurs with traumatic crush injuries, drug overdose, toxin exposure, severe metabolic abnormalities, and infections.257 Patients have swollen, tender muscles, with localized or diffuse weakness. There is breakdown of skeletal muscle, with leakage of its intracellular contents, causing secondary organ damage. The creatinine phosphokinase concentration is elevated, and there may also be a leukocytosis. Urine myoglobin is present, and acute renal failure may ensue. Other metabolic abnormalities include hyperkalemia, hyperuricemia, hypocalcemia or hypercalcemia, hyperphosphatemia, lactic acidosis, thrombocytopenia, and disseminated intravascular coagulation (DIC). EMG/NCS show increased spontaneous activity with myopathic changes. Muscle biopsy reveals diffuse muscle fiber necrosis. Management consists of controlling the renal failure, which may often require temporary hemodialysis (either standard intermittent dialysis or continuous venovenous hemodialysis), as well as correcting metabolic abnormalities and DIC as possible. The clinical course can be favorable, provided that the associated injuries are not severe, and the underlying pathology can be corrected. Central pontine myelinolysis (CPM) can occur in the ICU setting, where there are often rapid alterations in serum electrolytes, particularly sodium. The syndrome can occur with alcoholism, dehydration, or serious systemic illness, often following rapid correction of hyponatremia.258,259 It has also been described in burn patients who terminally develop severe hypernatremia, having previously been normonatremic, suggesting that the sudden rise in sodium or osmolality is the precipitating mechanism.260 Patients with CPM typically have an impaired level of consciousness, ranging from confusion to coma.261 Paresis involves the upper extremities more than the lower extremities, and sixth cranial nerve palsies and rigidity are common. Other ocular abnormalities include miotic or mydriatic pupils, conjugate gaze palsies, and ocular bobbing.261 Larger lesions can cause

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a “locked-in syndrome,” with preserved consciousness but profound tetraparesis and loss of horizontal eye movements. EMG/NCS are normal, and there is no underlying muscle or peripheral nervous system pathology. Neuroimaging and pathology reveal extensive myelinolysis in the central pontine region. The reason why the pons is so dramatically affected in this disorder is unclear, but it has been postulated that the oligodendrocytes in the pons are located close to the highly vascularized gray matter, causing it to be particularly susceptible to damage from vasogenic edema and leakage of myelinotoxic substances from the vessel.262 Other areas of brain that can be affected include the midbrain, basal ganglia, white matter of the folia cerebelli, and in the deep layers of the cerebral cortex and adjacent white matter.263–265 Treatment is limited to supportive care. Steroids have been found to be of no benefit.261 There is some suggestion of benefit from use of thyrotropin-releasing hormone, but this has been limited to case reports primarily.266,267 The outcome is generally quite poor, with many patients left with little or no improvement.261,268 Neuroleptic Malignant Syndrome Neuroleptic malignant syndrome (NMS) is a rare neuromuscular disorder, originally described by Delay in 1960,269 that occurs in the setting of neuroleptic medication. It is more common in males than females, and in two prospective studies the incidence rates were 0.07% and 0.9%.270,271 The disease has quite serious potential consequences, with a mortality rate ranging from 20% to 30%.272,273 The cardinal features are severe muscle rigidity with increased heat production, leading to hyperthermia and profound autonomic instability, secondarily resulting in hypertension, tachycardia, and tachypnea. Alteration of consciousness is common, ranging from confusion to coma. The hyperthermia is likely related to increased heat production with the increased muscle rigidity, to the point at which physiologic mechanisms to reduce heat (sweating, panting) are overwhelmed.274 Hyperthermia results in a hypermetabolic state, with subsequent tachycardia and tachypnea. Tachypnea can also result from decreased chest wall movement with the muscle rigidity. The autonomic dysfunction is theoretically possible on the basis of either the heightened peripheral hyperadrenergic state, or due to central effects of neuro-leptic medication. However, given the rapid resolution of autonomic dysfunction with appropriate therapy with dantrolene to decrease muscle rigidity, the first hypothesis is more likely.275 Despite numerous reports of the condition, it is still considered a relatively rare complication of treatment with antipsychotic medications, and given the patient population in which the alteration in consciousness appears (psychotic or agitated patients with an already altered sensorium), the diagnosis is considered quite difficult to make.276 The criteria for diagnosing NMS were established by Pope and associates in 1986.277 The first requirement is hyperthermia, with

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an oral temperature of at least 38°C without another known cause. Second, at least two of the following extrapyramidal signs must be present: lead pipe muscle rigidity, trismus, pronounced cogwheel rigidity, dysphagia, sialorrhea, choreiform movements, oculogyric crisis, dyskinetic movements, retrocollis, festinating gait, opisthotonus, and flexor/extensor posturing. Third, autonomic dysfunction must be manifested by two of the following: hypertension (defined as at least 20 mm Hg diastolic above baseline), tachycardia (defined as at least 30 beats above baseline), tachypnea (defined as at least 25 respirations per minute), prominent diaphoresis, and incontinence. Additional features that may support the diagnosis include alteration in consciousness, leukocytosis of greater than 15 ¥ 109/L, and creatine kinase greater than 1000 U/L. Essentially all neuroleptics can produce NMS, including atypical antipsychotics.278,279 Metoclopramide, an antiemetic medication, as well as tricyclic antidepressants have also caused NMS.280,281 Other agents can cause an NMS-like syndrome, including anticholinergics,282 selective serotonin reuptake inhibitors,283 and cocaine.284 The presumed pathologic mechanism underlying NMS is sudden and profound central dopamine blockade in the setting of receiving neuroleptic medications, particularly affecting the basal ganglia and hypothalamus.285,286 Some postulate that there may be an individual or genetic predisposition to developing the syndrome.287 Certain psychiatric states may also predispose toward the development of NMS, including catatonia288 and affective disorder.289 Other predisposing factors include the physical state of the patient, particularly the volume status, with dehydration playing a prominent role, as well as exhaustion and concurrent organic brain disease.290 Additionally, the potency of the neuroleptic used and its route have vital importance, with high potency neuroleptics given intramuscularly or intravenously carrying significant risk.290 Iron deficiency may also predispose the patient to developing NMS.291 Pathologically, the diagnosis can be suggested by exposing muscle tissue to caffeine or halothane in vitro, which has induced a hypercontractile state in patients with NMS, but only in a small case-control study.292 In another small series of three cases, pathologic features that were described included significant edema of muscle fibers, vacuolization in the sarcoplasm, and

contraction bands separating some myofibrils.293 There have been no large postmortem analyses, and thus the diagnosis remains clinical. A number of laboratory studies are helpful in the evaluation of a patient with suspected NMS, although none are specific for the disease. Creatine kinase is typically elevated above 1000 U/L. The white blood cell count is typically greater than 10,000 cells/mL. As with other patients with delirium, additional laboratory tests may be helpful, including urinalysis, arterial blood gas analysis, electrolytes, hepatic and renal function tests, thyroid function tests, and a cortisol level. Blood and urine cultures should be considered, as well as a lumbar puncture. Toxicology screens may be indicated for certain patients. Other tests to consider include EEG, CT, or MRI. The treatment of NMS first consists of stabilizing the patient from a cardiovascular and respiratory standpoint. All patients with a possible diagnosis of NMS should be admitted to an intensive care unit. Fluids should be administered to correct for dehydration, and all neuroleptic medications should be discontinued, as should lithium.294 Antipyretic medication should be administered, and a cooling blanket placed on the patient. Patients with severe tachypnea secondary to extreme muscle rigidity may require mechanical ventilation. Due to a decreased gag response, NMS patients are at high risk for aspiration pneumonia as well, which may also lead to the need for mechanical ventilation. Patients should be given subcutaneous heparin or low-molecularweight heparin to prevent deep venous thrombosis during immobility. Specific therapy for the syndrome typically follows conservative therapy, because patients typically improve within 2 to 14 days with removal of the offending medications.295 Bromocriptine and other dopamine agonists are reasonable options, at doses of 2.5 to 7.5 mg three times daily, up to a total of 45 mg/day. Dantrolene may be added, at 1 to 10 mg/kg intravenously, or divided oral doses of 50 to 600 mg/day, but with careful attention to possible hepatitis with this medication.296 Electroconvulsive therapy has also been advocated in the treatment of NMS, and this may have the added benefit of treating the underlying condition as well.297,298 Recently, clonidine has been suggested as acute treatment in the ICU.299

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P earls 1. Large vessel atherothrombosis encompasses approximately 15% of all strokes. Of these, 9% are of extracranial ICA origin, and 6% are due to intracranial atheromatous disease. 2. Small vessel or lacunar infarction encompasses approximately 25% of all ischemic strokes. 3. In a study by Ay and colleagues6 patients with acute stroke presenting with a classic lacunar syndrome were studied with diffusion-weighted MRI, and 16% (10 of 62) were found to have evidence of multiple emboli in addition to the suspected syndromecausing lacune, or “index lesion.” 4. Approximately 60% of all ischemic strokes are caused by cerebral embolism, only one third of which has known clinical sources. 5. Consideration should also be given for a hypercoagulable state, especially in a young patient or one with a known or occult carcinoma. 6. The initial evaluation of a patient with an acute stroke must also include the exclusion of other conditions that can mimic a stroke presentation. These include seizure (with subsequent Todd’s paresis or other postictal syndromes), cerebral neoplasm, encephalitis, complex migraine, and hypoglycemia. 7. Diffusion-weighted imaging gives useful information regarding tissue that is reversibly or irreversibly ischemic.22 Perfusion-weighted imaging, using a timed bolus of intravenous gadolinium contrast material, gives further insight to tissue destined for infarction, as well as tissue at risk for ischemic injury, the so-called ischemic penumbra. 8. An ECG should be performed shortly after admission to the emergency department, because stroke can commonly accompany an acute myocardial infarction. 9. The benefits of rt-PA were durable over one year, with an odds ratio for favorable outcome of 1.7 (95% CI, 1.2 to 2.3), and the rt-PA—treated patients were at least 30% more likely to have minimal or no disability than the placebo-treated patients. 10. With laser-induced microcavitation, a low energy laser is used as a transducer, creating an ultra short-lived microbubble that collapses and induces a series of waves that act to gently agitate the clot surface. 11. The Chinese Acute Stroke Trial (CAST)61 randomized 21,106 patients to receive either aspirin (160 mg/day) or placebo within 48 hours of symptom onset. Significant reductions were found in the aspirin-treated group for both recurrent ischemic strokes (1.6% vs. 2.1%) and for early mortality (3.3% vs. 3.9%). 12. The location of the hemorrhage and the age of the patient can give clues regarding the etiology of the ICH.

13. Primary intraventricular hemorrhage (PIVH) accounts for approximately 3% of all intracerebral hemorrhages. 14. Interestingly, some propose that the poor outcomes associated with ICH may be a “self-fulfilling prophesy,” in that patients may have care withdrawn when the outcome is presumed to be poor, and thus longterm clinical data about the true course of the illness and possible recovery may be lacking.89 15. Prophylactic anticonvulsant medications may be considered for patients with lobar or superficial subcortical bleeding, especially if they have had a seizure. Phenytoin remains the preferred agent. 16. Another potentially catastrophic secondary complication of ICH, especially in the right hemisphere or insula region, is the higher propensity for causing abnormal cardiac electrical activity, and “cerebrogenic sudden death.” 17. Patients with ICH and immobility are at high risk for developing deep venous thromboses (DVT) and subsequent pulmonary embolism. 18. In general patients with a GCS of 4 or less have a uniformly poor outcome (either death or severely disabled), regardless of whether or not surgery is performed, and thus these patients with ICH should be treated medically. 19. Features associated with a poor outcome in CVT include rapid onset of symptoms, early low GCS, focal neurologic signs, seizures, and a concomitant infection. 20. The incidence of GBS is approximately 1 to 2 per 100,000, with speculation that the rising incidence may simply be a reflection of improvements in diagnosis. 21. EMG/NCS tend to be the most useful tests in the evaluation of GBS. Characteristic findings include motor nerve conduction block, prolonged distal conduction, and slowing of nerve conduction. An important early finding is prolongation, dispersion or absence of F waves, suggesting root demyelination. 22. Hypotension in patients with GBS can be caused by sepsis, pulmonary embolus, venous pooling, or severe electrolyte disturbances, but wide fluctuations of blood pressure over minutes is suggestive of dysautonomia. The presumed cause is impaired baroreceptor buffering. 23. A frequently reported cause of sudden death in patients with GBS who experience dysautonomia is complete heart block. This is emergently treated with a temporary pacemaker. Few patients ultimately require permanent pacing.179 Untreated vagal activity can progress to profound bradycardia and asystole.

Continued

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24. Studies concluded that plasma exchange is the “first and only treatment that has been proven to be superior to supportive treatment alone in Guillain-Barré syndrome.” 25. Myasthenia gravis (MG) is an autoimmune disease characterized by an autoantibody reaction at the antigen epitopes of the acetylcholine receptor, leading to destruction and simplification of the junctional fold, with subsequent widening of the synaptic cleft. 26. Generalized weakness develops in approximately 85% of patients with MG, often affecting the diaphragm. 27. The edrophonium test is helpful in establishing the diagnosis of MG, but should only be performed in a well-monitored setting, such as the emergency department or ICU.

References 1. Kistler JP, Furie KL: Carotid endarterectomy revisited. N Engl J Med 2000;342:1743–1745. 2. Sacco RL, Ellenberg JH, Mohr JP, et al: Infarcts of undetermined cause: The NINDS stroke data bank. Ann Neurol 1989;25:382–390. 3. Fisher CM: Occlusion of the carotid arteries: Further experiences. Arch Neurol Psychiatry 1954;72:187–204. 4. Fisher CM, Gore I, Okabe M, et al: Atherosclerosis of the carotid and vertebral arteries—extracranial and intracranial. J Neuropathol Exp Neurol 1965;24:455–476. 5. Fisher CM: The arterial lesions underlying lacunes. Acta Neuropathol 1969;12:1–15. 6. Ay H, Oliveira–Filho J, Buonanno FS, et al: Diffusion–weighted imaging identifies a subset of lacunar infarction associated with embolic source. Stroke 1999;30:2644–2650. 7. Mohr JP, Thompson JL, Lazar RM, et al: A comparison of warfarin and aspirin for the prevention of recurrent ischemic stroke. N Engl J Med 2001;345:1444–1451. 8. Bogousslavsky J, Van Melle G, Regli F: The Lausanne Stroke Registry: Analysis of 1000 consecutive patients with first stroke. Stroke 1988;19:1083–1092. 9. Beghi E, Bogliun G, Cavaletti G, et al: Hemorrhagic infarction: Risk factors, clinical and tomographic features, and outcome: A case-control study. Acta Neurol Scand 1989;80:226–231. 10. Mohr JP, Caplan LR, Melski JW, et al: The Harvard cooperative stroke registry: A prospective registry of cases hospitalized with stroke. Neurology 1978;28:754–762. 11. Pruitt AA, Rubin RH, Karchmer AW, et al: Neurologic complications of bacterial endocarditis. Medicine 1978;57:329–343. 12. Roeltgen DP, Weimer GR, Patterson LF: Delayed neurologic complications of left atrial myxoma. Neurology 1981;31:8–13. 13. Bogousslavsky J, Pierre P: Ischemic stroke in patients under age 45. Neurol Clin 1992;10:113–123. 14. Schievink WI: Spontaneous dissection of the carotid and vertebral arteries. N Engl J Med 2001;344:898–906. 15. Moore PM: Vasculitis of the central nervous system. Semin Neurol 1994;14:307–312. 16. Seligsohn U, Lubetzky A: Genetic susceptibility to venous thrombosis. N Engl J Med 2001;344:1222–1231. 17. Lansberg MG, Albers GW, Beaulieu C, et al: Comparison of diffusion–weighted MRI and CT in acute stroke. Neurology 2000;54: 1557–1561.

28. Lambert-Eaton syndrome is distinguished from MG on the basis of the clinical presentation, in which there are commonly seen autonomic and sensory symptoms, as well as with EMG/NCS, in which there is an improvement in response to repetitive stimulation. 29. Critical illness myopathy is often difficult to distinguish from CIP, and there is commonly an overlap of the two. In fact, some have proposed the term critical illness polyneuromyopathy, or CIPNM. 30. Deconditioning syndrome occurs in immobile, poorly nourished patients, who reach a highly catabolic state.

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269. Delay J, Pichot P, Lemperier MT, et al: Un neuroleptique majeur non phenothiazinique et non reserpinique, l’ haldol, dans le traitment des psychoses. Ann Med Physiol (Paris) 1960;118:145–152. 270. Gelenberg AJ, Bellinghausen B, Wojcik JD, et al: A prospective survey of neuroleptic malignant syndrome in a short-term psychiatric hospital. Am J Psychiatry 1988;145:517–518. 271. Keck PE, Sebastianelli J, Pope HG, et al: Frequency and presentation of neuroleptic malignant syndrome in a state psychiatric hospital. J Clin Psychiatry 1989;50:352–355. 272. Guzé BH, Baxter LR: Neuroleptic malignant syndrome. N Engl J Med 1985;313:163–166. 273. Lenler-Petersen P, Hansen BD, Hasselstrom L: A rapidly progressing lethal case of neuroleptic malignant syndrome. Intens Care Med 1990;16:267–268. 274. Keck PE, Caroff SN, McElroy SL: Neuroleptic malignant syndrome and malignant hyperthermia: End of a controversy. J Neuropsychiatry Clin Neurosci 1995;7:134–155. 275. May DC, Morris SW, Stewart RM: Neuroleptic malignant syndrome: response to dantrolene sodium. Ann Intern Med 1983;98:183–184. 276. McDonough CM, Swift G, Sheehan MB: Neuroleptic malignant syndrome: A diagnosis easily missed. Ir Med J 2000;93:152–154. 277. Pope HG, Keck JP, Mcelroy SL: Frequency and presentation of neuroleptic malignant syndrome in a large psychiatric hospital. Am J Psychiatry 1986;143:1227–1233. 278. Kargianis JL, Phillips LC, Hogan KP, et al: Clozapine-associated neuroleptic malignant syndrome: Two new cases and a review of the literature. Ann Pharmacother 1999;33:623–630. 279. Hasan S, Buckley P: Novel antipsychotics and the neuroleptic malignant syndrome: A review and critique. Am J Psychiatry 1998;155: 1113–1116. 280. Friedman LS, Weinrauch LA, D’Elia JA: Metoclopramide-induced neuroleptic malignant syndrome. Arch Intern Med 1987;147: 1495–1497. 281. Madakasira S: Amoxapine-induced neuroleptic malignant syndrome. Drug Intel Clin Pharm 1989;23:50–51. 282. Catterson ML, Martin RL: Anticholinergic toxicity masquerading as neuroleptic malignant syndrome: A case report and review. Ann Clin Psychiatry 1994;6:4267–4269. 283. Mills KC: Serotonin syndrome. Am Fam Physician 1995;52: 1475–1482.

284. Daras M, Kakkouras L, Tuchman AJ, et al: Rhabdomyolysis and hyperthermia after cocaine abuse: A variant of neuroleptic malignant syndrome. Acta Neurol Scand 1995;92:2161–2165. 285. Buckley PF, Hutchinson M: Neuroleptic malignant syndrome. J Neurol Neurosurg Psychiatry 1995;58:271–273. 286. Smego RA, Durack DT: The neuroleptic malignant syndrome. Arch Intern Med 1982;142:1183–1185. 287. Caroff SN, Mann SC: Neuroleptic malignant syndrome. Med Clin North Am 1993;77:185–202. 288. White DAC, Robins AH: Catatonia: Harbinger of the neuroleptic malignant syndrome. Br J Psychiatry 1991;158:419–421. 289. Rosebush P, Stewart T: A prospective analysis of 24 episodes of neuroleptic malignant syndrome. Am J Psychiatry 1989;146:717–725. 290. Keck PE, Pope HG, Cohen BM, et al: Risk factors for neuroleptic malignant syndrome. Arch Gen Psychiatry 1989;46:914–918. 291. Lee JWY: Serum iron in catatonia and neuroleptic malignant syndrome. Biol Psychiatry 1998;44:499–507. 292. Araki M, Takagi A, Higuchi I: Neuroleptic malignant syndrome: Caffeine contracture of single muscle fibers and muscle pathology. Neurology 1988;38:297–301. 293. Behen WM, Madigan M, Clark BJ, et al: Muscle changes in the neuroleptic malignant syndrome. J Clin Pathol 2000;53:223–227. 294. Pelonero AL, Levenson JL, Pandurangi AK: Neuroleptic malignant syndrome: A review. Psych Serv 1998;49:1163–1172. 295. Addonizio G, Susman VL, Roth SD: Neuroleptic malignant syndrome: Review and analysis of 115 cases. Biol Psychiatry 1987;22:1004–1020. 296. Lazarus A, Mann SC, Caroff SN: The Neuroleptic Malignant Syndrome and Related Conditions. Washington DC, American Psychiatric Press, 1989. 297. Davis JM, Janicak PG, Sakkas P, et al: Electroconvulsive therapy in the treatment of neuroleptic malignant syndrome. Convulsive Ther 1991;7:111–120. 298. Addonizio G, Susman VL: ECT as a treatment alternative for patients with symptoms of neuroleptic malignant syndrome. J Clin Psych 1987;48:102–105. 299. Gregorakos L, Thomaides T, Stratouli S, et al: The use of clonidine in the management of autonomic overactivity in neuroleptic malignant syndrome. Clin Auton Res 2000;10:193–196.

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Chapter 14 Prehospital Care of the Patient with Neurologic Injury Andrea Gabrielli, MD, Ahamed H. Idris, MD, A. Joseph Layon, MD

Introduction Optimal neurologic survival after cardiac arrest can be achieved only if all the links of chain of survival are performed efficiently and rapidly. Prehospital care in the setting of cardiac arrest ranges from recognition of early signs of respiratory, neurologic or cardiovascular distress, to basic cardiopulmonary resuscitation (CPR), to the potential for the use of automatic external defibrillation by the lay rescuer; from prompt response of the emergency medical services (EMS) system with institution of advanced cardiac life support (ACLS), to safe transport to an appropriate facility. While neurologic emergencies require specialized and multidisciplinary critical care, the quality of the initial management is the primary determinant for improving survival and neurologic outcome. Therefore, many principles applicable to prehospital care in general can be used in the approach to the neurologically injured patient, regardless if the injury is secondary to trauma or a cerebrovascular event.

Organization of Prehospital Care in North America In North America, the initial response to an out-of-hospital cardiac arrest or central nervous system (CNS) trauma is usually via the police or fire departments. These responders are proficient in providing basic life support (BLS) including CPR, opening the airway, bag-valve-mask (BVM) ventilation, and manual tamponade of external bleeding sites.

Emergency medical technicians-basic (EMT-B) and emergency medical technicians–paramedics (EMT-P) are trained in vehicular extrication, immobilization in transport, and in the case of paramedics, advanced life support.1 Transportation of neurotrauma patients to the emergency department (ED) is usually provided with destination priority given to a certified trauma center. However, distance, geography, logistics, and patient condition may determine the choice and site of transport destination. For example, it may be in the patient’s best interests to have hemodynamic stabilization initiated in a smaller hospital if transportation to a major center is not readily available.2 Even if the destination hospital is not a designated trauma center, outcome is enhanced with the use of the acute CNS injury clinical pathway, in which an emergency physician, neuroradiologist, neurosurgeon, and intensivist are promptly available as the victim reaches the ED.3,4 Generally, ambulance transport is used for transport within a 50-mile radius, assuming that roadway traffic is not a limiting factor in transport time. A rotary wing aircraft is often used for distances between 51 and approximately 150 miles, while a fixed wing aircraft is used for longer distances, when available.5 EMS systems vary considerably throughout the world. In Europe, for example, physicians are often used in the ambulance. Improved resuscitation and survival to discharge when cardiac arrest is present has been reported. In a Danish study of cardiac arrest patients, the presence of a physician in the ambulance increased the hospital discharge rate after cardiac arrest from 1% to 13%.6 The presence of a physician in the 439

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field seems of less importance for major trauma, regardless of association with CNS injury. Recently, a large European study of patients with major trauma (injury severity score [ISS] > 16) and severe head injury attempted to resolve the controversy between the advantage of prolonged ACLS in the field, managed by physicians, and a short BLS resuscitation with immediate transport to a hospital via helicopter with EMS personnel on board. No differences in outcome were demonstrated in this study.7 In a British study, in the presence of a similarly severe neurologic injury not associated with severe multiple trauma, a favorable trend in survival and better outcome were found when the patient was immediately transported by helicopter to an ED where necessary invasive procedures could be performed safely and effectively,8 even if a physician was involved in ACLS provision in the field. These studies suggest that the advantage of a physician in the field is limited to patients in cardiac arrest, and that health resources for trauma patients be focused on providing rapid transport to the ED. Related to costs and availability, and in the face of such evidence-based data, the health care system of the United States will continue to rely on EMT and paramedic first responders.

Overview and Big-Picture Changes: Advanced Cardiac Life Support for Experienced Providers Course The scope of emergency cardiovascular care has been expanded to include prearrest interventions, arrest prevention, and postarrest stabilization. All new guidelines have been rigorously reviewed, adhering to the principles of evidence-based medicine. The class I, IIa, IIb, III, and indeterminate designations after many guidelines have been used to indicate the strength of scientific evidence. More emphasis has been placed on first aid, CPR, and defibrillation in the workplace. A unifying approach to ACLS assessment and management for both lay rescuer and EMS has been proposed. Primary Survey: Airway (open), Breathing (two breaths), Circulation (chest compressions), Defibrillation (use automatic external defibrillation [AED]). Secondary Survey: Airway (advanced airway techniques), Breathing (placement confirmation, check effectiveness), Circulation (access the circulation; administer drugs as indicated), and Differential diagnosis. Education, Training, and Examination Changes

Cerebral Resuscitation and the 2000 American Heart Association Cardiopulmonary Resuscitation Guidelines The pathophysiology and rationale of cerebral resuscitation after cardiac arrest are extensively reviewed in Chapter 15. The Guidelines of the American Heart Association (AHA) 2000 Conference are the result of the first international application of a rigorous, evidence-based approach to produce resuscitation parameters, including neurological outcome.9 The new guidelines also include a reappraisal of old recommendations that have been reaffirmed, assigned for review, or removed. Several issues, pertinent to cerebral outcome after resuscitation during both BLS and ACLS, will be discussed here. These include 1. Overview and big-picture changes from the previous guidelines 2. Education, training, and examination 3. Ethical concerns in resuscitation 4. BLS 5. Airway and ventilation (BLS and ACLS) 6. ACLS 7. Pediatric advanced life support (PALS) 8. Neonatal resuscitation 9. Circulatory adjuncts approved for clinical use 10. Future research on cerebral resuscitation in prehospital setting.

Commitment to education and training based on core learning objectives has been increased. These include education and training innovations such as videotape-mediated training, and auditory and/or visual prompts. The educational value of ACLS, PALS, and BLS has been increased. Ethical Concerns in Resuscitation Family presence during resuscitation has been encouraged and is considered valuable. Evaluating and honoring “Do Not Attempt Resuscitation” (DNAR) status in field, and Certification of Death has been re-evaluated and is encouraged when appropriate. Basic Life Support: Adult and Pediatric The importance of early defibrillation has been further emphasized. In fact, the value of reducing the interval between adult sudden cardiac arrest and first defibrillatory shock by 1 to 2 minutes has been shown to do more to improve the probability of survival for an individual patient than all the medications, airway interventions, and newly designed defibrillation waveforms combined. Special situations that modify the phone first (call 911 first) versus phone fast (resuscitate immediately, then call 911) guidelines have been clarified. BLS recognizes clinical exceptions to the phone fast guideline (applies to children younger than 8 years of age) and the phone first guideline (applies to children older than 8 years of age). The major exception of the phone fast rule is in those children (younger

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than 8 years of age) known to be at risk for ventricular fibrillation/ventricular tachycardia who experience sudden witnessed collapse. The new BLS guidelines for the following situations in adults have been altered to phone fast, that is, provide 1 minute of CPR before phoning the EMS system: 1. 2. 3. 4.

Submersion/near-drowning Poisoning/drug overdose Trauma Respiratory arrest.

Smaller Tidal Volumes During Adult Rescue Breathing More emphasis has been placed on proper BVM ventilation as a skill that all BLS health care providers must master to increase resuscitation efficacy and reduce complications. Rescuers have been given recommendations to deliver smaller tidal volumes during ventilation with BVM ventilation or when supplementary oxygen is available. Recommendations for rescue breaths delivered by mouth-to-mouth or mouth-to-barrier device have been set at an average of 700 to 1000 mL, delivered over 1.5 to 2 seconds. If supplementary oxygen is available, the skilled rescuer should attempt to provide smaller tidal volumes during mouth-tomouth and BVM ventilation, approximately 400 to 600 mL, with an inspiratory time of 1 to 2 seconds. If the smallest tidal volumes are used, the chest should rise visibly and the oxygen saturation should be maintained. Mouth-to-nose breathing has been accepted as an alternative to mouth-tonose-and-mouth or mouth-to-mouth rescue breathing for an infant. Cardiopulmonary Resuscitation The pulse check has been removed from the lay rescuer’s checklist. In its place are signs of circulation, which include normal breathing, coughing, or movement. If no signs of circulation are detected, the rescuer should begin chest compressions and attach an AED, if available. A new chest compression rate for adults has been recommended, irrespective of whether used in one- or two-rescuer CPR, by lay rescuers, or by health care professionals. This chest compression rate is approximately 100 compressions per minute. The adult compression-ventilation ratio has also been changed. For adult victims, two rescuers should no longer use a compression-ventilation ratio of 5 : 1. Instead, they should use a compression-ventilation ratio of 15 : 2 until the airway is secured. The 5 : 1 ratio should be used in pediatric arrest by professional responders regardless of whether one or two rescuers are involved. The two thumb-encircling hands chest compression technique has been recommended

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over the two-finger compression technique for two-rescuer infant CPR, when performed by health care providers. The use of AEDs has been encouraged for victims of cardiac arrest older than approximately 8 years of age, or heavier than approximately 25 kg (55 lbs). Although data regarding the use of AEDs in pediatric cardiac arrest victims is limited, the guidelines suggest the use of defibrillators with adjustable energy dose for in-hospital use in areas that routinely care for infants and children. CPR performed without mouth-to-mouth ventilation has been reviewed and is encouraged if the rescuer is unwilling to perform rescue breathing for an adult victim. The rescuer should access the EMS system, open the airway, and perform chest compressions at the rate of approximately 100 compressions per minute CPR without ventilation; good quality CPR in the presence of an open airway will allow for acceptable gas exchange. Management of the Airway and Ventilation The guideline sections on airway management and ventilation contain the greatest number of new recommendations. Most of these recommendations apply to health care providers at both the BLS and ALS level. Airway devices (BVM, laryngeal mask airway [LMA], and Combitube) have been introduced as valid alternatives to the endotracheal tube. Recommendations for secondary confirmation of proper tracheal tube placement have been emphasized. Any EMS system that authorizes endotracheal intubation must ensure proper initial training, monitoring of skill retention, and ongoing monitoring of safety and effectiveness. Providers should assess endotracheal tube placement by primary confirmation using physical examination techniques, plus one or more secondary confirmation techniques, including qualitative end-tidal CO2 detectors, quantitative and continuous CO2 measurement (capnometry versus capnography), as well as devices that specifically detect tubes located in the esophagus. Specific approaches to prevent tube dislodgment have been encouraged, such as use of commercially manufactured tube holders. This is especially true in the prehospital setting, in which patient and transportation movements greatly increase the risk of dislodgment. Airway issues are discussed in detail in Chapter 16. Advanced Cardiac Life Support A comprehensive cardiac arrest algorithm has been introduced. This algorithm also presents the primary and secondary “ABCD Surveys” as a manner to organize the rescuers’ thoughts, action sequences, and anticipations. In ventricular fibrillation (VF)/pulseless ventricular tachycardia (VT), after attempting electrical conversion with a rapid sequence of three voltage administrations, intravascular epinephrine 1 mg or vasopressin 40 U for refractory

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VF/pulseless VT has been recommended. The fourth shock should be given 30 to 60 seconds after either epinephrine or vasopressin, to allow circulation and distribution of the drugs. The most effective adult dose of epinephrine remains 1 mg every 3 to 5 minutes. Higher doses of epinephrine are suspected of causing harm and, while acceptable, are no longer a recommended option. Vasopressin has been introduced as an equivalent to epinephrine for refractory VF/pulseless VT. As a vasoconstrictor, vasopressin appears as effective as epinephrine, with fewer negative cardiac effects. A unique advantage of vasopressin has been described in that it may be superior to epinephrine in increasing diastolic blood pressure,10 a fundamental component of cerebral blood flow (CPP), where CPP = {([systolic blood pressure - diastolic blood pressure] ∏ 3) + diastolic blood pressure} - ICP where ICP is intracranial pressure. Thus, when compared with epinephrine, it appears that vasopressin has the theoretical advantage during resuscitation of increasing both cerebral blood flow and cerebral oxygen delivery.11-13 While this advantage can be demonstrated in animal models of early and late CPR, it has not been confirmed in a recent, small, prospective, randomized human study.14 At this time, data from a similar, but larger, multicenter study in Europe are being analyzed for survival and neurologic outcome. Because vasopressin lasts much longer (10 to 20 minutes) than epinephrine, only one dose is recommended. By consensus, epinephrine 1 mg every 3 to 5 minutes may be resumed after 5 to 10 minutes if there has been no response to the vasopressin. Amiodarone has been added to the list of antiarrhythmic agents to consider for shock-refractory VF/pulseless VT as better choice than lidocaine. Amiodarone requires several time-consuming steps before administration: a glass ampule must be opened, the drug aspirated into a syringe with a large-gauge needle and diluted with 0.9% saline solution, the needle changed, and then the drug administered slowly through the intravenous (IV) line. Bretylium has been eliminated in the ACLS list of recommended antiarrhythmics due to its unavailability. Lidocaine remains acceptable for the treatment of shock-refractory VF, but the level of supportive evidence is weak. Magnesium has demonstrated effectiveness for treatment of VF/pulseless VT in two clinical situations: Torsades de Pointes and other arrhythmias associated with known hypomagnesemia. The algorithm for pulseless electrical activity and asystole has essentially remained the same for more than a decade, with epinephrine, atropine, and pacing the only three interventions available. Pediatric Advanced Life Support The intraosseous (IO) route has been recommended when no intravenous access is promptly available in arrest victims

six years of age and older; there is no upper age limit for the use of an IO device. PALS uses the 90-second, suggested “reasonable” limit, for establishment of vascular access in cardiac arrest, but offers a little more flexibility if the patient is stable. Vagal maneuvers have been added to the treatment algorithm for supraventricular tachycardia. Vagal maneuvers are recommended for the treatment of supraventricular tachycardia (SVT) provided these maneuvers do not delay cardioversion or the administration of adenosine for the child with poor systemic perfusion. Ice water applied to the face is a most effective vagal-enhancing maneuver in infants and young children. The administration of amiodarone is now recommended for pediatric SVT and VF/VT. Amiodarone can be used for both supraventricular and ventricular arrhythmias; in particular, amiodarone may be considered for refractory VF that persists despite three shocks. As in adult arrests, the use of high dose epinephrine has been de-emphasized. The recommended initial resuscitation dose of epinephrine for pediatric cardiac arrest is 0.01 mg/ kg, given IV or IO, or 0.1 mg/kg by the tracheal route. Repeated doses are recommended every 3 to 5 minutes for ongoing arrest. The same dose of epinephrine is recommended for second and subsequent doses for unresponsive asystolic and pulseless arrest, but higher doses of epinephrine (0.1 to 0.2 mg/kg) by any intravascular route may be considered. Attempting to defibrillate VF/pulseless VT detected by an AED is acceptable and recommended for children 8 years of age or older. Neonatal Resuscitation Although most new recommendations are related to in-hospital treatment of the newborn, significant prehospital care is still provided in rural areas. The most important recommendations are: 1. The importance of ventilation in the newly born infant with heart rate less than 100 beats per minute has been reaffirmed. 2. The indications for chest compressions have been simplified. Chest compressions are initiated if the heart rate is absent or if the heart rate remains less than 60 beats per minute after 30 seconds of adequate assisted ventilation. Chest compressions must be coordinated with ventilation at a ratio of 3 : 1, with a rate of 120 events per minute, comprised of 90 chest compressions and 30 ventilations. 3. Chest compression with two thumbs and encircling fingers is the preferred method for two-rescuer health care providers. Compressions should be delivered to the lower one third of the sternum. Other acceptable, although not preferred, chest compression techniques include the two thumb-encircling hand technique and the two-finger compression technique; of these, the two

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thumb-encircling hands technique is preferred as the secondary technique. 4. The LMA is now available and acceptable for use in fullborn infants. The use of this device, while relatively intuitive, is considered appropriate only by properly trained prehospital providers. 5. As with the adult arrest victim, secondary confirmation of endotracheal tube placement is recommended, as are specific approaches to prevent tube dislodgment, such as the use of commercially manufactured tube holders. This is particularly true for the prehospital setting in which there is greater risk of dislodgment. 6. The use of isotonic crystalloid solutions for initial volume resuscitation instead of albumin-containing solutions has been confirmed. The fluid of choice for volume expansion in the prehospital phase is an isotonic crystalloid solution such as 0.9% saline or Ringer’s lactate solutions.

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cardiac arrest is still within the defined window of opportunity (<30 minutes) 6. The impedance threshold valve enhances negative intrathoracic pressure during the decompression phase of chest compression with the active compressiondecompression cardiopump. Early experience suggests some improvement in hemodynamic and expired CO2 during CPR.

The Future of Cerebral Resuscitation after Cardiac Arrest While research to help laypersons and EMS personnel to provide a higher quality of life support first aid continues, other more sophisticated ways to improve outcome in patients with severe CNS injury have been studied. While all are not fully accepted in clinical practice, we suspect that within a short time this will have changed.

Issues in Neonatal Cardiopulmonary Resuscitation There are circumstances in which noninitiation or discontinuation of resuscitation in the delivery room may be appropriate. Specific situations are suggested in the AHA guidelines and include infants with confirmed gestation less than 23 weeks, birthweight less than 400 g, anencephaly, or confirmed trisomy 13 or 18. Hypothermia during neonatal resuscitation cannot be recommended routinely until appropriate controlled studies in humans have been performed. Other Circulatory Adjuncts Approved for Clinical Use During Cardiopulmonary Resuscitation A handful of new devices are available for use in resuscitation. The role these will play is still to be determined, but we mention these so that the reader is aware of future possibilities. At this time, however, none of these devices have shown any statistical advantage to standard chest compression in humans. These new devices include 1. Active compression-decompression CPR (“plunger” CPR) as an alternative to standard CPR 2. Interposed abdominal compression CPR for in-hospital resuscitation as an alternative to standard CPR 3. Vest CPR as an alternative for standard CPR for hemodynamic support and short-term (6-hour) salvage 4. Mechanical (piston) CPR may provide hemodynamic support comparable to standard manual CPR, can eliminate rescuer fatigue, and can be helpful in improving the quality of CPR in situations where manual chest compressions are difficult 5. Direct cardiac massage CPR as an alternative technique for resuscitation, considered after initial attempts at external chest compressions have failed and time of

Hypothermia Hypothermia has been investigated in both animal and human models. Mild postresuscitation hypothermia (34°C to 35°C) has been beneficial to cerebral outcome in an animal model of cardiac arrest.15 A recent trial in cardiac arrest patients confirmed preliminary data from animals. Two resuscitation teams working independently in Europe and Australia used a cooling device consisting of a mattress delivering cold air over the entire body, and showed reduced mortality and improved neurologic outcome.16,17 These recent reports, in which body temperature was decreased to 36°C (mild hypothermia) within 12 to 24 hours of the arrest, bring new hope to the possible efficacy of therapeutic hypothermia altering the survival of cardiac arrest patients.16,17 The possible mechanisms of cerebroprotection from hypothermia include a reduction of the cerebral metabolic rate of oxygen, and mitigation or prevention of secondary injury to neurologic elements from hypoxia and hypotension.18,19 The unquestioned improved neurologic outcomes noted in these studies have raised new enthusiasm in those of us involved in prehospital critical care. There is a clear need for randomized trials to test mild hypothermia in stroke, TBI, spinal cord injury, and hemorrhagic shock. An accurate report of the neurological condition after resuscitation from cardiac arrest is fundamental to evaluate new technologies and strategies of resuscitation. For example, determination of Glasgow Coma Score (GCS; Table 14-1) as early as 20 to 30 minutes after restoration of spontaneous circulation has a significant correlation with neurologic outcome and survival.20 Thus, GCS should be assessed by the EMS personnel at the time of return of spontaneous circulation and included in their run reports so that comparison with later values is possible.

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Table 14-1  Glasgow Coma Scale

Antireperfusion Injury Therapy

Item

Factor

Score

Best motor response

Obeys Localizes Withdraws (flexion) Abnormal flexion Extensor response Nil Oriented Confused conversation Inappropriate words Incomprehensible sounds Nil Spontaneous To speech To pain Nil

6 5 4 3 2 1 5 4 3 2 1 4 3 2 1

Verbal response

Eye opening

GCS, sum of motor + verbal + eye scores.

New Indexes of Long-Term Neurologic Prognosis Despite advances in CPR, the rate of effective cerebral resuscitation remains less than 20%, and 50% of patients never regain consciousness.21 Long-term neurologic outcome is also discouraging. One year after cardiac arrest, 48% of survivors remained with moderate-to-severe neuropsychologic deficits.22 Traditionally, neurologic outcome depended on clinical factors such as duration of cardiac arrest, duration of CPR, time to return of spontaneous circulation, neurologic examination after return of spontaneous circulation, post-CPR extracerebral organ dysfunction, and premorbid and postmorbid disorders. Recent investigations have attempted to identify better predictors of neurologic outcome after CPR. Somatosensory-evoked potentials,23,24 proton magnetic spectroscopy for brain lactate,24 cerebral spinal fluid creatinine kinase BB isoenzymes,25 blood lactate,26 serum prostate-specific markers,27,28 serum neuronspecific enolase,29 and astroglial protein S-10028,30 among others, have shown interesting correlations with long-term neurologic prognosis. Despite promising studies, at the present time, none of these methods can be reliably used for clinical decision-making after resuscitation. Postresuscitation-Induced Hypertension Cardiac arrest is associated with an immediate postarrest cerebral low flow state (see Chapter 15). In a dog model of cardiac arrest, better neurologic outcome correlated with hypertensive therapy induced with norepinephrine when a systolic pressure of 200 mm Hg was achieved. Interestingly, hemodilution seems to enhance the effect of hypertension. These results suggest that when a CNS injury is present after cardiac arrest and in absence of penetrating injury or occult bleeding, hypertension and less aggressive correction of the hematocrit should be considered.31

Recent laboratory work has shown significant improvement of neurologic outcome with the use of cell-permeable antioxidant 4-hydroxy-2,2,6-tetramethyl-piperidine-1-oxyl (Tempol). This work was performed in a canine model of late cardiac arrest, in which brain hypothermia was achieved by flushing the cerebral arteries with an iced saline solution.32 The presence of accurate markers of reperfusion injury, such as F2-isoprostane, has allowed confirmation that reperfusion injury exists as an early phenomenon after cardiac arrest.33 At this time, the potential of and treatment for antireperfusion injury after cardiac arrest is being actively investigated.

Traumatic Central Nervous System Injury and Prehospital Care Two basic principles underlie the treatment of patients with severe CNS injury: 1. The CNS has minimal reserves to meet ongoing metabolic needs. 2. Regeneration of the CNS is complex and affected by secondary insults. Hypoxia and ischemia are by far the two most import secondary insults and the time interval between onset of injury and treatment is fundamental when considering the possibility of recovery.34 Closed Head Injuries Prompt and effective EMS response is fundamental to improve neurologic outcome, requiring significant investment and availability of heath care resources.35 Health care economics and prehospital care resources are significant factors impacting neurologic outcome after a CNS injury. For example, when compared with North America, the neurologic outcome of patients in India with GCS of 5 or less was significantly worse36; this difference has been attributed to delay in the EMS response. Interestingly, this trend is not observed in patients with GCS greater than 5, suggesting that most of the effectiveness of North American style of prehospital care is seen in patients in whom a shift from land to helicopter transportation is made. As discussed previously, the presence of a physician in the ambulance has not been consistently associated with a better neurologic outcome.6,7 For patients with closed head injury, rapid transport to the hospital by helicopter remains the main variable for improved survival.37,38 Quick and effective stabilization of the patient is as important as rapid mode of transportation. Regardless, the need for rapid transport after severe blunt trauma with suspected neurologic injury, as opposed to initial hemodynamic stabilization of the patient in the field, has been traditionally

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debated.39 For example, prehospital trauma life support (PHTLS) recommendations currently suggest, as a standard, to limit the time on scene by EMS to less than 10 (“platinum”) minutes to maximize the interventions in the ED in the first (“golden”) hour.39 However, a recent European review of 1200 trauma patients with high injury severity scores (ISS) showed that endotracheal intubation, proper ventilation, and chest tube placement can positively and dramatically influence survival and neurologic outcome. Surprisingly, this could not be demonstrated with the use of IV fluid therapy. On the contrary, it has been demonstrated that the need for fluid resuscitation of more than 2000 mL is an independent variable for a worse outcome; it is not clear if the use of this volume of IV fluid is simply a marker of more severe injury or represents over-resuscitation.3 The associated injuries may influence the decision on how rapidly to move the victim from the field and has implications for prehospital area policies. For example, injury to occupants of a motor vehicle has different features than that of pedestrians. In general, a policy of a “swoop and scoop” is advocated for injured car occupants in shock because of the high frequency of aortic and abdominal injuries. On the other hand, ALS measures at the scene should be considered in the injured pedestrian to stabilize the airway and to protect the entire spine because of the high frequency of brain injury or spinal trauma.40 Most head injuries do not occur in isolation. In fact, up to 60% of the cases of severe head trauma are associated with multiple trauma.41 Regardless, the presence of a brain injury with a GCS of 8 or less is the single most important predictor of mortality in patients with multiple trauma. A more robust transportation mode minimizes the need for “temporary stabilization” in facilities without personnel skilled in diagnosing and treating CNS injury. While any designated trauma center is the preferred transfer location for the patient, other, closer, centers with in-house neurosurgeons should be considered eligible for immediate transfer of an unstable patient.42,43 In fact, although the American College of Surgeons Committee on Trauma (ACS-COT) requires the presence of an in-house trauma surgeon for designation of a level 1 trauma center,44 outcome is thought to be as good when a surgeon is simply “promptly available” as required for designation as a level 2 trauma center.45 In our opinion, the ready availability of physicians with trauma experience is fundamental for successful treatment of neurologic injury, regardless of the hospital’s trauma designation. These individuals should be also involved in the organization of prehospital and ED care, acute hospital care including that delivered in the ICU, and discharge planning. In neurotrauma, it is essential that an interested neurosurgeon be actively involved in defining prehospital and treatment guidelines.46 The concept that prehospital care and intensive medical treatment might improve outcome has been understood since the 1950s.47 However, recent evidence-based medicine

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analysis reemphasizes the importance of prehospital care for the final neurologic outcome in closed head injuries. In a study in patients with acute subdural hematoma, a delay of treatment beyond four hours significantly affected the neurological outcome.48 The time between injury and treatment has been clearly associated with increased mortality in the absence of well-organized prehospital emergency care.49–51 An extensive MEDLINE review for 1966 through 1998, using head injury and prehospital care as keywords, confirmed that hypotension (systolic blood pressure < 90 mm Hg) and hypoxia (oxygen saturation < 90% or PaO2 < 60 mm Hg) were directly related to a poor outcome.52 Blood pressure after head trauma seems to show a biphasic pattern. In animal models of CNS trauma, hemodynamics immediately after impact typically are characterized by a catecholamine surge and hypertension.53,54 While it is possible that this initial hypertensive episode contributes to associated intracranial hemorrhage in humans, the initial pressure recorded by the EMS first responders usually documents profound hypotension. Systolic blood pressure of less than 90 mm Hg can be detected in between 16% and 31% of these patients,55,56 with hypoxia (SpO2 < 90%) reaching as high as 65% of the cases.57 The traumatic coma data bank58 demonstrated that a single observation of blood pressure less than 90 mm Hg during the prehospital period, PaO2 less than 60 mm Hg by blood gas analysis, or SpO2 less than 90% were statistically significant independent factors for increasing mortality to as high as 50%.59 While an initial blood pressure of 90 mm Hg is the usual empiric reference point for fluid resuscitation, especially if ongoing bleeding is suspected, it may not necessarily represent an adequate target after head trauma. Attention should be paid to the mean arterial pressure because it represents a fundamental part of the equation of a cerebral perfusion pressure. If resuscitation is inadequate and fluids are judged necessary, they should be given. In fact, there are overall data suggesting a negative relationship between the amount of fluid or blood infused and the intracranial pressure in patients with head injury and multiple trauma.60 Hypertonic saline and mannitol have been considered as adjunctive therapies in the prehospital phase of the patient with traumatic brain injury (TBI). The use of hypertonic saline has been correlated with better outcome,61 and a recent meta-analysis and trial both suggest clinical improvement when hypertonic saline is used in patients with TBI and a GCS less than 9.62,63 The use of mannitol in the field is still debated. Despite the theoretical benefit of acutely reducing ICP in patients with severe TBI, a prospective study showed no improved neurologic outcome when in-the-field mannitol was used. Remarkably, in this study the treatment group showed significant hypotension shortly after hospital arrival secondary to brisk osmotic diuresis aggravating other causes of hypovolemia.64 Although one prefers never to say “never” or “always,” patients with TBI and a GCS of 3 to 5 always require endo-

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tracheal intubation (achieved 27% of the time in the field). Additionally, 72% of patients with TBI and a GCS of 6 to 7 require endotracheal intubation (achieved 27% of the time in the field), and 61% of patients with TBI and a GCS of 8 to 9 require the same (achieved 8% of the time the field). Despite the general recommendation to immediately intubate all patients with TBI and a GCS less than 8 in the field, there are still a considerable number of patients for whom intubation was performed in the ED because it was judged unnecessary by EMS personnel. We cannot overemphasize the fact that mortality is significantly reduced when patients with TBI, low GCS, and isolated head injury are intubated.65 In general, the approach in the field to patients with head trauma follows the standard ABC protocol approach.“Impact apnea” has been described immediately after traumatic brain injury by EMS observation and confirmed by animal laboratory data.66,67 Impact apnea usually appears as spontaneous hypoventilation and can be followed by pulmonary aspiration of passively regurgitated gastric contents. Bystanders or EMS providers attending the victim can facilitate spontaneous ventilation with mild extension of the head or by moving the victim into the lateral decubitus position. This maneuver, while decreasing the chance of airway obstruction and aspiration, has the potential to exacerbate a concurrent cervical spine injury. Therefore, if performed at all, it must be performed with great care, the patient being rotated into the lateral position using the “log roll” technique with the head and cervical spine being continuously supported.68 A recent review from the European Brain Injury Consortium confirmed that respiratory failure requiring intubation is common in the prehospital arena in patients with severe brain injury (GCS £ 7).69 In a retrospective analysis of more than 1000 patients with a median GCS of 7 (range 4 to 11) intubation was performed in 78%. Because so many patients are intubated and ventilated before arrival at the neurosurgical unit, the eye opening and verbal response components of GCS may not be testable. In these cases, severe injury can be stratified with a modified GCS, using only motor response. While, since 1974, the GCS has been widely used clinically as the measurement of severity of injury in patients with severe traumatic brain injury,70 the predictive power of this tool has been better for very good outcome from a high score than for poor outcome from a low score. The need for endotracheal intubation in the field, and medications interfering with GCS measurement are the main reasons for an erroneous poor outcome prediction from an initial low GCS. Efforts to reliably obtain the GCS before using medications or performing intubation of the trachea should be maximized. Generally, approximately 20% of patients with the worst initial GCS will survive, and 8% to 10% will have some residual neurologic function if the GCS is between 4 and 5. As suggested by the latest neurotrauma guidelines, the reliability of prehospital GCS requires further investigation.71

Alcohol intoxication plays a major role in hospital outcome after acute brain injury. It has been shown that an alcohol level greater than 100 mg/dL is a risk factor for respiratory failure in the field, requiring endotracheal intubation.72 Unfortunately, alcohol intoxication may significantly decrease the GCS on examination in the field as well as in the ED. In fact, the placement frequency of an intracranial pressure monitoring device is statistically increased in patients with alcohol intoxication. Additionally, although the likelihood of intubation in the field in alcohol-intoxicated patients is estimated to be approximately 30% higher than in a less intoxicated matching group (alcohol level < 100 mg/dL), the number of patients requiring surgical intervention is not increased. While alcohol clearance is associated with a “miraculous” awakening from head trauma coma, this group of patients still presents a high hospital morbidity and length to stay secondary mostly to gramnegative pneumonia.41 Limiting long-acting sedatives and neuromuscular blocking agents is essential for an accurate definition of the GCS. In patients with subdural hematoma up to 10 mm in size and midline shift up to 5 mm, operative strategy was influenced by the use of sedation in the field.73 In general, some of these injuries can be treated with nonoperative management as long as physical examination and neuroradiology interpretation are reliable. Finally, combined devastating neurologic injuries of brain and spinal cord may confound the neurologic examination. For example, a partial resolution of spinal block in patients with concurrent coma may paradoxically facilitate the upper motor neuron segment and can be characterized by the presence of spinal reflexes. In such a situation, a presumptive diagnosis of brain death must be confirmed after arrival to the hospital, after ruling out or reversing intoxication and hypothermia, with an apnea test or cerebral blood flow scan.74 For these reasons, among others, a diagnosis of brain death is rarely made in the first 24 hours after injury. While intubation can be life saving and is fundamental to enhance neurologic recovery, low CO2 from hyperventilation can be an independent predictor of neurological deterioration and is, therefore, a parameter to follow in the prehospital phase of care. Acute hyperventilation in patients with TBI has potential adverse affects due to loss of cerebral vascular regulation, cerebral hypoperfusion, brain cell hypoxemia, and initial and/or rebound increase in ICP.75 A randomized prospective trial identified worse neurologic outcome in hyperventilated patients as compared to those kept at a normal PaCO2.76 Even when a transport ventilator and capnograph were used, low CO2 was observed in 70% of the cases. When mechanical ventilation was compared with manual ventilation, an almost equal amount of inappropriate hyperventilation was noticed (70% vs. 60%). Because clinical data as well as laboratory data document inappropriate hyperventilation in trauma patients, despite consen-

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sus guidelines and recommendations, monitoring of the end tidal CO2 and use of new ventilator technology that limits erroneous settings on transport ventilation should be encouraged.77 Other extracerebral factors, such as hypotension or hypoxemia, are confounding factors in the assessment of neurologic impairment. A quick stratification of patients on arrival to the ED based on motor response, although not a complete neurologic examination, can provide important baseline data that may influence initial clinical decisions, including frequency and type of neurologic monitoring. The effect of hypothermia on neurologic injury has been discussed previously. Hypothermia reduced high ICP in neurotrauma patients, but its relationship to neurologic outcome is unclear. While all trauma physicians would agree that mild hypothermia (35°C to 36°C) on admissions in a patient with cardiac arrest and CNS injury should not be actively reversed, a large multicenter, prospective, randomized study in which induction of hypothermia was performed with a temperature control pad incorporated into a kinetic treatment table showed no improvement in neurologic outcome.78 However, the study had flaws, including a significant portion of the study population who did not achieve the hypothermic goal and control patients who were hypothermic. Occasionally, hypothermia in a patient with head trauma is too severe and requires rewarming. A select category of severely hypothermic patients after CNS injury are near-drowning victims, asphyxiated patients, and avalanche victims. In these patients, core body temperature can drop below 30°C. In a recent series of patients with core body temperature between 24°C and 30°C, the use of forced air rewarming proved to be an efficient and safe method of managing the rewarming. In this category of patients, active rewarming usually stops when the temperature reaches 35°C.79 Head Trauma in the Pediatric Population Resuscitation and neurologic outcomes in children and infants have specific characteristics different than in adults. The GCS and the GOS have not been standardized in infants and children, affecting interpretations of any randomized controlled study.80 Because hypoxia is the predominant triggering mechanism of cardiac arrest in children, prevention and correction of hypoxia is fundamental to minimize secondary injury in this population.81 Both traumatic brain injury and asphyxic cardiac arrest in children share two common pathophysiologic mechanisms: glutamate neurotoxicity in an acid environment82 and a transitory, but remarkable, reduction of cerebral blood flow.83 Multiple mechanisms participate in the reduction of cerebral blood flow, including increased production of endothelin-184 and decreased production of nitric oxide.85 The presence of hypoperfusion after TBI in the pediatric population may

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imply that postresuscitation, transient, induced hypertension in brain-injured pediatric patients could lead to improved outcome. However, no studies are available in the pediatric population testing this hypothesis.86 Penetrating Head Injuries Prehospital treatment of the patient with penetrating head injuries has several specific implications, although neurologic assessment and initial treatment are similar to other patients with presumed increased ICP and severe neurologic injury.87 First responders will initiate CPR as needed. Generally, any patient with a penetrating head injury is immobilized in order to protect the skull and the cervical spine. If no other source of injury is present, the patient is placed on a long backboard and ventilation, if necessary, is provided by a BVM device. Immediate administration of oxygen is necessary to prevent secondary injury from hypoxia. Ventilation of the unprotected airway via a BVM device with O2 should be provided according to the new resuscitation guidelines published by the AHA. IV access should be immediately obtained; however, the lack of IV access is not a reason to delay immediate transport to a facility with a CT scanner and a neurosurgeon. Patients with penetrating head injuries, unless there is associated bleeding from scalp lacerations, usually do not require large volumes of IV fluids.88 Advanced life support is usually provided by paramedics. Once again, priority should be given to the airway. While nasal intubation has been a preferred method of intubation in most trauma, it has fallen out of favor in head injured patients because of a potential acute increase in ICP in closed head injuries, and the possible danger of ethmoid perforation in patients with a fracture of the posterior fossa.89 Technical details on intubation devices and backup procedures have been extensively described in the airway management chapter (see Chapter 16). Neurologic evaluation may be performed utilizing the GCS or the AVPU method (A = alert, V = response to verbal stimuli, P = responsive to painful stimuli, and U = Unresponsive to pain). In general, all the “P” and “U” patients will require assisted ventilation via a BVM device, and should have their tracheas cannulated as soon as possible. Poor gag reflex, hypoventilation, hyperventilation, hypoxia documented by pulse oximeter, and repeated seizures, are all indications for control of the airway by intubation as rapidly as possible.90 All patients with penetrating trauma to the head should be considered at high risk for cervical spine injury. A CT scan of the neck should be performed to evaluate damage to the cervical spine. In fact, approximately 5% to 10% of all patients with head injury have associated spinal injury.91 If oral intubation is necessary in these patients, it should be performed with in-line stabilization of the cervical spine (see Chapter 16). The Sellick maneuver should be performed during intu-

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bation to prevent gastric insufflation, vomiting, or passive regurgitation of gastric contents with pulmonary aspiration.92 A dose of lidocaine, between 1 to 1.5 mg/kg, followed by “minimal” dose of a hypnotic agent such as thiopental (0.5 to 2 mg/kg) or etomidate (0.2 mg/kg) should be administered intravenously before intubation.93 Etomidate is our choice in any hemodynamically unstable or hypovolemic patient. The use of neuromuscular blocking (NMB) agents is controversial. In our EMS system, the paramedics are not allowed to use NMB agents of any classification. It is appropriate to allow the use of the short-acting NMB agent, succinylcholine, in the hospital setting if personnel with airway expertise, preferably an anesthesiologist, are available. Backup devices to achieve access to the airway either above (LMA, Combitube) or below the vocal cords (tracheotomy kit, emergency tracheotomy) should be available. Intravenous short- or long-acting benzodiazepines may be used to break seizure activity (midazolam 2 to 4 mg, lorazepam 1 to 2 mg, diazepam 5 to 10 mg) or for sedation before intubation. The use of bolus doses of phenytoin has been shown to decrease the incidence of long-term posttraumatic epilepsy.94 Although routine hyperventilation is avoided in CNS trauma because it may acutely decrease cerebral blood flow, clinical signs of impending herniation— such as the onset of Cushing’s triad (acute hypertension, bradycardia, spontaneous hyperventilation) or new anisocoria—can be treated with short periods of hyperventilation. Arterial blood for PaCO2 analysis is typically unavailable in the field, and even an end-tidal CO2 of 25 to 30 mm Hg can be an unreliable marker of hyperventilation due to hypovolemia, low cardiac output state, or preexisting pulmonary disease. In general, squeezing one third of the Ambu bag volume (approximately 600 mL) 10 to 12 times per minute should be more than adequate to avoid unintentional hyperventilation.

Prehospital Care of Spinal Cord Injury In the United States, there are more than 10,000 spinal injuries annually, with males predominating in this pathophysiology (81.6%). The average age of patients is 32.1 years, and most of the injuries are related to motor vehicles crashes (38.5%), followed by acts of violence (24.5%), and falls (21.8%). Because trauma patients are typically young and healthy before the injury, the social and economic consequences of spinal cord injury are quite severe.95,96 Prehospital care is essentially related to treatment of hemodynamic instability and prevention of worsening of the neurologic injury. The initial approach to all trauma patients, spinal cord injuries included, begins with the usual “ABCs” (airway, breathing, and circulation). Airway and hemodynamic management in patients with spinal cord injuries present specific challenges for the prehospital

providers. In general, as the phrenic nerve is supplied from cervical levels three through five, injuries above the third cervical level result in almost immediate respiratory paralysis, with the need for intubation and ventilation. However, even spinal cord lesions below the fifth cervical level can be associated with hypercarbic, hypoxic, or mixed respiratory failure. Often, even patients with spinal cord injury with intact diaphragmatic function will have a reduced forced vital capacity (FVC) of at least 25% from the predicted value, secondary to paradoxical movement of the diaphragm and chest walls.97 Although the decision as to the need for intubation is individually taken based on concurrent trauma and mental status, a patient with an FVC of less than 15 mL/kg, or a negative inspiratory force (NIF) greater than -30 cm H2O (absolute number less than 30) will likely require intubation and ventilatory support. A rapidly deteriorating arterial blood gas, with saturation in the low 90s or a PaCO2 above 50 mm Hg, is another reason to rapidly place an endotracheal tube. The prehospital health provider should have a low index of suspicion for worsening respiratory status and should proceed to intubation before the patient reaches critical desaturation. Other conditions that will result in respiratory deterioration in a cervical-spine injured patient are failure of the respiratory accessory muscles, flail chest, tension pneumothorax, and open pneumothorax. If the patient is unconscious and a cervical spine injury is suspected, manipulation of the airway should be performed particularly carefully, minimizing movement to a gentle chin lift or forward mandibular thrust to maintain an open airway. The use of a plastic oral airway is not recommended if the patient is not intubated because it can contribute, in the presence of a strong gag reflex, to emesis with sudden neck movement and potential aspiration of gastric contents. If the patient is unconscious, immediate control of the airway with an endotracheal tube should be performed. While a blind nasal intubation is a practical way to proceed, it should not be performed where there is suspicion of intracranial injury with basal skull fracture or when there is obvious facial bone deformation. In such conditions, oral endotracheal intubation with in-line manual cervical immobilization and cricoid pressure (the Sellick maneuver) should be performed.98 The evidence-based medicine approach has demonstrated that use of an LMA or Combitube can be safely and effectively considered alternatives to control an unstable airway if intubation cannot be achieved with an endotracheal tube. An accurate description of these devices is available in Chapter 16, dedicated to the airway. Remarkably, the use of the latest version of the LMA, the intubating laryngeal mask airway, or Fastrach, has been associated with the potential to increase spinal cord damage by possibly dislocating the cervical spine due to the device’s rigid handle. However, this work has been described in cadavers where ligamentous and muscular tone are nonexistent and may not be easily transferred to the neck of an injured, living patient.99 The use of supplementary O2 is to

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be supported, irrespective of the SpO2. Because 100% O2 is the standard used by EMS in the field, the use of a transparent mask that allows observation of exhaled breath should be the rule.100,101 The EMS responders provide immediate medical attention and resuscitation, as well as a complete initial primary survey of the patient, and assessment of the security of the surrounding environment such as traffic patterns, if the injury is on the road. If the patient requires extrication from a motor vehicle, this delicate maneuver is performed either by EMS with the collaboration of the fire fighters (in a situation in which fire fighters are not also paramedics/EMTs) and law enforcement personnel. The patient’s head should be aligned with the axis of the body in neutral position, and the patient should be secured on a rigid long backboard as soon as possible; a strap across the forehead, restraining it between two semirigid plastic blocks should be placed to minimize movement of the head, and a hard cervical collar should be placed. The trunk and extremities should also be secured to the long backboard, even if no obvious bone deformations are noticed. When trauma has occurred in a body of water, the patient is slowly floated to a long backboard while still in the water. Again, immobilization of the neck in the water should be done gently, grasping the head and moving it into a neutral, in-line or “eyes forward” position. If the neck appears to be obviously deformed and the patient consciously manifests pain upon immobilization of the neck, the maneuver should be abandoned and the neck immobilized in the position found. Special considerations are to be taken for trauma victims wearing helmets, as may happen after a motorcycle (except in Florida where helmets were designated as “elective” by the legislature) or football injury. In general, the helmet should remain in place if there are no airway issues and removed with the proper tools in the ED; it is recommended that football helmets be removed only after removal of the shoulder pads to avoid involuntary neck extension.102 Helmet removal is a two-person job, with one holding the neck and mandible in place while the other slowly removes the helmet without a twisting motion. Prehospital hemodynamics of a victim of a spinal cord injury can be confused by the presence of neurogenic shock. Neurogenic, or spinal, shock typically presents as hypotension without tachycardia and is secondary to blunted or absent sympathetic nervous system outflow. The unopposed parasympathetic outflow is responsible for bradycardia and reduced cardiac contractility. While the presence of severe spinal cord injury above the second lumbar level is typically associated with spinal shock, one must also consider and rule out hypovolemic shock, cardiogenic shock from tension pneumothorax, cardiac tamponade, myocardial contusion, air embolus, and myocardial infarction in these patients. The initial approach to the hypotensive patient always includes the use of intravenous crystalloid fluid. Ringer’s lactate or 0.9% saline solution, 250 to 500 mL in repeated

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doses up to 2 L for the adult, or 20 mL/kg in the child, is initially appropriate. The most common adrenergic agonists utilized are Neo-Synephrine and norepinephrine, although mixed alpha and beta agonists such as dopamine or epinephrine are useful as well. Vasopressor/inotropic support should be titrated to the classic signs of perfusion such as normal mental status in conscious patients, and urine output of at least 0.5 mL/kg/hour. The target blood pressure in unconscious patients is unclear but, in our experience, is usually held close to a mean arterial pressure of 70 mm Hg. In any case, the blood pressure goal is a compromise between associated bleeding injuries and perfusion of the spinal cord. The use of military antishock pneumatic devices has fallen into disfavor over the past several years, largely secondary to anecdotal reports of a detrimental increase in abdominal pressure with compartment syndrome, increased ICP, severe lactic acidosis, and worsened lower lumbar spine neurologic injury. The device has been removed from EMS units in our jurisdiction. A full history and physical examination is usually performed only in the ED or the intensive care unit. However, a brief neurologic evaluation that includes the level of sensory impairment and muscle strength on a 6-point scale (where 0 = paralysis, 1 = palpable, visual contractions, 2 = range of motion with gravity eliminated, 3 = range of motion with gravity, 4 = active range of motion with moderate resistance, 5 = active range of motion with full resistance) is invaluable information that may be easily obtained in the field and transmitted by radio to the hospital’s ED physician or neurosurgeon. Transportation to the ED should be provided rapidly and safely. While it is usually in the best interest of the patient to transport to a trauma center, distance, geographical logistics, and the patient’s condition may obviate this option. It may be in the interest of the patient to transport, initially, to a smaller center for hemodynamic stabilization,103 and only then move the patient to the trauma center. The use of an acute CNS injury clinical pathway, in which emergency physician, neuroradiologist, neurosurgeon, and intensivist are promptly available once the victim reaches the ED, allows for proper care to the neurologically injured patient regardless of the hospital’s trauma designation.3,103 Transport requirements are as previously noted in the traumatic brain injury section. Use of steroids within 8 hours of injury in these patients has become the standard in all trauma centers and EDs.104 There is reported neurological improvement to pin prick and light touch in patients with either complete or incomplete spinal cord injury. In our EMS system, steroid treatment is begun in the field. Once the immobilized patient arrives in the ED, a detailed history of the presumed mechanism of injury—obtained from scene evaluation—should be given to the ED physician by EMS personnel, even before radiographic evaluation of the spine is performed. In an awake and conscious patient with no distracting injuries and without neurologic impairment, temporary removal of the cervical immobilization

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Table 14-2  Common Signs and Symptoms of Transient Ischemic Attack (TIA) and Stroke Unilateral paralysis—Weakness, clumsiness, or heaviness, usually involving one side of the body Unilateral numbness—Sensory loss, tingling, or abnormal sensation, usually involving one side of the body Language disturbance—Trouble understanding or speaking (aphasia) or slurred speech (dysarthria) Monocular blindness—Painless visual loss in one eye, often described as a curtain dropping Vertigo—Sense of spinning or whirling that persists at rest. Isolated vertigo is also a common symptom of many nonvascular diseases; therefore, at least one other symptom of TIA or stroke should also be present Ataxia—Poor balance, stumbling gait, staggering, lack of coordination of one side of the body

device may be considered as long as there is no tenderness of the spine, altered mental status, intoxication, or other painful injuries. A social worker should be involved in the case within 24 hours of admission to the hospital.

Prehospital Management of Stroke The chain of survival in stroke has been extensively reviewed in the latest edition of the AHA guidelines.9 In general, the patient with a suspected stroke has the same priority for dispatch as patients with acute myocardial infarction. Unless CPR is immediately required, the strategy of phone first has been recommended, that is, immediate notification of the EMS dispatch system of a suspected “brain attack.” This strategy has been recommended as a class I, which is the strongest recommendation for best outcome based on current evidence-based medicine. Transport priority should be given to institutions able to initiate fibrinolytic therapy within 1 hour of arrival. Because 85% of strokes occur at home,105 early recognition of stroke presentation by the public and EMS system dispatchers is fundamental to increase the window of therapeutic opportunity for fibrinolysis.106 However, despite many public educational programs sponsored by the AHA, only 50% of stroke victims use the EMS system for transport to hospital.105 Unfortunately, 25% of adults who’ve suffered a stroke die shortly after the event,107 and in the majority of survivors the therapy is mostly supportive.108 Although the presence of a transitory ischemic attack (TIA) is a significant indicator of predisposition to stroke, in the first few hours after onset a TIA cannot be distinguished from stroke itself (Table 14-2). Accordingly, both ischemic and hemorrhage stroke can present with identical symptoms and their differential diagnosis cannot be ruled out prior to

a CT scan of the head. Recognition of a stroke by laypersons may result from subtle neurologic deficits such as difficulty in speaking, sudden confusional state, and weakness of face, arm or leg. Brief, but more specific, neurologic evaluations such as the Cincinnati Prehospital Stress Scale (Table 14-3),109 the Los Angeles Prehospital Stroke Screen (Table 14-4),110,111 and the GCS112 are validated tools utilized by EMS for their prehospital assessment. Once the diagnosis of acute neurologic deficit is established, transport should be, as noted previously, to an ED facility where CT scan and fibrinolytic therapy are available. In nonrural areas, transport is usually feasible within 30 minutes of EMS arrival on the scene.113 On reaching the victim and performing the initial evaluation, EMS personnel should immediately communicate with ED physicians and transmit a tentative diagnosis. Immediate communication can minimize the lag-time required to prepare for a CT scan of the head and prepare the patient for intravenous thrombolytic therapy. A review of the prehospital care of stroke patients is summarized in Figure 14-1. Management principles of the stroke patient have been summarized in a mnemonic, the “seven Ds” of stroke management:9 detection, dispatch, delivery, door, data, decision, and drug (Fig. 14-2). Responders to the first three Ds are usually initially the laypersons (or the patient him/herself) and subsequently the EMS responder. The remaining four Ds represent the transition between immediate prehospital care and acute hospital care. They are, in order, “door” or rapid triage in the ED; “data” or quick neurologic examination by a physician, and performance and interpretations of the CT scan; “decision” or eligibility for fibrinolytic therapy; and “drug” or treatment with fibrinolytic therapy. At this time, the best therapeutic option for fibrinolysis is intravenous recombinant tissue plasminogen

Table 14-3  Cincinnati Prehospital Stroke Scale Facial droop (have patient show teeth or smile) Normal Both sides of face move equally Abnormal One side of face does not move as well as the other side Arm drift (patient closes eyes and holds both arms straight out for ten seconds) Normal Both arms move the same or both arms do not move at all (other findings, such as pronator grip, may be helpful) Abnormal One arm does not move or one arm drifts down compared with the other Abnormal speech (have the patient say “you can’t teach an old dog new tricks”) Normal Patient uses correct words with no slurring Abnormal Patient slurs words, uses the wrong words, or is unable to speak Interpretation: If any of these three signs is abnormal, the probability of a stroke is 72%.

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Table 14-4  Los Angeles Prehospital Stroke Screen For evaluation of acute, noncomatose, nontraumatic neurological complaint : If items I through 6 are ALL checked “yes” (or “unknown”), notify the receiving hospital before arrival of the potential stroke patient. If any are checked “no,” follow appropriate treatment protocol. Interpretation: Ninety-three percent of patients with stroke will have positive findings (all items checked “yes” or “unknown”) on the LAPSS (sensitivity = 93%), and 97% of those with positive findings will have a stroke (specificity = 97%). The patient may still be having a stroke if LAPSS criteria are not met. Criteria 1. 2. 3. 4. 5. 6.

Age > 45 years History of seizures or epilepsy absent Symptom duration < 24 hours At baseline, patient is not wheelchair bound or bedridden Blood glucose between 60 and 400 Obvious asymmetry (right vs left) in any of the following 3 categories (must be unilateral)

Facial smile/grimace Grip Arm strength From Kidwell CS, et al: Stroke 2000;31:71–76, with permission.

Figure 14-1. A review of prehospital care of patients with stroke.

Yes

Unknown

No

[] [] [] [] [] []

[] [] [] [] [] []

[] [] [] [] [] []

Equal

R Weak

L Weak

[] Droop [] Weak grip [] No grip [] Drifts down [] Falls rapidly

[] Droop [] Weak grip [] No grip [] Drifts down [] Falls rapidly

[] [] [] [] []

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Figure 14-2. The “seven Ds” of stroke management.

activator (r-tPA) within the first 3 hours of onset of symptoms. The use of r-tPA and pro-urokinase has also been found to improve neurologic outcome in patients treated within 3 to 6 hours of onset of stroke. However, in this last category, the evidence-based medicine classification is that of anecdotal data. We have been discussing stroke as if it were always thrombotic in nature. While this is often the case, stroke may also be hemorrhagic, due either to intracerebral or subarachnoid hemorrhage (SAH). An SAH (grade 3 or 4 of the Hunt and Hess scale; Table 14-5) is a form of cerebrovascular accident

Table 14-5  Hunt and Hess Scale for Subarachnoid Hemorrhage Grade 1 2 3 4 5

Neurologic Status Asymptomatic Severe headache or nuchal rigidity; no neurologic deficit Drowsy; minimal neurologic deficit Stuporous; moderate-to-severe hemiparesis Deep coma; decerebrate posturing

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that may be followed by cardiac arrest. In fact, aneurysmal SAH etiologically accounts for approximately 20% of the cardiac arrests reported in the prehospital arena or ED.114,115 Often, the patient cannot be resuscitated or remains devastated neurologically. Occasionally, however, aggressive CPR and rapid transport to an acute care facility where neurointensive care, including ICP monitoring, is available can be life-saving.116 In general, long-term survival in SAH patients in whom prehospital cardiac arrest occurred is quite poor, reported as less than 2%. Patients with SAH who present only with respiratory arrest have a better functional longterm survival than do those with full-blown cardiopulmonary arrest.118 The etiology of cardiac arrest in patients with SAH is complex, including sudden increase in intracranial pressure, brainstem compression with herniation, and respiratory arrest. Typically, a massive sympathetic discharge may result in a lethal cardiac arrhythmia. Common features characterize patients with SAH and cardiac arrest who survive, including bystander CPR that is initiated immediately, and return

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of spontaneous circulation or respiration shortly after CPR is initiated.117 If SAH is suspected after resuscitation of a patient from cardiac arrest, hypertension (as discussed previously) should be withheld until the diagnosis is ruled out with a CT scan of the head. Based on our clinical experience, acquired in patients with SAH and vasospasm before surgical ablation, maintaining systolic blood pressure between 120 and 140 mm Hg is usually safe. In conclusion, recent advances in cardiopulmonary resuscitation, EMS, and trauma organization have had a dramatic impact on survival and quality of life in the neurologically injured patient. Despite numerous ongoing animal and human trials of agents thought to provide neuroprotection, few specific acute interventions have been recommended and these are noted primarily in victims of thrombotic stroke. In severe head and cervical spine trauma, emphasis is placed on the immediate correction of factors, such as hypoxia and hypotension, that will result in secondary injury, rapid transport to adequate hospital facilities, and prompt communication with the ED.118

P earls 1. While neurologic emergencies require specialized and multidisciplinary critical care, the quality of the initial management is the primary determinant for improving survival and neurologic outcome. 2. The presence of a physician in the field seems of less importance for major trauma, regardless of association with CNS injury. 3. For adult patients, two rescuers should no longer use a compression-ventilation ratio of 5 : 1. Instead, they should use a compression-ventilation ratio of 15 : 2 until the airway is secured. 4. The intraosseous (IO) route has been recommended when no intravenous access is promptly available in arrest victims 6 years of age and older; there is no upper age limit for the use of an IO device. 5. Postresuscitation interventions that may improve neurologic outcomes are of particular interest. These have been reviewed and include: a. Maintenaning normal ventilation without hyperventilation b. Monitoring temperature and preventing/treating hyperthermia c. Allowing mild hypothermia (to 34°C to 35°C) without aggressive rewarming d. Managaging postischemic myocardial dysfunction e. Maintaining glucose levels between about 80 mg/dL and 120 mg/dL. 6. An extensive MEDLINE review for the years 1966 through 1998, using head injury and prehospital care

7.

8.

9. 10.

11.

as keywords confirmed that hypotension (systolic BP < 90 mm Hg) and hypoxia (oxygen saturation < 90% or PaO2 < 60 mm Hg) were directly related to a poor outcome. Alcohol intoxication plays a major role in hospital outcome after acute brain injury. It has been shown that an alcohol level greater than 100 mg/dL is a risk factor for respiratory failure in the field, requiring endotracheal intubation. While alcohol clearance is associated with a “miraculous” awakening from head trauma coma, this group of patients still presents a high hospital morbidity and length to stay secondary mostly to gramnegative pneumonia. Approximately 5% to 10% of all patients with head injury have associated spinal injury. In the United States, there are more than 10,000 spinal injuries annually, with males predominating in this pathophysiology (81.6%). The average age of patients is 32.1 years, and most of the injuries are related to motor vehicle crashes (38.5%), followed by acts of violence (24.5%), and falls (21.8%). Although the decision as to the need for intubation is individually taken based on concurrent trauma and mental status, a patient with an FVC less than 15 mL/kg, or a negative inspiratory force (NIF) greater than -30 cm H2O will likely require intubation and ventilatory support. Continued

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12. The use of a plastic oral airway is not recommended if the patient is not intubated because it can contribute, in the presence of a strong gag reflex, to emesis with sudden neck movement and potential aspiration of gastric contents. 13. When trauma has occurred in a body of water, the patient is slowly floated to a long backboard while still in the water. Again, immobilization of the neck

References 1. Ramzy AI, Parry JM, Greenberg J: Head and spinal injury: Pre-hospital care. In Greenberg J (ed): Handbook of Head and Spine Trauma. New York, Marcel Dekker, 1993, pp 29–44. 2. Pre-hospital Trauma Life Support Committee of the National Association of Emergency Medical Technicians in Cooperation with the Committee on Trauma of the American College of Surgeons. PHTLS: Basic and Advanced Pre-hospital Trauma Life Support. 4th ed. St. Louis, Mosby, 1999. 3. Kish DL: Pre-hospital management of spinal trauma: An evolution. Crit Care Nurs Q 1999;22(2):36–43. 4. Pre-hospital Trauma Life Support Committee of the National Association of Emergency Medical Technicians in Cooperation with the Committee on Trauma of the American College of Surgeons. PHTLS: Basic and Advanced Pre-hospital Trauma Life Support. 4th ed. St. Louis, Mosby, 1999. 5. Crosby LA, Lewallen DG (eds): Emergency Care and Transportation of the Sick and Injured, 6th ed. Rosemont, IL, American Academy of Orthopaedic Surgeons, 1995. 6. Frandsen F, Nielsen JR, Gram L, et al: Evaluation of intensified prehospital treatment in out-of-hospital cardiac arrest: Survival and cerebral prognosis—The Odense Ambulance Study. Cardiology 1991;79:256–264. 7. Bartolomeo SD, Sanson G, Nardi G, et al: Effects of 2 patterns of prehospital care on the outcome of patients with severe head injury. Arch Surg 2001;136(11):1–15. 8. Nicholl JP, Brazier JE, Snooks HA: Effects of London helicopter emergency medical service on survival after trauma. BMJ 1995;311:217– 222. 9. Guidelines 2000 for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. International Consensus on Science. Supplement to Circulation 2000;102(8). 10. Linder KH, Prengel AW, Brinkmann A, et al: Vasopressin administration in refractory cardiac arrest. Ann Intern Med 1996;124:1061–1064. 11. Wenzel, Lindner KH, Krismer AC, et al: Repeated administration of vasopressin but not epinephrine maintains coronary perfusion pressure after early and late administration during prolonged cardiopulmonary bypass. Circulation 1999;99:1379–1384. 12. Prengel AW, Lindner KH, Keller A: Cerebral oxygenation during cardiopulmonary resuscitation with epinephrine and vasopressin in pigs. Stroke 1996;27:1241–1248. 13. Wenzel V, Linder KH, Augenstein S, Prengel AW, Strohmenger HU: Vasopressin combined with epinephrine decreases cerebral perfusion compared with vasopressin alone during cardiopulmonary resuscitation in pigs. Stroke 1998;29:1462–1468. 14. Stiell IG, Hebert PC, Wells GA, et al: Vasopressin versus epinephrine for in hospital cardiac arrest: A randomized controlled trial. Lancet 2001;358(9276):105–109. 15. Safar P, Xiao F, Radovsky A, et al: Improved cerebral resuscitation from cardiac arrest in dogs with mild hypothermia plus blood flow promotion. Stroke 1996;27:105–113.

in the water should be done gently, grasping the head and moving it into a neutral, in-line or “eyes forward” position. 14. At this time, the best therapeutic option for fibrinolysis is intravenous recombinant tissue plasminogen activator (r-tPA) within the first 3 hours of onset of symptoms.

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57. Frost EAM, Aracibia CU, Schulman K: Pulmonary shunt as a prognostic indicator in head injury. J Neurosurg 1979;50:768– 772. 58. Chesnut RM, Marshall LF, Klauber MR, et al: The role of secondary brain injury in determining outcome from severe head injury. J Trauma 1993(II);34:216–222. 59. Stocchetti N, Furlan A, Volta F: Hypoxemia and arterial hypotension at the accident scene in head injury. J Trauma 1996;40:764–767. 60. Scalea TM, Maltz S, Yelon J, et al: Resuscitation of multiple trauma and head injury: role of crystalloid fluids and inotropes. Crit Care Med 1994;22:1610–1615. 61. Mattox KL, Maningas PA, Moore EE, et al: Pre-hospital hypertonic saline/dextran infusion for post-traumatic hypotension. Ann Surg 1991;213:482–491. 62. Wade CE, Grady JJ, Kramer CG, et al: Individual patient cohort analysis of the efficacy of hypertonic saline/dextran in patients with traumatic brain injury and hypotension. J Trauma 1997;42:561– 565. 63. Vassar MJ, Perry CA, Holcroft JW: Pre-hospital resuscitation of hypotensive trauma patients with 7.5% NaCl versus 7.5% NaCl with added dextran: a controlled trial. J Trauma 1993;34:622–632. 64. Sayre MR, Daily SW, Stern SA, et al: Out-of-hospital administration of mannitol to head-injured patients does not change systolic blood pressure. Acad Emer Med 1996;3:840–848. 65. Hsiano AK, Michaelson SP, Hedges JR: Emergent intubation and CT scan pathology of blunt trauma patients with Glasgow Coma Scale scores of 3-13. Pre-hospital Disaster Med 1998;32:26–32. 66. White JC, Brooks JR, Goldthwait JC, et al: Changes in brain volume and blood content after experimental concussion. Ann Surg 1943; 118:619–634. 67. Lyeth BG, Dixon CE, Hamm RF, et al: Effects of anticholinergic treatment on transient behavioral suppression and physiological responses following concussive brain injury to the rat. Brain Res 1988;448:88– 97. 68. Rosomoff HL, Kochanek PM, Clark R, et al: Resuscitation from severe brain trauma. Crit Care Med 1996;24(2)(Suppl):S48– S56. 69. Stocchetti N, Penny, KI, Dearden M, et al: Intensive care management of head–injured patients in Europe: A survey from the European Brain Injury Consortium. Intensive Care Med 2001;27:400– 406. 70. The Brain Trauma Foundation: Glasgow coma scale score. J Neurotrauma 2000;17:563–571. 71. The Brain Trauma Foundation: Neurotrauma Guidelines. J Neurotrauma, 2000;17:457–627. 72. Gurney JG, Rivara FP, Mueller BA, et al: The effects of alcohol intoxication on the initial treatment and hospital course of patients with acute brain injury. J Trauma 1992;33(5):709–713. 73. Servadei F, Nasi MT, Cremonini AM, et al: Importance of a reliable admission Glasgow Coma Scale Score for determining the need for evacuation of posttraumatic subdural hematomas. J Trauma Injury, Infect Crit Care 1998;44:868–873. 74. Ivan LP: Spinal reflexes in cerebral death. Neurology 1973;23:650– 652. 75. Bullock R, Chesnut RM, Clifton G, et al: Guidelines for the Management of Severe Head Injury. New York, Brain Trauma Foundation, 1995. 76. Muizelaar JP, Marmarou A, Ward JD, et al: Adverse effects of prolonged hyperventilation in patients with severe head injury: A randomized clinical trial. J Neurosurg 1991;75:731–739. 77. Thomas SH, Orf J, Wedel SK, Conn AK: Hyperventilation in traumatic brain injury patients: Inconsistency between consensus guidelines and clinical practice. J Trauma 2002;52:47–53. 78. Clifton GL, Miller ER, Choi SC, et al: Lack of effect of induction of hypothermia after acute brain injury. N Engl J Med 2001;344(8):556– 563.

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79. Kornberger E, Schwarz B, Lindner KH, Mair P: Forced air surface rewarming in patients with severe accidental hypothermia. Resuscitation 1999;41:105–111. 80. Safar P: On the future of reanimatology. Acad Emerg Med 2000;7:75– 89. 81. Kochanek PM, Clark RSB, Ruppel RA, Dixon CE: Cerebral resuscitation after traumatic brain injury and cardiopulmonary arrest in infants and children in the new millennium. Pediatr Clin North Am 2001;48(3):661–681. 82. Lucas DR, Newhouse JP: The toxic effect of sodium 1-glutamate on the inner layers of the retina. Arch Ophthalmol 1957;58:193–201. 83. Bouma GJ, Muizelaar JP, Stringer WA, et al: Ultra-early evaluation of regional cerebral blood flow in severely head-injured patients using xenon-enhanced computerized tomography. J Neurosurg 1992;77: 360–368. 84. Morris GF, Bullock R, Marshall SB, et al: Failure of the competitive N-methyl-d-aspartate antagonist Selfotel (CGS 19755) in the treatment of severe head injury: Results of two phase III clinical trials. J Neurosurg 1999;91:737–743. 85. Cherian L, Chacko G, Goodman JC, et al: Cerebral hemodynamic effects of phenylephrine and l–arginine after cortical impact injury. Crit Care Med 1999;27:2512–2517. 86. Sasser HC, Safar P, Kelsey SF, et al: Arterial hypertension after cardiac arrest is associated with good cerebral outcome in patients [abstract]. Crit Care Med 1999;27:A29. 87. Eckstein M: The pre-hospital and emergency department management of the penetrating head injuries. Neurosurg Clin North Am 1995;6(4):741–751. 88. Smith JP, Bodai BI, Hill AS, et al: Pre-hospital stabilization of critically injured patients. A failed concept. J Trauma 1985;25:65. 89. Walls RM: Airway management. Emerg Med Clin North Am 1993;11:55. 90. American College of Surgeons: Advanced Trauma Life Support Manual. Chicago, American College of Surgeons, 1993. 91. Wilberger JE: Emergency care and initial evaluation. In Cooper PR (ed): Head Injury. Baltimore, Williams & Wilkins, 1993, pp 27– 41. 92. Sellick BA: Cricoid pressure to control regurgitation of stomach contents during induction of anesthesia. Lancet 1961;2:404. 93. Steinhause JE, Gaskin L: A study of intravenous lidocaine as a suppressant of cough reflex. Anesthesiology 1963;24:285–290. 94. Benzel EC, Day WT, Kesterson L, et al: Civilian cranio-cerebral gunshot wounds. Neurosurgery 1991;29:67–72. 95. Spinal Cord injury Information Network: Spinal cord injury: Facts and figures at a glance [University of Alabama at Birmingham Web site]. May 2001. Available at: http://www.spinalcord.uab.edu/show.asp?durki = 21446. Accessed Jan 23, 2002. 96. Miglietta MA, Levins T, Robb TV: Evaluation of spine injury in blunt trauma. J Am Osteopath Assoc 2002;102(2):87–91. 97. Ledsome GR, Sharp JM: Pulmonary functions in acute cervical cord injury. Am Rev Resp Dis 1981;124:41–44. 98. Cohen M: Initial resuscitation of the patient with spinal cord injury. Trauma Q 1993;9:38–43. 99. Keller C, Brimacombe J, Keller K: Pressures exerted against the cervical vertebrae by the standard and intubating laryngeal mask airways: A randomized, controlled, cross-over study in fresh cadavers. Anesth Analg 1999;89(5):1296–1300.

100. Vaccaro AR, An HS, Betz RR, Cotler JM, Balderston RA: The management of acute spinal trauma: pre-hospital and in-hospital emergency care. In Greenberg J (ed): Handbook of Head and Spine Trauma. New York, Marcel Dekker, 1993, pp 113–125. 101. Ramzy AI, Parry JM, Greenberg J: Head and spinal injury: Pre-hospital care. In Greenberg J (ed): Handbook of Head and Spine Trauma. New York, Marcel Dekker, 1993, pp 29–44. 102. Swenson TM, Lauerman WC, Blank RO, et al: Cervical spine alignment in immobilized football players: Photographic analysis before and after helmet removal. Am J Sports Med 1997;20:226–260. 103. Pre-hospital Trauma Life Support Committee of the National Association of Emergency Medical Technicians in Cooperation with the Committee on Trauma of the American College of Surgeons. PHTLS: Basic and Advanced Pre-hospital Trauma Life Support, 4th ed. St. Louis, Mosby, 1999. 104. Bracken MB, Shepard MJ, Collins WF, et al: A randomized controlled trial of methylprednisolone or naloxone in the treatment of acute spinal-cord injury: Results of the Second National Acute Spinal Cord Injury Study. N Engl J Med 1990;322:1405–1411. 105. Lyden PD, RappK, Babcock T, Rothrock J: Ultra-rapid identification, triage, and enrollment of stroke patients into clinical trials. J Stroke Cerebrovasc Dis 1994;4:106–107. 106. Barsan WG, Brott TG, Broderick JP, et al: Time of hospital presentation in patients with acute stroke. Arch Intern Med 1993;2558–2561. 107. 1997 Heart and Stroke Statistical Update. Dallas, TX: American Heart Association, 1996. 108. Easton JD, Hart RG, Sherman DG, Kaste M: Diagnosis and management of ischemic stroke, I: Threatened stroke and its management. Curr Probl Cardiol 1983;8:1–76. 109. Kothari R, Pancioli A, Liu T, et al: Cincinnati prehospital stroke scale: reproducibility and validity. Ann Emerg Med 1999;33:373–378. 110. Kidwell CS, Saver JL, Schubert GB, Eckstein M, Starkman S: Design and retrospective analysis of the Los Angeles prehospital stroke screen (LAPSS). Prehosp Emerg Care 1998;2:267–273. 111. Kidwell CS, Starkman S, Eckstein M, Weems K, Saver JL: Identifying stroke in the field: Prospective validation of the Los Angeles. Prehospital stroke screen (LAPSS). Stroke 2000;31:71–76. 112. Prasad K, Menon GR: Comparison of the three strategies of verbal scoring of the Glasgow coma scale in patients with stroke. Cerebrovasc Dis 1998;8:79–85. 113. Scott PA, Temovsky CJ, Lawrence K, Gudaitis E, Lowell MJ: Analysis of Canadian population with potential geographic access to intravenous thrombolysis for acute ischemic stroke. Stroke 1998;29:2304– 2310. 114. Kitahara T, Masuda T, Soma S: The etiology of sudden cardiopulmonary arrest in subarachnoid hemorrhage. No Shinkei Geka 1996; 21:781–786. 115. Schievink WI, Wijdicks EF, Parisi JE, Piepgras DG, Wisnant JP: Sudden death from subarachnoid hemorrhage. Neurology 1995;45:871–874. 116. Inamasu J, Saito R, Nakamura Y, et al: Survival of a subarachnoid hemorrhage patient who presented with pre-hospital cardiopulmonary arrest: Case report and review of the literature. Resuscitation 2001;51:207–211. 117. Shapiro S: Management of subarachnoid hemorrhage patients who presented with respiratory arrest resuscitated with bystander CPR. Stroke 1996;27:1780–1782. 118. Biros MH, Heegaard W: Pre-hospital and resuscitative care of the head-injured patient. Curr Opin Crit Care 2001;7:444–449.

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Chapter 15 Cerebral Resuscitation from Cardiac Arrest* Peter Safar, MD and Wilhelm Behringer, MD†

Introduction Definitions Cerebral protection (pretreatment) and preservation (intrainsult treatment) before and during (anticipated) cerebral ischemia are important in the management of patients undergoing elective cerebral or cardiac anesthesia and surgery (Fig. 15-1). Cerebral resuscitation is treatment to reverse the insult and support recovery.1,2 This chapter concerns cerebral resuscitation from the temporary, complete global brain ischemia (GBI) of cardiac arrest (CA). This topic is relevant for emergency medical services (EMS),3–5 which should deliver not merely cardiopulmonary resuscitation (CPR),6 but rather cardiopulmonary-cerebral resuscitation (CPCR).1,2,7 CPCR leads to intensive care with focus on brain and heart. The fate of the brain for many patients who, after a variety of cerebral insults, are brought to the intensive care unit (ICU), from either outside or inside the hospital, has already been determined—during and immediately after the insult. Nevertheless, intensivists should know about novel opportunities for cerebral resuscitation because they are often consulted on such cases outside the ICU, and because brainfocused prolonged life support can mitigate brain damage. Temporary hypotension with mean arterial pressure (MAP) of about 30 to 60 mm Hg, can be tolerated by the normal brain, but even mild hypotension can cause perma*Sections of this chapter are based on Safar P: Resuscitation of the ischemic brain. In Albin MA (ed): Textbook of Neuroanesthesia. New York, McGraw-Hill, 1997. † On August 3, 2003, Dr. Peter Safar died. Dr. Wilhelm Behringer finalized this chapter in Dr. Safar’s honor.

nent brain damage when it occurs in a state of severe hypoxemia, after brain trauma, or in the presence of atherosclerotic cerebral arteries that fail to go into autoregulatory vasodilation. Much of what applies to cerebral resuscitation from the GBI of CA is also relevant for special operations on the brain that require temporary circulatory arrest. One must differentiate between the temporary, complete GBI of CA (see Fig. 15-1); the permanent, complete GBI of panorganic death without resuscitation; the temporary, incomplete GBI of shock states; the temporary or permanent focal brain ischemia of stroke (e.g., cerebral embolism); traumatic brain injury with unifocal, multifocal, or global ischemic components; and a variety of toxic, inflammatory, or degenerative cerebral insults. A treatment that is effective for one of the above conditions may not be effective for another; one effective for protection-preservation during an insult may not be effective for resuscitation; and one effective during incomplete ischemia may not be effective after complete ischemia. One must further differentiate between ischemic tissue hypoxia or anoxia that is caused by reduced cerebral blood flow (CBF); hypoxic hypoxia that is low arterial PO2 (PaO2); and anemic hypoxia that is caused by very low hemoglobin levels (low hematocrit [Hct] or carbon monoxide [CO] poisoning). One must also differentiate between process variables, such as electroencephalographic activity (EEG); CBF; or cerebral metabolic rates for oxygen, glucose, or lactate (CMRO2, CMRG, CMRL) during and early after the insult, and the much more important outcome in terms of cerebral functional and morphologic changes, after maturing of the postischemic encephalopathy over at least 3 days, perhaps weeks. 457

?

?

Pulmonary failure

Shock

Circulatory Arrest 10

EEG isoelectric

EEG abnormal

Neurologic deficit

Neurologically normal

Unconscious

Brain death

Unconscious Conscious or stuporous

Conscious

Apnea

20

Vegetative state

Spontaneous breathing

15

Spontaneous breathing

Restoration of Circulation

5

Spontaneous breathing

Approximate time, min

Clinical Death

Figure 15-1. Diagram of different causes of cardiac arrest and their reversibility, with present standard normothermic CPR. Flow chart illustrates diagrammatically the development of total circulatory arrest, as it happens suddenly (terminal states no. 1, as in VF, or no. 2, as in a primary asystole); over minutes (terminal states no. 3–5); or protracted (terminal states no. 6–8). “Clinical death” is defined as “total circulatory arrest with potential reversibility to survival without brain damage.11 Longest duration of clinical death that is reversible depends on terminal state, temperature, resuscitation methods, CPR (low-flow) time, and the postresuscitation disease. After restoration of circulation, there are various possible outcomes. (From Safar P: The pathophysiology of dying and reanimation. In Schwartz G, Safar P, Stone JH, et al (eds): Principles and Practice of Emergency Medicine. Philadelphia, WB Saunders, 1985, pp 2–41.)

Brain failure

?

5–12 min

(4) Asphyxia, Airway obstruction, Apnea

Exsanguination

2–3 min

0 min

Alveolar anoxia

Primary asystole

Primary ventricular fibrillation

Terminal States

Panorganic Death

?

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In ischemic insults such as CA (e.g., sudden cardiac death [SCD]), one must further differentiate between the many different mechanisms leading to CA, such as asphyxia, exsanguination, ventricular fibrillation (VF), electromechanical dissociation (EMD = pulseless electrical activity [PEA]) with mechanical asystole, or electric asystole; and slow, secondary CA (see Fig. 15-1). One must determine, or at least estimate, arrest time (no-flow), CPR time (low-flow), and temperature—the most important variables determining cerebral outcome. Reversal of CA calls for CPCR in three phases, that is, basic, advanced, and prolonged life support (BLS-ALSPLS).1,2 When initiated outside the hospital, the steps of resuscitation are to be delivered throughout the EMS system—from scene via transportation to the most appropriate hospital’s emergency department (ED), operating room (OR), and ICU.3–5 The combination of CPCR and EMS3 is now called the “chain of survival,”4,5 and is only as effective as the weakest step of CPCR in the weakest link of EMS. When talking about hypothermia—presently the most effective cerebral preservation and resuscitation strategy— one must differentiate between controlled (therapeutic) and uncontrolled (accidental) hypothermia; between temperature levels, such as normothermia (37°C to 38°C), and mild (33°C to 36°C), moderate (28°C to 32°C), deep (16°C to 27°C), profound (5°C to 15°C), or ultraprofound (<5°C) hypothermia; and between different temperaturemonitoring sites. Temperatures are measured for the brain as brain tissue (Tb), intraventricular (Tv), epidural (Tep), tympanic membrane (Tty), or nasopharyngeal (Tnp) temperature; and for the body-core as esophageal (Tes), central venous (Tcv), pulmonary artery (Tpa), rectal (Tr), or urinary bladder temperature (Tu). Importance The socioeconomic importance of attempts at mitigating any type of cerebral insult is obvious because survival in persistent vegetative state (PVS) is an enormous burden to families and society; conscious survival with partial paralysis, aphasia, mental and cognitive disturbances, or other neuropsychologic deficits, is not only a burden to family and friends, but also traumatic for the patients. Billions of dollars are spent each year on the care of such patients. The clinical importance of resuscitation from GBI goes beyond the cases of CA, because all resuscitation and intensive care life support efforts for the organism should focus on the brain. The scientific importance of research into cerebral resuscitation from CA is considerable because CA is experimentally controllable and gives clues for the treatment potentials also for the more variable and more complex insults like stroke, traumatic brain injury (TBI), or shock. Recent attempts at implementing national CPR guidelines6 or international CPCR guidelines1 through com-

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munity-wide EMS systems3 have yielded suboptimal results.2,6,8–21 At present, among prehospital or in-hospital CPR attempts outside special care units, fewer than 50% have achieved restoration of spontaneous circulation (ROSC), and fewer than 10% overall have resulted in conscious survival. Approximately 10% to 30% of long-term survivors of CA have some permanent brain damage. The main problems seem to be pre-existing heart disease obviating ROSC, and long arrest (no-flow) times due to delayed, suboptimal resuscitation, that is, “too little too late.” Remedies proposed include life-supporting first aid (LSFA) skill acquisition by all fit humans, starting in grammar school,22 for the immediate initiation of resuscitation, and uniform reporting for community-wide ongoing evaluation of outcome.15–24 In 1961, Safar assembled the CPCR system,1,25,26 which has consisted of three phases—basic, advanced, and prolonged life support (BLS-ALS-PLS). Each phase has three steps: step A (airway control),27–30 step B (breathing control),27,31,32 and step C (circulation support)33–35 are phase I, BLS.36,37 Cerebral resuscitation starts with optimizing BLS.1 To rapidly achieve ROSC, BLS has been followed by steps D, E, and F (drugs and fluids, electrocardiography, and fibrillation treatment), which are phase II, ALS, to rapidly achieve stable, optimal oxygen delivery.38–58 Now, BLS and ALS deserve some modifications (see later). Steps g (gauged), H (humanized = brain-oriented, with hypothermia [possibly]), and I (intensive care) are phase III, brain-oriented PLS.59–63 For PLS, respiratory ICUs were pioneered in Scandinavia in the early 1950s, and physician-staffed medical/surgical ICUs for any vital organ failure began in 1958.59 Critical care medicine (CCM) rapidly spread around the world.60–63 Ideally, for in-hospital CA, it is feasible for BLS-ALS to achieve ROSC within the critical 4 to 5 minutes. Around 1970, research began into cerebral resuscitation from CA, and CPR was extended to CPCR.1,2,25 The term and concept of CPCR were adopted by international guidelines in the 1980s,1 but the 2000 American Heart Association (AHA) Guidelines have not yet given appropriate priority to cerebral resuscitation potentials (Fig. 15-2).6,9,10 Promptly initiated, vigorously performed BLS (low flow) can often sustain the viability of heart and brain, even during prolonged transport.64–67 Reducing the response time of mobile ICU ambulances to less than 10 minutes is usually not feasible.6,8 The currently quoted maximal period of normothermic no-flow, induced suddenly, as by VF, that is consistently reversible to complete recovery of cerebral function and structure, is 4 to 5 minutes,17–21,68–77 shorter for CA caused by asphyxiation.78 If the brain-tolerated no-flow time were extended to 10 minutes, mobile ICU ambulances could arrive in time for an estimated 100,000 additional lives to be saved with good neurologic outcome in the United States every year. Recent dog outcome studies have shown that this might be possible (see later).2 A single pharmacologic, penicillin-like “magic bullet” with a unifactorial

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Figure 15-2. American Heart Association algorithm for out-of-hospital management of patients with sudden cardiac death. (From Guidelines 2000 for CPR-ECC. AHA, pp 1–67.)

breakthrough effect may never be found, because the postischemic-anoxic encephalopathy, that is, the cerebral postresuscitation disease, is complex and multifactorial (Figs. 15-3 and 15-4). Because of this complexity, Safar has called for the design and evaluation of treatments that attack several deleterious mechanisms simultaneously.2,71–75 Mild resuscitative

hypothermia proved to be just that (Fig. 15-5, p. 464).2 The CPCR alphabet of 196126 and present AHA guidelines6 therefore must be updated (Fig. 15-6, p. 464). Optimism is justified,79,80 because most (but not all) cerebral neurons81–86 and cardiac myocytes87–90 can tolerate much longer periods of complete normothermic ischemic anoxia

Figure 15-3. Diagram of postcardiac arrest reperfusion failure in brain and extracerebral organs. Reperfusion failure in brain (proven) and extracerebral organs (suspected) after VF-CA and CPR (or CPB) for ROSC. After CA no-flow of 10 to 15 minutes, despite control of normal MAP, CBF and cardiac output go through four postarrest stages: Stage I, multifocal no-reflow (*), which can be prevented or overcome with high reperfusion pressures. Stage II, brief diffuse global hyperemia. Stage III, delayed protracted global hypoperfusion (**), accompanied by normal or super-normal global cerebral O2 uptake between 2 hours and 12 to 24 hours (mismatching). Stage IV, normalization of CBF and CMRO2 with awakening; or persistent coma with low CBF and CMRO2.

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Figure 15-4. How cerebral neurons die after temporary ischemia. Diagram of the very complex, partially hypothesized, biochemical cascades in vital organ cells (e.g., cerebral neurons) during and after cardiac arrest. Normally, intracellular ([Ca2+]i ) to extracellular([Ca2+]i) calcium gradient is 1:10,000 (i.e., 0.1 mM: 1 mM). Calcium regulators include calcium/magnesium–ATPase; the endoplasmic reticulum (ER); mitochondria (M); and arachidonic acid (AA). With stimulation, different cell types respond with an increase in [Ca2+]i, because of release of bound Ca2+ in the ER, and influx of [Ca2+], or both. During sudden, complete ischemic anoxia (cardiac arrest) (left side), oxygen stores in the brain are consumed in about 15 seconds. The level of energy (phosphocreatine [PCr] and adenosine triphosphate [ATP]) decreases to near zero in all tissues at different rates, depending on stores of oxygen and substrate; it is fastest in the brain (approximately 5 minutes), and slower in the heart and other vital organs. This energy loss causes membrane pump failure, which causes a shift of sodium (Na+) ions, water (H2O) and (Ca2+) from the extracellular into the intracellular space (cytosolic edema); and potassium (K+) leakage from the intracellular into the extracellular space. Increase in [Ca2+]i activates phospholipase A2, which breaks down membrane phospholipids (PL) into free fatty acids (FAA), particularly arachidonic acid (AA). Increase in [Ca2+]i also activates proteolytic enzymes, such as calpain, which may disrupt the cytoskeleton (CS) and possibly the nucleus. In mitochondria, hydrolysis of ATP to adenosine monophosphate (AMP) leads to an accumulation of hypoxanthine (HX). Increased [Ca2+]i may enhance conversion of xanthine dehydrogenase (XD) to xanthine oxidase (XO), priming the neuron for the production of the oxygen free radical (O2-), although this pathway is of questionable importance in neurons. X, xanthine; UA, uric acid. Excitatory amino acid neurotransmitters (EAA), particularly glutamate and aspartate, increase in extracellular fluid. Increased [EAA]e activates nmethyl-d-aspartate (NMDA) and non-NMDA receptors (R), thereby increasing calcium and sodium influx and mobilizing stores of [Ca2+]i. Increased extracellular potassium activates EAA receptors by membrane depolarization. Glycolysis during hypoxia results in anaerobic metabolism and lactic acidosis, until all glucose is used (in the brain, during anoxia after approximately 20 minutes). This lactic acidosis, plus inability to wash out CO2, results in a mixed tissue acidosis that adversely influences neuronal viability. The net effect of acidosis on the cascades during and after ischemia is not clear. Mild acidosis may actually attenuate NMDA-mediated [Ca2+]i accumulation. Without reoxygenation, cells progress via first reversible, later irreversible structural damage to necrosis of all neurons or myocytes, homogeneously, at specific rates for different cell types. During reperfusion and reoxygenation (right side), lactate and molecular breakdown products can create osmotic edema and rupture of organelles and mitochondria. Recovery of ATP and PCr and of the ionic membrane pump may be hampered by hypoperfusion as a result of vasospasm, cell sludging, adhesion of neutrophils (granulocytes) (N), and capillary compression by swollen astrocytes, which also help to protect neurons by absorbing extracellular potassium. Capillary (blood-brain barrier [BBB]) leakage results in interstitial (vasogenic) edema. Increased concentrations may be formed of at least four free radical species that break down membranes and collagen, worsen the microcirculation, and possibly also damage the nucleus. These species include superoxide (O2-) leading to hydroxyl radical (·OH) (via the iron-catalyzed Fe3+ ÆFe2+, Haber-Weiss/Fenton reaction); free lipid radicals (FLR); and peroxynitrite (OONO-). O2- may be formed from several sources: (1) directly from AA metabolism by cyclooxygenase; (2) by the previously described XO system; (3) via quinone-mediated reactions within and outside the electron transport chain (from M); and (4) by activation of NADPH-oxidase in accumulated neutrophils in the microvasculature or after diapedesis into tissue. Increased O2- leads to increased hydrogen peroxide (H2O2) production as a result of intracellular action of superoxide dismutase (SOD). H2O2 is controlled by intracellular catalase (c). Increased O2- further leads to increased ·OH because of conversion of H2O2 to ·OH, via the Haber-Weiss/Fenton reaction, with iron liberated from mitochondria. This reaction is promoted by acidosis: ·OH and OONO- damage cellular lipids, proteins, and nucleic acids. Also, AA increases activity of the cyclooxygenase pathways to produce prostaglandins (PGs), including thromboxane A2, the lipoxygenase pathway to produce leukotrienes (LTs); and the

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in vivo than previously assumed. A few selectively vulnerable dead cerebral neurons can impair human mentation, whereas the heart can pump in spite of losing up to 40% of myocytes. Normothermic no-flow of 5 to 20 minutes, in animals and patients, can be reversed to cardiovascular survival74 and recovery of cerebral oxygen metabolism,76,84 but not survival of all cerebral neurons.74,83 A clinically realistic combination of CBF promotion and mild hypothermia, however, has recently achieved complete functional recovery in dogs after 11 minutes of normothermic CA (no-flow) (see Fig. 15-5; see later).2

History Cardiopulmonary Resuscitation Occasional attempts to reverse sudden coma, airway obstruction, and cessation of breathing have been made since prehistoric times91,92; however, potentially reversible

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apnea and pulselessness (CA) was not recognized until the Renaissance.93 The early history of CPR91 has many sparks, which failed to benefit patients over centuries probably because of lack of communication and collaboration among laboratory researchers, clinicians, and rescuers. Searching for effective resuscitation measures was provoked by the introduction of general anesthesia, which, starting in the late 1800s occasionally led to airway obstruction, apnea, or pulselessness, as the introduction of asepsis enabled laparotomies which required deep anesthesia. Modern effective CPR (without thoracotomy), however, did not come about until the 1950s.25–42 The recent history of modern standard external CPR (SECPR)92 shows a series of landmark developments, starting in the 1950s: Proof (in curarized adult human volunteers without tracheal tube) that soft-tissue obstruction of the upper airway in unconscious patients can be prevented or corrected by backward tilt of the head, forward displacement of the mandible, and opening of the mouth (step A).27,28

cytochrome P-450 pathway. These products can act as neurotransmitters and signal transducers in neurons and glia, and can activate thrombotic and inflammatory pathways in the microcirculation. Inflammatory reactions after ischemia have been proven to occur in extracerebral organs, focal brain ischemia, or brain trauma; but so far, they have not been proven after temporary complete global brain ischemia. Neuronal injury can signal interleukin-1 and other cytokines to be produced and trigger endogenous activation of microglia, with additional injury via QA, quinolinic acid, or other neurotoxins. In addition, tissue and/or endothelial injury—particularly associated with necrosis—can signal the endothelium to produce adhesion molecules (intracellular [ICAM], a-selectin, p-selectin), cytokines, chemokines, and other mediators, triggering local involvement of systemic inflammatory cells in an interaction between blood and damaged tissue. Reoxygenation restores ATP through oxidative phosphorylation, which may result in massive uptake of [Ca2+]i into mitochondria, which are swollen from increased osmolality. Thus, mitochondria loaded with bound Ca2+ may self-destruct by rupturing and releasing free radicals. Increased [Ca2+]i by itself and by triggering free-radical reactions may result in lipid peroxidation, leaky membranes, and cell death. Neuronal damage can be caused, in part, by increased [EAA]e (excitotoxicity), resulting in increased [Ca2+]i. During reperfusion, [Ca2+]i and increased [EAAs]e normalize. Their contribution to ultimate death of neurons is more likely through the cascades they have triggered during ischemia. During ischemia and subsequent reperfusion, loading of cells and maldistribution of calcium in cells is believed to be the key trigger common to the development of cell death. This calcium loading signals a wide variety of pathologic processes. Proteases, lipases, and nucleases are activated, which may contribute to activation of genes or gene products (i.e., interleukin-converting enzyme, ICE or P53) critical to the development of programmed cell death (PCD, i.e., apoptosis); or inactivation of genes or gene products normally inhibiting this process. Activation of neuronal nitric oxide synthase (nNOS) by calcium can lead to production of NO, which can combine with superoxide to generate peroxynitrite (OONO-). OONO- and ·OH both can lead to DNA injury and PCD, or protein and membrane peroxidation and necrosis, respectively. Nerve growth factor (NGF), nuclear immediate early response genes (IERG) such as heat-shock protein, free radical scavengers (FRSs), adenosine, and other endogenous defenses (ED) work to lessen the damage. There is substantial evidence that delayed cell death execution pathways are activated after ischemia, involving mitochondrial injury, cytochrome C release and caspase activation (right side of diagram). Neurotrophins, cytokines and other growth factors activate multiple receptor tyrosine kinases (RTK) signaling pathways linked to either pro-survival or pro-death activities. Several protein kinase cascades play a major survival role. The mitogen activated protein kinase (MAPK) cascade, involving multiple MAPKs, kinase RAF, MEK, and extracellular signal-regulated kinase (ERK), as well as phosphoinositide 3-kinase (PI3-K)/protein kinase B(PKB) pathways are best defined, but interactions involving phospholipase C gamma (PLCg) protein kinase C (PKC) isoforms are also important. PKB mediates trophic signals via PI3-K and has numerous pro-survival actions. ERKs are also activated via neurotransmitter-linked protein kinase cascades involving small G protein-binding proteins (Ras) that activate Raf kinase and other MAPKs. ERKs have been implicated in both pro-survival and pro-death cascades. c-Jun NH2-terminal kinase (JNK) and other stress-activated protein kinases (SAPK) are also MAPKs that target similar nuclear transcription factors that modulate pro-death activity.

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VF No-Flow 12.5 min—CPB Hypothermia Tcv 34°C during VF or reperfusion

Controls Tcv 37.5°C

Best OPC 24–96 h

VF No-Flow 10 min—CPB Controls Tcv 37.5°C

VF No-Flow 11 min

Hypothermia Tcv 34°C after ROSC

Hypothermia Tcv 34°C during CPR

<0.01

<0.005

S

S

Hypothermia Tcv 34°C plus CBF Promotion

Controls Tcv 37.5°C

5 Brain death Death

4 Coma, PVS

3 Severe disability 2 Moderate disability

1 Normal p-values vs controls References

<0.01 <0.05 <0.05 L

W

K

S

L

W

K

S

<0.01 SP

Figure 15-5. Improved cerebral and overall outcome after ventricular fibrillation (VF) cardiac arrest in reliable dog outcome models with immediate postarrest (resuscitative) mild cerebral hypothermia (34°C). Cooling was induced within 15 minutes of reflow. Each dot represents one experiment with 72 or 96 hours postarrest intensive care. Outcome as overall performance categories (OPCs). Control experiments after VF no flow 12.5 minutes and CPB achieved severe disability or coma (OPC 3 or 4) in 30 of 32 experiments (left). Control experiments after VF no flow 10 minutes and external CPR achieved OPC 3 or 4 in nine of ten experiments (center). No controls achieved OPC 1 or OPC 5, documenting the models’ reproducibility. Mild early postarrest hypothermia increased significantly the proportion of experiments with good outcome (OPC 1 or 2). Data from the fifth mild hypothermia study of 1994,67 as a model for clinical trials, as shown on the right and in open circles (right). (L = ref 63; W = ref 65; K = ref 66; S = ref 56,64; SP = ref 67).

Figure 15-6. The CPCR system of 2000 CE by Safar, modification of the ABC of 1961.14 It consists of basic, advanced, and prolonged life support (BLS-ALS-PLS).

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Proof that ventilation with the operator’s exhaled air is physiologically sound27,31; and that mouth-to-mouth (nose) ventilation is superior to manual chest-pressure arm-lift methods in adults (step B).27,31,32 The serendipitous rediscovery, laboratory documentation, and first clinical uses of emergency artificial circulation by external cardiac (chest) compressions (step C)33,34; combining steps A, B and C into BLS36,37; the first successful electric defibrillation of a human heart via thoracotomy40; and the first successful external electric defibrillation and pacing of human hearts.42 Finally, the concepts of “hearts too good to die” (reversible sudden cardiac death) and “brains too good to die”.

Cerebral Resuscitation The extension of CPR to CPCR occurred conceptually in 1961.25,26 Guthrie of Pittsburgh drew attention to the brain in resuscitation research much earlier.94 It required experimental proof, which began around 1970 with (1) the recognition by Hossmann that many cerebral neurons can tolerate longer no-flow times than previously assumed81–84; (2) the description by Negovsky and associates of the cerebral postresuscitation disease70,95–99; (3) the development by Safar of clinically realistic GBI and CA models in animals high on the phylogenetic scale (monkeys, dogs), including intensive care life support over several days to let the encephalopathy mature, and to evaluate outcome2,74,77,100–103; and (4) the design by the Pittsburgh group of the first (multicenter) randomized clinical trials of CPCR, the Brain Resuscitation Clinical Trials I-III (BRCT). Subsequently, many neuroscientists have added knowledge about the mechanisms of cell death. This has revealed the increasingly complex molecular and cellular mechanisms of postischemic encephalopathies (see Fig. 15-4).2,76 Many seemingly positive trials of novel drug treatments in rat models of incomplete forebrain ischemia104,105 are clinically not realistic, and could not be duplicated in outcome models in dogs.2,80 Rodent models of CA106–116 are clinically more relevant, but long-term life support is difficult or impossible. There are many models of hypoxic insults to neurons that are clinically not realistic, ranging from in vitro models117 to increased intracranial pressure (ICP) in dogs.118 For almost 100 years before 1970, some pathologists, neurosurgeons, neurologists and—since the 1950s, neuroanesthesiologists—studied the brain after operative trauma, accidental trauma, intracranial hemorrhage, or focal ischemia (stroke). Present cerebral resuscitation researchers stand on the shoulders of the pioneers of therapeutic cerebral hypothermia of the 1950s and 1960s. In the 1960s, neuropathologists documented that after GBI there is delayed dying of scattered cerebral neurons. Studies of postischemic encephalopathies were encouraged by the introduction of CBF methods.119–128 The brain has remained relatively unexplored concerning traumatic shock (i.e., incomplete GBI),

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which has been studied for extracerebral organ failure since the 1930s. Around 1970, Hossmann81–84 showed that the majority of cerebral neurons (by far not all) in cats or monkeys can tolerate up to 60 minutes of complete normothermic GBI—in terms of recovery of EEG activity and protein synthesis—provided reperfusion is good. The Pittsburgh group, after an EEG recovery study in 1968,129 documented in 1971, for the first time, the transient hyperemia-protracted cerebral hypoperfusion sequence after prolonged CA in dogs (see Fig. 15-3).123,124 This hypoperfusion had to be overcome to improve outcome.130–132 How to prevent delayed post-CA dying of selectively vulnerable neurons remains an important challenge for resuscitation researchers.79 That challenge was partially met through the discovery of mild resuscitative (post-CA) hypothermia in the 1980s. For the history of therapeutic hypothermia, see the section on hypothermic strategies. The main incremental risk of increasingly effective CPCR methods is survival with severe brain damage. Since the mid1960s, the topics of determination and certification of brain death, and the decision to “let die” regarding patients in prolonged vegetative state after CA, have assumed increasing socioeconomic importance.

Pathophysiology Postischemic Encephalopathy The temporary complete GBI of CA can occur instantly, as in VF; over minutes, as in asphyxiation or exsanguination; or over hours, as in shock or hypoxemia (see Fig. 15-1).1,2 Sudden cardiac death and resuscitation create a cerebral insult that is often caused by the initial no-flow, followed by the incomplete ischemia of CPR (low-flow), and, after ROSC, by the postresuscitation disease in brain and other vital organs.70,96 While extracerebral derangements after normothermic CA of 5 to 20 minutes, ROSC, and controlled normotension seem to be reversible under adequate life support, selectively vulnerable cerebral neurons continue to die. This was first described by Spielmeyer. The main mechanisms, we have learned recently, are post-CA hypoperfusion (see Fig. 15-3) and complex destructive chemical cascades (see Fig. 15-4).133 In normal brain, autoregulation maintains global CBF of approximately 50 mL/100 g brain per minute, despite cerebral perfusion pressure (CPP) changing between 50 and 150 mm Hg. CPP is mean arterial pressure (MAP) minus ICP or internal jugular vein pressure, whichever is higher. When CPP decreases below about 50 mm Hg, CBF decreases. During incomplete ischemia (e.g., shock or CA with external CPR), the viability of normal neurons seems to be threatened only when CPP decreases to or below 30 mm Hg,134–138 CBF to less than 15 mL/100 g of brain per minute,137 or cerebral venous PO2 to less than 20 to 25 mm Hg137–140 (normal value >40 mm Hg). The brain apparently tolerates low-flow

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(e.g., global CBF 10% of normal, i.e., 5 mL/100 g of brain per minute) better than no flow141; however, trickle-flow (CBF less than 10% normal) can be worse than no-flow.142 With sudden circulatory arrest at normothermia, loss of brain oxygen stores143 and unconsciousness (in normal humans with neck tourniquet inflation)144 occur within 10 to 20 seconds. For complete reversibility, the 4- to 5-minute limit established clinically68–78 is supported by evidence that brain glucose and adenosine triphosphate (ATP) stores are depleted145,146 and the cell membrane ion pumps arrested143,147,148 within 3 to 5 minutes of normothermic circulatory arrest. Distinct events during ischemia (energy loss) and after reperfusion (see Fig. 15-4) lead to abnormal activation of lipases, proteases, and nucleases2; and suppression of translation, signal transduction, and growth factors. In dog outcome experiments, VF no-flow of 1 to 4 minutes is reversed to complete functional recovery and normal brain histology, whereas VF no-flow of 5 minutes77 or asphyxial asystole of only two minutes78,149,150 is followed by complete functional recovery, but with mild histologic damage in vulnerable regions. The 4- to 5-minute limit is being challenged by the occasional survival without severe neurologic deficit after normothermic no-flow of 10 to 20 minutes in dogs74,77,151 or in patients.86,152,153 These cases might be explained by unrecognized spontaneous mild hypothermia. Normothermic no-flow of 60 minutes was survived in one cat with only slightly abnormal behavior, but with some histologic brain damage.83 Multiple factors— some understood (e.g., spontaneous hypothermia, see following) and others as yet unknown—might explain these occasional “miraculous” recoveries. During complete cerebral ischemia, calcium shifts,76,143,154,155 brain tissue lactic acidosis,156 and increases in the brain of free fatty acids,157 osmolality,158 and extracellular concentration of excitatory amino acids (particularly glutamate and aspartate),159–162 set the stage for reoxygenation injury (see Fig. 15-4). Greater cerebral lactic acidosis with incomplete ischemia156 or prearrest hyperglycemia163 is followed by greater histologic brain damage. Brain acidosis caused by high CO2 without hypoxia, however, seems to be better tolerated, at least by the normal brain.164,165 Why do some neurons die while neighboring ones survive? Are the more vulnerable neurons those that are more stimulated post-CA (excitotoxicity), or those that had been programmed to die sooner than others without CA, but were triggered by CA into earlier programmed DNA damage? Present research interests include how selectively vulnerable neurons die alongside surviving neurons, predominantly in the CA-1 region of the hippocampus, neocortex, thalamus, and cerebellum (Purkinje cells). There is a possibility that temporary, complete ischemia can damage DNA and thereby trigger programmed cell death of some (scattered) and not other neurons, that is, “apoptosis” (from the Greek, “falling apart”).166 This might differ from primary necrotizing processes and membrane breakdown in the majority of neurons.

Postinsult intracranial pressure (ICP) increases, due to vasogenic cerebral edema, hyperemia (increased blood volume), or cerebral venous obstruction, is more an issue for resuscitation from TBI or severe ischemic stroke or cerebral hemorrhage, than for CA,123 except for cases of very prolonged CA which is followed by ICP rise to brain death. For ICP control after insults other than CA (or GBI), see the section on hypothermia. Postischemic Hypoperfusion Cerebral perfusion changes (i.e., CBF changes during normotensive reperfusion after 10 min or longer of normothermic CA no-flow) seem to progress through four stages (see Fig. 15-3): 1. Multifocal (heterogeneous) no-reflow, observed immediately with reperfusion.70,167–172 It is most likely caused by blood cell sludging. It seems to be readily prevented or reversed in animals with normotensive or hypertensive reperfusion173–186 with or without hemodilution.130–132,181 These measures improve outcome,130–132 perhaps even leukocyte adhesion, endothelial swelling, and clotting.172 2. Transient global “reactive” hyperemia (vasoparalysis), which lasts 15 to 30 minutes123–125,173–180; may be beneficial. 3. Delayed, prolonged global and multifocal hypoperfusion,123–125,173–180 from approximately 1 to 2 hours to 12 hours after CA and ROSC. Global CBF is reduced to approximately 50% of baseline, while global CMRO2, which had become zero during complete ischemia, is recovering with reperfusion to moderately low levels in the first 1 to 2 hours.187 From 2 hours on, however, CMRO2 returns to or above baseline values, causing a potential mismatching of O2 delivery vs. O2 demand.82,123–125,173–175,178 Cerebral-venous PO2 may decrease to less than the critical level of about 25 mm Hg or ScvO2 to <50% or cerebral O2 extraction ratio (Ca-vO2 / CaO2) to >50%.177–179 Hypoperfusion is worse after long arrest times.188 The pathogenesis of this third stage (protracted hypoperfusion) needs clarification. Vasospasm,175,189–191 endothelial and tissue edema,123 blood cell aggregates,172 leukocyte adhesion, and perhaps even intravascular coagulation192–197 are possibilities. Inflammation, so important after brain trauma,198 seems less important after GBI,199–201 although there is a mild response of glial elements.202 The delayed protracted global cerebral hypoperfusion after CA has been documented also in patients.203,204 4. Resolution, occurring many hours after ROSC, results in either normal global CBF and CMRO2174 accompanying return of consciousness in a canine model,132 or both remain low in comatose patients.203–205 Intracranial hypertension does not develop in most patients going into permanent coma (persistent vegetative state). After very long normothermic CA, and ROSC, with persistent deep coma, there is first transiently some improvement

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(narrowing of pupils) only to be followed by fixed, dilated pupils, intracranial hypertension (cerebral edema),206,207 decrease in oxygen uptake, high cerebral venous PO2 due to arterio-venous shunting, EEG silence, nonfilling of intracranial vessels on angiogram, and the clinical picture of brain death.1,2,208–213 There is a need to clarify the pathophysiology of brain death development, in dogs or monkeys, after very long CA and ROSC. Deleterious Chemical Cascades What is the complex multifactorial pathogenesis of the postCA encephalopathy? Starting at about 24 hours after arrest, irreversible morphologic changes can be seen by light microscopy in some neurons scattered throughout the brain (see Fig. 15-4).77,103,214–221 Reperfusion leads to scattered neurons in selectively vulnerable regions developing irreversible changes. These start, depending on the insult, at less than 1 hour with vacuolization of mitochondria, seen by electron microscopy. There follows, in 2 to 4 days, shrinkage and eosinophilia of cytoplasm on light microscopy (with HE staining) and pyknosis of nuclei, that is, “irreversible” ischemic neuronal changes. After more than 7 days, absorption of dead neurons leads to a reduction in the number of morphologically normal neurons.2,69,77,84,101–105,109,110,214–221 Without reperfusion, all cells of the brain seem to die uniformly as part of panorganic death (see Fig. 15-1). Necrosis is the ultimate result of no energy.219,220 With reperfusion, energy is rapidly restored. Why do only some neurons die and why do we see patterns of apoptosis and/or necrosis? The final answer is still elusive. Since the 1970s, many scientists have helped increase our knowledge about how neurons die after temporary GBI in the absence of post-CA secondary ischemia. Derangements during GBI, summarized previously, set the stage for reoxygenation injury—the cerebral postresuscitation disease (see Fig. 15-4).2,70–72 After normothermic no-flow of 5 to 20 minutes duration followed by reperfusion, many secondary derangements can be considered. Brain energy charge, ion pump, and normal pH are restored fairly quickly.76,83,143 Postarrest inflammatory processes, which are proven to occur after TBI or in ischemic stroke, seem to be absent or minimal after CA,198 unless trauma and ischemia are combined.216 A new area of brain ischemia research is “proteomics,” the changes in brain protein concentrations and the recovery of protein synthesis.222 Even when, after CA of up to 15 minutes, ICP remains normal,103,123,124 extracellular-to-intracellular fluid and electrolyte shifts occur early during ischemia (cytotoxic edema).123,148,206 Vasogenic edema may develop late after reperfusion from very prolonged ischemia.103,207 Reoxygenation, although essential and effective in restoring energy charge, can provoke chemical cascades that result in lipid peroxidation of membranes.223–228 These processes, possibly first triggered by calcium shifts,229–231 also involve free iron, free radicals, acidosis, catecholamine release,232 excitatory amino acid release,159–162 and induction of pro-

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teases,233,234 leading to destruction of membranes and nuclear DNA. Earlier studies suggested no direct nuclear DNA damage after CA.235,236 Recent evidence suggests that profound cell death may occur in selectively vulnerable neurons with DNA fragmentation.237–242 Cerebral viability also depends on the DNA in mitochondria which can be damaged by late calcium fluxes through mitochondrial transition pores (MTP)241; and mitochondrial cytochrome-c— inducing apoptosis. Many of the above cascades (see Fig. 15-4) have been partially documented in vitro and in extracerebral organs, but have not been documented convincingly in vivo in the brain. The optimal PO2 and rate of reoxygenation during resuscitation need to be determined. The increase of lactic acid156 and excitatory amino acids159–162 that occur during ischemia are rapidly washed out with reperfusion, and ionic balance is partially restored.143 Although there might be a delayed postarrest increase in total brain calcium,230 treatable surges in brain intracellular calcium or glutamate release after arrest remain to be documented. Some of these molecular changes could be merely epiphenomena of permanent tissue damage, whereas others might explain why dying neurons and dying cardiac myocytes can be found alongside surviving cells. Extracerebral derangements can worsen cerebral outcome.70,243 CA in patients with previously sick hearts often is followed by recurrent VF or cardiovascularpulmonary failure.15–21 CA in previously healthy dogs is followed by delayed reduction in cardiac output despite controlled normotension.89 Postarrest pulmonary edema, however, can be prevented by prolonged controlled ventilation.89,101,102 Intoxication of the brain from postischemic viscera has been suggested,70 but convincing documentation is lacking. After no-flow of 10 minutes in healthy dogs and modern post-CA life support, neither pulmonary failure nor permanent renal or hepatic dysfunction appear to occur.89,244,245 Disseminated intravascular coagulation (DIC) is a possibility.197 Blood derangements include aggregates of polymorphonuclear leukocytes and macrophages that might obstruct capillaries, release free radicals, and damage endothelium in all organs.246–248 Their role after CA has not been clarified. The roles of inflammatory mediators and endothelium-derived nitrogenous vasodilators, which play roles in septic shock, need to be conclusively studied as to their roles in brain damage after CA.198,199

Therapeutic Considerations Guidelines for CPR and Cardiopulmonary-Cerebral Resuscitation Since the 1970s, one of us (PS) has written CPCR guidelines for the World Federation of Societies of Anaesthesiologists (WFSA) (see Fig. 15-6).1 The American Heart Association (AHA) guidelines committees have continued focusing on CA-ROSC by CPR, and on hospital discharge rates. Little attention has been paid to therapeutic potentials for saving

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cerebral neurons, although cerebral resuscitation starts with steps A-B-C of BLS, and continues through ALS and PLS1 (see Fig. 15-6). The AHA Guidelines 2000 Conference on CPR and Emergency Cardiovascular Care (ECC) updated previous recommendations6 by emphasizing evidence from randomized clinical outcome studies as the basis for all new clinical recommendations. Such trials are considered the “gold standard” for evaluating novel treatment potentials for subacute or chronic diseases (e.g., oncology, heart failure). We agree. We do not, however, consider them to be the “gold standard” for evaluating physiologically effective cerebral resuscitation potentials.2,15–21 The results from clinically realistic outcome studies are more controllable in animals high on the phylogenetic scale, such as dogs. The discrepancies between negative results in clinical trials and positive animal outcome data in acute medicine (e.g., for shock, brain trauma, sepsis, or stroke) can be explained by the limitations of randomized clinical outcome trials, which include2: cases within the therapeutic window cannot be selected in the seconds available to initiate (novel) resuscitation; numerous variables that can influence outcome, particularly the initial insult, cannot be accounted for in the randomization nor can they be controlled during the trial; despite standardized protocols, there is inevitably a great variability in the timing and quality of life support between cases and centers; subgroup analyses may be revealing, but creation of subgroups by postrandomization characteristics is considered by statisticians to be unreliable and may be misleading. It may be impossible to statistically document anything less than a consistent breakthrough effect. We know of no method to overcome these problems, except to rely more on large-animal outcome data, and on “sequential trials” within regions with CPCR case registries. In those studies, one would compare standard therapy results of the recent past with those of a novel therapy for cases considered “unresuscitable” in the past. Clinical feasibility and side effects of novel treatments in sick people can be determined without randomization. Therefore, based on personal experience and the literature, one of us (PS) thinks that novel cerebral resuscitation strategies that are simple and inexpensive, and that have shown clinically significant cerebral outcome benefit in several clinically realistic outcome models in animals high on the phylogenetic scale, should be taken, via clinical feasibility and side-effect studies (which are inexpensive), to general clinical use. AHA committees base their recommendations of 20006 on the following categorization: • Class I means evidence of benefit is excellent and the measure is acceptable, safe, and definitely useful. • Class IIa means that the evidence is good to very good, and considered a choice by the majority of experts. • Class IIb means that evidence is fair to good, useful as an alternative. • Class “indeterminate” means that evidence is insufficient.

• Class III means that the treatment is unacceptable because of either documented harm or no documented benefit. The newly designed AHA algorithm (see Fig. 15-2) seems to represent the consensus of panel leaders, but is not necessarily the opinion of the authors of this chapter. Novel brain-oriented therapies during and after CA, not included in the AHA recommendations of the 2000 conference, are included in the authors’ recommendations for a CPCR system of 2000 (see Fig. 15-6). Adult Basic Life Support The AHA recommends that rescuers confronted with a suddenly unresponsive adult should “phone first” (except in cases of submersion, trauma, or drug intoxication); that volumes for bag-mask ventilation be smaller to prevent gastric inflation; that the laryngeal mask and esophageal tracheal tube be acceptable; that the pulse-check requirement for lay rescuers be eliminated; and that the chest compression rate be 100/minute, with a compression : ventilation ratio of 15 : 2 for either one or two rescuers. For foreign body obstruction, abdominal thrusts (Heimlich maneuver) are retained for the still conscious victim, although efficacy is based on anecdotes. For unresponsive adults, lay rescuers do not have to treat foreign-body obstruction with an abdominal thrust. Sternal compressions may act as thrusts. Finger sweep of mouth and pharynx is retained. Use of an automatic external defibrillator (AED) by BLS responders (police, firefighter, security personnel, etc.) is a class IIa recommendation. We agree with all of the preceding recommendations, except that we recommend initiating steps A-B-C first, and calling EMS as soon as possible, preferably by a second person. In out-of-hospital cases of sudden coma, fewer than 20% of resuscitation attempts so far have been started by a lay bystander.22 This is now the weakest link of the life support chain.249 Safar, Laerdal, and Eikeland have, since the 1960s, developed and documented the superiority of simplified self-acquisition of life-supporting first aid (LSFA) skills by lay persons250; LSFA now should include CPR-BLS (steps A-B-C), clearing of foreign matter, AED, external hemorrhage control, positioning for shock or coma, “rescue pull,” and calling the EMS system for help. We recommend as part of LSFA more emphasis on backward tilt of the head, the use of an AED (when available) immediately following initiation of steps A-B-C, and starting external cooling as feasible (see Fig. 15-6). We have recommended ongoing community programs, including media, internet, and selftraining systems in schools and driver’s licensure stations. Self-training systems with individualized videotape-coached mannequin practice were found to be more effective than standard courses by instructors.250 The AHA guidelines committee suggested that if the rescuer is unwilling or unable to perform direct mouth-tomouth ventilation, he or she should at least perform chest

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compressions, which may be more effective than doing nothing.251 They did not mean to teach only chest compressions without ventilation. The AHA committee ignored the only human data on ventilation by sternal compressions alone,36 which showed no reliable ventilation, with or without tracheal tube. Also ignored were dog data showing that during CA, in the presence of airway obstruction, the still-oxygenated aortic blood will become rapidly deoxygenated under sternal compressions alone.252 Animals have straight upper airways, but comatose humans’ upper airways are kinked and obstruct without backward tilt of the head.27,28 The AHA should not give up teaching one BLS approach, steps A-B-C, for simplicity (lay persons cannot diagnose the cause of sudden coma); and stress step A, airway control by backward tilt of the head.253,254 This should be provided throughout sternal compressions by keeping the victim’s chest and shoulders elevated to sustain spontaneous head-tilt (see Fig. 15-6). Adult Advanced Life Support Pharmacology. The AHA recommendations state (and we agree) that the supporting evidence in general for all drugs in use for ALS is only fair. All anti-arrhythmics are determined as class IIb.6 References to bretylium have been dropped. Amiodarone is regarded as having better evidencebased support than any other anti-arrhythmic. Lidocaine remains acceptable as an anti-arrhythmic for countershock-refractory VF and pulseless VT, but is considered “indeterminate.” Magnesium is recommended only for hypomagnesemia and “torsades de pointes” as class IIb. Vasopressors, such as epinephrine, remain important to cause peripheral vasoconstriction, which enhances ROSC by increasing coronary perfusion pressure.48,49,255–257 Other vasopressors are also effective.48–51,258,259 Cardiac stimulants without vasopressor effect do not enhance ROSC.48,257 Escalating doses or high doses of epinephrine21,50,186,260,261 are not recommended by the AHA for routine use during CA (indeterminate), although they enhance ROSC.21 There is some evidence that cardiac arrest survivors who received highdose epinephrine have more cardiac complications after ROSC.21,260–262 Vasopressin (40 U IV as a single dose) may be substituted for epinephrine (1 mg IV) as an alternative vasopressor in VF or VT with CA (class IIb).51,263 Interestingly, the AHA considered epinephrine as “indeterminate” due to the lack of placebo-controlled clinical trials. In patients, randomized withholding of epinephrine or an alternative vasopressor would be unethical, considering the powerful animal data in support of increasing coronary and cerebral perfusion pressures during steps A-B-C. Buffer therapy to correct metabolic acidemia during CPR-ABC, although found beneficial in enhancing ROSC,48,53–58,264–267 has remained controversial because of some suspicions of its being unnecessary or harmful.7,56,57,268,269 Other recent data support the use of NaHCO3, because tissue lactic acidosis depresses the

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myocardium and is associated with enhanced ischemic brain damage.156 Tissue hypercarbic acidosis without hypoxia (correctable by perfusion and ventilation) may temporarily hamper function, but does not cause permanent damage to heart or brain.164,165 One must differentiate between NaHCO3 (or tri-buffer) administration before Vs after ROSC. We recommend that before ROSC, during CPR steps A-B-C, NaHCO3 1 to 2 mM/kg be given IV only when estimated arrest time or CPR time is long. In these cases, buffer therapy can enhance ROSC. After ROSC, during acid washout, bloodbase deficit worse than approximately 10 mEq/L may depress the myocardium and worsen the cascades of encephalopathy, and therefore should be normalized with titrated NaHCO3 IV. CO2 washout should be controlled by ventilation. Airway. The AHA recommends6 that tracheal intubation

in unconscious patients be attempted only by experienced health care providers. In patients not in CA, emergency responders should confirm tracheal tube position with a nonphysical examination technique (e.g., esophageal detector device, end-tidal CO2 indicator) (class IIa). In CA patients with low pulmonary blood flow, these devices are considered class IIb. ALS providers without regular field experience should use noninvasive techniques for airway management, such as pharyngeal tube and exhaled air ventilation via valved mask with O2 enrichment270 or laryngeal mask. Mouth-to-mask ventilation frees both hands for mask fit, head-tilt, and jaw thrust, which are more difficult to provide with bag-valve-mask ventilation.29 Defibrillation. Health care providers who perform CPR

should be trained, equipped, and authorized to use an AED (class IIa). Hospitals should establish programs to achieve early defibrillation throughout their facilities (class I).6 Step C Modifications.6 To date, no pneumatic modification

or adjunct has been shown to be universally superior to standard sternal compressions for prehospital closed-chest artificial circulation, in terms of blood flows produced and ROSC achieved. Weisfeldt and colleagues271 documented the chest-pump mechanism of blood flow produced by sternal compressions, that is, overall intrathoracic pressure fluctuations with functional venous valving.272 We now know that the chest pump mechanism prevails in keel-chested dogs, the heart compression mechanism in children and broadchested dogs, and individual combinations exist in adult humans.273 Simultaneous ventilation/compression (SVC) CPR37,271–275 requires tracheal intubation, which makes synchronizing unnecessary. Intermittent or sustained abdominal compression (IAC) CPR276–279 for in-hospital resuscitation is recommended by the AHA as an alternative intervention to standard CPR (class IIb). It improves blood flow and does not require intubation, but requires two operators. High-frequency CPR (>100 compressions/minute)280 lacks clinical studies and is considered as “indeterminate.” Active compression-decompression (ACD) CPR281,282 is con-

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sidered as an acceptable alternative (class IIb). Vest CPR283,284 may be considered an alternative for in-hospital use or during ambulance transport (class IIb). Mechanical (piston) CPR285,286 is considered as an acceptable alternative in circumstances that make manual chest compressions difficult (class IIb). Phased thoracic-abdominal compressiondecompression CPR lacks287 clinical outcome data (“indeterminate”). The impedance threshold valve288 for use with standard CPR is not recommended, but is acceptable as an adjunct to ACD-CPR (class IIb). Open-chest direct cardiac massage (OC-CPR)1 can be considered under special circumstances, but should not be done simply as a late lastditch effort (class IIb). Emergency cardiopulmonary bypass (CPB)151 lacks clinical outcome studies and is considered “indeterminate.” We would like to see OCCPR and CPB tried for very early application in cases of CA where SECPR-ALS of a few minutes fails to achieve ROSC. Ventilation. Inflation

volumes (which correlate with PaCO2), inhaled O2 (FiO2), and inflation pressures are under consideration.7,289 The fear of gastric distension due to high inflation pressures seems exaggerated.27 The fear that high FiO2 (PaO2) during ROSC attempts may worsen cerebral outcome by increasing reactive oxygen species (ROS) may

also be exaggerated.290–292 The re-examinations of exhaled air vs. air vs. O2 for ventilation during BLS and ALS, by Idris,289 is laudable; they should be extended to evaluating these effects on the postischemic encephalopathy. Standard Brain-oriented Life Support Early after ROSC, while the patient is unresponsive, hypotension, hypoxemia, hypercarbia, hyperthermia (even mild), hypoglycemia, and fluid and acid-base derangements must be avoided as they can worsen cerebral outcome.2 Accurate control of these variables can mitigate the postischemic encephalopathy (see Figs. 15-3 and 15-4). The effects of these general measures, and of novel cerebral resuscitation strategies to be described subsequently, require more intensive patient monitoring than is usually practiced for PLS after CA. Early after CA, the progression of recovery from coma should be followed (usually in the ICU) by monitoring the Glasgow Coma Score (GCS) (Table 15-1).1,293 The Pittsburgh Brain Stem Scale (PBSS) may also be determined (see Table 15-1),1,15–21 because it includes specific cranial nerve reflexes that have value for outcome prediction. Later, the patient’s progress should be monitored in terms of overall perform-

Table 15-1  Glasgow Coma Score and Pittsburgh Brain Stem Scale for Early Postarrest Evaluation of Patients Glasgow Coma Score (GCS) (Teasdale and Jennett: Lancet 1974; 2:81.)

Pittsburgh Brain Stem Scale (PBSS) (Brain Resuscitation Clinical Trial [BRCT], 1980s.)

If patient is under the influence of anesthetics, sedatives, Lash reflex present (either side) or neuromuscular blockers, give best estimate of each item. Write number in box to indicate status at time of Corneal reflex present (either side) this examination. (A) Eye Opening Spontaneous =4 Doll’s eye or ice water calorics reflex present To speech =3 (either side) To pain =2 Right pupil reacts to light None =1䊐 (B) Best Motor Response (extremities of best side) Left pupil reacts to light Obeys =6 Localizes =5 Gag, cough, or carinal reflex present Withdraws =4 Abnormal flexion =3 Total PBSS Extends =2 (best PBSS = 15) None =1䊐 (worst PBSS = 6) (C) Best Verbal Response (if patient intubated, give best estimate) Patient condition at time of examination: Oriented =5 Confused conversation =4 Inappropriate words =3 Incomprehensible sounds =2 None =1䊐 Total GCS (best GCS = 15) (worst GCS = 3) Patient condition at time of examination: Check all that apply: 䊐 Anesthesia/heavy sedation. 䊐 Paralysis (partial or complete neuromuscular blockade). 䊐 Intubation. 䊐 None of the above.

yes = 2 no = 1 䊐 yes = 2 no = 1 䊐 yes = 5 no = 1 䊐 yes = 2 no = 1 䊐 yes = 2 no = 1 䊐 yes = 2 no = 1 䊐

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Table 15-2  Overall and Cerebral Performance Categories for Outcome Evaluation of Patients Cerebral Performance Category (CPC)

Overall Performance Category (OPC)*

Evaluate only cerebral performance capabilities

Check one

CPC 1. Good cerebral performance Conscious, alert, normal cerebral function. May have minor psychologic or neurologic deficits that do not significantly compromise cerebral or physical function.

䊐

CPC 2. Moderate cerebral disability Conscious, alert, normal cerebral function for activities of daily life (e.g., dress, travel by public transportation, food preparation). May have hemiplegia, seizures, ataxia, dysarthria, dysphasia, or permanent memory or mental changes. 䊐 CPC 3. Severe cerebral disability Conscious, has at least limited cognition. Dependent on others for daily support (i.e., institutionalized or at home with exceptional family effort) because of impaired brain function. Includes wide range of cerebral abnormalities, from ambulatory patients who have severe memory disturbance or dementia precluding independent existence to paralyzed patients who can only communicate with their eyes (e.g., the locked-in syndrome).

䊐

CPC 4. Coma/vegetative state Not conscious, unaware of surroundings, no cognition. No verbal or psychologic interaction with environment. May appear awake because of spontaneous eye opening or sleep-wake cycle. Includes all degrees of unresponsiveness that are neither CPC 3 (conscious) nor CPC 5 (coma that satisfies brain death criteria). 䊐 CPC 5. Brain death (with beating heart) or death (without beating heart). Apnea, areflexia, “coma,” EEG silence. CPC A. Anesthesia (CNS depressant)

䊐

Evaluate actual overall performance OPC 1. Good overall performance Conscious, alert, capable of normal life. Good cerebral performance (CPC 1). Generally fit or only minor noncerebral organ system dysfunction.

䊐

OPC 2. Moderate overall disability Conscious, alert. Moderate cerebral disability alone (CPC 2) or moderate disability from noncerebral organ system dysfunction alone or both. Performs independent activities of daily life (dress, travel, food preparation) or able to work in part-time sheltered environment. Disabled for competitive work.

䊐

OPC 3. Severe overall disability Conscious. Severe cerebral disability alone (CPC 3) or severe disability from noncerebral organ system dysfunction alone or both. Dependent on others for daily support.

䊐

OPC 4. Coma/vegetative state Definition same as CPC 4. With or without extracerebral organ dysfunction.

䊐

OPC 5. Death (without beating heart) Apnea, areflexia, “coma,” no pulse.

䊐

OPC A. Anesthesia (CNS depressant) Uncertain as to above categories because of anesthetic, other CNS depressant drug, or relaxant effects.

䊐

䊐 Date

Time of determination Uncertain as to above categories because of anesthetic, other CNS depressant drug, or relaxant effects. Time achieved

䊐 Hour

䊐

䊐 Minute

Check one

䊐 Hour

䊐 Minute

Compared with baseline status before the insult, the patient’s intellectual functions now are (check one in each column): Patient opinion 䊐 䊐 䊐

Family opinion 䊐 䊐 䊐

Examiner opinion 䊐 䊐 䊐

Unchanged(1) Worsened(2) Unsure(3) Other or unable to determine(4) 䊐 䊐 䊐 Explain __________________________________________ *Reflects cerebral plus noncerebral status. Source: References 1 (CPC and OPC) and 294 (OPC).

ance categories (OPC) 1-5,294 and, separately, cerebral performance categories (CPC) 1-51,15–21 (Table 15-2). These measurements have become standard international recommendations.1,23 We added CPC to OPC because a patient can be severely handicapped by extracerebral organ dysfunction (OPC 3) while rational (CPC 1). Standard brain-oriented life support by control of extracerebral organ function is covered only partially in the AHA guidelines,6 and is more detailed in the recommendations

of the authors of this chapter1,2 (Table 15-3). Normotension, normoxia, and normocarbia are self-understood. For control of MAP early after ROSC, a titrated IV infusion of epinephrine or norepinephrine may be more effective than infusion of phenylephrine, dopamine, or dobutamine. The latter may have advantages later after CA. In cardiac failure later after CA, a spectrum of possibilities, from titrated dobutamine or norepinephrine to assisted circulation with CPB or aortic balloon pumping, is available. Throughout coma, controlled

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Table 15-3  Recommended Brain-Oriented Standard Basic-Advanced-Prolonged Life Support (BLS-ALS-PLS) BLS-ALS Life-supporting first aid (LSFA) skill acquisition by the lay public. vigorous CPR-BLS steps A-B-C Start external exposure cooling of head and trunk Minimize arrest time with earliest automatic external defibrillation (AED), even by laypersons Increase perfusion pressure during external CPR with early (IV or intratracheal) epinephrine or other vasopressor Titrate IV vasopressor after ROSC Explore prolonged mechanical external CPR Give buffer in prolonged no-flow, low-flow In ALS-resistant cases, switch early to open-chest CPR or CPB After ROSC, give brief hypertensive bout (systolic arterial pressure 150 to 200 mm Hg) Use epinephrine, norepinephrine or dopamine Continue with controlled normotension, or mild hypertension (titrated fluids, dopamine, dobutamine, or other cardiovascular drugs) Control normoxia, normocarbia Aim for Tty 34°C as soon as possible during A-B-C or after ROSC (see Table 15-4) Check blood glucose level and keep it at 100-200 mg/dL (give glucose load IV if prearrest coma or seizures) PLS Control normotension or mild hypertension, normoxia, normocarbia Restore blood volume Control base deficit at ± 5 mmoL/L Monitor brain temp. (Tty or Tnp) and core temp. (Tpa or Tcv or Tes) Maintain mild (34°C) resuscitative cerebral hypothermia from ROSC to 12-24 hours Prevent or correct even mild hyperthermia Immobilize with softening doses of relaxant Sedate as needed to prevent shivering (titrated meperidine, diazepam, barbiturate) Control seizures Keep pupils small Conduct hemodynamic monitoring as feasible to guide administration of drugs and fluids Keep hematocrit at 30% to 35%; electrolytes normal; plasma COP 15 mm Hg; Serum osmolality 280-330 mosm/L Fluids IV (no dextrose in H2O; give dextrose 5% or 10% in NaCl 0.25% or 0.5%, e.g., 50 mL/kg per 24 hours) Maintain fluid balance; acid-base balance; alimentation Use standard intensive care life support, including head slightly elevated, turning trunk side to side

ventilation for at least 12 hours postarrest seems desirable to combat cardiovascular-pulmonary failure. To control “fighting” tracheal tube and ventilator, we favor use of low (softening, not apneic) doses of a relaxant, titrated IV, to permit monitoring of neurologic recovery, to avoid overcurarization, and to allow titration of sedatives and narcotics. A hypnotic or narcotic agent should be titrated IV to control hypertension and mydriasis (sympathetic dis-

charge). Corticosteroid therapy is controversial.295 Optimal postarrest levels for PaO2, PaCO2, base deficit, serum osmolality, and blood glucose are not yet clarified. Prolonged hypoglycemia (blood glucose less than 50 mg/dL) is deleterious to the brain.143,296 Severe hyperglycemia present before and during GBI, in animal models, seems to worsen neurologic damage,143,163,296 most likely because it increases brain lactic acidosis, which decreases brain pH.156 During and after CPR, there is usually a spontaneous moderate hyperglycemic response, which may be desirable. Three animal studies showed worsened outcome with glucose IV during or after reperfusion297–299; other studies suggest improved neuronal recovery with hyperglycemia in focal ischemia,300 in vitro hypoxia,301 or after asphyxial CA,111 using our group’s asphyxial CA rat outcome model.107–109 The last study by our group showed that postarrest moderate hyperglycemia, by glucose administration plus insulin (blood glucose of approximately 150 mg/dL), can improve functional and histologic cerebral outcome over glucose alone, insulin alone, or no treatment with moderate hyperglycemia without insulin.111 In cases of prehospital CPR, high blood glucose levels at the time of arrival at the hospital correlated with poor neurologic recovery302–304; in one study, however, these hyperglycemic patients were diabetic.303 High glucose levels correlated with the duration of CPR attempts.303 Immediately after acute stroke, hyperglycemia might be helpful300 or harmful.305 Because sudden coma can be caused by hypoglycemia, routine withholding of IV glucose after CA is debatable. We currently recommend reperfusion without added glucose and postarrest monitoring and titration of blood glucose levels to 100 to 200 mg/dL. Suspected hypoglycemia should be treated immediately with glucose infusion. Cerebral Blood-Flow Promotion Support of hypertensive reperfusion can be found in papers documenting this treatment’s ability to overcome the immediate no-reflow phenomenon (see Fig. 15-3),167–179 to open highly resistant areas of the cerebral microcirculation,171 to improve EEG recovery after prolonged GBI in cats,81–84 and to have a variety of other positive physiologic effects in acute animal models.81–84,130,132,168–175,183–186 In 1974, using a dog model of VF with 12 minutes no-flow and external CPR, an immediate post-ROSC combination of norepinephrineinduced hypertension, intracarotid hemodilution with dextran 40, and heparinization improved outcome.130 That was the first positive outcome study of cerebral resuscitation after CA. Heparinization plus thrombolytic therapy immediately after CA looks promising.172,192–197,306 Thrombolysis would make sense to accompany the hypertensive bout because there is hypercoagulability195 and suggestion of benefit in patients,197 possibly for both heart and brain. In a recent dog outcome study, a brief hypertensive bout (MAP of 150 to 200 mm Hg for 1 to 5 minutes), followed by controlled mild hypertension, abolished evidence of immediate

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no-reflow175 and correlated with improved neurologic and brain histologic outcome. A vasodilating endothelin antagonist189–191 is only one possibility among many to provide CBF promotion after CA. Induced hypertension has not undergone a prospective clinical trial, but after ROSC in patients, four retrospective patient studies have shown that brief (spontaneous or induced) arterial hypertension early after CA was associated with good cerebral outcome, and/or hypotension with poor cerebral outcome.307–310 One study in human CA survivors showed that good functional neurologic recovery was independently and positively associated with arterial blood pressure after initial reperfusion, during the first 2 hours after CA.309 In a recent retrospective study of over 1,000 CA patients,310 good cerebral outcome was associated with higher SAP early after ROSC; this also held true in multivariate analysis. Prolonged severe hypertension late after arrest, however, might not be tolerated by the ischemic heart and might worsen vasogenic cerebral edema.311 The effect of normovolemic or hypervolemic hemodilution alone312 on cerebral outcome after CA is uncertain,130–132,313–315 possibly because hematocrit values less than 25% can reduce arterial oxygen content below that compensated for by increased flow, and thus decrease oxygen delivery.312 Post-CA cerebral hypoperfusion in dogs, however, could be prevented by hypertensive reperfusion plus normovolemic hemodilution with plasma substitute to a hematocrit of 20%.175 Our current recommendation for clinical use is in favor of a hypertensive bout as early as possible following ROSC. Indeed, this often occurs spontaneously, as a result of prior epinephrine administration. If not, it should be induced as early as possible after ROSC, by using a titrated IV infusion of a vasopressor. In dogs, norepinephrine by careful titration proved more effective than use of other vasopressors. Aiming for a systolic arterial pressure of 150 to 200 mm Hg for 1 to 5 minutes seems reasonable. After reperfusion for 15 to 30 minutes, a combination of Hct 30%, PaCO2 40 mm Hg, plus titrated moderate hypertension seems more beneficial for the brain than Hct 40% and PaCO2 30 mm Hg. After ROSC, during coma, monitoring mixed cerebral venous PO2 or SO2 (measured in the superior jugular bulb)140,316,317 could guide titration of MAP, hematocrit, and PaCO2175,318 to keep cerebral venous PO2 at >25 mm Hg (SO2 > 50%),137–139,175–179 to avoid major global underperfusion in relation to oxygen uptake. This will not detect multifocal hypoperfusion. Open-Chest Cardiopulmonary Resuscitation In CA cases in which external CPR-ALS attempts of longer than 5 minutes fail to restore stable spontaneous normotension (usually patients with acute myocardial infarction), artificial circulation methods that are physiologically more powerful should be tried. Chest compressions raise venous (right atrial) pressure peaks almost as high as arterial pres-

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sure peaks319 and increase ICP,320,321 thus usually causing very low cerebral and myocardial perfusion pressures during “thoracic diastole.”322–329 Open-chest CPR (direct manual compressions of the ventricles) does not raise right atrial pressure, provides better cerebral and coronary perfusion pressures and flows than does external CPR in animals320–332 and patients,323 and achieves better ROSC and outcome in dogs326 and patients.333 Open-chest CPR, which was introduced clinically around 1900,92,333 and used until 1960, inside hospitals, mostly for CA in operating rooms, yielded good clinical outcome results when applied promptly.333 In four studies, the switch from external to open-chest CPR in patients, even out-of-hospital, has been shown to enhance the chance of ROSC, but has failed so far to increase the proportion of patients with good cerebral outcome.334–338 This was to be expected because open-chest CPR has been initiated too late. The importance of early initiation of openchest CPR was documented in an uncontrolled clinical study from Japan, where the rate of ROSC was highest in patients with early thoracotomy338; survival rate was 12% with openchest CPR vs. 1% with conventional CPR. In a European study of mostly asystolic patients,336 out-of-hospital openchest CPR, after very long futile external CPR, increased the rate of ROSC, but survival rate was only 6%. In our opinion, medical students should learn open-chest CPR on dogs or pigs, as was done in the 1950s: how to assess the heart and begin massage within 60 seconds, how to ventilate with IPPV plus PEEP, and how to perform open-chest defibrillation.1,339 Trained physicians should consider switching to open-chest CPR much earlier than in the previously mentioned studies, perhaps even outside the hospital, and not only in victims of trauma.1,2 Bystanders have not objected to open-chest CPR when it was tried in the field335,336; openchest CPR attempts seem to be generally accepted (and admired) by the patients’ families. In the hospital, if the stunned heart cannot be started up even with open-chest CPR, prolonged direct heart compressions can be performed with a mechanical device.340 A method of minimally invasive direct heart compression, not requiring thoracotomy, is being evaluated.341 In a recent pig study, this device was shown to be superior to standard external CPR in terms of higher coronary perfusion pressure and rate of ROSC (7 of 10 vs. 2 of 10).342 Open-chest CPR can be initiated rapidly and serve as a bridge to long-term CPB and definitive cardiac repair. Emergency Cardiopulmonary Bypass For cardiac arrest, emergency cardiopulmonary bypass (CPB), that is, veno-arterial pumping via oxygenator, without the need for thoracotomy, was tried in dogs343 and in patients344 in the 1970s, but not pursued further. Because CPB provides full control over blood pressure, flow, composition, and temperature, in the 1980s Safar initiated a systematic comparison in eight CA outcome studies in dogs,151 comparing emergency CPB (by closed-chest

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veno-arterial pumping via oxygenator) with SECPR-ALS. CPB provided greater cardiovascular resuscitability than CPR-ALS and thereby improved cerebral recovery.90,151,345–350 In CA dog models, brief CPB provides controlled reperfusion that results in more reproducible outcomes.345–351 Emergency CPB has been tried in hospital emergency departments for CPR-resistant CA cases.352–354 Late initiation of CPB, and the excessive time (longer than 10 minutes) taken for cannulation of femoral vessels,352 have so far led understandably to disappointing results. A more rapid method of vessel cannulation is needed for use by ambulance physicians, to use a portable CPB device for ultra-ALS to be initiated in the prehospital setting.355–357 CPB might be initiated more rapidly via emergency thoracotomy. When, during prolonged CPB, the heart is in intractable asystole or VF, the need for decompressing the left ventricle or the pulmonary circulation is debatable. Closed-chest CPB during VF of up to 8 hours proved possible in dogs.358 Experimental VF and closed-chest CPB in sheep with inadequate decompression of the left heart caused an increase in left heart filling pressure, left ventricular pressure, and pulmonary artery pressure, as well as lung failure.356–358 Decompression of the left ventricle in sheep was achieved by keeping the pulmonary valve open with a spreading catheter (a helical spring).359–362 In humans, after normothermic CA, in some cases, closed-chest CPB without the need for venting the left ventricle was sometimes applied for up to five hours, and even for a day, without causing pulmonary edema.358,363,364 Prolonged emergency CPB151,358 or open-chest mechanical cardiac massage,340 for many hours, could give the stunned heart a chance to recover from reversible cardiac failure or could be a bridge to coronary angioplasty, bypass procedure, insertion of a left ventricular assist device, or emergency heart replacement. When brain death is determined, prolonged CPB could become a bridge to organ donation. These possibilities make present guidelines for discontinuing CPR in the field after a failed ROSC attempt of 30 to 60 minutes as being too pessimistic.3,365–367 Emergency (portable) CPB would give presently “unresuscitable” sudden cardiac deaths with “hearts and brains too good to die” (Beck-Safar) a new chance. These cases amount to up to 50% of out-of-hospital CPR attempts.1,6,8 Hyperbaric oxygenation (OHP, HBO) as a possibility for enhancing the recovery of the brain after CA and ROSC is a separate topic, beyond the scope of this chapter. HBO makes physiologic sense, lacks convincing outcome data so far for use after CA, and is logistically too problematic for use in emergency resuscitation. Pharmacologic Strategies Results with the pharmacologic cerebral resuscitation potentials for CA, explored so far2,368,369 have paled in comparison with hypothermia (see subsequently; see Fig. 15-4). In 1976,

the Pittsburgh group began to devote 10 years to evaluating the efficacy of thiopental loading, starting with GBI in monkeys,370 using for the first time a reproducible longterm intensive care outcome model103 to determine the neuron-saving potential of a drug administered after reperfusion. Thiopental caused a significant reduction in postarrest neurologic deficit and morphologic brain damage.370 The choice of barbiturate as the first drug tested (in a plan to explore many drugs) was based on positive results with use of barbiturates for experimental ischemic stroke,371–373 for incomplete ischemia,374 and for protection before global ischemia.375 Because no other reliable animal outcome model was available at the time, a second study with more accurate blood pressure control was conducted in monkeys with GBI, by the same group.376 This failed to duplicate the outcome benefits of the first study.370 In a cat VF model,377 barbiturate suppressed seizures.378 Several beneficial mechanisms justified barbiturate trials.2,379–382 Subsequent studies by others also gave mixed results.378,383,384 Because of the uncontrolled clinical use of barbiturate loading at that time, and promising clinical feasibility trials,153 a multicenter clinical trial was conducted.15 In this Brain Resuscitation Clinical Trial (BRCT I, 1979 to 1984) the proportion of patients with good cerebral outcome was statistically the same in thiopental and control groups, but a subgroup with long arrest or CPR times showed a trend toward better cerebral outcome after thiopental treatment. Because barbiturate loading proved hazardous for the cardiovascular system,15 we have recommended that anesthetic (not loading) doses should be titrated after CA to control seizures or intracranial hypertension. However, even smaller doses than those that silence the EEG can be expected to be somewhat beneficial.385 Barbiturates suppress active cerebral metabolism to, maximally, 50% normal. Basal metabolism, which is suppressed by hypothermia, is not decreased by barbiturates. Because we saw microinfarcts after GBI, we hypothesized that a beneficial effect could be expected. The cognitive dysfunction in some patients after cardiac surgery with CPB, probably mainly the result of microinfarcts, was mitigated with barbiturate.386 A barbiturate combination treatment in dogs after CA seems to give some cerebral benefit.387 Present conclusion is that some barbiturate treatment protocols can benefit the brain, but only if cardiovascular-pulmonary complications are avoided. Calcium entry blockers also seemed promising because of multiple beneficial mechanisms, including mitigation of cerebral hypoperfusion after CA.388 We found an IV infusion of lidoflazine after CA to significantly reduce neurologic damage in dogs.389 The same was found with the calcium entry blocker nimodipine in our GBI monkey model.390 In the second major clinical trial (the BRCT II, 1984 to 1989)17–20 post-CA lidoflazine also failed to achieve a significantly higher proportion of patients overall with good cerebral outcome compared to the placebo group, but a

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subgroup of patients without postarrest hypotension or rearrest did achieve a significant benefit.20 A similar clinical study of nimodipine, in Helsinki, also failed to show a statistically significant overall improvement, but in subgroups with prolonged CPR times, nimodipine had a significantly higher proportion with good cerebral outcome.391 We do not recommend the routine use of barbiturate loading or calcium entry blocker therapy after CA, because in both major clinical trials these drugs were difficult to manage. Their use was associated with a higher incidence of hypotension and re-arrest. For managing surgical anesthesia or sedation in the ICU after CA or TBI, the optimal agents remain to be determined. Barbiturates and halogenated inhalation anesthetics392–397 look better than opiates,398 which in large doses are excitotoxic.398,399 One cannot, however, assume that a slight benefit in a rodent focal brain ischemia or TBI model translates into benefit after CA in dogs or patients. Many other drugs with suspected cerebral resuscitation potentials have been studied in neuron cultures, rat hippocampus slice models, and (incomplete) forebrain ischemia rodent models. In some there was a suspicion of benefit. When studied in larger animals after CA or GBI, with appropriate temperature controls, however, outcome data were unconvincing or only suggestive in terms of cerebral benefit. There have been no more randomized clinical outcome studies with drugs after CA. Drugs explored for administration after ROSC, in animals, and found to possibly do some good, but without a breakthrough effect in clinically relevant large animal outcome models, include phenytoin,400,401 the antioxidant tocopherol (Safar et al., unpublished), the excitatory neurotransmitter NMDA receptor blocker MK-801,402–404 the AMPA receptor blocker NBQX,405,406 the aminosteroid trilizad,407,408 the neuronspecific calcium entry blocker SNX-111,409–413 lidocaine414,415 (Safar et al., unpublished), various other calcium entry blockers (some of which are not available for IV use in the United States),416–429 fructose biphosphate,430–432 the good gene bcl-2,433 insulin with glucose and moderate hyperglycemia,111,434 estrogen,435 and a PARP inhibitor436 (see Fig. 15-4). Of course, there are also lessons to be learned about possible intravascular clotting after CA as established for stroke.437,438 Unconvincing results in large-animal outcome models2 were often preceded by beneficial effects on mechanisms and even on histologic damage of the hippocampus in rodents. Some of these drugs were expected to fail, either because uni-mechanistic effects cannot mitigate the multifactorial pathology (see Fig. 15-4), or because they fail to penetrate the blood-brain barrier, which is not grossly damaged after CA of up to 30 minutes no-flow.369 Drugs given at the start of ischemia might be more effective. Even there, however, of 14 drugs we explored for preservation by aortic flush at the start of 20 minutes of CA in dogs,369 13 drugs failed to improve cerebral outcome, while mild hypothermia normalized outcome. Only the antioxidant tempol, which is water soluble and penetrates the blood-brain

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barrier, was found to give benefit, and that only when present during ischemia (preservation), but not when given for resuscitation after CA (see following section, Suspended Animation).439 Other antioxidants that do not penetrate into the brain may have beneficial effects on the microcirculation,440–442 but not on neurons.443–445 Mechanistically intriguing is the discovery of mitochondrial transition pores (MTP) late after GBI, as a culprit in causing DNA damage through calcium flux.446 This mechanism could be mitigated with cyclosporin-A, but only if the blood-brain barrier is broken in GBI with a needle puncture447 or in focal ischemia448; but not after temporary GBI with the blood-brain barrier intact.369 Combination treatments would make more sense than drug effects with single mechanisms (see Fig. 15-4). Many combination treatments remain to be evaluated, but a practical method to accomplish this is still elusive. Drugs that seem to have a slightly beneficial effect after an insult other than CA, such as MCA occlusion, should not be expected to benefit the brain after GBI. Other limiting factors are solubility, toxicity of vehicle (such as DMSO), methemoglobinemia (as with tempol), and exorbitant costs of some experimental drugs. For more references on the exploration of pharmacologic strategies in various brain insults, see reviews.2,368,369 Hypothermic Strategies Accidental exposure hypothermia causing loss of limb or life has been described throughout human history (Table 15-4; see Fig. 15-5). So has the use of therapeutic local application of cold to reduce inflammation and pain. Therapeutic whole body cooling was first used empirically in the 1940s for cancer pain and brain trauma in patients.449 The history of

Table 15-4  Rapid Induction of Mild Resuscitative Cerebral Hypothermia in Comatose Patients After CA Clinical Cooling Methods Ranked by Rapidity to Low Brain Temperature Intracarotid cold perfusion Intra-aortic cold flush Cardiopulmonary bypass with heat exchanger Whole body ice-water immersion Veno-venous extracorporeal blood shunt cooling Peritoneal cold lavage Esophagogastric, nasopharyngeal, IV cold infusion Fanning or ice bags on skin

Ranked by Feasibility to Initiate Tty 34°C in Patients with Circulation * * * Impractical 3 4 2 1

*Limited by vessel access time and availability of (portable) pump-heat exchanger.

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therapeutic hypothermia began in the 1950s with elective moderate hypothermia of the brain, introduced under anesthesia, for the protection-preservation during brain ischemia needed for surgery on heart or brain. All began with the pioneering work of Bigelow,450,451 Dripps,452 Rosomoff,453–458 and Negovsky.95,459 In the 1960s, R. White and Albin460–470 pioneered the experimental documentation of local hypothermia after spinal cord injury. When induced before CA (protection), moderate hypothermia (28°C to 32°C) can preserve the brain during no-flow of up to 20 minutes.450–452 Deep hypothermia (16°C to 27°C) causes VF or asystole but, when induced and reversed by CPB, preserves brain viability during 30 to 45 minutes no-flow, whereas profound hypothermia (5°C to 15°C) could preserve the viability of brain and organism for at least 1 hour of total circulatory arrest in dogs, and for 45 minutes arrest in patients. These trials in large animals471–483 and patients484–488 were under anesthesia, with slow, elective induction of hypothermia by surface cooling or rapid cooling with CPB. Lessons were learned from experiments and clinical data on drowning.489–494 One must differentiate between neardrowning with circulation (pulse) continuing, when the main injury is that of the lungs; and full drowning, that is, to clinical death (no pulse). The “miraculous” recoveries of humans after icewater drowning (with asphyxia) or exposure hypothermia (without asphyxia),495–498 from estimated CA times of up to 1 hour, can be explained by the fact that the brain reaches protective hypothermic levels before the heart stops.345,499 This is in contrast to severe brain damage after even brief CA as the result of normothermic asphyxiation or normothermic drowning.490–494 Moderate resuscitative (postinsult) hypothermia (30°C) after CA was explored already in the 1950s in animals500,501 and patients.458,502–504 The summary of the physiology of hypothermia by Dripps and Severinghaus of 1956452 is a classic. Safar included resuscitative hypothermia in 1961 as one step in his recommended CPCR system.25,26 Resuscitative hypothermia research was then given up for 25 years, probably because of uncertain benefit, management difficulties, and fear of side effects (VF, coagulopathy, infection). In the early 1980s, disappointed with drug treatments,2,15–21 Safar’s group revived research into resuscitative moderate hypothermia (30°C) after CA.505–507 Outcome benefit was modest. The subsequent discovery by Safar’s group in dogs in 1987 that mild hypothermia (33°C to 36°C), which is simple and safe compared to moderate hypothermia, is protectivepreservative,74,151 was followed by documentation of resuscitative effects on the brain after prolonged CA,508–514 and after asphyxial CA in rats.515,516 Simultaneously with these dog studies, other investigators discovered mild protective, preservative, and resuscitative hypothermia in incomplete forebrain ischemia rat models.517–524 All this rekindled widespread hypothermia research in the 1990s. The neuroscientists in Miami, Lund, and Detroit who used rats documented the ability of mild resuscitative hypothermia to reduce hip-

pocampal histologic damage. They also examined many biochemical mechanisms. Now, mild cerebral resuscitative hypothermia after prolonged normothermic CA and ROSC remains at the cutting edge of reanimatology. External cooling of the conscious organism causes potentially hazardous shivering and a sympathetic discharge with vasoconstriction, arrhythmias, and thermogenesis, through the homoiothermic defenses dictated from the hypothalamus.525 Internal cooling of blood is less likely to cause shivering, even in the conscious organism. To make hypothermia therapeutic and safe, these defenses must be blocked and poikilothermia achieved, either by the insult (ischemia or trauma) suppressing the temperature regulating hypothalamus-pituitary system, or by drugs (sedatives, anesthetics, relaxants).526 When some normothermic mammals hibernate they release a still putative hibernation induction trigger527 or a “hibernation specific protein” (HSP)528 from the liver to induce poikilothermia. That lowers body functions parallel with body temperature dropping to 20°C to 30°C in cool environments, without tissue hypoxia. Resuscitation researchers can probably learn more from the physiology of profoundly hypothermic hibernating turtles with tissue hypoxia.529 Risks of moderate hypothermia, even with poikilothermia, include arrhythmias452,530; coagulopathy as a result of reversible platelet sequestration and depression of coagulation enzymes452,531–534; and—if prolonged—pulmonary infection,452,535,536 at least when life support is not ideal. Deep-to-profound hypothermia slows the microcirculation and causes myocardial depression, hypotension, arrhythmias, and CA at 22°C to 27°C. Moderate resuscitative hypothermia, induced immediately after an insult, when first studied around 1960, suggested benefit in dogs with focal brain ischemia455 or brain contusion,457 and yielded unconvincing results after CA in dogs and in patients.501–504 It was discontinued, probably because of clinical management problems and perceived risks. In the early 1980s, resuscitative hypothermia research for CA was revived, using reliable, clinically relevant large-animal outcome models.505–515 Moderate hypothermia (30°C) gave borderline benefit for the brain, but had side effects for the heart.507 In 1987, at a conference in Pittsburgh, Hossmann84 reported that in cats with GBI there was a correlation between mild (unintentional) precooling and enhanced EEG recovery. At the same meeting, Safar74,151 discovered a correlation between good cerebral outcome and mild (unintentional) hypothermia (34°C to 36°C) present at the onset of VF in dog experiments. This led to a systematic series of five major outcome studies in dogs of prolonged normothermic CA followed by mild resuscitative cerebral hypothermia (34°C), induced immediately after reperfusion and maintained for 2 to 3 hours508–511 or 12 hours512 (see Fig. 15-5). In the first study,508 12.5-minute no-flow VF was accompanied by head immersion in iced water (which reduced

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brain temperature by only 1°C) and followed by reperfusion cooling with brief CPB to 34°C. Functional and morphologic brain outcome variables were significantly improved in the hypothermic groups. In the second study,509 10-minute no-flow VF was reversed by standard external CPR; mild hypothermia induced within 5 to 10 minutes after reperfusion achieved the same significant improvement as in the first study. Cooling was performed with a clinically feasible but complex combination of head-neck-trunk surface cooling, plus cold fluid loads administered intravenously, intragastrically, and nasopharyngeally. In the third study,510 12.5-minute no-flow VF, brief CPB, and immediate mild (34°C) or moderate (30°C) hypothermia improved functional and morphologic brain outcome, but deep postarrest hypothermia (15°C with CPB) did not improve function and worsened brain histology. This contrasts with the greater brain protection (with prearrest induction) achieved with deep, as compared to moderate, hypothermia. Moderate or deep postarrest hypothermia also worsened necrotic foci in the myocardium. It could worsen reperfusion. In the fourth study,511 with the same model as in the first study, a 15-minute delay in the initiation of mild cooling after normothermic reperfusion offset the mitigation of functional deficit and decreased the mitigation of histologic damage, compared to the more effective immediate postROSC cooling. In studies 1 through 4, even dogs with complete functional recovery had some histologic brain damage. In the fifth study of 11 minutes of normothermic VFCA,512 a combination treatment of mild hypothermia for 12 hours and CBF promotion led to the best outcome yet encountered in dogs (see Fig. 15-5). We compared a control group 1 (normothermic standard therapy) with a combination treatment group 2, which received mild hypothermia by head-neck-surface cooling plus peritoneal instillation of cold Ringer’s solution to keep brain temperature 34°C for 12 hours starting from reperfusion. Prolonged emergency CPB151,358 or open-chest mechanical cardiac massage,340 for many hours, could give the stunned heart a chance to recover from reversible cardiac failure or could be a bridge to coronary angioplasty, bypass procedure, insertion of a left ventricular assist device, or emergency heart replacement. When brain death is determined, prolonged CPB could become a bridge to organ donation. In addition, group 2 received CBF promotion by induced moderate hypertension (MAP 140 mm Hg) for 4 hours, colloid (dextran 40)-induced reduction of Hct from 40% to 30% for 12 hours, and PaCO2 of 40 mm Hg (instead of 30 mm Hg as in control group 1) from 3 to 20 hours. At 96 hours after resuscitation, all eight dogs in control group 1 remained severely damaged, while six of eight dogs in treatment group 2 had recovered to functional normality. The histopathologic damage scores in the treatment group were the lowest ever achieved. Final 96hour overall performance category, neurologic deficit scores,

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and brain histopathologic damage scores showed highly significant group differences (P < .001). Also significant was the difference between the outcome in treatment group 2 of this study versus outcomes in previous studies using the same model and comparable insult, with CBF promotion alone132 or mild hypothermia alone.511 The control group had the same poor outcome results as in 50 control experiments with a comparable insult and the same model in the past. We recommend clinical trials of a combination treatment protocols based on experimental group 2 in this study.512 Mild cooling in all five studies caused no cardiovascular or other side effects. We found in our asphyxial cardiac arrest rat model—as expected—that mild protective-preservative hypothermia reduces brain damage better than resuscitative hypothermia.516 The mechanism by which mild hypothermia protects and resuscitates is multifactorial.2,508 The ability of hypothermia in normal brain to reduce CMRO2 by about 7% per degree centigrade alone (in the absence of shivering), in animals453,537–540 or humans,122 cannot explain the resuscitative effect of mild hypothermia. The temperature coefficient Q10 expresses CMRO2 at one temperature divided by CMRO2 at 10°C lower. A Q10 of 2 expresses a 50% reduction in CMRO2, because it occurs in the normal brain between about 38°C and 28°C. Then, with artificial circulation, a Q10 of 5 expresses a reduction in CMRO2 from 50% to 10% between 28°C and 18°C. The latter is caused by depression of basal metabolism.541 After CA, however, mild hypothermia seems to have no significant effect on CBF and CMRO2.177,179 The beneficial mechanisms include preservation of ATP,145,146 mitigation of abnormal ion fluxes147; reduction of lactic acidosis,542 free fatty acid production,543 and excitatory neurotransmitter release543,544; slowing of destructive enzymatic reactions by 1.5% per degree centigrade (Arrhenius effect); protection of lipoprotein membrane integrity (assumed),223 reduced edema and leukotrienes,545 improved glucose utilization; slowing of free radical reactions546,547; reduced protease activity548; inflammation548,549; and stress protein formation550,551; and protection of the blood-brain barrier.552 The possibility of hypothermia mitigating “apoptosis” (acceleration of naturally programmed cell death), triggered by ischemia-induced DNA damage,230–240 remains to be examined in clinically relevant CA studies in phylogenetically high species. Is the benefit permanent? The benefit of intra-ischemic hypothermia on neuronal death is indeed permanent.553 Brief (4 hours) mild hypothermia after normothermic incomplete forebrain ischemia in rats postponed but did not permanently salvage hippocampal neurons at two months.554 Delay and duration of hypothermia seem to be of critical importance. In gerbils, moderate hypothermia (32°C) initiated 1 hour after the insult and sustained for 24 hours was highly resuscitative in terms of behavior and histologic damage at 30 days,555 while neuroresuscitation was less when

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hypothermia was initiated 4 hours after the insult.556 Increasing the duration of hypothermia to 48 hours resulted in long-lasting preservation of neurons at 1 month, even when initiation of hypothermia was delayed to 6 hours.557 The long-lasting effect of delayed (6 hours), prolonged (48 hours) hypothermia (32°C to 34°C) on functional and histologic outcome at 1 month was confirmed in rats.558 Our dog experiments with 1 to 2 hours of profound hypothermic CA, followed by mild hypothermia for 12 hours, led to OPC 1 and normal cognitive function many months later (see the section on Suspended Animation). Cooling methods available at present are not ideal for clinical use (see Table 15-4).2,509,559,560 With normal circulation, brain and core temperature equilibrate rapidly. Cerebral hyperthermia adds injury to the ischemic or traumatized brain,561–566 while normal brain can tolerate up to 42°C for up to 1 hour.567,568 Gradients between warm, focally injured brain and core body temperature can be 3°C. Thus, mild systemic hypothermia can prevent local cerebral hyperthermia. Clinical methods for rapidly inducing mild cerebral or whole-body hypothermia in acutely comatose patients, outside and inside hospitals, are now under development (see Table 15-4). They are plagued by secrecy due to commercial (patent) considerations. Whole-body immersion in ice water is rapid, but impractical.452 Surface cooling by evaporation or ice bags is slow,569 particularly under shock with vasoconstriction.570 Peritoneal cooling is fairly rapid.571 In dogs, nasal lavage with ice water achieved mild cerebral (and systemic) hypothermia only slowly.509,572 Gastric, rectal, and IV cooling are also adjunctive.509 Veno-venous or arterio-venous extracorporeal blood-shunt cooling is rapid560 and may become the most practical for the induction of whole-body mild hypothermia, even out-of-hospital. Vena-cava cold rod intravascular cooling, as well as transpulmonary cooling with oxygenated very cold fluorocarbon solution, perhaps even with ice slush, are under evaluation by others. Isolated head-brain cooling would be ideal, thereby preserving the brain with moderate to deep hypothermia while protecting spontaneous circulation by keeping core temperature above 32°C.463–470,559,573–584 Several attempts at selective brain cooling by head-neck-surface cooling were successful only in small children and animals. Cooling the brain through cold infusion into a carotid artery would be the most rapid method; it would, however, outside hospitals, require common carotid cannulation, which is feared by some neurologists. Selective perfusion of the carotid artery with cold fluid or blood most rapidly induces deep-to-moderate cerebral hypothermia. In one study in baboons,576,577 perfusion of one carotid artery from the femoral artery, with fluoroscopic guidance, with blood pumped via a cooling water bath, rapidly achieved moderate to deep bilateral cerebral hypothermia with minimal systemic cooling and without cardiovascular instability. Cold perfusion of the brain arteries via an aortic balloon catheter

or “cobra-catheter” inserted via the femoral artery, is under evaluation (Cardeon Co., Cupertino, CA). Systemic blood shunt cooling via hemodialysis coil was slow.585 During CA, the most rapid cooling is via aortic cold flush (see later, Suspended Animation), or CPB with heat exchanger, once vessel cannulation is accomplished.507–515 Clinical implementation must consider that mild hypothermia (34°C) benefits the brain, moderate hypothermia (28°C to 30°C) might induce VF, and mild cerebral hyperthermia (which can occur in brain-injured patients even with normal core temperature) is deleterious for the injured brain. Therefore, we recommend that all comatose patients have immediate monitoring and control of brain temperature (Tty or Tnp), as well as heart temperature (Tes or Tcv or Tpa or Tu). Shivering and vasospasm, if not absent because of postanoxic coma or brain trauma, should be prevented with muscle relaxant and meperidine, diazepam, barbiturate, or other sedative. Although a 15-minute delay in achieving mild hypothermia after reperfusion decreases the effectiveness,511 even much later induction of mild cooling might have some beneficial effect on the brain that is permanent if prolonged.555–558,586–595 Clinical trials of mild hypothermia after prolonged CA followed the dog studies and are all positive.589–595 Exploratory studies in Japan593–595 have been followed by randomized clinical outcome trials on 273 patients in Europe,589,590 and 77 patients in Australia.591,592 The data submitted are positive for mild hypothermia in all three clinical trials, although slow surface cooling was used, with the desired Tpa reached only after 1.5 to 6 hours. In the Australian study,592 49% of hypothermic vs. 26% of normothermic patients achieved good cerebral outcome (CPC 1 or 2); in the European study590 the difference was 55% vs. 39% (P = .006). There were no group differences in complications. The benefit of even more delayed and risks of longer lasting mild hypothermia after CA in dogs and patients need to be determined. Rewarming596,597 from mild to moderate hypothermia should be slow, perhaps once spontaneous circulation is restored, not faster than 1°C per hour. In CA, when the goal is ROSC, deep or profound hypothermia may need to be reversed to moderate hypothermia more rapidly, using CPB or CPCR. For cerebral resuscitation from normothermic GBI in monkeys, a combination of moderate hypothermia and barbiturate gave a modest beneficial effect.505,513,514 It was logical to explore drugs that proved ineffective at normothermia, to perhaps add benefit to mild hypothermia (see Fig. 15-5). We found suggestive evidence in dogs that post-CA neuronsaving is progressively enhanced by adding, to mild hypothermia and hypertensive reperfusion,512 thiopental and phenytoin,513 and more so by including methylprednisolone and antioxidants.514 The combination of thiopental loading and magnesium sulfate caused serious blood pressure prob-

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lems. The combination of low-dose thiopental, phenytoin, magnesium sulfate, and mild hypothermia gave significant improvement over individual measures. Further improvement was seen by adding CBF promotion with moderate hypertensive hemodilution with sagital sinus PO2 normalization.515 None of these treatments, however, gave a breakthrough effect comparable to that of mild hypothermia (see Fig. 15-5). The discovery of mild hypothermia in dogs after CA has triggered increasing interest in its resuscitative application for other insults. Acute stroke can also benefit from hypothermia. Postinsult mild-to-moderate hypothermia has been shown to be beneficial after experimental focal ischemia in dogs454,455 and rats,598–602 and is beginning to be investigated in patients.603–606 In the future, earliest out-of-hospital initiation of selective brain cooling (e.g., arterial-carotid) by emergency physicians might preserve viability during transport, CT evaluation, and thrombolysis. Traumatic brain injury benefits not only from normoxia607 and normocapnia,608 but also from moderate hypothermia after experimental brain contusion in dogs456,457 and rats,609–615 and after epidural brain compression (brain trauma) in dogs.616,617 For prevention of posttraumatic intracranial hypertension in dogs, which can lead to herniation and brain death, moderate hypothermia (31°C) was more effective than mild hypothermia (35°C).616 The first well-controlled randomized clinical trial of resuscitative mild to moderate hypothermia after TBI was conducted at the University of Pittsburgh. That study showed more patients with good outcome in the treatment group.618 A subsequent multicenter randomized clinical trial in TBI patients, coordinated out of Houston, showed no overall benefit.619 This can be explained by 8 hours delay to achieve 33°C, inadequate life support, and other flaws.620 Recent guidelines for resuscitation from TBI621 ignore hypothermia for ICP control. Other important considerations for the management of TBI cases are beyond the scope of this chapter.622–629 Spinal cord injury in animals had shown, in the 1960s, to benefit from local cord cooling; this could prevent or mitigate paralysis in a most dramatic way.462,468 Because of colleagues’ conservatism, this has not been taken to patients.630 Traumatic hemorrhagic shock, that is, hypovolemic hypotension, requires preservation not of the brain, which protects itself with vasodilation,134–137 but rather of the abdominal viscera, which vasoconstrict. Mild hypothermia during severe hemorrhagic shock in rats increases survival time and rate.631–639 Mild titrated hypothermia for septic shock should be explored.640,641 Deleterious cytokine reactions and ischemic tissues may benefit from titrated cooling, but inflammation to combat infection may be compromised.

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Myocardial infarction (with spontaneous circulation) should be included among potential indications for mild hypothermia to be studied in animals and patients. It looks promising for reducing infarct size642,643 which must be balanced against arrhythmogenicity of cooling to <33°C. A challenge lies in very rapid induction of cerebral hypothermia (already out-of-hospital) in conscious patients560,606 with shock, stroke, or myocardial infarction— without producing shivering. Shivering can be prevented or controlled with titrated IV sedation, as for example using meperidine (Demerol, Pethidine). Suspended Animation For (temporarily) unresuscitable CA, such as CA in combat casualties who exsanguinate internally to death over a few minutes, Safar and Bellamy in 1984 recommended research into “suspended animation” (SA), that is, rapid preservation of the organism, to buy time for transport and repair under CA of 1 to 2 hours, to be followed by delayed resuscitation.644 In such cases, CPR plus infusions would be useless before surgical hemostasis. Civilian cases of traumatic exsanguination CA have had a near 100% mortality so far, in spite of emergency room thoracotomy.645 A totally new approach is needed: suspended animation for delayed resuscitation. Preservation must be induced before loss of brain viability, which means before 5 minutes normothermic no-flow. Resuscitation will have to be with CPB. In the late 1980s, Safar’s group under Tisherman developed and used a new dog model of normothermic hemorrhagic shock followed by exsanguination to CA.646–648 Cooling to profound hypothermia with CPB and heat exchanger, to Tty 10°C,479 gave better outcome than cooling only to deep hypothermia (15°C).478 Profound hypothermia during CA of 2 hours resulted in survival with brain damage,479 while profound hypothermia with CA of 1 hour resulted in complete recovery of the brain in terms of function and histology.483 Cerebral recovery was not influenced by lack of anticoagulant,481 use of the University of Wisconsin organ preservation solution,480 or moderate differences in diluted hematocrit.482 Profound hypothermia, induced electively with CPB, followed by circulatory arrest up to 1 hour, has been survived to consciousness before in dogs471–477 and in patients undergoing open-heart surgery.484,485 Needed for SA are rapid emergency induction of hypothermic preservation, and a systematic search for the limits of no-flow time with reliable functional and histologic studies. Also, CPB by medics in the field is not feasible. Safar’s group therefore explored the use of an aortic balloon catheter, which might be inserted rapidly into casualties at onset of coma, via thoracotomy, from the groin, or parasternally.649 An aortic balloon catheter, inserted via the femoral artery, has been tried to increase coronary and cerebral perfusion pressures during

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sternal compressions, and to flush brain and heart with special solutions to enhance ROSC.650–653 A rapid vesselaccess method for use in the field must be developed. This would enable flushing (on onset of apnea, i.e., CA) an appropriate cold (perhaps medicated) solution, first into brain and heart, and then into the viscera. Cold Aortic Flush for SA The objective is to immediately induce preservation of brain and heart during the end-stage of bleed-out, within 5-minute no-flow. The ultimate goal is to preserve the organism first for at least 30-minute no-flow, and when more fluid or CPB becomes available, to lower Tty further to 5°C to 10°C, to gain 1 to 2 hours of preservation. In exsanguination CA outcome experiments to 72 hours in dogs, aortic arch flush at CA 2 minutes with 0.9% (normal) saline solution (NSS) at ambient temperature (24°C) lowered Tty to 36°C and achieved cerebral recovery after CA 15 minutes.654 A flush of NSS at 2°C, which lowered Tty to 34°C, achieved complete cerebral recovery after CA 20 minutes.655 To achieve complete cerebral recovery with histologically normal brains after CA 30 minutes, Tty 25°C to 30°C was needed, and the 2°C flush of NSS, in very large volumes, had to be introduced into the abdominal aorta to prevent ischemic damage to spinal cord and viscera as well.656 Large aortic flush volumes require a second cannula at the venous side, as overflow must be drained or recirculated. This method could lower Tty by approximately 3°C per minute of flushing. Finally, Safar’s group has recently achieved survival without neurologic deficit in dogs after exsanguination CA of 60, 90, and 120 minutes, using protracted aortic flush of NSS 2°C until Tty was 10°C.657,658 That required, however, approximately 0.5 L/kg flush solution. That method would be feasible, in trained hands, where electric power and cold storage of very large volumes of fluid are available, as in major trauma hospitals’ emergency departments. Clinical feasibility trials are being planned for SA via emergency thoracotomy, on exsanguinated trauma patients who are pulseless in the emergency department. Once CPB is available, preservation time could be extended further by asanguineous profound hypothermic low-flow.659 Clinically, before more rapid vessel access is available with the chest closed, emergency thoracotomy would give quick access to aorta and right atrium.660 For profound hypothermic SA of 1 to 2 hours in trauma cases, laboratory clarifications are needed on the effects of tissue trauma and coagulopathy (from ischemia, trauma, hemodilution, anticoagulants, and hypothermia). Medicated Aortic Flush for SA Combat medics would not have large volumes of cold fluid available. We therefore systematically explored aortic flush induction for preservation during CA 20 minutes no-flow,661 using a small (portable) volume of NSS at ambient temperature (24°C), reinforced by pharmacologic preservation

potentials. Without drugs, this led to survival with severe brain damage. In miniseries, 14 different drugs, one at a time, were tested as to outcome effect, following six pharmacologic strategies: 1. delaying energy failure (adenosine, thiopental, fructose biphosphate) 2. Protecting ion exchange through depolarized membranes (phenytoin, MK-801, nimodipine) 3. Inhibiting proteases (no drug available) 4. Inhibiting apoptosis (cycloheximide, calmoduline antagonist W-7) 5. Protecting mitochondrial permeability pores (cyclosporin-A) 6. Combating reoxygenation injury (tempol). None of the 14 drugs, in various doses, and with mild cerebral hypothermia, gave consistent OPC 1 (see Table 15-2) after CA 20 minutes in dogs.661–665 The antioxidant, tempol, which in aqueous solution permeates the bloodbrain-barrier, looks promising when given in high doses added to the flush.665 SA strategies may not only be an answer to military and civilian trauma cases with presently unresuscitable CA. Some victims of normovolemic out-of-hospital sudden cardiac death may also benefit from SA, used to “buy time.” At present, an estimated 50% of out-of-hospital CPR attempts in the United States (over 200,000 cases per year) are given up because ROSC is not achieved with standard external CPR-ALS. Aortic cold flush to profound hypothermic CA by emergency physicians in the field, or mild-to-moderate hypothermia with continued CPR-BLS-ALS during transport, might bridge the patient over 30 to 60 minutes, with cerebral viability not lost, to initiate prolonged CPB in the hospital emergency department. CPB could then be continued for hours or days—with heparin-bonded equipment, to permit evaluation of brain and heart, and, if indicated, for the heart to be repaired, assisted, or replaced. In cases of brain death, this procedure could serve organ donation.

Ethics and Predictions Every case of sudden coma or shock, with or without CA, deserves an all-out emergency resuscitation attempt (which is inexpensive), followed by life support long enough to predict outcome—at least 2 days after CA.666–669 When to stop (expensive) prolonged life support is the greater challenge and dilemma. Ideally, CPCR should not be permitted to result in long-term survival with persistent severe brain damage (CPC 3 or 4). Cerebral resuscitation research should include studies on how to predict with certainty, as early as possible after CA, severe permanent brain damage (see Table 15-2) with OPC 3 (consciousness but severely disabled) or

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CPC 4 (persistent vegetative state [PVS], permanent coma). “Good outcome” is CPC 1 or 2, with the survivor able to take care of himself; CPC 5 = OPC 5 = brain death. Early obstacles and confusion about determination and certification of brain death (which is only possible hours to days after restoration of normotension) organ donation, and discontinuance of controlled ventilation, have been overcome.670,671 In patients with PVS, discontinuance of all life support (including artificial airway, ventilation, feeding, and hydration; antibiotics; and emergency surgery) has been declared ethically justified.670–676 Extraordinary means of life support in futile situations is considered unethical. The most challenging ethical dilemmas are CPC 3 and the gray zone between CPC 3 and 4, namely unresponsive patients in endstage senile dementia (Alzheimer’s disease). When CCM has nothing to offer, we consider prolonging undignified dying in the end-stages of life, which are painful to patients, their families, and health care staff, as unethical deviations of modern medicine. PVS is cerebral (supratentorial) death (apallic syndrome), without destruction of the medulla, that is, with continued spontaneous breathing. This state can also be called “death.”672–676 Determination with 100% certainty of the irreversibility of PVS is not always possible. To our knowledge, after CA and ROSC, fixed pupils or no purposeful response to stimuli for 1 week after CA (even as early as three days), in the absence of hypotension, hypothermia, CNS depressants, or relaxants has not been followed by any case of “good” cerebral recovery (CPC 1 or 2) in clinical correlation studies. Even absent cranial nerve reflexes (corneal and/or carinal and/or gag reflex) as early as 12 to 24 hours after CA, correlated with 100% poor outcome. Certain clinical and laboratory measurements (e.g., somatosensoryevoked potentials; CSF enzyme levels) on day three after CA permit prognostication of PVS with near-certainty in the majority (but not all) cases of postcardiac arrest coma. Cerebrospinal fluid (CSF) analysis might have adjunctive value. There were correlations of creatine-kinase BB and lactate dehydrogenase peaks in the CSF at 2 to 3 days after CA, in dogs149 and patients,677–681 with severity of insult and with poor neurologic outcome. Correlations with outcome of CBF and cerebral metabolism and/or noninvasive NMR spectroscopic noninvasive evaluation of brain chemistry (e.g., energy charge) should be explored. In coma after TBI or GBI, reliable early prognostication is not possible. CSF analysis can reveal high enzyme levels from small, not incapacitating lesions. Coma or stupor after TBI can last for months, due to edema or hemorrhages, and be followed by late awakening. Decisions to “let die” are difficult in coma after CA and ROSC. The primary physician and intensivist, with input from other specialists, and in communication with the patient’s proxies, should decide on the appropriate level of care: all-out life support; general medical care; general

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nursing care; or no extraordinary measures and compassionate terminal care. Clinical resuscitation research is possible only with waiving of the prospective informed consent requirement for entering patients into studies. This must be done within seconds of recognition of the emergency. Waiving consent has proved to be feasible and acceptable.682–685 This procedure must be legalized, provided the incremental (relative) risk is low and the study is approved by an institutional peerreview board. Randomized clinical trials are meant for evaluating novel methods to reverse death. These methods should have proven beneficial physiologic effects in clinically realistic animal models. This raises the ethical dilemma of randomly withholding a simple, safe, inexpensive treatment, such as mild hypothermia, which was proven to enhance the chance of survival without brain damage in clinically realistic animal models.

Conclusions and Recommendations Since the 1970s, CPCR research has yielded much new information of scientific importance and documentation of several promising new therapies of clinical importance: hypertensive reperfusion after CA and ROSC; and mild hypothermia (induced as soon as possible and continued for at least 12 hours). There has so far been no documented breakthrough effect of pharmacologic resuscitation potentials, probably because of the multifactorial complexity of the cerebral postresuscitation syndrome. Clinical feasibility and side-effect trials are needed in patients with sick hearts. The unreliability of outcome data in rodent models, the limitations of clinical trials, and the inadequate funding of reliable outcome models in high animal species have retarded implementation in patients of resuscitation potentials to save at least some “hearts and brains too good to die.”2,686 For clinicians, we recommend the “CPCR system 2000” (see Fig. 15-6): (A) a brain orientation of standard CPR BLSALS-PLS (see Table 15-3); (B) for cases resistant to external CPR-ALS, clinical feasibility and ROSC trials of improved external CPR methods and of an early switch to open-chest CPR or emergency CPB; (C) clinical feasibility and sideeffect trials of the physical combination treatment of CBF promotion and mild hypothermia (the most effective cerebral resuscitation protocol yet documented in dogs and patients). This requires clinical feasibility trials of novel methods for rapid brain cooling (see Table 15-4). Therapeutic hypothermia—in general—is the only treatment from which some patients may benefit, even when mild cooling is induced late, as in the ICU. All cerebral resuscitation attempts after normothermic insults can be expected to be beneficial the earlier the cooling is initiated. The medical and lay public need clarification of differences: (1) between spontaneous-uncontrolled-accidental

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hypothermia and induced-controlled-therapeutic hypothermia; (2) between cooling in the presence of circulation vs. during CA; (3) between different temperature levels; and (4) between the following ten emergency conditions for which different therapeutic hypothermia strategies might be beneficial. Some benefit from various hypothermic strategies’ has already been documented for the following indications: 1. Protection-preservation for elective or emergency surgery on heart, large vessels, or brain. 2. Resuscitation after normothermic CA (the main topic of this chapter). 3. Resuscitation from stroke (ischemic or hemorrhagic). 4. Resuscitation from traumatic brain injury. 5. Resuscitation from spinal cord injury. Hypothermic strategies’ benefit is suspected for at least five other conditions, which, however, are in need of more laboratory investigations before embarking on clinical trials: 6. Suspended animation for presently unresuscitable CA (as discussed previously). 7. Traumatic hemorrhagic shock. 8. Sepsis and septic shock. 9. Myocardial infarction without CA, where mild hypothermia might reduce infarct size, but moderate hypothermia should be avoided as it can cause lethal arrhythmias. 10. Intractable status epilepticus (very rare). Some of the greatest breakthroughs in medicine, such as anesthesia, antibiotics, insulin, and cortisone, saved many lives prior to any discovery of the molecular mechanisms of these treatments. Mechanism-oriented studies in rodents or in vitro, although scientifically important, are of only preliminary value, leading to the decisive outcome-oriented studies in whole organisms of animals high on the phylogenetic scale. Cerebral resuscitation potentials to be researched further should be ranked according to (1) their scientific (theoretical, mechanism-oriented) importance; (2) their clinical importance for some cases; and (3) their socioeconomic importance for many humans. Implementation should depend also on feasibility and affordability. A combination of these rankings might guide funding priorities. The US Food and Drug Administration must recognize the limitations of randomized clinical outcome studies in resuscitation research; the limitation of studies in rats; and the importance of CPCR research with outcome models in large animals. Conditions causing sudden coma without CA

should also be evaluated. The multifactorial pathogenesis of the postresuscitation syndrome calls for more than one agent, namely the need to evaluate combination treatments. How to explore and document outcome effects of combination treatments in a cost-effective manner is a challenge. The transfer to general patient care of novel CPCR methods found effective in large-animal outcome models should begin in community EMS systems with ongoing case registries that incorporate ongoing evaluation of all cases of sudden coma or shock. We recommend that novel CPCR methods that are simple and inexpensive, and that significantly improved overall and cerebral outcome (without undesirable side effects) in two to three reliable reproducible large-animal outcome studies, should first be tested for safety and feasibility in clinical trials. If found safe, feasible, and economically possible for use in patients, such novel treatments should then be approved for general clinical use, without insisting on statistical “benefit” in expensive, timeconsuming, randomized clinical trials, which are unreliable, uncontrollable, and often misleading. Pathophysiologic-therapeutic facts cannot be proved by epidemiologic correlation statistics. Randomized clinical trials of cerebral resuscitation cannot discriminate between the ability of a treatment to mitigate brain damage in selected cases and the absence of any treatment effect. Those who insist on such studies should at least increase the ability to reveal benefit in some cases, by excluding obviously hopeless cases and immediately reversible arrests, and including only skilled, specially trained resuscitation teams and EMS systems.2 The goal of cerebral resuscitation research remains unchanged687,688: to help an increasing proportion of people stricken with an unexpected brain-damaging terminal state or clinical death, to return to full lives with healthy minds— to restore “mens sana in corpore sano” (Decimus Iunius Juvenalis, Roman poet and satirist, about 100 ad).

Acknowledgments Asmund and Tore Laerdal, Lyn Yaffe, MD, and the US Department of Defense enabled much of the research in Pittsburgh summarized in this chapter. We are grateful for input from Drs. N. Abramson, R. Basford, N. Bircher, L. Ernster, R. Hayes, P. Kochanek, L. Jenkins, A. Nozari, J.W. Severinghaus, B. Siesjo, F. Sterz, S. Tisherman, and X. Wu. Fran Mistrick, Valerie Sabo, and Brad Stezoski helped with preparation of the manuscript and images. Patricia Boyle helped with editing.

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P earls 1. . . . after prolonged CA in dogs (or global brain ischemia in monkeys), cerebral blood flow goes through transient cerebral hyperemia to protracted (inhomogeneous) hypoperfusion, which is mismatched to increasing oxygen uptake. Vasospasm, endothelial swelling, blood sludging, and coagulation are suspected mechanisms. 2. Moderate prolonged hypertensive hemodilution normalizes cerebral blood flow after CA. 3. When combined with hypertension and normocapnia in dogs, mild hypothermia after normothermic CA increases the longest reversible no-flow time from 5 to 10 minutes. 4. Cold flush (2°C) into the aorta, within 5 minutes of CA, of saline or novel cerebral preservation solutions, can reduce cerebral temperature by 3°C/minute and preserve viability of brain and organism during up to 90 minutes (perhaps even 120 minutes) no-flow at tympanic temperature of 10°C. 5. Temporary hypotension with mean arterial pressure (MAP) of about 30 to 60 mm Hg, can be tolerated by the normal brain, but even mild hypotension can cause permanent brain damage when it occurs in a state of severe hypoxemia, after brain trauma, or in the presence of atherosclerotic cerebral arteries that fail to go into autoregulatory vasodilation.

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6. One must determine or at least estimate arrest time (no-flow), CPR time (low-flow), and temperature— the most important variables determining cerebral outcome. 7. A clinically realistic combination of CBF promotion and mild hypothermia has recently achieved complete functional recovery in dogs after 11 minutes of normothermic CA (no-flow). 8. During incomplete ischemia (e.g., shock or CA with external CPR), the viability of normal neurons seems to be threatened only when CPP decreases to or below 30 mm Hg,134–138 CBF to less than 15 mL/100 g of brain per minute,137 or cerebral venous PO2 to less than 20 to 25 mm Hg137–140 (normal value >40 mm Hg). 9. Reoxygenation, although essential and effective in restoring energy charge, can provoke chemical cascades that result in lipid peroxidation of membranes.223–228 These processes, possibly first triggered by calcium shifts,229–231 also involve free iron, free radicals, acidosis, catecholamine release,232 excitatory amino acid release,159–162 and induction of proteases,233,234 leading to destruction of membranes and nuclear DNA. 10. Vasopressin (40 U IV as a single dose) may be substituted for epinephrine (1 mg IV) as an alternative vasopressor in VF or VT with CA (class IIb).

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97. Gurvitch AM: Role of neurophysiological mechanisms in postresuscitation pathology and postresuscitation restoration of CNS functions. Minerva Anesthes 1994;60:501. 98. Negovsky VA: Fifty years of the Institute of General Reanimatology of the USSR Academy of Medical Sciences. Crit Care Med 1988;16:287. 99. Safar P: The resuscitation greats: Vladimir A. Negovsky the father of “reanimatology.” Resuscitation 2001;49:223. 100. Lind B, Snyder J, Kampschulte S, et al: A review of total brain ischaemia models in dogs and original experiments on clamping the aorta. Resuscitation 1975;4:19. 101. Safar P, Gisvold SE, Vaagenes P, et al: Long-term animal models for the study of global brain ischemia. In Wauquier A, Borgers M, Amery WK (eds): Protection of Tissues Against Hypoxia. Amsterdam, Elsevier, 1982, pp 147-170. 102. Safar P: Long-term animal outcome models for cardiopulmonarycerebral resuscitation research. Crit Care Med 1985;13:936. 103. Nemoto EM, Bleyaert AL, Stezoski SW, et al: Global brain ischemia: A reproducible monkey model. Stroke 1977;8:558. 104. Pulsinelli W, Brierley J, Plum F: Temporal profile of neuronal damage in a model of transient forebrain ischemia. Ann Neurol 1982;11:491. 105. Smith ML, Bendek G, Dahlgren N, et al: Models for studying longterm recovery following forebrain ischemia in the rat. A two vessel occlusion model. Acta Neurol Scand 1984;69:385. 106. Hendrickx HHL, Rao GR, Safar P, et al: Asphyxia, cardiac arrest and resuscitation in rats. I. Short term recovery. Resuscitation 1984;12:97. 107. Hendrickx HHL, Safar P, Miller A: Asphyxia, cardiac arrest and resuscitation in rats. II. Long-term behavioral changes. Resuscitation 1984;12:117. 108. Hendrickx HHL, Safar P, Miller A: Delayed recovery of behavior after anesthesia in rats. Resuscitation 1984;12:213. 109. Katz L, Ebmeyer U, Safar P, et al: Outcome model of asphyxial cardiac arrest in rats. J Cereb Blood Flow Metab 1995;15:1032. 110. Radovsky A, Katz L, Ebmeyer U, et al: Ischemic neurons in rat brains after 6, 8, or 10 minutes of transient hypoxic ischemia. Toxicology 1997;25:500. 111. Katz L, Wang Y, Ebmeyer U, et al: Glucose plus insulin infusion improves cerebral outcome after asphyxial cardiac arrest. Neuroreport 1998;9:3363. 112. Katz LM, Callaway CW, Kagan VE, et al: Electron spin resonance measure of brain antioxidant activity during ischemia/reperfusion. Neuroreport 1998;9:1587. 113. Neumar RW, Bircher NG, Sim KM, et al: Epinephrine and sodium bicarbonate during CPR following asphyxial cardiac arrest in rats. Resuscitation 1995;29:249. 114. Ebmeyer U, Safar P, Katz L, et al: Intra-aortic (IA) vs. intravenous (IV) epinephrine for cardiopulmonary resuscitation in rats. Anesthesiology 1992;77:A291. 115. Blomqvist P, Wieloch T: Ischemic brain damage in rats following cardiac arrest using a long-term recovery model. J Cereb Blood Flow Metab 1985;5:420. 116. Sieber FE, Palmon SC, Traystman RJ, et al: Global incomplete cerebral ischemia produces predominantly cortical neuronal injury. Stroke 1995;26:2091. 117. Choi DW: Limitations of in vitro models of ischemia. In Current and Future Trends in Anticonvulsants, Anxiety and Stroke Therapy. New York, Wiley Liss Publ, 1990, pp 291–299. 118. Lanier WL, Fleischer JE, Milde JH, et al: Post-ischemic neurologic recovery and cerebral blood flow using a compression model of complete “bloodless” cerebral ischemia in dogs. Resuscitation 1988;16:271. 119. Kety SS, Schmidt CF: The nitrous oxide method for quantitative determination of cerebral blood flow in man: Theory, procedure, and normal values. J Clin Invest 1948;27:476. 120. Wechsler RL, Dripps RD, Kety SS: Blood flow and oxygen consumption of the human brain during anesthesia produced by thiopental. Anesthesiology 1951;12:308.

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145. Kramer RS, Sanders AP, Lesage AM, et al: The effect of profound hypothermia on preservation of cerebral ATP content during circulatory arrest. J Thorac Cardiovasc Surg 1968;56:699. 146. Michenfelder JK, Theye RA: The effects of anesthesia and hypothermia on canine cerebral ATP and lactate during anoxia produced by decapitation. Anesthesiology 1970;33:430. 147. Astrup J, Rehncrona S, Siesjo BK: The increase in extracellular potassium concentration in the ischemic brain in relation to the preischemic functional activity and cerebral metabolic rate. Brain Res 1980;199:161. 148. VanHarreveld A, Ochs S: Cerebral impedance changes after circulatory arrest. Am J Physiol 1957;187:180. 149. Vaagenes P, Safar P, Diven W, et al: Brain enzyme levels in CSF after cardiac arrest and resuscitation in dogs: Markers of damage and predictors of outcome. J Cereb Blood Flow Metab 1988;8:262. 150. Vaagenes P, Safar P, Moossy J, et al: Asphyxiation versus ventricular fibrillation cardiac arrest in dogs. Differences in cerebral resuscitation effects—a preliminary study. Resuscitation 1997;35:41. 151. Safar P, Abramson NS, Angelos M, et al: Emergency cardiopulmonary bypass for resuscitation from prolonged cardiac arrest. Am J Emerg Med 1990;8:55. 152. Safar P: Resuscitation after brain ischemia. In Grenvik A, Safar P (eds): Brain Failure and Resuscitation. Clinics in Critical Care Medicine. New York, Churchill Livingstone, 1981, pp 155–184. 153. Breivik H, Safar P, Sands, et al: Clinical feasibility trials of barbiturate therapy after cardiac arrest. Crit Care Med 1978;6:228. 154. Schanne FA, Kane AB, Young EE, et al: Calcium dependence of toxic cell death: A final common pathway. Science 1979;206:700. 155. Miller RJ: Multiple calcium channels and neuronal function. Science 1987;235:46. 156. Rehncrona S, Rosen I, Siesjo BK: Excessive cellular acidosis: An important mechanism of neuronal damage in the brain? Acta Physiol Scand 1980;110:435. 157. Nemoto EM, Evans RW, Kochanek PM: Free fatty acid liberation in the pathogenesis and therapeutic brain damage. In Bazan NG, Braquet P, Ginsberg MD (eds): Advances in Neurochemistry, Neurochemistry Correlates of Cerebral Ischemia, vol 7. New York, Plenum Press, 1992, pp 183–218. 158. Bandaranayke NM, Nemoto EM, Stezoski SW: Rat brain osmolality during barbiturate anesthesia and global brain ischemia. Stroke 1978;9:249. 159. Benveniste H: The excitotoxine hypotheses in relation to cerebral ischemia. Cerebrovasc Brain Metab Rev 1991;3:213. 160. Benveniste H, Drejer J, Schousboe A, et al: Elevation of the extracellular concentrations of glutamate and aspartate in rat hippocampus during transient cerebral ischemia monitored by intracerebral microdialysis. J Neurochem 1984;43:1369. 161. Globus MYT, Ginsberg MD, Busto R: Excitotoxic index—a biochemical marker of selective vulnerability. Neurosci Lett 1991;127:39. 162. Rothman SM, Olney JW: Glutamate and the pathophysiology of hypoxic-ischemic brain damage (review). Ann Neurol 1986;19:105. 163. Ginsberg MD, Welsch FA, Budd WW: Deleterious effect of glucose pretreatment on recovery from diffuse cerebral ischemia in the cat. Stroke 1980;11:347. 164. Frumin MJ, Epstein RM, Cohen G: Apneic oxygenation in man. Anesthesiology 1959;20:789. 165. Holmdahl MH: Pulmonary uptake of oxygen, acid-base metabolism, and circulation during prolonged apnea. Acta Chir Scand 1956; 212(suppl):S1. 166. Clark RS, Kochanek PM, Chen M, et al: Increases in BCL-2 and cleveage of caspace-1 and caspace-3 in human brain after head injury. FASEB J 1999;13:813. 167. Ames A III, Wright RL, Kowada M, et al: Cerebral ischemia. II. The no-reflow phenomenon. Am J Pathol 1968;52:437. 168. Cantu R, Ames A, DiGancinto G: Hypotension: A major factor limiting recovery from cerebral ischemia. J Surg Res 1969;9:525.

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215. Jenkins LW, Povlishock JT, Lewelt W, et al: The role of postischemic recirculation in the development of ischemic neuronal injury following complete cerebral ischema. Acta Neuropathol (Berl) 1981;55:205. 216. Jenkins LW, Lu YC, Johnston WE, et al: Combined therapy affects outcomes differently after mild traumatic brain injury and secondary forebrain ischemia in rats. Brain Res 1999;817:132. 217. Jenkins LW, Moszynski K, Lyeth BG, et al: Increased vulnerability of the mildly traumatized rat brain to cerebral ischemia: The use of controlled secondary ischemia as a research tool to identify common or different mechanisms contributing to mechanical and ischemic brain injury. Brain Res 1989;477:211. 218. Graham DI: The pathology of brain ischemia and possibilities for therapeutic intervention. Brit J Anaesth 1985;57:3. 219. Jenkins LW, Becker DP, Coburn TH: A quantitative analysis of glial swelling and ischemic neuronal injury following complete cerebral ischemia. In Go KG, Baethmann (eds): Recent Progress in the Study and Therapy of Brain Edema. New York, Plenum, 1984, p 523. 220. Kalimo H, Garcia JH, Kamijyo, et al: The ultra-structure of “brain death.” II. Electron mycroscopy of feline cortex after complete ischemia. Virch Arch B (Cell Pathol) 1977;25:207. 221. Petito CK, Feldmann E, Pulsinelli WA, Plum F: Delayed hippocampal damage in humans following cardiorespiratory arrest. Neurology 1987; 37:1281. 222. Jenkins LW, Peters GW, Dixon CE, et al: Conventional and functional proteomics using large format two-dimensional gel electrophoresis 24 hours after controlled cortical impact in postnatal day 17 rats. J Neurotrauma 2002;19:715–740. 223. Ernster L: Biochemistry of reoxygenation injury. Crit Care Med 1988;16:947. 224. Fridovich I: Superoxide radical: An endogenous toxicant. Annu Rev Pharmacol Toxicol 1983;23:239. 225. McCord JM: Oxygen-derived free radicals in postischemic tissue injury. N Engl J Med 1985;312:159. 226. Kontos HA: Oxygen radicals in CNS damage. Review article. Chem Biol Interactions 1989;72:229. 227. Traystman RJ, Kirsch JR, Koehler RC: Oxygen radical mechanisms of brain injury following ischemia and reperfusion. J Appl Physiol 1991;71:1185. 228. Böttiger BW, Schmitz B, Wiesser C, et al: Neuronal stress response and neuronal cell damage after cardiocirculatory arrest in rats. J Cereb Blood Flow Metab 1998;18:1077. 229. Siesjo BK, Bengtsson F: Calcium fluxes, calcium antagonists, and calcium-related pathology in brain ischemia, hypoglycemia, and spreading depression: A unifying hypothesis. J Cereb Blood Flow Metab 1989;9:127. 230. Deshpande JK, Siesjo BK, Wieloch T: Calcium accumulation and neuronal damage in the rat hippocampus following cerebral ischemia. J Cereb Blood Flow Metab 1987;7:89. 231. Deshpande JK, Siesjo BK, Wieloch T: Calcium accumulation and neuronal damage in the rat hippocampus following cerebral ischemia. J Cereb Blood Flow Metab 1987;7:89. 232. Globus MYT, Busto R, Dietrich WD, et al: Direct evidence for acute and massive norepinephrine release in the hippocampus during transient ischemia. J Cereb Blood Flow 1989;9:892. 233. Gillardon F, Böttiger BW, Schmitz B, et al: Activation of CPP-32 protease in hippocampal neurons following ischemia and epilepsy. Brain Res Mol Brain Res 1997; 50:16. 234. Chen J, Nagayama T, Jin K, et al: Induction of caspase-3-like protease may mediate delayed neuronal death in the hippocampus after transient cerebral ischemia. J Neurosci 1998; 18:4914. 235. White BC, DeGarcia DJ, Grossman LI: Brain nuclear DNA survives cardiac arrest and reperfusion. Free Radical Biol Med 1991;10:125. 236. White BC, Tribhuwan RC, Vander Laan DJ, et al: Brain mitochondrial DNA is not damaged by prolonged cardiac arrest or reperfusion. J Neurochem 1992;58:1716.

237. MacManus JP, Buchan AM, Hill IE, et al: Global ischemia can cause DNA fragmentation indicative of apoptosis in rat brain. Neurosci Lett 1993;164:89. 238. Nitatori T, Sato N, Waguri S, et al: Delayed neuronal death in the CA 1 pyramidal cell layer of the gerbil hippocampus following transient ischemia is apoptosis. J Neurosci 1995;15:1001. 239. Prueckner S, Clark R, Woods R, et al: Cold aortic arch flush decreases apoptosis after exsanguination cardiac arrest in dogs [abstract]. Crit Care Med 1999;27:A30. 240. Clark RSB, Kochanek PM, Chen M, et al: Caspase-3 mediated neuronal death after traumatic brain injury in rats. J Neurochem 2000; 74:740. 241. Siesjo BK, Ouyuang YB, Kristian T, et al: Role of mitrochondria in immediate and delayed reperfusion damage. In Ito U, Kirino T, Kuroiwa T, et al (eds): Maturation Phenomenon in Cerebral Ischemia III. Berlin, Springer-Verlag, 1999. 242. Bottiger BW, Teschendorf P, Krumnikl J, et al: Global cerebral ischemia due to cardiocirculatory arrest in mice causes neuronal degeneration and early induction of transcription factor genes in the hippocampus. Mol Brain Res 1999;65:135. 243. Safar P: Effects of the postresuscitation syndrome on cerebral recovery from cardiac arrest. Crit Care Med 1985;13:932. 244. Cerchiari EL, Safar P, Klein E, et al: Visceral hematologic and bacteriologic changes and neurologic outcome after cardiac arrest in dogs. The visceral post resuscitation syndrome. Resuscitation 1993;25:119. 245. Sterz F, Safar P, Diven W, et al: Detoxification with hemabsorption after cardiac arrest does not improve neurologic recovery. Review and outcome study in dogs. Resuscitation 1993;25:137. 246. Baethmann A, Maier-Hauff K, Kempski O, et al: Mediators of brain edema and secondary brain damage. Crit Care Med 1988;16:972. 247. Furchgott RF, Vanhoutte PM: Endothelium-derived relaxing and contracting factors. FASEB J 1989;3:2007. 248. Fink MP (ed): Nitric oxide. New Horizons 1994;3:1. 249. Jackson RE, Swor RA. Who gets bystander cardiopulmonary resuscitation in a witnessed arrest? Acad Emerg Med 1997;4:540. 250. Safar P, Berkebile P, Scott MA, et al: Education research on life supporting first aid (LSFA) and CPR self-training system (STS). Crit Care Med 1981;9:403. 251. Becker LB, Berger RA, Pepe PE, et al: A reappraisal of mouth-tomouth ventilation during bystander-initiated cardiopulmonary resuscitation: a statement for healthcare professionals from the Ventilation Working Group of the Basic Life Support and Pediatric Life Support and Pediatric Life Support Subcomittees, American Heart Association. Circulation 1997;96:2102. 252. Lesser R, Bircher N, Safar, et al: Sternal compression before ventilation in cardiopulmonary resuscitation. Prehospital Disaster Med 1985;1 (Suppl):239. 253. Safar P, Bircher N, Pretto E, et al: Reappraisal of mouth-to-mouth ventilation during bystander-initiated cardiopulmonary resuscitation [letter to editor]. Circulation 1998;98:608. 254. Safar P: Ventilation and cardiopulmonary resuscitation. Curr Opin Anaesthesiol 1999;12:165. 255. Redding J, Pearson JW: Resuscitation from ventricular fibrillation. JAMA 1968;203:255. 256. Redding J, Pearson JW: Resuscitation from asphyxia. JAMA 1962; 182:283. 257. Otto CW: Cardiovascular pharmacology II: The use of catecholamines pressor agents, digitalis, and corticosteroids in CPR and emergency cardiac care. Circulation 1986;74(suppl IV):S80. 258. Brown CG, Robinson LA, Jenkins J, et al: The effect of norepinephrine versus epinephrine on regional cerebral blood flow during cardiopulmonary resuscitation. Am J Emerg Med 1989;7:278. 259. Lindner KH, Ahnefeld EG, Pfenninger EG, et al: Effects of epinephrine and norepinephrine on cerebral oxygen delivery and consumption during open-chest CPR. Ann Emerg Med 1990;19:249.

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283. Halperin HR, Goerci AD, Chandra N, et al: Vest inflation without simultaneous ventilation during cardiac arrest in dogs. Improved survival from prolonged CPR. Circulation 1986;74:1407. 284. Weisfeldt ML: Physiology of cardiopulmonary resuscitation. Annu Rev Med 1981;435–442. 285. Barkalow CE: Mechanized cardiopulmonary resuscitation: Past, present, and future. Am J Emerg Med 1984;2:262–269. 286. Wik L, Bircher N, Safar P, et al: Survival after cardiac arrest with prolonged manual vs mechanical external cardiopulmonary resuscitation (CPR) in dogs. Crit Care Med 1993;21:S191. 287. Tang W, Weil MH, Schock RB, et al: Phased chest and abdominal compression-decompression: A new option for cardiopulmonary resuscitation. Circulation 1997;95:1335. 288. Lurie K, Zielinski T, McKnite S, et al: Improving the efficacy of CPR with an inspiratory impedence threshold valve. Crit Care Med 2000;28 (Suppl):N207. 289. Idris AH: Effects of inspired gas content during respiratory arrest and CPR. Crit Care Med 2000;28 (Suppl):N196. 290. Zwemer CF, Whitesall SE, D’Alecy LG: Cardiopulmonary-cerebral resuscitation with 100% oxygen exacerbates neurological dysfunction following nine minutes of normothermic cardiac arrest in dogs. Resuscitation 1994;27:159. 291. Zwemer CF, Whitesall SE, D’Alecy LG. Hypoxic cardiopulmonarycerebral resuscitation fails to improve neurologic outcome following cardiac arrest in dogs. Resuscitation 1995;29:225. 292. Liu Y, Rosenthal RE, Haywood Y, et al: Normoxic ventilation after cardiac arrest reduces oxidation of brain lipids and improves neurological outcome. Stroke 1998;29:1679. 293. Teasdale G, Jennett B: Assessment of coma and impaired consciousness. A practical scale. Lancet 1974;2(7872):81. 294. Jennett B, Bond M: Assessment of outcome after severe brain damage: a practical scale. Lancet 1975;1(7905):480. 295. The Brain Resuscitation Clinical Trial Study Group: Glucocorticoid treatment does not improve neurologic recovery following cardiac arrest. JAMA 1989;262:3427. 296. Sieber FE, Traystman RJ: Special issues, glucose and the brain. Crit Care Med 1992;20:104. 297. D’Alecy LG, Lundy EF, Barton KJ, et al: Dextrose containing intravenous fluid impairs outcome and increases death after eight minutes of cardiac arrest and resuscitation in dogs. Surgery 1986;100:505. 298. Lanier WL, Stangland KJ, Scheithauer BW, et al: The effects of dextrose infusion and head position on neurologic outcome after complete cerebral ischemia in primates: Examination of a model. Anesthesiology 1987;66:39. 299. Luncy EF, Kuhn JE, Kwon JM: Infusion of 5% dextrose increases mortality and morbidity following six minutes of cardiac arrest in resuscitated dogs. J Crit Care 1987;2:4. 300. Ginsberg MD, Prado R, Dietrich WD, et al: Hyperglycemia reduces the extent of cerebral infarction in rats. Stroke 1987;18:570. 301. Schurr A, West CA, Reid KH, et al: Increased glucose improves recovery of neuronal function after cerebral hypoxia in vitro. Brain Res 1987;421:135. 302. Longstreth WT Jr, Inui TS: High blood glucose level on hospital admission and poor neurological recovery after cardiac arrest. Ann Neurol 1984;15:59. 303. Longstreth WT Jr, Diehr P, Cobb LA, et al: Neurologic outcome and blood glucose levels during out-of-hospital cardiopulmonary resuscitation. Neurology 1986;36:1186. 304. Mullner M, Sterz F, Binder M, et al: Blood glucose concentration after cardiopulmonary resuscitation influences functional neurological recovery in human cardiac arrest survivors. J Cereb Blood Flow Metab 1997;17:430. 305. Pulsinelli WA, Leve DE, Sigsbee B, et al: Increased damage after ischemia stroke in patients with hyperglycemia with or without established diabetes mellitus. Am J Med 1983;74:540.

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306. Newman DH, Greenwald I, Callaway CW: Cardiac arrest and the role of thrombolytic agents. Ann Emerg Med 2000;35:472. 307. Spivey WH, Abramson NS, Safar P, et al: Correlation of blood pressure with mortality and neurologic recovery in comatose postresuscitation patients [abstract]. Ann Emerg Med 1991;20:453. 308. Martin DR, Persse D, Brown CG, et al: Relation between initial postresuscitation systolic blood pressure and neurologic outcome following cardiac arrest [abstract]. Ann Emerg Med 1993;22:206. 309. Mullner M, Sterz F, Binder N, et al: Arterial blood pressure after human cardiac arrest and neurological recovery. Stroke 1996;27:59. 310. Sasser HC, Safar P, Kelsey SF, et al: Arterial hypertension after cardiac arrest is associated with good cerebral outcome in patients [abstract]. Crit Care Med 1999;27 (Suppl):A29. 311. Bleyaert AL, Sands PA, Safar P, et al: Augmentation of post-ischemic brain damage by severe intermittent hypertension. Crit Care Med 1980;8:41. 312. Takaori M, Safar P: Treatment of massive hemorrhage with colloid and crystalloid solution. JAMA 1967;199:297. 313. Heros RC, Korosue K: Hemodilution for cerebral ischemia. Curr Concepts Cerebrovasc Dis Stroke 1988;23:31. 314. Kusunoki M, Kimura K, Nakamura M, et al: Effects of hematocrit variations on cerebral blood flow and oxygen transport in ischemic cerebrovascular disease. J Cereb Blood Flow Metab 1981;1:413. 315. Grotta JC, Pettigrew LC, Allen S, et al: Baseline hemodynamic state and response to hemodilution in patients with acute cerebral ischemia. Stroke 1985;16:790. 316. Macmillan CS, Andrews PJ: Cerebrovenous oxygen saturation monitoring: practical considerations and clinical relevance. Intens Care Med 2000;26:1028. 317. Van der Hoeven JG, DeKoning J, Compier, et al: Early jugular bulb monitoring in comatose patients after an out-of-hospital cardiac arrest. Intens Care Med 1995;21:567. 318. Takasu A, Yagi K, Ishihara S, et al: Combined continuous monitoring of systemic and cerebral oxygen metabolism after cardiac arrest. Resuscitation 1995;29:189–194. 319. McKenzie GJ, Taylor SH, McDonald AH, et al: Hemodynamic effects of external cardiac compression. Lancet 1964;i:1342.218. 320. Bircher N, Safar P: Comparison of standard and “new” closed-chest CPR and open-chest CPR in dogs. Crit Care Med 1981;9:384. 321. Rogers MC, Nugent SK, Stidham GL: Effects of closed-chest cardiac massage on intracranial pressure. Crit Care Med 1979;7:454. 322. Redding J, Cozine R: A comparison of open-chest and closed-chest cardiac massage in dogs. Anesthesiology 1961;22:280. 323. Del Guercio LRM, Feins NR, Cohn JD, et al: A comparison of blood flow during external and internal cardiac massage in man. Circulation 1965;31 (suppl I):S171. 324. Bircher N, Safar P, Stewart R: A comparison of standard, “MAST”augmented, and open-chest CPR in dogs. Crit Care Med 1980;8:147. 325. Bircher N, Safar P: Manual open-chest cardiopulmonary resuscitation. Ann Emerg Med 1984;13:770. 326. Bircher NG, Safar P: Cerebral preservation during cardiopulmonary resuscitation in dogs. Crit Care Med 1985;13:185. 327. Stajduhar K, Safar P, Steinberg R, et al: Cerebral blood flow and other benefits from wider use of open-chest cardiopulmonary resuscitation [abstract]. Crit Care Med 1983;11:226. 328. Angelos M, Reich H, Safar P, et al: Coronary perfusion pressure during external CPR versus cardiopulmonary bypass after prolonged cardiac arrest in dogs. Ann Emerg Med 1987;16:1102. 329. Ditchey RV, Winkler JV, Rhodes CA: Relative lack of coronary blood flow during closed-chest resuscitation in dogs. Circulation 1982;66: 297. 330. Byrne D, Pass HL, Neely WA, et al: External vs. internal cardiac massage in normal and chronically ischemic dogs. Am Surg 1980;46:657. 331. Arai T, Dote K, Tsuahara I, et al: Cerebral blood flow during conventional, new and open-chest CPR in dogs. Resuscitation 1984;12:147.

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560. Behringer W, Safar P, Wu X, et al: Veno-venous extracorporeal blood shunt cooling to induce mild hypothermia in dog experiments and review cooling methods. Resuscitation 2002;54:89–98. 561. Sternau LL, Globus MYT, Dietrich WD, et al: Ischemia-induced neurotransmitter release: effects of mild intraischemic hyperthermia. In Globus MYT, Dietrich WD (eds): The Role of Neurotransmitters in Brain Injury. New York, Plenum Press, 1992, pp 33–38. 562. Dietrich WD, Busto R, Valdes I, et al: Effects of normothermic versus mild hyperthermic forebrain ischemia in rats. Stroke 1990;21:1318. 563. Kim Y, Busto R, Dietrich WD, et al: Delayed postischemic hyperthermia in awake rats worsens the histopathological outcome of transient focal cerebral ischemia. Stroke 1996;27:2274. 564. Baena RC, Busto R, Dietrich WD, et al: Hyperthermia delayed by 24 hours aggravates neuronal damage in rat hippocampus following global ischemia. Neurology 1997;48:786. 565. Chen H, Chopp M, Welch KMA: Effect of hyperthermia on the ischemic infarct volume after middle cerebral artery occlusion in the rat. Neurology 1991;41:1133. 566. Dietrich WD, Busto R, Halley M, et al: The importance of brain temperature in alterations of the blood-brain barrier following cerebral ischemia. J Neuropathol Exp Neurol 1990;49:486. 567. Sassano J, Eshel G, Safar P, et al: Hyperthermic cardiac arrest in monkeys. Crit Care Med 1981;9:409. 568. Eshel G, Safar P, Radovsky A, et al: Hyperthermia-induced cardiac arrest in monkeys: limited efficacy of standard CPR. Aviat Space Environ Med 1997;68:415. 569. Eshel GM, Safar P, Stezoski W: Evaporative cooling as an adjunct to ice bag use after resuscitation from heat-induced arrest in a primate model. Pediatr Res 1990;27:264. 570. Takasu A, Ishihara S, Anada H, et al: Surface cooling, which fails to reduce the core temperature rapidly, hastens death during severe hemorrhagic shock in pigs. J Trauma 2000;48:942. 571. Xiao F, Safar P, Alexander H: Peritoneal cooling for mild cerebral hypothermia after cardiac arrest in dogs. Resuscitation 1995;30:51. 572. Natale JA, D’Alecy LG: Protection from cerebral ischemia by brain cooling without reduced lactate accumulation in dogs. Stroke 1989;20:770. 573. Gelman B, Schleien CL, Lohe A, et al: Selective brain cooling in infant piglets after cardiac arrest and resuscitation. Crit Care Med 1996;24:1009. 574. Wolfson SK, Selker RG: Carotid perfusion hypothermia for brain surgery using cardiac arrest without bypass. J Surg Res 1973;14:449. 575. Wolfson SK, Inouye WY, Kavianian A, et al: Preferential cerebral hypothermia for circulatory arrest. Surgery 1965;57:846. 576. Schwartz AE, Stone JG, Pile-Spellman J, et al: Selective cerebral hypothermia by means of transfemoral internal carotid artery catheterization. Radiology 1996;201:571. 577. Schwartz AE, Stone JG, Finck AD, et al: Isolated cerebral hypothermia by single carotid artery perfusion of extracorporeally cooled blood in baboons. Neurosurgery 1996;39:577. 578. Parkins WM, Jensen JM, Vars HM: Brain cooling in the prevention of brain damage during periods of circulatory occlusion in dogs. Ann Surg 1954;140:284. 579. Ohta T, Sakaguchi I, Dong LW, et al: Selective cooling of brain using profound hemodilution in dogs. Neurosurgery 1992;31:1049. 580. Ohta T, Kuroiwa T, Sakaguchi I, et al: Selective hypothermic perfusion of canine brain. Neurosurgery 1996;38:1211. 581. Kuhnen G, Bauer R, Walter B: Controlled brain hypothermia by extracorporeal carotid blood cooling at normothermic trunk temperatures in pigs. J Neurosci Methods 1999;89:167. 582. Walter B, Bauer R, Kuhnen G, et al: Coupling of cerebral blood flow and oxygen metabolism in infant pigs during selective brain hypothermia. J Cereb Blood Flow Metab 2000;20:1215. 583. Gunn AJ, Gunn TR, de Haan HH, et al: Dramatic neuronal rescue with prolonged selective head cooling after ischemia in fetal lambs. J Clin Invest 1997;99:248.

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584. Gunn AJ, Gluckman PD, Gunn TR: Selective head cooling in newborn infants after perinatal asphyxia: A safety study. Pediatrics 1998; 102:885. 585. Okamoto K, Nagao K, Miki T, et al: New hypothermia method using blood cooling system: MONAN and KANEM method. In Hayashi N (ed): Brain Hypothermia. Tokyo, Springer-Verlag, 2000, pp 203–209. 586. Coimbra C, Drake M, Boris-Moller F, et al: Long-lasting neuroprotective effect of postischemic hypothermia and treatment with an anti-inflammatory/antipyretic drug. Evidence for chronic encephalopathic processes following ischemia. Stroke 1996;27:1578. 587. Coimbra C, Wieloch T: Moderate hypothermia mitigates neuronal damage in the rat brain when initiated several hours following transient cerebral ischemia. Acta Neuropathol 1994;87:325. 588. Hickey RW, Ferimer H, Alexander HL, et al: Delayed, spontaneous hypothermia reduces neuronal damage after asphyxial cardiac arrest in rats. Crit Care Med 2000;28:3511. 589. Zeiner A, Holzer M, Sterz F, et al, for the Hypothermia after Cardiac Arrest (HACA) Study group: Mild resuscitative hypothermia to improve neurological outcome after cardiac arrest: A clinical feasibility trial. Stroke 2000;31:86. 590. Hypothermia after Cardiac Arrest Study Group. Mild therapeutic hypothermia to improve the neurologic outcome after cardiac arrest. N Engl J Med 2002;346:549–556. 591. Bernard SA, Jones BM, Horne MK. Clinical trial of induced hypothermia in comatose survivors of out-of-hospital cardiac arrest. Ann Emerg Med 1997;30:146. 592. Bernard SA, Gray TW, Buist MID, et al: The treatment of comatose survivors of prehospital cardiac arrest with induced hypothermia. New Engl J Med 2002;346:557–563. 593. Yamashita C, Nakagiri K, Yamashita T, et al: Mild hypothermia for temporary brain ischemia during cardiopulmonary support systems: report of three cases. Surg Today 1999;29:182. 594. Yanagawa Y, Ishihara S, Norio H, et al: Preliminary clinical outcome study of mild resuscitative hypothermia after out-of-hospital cardiac arrest. Resuscitation 1998;39:61. 595. Nagao K, Hayashi N, Kanmatsuse K, et al: Cardiopulmonary cerebral resuscitation using emergency cardiopulmonary bypass, coronary reperfusion therapy and mild hypothermia in patients with cardiac arrest outside the hospital. J Am Coll Cardiol 2000; 36:776. 596. Cheney F, et al: Burns from warming devices in anesthesia: a closed claims analysis. Anesthesiology 1994;80:806. 597. Hayashi N, Kushi H, Utagawa A, et al: The clinical issue and effectiveness of brain hypothermia treatment for severely brain-injured patients. In Hayashi N (ed): Brain Hypothermia. Tokyo, SpringerVerlag 2000, pp 121–151. 598. Onesti S, et al: Transient hypothermia reduces focal ischemic brain damage in the rat. Neurosurgery 1991;29:369. 599. Morikawa E, Ginsberg MD, Dietrich WD, et al: The significance of brain temperature in focal cerebral ischemia: Histopathological consequences of middle cerebral artery occlusion in the rat. J Cereb Blood Flow Metab 1992;12:380. 600. Ridenour T, et al: Mild hypothermia reduces infarct size resulting from temporary but not permanent focal ischemia in the rat. Stroke 1992;23:733. 601. Chen H, et al: The effect of hypothermia on transient middle cerebral artery occlusion in the rat. J Cereb Blood Flow Metab 1992;12: 621. 602. Zhang RL, Chopp M, Chen H, et al: Postischemic (1 hour) hypothermia significantly reduces ischemic cell damage in rats subjected to 2 hours of middle cerebral artery occlusion. Stroke 1993;24:1235. 603. Naritomi H, Shimizu T, Oe H, et al: Mild hypothermia therapy in acute embolic stroke: A pilot study. J Stroke Cerebrovasc Dis 1996;6(suppl 1):193. 604. Schwab S, Schwarz S, Spranger M, et al: Moderate hypothermia in the treatment of patients with severe middle cerebral artery infarction. Stroke 1998:29:2461.

605. Krieger DW, De Georgia MA, Abou-Chebl A, et al: Cooling for acute ischemic brain damage (cool aid): an open pilot study of induced hypothermia in acute ischemic stroke. Stroke 2001;32:1847. 606. Kammersgaard LP, Rasmussen BH, Jorgensen HS, et al: Feasibility and safety of inducing modest hypothermia in awake patients with acute stroke through surface cooling: A case-control study: the Copenhagen Stroke Study. Stroke. 2000;31:2251. 607. Ishige N, Pitts LH, Berry I, et al: The effect of hypoxia on traumatic head injury in rats: alterations in neurologic function, brain edema, and cerebral blood flow. J Cereb Blood Flow Metab 1987;7:759. 608. Muizelaar JP, Marmarou A, Ward JD, et al: Adverse effects of prolonged hyperventilation in patients with severe head injury; a randomized clinical trial. J Neurosurg 1991;75:731. 609. Clifton GL, Jiang JY, Lyeth BG, et al: Marked protection by moderate hypothermia after experimental traumatic brain injury. J Cereb Blood Flow Metab 1991;11:114. 610. Dixon CE, Markgraf CG, Angileri F, et al: Protective effects of moderate hypothermia on behavioral deficits but not necrotic cavitation following cortical impact injury in the rat. J Neurotrauma 1998;15:95. 611. Dietrich WD, Alonso O, Busto R, et al: Post-traumatic brain hypothermia reduces histopathological damage following concussive brain injury in the rat. Acta Neuropathol 1994;87:250. 612. Koizumi H, Povlishock JT: Posttraumatic hypothermia in the treatment of axonal damage in an animal model of traumatic axonal injury. J Neurosurg 1998;89:303. 613. Marion DW, White MJ: Treatment of experimental brain injury with moderate hypothermia and 21-aminosteroids. J Neurotrauma 1996;13:139. 614. Smith SL, Hall ED: Mild pre- and posttraumatic hypothermia attenuates blood-brain barrier damage following controlled cortical impact injury in the rat. J Neurotrauma 1996;13:1. 615. Clark RS, Kochanek PM, Marion DW, et al: Mild posttraumatic hypothermia reduces mortality after severe controlled cortical impact in rats. J Cereb Blood Flow Metab 1996;16:253. 616. Pomeranz S, Safar P, Radovsky A, et al: The effect of resuscitative moderate hypothermia following epidural brain compression on cerebral damage in a canine outcome model. J Neurosurg 1993;79:241. 617. Ebmeyer U, Safar P, Radovsky A, et al: Moderate hypothermia for 48 hours after temporary epidural brain compression injury in a canine outcome model. J Neurotrauma 1998;15:323. 618. Marion DW, Penrod LE, Kelsey SF, et al: Treatment of traumatic brain injury with moderate hypothermia. N Engl J Med 1997;336:540. 619. Clifton GL, Miller ER, Choi SC, et al: Lack of effect of induction of hypothermia after acute brain injury. N Engl J Med 2001;344:556. 620. Safar P, Kochanek PM: Resuscitative hypothermia after acute brain injury. Editorial comment on Clifton, et al, New Engl J Med 2001;344:556. 621. Bullock R, Chesnut RM, Clifton G, et al: Guidelines for the management of severe head injury. Joint Section on Neurotrauma and Critical Care. The Brain Trauma Foundation, 1995. 622. White RJ, Likavec MJ: The diagnosis and initial management of head injury. N Engl J Med 1992;327:1507. 623. Rosomoff HL, Kochanek PM, Clark R, et al: Resuscitation from severe brain trauma. Crit Care Med 1996;24:548. 624. Levine JE, Becker DP: Reversal of incipient brain death from head injury apnea at the scene of accident. N Engl J Med 1979;301:109. 625. Hayashi N, Hirayama T, Utagawa A: Systemic management of cerebral edema based on a new concept in severe head injury patients. Acta Neurochir 1994;60 (suppl):541. 626. Hayashi N: Combination therapy of cerebral hypothermia, pharmacological activation of the dopamine system, and hormonal replacement in severely brain damaged patients. J Jpn Intensive Care Med 1997;4:191. 627. McIntosh TK, Hyes R, De Witt D, et al: Endogenous opiods may mediate secondary damage after experimental brain injury. Am J Physiol 1987;258:E565.

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Chapter 15  628. Henker RA, Brown SD, Marion DW: Comparisons of brain temperature with bladder and rectal temperature in adults with severe head injury. Neurosurgery 1998:42:1071. 629. Sternau L, Thompson C, Dietrich WD, et al: Intracranial temperature: Observations in human brains. J Cereb Blood Flow Metab 1991; 11:S123. 630. Bricolo A, Ore GD, Da Pian R, et al: Local cooling in spinal cord injury. Surg Neurol 1976;6:101. 631. Crippen D, Safar P, Porter L, et al: Improved survival of hemorrhagic shock with oxygen and hypothermia in rats. Resuscitation 1991; 21:271. 632. Leonov Y, Safar P, Sterz F, et al: Extending the golden hour of hemorrhagic shock tolerance with oxygen plus hypothermia in awake rats— an exploratory study. Resuscitation 2002;52:193–202. 633. Capone AC, Safar P, Stezoski W, et al: Improved outcome with fluid restriction in treatment of uncontrolled hemorrhagic shock. J Am Coll Surg 1995;180:49. 634. Kim SH, Stezoski SW, Safar P, et al: Hypothermia and minimal fluid resuscitation increase survival after uncontrolled hemorrhagic shock in rats. J Trauma 1997;42:213. 635. Takasu A, Carrillo P, Stezoski SW, et al: Mild or moderate hypothermia, but not increased oxygen breathing, prolongs survival during lethal uncontrolled hemorrhagic shock in rats with monitoring of visceral dysoxia. Crit Care Med 1999;27:1557. 636. Takasu A, Stezoski SW, Stezoski J, et al: Mild or moderate hypothermia, but not increased oxygen breathing, increases long term survival after uncontrolled hemorrhagic shock in rats. Crit Care Med 2000;28:2465. 637. Prueckner S, SafarP, Kentner R, et al: Mild hypothermia increases survival from severe pressure controlled hemorrhagic shock in rats. J Trauma 2001;50:253. 638. Wu X, Kentner R, Stezoski J, et al: Systemic hypothermia, but not regional gut cooling, improves survival from prolonged hemorrhagic shock in rats [abstract]. Sept 2001 AAST meeting. 639. Kentner R, Wu X, Safar P, et al: Doubling the golden hour of traumatic hemorrhagic hemorrhage shock tolerance with mild hypothermia and an antioxidant [abstract]. Anesthesiology, ASA meeting 2001. 640. Villar J, Slutsky: Effects of induced hypothermia in patients with septic adult respiratory distress syndrome. Resuscitation 1993;26:183. 641. Clemmer TP, Fisher CJ, Bone RC, et al: Hypothermia in the sepsis syndrome and clinical outcome. Crit Care Med 1992;20:1395. 642. Hale SL, Kloner RA: Myocardial temperature in acute myocardial infarction: Protection with mild regional hypothermia. Am J Physiol 1997;273:H220. 643. Hale SL, Kloner RA: Myocardial hypothermia: A potential therapeutic technique for acute regional myocardial ischemia. J Cardiovasc Electrophysiol 1999;10:405. 644. Bellamy R, Safar P, Tisherman SA, et al: Suspended animation for delayed resuscitation. Crit Care Med 1996;24 (Suppl):S24. 645. Rhee PM, Acosta J, Bridgeman A, et al: Survival after emergency department thoracotomy: Review of published data from the past 25 years. J Am Coll Surg 2000;190:288. 646. Kirimli B, Kampschulte S, Safar P: Resuscitation from cardiac arrest due to exsanguination. Surg Gynecol Obstet 1969;129:89. 647. Tisherman SA, Safar P, Sterz F, et al: Exsanguination cardiac arrest in dogs: physiology of dying [abstract]. Ann Emerg Med 1989;18:460. 648. Tisherman SA, Safar P, Sterz F, et al: Exsanguination versus ventricular fibrillation cardiac arrest in dogs: comparison of neurologic outcome—preliminary data [abstract]. Ann Emerg Med 1989;18:460. 649. Safar P, Tisherman S, Behringer W, et al: Suspended animation for resuscitation from prolonged cardiac arrest that is unresuscitable by standard cardioipulmonary cerebral resuscitation. Crit Care Med. 2000;28 (suppl):N214. 650. Manning JE, Murphy CA, Jr., Hertz CM, et al: Selective aortic arch perfusion during cardiac arrest: A new resuscitation technique. Ann Emerg Med 1992;21:1058.

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651. Tang W, Weil MH, Noc M, et al: Augmented efficacy of external CPR by intermittent occlusion of the ascending aorta. Circulation 1993;88(4 part 1):1916. 652. Paradis N, Davison C, Fuller J, et al: Intra-aortic epinephrine and perfusion pressures during ACLS and selective aortic perfusion and oxygenation [abstract]. Crit Care Med 1994;22:A224. 653. Rubertsson S, Bircher NG, Smarik SD, et al: Intra-aortic administration of epinephrine above aortic occlusion does not alter outcome of experimental cardiopulmonary resuscitation. Resuscitation 1999; 42:57. 654. Woods RJ, Prueckner S, Safar P, et al: Hypothermic aortic arch flush for preservation during exsanguination cardiac arrest of 15 minutes in dogs. J Trauma 1999;47:1028. 655. Behringer W, Prueckner S, Safar P, et al: Rapid induction of mild cerebral hypothermia by cold aortic flush achieves normal recovery in a dog outcome model with 20-minute exsanguination cardiac arrest. Acad Emerg Med 2000;7:1341. 656. Behringer W, Prueckner S, Kentner R, et al: Rapid hypothermic aortic flush can achieve survival without brain damage after 30 min cardiac arrest in dogs. Anesthesiology 2000;93:1491. 657. Behringer W, Safar P, Kentner R, et al: Intact survival of 60, 90, and 120 min cardiac arrest in dogs with 10°C cerebral preservation by cold aortic flush. Study II. (Abstract 128). Crit Care Med 2000;28 (suppl):A65. 658. Behringer W, Safar P, Wu X, et al: Survival without brain damage after clinical death of 60–120 mins in dogs using suspended animation by profound hypothermia. Crit Care Med 2003;31:1523–1531. 659. Taylor MJ, Bailes JE, Elrifai AM, et al: A new solution for life without blood: Asanguinous low-flow perfusion of a whole-body perfusate during 3 hours of cardiac arrest and profound hypothermia. Circulation 1995;91:431. 660. Rhee P, Talon E, Eifert S, et al: Induced hypothermia during emergency department thoracotomy: An animal model. J Trauma 2000;48:439. 661. Behringer W, Prueckner S, Kentner R, et al: Exploration of pharmacologic aortic arch flush strategies for rapid induction of suspended animation (SA) (cerebral preservation) during exsanguination cardiac arrest (ExCA) of 20 min in dogs [abstract]. Crit Care Med 1999;27 (suppl):A65. 662. Woods RJ, Prueckner S, Safar P, et al: Adenosine by aortic flush fails to augment the brain preservation effect of mild hypothermia during exsanguination cardiac arrest in dogs. An exploratory study. Resuscitation 2000;44:47. 663. Behringer W, Kentner R, Wu X, et al: Thiopental and phenytoin by aortic arch flush for cerebral preservation during exsanguination cardiac arrest of 20 minutes in dogs. An exploratory study. Resuscitation 2001;49:83. 664. Behringer W, Kentner R, Wu X, et al: Fructose—1,6-bisphosphate and MK-801 by aortic arch flush for cerebral preservation during exsanguination cardiac arrest of 20 minutes in dogs. An exploratory study. Resuscitation 2001;50:205–216. 665. Behringer W, Wu X, Radovsky A, et al: Tempol by aortic arch flush (AAF) for cerebral preservation during 20 min exsanguination cardiac arrest (CA) in dogs. Exploratory experiments [abstract]. Anesthesiology 2000;91 (suppl):U158. 666. Edgren E, Hedstrand U, Kelsey S, et al: Assessment of neurological prognosis in comatose survivors of cardiac arrest. Lancet 1994; 343:1055. 667. Mullie A, Buylaert W, Michen N, et al: Predictive value of Glasgow coma score for awakening after out-of-hospital cardiac arrest. Lancet 1988;i:137. 668. Madl C, Grimm G, Kramer L, et al: Early prediction of individual outcome after cardiopulmonary resuscitation. Lancet 1993;341:855. 669. Sasser HC, Safar P, BRCT Study Group: Clinical signs early after CPR predict neurologic outcome [abstract]. Crit Care Med 1999;27 (suppl):A30.

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670. Grenvik A, Powner DJ, Snyder JV, et al: Cessation of therapy in terminal illness and brain death. Crit Care Med 1978;6:284. 671. President’s Commission (USA) for the Study of Ethical Problems in Medicine and Biomedical and Behavioral Research. Deciding to Forgo Life-Sustaining Treatment. Government Printing Office, Washington, DC, 1983, p 232. 672. Wanzer SH, Adelstein SJ, Federmann DD, et al: The physician’s responsibility toward hopelessly ill patients: N Engl J Med 1984;310:955. 673. Wanzer SH, Federman DD, Adelstein SJ, et al: The physician’s responsibility toward hopelessly ill patients, a second look. N Engl J Med 1989;320:844. 674. Safar P: The physician’s responsibility towards hopelessly critically ill patients. Ethical dilemmas in resuscitation medicine. Acta Anaes Scand 1991;35 (Suppl):147. 675. Safar P, Winter P: Helping to die. Crit Care Med 1990;18:788. 676. Youngner SJ, Bartlett ET: Human death and high technology: the failure of the whole-brain formulations. Ann Intern Med 1983;99:252. 677. Vaagenes P, Kjekshus TK, Torvik A: The relationship between cerebrospinal fluid creatine kinase and morphological changes in the brain after transient cardiac arrest. Circulation 1980;61:1194. 678. Vaagenes P, Mullie M, Fodstad DT, et al, and the Brain Resuscitation Clinical Trial I Study Group: The use of cytosolic enzyme increase in cerebrospinal fluid of patients resuscitated after cardiac arrest. Am J Emerg Med 1994;12:621. 679. Mullie A, Lust P, Penninckx J, et al: Monitoring of cerebrospinal fluid enzyme levels in postischemic encephalopathy after cardiac arrest. Crit Care Med 1981;9:399.

680. Edgren E, Terent A, Hedstrand U, et al: Cerebrospinal fluid markers in relation to outcome in patients with global cerebral ischemia. Crit Care Med 1983;11:4. 681. Schoerkhuber W, Kittler H, Sterz F, et al: Time course of serum neuron-specific enolase. A predictor of neurological outcome in patients resuscitated from cardiac arrest. Stroke 1999;30:15998. 682. Abramson NS, Meisel A, Safar P: Informed consent in resuscitation research. JAMA 1981;246:2828. 683. Abramson NS, Meisel A, Safar P: Deferred consent: A new approach for resuscitation research on comatose patients. JAMA 1986;255:2466. 684. Abramson NS, Safar P, Brain Resuscitation Clinical Trial II Study Group: Deferred consent: Use in clinical resuscitation research. Ann Emerg Med 1990;19:781. 685. Biros MH, Lewis RT, Olson CM, et al: Informed consent in emergency research. Consensus statement from coalition conference of acute resuscitation and critical care. JAMA 1995;273:1283. 686. Idris AH, Becker LB, Ornato JP, et al: Utstein-style guidelines for uniform reporting of laboratory CPR research. Circulation 1996; 94:2324. 687. Safar P, Khachaturian Z, Klain M, et al: Recommendations for future research on the reversibility of clinical death. Crit Care Med 1988;16:1077. 688. Safar P: Resuscitation medicine research: quo vadis. Ann Emerg Med 1996;27:542.

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Chapter 16 Airway Management in the Neurointensive Care Unit Andrea Gabrielli, MD and A. Joseph Layon, MD

A systematic approach to airway management has been shown to reduce the likelihood of an adverse outcome in the operating room.1–4 Accordingly, this chapter discusses the unique challenges involved in the airway management of the patient requiring neurointensive care and offers a strategy that can improve neurologic outcome in acute brain injury.

General Consequences of Hypoxia and Hypercapnia DO2 (oxygen delivery, in mL/min) represents the bulk movement of oxygen in the blood and is proportional to cardiac output and arterial oxygen content. It is described by the equation: DO2 = [(cardiac output ¥ CaO2 ) + 0.003(PaO2 )] Thus, while the PaO2 is an essential component of DO2, it is clearly the least important element. However, the presence of bulk O2 delivered to tissue does not guarantee tissue oxygenation, because the passive movement of O2 down a concentration gradient to the mitochondria is ultimately responsible for cellular O2 delivery. Nevertheless, when ventilation fails, both arterial partial pressure of oxygen (PaO2) and systemic O2 delivery rapidly fall, resulting in, respectively, hypoxia and hypoxemia. As a consequence, progressive global hypoxia will rapidly follow. The tolerance to hypoxia of various tissues is different (Table 16-1),5 with the central nervous system (CNS) being the most sensitive organ to hypoxia; irreversible damage starts approximately 3 minutes after the PaO2 falls below 30 mm

Hg.5 The neurovegetative response to hypoxia often implies a brief period of hypertension and tachycardia. However, if not promptly corrected, hypoxia triggers cardiac dysrhythmias, leading to low cardiac output state, severe bradycardia, peripheral vascular dilatation, systemic hypotension, metabolic acidosis, and death. Adequate ventilation is necessary to remove CO2 from the tissues. The immediate consequence of hypoventilation is hypercapnia with acute respiratory acidosis and acidemia (pH < 7.35). In an apneic nonhypermetabolic patient not receiving intravenous bicarbonate, the increase in arterial partial pressure of CO2 (PaCO2) is predictable with time, at about 3 mm Hg per minute. Respiratory acidosis in the absence of hypoxia may provoke sympathetic nervous system activity with consequent hypertension, tachycardia, cerebral vasodilatation, and increased intracranial pressure (ICP). While, in healthy individuals, altered mental status, severe acidemia, and cardiac arrest occur only with significant hypercapnia (PaCO2 > 80 to 100 mm Hg), small increases in PaCO2 beyond normal may cause significant worsening of intracranial pressure and hemodynamic instability in patients with CNS injuries. In the presence of combined hypoventilation and hypoxia, the hemodynamic consequences of hypoxia prevail with severe bradycardia and rapid deterioration of neurologic status. Hypoxia and Secondary Central Nervous System Injury While the CNS may be immediately damaged by the primary pathology, secondary injury from hypoxia (PaO2 < 60 mm 499

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Table 16-1  Tolerance to Hypoxia of Various Tissues Tissue Brain Kidney and liver Skeletal muscle Vascular smooth muscle Hair and nails

Survival Time <3 min 15–20 min 60–90 min 24–72 h Several days

From Leach RM, Treacher DS: ABC of oxygen: Oxygen transport—2. Tissue hypoxia. BMJ 1998;317:1370–1373, with permission.

Hg) can be responsible for further rapid clinical deterioration. When hypoxia is associated with neurological injury, secondary damage will result, causing a complex cascade of inflammatory and biochemical processes involving both neurons and supportive cells. While hypoxia, generically, means a condition of low arterial PaO2, in CNS pathology one has to clinically differentiate ischemic hypoxia (reduced cerebral blood flow) from anemic hypoxia (reduced O2 delivery secondary to very low hemoglobin levels or cellular [mitochondrial] poisoning). In general, CNS damage from decreased O2 delivery to the brain has a multifactorial pathogenesis described following, with failure of the Na+/K+ pump and intracellular shift of sodium, H2O, and ionized calcium as the subsequent events.6 A severe inflammatory reaction follows, triggered by the intracellular release of O2 free radicals, free fatty acid, and proteolytic enzymes, which result in intracellular and then intravascular lactic acidosis. On reperfusion of previously ischemic CNS cells, ionic membrane pump inefficiency results in osmotic edema (interstitial or vasogenic), disruption of the blood-brain barrier (BBB), and further brain hypoperfusion. Oxygen free radical burst, activation of lipase, nucleases, and proteases can cause deoxyribonucleic acid (DNA) injury and programmed cell death (apoptosis).

The Importance of an Organized Approach to the Airway Recognizing the importance of delivering O2 and controlling PaCO2 in the injured CNS, the technique chosen for securing an airway depends on the anatomic characteristics of the airway itself and specific clinical factors associated with the injury. An organized treatment algorithm can provide immediate correction of oxygenation and ventilation, while minimizing iatrogenic events. Both the American and the Canadian Societies of Anesthesiologists (ASA, CSA, respectively) have set standards for managing the airway in the operating room. Recently published guidelines on the management of the difficult airways from these two organizations can be used here as guidelines in the systematic review of available airways and techniques in the neurosurgical intensive care unit.2,3,7

Predicting a Difficult Airway A systematic examination of the airway is the key to recognizing anatomy that may result in a difficult intubation and planning for its safe management.8 A comprehensive noninvasive systematic review of upper airway anatomy has recently been described and is illustrated (Table 16-2).9 Such a systematic approach takes into consideration several important risk factors such as weight, head and neck movement, jaw movement, receding mandible, and upper incisor angulation.8 An index score of 0 to 2 has to be assigned to each of the preceding risk factors, and predicts difficult intubation. This index was tested prospectively and found useful as a positive predictor of difficult intubation in 92% of the cases.9 Anatomic observation of the upper airway should be integrated with knowledge of other possible airwaycompromising, congenital, or acquired clinical conditions (Table 16-3). Mallampati10 has described the clinical correlation between the anatomy of the oropharyngeal structures and the degree of difficulty of laryngeal exposure (Fig. 16-1). The basis of the Mallampati airway classification is the relative size of the tongue to the size of the oropharyngeal opening. A subsequent modification of the Mallampati specification, described by Samsoon and Young,11 is now in widespread use as the “modified Mallampati classification” (Fig. 16-2). This modification of the Mallampati classification represents a subdivision of the Mallampati class III airway into classes III and IV; class IV describing a condition in which the oropharynx is completely obscured by the tongue when the mouth is wide open. A clear clinical correlation exists between the Mallampati classification and the difficulty of direct laryngoscopy in both prospective and retrospective studies.10 Visualization of the larynx by direct laryngoscopy (DL) can also be divided into four classes as designated by Cormack and Lehane12 (Fig. 16-3). Overall failure to intubate the trachea after direct laryngoscopy can be observed in one to three cases per 103 attempts, and failure to bag-valvemask ventilate can be seen in one to three cases per 104 attempts.2 When the patient is comatose or uncooperative, the distance between the chin and the laryngeal cartilage prominence can be used as a rapid measurement to evaluate the airway. A distance of three fingerbreadths or more suggests adequate room for a successful DL. A quick review of a previous anesthesia or intubation record is also an invaluable tool to evaluate the airway in an emergency situation.

Aspiration of Gastric Contents and the Difficult Airway Tracheo-bronchial aspiration of oral or gastric contents has been described in between 16% and 27% of all patients requiring intubation.13 Usually, the aspirated material represents saliva or blood and has minimal clinical consequences. In the neurologically injured patient, aspiration of gastric

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Table 16-2  Preoperative Airway Examinations: Acceptable Endpoints and Significance of Endpoints Preoperative Examination Dental Length of upper incisors with mouth fully open Involuntary: Maxillary teeth anterior to mandibular teeth (buck teeth) Voluntary: Protrusion of mandibular teeth anterior to the maxillary teeth

Acceptable Endpoints

Significance of Endpoints

Qualitative/short incisors

Long incisors. Blade enters mouth in cephalad direction Overriding maxillary teeth. Blade enters mouth in a more cephalad direction Test of TMJ function: means good mouth opening and jaw will displace anteriorly with laryngoscopy 2-cm phalange on blade can be easily inserted between teeth

Inter-incisor distance

No overriding of maxillary teeth anterior to the mandibular teeth Anterior protrusion of the mandibular teeth relative to the maxillary teeth > 3 cm

Pharynx Oropharyngeal class Samsoon & Young*

£ Class II

Narrowness of palate Mandibular space length (thyromental distance) Mandibular space compliance

Neck Length of neck Thickness of neck Range of motion of head and neck

Should not appear very narrow and/or highly arched ≥ 5 cm or ≥ 3 ordinary-sized finger breadths Qualitative palpation of normal resistance/softness

Qualitative. A quantitative index is not yet available Qualitative. A quantitative index is not yet available Head extended on neck 80° = sniff position

Tongue is small in relation to size of oropharyngeal cavity A narrow palate decreases the oropharyngeal volume and room for both blade and ETT Larynx is relatively posterior to other upper airway structures Laryngoscopy retracts tongue into the MS. Compliance of the MS determines if tongue fits into MS A short neck decreases the ability to align the upper airway axes A thick neck decreases the ability to align the upper airway axes The sniff position aligns the oral, pharyngeal and laryngeal axes to create a favorable line of sight

ETT, endotracheal tube; MS, mandibular space compliance; TMJ, temporomandibular joint. *Modification of Mallampati airway classification. Modified from Benumof JL: American Society of Anesthesiology Refresher Course 1998–1999, lecture 134: The ASA difficult airway algorithm: New thoughts/considerations.

contents may be seen secondary to regurgitation or vomiting in the patient with incompetent laryngeal reflexes due to altered mental status, or simply with the use of a hypnotic agent to facilitate intubation. In the operating room, the incidence of pulmonary aspiration of gastric contents ranged from 1.1% in a series of 10,000 elective anesthetics of ASA Physical Status class I, to 29% in 10,000 emergency

Figure 16-1. Mallampati Airway Classification. Relative size of the tongue to the oropharyngeal opening. A, Class I. B, Class II. C, Class III. (Modified from Benumof JL: Airway Management: Principles and Practice. St. Louis, Mosby Yearbook, 1996, p 132 and Mallampati et al.10, with permission.)

anesthetics in ASA Physical Status classes IV and V.14,15 Although no specific data have been described in the patient with CNS injury, the incidence of gastric aspiration may be up to 30-fold more likely in emergency cases. Hypoxemia from severe ventilation-perfusion (V/Q) mismatch is the most serious consequence of pulmonary aspiration of gastric contents. As a consequence of the aspiration-induced

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Table 16-3  Airway Compromising Conditions Pathologic Condition Supralaryngeal Pierre Robin syndrome Treacher Collins syndrome Goldenhar’s syndrome Down syndrome Klippel-Feil syndrome Sublaryngeal Goiter Infections Supraglottis Croup Abscess (intraoral, retropharyngeal) Ludwig’s angina Arthritis Rheumatoid arthritis Ankylosing spondylitis Benign tumors Cystic hygroma, lipoma, adenoma, goiter Malignant tumors Carcinoma of tongue, larynx, or thyroid Trauma Facial injury, cervical spine injury, and laryngeal-tracheal trauma Obesity Acromegaly Acute burns

Principal Pathologic/Clinical Features

Micrognathia, macroglossia, cleft soft palate Auricular and ocular defects; malar and mandibular hypoplasia Auricular and ocular defects; malar and mandibular hypoplasia; occipitalization of atlas Poorly developed or absent bridge of the nose; macroglossia Congenital fusion of a variable number of cervical vertebrae; restriction of neck movement Compression of trachea, deviation of larynx-trachea Laryngeal edema Laryngeal edema Distortion of the airway and trismus Distortion of the airway and trismus Temporomandibular joint ankylosis, cricoarytenoid arthritis, deviation of larynx, restricted mobility of cervical spine Ankylosis of cervical spine; less commonly, ankylosis of temporomandibular joints; lack of mobility of cervical spine Stenosis or distortion of the airway Stenosis or distortion of the airway; fixation of larynx or adjacent tissues secondary to infiltration or fibrosis from irradiation Edema of the airway, hematoma, ongoing nose/sinus/laryngeal bleeding, unstable fracture(s) of the maxillae, mandible and cervical vertebrae Short, thick neck; redundant tissue in the oropharynx; sleep apnea Macroglossia; prognathism Edema of airway

From Benumof JL: Airway Management: Principles and Practice. St. Louis, Mosby YearBook, 1996, with permission.

Figure 16-2. Samsoon and Young Airway Classification. (From Benumof JL: Airway Management: Principles and Practice. St. Louis, Mosby Yearbook, 1996, p 132, with permission.)

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decreases the risk of an adverse outcome. This is essential for patients who are found to have an unrecognized difficult airway on first intubation attempt or when a difficult airway is recognized but the patient is uncooperative or rapidly deteriorating due to CNS pathology or hypoxia. A good example of management strategy is summarized in the difficult airway algorithm presented by the ASA in 1993 (Fig. 16-4)3 or more recently by the CSA2 (Fig. 16-5). Patient Preparation Before Attempting Intubation Regardless of the intubation technique planned and the urgency of intubation, pre-oxygenation should be always attempted before using an induction agent, to minimize the chance of hemoglobin desaturation. However, the apnea

Figure 16-3. Cormack and Lehane direct laryngoscopy classification. (From Benumof JL: Airway Management: Principles and Practice. St. Louis, Mosby Yearbook, 1996, p 123, with permission.)

alveolar capillary membrane damage, capillary leak can occur with loss of circulating fluid volume into the lung, resulting in increased extra vascular lung water, systemic hemoconcentration, hypotension, tachycardia and, possibly, hypovolemic shock aggravating the hypoxemia. Pulmonary hypertension may occur secondary to bronchospasm, loss of functioning alveoli, and left ventricular dysfunction.16 In patients with neurologic injuries, pulmonary aspiration can contribute to secondary CNS injury through a mechanism of hypoxia, hypotension, and pulmonary hypertension, with decreased cerebral venous return causing acute increase of ICP.

Strategy for Airway Management in the Neurointensive Care Unit A management strategy organized in algorithm form facilitates a systematic approach to the airway in the neurointensive care unit (neuro-ICU), decreases time of reaction, and

Figure 16-4. The Difficult Airway Algorithm presented by the American Society of Anesthesiology in 1993. The algorithm includes conscious intubation.

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Figure 16-5. The Difficult Airway Algorithm presented by the Canadian Society of Anesthesiology in 1999, after induction of general anesthesia. OELM = optimal external laryngeal manipulation; BURP = backward upward rightward pressure (of larynx).

time necessary to reach critical SpO2 (<90%) after an induction dose of hypnotic agent cannot always be predicted with ease, and it is expected to be decreased in critically ill and neurologically injured patients due to decreased functional residual capacity (FRC), pulmonary dysfunction, or increased metabolic rate.17 An FiO2 of 1.0 is used to attempt rapid and full tissue denitrogenation. This may require several minutes to achieve, and it is possible only with a tight mask fit on the patient, using either a rubber mask-strap or providing firm pressure to a mask connected to an Ambu bag or a Mapleson D system. Adequate pre-oxygenation is particularly important if the use of succinylcholine is contemplated. In fact, even in patients with healthy lungs, the average time to critical desaturation (<90%) is usually shorter than the mean recovery time from an intubating dose of succinylcholine (Fig. 16-6).17 Other factors may influence rapid desaturation when intubation is attempted in the neurologically impaired patient. Obese patients, and those with underlying pulmonary disease, have a decreased FRC, as well as V/Q mismatch. Low FRC may be further aggravated by the supine position and paralysis. Metabolic rate and oxygen consumption are higher in the pediatric population. Critically ill patients are at high risk of rapid desaturation because of the combination of increased oxygen consumption, V/Q mismatch, and decreased oxygen delivery. Aspiration prophylaxis should be considered in all “full stomach” patients when there is time. However, neutralization of gastric secretions with sodium citrate (15 to 30 mL by mouth) shortly before intubation is often impossible if an adequate level of consciousness and gag reflex are not

present. The use of H2 blockers, proton pump inhibitors, or metoclopramide do not provide adequate suppression of acid production or enhanced gastric emptying in these patients because of slow onset of action. Therefore, protection against acid aspiration relies mainly upon effective cricoid pressure.

Achieving Effective Mask Ventilation Ventilation by bag-valve-mask is a fundamental step in managing the airway. A high-flow, fresh gas source must be available to provide sufficient gas to compensate for facemask leaks and allow generation of sufficient positive pressure to overcome respiratory system resistance to gas flow. Jaw thrust and neck extension is usually necessary to provide a patent airway. This option is not available if neck injury is present or suspected, and will be discussed separately. Proper seal of the facemask should be obtained by adjusting the cushion tension. With many masks, the cushion inflation volume can be adjusted by adding or removing air with a syringe via a valve in the mask. The mask should be sized to cover the nose at the level of the bridge of the nose and the mouth just above the chin, and held tightly. Circumferential mask-straps should not be applied if increased ICP is a concern because of the risk of reducing the venous return from the brain, thus increasing ICP. A number of alternative methods can be used to overcome lack of seal secondary to facial hair. Applying gauze soaked in petroleum jelly can help to fill facial contours under the mask cushion. Other “homemade” devices have been used, such as plastic film over the

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Figure 16-6. Mathematical extrapolations of arterial oxygen saturation after induction and paralysis with succinylcholine in obese (A), pediatric (B), moderately critically-ill (C), and normal patients (D). Without ventilation, critical desaturation precedes full recovery from succinylcholine in all the patients. (From Benumof JL, Dagg R, Benumof R: Critical hemoglobin desaturation will occur before return to an unparalyzed state following 1 mg/kg intravenous succinylcholine. Anesthesiology 1997;87:478–482.)

facial hair or even a defibrillator contact pad with a small hole cut in the middle at the level of the mouth opening.18 While ventilating the patient, one must pay careful attention that the chest does not rise excessively, as this usually implies lung overinflation, with increased risk of gastric insufflation and decreased venous return with hypotension. Adding a pressure manometer to a Mapleson D and ensuring airway pressure less than 20 cm H2O may minimize the incidence of gastric insufflation. An inspiratory time of at least 1.5 seconds minimizes peak inflation pressure (PIP) and risk of aspiration.19 Finally, effective cricoid pressure should always be applied because it is the most effective maneuver to limit gastric insufflation during ventilation of the unprotected airway.

inadequate/absent ventilation. Finally, hypoxia by pulse oximeter (SpO2 < 90%) can occur as an objective sign of airway obstruction. The presence of cyanosis is a late and inconsistent sign that should not be relied upon to determine adequacy of ventilation and oxygenation. Table 16-4  Clinical Signs of Airway Obstruction During Positive and Negative Pressure Ventilation Auditory

Tactile

Overcoming Airway Obstruction Due to Soft Tissue Collapse The upper airway of the patient with altered mental status often totally obstructs, particularly in obese patients. The combination of stupor, redundant oropharyngeal soft tissue, a bulky tongue, and a thick chin and neck pad may interfere with the ability to ventilate. Various clinical signs may be noted during airway obstruction (Table 16-4). Gas passing through an obstructed airway may generate a characteristic bubbling noise. A rocking motion of the chest wall and abdomen (paradoxical breathing), along with neck retraction when spontaneous ventilation is present, correlate with airway obstruction. Absence of breath sounds appreciated from the precordial stethoscope also strongly suggests

Visual

Objective

Gurgling over epiglottic area (esophageal ventilation) Crowing or stridor (laryngeal) Stridor (laryngeal) Snoring (pharyngeal) Wheezing (small airway) Absent breath sounds Decreased reservoir compliance Decreased expiratory return Airway vibration Large facemask leak Decreased chest wall/inward abdominal excursion Accessory muscle recruitment Puffed cheeks/neck Abdominal rocking Abdominal distention Cyanosis Nasal flaring Suprasternal notch retraction Increased airway pressure Absence of CO2 waves on capnograph Low measured expired volume Hypoxemia (pulse oximeter)

From Gravenstein N, Kirby RR (eds): Clinical Anesthesia Practice. Philadelphia, WB Saunders, 1996, with permission.

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Figure 16-7. A and B, Twoperson mask ventilation. (From Benumof JL: Airway Management: Principles and Practice. St. Louis, Mosby Yearbok, 1996, p 153, with permission.)

Several methods may be used to overcome upper airway obstruction, but are limited to the patient without significant neck pathology or trauma. Lifting the chin pad while applying a jaw thrust can straighten anterior pharyngeal wall soft tissue and facilitate ventilation. Early insertion of a plastic oral airway or tilting the head laterally while ventilating may reduce the risk of the tongue falling backward against the soft palate. Finally, two-person mask ventilation should be attempted. Two versions are displayed in Figure 16-7. The second version can be applied in conditions when the assistant present at bedside has no expertise in airway management (Fig. 16-7B).

laryngoscopy; either of these can be very useful maneuvers to enhance visualization of the larynx under difficult conditions. The OELM is described as posterior and cephalic pressure over the thyroid or cricoid cartilage. The majority of the time, the best view is obtained simply by pressing the thyroid cartilage posteriorly. The BURP maneuver implies the manual displacement of the larynx posteriorly against the cervical vertebrae, then superiorly and as far as possible to the right. Both these maneuvers are indicated in laryngoscopy grades 2 through 4, usually improving the view by at least one grade (Fig. 16-9). Choosing the Laryngoscope Blade

Achieving the Best Laryngoscopic View The patient should always be placed in optimal position before an intubation attempt. In most patients, the “sniffing” position (slight flexion of the neck and extension of the head and the neck) is the best way to align the oropharyngeal and laryngeal axes (Fig. 16-8). In an obese patient, the sniffing position can be better obtained by placing a pad under both the shoulders and the head. Elevation of the shoulders and scapulae, in particular, allows better extension of the neck in obese patients with redundant subcutaneous tissue. In the ICU or ED, temporary removal of the bed rail or frames should be considered to facilitate operator access to the airway. Visualization of the larynx can be optimized through external manipulation, usually applied by the operator’s right hand or by an assistant while that individual applies cricoid pressure. The optimal external laryngeal manipulation (OELM)20 and the backward, upward, rightward laryngeal displacement (BURP)21 describe, respectively, the American and Canadian approaches to external manipulation of the larynx to improve vocal cord visualization during

McIntosh blades are recommended when a relatively small mouth opening, large tongue and/or redundant subcutaneous tissue are present. A McIntosh no. 4 is our blade of choice because it can be adapted to either a small or large adult. On the other hand, the Miller blade may be optimal for visualization of the vocal cords in patients with a small mandibular space, large incisors, and/or a large, floppy epiglottis. The Miller blade remains the blade of choice for the pediatric population, due to their relatively larger epiglottic size. A commonly used adjunct device for direct laryngoscopy in the patient with brain injury is the gum elastic stylet.22 Under direct laryngoscopy, the tip of the flexible stylet is blindly passed under the epiglottis into the trachea. The endotracheal tube (ETT) is then passed over the stylet, thereby allowing tracheal intubation. During insertion of the endotracheal tube, counter-clockwise rotation of the ETT by 90 to 180 degrees is recommended to avoid impingement of the tip of the ETT on the right vocal cord. The gum elastic stylet can be used to limit the extension of the neck in patients with a neck injury in the presence of a hard cervical collar. A number of laryngoscopic blades have recently

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Figure 16-8. A–D, Head and neck position, and the axes of the head, neck, and upper airway. LA, laryngeal axis, OA, oral axis, PA, pharyngeal axis.

been introduced to improve access to the vocal cords when the larynx is anterior, all anecdotally advantageous in cases of difficult airway or limited mouth opening. A detailed review is available in the literature.23 When to Consider Alternatives to Direct Laryngoscopy after an Unsuccessful Attempt

Figure 16-9. External manipulation to visualize the larynx during direct laryngoscopy: Optimal external laryngeal manipulation (OELM); backward, upward, rightward external displacement of the larynx (BURP, modified). (From Benumof JL: Airway Management: Principles and Practice. St. Louis, Mosby Yearbok, 1996, p 152, with permission.)

Numerous attempts at DL or edema from previous intubation or trauma may degrade the quality of the airway due to laryngeal edema and bleeding. This may also make mask ventilation progressively more difficult or even impossible. A degraded airway after numerous attempts at DL is the most common reason for the “cannot ventilate” scenario, and adverse respiratory events.1 It is generally accepted that three to four attempts at DL are the maximum number before switching to an alternative plan or resuming mask ventilation. It is our impression that the number of DL attempts is often proportional to the experience of the physician/physician-in-training. To limit the possibility of adverse respiratory events, we recommend that the inexperienced operator not be allowed to perform laryngoscopy in patients with anatomy compatible with difficult intubation, or when positioning is limited by in-line axial stabilization of the head, until he or she has a track record of successfully

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intubating less challenging airways. An expert laryngoscopist should always stand by to assure patient’s safety in an academic training program.

Developing a Difficult Airway Algorithm in the Neurointensive Care Unit A systematic approach to the difficult airway in the neuroICU is the key to preventing disastrous secondary injuries caused by hypoxia. As a general rule, an intensivist skilled in airway manipulation, including emergency tracheostomy, should be immediately available in the neuro-ICU. Anesthesiologists and surgical intensivists are natural first choices to cover this role. A difficult airway algorithm in the neuro-ICU can generally be organized into three different parts: 1. Predictable difficult intubation due to recognized difficult airway 2. Unpredictable difficult airway with ability to ventilate by mask 3. Unpredictable difficult airway, with inability to ventilate or oxygenate the patient, immediately after the use of hypnotic agents and/or muscle relaxant, or after a short period of successful ventilation (Fig. 16-10).

Part One: The Predictable Difficult Airway Satisfactory management of these patients often entails endotracheal intubation utilizing a flexible fiberoptic bronchoscope (FOB) and maintaining spontaneous ventilation.While this technique is usually feasible only in awake and cooperative patients, it can occasionally be extended to the obtunded patient with central nervous system injury, as long as planned very carefully. While there is usually no time to administer H2 blockers or proton pump inhibitors, the awake patient may be given a small amount of sodium citrate (15 to 30 mL) to neutralize gastric acid just before initiating the procedure. A small dose (0.2 mg) of glycopyrrolate given intravenously 10 to 15 minutes before intubation, may improve fiberoptic visualization of the airway due to the antisialagogue properties of this agent. The tip of the FOB is wetted with an antifogging agent and the ETT is preheated in warm saline for five to 10 minutes before the procedure to, respectively, maximize visualization and minimize trauma. Our topical anesthetic of choice is 4% lidocaine (4 to 6 mL or up to 4 mg/kg) nebulized into an aerosolized facemask 10 minutes before beginning the procedure. Bilateral superior laryngeal nerve and glossopharyngeal nerve blocks, using 2 to 3 mL of 1% lidocaine are performed when feasible, but are rarely necessary if adequate local anesthetic administration is provided to the pharynx; the same is true

Figure 16-10. Navigating the difficult airway algorithm: Section one, the predictable difficult intubation approached while conscious; section two, the unpredictable difficult intubation with ability to ventilate by mask; section three, the unpredictable difficult intubation with inability to ventilate by mask. +Always consider calling for help (e.g., technical, medical, surgical, etc.) when difficulty with mask ventilation and/or tracheal intubation is encountered ++Consider the need to preserve spontaneous ventilation TTJV, transtracheal jet ventilation.

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of the transtracheal block. The total amount of local anesthetic should not exceed the calculated toxic dose. Local anesthesia may also be provided on a “spray as you go” basis, using aerosolized 2% or 4% lidocaine through the operative channel while advancing the FOB. Gentle external pressure on the larynx without neck extension may facilitate the exposure of the vocal chords. The Berman, Ovassapian, and Williams specialized airways may facilitate placement of the ETT in front of the vocal cords, deep into the hypopharynx. Because conscious sedation is not an option for many neurosurgical patients, we cannot overemphasize the need for adequate topical anesthesia of the pharynx before attempting an elective intubation. Nasotracheal intubation is an alternative to the oral route for patients with a large tongue or edema of the oropharynx, and a valid alternative for the spontaneously breathing, uncooperative patient, or when the patient’s secretions are excessive. The presence of facial or posterior fossa trauma and coagulopathy are absolute contraindications to this approach. Absent these conditions, however, we quickly pretreat the mucosa of both nostrils with a solution of 0.1% phenylephrine, followed by progressive dilation, using nasal trumpets lubricated with 2% lidocaine jelly. Labetalol and esmolol should be available to blunt the hypertensive response to manipulation of the airway. Oxygen is provided with nasal cannulae placed between the lips or via a facemask. When conscious intubation is not feasible in the patient with neurologic injuries and imminent respiratory failure, parts two and three of the difficult airway algorithm should be immediately executed (see following discussion). Part Two: Strategy for the “Cannot Intubate” Patient, when Bag-Valve-Mask Ventilation Is Still Possible If laryngoscopy does not result in visualization of the glottis after 3 to 4 attempts, despite use of OELM or BURP, the patient should be ventilated and a preplanned alternative route of intubation immediately carried out. A specialized LMA, the LMA-Fastrach, is our primary choice to facilitate placement of the ETT (Fig. 16-11). The LMA-Fastrach is a latex-free device that permits single-handed insertion from a neutral position and without placing fingers in the mouth (Fig. 16-12). A straight, silicone wire-reinforced, cuffed ETT sized 7 to 8 mm internal diameter is available for placement through the Fastrach. The LMA-Fastrach is available in sizes 3, 4, and 5, for, respectively, small, normal, and large adults. Our second alternative, after LMA placement, is FOB intubation. This maneuver can be performed quickly while the patient is breathing spontaneously but still under the induction agent’s hypnotic effect. Ventilation may be provided during the procedure through a swivel right angle adapter (Fig. 16-13).15 To minimize air trapping and barotrauma, ventilation should be provided manually rather than mechanically.

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Figure 16-11. Fastrach intubating LMA. A silicone wirereinforced cuffed ETT is placed in the LMA with the help of a silicone extension.

Part Three: Strategy for the “Cannot Ventilate, Cannot Intubate” Scenario The “cannot ventilate, cannot intubate” scenario is the neurointensivist’s worst nightmare. Oxygen desaturation is rapid, depending on the length of pre-oxygenation time, the patient’s oxygen consumption, intrapulmonary shunting, and FRC. As noted previously, pediatric, obese, pregnant, and critically ill patients are particularly prone to early and

Figure 16-12. A–D, Placement of an ETT with the intubating LMA.

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Figure 16-13. Fiberoptic intubation of an LMA with a Rae ETT. The swivel adapter in place allows ventilation during the procedure.

deep desaturation. The first step in this scenario is to immediately request more help, including a surgical backup. In many cases, this help may be lifesaving. Two-person mask ventilation, executed as recommended previously, should be attempted before moving to another portion of the algorithm. Other personnel may be delegated to perform cricoid pressure or in-line manual axial stabilization, obtain supplies, and/or to control hemodynamics pharmacologically. The presence of large masses or severe swelling above the vocal cords (including tumor masses or facial trauma) may preclude the successful use of noninvasive alternative airway devices. This problem will be reviewed in the section dedicated to the transtracheal approach to the airway. In general, the “cannot ventilate, cannot intubate” scenario situation can be resolved only in the manner discussed in one of the following sections. Placement of a Laryngeal Mask Airway Placing an LMA should be attempted first. In fact, the track record of the successful positioning of an LMA is excellent even in nonexpert hands.24 Paramedical personnel and medical students, attempting to access known difficult airways, were successful on the first attempt with the LMA 94% of the time. None of them had experience with the LMA.25 The LMA has proved to be relatively easy to use in the case of difficult intubations, including class III and IV airways, and laryngoscopy grades three or four.26 A unique advantage of the LMA for neurosurgical patients is minimal stimulation of laryngeal reflexes associated with its insertion.27 However, the LMA does not protect the airway from regurgitation and may, in fact, promote gastro-esophageal regurgitation through a reflex relaxation of the lower esophageal sphincter.28 The risks of aspiration may also be increased

because regurgitated gastric contents cannot be expelled from the mouth. Cricoid pressure may be applied, but it can interfere with ventilation.29 Despite these limitations, the LMA is our first backup airway device in the neuro-ICU. The Intubating LMA and ProSeal LMA, which represent a design evolution of the LMA, will be discussed separately and in detail later. Placement of a Combitube The Combitube has recently been introduced into the prehospital and hospital environments as an alternative device in difficult airway management. It has replaced some of the nonsurgical techniques for airway control that do not rely on direct visualization of the airway, including the esophageal obturator airway, the esophageal gastric tube airway,30,31 and the pharyngeal lumen airway.32 The Combitube is a double-lumen tube with distal and proximal cuffs (Fig. 16-14), presently available in sizes 37F (women and young adults) and 41F (adult male). Despite its bulky appearance, the Combitube has a good safety record with only rare case reports of esophageal rupture.33,34 The device was initially introduced as a nonsurgical technique for airway control in cardiac arrest and respiratory arrest.35 It has been successfully used in hospitalized patients with sustained, nontraumatic cardiopulmonary arrest,36 as well as in patients undergoing elective surgery under general anesthesia.37 Another indication for the Combitube is facial burn or massive upper airway bleeding.38,39 Placement of a Cuffed Pharyngeal Airway Although limited information has been published about this device, the use of a cuffed pharyngeal airway (COPA) is intuitive.40–43 One of the main advantages of this device is that,

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Figure 16-14. A–C, Placement of a Combitube. A, Minimal mouth opening is required. B, Combitube in the esophagus, with ventilation through the pharyngeal openings. C, Combitube in the trachea, with ventilation through the distal opening.

once in place, its presence in the pharyngeal space does not interfere with the advancement of the FOB. The cuff can lift the tongue, creating a space for a better bronchoscopic view. Unlike the LMA, the COPA does not limit the size of the ETT because the tube is lateral to the COPA, not passed through it. Unfortunately, the availability of this airway device is now limited. A limitation of the preceding techniques is that none will be effective when the difficult airway is secondary to pathology above the vocal cords, as with hematoma, pharyngeal abscess, neoplasia, airway edema, or massive facial trauma. In these cases, the only approach likely to be successful is transtracheal catheter placement and/or emergency surgical airway. Both are reviewed in the following sections. Alternatives for the “Cannot Ventilate, Cannot Intubate” Scenario Due to Supraglottic Pathology When the airway is compromised by trauma or when significant oropharyngeal or hypopharyngeal pathology is present, emergency access to the airway may be obtained only via emergency surgical airway (tracheostomy or cricothyroidotomy) or a percutaneous cricothyroidotomy. 1. Emergency tracheostomy is usually performed via a vertical incision from the cricoid cartilage down, for approximately 1 cm, in the direction of the sternal notch. A no. 11 surgical blade is preferable. A skilled, surgically trained operator can rapidly approach the trachea through this route. However, serious bleeding may occur via laceration of the anterior jugular and superior thyroid veins, the cricothyroid artery, and other vessels of the thyroid isthmus. If the procedure is successful and tracheal intubation is confirmed, as soon as the patient is stabilized the next step is to immediately surgically revise the tracheostomy. 2. Emergency cricothyrotomy is a valid alternative to the emergency tracheostomy for the neurointensivist not skilled or trained in the surgical approach to the airway. This technique requires identification of the cricothyroid membrane.

The cricothyroid membrane (ligament) is directly under the skin and is composed primarily of elastic tissue.44 It covers the cricothyroid space, which averages 9 mm in height and 3 cm in width. The membrane is located in the anterior neck between the thyroid cartilage superiorly and the cricoid cartilage inferiorly. It consists of a central triangular portion (conus elasticus) and two lateral portions. It is often crossed horizontally in its upper third by the superior cricothyroid arteries. Because the vocal cords are usually located 1 cm or more above the cricothyroid space, they are usually not injured, even during emergency cricothyrotomy. The anterior jugular veins run vertically in the lateral aspect of the neck and are usually spared injury during the procedure. There is, however, considerable variation in both the arterial and venous vessel patterns. While the arteries are always located deep to the pretracheal fascia and are easily avoided during a skin incision, veins may be found in both the pretracheal fascia and between the pretracheal and superficial cervical fascias. To minimize the possibility of bleeding, the cricothyroid membrane should be incised at its inferior third. To locate the cricothyroid membrane, external visible and palpable anatomic landmarks are used. The laryngeal prominence and the hyoid bone above it are readily palpable. The cricothyroid membrane usually lies 1 to 1.5 fingerbreadths below the laryngeal prominence (Fig. 16-15). The cricoid cartilage is also easily felt caudal to the cricothyroid membrane. It takes only seconds to identify these landmarks but their importance must be emphasized, as it may be disastrous to surgically manipulate, in error, the thyroid space instead of the cricothyroid space. Conscious effort to identify these landmarks reduces the possibility of committing this preventable error. However, there will be instances in which the normal anatomy is distorted and identification of landmarks is difficult or impossible. In such cases, all attempts must be made to identify anatomic landmarks while salvaging the patient’s life. The incision is placed vertically, preferably with a no. 11 surgical blade, over the cricothyroid membrane. A small

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LARYNGEAL PROMINENCE

Figure 16-15. Anatomy of the cricothyroid membrane.

ETT, preferably armored, is placed through the membrane and aimed downward. This technique has the advantage of achieving access to the airway through a relatively avascular part of the neck, especially in lean individuals. However, the cricothyroid membrane is not always easy to appreciate in obese patients or those with a short neck. In any event, the successful placement of cricothyroidotomy should be followed by an elective tracheostomy, or FOB intubation, as soon as possible, since long term cricothyroidotomy may be associated with cricoid malacia, stenosis and/or lesions of the vocal cords. 3. Percutaneous cricothyroidotomy was described by Melker using the Seldinger technique (Figs. 16-16 and

16-17) and is our airway salvage technique of choice. The main advantage of this technique is the blunt dissection of the subcutaneous tissues all the way to the cricothyroid membrane.44 An airway catheter is then introduced over a dilator threaded over the guidewire. This technique allows the ultimate insertion of an airway considerably larger than the initial needle or catheter, and often of sufficient internal diameter to allow ventilation with conventional ventilation devices, suctioning, and spontaneous ventilation. While this technique is relatively atraumatic, it does require some knowledge of the anatomy of the neck, and previously established proficiency in using the kit. Thus, this technique is not recommended for the physician unfamiliar with this device. When established successfully, the airway placed is an uncuffed tracheostomy tube. At the time of this writing, a cuffed version of the tube has been released. A variation of the Melker technique is the Patil cricothyroidotomy, inserted without the use of the guidewire by direct needle puncture of the cricothyroid membrane and advancement of a dilator loaded on the needle, after skin incision with a scalpel, and the insertion of an 18F curved dilator (Fig. 16-18). 4. Needle cricothyroidotomy is an alternative to use of the more technically demanding cricothyroidotomy or tracheostomy. This can be achieved with a large caliber catheter, usually no. 12 or no. 14 gauge, or a specialized armored catheter (Fig. 16-19). Needle cricothyroidotomy always requires the use of a jet device to provide ventilation (Fig. 16-20).

Figure 16-16. Melker emergency cricothyrotomy catheter kit. (Courtesy of Cook Critical Care, Bloomington, IN.)

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Figure 16-17. Percutaneous approach to the cricothyroid membrane with the Melker cricothyrotomy kit. (Courtesy of Cook Critical Care, Bloomington, IN.)

Transtracheal catheter ventilation is a relatively easy method to temporarily oxygenate patients who cannot be ventilated with a mask or intubated. We consider it to be a “bridge” technique that buys time until the patient is conscious or a definitive airway can be secured. The cricothyroid membrane is punctured percutaneously with a needle, or, preferably, with an over-the-needle catheter. In the latter case, the needle is removed and the catheter is attached to a high-frequency jet device. Although oxygenation may be adequate with transtracheal catheter ventilation, passive exhalation is often insufficient to sustain ventilation, and hypercarbia as well as

Figure 16-18. Patil cricothyrotomy kit. (Courtesy of Cook Critical Care, Bloomington, IN.)

significant air trapping may result, with disastrous consequences for the patient with increased ICP or low intracranial compliance. Other complications, directly related to needle jet ventilation with the required high pressure oxygen source, include needle displacement in the subcutaneous tissue with massive subcutaneous emphysema, barotrauma with pneumothorax or tension pneumothorax, air trapping with severe hemodynamic instability due to impeded venous return to the right atrium, and right-to-left ventricular septal shift. The needle or catheter may break or bend if the patient coughs or moves, resulting in respiratory obstruction. Of these complications, subcutaneous air injection—some-

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Figure 16-19. Six French reinforced transtracheal catheter. (Courtesy of Cook Critical Care, Bloomington, IN.)

times massive—with loss of anatomic landmarks and pneumothorax and catheter kinking appear to be the most serious and widely encountered. The use of this technique for more than short “bridging” intervals to another technique is inappropriate because displacement with resultant subcutaneous emphysema or kinking can be lethal. In order to minimize barotrauma, airway patency should be maintained with head extension, jaw thrust, and chin lift by an assistant. For this reason needle jet ventilation is very risky in patients with a spinal cord injury, and provisions should be made rapidly to secure the airway in a more permanent fashion, such as with a surgical approach. In summary, a systematic approach to airway management in the neuro-ICU is necessary and provides a stepwise analysis of the best alternative options to avoid hypoxia and hypoventilation. Furthermore, any algorithm will work best when the physician applies, within the general guidelines of difficult airway management, the technique he or she is most familiar with, thus using the technique with the best chance of success. Confirming Endotracheal Intubation Several methods to confirm tracheal intubation have been recommended.

Visual Inspection of the Airway after Passage of the Tube Despite one’s best efforts, direct observation of the ETT tip and cuff passing through the vocal cords is not always possible, especially in a patient with an anterior larynx or redundant epiglottis. Several other maneuvers can be used to assess proper placement of the ETT. When the use of these maneuvers is rapid and systematic, they do not substantially increase the time to confirm endotracheal intubation. Moisture Condensation into the Endotracheal Tube on Exhalation. Condensation implies humidified gas is being exhaled. Pulmonary Inflation. Chest rise on inflation and bilateral breath sounds with a slight decrease in perceived compliance toward the end of expansion as well as the lack of gurgling sounds in the epigastric area are quite useful for confirmation. This may be somewhat unreliable in the patient who is obese or who has a rigid chest wall. Suction Bulb. Recently, a suction bulb connected to the

proximal end of the ETT has been utilized to confirm tracheal intubation during CPR (Fig. 16-21). If the ETT is properly placed, negative pressure will result in the bulb filling with air. If the ETT is placed into the esophagus, when negative bulb pressure is applied the esophagus will collapse, and the bulb will not inflate. The device is disposable, small, and lightweight. The compressed 75-mL self-inflating bulb is attached to the EET through a standard 15 mm plastic fitting. The biggest advantage of this method is that it does not rely on end tidal CO2 to confirm intubation of the trachea, an advantage in situations of extreme low cardiac output,

Figure 16-20. Manual jet ventilator with pressure regulator, to be connected to a wall oxygen source or to an oxygen tank regulator.

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Management of the Endotracheal Tube after Detected Esophageal Misplacement Once an esophageal intubation is detected, the tube should be left in place if vomitus from a distended stomach is present. The misplaced tube may be used to facilitate suctioning with a large bore catheter. Subsequent attempts at intubation should ideally be performed with the misplaced ETT left in the esophagus. However, the presence of an esophageal tube may interfere with visualization of the larynx or manipulation of the airway in a difficult airway scenario. Thus, the physician in charge must quickly evaluate the risks versus benefits of removal prior to manipulating the tube. Airway suction with a large bore Yankauer should be always available and used if regurgitation of gastric material follows the extubation of the esophagus. Figure 16-21. Syringe (A) and suction bulb (B) to detect esophageal intubation during cardiopulmonary resuscitation.

cardiac arrest, or sudden increase of dead space ventilation (e.g., pulmonary embolism).45,46 Syringe Air Aspiration. The device consists of a 60-mL dis-

posable lightweight syringe. The barrel is connected to a standard 15-mm plastic fitting (see Fig. 16-21). When the ETT is in the esophagus, withdrawal of the plunger will cause the wall of the esophagus to collapse, preventing free aspiration of air. This device shares the advantage with the selfinflating bulb of being reliable even in condition of low cardiac output.47 Detection of Exhaled CO2. The most reliable method of

ensuring tracheal intubation is the presence and persistence of CO2 in gas collected from the ETT. This may be appreciated using a color indicator (more often) or a capnograph. On occasion, in an esophageal-placed tube, a very brief presence of CO2 in exhaled gas may be seen. However, in these cases the CO2 does not persist for more than a few breaths. The interpretation of correct endotracheal intubation in patients with severe reduction of cardiac output or total cardio-circulatory arrest is more difficult. Because the amount of the CO2 exhaled is directly proportional to the cardiac output, it may not be displayed at all in case of total cardio-circulatory arrest or with inefficient CPR. Oxygen Saturation. Oxygen saturation by pulse oximeter is somewhat insensitive, as previous effective oxygenation may delay the time of onset of desaturation, even in the presence of prolonged respiratory arrest. This should be the last maneuver used to evaluate for proper ETT placement.

Alternatives to Bag-Mask Ventilation and Direct Laryngoscopy The Laryngeal Mask Airway in Management of a Difficult Airway The LMA now has a primary role in achieving airway control, oxygenation, and ventilation in an unpredictable difficult airway when endotracheal intubation has failed. Once placed, the LMA may be left in position to provide ventilation and oxygenation. Although only recently introduced, the LMA already has a solid track record of “saves” in the established difficult airway and in specific unpredictable situation situations, such as emergency Caesarian sections, airway trauma, and the newborn infant, with minimal reports of failure.48 The LMA has been invaluable, in our experience, on many occasions when endotracheal intubation was impossible in the neuro-ICU or ED. At this time, the LMA should be considered first among the alternative airway devices to be used in the management of the difficult airway. The presence of known pathology at the level of or above the vocal cords is a contraindication to the use of this airway device because it is normally inserted blindly into the pharynx. However, a recent random survey of 1000 active members of the ASA showed that experienced anesthesiologists (> 10 years in practice, age > 50 years) would consider use of the LMA even in these cases.49 This may be due to the familiarity of the anesthesiologist with the technique, and its relative simplicity to master, compared to the alternatives. No similar data are available for nonanesthesiologist intensivists but we suspect that the “awareness” of the LMA as an alternative emergency airway is rapidly growing among these physicians. The LMA can be considered a temporary airway to facilitate the introduction of an ETT with the aid of an FOB.15 A recently introduced, modified version of the LMA, the LMA-Fastrach, has been developed to solve some of the

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disadvantages of the LMA when it is used to facilitate endotracheal intubation, with or without an FOB.50–53 These limitations include the relatively small caliber of ETT allowed through the LMA (no. 6 mm diameter), the difficulty in passing the ETT cuff through the grill of the LMA, and the possible laryngeal injury caused by an ETT inserted blindly through an off-centered LMA.54 Another modification of the LMA, the LMA-ProSeal, has been designed to limit regurgitation and pulmonary aspiration of gastric contents while the LMA is being used.55–57 Furthermore, it is the first device of this type that specifically allows positive pressure ventilation in patients without spontaneous minute ventilation. The LMA-ProSeal differs from previous versions of the LMA in that it has a rear cuff that improves the hypopharyngeal seal and a drainage tube providing a conduit to the stomach (Fig. 16-22). When the LMA-ProSeal is properly placed (Fig. 16-23), the orifice of the drainage port is aligned with the upper esophageal sphincter. Thus, a standard gastric tube can be inserted blindly into the esophagus to decompress the stomach and allow suctioning of liquid gastric contents. The anti-esophageal reflex potential of the LMA-ProSeal has been studied in cadavers.58 When 40 mL of air was used

r

Figure 16-22. LMA-ProSeal from the front.

Figure 16-23. Schematic profile of the LMA-ProSeal when correctly placed.

to inflate the cuff, the LMA-ProSeal proved to be superior to the LMA in providing protection from esophageal regurgitation, although the LMA-ProSeal was also somewhat more difficult to insert. Protection from esophageal reflux was even more striking when a gastric tube was correctly inserted through the LMA-ProSeal drainage port, advanced distally through the esophagus into the stomach, and placed on continuous suction. The increased protection from esophageal-gastric reflux is not due to higher sealing pressure but rather to the innovative design of the new airway (e.g., a larger and different cuff). In fact, when the pharyngeal pressure from an LMAProSeal is compared with that of the classic LMA, no significant difference could be demonstrated.56 The insertion of the LMA-ProSeal may be facilitated with a removable metal introducer. The presence of an armored tube and a built-in bite block minimizes the chance of tube occlusion or kinking. The LMA-ProSeal has not been used in neurosurgical patients who are critically ill, although its anti-esophageal reflux features and placement above the vocal cords makes it a potentially useful alternative of airway control in the neurosurgical patients needing positive pressure ventilation. At this time, LMA-ProSeal sizes 3 (young adults), 4 (women), and 5 (men) are available. Main Contraindications of the Use of the Laryngeal Mask Airway The LMA offers little or no protection against pulmonary aspiration of gastric contents. However, this complication has been rarely reported even in patients considered at risk.24 The incidence of regurgitation during insertion of the LMA is controversial. The LMA is associated with relaxation of the lower esophageal sphincter through distention of the hypopharyngeal muscles.28 In conditions such as glottic edema, it is possible that the laryngeal mask’s low-pressure cuff will seal around the laryngeal inlet, adapting to the

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edema. Experienced practitioners consider the LMA in selected difficult airway conditions only when fiberoptic bronchoscopy is available. Nonetheless, and we wish to emphasize this, there are no absolute contraindications to the LMA if the alternative is loss of the airway with its lifethreatening associated complications. Role of the Laryngeal Mask Airway in Prehospital Airway Management of the Patient with Neuroinjuries In the United States, paramedics perform airway management in the field. While there is no controversy that control of the airway via an ETT is recommended in patients with GCS score £ 8 or after cardiac arrest, intubation of the severely traumatized patient can often be a difficult task for the paramedics.59 A prospective comparison between LMA and ETT management by paramedic students showed successful first attempt LMA placement 94% of the time, compared with 69% in the ETT group (P < .01). The insertion of the LMA was also statistically faster to detection of end tidal CO2. The same observation was confirmed when respiratory therapists or medical students manipulated the airway.25,60,61 Since the introduction of the LMA, it is anticipated that the success of ventilation and oxygenation of difficult airways in the field will increase.62 For this reason, we believe that the LMA should always be available for EMS providers on the street, and for physicians in the ED and the neuro-ICU as first backup alternative to a failed intubation. Techniques to Establish an Airway with an Endotracheal Tube after Laryngeal Mask Airway Insertion While placement of an LMA in the neuro-ICU can be a lifesaving maneuver, the usual LMA pressure limitation is at 15 to 20 cm H2O. Critically ill neurologic patients often present with abnormal pulmonary mechanics. Associated chest trauma, aspiration pneumonia, and pulmonary edema are often present and can significantly decrease lung compliance. Increased airway resistance can be associated with both cardiogenic and noncardiogenic pulmonary edema, together with decreased lung compliance increasing PIP from 15 to 30 cm H2O, progressively decreasing the tidal volume from 13% to 27%, and increasing gastric inflation from 2% to 35% in patients with LMAs.63 Therefore, as soon as the patient is stabilized and proper oxygenation is provided, the LMA should be replaced with an ETT. The blind passage of an ETT through the LMA has been associated with a low rate of success because the LMA can fail to negotiate the hypopharynx up to 65% of the time.54 Thus, the ETT is most frequently placed through the LMA via FOB. The rate of success in placement of an ETT with this method has been close to 100%.53 There are two limitations to this technique: (1) cricoid pressure cannot be applied as it may further displace the LMA,64,65 and (2) the size of the ETT that can be used is

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limited. The largest ETT that can be placed inside the LMA is no. 3.5 for LMA size 1; no. 4.5 for size 2; no. 5.0 for size 2.5; and no. 6 cuffed for size 3, and 4, and no. 7.0 cuffed for size 5. In adults, we recommend using a small caliber Rae tube, because it is approximately 3 to 5 cm longer than the standard ETT and is thus easier to pass into the trachea. We use a bronchoscopy elbow adapter on the ETT to allow ventilation and oxygenation during placement of the ETT using the fiberoptic technique (see Fig. 16-13). Several modifications of this technique have been described, each using the removal of the laryngeal mask airway after insertion of a gum elastic bougie, a tube exchanger or a guidewire. The recent introduction of the LMA-Fastrach greatly facilitates endotracheal intubation in patients with difficult airways. The LMA-Fastrach is a curved short stainless steel tube with an LMA and guiding handle (see Fig. 16-12).50–52 In a study of 31 patients, all modified Mallampati class III or IV, the success rate with blind intubation through use of the LMA-Fastrach was 97%, greater than when compared with the LMA.52 In some patients, the LMA-Fastrach can be placed with local anesthesia in the conscious state.66 The LMA-Fastrach is available in sizes 3, 4, and 5 corresponding respectively to small, normal, and large adult. The largest ETT that can be placed through LMA-Fastrach is a number 8.0 ID; it can be placed both blindly or with an FOB. For safety, we recommend the use of the FOB if the instrument is available when an ETT is placed through the LMAFastrach in the hospital. The LMA-Fastrach is available with a cuffed silicon ETT, giving it the advantage of not retaining any significant curvature after passing through the LMA, thereby limiting the possibility that the tip of the ETT will deviate from the vocal cords. To summarize, the LMA-Fastrach is an improvement in design of the LMA, particularly adapted to management of patients with difficult airway. Experience with this device is accumulating rapidly in both operating rooms and emergency departments. It will likely find increased use in the field by paramedics and in the intensive care unit. Use of the Combitube in the Management of the Difficult Airway The Combitube, an evolutionary step in the design of the esophageal obturator airway,67 provides a complete seal of the upper airway, and therefore can be used in patients at high-risk of regurgitation and aspiration of gastric contents. At the time of this writing, the main indication for the Combitube has been in the rapid establishment of an airway during cardiopulmonary resuscitation (CPR).68,69 However, this device has not found widespread use in North America, mainly because it is relatively expensive (approximately $200) and available only as a disposable item. The Combitube (Fig. 16-24) is essentially a double lumen tube that is inserted blindly through the mouth into either the esophagus or the trachea; most of the time (approximately 85%), blind insertion will result in an esophageal

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Neurointensive Care: General Issues version has a higher chance of success and a lower risk of damaging the hypopharynx and the esophagus.72,73 The Combitube can be inserted safely in patients with cervical spine injuries because flexion of the neck is not required. However, it is not well-tolerated in conscious patients with a strong gag reflex. The device has been used as a temporary means of airway control while FOB placement of an ETT through the nose is carried out, and for airway maintenance during percutaneous dilation tracheostomy.74,75 While the Combitube has been successful to rescue the airways in prehospital and in-hospital patients, its insertion provides a great deal of sympathetic stimulation caused by its bulkiness and the presence of a large cuff in the pharynx. While its possible role as a rescue technique of the airway in the neuro-ICU has not yet been defined, the Combitube can provide an effective way to control the airway after failed rapid sequence intubation or when a cervical collar is in place.76–78

Figure 16-24. End-on view of the Combitube, detailing the esophageal and tracheal lumens.

intubation. Both lumens are color-coded: blue for esophagus (1A), clear for trachea (2A). A proximal latex esophageal balloon (7, inflated first after placement) is filled with 100 mL of air and a distal plastic cuff (6) with 10 to 15 mL of air. These cuffs allow good seal of the hypopharynx and stability in the trachea or esophagus. The esophageal lumen is closed distally (4) and perforated at the hypopharyngeal level with several small openings (3). The trachea lumen is open distally (5). The Combitube has the same limitations as the LMA, and thus may not be easily inserted in patients with hypopharyngeal pathology. In addition, although its safety record has been good, it can potentially exacerbate preexisting esophageal pathology such as with a tumor or esophageal varices.34 Until recently, the Combitube has found its widest use in prehospital cardiac arrest in which paramedics managed the airway.69 Direct laryngoscopy is unnecessary and there is minimal risk of aspiration. The Combitube has also been used with success in managing difficult intubations in simulated combat situations70 and in obese pregnant patients,71 where risk of aspiration is high. The Combitube is available in a standard size and an SA (small adult) version. The most common reason for failure to ventilate with this device is advancement of the device too deeply, so that the perforated pharyngeal tube section has entirely entered the esophagus. Pulling the device back 3 to 4 cm usually resolves the problem. The use of the SA version, for patients under 5 feet in height, is recommended by the manufacturer to minimize this problem. While our experience with this device is limited, that of others seems to suggest that the smaller

Providing Ventilation after Placement of a Transtracheal Airway Transtracheal ventilation can be a quick and inexpensive way to solve the equation of a “cannot ventilate, cannot intubate” difficult airway, but it contains many hidden dangers. The oxygen pressure from the wall is normally 50 psi. A direct connection from the wall to the transtracheal catheter is unacceptable, because it may be associated with a large tidal volume breath and barotrauma. Additionally, whipping and/or displacement of the catheter in subcutaneous tissue may occur, with consequent massive subcutaneous emphysema. Several commercially available down regulators of wall oxygen pressure are available to titrate gas flow through a transtracheal airway.79 In the ICU, the source of high-pressure oxygen is usually a wall flow meter turned up to 15 to 20 L/min (“flush”); as an alternative, an oxygen tank with a dual stage regulator can be used. Low-flow regulators usually necessitate a longer inspiratory-to-inspiratory ratio. Although transtracheal ventilation may be temporarily lifesaving, adequate control of ventilation is often impossible and we recommend establishing a surgical airway as soon as possible after placement of the catheter. When transtracheal jet ventilation (TTJV) is the only choice available, it should, if at all possible, be performed by two people—one to hold the catheter in place and the other to titrate the oxygen flow. The driving pressure of the regulator should be titrated slowly up from 5 psi to maintain a steady chest rise (1 to 2 cm) at each inhalation. Ventilation should be provided starting with an approximate inspiratory time (Ti) of 0.5 seconds, maintaining an I : E ratio of at least 1 : 1 to minimize air trapping.80 After this procedure has been initiated, a third assistant may be needed for the placement of an oral airway to maintain patency of the upper airway. In fact, transtracheal ventilation without a patent upper airway inevitably results in progressive air trapping and

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barotrauma.81–85 Energetic jaw thrust and chin lift is also recommended, but it should be applied only if no neck trauma is involved. We cannot overemphasize that in TTJV, the catheter must be kept steady and aimed slightly downward to avoid kinking at the posterior wall of the trachea. Accidental dislodgment of the catheter into the subcutaneous space or perforation of the posterior wall of the trachea will result in several liters of oxygen being injected into the subcutaneous tissue and mediastinum in a fraction of a second, distorting all landmarks of the neck. Aspiration of gastric or oropharyngeal secretions during TTJV is not well studied, and is somewhat controversial; but it is expected to be high in unconscious neurologically injured patients. While we have used TTJV, our preference in an airway disaster in which an LMA or Combitube is inappropriate or failed, is the immediate use of the Cook cricothyroidotomy kit, or a surgical cricothyroidotomy with insertion of a number 5 or 6 ETT through the cricothyroid membrane. Although accidental perforation of the posterior tracheal wall has been described,86 cricothyroidotomy has a long track record of success both in trauma patients and inhospital emergency use, and ready-to-use kits should always be available in the neuro-ICU.87–91 The Role of the Rigid Fiberoptic Laryngoscope, Lighted Stylet, and Retrograde Intubation Each of these three devices may be used in a “can ventilate, can’t intubate” situation. In general these techniques apply to the neurologically injured patient in the more controlled operating room environment and have minimal applicability to the neuro-ICU. However, they can be selectively used by airway experts as a personal preference. Because each has a specific clinical application, they will be analyzed separately. Rigid Fiberoptic Laryngoscopes. The Bullard laryngoscope,

the UpsherScope, and the Wu scope have each been used as aids to gain access to the trachea in the patient with limited mouth opening or neck extension, morbid obesity, or a hypopharyngeal mass. The use and application of these devices in the difficult airway algorithm is still controversial and specific training similar to fiberoptic endoscopy is needed to acquire proficiency. The Bullard laryngoscope is more commonly used than the other rigid fiberoptic laryngoscopes, and is available in three sizes: pediatric (newborn to 2 years), pediatric long (3 to 10 years), and adult (older than 10 years). Illuminating Stylet. The illuminating stylet (lightwand) uses

the principle of transillumination of the trachea and soft tissue to blindly guide the stylet beyond the vocal chords.92,93 This technique differs from the use of a gum-elastic bougie, because a blind intubation can be achieved with minimal mouth opening, relying on the transillumination of soft

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tissue. Indications for the device are a hypoplastic mandible, prominent upper incisors, restricted cervical spine movement or spinal immobilization, glossomegaly, and restricted access to the airway (e.g., presence of halo frame). This technique is contraindicated in any condition where pathology of the upper airway is known or suspected. Retrograde Intubation. This method can be achieved with

the use of a long, J-tip guidewire (usually 100 to 120 cm in length), a flexible epidural catheter, or a kit such as the Retrograde Guidewire Kit (Cook Critical Care, Bloomington, IN). Known pathology above or below the vocal cords is a contraindication to this technique. In the retrograde technique, the guidewire is inserted through the cricothyroid membrane with the same technique as cricothyroid puncture described for the dilational cricothyroidotomy. However, once inserted through the cricothyroid membrane, the needle is aimed at an upward angle of approximately 45 degrees. The wire is passed cephalad through the needle and, once secured through the mouth, may be used as a direct guide for the ETT or indirectly through use of an intubating stylet. As described with other blind techniques, possible problems on insertion include failure to proceed beyond the vocal chords because the tube may impinge on the right vocal cord. Maneuvers recommended to overcome this problem include 1. Twisting the ETT 90 to 180 degrees counterclockwise. 2. Gentle direct laryngoscopy to displace the tongue anteriorly. 3. When a simple guidewire or an epidural catheter are used, threading the guidewire through the Murphy eye end of the ETT instead of the distal opening will allow an additional 1 cm of the ETT to pass beyond the vocal cords and facilitate the passage of the tip of the ETT in the trachea (Fig. 16-25). 4. A modification of this technique provides for passing the J-wire, once retrieved from the oropharynx, into the suction port of a fiberoptic bronchoscope and then advancing the ETT through the FOB, under direct vision. Use of the Patil-Syracuse mask allows ventilation to be continued during the procedure.

Specific Airway Problems in the Neurointensive Care Unit Airway Management and Central Nervous System Trauma Treatment of patients with blunt and closed (CHI) or penetrating head injury requires specific skills. Elevated ICP can severely depress the level of consciousness and rapidly evolve to a herniation syndrome or be associated with decreased function of other vital organs. Some form of respiratory failure is associated in 20% of patients with isolated head

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Figure 16-25. Retrograde guidewire passed through the tip of the ETT (A) and the Murphy eye (B). Position B facilitates the passage of the tip of the ETT beyond the vocal cords.

injury, regardless of the GCS.94 Overall, respiratory failure is directly responsible for 25% of all surgical deaths associated with CHI and is a contributing factor in about 50%.94 Hypoxia (PaO2 < 60 torr) is the most powerful determinant of comorbidity-related outcome from severe head injury, along with hypotension (systolic blood pressure <95 mm Hg). In fact, approximately 90% of adults suffering brain injury show some evidence of hypoxic ischemia at autopsy.94,95 Characteristically, autopsies of patients affected by posttraumatic severe intracranial hypertension can be associated with medial occipital necrosis from posterior cerebral artery compression against the tentorium cerebelli, and boundary zone ischemia between anterior and middle cerebral arteries. However, in many cases, secondary brain insult from hypoxia (systemic insult) cannot be differentiated from intracranial hypertension (intracranial insult). Therefore, effective management of the airway and respiratory failure is essential in these patients.96 Traumatic brain injury is often associated with respiratory dysfunction, hypoxia, and hypercarbia. Furthermore, CHI patients may demonstrate several abnormal patterns of breathing. Central neurogenic hyperventilation is the most common breathing pattern associated with head injury. However, regular cycles of hypercapnia and apnea (Cheyne-Stokes), ataxic or chaotic breathing, and

central apnea may all be observed after head trauma. While abnormal respiratory patterns are usually seen only with a GCS score < 8, specific patterns of breathing are unreliable at predicting the type and severity of brain damage. Absence of airway (gag and cough) reflexes and intermittent obstructive apnea in a stuporous or comatose patient are common and require immediate control and protection of the airway. The onset of acute hypoxia in patients with head injury may also be secondary to other respiratory dysfunction. Acute respiratory failure can be secondary to direct pulmonary injury in the setting of blunt chest trauma. Pneumonia secondary to depressed gag and cough reflexes can be particularly severe if aspiration of particulate matter or gastric contents with a pH of < 2.5 and volume of > 25 cc is involved; it may rapidly lead to ARDS and severe hypoxia. Even when the airway is immediately secured, pneumonia can be common in these patients, occurring within the first week of hospitalization, contributing to increased ICU hospital stay, and impacting long-term outcome. In selected cases, patients with mild alteration of mental status can be observed in the ICU without intubation, while maintained in a 45-degree head up position, providing aggressive control of gastric pH with H2 blockers and/or proton pump inhibitors, aggressive pulmonary toilet, and frequent oropharyngeal suctioning. Hypoxia in patients with head injury is common in the ICU and can also be seen without aspiration. Neurogenic pulmonary edema can be observed shortly after the brain insult and is probably caused by a generalized sympathetic response. A massive catecholamine discharge secondary to the traumatic stress causes transient peripheral vasoconstriction, systemic arterial hypertension, pulmonary hypertension, and altered pulmonary capillary permeability. However, despite the documented increase of extravascular lung water in approximately 40% of patients with head trauma,97 the existence of a real neurogenic pulmonary edema is still debated because it is possible that many of these episodes can be related to negative pressure pulmonary edema from intermittent airway obstruction due to altered mental status.98 Finally, hypoxia can be due to pulmonary dysfunction from fibrin, pulmonary microemboli, and a large thromboembolism. In all of the preceding conditions, rapid control of the airway and correction of hypoxia is fundamental to minimize a secondary brain injury. Emergency airway management techniques in patients who have sustained severe head injury should be quick and effective, minimizing the adverse effect of intubation, and permitting rapid and effective management of the elevated intracranial pressure and/or associated injuries. Nevertheless, endotracheal intubation in the patient with head injuries should avoid worsening a potentially injured cervical spinal cord. While effective resuscitation is taking place, pre-oxygenation with cricoid pressure is always recommended. Direct stimulation of the hypopharynx by direct laryngoscopy is expected to increase the intracranial pressure through release of endogenous

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catecholamines and, in the case of succinylcholine use, muscular fasciculation.99 Lidocaine at 1.5 mg/kg has been shown to minimize the increase of intracranial pressure in response to intubation and blunt the effect of airway suctioning.99–101 The most common hypnotic agents used in airway manipulation of the patient with head injury are thiopental and etomidate. Thiopental is an ultra short-acting barbiturate often used for induction of general anesthesia and associated with a decrease in cerebral blood flow, cerebral metabolic rate, and intracranial pressure. While these features are desirable on intubation of the patient with poor intracranial compliance, the use of thiopental may be associated with unacceptable hypotension in patients who are hypovolemic or affected by myocardial dysfunction, via the mechanisms of vasodilatation and myocardial depression. Thiopental is administered at a dose between 2 to 4 mg/kg. Dosage can be modified to 1 to 2 mg/kg in the elderly or when cardiac dysfunction and relative hypovolemia are preexisting conditions. Etomidate is a hemodynamically better tolerated induction agent that has been extensively used in patients with increased intracranial pressure. Succinylcholine remains the most rapid-onset agent to induce paralysis to facilitate intubation. Remarkably, ACh-like activity of succinylcholine has the potential to dangerously increase the ICP.102,103 While pretreatment with a small dose of intravenous pancuronium (0.01 to 0.03 mg/kg) has been described to attenuate the ICP increase,104 we strongly discourage its use because it can be associated with unpredictable and potentially life threatening muscle weakness and hypoxia. Alternatively, small doses of relatively shortacting agents such as rocuronium and mivacurium have been used successfully in patients without difficult airways. Ketamine has been shown to be associated with increased cerebral blood flow, oxygen consumption and intracranial pressure and is therefore not recommended.105 Endotracheal intubation in patients with head trauma can cause significant hemodynamic response. Maintenance of the cerebral perfusion pressure of at least 70 mm Hg is always desirable and associated with a good long-term cerebral outcome.96 However, in the context of a disrupted blood-brain barrier, uncontrolled increase of arterial blood pressure may potentially increase cerebral edema or worsen the intracranial pressure.106 Three classes of drugs have been used to blunt hypertensive response to intubation: (1) intravenous lidocaine (1.5 to 2 mg/kg); (2) beta-blockers, such as the ultra shortacting esmolol (0.5 to 2.0 mg/kg) or mixed alpha/beta blocker, labetalol (0.1 to 1.5 mg/kg); (3) opiates (morphine, 2 to 5 mg or fentanyl, 3 to 5 mcg/kg IV). Airway Management and Spinal Cord Injury The incidence of spinal cord injury in patients sustaining major trauma is 1.5% to 4%, and up to 10% in high-speed motor vehicle accidents, most often from fracture dislocation.107,108 Emergency management of the airway may be

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necessary due to diaphragmatic failure from high cervical spine injury, associated head injury, or hemodynamic instability. Although intubation is usually performed in the field, the patient may become hypoxic on arrival to the ED or in the neuro-ICU. Prompt assisted ventilation should be initiated with an Ambu or Mapleson D circuit connected to a clear plastic mask. Cricoid pressure should be applied to prevent gastric insufflation or passive regurgitation. While anteroposterior pressure is held on the cricoid cartilage, gentle posteroanterior support should be provided with the assistant’s other hand at the dorsal aspect of the cervical spine to prevent inadvertent movement of a potentially injured cervical spine. The route of intubation is still controversial. Nasal intubation has been advocated to eliminate any movement of the neck. However, nasal intubation is unfeasible and possibly dangerous if the patient is intermittently apneic or has a basilar skull fracture, profuse bleeding from multiple facial fractures, or is simply combative and uncooperative. If oral intubation is attempted, stabilization of the spinal cord is necessary. The absence of radiologic evidence of cervical spine trauma should not obviate stabilization of the spinal cord, because significant injuries can be missed in up to 20% of the cases of patients with negative cervical spine series. The anesthesiology group of the Shock Trauma Center at the University of Maryland has described the technique of in-line axial stabilization in detail.109 In their experience, after a brief evaluation of the airway and pre-oxygenation and/or mask ventilation with cricoid pressure and in-line axial stabilization, oral intubation has always been performed easily and without worsening of the spinal cord function (Fig. 16-26). The need for cervical spine immobilization on intubation in patients with suspected spinal cord injury has been challenged.110–112 A recent retrospective study comparing spinal cord injury rate in two different hospitals (in two different countries), one with and one without an out-of-hospital spinal immobilization protocol, showed more neurologic disability overall in the immobilized patient.112 While the group population and the logistics of the patient care cannot be entirely compared (United States vs. Malaysian emergency medical systems), such a provocative study indicates the lack of biomechanical data showing that spinal immobilization could be sufficient to prevent more injury of the cord. Despite the lack of uniform approval of spinal cord immobilization protocols on on suspected injury, we believe that the use of the sniffing position to improve laryngeal view during tracheal intubation can be extremely dangerous and should be avoided in any case. Neurologic deterioration after endotracheal intubation is difficult to evaluate in trauma patients and is probably underreported. To our knowledge, only one case of a neurologic deterioration associated with airway management in a patient with cervical spine injury has been published.113 This case described new paraplegia that was noticed postoperatively after a routine approach to airway management that turned unpredictably

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Figure 16-26. In-line axial stabilization technique for oral intubation in the patient with cervical spine trauma.

difficult and required multiple laryngoscopes and, eventually, cricothyroidotomy. The new onset of paraplegia was retrospectively attributed to an unrecognized disruption of the anterior longitudinal ligament at the C6 to C7 level. Several alternatives have been evaluated to gain access to the airway in patients with suspected or established spinal cord injury. While the LMA has been proven easy to use in case of difficult intubation, including class III and IV airways, and laryngoscopy grades II through IV, its use in patients with cervical spine injury needs a note of caution. In fact, it has been noted that both the LMA and intubation LMA (ILMA; Fast-Trach), once placed into the airway, typically exert pressure against the tissue overlying the C2 to C6 vertebral bodies. A prospective study in fresh cadavers showed that the cervical pressure generated by laryngeal mask devices can produce posterior displacement of a normal cervical spine.114 It is anticipated that such displacement would be greater in the injured cervical spine. In particular, the ILMA with its stiff metal arm greatly increases vertebral pressure at the C2 to C3 level during insertion and positioning. This pressure can be almost totally relieved by forward handle elevation. This same observation was reported when the standard LMA was used, but the compression pressure was more limited. Although the limitation of this study on fresh cadavers is clear, we believe that use of a laryngeal mask device should be recommended only when a difficult airway is anticipated or encountered in an unstable cervical spine, and no other viable option is present. If ILMA placement is planned in a patient with cervical spine injury,

we recommend removal of the anterior portion of the collar, forward displacement of the ILMA and in-line manual axial stabilization. In fact, when the neck collar is in place, the strap under the chin typically lifts up and tips the larynx anteriorly, making intubation by ILMA very difficult or impossible.115,116 The esophageal tracheal Combitube has been used to facilitate airway control in trauma patients with possible cervical spinal injury, and has been considered an effective prehospital airway device, a backup to the ETT, and permanent airway.76–78,117 In a prospective randomized study, the Combitube was used in healthy patients undergoing elective surgery who volunteered to wear a rigid cervical collar upon induction.118 Successful insertion with the Combitube was achieved only in 33% of the patients when the blind technique was used. However, 75% of the failures could be intubated into the esophagus with the help of a MacIntosh laryngoscope on the second attempt. Pharyngeal trauma consisting of tears in the pharyngeal mucosa was observed in 47% of patients. For this reason, we believe that elective use of the Combitube in a patient whose neck is immobilized in a rigid cervical collar should be limited to out-ofhospital management, when routine use of the ETT is unfeasible or has failed, and there is a need to provide ventilation while protecting against aspiration.118 As an out-ofhospital airway device, the Combitube can be considered an evolution of similar devices such as the esophageal obturator airway and the pharyngeal tracheal lumen that have been used extensively in a prehospital arena for many years to

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ventilate the lungs, providing protection against gastric regurgitation. Another interesting application of the Combitube has been its use in combat trauma airway management, by the U.S. Navy SEALS, in a trauma scenario with cervical-spine–injured mannequins. The uniqueness of this airway device is its efficacy when visibility conditions are precarious, as under fire in combat conditions. It is reasonable to think that in the future, patients with head or cervical spine injuries could be handled more frequently with this device during combat situations.119 In summary, despite its good track record in prehospital airway care, there is little indication for the use of the Combitube in the neuro-ICU at this time. We strongly recommend that it be exchanged for a definitive airway on transfer to the ICU from the field or ED. Rigid fiberoptic laryngoscope, lighted intubated stylet, and fiberoptic bronchoscopes have all been extensively described in the elective tracheal intubations of the cervical spine injured patients. None of these alternative techniques, when used in elective conditions, has been shown to be optimal.120,121 Our preference is to use oral fiberoptic intubations after proper preparation, only when the patient is awake and cooperative. The track record and safety of conscious tracheal intubation in patients with cervical spine injury has been impeccable and this technique should be considered the gold standard to minimize worsening cervical spine injury.122 The technique of airway anesthesia, topical versus multiple nerve blocks, does not differ in terms of efficacy and safety,123 and the few cases of complications noted during manipulation of the airway are probably secondary to oversedation, inadequate local anesthesia, or the presence of an extremely uncooperative patient.124 No matter what the planned approach to establish the airway in these patients, manual in-line stabilization should always be used. An exception to this rule seems to be represented by patients with gunshot wounds to the head, whose cervical spine clearance cannot be determined either clinically or radiographically. A recent series of 215 patients showed that no indirect spinal injury was associated with gunshot wounds to the head and that cervical spine immobilization was unnecessary and contributed to complications in airway management.125 The airway management of penetrating neck injuries needs special consideration.126 The incidence of trachealbronchial injury in patients with penetrating neck trauma ranges from 10% to 20%, with a mortality rate of up 33% as a direct result of airway complication.127 Ideally, endotracheal intubation should be achieved early with fiberoptic bronchoscopy to avoid further injury by placement of the ETT. Blind nasal intubation should never be performed and cricothyroidotomy should be avoided in the presence of an anterior hematoma or performed only in the presence of a surgeon able to achieve immediate control of the bleeding, if necessary. The use of muscle relaxants deserves early consideration because cough, gag, or the Valsalva maneuver may severely worsen vascular airway injury, but needs to be

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balanced with the feasibility of the intubation. Finally, any air bubbling through the wound should be immediately treated using Vaseline gauze to cover the injured area, to avoid massive mediastinal and subcutaneous emphysema. While immediate surgical exploration of a penetrating neck trauma is now being challenged by a more conservative selective approach, the presence of exsanguinating hemorrhage or expanding hematoma unresponsive to resuscitative measures demands immediate surgical exploration. In any case, the presence of cervical spine injury adds a formidable challenge to airway management in the trauma patient. While the approach to the algorithm remains debated in the literature, it is clear that the skill and personal experience of the airway operator are the most important aspects in decision-making and outcome. Airway Management and Elective Neurosurgical Procedures: Special Problems Intracranial Vascular Procedure Hemodynamic control during intubation is a fundamental goal of the intensivist who plans to manipulate the airway in patients with intracranial vascular pathology. The threshold of blood pressure tolerance is somewhat higher in arteriovenous malformation (AVM) than in subarachnoid hemorrhage (SAH). While hypertension in an AVM is usually inconsequential, because of the presence of ectatic vessels at low pressure,128,129 any change in stress on the vascular wall of an intracranial aneurysm that bled may trigger a disastrous recurrent hemorrhage.130 An arterial line should be placed before manipulation of the airway and special attention should be focused to maintain systolic blood pressure within baseline limits. Carotid Endarterectomy The management of the difficult airway in this condition needs to take into consideration issues that can be summarized under three major headings. The use of succinylcholine in patients with previous stroke and major neurologic injury scheduled for CEA should, in general, be avoided because the drug has been associated with increased release of potassium due to up-regulation of skeletal neuromuscular receptors.131,132 A consistent time period between onset of the stroke and the hyperkalemic response to succinylcholine is not well established. Because alternative nondepolarizing muscle relaxants are available, mivacurium and rocuronium should be considered when in doubt. The frequent association between carotid arteriosclerotic disease and coronary disease, including left ventricular systolic and diastolic dysfunction, should be considered. While the general recommendation is to maintain mean arterial pressure within a 20% range of the baseline pressure, careful attention should be focused on avoiding severe blood pressure swings on intubation. Beta-blockers are indicated to reduce myocardial oxygen demand. Only short-acting

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beta-blockers (esmolol) should be considered in patients with marked left ventricular dysfunction (left ventricular ejection fraction <40%). Airway manipulation may be necessary on an emergent basis in the neuro-ICU, recovery room, or ward when an expanding wound hematoma compromises the patency of the airway. Surgical manipulation of large neck vessels, intraoperative use of heparin, and the presence of a close anatomic relationship between the carotid artery and the trachea put these patients at high risk for airway stenosis due to a wound hematoma.133 In some situations, CEA patients with normal ventricular function and nonsignificant coronary artery disease can be scheduled for direct admission to the ward after surgery. While the wound hematoma usually forms within three hours from the end of the operation, we recommend observation in the recovery room for up to six hours before transferring the patient to the surgical ward. The rapid formation of a wound hematoma is often an airway emergency. Physician vigilance and awareness of the problem are the keys to prevent a possible airway disaster. Worsening incisional pain and obvious wound swelling require immediate attention. Quick opening of the wound should be considered even in absence of the surgeons. If neck re-exploration is planned, an immediate direct laryngoscopy should be performed after rapid application of a topical anesthetic to the airway to evaluate the feasibility of a regular induction. When the patient is already symptomatic with dyspnea and/or stridor, rapid application of 4% lidocaine to the airway and conscious oral intubation is the safest choice. In any case where a re-exploration of the wound hematoma is planned, a surgeon with expertise in emergency tracheostomy or cricothyroidotomy should stand by as the patient is being intubated. A tracheostomy kit and a difficult airway cart should be available at bedside.

The Acromegalic Patient Abnormal airway anatomy is common in the acromegalic patient and hypophysectomy is a common neurosurgical procedure requiring postoperative admission to the ICU. Several acquired modifications of bone and soft tissue can make an endotracheal intubation very challenging.134 Anatomic abnormalities interfering with endotracheal intubation include prognathism, macroglossia, and redundant soft tissue at the lips, epiglottis, and pharyngeal mucosa. Reduced mobility of the vocal cords and cricoarytenoid cartilage, as well as cervical spine fibrosis may interfere with a direct laryngoscopy. Subglottic narrowing can be suspected in patients with a history of hoarseness or stridor. When the intubation is elective, a conscious fiberoptic technique should always be considered first in these patients. A backup technique to endotracheal intubation should be readily available to control this potentially difficult airway.

Patients with a Head Frame The presence of a head frame (halo) represents a formidable obstacle to direct laryngoscopy. Elective manipulations of the airway in these patients should always include conscious fiberoptic intubation. A well-stocked difficult airway cart must be immediately available, as well as an extra pair of expert hands and a neurosurgeon geared with the proper tools for quick removal of the frame, if necessary. Once again, conscious intubation should always be considered first, if there is opportunity. The Pediatric Neurosurgical Patient Severe abnormality of both intracranial and extracranial structures interfering with airway management have been described in approximately 60 congenital syndromes associated with craniofacial defects. Airway management of these patients is especially difficult because some of these syndromes have associated increased ICP and congenital heart disease. Management of the airway in these patients should be limited to anesthesia personnel with special expertise in pediatric neuroanesthesia and in-depth knowledge of the neurologic features of the congenital disease. Airway Management in Patients with Neuromuscular Disease Respiratory muscle weakness, alterations of respiratory system mechanics, and impairment of central control of respiration can all be associated with respiratory failure requiring airway manipulation and admission into the neuro-ICU. Several noninvasive alternatives are available to provide positive pressure ventilation in a patient with neuromuscular diseases—all using special airway devices.135 Three different devices are commonly used: (1) a mouthpiece with or without a lip seal, (2) a nasal mask, and (3) a full facemask. Generally, the use of noninvasive positive pressure ventilation results in effective ventilation if the patient cooperates, and it may allow avoidance of a tracheostomy. However, common contraindications exist, such as co-existing severe lung disease where secretions are a constant problem, altered mental status, lack of cooperation, poor oropharyngeal muscle strength, uncontrolled seizure disorder, history of severe esophageal regurgitation, recent upper GI surgery with intestinal anastomosis, and any orthopedic condition interfering with placement of the device. In all these cases the patient will usually require a tracheostomy and longterm mechanical ventilation.

Extubation of the Difficult Airway The percentage of patients requiring re-intubation in the neuro-ICU following tracheal decannulation is not known. However, it is reasonable to consider that altered mental

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status can increase the rate of recurrent respiratory failure after extubation. Among other reasons, neurosurgical patients have a poor ability to handle secretions and increased work of breathing. It is known that re-intubation of patients with a difficult airway carries a high rate of complications.136 Therefore, when tracheal extubation in a patient with a history of difficult intubation is anticipated, a plan is necessary to minimize risk to the patient of needing to be re-intubated. The risk factors for difficult extubation are summarized (Table 16-5).137 In complex airways, we most frequently use the Cook disposable 11Fr reintubation catheters, placed through the ETT as the ETT is removed. The catheter is taped into position the same distance from the alveolar ridge of the upper incisors as was the ETT. If necessary, the one-time use of aerosolized 4% lidocaine (3 to 4 mL) may increase tolerance to an airway exchange catheter, without compromising airway reflexes or increasing the risk of pulmonary aspiration.138 If reintubation is necessary, the use of a laryngoscope to displace the tongue and soft tissues forward and facilitate the passage of the tube into the hypopharynx may be needed. A common problem in replacing the ETT is due to impingement of the tube on the right vocal cord. This is usually offset with a gentle counterclockwise rotation of the ETT between 90 and 180 degrees, better lubrication of the ETT, and/or gentle anterior displacement of the tongue with a laryngoscope. Before removal of the airway exchange catheter, successful endotracheal intubation is confirmed with an end-tidal CO2 detector connected to the ETT by a swivel bronchoscopy adapter.

Table 16-5  Risk Factors for Difficult Extubation • Known difficult anatomy confirmed on intubation • Any patient with an unexpected difficult airway on intubation • Airway edema secondary to surgical manipulation or massive volume resuscitation • Prolonged prone position • Tongue swelling • Cervical immobility or instability • Head frame • Morbid obesity (body mass index > 40) • Altered mental status, even in the presence of strong gag reflex • Posterior fossa surgery and brainstem surgery • Any condition where standard extubation criteria cannot be evaluated • Prolonged mechanical ventilation (> 2 weeks) • Copious amount of tracheo-bronchial secretions in patients without brisk cough reflex • Residual analgesia and/or anesthesia post surgical procedure • Residual neuromuscular paralysis and respiratory weakness • Accidental extubation

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Accidental Extubation in the Neurointensive Care Unit Accidental extubation in the ICU can be secondary to uncontrolled agitation or inadvertent displacement of the ETT during patient positioning or transfer. Proper taping of the ETT minimizes accidental extubations. Cloth tape can be used in bearded patients or those with thick mustaches. Adhesion to the skin can be maximized by drying the skin with an alcohol solution and/or applying benzoin at the site where the ETT is taped to the skin. One should pay attention to protecting the eyes or a fresh wound during this procedure, because eye and wound contact with benzoin may result in painful corneal irritation or incisional pain, respectively. Intermittent use of an antisialagogue such as glycopyrrolate can reduce exaggerated orotracheal secretions and loosening of the tape. Trimming or shaving of facial hair may be necessary to facilitate the adhesiveness of the tape. To minimize loosening of the edges of the cloth tape due to the amount of secretions, oily skin, or sweat, the ETT is commonly secured with a tape passed circumferentially around the neck. In doing so, one should pay attention not to tighten the tape to a degree that might interfere with venous return from the head. In fact, the consequences of passive venous congestion secondary to compression of the internal jugular veins may be disastrous in patients with elevated ICP. Accidental extubation of the trachea in the neuro-ICU is an airway emergency by definition, because many of these patients have severe underlying respiratory dysfunction and/or altered mental status. For this reason, the armamentarium needed to successfully manipulate the airway in a “cannot intubate cannot ventilate” situation, after “selfextubation,” should be promptly available in both the operating rooms and the neuro-ICU. Despite the presence of a well-stocked difficult airway cart available in the ICU, the intensivist without experience in emergency tracheostomy should immediately seek the help of colleagues from anesthesiology or surgery. Criteria for and Timing of Elective Tracheostomy in the Neurointensive Care Unit If the patient does not fulfill the criteria for safe extubation, a tracheostomy should be planned. Indication and timing of tracheostomy in the neuro-ICU patient may differ from those in other ICUs.139 Catastrophic neurologic problems requiring neuro-ICU admission are often associated with severe respiratory failure. Pulmonary infection as a result of aspiration or nosocomial infection is common, and concurrent factors include severely altered mental status, the inability to clear secretions, poor cough reflex, or continuous tracheal trauma secondary to severe agitation while on mechanical ventilation. Timing of extubation in the neuro-ICU can be difficult to evaluate and recurrent respiratory failure after extubation

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is common due to fluctuating mental status and airway reflexes. Furthermore, central hyperventilation and CheyneStoke breathing are common in these patients and may be misinterpreted as a clinical index of increased work of breathing, delaying extubation. While the early application of elective tracheostomy can raise concerns of unnecessary surgical procedures in subjects with the potential for rapid neurologic recovery, a recent retrospective study in neuro-ICU patients, mostly suffering from traumatic blunt injury or intracerebral or subdural hemorrhage, showed a rate of re-intubations of 22% and an increased ICU and hospital length of stay. Interestingly, one patient who underwent early tracheostomy (within 7 days) had had lower ICU length of stay (11.7 vs. 16.8 days) when compared with the more traditional 2 to 3 weeks postintubation, despite a worse GCS score (5 vs. 8). All the early tracheostomized patients were weaned from mechanical ventilation within 48 hours of tracheostomy.139 Another possible advantage of early tracheostomy is decreased laryngeal injury, commonly found in 6% of the patients after intubation for more than 5 days.140 While a tracheostomy greatly facilitates handling of the airway and weaning from mechanical ventilation, the procedure itself has a small but well-defined morbidity when performed in critically ill patients.141–144 Overall timing of tracheostomy is still debated in the surgical literature, but a conservative approach to airway management is always recommended when feasible. Medical personnel with expertise in management of conventional and alternative airway devices should be immediately available.

Exchanging the Endotracheal Tube As a general rule, the ETT should be exchanged only when strictly necessary. Ineffective pulmonary toilet due to small ETT size or inability to perform positive pressure ventilation due to ETT balloon rupture are the most common indications. Tachypnea from increased imposed work of breathing due to small ETT size may be compensated for through the appropriate use of pressure support ventilation.145 However, one should differentiate this clinical picture from central hyperventilation due to neurologic disease. An alternative to improve safety of an airway-catheter ETT exchange is to place a second ETT via FOB. With this procedure, the balloon of the in-place, but defective defective ETT is deflated and an ETT-loaded pediatric FOB is advanced into the trachea parallel to and at the level of the defective ETT. The defective ETT is removed and exchanged using a tube exchanger as previously described. In case of accidental displacement of the tube exchanger, the second ETT-loaded FOB in place can be used for intubation of the trachea.146 In summary, exchanging an ETT or extubating a difficult airway in the neuro-ICU can be dangerous, even in expert

hands, and the potential for secondary brain injury is great. The rate of complications is potentially high and specialized personnel should be readily available.

The Difficult Airway Cart Just as different physicians bring different preferences and skills in managing difficult airways, there is no one standard difficult airway cart. However, because a difficult airway cart will be used in emergency conditions by personnel of different skill levels in the neuro-ICU, some standard equipment should be stocked (Table 16-6).147

Special Considerations for the Pediatric Difficult Airway The airway anatomy of a child progressively approaches that of the adult over the first several years of life. A newborn’s airway anatomy, however, substantially differs from that in the adult. Common findings include a large tongue and epiglottis, large tonsils and adenoids, and a relatively anterior position of the larynx. Neonatal or pediatric airway anatomy in children with neurologic abnormalities and associated congenital craniofacial pathology represents a formidable challenge to the physician attempting to obtain tracheal access. Other clinical concerns are a small functional residual capacity and high oxygen consumption, leading to a faster rate of desaturation and an immature autonomic nervous system exquisitely sensitive to hypoxemia and airway manipulation, which may lead to bradycardia. Adequate topical anesthesia of the airway for fiberoptic intubation of the trachea may be impractical or impossible in children in the ICU scheduled for an elective neurosurgical procedure or radiologic test. In these cases, the patient is transported to an anesthetizing station and inhalation anesthesia, while maintaining spontaneous ventilation, is often used to control the airway. Nevertheless, a difficult airway kit should be available and pediatric airway manipulation should be managed by neuro-ICU personnel with appropriate pediatric airway skills. The devices that we believe should be immediately available when dealing with pediatric difficult intubation in the pediatric or neonatal neurologic or neurosurgical ICU include 1. Flexible pediatric/neonatal FOB 2. Small size LMAs (sizes 1, 2, and 3) 3. Pediatric lighted stylet (available as small as 2.5 mm OD) 4. Pediatric retrograde endotracheal intubation kit (22gauge catheter that will accommodate 0.018-inch guidewire).

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Table 16-6  Suggested Content of the Difficult Airway Cart Adult Nasal nasopharyngeal airways: sizes 6, 7, 8 nasal endotracheal tubes: sizes 6.0, 7.0, 8.0 Oral oropharyngeal airways: sizes 8, 9, 10, 11 stylets/intubating guides endotracheal tube stylet gum elastic bougie: sizes 10F, 15F illuminating stylet endotracheal tubes: cuffed sizes 5.0, 5.5, 6.0, 6.5, 7.0, 7.5, 8.0 laryngoscope blades curved: Macintosh 3, 4 straight: Miller 2, 3, 4 laryngoscope handles: regular length, short length laryngeal mask airway sizes 3, 4, 5 Fastrach intubating laryngeal masks: sizes 3, 4 endotracheal tubes for laryngeal masks: sizes 6.0, 6.5, 7.0 cuffed Combitube: adult, small adult lung isolation bronchial blockers: Fogarty occlusion catheter; size 8/14F double lumen endotracheal tubes: sizes 35, 37, 39, 41F Cricothyroid membrane transcricothyroid membrane jet ventilation: intravenous catheters: 14, 12 gauge (length: 2 inches) jet ventilation hose with controller handle, pressure down-regulator, and Luer lock connector retrograde transcricothyroid membrane kit Melker percutaneous dilational cricothyroidotomy set: sizes 3, 4, 6 Patil cricothyroidotomy catheter surgical cricothyroidotomy: 3 scalpel handle, 11 blade, tracheal retraction hook size 6.0 endotracheal tube Shiley cuffed tracheostomy tubes: sizes 4, 6, 8

Accessory equipment confirming position of endotracheal tube: ETCO2 colorimetric detector esophageal detector syringe or self-inflating bulb endotracheal tube exchange catheters: with jet ventilation capability Patil-Syracuse mask Bronchoscopy swivel adapter oxygen delivery Ambu manual resuscitation bag with masks Mapleson D with pressure gauge oxygen tubing with nipple for connecting to oxygen wall outlet or tank stethoscope suction endotracheal suction catheters: sizes 10, 12, 14 Yankauer oral suction and suction tubing other spare batteries and bulbs for laryngoscope bite blocks Magill forceps local anesthetic and nasal vasoconstrictor atomizer for spraying lidocaine, 4% solution benzocaine spray, 20% solution 1% neosynephrine spray fiberoptic bronchoscope with intubating airway and defogger dedicated neuro-ICU adult rigid fiberoptic laryngoscope of your choice Pediatric Laryngoscope Miller 1 and 2 Esophageal airway 4, 5, 6, 7 Masks: neonatal, infant, toddler, child Dedicated neuro-ICU flexible pediatric FOB Small size LMA: 1 and 2 Pediatric lighted stylet Pediatric Bullard laryngoscope Pediatric retrograde intubation kit

Modified from McGuire GP, Wong DT: Airway management: Contents of a difficult intubation cart. Can J Anaesth 1999;46:190–191.

Training Issues in Managing Difficult Airways The inability to successfully intubate the trachea in neurologically injured patients is a leading cause of morbidity and mortality. A dedicated intensivist physician in charge of the neuro-ICU should be familiar with the evaluation and management of difficult airways in the critically ill patient. Supervision of the junior staff, as well as expert consultation, should be immediately available and provided in the neuroICU 24 hours a day, to avoid unnecessary patient risk. Train-

ing with mannequins and simulated drills of difficult airways in human cadavers are also recommended in order to improve and maintain skill levels.148–153 In summary, the management of the airway in the neuroICU is an important skill that can dramatically impact the patient’s outcome and survival. There is no easy answer to the question of how to rapidly acquire such skills. We recommend constant presence in the unit of specialized medical personnel with proven skills in the management of difficult airways and airway equipment as well as in-depth knowledge of unique problems of the patient with neurologic injuries.

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P earls 1. . . . even in patients with healthy lungs, the average time to critical desaturation (< 90%) is usually shorter than the mean recovery time from an intubation dose of succinylcholine. 2. . . . circumferential mask-straps should not be applied if increased ICP is a concern because of the risk of reducing the venous return from the head. 3. The presence of cyanosis is a late and inconsistent sign that should not be relied on to determine adequacy of ventilation and oxygenation. 4. The presence of large masses or severe swelling above the vocal cords (including tumor masses or facial trauma) may preclude the successful use of supraglottic noninvasive alternative airway devices. 5. Paramedic personnel and medical students attempting to access known difficult airways were successful

References 1. Caplan RA, Posner KL, Ward RJ, et al: Adverse respiratory events in anesthesia: A closed claims analysis. Anesthesiology 1990;72:828–833. 2. Crosby ET, Cooper RM, Douglas MJ, et al: The unanticipated difficult airway with recommendations for management. Can J Anaesth 1998;45:757–776. 3. Am Society of Anesthesiologists Task Force on Management of the Difficult Airway. Practice guidelines for management of the difficult airway. Anesthesiology 1993;78:597–602. 4. Benumof JL: Management of the difficult adult airway: With special emphasis on awake tracheal intubation. Anesthesiology 1991;75: 1087–1110. 5. Leach RM, Treacher DS: ABC of oxygen: Oxygen transport—2. Tissue hypoxia. BMJ 1998;317:1370–1373. 6. Safar P: Resuscitation of the ischemic brain. In Albin MS (ed): Textbook of Neuroanesthesia. New York, McGraw-Hill, 1997, pp 557–593. 7. Benumof JL: The unanticipated difficult airway (correspondence). Can J Anesth 1999;46:510–515. 8. Benumof JL: Am Society Anesthesiology Refresher Course 1998–1999, lecture no. 134: The ASA difficult airway algorithm: New thoughts/considerations. 9. Wilson ME, Spiegelhalter D, Robertson JA, et al: Predicting difficult intubation. Br J Anaesth 1988;61:211–216. 10. Mallampati SR, Gatt SP, Gugino LG, et al: A clinical sign to predict difficult tracheal intubation: A prospective study. Can Anaesth Soc J 1985;32:429–434. 11. Samsoon GLT, Young JRB: Difficult tracheal intubation: A retrospective study. Anaesth 1987;42:487–490. 12. Cormack RS, Lehane J: Difficult tracheal intubation in obstetrics. Anaesth 1984;39:1105–1111. 13. LoCicero J: Bronchopulmonary aspiration. Surg Clin North Am 1989;69:71–76. 14. Warner MA, Warner ME, Weber JG: Clinical significance of pulmonary aspiration during the perioperative period. Anesthesiology 1993;78:56–62.

on the first attempt with the LMA 94% of the time. None had experience with the LMA. 6. The Combitube has recently been introduced in the prehospital and hospital environment as an alternative device in difficult airway management. It has replaced some of the nonsurgical techniques for airway control that do not rely on direct visualization of the airway, including the esophageal obturator airway, the esophageal gastric tube airway, and the pharyngeal lumen airway. 7. Airway suction with a large-bore Yankauer should be always available and used if regurgitation of gastric material follows the extubation of the esophagus. 8. . . . there are no absolute contraindications to the LMA if the alternative is loss of the airway with its life-threatening associated complications.

15. Benumof JL: Laryngeal mask airway and the ASA difficult airway algorithm. Anesthesiology 1996;84:686–699. 16. Kinni ME, Stout MM: Aspiration pneumonitis: Predisposing conditions and prevention. J Oral Maxillofac Surg 1986;44:378–384. 17. Benumof JL, Dagg R, Benumof R: Critical hemoglobin desaturation will occur before return to an unparalyzed state following 1 mg/kg intravenous succinylcholine. Anesthesiology 1997;87:979–982. 18. Thomas DI: Letter: Overcoming the beard. Anaesthesiology 1999; 54:100. 19. Ruben H, Knudsen EJ, Carugati G: Gastric inflation in relation to airway pressure. Acta Anaesth Scand 1961;5:107–116. 20. Benumof JL, Cooper SD: Quantitative improvement in laryngoscopic view by optimal external laryngeal manipulation. J Clin Anesth 1996;8:136–140. 21. Takahata O, Kubota M, Mamiya K, et al: The efficacy of the “BURP” maneuver during a difficult laryngoscopy. Anesth Analg 1997;84:419– 421. 22. Dogra S, Falconer R, Latto IP: Successful difficult intubation: Tracheal tube placement over a gum-elastic bougie. Anaesthesiology 1990;45: 774–776. 23. Cooper SD: The evolution of upper airway retraction: New and old laryngoscopy blades. In Benumof JL (ed): Airway Management. St. Louis, Mosby-YearBook, 1996, pp 374–411. 24. Verghese C, Brimacombe JR: Survey of laryngeal mask airway usage in 11,910 patients: Safety and efficacy for conventional and nonconventional usage. Anesth Analg 1996;82:129–133. 25. Pennant JH, Walker MB: Comparison of the endotracheal tube and the laryngeal mask in airway management by paramedical personnel. Anesth Analg 1992;74:531–534. 26. Mahiou P, Narchi P, Beyrac P, et al: Is laryngeal mask easy to use in case of difficult intubation? Anesthesiology 1992;77:a1228. 27. Akbar AN, Muzi M, Lopatka CW, et al: Neurocirculatory responses to intubation with either an endotracheal tube or a laryngeal mask airway in humans. J Clin Anesth 1996;8:194–197. 28. Rabey PG, Murphy PJ, Langton JA, et al: Effect of laryngeal mask airway on lower oesophageal sphincter pressure in patients during general anaesthesia. Br J Anaesth 1992;69:346–348.

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Chapter 16  29. Brimacombe JR, Berry AM: Cricoid pressure. Can J Anaesth 1997;44:414–425. 30. Michael TAD: The esophageal obturator airway: A critique. JAMA 1981;246:1098–1101. 31. Hammargren Y, Clinton JE, Ruiz E: A standard comparison of esophageal obturator airway and endotracheal tube ventilation in cardiac arrest. Ann Emerg Med 1985;14:953–958. 32. Bartlett RL, Martin SD, McMahon JM, et al: A field comparison of the pharyngeotracheal lumen airway and the endotracheal tube. J Trauma 1992;32:280–284. 33. Klein H, Williamson M, Sue-Ling HM, et al: Esophageal rupture associated with the Combitube. Anesth Analg 1997;85:937–939. 34. Vézina D, Lessard MR, Bussières J, et al: Complications associated with the use of the esophageal-tracheal CombitubeTM. Can J Anesth 1998;45:76–80. 35. Atherton GL, Johnson JC: Ability of paramedics to use the Combitube in prehospital cardiac arrest. Ann Emerg Med 1993;22:1263– 1268. 36. Frass M, Frenzer R, Zdrahal F, et al: The esophageal tracheal Combitube: Preliminary results with a new airway for CPR. Ann Emerg Med 1987;16:768–772. 37. Staudinger T, Brugger S, Watschinger B, et al: Emergency intubation with the Combitube: Comparison with the endotracheal airway. Ann Emerg Med 1993;22:1573–1575. 38. Wagner A, Roeggla M, Roeggla G, et al: Emergency intubation with the Combitube in a case of severe facial burn (correspondence). Am J Emerg Med 1995;13:681–683. 39. Klauser R, Roeggla G, Pidlich J, et al: Massive upper airway bleeding after thrombolytic therapy: Successful airway management with the Combitube. Ann Em Med 1992;21:431–433. 40. Rogers SN, Benumof JL: New and easy techniques for fiberoptic endoscopy-aided tracheal intubation. Anesthesiology 1983;59:569– 572. 41. Hawkins M, O’Sullivan E, Charters P: Fiberoptic intubation using the cuffed oropharyngeal airway and Aintree intubation catheter. Anesthesiology 1998;53:891–894. 42. Uezono S, Goto T, Nakata Y, et al: The cuffed oropharyngeal airway, a novel adjunct to the management of difficult airways. Anesthesiology 1998;88:1677–1679. 43. Charters P, O’Sullivan E: The “dedicated airway”: A review of the concept and an update of current practice. Anaesthesiology 1999; 54:778–786. 44. Caparosa RJ, Zavatsky AR: Practical aspects of the cricothyroid space. Laryngoscope 1957;67:577–591. 45. Zaleski L, Abello D, Gould MI: The esophageal detector device: Does it work? Anesthesiology 1993;79:244–247. 46. Kasper CL, Deem S: The self-inflating bulb to detect esophageal intubation during emergency airway management. Anesthesiology 1998;88:898–902. 47. Cardoso MMSC, Banner MJ, Melker RJ, et al: Portable devices used to detect endotracheal intubation during emergency situations: A review. Crit Care Med 1998;26:957–964. 48. Brimacombe JR: Difficult airway management with the intubating laryngeal mask. Anesth Analg 1997;85:1173–1175. 49. Rosenblatt WH, Wagner PJ, Ovassapian A, et al: Practice patterns in managing the difficult airway by anesthesiologists in the United States. Anesth Analg 1998;87:153–157. 50. Brain AIJ, Verghese C, Addy EV, et al: The intubating laryngeal mask. I: Development of a new device for intubation of the trachea. Br J Anaesth 1997;79:699–703. 51. Joo H, Rose K: Fast-Trach—a new intubating laryngeal mask airway: Successful use in patients with difficult airways. Can J Anaesth 1998;45:253–256. 52. Brain AIJ, Verghese C, Addy EV, et al: The intubating laryngeal mask. II: A preliminary clinical report of a new means of intubating the trachea. Br J Anaesth 1997;79:704–709.

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53. Fukutome T, Amaha K, Nakazawa K, et al: Tracheal intubation through the intubating laryngeal mask airway (LMA) in patients with difficult airways. Anesth Intensive Care 1998;26:387–391. 54. Lim SL, Tay DHB, Thomas E: A comparison of three types of tracheal tube for use in laryngeal mask assisted blind orotracheal intubation. Anaesth 1994;49:255–257. 55. Brain AIJ, Verghese C, Strube PJ: The LMA “ProSeal”—A laryngeal mask with an esophageal vent. Br J Anaesth 2000;84:650–654. 56. Keller C, Brimacombe J: Mucosal pressure and oropharyngeal leak pressure with the ProSeal versus laryngeal mask airway in anaesthetized paralyzed patients. Br J Anaesth 2000;85:262–266. 57. Brimacombe J, Keller C: The ProSeal Laryngeal Mask Airway. A randomized, crossover study with the standard laryngeal mask airway in paralyzed, anesthetized patients. Anesthesiology 2000;93:104–109. 58. Keller C, Brimacombe J, Kleinsasser A, Loeckinger A: Anesth Analg 2000;91:1017–1020. 59. Rhee KJ, O’Malley RJ, Turner JE, et al: Field airway management of the trauma patient: The efficacy of bag mask ventilation. Am J Emerg Med 1988;6:333–336. 60. Reinhart DJ, Simmons G: Comparison of placement of the laryngeal mask airway with endotracheal tube by paramedics and respiratory therapists. Ann Emerg Med 1994;24:260–263. 61. Davies PRF, Tighe SQM, Greenslade GL, et al: Laryngeal mask airway and tracheal tube insertion by unskilled personnel. Lancet 1990;336: 977–979. 62. Baskett PJF, Parr MJA, Nolan JP: The intubating laryngeal mask: Results of a multicentre trial with experience of 500 cases. Anaesthesiology 1998;53:1174–1179. 63. Devitt JH, Wenstone R, Noel AG, et al: The laryngeal mask airway and positive-pressure ventilation. Anesthesiology 1994;80:550–555. 64. Brimacombe J, White A, Berry A: Effect of cricoid pressure on ease of insertion of the laryngeal mask airway. Br J Anaesth 1993;71:800–802. 65. Brimacombe J, Berry A: Cricoid pressure and the LMA: Efficacy and interpretation (letter). Br J Anesthesiol 1994;73:862–863. 66. Shung J, Avidan MS, Ing DC, et al: Awake intubation of the difficult airway with the intubating laryngeal mask airway. Anaesthesiology 1998;53:645–649. 67. Schofferman J, Oill P, Lewis AJ: The esophageal obturator airway: A clinical evaluation. Chest 1976;69:67–71. 68. Shea SR, MacDonald JR, Gruzinski G: Prehospital endotracheal tube airway or esophageal gastric tube airway: A critical comparison. Ann Emerg Med 1985;14:102–112. 69. Rumball CJ, McDonald D: The PTL, Combitube, laryngeal mask and oral airway: A randomized prehospital comparative study of ventilatory device effectiveness and cost-effectiveness in 470 cases of cardiorespiratory arrest. Prehosp Emerg Care 1997;1:1–10. 70. Calkins MD, Robinson TD: Combat trauma airway management: Endotracheal intubation versus a laryngeal mask airway versus Combitube. Use by Navy SEAL and reconnaissance combat corpsmen. J Trauma 1999;46:927–932. 71. Wissler RN. The esophageal-tracheal. Combitube. Anesth Rev 1993; 20:147–152. 72. Walz R, Davis S, Panning B: Is the Combitube a useful emergency airway device for anesthesiologists? (Letter) Anesth Analg 1999;88: 233. 73. Green KS, Beger TH: Proper use of the Combitube. (Letter) Anesthesiology 1994;81:513. 74. Gaitini LA, Vajda SJ, Fradis M, et al: Replacing the Combitube by an endotracheal tube using a fibre-optic bronchoscope during spontaneous ventilation. J Laryng Otol 1998;112:786–787. 75. Mallick A, Quinn AC, Bodenham AR, et al: The use of the Combitube for airway maintenance during percutaneous dilatational tracheostomy. Anesthesiology 1998;53:249–255. 76. Blostein PA, Koestner AJ, Hoak S: Failed rapid sequence intubation in trauma patients: Esophageal tracheal Combitube is a useful adjunct. J Trauma 1998;44(3):534–537.

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77. Mercer MH, Gabbott DA: Insertion of the Combitube airway with the cervical spine immobilised in a rigid cervical collar. Anaesthesiology 1998;53:971–974. 78. Mercer MH, Gabbott DA: The influence of neck position on ventilation using the Combitube airway. Anaesthesiology 1998;53:146–150. 79. Benumof JL, Scheller MS: The importance of transtracheal jet ventilation in the management of the difficult airway. Anesthesiology 1989;71:769–778. 80. Gaughan SD, Ozaki GT, Benumof JL: Comparison in a lung model of low- and high-flow regulators for transtracheal jet ventilation. Anesthesiology 1992;77:189–199. 81. Benumof JL, Gaughan SD: Concerns regarding barotrauma during jet ventilation. (Letter) Anesthesiology 1992;76:1072–1073. 82. Nicklaus TJ: Airway complications of jet ventilation in neonates. Ann Otol Rhinol Laryngol 1995;104:24–30. 83. Peak DA, Roy S: Needle cricothyroidotomy revisited. J Ped Emerg Care 1999;15:224–226. 84. Jawan B, Lee JA: Aspiration in transtracheal jet ventilation. Acta Anesth Scan 1996;40:684–686. 85. Gaughan SD, Benumof JL, Ozaki GT: Quantification of the jet function of a jet stylet. Anesth Analg 1992;74:580–585. 86. Trottier SJ, Hazard PB, Sakabu SA, et al: Posterior tracheal wall perforation during percutaneous dilational tracheostomy: An investigation into its mechanism and prevention. Chest 1999;115:1383–1389. 87. Salvino CK, Dries D, Gamelli R, et al: Emergency cricothyroidotomy in trauma victims. J Trauma 1993;34:503–505. 88. Leibovici D, Fredman B, Gofrit ON, et al: Prehospital cricothyroidotomy by physicians. Am J Emerg Med 1997;15:91–93. 89. Jacobson LE, Gomez GA, Sobieray RJ, et al: Surgical cricothyroidotomy in trauma patients: Analysis of its use by paramedics in the field. J Trauma 1996;41:15–20. 90. Isaacs, Jr JH, Pederson AD: Emergency cricothyroidotomy. Am Surg 1997;63:346–349. 91. Barrachina F, Guardiola JJ, Añó T, et al: Percutaneous dilatational cricothyroidotomy: Outcome with 44 consecutive patients. Intensive Care Med 1996;22:937–940. 92. Hung OR, Stewart RD: Lightwand intubation: I—A new lightwand device. Can J Anesth 1995;42:820–825. 93. Hung OR, Pytka S, Morris I, et al: Lightwand intubation: II—Clinical trial of a new lightwand for tracheal intubation in patients with difficult airways. Can J Anesth 1995;42:826–830. 94. Baigelman W, O’Brien JC: Pulmonary effect of head trauma. Neurosurgery 1981;9:729–740. 95. Graham DI, Ford I, Hume-Adams J, et al: Ischemic brain damage is still common in fatal non-missile head injury. J Neurol Neurosurg Psychiatry 1989;52:346–350. 96. Chesnut RM: Secondary brain insults after head injury: Clinical perspectives. New Horizons 1995;3:366–375. 97. MacKersie RC, Christiensen JM, Pitts LH, Lewis FR: Pulmonary extravascular fluid accumulation following intracranial injury. J Trauma 1983;23:968–997. 98. Sulek CA: Negative-pressure pulmonary edema. In Gravenstein N, Kirby RR (eds): Complications in Anesthesia, 2nd ed. Philadelphia, Lippincott-Raven, 1996, pp 191–198. 99. Minton MD, Grosslight K, Stirt JA, et al: Increases in intracranial pressure from succinylcholine: Prevention by prior non-depolarizing blockade. Anesthesiology 1986;65:165–169. 100. Hamill JF, Bedford RF, Weaver DC, et al: Lidocaine before endotracheal intubation: Intravenous or laryngotracheal. Anesthesiology 1981;55:578–581. 101. Yano M, Nischiyama H, Yokota H, et al: Effect of lidocaine on ICP response to endotracheal suctioning. Anesthesiology 1986;64:651– 653. 102. Cottrell JE, Haartung J, Giffin JP, Shwirey B: Intracranial and hemodynamic changes after succinylcholine administration in cats Anesthesia Analg 1983;62:1006–1009.

103. McLeskey CH, Cullen BF, Kennedy RD, Galindo A: Control of cerebral perfusion pressure during induction of anesthesia in high risk neurosurgical patients. Anesth Analg 1974;53:985–992. 104. Stirt JA, Grosslight KP, Bedford RF, Volimer D: Defasciculation with metocurine prevents succinylcholine induced increased of intracranial pressure. Anesthesiology 1987;67:50–53. 105. Wyte SR, Shapiro HM, Turner P, Harris AB: Ketamine induced intracranial hypertension. Anesthesiology 1972;36:174–176. 106. Lanfitt TW, Weinstein JD, Kassell NF: Cerebral vasomotor paralysis produced by intracranial hypertensions. Neurology 1965;15:622–641. 107. Shatney CH, Brunner RD, Nguyen TQ: The safety of orotracheal intubation in patients with unstable cervical spine fracture or high spinal cord injury. Am J Surg 1995;170:676–680. 108. Hastings RH, Marks JD: Airway management for trauma patients with potential cervical spine injuries. Anesth Analg 1991;73:471–482. 109. Grande CM, Barton CR, Stein JK: Appropriate techniques for airway management of emergency patients with suspected spinal cord injury. Anesth Analg 1988;67:714–715. 110. Orledge JD, Pepe PE: Out-of-Hospital spinal immobilization; Is it really necessary? (Commentary). Acad Emerg Med 1988;5:203–204. 111. Kish DL: Pre-hospital management of a spinal trauma: An evolution. Crit Care Nursing Q 1999;22:36–43. 112. Hausweld M, Ong G, Tandberg D, Omar Z: Out-of-Hospital spinal immobilization: Its effect on a neurologic injury. Acad Emerg Med 1998;5:214–219. 113. Hastings RH, Kelley SD: Neurologic deterioration associated with airway management in a cervical spine injured patient. Anesthesiology 1993;78:580–583. 114. Keller C, Brimacombe J, Keller K: Pressure exerted against the cervical vertebrae by this tender and intubating laryngeal mask airways: A randomized control led crossover study in fresh cadavers. Anesth Analg 1999;89:1296–1300. 115. Schuschnig C, Waltl B, Erlacher W: Intubating laryngeal mask and rapid sequencing induction in patients with cervical spine injury. Anesthesia 1999;54:787–797. 116. Wakeling HG, Nightingale J: The intubating laryngeal mask airway does not facilitate tracheal intubation in the presence of a neck collar in simulated trauma. Br J Anaesth 2000;84:254–256. 117. Atherton GL, Johnson JC: Ability of paramedics to use the Combitube in pre-hospital cardiac arrest. Ann Emerg Med 1993;8:27–32. 118. Mercer MH, Gabbott DA: Insertion of the Combitube in the way of a cervical spine immobilized in the rigid cervical collar. Anesthesia 1998:53:971–974. 119. Kalkins ND, Robinson TD: Combat trauma airway management: Endotracheal intubation versus laryngeal mask airway vs Combitube use by Navy seals, and reconnaissance combat corpse man. J Trauma 1999;46:927–932. 120. Smith CE, Pinchak AB, Sidhu TS, et al: Evaluation of tracheal intubation difficulty in patients with cervical spine immobilization. Fiberoptic Wu scope versus conventional laryngoscopy. Anesthesiology 1999;91:1253–1259. 121. Saha AK, Higgins N, Walker G, et al: Comparison of awake endotracheal intubation in patients with cervical spine disease: The lighted intubating stylet versus the fiberoptic bronchoscope. Anesth Analg 1998;87:477–479. 122. Meschino A, Debitt JH, Koch G-P, et al: The safety of awake tracheal intubation in cervical spine injury. Can J Anesth 1992;39:114–117. 123. Reasoner DK, Warner DS, Todd MM, et al: A comparison of anesthetic techniques for awake intubation in a neurosurgical patient. J Neurosurg Anesthesiol 1995;7:94–99. 124. McGuire G, El-Behery H: Complete upper airway obstruction during awake fiberoptic intubation in patients with unstable cervical spine fractures. Can J Anes 1999;46:176–178. 125. Kaups KL, Davis JW: Gunshot wound to the head does not require cervical spine immobilization and evaluation. J Trauma 1998;44:865– 867.

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Chapter 16  126. Kendall JL, Anglin D, Demetriades D: Penetrating neck trauma. Emerg Med Clin North Am 1998;16:85–104. 127. Kelly JP, Webb WR, Moulder PV, et al: Management of airway trauma, tracheal bronchial injuries. Ann Thorac Surg 1985;40:551–555. 128. Young WL, Kader A, Prohodnik D: Pressure regulation is intact after arterial venous malformation resection. Neurosurgery 1993;32:491– 496. 129. Szabo MD, Crosby G, Sundaram P, et al: Hypertension does not cause spontaneous hemorrhage of intracranial arterial venous malformation. Anesthesiology 1989;70:761–763. 130. Ferguson GG: Direct measurement of mean and pulsatile blood pressure at operation in human intracranial saccular aneurysm. J Neurosurg 1972;36:560–563. 131. Gronert GA, Ptheye RA: Pathophysiology of hyperkalemia induced by succinylcholine. Anesthesiology 1975;43:89–99. 132. Martyn JAJ, White DA, Gronert GA, et al: Up-and-down, regulations of skeletal muscle succinylcholine receptors effect on neuromuscular blockers. Anesthesiology 1992;76:822–843. 133. Bukht D, Langford RM: Airway obstruction after surgery in the neck. Anaesthesia 1982;37:389–390. 134. Kitahata LM: Airway difficulties associated with anesthesia in acromegaly. Three case reports. Br J Anesth 1971;43:1187–1190. 135. Benditt JO: Management of pulmonary complications in neuromuscular disease. Phys Med Rehab Clin North Am 1998;9:167–185. 136. Lee PJ, O’Reilly M, Tremper K, et al: An analysis of reintubations from a quality assurance database of 47,000 cases (abstract). Anesth Analg 1996;82:S270. 137. Miller KA, Harkin CP, Bailey PL: Postoperative tracheal extubation. Anesth Analg 1995;80:149–172. 138. Hartmannsgruber MWB, Loudermilk EP, Stoltzfus DP: Prolonged use of a Cook airway exchange catheter obviated the need for postoperative tracheostomy in an adult patient. J Clin Anesth 1997;9:496–498. 139. Twk W, Chin NN, et al: Tracheostomy in a new intensive care setting; indication and timing. Anesth Intensive Care 1997;25:365–368. 140. Whited RE: A prospective study of laryngeal tracheal in long term intubation. An extensive laryngeal synopsis has found up to 12% of

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146. 147. 148.

149. 150.

151.

152.

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the cases in patients intubated for 11–24 days. Laryngoscope 1984;94: 367–377. Chuw JEW, Cantrell RW: Tracheostomy; complication and near management. Archives Otolaryngol 1972;96:538–545. Dane TEB, King EG: A prospective study of complications of the tracheostomy for assisted ventilation. Chest 1975;67:398–404. Goldstein FI, Breda SD, Schneider KL: Surgical complications of a tracheostomy in intensive care setting. Laryngoscope 1986;96:58–60. Marsh HM, Gillispe DJ, Baum Gartner AE: Timing of tracheostomy in the critically ill patient. Chest 1989;91:190–193. Banner MJ, Kirby RR, Blanch PB, et al: Decreasing imposed work of the breathing apparatus to zero using pressure-support ventilation. Crit Care Med 1993;21:1333–1338. Benumof JL: Airway exchange catheters: Simple concept, potentially great danger (editorial). Anesthesiology 1999;91:342–344. McGuire GP, Wong DT: Airway management: Contents of a difficult intubation cart. Can J Anaesth 1999;46:190–191. Goldberg JS, Bernard AC, Marks RJ, et al: Simulation technique for difficult intubation: Teaching tool or new hazard? J Clin Anesth 1990;2:21–26. Mason RA: Learning fiberoptic intubation: Fundamental problems (editorial). Anaesthesiology 1992;47:729–731. From RP, Pearson KS, Albanese MA, et al: Assessment of an interactive learning system with “sensorized” manikin head for airway management instruction. Anesth Analg 1994;79:136–142. Orlowski JP, Kanoti GA, Mehlman MJ: The ethics of using newly dead patients for teaching and practicing intubation techniques (editorial). N Engl J Med 1988;319:439–441. Cooper SD, Benumof JL: Teaching the management of the difficult airway: The UCSD airway rotation (abstract). Anesthesiology 1994;81:A1241. Koppel JN, Reed AP: Formal instructions in difficult airway management: A survey of anesthesiology residency programs. Anesthesiology 1995;83:1343–1346.

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Chapter 17 Cardiac Care in Neurosurgery Emilio B. Lobato, MD and Cheri A. Sulek, MD

Introduction The intimate connection between the central nervous system (CNS) and the heart has long been recognized.1,2 Whereas the heart is capable of spontaneous rhythmic activity, as in the case of a transplanted organ, it is through neural modulation that both electrical and mechanical activities can be finely adjusted to meet the needs of the organism. In fact, visceral and somatic responses to internal and environmental stimuli are integrated through the CNS, which then alters cardiovascular activity in response to or anticipation of behavioral events.2 The most important component of this heart-brain interaction is the autonomic nervous system with its afferent and efferent loops (Fig. 17-1). In addition, numerous humoral substances released by the brain into the circulation influence cardiac activity in response to either biologic or psychologic stress; for example, the hypothalamic-pituitaryadrenal axis and the renin-angiotensin system (Fig. 17-2). It is, therefore, not surprising that disorders of the CNS may have a significant impact on cardiac function whether through direct effects on the myocardium or via changes in the vasculature. Individuals without preexisting cardiac disease are often able to tolerate the cardiac consequences of CNS events. However, as the population ages, chronic disease states such as hypertension, coronary artery disease (CAD), and heart failure become commonplace. Cardiovascular homeostatic mechanisms may be disrupted; consequently, the degree of cardiac impairment following cerebral events or neurosurgery may be disproportionately severe and ultimately

responsible for the patient’s prognosis, even if the CNS event has been resolved. This chapter will address the most frequent cardiac complications associated with acute intracerebral and spinal cord pathology, as well as the additional risks imposed on neurosurgical patients by the presence of preexisting cardiac disease.

The Patient Without Preexisting Cardiac Disease Cardiac abnormalities attributed to a neurogenic etiology are frequently detected in patients with acute or chronic intracranial pathologies. Although electrocardiographic (ECG) changes have been associated with many neurologic diseases, they are most often associated with aneurysmal subarachnoid hemorrhage (SAH), intracerebral hemorrhage, and ischemic stroke. Cardiac abnormalities documented include ECG changes, cardiac enzyme concentration increases, arrhythmias, left ventricular wall motion abnormalities by echocardiography (ECHO), depressed left ventricular ejection fraction (LVEF) by ECHO, and reversible perfusion defects by thallium scintigraphy.3–5 Historically, ECG changes, often mimicking myocardial ischemia or infarction, were not considered clinically significant and were believed to reflect the neurologic insult and not underlying cardiac injury. There is increasing evidence that in as many as 20% to 30% of patients, these ECG changes signify underlying myocardial injury that can be severe.5 The 533

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Figure 17-1. Diagram illustrating the pathways for heart-brain interaction. The autonomic nervous system constitutes the main neural pathway. Humoral factors include the hypothalamo-pituitary-adrenal axis, renin-angiotensin system, cytokines, and endorphins. RAS, renin angiotensin; PIT, pituitary; ACTH, adrenocorticotropic hormone. (Modified from Ter Horst GJ [ed]: The Nervous System and the Heart. Totowa, NJ, Humana, 2000.)

optimal perioperative and intensive care unit treatment of these patients continues to be a matter of debate and is a formidable challenge for the anesthesiologist, neurosurgeon, and intensivist. Background Electrocardiographic abnormalities have been reported in patients with aneurysmal SAH, intracerebral hemorrhage, ischemic stroke, head injury (e.g., traumatic SAH), seizures, meningitis, brain tumors, brain death, hydrocephalus, and during neurosurgical procedures.6–10 The abnormalities have been most commonly associated with aneurysmal SAH. The first association between ECG changes and SAH was observed in 1947.11 In the past, ECG changes suggestive of myocardial ischemia or infarction were often considered the primary presenting problem and not the result of intracranial pathology. This frequently led to the delayed diagnosis of SAH or other neurologic disease; delayed surgery (e.g., aneurysm clipping); or inappropriate initiation of medical therapy (e.g., anticoagulants). For many years, it was postulated that these changes were solely the result of central nervous system influences and not representative of underlying myocardial injury. However, recent autopsy findings, ECHO data, and thallium scintigraphy results provide evi-

dence that these ECG changes may reflect actual cardiac injury. Presentation Electrocardiographic Abnormalities ECG abnormalities are evident in 50% to 80% of patients following aneurysmal SAH; in 60% to 70% with intracerebral hemorrhage; and in 15% to 40% with ischemic stroke, usually involving the insular cortex.12,13 The most common ECG patterns are abnormal repolarization (peaked or inverted T waves, ST-T wave changes), conduction alterations (shortened PR interval, QTc prolongation), peaked P waves, U waves, and new Q waves.6,14,15 The most frequent abnormalities that accompany SAH are ST segment or T wave alterations and new QTc prolongation.6,9 ST segment and T wave alterations may suggest myocardial ischemia or infarction in 25% to 75% of patients with SAH.16 In a study of 270 patients with ruptured and unruptured intracranial aneurysms, 52% had an abnormal preoperative ECG with the highest percentage in those with a poor clinical grade.6 Additional intraoperative and postoperative ECG changes occurred in 35% and 65% of patients, respectively. The most frequently observed patterns involved the T wave or ST segment. Often, the ST segment or T wave changes are

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Figure 17-2. The frequency of cardiac involvement with CNS disease can be explained by the rich neural network intimately connecting the CNS and the heart. Efferent sympathetic fibers originate from the cell bodies of the paravertebral chain (derived from cervical and stellate ganglia). These fibers constitute the cardiac plexus and innervate different cardiac tissues. Efferent parasympathetic fibers reach the heart via large vagal nerves with their cell bodies located in either the dorsal motor nucleus or the nucleus ambiguous of the medulla oblongata. The mixed nerves of the cardiac plexus thus contain pre- and postganglionic parasympathetic and sympathetic fibers as well as afferent fibers from cardiopulmonary receptors. (Modified from Crick SJ, Sheppard MN, Anderson RH: Cardiac care in neurosurgery. In Ter Horst GJ [ed]: The Nervous System and the Heart. Totowa, NJ, Humana Press, 2000.)

diffuse and not consistent with a specific coronary artery distribution (Fig. 17-3). Prolongation of the QT interval is commonly identified after SAH and stroke involving the insular cortex and is an independent risk factor for sudden cardiac death.14 In a recent study of 40 patients with unilateral ischemic stroke, patients with insular involvement had significant QTc prolongation compared to those without insular involvement.14 Increasing data suggest that the insula is a modulator of cardiac autonomic tone and, as such, an important arrhythmogenic center. ECG changes are usually transient, resolving within weeks; QTc prolongation and U waves can be permanent.13 Arrhythmias Arrhythmias have been reported in as many as 90% of patients following SAH when studied by Holter monitoring, but can occur after any neurologic insult.3,17 They can be

benign or life-threatening and include premature ventricular contractions, ventricular tachycardia, ventricular fibrillation, premature atrial contractions, atrial fibrillation, supraventricular tachycardia, heart block, idioventricular rhythm, and Torsades de Pointes.3 They are more frequent and severe within 48 hours of SAH.3 Ten percent of patients with aneurysmal SAH die before reaching the hospital; sudden death due to an acute arrhythmia may account for a significant percentage of these deaths that occur immediately after the neurologic injury. The incidence of sudden cardiac death remains unknown. In patients with acute stroke, it is estimated that 6% of deaths result from arrhythmias.18 Ventricular arrhythmias are frequently associated with underlying myocardial dysfunction. ECG changes and arrhythmias have consistently been reproduced in animal models of experimental SAH.19 Arrhythmias occur immediately after blood is introduced

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Figure 17-3. ECG demonstrating the presence of diffuse T wave inversions in a female SAH patient without a history of coronary artery disease. Serial echocardiograms performed during her hospitalization demonstrated severe hypokinesis of the mid-septal, mid-anteroseptal, and anteroapical walls. All wall motion abnormalities normalized by the time of discharge.

into the subarachnoid space and are associated with acute increases in intracranial pressure. Denervation of the heart results in delayed onset of arrhythmias. Strokes that involve the right insular cortex may result in an autonomic imbalance that favors the sympathetic system.13,18 Decreased heart rate variability seen after ischemic stroke (especially the right insula) is a significant predictor of arrhythmias and sudden cardiac death.18 Cardiac Enzyme Concentration Increases Increases in cardiac enzyme concentrations (creatine kinase [CK], MB fraction, cardiac troponin T and I) accompany ECG abnormalities in 20% to 50% of patients following SAH, but usually do not approach the levels observed with transmural infarction.20,21 Creatine kinase, CK-MB, and MB fraction have proven to be less sensitive markers for myocardial injury following SAH or other neurologic insults than cardiac troponin I (cTnI) or T. Increases in CK and CK-MB can be attributed to noncardiac muscle injury. In the neurosurgical population, CK can be increased due to release of brain isoenzyme. Also, when sublethal injury to the myocytes occurs, the release of CK and CK-MB may be small and not approach levels compatible with subendocardial injury.21 The cardiac troponins, particularly cTnI, are more specific determinants for cardiac muscle than CK. In a recent study of 39 patients with aneurysmal SAH, 20% had increased serum cTnI levels and of those, 62% had left ventricular dysfunction on ECHO.21 Cardiac troponin I was more sensitive

than CK-MB for predicting myocardial injury. Not every patient with increased cardiac enzymes will have underlying myocardial injury, but this provides a simple diagnostic test to identify a subset of patients that may need additional cardiac workup or more aggressive hemodynamic monitoring perioperatively. Cardiac Testing Cardiac injury following a neurologic insult has been documented by thallium scintigraphy and ECHO. Reversible perfusion defects indicative of myocardial ischemia have been detected by thallium scintigraphy in patients following acute SAH. In a study of 19 patients with SAH, thallium scintigraphy revealed abnormal perfusion, with redistribution in six patients with ECG abnormalities.4 Not all patients with ECG abnormalities had abnormal thallium scan results, and there were no specific ECG patterns predictive of underlying myocardial injury. Regional wall motion abnormalities with either normal or depressed left ventricular function have been documented with ECHO in 10% to 30% of SAH patients with associated ECG abnormalities.5,22 Ten percent to 40% of brain-dead patients will have echocardiographic evidence of significant myocardial dysfunction and pose a problem for organ donation.10 The spectrum of injury can range from mild to severe systolic dysfunction (LVEF <30%) with associated clinical symptoms. A subset of patients with SAH will also have evidence of diastolic dysfunction.

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Pollick and colleagues studied 13 patients within 48 hours of SAH.5 Left ventricular abnormalities on ECHO were observed in four patients, and all had inverted T waves on ECG. Two patients (15% of total) survived longer than 7 days, and repeat ECHO revealed normalization or improvement in wall motion abnormalities. In a separate study by Kono and associates, seven patients with SAH and ST segment elevation by ECG were studied with coronary angiography within 10 hours of injury.23 All seven patients had left ventricular apex hypokinesis and no demonstrable coronary artery stenosis or vasospasm. Of those who survived, repeat studies demonstrated improvement in left ventricular wall motion abnormalities. In a recent retrospective analysis of SAH patients with echocardiographydocumented left ventricular dysfunction, there was preservation of apical function in 57% of patients.24 This finding further substantiates a neurally mediated mechanism of injury because the left ventricular apex is relatively devoid of sympathetic nerve terminals. The ECG patterns most often associated with left ventricular dysfunction are T wave inversions and prolonged QTc25; However, not all patients with these ECG patterns or other abnormalities will have underlying myocardial injury. The echocardiographic patterns of myocardial injury often do not correlate with a specific coronary artery distribution. Available ECHO data appear to substantiate that left ventricular dysfunction is reversible, with improvement or normalization of wall motion abnormalities within days or weeks. Nonetheless, permanent injury does occur as evidenced by biochemical data and autopsy studies. Mortality appears to be related directly to neurologic complications from the neurologic insult (e.g., cerebral vasospasm following aneurysmal SAH) and not to cardiac-related events.16 The incidence of fatal arrhythmias contributing to initial mortality, particularly following SAH or stroke, is not known. There are few identifiable factors associated with the development of cardiac injury following a neurologic insult. In patients with SAH, there seems to be an association between female gender, poor neurologic grade, and the development of myocardial dysfunction.5,22 Postmortem Data Myocardial lesions have been identified at postmortem examination in patients with neurologic diseases and clinical evidence of cardiac injury. The most common patterns of injury at autopsy include focal myocytolysis, myofibrillar degeneration, contraction band necrosis, subendocardial congestion and hemorrhages, lipofuscin deposition in myofibrils, and histiocytic infiltration.26 Focal myocytolysis has been demonstrated in approximately 10% of patients with lethal intracranial injury.27 The myocardial lesions at autopsy are often evident in the absence of demonstrable coronary artery stenosis and usually are subendocardial, diffuse, and involve the left ventricle. Similar pathologic

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findings are present in patients with pheochromocytoma and can be reproduced experimentally by (1) simulating intracranial hemorrhage; (2) electrical stimulation of the left stellate ganglion; and (3) infusion of catecholamines in the left anterior descending artery of the heart.28–31 Not all patients with electrocardiographic or echocardiographic abnormalities have myocardial pathology at the time of postmortem examination. Mechanism of Injury The etiology of ECG abnormalities, arrhythmias, and myocardial injury is not well understood but, in part, reflects increased catecholamine release and reduction in parasympathetic activity at the time of the neurologic insult. Following SAH, it is postulated that intense catecholamine release from the hypothalamus occurs. Doshi and NeilDwyer reported the presence of hypothalamic and myocardial lesions in 42 of 54 (78%) SAH patients studied at autopsy.26 Stimulation of the lateral hypothalamus in animals results in profound sympathetic activity and development of tachyarrhythmias and hypertension.32 In experimental animal models of SAH, ECG changes and arrhythmias can be consistently attenuated or prevented by C2 cordotomy, propranolol, or cocaine.19,32,33 Phentolamine and propranolol have been used successfully to block the sympathetic response in patients following SAH and to prevent the development of myocardial injury.34 At the onset of SAH, damage to the hypothalamus (hemorrhage, infarction, or vasospasm) may trigger the release of catecholamines and begin the cascade of events that leads to myocardial injury. The left ventricular apex is spared of injury in a significant number of SAH and brain-dead patients,10,24 which further supports the proposed mechanism of injury because the apex is relatively devoid of sympathetic nerve terminals. Norepinephrine levels are increased at the time of SAH; the mechanism of injury may be related to systemic effects, local release of catecholamines by myocardial sympathetic nerve terminals, spasm of the coronary microvasculature, or increased myocardial oxygen requirements. There has been considerable interest in the role of the insula as an important arrhythmogenic center and control center for autonomic tone. The amygdala also appears to be an important cardiovascular control center within the limbic system that has direct connections to the insula. Ischemic and hemorrhagic stroke or SAH involving predominantly the right insula has been associated with ECG abnormalities, decreased heart rate variability, arrhythmias, and sudden cardiac death.13,18,35 Although the insular cortices are both regulators of autonomic tone, there is distinct lateralization, with the right side predominantly modulating sympathetic tone and the left involved with parasympathetic control.36 Insult to the right insular cortex leads to autonomic imbalance favoring the sympathetic system.

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Clinical Presentation and Differential Diagnosis The clinical presentation of myocardial dysfunction following a neurologic insult depends on the extent of underlying injury. In the majority of patients, the injury is subclinical and will manifest as ECG abnormalities. A small subset of patients will exhibit symptoms of severe left ventricular dysfunction and depressed ejection fraction (LVEF <30%). The incidence of severe myocardial dysfunction following neurologic injury remains unknown. Sudden death due to fatal arrhythmias probably accounts for a significant number of patients that die before reaching the hospital. The diagnosis of neurogenic myocardial dysfunction can be difficult to differentiate from that associated with coronary artery disease because the presentation may be similar. It is important to make the differentiation because treatment approaches and long-term prognosis differ significantly. Many patients with aneurysmal SAH and stroke have risk factors for coronary artery disease including hypertension, smoking, and hyperlipidemia. The affected patient population is frequently middle-aged to elderly. A presumptive diagnosis may be made from stratification of risk factors and history (including family) of cardiac disease. The definitive diagnosis of coronary artery stenosis can only be made with coronary angiography; however, this diagnostic test is associated with risk, is unnecessary in some patients, and usually requires heparinization (contraindicated in many patients with acute intracranial pathology). Arrhythmias may be the result of ischemic heart disease, high sympathetic tone, or electrolyte disturbances. If pulmonary compromise is present and not associated with myocardial dysfunction, other causes should be sought including neurogenic pulmonary edema, pulmonary embolus, iatrogenic causes (e.g., hypertensive, hypervolemic, hemodilutional therapy for cerebral vasospasm), or aspiration of gastric contents.

Treatment The optimal treatment of patients with neurologic disease and myocardial dysfunction attributed to a neurogenic origin remains controversial. There are no large prospective trials documenting the significance of myocardial dysfunction in this setting. Cardiac morbidity and mortality do not appear to be significantly increased, but this may not be applicable to those patients with severe left ventricular dysfunction. An ECG should be performed in a patient of any age with documented intracranial pathology. If the ECG is abnormal or arrhythmias are present, a transthoracic or transesophageal ECHO should be considered. However, a transesophageal ECHO is not feasible unless the patient is intubated and sedated or anesthetized in the intensive care unit or operating room. Further workup for the patients with suspected coronary artery stenosis is addressed elsewhere in this chapter. The performance of cardiac catheter-

ization frequently requires heparinization; the use of antiplatelet therapy is mandatory after any intervention (e.g., percutaneous transluminal coronary angioplasty, or stent placement). The use of anticoagulation is contraindicated in patients with SAH, traumatic brain injury, brain tumor, or hemorrhagic stroke. The timing of surgical intervention becomes an important issue in SAH patients with underlying myocardial injury. The recent trend is early surgical intervention to prevent rebleeding and allow the aggressive treatment of established cerebral vasospasm. In the North American limb of the International Cooperative Study on the Timing of Aneurysm Surgery, mortality was two times higher for patients who underwent surgery 7 to 10 days after SAH compared to those with early (0 to 3 days) or delayed (11 to 32 days) surgical intervention.37 Those patients undergoing surgery early had the highest rate of good recovery at 6 months. When myocardial depression is severe, the risks and benefits of early surgery must be weighed carefully because further cardiovascular decompensation may occur intraoperatively. Surgical evacuation of a hematoma following hemorrhagic stroke, aneurysm rupture, or arteriovenous malformation may need to be performed emergently, and delaying intervention due to myocardial injury is not an option. Invasive monitoring is recommended intraoperatively because major hemodynamic stressors, such as excessive blood loss or use of myocardial depressants (e.g., barbiturates for cerebral protection during aneurysm clipping), may not be well tolerated in these patients. Postoperative management may also require modification, particularly when aggressive medical therapy is required for the treatment of cerebral vasospasm in patients with SAH. The incidence of pulmonary edema associated with hypertensive, hypervolemic, hemodilutional (HHH) therapy, for instance, approaches 30% in patients without coexisting cardiac disease and is likely to be even higher in the presence of cardiac dysfunction.38 In our center, the use of invasive hemodynamic monitoring, with Starling curve generation and optimization of volume status has made pulmonary edema quite uncommon. The treatment of head injury and control of intracranial pressure also requires aggressive medical management that includes elevation of mean arterial pressure to maintain cerebral perfusion pressure (CPP); use of mannitol; maintenance of euvolemia; and, as a last resort, use of barbiturates for refractory intracranial hypertension. In the presence of concomitant myocardial dysfunction, these treatment modalities may not be well tolerated, and thus the maintenance of an adequate CPP may be difficult or impossible. Patients with mild-to-moderate myocardial dysfunction often require no specific therapeutic interventions and tolerate surgery well. The underlying myocardial injury is frequently not recognized clinically and only detected with more sophisticated diagnostic testing (e.g., ECG, ECHO).

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The majority of patients with neurogenic myocardial dysfunction are placed into this category. In this subset of patients, timing of surgical intervention need not be altered. The treatment of arrhythmia is based on severity and is performed in accordance with the Advanced Cardiac Life Support guidelines (Table 17-1).39 The treatment of patients with severe myocardial dysfunction is directed toward optimization of cardiac contractility in the perioperative period until improvement in function occurs. The treatment options available are: (1) inotropic agents and vasodilators to improve systolic function in conjunction with a pulmonary artery catheter or transesophageal ECHO to guide treatment; (2) close monitoring of volume status, particularly when HHH therapy is used; (3) mechanical ventilation with positive end-expira-

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tory pressure when pulmonary status is compromised; and (4) consideration of intra-aortic balloon counterpulsation (IABP). Inotropic agents can be used until cardiac function improves or normalizes. Epinephrine and norepinephrine are the most commonly used agents when dysfunction is severe but may not be the most appropriate when the presumed etiology is excess catecholamine release. Milrinone is an inodilator that is currently used for short-term cardiovascular support in patients with congestive heart failure and to improve cardiac function during separation from cardiopulmonary bypass. Milrinone not only improves myocardial contractility but has both arterial and venodilation properties. However, its cerebral vasodilating properties could be detrimental in patients with abnormal intracranial

Table 17-1  Pharmacologic Treatment of Arrhythmias

Adapted from Cummings OR (ed): ACLS Provider Manual 2001. American Heart Association, pp 1–252.

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elastance.40 In patients with aneurysmal SAH at risk for cerebral vasospasm and associated myocardial dysfunction, the increased cerebral blood flow (CBF) from milrinone may be beneficial. The treatment of pulmonary edema with diuretics should be performed judiciously when the maintenance of euvolemia is important for the underlying neurologic disease process (e.g., following SAH or head injury). Vasodilating agents such as sodium nitroprusside and nitroglycerin may not be acceptable when intracranial elastance is abnormal. The use of an IABP has been reported in patients with symptomatic cerebral vasospasm and associated myocardial dysfunction, not only to optimize cardiac performance, but to augment CBF.41 Intra-aortic balloon pump placement should be considered only when all other treatment options have been exhausted, due to its invasiveness and high incidence of complications. An alternate approach in patients with aneurysmal SAH is to delay surgery until cardiac function improves. However, while the cardiac risk decreases with time, the risk of rebleeding and development of cerebral vasospasm increase and are both associated with significant morbidity and mortality. Endovascular embolization may prove to be an acceptable alternative to surgery in some patients, with aneurysms approachable by neuroradiologic intervention. Although embolization is less invasive than a craniotomy and associated with less surgical stimulation, invasive hemodynamic monitoring and pharmacologic support of the circulation may prove beneficial because the procedure may require the administration of general anesthesia. Conclusion ECG abnormalities are common, particularly following aneurysmal SAH and, in a significant number of patients, indicate underlying cardiac injury. Interestingly, not all patients with ECG changes will have evidence of injury according to biochemical data or ECHO. In most patients, the degree of dysfunction is not severe enough to warrant alteration of perioperative care and would go undetected if not actively screened. However, in a small subset of patients, the severity of myocardial injury may require modification of care in the perioperative period. In these patients, anesthetic and surgical risks may outweigh the benefits of early surgery. Even though long-term cardiac outcome appears to be favorable, there is reason to suspect that morbidity may be increased in the perioperative period until ventricular function improves.

The Patient with Preexisting Cardiac Disease The term, “cardiac patient,” is predominantly used to identify individuals with acquired heart disease or significant risk factors. In the economically developed world, the over-

whelming majority of patients with cardiovascular disease suffer from CAD, heart failure, or valvular disease. It is in this patient population that the majority of experience has been acquired in identifying risk factors for perioperative complications and developing therapeutic strategies for prevention and treatment. Recently published guidelines for perioperative evaluation take into consideration that patients with stable cardiac disease undergoing neurosurgical procedures not associated with significant blood loss carry a moderate risk for perioperative cardiac complications.42 In some patients, however, significant alterations in hemodynamics that are detrimental to cardiac function can occur, whether as a result of disease (intracranial hypertension) or treatment (hypertensive hypervolemic hemodilution), thus leading to acute cardiac decompensation, and increased morbidity and mortality. In addition, some CNS disorders (e.g., SAH) can be associated with cardiac manifestations that are indistinguishable from primary cardiac events.43–45 In patients with preexisting cardiac disease, this represents a diagnostic and therapeutic challenge, such as the use of anticoagulation and early revascularization in a postoperative patient following SAH, who is suspected of suffering from a myocardial infarction (MI). This section will address the different presentations of the patient with cardiac disease and their implications in the diagnosis, prevention, and treatment as it applies to the neurosurgical patient. Coronary Artery Disease Patients with coronary artery disease undergoing surgery incur significant morbidity.46,47 Perioperative MI may also impair the patient’s functional status and is frequently lethal.48,49 Of the three periods comprising perioperative care, evidence suggests that the postoperative period is the one with the highest risk.50,51 Attempts to improve perioperative outcome have focused on three predominant approaches: 1. Perioperative risk stratification 2. Increased perioperative surveillance 3. Pharmacologic strategies to decrease myocardial ischemia/infarction. Risk Stratification Preoperative Predictors. Patients with the highest risk for postoperative cardiac events include those with unstable coronary syndromes (unstable angina and NST-T elevation MI) and recent MI51–53 (defined as older than 7 days, but less than a month). These conditions carry a prohibitive incidence of postoperative mortality. Elective surgery should be deferred, and only emergency surgery should be carried out (e.g., evacuation of an acute epidural hematoma). Patients with mild or stable angina, as well as MI by history or pathologic Q waves, pose a moderate risk.

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Chapter 17  Postoperative Factors. Postoperative factors that increase the risk for myocardial ischemia include hypothermia, anemia, tachycardia, inadequate analgesia, and extreme changes in blood pressure. These factors contribute to increased adrenergic stress, which can increase oxygen demand on the myocardium, as well as increased platelet aggregation and coronary vasoconstriction.52–55 The postoperative period is also characterized by hypercoagulability due to increased platelet number, diminished fibrinolysis, and decreased natural anticoagulants (protein C and antithrombin III), factors which in turn increase the tendency for thrombus formation.56 The majority of MIs that occur in the postoperative period are almost invariably preceded by prolonged periods of myocardial ischemia.54,57 Postoperative myocardial ischemia has been associated with a nine- to 32-fold increase in cardiac events; this risk seems to extend long term as well.53–56,58 Detection of postoperative myocardial ischemia is, therefore, of paramount importance for therapeutic interventions to take place and prevent an infarction.

Surveillance Diagnosis. The diagnosis of myocardial ischemia and infarction in neurosurgical patients can be quite challenging. Common tools available to the clinician include (1) the patient’s symptoms, (2) the electrocardiogram, (3) echocardiography, and (4) serum markers of myocardial injury. Symptoms of postoperative myocardial ischemia carry a low diagnostic yield, because the majority of ischemic episodes are “silent.” Moreover, even if angina is present, it may be masked by stronger symptoms such as incisional pain, shivering, headache, or the presence of an endotracheal tube. To complicate the diagnosis even further, some neurosurgical patients suffer from postoperative depression of the sensorium, either as a result of surgery or pharmacologically induced (barbiturates), and thus are unable to communicate any symptoms they may be experiencing. Nevertheless, in conscious patients, the presence of anginal pain merits further diagnosis and treatment in a timely fashion.

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myocardial ischemia

The diagnosis of myocardial ischemia is made most often based on abnormalities of ventricular repolarization seen on the ECG or segmental wall motion assessed by twodimensional ECHO. In patients at risk, the occurrence of new ST-T depressions 1 mm or larger in two or more contiguous ECG leads is highly suggestive of myocardial ischemia. In addition, the magnitude and extent of ST-T depression seem to correlate with the severity of coronary disease. The differential diagnosis of ST-T depression includes left ventricular hypertrophy, digitalis effect, left bundle branch block, and electrolyte abnormalities (hypokalemia, hypomagnesemia). Other ECG signs of myocardial ischemia include the presence of ventricular irritability or new-onset atrial fibrillation. Transthoracic or transesophageal echocardiography can identify new abnormalities in segmental wall motion.59,60 Using the American Society of Echocardiography criteria to evaluate regional wall motion61 (Table 17-2), a new wall motion abnormality is diagnosed as worsening of two grades or the development of akinetic segments from hypokinesia. Ischemic mitral regurgitation due to papillary muscle dysfunction may also be detected. Patients suffering from SAH can have ECG and echocardiographic abnormalities that are indistinguishable from myocardial ischemia and infarction due to CAD.4 In patients with preexisting CAD, the diagnosis of myocardial ischemia from SAH-associated mechanisms versus cardiac injury from abnormalities in coronary flow is extremely difficult, if not impossible. This problem is compounded because increases in serum markers of myocardial necrosis can occur with either condition.62,63 There are no current guidelines to suggest a particular approach, although it is reasonable to assume that the patient has suffered a complication from CAD, which carries a poorer prognosis, and therefore, aggressive treatment should be pursued.

Table 17-2  Segmental Wall Motion Abnormality Scoring Class Uninterpretable Normal Normal Abnormal Abnormal Abnormal

Grade 0 1 2 3 4 5

Title

Excursion

Thickening

NA Normal Mild HK Severe HK Akinesis Dyskinesis

Uninterpretable >30% 10%-30% <10% 0 Outward

Uninterpretable 30%–50% 30%–50% <30% 0 0

HK, hypokinesia. Normal systolic wall motion is characterized by synchronized inward motion toward an imaginary center and concomitant wall thickening. From Shanewise JS, Cheung AT, Aronson S, et al: ASE/SCA guidelines for performing a comprehensive intraoperative multiplane transesophageal examination: Recommendations of the American Society of Echocardiography Council for Intraoperative Echocardiography and the Society of Cardiovascular Anesthesiologists Task Force for Certification in Perioperative Transesophageal Echocardiography. Anesth Analg 1999;89:870.

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myocardial infarction electrocardiography. The electrocardiographic diagnosis of an acute MI is made by the presence of ST-T elevation or persistent ST-T depression. With a few exceptions, characteristic ST-T segment elevation is almost diagnostic of myocardial injury (Fig. 17-4). The appearance of Q waves on the ECG indicates established myocardial necrosis. In general, Q waves are indicators of chronicity, therefore rendering attempts at early reperfusion useless. Published evidence shows that the majority of postoperative infarctions present with ST-T depressions (Fig. 17-5), thus making the diagnosis more difficult and requiring confirmation with serum markers of myocardial necrosis.64,65 echocardiography. Persistent segmental wall motion abnormalities are compatible with an MI, particularly if they occur despite treatment targeted for the relief of myocardial ischemia. serum markers. The cornerstone of the diagnosis for infarction remains the increase in serum markers, which indicate myocardial damage. The increase of CK isoenzymes from the myocardium (MB fraction) is rather sensitive. CK-MB activity increases within 6 to 8 hours and remains elevated for 48 hours. In the surgical patient, CK-MB elevations have been associated with a high false-positive rate due to the expression of MB fraction in the skeletal muscle.66 Patients undergoing spinal surgery often demonstrate postoperative elevations of CK-MBs in the absence of myocardial injury.67 Nevertheless, in some neurosurgical patients, the expected increase in MB fraction from noncardiac sources is minimal, and thus an exaggerated elevation should suggest a myocardial etiology. More specific are the proteins of the troponin complex. Two assays are commonly utilized: troponin T and troponin I. Troponin T increases at 4 hours and remains elevated for 10 to 14 days; levels exceeding 0.1 ng/mL are indica-

Figure 17-4. 12-Lead electrocardiogram from a patient suffering from an acute anteroseptal myocardial infarction on the second postoperative day. Note the elevation of the ST-T segment in precordial leads V1-V4 (most pronounced in leads V2-V3), and the absence of Q waves. The rhythm is sinus tachycardia with a rate of 120 beats per minute.

Figure 17-5. 12-Lead electrocardiogram obtained 24 hours postoperatively. The underlying rhythm is sinus tachycardia (rate of 100 beats per minute). There is “upsloping” ST-T depression present in leads V2-V5. Serum markers were positive for myocardial infarction.

tive of myocardial damage.68 Although more specific than CK, there are some small amounts present in skeletal muscle. Troponin I is the most specific serum marker, because it exists only in the myocardium. Serum levels also begin to increase around 4 hours and remain elevated for 7 to 10 days. Levels greater than 1 ng/mL are indicators of myocardial injury.69,70 The incidence of postoperative MI appears to peak within 48 to 72 hours of surgery (range, 24 hours to 5 days).65,71 Patients at high risk for perioperative MI should be placed under increased surveillance. The current American College of Cardiology/American Heart Association guidelines state that patients at risk should undergo an electrocardiogram immediately after surgery and daily for at least 2 days.42 In patients in whom the suspicion for perioperative MI is high, serum markers of myocardial injury can aid in the diagnosis. Management Strategies Myocardial Ischemia beta blockers. Beta-adrenergic blocking drugs are most efficacious in preventing postoperative myocardial ischemia, predominantly through their ability to suppress tachycardia and hypertension.55,57,72 There is solid evidence to support the use of beta blockers to decrease the incidence of postoperative myocardial ischemia and infarction.57,72,73 In neurosurgery patients, the use of ordinary doses of beta blockers do not have significant effects on intracranial pressure (ICP) and are the preferred agents if there are no contraindications.74,75 Ideally, beta blockers should be initiated preoperatively and continued though the postoperative period.76 Suggested criteria for patient eligibility and dosing regimens are shown in Tables 17-3 and 17-4. In the postoperative period, intravenous doses of either atenolol or metoprolol are administered to the stable patient who is unable to take oral medications. In the unstable patient, the use of esmolol by continuous infusion allows for

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Table 17-3  Criteria for the Use of Perioperative Beta Blockers

Table 17-4  Guidelines for Perioperative Beta Blockade

Minor clinical criteria* Age 65 y or older Hypertension Current smoker Serum cholesterol > 240 mg/dL (6.2 mmol/L) Diabetes mellitus not requiring insulin

Preoperative Period

Revised cardiac risk index criteria† Documented ischemic heart disease Cerebrovascular disease (TIAs or CVA) Diabetes mellitus requiring insulin Chronic renal insufficiency (serum creatinine 2.0 mg/dL, 177 mmol/L)

543

Outpatients or following hospitalization No previous beta blockers Begin atenolol 50–100 mg or bisosprolol 5–10 mg daily up to 30 days before surgery Titrate to heart rate 65 bpm Already on long-term beta blockers Continue long-term treatment Titrate to heart rate 65 bpm Immediately before induction of anesthesia Atenolol 5–10 mg IV: titrate to a target heart rate 65 bpm

In the absence of contraindications, perioperative beta blockade should be instituted in the presence of two minor criteria, or any of the Revised Cardiac Risk Index. *Modified from Mangano DT, Layug EL, Wallace A, et al: Effect of atenolol on mortality and cardiovascular morbidity after noncardiac surgery. Multicenter Study of Perioperative Ischemia Research Group. N Engl J Med 1996;335:1713. † Modified from Boersma E, Poldermans D, Bax JJ, et al: Predictors of cardiac events after major vascular surgery: Role of clinical characteristics, dobutamine echocardiography, and beta-blocker therapy. JAMA 2001;285:1865.

Immediate Postoperative Period

rapid titration of beta blockade until longer acting medications can be tolerated. The evidence thus far provides a compelling case for the use of b1 selective blockers; nonspecific beta blockers such as propranolol have been associated with hypotension and increased bronchospasm and should not be used.77,78 Beta blockers should be continued at least for the rest of the patient’s hospitalization and the need for prolonged outpatient therapy assessed. If beta blockers are discontinued, it must be done gradually; abrupt withdrawal is associated with a high incidence of rebound cardiac ischemia and infarction.79,80 The use of beta blockers is contraindicated in patients with asthma and severe bronchospastic disease, severe bradycardia, and heart block greater than first degree (prolonged P-R interval).

bpm, beats per minute; IV, intravenous. Modified from Auerbach AD, Goldman L: b-blockers and reduction of cardiac events in noncardiac surgery. JAMA 2002;257:1435–1444.

Patient NPO and stable hemodynamics: atenolol 5–10 mg IV bid or Metoprolol 5–10 mg IV BID to target heart rate Patient unstable or fine titration desired: esmolol 20–200 mg/ kg/min titrated to target heart rate Patient taking oral medications: Resume perioperative beta blockers at previous dose; titrate to target heart rate 65 bpm Overlap first oral dose (atenolol 50–100 mg for patients not previously on beta blockers) with continued intravenous agents to maintain heart rate 65 bpm

postoperative sedation and somnolence, and therefore should not be used in neurosurgical patients.

central alpha agonists. Drugs such as clonidine, mivaze-

nitroglycerin. Prophylactic nitroglycerin has not been found to reduce the prevalence of myocardial ischemia.91,92 Currently, its use is reserved for the treatment of established ischemia. Its anti-ischemic effects are achieved by decreasing ventricular filling pressures and dilating epicardial coronary arteries. In the cerebral circulation, nitroglycerin dilates conductance vessels, and tends to increase cerebral blood flow and cerebral blood volume.93–95 Neurologic deterioration may occur due to increases in ICP. Following aneurysm clipping, the efficacy of nitroglycerin and nitrosodilators in dilating cerebral vessels may be diminished due to inactivation of nitric oxide by free oxyhemoglobin in the subarachnoid space.96 If the status of ICP is not a concern, intravenous nitroglycerin can be administered with a starting dose of 10 mg/min and gradually titrated to achieve a decrease in blood pressure and relieve ischemia or the appearance of other symptoms (e.g., headache).

rol, and dexmedetomidine act by reducing central sympathetic activity, and thus may decrease perioperative ischemia.88–90 Although some small trials suggest that these drugs may be effective, currently there is no evidence to support their routine use. These agents tend to produce

Normothermia. Recovery from intraoperative hypothermia is associated with postoperative myocardial ischemia due to an increase in systemic oxygen demand and increased catecholamine release.97 Aggressive postoperative rewarming and

calcium channel blockers. Intravenous diltiazem can be

used to decrease heart rate and has been reported to decrease myocardial ischemia.81,82 However, both diltiazem and verapamil can increase ICP, probably by inducing cerebral hyperemia,83 and are not cerebral protectants, such as nimodipine and nicardipine, against vasospasm.84–86 The use of nifedipine has been found to increase mortality after acute MI.87

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heat conservation measures are warranted to minimize myocardial stress. Anemia. Anemia is also associated with postoperative

myocardial ischemia, although a fixed “transfusion trigger” in anemic patients with CAD has not been established. It seems reasonable to increase the hematocrit above 30% in high-risk patients and those with myocardial ischemia. Hypertension. Hypertension can occur as a direct effect of lesions at the medulla oblongata and the hypothalamus98 as a consequence of intracranial hypertension or traumatic injuries due to an increase in sympathetic discharge.99,100 The increase in afterload, contractility, and heart rate is detrimental to the myocardial oxygen supply/demand relationship and can exacerbate myocardial ischemia. By decreasing blood pressure, wall tension is decreased and stroke volume is increased, thereby improving coronary perfusion. In choosing among the various drugs to treat hypertension to decrease myocardial oxygen demand, one must also consider their effects on cerebral blood flow and ICP. Clinical doses of these agents are shown in Table 17-5. Nitrosodilators (nitroglycerin and sodium nitroprusside) and nicardipine produce systemic vasodilation and increase ICP, presumably by increasing CBF, with a concomitant increase in cerebral blood volume. Beta-adrenergic agents, such as labetalol and esmolol, have little or no effect on ICP, and angiotensin-converting enzyme inhibitors do not seem to increase ICP.101,102 Fenoldopam is a new antihypertensive drug that acts by stimulating dopaminergic receptors.103,104 Fenoldopam also has moderate affinity for vascular alpha-2 receptors, which tend to produce cerebral vasoconstriction. While some animal studies suggest that fenoldopam increases CBF, a recent study in human volunteers documented decreased regional and global CBF.105 The effects of fenoldopam in patients with disordered cerebral autoregulation are currently unknown. Hypotension. Hypotension produces myocardial ischemia

by decreasing coronary profusion pressure (CPP = DAoP-

VEDP, where DAoP = diastolic aortic pressure and VEDP = ventricular end-diastolic pressure). The most common causes of postoperative hypotension are volume depletion (diuresis, salt wasting) and vasodilatation (spinal shock). Fluid replacement, if indicated, should consist of isoosmolar or, preferably, slightly hyperosmolar solutions. Vasopressors used within the normal cerebral autoregulatory limits have no impact on cerebral blood flow, provided that the blood-brain barrier is intact. When CBF is disrupted, these drugs may exhibit an excitatory effect on brain function.103 If poor contractility is present, inotropic therapy should be considered (see following discussion). Myocardial Infarction. If MI is suspected, a cardiology con-

sultation should be requested as soon as possible. The immediate goals for treatment of a perioperative MI are the same as those for the treatment of MI in the nonsurgical population. These include (1) reperfusion of the ischemic myocardium that is supplied by the occluded coronary artery, (2) antithrombotic therapy to prevent re-thrombosis, (3) adjunctive measures to improve myocardial oxygen supply/demand, and (4) treatment of complications, such as dysrhythmias and pump failure. In patients with a complicated clinical picture (e.g., congestive heart failure [CHF], pulmonary edema, concomitant HHH therapy), invasive monitoring with a pulmonary artery catheter and bedside echocardiographic imaging are invaluable to guide therapy, identify the extent and location of myocardial damage, evaluate biventricular function, and diagnose mitral insufficiency. The use of intravenous thrombolytic therapy within 2 weeks of the surgical procedure is generally contraindicated. Instead, urgent cardiac catheterization with percutaneous coronary intervention should be considered as a primary strategy for myocardial reperfusion. Beta blockers decrease infarct size, postinfarction ischemia, dysrhythmias, and overall morbidity and mortality and should be administered in all patients with no contraindications.106 The dose is titrated to decrease heart rate to less than 70 beats per minute.

Table 17-5  Intravenous Therapy for Severe Hypertension Drug

Dose Range

Comments

Nitroprusside

0.5–10 mg/kg/min

Nitroglycerin Nicardipine

0.5–10 mg/kg/min Initially 5–15 mg/kg/h Maintenance, 0.5–2 mg/h 0.1–0.5 mg/kg/min 0.625–1.25 mg q 6h 5–80 mg as IV bolus q 5–10 min 1–2 mg/min by infusion 25–300 mg/kg/min

Rapid onset; 2–3 min duration of action. May cause myocardial ischemia. Potential for cyanide accumulation at large doses. Increases CBF. Useful with coexistent myocardial ischemia. Increases CBF. Onset 5–10 min. Increases CBF. May be useful against cerebral vasospasm. Rapid onset. Effects on CBF unclear at this time. Delayed onset. Long acting. Useful in patients already on ACE inhibitors. No change in CBF. Contraindicated in severe bradycardia, heart block, or poor LV function. Same as above.

Fenoldopam Enalaprilat Labetalol Esmolol

ACE, angiotensin-converting enzyme; CBF, cerebral blood flow; LV, left ventricle.

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Nitroglycerin is effective in decreasing ongoing myocardial ischemia and in cases where acute MI is complicated by CHF and pulmonary edema. Titration should be carried out to decrease the mean arterial pressure by approximately 10% in normotensive individuals or 30% in patients with chronic hypertension. Antiplatelet therapy with aspirin (160–325 mg orally) should be initiated as soon as possible after an acute MI to decrease mortality. Postoperative aspirin appears to be safe in patients following aneurysm clipping. In a recent prospective trial, the administration of aspirin, 100 mg/day, to prevent delayed cerebral ischemia was not associated with a higher incidence of hemorrhage than placebo.107 In patients unable to tolerate oral medications, a suppository of 325 mg aspirin can be administered; in those allergic to aspirin, the platelet adenosine receptor antagonist, clopidogrel, may be used orally at a daily dose of 300 mg.108 Intravenous platelet glycoprotein IIb-IIIa receptor antagonists (eptifibatide, tirofiban and abciximab) are predominantly used in conjunction with percutaneous coronary interventions (angioplasty, stenting, arthrectomies).109 Currently, there is no clinical experience with either clopidogrel or glycoprotein IIb-IIIa antagonists in postoperative neurosurgical patients. The use of these agents can increase the risk of hemorrhage, and, therefore, a high index of suspicion for rebleeding must be maintained. Unfractionated heparin and low-molecular-weight heparins (LMWH) reduce morbidity and mortality in patients with unstable angina and MI.110 Experience in postoperative neurosurgical patients (excluding carotid endarterectomy) is limited to the use of low-dose heparin for the prevention of venous thromboembolism. Full heparinization increases the risk of hemorrhage, although it is reasonable to assume that the risk is reduced the more time elapses from the day of surgery. Because the majority of MIs occur on the first postoperative week, careful consideration should be given to the risk-benefit ratio of full anticoagulation. If hemostasis is stable, heparin should be administered by an intravenous bolus of 5000 to 10,000 units followed by a continuous infusion. Studies in animals following craniotomy suggest titrating the heparin dose to a twofold elevation of activated partial thromboplastin time (aPTT). Higher aPTT values and supratherapeutic levels of heparin were associated with an increased incidence of intracranial hemorrhage.111,112 The administration of subcutaneous LMWHs (e.g., enoxaparin 1 mg/kg every 12 hours) is more effective than unfractionated heparin in decreasing mortality after an MI in nonsurgical patients.113 The role of LMWHs in the treatment of postoperative MI remains to be determined but appears to represent an acceptable alternative. Congestive Heart Failure It is estimated that approximately four million people have CHF, with 400,000 new cases diagnosed every year.114 The

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syndrome of CHF, particularly in a decompensated state, has consistently proven to be a major predictor for perioperative cardiac morbidity and mortality, as well as for pulmonary, renal, and other complications.115,116 On the other hand, compensated CHF carries a better prognosis.42 Complications of CNS disorders can precipitate acute decompensation by producing acute changes in systemic blood pressure, triggering dysrhythmias, or by direct actions on myocardial function (e.g., SAH). In addition, because coronary disease accounts for two thirds of the patients with CHF, postoperative ischemic events may result in acute heart failure. Diagnosis The diagnosis of chronic decompensated CHF carries a significant prognostic risk, and therefore its recognition is paramount to optimize therapy and prevent acute exacerbations. The most reliable signs that indicate chronic decompensated CHF include the presence of jugular venous distention and a third heart sound.117–119 Other signs, such as pulmonary crackles and peripheral edema, are less specific. In contrast, acute decompensated CHF is manifested by increased pulmonary congestion, dyspnea, and radiographic findings compatible with pulmonary edema, with or without low cardiac output. After the diagnosis is made, it is necessary to establish whether the predominant mechanism is depressed contractility (systolic dysfunction), decreased ventricular compliance (diastolic dysfunction), or both. The symptoms of CHF frequently overlap between systolic and diastolic dysfunction, thus making the clinical diagnosis difficult. The importance of establishing the predominant mechanism for myocardial dysfunction has therapeutic implications because treatment often differs (Table 17-6). Echocardiography is a useful tool that allows for bedside assessment of systolic and diastolic function. The presence of a LVEF equal to or less than 40% is considered indicative of impaired systolic function regardless of the status of ventricular filling pressures. In contrast, the diagnosis of diastolic dysfunction requires documentation of increased

Table 17-6  Treatment of Ventricular Dysfunction Based on Predominant Mechanism Systolic dysfunction Minimize myocardial depressants Increase myocardial contractility (inotropes) Decrease afterload (vasodilators) Intraaortic counterpulsation Ventricular assist device Diastolic dysfunction Rate control (e.g., beta blockers) Preload reduction (diuretics, venodilators) Afterload reduction if hypertension present (arterial vasodilators) Improve coronary flow

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pulmonary wedge pressure or elevated left ventricular diastolic pressure. Doppler analysis of mitral valve and pulmonary venous inflow may identify different grades of impaired filling.120 The main therapeutic goals for patients with CHF should focus on (1) prevention of acute exacerbations and (2) pharmacologic treatment of myocardial dysfunction. Exacerbating Factors Multiple factors can precipitate acute heart failure associated with neurosurgery (Table 17-7). Severe hypertension due to increased ICP, massive adrenergic stress associated with SAH, or volume overload as a result of treatment for vasospasm may result in acute cardiac decompensation and low cardiac output due to the inability of the heart to handle the additional stress. Frequently, multiple factors coexist, and the impact of individual therapies on cardiac function must be considered (e.g., volume overload to correct anemia, myocardial depression with beta blockers or calcium channel blockers). Pharmacologic Strategies Pharmacologic therapy is frequently guided by the information provided by pulmonary artery catheterization. In addition, as mentioned previously, echocardiography can provide useful information whether the predominant mechanism is depressed myocardial contractility or decreased compliance. Hemodynamic assessment is based on the evaluation of systemic perfusion (cardiac output) and left ventricular filling pressure (pulmonary artery occlusion pressure). In the absence of a pulmonary artery catheter, clinical surrogates of tissue perfusion (e.g., urine output, pulse pressure, and systemic blood pressure) and pulmonary vascular congestion such as dyspnea, S3 gallop, and chest radiography findings may provide the diagnosis of CHF; however, their predictive value in an intensive care environment is poor and may lead to inappropriate therapy.121,122 Hemodynamic Profiles. The hemodynamic profile exhibited

by a patient with heart failure may fall into one of four categories (Fig. 17-6). It is important to highlight the dynamic nature of these profiles; therefore, frequent reevaluation is

Table 17-7  Precipitating Factors of Acute Heart Failure Myocardial ischemia Dysrhythmias Anemia Hypoxemia Acidosis Volume overload Hypertension Hypotension Drugs (beta blockers, calcium channel blockers)

imperative because multiple therapies may require simultaneous adjustment.122,123 The different agents available to treat acute decompensated heart failure are listed in Table 17-8. profile a (dry and warm). Signs in this category are characterized by adequate perfusion and normal filling pressures. In this profile, cardiac output is adequate and pulmonary vascular congestion/edema is absent. Therapy is adjusted to maintain normal volume status and avoid precipitating factors. Chronic medications (angiotensin-converting enzyme inhibitors, digoxin) should be initiated as soon as it is feasible. profile b (warm and wet). Signs in this category are characterized by an acute increase in filling pressure, leading to pulmonary vascular congestion and edema; however, tissue perfusion is normal or only slightly impaired. The main therapeutic goal is to relieve pulmonary vascular congestion. If not contraindicated, intravenous nitroglycerin will decrease preload, whereas the administration of diuretics will remove excess water from the lungs. If hypertension is present, afterload reduction will improve stroke volume, with a concomitant decrease in filling pressures. For severe systolic dysfunction (LVEF £30%), therapy with inodilators may be indicated. Drugs in this category include the phosphodiesterase type III (PDEIII) inhibitors, milrinone, amrinone, and enoximone. These compounds inhibit the activity of PDEIII, the enzyme responsible for cyclic adenosine monophosphate breakdown in myocardial and vascular smooth muscle. The end result is an increase in contractility and vasodilatation.124 Amrinone was the first PDEIII inhibitor available for clinical use. The administration of amrinone is commonly associated with thrombocytopenia; thus, it has been largely replaced by milrinone, which has no significant effects on platelet function. Enoximone is not currently available in the United States. Unlike beta-adrenergic agents, PDEIII inhibitors do not require interaction with membrane receptors, and their use is associated with minimal increases in myocardial oxygen consumption.124 These agents also produce pulmonary and systemic vasodilatation; hypotension may result, particularly in patients with decreased preload. Preliminary evidence suggest that PDEIII inhibitors increase cerebral blood flow and may provide beneficial effects against cerebral vasospasm due to direct effects on cerebral vessels.40,125,126 profile c (cold and dry). These patients exhibit low cardiac

output without clinical evidence of elevated filling pressures. Determining optimal preload guided by frequent reassessment of cardiac output and filling pressures will improve perfusion while avoiding volume overload. In patients with severe systolic dysfunction or those with hypotension, inotropic agents may be required to “accommodate” intravenous fluid therapy.

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Figure 17-6. Diagram indicating the hemodynamic profiles for patients presenting with acute heart failure. This classification helps guide initial therapy; however in practice, most patients may be on the border between the warm-and-wet and cold-and-wet profiles. Although most patients presenting with hypoperfusion also have elevated filling pressures (cold and wet profile), many patients present with elevated filling pressures without major reduction in perfusion (warm and wet profile). Patients with hypoperfusion and low/normal filling pressures (cold and dry profile) usually suffer from severe vasodilatation (e.g., spinal cord injury) or hypovolemia in the presence of preexisting ventricular dysfunction. CO, cardiac output. (Modified from Nohria A, Lewis E, Stevenson LW: Medical management of advanced heart failure. JAMA 2002;287:628–640.)

profile d (wet and cold). This state is characterized by decreased tissue perfusion (low cardiac output) and pulmonary congestion (increased filling pressures). Treatment includes the use of inotropic drugs and perhaps intra-aortic counterpulsation. Frequently, the combination of inotropic drugs with different mechanisms of action (e.g., a PDEIII inhibitor and a beta-adrenergic agent) produces better results, allowing for lower doses of each agent, thereby minimizing side effects.127 Intra-aortic counterpulsation improves systolic function by decreasing the impedance to left ventricular ejection and enhancing coronary perfusion. The use of IABP counterpulsation increases cerebral blood flow and may decrease the severity of cerebral vasospasm.41,128

Valvular Disease Patients with valvular disease who undergo major neurosurgical procedures are at risk for developing cardiovascular complications whether from changes in loading conditions, the occurrence of dysrhythmias, or as a result of hemodynamic-oriented therapy. In general, the risk is higher for patients with stenotic lesions. This section will address the

evaluation and postoperative management of the most common valvular lesions seen in adult patients. Aortic Stenosis Valvular aortic stenosis (AS) is usually congenital or degenerative in origin. In the natural history of AS, there is a long latent period during which there is gradually increasing obstruction and pressure load on the myocardium while the patient remains asymptomatic, while at the same time morbidity and mortality are very low.129 When the classic symptoms of angina, syncope, and heart failure develop, the prognosis changes dramatically. Severe AS is considered an independent major risk factor for perioperative cardiovascular complications following noncardiac surgery.130,131 Nevertheless, recent data have reported a decrease in perioperative mortality (although morbidity remains high), probably reflecting advances in monitoring and early treatment of complications.131 The normal aortic valve area is 2.6 to 3.5 cm2. Symptoms generally occur when the valve area has narrowed to one fourth its normal size (i.e., 0.5 cm2/m2), and the peak systolic gradient across the valve exceeds 50 mm Hg in the presence of a normal cardiac output.

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Table 17-8  Drugs Used in the Treatment of Acute Heart Failure Vasodilators

IV Dose Range

Comments

Nitroprusside (arterial = venous)

0.5–3 mg/kg/min

Nitroglycerin (Venous > Arterial)

0.5–5 mg/kg/min

Nesiritide (brain natriuretic peptide) Arterial and venous vasodilator

0.015–0.03 mg/kg/min

Fenoldopam (arterial)

0.01–0.03 mg/kg/min

Enalaprilat (arterial > venous) Morphine sulfate

0.625–1.25 mg q6h

Rapid onset and duration of action. May produce coronary steal and reflex tachycardia. Increases CBF. Useful with coexistent myocardial ischemia. Tolerance develops quickly. Increases CBF Onset 5–10 minutes. Increases CBF. Associated with “salt wasting” and hyponatremia following SAH. May exacerbate cerebral vasospasm. Rapid onset. May cause reflex tachycardia. Effects on CBF unclear at this time Delayed onset. Long acting. Not useful for immediate treatment. Decreases anxiety and relieves angina. May cloud sensorium. Nausea and vomiting may confuse clinical examination in patients with increased ICP.

3–10 mg as needed

Diuretics Furosemide

20–80 mg (Infusion: 5–10 mg/h)

Torsemide

5–10 mg

Bumetamide

0.5–2 mg

Inotropes Epineprhine Norepinephrine Dopamine Dobutamine Inodilators Dopexamine Isoproterenol Amrinone Milrinone

Loop diuretic. Concomitant kaliuresis may precipitate dysrhythmias. Also a venodilator More potent than furosemide. Similar mechanism of action and side effects. Strongest diuretic available. May work in patients already on high doses of furosemide. Adrenergic receptor effects b (b1 = b2) a and b a = b1 Dopaminergic b (b1 > b2) a>b b1 > b2 = a

0.01–0.03 mg/kg/min 0.04–0.15 mg/kg/min 0.01–0.15 mg/kg/min 2–5 mg/kg/min 5–10 mg/kg/min 10 mg/kg/min 5–20 mg/kg/min 2.5–10 mg/kg/min 1–4 mg/min Loading dose: 0.75 mg/kg over 10 min Continuous infusion: 5–10 mg/kg/min Loading dose: 50 mg/kg over 10–20 min Continuous infusion: 0.375–0.50 mg/kg/min

b2 and dopaminergic effects b1 = b2 effects

CBF, cerebral blood flow; ICP, intracranial pressure; SAH, subarachnoid hemorrhage.

Stenosis at the level of the aortic valve results in a pressure gradient from the left ventricle (LV) to the aorta. In adults with AS, this obstruction usually increases gradually over a prolonged period, and left ventricular output is maintained by the presence of left ventricular hypertrophy. However, the LV chamber size is essentially unchanged, and wall tension remains essentially normal in well-compensated patients with AS. With long-standing AS, myocardial contractility progressively deteriorates and further compromises left ventricular function. Myocardial ischemia can occur with AS due to the combination of increased oxygen needs by the hypertrophied myocardium and reduction of oxygen delivery secondary to the excessive compression of coronary vessels. In

addition, approximately 50% of patients have concomitant CAD.132 Hemodynamic Goals. Prevention of significant decreases in systemic vascular resistance is of paramount importance in management of patients with AS. Vasodilatation will not reduce the work of the left ventricle but will reduce coronary perfusion pressure leading, to life-threatening ischemia. Avoidance of bradycardia, maintenance of sinus rhythm, and normal intravascular volume are also important. The hypertrophied and noncompliant left ventricle requires a coordinated atrial contraction to provide adequate left ventricular filling; otherwise, a sudden decrease in cardiac

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output may cause severe hypotension. Likewise, atrial fibrillation with rapid ventricular response may cause ischemia and should be treated aggressively. Bradycardia is also poorly tolerated because of the inability of the left ventricle to generate a compensatory response to maintain cardiac output by increasing stroke volume. Aortic Regurgitation Left ventricular volume overload is the characteristic feature of aortic insufficiency. As a result of increased end-diastolic wall tension, serial replication of sarcomeres occurs, producing the pattern of eccentric ventricular hypertrophy. As the disease progresses, recruitment of preload reserve and compensatory hypertrophy allow the ventricle to maintain normal ejection performance despite the elevated afterload. Left ventricular systolic dysfunction is initially reversible. However, as the amount of aortic regurgitation exceeds more than 60% of the stroke volume, progressive LV dilatation and hypertrophy occur, leading to irreversible myocardial damage.132–134 Hemodynamic Goals. Maintenance of normal intravascular

volume and normal or decreased systemic vascular resistance is crucial because the primary mechanism for the regurgitant flow is an increase in stroke volume. However, overzealous fluid replacement can result in pulmonary edema, and excessive decreases in afterload may result in myocardial ischemia because the aortic diastolic pressure is already low. Avoidance of bradycardia is beneficial because the increased diastolic time will exacerbate regurgitation. Mitral Stenosis Mitral stenosis (MS) is typically rheumatic in origin and primarily affects women. Only 25% of patients have isolated MS, while 40% have MS and mitral regurgitation (MR).135,136 The normal mitral valve area is 4.0 to 6.0 cm2. Narrowing of the valve area to less than 2.5 cm2 must occur before the development of symptoms.135,136 With a valve area less than 1 cm2, a significant left atrioventricular pressure gradient is required to maintain a normal cardiac output at rest. In turn, the elevated left atrial pressure increases pulmonary capillary pressures, resulting in exertional dyspnea.137 The pathophysiology of MS stems from increased left atrial pressure and reduced cardiac output, primarily caused by impaired filling of the left ventricle from the obstructed left atrium. In patients with a markedly increased pulmonary vascular resistance, right ventricular function is often impaired. Pulmonary hypertension increases the risk associated with surgery.136,137 Hemodynamic Goals. Maintenance of sinus rhythm and

avoidance of tachycardia is extremely important. In patients with MS, the gradient across the mitral valve is critically dependent on heart rate. In the presence of tachycardia, left atrial pressure will increase and is rapidly transmitted back

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to the pulmonary capillaries, which may result in pulmonary edema and right ventricular failure. Moreover, the inability to maintain left ventricular filling may result in hypotension. Systemic vascular resistance must be maintained because stroke volume is unlikely to increase with afterload reduction. On the other hand, vasodilatation may induce right ventricular ischemia by decreasing the aortic diastolic pressure necessary for adequate perfusion of the right ventricle. Factors that increase pulmonary hypertension such as hypoxemia, hypercarbia, acidosis, and hypothermia should be avoided. Otherwise, the already compromised right ventricle can acutely fail. Preload must be maintained or slightly increased to provide adequate flow across the mitral valve for left ventricular filling. However, excessive fluid administration may result in pulmonary edema. Mitral Regurgitation MR occurs from defects of any of the structures of the mitral valve apparatus, which include the valve leaflets per se, the mitral annulus, the chordae tendineae, and the papillary muscles.133,138 In acute MR, the volume overload increases LV end-diastolic pressure. Although the measured ejection fraction increases, the forward stroke volume is reduced because part of the stroke volume is regurgitated into the left atrium. Severe MR causes a sudden increase in left atrial pressure due to the relatively noncompliant left atrium, leading to severe pulmonary edema and symptoms of acute left ventricular failure. Unless such patients are treated aggressively, a fatal outcome is almost certain. In contrast, chronic MR is compensated for by the development of ventricular dilatation, which allows for an increase in both the ejection fraction and the forward stroke volume. Accordingly, enlargement of the left atrium allows the volume overload to generate lower filling pressures. In this phase of compensated MR, the patient may be entirely asymptomatic, even during vigorous exercise. The transition to chronic decompensated MR is characterized by LV dysfunction. In this phase, end-systolic volume is increased, and forward stroke volume is decreased, resulting in increased LV filling pressure and pulmonary congestion.138 Hemodynamic Goals. Decreased systemic vascular resistance

is the basis for the care of patients with MR. Increases in afterload worsen the regurgitant fraction. In addition, faster than normal heart rates are beneficial because bradycardia can increase the regurgitant volume by increasing left ventricular end-diastolic volume and mitral annular distension. Tachycardia should be avoided if the MR is secondary to myocardial ischemia.139,140 Preload reduction may be beneficial, as long as it is not excessive, because adequate volume to maintain adequate forward stroke volume is essential. Similarly, excessive volume expansion can also worsen the regurgitation by increasing the radius of the left ventricle.

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P earls 1. Increasing data suggest that the insula is a modulator of cardiac autonomic tone and, as such, an important arrhythmogenic center. ECG changes are usually transient, resolving within weeks; QTc prolongation and U waves can be permanent. 2. Arrhythmias occur immediately after blood is introduced into the subarachnoid space and are associated with acute increases in intracranial pressure. 3. The ECG patterns most predictive of left ventricular dysfunction are T wave inversions and prolonged QTc.25 Not all patients with these ECG patterns or other abnormalities will have underlying myocardial injury. The echocardiographic patterns of myocardial injury often do not correlate with a specific coronary artery distribution. 4. In patients with SAH, there seems to be an association between female gender, poor neurologic grade, and the development of myocardial dysfunction. 5. An ECG should be performed in a patient of any age with documented intracranial pathology. If the ECG is abnormal or arrhythmias are present, a transthoracic or transesophageal ECHO should be considered. 6. Milrinone not only improves myocardial contractility but has both arterial and venodilation properties. However, its cerebral vasodilating properties could be detrimental in patients with abnormal intracranial elastance. 7. Postoperative factors that increase the risk for myocardial ischemia include hypothermia, anemia, tachycardia, inadequate analgesia, and extreme changes in blood pressure. 8. The differential diagnosis of ST-T depressions includes left ventricular hypertrophy, digitalis effect, left bundle branch block, and electrolyte abnormalities (hypokalemia, hypomagnesemia). 9. The increase of CK isoenzymes from the myocardium (MB fraction) is rather sensitive. CK-MB activity

References 1. Talman WT, Kelkar P: Neural control of the heart. Central and peripheral. Neurol Clin 1993;11:239. 2. Crick SJ, Sheppard MN, Anderson RH: In Ter Horst GJ (ed): The Nervous System and the Heart. Totowa, NJ, Humana Press, 2000, pp 3–54. 3. Di Pasquale G, Pinelli G, Andreoli A, et al: Holter detection of cardiac arrhythmias in intracranial subarachnoid hemorrhage. Am J Cardiol 1987;59:596. 4. Szabo MD, Crosby G, Hurford WE, et al: Myocardial perfusion following acute subarachnoid hemorrhage in patients with an abnormal electrocardiogram. Anesth Analg 1993;76:253.

10.

11.

12.

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17.

increases within 6 to 8 hours and remains elevated for 48 hours. Troponin T increases at 4 hours and remains elevated for 10 to 14 days; levels exceeding 0.1 ng/mL are indicative of myocardial damage. Troponin I is the most specific serum marker, because it exists only in the myocardium. Serum levels also begin to increase around 4 hours and remain elevated for 7 to 10 days. Levels greater than 1 ng/mL are indicators of myocardial injury. The incidence of postoperative MI appears to peak within 48 to 72 hours of surgery (range, 24 hours to 5 days). The evidence thus far provides a compelling case for the use of b1-selective blockers; nonspecific beta blockers such as propranolol have been associated with hypotension and increased bronchospasm and should not be used. In the cerebral circulation, nitroglycerin dilates conductance vessels, and tends to increase cerebral blood flow and cerebral blood volume. Neurologic deterioration may occur due to increases in ICP. It is estimated that approximately four million people have CHF, with 400,000 new cases diagnosed every year. The most reliable signs that indicate chronic decompensated CHF include the presence of jugular venous distention and a third heart sound.117-119 Other signs, such as pulmonary crackles and peripheral edema, are less specific. In the absence of a pulmonary artery catheter, clinical surrogates of perfusion (e.g., urine output, pulse pressure and systemic blood pressure) and pulmonary vascular congestion such as dyspnea, S3 gallop, and chest radiography findings may provide the diagnosis of CHF; however, their predictive value in an intensive care unit is poor and may lead to inappropriate therapy.

5. Pollick C, Cujec B, Parker S, et al: Left ventricular wall motion abnormalities in subarachnoid hemorrhage: an echocardiographic study. J Am Coll Cardiol 1988;12:600. 6. Manninen PH, Gelb AW, Lam AM, et al: Perioperative monitoring of the electrocardiogram during cerebral aneurysm surgery. J Neurosurg Anesthesiol 1990;2:16. 7. Hersch C: Electrocardiographic changes in subarachnoid haemorrhage, meningitis, and intracranial space-occupying lesions. Br Heart J 1964;26:785. 8. Hersch C, Med D: Electrocardiographic changes in head injuries. Circulation 1961;23:853. 9. Goldstein DS: The electrocardiogram in stroke: Relationship to pathophysiological type and comparison with prior tracings. Stroke 1979;10:253.

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Chapter 17  10. Dujardin KS, McCully RB, Wijdicks EFM, et al: Myocardial dysfunction associated with brain death: Clinical, echocardiographic, and pathologic features. J Heart Lung Transplant 2001;20:350. 11. Byer E, Ashman R, Toth LA: Electrocardiograms with large, upright T waves and long Q-T intervals. Am Heart J 1947;33:796. 12. Oppenheimer SM, Cechetto DF, Hachinski VC: Cerebrogenic cardiac arrhythmias. Cerebral electrocardiographic influences and their role in sudden death. Arch Neurol 1990;47:513. 13. Cheung RTF, Hachinski V: The insula and cerebrogenic sudden death. Arch Neurol 2000;57:1685. 14. Eckardt M, Gerlach L, Welter FL: Prolongation of the frequency-corrected QT dispersion following cerebral strokes with involvement of the insula of Reil. Eur Neurol 1999;42:190. 15. Umali F, Gould L, Gomprecht RF: Electrocardiographic changes in intracranial lesions. Angiology 1971;22:616. 16. Zaroff JG, Rordorf GA, Newell JB, et al: Cardiac outcome in patients with subarachnoid hemorrhage and electrocardiographic abnormalities. Neurosurgery 1999;44:34. 17. Andreoli A, di Pasquale G, Pinelli G, et al: Subarachnoid hemorrhage: Frequency and severity of cardiac arrhythmias. A survey of 70 cases studied in the acute phase. Stroke 1987;18:558. 18. Tokgozoglu SL, Batur MK, Topcuoglu MA, et al: Effects of stroke localization on cardiac autonomic balance and sudden death. Stroke 1999;30:1307. 19. Estanol BV, Loyo MV, Mateos JH, et al: Cardiac arrhythmias in experimental subarachnoid hemorrhage. Stroke 1977;8:440. 20. Horowitz MB, Willet D, Keffer J: The use of cardiac troponin-I (cTnI) to determine the incidence of myocardial ischemia and injury in patients with aneurysmal and presumed aneurysmal subarachnoid hemorrhage. Acta Neurochir (Wien) 1998;140:87. 21. Parekh N, Venkatesh B, Cross D, et al: Cardiac troponin I predicts myocardial dysfunction in aneurysmal subarachnoid hemorrhage. J Am Coll Cardiol 2000;36:1328. 22. Mayer SA, Lin J, Homma S, et al: Myocardial injury and left ventricular performance after subarachnoid hemorrhage. Stroke 1999;30:780. 23. Kono T, Morita H, Kuroiwa T, et al: Left ventricular wall motion abnormalities in patients with subarachnoid hemorrhage: Neurogenic stunned myocardium. J Am Coll Cardiol 1994;24:636. 24. Zaroff JG, Rordorf GA, Ogilvy CS, et al: Regional patterns of left ventricular systolic dysfunction after subarachnoid hemorrhage: Evidence for neurally mediated cardiac injury. J Am Soc Echocardiogr 2000;13:774. 25. Mayer SA, LiMandri G, Sherman D, et al: Electrocardiographic markers of abnormal left ventricular wall motion in acute subarachnoid hemorrhage. J Neurosurg 1995;83:889. 26. Doshi R, Neil-Dwyer G: A clinicopathological study of patients following a subarachnoid hemorrhage. J Neurosurg 1980;52:295. 27. Connor RC: Heart damage associated with intracranial lesions. BMJ 1968;3:29. 28. Yanowitz F, Preston JB, Abildskov JA: Functional distribution of right and left stellate innervation to the ventricles: Production of neurogenic electrocardiographic changes by unilateral alteration of sympathetic tone. Circulation Res 1966;18:416. 29. Klouda MA, Brynjolfsson G: Cardiotoxic effects of electrical stimulation of the stellate ganglia. Ann NY Acad Sci 1969;156:271. 30. Burch GE, Sun SC, Colcolough HL, et al: Acute myocardial lesions. Following experimentally induced intracranial hemorrhage in mice: A histological and histochemical study. Arch Pathol 1967;84:517. 31. Van Vliet PD, Burchell HB, Titus JL: Focal myocarditis associated with pheochromocytoma. N Engl J Med 1966;274:1102. 32. Melville KI, Blum B, Shister HE, et al: Cardiac ischemic changes and arrhythmias induced by hypothalamic stimulation. Am J Cardiol 1963;12:781. 33. Offerhaus L, van Gool J: Electrocardiographic changes and tissue catecholamines in experimental subarachnoid haemorrhage. Cardiovasc Res 1969;3:433.

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34. Neil-Dwyer G, Walter P, Cruickshank JM, et al: Effect of propranolol and phentolamine on myocardial necrosis after subarachnoid haemorrhage. BMJ 1978;2:990. 35. Svigelj V, Grad A, Tekavcic I, et al: Cardiac arrhythmia associated with reversible damage to insula in a patient with subarachnoid hemorrhage. Stroke 1994;25:1053. 36. Oppenheimer SM, Gelb A, Girvin JP, et al: Cardiovascular effects of human insular cortex stimulation. Neurology 1992;42:1727. 37. Haley EC Jr, Kassell NF, Torner JC: The International Cooperative Study on the Timing of Aneurysm Surgery. The North American experience. Stroke 1992;23:205. 38. Archer DP, Shaw DA, Leblanc RL, et al: Haemodynamic considerations in the management of patients with subarachnoid haemorrhage. Can J Anaesth 1991;38:454. 39. Cummings RO (ed): ACLS Provider Manual 2001, American Heart Association, pp 1–252. 40. Sulek CA, Blas ML, Lobato EB: Milrinone increases middle cerebral artery blood flow velocity after cardiopulmonary bypass. J Cardiothorac Vasc Anesth 2002;16:64. 41. Apostolides PJ, Greene KA, Zabramski JM, et al: Intraaortic balloon pump counterpulsation in the management of concomitant cerebral vasospasm and cardiac failure after subarachnoid hemorrhage: Technical case report. Neurosurgery 1996;38:1056. 42. Eagle KA, Berger PB, Calkins H, et al: ACC/AHA Guideline Update for Perioperative Cardiovascular Evaluation for Noncardiac Surgery-Executive Summary. A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee to Update the 1996 Guidelines on Perioperative Cardiovascular Evaluation for Noncardiac Surgery). Anesth Analg 2002;94:1052. 43. Davies KR, Gelb AW, Manninen PH, et al: Cardiac function in aneurysmal subarachnoid haemorrhage: A study of electrocardiographic and echocardiographic abnormalities. Br J Anaesth 1991; 67:58. 44. Mayer SA, Lin J, Homma S, et al: Myocardial injury and left ventricular performance after subarachnoid hemorrhage. Stroke 1999;30: 780. 45. Britton M, de Fairu, Helmers C, et al: Arrhythmias in patients with acute cerebrovascular disease. Acta Med Scand 1979;205:425. 46. Badner NH, Knill RL, Brown JE, et al: Myocardial infarction after noncardiac surgery. Anesthesiology 1998;88:572. 47. Ashton CM, Petersen NJ, Wray NP, et al: The incidence of perioperative myocardial infarction in men undergoing noncardiac surgery. Ann Intern Med 1993;18:504. 48. Tarhan S, Moffit EA, Taylor WF, et al: Myocardial infarction after general anesthesia. JAMA 1972;220:1451. 49. Mangano DT, Goldman L: Perioperative assessment of patients with known or suspected coronary disease. N Engl J Med 1995;333: 1750. 50. Goldman L, Caldera DL, Nussbaum SR, et al: Multifactorial index of cardiac risk in noncardiac surgical procedures. N Engl J Med 1997; 845:1977. 51. Lee TH, Marcantonio ER, Mangione CM, et al: Derivation and prospective evaluation of a simple index for prediction of cardiac risk of major noncardiac surgery. Circulation 1999;100:1043. 52. Mangano DT, Browner WS, Hollenberg M, et al: Association of perioperative myocardial ischemia with cardiac morbidity and mortality in men undergoing noncardiac surgery. The Study of Perioperative Ischemia Research Group. N Engl J Med 1990;323:1781. 53. Mangano DT, Wong MG, London MJ, et al: Perioperative myocardial ischemia in patients undergoing noncardiac surgery–II: Incidence and severity during the 1st week after surgery. The Study of Perioperative Ischemia (SPI) Research Group. J Am Coll Cardiol 1991;17:851. 54. Landesberg G, Luria MH, Cotev S, et al: Importance of long-duration postoperative ST-T depression in cardiac morbidity after vascular surgery. Lancet 1993;341:715.

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55. Mangano DT, Layug EL, Wallace A, et al: Effect of atenolol on mortality and cardiovascular morbidity after noncardiac surgery. Multicenter Study of Perioperative Ischemia Research Group. N Engl J Med 1996;335:1713. 56. Sprung J, Abdelmalak B, Gottlieb A, et al: Analysis of risk factors for myocardial infarction and cardiac mortality after major vascular surgery. Anesthesiology 2000;93:129. 57. Ellis J: Perioperative myocardial ischemia and infarction in noncardiac surgery. Curr Rev Clin Anesth 2002;22:233. 58. Mangano DT, Browner WS, Hollenberg M, et al: Long-term cardiac prognosis following noncardiac surgery. The Study of Perioperative Ischemia Research Group. JAMA 1992;268:233. 59. Skidmore KL, London MJ: Myocardial ischemia. Monitoring for myocardial ischemia: how do I monitor therapy? Anesthesiol Clin North Am 2001;19:651. 60. Massie BM, Botvinick EH, Brundage BH, et al: Relationship of regional myocardial perfusion to segmental wall motion. A physiological basis for understanding the presence of reversibility of asynergy. Circulation 1978;58:1154. 61. Shanewise JS, Cheung AT, Aronson S, et al: ASE/SCA guidelines for performing a comprehensive intraoperative multiplane transesophageal examination: Recommendations of the American Society of Echocardiography Council for Intraoperative Echocardiography and the Society of Cardiovascular Anesthesiologists Task Force for Certification in Perioperative Transesophageal Echocardiography. Anesth Analg 1999;89:870. 62. Mayer SA, Lin J, Homma S, et al: Myocardial injury and left ventricular performance after subarachnoid hemorrhage. Stroke 1999; 30:780. 63. Parekh N, Venkatesh B, Cross D, et al: Cardiac troponin I predicts myocardial dysfunction in aneurysmal subarachnoid hemorrhage. J Am Coll Cardiol 2000;36:1328. 64. Charlson ME, MacKenzie CR, Gold J, et al: The postoperative electrocardiogram and creatine kinase: Implications for diagnosis of myocardial infarction after non-cardiac surgery. J Clin Epidemiol 1989;42:25. 65. Weitz HH: Perioperative cardiac complications. Med Clin North Am 2001;85:1151, vi. 66. Lenke LG, Bridwell KH, Jaffe AS: Increase in creatine kinase MB isoenzyme levels after spinal surgery. J Spinal Disord 1994;7:70. 67. Healy JH, Kagen LJ, Velis KP, et al: Creatine kinase MB in skeletal muscle and serum of spine-fusion patients. Clin Orthop 1985;195:282. 68. Mair J, Artner-Dworzak E, Lechleitner P, et al: Cardiac troponin T in diagnosis of acute myocardial infarction. Clin Chem 1991;37:845. 69. Adams JE III, Sicard GA, Allen BT, et al: Diagnosis of perioperative myocardial infarction with measurement of cardiac troponin I. N Engl J Med 1994;330:670. 70. Haggart PC, Adam DJ, Ludman PF, et al: Comparison of cardiac troponin I and creatine kinase ratios in the detection of myocardial injury after aortic surgery. Br J Surg 2001;88:1196. 71. Mangano DT, Browner WS, Hollenberg M, et al: Association of perioperative myocardial ischemia with cardiac morbidity and mortality in men undergoing noncardiac surgery. The Study of Perioperative Ischemia Research Group. N Engl J Med 1990;323:1781. 72. Boersma E, Poldermans D, Bax JJ, et al: Predictors of cardiac events after major vascular surgery: Role of clinical characteristics, dobutamine echocardiography, and beta-blocker therapy. JAMA 2001; 285:1865. 73. Fleisher LA, Eagle KA: Lowering cardiac risk in noncardiac surgery. N Engl J Med 2001;345:1677. 74. Orlowski JP, Shiesley D, Vidt DG, et al: Labetalol to control blood pressure after cerebrovascular surgery. Crit Care Med 1988;16:765. 75. Poldermans D, Boersma E, Bax JJ, et al: The effect of bisoprolol on perioperative mortality and myocardial infarction in high-risk patients undergoing vascular surgery. Dutch Echocardiographic

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Cardiac Risk Evaluation Applying Stress Echocardiography Study Group. N Engl J Med 1999;341:1789. Auerbach AD, Goldman L: Beta-blockers and reduction of cardiac events in noncardiac surgery: Scientific review. JAMA 2002;287:1435. Bayliff CD, Massel DR, Inculet RI, et al. Propranolol for the prevention of postoperative arrhythmias in general thoracic surgery. Ann Thorac Surg 1999;67:182. Fallowfield JM, Marolw HF: Propranolol is contraindicated in asthma. BMJ 1996;313:1486. Shammash JB, Trost JC, Gold JM, et al: Perioperative beta-blocker withdrawal and mortality in vascular surgical patients. Am Heart J 2001;141:148. Miller RR, Olson HG, Amsterdam EA, Mason DT: Propranolol-withdrawal rebound phenomenon: Exacerbation of coronary events after abrupt cessation of antianginal therapy. N Engl J Med 1975;293:416. Gabrielli A, Gallagher TJ, Caruso LJ, et al: Diltiazem to treat sinus tachycardia in critically ill patients: A four-year experience. Crit Care Med 2001;29:1874. Caramella JP, Goursot G, Carcone B, et al: Prevention of pre- and postoperative myocardial ischemia in non-cardiac surgery by intravenous diltiazem. Ann Fr Anesth Reanim 1988;7:245. Bedford RF, Dacey R, Winn HR, et al: Adverse impact of a calcium entry-blocker (verapamil) on intracranial pressure in patients with brain tumors. J Neurosurg 1983;59:800. A multicenter trial of the efficacy of nimodipine on outcome after severe head injury. European Study Group on Nimodipine in Severe Head Injury. J Neurosurg 1994;80:797. Feigin VL, Rinkel GL, Algra A, et al: Calcium antagonists in patients with aneurysmal subarachnoid hemorrhage: a systematic review. Neurology 1998;50:876. Karinen P, Kouvikangas P, Ohinmaa A, et al: Cost-effectiveness analysis of nimodipine treatment after aneurysmal subarachnoid hemorrhage and surgery. Neurosurgery 1999;45:780. Sleight P: Calcium antagonists during and after myocardial infarction. Drugs 1996;51:216. Talke P, Li J, Jain U, et al: Effects of perioperative dexmedetomidine infusion in patients undergoing vascular surgery. The Study of Perioperative Ischemia Group. Anesthesiology 1995;82:620. Quintin L, Boullioc X, Butin E, et al: Clonidine for major vascular surgery in hypertensive patients: A double-blind, placebo controlled, randomized study. Anesth Analg 1996;83:687. Oliver MF, Goldman L, Julian DG, et al: Effect of mivazerol on perioperative cardiac complications during non-cardiac surgery in patients with coronary heart disease: the European Mivazerol Trial (EMIT). Anesthesiology 1999;91:951. Landesberg G, Erel J, Anner H, et al: Perioperative myocardial ischemia in carotid endarterectomy under cervical plexus block and prophylactic nitroglycerin infusion. J Cardiothorac Vasc Anesth 1993;7:259. Dodds TM, Stone JG, Coromilas J, et al: Prophylactic nitroglycerin infusion during noncardiac surgery does not reduce perioperative ischemia. Anesth Analg 1993;76:705. Ohar JM, Fowler AA, Selhorst JB, et al: Intravenous nitroglycerininduced intracranial hypertension. Crit Care Med 1985;13:867. Dahl A, Russell D, Nyberg-Hansen R, et al: effect of nitroglycerin on cerebral circulation measured by transcranial Doppler and SPECT. Stroke 1989;20:1733. Lagerkranser M: Effects of nitroglycerin on intracranial pressure and cerebral blood flow. Acta Anaesthesiol Scand Suppl 1992;97:34. Yamamoto S, Nishizawa S, Yokoyama T, et al: Subarachnoid hemorrhage impairs cerebral blood flow response to nitric oxide but not to cyclic GMP in large cerebral arteries. Brain Res 1997; 757:1. Frank SM, Fleisher LA, Breslow M, et al: Perioperative maintenance of normothermia reduces the incidence of morbid cardiac events. JAMA 1997;277:1127.

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Chapter 17  98. Bealer SL: Acute hypertensive and natriuretic responses following preoptic hypothalamic lesions. Am J Med Sci 1988;295:346. 99. Clifton GL, Robertson CS, Kyper K, et al: Cardiovascular response to severe head injury. J Neurosurg 1983;59:447. 100. Robertson CS, Clifton GL, Taylor AA: Treatment of hypertension associated with head injury. J Neurosurg 1983;59:455. 101. Cutler NR, Sramek JJ, Luna A, et al: Effect of the ACE inhibitor ceronapril on cerebral blood flow in hypertensive patients. Ann Pharmacother 1996;30:578. 102. Demolis P, Chalon S, Annane D, et al: Effects of an angiotensin converting enzyme, ramipril, on intracranial circulation in healthy volunteers. Br J Clin Pharmacol 1992;34:224. 103. Jover BF, McGrath BP: Beneficial effects of fenoldopam on systemic and regional hemodynamics in rabbits with congestive heart failure. J Cardiovasc Pharmacol 1988;11:483. 104. Olesen J: The effect of intracarotid epinephrine, norepinephrine, and angiotensin on the regional cerebral blood flow in man. Neurology 1972;22:978. 105. Prielipp RC, Wall MH, Groban L, et al: Reduced regional and global cerebral blood flow during fenoldopam-induced hypotension in volunteers. Anesth Analg 2001;93:45. 106. Ryan TJ, Antman EM, Brooks NH, et al: 1999 update: ACC/AHA Guidelines for the Management of Patients with Acute Myocardial Infarction. Executive Summary and Recommendations: A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee on Management of Acute Myocardial Infarction). Circulation 1999;100:1016. 107. Hop JW, Rinkel GJ, Algra A, et al: Randomized pilot trial of postoperative aspirin in subarachnoid hemorrhage. Neurology 2000;54:872. 108. Calvin JE, Klein LW: The use of antiplatelet agents in acute cardiac care. Crit Care Clin 2001;17:365. 109. Konstantopoulos K, Mousa SA: Antiplatelet therapies: Platelet GPIIb/IIIa antagonists and beyond. Curr Opin Investig Drugs 2001;2:1086. 110. Pineo GF, Hull RD: Unfractionated and low-molecular-weight heparin. Comparisons and current recommendations. Med Clin North Am 1998;82:587. 111. Schaible KL, Smith LJ, Fessler RG, et al: Evaluation of the risks of anticoagulation therapy following experimental craniotomy in the rat. J Neurosurg 1985;63:959. 112. Lahoaprasit V, Mayberg MR: Risks of anticoagulation therapy after experimental corticectomy in the rat. Neurosurgery 1993;32:625. 113. Kaul S, Shah PK: Low molecular weight heparin in acute coronary syndromes: Evidence for superior or equivalent efficacy compared with unfractionated heparin? J Am Coll Cardiol 2000;35:1699. 114. Adams K Jr, Zannad F: Clinical definition and epidemiology of advanced heart failure. Am Heart J 1998;135:S204. 115. Pedersen T, Kelbaek H, Munck O: Cardiopulmonary complications in high-risk surgical patients: The value of preoperative radionuclide cardiography. Acta Anaesthesiol Scand 1990;34:183. 116. Halm EA, Browner WS, Tubau JF, et al: Echocardiography for assessing cardiac risk in patients having noncardiac surgery. Study of Perioperative Ischemia Research Group. Ann Intern Med 1996;125:433. 117. Hunt SA, Baker DW, Chin MH, et al: ACC/AHA Guidelines for the Evaluation and Management of Chronic Heart Failure in the Adult. Executive summary. A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee to revise the 1995 Guidelines for the Evaluation and Management of Heart Failure). J Am Coll Cardiol 2001;38:2101. 118. Cheng V, Kazanagra R, Garcia A, et al: A rapid bedside test for B-type peptide predicts treatment outcomes in patients admitted for decompensated heart failure: A pilot study. J Am Coll Cardiol 2001;37:386.

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119. Lobato EB: Perioperative care of the patient with congestive heart failure. Curr Rev Clin Anesth 2000;21:25. 120. Ommen SR, Nishimura RA, Appleton CP, et al: Clinical utility of Doppler echocardiography and tissue Doppler imaging in the estimation of left ventricular filling pressures, A comparative simultaneous Doppler-catheterization study. Circulation 2000;102:1788. 121. Nohriah A, Tsang S, Dries DL, et al: Bedside assessment of hemodynamic profiles identifies prognostic groups in patients admitted with heart failure. J Card Fail 2000;6:64. 122. Nohriah A, Lewis E, Stevenson LW: Medical management of advanced heart failure. JAMA 2002;287:628. 123. Felker GM, O’Connor CM: Inotropic therapy for heart failure: An evidence-based approach. Am Heart J 2001;142:393. 124. Rettig GF, Schieffer HJ: Acute effects of intravenous milrinone in heart failure. Eur Heart J 1989;10:39. 125. Arakawa Y, Kikuta K, Hojo M, et al: Milrinone for the treatment of cerebral vasospasm after subarachnoid hemorrhage: Report of seven cases. Neurosurgery 2001;48:723. 126. Drexler H, Hoing S, Faude F, et al: Central and regional vascular hemodynamics following intravenous milrinone in the conscious rat: Comparison with dobutamine. J Cardiovasc Pharmacol 1987;9: 563. 127. Royster RL, Butterworth JF 4th, Prielipp RC, et al: Combined inotropic effects of amrinone and epinephrine after cardiopulmonary bypass in humans. Anesth Analg 1993;77:662. 128. Montessuit M, Chevalley C, King J, et al: The use of intraaortic counterpulsation balloon for the treatment of cerebral vasospasm and edema. Surgery 2000;127:230. 129. Carabello BA, Crawford FA Jr: Valvular heart disease. N Engl J Med 1997;337:32. 130. Raymer K, Yang H: Patients with aortic stenosis: Cardiac complications in non-cardiac surgery. Can J Anaesth 1998;45:855. 131. Torsher LC, Shub C, Rettke SR, et al: Risk of patients with severe aortic stenosis undergoing noncardiac surgery. Am J Cardiol 1998;81: 448. 132. Guidelines for the management of patients with valvular heart disease. A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Committee on Management of Patients with Valvular Heart Disease. Circulation 1998;98:1949. 133. Carabello BA: Progress in mitral and aortic regurgitation. Prog Cardiovasc Dis 2001;43:457. 134. Tornons MP, Olona P, Permanyer-Miralda G, et al: Clinical outcome of severe asymptomatic chronic aortic regurgitation: A long-term prospective follow-up study. Am Heart J 1995;130:333. 135. Barrington WW, Boudoulas H, Bashore T, et al: Mitral stenosis: Mitral dome excursion at M1 and the mitral opening snap—the concept of reciprocal heart sounds. Am Heart J 1988;115:1280. 136. Delahaye F, Delaye J, Ecochard R, et al: Influence of associated valvular lesions on long-term prognosis of mitral stenosis: A 20-year follow-up of 202 patients. Eur Heart J 1991;12:77. 137. Ward C, Hancock BW: Extreme pulmonary hypertension caused by mitral valve disease: Natural history and results of surgery. Br Heart J 1975;37:74. 138. Carabello BA: Mitral regurgitation: Basic pathophysiologic principles. Mod Concepts Cardiovasc Dis 1988;57:53. 139. Boltwood CM, Tei C, Wong M, et al: Quantitative echocardiography of the mitral complex in dilated cardiomyopathy: The mechanism of functional mitral regurgitation. Circulation 1983;68:498. 140. Schreiber TL, Fisher J, Mangla A, et al: Severe “silent” mitral regurgitation: A potentially reversible cause of refractory heart failure. Chest 1989;96:242.

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Chapter 18 Body Water and Electrolytes Alejandro A. Rabinstein, MD and Eelco F.M. Wijdicks, MD

The controlling mechanisms of homeostasis may become disturbed by acute injury to the brain, craniotomy, or a systemic complication. Perturbations of volume and electrolyte balance may develop rapidly and, if not adequately corrected, they may become a grave clinical problem that is difficult to solve. Most of the time, critical neurologic or neurosurgical patients are particularly prone to develop abnormalities in conservation of sodium and water. Other electrolyte abnormalities are germane to intensive care unit (ICU) stay and may be the result of certain necessary actions (e.g., intravenous fluid administration and drugs). When unrecognized and persistently severe, the potential consequences may be serious, even life threatening, when cardiac arrhythmias occur. Throughout this chapter, we will present general principles that apply to the care of any ICU patient regarding the diagnosis and management of fluid and electrolyte disorders. Additionally, we will address in detail the physiologic concepts that are most necessary for an in-depth understanding of frequently encountered clinical problems in the neurointensive care unit (neuro-ICU). Each section will start with a brief description of the basic physiologic elements required to maintain homeostasis, followed by a discussion of derangements (excess or deficiency) and their proper management illustrated with clinical examples. When appropriate, the consequences of mismanagement will be discussed. Finally, the chapter closes with a summary of essential clinical messages.

Disorders of Sodium and Water Homeostasis Before embarking on the discussion of the disorders and their clinical consequences, we will summarize the principles of homeostasis of body water. To begin with, two thirds of the total fluid content of the human body resides inside cells, while the remaining one third resides in the extracellular space. This extracellular space is further divided into two compartments: the vascular compartment, containing the plasma fluid that represents one-third of the total extracellular fluid volume, and the interstitial compartment, with the other two-thirds of the extracellular volume (Fig. 18-1). Osmotic forces exerted across the cellular membrane regulate the movement of water between the intracellular and the extracellular fluid compartments. These forces (osmotic activity) are determined by the concentration of solute particles in the plasma. The osmotic activity of the solutes in our body fluids is usually expressed in relation to the volume of water in which they are present, measured as serum osmolality and expressed as mOsm/kg H2O. In normal persons, serum osmolality can be estimated using the following formula: Serum osmolality (in mOsm kg H2 O) = 2(Na) + BUN 2.8 + glucose 18 where BUN represents blood urea nitrogen and both BUN and glucose are expressed in milligrams per deciliter. 555

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Figure 18-1. Distribution of total body fluid in the human organism. Two-thirds of total body fluid is intracellular. Of the remaining 1/3 (extracellular), 1/3 is intravascular and 2/3 is interstitial.

Not all solutes contribute to the movement of water across the cellular membrane to the same degree. Obviously, only solutes that are unable to freely cross the membrane are capable of producing an osmotic gradient and influence the distribution of water in the two compartments. This relative

osmotic activity in two solutions (in this case the intracellular and extracellular fluids) separated by a semipermeable membrane (the cellular membrane) is called effective osmolality or tonicity.1 This concept becomes clear when comparing sodium and urea (Fig. 18-2). Sodium is a solute that cannot move freely across the cellular membrane, thus increasing tonicity in the compartment where it is added. Urea, instead, can diffuse freely across the membrane and equilibrate its concentrations in both compartments, creating no net change in the tonicity of the solutions. Hence, both hypernatremia and azotemia are hyperosmotic conditions, but only hypernatremia represents a hypertonic state and leads to a change in the distribution of body water. The regulation of total body water is based primarily on a sensing system designed to respond to plasma osmolality and keep it relatively constant. As alluded earlier, plasma osmolality is determined by the total solute content in the plasma and the total plasma water volume. In normal conditions, the primary determinant of plasma osmolality (and most importantly, plasma effective osmolality or tonicity) is the plasma sodium concentration. And since effective osmolality determines the tendency of water to move across the cellular membrane, plasma sodium concentration is the principal determinant of the relative volumes of the intracellular and extracellular fluids.2 While the mechanisms of sodium conservation aim at maintaining a relatively constant effective circulating volume, the goal of those mediating (free) water balance is to maintain a relatively constant plasma tonicity. Baroreceptors sense intravascular volume status and regulate sodium conservation and excretion, while osmoreceptors sense plasma tonicity and regulate water intake and loss. Hypervolemia and hypovolemia are disorders of sodium balance; in contrast, hypotonic and hypertonic states are disorders of water balance (Fig. 18-3). Accurate assessment of total body sodium relies on a careful physical examination (with the extreme situations being hypovolemic shock and hypervolemic edematous states) and does not require any laboratory measurement. Meanwhile, water balance is best represented by serum sodium concentration (hyponatremia or hypernatremia). Thus, it is important to recognize that serum sodium concentration depends on water balance and not on total body sodium content.

Mechanisms of Water Balance (Regulation of Plasma Tonicity) Figure 18-2. Differences in contribution of sodium and urea to extracellular tonicity. The cellular membrane is relatively impermeable to sodium, thus, addition of sodium to the extracellular compartment will increase extracellular tonicity. Conversely, the cellular membrane allows free passage of urea resulting in rapid equilibration of urea concentrations between the intracellular and extracellular compartments and no net change of extracellular tonicity.

Plasma tonicity is regulated by thirst and the ability of the kidney tubules to conserve or excrete water. In addition, there are normal obligate water losses through the skin and lungs (so called “insensible losses”) and measurable minor losses through the gastrointestinal tract (when added to renal excretion they account for the “sensible losses”). A 70kg person loses a minimum of 1.5 L of water every day,

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Figure 18-3. Differences between total body sodium and total body water. Changes in total body sodium lead to alterations in extracellular fluid volume (including blood volume) and are sensed by baroreceptors, whereas changes in total body water result in alterations of extracellular tonicity and are sensed by osmoreceptors.

and this loss needs to be offset by an intake of at least the same volume of water to avoid dehydration and plasma hypertonicity. Body tonicity is tightly regulated with a normal set point between 280 and 290 mOsm/kg. This tight control is accomplished by the action of osmoreceptors present in the brain that regulate the mechanism of thirst and modulate the secretion of antidiuretic hormone (ADH), both functions of the hypothalamus. ADH-responsive cells are present along the collecting duct. When ADH binds to its receptor, the permeability of the cells to water increases by the activation of water channel proteins known as aquaporin 2. Cell volume depends on the tonicity of the extracellular compartment. Extracellular hypotonicity leads to cell swelling, and cells must eliminate low-molecular-weight solutes (known as osmolytes) to recover their normal volume. Conversely, extracellular hypertonicity produces cell shrinking and subsequent compensatory accumulation of osmolytes to achieve restoration of volume. There are two types of osmolytes: inorganic (such as sodium, potassium and chloride) and organic (including amino acids, methylamines, myoinositol, and sorbitol, among others). Inorganic osmolytes can be shifted in and out of the cells rapidly in response to changes in tonicity gradients. But changes in the concentration of organic osmolytes take longer because the process implies genetic upregulation or downregulation of their synthesis and uptake.

Mechanisms of Total Body Sodium Balance (Regulation of Effective Circulating Volume) Multiple mechanisms contribute to regulate total body sodium balance. The occurrence of either true or perceived hypovolemia, caused by low extracellular fluid volume

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or low tissue perfusion states such as cardiac failure, respectively, triggers a response by a series of vasopressor hormones. These include ADH ([antidiuretic hormone] arginine-vasopressin), renin, and norepinephrine. ADH increases water and secondarily sodium reabsorption by renal collecting ducts, and levels of ADH are elevated in hypovolemic states regardless of plasma tonicity. Renin leads to the activation of angiotensin II, and this hormone increases sodium by directly enhancing its reabsorption by the proximal tubule cells, stimulating the secretion of aldosterone (that, in turn, increases reabsorption of sodium by the distal tubule and collecting duct), and reducing the glomerular filtration rate thereby decreasing sodium delivery to the tubules. Norepinephrine, and epinephrine released by the adrenal medulla, also decrease glomerular filtration rate and stimulate sodium reabsorption at the proximal tubule level. (Fig. 18-4). In contrast, the release of these vasopressor hormones is suppressed in patients with hypervolemic states. In those situations, activation of a family of natriuretic peptides promotes sodium secretion. There are four recognized members of this family: atrial natriuretic peptide, brain natriuretic peptide, C-type natriuretic peptide, and the very recently discovered Dendraspis natriuretic peptide (DNP).3,4 Atrial natriuretic peptide is produced primarily by the heart atria, while brain natriuretic peptide predominates in the ventricles. In addition, all three peptides are produced in the brain, particularly the C-type, and have central as well as peripheral actions. In essence, these substances exert potent natriuretic, diuretic, and vasorelaxant activities. Currently available data suggest they do so by directly acting on renal tubules, increasing glomerular filtration rate, antagonizing the renal effects of ADH, suppressing the renin-angiotensin II-aldosterone axis, reducing sympathetic tone and the peripheral

Figure 18-4. Schematic summary of the physiologic response to hypovolemia. Increased release of “pressor hormones” including antidiuretic hormone (ADH), the members of the renin-angiotensin II-aldosterone (R/AGII/Ald) axis, and norepinephrine (NE) result in water and sodium conservation.

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Figure 18-5. Schematic summary of the physiologic response to hypervolemia. Activation of natriuretic peptides and inhibition of “pressor hormones” combine with peritubular changes to promote natriuresis.

release of catecholamines, and centrally inhibiting salt appetite and thirst. Other effects of hypervolemia that contribute to augment sodium excretion include a fall in plasma colloid osmotic pressure and an increase in interstitial hydraulic pressure; both favoring a lower uptake of sodium and water by the peritubular capillaries. This eventually results in increased interstitial hydrostatic pressures, increased backflow of fluid into the proximal tubule cells, and decreased reabsorption of water and sodium by those cells (Fig. 18-5). The contribution of a different type of natriuretic substance known as ouabain-like factor (OLF), a glycoside acting by inhibition of the Na+-K+ ATPase, is less well established, and interest in this poorly characterized substance has waned after the discovery of the family of natriuretic peptides.

Hypernatremia Hypernatremia is defined as serum sodium concentration exceeding 145 mmol/L. It always represents a deficit of water in relation to the total body sodium stores. This can occur as a consequence of net water loss or a hypertonic sodium gain. The presence of hypernatremia does not signify that there is an excess of sodium content in the body. Indeed, sodium stores may be either normal (in cases of pure water loss) or decreased (in cases of hypotonic fluid loss, such as vomiting or diarrhea).5 Sustained hypernatremia can only be perpetuated when thirst mechanisms are impaired or there is an inability to access water. Critical care patients frequently meet these conditions, especially those that are elderly or have altered states of consciousness. Patients presenting with altered consciousness may have been unable to access water for a pro-

longed period of time, which may be unknown at the time of first evaluation. Hypodipsia may be part of a variety of neurologic and neurosurgical entities. Excessive diaphoresis from agitation or fever can further exacerbate hypotonic fluid losses. The effects of hypernatremia on brain tissue activate a series of compensatory responses aimed at restoring brain volume. These involve the generation of osmotically active substances known as idiogenic osmoles or organic brain osmoles.6,7 Normalization of brain volume ensues, but this new equilibrium counts on the persistence of hyperosmolality. Rapid correction of hyperosmolality (especially when chronic) can render the brain incapable of eliminating the accumulated osmoles promptly enough, resulting in cerebral edema, generalized tonic-clonic seizures, coma, and death (Fig. 18-6).8 Careful assessment of the extracellular fluid volume should be the initial step in the evaluation of hypernatremia. Attention should be focused on recent changes in body weight, presence of peripheral edema, pulse rate, orthostatic changes in blood pressure, hourly urine output, and presence of gallop or jugular venous distention. A random (spot) urine sample can be used to measure sodium concentration (decreased extracellular fluid volume is suggested by a concentration lower than 10 mmol/L), and urine specific gravity (a contracted extracellular volume can be suspected when the urine is very concentrated). A fractional excretion of sodium lower than 1% is suggestive of volume depletion in nonedematous patients. Hypernatremia with low extracellular fluid volume implies a loss of hypotonic fluids. Excessive diuresis, vomiting, and diarrhea are the usual suspects in those situations. Hypernatremia with normal extracellular fluid volume indicates a loss of free water. Diabetes insipidus should be excluded and the appropriateness of the tonicity of fluids used for ongoing replacement reassessed. Hypernatremia with high extracellular fluid volume results from a gain of hypertonic fluids. It is usually iatrogenic, secondary to the use of hypertonic NaCl or NaHCO3 solutions, or hypertonic feeding; but it can also occur in cases of mineralocorticoid excess (Table 18-1). Clinical Manifestations of Hypernatremia Hypernatremia usually becomes symptomatic only when serum sodium concentration exceeds 160 mmol/L9,10 but the rapidity of the elevation of serum sodium levels is equally important; with rapid elevation, stupor emerges more frequently. The signs and symptoms of hypernatremia mostly reflect central nervous system dysfunction caused by the reduction of intracellular fluid volume in the brain. The clinical manifestations may go undetected in patients with other more obvious causes for the neurologic symptoms, such as extensive and prolonged brain injury. Decreased level of consciousness and confusion are the most

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Figure 18-6. Effects of hypernatremia on the brain, adaptive responses, and the potential for iatrogenic damage. Within minutes after development of hypertonicity, loss of brain water results in a reduction in brain volume. Restitution of brain volume commences within a few hours with the entry and accumulation of electrolytes into brain cells (rapid adaptation). Volume normalization is then completed within several days by intracellular accumulation of organic osmolytes (slow adaptation). At that point, brain volume is normal despite persistent extracellular hypertonicity. Slow correction of the hypernatremia permits elimination of accumulated electrolytes and osmolytes from brain cells, thus uneventfully reestablishing the normal equilibrium. In contrast, rapid correction (exceeding 10 mmol/day) renders the brain incapable of eliminating the accumulated osmotically active substances. This leads to water uptake and may result in cerebral edema. (Reproduced with permission of the Massachusetts Medical Society from Adrogué HJ, Madias NE: Hypernatremia. N Engl J Med 2000;342:1493.)

Table 18-1  Common Causes of Hypernatremia in the Neurointensive Care Unit With hypovolemia Gastrointestinal losses (diarrhea, vomiting, nasogastric suctioning) Excessive insensible losses (tachypnea) Diabetes insipidus with insufficient fluid replacement Excessive diuresis (mannitol, loop diuretics) With normovolemia Diabetes insipidus with sufficient fluid replacement (reassess tonicity of replacement solution) With hypervolemia Iatrogenic (hypertonic sodium solutions, inadequate feeding preparations) Corticosteroid excess

common manifestations, and the level of consciousness tends to correlate with the severity of hypernatremia.11,12 Generalized tonic-clonic seizures can occur,13 but rapid progression to deep levels of coma is rare, and should prompt the search for other potential causes using brain imaging and additional laboratory tests. The hypothesis that brain shrinkage caused by the effects of hypernatremia could result in intracranial hemorrhages in pediatric patients has been proposed but never systematically studied,14 nor ever published in adults. Intense thirst may be present initially, but tends to gradually disappear with progression of the disorder. Absence of thirst in a patient with pronounced hypernatremia and preserved level of consciousness should raise suspicion for hypothalamic dysfunction. Finally, neuromuscular manifestations are uncommon, but rhabdomyolysis has been reported in a series of anecdotal cases.15,16

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Common Causes of Hypernatremia in the Neurointensive Care Unit Hypernatremia in the neuro-ICU is most commonly due to net free water loss, often related to a defective central release of ADH, or induced osmotic diuresis. Acute severe hypernatremia is most often iatrogenic. It may be produced by the intravenous administration of hypertonic saline solutions (e.g., 1.5% or 3% NaCl given as treatment of increased intracranial pressure, or as hypervolemic therapy in patients with subarachnoid hemorrhage and symptomatic vasospasm), or sodium bicarbonate (for correction of lactic acidosis). Less commonly, acute hypernatremia can be caused by nutritional formulas or repeated use of hypertonic saline enemas. Induced Osmotic Diuresis Although to a lesser degree than hypertonic saline infusion, mannitol is expected to cause hypernatremia from free water loss. This is a predicted and calculated risk that is acceptable as long as the indication for the use of osmotic agents is clear. Serum osmolality must be monitored and should not exceed 320 mOsm/kg because this dehydrated state correlates with a risk of renal failure.17 Tromethamine (THAM), an alkalinizing agent, can represent a useful therapeutic alternative to mannitol in patients with increased intracranial pressure and hypernatremia.18 Diabetes Insipidus Theoretically, patients with head injury, primary or metastatic brain neoplasms, global anoxic brain damage, meningitis or encephalitis, massive cerebral edema, or rapid diencephalic herniation are at increased risk for the development of diabetes insipidus.19 However, diabetes insipidus is mostly encountered after pituitary or diencephalic surgery (e.g., removal of a hypothalamic hamartoma).20 It is almost an obligatory feature in patients fulfilling brain death criteria. Diabetes insipidus is diagnosed in patients with hypotonic urine (urine osmolality <300 mOsm/kg or specific gravity <1.010) and polyuria (>30 mL/kg/day).21 Although diabetes insipidus can also develop as a consequence of renal unresponsiveness to the effects of ADH (nephrogenic diabetes insipidus; possible causes for this disorder in critically ill patients include aminoglycosides, amphotericin B, lithium use for a pre-existent condition, radiocontrast dyes, and polyuric phase of acute tubular necrosis), most cases in the neuro-ICU are secondary to hypothalamic damage leading to ADH deficiency (central or hypothalamic diabetes insipidus). Clinically significant polyuria does not develop until more than three fourths of the ADH-producing neurons are destroyed. The clinical hallmarks of diabetes insipidus are polyuria and polydipsia. Nocturia is usually present. Central diabetes insipidus frequently shows an abrupt onset. When water sensation is impaired or access to water restricted, as is com-

monly the case in the neuro-ICU, a hyperosmolar state may ensue. Hypertonic encephalopathy and circulatory collapse may follow. In addition to dehydration, the “wash out” effect induced by the polyuria leads to hypomagnesemia, hypocalcemia, hypokalemia, and hypophosphatemia.22 In the neuroICU, it is usually sufficient to measure random plasma and urine osmolality levels, and register urinary output to make the diagnosis of diabetes insipidus. The improvement of polyuria in response to vasopressin will further categorize the disorder as central diabetes insipidus. Unless the hypothalamic damage is severe and irreversible, the disruption of ADH secretion may be partial and temporary. This is often the case in patients with head trauma and after neurosurgical interventions. In more than half of those cases, normal osmoregulation returns after 3 to 5 days. This return of normal hypothalamic function needs to be anticipated and monitored to avoid excessive treatment with fluids or exogenous vasopressin. Brain death may well be the most common cause of diabetes insipidus in the neuro-ICU.19,23 Sometimes it may actually precede the diagnosis of brain death in patients with severe diencephalic herniation, with the centrally herniating tissue compressing the pituitary stalk against the diaphragma sellae. In brain-dead patients, the death of the neurosecretory neurons of the hypothalamus is rapidly followed by a sudden decrease in blood pressure, often preceded by massive diuresis.24 When organ donation is seriously considered, this situation calls for a very aggressive treatment with intravenous fluid replacement and intravenous vasopressin, to avoid hypoperfusion to those organs.

Management of Hypernatremia When treating a patient with hypernatremia, the first priority is assessing volume status and treating hypovolemia.25,26 Volume replacement with crystalloids (0.9% NaCl) usually suffices to maintain cardiac output and adequate perfusion pressures. However, cases of severe hemodynamic compromise may require the use of colloids, typically in the form of 5% albumin. Once the hemodynamic status is deemed stable, the attention focuses on correcting the free water deficit. The calculation of this deficit relies on the assumption that the product of total body water (TBW) and serum sodium concentration (sNa) is always constant. Hence, Current TBW ¥ Current sNa = Normal TBW ¥ Normal sNa After rearranging the terms and using a normal sNa of 140 mmol/L, the formula appears as follows: Current TBW = Normal TBW ¥ (140 current sNa) Normal TBW in liters usually accounts for 60% of lean body weight in kilograms in men and 50% in women. The pro-

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portion of TBW decreases with age, representing 50% of lean body weight in elderly men and 45% in elderly women.27 Water deficit will be the difference between normal TBW and current TBW: Free water deficit = Normal TBW - Current TBW Thus, in an elderly man with a lean body weight of 68 kg and an sNa of 168 mmol/L, deemed to be caused by pure water depletion, the calculation of water deficit will proceed as follows: Normal TBW = 0.5 ¥ 68 = 34 L Current TBW = 34 ¥ (140 168) = 28 L Water deficit = 34 - 28 =6L The actual volume of replacement fluid needed to correct the water deficit will depend on the sodium concentration present in the replacement fluid chosen (Table 18-2). Hypotonic solutions are preferred in these situations. The volume of replacement fluid can be calculated using the following formula: Replacement fluid volume (in liters) = Water deficit ¥ (1 1 - X ) where X = replacement fluid Na/isotonic fluid Na. Thus, going back to our previous example, if we chose to replace the deficit with 0.45% NaCl solution, the calculation would continue as follows: Replacement fluid volume ( in liters ) = 6 ¥ (1 1 - 0.5) = 12 L When hypernatremia develops over a period of hours, rapid correction of water deficit is safe, because accumulated electrolytes can be rapidly eliminated from brain cells.5 A reduction of sNa by 1 mmol/hour is appropriate for these patients. However, much more caution must be exercised when treating patients with hypernatremia of longer or unknown duration. In these cases, it is prudent to assume that accu-

Table 18-2  Sodium Concentrations in Commonly Used Intravenous Solutions Intravenous Solution

Sodium Concentration (mmol/L)

5% dextrose in water 0.45% NaCl in water Ringer’s lactate 0.9% NaCl in water 1.5% NaCl in water 3% NaCl in water

0 77 130 154 256 513

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mulation of organic brain osmoles (idiogenic osmoles) has already occurred. Because the process of eradication of these osmoles will take several days to be completed, the rate of correction of hypernatremia in these patients needs to be slower to avoid the risk of cerebral edema. A maximal rate of 0.5 mmol/L/hour or 10 mmol/L/day is usually recommended.5 It is somewhat problematic that the preceding traditional formulas provide the total water deficit and the total volume of replacement fluid that needs to be given to the patient to achieve a normal sodium concentration, but fail to indicate a rate of infusion. Traditionally, half of the total volume is given over the first 24 hours while carefully monitoring the decline in serum sodium level. While usually satisfactory, this practice is imprecise. An alternative formula that estimates the change in sNa caused by the retention of 1 liter of any replacement fluid can be used to estimate the rate of infusion.5 This formula Change in serum Na = replacement fluid Na - sNa TBW + 1 does not focus on the calculation of free water deficit and should be used in place of the traditional formulas described previously. The required volume of replacement fluid is then obtained by dividing the change in sNa targeted for a given treatment period (usually 10 mmol/L/day) by the result obtained from this formula. Once more, back to our previous example: Change in serum Na = 77 - 168 34 + 1 = -2.6 This result means that the retention of 1 L of 0.45% NaCl will reduce the sNa by 2.6 mmol/L. Thus, assuming we want to reduce sNa by 10 mmol/L over 24 hours, we would need to provide approximately 3.8 L (10/2.6) of the solution, hence nearly 160 mL of 0.45% NaCl/hour. It is always necessary to compensate for ongoing fluid losses (obligatory or incidental, measurable and insensible) while correcting an existing water deficit. Therefore, an average of 1.5 L per day will be required in addition to the volume given to correct the deficit. This amount may vary according to individual cases, and it may be much greater in patients with profuse continuous losses (e.g., gastric suctioning, excessive sweating). Close monitoring of electrolyte concentrations (every 2 to 4 hours) and fluid balance (hourly) is the best way to ensure a safe and adequate correction of hypernatremia. Obviously, the underlying cause for the hypernatremia needs to be addressed. Often, the hypernatremia cannot be fully corrected until its cause is identified and treated. Furthermore, mild cases of hypernatremia can be fully reversed by managing the underlying cause, such as stopping gastrointestinal fluid losses, controlling fever, avoiding glyco-

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suria, changing a nutritional formula, withholding diuretics and so forth.5 Management is particularly essential when treating patients with diabetes insipidus. Patients with diabetes insipidus require careful monitoring of fluid balance, body weight, serum, and urine sodium concentrations, and urine specific gravity. Replacement of urine output and insensible losses may suffice to control mild cases. However, hormonal replacement is recommended when urine output exceeds 300 mL/hour for 2 consecutive hours. Since most cases of diabetes insipidus found in the neuro-ICU are central in origin, patients usually respond favorably to the administration of desmopressin (starting dose of 0.5 to 2 mg every 3 hours intravenously). Drug therapy should be titrated to achieve a reduction in urinary output to less than 300 mL/hour.

Hyponatremia Hyponatremia is defined as an sNa less than 135 mmol/L. Whereas hypernatremia always denotes hypertonicity, hyponatremia can be associated with low, normal, or high tonicity.28 Most often, especially in the neuro-ICU, hyponatremia is associated with hypotonicity and is due to either inappropriate water retention or excessive sodium excretion. Hypotonicity, in turn, carries a risk of inducing cerebral edema. Hyponatremia is a common problem in the neuro-ICU, especially among postoperative patients and patients with intracranial diseases. Identifying the correct mechanism leading to the production of hyponatremia is paramount to a successful correction of the disorder. Sometimes, more than one cause can contribute to the decline in sNa, and iatrogenic causes are not infrequently part of the problem. Inadequate or excessive supply of free water and the use of mannitol, corticosteroids, or diuretics are some of the most conspicuous contributors to the development or persistence of hyponatremia in the neuro-ICU. Initial Evaluation of Hyponatremia Measuring serum osmolality is the first step in the evaluation of any patient with hyponatremia. A high serum osmolality can occur in the presence of solutes confined to the extracellular compartment (such as glucose) resulting in a translocation of water from cells to the extracellular space (hypertonic hyponatremia). An increase in serum glucose concentration of 100 mg/dL (5.61 mmol/L) accounts for a fall of approximately 1.6 mmol/L in serum sodium level (and a rise in serum osmolality of approximately 2 mOsm/kg). A normal serum osmolality can be observed in patients with renal failure who have accumulated urea, an osmole that rapidly equilibrates across the cellular membrane, leading to hypotonic hyponatremia despite normal measured osmolality. Serum osmolality will also be normal in patients

with pseudohyponatremia secondary to severe hypertriglyceridemia or hyperglobulinemia; the latter is a laboratory artifact, rarely a problem nowadays due to the use of ionspecific electrodes to measure sodium concentration.28 The evaluation should then continue with measurement of urine osmolality on a random specimen. An increased water load will normally produce a decreased serum osmolality, leading to ADH suppression and excretion of the excess free water in very diluted urine (urine osmolality as low as 50 mOsm/kg). Therefore, patients with hyponatremia should be expected to have low urine osmolality (often <100 mOsm/kg). A urine osmolality greater than 200 mOsm/kg should be regarded as inappropriately high and reflects impaired mechanisms of water excretion. Assessing the effective volume status is the next priority. Useful clinical signs include weight changes, orthostatic changes in blood pressure and heart rate, skin turgor, and presence of jugular venous distension. Laboratory tests will further help determine the patient’s volume status. Hematocrit, blood urea nitrogen, bicarbonate, albumin, and uric acid will all be elevated in cases of volume depletion. However, when formally studied, the prediction of volume status based on clinical signs and routine laboratory workup in hyponatremic patients has a limited sensitivity (47%) and specificity (41%).29,30 A low urinary sodium concentration (<20 mmol/L) on a random sample suggests hypovolemia; however, high urinary sodium concentrations can be found in hypovolemic patients with salt wasting syndromes (e.g., cerebral salt wasting or adrenal insufficiency), metabolic alkalosis (sodium urinary excretion increases to neutralize the increased bicarbonate load), recent diuretic use, or even large sodium intake. Invasive measurement of central venous pressure may be advisable in those patients in whom volume status remains unclear after the initial evaluation31; however, depressed cardiac function can lead to erroneous interpretations. Echocardiography or pulmonary artery catheterization with monitoring of pulmonary capillary wedge pressures may be necessary in the most severe cases or when there is suspicion of coexistent heart failure. Clinical Manifestations of Hyponatremia As seen with hypernatremia, the clinical features of hypotonic hyponatremia are mostly related to central nervous system dysfunction, and their prominence largely depends on the severity and acuteness of the decline in sNa. Patients usually do not become symptomatic until after the sNa has dropped below 120 mOsm/L; however, symptoms can be observed at higher levels when the hyponatremia has developed very rapidly.32,33 Most symptomatic patients will present with a combination of headache, anorexia, nausea, vomiting, muscle cramps, and aches. They may be restless and confused or rather lethargic and apathetic. Neurological examination will be fairly unremarkable with the exception

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B

Figure 18-7. Serial magnetic resonance images (T2 weighted) showing resolution of central pontine myelinolysis. “Bat-like” shape area of demyelination in the central pons (A) evolving 1 month later into a fading “trident” shape signal abnormality (B). The patient recovered with minimal residual deficits.37

of cognitive changes and, occasionally, depressed deep tendon reflexes. However, if these patients are not treated, severe complications including generalized tonic-clonic seizures, apnea, and eventually coma and death from brain herniation may rapidly develop from cerebral edema.34 When hyponatremia develops slowly, even very low concentrations of serum sodium can be present without resulting in cerebral edema. This resilience of the brain can be explained by the extrusion of inorganic solutes from brain cells beginning within hours of the onset of hyponatremia. The exit of solutes is followed by water loss, thereby ameliorating cellular swelling. The negative side of this adaptive process is that it creates a risk of osmotic myelinolysis when hyponatremia is corrected too rapidly.35,36 Although the exact pathogenesis of this disorder has not been fully elucidated, it is well known that rapid reversion of hyponatremia can trigger demyelination of susceptible neurons. Although initially described in the pons, myelinolysis can affect extrapontine brain areas as well.35 Symptoms and signs usually evolve over several days after correction of hyponatremia. Typical manifestations include spastic quadriparesis or quadriplegia, pseudobulbar palsy, and changes in the level of consciousness. Severe cases may result in “locked-in syndrome,” coma, or even death. Magnetic resonance imaging is an extremely

valuable diagnostic aid and displays the extent of demyelination (Fig. 18-7).37 Its use remains an uncommon occurrence in the neuro-ICU, however, probably because hyponatremia is not usually very severe, although it has been particularly reported after correction of hyponatremia following pituitary surgery.38,39 Common Causes of Hyponatremia in the Neurointensive Care Unit Hyponatremia is the most common electrolyte disturbance in the neuro-ICU. It complicates the course of many neurologic and neurosurgical conditions but can also occur iatrogenically (Table 18-3). Naturally, the causes and management of hyponatremia in the neuro-ICU differ from those that apply to the general population or to patients in other ICUs. There are two main mechanisms responsible for the production of most cases of hyponatremia in the neuro-ICU: inappropriate secretion of ADH and cerebral salt wasting. Although they are physiologically very different, these two mechanisms may be difficult to distinguish in individual cases. This distinction is fundamental because these two derangements require opposite therapeutic approaches and

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Table 18-3  Common Causes of Hypotonic Hyponatremia in the Neurointensive Care Unit With hypovolemia Cerebral salt wasting Diuretics Acute corticosteroid withdrawal Gastrointestinal losses (diarrhea, vomiting) Skin losses (excessive sweating) Ketonuria Iatrogenic (hypotonic solutions, insufficient volume) With normovolemia SIADH Hypothyroidism Adrenal insufficiency Iatrogenic (hypotonic solutions, sufficient volume) With hypervolemia SIADH Congestive heart failure Acute renal failure Cirrhosis Iatrogenic (hypotonic solutions, excessive volume)

improper treatment selection can result in irreparable consequences. Syndrome of Inappropriate Secretion of Antidiuretic Hormone We should be cautious when diagnosing the syndrome of inappropriate secretion of ADH (SIADH) because it seems to be the most “popular” explanation for hyponatremia in neuro-ICUs. The primary pathogenic mechanism underlying SIADH is excessive ADH release in the absence of low serum osmolality, causing water reabsorption and, consequently, expansion of the extracellular fluid volume. This leads to dilutional, hypotonic hyponatremia despite normal renal sodium handling. Hence, SIADH is a volumeexpanded state, although most patients do not show overt signs of hypervolemia (only one third of the total retained water remains in the extracellular compartment).40 These patients have a neutral sodium balance; urinary sodium excretion closely parallels sodium intake. Diagnosis of SIADH requires the demonstration of hyponatremia, low serum osmolality, inappropriately concentrated urine (>100 mOsm/kg), persistent urinary sodium excretion (>20 mmol/L), and exclusion of renal or endocrine disease (hypothyroidism, hypoadrenalism) that could explain these findings. There must also be no stimuli that could stimulate nonosmotic release of ADH, such as hypovolemia, hypotension, positive-pressure ventilation, pain, stress, nausea, and drugs (most conspicuously narcotics and carbamazepine).41 Remembering this last caveat is particularly relevant in the neuro-ICU, where one or more of these factors may frequently play a role. For example, patients with subarachnoid hemorrhage often will have severe pain, nausea,

and stress; frequently receive narcotics to ameliorate the headache; and occasionally may be hypotensive from myocardial stunning or vasomotor collapse. These patients will surely have elevated serum levels of ADH, regardless of the serum osmolality, but calling this elevation “inappropriate” is questionable. Cerebral Salt Wasting Syndrome Although the concept of cerebral salt wasting (CSW) syndrome was first proposed in 1950,42 the subsequent recognition of SIADH41 relegated this clinical entity to obscurity for decades. During that time, many authors ceased to regard CSW as a distinct disorder and hyponatremia in patients with central nervous system disease was almost uniformly ascribed to SIADH. Only recently has CSW regained a prominent place in the literature and, most importantly, in everyday practice.43–47 Contrary to SIADH, CSW is a volume-depleted state secondary to primary natriuresis.41 Patients with CSW show a negative sodium balance. The mechanism responsible for the renal salt wasting is not fully understood, but the most likely site for impaired sodium reabsorption is the proximal nephron. Two main processes have been proposed to explain this derangement: decreased sympathetic input to the kidney and presence of a circulating natriuretic factor.40,48 Reduced sympathetic tone may explain the failure of renin and aldosterone levels to rise in patients with CSW despite volume depletion. The absence of aldosterone response would then account for the lack of renal potassium loss despite increased distal sodium load, explaining why hypokalemia is not encountered in patients with CSW. The actions of potent natriuretic peptides could also contribute to the natriuresis by increasing glomerular filtration rate and blocking sodium reabsorption mainly in the inner medullary collecting duct.3 These peptides also have inhibitory actions on aldosterone and are capable of decreasing autonomic flow through proposed effects on the brainstem.49 There is some evidence suggesting that brain natriuretic peptide may be the more likely candidate to mediate renal salt wasting.50 The role of a brain ouabain-like compound in the pathogenesis of CSW is still largely speculative.48 Once volume depletion is established it stimulates ADH secretion, overriding the usual inhibition exerted by the coexistent low serum osmolality.51 Therefore, most patients with CSW have elevated circulating levels of ADH and meet the laboratory criteria for SIADH. Failure to recognize volume contraction and a negative sodium balance in these patients will lead to the incorrect diagnosis of SIADH when, in fact, the elevation of ADH is appropriate for the clinical situation. Syndrome of Inappropriate Antidiuretic Hormone Secretion versus Cerebral Salt Wasting Syndrome Determination of the extracellular fluid volume remains the only reliable discriminatory element to differentiate SIADH

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Table 18-4  Differential Diagnosis of Cerebral Salt Wasting and Syndrome of Inappropriate Secretion of ADH Parameters

CSW

SIADH

Extracellular fluid volume Body weight Fluid balance Urine volume Tachycardia Hematocrit Albumin Serum bicarbonate Blood urea nitrogen Serum uric acid Urinary sodium Sodium balance Central venous pressure

Ø Ø Negative ´ or ≠ + ≠ ≠ ≠ ≠ ´ or Ø ≠ Negative Ø (<6 mm Hg) Ø

≠ ≠ Positive ´ or Ø ´ ´ ´ or Ø ´ or Ø Ø ≠ Neutral or + ´ or slightly ≠ (6–10 mm Hg) ´ or slightly ≠

Wedge pressure

CSW, cerebral salt wasting syndrome; SIADH, syndrome of inappropriate antidiuretic hormone secretion.

and CSW.40,48,52,53 This concept cannot be overemphasized, because the adequate therapy for one disorder can be extremely harmful in the other.46 Both disorders are commonly associated with intracranial diseases and their clinical presentations and laboratory features may overlap. However, extracellular fluid volume tends to be slightly increased in SIADH, whereas it is decreased in CSW. As noted previously, the assessment of extracellular fluid volume status is often far from simple (see section on Initial Evaluation of Hyponatremia). Weight loss and negative fluid balance in a patient with hypotonic hyponatremia in the neuro-ICU are strongly suggestive of CSW. Physical signs such as orthostatic hypotension and tachycardia, and laboratory values such as elevations of hematocrit, bicarbonate, and blood urea nitrogen serum concentrations can provide further support for the diagnosis of CSW. Serum uric acid levels can be deceiving; although usually elevated in patients with volume depletion, they tend to be unexpectedly low in cases of CSW.54 Measuring urinary sodium on a random sample is not helpful because its concentration is elevated in both conditions. However, it may be possible to estimate mass balances for urinary electrolytes over 1 or several days; a negative sodium balance would support the clinical diagnosis of CSW.55 Table 18-4 displays a summary of the clinical features that can aid in the differentiation of SIADH and CSW. When, after revision of hospital flow sheets, physical findings, and laboratory values the diagnosis remains uncertain, invasive monitoring is indicated. A low central venous pressure (<6 mm Hg) and a low pulmonary capillary wedge pressure (<8 mm Hg) will imply volume contraction, hence favoring the diagnosis of CSW.56 However, even these data need to be interpreted with caution in patients with abnormal cardiac or pulmonary function.

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Hyponatremia in Patients with Aneurysmal Subarachnoid Hemorrhage Hyponatremia is the most common and severe electrolyte disturbance after aneurysmal subarachnoid hemorrhage (SAH). Serum sodium concentrations less than 134 mmol/L have been reported in 34% of patients with SAH.57 Severe hyponatremia (<120 mmol/L) is rarely observed in these patients, and neurologic deterioration can seldom be primarily attributed to hyponatremia alone.19 The decline in serum sodium levels tends to occur between the second and tenth days after the initial hemorrhage, closely paralleling the period of cerebral vasospasm.46 The risk of developing hyponatremia is significantly increased in patients with enlargement of the third ventricle (regardless of the size of the lateral ventricles) on initial computed tomographic scan,58 and patients with ruptured anterior communicating artery aneurysms.59 Hyponatremia in SAH was initially attributed to SIADH.56 However, studies demonstrating volume contraction in patients with SAH and hyponatremia subsequently challenged this notion.43,44 The pathogenic role of CSW was further supported by a prospective study that measured plasma volume (using an isotope dilution technique) in 21 patients within the first week after SAH. Plasma volume was decreased in most patients with hyponatremia and negative sodium balance preceded the development of hyponatremia in all cases. Serum ADH levels were elevated early but declined during the first week, regardless of the presence of hyponatremia.47 Circulating plasma natriuretic peptides concentrations are consistently increased after SAH50,60–65 and they remain elevated in patients with persistent hyponatremia.61,62 Earlier studies had focused on atrial natriuretic peptide measurements,60–62,65 but lately brain natriuretic peptide has become the center of attention.50,63,64 Meanwhile, ADH levels show an initial surge shortly after SAH that is followed by a rapid decline even in patients in whom hyponatremia develops.61,62,65 Still, detectable levels of ADH have been documented in patients with hyposmolar hyponatremia treated with hypervolemic therapy to avoid volume contraction.66 This finding could suggest that disturbed regulation of ADH secretion may also play a role in the generation of hyponatremia. However, it is important to remember that other nonosmolar stimuli different from hypovolemia (e.g., pain, stress, opioids, and nausea) can also induce increased ADH levels in patients with SAH. It is presently unclear how SAH triggers CSW. Pressor hormones and amines that are elevated shortly after aneurysmal rupture, such as endothelin, arginine vasopressin and catecholamines, can stimulate atrial natriuretic peptide secretion. However, the persistence of high concentrations of natriuretic peptides for several days—for example, natriuretic peptides remain increased after arginine vasopressin have already decreased days after the bleeding— is less easy to explain. As discussed in the following sections,

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the common timing shared by CSW and vasospasm makes it plausible to think of a common factor (or factors) capable of both producing the vascular changes responsible for vasospasm and also stimulating the secretion of natriuretic substances. Adrenomedullin is a recently recognized endogenous peptide with vasorelaxant and natriuretic properties. Peripheral administration of adrenomedullin produces vasodilatation of peripheral as well as cerebral arteries. Adrenomedullin levels are elevated in patients with SAH and vasospasm but their regulation seem uncoupled from the natriuretic peptide system. These early findings suggest a possible role of adrenomedullin in a physiologic compensatory response to counteract cerebral vasoconstriction.67 The presence of hyponatremia is significantly associated with the occurrence of cerebral infarctions from delayed cerebral ischemia.46,57 Although this association between hyponatremia and risk of vasospasm is well established, the meaning of the relationship is less certain. Plasma levels of brain natriuretic peptide have been found to be significantly increased in patients with severe symptomatic vasospasm.63 Natriuresis could contribute to the development of severe vasospasm by inducing volume depletion, while at the same time accounting for the hyponatremia. Alternatively, a common driving force for the generation of vasospasm and the increased secretion of natriuretic substances could exist. Hyponatremia in Patients with Head Injury In clinical practice, hyponatremia is observed fairly often after traumatic brain injury, although the incidence of this association has not been formally studied. Hyponatremia is more commonly seen days after the injury, although severe acute hyponatremia has been documented after head trauma in elderly patients.68 Acute hypernatremia secondary to dehydration is frequently present shortly after trauma.69 Also in this condition, the mechanism responsible for the hyponatremia appears to be a combination of hormonal water retention and sodium wasting. Increased levels of ADH are often found and they usually represent an appropriate response to decreased circulating blood volume68,70,71 or other nonosmotic stimulants. Cerebral salt wasting with high levels of atrial natriuretic peptide has been elegantly documented in a pediatric case report72 and this process is likely to be an important contributor to most cases of hyponatremia patients who are volume depleted after head trauma.71,73 Hyponatremia, when severe, can be symptomatic in certain patients with acute head injury. It can also be associated with increased risk of symptomatic vasospasm in patients with traumatic SAH. The effects of hyponatremia on cognitive outcome after traumatic brain injury remain to be defined.74 However, experimental data from animal

studies suggest that acute hyponatremia potentiates secondary brain damage in severe traumatic brain injury by augmentation of both focal contusion and diffuse axonal injury.75 Hyponatremia in Neurosurgery for Brain Tumors Hyponatremia is a relatively common finding in postoperative patients in general. The risk of permanent brain damage from hyponatremia after any kind of surgery is much greater in women (especially menstruant) than in men.76,77 This condition, known as acute postoperative hyponatremic encephalopathy, can lead to convulsions, coma, respiratory arrest, and death. Patients show hypo-osmolality and fluid retention, suggesting SIADH.76 Animal data indicate that the Na+-K+ ATPase pump function is less effective in synaptosomes of female brain when compared with males; additionally, ADH administration was associated with impaired cerebral energy metabolism in female rats but not in their male counterparts.78 However, more recent data suggest that severe postoperative hyponatremia resulting in respiratory arrest is very uncommon.79 In addition, recent experiments in rats demonstrated no difference in mortality after induced hyponatremia between estrogen-pretreated and testosterone-pretreated animals.80 Hyponatremia can occur after neurosurgery for brain tumors, particularly after transsphenoidal resection of pituitary region tumors.81–86 Although commonly mild and asymptomatic, hyponatremia occasionally can be severe and require attention in the ICU. The incidence of hyponatremia after transsphenoidal resection of pituitary tumors has been reported to be between 8% and 35%, with associated symptoms encountered in 2% to 20% of operated patients.83,85 Hyponatremia is more common in patients operated for Cushing’s disease but its incidence is unrelated to sex, age, adenoma size, or intrasellar expansion of the tumor.83,86 Disturbances of osmoregulation often occur after surgery in the sella region;87 this may be due to manipulation of the pituitary stalk or vascular changes in the posterior pituitary. Immediate postoperative polyuria, a form of transient DI with proven low circulating ADH levels, is present in up to one third of cases83; it is often followed by an oliguric interphase thought to be due to the release of preformed ADH from damaged magnocellular neurons. It is during this oliguric interphase, usually 4 to 13 days after surgery, that hyponatremia most frequently begins to occur.83,85,86 The mechanism accounting for the hyponatremia, however, seems to be mostly unrelated to excessive levels of circulating ADH.84,88 Conversely, hyponatremia is strongly associated with elevated levels of atrial natriuretic peptide,84 supporting the diagnosis of CSW.81 Hypoadrenalism (hyperkalemia should be seen as a red flag for this diagnosis) and hypothyroidism should always be ruled out in patients presenting with hyponatremia after surgery for a pituitary tumor.

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Hyponatremia in Patients with Meningitis Hyponatremia has been reported in 7% to 32% of patients with different forms of meningitis.89,90 However, most of the published data refer to children; data in adults are virtually nonexistent. Hyponatremia in patients with meningitis has been traditionally thought to be a consequence of SIADH.91,92 However, this concept cannot be sustained after careful review of the available information.93 Even though patients with meningitis frequently meet the laboratory criteria for the diagnosis of SIADH and have increased ADH levels despite coexistent hyponatremia,91,92,94 their fluid balance is usually negative.95,96 Thus, volume depletion can be responsible for the raised ADH concentrations, as well as other nonosmotic stimuli. Evidence favoring CSW has emerged in more recent years.97,98 The discussion regarding the underlying mechanism of hyponatremia in patients with meningitis has vital practical implications. Prophylactic fluid restriction has been traditionally recommended to counter the presumed threat of SIADH and reduce the risk of cerebral edema. However, no evidence supports that restricting fluid intake reduces the incidence or severity of cerebral edema. Furthermore, in the only prospective, controlled study evaluating fluid therapy in patients with meningitis, fluid restriction did not improve outcome and contraction of the extracellular volume was associated with greater likelihood of adverse outcome.99 Therefore, not only should prophylactic fluid restriction be discouraged in patients with meningitis, but hypovolemia should be treated with fluid therapy aiming at isoosmolality to avoid cerebral hypoperfusion.93 Hyponatremia in Other Specific Neurosurgical Conditions Hyponatremia has been reported to occur in at least 5% of patients recovering from spinal fusion operations.100 Although attributed to SIADH, hyponatremia was more common in those patients who had suffered more intraoperative blood loss100; once again, raised ADH levels may have represented a physiologic response to hypovolemia. Cases of hyponatremia have also been observed in patients with normal pressure hydrocephalus, perhaps related to the mechanical pressure exerted on the hypothalamus,101 obstructive hydrocephalus, sagittal sinus thrombosis102 after endoscopic third ventriculostomy,103 and carotid endarterectomy.104 However, in all these cases, dilutional hyponatremia secondary to aggressive fluid replacement with hypotonic solutions remains possible. Management of Hyponatremia Achieving euvolemia and correcting hypotonicity is always the goal in treating hyponatremia. When designing the therapeutic plan, the risks of hypotonicity should be balanced against those of therapy. The rate of correction of hypona-

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tremia will depend on the presence of symptoms and their severity. Asymptomatic Hyponatremia In patients with asymptomatic hyponatremia associated with volume depletion, ADH levels are appropriately increased as a compensatory response. Isotonic saline solution should be administered and titrated to restore intravascular volume. Free water intake must be minimized. Once intravascular volume is nearly normalized, the nonosmotic stimulus to ADH release is eliminated and excretion of excess free water leads to gradual correction of the hyponatremia. However, when CSW is the underlying mechanism of volume depletion, continued administration of fluids is required as long as sodium wasting is present. If the patient is euvolemic or hypervolemic, true SIADH is the most likely mechanism, and free water restriction alone is usually sufficient treatment. Treating pain and nausea, avoiding or minimizing narcotic use, and providing adequate sedation to reduce stress are also helpful and frequently overlooked therapeutic measures. Symptomatic Hyponatremia Acute symptomatic hyponatremia requires cautious administration of hypertonic saline solution, usually 3% NaCl solution administered through a central venous line. Tightly controlled infusion of hypertonic saline is safe and very effective in reversing hyponatremia and hypotonicity.28,105,106 In less severe cases, 1.5% NaCl solution may be preferable because it can be safely infused through a peripheral venous line. Furosemide may be concomitantly used to induce hypotonic diuresis (furosemide-induced diuresis is approximately equivalent to one-half normal saline) and limit extracellular volume expansion. When the hyponatremia is clearly due to excessive water intake and the symptoms are not severe, treatment with furosemide alone may suffice. In all cases, free water intake must be eliminated and anticonvulsant agents are indicated if the patient has seizures; carbamazepine should be avoided due to its risk of SIADH. Aggressive therapy can be tapered or discontinued once symptoms abate. The risk of correcting hyponatremia too quickly is inducing osmotic demyelination (central pontine or extrapontine myelinolysis).35,36 Most reported cases of osmotic demyelination occurred after rates of correction exceeding 12 mmol/L/day, but isolated cases occurred after corrections of only 9 to 10 mmol/L over 24 hours or 19 mmol/L over 48 hours.28,35,107 Current recommended rates of correction vary between 8 to 10 mmol/L over any 24-hour period.28,35,108,109 However, in severely symptomatic patients, the initial pace of correction may be slightly faster (1 to 2 mmol/L/hour) over the first few hours, but always remaining within the previously specified daily target. Given the magnitude of the risk, it is not safe to prescribe a faster rate of correction.

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The same formula described in the section, Management of Hypernatremia, can allow a simple and expedient determination of the correct rate of infusion of the chosen solution: Change in serum Na = replacement fluid Na - sNa TBW + 1 The required volume of replacement fluid is then obtained by dividing the change in sNa targeted for a given treatment period (usually 8 to 10 mmol/L/day) by the result obtained from this formula.28 Table 18-2 shows the sodium concentrations of different replacement solutions. For example, if we chose 1.5% saline solution to treat a 50-year-old man who weighs 60 kg and has a sNa of 120 mmol/L, the calculation would proceed as follows: Change in serum Na = 256 - 120 (0.6 ¥ 60) + 1 = 3.7 This result means that the retention of 1 L of 1.5% saline solution will increase sNa by 3.7 mmol/L. Thus, assuming we want to correct hyponatremia by 8 mmol/24 hours, we would need to provide approximately 2.2 L (8/3.7) of the solution per day, or around 90 mL/hour. Management of Hyponatremia in Patients with Aneurysmal Subarachnoid Hemorrhage The treatment of hyponatremia in patients with SAH merits special consideration due to the complexity and importance of this problem. The impact of medical treatment on the improved outcome of patients with SAH over the last several years is due in large part to a better understanding of the mechanism of hyponatremia.110 Recognition that these patients are usually volume depleted as a consequence of excessive natriuresis led to the realization that fluid restriction increases the risk of delayed cerebral ischemia secondary to vasospasm.46 In patients with SAH, negative fluid balance must be aggressively avoided20 and fluid therapy should also compensate for sodium losses occurring from CSW. Ideally, hemodynamic monitoring via a central venous catheter to measure central venous pressure, or using a Swan-Ganz catheter in more complicated cases should be performed in all patients. A less invasive and probably equally effective approach consists of clinically monitoring those with symptomatic vasospasm or at risk of developing it. All patients should initially receive crystalloids to expand the intravascular volume. Using isotonic (0.9%) saline solution is usually appropriate in the early phases, unless hyponatremia is already present. Colloids (such as 5% albumin) can be added when there are persistent signs of volume contraction.111 As hyponatremia develops, switching to hypertonic (1.5% or 3%) saline solutions becomes appropriate.112 In addition, fludrocortisone may be added to curtail ongoing natriuresis.113,114 It is given twice a day and

the usual maximal dose is 0.4 mg/day. Fludrocortisone effects become apparent just hours after administration and can induce positive sodium balance for at least five days. After that period, the effects of fludrocortisone may diminish as a consequence of the “mineralocorticoid escape” phenomenon.

Disorders of Potassium Homeostasis As sodium is the predominant extracellular cation, potassium is the major intracellular cation and a sodium-potassium exchange pump conserves potassium while extruding sodium. Only 2% of the total pool of body potassium is present in the extracellular compartment and approximately 0.4% in plasma. Thus, serum potassium concentrations are poor indicators of the status of total body potassium stores. This marked difference in potassium content between the intracellular and extracellular compartments has an important practical implication: The abundant pool of intracellular potassium is very effective in replenishing extracellular stores when potassium is lost. Therefore, potassium depletion must be twice as great as potassium accumulation to produce degree of change in serum potassium concentration.115,116 Nearly 90% of the potassium ingested is absorbed by the small intestine and this absorption is fairly constant. Increased dietary loads are rapidly accommodated inside the cells; increased transcellular movement of potassium prevents dangerous swings in serum potassium concentration. Renal excretion is tightly regulated through the mechanisms of tubular reabsorption (proximal tubules) and secretion (distal tubules), but changes in urine potassium concentration in response to different dietary loads occur more slowly. Factors affecting internal potassium balance (transcellular shift) are: 1. Acid-base changes. Acidosis (in particular that induced by inorganic acids) promotes potassium exit from the cells, while alkalosis or even increased serum bicarbonate concentration in the absence of alkalemia stimulate potassium movement into the cells. These effects are explained by changes in the electrical gradient. 2. Insulin. It stimulates cellular uptake of potassium by enhancing Na+-K+ ATPase activity. 3. Catecholamines. Beta2-adrenergic agonists increase potassium uptake by peripheral muscle, and beta1adrenergic agonists have the same effect in the heart. These actions would also be mediated by modulation of the Na+-K+ ATPase pump. Conversely, alpha-adrenergic agonists can promote cellular potassium loss. 4. Tonicity. Serum hypertonicity and cellular dehydration favor movement of potassium out of cells by exacerbating the chemical gradient.

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Factors affecting external potassium balance (renal excretion) are: 1. Distal tubular flow rate and sodium delivery. Potassium is secreted into the distal tubular lumen in exchange for sodium. Increased tubular flow rate (secondary to increased glomerular filtration rate) and distal sodium delivery favor potassium secretion and subsequent urinary excretion. 2. Mineralocorticoids. Aldosterone stimulates potassium secretion in the distal nephron. In turn, serum potassium levels regulate adrenal secretion of aldosterone (hyperkalemia stimulates and hypokalemia suppresses aldosterone secretion). The effect of aldosterone on tubular potassium excretion can be estimated by calculating the transtubular potassium gradient: Transtubular K + gradient = {[U(K + ) (U osm Posm )] ∏ P(K + )},

where U(K+) is the urinary concentration of potassium, (Uosm / Posm) is the ratio between urine and plasma osmolalities, and P(K+) is the serum potassium concentration. This index is useful in cases of hypokalemia to document if potassium is being inappropriately lost in the urine. A result greater than 5 indicates an aldosterone effect, while a result less than 3 indicates lack of effect. 3. Antidiuretic hormone. ADH also stimulates potassium secretion independently of other factors. Thus, ADH compensates for the effects of changes in distal tubular flow on potassium secretion (e.g., water ingestion would induce potassium loss in the urine by increasing distal tubular flow if it did not concomitantly inhibit the secretion of ADH). 4. Acid-base effects. Acute systemic acidosis increases hydrogen ion concentrations and decreases potassium concentration inside renal epithelial cells. These effects lead to a decline in potassium secretion. Opposite changes occur with acute systemic alkalosis. These effects are mitigated or reversed in chronic acid-base disorders. In addition, potassium depletion stimulates renal acid excretion and renal ammoniagenesis; in turn, these changes have a sparing effect on the bicarbonate pool. 5. Dietary potassium. Renal adaptation to changes in dietary potassium intake can be profound (urinary potassium concentration can range from 20 to 150 mmol/L) but full expression of this response occurs only after days. Hyperkalemia Hyperkalemia is not particularly common in the neuro-ICU but it deserves attention because it can be life threatening when severe.117 Hyperkalemia is usually defined as a serum

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Table 18-5  Common Causes of Hyperkalemia in the Neurointensive Care Unit Pseudohyperkalemia Renal insufficiency Hypoadrenalism Diabetic ketoacidosis Drugs ACE inhibitors Beta-blockers Digoxin Heparin Nonsteroidal antiinflammatory drugs Potassium-sparing diuretics Antibiotics (such as trimethoprim-sulfamethoxazole, potassium penicillin) THAM Succinylcholine In trauma patients Rhabdomyolysis Rewarming after (induced) hypothermia Massive blood transfusions ACE, angiotensin-converting enzyme; THAM, tromethamine.

potassium concentration exceeding 5.5 mmol/L. However, serious complications are typically not observed until levels are greater than 7.0 mmol/L. In addition, spurious elevations of serum potassium concentrations (pseudohyperkalemia) are quite common and the unexpected finding of hyperkalemia in an asymptomatic patient should always prompt a repeat confirmatory measurement before any therapeutic measures are taken. Pseudohyperkalemia can occur secondary to hemolysis during venipuncture and in patients with severe thrombocytosis or leukocytosis. Causes of true hyperkalemia in the ICU are listed in Table 18-5. Cases of hyperkalemia in the neuro-ICU usually share the same causes with those in any other ICU. However, trauma patients are particularly at risk due to myonecrosis and higher incidence of prerenal insufficiency and blood transfusions. In addition, when hypothermia is induced in patients with head trauma and increased intracranial pressure, hyperkalemia can occur during the rewarming phase and exacerbate the risk of cardiac arrhythmia. Several drugs have been associated with the development of hyperkalemia, but more pertinent to the neuro-ICU are THAM (alkalinizing agent used for control of raised intracranial pressure) and succinylcholine, the latter being especially dangerous in patients with spinal cord injuries and prolonged immobilization. Clinical Manifestations of Hyperkalemia The most dangerous consequences of hyperkalemia are cardiac conduction abnormalities due to changes in the electrical excitability of cellular membranes. Initial “peaking” of the T waves (tall, tented T waves best seen in precordial leads) is followed by diminished amplitude of P waves, and

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progressive widening of the PR interval and QRS complexes. Eventually, ventricular fibrillation and asystole ensue.26 Neurologic manifestations may include proximal limb weakness and burning dysesthesias. Progression to generalized paralysis with respiratory compromise has been reported but is rare.118,119 Patients may exhibit myotonia that can be elicited by muscle percussion. Weakness should recover within hours of reversal of the hyperkalemia; failure to recover shortly after treatment should suggest other causes are responsible for the weakness. Management of Hyperkalemia Acute management of hyperkalemia should be focused on avoiding life-threatening cardiac arrhythmias. The effect of the therapeutic maneuvers can be monitored using the electrocardiogram. In cases of severe hyperkalemia, calcium carbonate should be administered immediately (calcium carbonate 10%, 10 mL over 3 minutes; can repeat once after 5 minutes if needed) to antagonize the actions of potassium on the cellular membrane. The response to calcium will last for approximately 20 to 30 minutes and will allow time for the administration of other therapies aimed at enhancing potassium clearance. A combination of insulin and dextrose can be administered to promote a shift of potassium into cells (10 U of regular insulin added to 500 mL of 10% dextrose infused over 10 minutes). Bicarbonate infusion can also stimulate this transcellular shift but its use is not advisable because it can bind calcium, rendering it ineffective. Removal of potassium from the organism can be achieved by using cation-exchange resins such as polystyrene sulfonate (Kayexalate, 50 to 100 g mixed with 200 mL 20% dextrose and water, in a retention enema) that increase gastrointestinal clearance of potassium, or furosemide (20 to 80 mg) to increase its urinary excretion. Hemodialysis may be indispensable in patients with renal failure.26 Hypokalemia Hypokalemia is defined as a serum potassium concentration less than 3.5 mmol/L. Although most commonly mild and well tolerated, it may represent considerable danger in patients with underlying heart disease because it can trigger cardiac arrhythmias, or advanced liver failure because it can precipitate hepatic coma.120 Hypokalemia generally occurs as a result of insufficient dietary potassium intake, excessive gastrointestinal or renal losses, or increased cellular sequestration. In many ICU patients, hypokalemia is multifactorial in origin. For the most part, the causes of hypokalemia in the neuro-ICU also resemble those in other intensive care settings (Table 18-6). However, certain elements specific to neurologic and neurosurgical patients can contribute to the decrease in serum potassium concentration. Potassium depletion can result from the use of osmotic diuretics in patients with raised intracranial pressure or high doses of corticosteroids in acute spinal cord injury. It can also occur

Table 18-6  Common Causes of Hypokalemia in the Neurointensive Care Unit Decreased potassium intake Potassium shift into cells Alkalosis Beta-adrenergic agonists Insulin Hypothermia (induced) Total parenteral nutrition Increased potassium losses (potassium depletion) Vomiting or nasogastric suctioning Diarrhea Excessive sweating Potassium-wasting diuretics (loop diuretics, thiazides) Hypomagnesemia Other drugs (amphotericin B, penicillin derivatives)

in cases of diabetes insipidus, severe trauma (due to the catabolic state and high levels of catecholamines), and hypovolemia (which leads to increased secretion of aldosterone). Finally, induced hypothermia can produce hypokalemia by promoting the transcellular shift of potassium into the cells (the caveat is that severe hypothermia typically produces hyperkalemia secondary to massive cell death). Clinical Manifestations of Hypokalemia Severe hypokalemia (serum potassium concentration less than 2.5 mmol/L) can be complicated with diffuse muscle weakness and mental status changes. Cardiac arrhythmias (especially in patients with pre-existing heart disease, or concomitant hypomagnesemia, and those taking digoxin) and paralytic ileus are also possible. It can precipitate coma in patients with advanced hepatic cirrhosis and lower the threshold for multifocal atrial tachycardia in patients with obstructive lung disease. Electrocardiographic abnormalities include prominent U waves, flattening and inversion of T waves, and prolongation of the QT interval. Ventricular arrhythmias constitute the ultimate danger.121 The muscle weakness induced by hypokalemia can be profound and, in the extreme form, can result in flaccid quadriplegia and neuromuscular respiratory failure. Cramps, myalgias, and occasional myoclonus can accompany the weakness. In addition, patients with severe hypokalemia frequently have some degree of rhabdomyolysis; although usually mild, hypokalemic rhabdomyolysis can be severe and result in acute renal failure.122,123 Management of Hypokalemia Treatment of hypokalemia consists of providing adequate potassium supplementation to replenish body stores and eliminating or treating all potential causes of increased transcellular shift (such as alkalosis) or excessive loss (such as diuretics). The standard method of intravenous potassium replacement is adding 20 mEq of potassium chloride (KCl)

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to 100 mL of isotonic saline and infusing this mixed solution over 1 hour.124 When rapid administration of higher concentrations of potassium is necessary, it is safer to use central venous access or two peripheral lines because of the irritating properties of the hyperosmotic potassium solutions. Dose rates as high as 80 mEq per hour have been used safely in cases of severe hypokalemia.120 Because the redistribution of potassium is difficult to predict in critically ill patients, monitoring the response to treatment by serially measuring serum potassium concentrations becomes essential. Ongoing potassium losses must be considered when calculating daily replacement rates. Measuring serum magnesium level is always recommended in patients with refractory hypokalemia because hypomagnesemia promotes excessive urinary potassium losses.

Disorders of Calcium, Phosphorus, and Magnesium Homeostasis Calcium Calcium is a predominantly extracellular cation that is primarily stored in bones. Circulating calcium levels are tightly regulated by parathyroid hormone (PTH) and vitamin D. PTH is primarily responsible for mediating the responses to acute changes in serum calcium concentration; its secretion is stimulated by ionized hypocalcemia (calcium is heavily protein-bound in the circulation and only the free fraction is physiologically active) and leads to release of calcium from bone, absorption from the gastrointestinal tract (through vitamin D) and reabsorption by the renal tubules. Conversely, PTH secretion is inhibited by ionized hypercalcemia and elevated 1,25-dihydroxyvitamin D levels. Meanwhile, vitamin D is synthesized in the skin (requiring ultraviolet light exposure) or absorbed from the diet, and it then undergoes two steps of hydroxylation in the liver (25-hydroxylase) and the kidney (1-hydroxylase, stimulated by PTH, hypophosphatemia, acidemia, and calcitonin) to reach its active form as 1,25-dihydroxyvitamin D. Vitamin D increases renal calcium reabsorption and intestinal tract absorption. Calcitonin, another calciotropic hormone, also plays a role in maintaining calcium homeostasis by inhibiting bone resorption and increasing calcium urinary excretion. Phosphorus Phosphorus is predominantly an intracellular anion; thus, serum levels are poor indicators of total body stores (most phosphorus is deposited in bone). Circulating phosphorus binds to protein less avidly than calcium or magnesium. Its homeostasis is primarily maintained by renal regulation, where urinary phosphorus excretion is increased in the presence of PTH and calcitonin, and decreased by the actions of vitamin D. In addition, PTH induces phosphorus

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Table 18-7  Common Causes of Calcium Imbalance in the Neurointensive Care Unit Hypercalcemia Renal failure Prolonged immobilization Disseminated malignancy Phosphorus depletion Drugs (especially calcium supplements) Hypocalcemia Sepsis Rhabdomyolysis Renal insufficiency Neck surgery (transient or permanent hypoparathyroidism) Hypomagnesemia Alkalosis Drugs (phenytoin, phenobarbital, cimetidine, aminoglycosides)

release from bone while calcitonin secretion has the opposite effect. Intestinal absorption of phosphorus is enhanced by vitamin D. Magnesium Magnesium is the second most abundant intracellular cation in the organism, after potassium. More than half of the total body stores are located in bone, whereas less than 1% is present in plasma. Hence, there is poor correlation between serum magnesium levels and total body magnesium pool. Magnesium depletion is usually prominent when a patient presents with hypomagnesemia. Only 55% of the total serum magnesium concentration circulates in the ionized (physiologically active) form, while the rest is either protein-bound or chelated (by phosphate or sulfate in general). Techniques to measure the free fraction are not routinely available for clinical use.125 Hypercalcemia Ionized hypercalcemia is defined as ionized serum calcium concentration exceeding 1.3 mmol/L (or 5.1 mg/dL). Common causes include malignancies, hyperparathyroidism, renal failure, prolonged immobilization, granulomatous diseases, phosphorus depletion, and drugs (calcium itself, lithium, thiazides, vitamin D; Table 18-7). Severe hypercalcemia is very rarely encountered in the neuro-ICU. The clinical manifestations of hypercalcemia involve the gastrointestinal (nausea, vomiting, peptic ulcers, ileus, and pancreatitis in the most severe cases), cardiovascular (hypercalcemia increases vascular resistance but blood pressure may be low secondary to volume depletion, increased resistance to catecholamines, lower threshold for digitalis toxicity, QT interval shortening, and occasional arrhythmias),126 renal (polyuria, nephrolithiasis, nephrocalcinosis), and neurologic systems. Typical neuropsychiatric features include

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confusion, lethargy, depression, and memory impairment. Neuromuscular manifestations such as weakness, hypotonia, and hyporeflexia may also be present. The most severe cases can lead to psychosis, obtundation, and even coma.127 Management should begin with the use of saline solution for volume repletion and then concentrate on correcting the hypercalcemia per se. Reduction of serum calcium concentration can be achieved using furosemide, calcitonin, steroids, pamidronate, plicamycin or, in patients with renal failure, hemodialysis. Mobilization of the patient and correction of concomitant electrolyte abnormalities are also important.

Hypocalcemia Ionized hypocalcemia is defined as ionized serum calcium concentration less than 1.1 mmol/L (or 4.5 mg/dL). It is often encountered in critically ill patients128 but is not frequent in the neuro-ICU. Common causes include renal dysfunction, sepsis, rhabdomyolysis, hypoparathyroidism (always a risk after neck surgery), blood transfusions, hypomagnesemia, fat embolism, alkalosis, and drugs such as phenytoin, phenobarbital, cimetidine, theophylline, and aminoglycosides (see Table 18-7). Clinical manifestations are mainly related to enhanced cardiac and neuromuscular excitability and depressed myocardial contractility. Thus, patients with hypocalcemia may present with hypotension, decreased cardiac output, bradycardia, QT and ST prolongation and, in advanced stages, ventricular arrhythmias and cardiac arrest.128,129 Neuromuscular manifestations include tetany, paresthesias, weakness, and seizures. Patients are often confused and irritable and occasionally they may be frankly psychotic.130 Laryngeal spasm is a rare but dreadful complication. Management of symptomatic hypocalcemia consists of appropriate intravenous calcium replacement therapy (calcium chloride 10% contains three times more elemental calcium than calcium gluconate 10%), correction of coexistent electrolyte imbalances, and treatment of the underlying cause.128

Hyperphosphatemia Hyperphosphatemia is defined as serum phosphorus concentration exceeding 1.45 mmol/L (4.5 mg/dL). Most cases are the result of renal insufficiency or widespread cell necrosis, as seen in sepsis, rhabdomyolysis, multiple trauma, fulminant hepatitis, tumor lysis, and other conditions (Table 18-8). When symptoms are present, they are usually related to the associated hypocalcemia. Deposits of ectopic calcification can result from the formation of insoluble calciumphosphorus complexes. Treatment is based on eliminating the underlying cause and promoting phosphorus clearance by using saline plus furosemide or hemodialysis. In addition,

Table 18-8  Common Causes of Phosphorus Imbalance in the Neurointensive Care Unit Hyperphosphatemia Renal insufficiency Sepsis Rhabdomyolysis Multiple trauma with widespread cell necrosis Hypophosphatemia Head trauma (especially after fluid resuscitation) Sepsis Nasogastric suctioning Sucralfate Hypercalcemia Hypomagnesemia Refeeding syndrome Chronic alcoholism Drugs (diuretics, steroids, beta-adrenergic agonists)

aluminum oxide and calcium acetate or carbonate can bind phosphorus in the lumen of the gastrointestinal tract and prevent its absorption. Hypophosphatemia Hypophosphatemia is defined as a serum phosphorus concentration less than 0.8 mmol/L (or 2.5 mg/dL). It may be caused by nasogastric suctioning, use of phosphorusbinding antacids (aluminum salts, sucralfate), renal tubular defects, hypercalcemia (especially if due to hyperparathyroidism), hypomagnesemia, carbohydrate loading, refeeding syndrome, sepsis, chronic alcoholism, and drugs such as diuretics, insulin, salicylates, beta-adrenergic agonists, or steroids (see Table 18-8). Although clinically silent when mild to moderate, severe hypophosphatemia can impair cellular energy production and produce cardiac failure, hemolytic anemia (by reducing deformability of erythrocytes), tissue hypoxia (by depletion of 2,3-diphosphoglycerate), and extreme muscle weakness that may result in respiratory insufficiency131 as well as weaning failure in ventilated patients. Other neurologic symptoms may include ataxia, tremor, confusion, irritability, and seizures. Appropriate management of hypophosphatemia requires treating the underlying cause, correcting other electrolyte derangements and replacing phosphorus sufficiently. When administering phosphorus intravenously (usually as potassium phosphate), it is necessary to be cautious because it may induce hypocalcemia and calcium phosphate precipitation in the blood.128 Hypermagnesemia Hypermagnesemia is defined as a serum magnesium concentration exceeding 1.1 mmol/L (or 2.0 mEq/L or

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Table 18-9  Common Causes of Magnesium Imbalance in the Neurointensive Care Unit

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Hypomagnesemia

Hypermagnesemia Renal failure Excessive magnesium intake (supplements, parenteral nutrition) Adrenal insufficiency Hypomagnesemia Head trauma (especially after fluid resuscitation) Nasogastric suctioning Chronic alcoholism Refeeding syndrome Hypercalcemia Hypophosphatemia Drugs (diuretics, aminoglycosides, amphotericin B)

2.4 mg/dL). Frequent causes are renal failure, excessive magnesium intake (antiacids, parenteral nutrition, supplements), and adrenal insufficiency (Table 18-9). It is usually well tolerated, but extreme levels of hypermagnesemia can impair neuromuscular transmission leading to areflexic paralysis and respiratory failure. Hypermagnesemia can also produce vasodilatation, hypotension, heart block, and even cardiac arrest. Acute treatment must focus in antagonizing the neuromuscular and cardiac effects by administering intravenous calcium (1 g of calcium chloride 10% over 5 to 10 minutes). Reduction of magnesium levels can be accomplished by infusing saline and furosemide to increase urinary excretion or by prescribing phosphate-containing chelators to prevent intestinal absorption.

Hypomagnesemia is defined as serum magnesium concentration less than 0.65 mmol/L (or 1.3 mEq/L or 1.7 mg/dL). It is a very prevalent derangement in any ICU and it frequently complicates other electrolyte imbalances, particularly hypokalemia and hypophosphatemia. Often undiagnosed, magnesium depletion can exist even in the absence of hypomagnesemia. It is usually due to exaggerated gastrointestinal or renal losses. Among its multiple causes, some of the more common are nasogastric suction, malnutrition, diarrhea, hyperalimentation, refeeding syndrome, various renal disorders, hypercalcemia, hypophosphatemia, diabetic ketoacidosis, excessive sweating, and drugs such as diuretics, laxatives, aminoglycosides, amphotericin B, ethanol, digoxin, and calcium supplementation (see Table 18-9). Hypomagnesemia, as well as hypokalemia and hypophosphatemia, are very often present at admission in patients with head trauma.132 The most conspicuous clinical presentations are related to cardiac abnormalities, typically torsade de pointes and QT prolongation, but it also can produce coronary artery spasm and exacerbate digitalis toxicity and neurologic dysfunction, including altered cognition, apathy, delirium, seizures, tremors, ataxia, nystagmus, hyperreflexia, muscle weakness, spasms, paresthesias and, rarely, tetany. As previously mentioned, hypomagnesemia can have metabolic effects leading to hypokalemia, hypocalcemia, and hypophosphatemia. Intravenous magnesium sulfate should be administered immediately in severely symptomatic patients (2 g over 2 minutes followed by 10 g in 500 mL of isotonic saline over the next 12 hours). It is essential to correct all associated electrolyte disorders and eliminate all potential causes while ensuring adequate replacement.

P earls 1. The most common causes of hypernatremia in the neuro-ICU are diabetes insipidus and iatrogenic (mannitol-induced osmotic diuresis or hypertonic saline infusions). 2. Urinary output must be monitored closely in all patients with intracranial catastrophes. Urinary output greater than 300 mL/hour should raise the suspicion of diabetes insipidus. 3. Diabetes insipidus almost invariably occurs shortly after patients meet criteria for brain death. Anticipating its occurrence in potential organ donors is important to ensure appropriate fluid replacement and avoid dehydration.

4. Excessively rapid correction of hypertonic states can lead to cerebral edema. The rate of correction of hypernatremia should not exceed 10 mmol/L/24 hours. 5. Hypotonic hyponatremia must be evaluated in view of the volume status. Volume depletion favors the diagnosis of CSW, whereas SIADH is usually associated with normovolemia. Laboratory features of CSW and SIADH can be identical. Thus, the differential diagnosis depends on a correct assessment of volume status using physical signs (serial body weights, fluid balance, orthostatic changes in blood pressure and heart rate) and, when necessary,

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measuring central venous pressure or pulmonary artery wedge pressure. 6. Treatment of CSW, the most common form of hyponatremia in patients with subarachnoid hemorrhage, consists of adequate fluid resuscitation. Fluid restriction (the proper treatment for SIADH) increases the risk of delayed ischemic damage. 7. Hyponatremia is common after surgical interventions in the sella region, particularly after transsphenoidal resections of pituitary tumors. In these patients, transient polyuria can precede the development of hyponatremia. 8. Rapid correction of hyponatremia can result in osmotic demyelination affecting preferentially, but not exclusively, pontine structures. This complication

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Chapter 19 Respiratory Function and Mechanical Ventilation in the Patient with Neurologic Impairment Shahram Amini, MD, Andrea Gabrielli, MD, and A. Joseph Layon, MD

Respiratory Physiology Introduction The main function of the lung is gas exchange; however, it has other functions such as metabolism, filtering of unwanted materials from the circulation, and acting as a reservoir for blood. Primary respiratory diseases and neurologic impairment can affect ventilation, blood flow, and gas exchange; any of these effects or their combination may finally lead to respiratory failure and death.1 Respiratory cycles are described by three variables: volume (V), driving pressure (P), and airway airflow. The change in the volume and the amount of time required to effect that change—that is, the rate of change of volume—defines flow. The fundamental act of spontaneous breathing requires the generation of driving pressure secondary to inspiratory contractile force, which institutes flow and overcomes the elastic flow resistance and inertia properties of the entire respiratory system. This relationship has been best described by a formal Equation of Motion: P = EV + R V + IV , where E is the elasticity of the respiratory tract, R is airflow and tissue frictional resistance, and I is an inertia term to account for air flow and tissue acceleration. Tidal volume is the volume of each breath as measured either during the inspiratory or expiratory respiratory cycles. When measured while on respiratory support, the tidal volume refers to that

provided by the mechanical ventilatory support, unless otherwise stated. The driving pressure is the net pressure change during inspiration. During spontaneous breathing, the gradient between the mouth and the alveolus is the transpulmonary pressure. The driving pressure is distinguished from the mean airway pressure by the impact of the inspiratory time, distending pressure, and respiratory rate. While the mean airway pressure has a direct relationship to oxygenation—that is to say, with decreased compliance greater mean airway pressure is needed to obtain acceptable oxygenation—the driving pressure is related to respiratory elastic pressure. Inspiratory and expiratory airflow define flow during these two phases of the respiratory cycle, obtained by active contraction of the respiratory muscle in patients breathing spontaneously or passively in response to change of transmural pressure in patients mechanically ventilated. It is important to differentiate circuit airflow from the inspiratory and expiratory airflow that moves through the endotracheal tube. Modern ventilators have high-pressure driving systems. The airflow resulting from mechanical breath initiation increases circuit pressure at the initiation of the respiratory cycle, reaches a maximum at (usually) mid-cycle, and returns to zero flow at the end of each phase. During volume-preset ventilation, airway pressure is dependent on the inspiratory flow profile, airway resistance, and lung compliance. On the other hand, if a pressure-preset mode is used, increased airway resistance and decreased lung compliance affect volume and flow profile (Fig. 19-1). At the beginning and end of each phase (inspiration and expiration), there is no airflow. 579

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Figure 19-1. A–D, During volume preset ventilation airway pressure waveform changes depend on changes of inspiratory flow profile, airway resistance, and lung compliance. E–F, When a pressure preset mode is used, increased airway resistance and decreased lung compliance affect volume and flow waveform profile. E, respiratory tract elasticity; R, resistance. (Modified from Irwin RS, Cerra FR, Rippe JM [eds]. Intensive Care Medicine, 5th ed. Philadelphia, Lippincott Raven, with permission.)

Lung Volumes Total lung capacity is the volume of gas contained in the lungs at maximal inspiration.2 Vital capacity is the volume of gas that can be expelled by a maximal expiration from total lung capacity. The volume remaining in the lungs, after maximal expiration, is the residual volume. Tidal volume (VT) refers to the normal resting respiratory volume moved during a respiratory cycle. Normal values for VT in healthy adults are from 5 to 8 mL/kg. The lung volume at the end of a normal expiration is the functional residual capacity (FRC). Normal lung volumes are shown in Figure 19-2. The relationship between lung volumes and the transmural pressure gradient is almost linear over the range of normal tidal volumes, and represents lung compliance (Fig. 19-3). Total ventilation or respiratory minute volume (VE) is the amount of gas exhaled per minute and is equal to VE = VT ¥ respiratory frequency Normal values for minute ventilation are from 240 to 480 mL/kg. Interestingly, the volume of air entering the lung is slightly greater than that during exhalation because more oxygen is inhaled than carbon dioxide is expired; however, the difference is usually less than 1%. Alveolar ventilation is the amount of fresh, inspired gas that enters the alveoli per minute and takes part in gas exchange. The anatomic dead space—the airway starting from the mouth or nose, down to the terminal bronchioles—makes up the conducting airways and leads inspired gas to the gasexchanging region of the lung; the anatomic dead space is

approximately 2 mL/kg. Physiologic dead space is the volume of gas that enters the alveoli, but does not take part in gas exchange, because there is no blood flow to that area. Physiologic dead space is very nearly the same as anatomic dead space when the lung is normal. However, in disease states where there is a ventilation-perfusion mismatch, physiologic dead space is increased, because the ventilation goes to the units with an abnormally high ventilation-perfusion ratio. In healthy adult subjects, the physiologic dead space is approximately 150 mL, approximately 20% to 25% of each tidal volume breath. This value represents the anatomic dead space from the mouth, pharynx, larynx, trachea, bronchi, and bronchioles, as well as the contribution of any alveoli that are overinflated with respect to perfusion. In this condition, the alveolar CO2 concentration is easy to predict because it is equal to the ratio between CO2 output and alveolar ventilation. Positive pressure ventilation alone can increase dead space. In respiratory failure, the physiologic dead space is increased because of continued ventilation of alveoli whose perfusion is either absent or decreased.3

Distribution of Ventilation Not all alveoli are equally ventilated, even in the normal lung (Fig. 19-4). This is related to both gravitational and nongravitational influences on gas distribution. In spontaneously breathing, upright, normal subjects, most of the ventilation per unit-volume of the lung goes to the base of the lung, becoming progressively less toward the apex. In the

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Figure 19-2. Static lung volumes. The spirometer curve indicates the lung volumes that can be measured by simple spirometry. (From Lumb AB: Nunn’s Applied Respiratory Physiology, 5th ed. Butterworth Heinemann, with permission.)

supine position, the ventilation of the lowermost lung exceeds that of the uppermost portion. In the lateral decubitus position, the dependent lung is better ventilated. Airway Closure When the small airways, considered to exist in the region of the respiratory bronchioles, close before the end of exhala-

tion, the alveoli distal to this point cannot eliminate gas. Such gas trapping due to small airways closure is seen in healthy subjects only at lung volumes below functional residual capacity. The volume at which the small airways close, known as closing volume, increases with age, with disease processes affecting lung elasticity, or simply by placing the patient on mechanical ventilation, and may encroach on the FRC. Time Constants Another reason for inequality of ventilation is the existence of uneven time constants. The time constant is the time required for evacuation of a certain percentage of lung volume. The time constant for a region of lung is given by the product of its resistance and compliance. Therefore, lung units with different time constants fill and empty at different rates. A unit with a large time constant empties very slowly, while a unit with a small time constant empties more rapidly. If the respiratory rate increases and inspiratory time decreases the unit with the large time constant does not complete its emptying, while the unit with the small time constant does.

Figure 19-3. Static pressure/volume relations for the intact thorax in a conscious patient in the upright position. The relaxation or compliance curve represents the relationship between transmural pressure gradient and lung volume.

Blood Flow Blood flow is as important as ventilation in pulmonary gas exchange. The normal pressures in the human pulmonary artery are approximately 25 mm Hg systolic, 8 mm Hg diastolic, and 15 mm Hg mean. Because of these low pressures, hydrostatic effects within the pulmonary circulation from postural changes are very important. The hydrostatic difference in pressure between the extreme apex and the base is 30 cm H2O, equal to approximately 23 mm Hg, because the human lung is about 30 cm in height. Thus, there are very

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Figure 19-4. Regional differences in ventilation measured with radioactive xenon. Ventilation decreases from the lower to upper regions of the upright chest. (From West JB: Respiratory Physiology, 6th ed. Philadelphia, Lippincott Williams & Wilkins, 2000, p. 18, with permission.)

substantial differences in pressure within the small pulmonary arterioles and capillaries between the top and bottom of the lung in the lung upright position. As a result, most of the blood goes to the lower part of the lung because of the gravitational effects, where—during spontaneous ventilation—there is also more ventilation, and less blood goes to the top of the lung where ventilation is less. Based on the pulmonary arterial, alveolar, and venous pressures, the lung is divided into three zones (Fig. 19-5). The pressure gradient and lung zones become less well defined with the patient in

the supine position, where gravitational gradients are from the anterior to the posterior part of the chest. In Zone 1, alveolar pressure exceeds arterial and venous pressure. Therefore, there is no blood flow in this area of the lung, resultant from closure of the capillaries, because pressure outside the capillary exceeds the pressure inside. In Zone 2, the alveolar pressure is less than the pulmonary artery pressure but greater than the venous pressure. Therefore, flow is determined by the difference between arterial and alveolar pressure, rather than by the expected arterial-

Figure 19-5. Uneven distribution of blood flow in the lung, based on the pressure affecting the capillaries. (From West JB: Respiratory Physiology, 6th ed. Philadelphia, Lippincott Williams & Wilkins, 2000, p. 37, with permission.)

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venous pressure difference; this has been termed the “waterfall effect.” In Zone 3, the venous pressure exceeds alveolar pressure. Therefore, the pressure difference responsible for flow is arterial-venous pressure. Much of the blood distribution within the normal lung is similar to that described as occurring in these three zones. However, other factors also may play a role in determining the distribution of flow; one of these factors is lung volume. In the lowermost region of the upright human lung, another region, Zone 4, with reduced blood flow, is noted. This zone becomes smaller as lung volume is increased. Careful measurements indicate that a small area of reduced blood flow is present along the lung base at total lung capacity. As lung volume is reduced, this region of reduced blood flow extends further up the lung, so that at FRC, blood flow decreases to the bottom half of the lung. At residual volume, the zone of reduced blood flow extends all the way up the lung, so that blood flow at the apex exceeds that at the base. This is related to the contribution of the extra-alveolar vessels. As lung volume decreases, the caliber of the extra-alveolar vessels decreases. At residual volume, they become so narrow as to completely dominate the picture and determine the distribution of blood flow. Administration of vasoconstrictive drugs, such as serotonin, can further exaggerate the role of the extraalveolar vessel and extend Zone 4 further up the lung. The opposite effect is seen if a vasodilator drug, such as isoproterenol, is infused into the pulmonary circulation. In the presence of interstitial pulmonary edema, the fluid around the vessel results in increased pulmonary vascular resistance seen at the base of the human lung. In this condition, the distribution of blood flow often becomes inverted. Thus, in such a situation, blood flow to the apex of the upper lung consistently exceeds that to the basal regions.

Pulmonary Vascular Resistance Pulmonary vascular resistance (PVR) is defined mathematically as follows: PVR = (mean PAP - mean pulmonary venous pressure) CO, where PAP is pulmonary arterial pressure. PVR is affected by lung volume; as lung volume is increased from very low values, PVR first decreases, then increases (Fig. 19-6). Thus, at lung volumes either above or below FRC, the PVR increases. The normal lung, therefore, functioning best at FRC, has the lowest PVR in this “window” of optimal volume. Additional factors that may influence the distribution of pulmonary blood flow include regional differences of conductivity, with some regions of the pulmonary vasculature having intrinsically higher vascular resistance than others; differences of blood flow between the central and peripheral regions of the lung; and inequality of blood flow at the al-

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Figure 19-6. Effect of lung volume on pulmonary vascular resistance. Lowest resistance at FRC. Low lung volumes or overstretching increases pulmonary vascular resistance. (From West JB: Respiratory Physiology, 6th ed. Philadelphia, Lippincott Williams & Wilkins, 2000, p. 35, with permission.)

veolar level. Lung diseases, both localized—such as fibrosis and cyst formation—and generalized—such as chronic obstructive pulmonary disease (COPD) and bronchial asthma—frequently alter the normal distribution of pulmonary blood flow. Disorders of cardiac function, such as pulmonary hypertension or intracardiac shunts, may also alter the distribution of blood flow. The distribution of pulmonary blood flow basically depends on the passive effects of the hydrostatic pressure gradient, as noted previously. Therefore, gravity and the mechanisms of recruitment can be significant in the behavior of normal circulation. Active control of vascular tone is weak in the normal adult pulmonary circulation because the vessels have little smooth muscle. Hypoxic pulmonary vasoconstriction (HPV), a protective mechanism under hypoxic conditions that has the effect of directing blood flow away from the hypoxic regions of the lung, is an example of active control. It consists of contraction of smooth muscle in the walls of blood vessels in the region of the lung with alveolar hypoxia. When the alveolar O2 (PAO2) is reduced to approximately 70 mm Hg, obvious arteriolar constriction may occur. At very low PAO2, approaching that of mixed venous blood (approximately 40 mm Hg), local blood flow may be almost abolished. The exact mechanisms of HPV remain unknown, but endothelium-derived vasoactive substances, such as nitric oxide, may play a role. In addition to nitric oxide, many peptides and substances—such as angiotensin II, bradykinin, vasopressin, atrial natriuretic peptide, endothelin, somatostatin, and calcium-generated peptides; as well as biogenic amines, such as acetylcholine, histamine,

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serotonin, and norepinephrine—also affect pulmonary vascular smooth muscle and blunt HPV. Metabolic Functions of the Pulmonary Circulation Although the basic function of the pulmonary circulation is the exchange of oxygen and carbon dioxide at the alveolar level, it has other metabolic functions. These functions include conversion of the relatively inactive polypeptide angiotensin I into the potent vasoconstrictor angiotensin II, as well as the inactivation of a number of vasoactive substances, such as bradykinin (up to 80%), norepinephrine (up to 30%), and prostaglandins E1, E2, and F2. In addition, the lung has the ability to synthesize or store several substances and release them into the circulation in pathologic conditions, such as in anaphylaxis. There is also evidence that the lungs play a role in the clotting mechanism of blood under both normal and abnormal conditions. Surfactant synthesis and carbohydrate metabolism are other functions of normal lungs. The lung also acts as a reservoir for blood. It can increase its blood volume with relatively small increases in pulmonary arterial or venous pressures, for example, when a subject lies down after standing. Finally, it also acts as a blood filter, removing intravascular thrombi from the circulation before they reach the brain or other vital organs, or sequestering white blood cells, although the significance of this latter function is not yet clear. Gas Exchange Gas exchange, that is, moving oxygen into and carbon dioxide out of the blood, occurs by simple passive diffusion. Because of the thinness of the blood-gas barrier (only 0.3 mm for much of its extent) and its large area (between 5 and 100 m2), the lung is ideal for this gas-exchanging function. The ideal gas equation plays an important role in gas exchange. The partial pressure of a gas is found by multiplying its concentration by its total pressure. Therefore, in the lung at sea level, the alveolar partial pressure of oxygen is described as follows: PAO2 = Fi O2 X (Barometric pressure - Water pressure), = 0.21 ¥ (760 mm Hg - 47 mm Hg)

A remarkable decrease in PO2 occurs in the peripheral tissues, when O2 is consumed by the mitochondria. The movement in the oxygen in the peripheral tissue is essentially by passive diffusion. The same scenario occurs with regard to carbon dioxide, but in a reverse direction, being the alveolar concentration of CO2 equal to CO2 output or alveolar ventilation. Under normal conditions, arterial and alveolar PCO2 values are almost the same, approximately 40 mm Hg, with a small arterial-end tidal CO2 gradient of approximately 3 to 5 mm Hg; however, the PCO2 of mixed venous blood is 45 to 47 mm Hg. Tissue gas exchange occurs down this concentration gradient. Gas exchange may be impaired for four major reasons, outlined in the following sections. Hypoventilation Hypoventilation occurs when alveolar ventilation is reduced to such a low level that oxygen uptake, carbon dioxide output, or both, are impaired. Therefore, hypoventilation always results in arterial hypercarbia and hypoxemia, although the latter may not be seen if the patient breathes an enriched oxygen mixture. In this case, even when hypoventilation evolves to apnea, hypoxia is delayed by high concentration of oxygen. Etiologic causes for hypoventilation are shown in Table 19-1. In all of these conditions, the lungs are normal; thus, this table may be used as a diagnostic tool to differentiate these conditions from disorders in which carbon dioxide retention is associated with chronic lung disease. Diffusion Limitation According to the Law of LaPlace, described mathematically as PT = 2T ∏ r, where P is the pressure within any bubble, T is the surface tension, and r is the radius of the bubble, diffusion of a gas Table 19-1  Etiologies of Hypoventilation 1. 2. 3. 4.

= 0.21 ¥ 713 mm Hg

5.

= 149.73 mm Hg,

6.

where FiO2 is the fraction of inspired oxygen. In the ideal lung, the effluent pulmonary venous blood would have the same PO2 as that of the alveolar gas. This is not quite what is seen, however, as there is a small gradient between alveolar and arterial blood oxygen. The gap between ideal PAO2 and the partial pressure of arterial oxygen (PaO2) is known as venous admixture or shunt and can be used as a basis for oxygen therapy.

7. 8. 9. 10.

Depression of the respiratory center by drugs such as morphine derivatives or barbiturates Diseases of the brainstem, such as encephalitis Abnormalities of spinal cord conduction pathways, such as in high cervical spinal cord transection Anterior horn cell diseases, including poliomyelitis, affecting the phrenic nerves or those supplying the intercostal muscles Disease of nerves to respiratory muscles, such as GuillainBarré syndrome Diseases of the myoneural junction, such as myasthenia gravis Diseases of the respiratory muscles themselves, such as progressive muscular dystrophy Thoracic cage abnormalities, such as kyphoscoliosis Upper airway obstruction (e.g., thymoma) Hypoventilation associated with extreme obesity, such as in Pickwickian syndrome*

*Other miscellaneous causes include metabolic alkalosis and idiopathic states.

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is directly related to the tissue area and inversely proportional to the thickness of the area involved. It is also dependent on the solubility of the gas and the molecular weight being proportional to the solubility of the gas and inversely proportional to the square root of the molecular weight. This is why CO2 diffuses through tissue about 20 times more rapidly than O2, because CO2 has a much higher solubility (24 : 1 at 37°C). Obviously, any condition that affects these variables can impair diffusion of a gas. Shunt Shunt refers to a condition in which blood passes through unventilated areas of the lung. As a result, blood enters the systemic arteries without having been oxygenated. It is seen even in the presence of a normal cardiopulmonary system because physiologic shunt may be of thebesian or bronchial venous origin. Ventilation-Perfusion Mismatch Ventilation-perfusion (V/Q) mismatch is perhaps the most common cause of hypoxemia. As stated previously, there is an inequality of gas exchange in the normal, upright lung due to V/Q mismatching. This results from a decrease in both ventilation and blood flow per unit-volume lung from the bottom to the top of the upright lung. However, the changes of blood flow are more marked than those for ventilation. Thus, the ventilation-perfusion ratio decreases from high values at the apex to lower values at the base of the normal upright lung. There are some clinical indices that may be used to assess the amount of V/Q mismatching; these include arterial PO2, where a decrease in PO2 indicates mismatching of ventilation and blood flow. Although a simple measurement, it is very sensitive to overall ventilation and pulmonary blood flow. The alveolar-to-arterial PO2 difference is more frequently measured as an indicator of V/Q mismatch because it is less sensitive to the level of overall ventilation. The normal value in an adult with a normal lung is about 15 to 20 mm Hg. It increases by 5 mm Hg per decade, after age 20, but its absolute value cannot be predicted without measuring PaO2. Another useful index of V/Q mismatch is the physiologic shunt. As previously stated, it is caused by blood flow to lung units with abnormally low V/Q ratios. The value in the normal lung is less than 5%. It can be calculated using the following equation: Q sp Q t = (CIO2 - CaO2 ) (CIO2 - C V O2 ), where Qsp refers to physiologic shunt; Qt to total blood flow to the lung; and CIO2, CaO2, and CvO2, refer to the oxygen contents of ideal (based on the alveolar gas equation), arterial, and mixed venous blood, respectively. Another index of V/Q mismatch is physiologic dead space (VD). In contrast to the physiologic shunt, the ventilation of lung units with abnormally low V/Q ratios, VD refers to the amount of ventilation going to units with

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abnormally high V/Q ratios. The normal value for VD is less than 0.3, that is, about one third of the VT. The VD-to-Vt ratio is used as a criterion for weaning patients from mechanical ventilation.

Oxygen Transport Oxygen is transported either in dissolved form or in combination with hemoglobin. Dissolved oxygen only plays a slight role in oxygen transport because of its low solubility (0.003 mL O2/100 mL of blood). On the other hand, hemoglobin plays the most important role in oxygen transport. Blood is able to transport large amounts of oxygen due to this reversible combination with hemoglobin, yielding oxyhemoglobin. Arterial oxygen concentration, or O2 content (CaO2), is an important indicator of how much oxygen reaches the tissues and includes the oxygen combined with hemoglobin as well as the dissolved oxygen. It is easily calculated by the following equation: CaO2 = [1.39 ¥ hemoglobin(g 100 mL) ¥ SaO2 ] +(0.003 ¥ PaO2 ), where SaO2 is the oxygen percent saturation. As is seen from the equation, O2 content depends more on SaO2 than PaO2. Unless the patient is breathing a high concentration of oxygen, for example in the hyperbaric chamber, the dissolved portion of the arterial O2 content is essentially irrelevant. The shape of the oxygen dissociation curve is beneficial for the human being. The flat, upper portion of the curve indicates that a decrease of 20 mm Hg in PaO2, in an otherwise healthy individual, results in only a minor reduction in arterial oxygen content. The physiology of the oxyhemoglobin dissociation curve also ensures rapid loading of O2 in the pulmonary capillaries. Furthermore, the lower part of the O2 dissociation curve indicates that a considerable amount of oxygen can be taken by the peripheral tissues with only a small decrease in capillary PO2. Several factors affect the position of the oxygen dissociation curve. Hyperthermia, acidosis, hypercapnia, and an increased concentration of 2,3-diphosphoglycerate cause a right shift in the curve, resulting in a decrease in the affinity of hemoglobin for oxygen (which means that the hemoglobin more easily gives up the carried oxygen to tissues). Increased PaCO2 reduces the affinity of hemoglobin for oxygen, because of an increased hydrogen ion concentration. The net effect is that, as the blood loads carbon dioxide, the unloading of oxygen is improved. On the other hand, hypothermia, alkalosis, hypocapnia, and a decreased concentration of 2,3-diphosphoglycerate result in a left shift in the oxygen dissociation curve. A leftshifted oxyhemoglobin dissociation curve does not easily give up oxygen to tissues.

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Carbon Dioxide Transport Carbon dioxide is transported by the blood in three forms: dissolved (13%), as bicarbonate (80%), and in combination with proteins as carbamino compounds (7%).4 Most of the CO2 in the blood—approximately 80%—is in the form of bicarbonate, with approximately two thirds in the plasma and one third in the red blood cells.

Control of Breathing Ventilation is under sensitive control from higher centers.5 Normally, control of respiration depends on numerous stimuli, acting directly or reflexively on the medullary respiratory center. Changes in CO2 tension and pH are normally the primary stimuli to ventilation, with variations in PaO2 being less important. Proprioceptors in the chest wall, respiratory muscles, lungs, and limbs are additional stimuli of even lesser importance. Neuroreceptors Peripheral chemoreceptors are sensitive to changes in the chemical composition of blood. They are contained in groups of cells found close to the bifurcation of the carotid arteries (carotid bodies) and close to the arch of the aorta between the aorta and the pulmonary arteries (aortic bodies). The major stimulus for increased activity of these bodies is a decrease in PaO2. The activity of the chemoreceptors is also influenced by the partial pressure of arterial carbon dioxide (PaCO2) and by pH. Increasing PaCO2 at constant PaO2 and pH causes an almost linear increase in neural output. Stimulation of peripheral chemoreceptors causes an increase in the rate and depth of breathing, playing a major role in the defense against hypoxia. Central chemoreceptors are located within 2 mm of the ventral surface of the medulla oblongata. This area can be stimulated in experimental animals by administration of solutions of low pH or a high CO2 concentration to the surface of the brain. Stimulation in this way results in an increase in the rate and depth of breathing. Changes in blood pH have less of an effect than changes in CO2, as hydrogen ions diffuse less readily across the blood-brain barrier. There are sensory nerve endings in the airways, lung, and chest. Stimulation of nasal receptors causes sneezing, but may also cause apnea. The pharyngeal and laryngeal receptors are stimulated by irritants or the presence of foreign bodies. Stimulation causes coughing, but also may cause laryngeal spasm. Receptors in the lungs are divided into three groups: 1. Bronchopulmonary stretch receptors, which are activated by lung distension, and result in shortening of inspiration and prolonging expiration. They are also stimulated by a decrease in PaCO2.

2. Tracheobronchial irritant receptors, which are stimulated by large inflations and deflations of the lungs and by a large number of inhaled irritants. Their stimulation results in cough, bronchoconstriction, laryngeal constriction, and hyperpnea, and is usually associated with increased mucus secretion. 3. Pulmonary and bronchial C receptors, which are triggered by harmful stimuli such as pulmonary edema and congestion, and by emboli to the pulmonary vascular bed. Stimulation causes rapid, shallow breathing, bronchoconstriction, and increased airway secretions; triggering of these receptors may often be associated with cardiovascular depressive effects. Respiratory Responses to Hypercapnia Under normal conditions, respiration is regulated to maintain PaCO2 at or close to 40 mm Hg. An increase in PaCO2 results in an increase in minute ventilation, resulting from both an increase in VT and frequency; this occurs almost linearly over the range of PaCO2 from 40 to 70 mm Hg. The maximum ventilatory response induced by CO2 is about 70 to 80 L per minute. When PaCO2 increases to 70 mm Hg in a healthy subject, there may be depression of ventilation, and even coma and death. An increase in PaCO2 is usually accompanied by a decrease in arterial pH, and it is sometimes difficult to separate the ventilatory effects of an increased PaCO2 from those of pH. The changes in minute ventilation in response to changes in PaCO2 are 1 to 6 L per minute per mm Hg. Response to Hypoxia Because the stimulation of ventilation by hypoxia decreases PaCO2, the ventilatory response to hypoxia is small and, in fact, limited by the decrease in PaCO2. The relationship between minute ventilation and alveolar PO2 is hyperbolic. The ventilatory response to hypoxia is variable between individuals, averaging approximately 0.6 L per minute per percent desaturation. Respiratory Muscle Fatigue The location of fatigue may be at the muscle level—peripheral fatigue—or at higher levels—central fatigue—such as at the neuromuscular junction. In general, fatigue follows prolonged high oxygen consumption of the respiratory muscle, normally 2% of the metabolic rate, secondary to increased flow resistive or elastic workload. The clinical manifestations of inspiratory muscle fatigue include tachypnea, paradoxical abdominal motion, and respiratory alternans— variations between normal expansion and abdominal paradox—hypercapnia, and, preterminally, even bradycardia. Respiratory muscle weakness is more common in older age

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groups, and its degree is reflected in the vital capacity, the expiratory reserve volume, and, particularly, the inspiratory capacity. Patients whose vital capacity has fallen below 30% of the predicted value usually require assisted ventilation. Patients who contract poliomyelitis when older are at increased risk of developing respiratory failure after the convalescent period. Respiratory system compliance is reduced in these patients even when a relatively short duration of paralysis (6 to 18 months) requires negative pressure ventilation. Myasthenia gravis, an autoimmune disorder affecting the acetylcholine receptors of skeletal muscle, has a significant mortality related to respiratory muscle or bulbar involvement. Hypercapnic respiratory failure occurs in myasthenia gravis in some well-defined circumstances. Electrolyte disturbances may also compromise respiratory muscle function; hypokalemia, hypophosphatemia, and hypomagnesemia can precipitate respiratory failure. A reduction in vital capacity is characteristic of restrictive ventilatory defect. This may result from diseases affecting the chest cage, sclerodermal spondylitis, neuromuscular diseases, poliomyelitis, diseases of the pleura, or interstitial diseases of the lung. FRC comprises 25% to 30% of the total lung capacity but this value may increase in the elderly. It has been estimated that the vital capacity decreases and the residual volume increases by about 200 mL per decade after the age of 20 years.

Pulmonary Mechanics For a given change in driving pressure (P), tidal volume (VT) increases in proportion to lung compliance: VT = compliance ¥ P As the lungs become stiffer and more difficult to expand, the compliance decreases. When lung compliance increases, the lungs become easier to expand: Compliance = VT Inflation pressure A typical value for lung compliance in a healthy newborn2 is 1.5 to 2 mL/cm H2O/kg. Airway Pressure The peak inflation pressure (PIP) is the highest pressure recorded at the end of inspiration.6 The pressures measured during inspiration are the sum of two pressures: (1) that required to force gas through the resistance of the airway, and (2) that of the gas volume as it fills the alveoli. Hence, PIP is not the pressure that the alveolus “sees.” Plateau pressure is the pressure measurement taken after a breath has been delivered to the patient and before exhalation has begun; it is measured with an inspiratory pause, which eliminates both the flow and resistive components that are measured in the peak inspiratory pressure. The pressure

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measured during this plateau is indicative of alveolar pressure. The compliance of any structure is the relative ease with which the structure expands, and elasticity is the tendency of the structure to return to its original form after being stretched or acted on by an outside force. Compliance is defined as the change of volume that corresponds to the change in pressure, described mathematically as Compliance = DV DP, where DV stands for the change in volume and DP for the change in pressure. Compliance is normally measured in L or mL/cm H2O. Normal compliance of the lung is the sum of the lung tissue and the surrounding thoracic structure compliance values. The value for compliance varies a great deal depending on the posture, position, and the level of the consciousness of the subject3; it may be 50 to 200 mL/cm H2O. In the intubated and mechanically ventilated patient with normal lungs, the compliance value will vary, at the low end, from 40 to 50 mL/cm H2O in males, and 35 to 45 mL/cm H2O in females, to as high as 100 mL/cm H2O in both groups. In patients on mechanical ventilatory support, compliance calculations use the plateau pressure measure at static or no flow conditions and the pressure at end exhalation. The result is thus static compliance. In the presence of positive end-expiratory pressure (PEEP), the pressure at no flow conditions should be reduced by the amount of PEEP: Static compliance = VT (Pplateau - PEEP) Resistive Properties Nonelastic properties of the respiratory system characterize its resistance to motion. Because motion between two surfaces in contact usually involves friction or loss of energy, resistance to breathing occurs in any moving part of the respiratory system. This resistance includes frictional resistance to airflow, tissue resistance, and inertial forces. By definition, resistance to airflow is equal to driving pressure (P) divided by airflow: Resistance = P ∏ airflow Normal airway resistance in a term newborn is approximately 22 to 40 cm H2O/L/sec, which is about 16-fold higher than values observed in adults (1 to 2 cm H2O/L/sec).4 Nearly 80% of the total resistance to airflow occurs in large airways up to about the fourth to fifth generation of bronchi. Factors influencing airway resistance are numerous and include those discussed in the following sections. Lung Volume Airway resistance decreases in hyperbolic fashion because of the increase in the diameter of the airway as lung volume increases. At very low lung volumes, the small airways may close completely, especially in dependent lung zones.

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Phase of Respiration At any lung volume, resistance is less during inspiration than during expiration. Vagal and Sympathetic Tone Stimulation of the bronchial beta-2 receptors produces bronchodilation and increased airway conductivity in both large and small airways. Conversely, beta blockade may be associated with increased airway resistance. Respiratory Gases Hypercapnia is associated with bronchoconstriction and increased resistance, apparently as a result of direct action on bronchiolar smooth muscle. This may, thus, provide a mechanism by which the ventilation is reduced to an area of the lung that is poorly perfused. The density of the inspired gas affects the resistance to flow; as gas density increases, resistance increases. Time Constants The amount and rate of filling of each lung depends on the compliance and resistance of that unit. The rate at which individual units fill is called the time constant. One time constant allows 63% of either the inspiratory phase or the expiratory phase to occur. Two time constants allow about 86%, three time constants 95%, and four time constants allow 98% of inspiration or expiration to occur. A time constant is the product of compliance and resistance: Time constant = Compliance ¥ Resistance Synchronous and Asynchronous Breathing Asynchrony of the respiratory cycle may be evident with airway obstruction, increased secretions, bronchospasm, and so forth. Presentation may be with “bucking” or fighting against the ventilator breath during mechanical ventilation, or with involuntary Valsalva maneuvers, agitation, or impaired gas exchange. Objective evaluation of asynchrony may be difficult to quantify. On the other hand, synchronous ventilation is easily observed.7 Work of Breathing The work performed on the lung during the breathing cycle may be described by mathematics that take into consideration the area under the pressure-volume curve of the lung. The work calculated with such an analysis includes the elastic work required to inflate the lungs and the flow resistive work required to generate the flow through the airways.4 The work per breath is measured as force times distance and is reported in units termed Joules. The rate of work (work X time) is called power and is measured in Watts.

Mechanical Ventilation Introduction Mechanical ventilation is used when the patient’s spontaneous ventilation is not adequate to sustain life, as with respiratory failure, extreme respiratory muscle fatigue, and increased work of breathing, or when it is necessary to take control of ventilation to prevent impending collapse of another organ’s function. Although often life-saving, mechanical ventilation is invasive, expensive, and associated with a variety of potentially serious complications. Just as the standard organization of patient management has increasingly used protocols and guidelines as a means to monitor and improve quality of care and reduce costs, a ventilator management protocol (VMP) has been designed for use in reducing the duration of mechanical ventilatory support without (ideally) any adverse effects on patient outcome. The VMP has also been associated with a decrease in the incidence of ventilator-associated pneumonia (VAP) in trauma patients and has moved in that direction in combined medical and surgical patients. VMPs are highly effective means of improving care even in university intensive care units, where physicians are present around the clock.8 Types of Mechanical Ventilation Negative Pressure Ventilation Although the mainstay of ventilatory support during the polio epidemics of the mid-20th century, negative pressure ventilation is now uncommon. Nonetheless, data suggest that negative pressure ventilation is as effective as conventional mechanical ventilation in preventing death that may occur during acute respiratory failure in patients with COPD.9 Positive Pressure Ventilation Pressure and volume modes of mechanical ventilation have been available for many years.10 Flow is the parameter that is controlled and cycled in volume control ventilation, although, for simplicity, it is commonly referred to as volume-controlled ventilation (VCV). Pressure modes of ventilation include pressure support; airway pressure release ventilation (APRV); and pressure-controlled ventilation (PCV), with or without an inversed inspiratory-expiratory ratio. Additionally, several options, such as synchronized intermittent mandatory ventilation (SIMV) with pressure support, exist for combination modes, as well as several new modes available in the latest generation of ventilators such as pressure-regulated volume control, volume-assured pressure support, and volume support. The primary difference between PCV and the more commonly used VCV is that the clinician-set inputs and measured outputs are reversed. PCV does not deliver a predetermined VT but rather maintains a set airway pressure throughout inspiration for a prescribed

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length of time; VT depends on compliance. In VCV, VT is set while pressure is variable. The measured outputs in both modes are governed by the impedance characteristics of the respiratory system (resistance and compliance) and the ventilator settings (frequency, and inspiratory time). Positive pressure ventilation produces flow at the airway opening that generates a pressure in opposition to the impedance of the respiratory system. Impedance forces include resistive forces in the airways, ventilator circuit, and the endotracheal tube, which are proportional to the gas flow, and elastic forces, which are proportional to the distensibility or compliance of the respiratory system. Additionally, any volume remaining in the lung at end exhalation generates a pressure known as “auto-PEEP” or “intrinsic PEEP.” Although it was initially thought that PCV was superior to VCV in terms of gas exchange and lung mechanics, no superiority of one over the other was demonstrated. Selection of either pressure or volume control ventilation depends on the primary concern of the clinician for the patient. VCV is associated with an increased risk of developing high airway and alveolar pressures, whereas with PCV, the main concern is variation of VT, its effect on PaCO2, and the potential for barotrauma. These two different ventilatory mode characteristics will be analyzed separately. Therefore, peak airway and plateau pressures and VT should be monitored, respectively, in volume and pressure control modes. Modes of Mechanical Ventilation Controlled Mechanical Ventilation In controlled mechanical ventilation (CMV), the ventilator delivers a predetermined VT or pressure at a certain rate, flow, and inspiratory-expiratory ratio. In this mode the entire respiratory work is performed by the ventilator; the patient has no role except as a passive recipient. CMV is most frequently used when the patient is apneic from sedation, neuromuscular blockade, or disease. Intermittent Mandatory Ventilation Intermittent mandatory ventilation (IMV) is a combination of spontaneous ventilation and volume assist ventilation. In this mode, the ventilator delivers a volume preset breath at a predetermined frequency. Between these mechanically controlled breaths, the patient may breathe spontaneously. However, such systems do not always synchronize the patient’s breaths with the mechanical breaths and the result may be patient “fighting” or asynchrony with the ventilator. Synchronized Intermittent Mandatory Ventilation This improvement over IMV ventilators allows the patient to receive mandatory breaths in synchrony with the patient’s inspiratory efforts. The assisted breaths occur only during inspiratory “windows,” established by the manufacturer and

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set by the clinician. The time available within each window for the patient varies, but it usually is a function of the preset respiratory rate. The patient’s inspiratory effort is detected and, while the window is open, a synchronized breath is delivered. If no patient effort is detected at the time the window closes, the ventilator delivers a mandatory breath. Spontaneous breaths taken by the patient in between the SIMV breaths may be supported by expiratory pressure (i.e., continuous positive airway pressure/PEEP), pressuresupported ventilation (PSV), in which spontaneous breaths are fully or partially supported, or both. Assist-Controlled Ventilation In assist-controlled ventilation (ACV), each spontaneous breath that exceeds the trigger threshold results in the delivery of a completely supported mechanical breath. If the patient fails to breathe or the spontaneous breath fails to exceed the trigger threshold, a mechanically controlled breath is provided, generally at a rate set by the clinician, to ensure adequate ventilation. Weaning during ACV is different from that for IMV or SIMV, because many of the parameters, previously set by the clinician, are now patient controlled. During ACV, as long as the patient is breathing above the control rate, reduction in the rate brings about no change in ventilator cycling. Because the patient is setting his or her inspiratory time, the inspiratory-expiratory ratio cannot generally be changed. Unlike pressure-limited ACV, where reduction of PIP is the primary weaning parameter, in volume-control modes, reduction in VT delivery or the use of PSV is the preferred method of weaning. Volume-Controlled Ventilation In VCV, the VT is preset and usually guaranteed.11 However, if total respiratory system compliance (chest wall plus lung compliance) is extremely low, elevated PIP, gas trapping, barotrauma, and circulatory compromise may result. If an air leak is present—perhaps due to a suboptimally inflated endotracheal tube cuff—the effective VT will decrease due to a lack of added flow reserve. Pressure-regulated volume control (PRVC), in which inspiratory pressure is minimized for a given preset VT, may confer added safety but cannot compensate for large or variable air leaks.11 Depending on the ventilator design, VT, respiratory rate, FiO2, peak flow rate, inspiratory-expiratory ratio, and VE are all set separately by the clinician. Longer inspiratory time and a decelerating waveform pattern are associated with a lower peak airway pressure.12 Pressure-Controlled Ventilation PCV is the most common alternative to VCV. PCV is a patient- or time-initiated, pressure-limited, and time-cycled mode of ventilatory support. It is characterized by rapid increase of airway pressure with decelerating inspiratory flow pattern.

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In PCV the practitioner sets the maximum pressure generated by the ventilator—termed the preset pressure— frequency, and the time the pressure is sustained (inspiratory time, Ti). VT is the primary output in PCV and varies with the impedance, resistance, and compliance of the patient’s respiratory system. Changes in inspiratory and expiratory resistance, compliance, secretions, and bronchospasm, pneumothorax, and importantly, the development of intrinsic PEEP, all impact delivered VT in PCV.10 PCV may augment the recruitment of closed alveolar units and improve oxygenation by changing the inspiratory flow pattern from a square wave, as used with controlled mechanical ventilation, to an exponentially decaying curve, and by maintaining airway pressure at a constant level throughout the inspiratory phase.13 This mode of ventilation is most advantageous in the patient with heterogeneous lung pathology. Higher inspiratory flow rates result in better distribution of gas to lung units with different time constants and a low level of intrinsic PEEP. Furthermore, the airway pressure limit may prevent barotrauma. Common pressure control modes include PCV, APRV, PSV, and bilevel positive airway pressure (BiPAP). The flow, volume, and pressure waveforms in PCV are illustrated in Figure 19-1. With these modes, the clinician adjusts the target pressure and inspiratory time to achieve the desired tidal volume. The pressure limit is set initially at 10 to 20 cm H2O less than the peak airway pressure or the same as the plateau pressure while the patient was on volume preset ventilation using conventional parameters. The pressure limit is then adjusted based on the desired VT (usually 6 to 8 mL/kg ideal body weight). In this mode of ventilation, the set pressure, inspiratory time, flow rate, and the lung compliance are the factors that determine the tidal volume.12 The following should be considered with use of PCV: 1. When inspiratory time is increased, the VT may not increase because of air trapping and subsequent shortening of the expiratory time resulting in auto PEEP. 2. When respiratory rate is increased, the minute ventilation may increase or decrease depending on air trapping and decreased VT. 3. Finally, when PEEP is applied it may decrease or increase VT, depending on whether it decreases or increases compliance. No significant differences between PCV and CMV with decelerating inspiratory flow waveform have been demonstrated. There are two basic methods of applying PCV. The first method is simply to use PCV as described previously, as a substitute for conventional CMV. The second and more extensively studied method is to invert the inspiratoryexpiratory (I : E) ratio. This is called pressure-control inverse ratio ventilation (PC-IRV). The utility of this ventilatory mode remains controversial.13

PC-IRV may be a beneficial mode of ventilation in patients with acute respiratory distress syndrome (ARDS). It has been reported to improve oxygenation, ventilation, decrease PIP, and lower PEEP requirements. PCV is most frequently used in combination with a prolonged inspiratory time in patients with ARDS, when conventional VCV has failed. PCV may also be considered in a patient with bronchopulmonary fistulae, as a way to reduce pressure to and flow through the fistula, thereby promoting its early closure.14 One study suggested that the clinical utility of PC-IRV is limited, except in the setting of ARDS with hypoxemia or hypercapnia, refractory to other therapeutic options.15 In this study, inversion of the I : E ratio from 1 : 2 to 2 : 1 resulted in significant improvement in PaO2 and shunt, but at the expense of decreasing cardiac output. Despite the decreased cardiac function, improvements in CaO2 associated with PC-IRV were sufficiently great to prevent significant alteration in O2 consumption in the patient population with severe ARDS included in this study. Use of a prolonged Ti most often requires sedation and paralysis, increasing the complexity of care. In a second study, at constant mean airway pressure, PC-IRV did not improve arterial oxygenation, global oxygenation indices (oxygen delivery [DO2] and oxygen consumption [VO2]), gastric mucosal PCO2 or pHi (gastric mucosal pH) more than did PCV with a normal I : E ratio and extrinsically administered PEEP.16

Pressure-Supported Ventilation PSV is a form of mechanical ventilatory support that assists the patient’s spontaneous inspiration effort with a clinicianselected degree of positive airway pressure. As with any form of support that is designed to respond to the patient’s effort, the inspiratory pressure assist of PSV requires a signal to trigger the demand valve to initiate flow. The inspiratory effort of the patient is sensed as a decrease in the airway pressure, which triggers PSV. With initiation, the ventilator delivers high flow to achieve the positive pressure level set by the operator. The flows that are delivered may reach rates of 150 to 250 L/minute, and are typically much higher than the flow rates available during mandatory breaths. PSV could be an alternative to ACV in patients with respiratory failure.17 Although PSV can be used as a standalone ventilatory modality, provided that the patient has sufficient respiratory drive, it is most commonly used in combination with volume-controlled SIMV.18 Noninvasive PSV, using a tightly fitting facemask, is comparable to invasive PSV in terms of blood gases and respiratory pattern. An uncontrolled study indicated that noninvasive PSV could be used in selected trauma patients19 and in patients with acute respiratory failure.20 Although PSV may be safely used in many patients with acute lung injury who would otherwise receive conventional positive pressure ventilation, failure of PSV appears to be more likely in patients with lower respiratory compliance, higher venti-

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latory needs, and relatively longer duration of acute lung injury.21 As mentioned previously, PSV is commonly combined with SIMV. This combination significantly increases minute volume when compared with ACV or SIMV alone.22 It has been shown, in a selected population of patients with COPD failing removal of the endotracheal tube after mechanical ventilation, that noninvasive positive pressure ventilation (NIPPV) with PSV is associated with maintenance of satisfactory gas exchange and similar diaphragmatic effort and respiratory mechanics. The feeling of breathlessness as well as the efficiency of the diaphragm in generating VT are better using NIPPV.23 PSV can also be used in asthmatic and postoperative patients, and as a mode of noninvasive mechanical ventilation.24 Reduced respiratory frequency resulting from reduction of excessive work of breathing is seen with use of PSV; one may also note increased VT and alveolar recruitment with this mode of support.25 Breathing frequency and pattern are poor predictors of work of breathing in patients receiving PSV.26 As a method of ventilation for patients with acute respiratory failure, high-frequency oscillatory ventilation combined with PSV may have potential advantages over conventional mechanical ventilation. When drainage of secretion is facilitated, the beneficial effects of high-frequency oscillatory ventilation may appear after several hours.27 Each pressure support ventilation breath is patient triggered (on) and flow-cycled (off). Either pressure or flow may be used as triggers. Thus, the patient produces an inspiratory effort to trigger the ventilator to give a positive pressure breath. Triggering the ventilator and controlling airway pressure at the cranial end of the endotracheal tube may decrease imposed work of breathing essentially to zero.28 The breath termination criteria are sometimes adjustable. Termination criteria (TC) are either a fixed terminal flow, usually 5 L/minute or a percentage of peak inspiratory flow, usually 5% or 25%.24,29 When the TC do not match the interaction between the patient’s breathing effort and the opening and closing of the inspiratory and expiratory valves in the ventilator, patient-ventilator asynchrony may occur and the patient’s inspiratory effort may increase. The proper adjustment of TC improves patient-ventilator synchrony and decreases work of breathing during PSV.29 As long as the patient’s inspiratory effort is maintained, the preselected airway pressure stays constant with a variable flow rate of gas from the ventilator ranging from 150 to 250 L/minute. Many ventilators also incorporate backup flow TC, such as a duration of inspiration greater than 5 seconds, or an increase in the airway pressure above the set pressure support level—for example, when a patient attempts to cough. PSV is thus patient-triggered, pressure-limited, and flow-cycled. If the inspiratory flow supply during PSV does not match the patient’s demand, a ventilator may neither provide appropriate PSV nor reduce patient’s work of breathing. High inspiratory flow supply is needed to maintain good

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patient-ventilator synchrony in patients who have a high inspiratory drive. Initial inspiratory flow of PSV is usually system specific and nonadjustable, but it can be changed on some ventilators by adjusting the inspiratory rise time, the theoretical interval between the beginning of inspiration and the point at which airway pressure reaches the selected level.30,31 Major differences exist for rise time and inspiration TC among different ventilators at similar settings. For example, inspiration TC adjustment markedly affects the transition to exhalation in the Puritan Bennett 840.32,33 Pressure-Supported Ventilation and Work of Breathing PSV can unload, either totally or partially, ventilatory muscles and decrease the work of breathing (WOB) during spontaneous breathing in adults and children. Total unloading of the inspiratory muscles occurs when the only effort needed is that required to trigger the PSV breaths. Total unloading usually correlates with levels of PSV that result in a VT between 10 and 12 mL/kg; this is termed PSVmax. The use of pleural, instead of airway, pressure as a target pressure allows one to accomplish a new mode of mechanical pressure called pleural pressure-supported ventilation (PPSV). PPSV is accomplished by putting the ventilator into a PSV mode at either a pressure support of 0 cm H2O or greater than 0 cm H2O. Although PPSV targets pleural pressure in attempting to maintain the constant pleural pressure of 0 cm H2O, a positive pressure is actually added to the airway to overcome the resistance and compliance of the lung during inspiration, resulting in a reduction of lung work to zero, while the chest wall work remains. In a study comparing inspiratory WOB utilizing T-piece breathing, PSV, or PPSV on a lung model with variable compliance and airway resistance, PPSV was shown to maximally reduce WOB.34 Potential Hazards of Pressure-Supported Ventilation Because PSV is an assisted mode, patients with unreliable respiratory drives may not trigger the ventilator at the appropriate time to ensure an adequate respiratory frequency and minute volume. Similarly, unreliable inspiratory effort may cause fluctuations in the Ti and, consequently, in the VT. PSV should thus be used with caution in patients with unstable ventilatory drives or respiratory system mechanics. One solution for assuring adequate minute ventilation has been the incorporation of backup or apnea ventilation. This allows the clinician to select the time in which, if the ventilator does not recognize a respiratory attempt by the patient, it switches to a mandatory mode. Another solution to ensure the maintenance of minute ventilation is the concomitant use of PSV with IMV or SIMV.33 Circuit leaks during PSV can produce continuous flow demand such that expiratory criteria are not met, resulting in inspiratory pressure assist. This phenomenon is seen with air leakage from an uncuffed

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endotracheal tube, especially in small children, and among patients with bronchopleural fistulae. Most ventilators have secondary breath TC, usually cycling off after 3 to 5 seconds of inspiration, to reduce the associated potential hazard.24 Autocycling of PSV in a patient with low respiratory impedance can produce hyperventilation sufficient to cause respiratory alkalosis35; altering the airway pressure at which the PSV is triggered may alleviate this problem. High-Frequency Ventilation While high-frequency ventilation (HFV) is known to result in better short- and long-term outcomes in pediatric patients with respiratory distress syndrome, the application of HFV in the respiratory management of ARDS in adult patients is no longer recommended.36 Although high-frequency positive-pressure ventilation and high-frequency jet ventilation are of unquestionable value during laryngoscopy, bronchoscopy, and surgery of the upper respiratory tract, the only unequivocally successful application of HFV in the intensive care unit is in the treatment of bronchopleural fistula. A number of studies have focused on the efficiency of HFV in acute respiratory failure and ARDS, but no studies have convincingly demonstrated any advantage of HFV over conventional VCV. Provided the mean lung volumes are similar, oxygenation during HFV has proved to be equivalent to that obtained during CMV. Experimental and clinical results regarding arterial oxygenation and oxygen transport obtained by Lachmann and colleagues indicated that the evolution of pulmonary damage in ARDS is closely related to the airway pressure required to allow reopening of collapsed alveoli and maintenance of alveolar patency without overdistention of complaint lung units.37 Switching Ventilatory Modes Selecting a ventilatory mode depends essentially on the experience and preference of the clinician. Comparisons of one mode to another have not shown differences in terms of duration of mechanical ventilation, mortality, morbidity, or ability to wean. However, under certain conditions the clinician may decide to switch from one mode to the other. The following sections detail how to make this switch safely. Volume Control to Pressure Control Patients are most commonly placed on mechanical ventilation in a VCV mode and then converted to PCV when the airway pressures increase or when gas exchange deteriorates. The initial goal of conversion is to transfer the patient from VCV to PCV while matching VT, Ti, and mean airway pressure, and keeping frequency and PEEP constant. In conversion of VCV to PCV the following steps can be taken: 1. In VCV mode, note exhaled VT, mean airway pressure, and I : E ratio. If there is a Ti fraction that is clinician set, it will not be changed.

2. Measure static or plateau airway pressure. 3. Set pressure, sometimes termed the delta-P, is equal to the airway pressure measured in step 2. On some ventilators, only the pressure above PEEP is set. 4. Set Ti to match the I : E ratio from VCV mode. Absolute Ti is sometimes set instead of I : E ratio: Ti in sec = VT Mean inspiratory flow L sec. 5. Adjust set pressure further to obtain the desired VT. Doing this will also change mean airway pressure. 6. Adjust Ti to further fine-tune mean airway pressure, as needed. Pressure Control to Volume Control When converting from PCV to VCV, the most straightforward conversion is to decelerated flow VCV. Note the exhaled VT, set Ti, and mean airway pressure. Choose a VT for the VCV mode that closely matches the PCV exhaled VT. Next, the peak flow must be chosen. The choice must made carefully because the goal is to convert the patient from one mode to the other mode as smoothly as possible. No studies with good controls for I : E ratio, mean airway pressure, or total PEEP show an unambiguous advantage for either VCV or PCV. The knowledge and familiarity of the operator with the ventilatory mode being employed may be the most important factor in choosing between PCV and VCV, especially when decelerating flow mode is available as an option. In the setting of ARDS, a decelerating flow may improve gas exchange, but this may be accomplished with either PCV or VCV. Positive End Expiratory Pressure or Continuous Positive Airway Pressure The main rationale for utilizing PEEP is to recruit perfused alveolar units that have collapsed or are unstable.38 In one study, during low tidal volume ventilation in patients with acute lung injury, a PEEP value of at least 15 cm H2O was needed to prevent deterioration of pulmonary compliance.39 An improvement in PaO2 and decreased shunt fraction following a PEEP trial foretells a favorable outcome, but continued use appears not to impact hospital mortality. Survival appears to be more related to the maintenance of adequate oxygen delivery, as manifested by an elevated mixed venous oxygen, than to increasing PaO2.40 There is controversy over how much PEEP should be applied. The magnitude of PEEP required should be determined for each patient and reevaluated frequently because PaO2 is directly related to cardiac output and intrapulmonary shunt, variables that should be considered when treating adult patients in acute respiratory failure.41 Improved compliance has been suggested as the determinant of “best” PEEP. Optimal PEEP is defined as that amount of PEEP producing the lowest shunt without other considerations related to lung mechanics. Murray and colleagues

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recommended titration of PEEP by monitoring the PaCO2 to end-tidal carbon dioxide pressure (ETCO2) gradient.42 They suggested that the PaCO2 to ETCO2 gradient should be made as narrow as possible through titration of PEEP. In one study, PEEP did not produce clinically significant hemodynamic changes. The investigators concluded that the avoidance of hypovolemia, limited use of sedative and paralytic drugs, and the use of assisted ventilation in management of their patients contributed substantially to these results.43 The efficacy of high levels of PEEP to reduce shunt in acute respiratory failure, as well as the ability to use this modality without significant reduction of cardiac performance, has been shown. Additionally, the inefficiency of PEEP in improving pulmonary function in single lung injury has also been demonstrated. A higher level of PEEP will often not improve pulmonary function in patients with acute respiratory failure and asymmetric lung damage.44 Decreasing PEEP inappropriately has been shown to decrease PaO2. The time for recovery of oxygenation when PEEP has been inappropriately reduced, and then resumed, may be as long as 40 minutes. Transient hypoxia during loss of PEEP during a brief ventilator circuit disconnection may be prevented with the administration of 100% oxygen and use of a bag-valve device during the procedure. However extreme caution should be taken in cases where pulmonary edema and alveolar flooding are present, as well as with patients with severe cardiac compromise where discontinuation of PEEP can be detrimental.45 Our preference is to use a Mapleson D bag-valve system in these situations. Use of this system allows continuous administration of PEEP during ventilator disconnect. ARDS with sepsis appears to result in a more severe pulmonary insult that is less amenable to improvement with low levels of PEEP than ARDS without sepsis.46 High levels of PEEP are generally associated with diminution of venous return, which can decrease ventricular filling pressures and cardiac output. Elevated levels of PEEP may also alter renal function, decreasing urine output and sodium excretion, likely as a result of a decrease in total renal perfusion, modifications in the distribution of intra-renal blood flow, and increased antidiuretic hormone secretion. Dopamine in small doses is known to increase cardiac contractility, in particular increasing right ventricular filling pressures by increasing venous return via a vasoconstrictive mechanism. Dopamine had also been thought to increase total renal blood flow by renal vasodilation, although this is no longer the case. Improved cardiac function, systemic oxygen transport, and renal function have been noted with low-dose dopamine at a rate of approximately 5 ± 0.05 mg/kg/min in normovolemic patients.47 Contraindications to Positive End-Expiratory Pressure and Continuous Positive Airway Pressure PEEP and CPAP should be used with caution in hypovolemic patients, in patients with elevated intracranial pres-

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sure, and whenever there is unilateral pathology in the lung. An absolute contraindication for PEEP and CPAP is an untreated significant pneumothorax or a tension pneumothorax, as the positive pressure might further increase the air present in the intrapleural space, causing death. Auto–Positive End-Expiratory Pressure If the flow-time tracings show no flow at end expiration during tidal ventilation, it is unlikely that any significant amount of auto-PEEP is present. Auto-PEEP is most likely to occur in clinical situations of increased resistance, increased compliance, less elastic recoil, and short expiratory time. In VCV an increase in VT may cause an increase in auto-PEEP because more volume must be exhaled during the expiratory time.10 Noninvasive Positive Pressure Ventilation Noninvasive ventilatory support with a nasal or full-face system (BiPAP) may improve the efficiency of pulmonary gas exchange in selected cases without the undesirable effects of endotracheal intubation. In several controlled studies of patients with acute exacerbation of COPD, NIPPV reduced the need for endotracheal intubation and mechanical ventilation as well as the risk of lower respiratory tract infection and pneumonia, thereby reducing in-hospital mortality and morbidity.48 Noninvasive ventilation may reduce the duration of ventilatory support without increasing the risk of weaning failures. Noninvasive ventilation should be systematically considered as an approach to weaning in patients with acute or chronic respiratory failure who are difficult to wean.49 NIPPV has also been used via facemask in patients with acute respiratory failure who refused endotracheal intubation.50 However, one study failed to show any beneficial effect of noninvasive PSV in the heterogeneous population of patients with severe acute respiratory failure not due to COPD.51 During noninvasive ventilation for acute hypercapnic respiratory failure using ventilator settings adapted to patient tolerance, the PSV mode provided respiratory muscle rest and improved breathing pattern and gas exchange.52 Early leaks around the facemask are likely to occur during NIPPV, particularly when prolonged ventilatory treatment is required. Because it has been suggested that leaks around the mask may impair the expiratory trigger cycling mechanism when inspiratory PSV is used, a time-cycled expiratory trigger may provide better patient-machine interaction than a flow-cycled expiratory trigger in the presence of air leaks.53

New Modes of Ventilation Volume-Supported Ventilation To eliminate the problem of VT instability during PSV, volume-supported ventilation (VSV) has been proposed.

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Using VT as a feedback control during VSV, the pressure support level is continuously adjusted to deliver a constant preset VT. Basically, VSV acts like PSV, except that the applied inspiratory pressure support is calculated by the ventilator to deliver a preset VT. The specific aim of this new ventilator mode is to avoid the VT instability that may be observed during PSV.54 Volume-Assured Pressure-Supported Ventilation Volume-assured pressure-supported (VAPS) ventilation combines the advantages of pressure and volume ventilation on a breath-to-breath basis, and can be used with both assistcontrolled and SIMV modes. It can be described as variableflow volume ventilation, which is a blended mode with decelerating, nonlimited, variable flow and guaranteed VT delivery. Spontaneously triggered breaths begin as pressuresupported breaths. The ventilator measures the delivered volume when inspiratory flow has decelerated to the minimum set value. As long as the minimum volume meets or exceeds the desired level set by the clinician, the breath behaves like a pressure-supported breath in its flow cycle. If the preset VT has not been achieved, the breath undergoes a change to a volume-controlled breath. The set flow persists and the Ti is prolonged until the desired volume has been reached. In summary, VAPS is a hybrid mode of ventilation that optimizes two types of inspiratory flow patterns: VAPS = PSV ¥ VCV There is also a clinician-adjustable rise time that controls the rate of rise of airway pressure. VAPS is equally suitable to treat both acute respiratory illness and to facilitate weaning, because of its advantages in reducing patient WOB and improving synchrony between patient and ventilator.18 Pressure-Regulated Volume Control Pressure-regulated volume control (PRVC) is a form of closed-loop ventilation that attempts to combine the features of volume and pressure control ventilation. Essentially, the clinician sets the target VT and maximum pressure level. The ventilator attempts to achieve the volume target using a decelerating flow gas delivery pattern power at the lowest possible airway pressure. When PRVC is activated, a test breath is first delivered at 10 cm H2O; this is used to calculate the patient’s compliance. The next three breaths are delivered at the pressure that is 75% of the calculated pressure needed to deliver the target VT. After this, the PIP is increased, up to 3 cm H2O for each breath, until the target volume is delivered. If the target volume is exceeded, the PIP is decreased by 3 cm H2O with each breath. The inspiratory pressure is automatically regulated so that the PIP is kept 5 cm H2O below the preset upper pressure limit. PRVC is intended for use in patients who

demonstrate high peak airway pressures in volume-control modes and who may be at risk for barotrauma, as well as those with large endotracheal tube leaks or airway obstruction. Clinician-set parameters include VT, Ti, ventilator rate, PIP, FIO2, high and low minute-ventilation alarms, highpressure alarm, and trigger sensitivity level. This mode of ventilation provides the guarantee of volume delivery with the advantages of pressure-limited ventilation. It has been noted, in the surfactant-deficient piglet, that PRVC with an I : E ratio of 2 : 1 produces better O2 delivery at reduced risk of barotrauma, compared to VCV at the same mean peak airway pressure. Reducing the I : E ratio to 1.5 : 1.0 with PRVC, without interfering with gas-exchange, further enhances O2 delivery at reduced airway pressure.55 Volume-Guaranteed Pressure Limit Ventilation Volume-guarantee is a feature that primarily ventilates with a time-cycled, pressure-limited breath, but allows the pressure to be increased to a useful, adjustable, maximum pressure setting to guarantee volume. Pressure may also be lowered with improving compliance. This is performed via an auto-feedback feature that guarantees VT. Volumeguaranteed mode may be combined with assist-controlled SIMV and pressure-supported modes. In setting up this mode of ventilation, the inspiratory pressure is set at the optimal, desired pressure limit. If this pressure is reached and the set VT is not, an alarm sounds. Automatic pressure changes are made in increments to avoid overcompensation. The usual starting target is a VT of 4 to 5 mL/kg. The PIP limit is preset at approximately 15% to 20% above the PIP needed to consistently deliver the target VT.18 Automatic Tube Compensation Mode In contrast to conventional ventilation modes, the automatic tube compensation mode automatically and continuously adjusts delivery of pressure support to the current flow rate.56 This adjustment is to compensate for the concurrent pressure drop across the endotracheal tube, and thus tube resistance during both inspiration and expiration (imposed WOB). The resistance of the endotracheal or tracheostomy tube and, to a lesser extent, the nonideal demand characteristics of the ventilator can critically increase the ventilatory spontaneous WOB of patients; this mode of support sets as its target the elimination of the increased work. Proportional Assisted Ventilation Proportional assisted ventilation (PAV) is a new mode of ventilatory support whose main feature is the provision of ventilatory support in proportion to the flow and/or the volume generated by the patient.57,58 Thus, during PAV, applied pressure is a fraction of patient effort—the greater

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the inspiratory effort, the greater the increase in applied pressure. Flow and VT will therefore be determined by the level of proportionality between applied pressure and the patient’s effort and the impedance of the respiratory assistance. Ventilator assistance terminates with the end of the inspiratory effort and respiratory frequency is determined by the patient’s needs. In mechanically ventilated patients in whom respiratory impedance is acutely increased by chest wall and abdominal binding, the ability to keep VT and VE constant through increases in inspiratory effort was preserved only during PAV. With PSV, despite a similar increase in inspiratory effort to that seen in PAV, VT decreased and an increase in respiratory rate was required to preserve VE.59 Liquid Ventilation Therapeutic use of the saline-filled lung dates back to the early 20th century, as treatment of poison gas inhalation in World War I. It was demonstrated then that the lungs could be filled and lavaged with large quantities of saline without being injured. Fluorocarbons are colorless, clear, odorless, inert, nontoxic, and chemically and thermally stable liquids. They display high-density, low surface tension, and a high solubility for O2 and CO2. These compounds are able to exchange adequate amounts of O2 and CO2 at ambient pressure, and lack the toxicity of other organic compounds.60,61 Human studies appear to have stopped after an interesting and successful start. Further discussion should be sought beyond this chapter.

Complications of Mechanical Ventilation Although mechanical ventilation can save the lives of critically ill patients, it may be associated with multiple complications. Some of these may be related temporally and not caused by ventilatory support per se, but many are a direct result of PPV. Problems During Initiation of Positive-Pressure Ventilation When ventilatory support is first established, several important adverse effects may occur. Spontaneous and ventilatordelivered breaths have opposite effects on hemodynamics. PPV increases intrathoracic pressure during inspiration, decreasing venous return, which results in decreased right ventricular preload and right ventricular output. Low rightside output results in lower left ventricle preload and, because of diminished left ventricular end-diastolic volume, left ventricular output also decreases. Hypotension immedi-

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ately following intubation and initiation of mechanical ventilation is a common clinical consequence caused by the mechanisms just listed, particularly in the presence of hypovolemia. The potential causes of hypotension in mechanically ventilated patients include hypovolemia, impedance to venous return, cardiac dysfunction, the systemic inflammatory response syndrome, and the effects of medications used for intubation or sedation. Respiratory distress, commonly referred to as “fighting the ventilator,” frequently develops during the course of mechanical ventilation and may indicate a potentially life-threatening problem. Physical signs can provide early diagnosis; these include anxiety, tachypnea, use of accessory respiratory muscles, thoracic cage abdominal asynchrony, tachycardia, hypotension, and arrhythmias. The first therapeutic and diagnostic step for any patient with sudden respiratory distress is removal from the ventilator and manual ventilation with 100% oxygen followed by a stepwise search for the cause. If the patient improves promptly on removal from the ventilator, problems exist in the ventilator and an entirely new ventilator and tubing should be used while the machine is systematically checked by the respiratory therapist. If the distress does not improve with manual ventilation, the problem is with the endotracheal tube or the patient.62 Common complications related to the endotracheal or tracheostomy tube include right mainstem bronchus intubation with the endotracheal tube, or cuff herniation over the end of either the endotracheal or tracheostomy tubes. The diagnosis includes increased PIP, low VT, and increased resistance when delivering manual breath or passing a suction catheter. Lower airway obstruction, bronchospasm, pneumonia, and pulmonary edema may also cause respiratory distress; these are usually evident upon physical examination. Dynamic hyperinflation or auto-PEEP occurs in patients with airway collapse. Measures to prevent or reverse autoPEEP include: 1. Prolonging expiratory time, increasing peak airway flow rates, and using nondistensible ventilator tubing that decreases the total VT required so it can be delivered over a shorter period. 2. Minimizing expiratory airflow obstruction by using a larger diameter endotracheal tube and treating bronchospasm aggressively with bronchodilators and steroids. Suction frequently to remove secretions. 3. Using appropriate ventilator strategies that use lower VT. 4. Remedying respiratory alkalosis with lower respiratory rates or VTs. 5. Using PEEP to reduce inspiratory force necessary to trigger the ventilator, thereby decreasing the WOB. Causes of fighting the ventilator include pneumothorax and inadequate pain relief or sedation. Increased airway resistance has six major causes.

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1. Narrowing of the inspiratory passages because of fluid or kinking in the ventilatory tubing. 2. Herniation of the cuff over the tube. 3. Smaller gauge endotracheal or tracheostomy tube. 4. Neoplasms, stenosis, or foreign bodies. 5. Secretions. 6. Bronchospasm. Hypoxia represents a complication encountered frequently in ventilated patients and presents as a low PaO2, desaturation on the pulse oximeter, or the need for a high FiO2 to maintain satisfactory oxygenation. Physiologic mechanisms of impaired oxygenation include hypoventilation, diffusion abnormalities, shunting, V/Q mismatch, and a low alveolar oxygen concentration. Autopsy series show that pulmonary thromboembolism may occur in up to 10% in critically ill patients. Body position changes, especially in those with unilateral lung disease, can result in a decreased PaO2 as gravity acts to shunt blood to the abnormal lung. Thoracentesis has been associated with a decrease in PaO2 in some studies, possibly because of reexpansion pulmonary edema. Chest physiotherapy, which includes postural drainage, percussion, and coughing, may induce bronchospasm or move secretions into larger more proximal airways and worsen V/Q mismatch. Bronchoscopy occasionally induces hypoxemia because of bronchospasm or hypoventilation. Bronchodilators have inotropic and vasodilator properties that may increase perfusion to the poorly ventilated lung, augmenting preexisting V/Q mismatch. Vasodilators may induce hypoxemia because of inhibition of hypoxic pulmonary vasoconstriction and beta-blockers because of their induction of bronchospasm and negative inotropic effects. The FiO2 should be increased routinely during administration of the aforementioned medications. Blood from the endotracheal tube or tracheostomy tube can be one of the most dramatic and alarming developments in a ventilated patient; this may be either benign or critical. The most common cause is iatrogenic, in the form of suction catheter trauma. Other causes include necrotizing pneumonia; tracheobronchitis; cardiogenic pulmonary edema producing pink frothy sputum; pulmonary thromboembolism; dissection and rupture of the pulmonary artery due to the pulmonary artery catheter balloon; erosion of arteries secondary to endotracheal tube; cough; and underlying diseases, such as vasculitis syndromes, Goodpasture syndrome, primary or metastatic tumors, and disseminated intravascular coagulopathy. Massive intracranial air embolism63 and venous and arterial gas embolism64 have also been reported as complications of mechanical ventilation. Adverse Effects of Positive End-Expiratory Pressure PEEP, while very useful, has many untoward effects; these are detailed in the sections that follow. Bronchiectasis, the dila-

tion of terminal and respiratory bronchioles, has been described by Salvin and colleagues.65 Sequelae of bronchiectasis include increased dead space and hypercapnia, which appear to correlate with the degree of the disorder. It is reversible as the lung recovers from acute injury. Pulmonary Barotrauma Pulmonary barotrauma, in the form of pneumothorax, pneumomediastinum, or subcutaneous emphysema, reportedly occurs in 10% to 20% of patients who need mechanical ventilation with or without the use of PEEP.66,67 In case of high levels of PEEP, pneumothorax may occur in up to 25% of patients.68 However, it has been noted that the addition of PEEP to intermittent PPV during therapy for acute respiratory failure did not increase the incidence of pulmonary barotrauma.69 Several factors have been implicated in the causation of pulmonary barotrauma: high levels of PEEP, patients who strain and cough vigorously against volume-cycled ventilation, high peak and plateau airway pressures, duration of ventilation,66,67 COPD, VT greater than 15 mL/kg, and subclavian line placement during mechanical ventilation.70 Barotrauma has also been observed due to improperly set demand valve of the ventilator71 and after use of perfluorocarbon for liquid ventilation.72 Massive pneumoperitoneum developing immediately following initiation of artificial ventilation is an unusual sign of pulmonary barotrauma and must be distinguished from pneumoperitoneum following rupture of an abdominal viscus.73 High airway pressures might contribute to the development of bronchopleural fistulae.74 Venous air embolism in patients with pulmonary barotrauma has been reported.75 Clinical Manifestations. Any of the following should alert the physician to the possibility of pneumothorax in a patient during or after mechanical ventilation76:

1. Changes in preset parameters of the ventilator, including airway pressure, expired volume, and I : E ratio. 2. Restlessness, irritability, and fighting the ventilator. 3. Subcutaneous emphysema. 4. Chest pain and shortness of breath in a patient breathing spontaneously after mechanical ventilation has been discontinued also may suggest pneumothorax. Pneumomediastinum may present with signs of hypertension, hypotension, arrhythmias, electrocardiographic signs of ischemia, QRS-axis rotation, or cardiac tamponade. The hemodynamic changes of tension pneumothoraces in critically ill patients whose lungs are being ventilated are complex and variable. In patients who are being ventilated, most hemodynamic variables are unreliable and may be further complicated by the underlying clinical condition and treatment. A specific elevation of the pulmonary artery diastolic pressure and a decrease in mixed venous O2 saturation

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should suggest a tension pneumothorax77; however, these measurements may be unavailable or misinterpreted. The decrease of cardiac output is a striking and inevitable concomitant of tension pneumothorax in a patient who is being ventilated and should be considered highly suggestive of this diagnosis.77 A rapid unexplained elevation of pulmonary artery pressure can be a useful clinical sign of development of a pulmonary barotrauma and may indicate development of pneumothorax in patients with ARDS.68

Necrotizing tracheobronchitis has been reported as a complication of mechanical ventilation in adults. Inadequate humidification may play a role.81 There is a report of a patient in whom pneumopericardium developed while being treated with facemask CPAP for hypoxic respiratory failure following a coronary artery bypass graft surgery.82

Management. The best treatment of pulmonary barotrauma

Nitric oxide (NO) added to the inspired gas mixture can significantly decrease pulmonary artery pressure (PAP) and improve oxygenation and V/Q matching without significant effects on the systemic circulation. Causes of dynamic, thus reversible, pulmonary hypertension include acute right ventricular failure, lung reperfusion injury, severe bronchoalveolar disease, and increased dead space ventilation.83 NO accelerates the conversion of guanosine triphosphate to cyclic guanosine monophosphate, resulting in dilatation of vascular smooth muscle. Inhaled NO only affects the pulmonary circulation where ventilation is still possible, selectively enhancing pulmonary V/Q matching.84 The recommended dose is 2 to 20 parts per million, based on patient response. In spite of its beneficial effect on gas exchange, no statistical improvement in outcome has been demonstrated in adults with the use of NO. Further, because of the drug’s artificially high cost—resultant from the DatexOhmeda delivery device approval by the U.S. Food and Drug Administration—the use of NO is now limited to life threatening pulmonary hypertension and hypoxia refractory to toxic levels of O2.84 In numerous studies evaluating the acute response to inhaled NO, there has been a consistent finding that approximately 50% to 75% of patients show improved oxygenation.85 Inhaled NO can be combined with other inhaled vasodilators such as prostacyclin or with agents such as almitrine dimesylate, a respiratory stimulant used in acute respiratory failure associated with conditions such as COPD. One important risk of inhaled NO therapy should be noted if continuous delivery of NO is interrupted, for example during patient transport. Supply exhaustion may precipitate life-threatening hypoxemia, and right-sided heart failure can occur.85 Inhaling Heliox, a gas consisting of 20% oxygen and 80% helium, results in prompt improvement in dyspnea, WOB, and arterial blood gas abnormalities in patients with upper airway obstruction. These benefits stem from the density dependence of the flow-related pressure drop across the upper airway in cases of severe upper airway obstruction in disorders typically producing highly turbulent flow across the narrow airway.85 An increased FIO2 can be obtained by bleeding in an enriched O2 supply. Prostaglandins E1 and I2 have been used to decrease PAP and PVR. They are administered intravenously and have a

is prevention. This may be accomplished by using appropriate ventilator settings, such as low tidal volumes (6 to 8 mL/kg), maintaining plateau pressure less than 35 cm H2O and PIP less than 50 cm H2O, and using the lowest level of PEEP possible. The clinician should pay particular attention to technique when attempting to place a central line— especially by the subclavian approach—in a patient who is being mechanically ventilated. Whenever airway obstruction is suspected in an intubated patient, prompt thoughtful intervention is necessary to locate and relieve the obstruction. By using physical examination findings, manual ventilation, a suction catheter, and by deflating the endotracheal cuff, the problem should be localized either to the patient, the endotracheal tube, or the ventilator circuit.78 Treatment of a patient with established pneumothorax is prompt placement of a chest tube in the pleural space to evacuate the air. Management of hemodynamic impairment is also warranted. Extracorporeal membrane oxygenation (ECMO), apnea, and lung rest have been proposed in the management of pulmonary barotrauma. To avoid further barotrauma, ventilator settings are usually reduced once ECMO is instituted.79 Swallowing Abnormalities Recent studies have suggested that swallowing dysfunction and pulmonary aspiration may occur in patients receiving ventilator support by translaryngeal intubation followed by cuffed tracheal tube for more than 21 days.80 Multiple factors may be present that increase the prevalence of swallowing dysfunction. These include carotid injury, injury preceding translaryngeal intubation, the effect of tracheostomy on laryngeal movement, prolonged inactivity of the skeletal muscles of the larynx, the use of neuromuscular blocking agents, and underlying neuromuscular illness. Patients with neuromuscular disorders requiring prolonged translaryngeal intubation followed by tracheostomy and PPV have a high incidence of swallowing abnormalities. Swallowing abnormalities in patients with tracheostomies were as low as 7%. Parkinson disease is also associated with an increased incidence of swallowing dysfunction. It is possible that in some patients with underlying neuromuscular disease, swallowing abnormalities are primarily related to the neurologic condition rather than intubation, tracheostomy, or PPV.80

Strategies to Improve Oxygenation Pulmonary Vasodilators

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short half-life. Because of induced systemic hypotension, they cannot be used at their maximum dose intravenously. Inhaled prostaglandin E1 has been used in these situations without significant systemic effects.55 Pulmonary Bronchodilators Medications that have been proposed for inhalation therapy include bronchodilators, surfactant, antibiotics, immunosuppressive agents, and antiproteases. Factors influencing deposition of aerosols in mechanically ventilated patients include the delivery system, particle size, characteristics of the ventilator circuit, and ventilatory mode. Heating and humidification of inhaled gas may reduce aerosol deposition by approximately 40%, while breathing a helium-oxygen mixture may enhance it by improving laminar flow in the upper airways. It is recommended that a nebulizer be placed at a distance of 30 cm from the endotracheal tube to operate during inspiration. This maneuver provides a more efficient delivery of aerosols to the patient. Attaching a long catheter (spacer) to the nozzle of a metered dose inhaler (MDI), using a VT of over 500 mL, a long Ti, and synchronizing delivery with inspiration improves efficacy of drug delivery. Therapeutic aerosols are commonly used in patients who are mechanically ventilated to deliver bronchodilators and other therapeutic agents because it is a safe and rapid way to administer drugs, with few adverse effects.86 MDIs and nebulizers are used to deliver drugs to the ventilator circuit. MDIs are often used for delivery of anticholinergic and betaadrenergic drugs, and nebulizers are used for administration of bronchodilators, antibiotics, and surfactant. Because of convenience and cost issues, bronchodilators have been delivered through MDIs rather than nebulizers. Adverse effects of bronchodilators are numerous, including cardiovascular stimulation (tachycardia) and electrolyte imbalance (hypokalemia). Therefore, their use requires careful monitoring of electrolytes and cardiac parameters. A positive response to bronchodilator therapy is a reduced peak airway pressure of 10% to 20% from baseline or a reduction of expiratory wheezing. Postoperative bronchodilators have been used successfully in patients with known preoperative COPD, asthma, ARDS, and intraoperative wheezing with or without a history of bronchospasm. Bronchodilator therapy is termed effective if airway resistance is reduced or forced expiratory volume at 1 second (FEV1) improves. Because FEV1 cannot be measured in patients who are mechanically ventilated, a change in peak airway pressure or airway resistance is used to assess the efficacy of bronchodilators. The airway resistance is calculated as R resp = (Ppeak - Pplateau ) flow rate, where Ppeak is the peak airway pressure and Pplateau is the plateau pressure. A value of 0.2 to 2 cm H2O/L/second is in the normal range in a nonintubated normal adult.87

Bronchodilator therapy efficacy can be also assessed by measuring its effects on the respiratory WOB in intubated, spontaneously breathing patients. This work is dependent on the mechanical load imposed on the respiratory muscles. Administration of bronchodilators can reduce work performed by the inspiratory muscles in patients with bronchoconstriction. In general, if a patient does not show significant improvement in airway resistance (>10%) after bronchodilator therapy, use of the agents should be questioned and revised. If the drug has been properly administered, most stable mechanically ventilated patients with COPD achieve near maximal bronchodilation after four puffs of a beta-2 agonist via MDI. In patients with acute exacerbation of asthma or COPD, higher doses may be required. Inhaled betaadrenergic and anticholinergic bronchodilators and steroids are all effective in mechanically ventilated patients; MDI delivery works better than nebulized drug delivery. Inhaled isoproterenol hydrochloride, isoetharine mesylate, metaproterenol sulfate, fenoterol, albuterol, and ipratropium bromide all produce significant bronchodilation. A combination of fenoterol and ipratropium was more effective than ipratropium alone in patients with COPD who were being mechanically ventilated. Albuterol (also known as salbutamol) is one of the most widely used inhaled beta-2 agonists for bronchodilation. It is a short-acting agent with a T1/2 of 4 to 6 hours. The time to maximum plasma concentration ranges from 30 minutes for nebulized delivery to 2 to 4 hours for MDI delivery. The time to maximum clinical effect is approximately 1 hour with the inhaled drug and approximately 2 to 3 hours with the systemically delivered drug. In normal adults, 1 to 4 mg of inhaled albuterol can be administered via MDI; the doses are separated by about 40 minutes. Ipratropium bromide is an anticholinergic drug used to relieve bronchoconstriction either through the intravenous route or by inhalation. Inhalation is the most appropriate route of administration, especially in mechanically ventilated patients with bronchoconstriction, as this route avoids systemic anticholinergic side effects. Corticosteroids have been used in patients with asthma or COPD for their anti-inflammatory properties. They can be used orally, intravenously, or via inhalers.86,88 Although there is some debate as to whether drugs should be delivered via a nebulizer or a MDI, when doses are calculated on the basis of the percentage of the total drug that reaches the lower airway, there was equivalent bronchodilation after salbutamol administered by either MDI with a spacer or nebulizer in patients with acute severe asthma. In this setting, frequent administration of beta agonists was associated with minimal signs or symptoms of drug toxicity.89 There was no difference in effectiveness between MDI with spacer and nebulizer for the administration of beta-agonists in the treatment of acute bronchospasm, but the use of the MDI with a spacer (as

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compared to without) demonstrated improved patientoriented outcomes.90

Weaning from Mechanical Ventilation Weaning involves a change in the interaction between the patient and the ventilator. Weaning from mechanical ventilation involves gradual withdrawal of mechanical ventilator support and the transfer of mechanical WOB from the ventilator to the patient respiratory muscles, while avoiding respiratory muscle fatigue. The factors that influence the decisions to wean mechanical ventilation are complex. The clinical characteristics of patients who have had unsuccessful attempts at weaning in medical and surgical intensive care units have been well studied and include severity of illness, number of co-morbidities, multi-organ dysfunction, and poor functional status.91 Many patients, particularly those requiring short-term ventilator support, pose little difficulty in removal of the ventilator. For patients recovering from major injuries or acute respiratory failure, however, discontinuation of mechanical ventilation may be associated with considerable difficulty. The three general approaches to weaning are the spontaneous breathing trial (SBT), PSV wean, and SIMV wean. T-Piece Wean SBT by use of a T piece is the oldest ventilator weaning technique. In this approach, the patient is removed from the ventilator and humidified supplemental oxygen is provided to the airway. There are two distinctly different applications of the SBT. The first application is to identify readiness for extubation. Toleration of 2-hour SBT may be an “extubationreadiness” indicator. The second application of the SBT is for weaning, in which the length of each trial is increased with alternating periods of ventilatory support afterward. The SBT can be conducted without removing the patient from the ventilation. There are several advantages to performing the SBT without removing the patient from the ventilator. First, no additional equipment is required: if the patient fails the SBT, ventilatory support can be reestablished quickly. Also, all of the monitoring systems and alarms on the ventilator are available during the SBT, which may allow prompt recognition that the patient is failing the SBT.92 There are several approaches to SBT. It can be performed with no positive pressure applied to the airway, with a low level of CPAP (5 cm H2O), or with a low level of PSV, for example 5 to 8 cm H2O. Pressure-Supported Ventilation Weaning With PSV, all breaths are patient-triggered and pressurelimited. When the level of pressure support is high relative

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to patient effort, nearly full ventilatory support is provided. As the level of pressure support is decreased, more patient effort is required to maintain the minute ventilation. With pressure support weaning, the PSV level is decreased as tolerated by the patient. When at a low level of PSV, for example 5 to 10 cm H2O, the patient is considered to be ready for extubation. The use of PSV has resulted in significant improvement compared with other strictly defined weaning protocols using T-piece or SIMV.93 PSV and BiPAP are more useful in weaning patients gradually from the ventilator. BiPAP may be advantageous in patients not breathing sufficiently with PSV because minimal patient effort is necessary with use of this ventilation mode.94 Low level PSV offers no advantage over SBT in approximating postextubation work of breathing; PSV at 5 cm H2O may increase VT to levels that are significantly greater than those after extubation.95,96 Banner and colleagues have studied the relationship between breathing frequency, breathing pattern, and patient WOB. They concluded that WOB should be measured directly because the frequency to VT ratio may be inaccurate or misleading in determining WOB. However, direct measurement of WOB is invasive, expensive, and unfamiliar to many clinicians. Further, it may be confusing or misleading. Momentary frequency to VT ratio may be useful when monitoring patients’ response to changes in the PSV level because it is easily and reliably obtained. It is more familiar and meaningful to clinicians caring for patients who are mechanically ventilated.97 Synchronized Intermittent Mandatory Ventilation Weaning Weaning using the SIMV approach is achieved by decreasing the mandatory breath rate, thus requiring more spontaneous breathing effort to maintain the minute ventilation. In patients ventilated for longer than 1 week, the rate is decreased to one to two breaths per minute. However, the rate of decreasing respiratory frequency is individualized. Weaning Failure Difficult weaning is encountered in as many as 25% of patients on prolonged mechanical ventilation.98 Breathing pattern alterations and respiratory muscle performance impairment lead to ventilator dependency after prolonged mechanical ventilation. The measurement of variables such as noninvasive tracheal occlusion pressure, inspiratory power of breathing, and tension time index of the inspiratory muscles facilitate the management of difficult weaning patients.98 An excessive inspiratory load imposed on the respiratory muscles seems to be the essential determinant of difficult weaning. This excessive inspiratory load leads to breathing pattern abnormalities and the development of respiratory muscle fatigue. These two elements, either alone or with

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other abnormalities, can hinder weaning. Criteria commonly used for discontinuation of weaning trial include tachypnea, a respiratory rate greater than 35 breaths per minute for more than 5 minutes; hypoxia, SpO2 less than 90%; tachycardia, heart rate more than 140 beats per minute or sustained heart rate increase of more than 20%; bradycardia, a sustained heart rate decrease more than 20%; hypertension, systolic blood pressure more than 180 mm Hg; hypotension, systolic blood pressure less than 90 mm Hg; and agitation, diaphoresis, or anxiety. In some patients these criteria are not due to weaning failure and are appropriately treated with verbal reassurance or pharmacologic support. However, when weaning failure is recognized, ventilatory support should promptly be reestablished. Because the diaphragm is responsible for approximately 75% of breathing, it is important to promote diaphragm shortening to optimize weaning from mechanical ventilation. When an increasing level of CPAP was added to PSV, decreased diaphragm shortening was observed99; this diaphragmatic unloading will require minimizing as weaning is attempted. In one study, weaning failure was associated with gastric intramucosal acidosis.100 The intramucosal pH (pHi) of gastric tissue may be helpful to predict weaning outcome. Further controlled clinical trials in a large group of patients are needed to answer this question. Strategies to Improve Weaning The process of discontinuing mechanical ventilation may constitute a major clinical challenge and become the principal cause of prolonged patient stay in the neurointensive care unit. Patients with weaning difficulties may have inadequate resolution of the illness that required mechanical ventilation, or development of new problems. Correctable factors that may cause ventilator dependence should be eliminated. When appropriate, the patient and family members may also be involved in the weaning process. Psychological considerations are extremely important in achieving successful outcome. Stress may be minimized by informing the patient of the weaning plan. During weaning, patients should be placed in their preferred body position, which varies according to underlying pathophysiology. For example, the patient with diaphragmatic paralysis does better in an upright position because vital capacity may fall by 50% when these individuals are supine. This is probably the result of gravitational forces displacing the paralyzed diaphragm, causing decreased functional residual capacity. On the other hand, patients with intercostal muscle weakness, resulting from low cervical spinal cord lesions, show an increase of lung volumes when changing from upright to supine position. Diminished pulmonary function in an upright tetraplegia patient may be caused by paralysis of abdominal muscles and gravitational bulging of abdominal contents. This condition may be minimized through the use of elastic binders. For

patients with COPD, the optimal posture is variable; some patients notice less dyspnea when lying supine, while others are more comfortable when leaning forward. Ventilator settings during periods of mechanical ventilation may affect progress during subsequent weaning trials. One of the major purposes of mechanical ventilation is to provide rest for the respiratory muscles and to allow them to recover from fatigue. With most of the assisted modes of ventilation—ACV, SIMV, and PSV—inspiratory muscles do not stop contracting once the ventilator has been triggered. Therefore, ventilator support should not be considered synonymous with respiratory muscle rest. Careful manipulation of the ventilator settings is necessary to minimize respiratory work. Even if they are optimally adjusted, the patient may still perform a considerable portion of the work of inflation during assisted ventilation. When ventilator settings are not optimal, the patient’s active work may be even greater than that required for spontaneous chest inflation, during ventilator support. For the patient with chronic hypercapnia, minuteventilation, delivered by the ventilator, may be adjusted to maintain the patient’s usual PaCO2. If a patient’s “normal” hypercapnia is lowered to the normocapnic range during mechanical ventilation, renal compensation by excretion of bicarbonate and pH normalization occur. Subsequently, when patients resume their usual level of spontaneous ventilation, respiratory acidosis may occur, because the reduced bicarbonate store is inadequate for buffering. If difficulty is expected during weaning, the PaCO2 should be allowed to gradually increase to the patient’s normal range during the period of mechanical ventilatory support. Airway secretions should be suctioned before a weaning trial and the administration of bronchodilators may be helpful. Beneficial effects of bronchodilators delivered by an MDI-spacer device have been noted with patients being weaned from mechanical ventilation, regardless of whether the patient had preexisting chronic airway obstruction.101 Optimizing the respiratory circuit is another major consideration in minimizing the patient’s respiratory work during a trial of spontaneous breathing. A tracheostomy can be advantageous for the patient requiring prolonged mechanical ventilation, because of increased comfort, enhanced ability to eat food, and improved oral hygiene. Additionally, when the patient is removed from the ventilator, the inner cannula of the tracheostomy may be removed and the cuff deflated to decrease the WOB imposed on the patient. This is only done with a “mature” tracheostomy stoma, defined by us as at least 14 days old. A variety of approaches may be used to improve respiratory muscle performance. Theophylline has been reported to improve respiratory muscle contractility, but its effect appears to be small and remains controversial. Resting the respiratory muscles with mechanical ventilation is the only satisfactory method of treating respiratory muscle fatigue. Nutritional repletion has been shown to increase muscle

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mass and decrease fatigability of nonrespiratory muscles. Malnutrition produces a decrease in the ventilatory response to hypoxia, reduction of muscle mass, and loss of muscle strength and endurance. Additionally, respiratory compromise related to nutritional depletion may contribute to pneumonia, which places an additional burden on the respiratory system. For the malnourished, critically ill patient, nutritional supplementation (see Chapter 20) has been shown to increase inspiratory force, and proper nutritional support may facilitate weaning. The choice of calories is also important for patients with respiratory disease. Administration of carbohydrate calories more than metabolic demands may lead to a significant increase in CO2 production. Combustion of glucose results in approximately 22% greater increase in CO2 production than does fat and, in a borderline situation, may result in weaning failure. Administration of carbohydrate more than metabolic demands results in conversion to fat with a shift of the respiratory quotient in favor of CO2 production. Carbohydrates and fats are metabolized at respiratory quotients of 1.0 and 0.7, respectively. The recommended source of calories for patients requiring ventilator support for respiratory failure includes 50% to 60% from carbohydrates and 40% to 50% from fats. In addition to ensuring adequate nutritional supplementation, abnormalities in acid-base status, electrolytes, and minerals should be corrected, because they may impair the performance of the respiratory system. During the weaning process, all aspects of general patient care should be optimized, including fluid balance, infection management, and other concurrent problems. Endocrine disturbances, such as hyperthyroidism or hypothyroidism, and administration of corticosteroids may impair respiratory muscle function. Administration of pancuronium and succinylcholine, especially in combination with aminoglycoside antibiotics, can impair respiratory muscle function even after the drugs have been discontinued (See Chapter 13). Myasthenia gravis may be unmasked or aggravated for some patients by agents such as quinidine, propranolol, or lithium. Furthermore, respiratory muscle atrophy may develop during a period of prolonged mechanical ventilation. Even when all the usual causes of failure to wean from mechanical ventilation are considered and management is

optimized, some patients will continue to remain dependent on mechanical ventilation. Extubation Generally, the patient is considered ready for extubation when there is good oxygenation on minimal ventilator settings: a VT of 6 to 8 mL/kg, mechanical rate of two breaths per minute, FIO2 of 0.4, PSV of 10 cm H2O, and CPAP of 5 cm H2O; PaCO2 should be in the normal range for the particular patient; no new or significant changes on chest radiograph; no upper or lower airway edema; and acceptable neurologic status. Common criteria for extubation include:102 1. Vital capacity of at least 15 mL/kg ideal body weight 2. Negative inspiratory force of -25 cm H2O or less (i.e., a larger negative number) 3. PaO2 > 60 mm Hg with an FiO2 < 0.5 and CPAP £ 5 cm H2O 4. PaCO2 < 45 mm Hg 5. Respiratory rate of 20 to 30 breaths/minute 6. No new or acute organ failure 7. No new changes on chest radiograph More sophisticated criteria for extubation have been recently introduced. They include: P0.1 (threshold 4.5 cm H2O, sensitivity 1.00 and specificity 1.00), patient’s total WOB (threshold 1.3 J/L, sensitivity 0.92 and specificity 0.98), and spontaneous respiratory rate—spontaneous tidal volume (sRR/sVT) ratio (threshold 65 bpm/L, sensitivity 0.90 and specificity 0.80). Patients who cannot be weaned successfully from mechanical ventilation tend to have a faster respiratory rate (hence sRR/sVT ratio more than 65 in surgical patients and more than 105 in medical patients), a higher WOB, and higher P0.1103 P0.1 is the pressure measured in the airway 100 milliseconds after initiation of the inspiration with an inspiratory hold; it is an index of neuromuscular inspiratory drive. It has been shown that P0.1 may be increased during acute respiratory failure and acute exacerbation of COPD. In addition, this index has been proposed as a predictor of successful weaning from ventilation.104

P earls 1. The driving pressure is the net pressure change during inspiration. During spontaneous breathing, the gradient between the mouth and the alveolus is the transpulmonary pressure. 2. Tidal volume (VT) refers to the normal resting respiratory volume moved during a respiratory cycle. Normal values for VT in healthy adults are 5 to 8 mL/kg.

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3. The anatomic dead space—the airway starting from the mouth or nose, down to the terminal bronchioles—makes up the conducting airways and lead inspired gas to the gas-exchanging region of the lung; it is approximately 2 mL/kg. 4. Another reason for inequality of ventilation is the existence of uneven time constants. The time constant is

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9. 10.

11.

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the time required for evacuation of a certain percentage of lung volume. The time constant of a region of lung is given by the product of its resistance and compliance. . . . at lung volumes either above or below FRC, the PVR increases. The normal lung, therefore, functioning best at FRC, has the lowest PVR in this “window” of optimal volume. Although the basic function of pulmonary circulation is the exchange of oxygen and carbon dioxide at the alveolar level, it has other metabolic functions, including conversion of the relatively inactive polypeptide angiotensin I into the potent vasoconstrictor angiotensin II, as well as the inactivation of a number of vasoactive substances, such as bradykinin (up to 80%), norepinephrine (up to 30%), and prostaglandins E1, E2, and F2. Hyperthermia, acidosis, hypercapnia, and an increased concentration of 2,3-diphosphoglycerate cause a right shift in the curve, resulting in a decrease in the affinity of hemoglobin for oxygen (which means that the hemoglobin more easily gives up the carried oxygen to tissues). Increased PaCO2 reduces the affinity of hemoglobin for oxygen, because of an increased hydrogen ion concentration. The net effect is that, as the blood loads carbon dioxide, the unloading of oxygen is improved. Central chemoreceptors are located within 2 mm of the ventral surface of the medulla oblongata. This area can be stimulated in experimental animals by administration of solutions of low pH or a high CO2 concentration to the surface of the brain. The changes in minute ventilation in response to changes in PaCO2 are 1 to 6 L/minute/mm Hg. The ventilatory response to hypoxia is variable among individuals, averaging about 0.6 L/minute/percent desaturation. The clinical manifestations of inspiratory muscle fatigue include tachypnea, paradoxical abdominal motion, respiratory alternans—variations between normal expansion and abdominal paradox—hypercapnia, and, preterminally, even bradycardia. . . . PIP is not the pressure that the alveolus “sees.” Plateau pressure is the pressure measurement taken after breath has been delivered to the patient and before exhalation has begun; it is measured with an inspiratory pause, which eliminates both the flow and resistive components that are measured in the peak inspiratory pressure. It is the plateau pressure that the alveolus “sees.” The work per breath is measured as force times distance in Joules. The rate of work (work X time) is called power and is measured in Watts. The primary difference between PCV and the more commonly used VCV is that the clinician-set inputs and measured outputs are reversed. PCV does not deliver a predetermined VT but maintains a set airway

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pressure throughout inspiration for a prescribed length of time; VT depends on compliance. Tidal volume is set in VCV and pressures are variable. Although PSV can be used as a stand-alone ventilatory modality, provided that the patient has sufficient respiratory drive, it is most commonly used in combination with volume-controlled SIMV. The use of pleural, instead of airway, pressure as a target pressure allows one to accomplish a new mode of mechanical pressure called pleural pressuresupported ventilation (PPSV). PPSV is accomplished by putting the ventilator into a PSV mode at either a pressure support of 0 cm H2O or greater than 0 cm H2O. Although high-frequency positive-pressure ventilation and high-frequency jet ventilation are of unquestionable value during laryngoscopy, bronchoscopy, and surgery of the upper respiratory tract, the only unequivocally successful application of HFV in the intensive care unit is in the treatment of bronchopleural fistula. Experimental and clinical results regarding arterial oxygenation and oxygen transport obtained by Lachmann and colleagues indicated that the evolution of pulmonary damage in ARDS is closely related to the airway pressure required to allow reopening of collapsed alveoli and maintenance of alveolar patency without overdistention of complaint lung units. Decreasing PEEP inappropriately has been shown to decrease PaO2. The time course for recovery of oxygenation when PEEP has been inappropriately reduced and then resumed may be as long as 40 minutes. In several controlled studies of patients with acute exacerbation of COPD, NIPPV reduced the need for endotracheal intubation and mechanical ventilation as well as the risk of lower inspiratory tract infection and pneumonia, thereby reducing in-hospital mortality and morbidity. PPV increases intrathoracic pressure during inspiration, decreasing venous return, which results in decreased right ventricular preload and right ventricular output. Low right-sided output results in lower left ventricular preload and, because of diminished left ventricular end diastolic volume, left ventricular output also decreases. Physiologic mechanisms of impaired oxygenation include hypoventilation, diffusion abnormalities, shunting, V/Q mismatching, and a low alveolar oxygen concentration. Pulmonary barotrauma, in the form of pneumothorax, pneumomediastinum, or subcutaneous emphysema, reportedly occurs in 10% to 20% of patients who need mechanical ventilation with or without the use of PEEP. The best treatment of pulmonary barotrauma is prevention. This may be accomplished by using appropriate ventilator settings, such as low tidal volumes (6

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to 8 mL/kg), maintaining plateau pressure less than 35 cm H2O and PIP less than 50 cm H2O, and avoiding high levels of PEEP if possible. 25. A positive response to bronchodilator therapy is a reduced peak airway pressure of 10% to 20% from baseline or a reduction of expiratory wheezing. 26. Criteria commonly used for discontinuation of weaning trial include tachypnea, a respiratory rate greater than 35 breaths per minute for longer than 5 minutes; hypoxia, SpO2 less than 90%; tachycardia, heart rate more than 140 beats per minute or sustained heart rate increase of more than 20%; bradycardia, a sustained heart rate decrease more than 20%; hypertension, systolic blood pressure more than 180 mm Hg; hypotension, systolic blood pressure less than 90 mm Hg; and agitation, diaphoresis, or anxiety.

References 1. West JB: Ventilation, blood flow, and gas exchange. In Murray JF, Nadel JA (eds): Textbook of Respiratory Medicine, 2nd ed. Philadelphia, WB Saunders, 1994, pp 51–89. 2. Guyton AC: Textbook of Medical Physiology, 8th ed. Philadelphia, WB Saunders, 1991. 3. Irwin RS, Cerra FB, Rippe JM: Intensive Care Medicine, 4th ed. Philadelphia, Lippincott-Raven, 1999. 4. Benumof JL: Respiratory physiology and respiratory function during anesthesia. In Miller RD (ed): Anesthesia, 5th ed. Philadelphia, Churchill Livingston, 2000. 5. Canter HG: Practical pulmonary physiology. General Practice 1967;35:104–114. 6. Marino PA: The ICU Book, 2nd ed. Baltimore, Williams and Wilkins, 1998. 7. Bhutani VK, Sivieri EM: Clinical use of pulmonary mechanics and waveform graphics. Clin Perinatol 2001;28:487–503. 8. Marelich GP, Murin S, Batistella F, Inciardi J, Vierra T, Roby M: Protocol weaning of mechanical ventilation in medical and surgical patients by respiratory care practitioners and nurses. Effects on weaning time and incidence of ventilator associated pneumonia. Chest 2000;118:459–467. 9. Corrado A, Gorini M, Ginanni R, et al: Negative pressure ventilation versus conventional mechanical ventilation in the treatment of respiratory failure in COPD patients. Eur Respir J 1998;12:519–525. 10. McKibben AW, Ravenscraft SA: Pressure-controlled and volume-cycled mechanical ventilation. Clin Chest Med 1996;17:395–410. 11. Ghosh S, Latimer RD: Thoracic Anesthesia: Principles and Practice. Oxford, Butterworth Heinemann, 1999. 12. Youngberg JA: Cardiac, Vascular and Thoracic Anesthesia. New York, Churchill Livingstone, 2000. 13. Munoz J, Guerrero JE, Escalante JL, Palomino R, de la Calle B: Pressure-controlled ventilation versus controlled mechanical ventilation with decelerating inspiratory flow. Crit Care Med 1993;21:1143–1148. 14. Litmanovitch M, Joynt GM, Cooper PJF, Kraus P: Persistent bronchopleural fistula in a patient with adult respiratory distress syndrome. Treatment with pressure-controlled ventilation. Chest 1993;104:1901– 1902. 15. Chan K, Abraham E: Effects of inverse ratio ventilation on cardiorespiratory parameters in severe respiratory failure. Chest 1992;102:1556– 1561.

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27. . . . patients with intercostal muscle weakness resulting from low cervical spinal cord lesions show an increase of lung volumes when changing from upright to supine position. Diminished pulmonary function in an upright tetraplegic patient may be caused by paralysis of abdominal muscles and gravitational bulging of abdominal contents. This condition may be minimized through the use of elastic binders. 28. Nutritional repletion has been shown to increase muscle mass and decrease fatigability of nonrespiratory muscles. Malnutrition produces a decrease in the ventilatory response to hypoxia, reduction of muscle mass, and loss of muscle strength and endurance. Additionally, respiratory compromise related to nutritional depletion may contribute to pneumonia, which places an additional burden on the respiratory system.

16. Huang C-C, Shih M-J, Tsai Y-H, Chang Y-C, Tsao TCY, Hsu K-H: Effects of inverse ratio ventilation versus positive end-expiratory pressure on gas exchange and gastric intramucosal PCO2 and pH under constant mean airway pressure in acute respiratory distress syndrome. Anesthesiology 2001;95:1182–1188. 17. Tejeda M, Boix JH, Alvarez F, Balanz R, Morales M: Comparison of pressure support ventilation and assist-control ventilation in the treatment of respiratory failure. Chest 1997;111:1322–1325. 18. Sinha SK, Donn SM: Volume-controlled ventilation. Clin Perinatol 2001;28:547–560. 19. Gregoretti C, Beltrame F, Lucangelo U, et al: Physiologic evaluation of non-invasive pressure support ventilation in trauma patients with acute respiratory failure. Intensive Care Med 1998;24:785–790. 20. Wysocki M, Tric L, Wolff MA, Gertner J, Millet H, Herman B: Noninvasive pressure support ventilation in patients with acute respiratory failure. Chest 1993;103:907–913. 21. Cereda M, Foti G, Marcora B, Gili M, Giacomini M, Sparacino M-E, Pesenti A: Pressure support ventilation in patients with acute lung injury. Crit Care Med 2000;28:1269–1275. 22. Shelledy DC, Rau JL, Thomas-Goodfellow L: A comparison of the effects of assist-control, SIMV, and SIMV with pressure support on ventilation, oxygen consumption, and ventilatory equivalent. Heart Lung 1995;24:67–75. 23. Vitacca M, Ambrosino N, Clini E, Porta R, Rampulla C, Lanini B, Nava S: Physiological response to pressure support ventilation delivered before and after extubation in patients not capable of totally spontaneous autonomous breathing. Am J Respir Crit Care Med 2001;164: 638–641. 24. Dekel B, Segal E, Perel A: Pressure support ventilation. Arch Intern Med 1996;156:369–373. 25. Berger KI, Sorkin B, Norman RG, Rapoport DM, Goldring RM: Mechanism of relief of tachypnea during pressure support ventilation. Chest 1996;109:1320–1327. 26. Banner MJ, Kirby RR, Kirton OC, DeHaven CB, Blanch PB: Breathing frequency and pattern are poor predictors of work of breathing in patients receiving pressure support ventilation. Chest 1995;108:1338– 1344. 27. Takeda S, Nakanishi K, Takano T, et al: The combination of external high-frequency oscillation and pressure support ventilation in acute respiratory failure. Acta Anaesthesiol Scand 1997;41:670–674. 28. Messinger G, Banner MJ, Blanch PB, Layon AJ: Using tracheal pressure to trigger the ventilator and control airway pressure during continuous

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positive airway pressure decreases work of breathing. Chest 1995; 108:509–514. 29. Tokioka H, Tanaka T, Ishizu T, et al: The effect of breath termination criterion on breathing patterns and the work of breathing during pressure support ventilation. Anesth Analg 2001;92:161–165. 30. Uchiyama A, Imanaka H, Taenaka N: Relationship between work of breathing provided by a ventilator and patients’ inspiratory drive during pressure support ventilation; effects of inspiratory rise time. Anaesth Intensive Care 2001;29:349–358. 31. MacIntyre NR, Ho L-I: Effects of initial flow rate and breath termination criteria in pressure support ventilation. Chest 1991;99: 134–138. 32. Chatmongkolchart S, Williams P, Hess DR, Kacmarek RM: Evaluation of inspiratory rise time and inspiration termination criteria in newgeneration mechanical ventilators: A lung model study. Respiratory Care 2001;46:666–667. 33. Dekel B, Segal E, Perel A: Pressure support ventilation. Arch Intern Med 1996;156:369–373. 34. Takahashi T, Takezawa J, Kimura T, Nishiwaki K, Shimada Y: Comparison on inspiratory work of breathing in T-piece breathing, PSV, and pleural pressure support ventilation (PPSV). Chest 1991;100:1030– 1034. 35. Chui PT, Joynt GM: Severe hyperventilation and respiratory alkalosis during pressure-support ventilation: Report of a hazard. Anaesthesia 1995;50:978–980. 36. Brambrink AM, Brachlow J, Weiler N, et al: Successful treatment of a patient with ARDS after pneumonectomy using high frequency oscillatory ventilation. Intensive Care Med 1999;25:1173–1176. 37. Sjstrand UH: In what respect does high frequency positive pressure ventilation differ from conventional ventilation? Acta Anaesthesiol Scand 1989;33(Suppl 90):5–12. 38. Gattinoni L, Pesenti A, Bombino M, et al: Relationships between lung computed tomographic density, gas exchange, and PEEP in acute respiratory failure. Anesthesiology 1988;69:824–832. 39. Cereda M, Foti G, Musch G, Sparacino ME, Pesenti A: Positive endexpiratory pressure prevents the loss of respiratory compliance during low-tidal volume ventilation in acute lung injury patients. Chest 1996;109:480–485. 40. Springer RR, Stevens PM: The influence of PEEP on survival of patients in respiratory failure. A retrospective analysis. Am J Med 1979;66:196– 200. 41. Downs JB, Klein EF, Modell JH: The effect of incremental PEEP on PaO2 in patients with respiratory failure. Anesth Analg 1973;52:210– 215. 42. Jardin F, Genevray B, Pazin M, Margairaz A: Inability to titrate PEEP in patients with acute respiratory failure using end-tidal carbon dioxide measurements. Anesthesiology 1985;62:530–533. 43. Ellman H, Dembin H: Lack of adverse hemodynamic effects of PEEP in patients with acute respiratory failure. Crit Care Med 1982;10:706– 711. 44. Jardin F, Desfond P, Bazin M, Sportiche M, Margairaz A: Controlled ventilation with best positive end-expiratory pressure (PEEP) and high level PEEP in acute respiratory failure (ARF). A comparative study on patients with bilateral and unilateral lung disease. Intensive Care Med 1981;7:171–176. 45. O’Donohue WJ, Baker JP, Bell GM, Muren O, Parker CL, Patterson JL Jr: Respiratory failure in neuromuscular disease. Management in a respiratory intensive care unit. JAMA 1976;235:733–735. 46. Cotev S, Perel A, Katzenelson R, Eimerl D: The effect of PEEP on oxygenating capacity in acute respiratory failure with sepsis. Crit Care Med 1976;4:186–192. 47. Hemmer M, Suter PM: Treatment of cardiac and renal effects of PEEP with dopamine in patients with acute respiratory failure. Anesthesiology 1979;50:399–403. 48. Gosselink R, Schrever K, Cops P: Incentive spirometry does not enhance recovery after thoracic surgery. Crit Care 2000;28:679–683.

49. Girault C, Daudenthun I, Chevron V, Tamion F, Leroy J, Bonmarchand G: Noninvasive ventilation as a systematic extubation and weaning technique in acute-on-chronic respiratory failure. A prospective, randomized controlled study. Am J Respir Crit Care Med 1999;160:86– 92. 50. Meduri GU, Fox RC, Abou-Shala N, Leeper KV, Wunderink RG: Noninvasive mechanical ventilation via face mask in patients with acute respiratory failure who refused endotracheal intubation. Crit Care Med 1994;22:1584–1590. 51. Wysocki M, Tric L, Wolff MA, Millet H, Herman B: Noninvasive pressure support ventilation in patients with acute respiratory failure: A randomized comparison with conventional therapy. Chest 1995;107: 761–768. 52. Girault C, Richard J-C, Chevron V, et al: Comparative physiologic effects of noninvasive assist-control and pressure support ventilation in acute hypercapnic respiratory failure. Chest 1997;111:1639–1648. 53. Calderini R, Confalonieri M, Puccio PG, Francavilla N, Stella L, Gregoretti C: Patient-ventilator asynchrony during noninvasive ventilation: The role of expiratory trigger. Intensive Care Med 1999;25: 662–667. 54. Sottiaux TM: Patient-ventilator interactions during volume-support ventilation: Asynchrony and tidal volume instability—a report of three cases. Resp Care 2001;46:255–262. 55. Sjstrand UH, Lichtwarck-Aschoff M, Nielson JB, et al: Different ventilatory approaches to keep the lung open. Intensive Care Med 1995;21: 310–318. 56. Haberthür C, Elsasser S, Eberhard L, Stocker R, Guttmann J: Total versus tube-related additional work of breathing in ventilatordependent patients. Acta Anaesthesiol Scand 2000;44:749–757. 57. Mols G, von Ungern-Sternberg B, Rohr E, Haberthür C, Geiger K, Guttmann J: Respiratory comfort and breathing pattern during volume proportional assist ventilation and pressure support ventilation: A study on volunteers with artificially reduced compliance. Crit Care Med 2000;28:1940–1946. 58. Grasso S, Puntillo F, Mascia L, et al: Compensation for increase in respiratory workload during mechanical ventilation. Pressure-support versus proportional-assist ventilation. Am J Respir Crit Care Med 2000;161:819–826. 59. Wrigge H, Golisch W, Zinserling J, Sydow M, Almeling G, Burchardi H: Proportional assist versus pressure support ventilation: Effects on breathing pattern and respiratory work of patients with chronic obstructive pulmonary disease. Intensive Care Med 1999;25:790–798. 60. Diringer MN, Edwards DF, Aiyagari V, Hollingsworth H: Factors associated with withdrawal of mechanical ventilation in a neurology/ neurosurgery intensive care unit. Crit Care Med 2001;29:1792–1797. 61. Day SE, Gedeit RG: Liquid ventilation. Clin Perinatol 1998;25:711–722. 62. Keith RL, Pierson DJ: Complications of mechanical ventilation. Clin Chest Med 1996;17:439–451. 63. Banagale RC: Massive intracranial air embolism: A complication of mechanical ventilation. Am J Dis Child 1980;134:799–780. 64. Weaver LK, Morris A: Venous and arterial gas embolism associated with positive pressure ventilation. Chest 1998;113:1132–1134. 65. Sandur S, Stoller JK: Pulmonary complications of mechanical ventilation. Clin Chest Med 1999;20:223–247. 66. Cullen DJ, Caldera DL: The incidence of ventilator-induced pulmonary barotrauma in critically ill patients. Anesthesiology 1979;50:185–190. 67. Kirby RR: Ventilatory support and pulmonary barotrauma. Anesthesiology 1979;50:181–182. 68. McLoud TC, Barash PG, Ravin CE, Mandel SD: Elevation of pulmonary artery pressure as a sign of pulmonary barotrauma. Crit Care Med 1978;6:81–84. 69. Kumar A, Pontoppidan H, Falke KJ, Wilson RS, Laver MB: Pulmonary barotrauma during mechanical ventilation. Crit Care Med 1973;1:181– 186. 70. Hurd TE, Novak R, Gallagher TJ: Tension pneumopericardium: A complication of mechanical ventilation. Crit Care Med 1984;12:200–201.

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71. Banner MJ, Boysen PG: Demand valve improperly set resulting in pulmonary barotrauma. Anesthesiology 1984;61:86–87. 72. Demers B: Perflurocarbon fluid as a mediator of pulmonary barotrauma. A potential hazard of liquid ventilation. Chest 2000;117:8–10. 73. Beilin B, Shulman DL, Weiss AT, Mogle P: Pneumoperitoneum as the presenting sign of pulmonary barotrauma during artificial ventilation. Intensive Care Med 1986;12:49–51. 74. Peterson GW, Baier H: Incidence of pulmonary barotrauma in a medical ICU. Crit Care Med 1983;11:67–69. 75. Bricker MB, Morris WP, Allen SJ, Tonnesen AS, Butler BD: Venous air embolism in patients with pulmonary barotrauma. Crit Care Med 1994;22:1692–1698. 76. Estafanous FG, Viljoen JF, Barsoum KN: Diagnosis of pneumothorax complicating mechanical ventilation. Anesth Analg 1975;54:730–735. 77. Beards SC, Lipman J: Decreased cardiac output as an indicator of tension pneumothorax in the ventilated patient. Anesthesia 1994; 49:137–141. 78. Russomanno JH, Brown LK: Pneumothorax due to ball-valve obstruction of an endotracheal tube in a mechanically ventilated patient. Chest 1992;101:1444–1445. 79. Frattallone JM, Fuhrman B, Kochanek PM, et al: Management of pulmonary barotrauma by extracorporeal membrane oxygenation, apnea, and lung rest. J Pediatr 1988;112:787–789. 80. Tolep K, Getch CL, Criner GJ: Swallowing dysfunction in patients receiving prolonged mechanical ventilation. Chest 1996;109:167–172. 81. Partridge MR, Flood-Page P: Multiple tracheal strictures following mechanical ventilation. Resp Med 1997;91:503–504. 82. Combes P, Fauvage B, Oleyer C: Nosocomial pneumonia in mechanically ventilated patients, a prospective randomised evaluation of the stericath closed suctioning system. Intensive Care Med 2000;26:878– 882. 83. Gallagher TJ (ed): Postoperative Care of the Critically Ill Patient. Baltimore, Williams and Wilkins, 1995. 84. Youngberg JA: Cardiac, Vascular and Thoracic Anesthesia. New York, Churchill Livingstone, 2000. 85. Ullrich R, Lorber C, Röder G, Urak G, Faryniak B, Sladen RN, Germann P: Controlled airway pressure therapy, nitric oxide inhalation, prone position, and extracorporeal membrane oxygenation (ECMO) as components of an integrated approach to ARDS. Anesthesiology 1999;91:1577–1586. 86. Dhan R, Tobin MJ: Inhaled bronchodilator therapy in mechanically ventilated patients. Am J Respir Crit Care Med 1997;156:3–10. 87. Mancebo J, Amaro P, Lorino H: Effects of albuterol inhalation on the work of breathing during weaning from mechanical ventilation. Am Rev Respir Dis 1991;144:95–100. 88. O’Riordan TG, Palmer LB, Smaldone GC: Aerosol deposition in mechanically ventilated patients. Optimizing nebulizer delivery. Am J Respir Crit Care Med 1994;149:214–219.

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89. Rodrigo C, Rodrigo G: Salbutamol treatment of acute severe asthma in the ED: MDI versus hand-held nebulizer. Am J Emerg Med 1998;16:637–642. 90. Shaughnessy AF, Slawson DC: Metered-dose inhalers with spacers vs nebulizers for pediatric asthma. J Fam Pract 1996;42:29–30. 91. Chao DC, Scheinhorn DJ, Stearn-Hassenpflag M: Patient-ventilator trigger asynchrony in prolonged mechanical ventilation. Chest 1997;112:1592–1599. 92. Hess D: Ventilator modes used in weaning. Chest 2001;120:474S–476S. 93. Brochard L, Rauss A, Benito S, et al: Comparison of three methods of gradual withdrawal from ventilatory support during weaning from mechanical ventilation. Am J Respir Crit Care 1994;150:896–903. 94. Staudinger T, Kordova H, Roggla M, et al: Comparison of oxygen cost of breathing with pressure-support ventilation and biphasic intermittent positive airway pressure ventilation. Crit Care Med 1998;26:1518– 1522. 95. Mehta S, Nelson DL, Klinger JR, Buczko GB, Levy MM: Prediction of post-extubation work of breathing. Crit Care Med 2000;28:1341–1346. 96. Esteban A, Alia I, Gordo F, et al: Extubation outcome after spontaneous breathing trials with T-tube or pressure support ventilation. Am J Respir Crit Care Med 1997;156:459–465. 97. Vianello A, Bevilacqua M, Arcaro G, Gallan F, Serra E: Non-invasive ventilatory approach to treatment of acute respiratoy failure in neuromuscular disorders. A comparison with endotracheal intubation. Intensive Care Med 2000;26:384–390. 98. Capdevila X, Perrigault P-F, Ramontxo M, et al: Changes in breathing pattern and respiratory muscle performance parameters during difficult weaning. Crit Care Med 1998;26:79–87. 99. Isaacson J, Smith-Blair N, Clancy RL, Pierce JD: Effects of pressure support ventilation and continuous positive airway pressure on diaphragm performance. J Adv Nurs 2000;32:1442–1449. 100. Hurtado FJ, Bern M, Olivera W, et al: Gastric intramucosal pH and intraluminal PCO2 during weaning from mechanical ventilation. Crit Care Med 2001;29:70–76. 101. Dries DJ: Weaning from mechanical ventilation. J Trauma Injury Infection Crit Care 1997;43:372–384. 102. Banoub M, Nugent M: Thoracic anesthesia. In Rogers MC (ed): Principles and Practice of Anesthesia. St. Louis, Mosby, 1997, pp 1719–1930. 103. Rivera L, Weissman C: Dynamic Ventilatory Charactristics During Weaning in Postoperative Critically Ill Patients. Anesth Analg 1997;84:1250–1255. 104. Conti G, Cinnella G, Barboni E, Lemaire F, Harf A, Brochard L: Estimation of occlusion pressure during assisted ventilation in patients with intrinsic PEEP. Am J Respir Crit Care Med 1996;154:907–912.

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Chapter 20 Nutrition in the Neurointensive Care Unit Lawrence J. Caruso, MD and Ricardo Morales Laramendi, MD

Introduction Nutritional support is widely accepted as an important component in the care of critically ill patients. Prolonged starvation or underfeeding can lead to a state of “autocannibalism,” with breakdown of skeletal muscle and visceral protein to meet metabolic requirements. This leads to weight loss, organ dysfunction, and impairment of immune function. This chapter will review basic concepts of nutritional support as well as those issues pertinent to the patient with neurologic injury. Different routes of feeding will be discussed, as will different nutritional formulations.

Effects of Starvation Metabolic Effects The unstressed individual handles short periods of starvation fairly well. The decrease in glucose and insulin levels during fasting results in lipolysis and use of fat as the primary source of energy. Cells that require glucose (brain, red blood cells, and white blood cells) rely on glycogen reserves in the liver and muscle to supply approximately 180 g/day of glucose. After 1 to 2 days, however, these glycogen reserves are depleted, and muscle breakdown provides amino acids for gluconeogenesis. During this phase, approximately 75 g/day of protein are catabolized.1 After 1 week of starvation, the brain begins to shift its energy substrate from glucose to ketones, while the blood cells remain dependent on glucose. By the fifth week of star-

vation, this shift reduces the glucose requirement from 180 to approximately 80 g/day. The decreased need for glucose results in less muscle protein breakdown (20 vs. 75 g/day).1 Resting metabolic expenditure (RME) decreases within days of onset of starvation.2,3 This decrease is related to a decrease in the peripheral conversion of thyroxine to triiodothyronine,4 as well as decreased catecholamine levels.5 As muscle breakdown continues, the decreased lean tissue mass results in a further decrease in RME.6 The decreased activity of the sodium pump (Na+/K+-ATPase) also lowers the metabolic rate.7 When volunteers ingested two thirds of their initial daily energy requirements, the RME decreased by approximately 40% after 24 weeks of the diet.8 Effects on Organ Function The impact of malnutrition and starvation on organ function in humans is incompletely understood. The available data are from records of famines and people living in poorly developed areas; records of military detention camps; and from studies in animals, human volunteers, and hospitalized patients. Skeletal mass decreases to a greater proportion than does body weight. However, muscle function appears to correlate more closely with serum transferrin and pre-albumin levels than with actual mass. As such, muscle function may decrease before any significant decrease in muscle mass.9 Visceral organs also develop decreased mass as well as altered function as a result of starvation or malnutrition. Cardiac mass as well as cardiac output and stroke volume decrease in proportion to decreases in body weight. This 607

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altered function may simply reflect decreased metabolic demand.10 Intestinal atrophy leads to decreased absorption of glucose, fat, and protein.10–12 Pulmonary changes include decreased pulmonary muscle function10 and blunted ventilatory response to hypercarbia and hypoxia.13,14 Additional effects of malnutrition include anemia, impaired wound healing, and altered immune function. These changes place the malnourished patient at increased risk for multiple complications, including atelectasis, bronchopneumonia, intestinal malabsorption, and infection. Immune Effects, Infection, and Outcome The effects of malnutrition with regard to discrete components of the immune response have been well studied. Alterations in cellular immunity, complement activity, cytokine production, and antibody affinity have all been demonstrated in animal or human studies.15 The link between malnutrition, infectious risk, and mortality have also been described. In 1936, Studley16 reported a correlation between preoperative weight loss and postoperative mortality and infectious complications among patients undergoing surgery for gastric ulcer. In this retrospective analysis of 46 patients with chronic peptic ulcer disease, patients who had lost more than 20% of their baseline weight before surgery had a perioperative mortality rate of 33.3%, and all deaths were associated with infection. In patients who had lost less than 20% of their baseline weight, the mortality rate was only 3.5%. Furthermore, weight loss was a better predictor of mortality than the age of the patient, preoperative cardiorespiratory status, and the type and duration of the operation. Incidence of infection unassociated with mortality was not reported in this study. Rhoads and Alexander17 reported a higher infection rate in a group of general surgical patients with hypoproteinemia, defined as a serum protein concentration less than 6.3 g/dL. The infections were grouped as wound, urinary tract, respiratory, and miscellaneous. Patients with hypoproteinemia had higher rates of infection (total and within each group) than those with a serum protein concentration greater than 6.3 g/dL. However, the authors were unable to conclude that the reduced serum protein concentrations were causally related to the increased infection rate. In a prospective study of patients with severe head injury, Grahm and associates18 randomized 32 patients to receive either early (within 36 hours) or delayed (after 3 to 5 days) enteral feeding following injury. Patients in the early feeding group had improved caloric and nitrogen intake, as well as more positive nitrogen balance. In addition, patients fed early had significantly lower rates of early infection (up to 7 days following injury) than those who received delayed feeding. Length of stay in an intensive care unit was also decreased in the group fed earlier. In contrast to the benefits of early enteral nutrition in the study from Grahm and associates, a large, multicenter Vet-

erans Administration (VA) study found an increased risk of infection in patients receiving perioperative intravenous nutrition. In this prospective, randomized study of 395 malnourished patients undergoing major abdominal or thoracic surgical procedures, patients were randomly assigned to receive either total parenteral nutrition (TPN) for 7 to 15 days preoperatively and 3 days postoperatively, or to receive no perioperative TPN. The group receiving TPN had a higher rate of infection, particularly pulmonary infections, than did the control group.19 In subgroup analysis, the higher risk of infection with TPN held true for those who were classified as mildly malnourished but not those classified as borderline malnourished or severely malnourished. In the latter two groups, there was no difference in infection rates between TPN and control patients. In summary, it appears that malnutrition compromises certain discrete components of the immune system. However, based on the available data, it is difficult to determine whether malnutrition increases the rate of infection. More importantly, it is unclear whether aggressive attempts at intravenous feeding to correct the nutritional deficit will reduce the risk of infection, and if so, which patient populations will benefit most. Additional studies are needed to clarify these issues. Wound Healing There are several lines of evidence to support the claim that malnutrition leads to poor wound healing. Wound healing models using implanted fine-bore polytetrafluoroethylene tubing provide some insight. This tubing can be inserted subcutaneously and removed after 7 to 10 days. Measurement of hydroxyproline accumulation provides a measure of collagen deposition. In these studies, malnutrition has been associated with decreased hydroxyproline accumulation, suggesting reduced collagen deposition and impaired wound healing.20,21 Animal studies have demonstrated the adverse effects of protein-calorie malnutrition on the strength of colonic anastomoses22,23 and on abdominal wall wounds.24 The effects of these changes on clinical outcomes such as wound infection or dehiscence are not well defined. Human studies have primarily described the correlation between hypoalbuminemia and wound complications, although low albumin levels may occur independent of malnutrition. While malnutrition appears to impair wound healing, the ability of nutritional support to reverse this impairment has not been conclusively demonstrated. While Heatley and colleagues reported a decrease in wound infections in patients receiving supplemental preoperative intravenous nutritional support,25 others have failed to confirm these findings. Mueller and colleagues randomized preoperative patients with gastrointestinal cancer into two groups: 10 days of preoperative parenteral nutrition versus 10 days of enteral nutrition. They found no difference between groups in the rate of wound infections, although the group receiving par-

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enteral nutrition had lower rates of mortality and major complications.26 In the VA TPN Cooperative Study, the largest study of this type—involving 395 patients—there was no improvement in the rates of wound dehiscence or infection in patients receiving perioperative TPN.19 In summary, malnutrition leads to decreased collagen synthesis and likely increases the risk of wound complications. The ability to reverse these changes and the best method of doing so remain questionable. Intestinal Barrier Function Enteral starvation is associated with alterations in intestinal villous morphology and permeability. These changes also occur during administration of parenteral nutrition,27 suggesting they are a result of the lack of direct gut stimulation and not of malnutrition itself. The implications of these changes in the gut are discussed in more detail in a subsequent section, Enteral versus Parenteral Nutrition. Effects of Stress or Injury on Response to Starvation Starvation in the stressed individual differs from that in the unstressed person in several respects. The hormonal milieu following stress or injury is characterized by increases in catecholamine, glucocorticoid, glucagon, and growth hormone levels. Insulin levels are low given the level of hyperglycemia, and insulin resistance develops at the cellular level. Muscle breakdown provides amino acids for wound healing and for the synthesis of visceral proteins and acute phase reactants, in addition to providing substrate for gluconeogenesis. This increased protein catabolism continues until the levels of catecholamines and glucocorticoids decrease, which occurs when the inciting insult is controlled or reversed. Persistence of the stress state, with continued starvation, leads to rapid depletion of skeletal and visceral protein, resulting in weakness, impaired immune response, organ dysfunction, and ultimately death. Providing nutritional support decreases the net nitrogen loss, but positive nitrogen balance is not achieved until the hormonal milieu is restored toward normal. The hyperdynamic state that often follows severe neurologic injury is characterized by increases in catecholamine, glucocorticoid, glucagon, and growth hormone levels, as noted previously; increased cardiac output and cardiac work; tachycardia; and mild hypertension. Increased pulmonary shunting and increased oxygen delivery and use are also correlated with arterial levels of epinephrine and norepinephrine. The result is an increase in oxygen consumption and calorie requirements, which can be significant and prolonged for as long as 1 year. Biochemical consequences include hyperglycemia; poor wound healing; decreased levels of serum proteins, such as albumin, transferrin, retinol-binding protein, and prealbumin; increased C-reactive protein;

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increased interleukin-1 and interleukin-6; and depressed cell-mediated immune function. In addition, serum zinc levels are decreased and urinary zinc losses increase dramatically. Physiologic consequences include delayed upper gastrointestinal function, resulting in delayed gastric emptying and increased gastric residuals; sepsis; altered vascular permeability; and intestinal edema with mucosal damage, malabsorption, and bacterial translocation. All these changes are modified in the individual patient through increased energy needs related to the neurologic insult, flexion extension movements and generalized agitation; the varying effects of therapeutic agents, such as sedatives and relaxants on resting energy expenditure (REE)28; and increased incidence of septic complications, which increase and prolong the stress response.28 In summary, the metabolic responses to illness and injury differ significantly from those of starvation. During starvation, glycogen stores are exhausted and fat becomes the chief energy source. The body attempts to adapt by decreasing its metabolic rate and proteins are conserved until late in the process. In the neurologically injured patient, a marked negative nitrogen balance, diminished lipolysis, and the development of relative glucose intolerance characterize the hypermetabolic state.

Assessing Nutritional Needs Malnutrition escapes recognition in many affected patients and consequently they do not receive nutritional treatment. The implementation of nutritional screening tools will identify patients who are at risk and who need more formal assessment (Box 20-1). Many patients are malnourished on admission and there is a tendency for hospitalized patients to lose weight during a hospital stay; this particularly applies to patients who are malnourished at admission. Malnutrition is measured in terms of changes in body composition and structure, changes in organ and tissue function, and laboratory measurement of biochemical and immunologic variables.

Box 20-1  Assessment of Nutritional Status History of weight loss Physical examination Serum proteins Albumin Pre-albumin Transferrin Anthropometric measurements Triceps skinfold Mid-arm circumference

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The initial step in assessing nutritional needs is to recognize the presence of, or risk for, malnutrition. The best place to begin is with a thorough history obtained from the patient or the family, which should include questions regarding recent generalized health, eating habits, an approximation of nutrient intake, and recent or chronic weight loss. In the critical care setting, a body weight change is not a reliable predictor of outcome, and tends to reflect changes in fluid balance more than changes in lean body mass. Inspection of fat and muscle stores is important. Body habitus, edema, overall muscle bulk, and evidence of pretemporal muscle wasting should be assessed. Although anthropometric measures such as triceps skinfold thickness and midarm muscle circumference are more objective evaluations of these energy pools, they add little to clinical judgment, and are difficult to interpret because of acute fluid changes. Overall and as noted by Bistrian and associates almost 30 years ago, anthropometry is not generally useful in critically ill patients.29 Serum albumin levels have also been used to identify malnourished patients and their risk for morbidity. Unfortunately, the serum albumin level is affected by acute factors in the critically ill although it remains a strong predictor of outcome.30 Other serum proteins, such as transferrin and prealbumin, fail to increase sensitivity, and multiparameter indices are limited for the same reasons.30 Bioelectrical impedance analysis is a noninvasive method of assessment, which depends on the difference in electrical conductivity between the fat and fat-free mass. However, the technique assumes a normal hydration state that may not be the case in many patients hospitalized in the intensive care unit. Further validation is needed before this technique can be accepted into routine clinical practice in the neurointensive care unit.31 Nitrogen balance studies assess the adequacy of the present treatment more than an identification of past deficits: Dietary protein 6.25 Urine urea nitrogen -Ê + 4ˆ Ë ¯ 0.8

Nitrogen balance =

A positive nitrogen balance in the range of 2 to 4 g/day is desired, but is at times difficult to achieve in the critically ill patient. Furthermore, if the “fudge factor” (the number 4 in the equation) for stool losses is wrong, the patient in positive nitrogen balance may actually be in negative balance. A variation on the theme of Weir—the metabolic cart— allows the measurement of oxygen consumption and CO2 production to determine the caloric needs for a patient. The formulae for Weir’s equation32 and the Harris-Benedict equation,33 the latter of which was originally derived from

Box 20-2  Determination of Energy Requirements Weight-based estimate 25–30 kcal/kg ideal body weight Harris-Benedict formula BBE (males) = 66.47 + 13.75 (weight in kg) + 5 (height in cm) - 6.76 (age in years) BEE (females) = 665 + 9.6 (weight in kg) + 1.7 (height in cm) - 4.7 (age in years) Modified Weir equation REE = 3.9 ¥ oxygen consumption + 1.1 ¥ carbon dioxide production TEE = REE ¥ activity factor Activity factor is 1.15 for patients confined to bed, 1.25 for ambulating patients BEE, basal energy expenditure; REE, resting energy expenditure; and TEE, total energy expenditure

studying 136 men and 103 women using indirect calorimetry—and allowing a first approximation of caloric need— are shown in Box 20-2.

Timing of Nutritional Support There is some debate over the issue of how soon to start nutritional support. Clearly, prolonged starvation will eventually lead to death. However, we know that most wellnourished patients tolerate several days of postoperative semi-starvation without apparent adverse effects. The argument for delaying feeding in stressed patients rests on two related points. First, anorexia following injury may be an adaptive response. During an inflammatory response, tumor necrosis factor-a and interleukin-1 cause appetite suppression, which may provide some survival benefit. For example, elimination of the energy expenditure required to acquire food conserves energy for other processes such as wound healing, particularly if the individual failed to obtain food due to inability to effectively compete while injured. Also, diversion of blood flow to the gut after eating might be harmful in times of hemodynamic instability. Ingestion of specific substrates, such as omega-6 fatty acids, may potentiate the inflammatory response and possibly contribute to multi-organ failure. The timing of nutritional support is both art and science. The clinical decision to start nutrition is based on the patients’ pre-injury nutritional status, the nature of their injury, and the expectation of when they will be able to

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resume normal oral intake. Assessment of preoperative nutritional status includes the parameters mentioned previously, including assessment of previous nutrient intake and weight loss, and laboratory measurements, such as albumin and pre-albumin levels. The use of anthropometric measurements (triceps skin fold thickness, mid-arm muscle circumference) are unreliable in critically ill patients, and albumin levels may be altered independent of the nutritional status if large amounts of fluid are given or significant losses occur, leaving the history as perhaps the most reliable indicator (when available). Most previously nourished patients can tolerate several days of minimal nutritional support (protein-sparing levels of carbohydrate) without deleterious effects, while previously malnourished patients likely benefit from earlier nutritional support. Guidelines published by the American Society of Parenteral and Enteral Nutrition suggest that supplemental nutrition may be beneficial to mildly malnourished patients if they are not expected to resume feeding within 7 days. Severely malnourished patients should receive some form of nutrition within 1 to 3 days.34 Several studies in patients with severe head injuries suggest that early nutritional support may improve outcome. Rapp and colleagues35 prospectively randomized patients with head injuries to receive either TPN or enteral feeding. Because gastric feedings were poorly tolerated, patients in the TPN group received significantly more calories and protein compared with those in the enterally fed group. Over the 18-day study period, mortality was significantly lower in the TPN group (eight deaths vs. zero deaths, P < 100). In another prospective study, Young and associates36 also compared TPN to enteral feeding. Again, the TPN patients achieved higher caloric and protein intake compared to those receiving enteral nutrition, and this translated into better neurologic outcome at 3 months after the injury. At 6 and 12 months after the injury, the difference in neurologic outcome was no longer statistically significant. In contrast, a prospective study by Hadley and associates37 revealed no significant difference in morbidity or mortality between TPN-fed or enterally fed patients, despite higher nitrogen intake in the TPN group. Given the conflicting data, with possible benefit of early feeding and little risk, we recommend placing a feeding tube and starting enteral feeding within 24 hours of injury via nasojejunal or percutaneous endoscopic jejunostomy feeding tube if access is available. Gastric feeding may be considered if the previously noted access is not available, as long as residual feeding solution volumes are checked every 1 to 2 hours. If the patient cannot tolerate enteral feeding, TPN should be started usually within 48 hours. This approach is in keeping with the American Society of Parenteral and Enteral Nutrition recommendation to start early feeding in patients who are unlikely to resume oral intake within 5 to 7 days.34

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Nutritional Requirements Once we decide that a given patient will need nutritional support, we must decide specifically what to provide. There are several formulas available to estimate caloric requirements based on age, sex, weight, and height, with the HarrisBenedict equation being most widely cited. Caloric needs can also be measured precisely using indirect calorimetry. By measuring the patient’s oxygen consumption and carbon dioxide production, the respiratory quotient and caloric expenditure can be calculated (see Box 20-2). The resulting REE must then be multiplied by an activity factor ranging from 1.0 to 1.25, depending on how active the patient is during the remainder of the day.38 Indirect calorimetry is typically considered the gold standard, and metabolic requirements determined by this method are typically approximately 12% lower than those calculated using the Harris-Benedict equation.39 Simpler estimates of metabolic requirements are based solely on weight and the severity of injury (see Box 20-2). Typically, 25 to 30 kilocalories per kilogram ideal body weight provide an adequate estimate of caloric needs, with more precise estimates or direct measurement recommended for patients who will require longterm support. Patients with head injury typically have higher energy expenditures than other critically ill patients, with REE as much as 60% higher than predicted.40,41 The cause of this elevated energy expenditure is not completely understood but is at least partly due to increased muscle tone. Patient temperature and barbiturate use also influence energy expenditure. Due to significant variation in REE between patients, this population is likely to benefit from direct measurement of REE using indirect calorimetry. In the patient with a head injury, the goal of nutritional support is maintenance rather than repletion. Attempting to fully replete nutritional status can be harmful, leading to increased CO2 production, deposition of fat and glycogen in the liver, and hyperglycemia.

Sources of Calories Carbohydrates Carbohydrates are typically used to provide the majority of nonprotein calories during nutritional support. Patients can usually metabolize 5 g/kg/day of carbohydrate. With enteral nutrition, disaccharide and polysaccharides are used and provide 4 kcal/g of carbohydrate. Intravenous formulations contain dextrose, which provides only 3.4 kcal/g due to its water content. Patients with neurologic injury, particularly traumatic brain injury, may require higher levels of carbohydrate intake because of their high energy requirements. This increased carbohydrate load, together with the insulin resistance typically seen in these stressed patients, often leads

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to hyperglycemia. The use of steroids potentiates this insulin resistance, and patients may require large doses of insulin to maintain normoglycemia. Avoidance of hyperglycemia is of particular concern in the patient with neurologic injury, because several studies suggest that increased glucose levels may worsen neurologic outcome (see Chapter 27). Additionally, a recent study by Belgian colleagues strongly suggests that critically ill patients whose blood glucose levels are controlled within the range 80 to 120 mg/dL have a lower mortality related to infectioninduced multisystem organ failure.42 In animals, administration of intravenous glucose before or during resuscitation from cardiac arrest worsens neurologic outcome as compared to controls receiving no glucose.43,44 Observational studies in humans reveal that hyperglycemia is associated with worse neurologic outcome following traumatic brain injury. Young and colleagues45 followed glucose levels in 59 patients with brain injuries and found that patients with peak glucose levels greater than 200 mg/dL within 24 hours of admission had worse neurologic outcome at 3 and 12 months. Similarly, Rovlias and Kotsou46 prospectively studied 267 patients with traumatic brain injury who underwent general anesthesia for hematoma evacuation or placement of an intracranial pressure monitor. In patients with severe head injury (Glasgow Coma Scale £8), postoperative glucose levels greater than 200 mg/dL were associated with worse outcomes. Multivariate analysis confirmed that glucose levels were an independent predictor of outcome. There are no prospective, randomized studies to date comparing tight versus loose glucose control in patients with neurologic injury, and it is unlikely that such a study will be done. Based on the available data, we recommend monitoring carbohydrate intake and administering supplemental insulin as needed to keep the serum glucose concentration between 80 and 120 mg/dL in non-diabetics to avoid possible worsening of neurologic outcome following brain injury. The same approach seems reasonable for other forms of neurologic insult, including spinal cord injury. This latter group is at particular risk of hyperglycemia due to the large doses of corticosteroids frequently administered for 24 to 48 hours after injury. Hyperglycemia seems to be more of a problem with the use of parenteral nutrition compared to enteral nutrition. One approach to this problem is to use a tight intravenous sliding scale for regular insulin administration to maintain the glucose level between 80 and 120 mg/dL. Each day, the amount of insulin administered by sliding scale during the previous 24 hours is tabulated, and one third to one half of that amount is added to the TPN. We do not add more than 1 unit per kg of lean body mass of regular insulin to each bag of 1.5 to 2 L TPN solution. The rationale for this decision is that if more insulin is added and the patient becomes hypoglycemic, the entire bag of TPN will have to be stopped. If the patient requires—as many do—further amounts of insulin to maintain glycemic control, administration is as

noted in Table 20-1. We avoid longer-acting insulin preparations due to erratic absorption in critically ill patients and the risk of hypoglycemia if feedings are stopped, as frequently happens with enteral nutrition. If hyperglycemia remains a problem despite appropriate insulin supplementation, the amount of carbohydrate can be decreased and the calories can be provided with lipids. Lipids Administration of lipids provides additional calories and prevents fatty acid deficiency. There are several advantages to using fat as a calorie source. First, fewer glucose calories are needed, reducing the risk of hyperglycemia. Second, because fat has higher caloric density than dextrose, fluids can be more easily restricted if necessary. Finally, metabolism of lipids, with a respiratory quotient (RQ) of 0.7, generates less carbon dioxide than the metabolism of dextrose, which has an RQ of 1.0. This difference may be significant in a patient with marginal respiratory status. Typically, lipid is administered to provide 30% to 40% of non-protein calories. The type of lipid administered may have important implications in the critically ill patient. The omega-6 fatty acids, primarily linoleic acid, are precursors of arachidonic acid, giving rise to potent inflammatory mediators, which may have a pathologic role in sepsis and multi-organ failure. Omega-3 fatty acids give rise to less potent inflammatory mediators and may be beneficial in controlling the inflammatory response. In fact, some studies have shown improved outcome when enteral feedings were supplemented with omega-3 fatty acids in addition to ribonucleic acid and glutamine.47 However, decreasing the production of inflammatory mediators may impair the host response to infection, and these supplements should be used with caution until more data are available. Intravenous lipid formulations currently contain large amounts of linoleic acid with very little omega-3 fatty acid. We recommend the provision of a lipid source with 50% to 70% medium-chain triglycerides, and an omega-6 to omega-3 ratio of 2 : 1 to 8 : 1 to minimize negative effects of omega-6 fatty acids on the immune system, and to provide an easily absorbed and utilized source of lipids. Protein Nitrogen requirements vary depending on the severity of the patient’s stress response. Typically, unstressed individuals require roughly 0.5 g of protein (0.08 g nitrogen) per kilogram ideal body weight per day to maintain nitrogen balance. During periods of physiologic stress, however, protein catabolism significantly increases, leading to increased nitrogen excretion and negative nitrogen balance. In most patients, this net nitrogen loss can be attenuated or even eliminated by administering large amounts of calories and protein. In patients undergoing gastrectomy, Holden and colleagues48 showed that 40 kcal/kg/day and 0.34 g nitro-

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Table 20-1  Insulin Therapy in Intensive Care Patients 1. Insulin infusion: Prepare 100 units in 100 ml of normal saline. When blood glucose level exceeds 150 mg/dL, insulin infusion should start at 1 unit/hour. If the blood glucose level exceeds 220 mg/dL, insulin infusion should start at 4 units/hour. 2. Measurement of blood glucose levels: After ICU admission and until normoglycemia (120–150 mg/dL) is achieved, hourly or every other hour blood glucose measurements should be obtained. Once normoglycemia is achieved, then blood glucose measurements can be obtained every 2 hours. 3. Titration schedule Blood Glucose Level (mg/dL)*

Insulin Adjustment

<40 40–59† 60–120† 120–150 151–180 >180

Stop infusion; administer 1 amp of D50 and recheck blood glucose in 1 hour Stop infusion; administer 1/2 amp of D50 and recheck level in 1 hour Decrease by 1 unit/hour and recheck level in 1 hour No adjustment necessary Increase by 1 unit/hour Increase by 2 units/hour

†

4. Special concerns regarding alterations in caloric intake: Adequate caloric and glucose intake is essential. In order to avoid blood glucose fluctuations and frequent dosing adjustments, administer IV glucose-containing products by continuous infusion. During tube feed interruptions, the insulin infusion should be adjusted. Therapy may be stopped or administered at a rate of 0.5 unit/hour. Once the tube feeds have been restarted, reinitiate therapy at the previous dose. During transport to the operating room or radiology suite, discontinue insulin therapy when enteral or parenteral feeding is stopped. Check blood glucose prior to transfer to ensure an adequate level (>80 mg/dL) prior to transport and every hour if out of the ICU for procedures or tests. It is crucial to reduce insulin infusion rates proportionately to the reduction in enteral or parenteral therapy. (Example: If enteral feeds are decreased by half then decrease the insulin infusion by half. Regular insulin can be added to the TPN not to exceed 0.5 unit/kg ideal body weight.) *If blood glucose drops precipitously (>50% change) after initiation or dose adjustment, reduce insulin infusion by 50% and check blood glucose hourly until stabilized. † With these values, check blood glucose hourly for 6 hours.

gen/kg/day significantly decreased nitrogen loss compared to lower levels of calorie and protein intake. Some of these patients achieved nitrogen equilibrium. Effects on clinical outcome were not reported in this study. The patient with spinal cord injury represents a special situation with regard to nitrogen balance. In this group, it may be impossible to achieve positive nitrogen balance despite administration of large amounts of calories and protein. Rodriguez and colleagues49 compared ten patients with spinal cord injury with 20 control patients matched for time, gender, age, and injury severity score. Despite receiving 120% of predicted caloric needs and 2.4 g protein/kg/day, patients with spinal cord injury did not achieve positive nitrogen balance until 2 months after injury, while 85% of those without spinal cord injury achieved positive nitrogen balance by the third week after injury. Indirect calorimetry confirmed that the delivered calories were adequate, providing an average of 110% of measured energy needs. The mechanism of persistent negative nitrogen balance in patients with spinal cord injury is not fully understood but may be related to muscle breakdown from immobilization and denervation atrophy. Following the period of acute injury, energy expenditure may be significantly less than that predicted by standard formulae.50 In patients who cannot

regulate their own intake, indirect calorimetry may be useful to determine caloric requirements. We recommend the provision of 2 to 2.3 g protein/kg ideal body weight/day if renal function is normal. If the gut is used, protein should be administered as small peptides to improve tolerance, absorption, utilization, and gut integrity. Micronutrients Micronutrients are substances present in relatively small amounts in serum and tissue and include vitamins (organic) and trace elements (inorganic). These substances play important roles in various metabolic pathways, including macronutrient utilization, wound healing, antioxidant defense, nucleic acid synthesis, oxygen transport, and control of metabolic rate. The role of specific micronutrients and the effects of deficiency states have been reviewed elsewhere.51 Measurement of serum levels of specific micronutrients is difficult; deficiencies are best prevented by beginning supplementation early in the course of illness. Provision of 1 to 2 L/day of enteral nutrition will typically contain adequate doses of micronutrients. For patients receiving TPN, micronutrients should be added as commercial preparations of vitamins and trace elements.

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Route of Nutrient Administration Enteral It is generally accepted that the enteral route is the preferred method of nutritional support in the patient with a functional gastrointestinal tract. Potential advantages include maintenance of normal intestinal architecture and permeability, preservation of gut-associated lymphoid tissue,52 and possibly decreased bacterial translocation (BTL). The small bowel and colon harbor large numbers of potentially pathogenic bacteria, and many clinicians believe translocation of bacteria, toxins, or both contribute to multi-organ failure. By preventing villous atrophy and maintaining normal permeability, enteral nutrition could theoretically prevent BTL. However, this theory has yet to be proven. While animal studies show intestinal atrophy with TPN, gut atrophy and BTL are not necessarily related. Illig and colleagues examined histologic intestinal structure and intestinal permeability to lactulose and mannitol in rats fed parenterally or enterally.27 Parenteral feeding alone led to significant intestinal atrophy, cecal bacterial overgrowth, and increased lactulose permeability. However, bacterial translocation, as measured on culture specimens of mesenteric lymph nodes, blood, and peritoneal fluid, was not signficantly increased. Conversely, Helton and Garcia53 demonstrated that prevention of the intestinal atrophy associated with parenteral feeding does not prevent BTL. By orally administering 16, 16-dimethyl-PGE2, a synthetic prostaglandin with trophic effects on the gut, these investigators were able to prevent intestinal atrophy in rats receiving parenteral nutrition. However, the rate of BTL was similar with and without prostaglandin, and was much higher than the rate in animals receiving enteral feeds.53 Longer-term (7 to 14 days) studies in rats show that TPN, compared to enteral feeding, may increase BTL to mesenteric lymph nodes, but the effects on distal bacterial spread and mortality are not clear.54,55 Several human studies reported bacteria-positive mesenteric lymph nodes in patients undergoing abdominal surgery. Presumably, the source of bacteria was the gut.56,57 In the largest study, involving 267 patients, BTL occurred in 10% of patients, but there was no correlation between BTL and nutritional status or intestinal villous height.58 Others have been unable to demonstrate either gut atrophy59 or increased permeability60 following short periods (5 to 21 days) without enteral feeding, although there are decreases in enzyme activities of the brush border.59 While several studies suggest lower septic morbidity with enteral nutrition compared to TPN (see following section),61 there are no studies directly relating enteral nutrition and BTL in humans. In summary, BTL does occur in humans and could potentially lead to distal infection. However, short-term absence of enteral nutrition in humans causes neither gut atrophy nor

increased permeability. At this time, the relationship between BTL and enteral nutrition remains unclear. Reaching full nutritional goals by enteral feeding alone remains difficult in patients with poor appetites or inability to eat. Placement and maintenance of a post-pyloric feeding tube is often time-consuming and labor-intensive. While some studies have shown no difference in aspiration risk between gastric and intestinal feeding,62,63 these studies involved relatively small numbers of patients, and we continue to provide nutrition into the small bowel whenever possible. The rationale for this approach is supported by the findings of delayed gastric emptying64 and lower esophageal sphincter dysfunction in patients with traumatic brain injury.65 Furthermore, post-pyloric feeding is often better tolerated, allowing increased caloric intake and improved nitrogen balance.18 Other commonly encountered complications of enteral feeding include diarrhea and abdominal distention, which can typically be treated by reducing the volume of feeding. Infectious causes of diarrhea, such as Clostridium difficile toxin, should be ruled out. Once infection is ruled out, adding fiber to the formula or adding antimotility agents may be helpful. Parenteral TPN or hyperalimentation (HAL) is often used for nutritional support when the enteral route cannot be used. TPN has the advantage of being relatively well tolerated; often making it easier to achieve full nutritional support when compared to enteral feeding. In addition, the amounts of carbohydrate, fat, protein, and electrolytes can be easily adjusted on a daily basis. Disadvantages of TPN include the need for central venous access, risk of refeeding syndrome if nutrition is advanced too rapidly, relatively high risk of hyperglycemia, and possibly an increased risk of infection (see following section). Peripheral parenteral nutrition is less hypertonic and can be given through a peripheral vein. While full caloric support is not possible, peripheral parenteral nutrition may be useful to supplement enteral feeding when complete enteral nutrition cannot be achieved. Enteral versus Parenteral Given the preceding considerations, the preferred route of nutrient administration remains controversial. Parenteral nutrition is typically easier to administer and may allow full nutritional goals to be reached earlier, possibly improving outcome. However, several studies in critically ill trauma victims have demonstrated reduced morbidity in patients receiving enteral nutrition as compared to parenteral nutrition.61,66,67 In a meta-analysis of 230 high-risk surgical patients, patients being administered early enteral nutrition had lower rates of infection than those receiving early parenteral nutrition. The difference was most evident in blunt

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trauma patients. When catheter sepsis was factored out, the difference in infection rates remained. Based on the available data, we recommend starting early enteral feeding in patients with neurologic injury. If full nutrition cannot be tolerated within 24 to 48 hours, parenteral nutrition can be added as a supplemental or complete source of nutrition. Special Formulations In recent years, enteral feeding formulae have been supplemented with nutrients designed to enhance immune function and improve outcome. These additives include arginine, nucleotides, omega-3 fatty acids, and glutamine. While these specialized formulas are touted as immune enhancing, their benefits have only been demonstrated in select groups of patients, and many of the studies in humans have been limited by design flaws or small sample size. In a metaanalysis of immune-enhancing diets in critically ill patients, supplementation of enteral feeds with arginine; omega-3 fatty acids; and nucleotides, with or without glutamine, significantly reduced infection rates, ventilator days, and hospital length of stay. Mortality rates were not affected.49 While these findings are not insignificant, as of yet, these specialized enteral formulas have not been well studied in patients with severe neurologic injury and clinical information is inadequate to recommend routine use of these products.

Monitoring Nutritional Status Just as assessing initial nutritional status is difficult in critically ill patients, monitoring the response to nutritional

Nutrition in the Neurointensive Care Unit

Box 20-3  Monitoring Nutritional Status Nitrogen balance measurements Pre-albumin Wound healing

support is also somewhat challenging (Box 20-3). Weight gain is often unreliable due to large fluid shifts. Nitrogen balance can be measured at intervals of 2 to 3 days to assess trends, with the understanding that positive nitrogen balance is difficult or impossible to achieve in the early days following acute injury. Albumin levels are not useful due to the long half-life (about 20 days), but pre-albumin, with a half-life of 2 to 3 days,68 can provide a measure of protein synthesis. Serial measurements of resting energy expenditure will allow fine-tuning of caloric intake because the metabolic rate may decrease as the acute response to injury abates.

Summary Nutritional support plays an essential role in the care of the patient with severe neurologic injury. Benefits include attenuation of protein catabolism and improved respiratory function and immune response, potentially decreasing complications. Whenever possible, enteral feeding is preferred over parenteral nutrition. Delivery of 25 to 30 kcal/kg ideal body weight/day and 1.5 g of protein/kg ideal body weight/day is a reasonable starting point, with modification based on measured or calculated energy expenditure and measurement of nitrogen balance and/or pre-albumin levels.

P earls 1. Cells that require glucose (brain, red blood cells, and white blood cells) rely on glycogen reserves in the liver and muscle to supply approximately 180 g/day of glucose. 2. After 1 week of starvation, the brain begins to shift its energy substrate from glucose to ketones, while the blood cells remain dependent on glucose. 3. When volunteers ingested two thirds of their initial daily energy requirements, the RME decreased by approximately 40% after 24 weeks of the diet. 4. Alterations in cellular immunity, complement activity, cytokine production, and antibody affinity have all been demonstrated in animal or human studies. 5. However, based on the available data, it is difficult to determine whether malnutrition increases the rate of infection.

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6. . . . malnutrition leads to decreased collagen synthesis and likely increases the risk of wound complications. The ability to reverse these changes and the best method of doing so remains in question. 7. In the neurologically injured patient, a marked negative nitrogen balance, diminished lipolysis, and the development of relative glucose intolerance characterize the hypermetabolic state. 8. . . . we know that most well-nourished patients tolerate several days of postoperative semi-starvation without apparent adverse effects. 9. . . . supplemental nutrition may be beneficial to mildly malnourished patients if they are not expected to resume feeding within 7 days. Severely malnourished patients should receive some form of nutrition within 1 to 3 days. Continued

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10. Typically, 25 to 30 kcal/kg ideal body weight provide an adequate estimate of caloric needs, with more precise estimates or direct measurement recommended for patients who will require long-term support. 11. Based on the available data, we recommend monitoring carbohydrate intake and administering supplemental insulin as needed to keep the serum glucose between 80 and 120 mg/dL in nondiabetics, to avoid possible worsening of neurologic outcome following brain injury. 12. The omega-6 fatty acids, primarily linoleic acid, are precursors of arachidonic acid, giving rise to potent inflammatory mediators, which may have a pathologic role in sepsis and multi-organ failure. Omega-3

References 1. Cahill GF Jr.: Starvation in man. N Engl J Med 1970;282:668–675. 2. Grande F: Man under caloric deficiency. In Dill DB (ed): Handbook of Physiology. Washington DC, American Physiological Society, 1964, pp 911–937. 3. Fricker J, Rozen R, Melchior JC, et al: Energy-metabolism adaptation in obese adults on a very-low-calorie diet. Am J Clin Nutr 1991;53:826– 830. 4. Danforth E, Burger AG: The impact of nutrition on thyroid hormone physiology and action. Annu Rev Nutr 1989;9:201–227. 5. Shetty PS, Kurpad AV. Role of the sympathetic nervous system in adaptation to seasonal energy deficiency. Eur J Clin Nutr 1990;44[Suppl 1]:47–53. 6. Ravussin E, Lillioja S, Anderson TE, et al: Determinants of 24-hour energy expenditure in man. Methods and results using a respiratory chamber. J Clin Invest 1986;78(6):1568–1578. 7. Patrick J, Golden MHN: Leukocyte electrolytes and sodium transport in protein energy malnutrition. Am J Clin Nutr 1977;30:1478. 8. Keys A, Brozek J, Henschel A, et al: The Biology of Human Starvation. Minneapolis, University of Minnesota Press, 1950. 9. Moran L, Custer P, Murphy G, Grant J: Nutritional assessment of lean body mass. JPEN 1980;4:595. 10. Grant JP: Clinical impact of protein malnutrition on organ mass and function. In Blackburn GL, Grant JP, Young VR (eds): Amino Acids: Metabolism and Medical Applications. Boston, John Wright, 1983, pp 347–358. 11. Viteri FE, Schneider RE: Gastrointestinal alterations in protein-calorie malnutrition. Med Clin North Am 1974;58:1487–1505. 12. Adibi SA, Allen ER: Impaired jejunal absorption rates of essential amino acids induced by either dietary, calorie, or protein deprivation in man. Gastroenterology 1970;54:404–413. 13. Weissman C, Askanazi J, Rosenbaum S, et al: Amino acids and respiration. Ann Intern Med 1983;98(1):41–44. 14. Doekel RC, Zwillich CW, Scoggin CH, et al: Clinical semi-starvation: Depression of the hypoxic ventilatory response. N Engl J Med 1976;295: 358–361. 15. Chandra RK, Kumari S: Nutrition and immunity: An overview. J Nutr 1994;124[Suppl]:1433S. 16. Studley HO: Percentage weight loss, a basic indicator of surgical risk in patients with chronic peptic ulcer. JAMA 1936;106:458. 17. Rhoads JE, Alexander CE. Nutritional problems of surgical patients. Ann NY Acad Sci 1955;63:268–275.

fatty acids give rise to less potent inflammatory mediators and may be beneficial in controlling the inflammatory response. 13. BTL does occur in humans and could potentially lead to distal infection. However, short-term absence of enteral nutrition in humans causes neither gut atrophy nor increased permeability. At this time, the relationship between BTL and enteral nutrition remains unclear. 14. Based on the available data, we recommend starting early enteral feeding in patients with neurologic injury. If full nutrition cannot be tolerated within 24 to 48 hours, parenteral nutrition can be added as a supplemental or complete source of nutrition.

18. Grahm TW, Zadrozny DB, Harrington T. The benefits of early jejunal hyperalimentation in the head-injured patient. Neurosurgery 1989;25: 729–735. 19. Buzby GP: The Veterans Affairs Total Parenteral Nutrition Cooperative Study Group: Perioperative total parenteral nutrition in surgical patients. N Engl J Med 1991;325:525–532. 20. Haydock DA, Hill GL: Improved wound healing response in surgical patients receiving intravenous nutrition. Br J Surg 1987;74:320–323. 21. Schroeder D, Gillanders L, Mahr K, et al: Effects of immediate postoperative enteral nutrition on body composition, muscle function, and wound healing. JPEN 1991;15:376–383. 22. Daly JM, Vars HM, Dudrick SJ: Effects of protein depletion on strength of colonic anastomoses. Surg Gynecol Obstet 1972;134:15–21. 23. Irvin TT, Hunt TK: Effect of malnutrition on colonic healing. Ann Surg 1974;180:765–772. 24. Irvin TT: Effects of malnutrition and hyperalimentation on wound healing. Surg Gynecol Obstet 1978;146:33–37. 25. Heatley RV, Williams RHP, Lewis MH: Pre-operative intravenous feeding: A controlled trial. Postgrad Med J 1979;55:541–545. 26. Mueller JM, Brenner U, Dienst C, et al: Preoperative parenteral feeding in patients with gastrointestinal carcinoma. Lancet 1982;1:68–71. 27. Illig KA, Ryan CK, Hardy DJ, et al: Total parenteral nutrition-induced changes in gut mucosal function: Atrophy alone is not the issue. Surgery 1992;112:631–637. 28. Celaya-Pérez S: Soporte nutricional en situaciones especiales. En: Guía práctica de nutrición artificial. Zaragoza, Venus Industrias Gráficas, 1992, pp 216–221. 29. Bistrian BR, Blackburn GL, Vitale J, Cochran D, Naylor J: Prevalence of malnutrition in general medical patients. JAMA 1976;235:1567–1570. 30. Dabrowski GP, Rombeau JL: Practical nutritional management in the trauma intensive care. Surg Clin North Am 2000;80(3):921–932. 31. Pennington CR: Disease and malnutrition in British hospitals. Proc Nutr Soc 1997;56:393–407. 32. Weir JB: New method for calculating metabolic rate with special reference to protein metabolism. J Physiol (London) 1949;109:1–6. 33. Harris JA, Benedict FG: Standard basal metabolism constants for physiologists and clinicians. A biometric study of basal metabolism in man. Philadelphia, JB Lippincott, 1919. 34. A.S.P.E.N. Board of Directors: Guidelines for the use of parenteral and enteral nutrition in adult and pediatric patients. JPEN 1993;17(suppl 4):1SA. 35. Rapp RP, Young B, Twyman D, et al: The favorable effect of early parenteral feeding on survival in head-injured patients. J Neurosurg 1983;58:906–912.

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Chapter 20  36. Young B, Ott L, Twyman D, et al: The effect of nutritional support on outcome from severe head injury. J Neurosurg 1987;67:668–676. 37. Hadley MN, Grahm TW, Harrington T, et al: Nutritional support and neurotrauma: A critical review of early nutrition in forty-five acute head injury patients. Neurosurgery 1986;19:367–373. 38. Van Way CW III: Nutritional support in the injured patient. Surg Clin North Am 1991;71:537–548. 39. Garrel DR, Jobin N, de Jonge LH: Should we still use the HarrisBenedict equations? Nutr Clin Pract 1996;11:99–103. 40. Moore R, Najarian MP, Konvolinka CW: Measured energy expenditure in severe head trauma. J Trauma 1989;29:1633. 41. Clifton GL, Robertson CS, Grossman RG, et al: The metabolic response to severe head injury. J Neurosurg 1984;60:687. 42. Van den Berghe G, Wouters P, Weekers F, et al: Intensive insulin therapy in critically ill patients. N Engl J Med 2001;345(19):1359–1367. 43. D’Alecy LG, Lundy EF, Barton KH, et al: Dextrose containing intravenous fluid impairs outcome and increases death after eight minutes of cardiac arrest and resuscitation in dogs. Surgery 1986;100:505– 511. 44. Lundy EF, Kuhn JE, Kwon JM: Infusion of 5% dextrose increases mortality and morbidity following six minutes of cardiac arrest in resuscitated dogs. J Crit Care 1987;2:4–14. 45. Young B, Ott L, Dempsey R, et al: Relationship between admission hyperglycemia and neurologic outcome of severely brain-injured patients. Ann Surg 1989;2210(4):466–472. 46. Rovlias A, Kotsou S: The influence of hyperglycemia on neurological outcome in patients with severe head injury. Neurosurgery 2000;46(2): 335–342. 47. Beale RJ, Bryg DJ, Bihari DJ: Immunonutrition in the critically ill: A systematic review of clinical outcome. Crit Care Med 1999;27: 2799–2805. 48. Holden WD, Krieger H, Levey S, Abbott WE: The effect of nutrition on nitrogen metabolism in the surgical patient. Ann Surg 1957;146:563– 579. 49. Rodriguez DJ, Clevenger FW, Osler TM, et al: Obligatory negative nitrogen balance following spinal cord injury. JPEN 1991;15(3):319– 322. 50. Cox SA, Weiss SM, Posuniak EA, et al: Energy expenditure after spinal cord injury: An evaluation of stable rehabilitation patients. J Trauma 1985;25:419–423. 51. Demling RH, DeBiasse MA: Micronutrients in critical illness. In Lang CH, Abumrad NN (eds): Critical Care Clinics: Nutrition in the Critically Ill Patient. Philadelphia, WB Saunders, 1995. 52. Li L, Kudsk K, Gocinski B, et al: Effects of parenteral and enteral nutrition on gut-associated lymphoid tissue. J Trauma 1995;39:44–51. 53. Helton WS, Garcia R: Oral prostaglandin E2 prevents gut atrophy

54. 55.

56. 57. 58. 59.

60.

61.

62.

63.

64.

65.

66.

67.

68.

69.

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during intravenous feeding but not bacterial translocation. Arch Surg 1993;128:178–184. Alverdy JC, Aoys E, Moss GS: Total parenteral nutrition promotes bacterial translocation from the gut. Surgery 1988;104:185–190. Shou J, Lappin J, Minnard EA, et al: Total parenteral nutrition, bacterial translocation, and host immune function. Am J Surg 1994;167: 145–150. Dietch EA: Simple intestinal obstruction causes bacterial translocation in man. Arch Surg 1989;124:699–701. Brooks SG, May J, Sedman P, et al: Translocation of enteric bacteria in humans. Br J Surg 1993;80:901–902. Sedman PC, Macfie J, Sagar P, et al: The prevalence of gut translocation in humans. Gastroenterology 1994;107:643–649. Guedon C, Schmitz J, Lerebours E, et al: Decreased brush border hydrolase activities without gross morphologic changes in human intestinal mucosa after prolonged total parenteral nutrition of adults. Gastroenterology 1986;90:373–378. Elia M, Goren A, Behrens R, et al: Effect of total starvation and very low calorie diets on intestinal permeability in man. Clin Sci 1987;73: 205–210. Moore FA, Feliciano DV, Adrassy RJ, et al: Early enteral feeding, compared with parenteral, reduces postoperative septic complications: The results of a meta-analysis. Ann Surg 1992;216:172–183. Strong RM, Condon SC, Solinger MR, et al: Equal aspiration rates from postpylorus and intragastric-placed small-bore nasoenteric feeding tubes: A randomized, prospective study. JPEN 1992;16:59–63. Spain DA, DeWeese RC, Reynolds MA, Richardson JD: Transpyloric passage of feeding tubes in patients with head injuries does not decrease complications. J Trauma 1995;39:1100–1102. Ott L, Young B, Phillips R, et al: Altered gastric emptying in the head-injured patient: Relationship to feeding intolerance. J Neurosurg 1991;74:738–742. Saxe JM, Ledgerwood AM, Lucas CE, Lucas WF: Lower esophageal sphincter dysfunction precludes safe gastric feeding after head injury. J Trauma 1994;37(4):581–586. Kudsk KA, Croce MA, Fabian TC, et al: Enteral versus parenteral feeding: Effects on septic morbidity after blunt and penetrating abdominal trauma. Ann Surg 1992;215:503–513. Moore FA, Moore EE, Jones TN, et al: TEN versus TPN following major abdominal trauma—reduced septic morbidity. J Trauma 1989;29:916– 923. Socolow EL, Woeber KA, Purdy RH, et al: Preparation of I-131-labeled human serum prealbumin and its metabolism in normal and sick patients. J Clin Invest 1965;44:1600–1609. Twyman D: Nutritional management of the critically ill neurologic patient. Crit Care Clin 1997;13(1):39–49.

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Chapter 21 Neurologic Monitoring in the Neurointensive Care Unit Christoph N. Seubert, MD and Michael E. Mahla, MD

Introduction Monitoring the brain is a natural extension of medical care in neurointensive care units (neuro-ICU). Patients in neuro-ICUs have two important things in common. First, their basic neurologic examination and level of consciousness are frequently abnormal. Second, improvement or progression of their disease processes leads to changes in their neurologic status. Careful, repeated, and reliable assessment of their neurologic status therefore underlies therapeutic decisions and may affect ultimate outcome. Improvements in the disease process present opportunities to decrease the level of physiologic support and to initiate interventions for rehabilitation. Conversely, progression of the disease processes may require increased levels of physiologic support and additional medical or neurosurgical interventions to mitigate secondary injury to the central nervous system (CNS). As discussed in chapter 15, preventing such secondary injury is a central focus of neurointensive care. Neurophysiologic monitoring is performed on the premise that normal function and the ability to compensate for pathophysiologic processes cease before irreversible structural damage ensues. Removal of the secondary insult should allow continued structural integrity and eventual recovery of function. In the CNS, this therapeutic window may extend from a few minutes to a few hours, depending on the pathophysiologic reason that function failed and on the monitoring modality used to assess the change.

Monitoring modalities fall into two broad categories. The first aims to assess function of the nervous system. Examples of such monitoring modalities are the clinical examination, the electroencephalogram (EEG), and the recording of evoked potentials. The second category aims to determine the adequacy of cerebral perfusion. Examples are transcranial Doppler ultrasonography, near infrared spectroscopy, and jugular venous bulb oximetry. No single monitoring technique addresses all questions raised by a given patient. Multimodal approaches that combine assessment of cerebral blood flow, cerebral function, and intracranial pressure with appropriate respiratory and cardiac monitoring show the greatest promise of prospectively aiding therapeutic decision making. As clinicians decide what monitoring is used to facilitate patient treatment, neurologic monitoring should not be held to a higher standard than other monitors. In fact, no monitor in the operating room (OR) or ICU has been shown to change or reliably predict outcome. The electrocardiogram (ECG) used in the OR can detect only a small fraction of myocardial ischemia that occurs during surgery, even if it is watched continuously (which it often is not!). Certainly, patients with intraoperative ECG-detected ischemia have a higher likelihood of perioperative myocardial infarction (MI),1,2 but ECG detection of intraoperative ischemia neither reliably predicts MI, nor does its absence guarantee that an MI will not subsequently occur. Likewise, a prospective study of 20,000 patients failed to demonstrate an outcome advantage to the routine use of intraoperative pulse 619

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oximetry.3 Even in the absence of such studies, both ECG monitoring and pulse oximetry are standard monitors in the OR and ICU. Most clinicians who routinely use neurologic monitoring have become convinced of its utility, not because of prospective randomized studies, but rather, like other monitors, by cases in which major changes in therapy guided by monitoring have resulted in good outcome. For example, in a case series of 73 patients continuously monitored with EEG, Jordan and colleagues found that major therapeutic decisions were solely based on or significantly influenced by the EEG in 82% of these individuals.4 Numerous retrospective studies have examined the question whether neurologic monitoring accurately reflects nervous system function and predicts outcome. Most of these studies use either EEG, somatosensory-evoked potentials (SSEPs), or jugular venous oxygen saturation, and the results are compelling. For example, the bilateral persistence of a cortical response to SSEPs from median nerve stimulation has so far consistently predicted eventual awakening from hypoxic coma.5 Likewise, jugular venous oxygen saturation values outside the normal range are associated with worse neurologic outcome in patients with traumatic brain injury.6–9 However, cases have been reported in which neurologic monitoring was used and its results were at variance with the clinical status of the patient. Examples are reports of isoelectric EEG recordings from comatose patients not exposed to barbiturates, who recovered some neurologic function,10 just as there are reports of persistent EEG activity in patients who are clinically brain dead.11 Jugular venous oxygen saturation may be within the normal range, despite severely decreased cerebral blood flow, if the extracranial venous contribution balances the severely decreased cerebral venous drainage in the setting of severely increased intracranial pressure or if oxygen extraction is minimal because of extensive brain trauma.12 Yet another example is provided by patients who show normal or near-normal values in cerebral oximetry despite documented absence of intracranial blood flow.13,14 Given the extensive experience with neuromonitoring, it would be surprising if such cases were not reported. Even if all these cases are valid, the number of such events is small compared to the total number of cases monitored. Some of these cases were generated by an inappropriate use of the monitor, in which the monitored part of the CNS did not correspond to the part of the nervous system at risk, or by inadequate quality control resulting in technical problems with the recordings. Some of these reports, however, did reflect true false-negative results and have improved our understanding of how well the function of the monitored pathway predicts function of adjacent areas of the brain and spinal cord15 or how well the monitored parameter reflects the status of the CNS. Thus, we are better able to define the limitations of neurologic monitoring. Cases in which a perceived or real failure of the monitor occurred must be kept

in perspective. When used carefully and appropriately, neurologic monitoring appears to be useful in the early detection of a change in monitored function, and the initiation of therapeutic interventions to prevent permanent neurologic injury.

Monitors of Function When oxygen delivery to the brain falls below a level sufficient to meet the cerebral metabolic requirement for oxygen (CMRO2), function fails. Because function is disrupted before cellular integrity is lost, monitors of function provide early warning of inadequate oxygen supply and provide opportunity to correct this problem before irreversible damage occurs. Such monitors can be used to guide therapy when the CNS may be compromised by the natural progression of a disease process, for example, worsening cerebral edema after cardiac arrest or head trauma, or by a complication of a disease, for example, vasospasm in the wake of a subarachnoid hemorrhage. Alternatively, brain function may be abnormal despite adequate oxygen supply due to factors intrinsic or extrinsic to the brain. Examples of the former are convulsive or nonconvulsive seizures and postictal states, examples of the latter are metabolic abnormalities such as hepatic encephalopathy or intoxications. In a given patient, such depressant factors may coexist with inadequate oxygen supply. For example, seizure activity, which frequently occurs after delayed resuscitation from cardiac arrest, may coexist with and compound posthypoxic cerebral edema. The Neurologic Examination Of all neurophysiologic monitoring modalities, the neurologic examination of a conscious patient allows for the most comprehensive assessment of CNS function. It requires no special equipment or technologists to operate the equipment and can be applied continually, as needed. It should include a repeated focused assessment of CNS structures at risk in a given patient and a general overview such as the documentation of the level of consciousness, for example with the Glasgow Coma Scale, motor responses to verbal or painful stimuli, and evaluation of brainstem reflexes. In practice, however, the neurologic examination has important limitations. First, patients in neurointensive care frequently present in a state or with diseases that severely limit the information obtainable by a neurologic exam. Second, neurologic evaluations are usually done discontinuously and by examiners of varying skill; therefore, they may miss evolving changes or give variable results. Third, the results of neurologic examinations are confounded and constrained by therapeutic interventions that are frequently used in the ICU such as endotracheal intubation, sedatives/hypnotics, analgesics, or neuromuscular blocking

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agents. For example, the decrease and eventual absence of a pupillary light response in the syndrome of a transtentorial herniation will be preceded by extensive changes in the level of consciousness and higher cortical functions, which will be missed in an intubated patient treated with neuromuscular blocking agents. One area, which has brought both the merits as well as the limitations of the neurologic examination into clear focus, is determination of brain death for purposes of organ donation or withdrawal of support. Because the clinical determination of brain death requires a comprehensive and methodical assessment of the patient,16 its steps may serve as a guide to the neurologic examination of a comatose patient in the neuro-ICU and will be summarized here. An algorithm for the determination of brain death is provided in the Appendix at the end of the chapter. The first step in the neurologic examination for the determination of brain death is the determination of coma, that is, lack of responsiveness to external stimuli due to unconsciousness. Coma is typically assessed by searching for reproducible eye and motor responses to standard painful stimuli such as nail bed pressure and pressure on the supraorbital nerve or temporomandibular joint.17 Motor responses elicited by the examination need to be differentiated from spontaneous movements during the exam. The latter are typically brief, slow movements that originate from the spinal cord and do not become integrated into decerebrate or decorticate responses. Only rarely are they reproducible on repeat testing. Reproducible partial eye opening that failed to reveal the iris has been described in response to a peripheral painful stimulus in a patient who fulfilled clinical criteria of brain death.18 Conditions that may confound the clinical diagnosis of coma are listed in Table 21-1. In addition to considering such confounding conditions, the diag-

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nosis of coma should be consistent with imaging studies or the overall clinical picture. The next step in the neurologic examination is the assessment of brainstem function. As in the assessment of the level of consciousness, direct trauma to either afferent or efferent structures needs to be considered before any test results of brainstem function are considered negative. Typical tests, their afferent and efferent pathways, and potentially interfering clinical conditions, other than direct trauma to the tested pathways, are summarized in Table 21-2. To complete the diagnosis of brain death, an apnea test is performed. It tests the response to an acute decrease in the pH of cerebrospinal fluid due to hypercarbia. Hypercarbia is induced by disconnecting mechanical ventilation, while continued oxygenation is assured by both preoxygenation and apneic oxygenation. Absence of respiratory movements at an arterial pCO2 of 60 mm Hg or after an increase in pCO2 of 20 mm Hg is consistent with brain death. Arterial hypotension due to loss of arterial and autonomic tone is the most frequent complication of apnea testing.19 While such hypotension corroborates the diagnosis of brain death, it makes the hemodynamic stability required for apnea testing difficult to attain. The apnea test may trigger movement responses, which reflect residual spinal activity.20 Once all these criteria for brain death are met, either an observation period followed by repeat assessment or a confirmatory test is used to reach a final diagnosis (see Appendix). Cerebral angiography is the highest standard for reaching a final diagnosis. Contrast media are injected in the aortic arch and distribute to the external carotid circulation, whereas the internal carotid and vertebral arteries fill only to the level of the skull base and atlanto-occipital junction, respectively. Similar findings can be obtained with magnetic resonance angiography or with single-photon emission

Table 21-1  Neurologic States Resembling Brain Death Disease State

Diagnostic Aids

Comments

Hypothermia

Core temperature <32°C Osborne waves on ECG Drug screening

May cause central nervous system depression up to clinical brain death

Acute poisoning

Metabolic encephalopathy Akinetic mutism Locked-in syndrome

Serum concentration measurements Laboratory testing Intact lower brain stem function Intact sleep-wake cycle Clinical course and imaging studies

In differentiating from brain death consider antidote and/or document sub therapeutic drug concentration and/or wait for four elimination half-lives Direct central nervous system depressants may confound confirmatory testing of brain death because of CMRO2/CBF coupling Imaging studies should document structural central nervous system changes Imaging study shows frontal or mesencephalic brain lesion Central locked-in syndrome: corticobulbar and corticospinal tracts are interrupted at the level of the base of the pons, vertical eye movements are intact Peripheral locked-in syndrome: Guillain-Barré syndrome, advanced amyotrophic lateral sclerosis, neuromuscular blocking agents, organophosphate poisoning

CBF, cerebral blood flow; CMRO2, Cerebral metabolic requirement for oxygen; ECG, electrocardiogram. From Wijdicks EF: Brain Death. Philadelphia, Lippincott, Williams & Wilkins, 2001.

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Table 21-2  Neurologic Examination of Brainstem Function Brainstem Reflex

Afferent Path

Efferent Path

Caveats Not confounded by systemic drugs; absence may be caused by prolonged administration of neuromuscular blocking agents.* Confounded by damage from ototoxic drugs; cervical spine trauma may preclude testing of the oculocephalic reflex; voluntary ocular movements are sometimes the only finding that differentiates a “locked-in” syndrome from brain death.

Pupillary light reaction

II

III

Ocular movements (oculocephalic reflex or caloric nystagmus)

VIII

III, VI

Corneal reflex/pressure on supraorbital nerve Gag

V

VII

IX

IX, X

Cough

X

X, cervical roots

May be difficult to assess in orotracheally intubated patient. Best tested by assessing the response to tracheal suctioning.

*Schmidt JE, Tamburro RF, Hoffman GM: Dilated nonreactive pupils secondary to neuromuscular blockade. Anesthesiology 2000;92:1476–1480.

computed tomography (SPECT). EEG and transcranial Doppler (TCD) are also frequently used as confirmatory tests. Their role will be discussed in greater detail in the following section. Central Nervous System Electrical Activity The function of some motor and sensory pathways as well as the spontaneous electrical activity of the cerebral cortex are easily monitored in the ICU by motor- and sensoryevoked potentials and EEG, respectively. These pathways and spontaneous electrical activity of the cerebral cortex, however, reflect the function of only a portion of the entire nervous system. Changes in one monitored parameter may imply damage to other nearby areas of the nervous system; however, damage to unmonitored portions of the nervous system may occur without detection. Thus, when areas of the nervous system that cannot currently be monitored are at risk, “false-negative” monitoring patterns should be expected. The Electroencephalogram Theoretical Basis. The EEG recorded from the scalp is a summation of excitatory (EPSP) and inhibitory (IPSP) postsynaptic potentials produced in the pyramidal layer of the cerebral cortex. EPSPs or IPSPs are caused by spontaneous neurotransmitter release from the presynaptic nerve terminal. In the case of an EPSP, the quantity of neurotransmitter is insufficient to trigger an action potential in the postsynaptic neuron. These EEG signals are larger in children and adolescents than in adults and range in amplitude from less than 10 mV to around 100 mV. Due to this small signal size, EEG recordings are prone to a variety of artifacts (Fig. 21-1).21

Figure 21-1. Common EEG artifacts.

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Figure 21-2. The International Ten-Twenty Electrode System for the placement of EEG electrodes. The TenTwenty System places electrodes along circumferences and lines that are measured from easily identifiable reference points of a patient’s skull. Thus, the montage is not only reproducible and proportional to the size of the patient’s head, but also corresponds relatively closely to specific underlying brain structures.

A single channel of EEG almost exclusively reflects the functional activity of the cortex directly beneath it. As a consequence, multichannel recordings are necessary to adequately survey cortical function. Furthermore, spatial resolution is limited so that a small lesion, for example, a lacunar infarct, may not be detectable. Finally, because only cortical activity generates the EEG, isolated subcortical processes may not be reflected in the EEG at all. As with recording of the ECG, EEG electrodes are placed in a standardized fashion so that tracings from one individual may be compared either with later tracings from the same individual or with those of other individuals. The International Ten-Twenty Electrode System (Fig. 21-2) places EEG or evoked potential (EP) recording electrodes over specific areas of the cerebral cortex and is based on measurements made between pairs of specific sites on the patient’s head.22 Each recording point is designated with a letter and a number and can often be associated with underlying CNS structures; for example, C3 and C4 are all associated with the motor cortex. By convention, recording electrodes placed over the right hemisphere are evennumbered, those placed over the left are odd-numbered, and midline electrodes are designated by a “z” subscript. These electrodes are connected in pairs to a differential amplification system (Fig. 21-3), and the output is displayed, just as with the ECG, as a plot of voltage versus time. Each EEG channel represents the electrical activity of one electrode pair. The recording of multiple EEG channels simultaneously on paper moving at speeds up to 3 cm.sec-1 creates

Figure 21-3. Diagram of a differential amplification system. The differential amplifier accepts input from two separate electrodes. The (-) input is subtracted from the (+) input and the difference is amplified. If a signal is present in both inputs, differential amplification will cancel out this signal. This amplification characteristic is very useful when recording signals in a hostile electrical environment because noise will be present in both channels and will not be amplified. By the same token, a disconnected electrode or a difference in impedance between the input signals will lead to amplification of background noise in that channel.

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a large amount of on-line data (Fig. 21-4). Although these data contain a wealth of useful information, for example, absence or presence of a sleep-wake rhythm or seizure activity, it is not practical for the intensivist to extract these data in addition to all other tasks, and a neurophysiologist (e.g., PhD, or a physician-neurologist or anesthesiologist) with or without a technician must monitor the EEG output for maximum utility. Recognition of specific EEG states such as burst suppression or generalized seizures can be accomplished by ICU nurses trained to interpret EEG in the context of the patient’s status.4 Reduction in the number of channels or simplification and suitable formatting of data may enable intensivists with appropriate training to use the EEG for monitoring without the aid of a technologist or neurologist. The display can be simplified through signal processing techniques, which include power spectrum analysis, frequency analysis, filtering, and rectification and displayed in time-compressed formats such as compressed spectral array (CSA) and density spectral array (DSA) (Fig. 21-5). Functionally, most of these displays convert the standard plot of voltage versus time to a plot of frequency versus time. These techniques eliminate some of the morphologic information that is helpful in diagnosing and managing seizures. Further data reduction to single numerical parameters facilitates use of EEG data for patient care. Examples of such single-parameter measures are given in Table 21-3. Except for gross artifact rejection by voltage criteria, these simplified monitors do not yet have the ability to distinguish brain activity from other biologic

signals (e.g., ECG), noise, or artifact. Noise/artifact is processed just as if it were electrical brain activity (see Figs. 21-1 and 21-3). Therefore, the retention of access to the real time, unprocessed EEG is very important. Likewise, correlation with the clinical status is necessary in longterm recording in an artifact-prone environment such as the ICU. It is not clear just how much data reduction can occur before the sensitivity of EEG monitoring is compromised. Such data reduction occurs when the number of monitored channels is reduced or when processing of the signal is used to simplify interpretation. The number of EEG channels depends on the clinical question to be answered. While 16 to 21 channels are necessary to localize and document focal seizure activity, monitoring of burst suppression during barbiturate administration can be carried out with only two channels.23 Similarly, electrodes placed strategically over the watershed distribution of the middle cerebral and anterior cerebral arteries can improve the sensitivity of EEG monitoring in the context of hemispheric blood flow to greater than 90%, even when only four channels are used.24 A limited number of channels (8 to 11) is usually sufficient for general monitoring, for example, in head trauma or toxic coma. In this context, a polygraphic record that includes other physiologic parameters such as ECG, respiration, and body and eye movements is helpful to (1) separate artifacts from changes in cerebral activity and (2) improve diagnostic accuracy by relating clinical events (sleep cycles, arousal, abnormal movement, etc.) to the EEG.23

Figure 21-4. Unprocessed 16-channel EEG. Continuous monitoring of unprocessed EEG generates a very large amount of on-line data for analysis.

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Figure 21-5. Processed EEG. The most common types of processed EEG are compressed spectral array (top) and density spectral array (bottom).

For pattern recognition in the EEG, the complex waveforms are described in terms of frequency (cycles sec-1 = Hertz[Hz]) and amplitude (voltage). Four basic EEG rhythms or frequency patterns are analyzed (Fig. 21-6): Delta (0 to 4 Hz); theta (4 to 8 Hz); alpha (8 to 13 Hz); and beta (>13 Hz). Delta rhythm, or marked slowing, occurs during deep sleep, deep anesthesia, and many pathologic states such as ischemia, drug overdose, or severe metabolic derangements. Theta rhythm, or moderate slowing, is commonly seen during general anesthesia and may occur during the same pathologic states as delta rhythm.

Alpha rhythm can be recorded, mainly over the occipital region, in an alert, relaxed patient whose eyes are closed. During lighter surgical planes of anesthesia and in a subset of coma patients, this 8 to 13 Hz activity can be recorded over much of the cortex, especially in the anterior leads. Beta rhythm accompanies mental concentration or may be induced with low doses of many sedative-hypnotic drugs, such as barbiturates or benzodiazepines. Deep anesthesia, ischemia, or other pathologic states abolish both alpha and beta frequencies, following which slower frequencies predominate.

Table 21-3  Single-Parameter EEG Measurements Parameter Total EEG power Median frequency/ spectral edge frequency Asymmetry index Suppression ratio

Relative alpha activity (RA) Alpha/delta Ratio Bispectral Index

Relationship to Raw EEG EEG frequency (determined by Fourier transformation) below which 50%–95% of the EEG power lies Ratio of burst suppressed EEG epochs to total EEG Ratio of EEG activity in the frequency band from 6 Hz to 14 Hz, relative to the total activity from 1 Hz to 20 Hz Proprietary algorithm to determine the synchrony between frequency bands

Clinical Application Increased in generalized seizures Decreased by ischemia and sedatives Variability over time is prognostically good Can indicate global hemispheric ischemia Useful to monitor the physiologic endpoint of barbiturate coma Spontaneous burst suppression correlates with severe irreversible brain injury* RA is variable, if blood supply is normal. Absence of RA variability indicates ischemia† Decreases with depressed level of consciousness Assess the degree of sedation/anesthesia Usefulness for patients with neurologic abnormalities is unclear

EEG, electroencephalogram. *Vespa PM, Nenov V, Nuwer MR: Continuous EEG monitoring in the intensive care unit: Early findings and clinical efficacy. J Clin Neurophysiol 1999;16:1–13. † Nespa PM, Nuwer MR, Juhasz C, et al: Early detection of vasospasm after acute subarachnoid hemorrhage using continuous EEG ICU monitoring. Electroencephalogr Clin Neurophysiol 1997;103:607–615.

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Figure 21-6. Basic EEG frequency patterns: Beta (>13 Hz), alpha (8 to 13 Hz), theta (4 to 8 Hz), and delta (<4 Hz).

Changes in EEG amplitude normally result from synchronization or desynchronization of cortical electrical activity. Larger, synchronized EEG activity is seen during sleep, surgical anesthesia, or seizures. However, very deep levels of anesthesia cause a loss in EEG amplitude secondary to direct depression of cortical neuronal activity. Awakening usually desynchronizes the EEG and produces a decrease in amplitude, with the appearance of higher frequency patterns such as beta. In general, more complex (higher) functions are represented by faster, less synchronized (lower voltage) activity. For example, mental concentration is accompanied by the appearance of beta frequencies. Table 21-4 provides a summary of frequent EEG findings in ICU patients.

Electroencephalogram and Regional Ischemia. Electroencephalographic activity, that is, cortical electrical activity, requires roughly 50% of the total oxygen consumed by the brain; the remaining 50% is needed to maintain cellular integrity. When oxygen delivery is compromised by either hypoxemia or decreased blood supply, oxygen that ordinarily would be used to produce electrical activity instead will be diverted to maintain cellular integrity. Gray matter receives approximately 80% of the cerebral blood flow (CBF). Therefore, regional cortical blood flow closely correlates with regional CBF. Validation of the EEG as a monitor for the adequacy of regional CBF25 comes from large series of patients undergoing carotid endarterectomy. In these patients, the EEG was compared with regional CBF determined by using the Xenon (133Xe) washout method. Normal gray-white CBF averages 50 mL·100 g-1 min-1. The EEG begins to become abnormal when CBF decreases to 20 mL·100 g-1 min-1.25 Cellular survival is not threatened until CBF falls to 12 mL·100 g-1 min-1. Thus, a margin of safety is present between the time at which the EEG becomes abnormal and that at which cellular damage begins to occur. Severe anemia and decreases in oxygen saturation also decrease oxygen delivery. The EEG activity becomes abnormal once increased blood flow cannot compensate for decreased arterial oxygen content. Slowing of EEG activity reflects decreased oxygen delivery (Fig. 21-7). Interventions based on recognition of these patterns may be made in much the same fashion as interventions are made after recognition of ECG changes. Unfortunately, changes in EEG frequency and amplitude may also be caused by administration of anesthetic drugs

Table 21-4  EEG Features Frequently Encountered in the Neurointensive Care Unit Additional Patterns Background Activity

Symmetry

Normal alpha (occipital, reactive to eye opening) “Alpha coma” (frontal, areactive) Drug-induced activities in the alpha range (fronto-central) Theta “Theta coma”

Asymmetry (not posterior)

Beta (symmetric/asymmetric) Delta (diffuse) Delta (focal) Spindles (symmetric/asymmetric)

Posterior suppression Reactivity: voltage reduction K-complexes prolonged bursts of delta waves

Variability

Nonpathologic K-complexes

Pathologic Intermittent rhythmical delta activity (IRDA) (frontal or occipital): related to stimulation unrelated to stimulation Triphasic waves Episodic low-amplitude events (ELAE) Alternating pattern (related to Cheyne-Stoke respiration) Epileptiform activity: Generalized Periodic lateralized epileptiform discharges (PLEDs) Focal spikes Periodic spiking Low voltage pattern Electrocerebral silence

Adapted from Guerit JM: Medical technology assessment EEG and evoked potentials in the intensive care unit. Neurophysiol Clin 1999;29:301–317.

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vasospasm were increases in intracranial pressure (ICP), recurrent hemorrhage, and an embolic stroke during an endovascular procedure. Of note, EEG deterioration preceded clinical vasospasm by more than 2 days in more than half the patients. Similarly, EEG has provided early warning of ischemia in thrombotic stroke.27

Figure 21-7. Schematic representation of the EEG pattern seen in cerebral ischemia.

(Fig. 21-8). A steady level of sedation however, usually produces a stable EEG pattern regardless of the agent used. Continuous EEG monitoring for cerebral ischemia due to arterial vasospasm was used in a cohort of patients who presented with subarachnoid hemorrhage.26 The variability of relative alpha (RA) activity (see Table 21-4) was scored on a four-point scale. After carefully controlling for confounding variables, decreases of RA variability were found to be 100% sensitive, but only 50% specific for cerebral vasospasm as documented by angiography or transcranial Doppler. Clinical events that decreased RA variability in the absence of

Figure 21-8. Comparison of ischemia and anesthetic effect in processed EEG (density spectral array). Top, An EEG change primarily in one channel associated with carotid cross-clamping. Bottom, An EEG change associated with a dramatic change in anesthetic technique. Note that the anesthetic effect is global, while in this case (but not all), the ischemic effect is only regional.

Electroencephalogram and Seizures. Seizures are a common problem in the neuro-ICU. EEG is the technique of choice to either document the presence of seizure activity or conversely to rule out a seizure focus as the cause for abnormal movements such as myoclonia, extrapyramidal movements, infection-related rigors, or decerebrate and decorticate posturing. EEG monitoring should be considered early in a patient with a depressed level of consciousness even in the absence of tonic-clonic movements, especially if the depressed level of consciousness follows a convulsive seizure or is inconsistent with the underlying brain injury. In a series of consecutive patients admitted to a neuro-ICU, nonconvulsive seizures, that is, seizures not detectable by rhythmic movements, were documented in almost 20% of patients.28 A similar incidence of status epilepticus was reported in three additional cohorts of neuro-ICU patients.29–31 In processed EEG, generalized seizures present as an increase in both synchronization and EEG power (Fig. 21-9).32 More subtle features of seizure foci are easily missed on processed EEG. For example, sharp waves, spikes, or spike and dome complexes are best appreciated on raw EEG tracings. With EEG monitors that retain access to the raw EEG, signal extraction technology that is currently used in

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Figure 21-9. Seizure activity documented by processed EEG. This particular monitor (the cerebral function monitor) combines total EEG power and frequency spectrum into a single numerical value that is then displayed across time. The left side of the figure shows generalized seizure activity in a patient in status epilepticus. The seizure activity subsides briefly after administration of diazepam (downward arrow).

epilepsy monitoring units will likely improve diagnostic accuracy.33 Although seizures clearly represent an abnormal functional state, the question whether seizures are by themselves cause for additional brain damage or merely a phenomenon associated with more severe primary brain pathology is undecided.34–36 Status epilepticus may trigger two pathophysiologic mechanisms that may result in detrimental effects: (1) a local increase in CMRO2 with its associated increase in cerebral blood volume, ICP, and brain lactate and (2) a release of excitatory neurotransmitters, which may exacerbate excitotoxic neuronal loss.37 Evidence for a synergistic contribution of seizures to acute brain insults comes from two case series of stroke patients in whom seizures were an independent predictor of in-hospital mortality,38 and status epilepticus increased mortality threefold.39 Similarly, nonconvulsive status epilepticus increased mortality nearly threefold, if it was associated with an acute brain injury rather than a remote history of brain injury.31 Electroencephalogram and Coma. EEG monitoring may help to assess the clinical course and the ultimate prognosis of comatose patients. In determining prognosis, one important caveat has to be kept in mind: If the assessment of prognosis is done acutely and not separated from the insult that precipitated brain dysfunction by more than 24 hours, the EEG may reflect predominantly the effect of the insult and thus may not predict prognosis. Otherwise, spontaneous sustained burst suppression correlates strongly with severe irreversible brain injury.30 Absence of EEG variability portends a high likelihood of persistent vegetative state or death,30,40 whereas spontaneous variability and reactivity to external stimuli are associated with more favorable outcomes.41 Likewise, typical sleep patterns in the EEG or documentation of rapid eye movement sleep correlate with a good prognosis.42,43 A specific indication for EEG monitoring is the therapeutic induction of a coma by barbiturate administration. Because neither blood nor cerebrospinal fluid concentra-

tions of barbiturates reliably predict burst suppression and thus maximal reduction in CMRO2,44 and because barbiturate administration usually requires an increase in cardiovascular support, documentation of a burst suppression pattern on EEG allows the use of the minimal effective dose of barbiturate. EEG plays only a limited role in defining the cause of a comatose state. Focal findings are better clarified by imaging studies than by EEG. Global slowing of the EEG can be seen in a variety of intoxications and metabolic derangements, but lacks etiologic specificity. Likewise, body temperature affects EEG. Hypothermia slows EEG activity and causes electrical silence at 24°C.23 Hyperthermia may also reversibly silence the EEG.45 As indicated previously, EEG is helpful for the differentiation of a postictal state from nonconvulsive status epilepticus. Although some comatose patients present with a distinctive EEG pattern such as alpha rhythm or spindles, their treatment is governed by the underlying etiology of the coma.46,47 Electroencephalogram and Brain Death. EEG remains an

important confirmatory test in brain death. Its appeal results from its wide availability, noninvasiveness and the creation of an objective permanent record for documentation. However, in the ICU, it may be difficult to obtain the required artifact-free recording at the high gain settings.10 Because sensitivity and specificity of EEG in the setting of brain death is only 90%,11 and because the EEG contains very limited and indirect information from subcortical structures and the brainstem, it cannot substitute for a comprehensive assessment of brain death (see the algorithm in the Appendix). Evoked Potentials General Theoretical Concepts. The EEG records spontaneous

electrical activity produced by the CNS. EPs consist of CNS electrical activity that is evoked by sensory (electrical, audi-

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tory, visual) or motor (electrical, magnetic) stimuli. There are three types of sensory EPs: (1) peripheral or cranial nerve, (2) subcortical, and (3) cortical. Motor-evoked potentials (MEPs) are responses of the nervous system to electrical or magnetic stimuli applied directly to the motor cortex or spinal cord and may be recorded from spinal cord, peripheral nerve, and muscle. Sensory EPs are usually quite small in amplitude. Signal averaging must frequently be used to detect EPs because background EEG and other types of biologic noise are much larger than these evoked responses. MEPs are generally much larger and frequently do not require averaging to be readily recorded. Signal Averaging. The EP signals produced by a single stimulus are small and can be easily obscured by background activity including electromechanical interference, EEG, electromyograph (EMG), or ECG activity. Electrical noise generated from equipment in the ICU can be especially problematic and interfere with monitoring of the EP responses of clinical interest. Signal averaging is employed to improve the quality of EP monitoring by reducing or eliminating random background activity such as EEG, EMG, or electrical noise to allow identification of time-locked EP responses that are not random. The signal-to-noise ratio is improved by averaging the square root of the number of epochs (or events) (Fig. 21-10). The required number of epochs in the average is related to the amplitude of the EP response. A response that is small in amplitude requires a greater number of averaged responses to obtain an identifiable, reproducible response. SSEP recordings are generally obtained by averaging 1,000 responses. Brainstem auditoryevoked responses are smaller, subcortically generated signals

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Figure 21-11. Evoked potentials are described in terms of latency (time from delivery of stimulus to onset of response) and amplitude (size in microvolts).

that may require averaging of at least 2,000 responses to obtain an adequate recording. Additional methods used to improve the quality of the EP responses include selection of a stimulus repetition rate that is not synchronized with background activity (e.g., 60-cycle electrical noise), selection of appropriate high and low cut filters, acceptable electrode impedance levels, and elimination of background biologic activity when possible (e.g., administration of muscle relaxant to abolish EMG activity). Descriptive Terms. EPs are described in terms of latency and

amplitude (Fig. 21-11). Latency is the time measured from the application of the stimulus to the point of maximum amplitude of the EP. Some types of EPs have more than one peak. Latency measured between EP peaks (interpeak latency) measures transit time between signal generators along the pathway being stimulated and is often important clinically. Amplitude is defined as the voltage difference between two peaks of opposite polarity or between an EP peak and a reference level representing zero potential. Short-latency EPs predominantly reflect neuronal activity from the brainstem, subcortical sensory pathways, and the primary parietal cortical projection of the somatosensory pathway. Middle-latency EPs obtained from auditory, somatosensory, and visual input reflect neuronal activity of the temporal, frontoparietal, and occipital cortex, respectively. Long-latency exogenous and endogenous EPs depend on multiple cortical generators, and reflect complex cortical processing of sensory signals. Typical components of sensory EPs are summarized in Table 21-5. Somatosensory-Evoked Potentials

Figure 21-10. Signal averaging. The very small evoked potential is obscured by background EEG signal. Signal averaging, however, improves the signal-to-noise ratio by averaging out random background EEG, leaving only the evoked response, which is time-locked to the stimulus.

Theoretical Concepts. SSEPs monitor the function of the somesthetic sensory system, which extends throughout the peripheral and central nervous systems. Thus, peripheral nerve, spinal cord, subcortical, and cortical structures in the brain may be monitored. The somesthetic system carries sensory information including vibration, proprioception, and light touch. A SSEP is generated when repetitive electri-

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Table 21-5  Nervous System Structures Tested by Sensory-Evoked Potentials Sensory-Evoked Potential

Components

Latency (msec)

Corresponding Nervous System Structures

Cognitive EPs

MMN P300 Peak I Peak III Peak VII RAD Erb’s point N13 P14 P14-N20 N20 P22-N30 BAEP I BAEP II-V Middle latency Long latency

<200 >300 <60 <100 150–250 >250 <12 12–16 13–18 <7 18–25 28–35 <2 <6 <90 >100

Auditory cortex Cerebral cortex, brainstem modulation Retina Occipital cortex Associative cortex, brainstem modulation Occipital cortex, brainstem modulation Peripheral nerve Cervical spinal cord Medulla Brainstem and subcortical transmission time Parietal cortex, primary somesthetic area Central and frontal cortex Auditory nerve Pons Auditory cortex Associative cortex, brainstem modulation

Visual EPs (Flash)

Somatosensory EPs (median nerve)

Auditory EPs

EPs, evoked potentials; MMN, mismatch negativity; P#, positive peak and latency (ms); N#, positive peak and latency (ms); RAD, rhythmic after-discharge; BAEP, brainstem auditory-evoked potential. Adapted from Guerit JM: Medical technology assessment EEG and evoked potentials in the intensive care unit. Neurophysiol Clin 1999;29:301–317.

cal stimuli are applied to a peripheral nerve, and many single responses are averaged together to produce the evoked response. Responses may be recorded over the peripheral nerve, nerve plexus, spinal cord, brainstem, and cerebral cortex (Fig. 21-12). Recording sites are related directly to the somesthetic pathway.

As with the EEG, cortical recording electrode locations are based on the Ten-Twenty System22 of electrode placement. The number of recording channels will vary with the clinical scenario. In an ideal situation, recordings should be made over each peripheral nerve being stimulated, the spinal cord rostral to the nerve’s entry, the second cervical verte-

Figure 21-12. Somatosensory-evoked potentials may be recorded anywhere in the nervous system but most commonly over peripheral nerve, spinal cord, and cortex.

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bra, and the opposite cerebral cortex. In addition, if possible, a portion of the somatosensory system not at risk should be monitored as well to help differentiate pathologic changes in SSEPs produced by global factors such as anesthetic drugs or metabolic abnormalities. Generally, these requirements translate into at least four channels of data. The most important use of peripheral nerve recordings is to make certain that a stimulus is actually reaching the CNS. If the SSEP disappears or is not obtainable, one must ensure that the cause is not failure to stimulate adequately. A peripheral nerve response rules out this technical failure. Recordings over the spinal cord also provide insurance against technical failure. In addition, they monitor spinal cord function below the level of electrode placement. Recordings made over the spinal cord are much less sensitive to the effects of anesthetic drugs than recordings made over the cortex. Spinal recordings, however, give little information about cortical function except to show that a stimulus has reached the CNS. Somatosensory Pathway. SSEPs monitor the function of the somatosensory system, which carries sensory information including vibration, proprioception, and light touch, and extends throughout the peripheral and central nervous systems. Electrical stimuli have been shown to activate the largest peripheral nerve sensory fibers (group I) preferentially, which mediate primarily vibratory and proprioceptive sensation. The peripheral nerves most commonly used for stimulation include the median nerve, ulnar nerve, common peroneal nerve, and posterior tibial nerve, depending on which portion of the nervous system is being monitored. The propagated nerve action potential elicited by electrical stimulation can easily be recorded more proximally over the peripheral nerve (e.g., at Erb’s point over the supraclavicular brachial plexus or in the popliteal fossa over the tibial nerve). These signals are usually very large and easy to record. Barring technical problems, their absence is evidence for peripheral neuropathy. Most evidence indicates that upper extremity-evoked potentials are conducted rostrally in the spinal cord via dorsal column pathways (fasciculus cuneatus). The response is conducted across a synapse in the nucleus cuneatus, just above the cervicomedullary junction. This signal usually cannot be recorded near the cells or pathways producing EP. Instead, it is recorded from the skin overlying the spinal cord and brainstem, and thus has a smaller amplitude. After the synapse, the pathway crosses and projects onto the ventral posterolateral nucleus of the thalamus. From there, the response is conducted via the thalamocortical radiations to the postcentral gyrus (somatosensory cortex). Cortical EPs are produced by the summation of EPP and IPP in the pyramidal layer of the cerebral cortex and also have a very small amplitude. These EPs are recorded from scalp electrodes over the cerebral cortex. The amplitude of spontaneous background EEG activity is generally much larger than either subcortical or

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cortical EPs and easily obscures these smaller signals. This problem is solved through the filtering and signal averaging techniques explained previously. In the case of the somatosensory response to lower extremity stimulation, much data suggest that SSEPs are not entirely conducted by the posterior columns, but at least partially, if not substantially, by the lateral funiculus.48–51 Stimulation of the posterior tibial nerve or common peroneal nerve at or above motor threshold activates Group I fibers that synapse and travel rostrally through the dorsal spinocerebellar tract. After synapsing in nucleus Z at the spinomedullary junction, the pathway crosses and travels similarly to the SEP from upper extremity stimulation. Studies with dogs, cats, and monkeys support the concept that lower extremity sensory-evoked potentials are conducted in all quadrants of the spinal cord, but primarily in the dorsal lateral funiculus. This difference is quite important. One of the scenarios where lower extremity SEPs may produce a false-negative monitoring pattern is when damage occurs to the circulation of the anterior spinal artery. If the SEP is carried solely by the posterior columns, they would not be sensitive to damage to the anterior spinal artery. If, however, the SEP is carried in the lateral funiculus, which is supplied by the anterior spinal artery, sensitivity should be quite good. In summary, SSEPs directly monitor the function of the peripheral nerve sensory fibers, the posterolateral portion of the spinal cord, roughly 5% to 10% of the cross-sectional area of the brainstem, and a limited area of subcortical white matter and cortical gray matter. Nearby motor pathways, or pathways related to consciousness, are monitored only by assuming that changes in sensory function will reflect changes in the level of consciousness or in motor function. There are multiple factors other than disease processes of the CNS that may alter the SSEP and confuse the clinical picture. Depression of SSEPs can result from decreased body temperature, hypoxemia, and variations in PaCO2. Likewise, many anesthetic agents affect SSEPs (Table 21-6). Auditory-Evoked Potentials Theoretical Concepts. The brainstem auditory pathway

encompasses the cochlear hair cells, spiral ganglion, eighth cranial nerve, cochlear nuclei, superior olivary complex, lateral lemnisci, inferior colliculus, and medial geniculate thalamic nuclei. The stimulus is a loud, repetitive click delivered to the patient by small ear inserts placed in the external auditory canal (Fig. 21-13). Because recording electrodes cannot be placed close to the brainstem, the brainstem auditory-evoked potential (BAEP) is recorded from the scalp quite far from the generating structures. This far-field potential is thus very small, and as many as 2,000 repetitions may be required to produce a good averaged response. The typical waveform of BAEPs is composed of six or seven positive waveforms when recorded from the vertex, all within

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Table 21-6  Influence of Sedatives and Anesthetics on Somatosensory-Evoked Potentials Anesthetic Drug Barbiturates Volatile agents Narcotics Benzodiazepines Etomidate Ketamine Propofol Muscle relaxants

Peripheral and Subcortical Potential

Latency of Cortical Potential

No change 1 to 2+ D No change 1+ 1 to 4+ D No change No change No change 1+ No change 1+ No change 1+ No change 1 to 2+ D No change to either amplitude or latency, but may improve signal by abolishing EMG-induced noise

Amplitude of Cortical Potential 1 to 3- D 1 to 4- D No change 1 to 22 to 4+ D 1 to 2+ 1 to 2- D

1+: >10% increase 1-: >10% decrease 2+: >20% increase 1-: >20% decrease 3+: >50% increase 1-: >50% decrease 4+: >100% increase 1-: incompatible with monitoring D, Dose-related; EMG, electromyography.

10 mseconds of the stimulus presentation (see Fig. 21-13). Midlatency and cognitive auditory-evoked potentials are recorded predominantly over the temporal cortex. In an ideal situation, recording electrodes should be placed on the skin overlying each earlobe, the seventh cervical vertebra, and the vertex. A typical montage would be • • • •

Channel 1: Cz—Ipsilateral ear Channel 2: Cz—Contralateral ear Channel 3: Cz—Seventh cervical vertebra Channel 4: Ipsilateral ear—contralateral ear

The channel likely to provide the most information, showing all waves, is Channel 1 (Cz—ipsilateral ear). The Cz—contralateral ear shows the responses from the auditory pathway that has crossed to the opposite side of the brainstem and may help identify wave V. Channel 3 will often also empha-

size wave V of the response and may be used when wave V is only poorly seen in Channel 1. Occasionally, wave I will not be well visualized in Channel 1 and may be better seen in Channel 4. Wave I must be visualized adequately to make certain that a stimulus is actually reaching the cochlea. If wave I is seen clearly, changes in the auditory evoked potential are unlikely to be caused by failure of adequate stimulation. Auditory Pathway. Initially, investigators thought that each component of the BAEP represented the activity of a distinct structure along the brainstem auditory pathway. The sites of origin of each wave were thought to be: wave I, eighth cranial nerve; wave II, cochlear nucleus; wave III, superior olivary complex; wave IV, lateral lemniscus; wave V, inferior colliculus; wave VI, medial geniculate; and wave VII, primary audi-

Figure 21-13. BAEP waveform and associated structures that are thought to generate each wave.

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tory cortex. This schema seemed to hold up rather well when abnormalities of the potentials were compared with locations of clinical lesions.52,53 For example, lesions of the midbrain were reported to correlate well with abnormalities of waves IV and V; lesions in the pons altered wave III. Lesions of the eighth cranial nerve itself were associated with loss of the entire potential or prolongation of the latency of all components after wave I. Unfortunately, the types of lesions encountered in clinical situations usually involve more than one auditory structure and may also have remote effects via pressure or edema. Limitations in clinical correlation between anatomic lesions and BAEP abnormalities have led to both human and animal experimentation. Animal experimentation where recordings were made directly from brainstem structures suggests that, during most of the evoked potential, high-amplitude fields occur throughout the brainstem. This observation led to the conclusion that most of the BAEP waves are generated in multiple auditory structures. Many different discrete brainstem lesions in animals decrease the amplitude of but have no effect on the latency of the BAEP waveforms. Only with lesions of the eighth cranial nerve were all BAEP components suppressed. Large lesions elsewhere generally led to attenuation, but not loss, of these components. The BAEP waveforms beyond wave I thus likely represent a highly complex interaction between multiple structures (see Fig. 21-13).54–58 Several studies have involved recording from human brainstem structures during posterior fossa explorations. The compound eighth cranial nerve action potential latency recorded from the eighth cranial nerve just proximal to the internal auditory meatus occurred midway between surfacerecorded waves II and III.59 This finding indicated that the eighth cranial nerve plays a major role in the generation of both waves I and II. Potentials recorded near the cochlear nucleus have corresponded to the surface-recorded wave III.60 Although the precise generators of the various components of the BAEPs remain controversial, most investigators agree that longer latency components are generated in structures located progressively more rostrally along the brainstem auditory pathway. This schema continues to have great clinical utility. BAEPs assume an adult configuration in early childhood.61 Many factors will affect their latencies and amplitudes, including head size, body temperature, anesthetic drugs, and, especially important in the neuro-ICU, auditory acuity. Interpeak latencies (usually I to III and I to V), which tend to be less affected by these factors than are absolute latencies, are therefore the preferred measures of normality. Compared to somatosensory- or visual-evoked potentials, systemic factors are relatively unlikely to seriously alter the BAEP. Intravenous anesthetic agents, even in very high doses, have no significant effects on the BAEP. Middle latency- and cognitive auditory-evoked responses on the other hand are exquisitely sensitive to systemic factors and anesthetic drugs. In fact, dose-dependent changes in middle

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latency auditory-evoked potentials are being used as a measure of anesthetic depth. Visual-Evoked Potentials Visual-evoked potentials (VEPs) reflect the function of the visual pathway, which extends from the optic nerve, through the chiasm, to the visual cortex. The VEP is generated primarily by the visual cortex. The stimulus may consist of a repetitive bright flash of light or of a reversing black-andwhite checkerboard pattern. It is applied by goggles through closed eyelids or by contact lenses containing light-emitting diodes applied directly to the cornea. Recordings are from scalp electrodes placed over the calcarine cortex. The timing of peak I of the VEP coincides with the electroretinogram and confirms that the sensory input was processed in the eye. The electroretinogram or peak I, however, does not confirm input of the signal into the CNS, because conduction of the stimulus along an intact optic nerve is still required. Motor-Evoked Potentials Interest in the use of MEPs stems from the importance of motor function for the patient’s ultimate functional status and from the theoretical limitations of SSEPs in monitoring motor function. Although MEPs are not technically difficult to produce in the conscious patient, the lack of widespread use of MEPs in the OR and neuro-ICU suggests that their use may not be as simple as it seems. Theoretical Basis. The same type of system that is used to

monitor SEPs may also be used to monitor the motor system. The stimulus to the motor system is either electrical or magnetic in nature. Both of these types of stimuli have been used at several different stimulus sites: the motor cortex, the spinal cord (any level), or the peripheral nerve. MEPs recorded from the peripheral nerves and spinal cord are called neurogenic MEPs. Their application is limited to intraoperative use. These potentials are relatively small and usually require some signal averaging to be readily seen. MEPs recorded from muscle are called myogenic MEPs. These potentials are much larger and frequently do not require averaging. The reproducibility of MEPs may be increased by techniques such as facilitation by peripheral sensory stimulation and temporal summation of responses by short interval sequential stimulation.62 The use of transcranial magnetic stimulation to elicit myogenic MEPs was recently approved by the U.S. Food and Drug Administration.63 Use of MEPs to assess motor function may be difficult for several reasons. First, regardless of whether the stimulus is applied transcranially to the motor cortex or directly to the spinal cord, there is an uncertainty as to which structures are being activated by the stimulus and which structures are producing the recorded waveforms of neurogenic MEPs.64–71 While part of the stimulus is conducted via the corticospinal tract, other descending tracts are also involved.65,72 MEPs are

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exquisitely sensitive to many anesthetic and sedative drugs. Barbiturates, benzodiazepines, and volatile agents abolish MEPs, whereas low doses of propofol and narcotics appear to interfere less. Muscle relaxants may be used in amounts that will suppress most gross motor movement associated with stimulation provided quantitative neuromuscular blockade monitoring is used. Simple peripheral nerve stimulators are not suitable for MEP monitoring because they are unable to accurately quantify either the amount of stimulus given to the nerve or the amount of muscular response produced.

Applications of Evoked Potentials in the Neurointensive Care Unit Assessment of Motor and Somatosensory Function One obvious area of utility for EP testing is the assessment of the integrity of a pathway by the appropriate EP modality. This application represents a simple extension of the diagnostic use of EPs, but may be very helpful in the neuroICU to clarify a clinical picture at the bedside or at a time when imaging findings are still equivocal. In this respect, MEPs have been used successfully in patients with strokes or trauma to the brainstem to predict ultimate motor function.73–75 Cognitive VEPs may be useful to differentiate the de-efferented state of a locked-in syndrome from psychogenic unresponsiveness or isolated brainstem lesions.76 Absence of cortical SSEPs may signify a lesion high in the cervical spinal cord or at the craniocervical junction and thus explain the lack of reactivity to stimuli applied in the territory of the peripheral nervous system. BAEP wave I may be used to test for the presence of hearing. Absence of wave I, on the other hand, may be difficult to interpret outside of the clinical context as it may be due to such diverse etiologies as a preexisting hearing loss, a transverse petrosal fracture, the effect of ototoxic drugs, isolated damage to the auditory pathways in the brainstem, or brain death. Continuous EP monitoring expands the diagnostic possibilities further. If the patient’s condition or pathology puts a pathway that is amenable to EP monitoring at risk, continuous EP monitoring represents a unique modality to receive early warning and positively affect outcome. Likewise, continuous EPs can document the neurologic consequences of increased intracranial pressure. Coma Evaluation SSEPs combined with BAEPs are helpful in the treatment of comatose patients.77–85 In general, if both BAEPs and cortical SSEPs are intact at presentation and remain intact, ultimate outcome is good. A relatively good outcome may occur in this case even if all clinical signs indicate a very poor prognosis.78 If the cortical SSEPs are absent at presentation and

the BAEPs are present, the best outcome expected is a chronic vegetative state. If both cortical SSEPs and all BAEP waves beyond wave I are absent, brain death is very likely. It is important to note that drug overdose will not eliminate either the BAEP or the early and intermediate latency components of the SSEP. While the EEG may be entirely absent in the case of drug overdose or therapy such as in barbiturate coma, the BAEP and SSEP should be present if the patient has brain function. Slight differences in sensitivity, specificity, and predictive value of EPs exist that depend on the etiology of the comatose state. In anoxic-ischemic coma, absence of cortical SSEPs 24 hours after the precipitating event was found to be the best method to predict poor outcome.5 Similarly, bilateral loss or absence of cortical SSEPs is always associated with a poor outcome in comatose patients whose EEG reveal alpha, theta, or alpha-theta coma.76 Conversely, presence of cortical SSEPs is associated with a favorable outcome. AEPs are less useful in anoxic-ischemic coma. Brainstem responses may initially be absent, due to cochlear ischemia, but are otherwise only affected very late in the course of anoxia or ischemia. Presence of midlatency or late auditory potentials is predictive of a good outcome, but is subject to the same modulating influences as the EEG. In coma due to head trauma, both the cerebral hemispheres and the brainstem may be involved in a pattern of lesions that reflects more the mechanism of injury and less the intrinsic tolerance to hypoxia/ischemia of a given brain structure. Presence of cortical EPs such as the N20 of the median SSEP or midlatency AEPs is still associated with favorable outcomes even if the latency of the peaks is increased.86 Conversely, absence of cortical peaks and progressive rostro-caudal deterioration of BAEPs, as occurs with transtentorial herniation, leads to brain death.87 The decreased predictive power of absent cortical responses in post-traumatic coma is demonstrated by the fact that all cases of good clinical outcomes despite absent cortical SSEPs stem from such trauma patients.88,89 Confirmation of Brain Death The declaration of brain death is usually based on clinical criteria or radiographic evidence of absence of cerebral blood flow. In special clinical circumstances, neurophysiologic testing can be supportive of this diagnosis.83,84 The principal advantage of EP testing lies in the fact that EP signals from the brainstem are virtually unaffected by CNS depressant drugs. For BAEPs to support the diagnosis of brain death, wave I must be evident. Unfortunately, wave I is frequently absent in brain death.90 Although it is generated in the peripheral portion of the auditory nerve, the blood supply to the nerve and to the cochlea itself often has an intracranial origin. Thus, increased intracranial pressure, with resultant decreases in blood flow, can lead to cochlear damage and loss of wave I. If no components of the BAEP are evident, it is consistent with but not diagnostic of brain death. SSEP testing is faced with the opposite problem.

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Although documentation of the peripheral input to the brainstem is easily achieved, the evoked response from the cervico-medullary junction persists in the majority of brain dead patients, because it originates at the watershed between intracranial and extracranial blood supply.91

Monitoring Cerebral Blood Flow All of the previously discussed monitors are monitors of nervous system function. When function fails, they do not necessarily give information about the mechanism of nervous system damage. One of the most common mechanisms of CNS damage is inadequate blood flow. The remainder of this chapter will examine those methods that are available to monitor the adequacy of CBF. These monitors (Table 21-7) provide information that is complementary to the functional assessment discussed above, because function only becomes altered when CBF decreases by more than half. The most common clinical measure aimed at assuring adequate CBF is to maintain the cerebral perfusion pressure above the lower limit of cerebral autoregulation. While a markedly decreased or elevated cerebral perfusion pressure may lead to ischemia or spontaneous hemorrhage, respectively, a normal cerebral perfusion pressure by no means

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assures normal CBF. For example, increased cerebrovascular resistance because of carotid stenosis, cerebral vasospasm, or microcirculatory compromise may cause ischemia, despite normal cerebral perfusion pressure. Similarly, normal cerebral perfusion pressure may coexist with abnormally increased CBF in settings such as post-traumatic vasoparalysis or normal perfusion pressure breakthrough after resection of an arteriovenous malformation. Direct Cerebral Blood Flow Measurement The ideal clinical method for CBF measurement in the neuro-ICU should be a noninvasive inexpensive bedside procedure that is continuous, or at least frequently repeatable, and provides good spatial resolution for superficial and deep structures of all vascular territories.92 No currently available method comes close to having all these characteristics. Nonetheless, determinations of CBF served to validate other techniques of assessing cerebral perfusion and provided important insights into the pathophysiologic events in head injury or stroke. Direct measurement of CBF is possible by determining kinetics of either wash-in or wash-out of an inert tracer compound, in a variation of the method of originally described by Kety and Schmidt.93 The most widely used meas-

Table 21-7  Techniques for Measuring Cerebral Blood Flow Resolution Category

Technique

Temporal

Spatial

Indirect

Neurologic examination Electroencephalogram/ evoked potentials Cerebral perfusion pressure Kety-Schmidt 133 Xe wash-out AVDO2, Jugular venous oxygen saturation (SjvO2) Double indicator dilution

>3 min 1–3 min <1 min

Eloquent areas Cortex/sensory pathway Global

15 min 3–15 min <1 min

Hemispheric 3–4 cm Global

3 min

Global

<1 min

Local, bifrontal

<1 min <1 min 4–6 min/ section 4–6 min/ section 4–6 min/ section 4–6 min/ section

Local, 1–2 cm Local, 1–2 cm <1 cm

Bedside

Tomographic

Near-infrared spectroscopy Thermal clearance probe Laser Doppler flow probe Positron emission tomography Stable xenon computed tomography Single photon-emission tomography Magnetic resonance imaging

<1 cm <1 cm <1 cm

Invasiveness

Cost

No No

+ ++

Subdural, intraventricular or intraparenchymal probe Jugular catheter Jugular catheter, radiation Jugular catheter

+

Jugular catheter, descending thoracic aortic catheter No

+

+ + +

+

Exposed cortex Exposed cortex Radiation from positron emitter Radiation from CT scan

+ + +++++

Radiation from gamma emitter No

+++

+++

+++

Greater number of + in cost column equals higher cost. Adapted from Martin NA, Doberstein C: Cerebral blood flow measurement in neurosurgical intensive care. Neurosurg Clin North Am 1994;5:607–618; Madsen PL, Secher NH: Near-infrared oximetry of the brain. Prog Neurobiol 1999;58:541–560; Cottrell JE: Cerebral blood flow. In Cottrell JE (ed): Anesthesia and Neurosurgery. St. Louis, Mosby Year Book, 2001, pp 800–825; Keller E, Wietasch G, Ringleb P, et al: Bedside monitoring of cerebral blood flow in patients with acute hemispheric stroke. Crit Care Med 2000;28:511–516.

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urement involves administration of a radioactive isotope of 133 Xe, either per inhalation or intravenously, followed by measurement of the radioactivity wash-out with gamma detectors placed over specific areas of the brain (Fig. 21-14). This method provides a spatial resolution of approximately 3 to 4 cm, depending on the number of detectors. In a normal brain, flow at different depths may be inferred from the early wash-out, which should reflect high-perfusion cortical grey matter, and from low-perfusion deeper white matter. An important disadvantage of the technique is its lack of sensitivity for focal areas of hypoperfusion, a phenomenon described as “look-through.”94,95 Look-through occurs because only a small amount of 133Xe is delivered to the area of focal ischemia and the detector input is dominated by radioactivity washed out from adjacent areas. Despite its shortcomings, this method has been used at a few major centers92,96–101 in combination with other forms of continuous monitoring. Values of global or hemispheric cerebral blood flow must be interpreted in the context of the patient’s disease process. In normal brain, values of hemispheric cerebral blood flow of approximately 50 ml/100 g/min reflect adequate oxygen delivery for maintaining both structural integrity and function. Values of less than 20 to 25 ml/100 g/min are associated first with failure of function and subsequently with structural damage.92 In neuro-ICU patients, both structural integrity and function are altered. Thus, a CBF of 40 ml/ 100 g/min in a patient in a barbiturate coma after resection of an arteriovenous malformation may represent hyperemia, whereas the same CBF in a patient with a mass lesion may reflect a decrease in cerebral perfusion pressure due to increasing intracranial pressure. Despite these shortcomings, CBF measurements can be useful in a variety of circum-

Figure 21-14. Schematic of

133

Xe CBF measurement.

stances.92 For example, they can help assess the therapeutic response to hyperventilation or induced hypertension by documenting the desired decrease or increase in CBF, respectively. Radiologic methods such as SPECT, positron-emission tomography, xenon-enhanced computed tomography (CT), or magnetic resonance imaging provide excellent spatial resolution, but are not available at the bedside. Some are used clinically as confirmatory tests in the determination of brain death. SPECT and magnetic resonance angiography for example show a “hollow skull phenomenon” and absent intracranial flow, respectively. Xenon-enhanced-CT, which can be combined with standard CT scanning, has been used to obtain prognostic information and withhold unnecessarily aggressive therapy by assessing the severity of the decrease in CBF during stroke.102 As discussed in chapter 2, the scope of these functional radiologic methods will likely expand as they become more widely available and more integrated in the assessment of neuro-ICU patients.

Transcranial Doppler Ultrasound An easy-to-apply, continuous, and noninvasive monitor of relative changes in CBF uses transcranial Doppler (TCD) ultrasound. Theoretical Basis Ultrasound waves are used to measure the velocity of blood flow in the basal arteries of the brain and the extracranial portion of the internal carotid artery. These waves are transmitted through the relatively thin temporal bone, the orbit, or the foramen magnum (Fig. 21-15).103 When they contact moving red blood cells, they are reflected at a changed frequency through the brain and skull back to a detector. The change in frequency as blood cells move toward or away from the ultrasound transmitter and detector is an example of the Doppler effect and is related to velocity and direction of flow. Velocity increases during systole and decreases during diastole; blood in the center of the lumen moves faster than that near the vessel wall, producing a spectrum of flow velocities. This spectrum resembles the shape of the waveform produced by an intra-arterial pressure transducer (Fig. 21-16). The TCD probe emits ultrasound waves as short pulses. Because ultrasound travels through tissue at a constant velocity, assessment of flow at different distances from the transducer becomes possible by varying the time window during which the reflected ultrasound waves are received. Thus, each segment of the arteries at the base of the brain has a distinct signature in terms of depth of insonation and direction of flow. TCD measurements are most commonly and easily made in the middle cerebral and internal carotid arteries, but may also be measured in other vessels including the anterior cerebral, anterior communicating, posterior cerebral, posterior communicating, and basilar arteries. In

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Figure 21-15. Windows for insonating major cerebral arteries with a TCD device. Transtemporal, transorbital, suboccipital, and carotid artery measurements are used to comprehensively assess cerebral inflow.

approximately 10% of patients, particularly elderly females, technically satisfactory recordings cannot be obtained because of increased skull thickness.103 Although TCD allows interrogation of all arteries that supply the brain, TCD cannot provide a simple assessment

Figure 21-16. Normal TCD waveform. Note the close resemblance to an arterial waveform.

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of global or hemispheric CBF. In the setting of acute stroke or traumatic arterial dissection, the mere patency of a vessel is an important question that has diagnostic, therapeutic, and prognostic implications.103,104 For example, the presence of blood flow indicates recanalization of a vessel and may be used to spare a patient the risks associated with thrombolytic therapy. Beyond the question of vessel patency, the link between TCD measurements and CBF is indirect and subject to one technical limitation and two principal assumptions inherent in the link. The technical limitation is that the accuracy with which the flow velocity can be determined depends on the angle of insonation. Variability of repeated measurements can be minimized either by using a single examiner or by rigidly mounting the TCD probe on the patient’s head with a headset, provided a shift in brain structures caused by a mass lesion does not displace the artery. The two principal assumptions that have to be met for TCD-measured blood flow velocity to correspond to CBF are (1) flow and flow velocity are directly related only if the diameter of the artery remains constant and (2) the blood flow in the basal arteries of the brain must be directly related to cortical CBF. These assumptions likely represent an oversimplification and have not been supported adequately by evidence. Specifically, radioactive 133Xe-measured CBF does not correlate well with TCD-derived MCA velocity during carotid endarterectomy or cardiopulmonary bypass.105–107 Likewise, normal variations in blood flow velocities are large.108 Despite this limitation, TCD has found many applications in the neuro-ICU, particularly in combination with other monitoring modalities that assess CBF.

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Detection of Cerebral Vasospasm TCD has been very helpful in identifying vasospasm following aneurysmal subarachnoid hemorrhage.109–114 As the diameter of the arterial lumen decreases with vasospasm, the velocity of blood flowing through the narrowed vessel must increase if flow is to be maintained (Fig. 21-17). Using absolute flow velocity alone, detection and documentation of the severity and duration of vasospasm is possible with a specificity that approaches 100% but with limited sensitivity.108,115,116 Attempts have been made to improve the sensitivity by normalizing the flow velocity to that measured before the vasospasm108 or to the flow velocity of the ipsilateral extracranial internal carotid artery.114 One important setting, wherein absolute TCD flow velocity may underestimate the severity of vasospasm is that of increased ICP.117 Increases in ICP, however, lead to characteristic changes in the TCD waveform and increase the pulsatility index (see following discussion).

Figure 21-17. TCD monitoring for cerebral vasospasm after subarachnoid hemorrhage. A, Normal TCD waveform. B, Waveform from the same patient following development of cerebral vasospasm. Note the greatly increased flow velocity of the blood traveling through the narrowed vessel.

Although TCD has contributed much to our understanding of the natural history of vasospasm following aneurysmal subarachnoid hemorrhage, most studies predate the current therapeutic approach of early exclusion of the aneurysm and supportive therapy with hypertensive-hypervolemic-hemodilution and nimodipine. Another recent advance in the treatment of vasospasm that highlights the limitations of TCD is the therapeutic dilation of stenotic arteries. TCD flow velocities may remain elevated despite successful dilation as a result of impaired autoregulation in the poststenotic vascular bed.118 Transcranial Doppler Use in Traumatic Brain Injury TCD in combination with determinations of CBF has identified phases of hyperemia and cerebral arterial vasospasm in traumatic brain injury as important mechanisms that underlie increased ICP and secondary injury, respectively.96,97,99,119 Similar to vasospasm after aneurysmal subarachnoid hemorrhage, the severity of post-traumatic vasospasm correlates with the radiologic grade, although its onset may be earlier.120 TCD has also been used in traumatic brain injury to assess the degree to which CBF regulation is disrupted. Whereas normal carbon dioxide reactivity, pressure autoregulation, and flow/metabolism coupling are associated with a good outcome (Fig. 21-18),121 disrupted CBF regulation carries a bad prognosis.98,121 Assessment of Intracranial Pressure and Confirmation of Brain Death The TCD-generated waveform exhibits sequential characteristic changes as ICP increases (Fig. 21-19).122 As ICP increases, the systolic waveform becomes more peaked. As ICP nears diastolic blood pressure, diastolic flow diminishes and subsequently ceases. Once ICP exceeds diastolic blood pressure, TCD shows a pattern of to-and-fro movement of blood that indicates imminent intracranial circulatory arrest (see Fig. 21-19). This change in waveforms can be used to calculate a pulsatility index by relating the difference between peak systolic and end-diastolic velocity either to the mean or to the systolic velocity. Such waveform analyses correlate well with the ICP,117,123,124 especially if they take the arterial blood pressure curve into account.125 Serial TCD cannot, however, replace ICP monitoring, because in a given patient factors such as autoregulation, vasospasm, or proximal arterial stenosis may alter the TCD signal independent of the ICP.103 Clinical brain death demonstrates a characteristic blood flow velocity pattern (Fig. 21-20).126–130 There is a short systolic inflow of blood followed by an exit of blood (flow direction reverses) from the cranium during diastole. TCD is a validated confirmatory test in the diagnosis of brain death, with a sensitivity that exceeds 90% and a specificity of 100%.128,131–133 While TCD can ascertain the diagnosis in most patients at the bedside, a large craniotomy or an inadequate bone window may preclude the complete examination necessary to confirm brain death.

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Figure 21-18. Persistence of cerebral autoregulatory responses in patients with traumatic brain injury is associated with improved functional outcome. CO2 reactivity is assessed by the change in mean flow velocity (MVF) in the middle cerebral artery for a given change in PaCO2. GR, good recovery; MD, moderate disability; SD, severe disability; PVS, persistent vegetative state.

Cerebral Oxygen Supply and Demand Balance Cerebral oxygen demand (requirement) varies with changing CNS conditions. Reduction of brain temperature by 5°C may reduce oxygen needs by 35% or more. CBF may be adequate for cerebral function and cellular integrity at 32°C but inadequate at 37°C. Likewise, cerebral oxygen delivery varies

1

2

3

4

with CBF and oxygen content. The balance between cerebral oxygen demand and supply determines cerebral function. Thus, numerical values of CBF taken alone do not guarantee either preservation or loss of function; they must be interpreted with regard to oxygen demand and supply. Clinically applicable direct measurements of oxygen demand are not available at this time. Assessment of brain function can

5

6

TCD Waveform Panels

Figure 21-19. The flow velocity in intracerebral arteries shows a characteristic pattern of changes as ICP increases to the point of intracranial circulatory arrest and brain death. Top, Arterial blood pressure (systolic, diastolic, and mean) in light lines and ICP in bold lines. Bottom, Representative TCD waveforms obtained at the times indicated. Note that as ICP exceeds diastolic blood pressure, the diastolic component of the TCD waveform becomes progressively blunted (panels 2 and 3) and then disappears (panel 4). Further increases in ICP lead to flow reversal during diastole (panel 5) and, ultimately, to cessation of blood flow as ICP exceeds mean arterial pressure.

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Figure 21-20. Jugular venous oxygen saturation differs between the right and left side in patients with traumatic brain injury.

be used to assess oxygen demand indirectly. For example, spontaneous electrical activity as assessed by the EEG uses roughly 50% of the total oxygen consumed by the brain. As a corollary, if drugs are given to totally suppress spontaneous electrical activity, the oxygen demand will be reduced by about 50%. The oxyhemoglobin saturation can be used, in a manner analogous to mixed venous oxygen saturation, to determine whether oxygen supply and demand are in balance. As long as changes in CMRO2 are matched by concomitant changes in cerebral blood flow, oxygen extraction will stay the same, as will oxyhemoglobin saturation. If demand outstrips supply, oxygen extraction will increase, thereby decreasing oxyhemoglobin saturation. Jugular bulb oximetry and cerebral oximetry are two approaches to measure oxygen saturation. Both technologies use reflectance oximetry to determine saturation values. Reflectance oximetry relies on the fact that near-infrared light penetrates tissue for several centimeters and that hemoglobin, in its oxygenated and deoxygenated form, is the major tissue compound absorbing near-infrared light.134 Near-infrared light of at least two different wavelengths is emitted and the reflected light of each wavelength is quantified to determine an oxygen saturation value. While the technologies of jugular bulb oximetry and cerebral oximetry are similar in concept, different assumptions underlie the validity of jugular bulb oximetry and cerebral oximetry as monitors of global and regional oxygen supply and demand balance, respectively. Direct measurements of oxygen partial pressure in brain tissue (PbO2) can be derived from modified Clark electrodes implanted into the brain. The technology is relatively robust and provides information about actual tissue oxygenation,

albeit only from a highly localized area of metabolically heterogeneous brain. If the probe is situated in normal brain, PbO2 correlates with jugular bulb saturation.135 Severe or prolonged tissue hypoxia is associated with worse functional outcomes.136 For an injured brain, desirable values for PbO2 are not well defined and likely vary with the type and stage of a given disease process. More research is required to define optimal indications and locations for PbO2 sensors and their contribution to the assessment of patients in the neuro-ICU. Jugular Bulb Oxygen Saturation The measurement of jugular bulb oxygen saturation (SjvO2) requires placement of a catheter into the jugular vein. That catheter is advanced retrograde under fluoroscopic guidance until its tip lies in the jugular bulb. Oxygen saturation can be determined continuously by using a fiberoptic catheter or intermittently by blood gas analysis. Due to its invasive nature cannulation is usually only done on one side. There are several theoretical problems with this technique. The measurement technique evaluates the global balance between cerebral oxygen supply and demand. Inadequate CBF to a small area of cortex may be masked by blood, which has a higher SvO2, from areas of adequately perfused brain in either hemisphere. Thus, a high saturation can be falsely reassuring. Similarly, admixture of extracerebral venous blood, for example, through catheter malposition, may falsely increase SjvO2. Although virtually all blood from the brain drains via the jugular veins, mixing of venous blood is incomplete and results in differences between rightand left-sided measurements (see Fig. 21-20).137–139 Specifically, the dominant jugular vein (the right jugular vein in the

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majority of patients) drains predominantly cortical venous blood, whereas the contralateral jugular vein drains mostly blood from subcortical structures.139 To account for this asymmetry, many clinicians cannulate the jugular bulb on the side where jugular vein compression causes the largest increase in intracranial pressure.12,138,140,141 Placement of a catheter in the jugular vein may diminish jugular outflow or cause thrombosis after prolonged use, thus raising ICP in patients with decreased intracranial elasticity. However, in clinical practice such complications are rare142,143 and should be weighed against the benefit of the information obtained. Despite these limitations, SjvO2 monitoring is an integral part of multimodality monitoring in many neuroICUs.139,144–148 Jugular Bulb Oxygen Saturation Monitoring in Patients with Head Trauma Although SjvO2 monitoring has been used after cardiac surgery149 and subarachnoid hemorrhage,150 most reports involve management of patients with severe head injury. In patients with severe head injury, SjvO2 values of less than 50% or greater than 75% are associated with worse outcomes. Episodes of jugular venous oxygen desaturation thought to reflect episodes of relative ischemia were associated with worse neurologic deficits, even after adjusting for confounding factors such as age, Glasgow coma scale score, or type of injury.6,7 Similarly, SjvO2 values greater than 75%, which may reflect the decreased demand of traumatized tissue rather than hyperemia, were associated with worse patient outcomes.8,9 SjvO2-monitoring appears to be helpful in detecting cerebral ischemia associated with excessive hyperventilation.12,140,151 Although hyperventilation may lower ICP, the accompanying decrease in CBF can cause O2 delivery to fall below demand. Decreasing SjvO2 suggests that another technique to control ICP, for example, barbiturate coma, ventriculostomy, or lumbar catheter with CSF drainage, might be safer. The prompt feedback and straightforward conceptual framework for interpretation provided by SjvO2 monitoring has played an important role in limiting hyperventilation152 and shifting the focus away from controlling ICP and toward maintaining CPP. Cerebral Oxygen Supply and Demand Balance: Cerebral Oximetry The cerebral oximeter was developed as a noninvasive assessment of the adequacy of cerebral oxygenation. In addition to the brain tissue underlying the oximetry probe, the light also passes through the scalp and skull. The exact light path is not known; therefore, the relative contribution of extracranial and intracranial blood to the measured saturation may vary according to sensor design and placement. The sensor is usually placed on the skin overlying the frontopolar portion of the cerebral cortex (forehead). A schematic of the most commonly used cerebral oximeter is shown in Figure

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Figure 21-21. Schematic of the cerebral oximeter.

21-21. Arterial, capillary, and venous hemoglobin within the light path contributes to the measured saturation value. Because two thirds to four fifths of the cerebral blood volume is on the venous side, cerebral oximetry determines predominantly “local SVO2.”134 Cerebral oximetry has been compared to TCD and SjvO2, as a means to assess global cerebral perfusion during carotid endarterectomy.153,154 While neither of these monitors is currently considered the ultimate standard for measuring the adequacy of CBF, the relationships demonstrated were interesting. Decreases in cerebral oxygen saturation were accompanied by significant decreases in middle cerebral artery flow velocity (MCAv). The converse was not always true, however. Significant falls in MCAv could occur without any change in oxygen saturation at all, suggesting the presence of collateral circulation. There was also a strong correlation between SjvO2 and cerebral oxygen saturation. The degree of change in the two monitors was not necessarily similar, however. Placement of the probe over the parietal cortex produced a more similar degree of change in the two monitors than the standard frontal placement. Compared to accepted tests of adequate CBF during carotid artery occlusion, such as the neurologic exam of the conscious patient,155 the EEG156 or SSEPs,157,158 cerebral oximetry showed good sensitivity but relatively poor specificity. The poor specificity makes it difficult to define a relative or absolute threshold below which cerebral oxygen saturation indicates ischemia. Perhaps the greatest limitation of this monitor is the lack of multichannel capability. There is no reason to expect that oxygen saturation in one portion of the brain would reflect oxygen saturation in other areas of the brain. Indeed, EEG changes during ischemia are sometimes limited to a few channels. Likewise, most patients in the neuro-ICU are at risk for secondary focal or multifocal rather than generalized damage to CNS structures. Studies of cerebral oximetry in patients with traumatic brain injury failed to document consistent utility of the monitor.12,14,135,140,141,151 Thus, although SjvO2 and cerebral oximetry provide complementary information on the cerebral oxygen supply and demand balance, further study and technical development will be required before cerebral oximetry can claim a place in the multimodal assessment of neuro-ICU patients.

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Conclusion Neurologic monitoring in the neuro-ICU has advanced considerably from its early focus on neurologic examination and ICP. Despite a host of monitoring techniques, no single modality allows an assessment of neuro-ICU patients that is both comprehensive and sufficiently detailed. Multimodal approaches that combine carefully scheduled

imaging studies with continuous bedside monitoring of cerebral perfusion and cerebral function in a setting with adequately trained staff will likely provide the greatest utility. As advances in our understanding of the natural course of CNS diseases and novel strategies for treatment make their way from bench to bedside, such monitoring will become an ever more essential guide to therapy and prognosis.

P earls 1. In fact, no monitor in the OR or ICU has been shown to change or reliably predict outcome. 2. . . . the bilateral persistence of a cortical response to SSEPs from median nerve stimulation has so far consistently predicted eventual awakening from hypoxic coma.5 Likewise jugular venous oxygen saturation values outside the normal range are associated with worse neurologic outcome in patients with traumatic brain injury. 3. When oxygen delivery to the brain falls below a level sufficient to meet the cerebral metabolic requirement for oxygen (CMRO2), function fails. Because function is disrupted before cellular integrity is lost, monitors of function provide early warning of inadequate oxygen supply and provide opportunity to correct this problem before irreversible damage occurs. 4. Of all neurophysiologic monitoring modalities, the neurologic examination of a conscious patient allows for the most comprehensive assessment of CNS function. 5. Pathways amenable to evoked potential monitoring and spontaneous electrical activity of the cerebral cortex, however, reflect the function of only a portion of the entire nervous system. 6. Electroencephalographic activity, that is, cortical electrical activity, requires roughly 50% of the total oxygen consumed by the brain; the remaining 50% is needed to maintain cellular integrity. 7. Because sensitivity and specificity of EEG in the setting of brain death is only 90%,11 and because the EEG contains very limited and indirect information from

References 1. Smith RC, Leung JM, Mangano DT: Postoperative myocardial ischemia in patients undergoing coronary artery bypass graft surgery. S.P.I. Research Group. Anesthesiology 1991;74:464–473. 2. Cheng DC, Chung F, Burns RJ, Houston PL, Feindel CM: Postoperative myocardial infarction documented by technetium pyrophosphate scan using single-photon emission computed tomography: Significance of intraoperative myocardial ischemia and hemodynamic control. Anesthesiology 1989;71:818–826.

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11.

12.

subcortical structures and brainstem, it cannot substitute for a comprehensive assessment of brain death. SEPs monitor the function of the somesthetic sensory system, which extends throughout the peripheral and central nervous systems. Thus peripheral nerve, spinal cord, subcortical, and cortical structures in the brain may be monitored. The brainstem auditory pathway encompasses the cochlear hair cells, spiral ganglion, eighth cranial nerve, cochlear nuclei, superior olivary complex, lateral lemnisci, inferior colliculus, and medial geniculate thalamic nuclei. The stimulus is a loud, repetitive click delivered to the patient by small ear inserts placed in the external auditory canal. VEPs reflect the function of the visual pathway, which extends from the optic nerve, through the chiasm, to the visual cortex. The VEP is generated primarily by the visual cortex. If the cortical SSEPs are absent at presentation and the BAEPs are present, the best outcome expected is a chronic vegetative state. If both cortical SSEPs and all BAEP waves beyond wave I are absent, brain death is very likely. The change in frequency as blood cells move toward or away from the ultrasound transmitter and detector is an example of the Doppler effect and is related to velocity and direction of flow. Velocity increases during systole and decreases during diastole; blood in the center of the lumen moves faster than that near the vessel wall, producing a spectrum of flow velocities.

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Appendix Algorithm for the Determination of Brain Death

Comatose patient

Yes Exclude • Metabolic disorders • Drug intoxication • Residual effect from drug therapy

No

Reexamine • Drug screen • Laboratory results

No

Reexamine Consider baseline EEG

Yes Clinical brain death? • Normothermia? • Normotension? • Areactive coma? • Absent brainstem reflexes? • Apnea?

Yes Observation period • Neonates–2 months: 48 hrs • 2 months–1 year: 24 hrs • >1 year: 12–24 hrs • Adults: 6–12 hrs

Change in exam

Unchanged exam Consider confirmatory testing • Patients <1 year • Brain pathology not consistent with clinical course or neurologic exam

Brain death

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Chapter 22 Pharmacotherapy in the Neurosurgical Intensive Care Unit Steven A. Robicsek, MD, PhD, Richard J. Rogers, MD, PhD, and Hugh C. Hemmings, Jr., MD, PhD

Introduction Optimal management of the patient with neurologic injuries depends on rapid recognition of neurologic issues and knowledge of pharmacodynamic and pharmacokinetic properties of neuroactive drugs. Pharmacologic management is aimed at matching the metabolic needs of the brain and spinal cord with perfusion and oxygenation. Major advances in neurosurgical intensive care have come from a better understanding of the pathophysiologic mechanisms of neuronal injury and from the use of pharmacologic agents with shorter elimination half-lives. Examples of these agents are propofol for sedation, remifentanil for analgesia, and esmolol for heart rate control, which allow for rapid, complete control with rapid elimination when neurologic assessment is necessary.

Pharmacokinetic Principles Pharmacokinetics encompasses drug absorption, distribution, and elimination. Each of these phases of drug movement through the body involves passage across cell membranes. Therefore drug properties, including molecular size and shape, degree of ionization, lipid solubility, and protein binding all influence drug movement.1 Drugs may be administered by a variety of routes: enteral (oral, sublingual, rectal), parenteral (subcutaneous, intramuscular and intravenous, intraarterial, intrathecal), topical, transdermal, and inhalational. Absorption from each of these routes has specific advantages and disadvantages in the intensive care

unit. Enteral administration is the safest and most economic means of administering a drug; however, a variety of factors, including extensive hepatic and intestinal metabolism can influence absorption, making it highly variable. Protein Binding Drug distribution is a dynamic process and depends on the degree of protein binding. Within the circulation, the principal proteins that bind drugs are albumin and a1-acid glycoprotein. High degrees of protein binding of a drug can outweigh fat solubility for lipid-soluble drugs, because the drug does not easily leave the circulation. This results in a decrease in the volume of distribution (VD). The degree of protein binding can influence drug availability and toxicity such as during the administration of fosphenytoin in a patient already taking phenytoin. Because fosphenytoin has a higher affinity to plasma proteins than phenytoin, fosphenytoin will displace phenytoin and thereby increase plasma concentrations of phenytoin, rarely contributing to toxicity.2 Redistribution and Equilibrium Redistribution is the movement of drug from bound sites to unbound sites. This is usually considered a dynamic process where a drug can move away from sites of action (receptors) into the extracellular space and other tissues, usually via the blood. Equilibrium is eventually reached between bound and unbound drug (in both the tissues and blood). Movement from blood to tissues takes time, during which, if blood samples are analyzed, a higher concentration of the drug is 649

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found than would be predicted based simply on its Vd and the dose administered. This movement is referred to as the distribution phase (a-phase). Figure 22-1 depicts two drugs given intravenously. Drug A is highly distributed, as evidenced by the long, sloping, initial part of the curve. Because we measure drug concentration in the blood compartment, we would expect that as the drug moves from the blood into other tissues, its concentration in the blood would decrease rapidly at first and then more slowly as tissue equilibrium is approached. Elimination: Clearance and Half-Life Once blood and tissue equilibrium occurs, drug elimination by either metabolism or excretion accounts for the remainder of the curve. The elimination phase is the linear part of the log concentration versus time curve in Figure 22-1. The common log or natural log value usually is plotted versus time. Because the decay is so rapid, the decrease in concentration is an exponential function given by the equation:

Table 22-1  Dose Range, Lipid Solubility, and HalfLives of Several Intravenous Anesthetic Agents Agent

Dose Range (mg/kg)

Lipid Solubility

Thiopental Methohexital Propofol Etomidate Ketamine Midazolam Diazepam Lorazepam Morphine Meperidine Fentanyl Sufentanil Alfentanil Remifentanil

3–5 1.0–1.5 1.0–2.0 0.3–0.5 0.5–1.5 0.1–0.4 0.3–0.6 0.5–1.0 0.1–0.5 1.0–5.0 0.001–0.075 0.0001–0.005 0.0005–0.1 0.0005–0.001

High High High High High Medium Medium Medium Low High High High Low High

T1/2 (hr) 6.4–7.6 1.8–6.0 1.1–6.6 1.8–4.0 2–3 1.9–3.5 32–61 11–22 1.0–2.2 3.2–4.4 3.1–4.4 2.7 0.5–1.0 0.2–0.8

Modified from Kirby RR, Gravenstein N, Lobato EB, Gravenstein JS: Clinical Anesthesia Practice, 2nd ed. Philadelphia, WB Saunders, 2002, p 630.

Ct = Co e - kt where Ct represents the concentration of a drug at a given time, C0 is the initial concentration, -k is a rate constant, and t is the half-life. By plotting the common log or natural log values of these concentrations, we convert a curve to nearly a straight line. The slope of the latter part of this line then

represents the elimination constant for the drug, which is inversely proportional to the half-life (t1/2). Drug B has little or no distribution (see Fig. 22-1), as might occur with a water-soluble agent. Table 22-1 lists several commonly used intravenous anesthetic agents, their usual dose ranges for single-bolus administration, their relative lipid solubility, and the t1/2 of their terminal elimination phase (b phase).

10000

Ionization

Ln serum concentration (␮g/mL)

A = Lipophilic B = Polar A

1000

Distribution phase

100 B

Elimination phase

10

1

0.1 0

1

2

3

4

5

6

Time (hrs) Figure 22-1. Lipophilic versus polar drug level profiles. A, Hypothetical lipophilic drug profile, with distribution phase and elimination phase; B, polar drug profile with only elimination phase. (From Kirby RR, Gravenstein N, Lobato EB, Gravenstein JS: Clinical Anesthesia Practice, 2nd ed. Philadelphia, WB Saunders, 2002, p 630.)

7

Clearance is dependent on the Vd and the elimination constant. As mentioned previously, the Vd of a drug is dependent on its relative lipid solubility, the degree of protein binding, and its ionization. Ionization has an important role. Drugs are generally more soluble in the ionized state; however, they usually are not cleared from the body as well, because they have difficulty crossing cell membranes. They also tend to be more protein bound and are thus less available to their target tissues. Weak acids such as sodium thiopental (STP) are more ionized and more protein bound in a basic medium. Because a smaller amount of the drug is able to cross cell membranes, the drug effect will be diminished. For example, patients maintained in an alkalotic state during hyperventilation therapy for a closed head injury have less effect from similar levels of sodium thiopental than do nonalkalotic subjects. Increased ionization results in decreased drug availability to cross into the brain. Conversely, on termination of hyperventilation therapy, as the blood becomes less alkalotic, more drug is available for both therapeutic effect and clearance. Table 22-2 gives the pKa, protein binding, and acid-base characteristics of several commonly used intravenous agents.

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Table 22-2  Chemical Properties of Several Intravenous Anesthetic Agents Agent

pKa

Type

Protein Bound (%)

Thiopental Methohexital Propofol Etomidate Ketamine Midazolam Diazepam Lorazepam Morphine Meperidine Fentanyl Sufentanil Alfentanil Remifentanil

7.6 7.9 11 4.2 7.5 6.2 3.5 11.5 7.9 7.9 8.4 8.0 6.5 7.07

Acid Acid Acid Base Base Base Base Base Base Base Base Base Base Base

85 73 98 75 12 96 98 97 36 82 87 93 92 Not available

From Kirby RR, Gravenstein N, Lobato EB, Gravenstein JS: Clinical Anesthesia Practice, 2nd ed. Philadelphia, WB Saunders, 2002, p 631.

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Metabolism Drug metabolism may be increased by enzyme induction. Certain enzymes are modulated and can increase their function, thus increasing clearance of some agents. An example of this type is the accelerated clearance of muscle relaxants when a patient takes anticonvulsants such as phenobarbital or phenytoin. These agents increase the metabolic rate of the cytochrome P450 enzymes in the liver, which is responsible for metabolizing vecuronium and thus shortening its duration of action for any given dose. Enzyme induction generally takes days to weeks to occur, so it is not usually a concern after the acute administration of barbiturates. Therapeutic Index The therapeutic index is the ratio of the median lethal dose (LD50) to the median effective dose (ED50) of a drug. Agents with a high therapeutic index can be safely administered in large intermittent doses, because concern about overshooting the target concentration is less significant. If, however, the therapeutic index of an agent is small, continuous infusions minimize the overshoot that occurs with periodic boluses (Fig. 22-2).

Drug Interactions Saturable Effects If the desired effect sought with a particular drug is saturable with a single dose, then no advantage will be obtained with continuous infusion. An example of this behavior would be

A = Multidose B = Continuous infusion

3 Log concentration (␮g/mL)

Several other factors should be considered when assessing or predicting drug clearance. Considerable potential exists for drug interactions during the administration of anesthesia. First, patients often have concomitant medical conditions requiring medications. The conduct of anesthesia is by its very nature polypharmacy. Lastly, by acutely depressing central nervous system (CNS) responses, anesthetics may inhibit protective reflexes. Drug interactions come in many forms. Adverse interactions may result from physicochemical incompatibilities between drugs or intravenous fluids. Acidic drugs (e.g., barbiturates) dissolved in a basic solution may precipitate as the free acid if mixed with a drug in an acidic medium (e.g., nondepolarizing muscle relaxants). Anesthetic agents may affect the elimination of other drugs by altering the delivery of drug to the liver (i.e., hepatic blood flow) or hepatic enzymes (i.e., enzymatic induction or inhibition). For example, potent inhalational anesthetics are known to reduce liver blood flow and to prolong the clearance of drugs such as lidocaine, which is metabolized primarily by the liver and may have a prolonged duration of action in hepatic failure. Drug interactions may affect pharmacodynamics, when one drug increases (or decreases) the reactivity to another due to actions on similar membrane receptors or organ systems. Interactions involving CNS depressant drugs such as intravenous anesthetic agents (e.g., opioids and benzodiazepines) are among the most commonly seen by the intensivist.

2

Toxic concentration

A

Minimum effective concentration

1

B

0

1

2

3

4

5

6

Time (hrs)

7

8

9 10 End infusion

Figure 22-2. Multidose versus continuous infusions. A, Drug levels from multiple doses of a hypothetical drug. B, Continuous infusions of same hypothetical drug. Note repetitive decay below minimum effective concentration with intermittent dosing. (From Kirby RR, Gravenstein N, Lobato EB, Gravenstein JS: Clinical Anesthesia Practice, 2nd ed. Philadelphia, WB Saunders, 2002, p 642.)

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the H2 antagonists (e.g., cimetidine, ranitidine). At the maximal effective drug concentration, no further blockade of acid production occurs, regardless of additional drug administration. However, if the process is not saturable (as is the case for most intravenous anesthetic agents), providing the minimum effective concentration with a continuous infusion will maintain the desired pharmacologic effect.

cumulative doses. The marked prolongation of recovery time, with increasing duration of thiopental infusion, is reflected in an increase in its context-sensitive half time. At this point the duration of action is no longer related to redistribution but to a high volume of distribution and low clearance. In comparison, the context-sensitive half time of remifentanil remains virtually constant following prolonged infusions.

Offset of Action With the emergence of more intravenous agents with very short half-lives, the concept of offset of action—the time for resolution of pharmacologic effect once drug administration is discontinued—becomes more important. If the drug concentration is maintained just above the minimum effective concentration, discontinuing the infusion quickly allows the concentration to fall below the minimum effective concentration. If an intermittent bolus technique were used, prolonged distribution and elimination would be required for a recently administered bolus dose. Administrations of propofol or remifentanil are good examples of this approach. Maintenance of the drug level just high enough to provide anesthesia allows rapid emergence once the infusion is discontinued. A more delayed arousal would follow the administration of large intermittant boluses (see Fig. 22-2). Half-Life of Drug As previously mentioned, continuous infusions are best suited to drugs with short half-lives and rapid clearance.3 Because these drugs are eliminated from the blood rapidly, they would require numerous intermittent boluses. Clearly, remifentanil, with a half-life of 5 to 12 minutes, is much better administered by continuous infusion rather than intermittent boluses. Alternatively, morphine, with a half-life of 1.7 to 2.2 hours, can be delivered by intermittent bolus very effectively. Continuous infusions are also more cost effective because only enough of the drug is delivered to maintain the desired effect, thus, less of the total drug is administered. The decrease in costs can be substantial in the case of the newer, more expensive drugs. Finally, continuous infusions of drugs can be less labor intensive, because once the infusion is started less effort is required to maintain the pharmacologic effects. Context sensitive half-time is the time required for the central compartment drug concentration to decrease by 50% at the end of infusion as predicted by agent specific multicompartment pharmacokinetic models, where context refers to the duration of the infusion. The index is more useful in predicting the time course of recovery of many agents than is the elimination half-life.4,5 For example, barbiturates have a short duration of action that depends on redistribution. This is limited by lean mass and easily overwhelmed by larger

Continuous Infusions Maintenance of a particular steady-state drug level is required to sustain the desired pharmacologic effect.6 To achieve this, the amount of drug entering the body must equal the amount of drug being removed (cleared) from the body. We know that the concentration at steady state (Css) is determined by the following relationship: C ss = X o Cl where Xo is the amount of drug given per unit time, and Cl is the volume of blood cleared of the drug per unit time. Thus, for example, fentanyl (clearance of 12.7 mL/kg/min), administered by continuous infusion at a rate of 2 mg/kg/hr or 0.033 mg/kg/min, yields a steady state concentration of 0.0026 mg/mL (2.6 ng/mL). This value is within the minimum effective concentration range (1 to 5 ng/mL for analgesia and minimal respiratory depression). Knowledge of the clearance of a drug and the approximate minimum effective concentration in the blood allows prediction of the infusion rate necessary to achieve a particular level (Table 22-3). A steady-state drug concentration can be achieved with a constant infusion, but this is a slow process (see curve B in Fig. 22-2). This can be overcome by administering a loading dose (LD) as bolus or as a rapid priming infusion. The loading dose (LD) equals the target plasma concentration (Cp) multiplied by the volume of distribution (Vd): LD = Cp • Vd Thus, from the previous example, the loading dose of fentanyl (in a 70-kg patient using a Vd of 3.2 L/kg) would be: LD = (0.0026 mg mL) • (70 kg) • (3.2 L kg) • (1000 mL L) = 582 mg Intravenously administered agents require frequent dosing to maintain the minimum drug effect and concentration at the site of action, because they undergo redistribution and elimination according to the physicochemical properties of the drug. To eliminate the “peak and valley” effect of frequent intermittent administration, a continuous infusion technique is preferable.6 Figure 22-2 shows the relationship of multiple injections versus a continuous infusion of a drug with rapid clearance. It should be noted how continuous infusion dampens the oscillations in serum drug

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Table 22-3  Pharmacokinetic and Pharmacodynamic Parameters of Several Intravenous Anesthetic Agents

Agent Thiopental Methohexital Propofol Etomidate Ketamine Midazolam Diazepam Morphine Fentanyl Alfentanil Sufentanil Meperidine Remifentanil

Clearance Rate (mL/kg/min)

Volume of Distribution (L/kg)

Minimum Effective Concentration (mg/mL)

3.0–3.8 7.0–13.0 34–37 12–25 17–22 5.1–9.9 0.4 15–23 11–21 5.0–7.9 9.0–14 8.0–18 50–60

1.92–5.0 3.68 1.8–3.04 2.0–6.72 4.4–5.8 1.29–1.91 1.53 3.2–3.4 3.2–5.9 0.5–1.0 2.86 2.8–4.2 6.3–0.5

13–26 10 0.96–1.14 0.23–0.38 0.43–0.85 0.78–0.24 N/A 0.02–0.2 0.001–0.005 0.05–1.5 0.0005–0.001 0.1–0.5 N/A

From Kirby RR, Gravenstein N, Lobato EB, Gravenstein JS: Clinical Anesthesia Practice, 2nd ed. Philadelphia, WB Saunders, 2002, p 643.

levels that may cause toxicity at the peak or inadequate effect at the trough. Factors Affecting the Amount of Drug The minimum serum level of an intravenous agent for a particular procedure will vary with the type and degree of stimulus. Titration of the agent according to vital sign changes after surgical stimulus is necessary to fine-tune the requisite dose. This adjustment of the dose to the desired effect provides the best method of reaching steady-state levels that are appropriate for the stimuli provided. Pharmacokinetic parameters alone may lead to insufficient levels but do serve as a starting point from which one can increase the dose to provide the desired effect.

Commonly Used Agents in the Neurointensive Care Unit Anxiolytic and Hypnotic Drugs The ability to adequately assess neurologic function is paramount in neurosurgical patients. Thus, deep sedation is reserved for specific indications such as spine instability; severe increased intracranial pressure, or delirium. In the majority of neurologically injured patients, an artificial airway and mechanical ventilation are necessary. Whenever possible in these cases, sedation should be titrated to tolerance of the endotracheal tube or tracheostomy tube and to maintain the ability to rapidly perform a reliable neurologic examination.

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Barbiturates In the 1970s, Michenfelder demonstrated that barbiturates convey cerebral protection in primates during focal ischemia.7,8 They decrease cerebral metabolic rate for oxygen (CMRO2) up to 50%, in a dose-dependent fashion, coincident with an isoelectric electroencephalograph (EEG). Additional dosing beyond EEG suppression produces no further reduction in CMRO2, suggesting that the reduction in CMRO2 is secondary to the reduction in neuronal activity. This reduction is coupled with reduced cerebral blood flow and cerebral vasoconstriction and results in decreased intracranial pressure.9 Vasoconstriction occurs primarily in normal areas of the brain, as injured areas remain dilated, resulting in a reverse-steal redistribution of blood flow. Barbiturates are neuroprotective in focal but not global ischemia.10 Even in the most commonly used agent, sodium thiopental, the mechanism of neuroprotection is unclear. Many drug properties have been proposed to explain this effect, including decreased cerebral metabolic requirements, improvement of cerebral blood flow redistribution, suppression of catecholamine-induced hyper-reactivity, loss of thermoregulation, decreased intracerebral edema, decreased intracerebral pressure, decreased cerebrospinal fluid (CSF) secretion, scavenging of free radicals, membrane stabilization, calcium channel antagonism, and alteration of fatty acid metabolism.9 To date, thiopental is the only agent with prospective evidence of long-term cerebral protection in focal ischemia.11,12 The dose of thiopental in focal ischemia remains debated. Burst suppression of the EEG is commonly used as the end point for titration. Typically, 5 mg/kg of sodium thiopental is administered intravenously every 5 to 10 minutes until EEG burst suppression is achieved. An infusion of 15 to 20 mg/kg/hr is typically required to maintain burst suppression. The cerebral effects of pentobarbital are similar to thiopental. Methohexital is not a suitable agent for neuroprotection because it enhances epileptogenic activity in patients with focal seizures. Barbiturates cause a dose-dependent decrease in blood pressure, attributable to decreased vascular tone, decreased preload, and direct myocardial depression. For this reason, it is our practice to utilize a pulmonary artery catheter to monitor cardiac output and intravascular volume in all patients, even young ones, placed on prolonged barbiturates infusion for cerebral protection or intractable increased intracranial pressure. Hypotension, tachycardia, and lactic acidosis may be severe in hypovolemic patients.13 Anion gap metabolic acidosis often occurs and is secondary to a low cardiac output state and cerebral ischemia, and may be predicted by tachycardia following barbiturate loading.14 Resistant hypokalemia following severe life-threatening hyperkalemia has been reported following barbiturate coma with thiopental (Table 22-4).15

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Table 22-4  Barbiturate Characteristics Agents

• • •

Pentobarbital Thiopental Methohexital

CNS properties

• Vasoconstriction of normal cerebral arteries (direct?) • Decreased metabolic rate (CMRO2) • Free radical scavenger • Membrane stabilization • Lowers CPP • Anticonvulsant • Decreases CBF, CBV, ICP with preservation of carbon dioxide reactivity

Systemic properties

• Sedative-hypnotic • Dose-dependent cardiovascular and respiratory depression • Stimulate the hepatic cytochrome P450 mixed function oxidase microsomal enzyme system • Cardiovascular depression • Hyperalgesic • Venodilation • Diminished laryngeal reflexes

Mechanisms of action

• Facilitate inhibitory synaptic transmission by potentiating (GABA) mediated chloride influx at the GABAA receptor • Inhibit excitatory synaptic transmission by blocking glutamate receptors in the CNS • Antagonize postsynaptic glutamate receptors (NMDA) • Block voltage-dependent sodium channels

Pharmacokinetics

•

Redistribution

Metabolism

•

Hepatic

Excretion

• Renal (since barbiturates are weak acids, urinary pH will influence rate of excretion)

Adverse effects

•

(70% to 80%). They are both very lipid soluble with a short distribution (a phase) half-life (thiopental, 5 minutes; methohexital, 5 minutes), but with very different elimination (b phase, hepatic metabolism) half-lives (thiopental, 11 hours; methohexital, 4 hours). Drug redistribution is the basis for the short duration of effect and is most responsible for the clinical utility of the barbiturates.16

Pharmacodynamics In sufficient doses, barbiturates produce CNS depression that is termed general anesthesia and is attended by loss of consciousness (hypnosis) and amnesia. Although the response to pain and other noxious stimulation during general anesthesia appears to be obtunded, results of pain studies (tibial pressure in man) reveal that barbiturates may actually decrease the pain threshold.17 This antianalgesic effect only occurs at low blood levels of barbiturates, such as with small induction doses of thiopental or after emergence from thiopental when the blood levels are low. When given as a bolus, barbiturates decrease the mean arterial pressure (MAP) and cardiac output (CO), primarily due to depression of the medullary vasomotor center with a reflex increase in heart rate. The effect on central venous pressure is variable, but most agree that peripheral venous dilation causes reduced filling pressures, which in turn reduces CO and MAP. The barbiturates depress the medullary ventilatory center, resulting in a decreased tidal volume to the point of apnea. Apnea depends not only on the dose of barbiturate, but also to a great extent on any premedication used and any painful stimulus at the time. Induction doses of thiopental may suppress the adrenal cortex and decrease plasma cortisol levels. However, unlike etomidate, the adrenal suppression is rapidly reversible and responds to adrenocorticotropic hormone (ACTH).

Hypokalemia/hyperkalemia

CBF, cerebral blood flow; CBV, cerebral blood volume; CMRO2, cerebral metabolic rate for oxygen; CNS, central nervous system; CPP, cerebral perfusion pressure; GABA, gamma aminobutyric acid; ICP, intracerebral pressure.

Physicochemical Properties and Pharmacokinetics The barbiturates in clinical practice can be subdivided into two major groups, the oxybarbiturates and the thiobarbiturates, based on the substitution of the oxygen at the C2 position with sulfur. The substitution with a sulfur atom confers higher lipid solubility and a more rapidly acting drug (e.g., sodium thiopental). Addition of a methyl group in the C3 position of methohexital creates a fairly rapid-acting drug with fairly rapid recovery, but with a high incidence of excitatory phenomenon. The barbiturates are weak acids (thiopental pKa 7.6, methohexital pKa 7.9) that are also highly protein bound

Methohexital Sodium (Brevital) Methohexital is supplied as a sterile freeze-dried, nonpyogenic mixture of methohexital sodium with 6% anhydrous sodium carbonate added as a buffer. Vials of 500 mg can be reconstituted in 50 mL of sterile water, 5% dextrose in water, or 0.9% saline solution to a concentration of 10 mg/mL. It is recommended that reconstituted vials not be used after 24 hours. Methohexital is used as an induction agent, for supplementation of regional anesthesia, and as the sole anesthetic for short procedures requiring hypnotic induction (e.g., cardioversion). Suggested Dosing • Sedation: IV, 0.25 to 1 mg/kg

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• Induction: IV, 1.5 to 2.5 mg/kg IM, 7 to 10 mg/kg Rectal, 20 to 30 mg/kg; 5% aqueous solution for children (500 mg injectable powder in 10 mL sterile water given through a well-lubricated catheter) • Infusion: 50 to 150 mg/kg/min (0.2% solution; 500 mg in 250 mL of 5% dextrose in water or 0.9% saline solution to a concentration of 2 mg/mL). Do not administer intravenously in a concentration greater than 1% (10 mg/mL). Sodium Thiopental (Pentothal) Thiopental is supplied as a mixture of sterilized, yellowishwhite, hygroscopic powder of thiopental sodium (91.7%) with anhydrous sodium carbonate as a buffer. When reconstituted in sterile water as a 2.5% weight per volume (w/v) solution, it is strongly alkaline (pH 10.5) and will therefore precipitate many commonly used drugs. It is stable for 3 days at room temperature and for 7 days if refrigerated. Thiopental should not be used intravenously in concentrations exceeding 25 mg/mL because it may precipitate. Thiopental is used as an induction agent, for supplementation of regional anesthesia, as an anticonvulsant, for reduction of elevated intracranial pressure, and for cerebral protection (barbiturate narcosis). Suggested Dosing • Induction: IV, 3 to 5 mg/kg (children, 5 to 6 mg/kg; infants, 7 to 8 mg/kg) • Anesthesia supplementation: IV, 0.5 to 1 mg/kg • Anticonvulsant: IV, 0.5 to 2 mg/kg, repeat as necessary • Reduction in ICP: IV, 1 to 4 mg/kg • Barbiturate narcosis: IV bolus, 5 mg/kg as needed to maintain EEG burst suppression (mean total dose 40 mg/kg) Infusion, 5 to 20 mg/kg/hour, with inotropic support at high doses Adverse Effects/Precautions Premedication with opioids decreases the incidence of excitatory phenomena associated with induction doses of barbiturates, particularly with methohexital.18 It is recommended that the dosage be reduced in elderly, hypovolemic, hypertensive, uremic, septic, or high-risk surgical patients, especially when used concomitantly with narcotics or other sedative-hypnotics. Extravascular injection of barbiturates may cause necrosis, and intra-arterial injection may cause gangrene. Inadvertent intra-arterial injection is treated by injecting the artery with 10 ml of 1% procaine, 40 to 80 mg of dilute

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solution of papaverine, or local infiltration of phentolamine (2.5 to 5 mg in 10 ml) to produce vasodilation. Sympathectomy may be necessary and can be achieved by stellate ganglion block or brachial plexus block. Barbiturates are contraindicated in patients with latent or manifest porphyria (acute intermittent porphyria, variegate porphyria, and hereditary coproporphyria). Benzodiazepines Benzodiazepines (Table 22-5) were the mainstay of sedation in the ICU until 1986, when propofol was introduced in the United States. Benzodiazepines are excellent sedatives, and they also possess anticonvulsant, amnestic, hypnotic, and muscle-relaxant properties. The choice of which benzodiazepine to use is based primarily on pharmacokinetic parameters and cost. The elimination half-life of benzodiazepines increase with age and are decreased by agents that induce cytochrome P450 metabolic enzymes. Mild hemodynamic effects occur with continuous infusion. There is some evidence that midazolam causes direct vasodilation19; however, the agent decreases cerebral blood flow. Tolerance and dependence occur when benzodiazepines are administered chronically. Benzodiazepines alone have very little effect on the respiratory response to CO2 or hypoxia, but they have marked Table 22-5  Benzodiazepine Characteristics Agents

• Midazolam (t1/2 = 1.5–3 hr) • Lorazepam (t1/2 = 10–16 hr) • Diazepam (t1/2 = 20–50 hr)

CNS properties

• Anticonvulsant (including local anesthetic induced seizures) • Amnestic • Hypnotic • Decreases CBF (may be related to sedation) • Decreases CMRO2

Systemic properties

• Muscle-relaxant

Mechanism of action

• Binds GABAA receptors containing g subunits

Pharmacokinetics

• Redistribution • Elimination half-life increases with age

Metabolism

• Hepatic P450 • Long-acting active metabolites (oxazepam and desmethyldiazepam) with diazepam • No active metabolites with lorazepam, very short-acting metabolites with midazolam

Excretion

• Urinary excretion with minimal fecal clearance • Drowsiness, confusion, ataxia, paradoxical excitement

CNS adverse effects

CBF, cerebral blood flow; CMRO2, cerebral metabolic rate for oxygen; CNS, central nervous system; GABA, gamma aminobutyric acid.

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synergistic interactions with the effects produced by opioids. In a canine model, continuously infused midazolam decreases CBF and CMRO2 by up to 25%.20,21 Mechanism of Action Benzodiazepines act on specific receptor sites throughout the brain and spinal cord. Radioisotope binding studies have shown these to be most dense in the cerebral cortex, the hippocampus, and the cerebellum. Their effect is produced by the potentiation of certain inhibitory interneurons that use the neurotransmitter, gamma-aminobutyric acid (GABA). Upon release of GABA in the synapse, an increase in the flow of Cl- ions into the target neuron occurs, resulting in hyperpolarization. The nerve cell is thus made more refractory to any excitatory impulse. In the spinal cord, benzodiazepines cause increased availability of glycine, which acts as an inhibitory neurotransmitter. The benzodiazepines cause dose-related cerebral depression with increasing doses. All of these drugs can cause mild sedation, drowsiness, and even hypnosis. Certain pharmacokinetic differences determine the time of onset of intravenous benzodiazepines but in anesthetic practice, these are less important than their metabolism, particularly their breakdown to active metabolites and the duration of action of both the parent compound and the metabolite. Physicochemical Properties and Pharmacokinetics The benzodiazepines are all weak bases with high degrees of protein binding (Table 22-6). The distribution (a phase) half-lives and the elimination (b phase) half-lives of the benzodiazepines used in clinical practice vary considerably according to age and concomitant drug use. All are metabolized in the liver and excreted by the kidney. Because the metabolism of lorazepam is not entirely dependent on the hepatic microsomal enzymes, its elimination is less likely, as compared to diazepam, to be prolonged by alterations in hepatic function, age, or drugs such as cimetidine. Pharmacodynamics In a dose-related fashion, all of the benzodiazepines produce anxiolytic, sedative, hypnotic, amnesic, muscle relaxant, and

anticonvulsant effects, presumably due to facilitation of the inhibitory action of GABA or glycine on neuronal transmission. Additionally, all of these agents also decrease the CMRO2, cerebral blood flow (CBF), and ICP in the absence of hypoventilation. The benzodiazepines decrease MAP slightly as a result of a decrease in SVR with a modest increase in heart rate. More dramatic changes are seen with midazolam, possibly due to its high potency and rapid onset. It is recommended that doses are reduced in elderly, hypovolemic, and high-risk patients, as well as in those with concomitant use of other sedatives or narcotics. Unexpected hypotension and respiratory depression may occur when benzodiazepines are given with opioids, particularly in the elderly or in patients with other significant underlying medical conditions. In these patients, smaller doses should be considered. Modest respiratory depression will occur with all of the benzodiazepines; patients with chronic obstructive pulmonary disease (COPD) are unusually sensitive to the respiratory depressant effects. Diazepam (Valium) Diazepam is a colorless, crystalline base that is insoluble in water. The formulation available for IV injection contains 5 mg/mL in an aqueous vehicle composed of organic solvents consisting mainly of propylene glycol, ethyl alcohol, and sodium benzoate. With this formulation, to prevent thrombophlebitis, the agent must be slowly injected through large veins. Diazepam should not be mixed or diluted with other solutions or drugs. Diazepam, in addition to its use as a sedative-hypnotic, amnestic, anticonvulsant, and muscle relaxant, may be used for treatment of acute alcohol withdrawal. Suggested Dosing • Premedication/sedation: IV/IM/PO/rectal, 2 to 10 mg (0.1 to 0.2 mg/kg) • Induction: IV, 0.3 to 0.5 mg/kg • Anticonvulsant: IV, 0.05 to 0.2 mg/kg every 10 to 15 minutes; maximum dose 30 mg PO/rectal, 2 to 10 mg two to four times daily

Table 22-6  Properties of Commonly Used Benzodiazepines Benzodiazepine Properties

pKa

Percent Protein Binding

Distribution (min)

Elimination (hr)

Active Metabolites

Diazepam Lorazepam Midazolam

3.5 11.5 6.2

98.7 97 96

30–60 15–20 3–5

20–50 11–22 1.7–2.6

3 0 1

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• Acute alcohol withdrawal: IV, 5 to 10 mg (0.15 to 0.2 mg/kg) every 3 to 4 hours PO, 5 to 10 mg three or four times daily Lorazepam (Ativan) Lorazepam is a nearly white powder, almost insoluble in water. Each milliliter of injection contains either 2.0 or 4.0 mg of lorazepam and 0.18 ml polyethylene glycol in propylene glycol with 2.0% benzyl alcohol as a preservative. The drug must be refrigerated at 2°C to 8°C and protected from light and freezing. Lorazepam is used as a premedication for amnesia, as an anesthetic induction agent, as an anticonvulsant, for treatment of acute alcohol withdrawal, and for chemotherapyinduced or postoperative nausea and vomiting. Suggested Dosing • Sedation: IV/IM, 1 to 4 mg (0.002 to 0.08 mg/kg), it is recommended to dilute before IV administration with equal volume of 5% dextrose in water or 0.9% saline solution. For IM injection, use undiluted solution. PO, 2 to 3 mg twice or thrice daily (elderly 1 to 2 mg in divided doses) • Induction: IV, 0.5 to 1 mg/kg • Antiemetic: IV, 0.5 to 1.0 mg (0.01 to 0.02 mg/kg) PO, 1 to 2 mg two or three times daily Midazolam Hydrochloride (Versed) Midazolam is unique among the benzodiazepines in that it possesses the chemical property of a pH-dependent solubility. At a pH of less than 4.0, midazolam exists in an openring, water-soluble configuration. At pH values above 4.0, however, the ring closes, and the drug becomes highly lipid soluble. The drug is formulated in aqueous solution buffered to a pH of approximately 3.5; hence, it may burn when injected into a small caliber IV catheter. Because its pKa is 6.0, at the physiologic pH of 7.4, midazolam is largely unionized, as well as highly lipid soluble, and thus rapidly crosses the blood-brain barrier and other blood-tissue barriers. Midazolam is used as a premedication for amnesia, for conscious sedation, as an anesthetic induction agent, and for supplementation of anesthesia.22 Suggested Dosing • Premedication: IM, 2.5 to 10 mg (0.05 to 0.2 mg/kg) PO, 0.5 mg/kg (maximum 10 mg). Use high potency injectable solution (5 mg/mL). Dilute in 3 to 5 mL of

657

clear juice (may need extra sugar; solution is very bitter) or 5 mL of ibuprofen (Pediaprofen) for postoperative analgesia. Some may add atropine 0.03 mg/kg orally to reduce secretions Intranasal, 0.2 to 0.3 mg/kg. Use high-potency injectable solution (5 mg/mL) Rectal, 0.3 to 0.35 mg/kg. Dilute in 5 ml of normal saline. • Conscious sedation: IV, 0.5 to 5 mg (0.025 to 1.0 mg/kg). Titrate slowly to the desired effect (e.g., slurred speech) monitoring cardiac and respiratory function; continuous infusion, 0.25 to 1.0 mcg/kg/min with the same monitoring. Respiratory support may be required. • Induction: IV, I50 to 350 mg/kg Infusion, 0.25 to 5 mg/kg/min • Anticonvulsant: IV/IM, 2 to 5 mg (0.025 to 0.1 mg/kg) every 10 to 15 minutes as needed. Adverse Effects/Precautions Benzodiazepines are contraindicated in patients with acute narrow angle or open angle glaucoma unless they are receiving appropriate therapy for these problems. Respiratory depression and arrest may occur when used for conscious sedation, especially in the elderly when combined with other agents such as opioids, propofol, or both. Hypovolemic, high-risk surgical patients or patients with COPD are also at risk of respiratory depression with this drug. Flumazenil (Romazicon) Flumazenil is a benzodiazepine receptor antagonist with little or no agonist activity, which reverses sedation without causing respiratory depression. It competitively inhibits the binding of benzodiazepines at the benzodiazepine recognition site on the GABAA receptor complex and reverses sedation, respiratory depression, amnesia, and psychomotor effects of benzodiazepines. The administration of flumazenil to patients given agonists is remarkably free of cardiovascular effects, unlike opioid reversal with naloxone. Excessive sedation may occur and, in fact, is more common with larger doses of benzodiazepines and long procedures; it is in such cases that flumazenil is used. Recurrence of sedation is avoided by initiating a flumazenil infusion of 0.1 to 0.5 mg/hour, because the elimination half-time is short (0.7 to 1.3 hours) compared to that of the benzodiazepines. When benzodiazepines are administered chronically as an infusion, the effects of flumazenil are less pronounced and of shorter duration.19 Flumazenil reversal tends to have a greater effect on respiratory depression and sedation than on benzodiazepine amnestic properties. Contraindications include seizures and benzodiazepine dependence. Flumazenil produces withdrawal symptoms (seizures,

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emergent confusion, and agitation) in the presence of physical dependence. Suggested Dosing IV bolus: 0.2 to 1 mg (4 to 20 mg/kg) at a rate of 0.2 mg/min. Titrate to patient response. May repeat at 20-minute intervals. Maximum single dose, 1 mg. Maximum total dose, 3 mg in any one hour. Lack of patient response at five minutes after cumulative dose above 5 mg implies that the major cause of sedation is unlikely to be benzodiazepines.

Other Agents Propofol (Diprivan) Propofol (Table 22-7) is a lipophilic, hindered phenol that is chemically dissimilar to any of the other compounds used in anesthesia. It is insoluble in water and is currently available as a 1% w/v aqueous emulsion containing 10% w/v soybean oil, 1.2% w/v egg phosphatide (lecithin) and 2.25% w/v glycerol with a pH of 6 to 8.5. It should be stored at 4°C to 22°C. Refrigeration is not recommended. The emulsified drug must be shaken well before use. The soybean-fat emulsion vehicle of propofol supports rapid growth of bacteria; thus, strict aseptic technique must be maintained during handling. Recent formulations contain EDTA or metabisulfite as preservatives. The ampule should be discarded after a single use and the drug administered within 6 hours after the ampule has been opened.

Table 22-7  Propofol Characteristics Agent

•

Propofol

CNS properties

• Lowers CBF, CMRO2, ICP, CPP • EEG shift from alpha to delta waves, burst suppression at higher doses • Somatosensory evoked potentials show increased latency and decreased amplitude • Antiemetic • Antioxidant

Systemic properties

•

Cardiovascular effects

Mechanism of action

•

Potentiates and directly stimulates GABAA receptors at both spinal and supraspinal synapses

Pharmacokinetics

• “Context-sensitive” t1/2 approximately 40 minutes

Metabolism

• Hepatic and extrahepatic metabolism to inactive glucuronide and sulfate derivatives

Adverse effects

• Anaphylactic reactions • Pain on injection

Propofol may be used for conscious sedation, as an induction agent, and for maintenance of anesthesia.23,24 While propofol can cause EEG burst suppression,25 it has not been demonstrated clinically to be a neuroprotective to date. Thiopental decreases lipid peroxidation and improves ultrastructure, whereas propofol decreases lipid peroxidation without improving ultrastructure 1 hour after spinal cord injury in rats.26 Mechanism of Action Several studies have demonstrated that propofol enhances synaptic inhibition mediated by GABA, much like barbiturates and benzodiazepines. However, each individual anesthetic agent causes qualitatively different patterns of GABAA-mediated synaptic inhibition and consequently on the firing pattern of neurons. Although the GABAA receptorion channel complex is involved in the anesthetic state, no uniform action of anesthetics at the molecular level can explain the anesthetic action. Thus, it would appear that the actions of general anesthetics are amazingly complex. Physicochemical Properties and Pharmacokinetics Propofol is a weak acid (pKa 11) with a significant amount of protein binding (98%). The distribution (a phase) halflife is 2 to 8 minutes, and the elimination (b phase) half-life is 4 to 7 hours, with propofol undergoing hepatic and extrahepatic (pulmonary) metabolism. Much like any drug with a high degree of protein binding, in extremely hypoalbuminemic patients, propofol has an enhanced effect. However, the key pharmacokinetic parameter responsible for the rapid offset of the action of propofol compared to sodium thiopental or methohexital is its faster clearance,27 demonstrated in Figure 22-3. Suggested Dosing • Sedation: IV bolus, 0.1 to 1.0 mg/kg, titrate slowly to the desired effect (e.g., onset of slurred speech); infusion, 20 to 75 mg/kg/min, monitoring respiratory and cardiac function continuously • Anesthetic induction: IV, 2 to 4 mg/kg (give slowly over 30 seconds in two to three divided doses) • Anesthetic maintenance: IV bolus, 25 to 50 mg; infusion, 100 to 200 mg/kg/min • Antiemetic: IV, 10 mg Pharmacodynamics Propofol decreases the CMRO2, CBF, and ICP, but may significantly decrease cerebral perfusion pressure (CPP) due to its effect on MAP. It causes minimal excitatory activity (myoclonus) compared to etomidate. The proconvulsant effects of propofol may represent activation of epileptogenic foci, whereas the anticonvulsant effects are most likely due to nonspecific cortical depression, rather than elevation of seizure threshold.

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1.0 A B 0.1 C

0

4

8

12

16

20

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pain include injecting into a large vein and/or mixing IV lidocaine (0.1 mg/kg) with the dose of propofol. Other premedicants such as small doses of fentanyl (50 to 100 mg) or ketamine (50 mg) can lessen the pain on injection. The incidence of venous thrombophlebitis is much less common with the current formulation; the previously available cremophor preparation was much more irritating. Histamine release may occur with rapid injection, and allergic reactions may likely manifest as anaphylaxis. The use of propofol is contraindicated in patients allergic to eggs or soybeans. Compared with thiopental, induction doses of propofol may be associated with high umbilical vein concentrations, muscular hypotonia, and lower neonatal Apgar scores at 1 and 5 minutes. Therefore, it should be used with caution during cesarean section.

A = Thiopental B = Methohexital C = Propofol

10 Ln concentration (␮g/mL)

Pharmacotherapy in the Neurosurgical Intensive Care Unit

24

Time (hrs) Figure 22-3. Thiopental, methohexital, and propofol level profiles. A, Thiopental level profile for a single dose, 6.1 mg/kg, intravenous; B, methohexital level profile for a single dose, 2.9 mg/kg, intravenous; C, propofol level profile for a single dose, 2.5 mg/kg, intravenous. (From Kirby RR, Gravenstein N, Lobato EB, Gravenstein JS: Clinical Anesthesia Practice, 2nd ed. Philadelphia, WB Saunders, p 635.).

Propofol directly depresses myocardial contractility and decreases SVR, resulting in hypotension. The MAP may be decreased by as much as 15% to 31%, even in patients without cardiovascular disease, as a result of the decrement in CO and SVR.28 A single induction dose of propofol (2 to 4 mg/kg) causes a profound reduction of tidal volume with a period of apnea varying from 30 to 60 seconds. The incidence of apnea approaches 100% when administered with a premedication such as an opiate or benzodiazepine. While propofol has no effect on resting bronchomotor tone, it does significantly depress laryngeal reflexes much more than barbiturates or etomidate. Propofol does not cause significant hepatic enzyme derangements and, compared to other agents, in particular etomidate, causes less nausea and vomiting. In fact, propofol has intrinsic antiemetic effects. Similar to thiopental, propofol has no significant effect on adrenocortical function. Adverse Effects/Precautions As with other intravenous agents, it is recommended that the doses be reduced in elderly, hypovolemic, and high-risk surgical patients or with concomitant use of narcotics and sedative-hypnotics. Pain frequently occurs on injection into small veins, especially on the dorsum of the hand. Methods to minimize the

Etomidate (Amidate) Etomidate (Table 22-8) is a carboxylated imidazole derivative that is chemically unrelated to any other induction agent used in anesthesia. Etomidate is a pure hypnotic with no analgesic properties although it is an effective intravenous anesthetic agent exhibiting favorable hemodynamic properties with minimal respiratory depression. The agent produces rapid unconsciousness within about 30 seconds following IV administration. Etomidate is supplied as a white crystalline salt powder that is soluble in water but unstable in aqueous solution. Only the dextro (+) isomer is pharmacologically active as a hypnotic. The only formulation currently available in the United States is a 2 mg/mL solution in a 35% propylene glycol vehicle. This formulation has a pH of 6.9. Etomidate appears to be compatible in intravenous solution with all medications commonly utilized during induction, except for vecuronium. Like the barbiturates, etomidate causes cerebral vasoconstriction and decreases intracranial pressure.29 Anticonvulsant activity has been documented in animals;30 however, activation of seizure foci has been demonstrated in humans.31 CMRO2 is reduced in a less uniform way than with thiopental; cortical activity is reduced more than that of the brainstem. Adverse effects, however, have resulted in reduced clinical use. These adverse effects have included injection site pain (which may be prevented by local anesthetic preinjection), thrombophlebitis, myoclonus, nausea and vomiting, and most importantly, inhibition of steroid synthesis. Nausea and vomiting appear to be particularly associated with etomidate compared to other induction drugs and is made worse by concurrent use of opioids. Mechanism of Action Etomidate potentiates the CNS inhibitory neurotransmitter, GABA, at the GABAA receptor and depresses the reticular activating system. It has disinhibitory effects on parts of the

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Table 22-8  Etomidate Characteristics Agent

•

Etomidate

CNS properties

• Lowers PaCO2, CBF, ICP, CMRO2 without decreasing CPP • Myoclonic movements • EEG: delta waves and activation • SSEPs: significantly increased cortical amplitude and smaller increase in latency; however, SSEPs at the spinal cord are unchanged • Lowers seizure threshold

facturer’s package insert does not recommend use in children younger than 10 years old because of the lack of adequate data for dosage recommendations.

Physicochemical Properties and Pharmacokinetics Etomidate is a weak base (pKa 4.2) with a moderate degree of protein binding (75%). The distribution (a phase) halflife is 3 minutes, and the elimination (b phase) half-life is 3 to 5 hours.

Pharmacodynamics Etomidate decreases the CMRO2, CBF, and ICP. Because of its minimal effect on systemic blood pressure, it is more successful than thiopental or propofol in maintaining CPP. Etomidate appears to lower the seizure threshold in individuals with focal seizure disorders, but acts similarly to thiopental as a protectant against generalized seizure activity. Myoclonic movements occur in about one third of patients during induction and are due to disinhibition of subcortical suppression of extrapyramidal activity. A potentially significant disadvantage of etomidate is its lack of analgesic efficacy; thus, it does not blunt any transient sympathetic response to endotracheal intubation. Etomidate causes the least hemodynamic changes of any induction agent, with minimal decreases in heart rate, MAP, and SVR.32 The mean duration of apnea following an induction dose of 0.3 mg/kg is 20 seconds. Excitatory effects of coughing, vocalization, and hiccoughing are seen in approximately 10% of patients given etomidate. Postoperative nausea and vomiting can occur in up to 30% to 40% of patients. This incidence compares with an incidence of 10% to 20% with methohexital and thiopental, and even less with propofol. The diffusible fraction of etomidate increases in hepatic and renal disease, thus the induction dose may need to be decreased. Adrenocortical suppression of both cortisol and aldosterone production, which may occur after a single induction dose, is predominantly due to etomidate-induced inhibition of the enzyme, 11-b hydroxylase.33 The relative reduction of cortisol and aldosterone levels starts approximately 30 minutes after a single induction dose and lasts 5 to 15 hours. However, a single dose use of etomidate has not been shown to have any adverse clinical effect as a result of its transient inhibition of corticosteroid synthesis. The only reports of clinically important consequences of etomidate on corticosteroid production have been when used by continuous infusion for days or weeks in the ICU setting.34 If concern exists regarding adrenal suppression by etomidate, cortisone can be administered to protect against ongoing stress.

Suggested Dosing • IV induction: 0.1 to 0.6 mg/kg • Infusion: 0.25 to 1 mg/min (5 to 20 mg/kg/min). Continuous infusion is not recommended (see following) • Rectal: In children 6 months to 6 years old, 6.5 mg/kg produces reliable hypnosis in 4 minutes but maintains a rapid recovery without any untoward effects. The manu-

Adverse Effects/Precautions It is recommended that large veins be used for injection of etomidate, since pain occurs in the majority of patients, and is more likely if injected rapidly into small veins. Comparative studies have demonstrated that propofol and methohexital have similar or slightly lower incidence of pain on injection, whereas pain with thiopental injection is much less common. A high incidence of venous thrombophlebitis is associated with etomidate (24% compared to 4% with thiopental) and is thought to be related to the

Systemic properties

•

Hemodynamic stability with respect to cardiac index, blood pressure and preload • No histamine release

Mechanism of action

•

Pharmacokinetics

• Rapid onset and offset due to extensive redistribution (half-time 1 min)

Metabolism

• Hepatic and plasma ester hydrolysis as well as N-dealkylation • Metabolites are inactive and excreted by renal and biliary routes

Excretion

•

Adverse effects

• Lowers seizure threshold • Nausea and vomiting • Adrenocortical suppression (via 11-beta hydroxylase inhibition) • Pain on injection • Thrombophlebitis • Myoclonus

Same as propofol

Renal

central nervous system that control extrapyramidal motor activity. Etomidate can be used for induction or supplementation of anesthesia.

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propylene glycol vehicle. Etomidate does not cause histamine release. Myoclonus, often seen on induction, may be reduced by slower injection and by premedication with benzodiazepines or opioids 1 to 2 minutes before injection of etomidate. Ketamine HCl (Ketalar) Ketamine (Table 22-9) produces a condition known as dissociative anesthesia, which is quite different from conventional anesthesia. It is a sedative hypnotic used to provide anesthesia for short procedures, as an induction agent, as an adjunct to supplement low-potency anesthetics such as nitrous oxide, and as a supplement to local and regional anesthesia.35 Ketamine produces an anesthetic state characterized by profound analgesia, normal pharyngeal-laryngeal Table 22-9  Ketamine Characteristics Agent

•

Ketamine

CNS properties

• • • • • • • • •

Potent cerebral vasodilator Transient cortical blindness Emergence delirium Amnesia Analgesia Sedation Dissociative anesthesia at higher doses Tonic/clonic movements Nystagmus, diplopia

Systemic properties

•

Sympathomimetic resulting in tachycardia, hypertension, increased myocardial and cerebral oxygen consumption, increased cerebral blood flow, and increased intracranial and intraocular pressures Direct myocardial depressant Minimal respiratory depression Increased secretions Bronchodilation

• • • • Mechanism of action

•

Noncompetitive blockade of N-methylD-aspartate (NMDA) receptors

Pharmacokinetics

• Elimination half-life of ketamine is 2 to 3 hr • Typical anesthetic duration: 5 to 10 min • Typical analgesic duration: 15 to 30 min • Typical amnestic duration: up to 2 hr

Metabolism

• Redistribution and hepatic biotransformation to an active metabolite (norketamine)

Excretion

• Metabolites are primarily (90%) excreted by the kidney

Adverse effects

• • • •

Cerebral vasodilation Tremors Tonic clonic movements Hallucinations

661

reflexes, normal or slightly enhanced skeletal muscle tone, cardiovascular and respiratory stimulation, and occasionally transient, minimal respiratory depression. This state has been described as “a dissociation of the limbic from the thalamoneocortical systems.”36 Ketamine is used for induction and maintenance of anesthesia, especially in the hypovolemic or high-risk patient, as well as the sole anesthetic for short surgical procedures,37 but is a poor choice for sedation in patients with neurologic injury due to its propensity for delirium. In addition, ketamine has been shown to significantly increase CBF (and thus ICP) in both humans38,39 and dogs40; this increase can be blocked by pretreatment with thiopental in the canine model.40 Ketamine is supplied as a solution for injection in concentrations of 10 mg/mL, 50 mg/mL, and 100 mg/mL. It should be stored at room temperature (15°C to 30°C), and protected from light and heat. One must avoid mixing ketamine with barbiturates in same syringe because precipitates may form. Mechanism of Action Ketamine likely interacts with more than one type of pharmacologic receptor to produce its effects. The analgesia appears to be at least partially mediated by opioid receptors at the brain, spinal cord, and peripheral sites. Ketamine binds preferentially to mu, rather than the delta, opioid receptor. Ketamine has been shown to interact with sigma receptors, which may mediate the dysphoria that can be induced by ketamine. Ketamine has been shown to be a potent, noncompetitive, N-methyl-D-aspartate (NMDA) receptor antagonist. NMDA inhibition produces catalepsy, consistent with the effect of ketamine administration. It is suggested that this may be the mechanism for its anesthetic and behavioral effects. Physicochemical Properties and Pharmacokinetics Ketamine is a weak base (pKa 7.5) with minimal protein binding (12%). It is, however, highly lipid soluble (five to ten times more than thiopental). The distribution (a-phase) half-life is 15 minutes, and the elimination (b phase) halflife is 2 to 3 hours. Suggested Dosing • Sedation/Analgesia: IV, 0.5 to 1 mg/kg IM/Rectal, 2.5 to 5 mg/kg PO, 5 to 6 mg/kg. Dilute injectable solution in 5 to 10 mL (0.2 mL/kg) of flavored drink • Induction: IV, 1 to 2.5 mg/kg IM/Rectal, 5 to 10 mg/kg • Infusion: 15 to 80 mg/kg/min (augment with 2 to 5 mg IV diazepam or 1 to 2 mg IV midazolam as needed)

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Dilution for infusion, 250 mg ketamine in 250 mL 5% dextrose in water or 0.9% saline solution (1 mg/mL).41 • Epidural/Caudal: 0.5 mg/kg; dilute (preservative-free) NS or local anesthetic (1 mL/kg) Pharmacodynamics The major effects of ketamine administration involve the CNS. The “dissociative state” refers to a functional and electrophysiological separation of the thalamo-neocortical and limbic systems. In this state, it is believed that the brain fails to correctly transduce afferent impulses because of disruption in normal communication between the sensory cortex and the association areas. The result resembles catalepsy in which the eyes may remain open with slow nystagmus and intact corneal reflexes. Patients are generally noncommunicative though they may appear to be awake. Ketamine poses a unique problem when assessing the level of sedation or anesthesia, since it is often difficult to assess a clear endpoint when ketamine is administered. Although ketamine can activate epileptiform foci in patients with known seizure disorders, it paradoxically appears to possess anticonvulsant properties. Ketamine potently vasodilates cerebral blood vessels, increasing cerebral blood flow by 62% to 80%, and thus may increase ICP. In addition, ketamine causes an increase in CMRO2. This effect is reduced if diazepam, midazolam, or thiopental is administered before the ketamine. Nevertheless, increased intracranial pressure contraindicates the use of ketamine. Ketamine also differs from most anesthetic agents in that it appears to stimulate the cardiovascular system, producing increases in mean arterial pressure, pulmonary artery pressure, central venous pressure, heart rate, and cardiac output. The central sympathetic stimulation, neuronal release of catecholamines, and inhibition of neuronal uptake of catecholamines usually override the direct myocardial depressant effects of ketamine. These sympathomimetic effects of ketamine administration tend to increase myocardial oxygen demand, and thus are contraindicated in patients with significant ischemic heart disease. Alpha-blockers, betablockers, and calcium channel blockers may unmask the direct myocardial depressant effect of ketamine. Ketamine seems to be unique in its ability to maintain functional residual capacity (FRC) upon induction of anesthesia. In spontaneously breathing patients, the minute ventilation may be maintained at the same level as in the conscious state. Because skeletal muscular tone is maintained during ketamine anesthesia, atelectasis or changes in ventilation-perfusion and FRC do not occur. Ketamine has other beneficial effects on the respiratory apparatus, including increased lung compliance and decreased airway resistance. Bronchodilation induced by ketamine is not affected by histamine, acetylcholine, potassium chloride, propranolol, or indomethacin. While ketamine is reported to maintain laryngeal tone and reflexes with lower doses, care must

be taken as there are reported cases of pulmonary aspiration of secretions. Ketamine is a potent stimulator of salivary and tracheobronchial secretions, and diligent suction of the oral cavity is required in the nonintubated patient to decrease the possibility of coughing and aspiration, and to prevent laryngospasm, especially in children. The antisialogogue effects of glycopyrrolate and atropine are effective in reducing these secretions. Adverse Effects/Guidelines Emergence reactions are more common in adults, particularly those between 15 and 65 years of age, who have received rapid administration of high doses of ketamine. The incidence of these reactions can be reduced by premedication with benzodiazepines or droperidol; our preference is to use the former class of drugs for this reaction. As mentioned previously, critically ill patients with catecholamine depletion may respond to ketamine with unexpected reductions in blood pressure and cardiac output. Ketamine should be used with caution in patients with severe hypertension, ischemic heart disease, or aneurysms. It is also advised that one avoid the use of ketamine after topical nasal cocaine, in acute cocaine intoxication, in chronic alcoholics, the acutely alcohol-intoxicated patient, or with concomitant administration of sympathomimetics. Hypertension, dysrhythmias, and myocardial ischemia may occur. Ketamine-induced increases in intracranial pressure may be attenuated by hyperventilation and benzodiazepine pretreatment.

Opioids Opioids (Table 22-10) are stereospecific agonists acting at mu-(m-)receptors located at presynaptic and postsynaptic sites in the CNS and peripheral nervous system. All opioids produce dose-dependent depression of brainstem ventilatory centers primarily via the m-receptor.42 The depression is characterized by a shift in the CO2 response curve to the right. Pontine and medullary centers that regulate the rhythm of ventilation are also affected, possibly via acetylcholine. Physostigmine may antagonize this depression without affecting analgesia.43 Opioids administered in the epidural space can be detected in the CSF. Penetration is affected by lipid solubility and molecular weight. Fentanyl and sufentanil are 800 and 1600 times more lipid soluble than morphine, respectively. Epidural administration results in peak CSF concentrations of sufentanil in 6 minutes, fentanyl in approximately 20 minutes, and morphine in 1 to 2 hours. Absorption of opioids from the intrathecal space to the systemic circulation is similarly affected. Blood concentrations of sufentanil peak in 5 minutes, of fentanyl in 5 to 10 minutes, and of morphine in 10 to 15 minutes.44 These peak systemic concentrations are similar to concentrations produced by an intramuscular

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Table 22-10  Opiate Characteristics Opiates

• • • •

Morphine Fentanyl Sufentanil Remifentanil

CNS properties

• • • •

Decreased CBF and possibly ICP No change in CMRO2 Analgesia Euphoria/dysphoria

Systemic properties

• • • •

Respiratory depression Miosis Decreased gastrointestinal motility Increase smooth muscle tone in the antral portion of the stomach, the small intestine (especially the duodenum), the large intestine • Decreased secretions from the stomach, pancreas, and biliary tract • Increased tone of the bladder detrusor muscle, ureters, and vesical sphincter • Bradycardia

Mechanism of action

• mu-(m-), delta- (d-), kappa- (k-), sigma-(s-), and epsilon- (e-) opioid receptor agonist

Pharmacokinetics

• Peak analgesia occurs within minutes • 30 to 60 minute duration after a single dose • 80% to 85% protein bound but free fraction increased with acidosis

Metabolism

• Hepatic metabolism via cytochrome P450 (CYP) 3A4

Excretion

• Urine

Adverse effects

• Hypoventilation • Constipation

injection.45 Opioids decrease neurotransmission primarily by presynaptic inhibition of neurotransmitter release of acetylcholine, dopamine, norepinephrine, and substance P, as well as by postsynaptic inhibition of neuronal activity.43 In the absence of hypoventilation, opioids decrease cerebral blood flow and possibly intracranial pressure.46 In humans and animal models, and in the absence of other anesthetics, CMRO2 is either unchanged or decreased in the presence of sufentanil, fentanyl, or morphine.47 Opioids should be used with extreme caution in patients with acute head injury because of alteration in mental status, miosis (which interferes with the pupil neurologic examination), and ventilatory depression (which may increase PaCO2 and thereby increase ICP). Lack of blood-brain barrier integrity following head trauma and intracranial surgery may increase the sensitivity to opioids.48 Both sufentanil and fentanyl are associated with increases in ICP of 6 to 9 mm Hg despite constant tension PaCO2.49,50 These increases in ICP are accompanied by a decrease in mean arterial pressure and CPP, and may be linked, because prevention of hypotension prevents the increase in ICP.51 When used clinically,

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there is no evidence that opioids induce major changes in cerebral hemodynamics. Because opioids do not alter cerebrovascular CO2 reactivity, their use in combination with hypocapnia accounts for a favorable effect on brain volume and ICP.52 Receptor Activation and Mechanism of Action All opioid analgesics activate specific cell surface opioid receptors in both the CNS and peripheral nervous system. It is this receptor activation that is responsible for both the desirable and undesirable pharmacologic effects. Five receptor classes (m, d, k, s, and e) have been identified on the basis of pharmacologic studies. Subtypes of the m, d, and k receptors have not only been characterized pharmacologically, they also have been successfully molecularly cloned in the laboratory. A newer nomenclature classifies the opioid receptors as OP1 (d), OP2 (k), and OP3 (m). The different receptors activated by the opioid agents account for the spectrum of responses that are seen clinically. Mu (m) receptor activation by opioids within the brain is not only responsible for the analgesia, but also the ventilatory depression, euphoria, and physical dependence seen with this class of drugs. Kappa (k) receptor occupation in the spinal cord results in analgesia, as well as in depression of ventilation, sedation, and miosis when supraspinal k receptors are activated. The activation of sigma (s) receptors results in dysphoria, hallucinations, and vasomotor and ventilatory stimulation. Delta (d) receptors modulate the effect of the m receptors, which may account for some of the tolerance seen when narcotics are administered over a prolonged period. Although knowledge of the different receptors may not seem to have direct clinical application, it may help to understand how the various agents might interact. For example, if epidural morphine is administered to obtain analgesia by activating k receptors in the spinal cord, nalbuphine can be administered intravenously to attenuate the undesirable m-mediated side effects of pruritus or nausea. Interestingly, the side effects are activated by peripheral receptors, which can be blocked whereas the centrally mediated analgesia is unimpaired. Physicochemical Properties and Pharmacokinetics For highly lipid soluble drugs, such as fentanyl, the onset of action reflects their circulation time to the CNS, because they can rapidly penetrate cell membranes. Drugs that are much less lipid-soluble, such as morphine, have a slower onset due to the relatively slow penetration of the bloodbrain barrier. Opioids in blood are bound to proteins such as albumin and a1-acid glycoprotein. Chronic changes in plasma proteins, seen in debilitated, malnourished patients, or those with congestive heart failure, can result in higher concentra-

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tions of free opioid for a given dose, and the dose required for a given intensity of effect will be less. Protein binding varies considerably between the different narcotic agents. Morphine is 36% protein bound, whereas sufentanil is 92% protein bound. As noted previously, context sensitive half-time is important. At lower doses, redistribution plays a significant role in the short duration of effect for several opioids. As higher doses are given, particularly for longer periods of time, the peripheral tissues accumulate the opioid, with a lower concentration gradient between blood and the peripheral tissues. Hence, a lesser amount of drug moves into the tissues, and the decline in plasma (blood) concentrations due to redistribution is of progressively less importance. At that point, most of the decline depends on the elimination processes: metabolism and excretion. After a 4-hour infusion, the time required for a 50% reduction in concentration is markedly prolonged for fentanyl but only moderately prolonged for sufentanil and alfentanil, while it remains very short for remifentanil.53 For long operative cases with continuous narcotic infusions, this difference may be significant (Table 22-11). Most opioids are metabolized in the liver. Morphine is conjugated with glucuronic acid, resulting in active (morphine-6-glucuronide) and relatively inactive (morphine-3glucuronide) metabolites. Meperidine is N-demethylated to normeperidine, which is also hydrolyzed to meperidinic acid. Normeperidine has an elimination half-life that is five to six times that of meperidine and it can accumulate, producing CNS excitation manifested as tremors, muscular twitching, and seizures. Fentanyl, sufentanil, and alfentanil are also metabolized in the liver (N-dealkylation, hydroxylation, and conjugation), and their pharmacokinetics are altered by changes in liver blood flow. These metabolites are excreted by the kidneys, but since they are pharmacologically inactive, changes in renal function do not prolong the duration of action of these three opioids. Remifentanil is uniquely metabolized by ester-hydrolysis catalyzed by nonspecific esterases present in the blood and tissues. Because remifentanil is metabolized in multiple tissues, its elimination is essentially independent of hepatic or renal function. The metabolite

Table 22-11  Elimination of Opioids

Opioid Morphine Meperidine Fentanyl Sufentanil Alfentanil Remifentanil

Elimination Half-time (hr)

Context Sensitive Half-time Following a 4-hr Infusion (min)

1.7–3.3 3–5 3.1–6.1 2.2–4.6 1.4–1.5 0.17–0.33

— — 260 30 60 4

produced by the hydrolysis of remifentanil is pharmacologically active but its potency is extremely low and does not affect the duration of action of the parent drug. A small portion of remifentanil undergoes N-dealkylation. Pharmacodynamics Activation of m-type opioid receptors in the brain and spinal cord produces analgesia, sedation, cough suppression (antitussive effect), as well as obtundation of somatic, autonomic, and endocrine responses to noxious stimulation. Actions on m-type opioid receptors in other parts of the CNS lead to ventilatory depression to the point of apnea; nausea at small doses, due to stimulation of the chemoreceptor trigger zone, with large doses depressing the vomiting center; bradycardia, which is mediated by the vagal nerves; and hypotension, likely related to inhibition of reflexes modulating sympathetic nervous system activity, thereby reducing sympathetic outflow to vascular smooth muscle in veins and arterioles. Outside the CNS, m-type opioid receptors mediate the constriction of smooth muscle (e.g., the sphincter of Oddi causing biliary colic, the gastrointestinal tract causing constipation, and the ureter causing renal colic). Morphine and some of its derivatives, as well as meperidine, induce histamine release from mast cells, which can produce hypotension, cutaneous erythema, and pruritus. The latter can also result from effects on the CNS by an unknown mechanism involving sympathetic nerves. Another CNS action that is incompletely understood is the increase in skeletal muscle activity that is most prominent with relatively large doses of m-receptor agonists. It has a variety of manifestations including glottic closure, truncal rigidity, flexion, and, occasionally, flapping of the extremities in a seizure-like movement with no electroencephalographic manifestations of seizures. This so-called rigidity typically occurs at doses that induce apnea and may interfere with positive-pressure ventilation due to glottic closure or decreased thoracic compliance. Induction of Anesthesia Opioids have been used for induction of anesthesia, but this typically requires extremely high doses of narcotics: 25 to 100 mg/kg of fentanyl, 10 to 20 mg/kg of sufentanil, 50 to 250 mg/kg of alfentanil, or a bolus of 0.5 to 1 mg/kg ideal body weight, followed by a continuous infusion of from 0.025 to 0.4 mg/kg/minute of remifentanil. With such large doses, hormonal (cortisol or epinephrine release) and hemodynamic responses to surgical stimulation are blunted or prevented.54,55 Although analgesia with such doses is excellent, high-dose opioid techniques have associated problems. Muscle rigidity, particularly of the thoracic cage, is common, with the incidence of occurrence directly related to the potency of the narcotic used (remifentanil > sufentanil > alfentanil >

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fentanyl > morphine). Neuromuscular blocking agents are often necessary to inhibit this effect and allow ventilation. Another substantial problem with high-dose opioid techniques is recall. The addition of small doses of benzodiazepines or inhalational agents virtually eliminates this problem. Opioid Agonists Although activation of a specific opioid receptor produces a specific effect, all available opioid agents can variably activate all receptors. Some opioids, such as fentanyl, are more pure m-type receptor agonists; that is, they activate primarily one receptor and produce a positive response without activating multiple receptors or blocking other drug effects.

Morphine Sulfate The oldest opioid available for clinical use, morphine is an alkaloid extract of opium that exerts its primary effects on the CNS and organs containing smooth muscle. Morphine produces dose-related analgesia, drowsiness, euphoria, respiratory depression, blockade of adrenocortical response to stress at high doses,54 and reduction in peripheral resistance due to arteriolar and venous dilation. Morphine can be used for premedication, as an analgesic, as an induction agent for anesthesia, for treatment of ischemic myocardial pain, and for dyspnea associated with congestive heart failure. Suggested Dosing • Analgesia: IV, 2.5 to 15 mg (children 0.05 to 0.2 mg/kg, maximum 15 mg) Epidural, 2 to 5 mg (40 to 100 mg/kg) diluted in 10 mL preservative-free saline or local anesthetic can be given as a bolus with 0.1 to 1 mg/hour (2 to 20 mg/kg/hour) as an infusion Spinal, 0.1 to 1 mg (4 to 20 mg/kg) in preservative-free solution Adverse Effects/Precautions Epidural or intrathecal morphine may cause delayed respiratory depression (up to 24 hours after a single dose). Morphine as well as other opioids may cause spasm at the sphincter of Oddi in the biliary tract. This opioid-induced biliary tract spasm may be reversed with naloxone (IV/IM 0.2 to 0.4 mg) or glucagon (IV/IM 0.25 to 2 mg). Depression of the cough and gag reflex is a direct effect on the cough center in the medulla. Morphine may also produce vomiting by activating the chemoreceptor trigger zone. Morphine induces the release of histamine and can cause erythema and pruritus along the vein draining from the site

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of injection. This should not be confused with an allergic reaction. Direct binding of morphine (and other opioids) to opioid receptors in the medulla oblongata alter sensory modulation and may be the mechanism for pruritus after epidural/intrathecal administration. Antihistamines (e.g., diphenhydramine 12.5 to 25 mg IV/IM every 6 hours as needed) are usually effective in alleviating the symptoms. As with all narcotic agents, we recommend that doses be reduced in the elderly, hypovolemic, and high-risk surgical patients, as well as when used concomitantly with sedatives or other narcotics. All opioids tend to cross the placental barrier. The use of these agents during labor and delivery may produce respiratory depression and hypotonia in the neonate. Naloxone may be necessary and resuscitation may be required if these agents are used in this manner. Urinary retention that does not respond to naloxone may require bladder catheterization. Meperidine HCL (Demerol) Meperidine is a synthetic opioid agonist that is approximately one tenth as potent as morphine but with a slightly more rapid onset and shorter duration of action. It can be used as a premedicant, as an analgesic, and for treatment of postoperative shivering. Suggested Dosing • Analgesia: IV, 25 to 100 mg (0.5 to 2 mg/kg) • Treatment of shivering: IV, 25 to 75 mg (0.5 to 2 mg/kg) Adverse Effects/Precautions Due to the direct myocardial depressant effect at high doses, meperidine is not recommended for high opioid-based anesthesia. The other undesirable effects of opioids (e.g., respiratory depression, pruritus, nausea and vomiting, biliary spasm, and urinary retention) may occur with meperidine as well. Fentanyl (Sublimaze) Fentanyl is a synthetic phenylpiperidine derivative, which is a potent opioid agonist with analgesic properties and approximately 100 times more potent than morphine.56 The greater lipid solubility of fentanyl is responsible for its rapid onset and shorter duration of action. Suggested Dosing • Analgesia: IV, 25 to 100 mg (1 to 6 mg/kg) as a single dose or 0.5 to 20 mg/kg as a bolus or 0.25 to 10 mg/kg/hour as an infusion

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Epidural, bolus 50 to 100 mg (1 to 2 mg/kg) in 10 mL of preservative-free saline or local anesthetic or an infusion of 0.5 ot 0.7 mg/kg/hour Spinal, 5 to 20 mg (0.1 to 0.4 mg/kg) as a bolus • Induction of anesthesia: 10 to 50 mcg/kg as an IV bolus (to avoid chest wall rigidity, a muscle relaxant should be administered simultaneously with induction dose)

Epidural, bolus 500 to 1000 mg (10 to 20 mg/kg) in 10 mL of preservative-free saline or local anesthetic or an infusion of 2 to 5 mg/kg/hour • Induction of anesthesia: 50 to 300 mg/kg as a bolus (to avoid chest wall rigidity, a muscle relaxant should be administered simultaneously with induction dose)

Adverse Effects/Precautions Cardiovascular stability is maintained when used as the sole anesthetic; however, doses may need to be reduced in the elderly, hypovolemic, and high-risk surgical patients, as well as when used concomitantly with sedatives or other opioids.

Adverse Effects/Precautions The analgesia of alfentanil is enhanced and prolonged by a2 agonists such as clonidine. The serum levels of alfentanil are increased with the concomitant administration of propofol, and the clearance is reduced in patients taking erythromycin. As with all narcotics, doses should be reduced in elderly, hypovolemic, or high-risk surgical patients or when used with sedatives or other narcotics.

Sufentanil Citrate (Sufenta)

Remifentanil (Ultiva)

Sufentanil, a synthetic opioid, is a thiamylal analog of fentanyl with five to ten times the analgesic potency of that agent. The indications for sufentanil are the same as those for fentanyl.

Remifentanil is the first agent in a new class of very shortacting, synthetic, phenylpiperidine derivative with potent and selective m-opioid receptor agonist activity.58 Remifentanil contains an ester linkage, which makes it susceptible to rapid metabolism by esterase hydrolysis in the blood and other tissues. It appears to have similar pharmacodynamic properties to other potent m-agonists. Studies in human volunteers revealed that remifentanil had a rapid onset, a small volume of distribution, rapid redistribution, and clearance with an elimination half-life of eight to ten minutes (see Table 22-11), whereas the elimination half-life of alfentanil is 61 minutes.53 Regardless of the duration of infusion, the time for the plasma concentration of remifentanil to decrease by 80% is 15 minutes. In addition, a single bolus dose of remifentanil is 20 to 30 times as potent as a similar dose of alfentanil. Remifentanil is a titratable opioid that is useful for brief or prolonged painful procedures that require potent analgesia but require rapid recovery. It is not as useful for postoperative analgesia because it is so rapidly metabolized.

Suggested Dosing • Analgesia: IV, 10 to 30 mg (0.2 to 0.6 mg/kg) as a single bolus, or 0.05 to 2 mcg/kg as as an infusion Epidural, bolus 5 to 30 mg (0.2 to 0.7 mg/kg) in 10 mL of preservative-free saline or local anesthetic or an infusion of 0.1 to 0.6 mg/kg/hour Spinal, 1 to 10 mg (0.02 to 0.08 mg/kg) as a bolus • Induction of anesthesia: 2 to 10 mg/kg as a bolus (to avoid chest wall rigidity, a muscle relaxant should be administered simultaneously with induction dose) Adverse Effects/Precautions The cardiovascular effects of sufentanil are similar to fentanyl, but sufentanil may produce a dose-dependent bradycardia—possibly due to stimulation of the vagus nucleus in the medulla—especially when combined with nonvagolytic muscle relaxants such as vecuronium. Alfentanil HCl (Alfenta) Alfentanil is a synthetic opioid with characteristics of rapid onset and short duration, and is approximately 50 times less potent than fentanyl.57 Suggested Dosing • Analgesia: IV, 250 to 500 mg (5 to 10 mg/kg) as a single bolus, or 3 to 8 mg/kg/hour as an infusion

Suggested Dosing Induction of anesthesia: 0.5 to 1 mg/kg as a bolus over >30 seconds followed by an infusion at 1 to 100 mg/kg/minute when used with 66% N20, and up to 1.5 MAC Isoflurane, or 100 to 200 mg/kg/minute with propofol. Supplemental doses of remifentanil (1 mg/kg) may be administered for transient episodes of intense surgical stress. Adverse Effects/Precautions The most common adverse events associated with remifentanil are characteristic of m-opioid receptor agonists and include bradycardia, hypotension, skeletal muscle rigidity, respiratory depression, shivering, and nausea and vomiting. However, because of the pharmacokinetic characteristics of this drug, these adverse reactions resolve within minutes of discontinuing or decreasing the rate of administration.

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Opioid Agonist/Antagonists The agonist-antagonist drug group is a heterogeneous group of partially or totally synthetic opioids that are moderate to strong analgesics. They were introduced primarily because of the need for increased safety when administering opioids for the treatment of pain. This group of drugs differs from pure opioid agonists principally by the way in which they act at opioid receptors. A pure opioid agonist has both affinity and efficacy at the receptor; whereas, a partial agonist has affinity but reduced intrinsic activity. Therefore, the dose-response curve is relatively flat and does not provide the same maximal effect. The major clinical advantage of this group of drugs is to limit respiratory depression. The respiratory depressant effects also tend to parallel analgesic efficacy, thus limiting the clinical advantages. This class of drugs has limited utility in the neuro-ICU. Pentazocine (Talwin) Pentazocine produces its analgesic effects primarily by agonistic activity at kappa (k) receptors. It is only one fourth as potent as morphine and exhibits a ceiling to both its respiratory depressant and analgesic effects. Pentazocine is of little utility to the intensivist due to its limited analgesic effects as well as its dysphoric and cardiac effects, the latter of which are increased systemic and pulmonary artery pressures. In addition, sufficient doses of pentazocine can precipitate withdrawal symptoms in narcotic-dependent patients. Butorphanol Tartrate (Stadol) Butorphanol is a moderately potent analgesic, approximately five times more potent than morphine with weak antagonistic effects at m receptors. Use of butorphanol with morphine-like drugs does not alter their analgesic properties. The potential cardiovascular and dysphoric side effects of butorphanol are similar to those of pentazocine. Nalbuphine HCl (Nubain) Nalbuphine is structurally related to oxymorphone (agonist) and naloxone (antagonist). Nalbuphine is an agonist/ antagonist that binds to m, k, and d, but not to s opioid receptors. It as a moderately potent antagonist at m receptors and conveys its analgesic actions primarily as a k1 and k3 receptor agonist.59 It is approximately equipotent to morphine for analgesic doses. Like other agonist-antagonists, nalbuphine demonstrates a ceiling effect for analgesia and ventilatory depression. Unlike pentazocine or butorphanol, nalbuphine does not produce deleterious hemodynamic effects in patients with cardiac disease, nor pronounced dysphoria side effects.

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Buprenorphine (Buprenex) Buprenorphine is a partial m agonist that is highly lipophilic. It is 25 to 50 times more potent than morphine and produces analgesia and other CNS effects comparable to morphine. Although hemodynamic effects are mild, significant ventilatory depression has been reported. The incidence of psychomimetic effects is low. Dezocine (Dalgan) Dezocine is slightly more potent than morphine, with a more rapid onset and shorter duration of action. Side effects are similar to those of morphine, although dezocine does not appear to release histamine. Dezocine appears to be considerably more effective than other agonist-antagonists as an anesthetic supplement.

Opioid Antagonists The pure antagonists are oxymorphone derivatives that are competitive antagonists at m, d, k, and s opioid receptors. Even at moderately high doses, antagonists have no discernible intrinsic activity except when administered with opioid agonists, which stimulate opioid receptors. Naloxone HCl (Narcan) Naloxone is administered intravenously to reverse opioid agonist side effects, specifically, ventilatory depression, sedation, and pruritus. Unfortunately, all opioid effects will be reversed in parallel, including analgesia. If large doses of naloxone (0.1 to 0.4 mg) are used, the unmasked pain may result in significant sympathetic and cardiovascular stimulation, leading to hypertension, atrial and ventricular dysrhythmias, pulmonary edema, and cardiac arrest. Naloxone should be titrated intravenously in small incremental doses (20 to 40 mg) to achieve the desired effect without sudden onset of pain. Additionally, as the half-life of naloxone is 45 to 60 minutes, shorter than the half-lives of many of the available opioids, renarcotization may occur when naloxone is used to reverse longer-acting opioids. Prolonged reversal of opioid agonist activity may be achieved by administering an intramuscular dose of naloxone after titrating to effect intravenously. A more efficient method involves the use of a naloxone infusion (5 to 15 mg/kg/hour) following a loading dose (1 to 4 mg/kg), with infusion rates being adjusted according to patient response. Alternatively, half of the effective IV dose may be administered subcutaneously. Naltrexone (Revia) Naltrexone is a longer-acting antagonist with a half-life of 10 hours that is available for oral administration (100 mg or greater) and can be used to counteract the side effects of spinal opioids used for chronic pain.

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Alpha2 Agonists Alpha2-adrenoceptor agonists are being increasingly used in anesthesia and critical care (Table 22-12). They decrease sympathetic tone, attenuate the stress response, and cause sedation and analgesia. Clonidine was initially introduced as antihypertensive and is presently the most commonly used alpha2 agonist. The FDA approved dexmedetomidine in 1999 for use in humans for analgesia and sedation. Cerebral ischemia induces a release of norepinephrine that is associated with neuronal death. Alpha2-adrenoceptor agonists decrease release of this neurotransmitter as well as the turnover of noradrenaline. This is thought to be advantageous in counteracting the neurodegeneration in ischemic brain. Alpha2 receptors are found throughout the peripheral and central nervous systems, predominantly on presynaptic sympathetic neurons. Although the exact mechanism by which alpha2 agonists cause hypotension is not known, it is thought

Table 22-12  a-Adrenergic Agonist Characteristics a-Adrenergic agonists

• Clonidine (a2 : a1 = 200 : 1) • Dexmedetomidine (a2 : a1 = 1600 : 1)

CNS properties

• Sedative • Analgesic • Anxiolytic

Systemic properties

• Inhibition of ischemia-induced norepinephrine release • Antinociception • Renin suppression • Hyperglycemia • Decreased postoperative shivering • Decreased sympathetic tone reduces heart rate (HR), mean arterial pressure, cardiac output, and stroke volume • Urinary sodium and chloride excretion are increased

Mechanism of action

•

Pharmacokinetics

• t1/2 = 2 hr • 94% protein bound

Metabolism

• Hepatic cytochrome P450 direct glucuronidation

Excretion

• Excreted in the urine (95%) and in the feces (4%)

Adverse effects

• • • • • • • • •

Alpha-2 adrenergic agonist

Hypotension/hypertension Crosses the placenta Hypotension Hypertension Nausea Bradycardia Atrial fibrillation Hypoxia Atrioventricular blocks

that stimulation of the receptors in the brain and spinal cord decreases sympathetic outflow, resulting in hypotension, bradycardia, sedation, and analgesia.60 Additional effects include decreased salivation, decreased bowel motility, inhibition of renin release, increased glomerular filtration, increased renal secretion of sodium, decreased intraocular pressure, and decreased insulin release from the pancreas. Dexmedetomidine (Precedex) Dexmedetomidine is a much more effective sedative and analgesic agent than clonidine for several reasons including a selective alpha2-adrenoceptor agonism and a shorter halflife (2 hours compared to 6 to 10 hours).61 At lower doses, both clonidine and dexmedetomidine produce arousable, effective sedation, and decrease requirements for analgesics with minimal respiratory depression. At doses exceeding 2.0 mg/kg, dexmedetomidine can cause deep sedation with respiratory depression. Patients who received dexmedetomidine in the intensive care unit were arousable and alert when stimulated from sedation and quickly return to their sleeplike state with minimal respiratory depression.62 Although dexmedetomidine does not appear to have any direct effects on the heart, a biphasic cardiovascular response has been described following intravenous administration.63,64 A 2.0-mg/kg intravenous administration of dexmedetomidine produces transient mild hypertension (approximately a 20% increase in mean arterial blood pressure) followed by a 30% decrease in mean arterial blood pressure resulting in values 10% below baseline.65 Stimulation of the alpha2-adrenoceptor in vascular smooth muscle may be responsible for the initial rise in the blood pressure. Even at slower infusion rates however, the increase in mean arterial pressure over the first ten minutes was shown to be in the range of 7%, with a decrease in heart rate between 16% and 18%.64 This initial response is followed by a slight decrease in blood pressure due to the inhibition of the central sympathetic outflow and decreased norepinephrine release, which is more pronounced in hypovolemic patients.66 Dexmedetomidine undergoes almost complete hydroxylation through direct glucuronidation and cytochrome P450 metabolism in liver. Metabolites are predominantly excreted in the urine. The intrinsic activity of metabolites is unknown. The elimination half-life is approximately 2 hours. It may be necessary to decrease the dose in patients with hepatic failure because they will have lower rates of metabolism of the active drug. In cases of renal failure, accumulation of metabolites may have effects that are presently unknown. The average protein binding of dexmedetomidine is 94%, with negligible displacement from proteins by fentanyl, ketorolac, theophylline, digoxin, or lidocaine.67 Dexmedetomidine dosing is generally initiated with a loading infusion of 1 mg/kg over 10 minutes, followed by a maintenance infusion of between 0.2 and 0.7 mg/kg/hour.

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Dexmedetomidine must be diluted in 0.9% saline for infusion. The safety and effectiveness of dexmedetomidine has not been studied when it is infused over 24 hours; therefore, administration longer than this time period is not yet recommended. Dexmedetomidine has been continuously infused in mechanically ventilated patients through extubation. Dexmedetomidine should be used cautiously in patients with pre-existent severe bradycardia and cardiac conduction system problems, in patients with reduced ventricular function (ejection fraction <30%), and in patients who are hypovolemic or hypotensive. The drug’s effects on cerebral blood flow and carbon dioxide response are not completely understood. All effects of dexmedetomidine are antagonized by the alpha2-adrenoceptor antagonist atipamezole (A-17), which has a half-life of 1.5 to 2 hours.

Nonsteroidal Anti-Inflammatory Drugs Nonsteroidal anti-inflammatory drugs (NSAIDs) act by inhibiting the enzyme, cyclooxygenase, which is crucial for prostaglandin synthesis. This inhibition is responsible for decreasing the swelling and pain associated with prostaglandin production. Best results are obtained when these agents are administered before the surgical insult. The most frequently used intravenous NSAID is ketorolac.68 Nonsteroidal anti-inflammatory drugs do not possess respiratory depressant activity. However, they do inhibit prostaglandin-mediated renal blood flow, particularly in patients with intrinsic renal disease, hypovolemia, or congestive heart failure and thus must be used with caution. They also inhibit prostaglandin-mediated platelet aggregation, but, unlike aspirin, the effect is reversible when the drug concentration diminishes. Ketorolac (Toradol) Ketorolac is a NSAID with analgesic, anti-inflammatory, and antipyretic activity. The analgesic potency of 30 mg of ketorolac is equivalent to 9 mg of morphine with less drowsi-

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ness, less nausea and vomiting, and no significant respiratory depression. Suggested Dosing • IV/IM: Loading, 30 to 60 mg. IV doses should be infused slowly (>15 seconds) to reduce the risk of phlebitis; Maintenance, 15 to 30 mg every 6 hours as needed.

Corticosteroids Several synthetic corticosteroids (Tables 22-13 and 22-14) available for use vary in their relative mineralocorticoid and glucocorticoid potencies. They are used as anti-inflammatory agents, antiemetics, and as replacement therapy for adrenal and pituitary insufficiency. Methylprednisolone (Depo-Medrol, Medrol, Methylone, Solu-Medrol) Methylprednisolone is a synthetic glucocorticoid widely used in neuroanesthesia to reduce and prevent swelling of the brain when cytotoxic edema is present. Glucocorticoids prevent or suppress inflammation and elements of the immune response when administered at pharmacological doses. At the molecular level, unbound glucocorticoids readily cross cell membranes and bind with high affinity to cytoplasmic receptors. These receptors interact with transcription factors to modify transcription and protein synthesis. Actions include inhibition of leukocyte infiltration at the site of inflammation, interference with the function of mediators of inflammatory response, and suppression of humoral immune responses. High-dose methylprednisolone therapy is the only pharmacologic therapy shown to have efficacy in phase three randomized trials of neurologic outcome in spinal cord trauma. It has been shown to improve neurologic outcome up to 1 year after injury if administered within eight hours of injury (bolus 30 mg/kg administered over 15 minutes with a maintenance infusion of 5.4 mg/kg per hour infused for 23

Table 22-13  Corticosteroids—Relative Parameters

Corticosteroid Cortisol Cortisone Prednisolone Methylprednisolone Dexamethasone

Anti-inflammatory Potency

Sodium Retaining Potency

Equivalent Dose

Elimination Half-time (hr)

Duration of Action (hr)

1 0.8 4 5 10

1 0.8 0.8 0.5 0

20 25 5 4 0.75

1.5–3.0 0.5 3–4 2–4 5

8–12 8–36 18–36 12–36 36–54

Data from Stoelting RF (ed): Hormones and drugs. In: Pharmacology and Physiology in Anesthetic Practice, 3rd ed. St Louis, Mosby, 1999, p 416.

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Table 22-14  Corticosteroid Characteristics Corticosteroid

CNS properties

• • • • • •

Cortisol Cortisone Prednisolone Prednisone Methylprednisolone sodium succinate Dexamethasone

• • • • • • •

Insomnia Agitation Vertigo Seizures Psychoses Pseudotumor cerebri Delirium

Systemic properties

• Immunosuppression • Hyperglycemia

Mechanism of action

• Immunosuppression • Reversal of increased capillary permeability

Pharmacokinetics

•

See Table 22-13

Metabolism

•

Hepatic; cytochrome P450

Excretion

• Urinary and bile

Additional adverse effects

• Cushing’s syndrome • Hypersensitivity reactions

hours). A recent trial indicates additional benefit by extending the maintenance dose from 24 to 48 hours.69,70 However, data from the NASCIS III trial suggest an increase in pulmonary morbidity in the 48-hour group.71 In large doses, corticosteroids may reduce cerebral edema. There is no evidence supporting the use of steroids in the management of acute head injury to date. The management of nausea and vomiting in patients with intracranial pathology may be paramount in patients to avoid additional increases in intracranial pressure. There is growing evidence that dexamethasone (1 to 4 mg IV) is a useful adjunct, used in combination with 5-HT3 and dopamine antagonists.72

Neuromuscular Blockers

Table 22-15  Depolarizing Neuromuscular Blocking Agent Characteristics Agent

•

Succinylcholine

CNS properties

• Transient increase in intracranial and intraocular pressure

Systemic properties

• Muscular depolarization • May cause hyperkalemia

Mechanism of action

• Depolarizing agonist of cholinergic receptors

Pharmacokinetics

• IM: 2 to 3 min onset • IV: 45 to 60 sec onset

Metabolism

• Plasma cholinesterase

Adverse effects

• Hyperkalemia, malignant hyperthermia

to quickly gain control of the airway. The increase in ICP associated with the rise in PaCO2 from ineffective mask ventilation is much worse than the small rise in ICP associated with succinylcholine. Hyperkalemia has been demonstrated following the administration of succinylcholine to patients with muscular dystrophy, following denervation leading to atrophy, and with upper motor neuron lesions.75 Excessive potassium release has been detected from 96 hours to up to 6 months of denervation.76 By way of contrast, in burn patients hyperkalemia may be seen 6 to 7 days after injury. The mechanism of hyperkalemia is thought to occur by increased sensitivity and upregulation of extrasynaptic nicotinic cholinergic receptors. This exaggerated response may persist six to eight months following injury. Pretreatment with nondepolarizing neuromuscular antagonists does not prevent the magnitude of hyperkalemia. The metabolism of succinylcholine is accomplished by rapid hydrolysis by plasma cholinesterase to succinylmonocholine. Severe liver dysfunction or the genetic presence of atypical plasma cholinesterase may cause prolongation of neuromuscular blockade. Suggested Dosing • IM, 3 to 5 mg/kg • IV, 0.3 to 1.5 mg/kg

Depolarizing Neuromuscular Antagonists

Nondepolarizing Neuromuscular Blocking Agents

Succinylcholine (Anectine) Succinylcholine (Table 22-15) is a short-acting, depolarizing neuromuscular blocking agent and is relatively contraindicated in patients with intracranial lesions. Mild increases in ICP have been demonstrated, persisting as long as 30 minutes73; this can be attenuated by pretreatment with a nondepolarizing neuromuscular blocking agent (NMBA).74 The increase in ICP that occurs is not usually clinically significant. Alternatively, nonhistamine releasing nondepolarizing NMBAs may be used. The most important factor is

Numerous nondepolarizing NMBAs are available (Table 22-16) as paralytic agents for use in the neurointensive care unit. These drugs block acetylcholine from binding to receptors on the motor endplate, thus inhibiting depolarization. In patients without hepatic or renal failure most of these compounds can be used in intermittent doses, or continuous infusion to allow for immediate reversal of paralysis for neurologic assessment. Those with long half-lives, such as pancuronium, pipecuronium, and doxacurium, are usually avoided. Any patient who is pharmacologically paralyzed

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671

Table 22-16  Nondepolarizing Neuromuscular Agent Characteristics Nondepolarizing Neuromuscular Agent

Histamine Release

Atracurium

Slight

0.25

30–45

3–15

Cisatracurium Vecuronium Rocuronium Mivacurium

None None None Slight

0.05 0.05 0.3 to 0.4 3

40–75 45–90 45–75 15–20

1–2 0.8–1.2 6–16 1–15

ED95 (mg/kg)

Clinical Duration of Action (min)

Infusion Dose (mcg/kg/min)

Route of Elimination Kidney: Hoffmann elimination, ester hydrolysis Liver: Hoffman elimination Liver, kidney Liver, kidney Plasma cholinesterase hydrolysis

From Lein CA, Savarese JJ: Neuromuscular junction pharmacology. In Hemmings H, Hopkins P (eds): Foundations of Anesthesia, Basic and Clinical Sciences. London, Harcourt, 2000, p 342, with permission.

should be sedated adequately with benzodiazepines or propofol as a precaution to avoid awareness. Prolonged infusion of nondepolarizing NMBAs has been associated with myopathies. Nondepolarizing NMBAs may be reversed, if necessary, by administering an anticholinesterase agent such as neostigmine or physostigmine. The administration of a muscarinic cholinergic antagonist such as atropine or glycopyrrolate must be given before the anticholinesterase agent to avoid profound bradycardia. Mivacurium (Mivacron) is metabolized by plasma cholinesterase. Prolonged effects are possible if atypical or reduced levels are present. Histamine release occurs with rapid drug infusion or large doses. Atracurium (Tracrium) is a benzoisoquinolinium NMBA, which undergoes nonenzymatic chemical degradation in plasma. At two times the ED95, atracurium may cause significant histamine release with a resultant decrease in peripheral vascular tone and blood pressure.77 Cisatracurium (Nimbex) is a mixture of isomers of atracurium, which causes much less histamine release than atracurium. Vecuronium (Norcuron) and rocuronium (Zemuron) are steroid ring NMBAs that are largely devoid of cardiovascular and neurovascular effects in doses up to four to eight times the ED95.78,79

Inotropic Therapy Adrenergic Agents b-Adrenergic receptor agonists are the most potent and widely used inotropes. They work by binding to and stimulating b-adrenergic receptors that are coupled to the formation of the intracellular messenger, adenosine 3¢ : 5¢monophosphate (cyclic AMP). A number of different badrenergic agonists are available (Table 22-17) including the natural catecholamines epinephrine (Adrenaline), norepinephrine (Levartenol), L-noradrenaline and dopamine (Intropin), and the synthetic catecholamines dobutamine (Dobutrex) and isoproterenol (Isuprel, isoprenaline, iso-

propylarterenol). These drugs have varying actions at b1-, b2and a receptors and are initially selected based on their relative actions at each receptor type. Severe ventricular failure usually requires the maximal potency of epinephrine or norepinephrine, frequently in combination with vasodilator therapy (see following discussion). Epinephrine and norepinephrine are also useful when ventricular dysfunction is accompanied by peripheral vasodilatation, since they are also potent a-receptor agonists. The vasopressor effect of norepinephrine is greater than that of epinephrine because of the greater potency of epinephrine at b2-receptors, which produce considerable vasodilatation in skeletal muscle. Dobutamine and dopamine are useful when moderate inotropic support is desired. Dobutamine is a b1-receptor agonist with a minimal a-receptor activity, and is therefore useful when further vasoconstriction is undesirable. Dopamine is unique in that it has been said to stimulate renal dopamine receptors and causes an increase in both renal blood flow and sodium excretion. Although it may be useful in patients with renal dysfunction, there is considerable controversy as to whether the agent actually increases renal blood flow. Use of dopamine as an inotrope at higher doses (>10 mg/kg/minute) is complicated by its activity at a-adrenergic receptors, which may produce undesirable increases in systemic vascular resistance, and by its tendency to increase ventricular filling pressures and to induce tachycardia and atrial arrhythmias. The partial dependence of the inotropic effects of dopamine on endogenous catecholamines may also limit its efficacy in patients with chronic ventricular dysfunction. Isoproterenol is a nonselective b-receptor agonist that is a potent inotrope (b1-effect) and peripheral vasodilator (b2effect). The potent chronotropic effect of isoproterenol (b1 and b2) is not compensated for by the baroreceptor-mediated reflex bradycardia that occurs with b-receptor agonists that also possess intrinsic a-receptor activity such as epinephrine and norepinephrine. Isoproterenol or dobutamine may be useful in patients with severe pulmonary hypertension and right ventricular failure, because a-receptor stimulation—minimal to nonexistent in these agents—is a

672 a1-receptor (≠Ca2+) b1-receptor (≠cAMP) b2-receptor (≠cAMP)

b1-receptor (≠cAMP) a1-receptor (≠Ca2+)

Low-dose infusion 1–2 mg/min, primarily b Moderate dose infusion 2–10 mg/min, mixed a and b High dose infusion 10–20 mg/min, primary a, potent vasoconstriction 4–16 mg/min

Epinephrine

Norepinephrine

≠CA

2–10 mg/kg IV bolus effects last 10– 20 min

Calcium chloride or calcium gluconate

2+

Mechanism

Dose

Drug

Table 22-17  Inotropes Used in the Intensive Care Unit

Inotrope—b1 effect Vasopressor—a1 effect Chronotrope—b1 effect

Inotrope—b1 effect Vasopressor—a1 effect at higher doses Vasodilator—b2 effect primarily in muscle Chronotrope—b1 effect Bronchodilation— b2-effect

Inotrope if hypocalcemic; vasopressor if normocalcemic

Actions

Ventricular Dysfunction Vasodilation Anaphylaxis Shock

Ventricular dysfunction Vasodilation Anaphylaxis Bronchoconstriction

Hypocalcemia (from CPB, albumin, citrate) Hyperkalemia Hypotension (e.g., secondary to protamine) Myocardial depression (e.g., secondary to residual cardioplegia or hypocalcemia) Calcium channel blocker overdose

Indications

See Epinephrine

Idiopathic hypertropic subaortic stenosis (relative); tetralogy of Fallot (with RV outflow tract obstruction, relative)

Hypercalcemia, pancreatitis, digitalis toxicity

Contraindications

Vasoconstriction (splanchnic, renal), arrhythmias

Vasoconstriction (splanchnic, renal); arrhythmias

Coronary artery spasm, pancreatitis

Adverse Effects

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Inotrope—due to (≠cAMP) Vasodilator—due to (≠cAMP) Vasopressor—a1 effect Inotrope—b1 effect Ø Venous capacitance

b1-receptor (≠cAMP) b2-receptor (≠cAMP)

PDE III inhibition (≠cAMP) (≠Ca2+) a1 effect (≠Ca2+) b1 effect (≠cAMP)

1–5 mg/min

0.5–1.5 mg/kg IV bolus (slow) 5–30 mg/kg/min infusion 5–10 mg IV bolus

Isoproterenol

Amrinone

Ephedrine

Ventricular dysfunction Vasodilation

Ventricular dysfunction Vasoconstriction

Ventricular dysfunction especially RV Bronchoconstriction Bradycardia— profound b-blockade, AV block, cardiac transplant Pulmonary hypertension— primary, secondary

Vasoconstriction

Ventricular dysfunction Vasodilation Renal dysfunction/ oliguria

See Epinephrine

Thrombocytopenia

See Epinephrine

See Epinephrine

See Epinephrine

Tachycardia

Vasodilation

Tachycardia Vasodilation ≠MVO2

Tachycardia

Tachycardia, Peripheral vasoconstriction, Arrhythmias

AV atrioventricular; Ca2+ intracellular ionized calcium; cAMP, cyclic adenosine monophosphate; DA1 dopamine; MVO2 myocardial O2 consumption; PDE, phosphodiesterase; RV, right ventricular. From Kirby RR, Gravenstein N, Lobato EB, Gravenstein JS. Clinical anesthesia practice, 2nd ed. Philadelphia, WB Saunders, p. 1267.

Inotrope—b1 effect Vasodilator—b2 effect Bronchodilation— b2-effect Chronotrope—b1 effect

Inotrope—b1 effect Vasodilator—b2 effect Chronotrope—b1 effect

b1-receptor (≠cAMP) a1-receptor (≠Ca2+)

2–20 mg/kg/min

Dobutamine

Inotrope—b1 effect Vasopressor—a1 effect Renal vasodilator and natriuretic-DA1 Chronotrope—b1 effect

a1-receptor (≠Ca2+) b1-receptor (≠cAMP) DA1 receptors (≠cAMP)

0.5 mg/kg/min (activation of DA1 receptors) >2 mg/kg/min (activation of b1 receptors) >5 mg/kg/min (activation of a1 receptors)

Dopamine

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potent mechanism producing pulmonary vasoconstriction. Isoproterenol is also useful for the treatment of slow ventricular rates or atrioventricular conduction disturbances when other methods have failed because of the positive chronotropic and dromotropic effects of b-adrenergic stimulation. Epinephrine appears to be the most useful inotrope for adult cardiac surgical patients with its combined b1, b2, and a actions, while dopamine and isoproterenol are favored in the pediatric population because of advantages of a higher heart rate in this group. However, patterns of inotrope use show institutional variations, and many clinicians would choose dopamine or dobutamine as their first agent of choice for inotropic stimulation. In critically ill adults with severe ventricular dysfunction and low urine output, it is may be advantageous to use a low-dose dopamine infusion (1.5 to 5 mg/kg/min) to optimize renal perfusion, combined with a second inotrope (e.g., dobutamine) to increase contractility without increasing ventricular filling pressure, as can be seen with higher doses of dopamine. The use of dopamine or epinephrine as an inotrope in severe left ventricular dysfunction is limited by dose-dependent increases in afterload and preload. These undesirable side effects are the basis for the frequent clinical use of combined inotropic stimulation and afterload reduction with direct acting vasodilators such as nitroprusside or nitroglycerin or “inodilators” such as amrinone or milrinone. Amrinone is a selective inhibitor of fraction III of cyclic nucleotide phosphodiesterase (PDE III). This agent produces two actions that are beneficial in the treatment of ventricular dysfunction, namely a decrease in afterload and an increase in contractility without significant tachycardia or arrhythmias. The inotropic activity of amrinone appears to be synergistic with that of b-adrenergic agents, and may not be associated with increased myocardial oxygen consumption; these properties have made this agent particularly useful in patients with severe left ventricular dysfunction. Advantage can be taken of the inotropic activity of amrinone without its vasodilatory activity by combining it with an a-adrenergic agonist, usually norepinephrine. Another important application of amrinone and its congeners in combination with adrenergic agonists is its use in patients with antecedent congestive heart failure. The desensitization of b-adrenergic receptors that occurs in congestive heart failure significantly limits the efficacy of b-adrenergic agonists. Combined therapy with phosphodiesterase inhibitors enhances the inotropic effect of b-adrenergic receptor agonists by potentiating the rise in intracellular cyclic AMP and may permit use if a lower dose of b-adrenergic agonist. Inhibitors of phosphodiesterase also have a positive lusitropic, or myocardial relaxation, effect. This positive lusitropic effect enhances diastolic myocardial relaxation, improves ventricular compliance, facilitates ventricular filling, and decreases ventricular filling pressure and perhaps

end-diastolic wall tension at any given filling volume. Thus, myocardial oxygen consumption may be decreased while stroke volume is increased. Vasopressors Vasoconstrictors work by increasing systemic vascular resistance (afterload) and decreasing venous capacitance (increasing preload) due to their action at a-adrenergic receptors. Both phenylephrine (Neosynephrine) and methoxamine (Vasoxyl) are pure a1-agonists useful in the treatment of hypotension secondary to vasodilation while both metaraminol (Aramine) and ephedrine release endogenous norepinephrine in addition to direct stimulation of a (metaraminol) or both a and b receptors (ephedrine). In general, the use of pure a-agonists to increase arterial blood pressure in patients with poor ventricular function or pulmonary hypertension is best avoided because increased afterload without a compensatory increase in contractility results in a decreased stroke volume. If significant arterial vasodilation is combined with poor left ventricular function, norepinephrine, which possesses less b2-adrenergic activity than epinephrine, may be appropriate. Pure a-receptor agonists are useful in the treatment of hypotension in patients with good ventricular function; the beneficial increase in coronary and cerebral perfusion pressure usually outweighs the negative effects of decreased cardiac output and increased filling pressures in the patient with coronary artery disease or ventricular hypertrophy.

Vasodilators and Antihypertensive Agents Induced hypotension and the treatment of hypertension are both essential to the pharmacologic treatment of neurosurgical patients, and may be achieved with a variety of pharmacologic agents. In addition, the postoperative course of patients emerging from general anesthesia and in the intensive care unit is frequently complicated by the occurrence of hypertension.80 Cerebral perfusion pressure should be maintained between 70 and 90 mm Hg, or managed to ensure adequate cerebral perfusion using cerebral oximetry with a jugular venous catheter or brain tissue oxygen tension (PbtO2) monitoring. Sodium nitroprusside (SNP) and nitroglycerin (NTG) both cause cerebral vasodilation resulting in an elevation of intracranial pressure, pulmonary venous admixture due to shunting, reflex tachycardia,73 and may dilate capacitance vessels (NTG > SNP).81 Co-existing diseases may dictate the use of a particular agent. For example, use of NTG for the patient with ischemic cardiac disease may improve the endocardial-epicardial flow ratio without inducing coronary steal, and thus may improve

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myocardial ischemia. Infusions generally have less marked effects on ICP than boluses and may be preferable. Because both agents are widely used in the neurosurgical intensive care unit setting, they will be reviewed in detail. While positive inotropes are useful in improving the contractile state of the failing ventricle to improve cardiac output and arterial blood pressure, vasodilators can improve ventricular function by optimizing loading conditions. Severe heart failure is characterized by both poor left ventricular function (decreased cardiac output with elevated filling pressure) and elevated systemic vascular resistance, and added therapeutic benefit may be obtained by treating both abnormalities. Thus, the effects of inotropes and vasodilators are additive in augmenting cardiac output and decreasing filling pressures in the treatment of severe left ventricular failure. Sodium nitroprusside and nitroglycerin are the most useful vasodilators because of their potency, rapid onset and short duration of action. These properties make them ideal for rapid titration of arterial pressure. Other vasodilators that are used occasionally but which have slower onsets and longer durations of action include hydralazine and phentolamine (an a1-adrenergic antagonist). Sodium nitroprusside is a potent arterial vasodilator as well as venodilator, while nitroglycerin is a potent venodilator but is less potent as an arterial vasodilator. This is clinically evident in the greater efficacy of sodium nitroprusside in reducing arterial pressure in normovolemic patients, while both agents are effective in reducing ventricular filling pressures. Nitroglycerin, and to a lesser extent sodium nitroprusside, are also effective pulmonary vasodilators and inhibitors of hypoxic pulmonary vasoconstriction (hence, the increased pulmonary shunt frequently observed with their use). Other pulmonary vasodilators useful for the acute control if right ventricular afterload include prostaglandin E1, prostacyclin, and inhaled nitric oxide. Nitroglycerin also exhibits utility in treating myocardial ischemia. In the perioperative period, sodium nitroprusside (0.5 to 10 mg/kg/minute) and nitroglycerin (0.5 to 4 mg/kg/minute) are useful in treating ventricular dysfunction with elevated filling pressures, pulmonary hypertension, and systemic hypertension. Sodium nitroprusside appears to be particularly effective in treating postoperative hypertension in patients with hyperdynamic circulation and in reducing afterload and preload in patients with poor ventricular function and acceptable arterial blood pressure. Concurrent volume infusion may be required to maintain adequate filling pressures and achieve increased stroke volume. Both sodium nitroprusside and nitroglycerin have also been used to offset the vasoconstriction produced by inotropes with intrinsic a-adrenergic activity. The use of sodium nitroprusside is complicated by the potential for cyanide toxicity at higher doses, while nitroglycerin has the advantage of being relatively nontoxic.

675

Sodium Nitroprusside (Nitropress) Sodium nitroprusside (Table 22-18) is an intravenous vasodilator effective in the acute management of hypertensive crisis as well as in congestive heart failure. It is an extremely potent vasodilator, with rapid onset and a short duration of action, used primarily to manage hypertensive emergencies; it is also useful when immediate reduction of preload or afterload is needed. The peripheral vasodilatory effects of nitroprusside are due to a direct action of the drug on arterial and venous smooth muscle; other tissues containing smooth muscle are not affected by the drug. The hypotensive effects of SNP are enhanced by other hypotensive agents. Sympathomimetics that exert a direct stimulatory effect (e.g., epinephrine) are the only class of drugs that effectively increase blood pressure during nitroprusside therapy. As a direct vasodilator, SNP increases cerebral blood flow and volume. Nitroprusside administered to normocarbic subjects can produce significant increases in intracranial pressure, and cause neurologic dysfunction with only slight decreases in blood pressure.82 Increases in ICP produced by SNP are maximal during modest decreases (<30%) in mean arterial pressure. However, with reductions in mean arterial pressure greater than 30%, intracranial pressure is reduced.83 Slow infusions, in the presence of hypocarbia and hyperoxia, are associated with insignificant increases in intracranial pressure compared to rapid infusions.84 Increases in ICP can be attenuated, but not obliterated, by hyperventilation.85 In the presence of inadequate cerebral blood flow associated with increased intracranial pressure or carotid artery stenosis, hypertension should likely not be treated with SNP.86 Large differences in regional cerebral blood flow occur

Table 22-18  Sodium Nitroprusside Characteristics Agent

•

Sodium nitroprusside

CNS properties

• Intracranial hypertension

Systemic properties

• Relaxation of arterial and venous vascular smooth muscle with minimal effects on nonvascular smooth muscle • Inhibits hypoxic pulmonary vasoconstriction • Nausea • Diuresis • Platelet inhibition

Mechanism of action

• Reacts with oxyhemoglobin to form cyanide and NO; NO stimulates guanylyl cyclase to form cGMP

Pharmacokinetics

• Onset: within 2 min • Duration: 1–10 min after discontinuation

Metabolism

•

Hepatic and renal

Toxicity

•

Cyanide

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Table 22-19  Nitroglycerin Characteristics

nitrite (5 mg/kg IV) may be considered as well as an infusion of hydroxycobalamin (25 mg/hour).89

Agent

•

Nitroglycerin

CNS properties

• Transient increase in ICP

Nitroglycerin (Nitro-Bid, Nitrostat)

Systemic properties

• Primarily venodilation without reflex tachycardia • Decreases cardiac ventricular wall tension

Mechanism of action

• Releases NO resulting in guanylyl cyclase stimulation of cGMP synthesis

Pharmacokinetics

• t1/2: 1–4 min

Elimination

• Extensive first-pass metabolism

Adverse effects

• • • • •

Nitroglycerin (Table 22-19) is an organic nitrate releasing nitric oxide (NO) in the presence of thio-containing compounds (unlike SNP, which produces NO spontaneously). Cyclic GMP synthesis results following NO stimulation of soluble guanylyl cyclase. Its action is predominately on venous capacitance vessels, effecting arterial vascular smooth muscle at higher concentrations. Because NTG may cause a transient increase in ICP, its use in patients with increased ICP should only be with the exercise of significant caution.90

Headache Hypotension Reflex tachycardia Rebound hypertension Methemoglobinemia (rare)

Calcium Channel Blockers

experimentally during SNP-induced hypotension and may impair autoregulation and increase CBF when sympathetic activity is enhanced.87 The enzymatic degradation of nitroprusside produces cyanide. A single molecule of SNP releases five cyanide ions. Cyanide is converted to thiocyanate by renal and hepatic rhodanase or reacts with methemoglobin to form cyanomethemoglobin. The nonenzymatic release of cyanide from SNP is not inhibited significantly by hypothermia, however enzymatic conversion of cyanide to thiocyanate may be delayed.88 The infusion dose of SNP ranges between 0.5 and 15 mg/kg/minute. Enzymatic conversion of cyanide to thiocyanate is accomplished by hepatic and renal rhodanase, which is slowed with hypothermia. Both cyanide and thiocyanate are toxic compounds interfering with aerobic metabolism by binding cytochrome c. Thiocyanate toxicity occurs at plasma levels of between 50 to 100 mg/mL. Following prolonged infusions, cyanide and thiocyanate cause nausea, tinnitus and mental status changes. Recognition of subtoxic concentrations may be had by drug resistance, progressive metabolic acidosis, and increased mixed venous O2 saturation. Treatment of cyanide toxicity includes cessation of SNP administration, hemodialysis, and/or administration of thiosulfate (150 mg/kg IV). In severe situations, sodium

Calcium channel antagonists provide a safe means of decreasing blood pressure without inducing cerebral vasodilation, which occurs with direct acting vasodilators such as the nitrates and hydralazine (Table 22-20). Although calcium channel antagonists were initially thought to reduce cerebral ischemia by attenuation of vasospasm following subarachnoid hemorrhage, agents such as nimodipine may provide a direct cytoprotective effect by decreasing intracellular calcium accumulation91 or by improving blood flow through leptomeningeal pathways and increasing collateral flow. Beta-adrenergic Antagonists Labetalol (Tomodyne, Trandate) Labetalol (Table 22-21) is a mixture of four diastereomers resulting in complex pharmacokinetics. It is a mixed nonselective beta and alpha1 adrenergic antagonist with an elimination half-life of 5 to 8 hours. When given intravenously it has a sevenfold more potent effect on beta-receptors than on alpha1-receptors. Hypotension results from reductions in heart rate, contractility and systemic vascular resistance. Neither esmolol, a rapid onset, rapid offset b1-selective antagonist, nor labetalol has significant effects on intracranial pressure or cerebral blood flow.92-94 Thus both are useful agents for the treatment of hypertension or tachycardia in neurologic patients. Longer acting agents such as propranolol hydrochloride (Inderal), a mixed b1 and b2 antagonist, or metoprolol (Lopressor), a b1 selective agent, may be considered. Shorter acting agents such as esmolol may be

Table 22-20  Calcium Channel Blocker Characteristics Calcium Channel Antagonists

T1/2 (hr)

Contractility

AV Node

HR

CO

Arterial Selectivity

Nifedipine (Procardia) Verapamil (Calan) Diltiazem (Cardizem)

2–5 4–10 3.5–7

Ø ØØ Ø

0 ØØ Ø

+ +/0/-

≠ ≠Ø -/≠

Moderate Minimal Moderate

AV node, atrioventricular node; CO, cardiac output; HR, heart rate.

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Table 22-21  Adrenergic Antagonist Characteristics Propranolol

1 mg IV Q 5 minimum, maximum 5 mg; competitive nonselective beta antagonist; t1/2 = 4–6 hr; hepatic metabolism; primarily urinary excretion.

Metoprolol

2–5 mg IV Q 5 min; selective beta 1 antagonist; t1/2 = 3–4 hr; hepatic metabolism; primarily urinary excretion.

Esmolol

Selective beta 1 antagonist; 0.1–1.0 mg/kg IV; t1/2 = 9 min; Metabolized by blood esterases; Primarily urinary excretion.

Labetalol

Nonselective alpha 1 and beta antagonist; Alpha : beta = 1 : 7 IV; t1/2 = 4–8 hr; hepatic glucuronide conjugation.

advantageous following posterior fossa surgery because increases in pressure in this region result in bradycardia. Using higher doses of long-acting agents may confuse the clinical scenario if bradycardia develops. Hydralazine (Apresoline) Hydralazine (Table 22-22) is a phthalazine derivative that decreases systemic blood pressure by a direct action on arteriolar smooth muscle. Although the precise mechanism of action is not known, it is endothelium-dependent, suggesting a role for nitric oxide. Hydralazine also interferes with calcium mobilization. The use of hydralazine is associated with a baroreceptor-mediated increase in sympathetic activity, resulting in increased chronotropic and ionotropic Table 22-22  Hydralazine Characteristics Agent

• Hydralazine

CNS properties

• Increased intracranial blood flow • Headache

Systemic properties

• Direct arteriolar smooth-muscle dilator • Decreases systemic vascular resistance • Reflex tachycardia

Mechanism of action

• Direct action on arteriolar smooth muscle

Pharmacokinetics

• Onset of action 5–20 min (IV) • t1/2 = 2–8 hr (normal renal function) • t1/2 = 7–16 hours (end stage renal disease)

Excretion

•

14% excreted unchanged in urine

Adverse effects

•

Nausea and vomiting

677

activity, an increase in plasma renin activity, and fluid retention. The onset of action is relatively slow (15 to 30 minutes); the elimination half-life is 4 hours. Like nitroprusside82 and nitroglycerine,95 hydralazine can increase intracranial pressure.23

Antiepileptic Drugs Emergency therapy for status epilepticus includes thiopental, succinylcholine, endotracheal intubation, and ventilatory support. Phenobarbital may be used in patients who require ventilatory support but like diazepam, the elimination halflife is long. Phenytoin (Dilantin) Phenytoin (Table 22-23) is an oral and parenteral anticonvulsant, approved specifically for the prophylactic management of generalized tonic-clonic, partial complex, and focal seizures. Like the barbiturates, phenytoin is a central nervous system depressant and causes cerebellar-vestibular dysfunction. It is a weak acid with a pH of 10 to 12, and is soluble as a salt in solution or as an acid in propylene glycol. Phenytoin should be administered slowly, at a rate not to exceed 50 mg/minute IV, especially in patients with concurrent Table 22-23  Phenytoin and Fosphenytoin Characteristics Agent

• •

Phenytoin Fosphenytoin

CNS properties

• Limits the spread of seizure activity • Reduces seizure propagation

Systemic properties

•

Mechanism of action

•

Therapeutic range

•

10–20 mg/mL (phenytoin)

Pharmacokinetics

• • • •

Weak acid (pKa = 8.3) 85% protein bound in infants 90% to 95% protein bound in adults Fosphenytoin binds albumin more avidly than phenytoin

Excretion

• Highly variable hepatic clearance • Glucuronidation

Adverse effects

• • • • • • • •

Antiarrhythmic

Modulation of voltage-dependent sodium channels • Enhancement of Na+/K+ ATPase activity

Hypotension Hyperglycemia Glycosuria Arrhythmias Peripheral neuropathy Gingival hyperplasia Megaloblastic anemia (rare) Hepatotoxicity (rare)

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cardiac disease. Typical loading dose is 15 to 20 mg/kg for adults. Fosphenytoin (Cerebyx) Fosphenytoin is a water-soluble, parenteral pro-drug of phenytoin. Unlike phenytoin, fosphenytoin is soluble in standard intravenous solutions and is rapidly absorbed via the intramuscular route. Fosphenytoin has fewer local adverse effects, does not contain propylene glycol, and can therefore be administered at a faster intravenous rate. Because fosphenytoin is converted to phenytoin in vivo, systemic adverse effects are generally similar. Fosphenytoin causes transient paresthesias and pruritus that are not seen with phenytoin. Before infusion, fosphenytoin should be diluted in 5% dextrose in water or 0.9% saline solution to a concentration of 1.5 to 25 mg (phenytoin equivalents) PE/mL. Because of the risk of hypotension, fosphenytoin should not be administered faster than 150 mg PE/minute. For seizure prophylaxis or for seizure treatment during neurosurgery, the parenteral loading dose is 10 to 20 mg PE/kg IV or IM. The daily maintenance dose is 4 to 6 mg PE/kg/day IV or IM, divided into two or more doses. Phenytoin has an inhibitory effect on insulin release and can increase serum glucose concentrations in diabetic patients. Patients with diabetes mellitus should be monitored for hyperglycemia during fosphenytoin therapy. Phenytoin exerts its anticonvulsant effect mainly by limiting the spread of seizure activity unlike phenobarbital and carbamazepine, both of which elevate seizure threshold. Because phenytoin does not elevate seizure threshold, it is less effective against drug-induced or electroconvulsiveinduced seizures.

The cellular mechanisms thought to be responsible for phenytoin’s anticonvulsant activities include modulation of normal voltage-gated Na+ and Ca2+ channels of neurons, and the enhancement of Na+/K+-ATPase activity of neurons and glial cells. Reduced repetitive firing in neurons caused by slowing in the rate of recovery of channels due to enhanced inactivation of Na+ is thought to be its primary mechanism. Phenytoin exerts its anticonvulsant effects with less CNS sedation than does phenobarbital. In toxic concentrations, phenytoin is excitatory and can induce seizures. During rapid infusion, hypotension and dysrhythmias can occur, especially in the elderly. Phenytoin is also a weak antiarrhythmic. Due to its toxicity, therapeutic levels are monitored with clinical use.

Conclusion With the elevated severity of injury of our neurointensive care patients, including multisystem disorders that may predate the neurologic injury, the pharmacologic agents used for therapy are many and complex. There is an obvious need for a broad knowledge base of pharmacokinetics and dynamics, including therapeutic index and an understanding of the issue of drug interactions. One must also recognize that the behavior of drugs is somewhat unpredictable when the blood-brain barrier is impaired. Finally, our patients use many other drugs—be they over the counter or illicit—that may impact neurologic outcome as the result of an unpredictable “adverse effect.” The need to review the possible interactions of such agents with drugs that we commonly use in the neurointensive care unit cannot be overstated.

P earls 1. Pharmacokinetics encompasses drug absorption, distribution, and elimination. 2. High degrees of protein binding of a drug can outweigh fat solubility for lipid soluble drugs, causing the volume of distribution (Vd) to decrease, since the drug does not easily leave the circulation. 3. Weak acids like sodium thiopental are more ionized and more protein bound in a basic medium. Because a smaller amount of the drug is able to cross cell membranes, the drug effect will be diminished. 4. Drug interactions come in many forms. Adverse interactions may result from physicochemical incompatibilities between drugs or intravenous fluids. Acidic drugs (e.g., barbiturates) dissolved in a basic solution may precipitate as the free acid if mixed with a drug in an acidic medium (e.g., nondepolarizing muscle relaxants). Anesthetic agents may affect the elimina-

tion of other drugs by altering the delivery of drug to the liver (i.e., hepatic blood flow) or hepatic enzymes (i.e., enzymatic induction or inhibition). 5. The therapeutic index is the ratio of the median lethal dose (LD50) to the median effective dose (ED50) of a drug. 6. Context sensitive half-time is the time required for the central compartment drug concentration to decrease by 50% at the end of infusion as predicted by agent specific multicompartment pharmacokinetic models, where context refers to the duration of the infusion. The index is more useful in predicting the time course of recovery of many agents than is the elimination half-life. 7. The ability to adequately assess neurologic function is paramount in neurosurgical patients. Thus, deep sedation is reserved for specific indications such as

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spine instability; severe increased intracranial pressure, or delirium. In the majority of patients with neurologic injuries an artificial airway and mechanical ventilation are necessary. Whenever possible in these cases, sedation should be titrated to tolerance of the endotracheal tube or tracheostomy tube to maintain the ability to rapidly perform a reliable neurologic examination. 8. In a dose-related fashion, all of the benzodiazepines produce anxiolytic, sedative, hypnotic, amnesic, muscle relaxant, and anticonvulsant effects, presumably due to facilitation of the inhibitory action of GABA or glycine on neuronal transmission. Additionally, all of these agents also decrease the CMRO2, cerebral blood flow (CBF), and ICP in the absence of hypoventilation. 9. Propofol may be used for conscious sedation, as an induction agent, and for maintenance of anesthesia.

References 1. Wilkinson GR: Pharmacokinetics. In Hardman JG, Limbird LL (eds): Goodman & Gilman’s The Pharmacological Basis of Therapeutics, 10th ed. New York, McGraw-Hill, 2001, pp 3–30. 2. Clinical Pharmacology monographs on line. Available at: http://cpip.gsm.com. See fosphenytoin. 3. Rafferty S, Sherry E: Total intravenous anaesthesia with propofol and alfentanil protects against postoperative nausea and vomiting. Can J Anaesth 1992;39:37–40. 4. Bailey JM: Context-sensitive half-times: What are they and how valuable are they in anaesthesiology? Clin Pharmacokinet 2002;41:793– 799. 5. Hughes MA, Glass PS, Jacobs J: Context-sensitive half-time in multicompartment pharmacokinetic models for intravenous anesthetic drugs. Anesthesiology 1992;76:334–341. 6. White PF: Clinical uses of intravenous anesthetic and analgesic infusions. Anesth Analg 1989;68:161–171. 7. Michenfelder JD, Theye R: Cerebral protection by thiopental during hypoxia. Anesthesiology 1973;39:510–517. 8. Michenfelder JD, Milde JH, Sundt TM: Cerebral protection by barbiturate anesthesia. Use of middle cerebral artery occlusion in Java monkeys. Arch Neurol 1976;33:345–350. 9. Baughman VL: Brain protection during neurosurgery. Anesthesiology Clin North Am 2002;20:315–327. 10. Brain Resuscitation Clinical Trial 1 Study Group: Randomized clinical study of thiopental loading in comatose survivors of cardiac arrest. N Eng J Med 1986;314:397–403. 11. Nussmeier NA, Arlund C, Slogoff S: Neuropsychiatric complications after cardiopulmonary bypass: Cerebral protection by a barbiturate. Anesthesiology 1986;64:65–70. 12. Nehls DG, Todd MM, Spetzler RF, Drummond JC, Thompson RA, Johnson PC: A comparison of the cerebral protective effects of isoflurane and barbiturates during temporary focal ischemia in primates. Anesthesiology 1987;66:453–464. 13. Sonntag H, Helberg K, Schenk H, et al: Effects of thiopental (Trapanal®) on coronary blood flow and myocardial metabolism in man. Acta Anesth Scand 1975;19:69–78. 14. Robicsek SA, Black S: Acidosis following barbiturate administration for focal ischemia during EC-IC bypass. J Neurosurg Anesthesiol 2000;12:A–34.

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While propofol can cause EEG burst suppression, it has not been demonstrated clinically to be a neuroprotective to date. 10. Adrenocortical suppression of both cortisol and aldosterone production, which may occur after a single induction dose, is predominantly due to etomidateinduced inhibition of the enzyme, 11-b hydroxylase. The relative reduction of cortisol and aldosterone levels starts approximately 30 minutes after a single induction dose and lasts 5 to 15 hours. However, a single dose use of etomidate has not been shown to have any adverse clinical effect as a result of its transient inhibition of corticosteroid synthesis. 11. Regardless of the duration of infusion, the time for the plasma concentration of remifentanil to decrease by 80% is 15 minutes. In addition, a single bolus dose of remifentanil is 20 to 30 times as potent as a similar dose of alfentanil.

15. Cairns CJ, Thomas B, Fletcher S, Parr MJ, Finfer SR: Life-threatening hyperkalemia following therapeutic barbiturate coma. Intensive Care Med 2002;28:1357–1360. 16. Seltzer JL, Gerson JI, Allen FB: Comparison of the cardiovascular effects of bolus vs. incremental administration of thiopentone. Br J Anaesth 1980;52:527–530. 17. Briggs LP, Dundee JW, Bahar M, et al: Comparison of the effect of diisopropylphenol (ICI 35, 868) and thiopentone on response to somatic pain. Br J Anaesth 1982;54:307–311. 18. Barron DW: Effect of rate of injection on incidence of side effects with thiopental and methohexital. Anesth Analg 1968;47:171. 19. Veselis RA: Anesthetic adjuvants and other CNS drugs. In Hemmings HC, Hopkins PM (eds): Foundations of Anesthesia. London, Mosby, 2000, p 261. 20. Fleischer JE, Milde JH, Moyer TP, Michenfelder JD: Cerebral effects of high-dose midazolam and subsequent reversal with Ro 15–1788 in dogs. Anesthesiology. 1988;68:234–242. 21. Black S, Michenfelder JD: Cerebral blood flow and metabolism. In Cucchiara RF, Black S, Michenfelder JD (eds): Clinical Neuroanesthesia, 2nd ed. New York, Churchill Livingstone, 1998, pp 1–40. 22. Reves JG, Fragen RJ, Vinik HR, et al: Midazolam—pharmacology and uses. Anesthesiology 1985;62:310–324. 23. Bryson HM, Fulton BR, Faulds D: Propofol. An update of its use in anesthesia and conscious sedation. Drugs 1995;50:513–559. 24. Sebel PS, Lowdon JD: Propofol: A new intravenous anesthetic. Anesthesiology 1989;71:260–277. 25. Vandesteene A, Trempont V, Engelman E, et al: Effect of propofol on cerebral blood flow and metabolism in man. Anesthesia 1988;43:42–43. 26. Kaptanoglu E, Sen S, Beskonakli E, et al: Antioxidant actions and early ultrastructural findings of thiopental and propofol in experimental spinal cord injury. J Neurosurg Anesthesiol 2002;14:114–122. 27. Shafer A, Doze VA, Shafer SL, et al: Pharmacokinetics and pharmacodynamics of propofol infusions during general anesthesia. Anesthesiology 1988;69:348–356. 28. Hug CC, McLeskey CH, Nahrwald ML, et al: Hemodynamic effects of propofol: Data from over 25,000 patients. Anesth Analg 1993;77: 521–529. 29. Moss E, Powell D, Gibson M: Effect of etomidate on intracranial pressure and cerebral perfusion pressure. Br J Anaesth 1979;51:347–352. 30. Wanquier A: Profile of etomidate. Anaesthesia 1983;38:26–33. 31. Gancher S, Laxer KD, Krieger W: Activation of epileptogenic activity by etomidate. Anesthesiology 1984;61:616–618.

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32. Bergen JM, Smith DC: A review of etomidate for rapid sequence intubation in the emergency department. J Emerg Med 1997;15:221–230. 33. Wagner RL, White PF: Etomidate inhibits adrenocortical function in surgical patients. Anesthesiology 1984;61:647–651. 34. Fellows IW, Bastow MD, Byrne AJ, et al: Adrenocortical suppression in multiply injured patients: A complication of etomidate treatment. BMJ (Clin Res Ed) 1983;287:1835–1837. 35. White PF, Way WL, Trevor AJ: Ketamine—its pharmacology and therapeutic uses. Anesthesiology 1982;56:119–136. 36. Corssen G, Domino EF: Dissociative anesthesia: Further pharmacologic studies and first clinical experience with the phencyclidine derivative CI–581. Anesth Analg Curr Res 1966;45:29–40. 37. Haas DA, Harper DG: Ketamine: A review of its pharmacologic properties and use in ambulatory anesthesia. Anesth Prog 1992;39:61–68. 38. Sari A, Okuda Y, Takeshita H: Effect of ketamine on cerebral circulation and metabolism. Masui 1971;20:68–73. 39. Wyte SR, Shapiro HM, Turner P, et al: Ketamine-induced intracranial hypertension. Anesthesiology 1972;36:174–176. 40. Dawson B, Michenfelder JD, Theye RA: Effects of ketamine on canine cerebral blood flow and metabolism: Modification by prior administration of thiopental. Anesth Analg 1971;50:443–447. 41. Idvall J, Ahlgren I, Aronsen KF, et al: Ketamine infusions: Pharmacokinetics and clinical effects. Br J Anaesth 1979;51:1167–1171. 42. Atcheson R, Lambert DG: Update on opioid receptors. Br J Anaesth 1994;73:132–134. 43. Stoelting RK: Opioid Agonists and Antagonists. In Stoelting RK (ed): Pharmacology and Physiology in Anesthetic Practice. Philadelphia, Lippincott-Raven Publishers, 1999, pp 77–112. 44. Ionescu TI, Taverne RHT, Houweling PL, et al: Pharmacokinetic study of extradural and intrathecal sufentanil anaesthesia for major surgery. Br J Anaesth 1991;66:458–464. 45. Chaney MA: Side effects of intrathecal and epidural opioids. Can J Anaesth 1995;42:891–903. 46. Larsen CP, Maxxe RI, Cooperman LH, et al : Effects of anesthetics on cerebral, renal and splanchnic circulation: Recent developments. Anesthesiology 1974;41:161. 47. Black S, Michenfelder J: Cerebral blood flow and metabolism. In Cucchiara RF, Black S, Michenfelder JD (eds): Clinical Neuroanesthesia, 2nd ed. New York, Churchill Livingstone, 1998, p 24. 48. Stoelting RK: Opioid agonists and antagonists. In Stoelting RK (ed): Pharmacology and Physiology in Anesthetic Practice. Philadelphia, Lippincott-Raven, 1999, pp 77–112. 49. Albanese J, Durbec O, Viviand X, et al: Sufentanil increases intracranial pressure in patients with head trauma. Anesthesiology 1993;79:493. 50. Sperry RJ, Bailey PL, Reichman MV, et al: Fentanyl and sufentanil increase intracranial pressure in head trauma patients. Anesthesiology 1992;77:416–420. 51. Werner C, Kochs E, Bause H, et al: Effects of sufentanil on cerebral hemodynamics and intracranial pressure in patients with brain injury. Anesthesiology 1995;83:721–726. 52. Black S, Michenfelder J: Cerebral blood flow and metabolism. In Cucchiara RF, Black S, Michenfelder JD (eds): Clinical Neuroanesthesia, 2nd ed. New York, Churchill Livingstone, 1998, p 23. 53. Westmoreland DL, Hoke JF, Sebel PS, et al: Pharmacokinetics of remifentanil (GI87084B) and its major metabolite (GI90291) in patients undergoing elective inpatient surgery. Anesthesiology 1993;79:893–903. 54. George JM, Reier CE, Lanese RR, Rower M: Morphine anesthesia blocks cortisol and growth hormone response to surgical stress in humans. J Clin Endorcrinol Metab 1974;38:736–741. 55. Philbin DM, Coggins CH: Plasma antidiuretic hormone level in cardiac surgical patients during morphine and halothane anesthesia. Anesthesiology 1987;49:95–98. 56. Stanley TH, Philbin DM, Coggins CH: Fentanyl-oxygen anaesthesia for coronary artery surgery. Cardiovascular and antidiuretic hormone responses. Can Anaesth Soc J 1979;26:168–172.

57. White PF, Coe V, Shafer A, et al: Comparison of alfentanil with fentanyl for outpatient anesthesia. Anesthesiology 1986;64:99–106. 58. Burke H, Dunbar S, Van Aken H: Remifentanil: A novel, short-acting, opioid. Anesth Analg 1996;83:646–651. 59. Pick CG, Paul D, Pasternak GW: Nalbuphine, a mixed kappa 1 and kappa 3 analgesic in mice. J Pharmacol Exp Ther 1992;262:1044–1050. 60. Hoffman BB, Lefkowitz RJ: Catecholamines, sympathomimetic drugs, and adrenergic receptor antagonists. In Hardman and Limbard (eds): Goodman and Gilman’s The Pharmacological Basis of Therapeutics, 9th ed. McGraw-Hill, 1996, pp 217–218. 61. Kamibayashi T, Maze M: Clinical uses of alpha2-adrenergic agonists. Anesthesiology 2000;93:345–349. 62. Venn RM, Bradshaw CJ, Spencer R, et al: Preliminary UK experience of dexmedetomidine, a novel agent for postoperative sedation in the intensive care unit. Anaesthesia 1999;54:1136–1142. 63. Bloor BC, Ward DS, Belleville JP, Maze M: Effects of intravenous dexmedetomidine in humans. II. Hemodynamic changes. Anesthesiology 1992;77:1134–1142. 64. Hall JE, Uhrich TD, Barney JA, Arain SR, Ebert TJ: Sedative, amnestic, and analgesic properties of small-dose dexmedetomidine infusions. Anesth Analg 2000;90:699–705. 65. Veselis RA: Anesthetic adjuvants and other CNS drugs. In Hemmings HC, Hopkins PM (eds): Foundations of Anesthesia. London, Mosby, 2000, pp 261–274. 66. Aantaa R, Kanto J, Scheinin M, Kallio A, Scheinin H: Dexmedetomidine, an alpha 2-adrenoceptor agonist, reduces anesthetic requirements for patients undergoing minor gynecologic surgery. Anesthesiology 1990;73:230–235. 67. Gertler R, Cleighton Brown H, Mitchell DH, Silvius EN: Dexmedetomidine: A novel sedative-analgesic agent. BUMC Proc 2001;14:13– 21. 68. Buckley MM, Brogen RN: Ketorolac: A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic potential. Drugs 1990;30:86–109. 69. Bracken MB: Methylprednisolone and acute spinal cord injury: An update of the randomized evidence. Spine 2001;26:S47–S54. 70. Bracken MB: Steroids for acute spinal cord injury. Cochrane Database Syst Rev 2002;3:CD001046. 71. Bracken MB: Methylprednisolone and spinal cord injury. J Neurosurg Spine 2000;93:175–178. 72. Eberhart LH, Morin AM, Georgieff M: [Dexamethasone for prophylaxis of postoperative nausea and vomiting. A meta-analysis of randomized controlled studies]. Anaesthesist 2000;49:713–720. 73. Lanier WL, Milde JH, Michenfelder JD: Cerebral stimulation following succinylcholine in dogs. Anesthesiology 1986;64:551–559. 74. Minton MD, Grosslight K, Stirt JA, Bedford RF: Increases in intracranial pressure from succinylcholine: Prevention by prior nondepolarizing blockade. Anesthesiology 1986;65:165–169. 75. Stoelting RK (ed): Neuromuscular-blocking drugs. In: Pharmacology and Physiology in Anesthetic Practice, 3rd ed. St. Louis, Mosby, 1999, pp 192–193. 76. John DA, Tobey RE, Homer LD, Rice CL: Onset of succinylcholineinduced hyperkalemia following denervation. Anesthesiology 1976;45: 294–299. 77. Basta SJ, Ali HH, Savarese JJ, et al: Clinical pharmacology of atracurium besylate (BW 33A): A new non-depolarizing muscle relaxant. Anesth Analg 1982;61:723–729. 78. Anagnostou JM, Stoelting RK: Complications of drugs used in anesthesia. In Benumof JL, Saidman LJ (eds): Anesthesia and Perioperative Complications, 2nd ed. St. Louis, Mosby, 1999, pp 161–191. 79. Sparr HJ, Beaufort TM, Fuchs-Buder T: Newer neuromuscular blocking agents: How do they compare with established agents? Drugs 2001;61:919–942. 80. Gibson BE, Black S, Maass L, et al: Esmolol for the control of hypertension after neurologic surgery. Clin Pharmacol Ther 1988;44: 650–653.

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81. Black S, Michenfelder J: Cerebral blood flow and metabolism. In Cucchiara RF, Black S, Michenfelder JD (eds): Clinical Neuroanesthesia, 2nd ed. New York, Churchill Livingstone, 1998, p 29. 82. Marsh ML, Shapiro HM, Smith RL, et al: Changes in neurologic status and intracranial pressure associated with sodium nitroprusside administration. Anesthesiology. 1979;51:336. 83. Turner JM, Powell D, Gibson RM: Intracranial pressure changes. Br J Anaesth 1977;49:419–424. 84. Marsh ML, Aidinis SL, Naughton KVH, et al: The technique of nitroprusside administration modifies the intracranial pressure response. Anesthesiology 1979;51:538–541. 85. Cotrell JE, Patel K, Turndorf H: Nitroprusside pressure changes induced by sodium nitroprusside in patients with intracranial mass lesions. J Neurosurg 1978;48:329. 86. Stoelting RK (ed): Peripheral vasodilators. In: Pharmacology and Physiology in Anesthetic Practice. St. Louis, Mosby, 1999, p 319. 87. Miletich DJ, Gil KS, Albrecht RF, et al: Intracerebral blood flow distribution during hypotensive anesthesia in the goat. Anesthesiology 1980;53:210–214. 88. Moore RA, Geller EA, Gallagher JD, et al: Effect of hypothermic cardiopulmonary bypass on nitroprusside metabolism. Clin Pharmcol Ther 1985;37:680–683.

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89. Anagnostou JM, Stoelting RK. Complications of drugs used in anesthesia. In Benumof JL, Saidman LJ (eds): Anesthesia and Perioperative Complications, 2nd ed. St. Louis, Mosby, 1999, pp 161–191. 90. Lagerkranser M: Effects of nitroglycerin on intracranial pressure and cerebral blood flow. Acta Anaesthesiol Scand Suppl 1992;97: 34–36. 91. Kobayashi T, Mori Y: Ca2+ channel antagonists and neuroprotection from cerebral ischemia. Eur J Pharmacol 1998;363:1–15. 92. Orlowski JP, Shiesley D, Vidt DG, Barnett GH, Little JR: Labetalol to control blood pressure after cerebrovascular surgery. Crit Care Med 1988;16:765–768. 93. Bunegin L, Albin MS, Gelineau EF: Effect of esmolol on cerebral blood flow during intracranial hypertension and hemorrhagic hypovolemia. Anesthesiology 1987;67:A424. 94. Rogers MC, Hamburger C, Owen K, et al: Intracranial pressure in the cat during nitroglycerine-induced hypotension. Anesthesiology 1979;51:227–229. 95. Bryson HM, Fulton BR, Faulds D: Propofol. An update of its use in anesthesia and conscious sedation. Drugs 1995;50:513–559.

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Chapter 23 Intrahospital Transport of the Neurosurgical Patient Richard J. Melker, MD, PhD

Few would disagree that transporting critically ill patients from intensive care units (ICUs) to less sophisticated areas of the hospital carries potential risks. One need only observe the transfer of a seriously ill patient from an operating table to a hospital bed or from an ICU bed to a stretcher to envision the problems. Because of the exquisite interaction between the nervous system and the respiratory and cardiovascular systems, neurosurgical patients are at particular risk of complications when perturbations in cerebral oxygen delivery occur, as during patient transport. While transport of patients from the emergency department (ED) for diagnostic studies, to the operating room (OR), or to the intensive care unit (ICU) is essential, patient transport from the ICU is less essential. The clinician must seriously weigh the risks versus the benefits that might be afforded by transport. Some institutions that handle a high volume of trauma patients integrate the OR and ICU, while others emphasize bedside procedures1,2 or mobile diagnostic equipment, such as mobile computed tomography (CT) units.3 However, in most institutions, ICU patients are frequently transported, and the focus must be on maintaining optimal care with as few compromises as possible. Early publications reporting significant morbidity and mortality during transport are often cited. In 1975, Waddell4 prospectively studied 55 transports of ICU patients over a 5month period and reported one death per month, which he deemed directly related to the transport. More recent studies (see later discussion) demonstrate that with appropriate staffing, treatment, and monitoring, patients can be safely transported. These studies span a wide range of patient populations but reach similar conclusions and can be applied to

neurosurgical patients. Not surprisingly, the most acutely ill patients suffer the most complications during transport, but no more so than matched cohorts who are not transported. Many organizations have published standards of care for intrahospital transport including a joint publication by the American Association of Critical Care Nurses, the American College of Critical Care Medicine, the Society of Critical Care Medicine,5 and a publication from the American Association of Respiratory Therapists.6

Why Patients Are Transported While some ICU patients are transported back to the OR, the majority go for diagnostic studies, primarily CT. Kalisch and colleagues7 studied 471 patients with a wide range of neurologic diagnoses transported from neurologic ICUs at 17 institutions. The majority (63%) went to CT, followed by angiography (12%), the OR (10%), magnetic resonance imaging (8%), and other imaging studies. Many of these cases were emergent, unscheduled transports (30%). Time outside the ICU averaged 62 minutes, with some transports lasting longer than 7 hours. This did not include time for preparation for and reintegration after transport. Significant personnel resources including nurses, respiratory therapists, and physicians were used during transport and while the patients were being studied. Not surprisingly this impacted not only the care of the transported patient, but also those remaining in the ICU. Hurst and colleagues8 estimated the cost of an in-hospital transport to be $612 to the patient and $452 to the hospital. 683

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Complications Encountered During Transport A fundamental objective in patients with brain injury is to prevent or ameliorate secondary insults, which lead to additional cerebral ischemia and worsened outcome. Few studies specifically address complications encountered in neurosurgical patients and the criteria used for determining a complication vary widely. However, certain clear patterns become apparent. Andrews and associates9 prospectively assessed secondary pathophysiologic insults in 42 head-injured patients requiring intrahospital transport. Twenty-seven patients were transported at total of 35 times from the ICU, the remainder from the ED. Twenty-six patients had severe head injuries (Glasgow Coma Score [GCS] <8). Insults were graded on a scale of 1 to 3 (3 most severe) based on the degree of change in vital signs from normative values. Twenty insults during 18 transports were documented, including hypertension,5 intracranial hypertension,8 hypotension,3 and hypoxemia.3 In patients transported from the ICU, insults occurred in those who had had similar episodes during a 4-hour period of monitoring before transport; most instances were cardiovascular instability and changes in blood gases. Most studies reporting complication rates during transport fail to evaluate how often they occur while the patient is in the ICU. Hurst and colleagues8 found a similar frequency of physiologic changes in transported patients and a matched cohort who were not, confirming the observations of Andrews. Smith and associates10 prospectively studied 125 transports from the ICU. Mishaps, defined as the occurrence of any unplanned event that potentially could have a detrimental effect on patient stability, occurred in one third of the transports. While many could be considered minor (the majority being electrocardiograph lead disconnects) the authors believe they are as potentially dangerous as others: intravenous line infiltration, pulmonary artery catheter mishaps, and vasoactive drug disconnects. There was no relationship between the Acute Physiology and Chronic Health Evaluation (APACHE) II score and the likelihood of mishaps, but a correlation with the Therapeutic Intervention Scoring System (TISS) was noted. Many mishaps occurred during transport to or during CT scanning, likely reflecting the frequency of the procedure, the physical isolation of the patient, and the difficulty transferring the patient to and from the scanner. Szem and colleagues11 studied 759 surgical ICU patients, 175 of whom were transported a total of 203 times for diagnostic studies or to the OR. APACHE II and III scores were determined 24 hours after admission and the transported patients were stratified into low or high risk. Transported patients were matched by APACHE scores to a control cohort

(not transported). Although high-risk transported patients had a higher mortality rate than matched controls, it was not higher than the predicted rate, and the authors conclude that intrahospital transport is safe and carries a low risk of complications. The higher mortality in the high-risk transported group is explained by the likelihood that the transported patients were sicker. Almost half of all patients were transported for CT. Ventilation was performed manually by a respiratory therapist based on the ventilator settings before transport and the patient was placed back on a ventilator during the procedure. Evans and Winslow12 found clinically important changes in percent arterial oxygen saturation (SaO2), heart rate, and blood pressure in 53% of transported patients, usually during the procedure. Ventilation was performed manually by a respiratory therapist. Caruana and Culp provide an excellent compilation of literature on complications of intrahospital transport.13 Kollef and associates14 studied 521 medical and surgical ICU patients requiring mechanical ventilation to determine whether intrahospital transport is an independent predictor of ventilator-acquired pneumonia (VAP). Two hundred seventy-three patients underwent 993 transports, the majority for radiographic procedures. VAP occurred in 77 (14.8%) of patients who had statistically lower partial pressure of arterial oxygen to fractional inspired oxygen (PaO2/FiO2) ratios, higher APACHE II scores, and were more likely to be male and African American. (The PaO2/FiO2 ratio allows for comparison of the adequacy of oxygenation among patients on different FiO2 settings.) While transported patients had a significantly (4 times) greater incidence of VAP compared to those not transported, the authors conclude that transport is likely a marker for patients with an increased risk of VAP based on their higher APACHE II scores and greater prevalence of risk factors, but cannot exclude the possibility that the transport, per se, is also a risk factor. Waydhas,15 using a Medline search, analyzed publications for the type and incidence of adverse effects, risk factors, and risk assessment resulting from intrahospital transport of critically ill patients. Based on his analysis, adverse effects may occur in as many as 70% of patients, but his analysis included studies reported before 1990. More recent studies report adverse effects in 6% to 71% of cases. Most serious effects are related to disconnection of a ventilator or intravenous or intra-arterial lines, which may occur in as many as 8% of transports. Again, the incidence of respiratory complications was high (29%), including changes in respiratory rate and declines in arterial oxygen saturation, prompting the author to recommend the use of a transport cart with a standard ICU ventilator, in lieu of manual ventilation or a transport ventilator. Lovell and associates16 performed a prospective audit of 97 transports in 76 critically ill patients. A transport-related complication was defined as “any event that impacted

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adversely on the patient’s stability.” These were further divided into patient-related complications and equipmentrelated complications. As with previous studies, the majority of patients were taken for CT studies. A physician accompanied the patients on all transports. Manual ventilation was used during transport and a mechanical ventilator was used during the procedure in all but three instances. Problems were encountered during 60 transports (62%) with 30 related to “patient” problems and 44 related to “equipment” problems (both types occurring in some patients). Hypertension, hypotension, tachycardia, and oxygen desaturation were the most common patient-related problems; battery failure, poor visibility of monitors, and difficulty pushing the intravenous (IV) poles the most common equipment-related problems.

Ventilation During Transport Three commonly quoted papers from the late 1980s by Gervais and associates,17 Hurst and colleagues,8 and Braman and associates18 focused attention on the superiority of mechanical ventilation over manual ventilation during transport. In intubated patients, manual ventilation frequently leads to hyperventilation. While moderate hyperventilation is often used in neurosurgical patients to control intracranial pressure (ICP), marked degrees of hyperventilation, which could predispose to cerebral ischemia, were documented with manual ventilation. Tobias and colleagues19 measured end-tidal CO2 pressure (ETCO2) in children (7 months to 14 years) during intrahospital transport with manual ventilation and a goal of maintaining the ETCO2 between 25 and 30 torr. Thirty-one percent of measurements were in the desired range, 23% were less than 20 torr, 39% between 25 and 30 torr, and 6.3% were greater than 30 torr. Subsequent studies have confirmed that mechanical ventilation is superior to that provided manually, especially in preventing hyperventilation. Dockery and co-workers20 used arterial blood gases and ETCO2 to compare manual and mechanical ventilation in 49 pediatric postheart surgery patients transported from the OR to the ICU. There was a statistically wider variation in ventilation with the manual device compared with a mechanical ventilator and a statistically significant decrease in ETCO2, confirming the earlier studies. In a well-designed study, Bekar and associates21 studied changes in ICP before, during, and after transport of seven neurosurgical patients, all with a GCS of less than 8, who required CT. Six patients had closed head injuries and the other a spontaneous intracerebral hematoma. All patients were sedated with propofol, received fentanyl for analgesia and vecuronium for muscle relaxation, all by constant infusion. Before transport, PaO2 was maintained above 100 torr and partial pressure of arterial carbon dioxide (PaCO2) was maintained between 27 and 30 torr with mechanical ventila-

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tion. Manual ventilation was used during transport. All patients were transported for CT in their ICU bed with the head maintained in a neutral position and elevated 25% to 30 degrees. ICP, PaCO2, PaO2, and mean arterial pressure were recorded just before transport, during transport, in the CT scanner and after return to the ICU. Although not statistically significant (probably due to the small sample size), PaCO2 decreased by an average of 16% although there were wide variations above and below the pretransport levels. Likewise, PaO2 and MAP declined during transport and during the studies, with PaO2 remaining below pretransport values after return, while mean arterial pressure increased to above pretransport levels upon return. Most importantly, there was a statistically significant increase in ICP (27% on average) upon return to the unit as compared to pretransport values. ICP was even higher, on average, during CT scanning, probably because the head had to be placed flat for the procedure. The authors stated that careful attention to ventilatory status, analgesia, and proper sedation could have ameliorated many of the changes and clearly implicate manual ventilation as a factor in the increased ICP. In a carefully designed study, Marx and colleagues22 evaluated 98 mechanically ventilated patients before, during, and after transport. APACHE II and TISS scores were obtained for all subjects and were used as a measure of severity and predictor for deterioration of respiratory function after transfer. Hemodynamic measurements and arterial blood gas measurements were obtained at 11 different times beginning 24 hours before transport and ending 24 hours after transport. In addition, derived data including the PaO2/FiO2 ratio were calculated. In 55% of the transports, there was a decrease in the PaO2/FiO2 ratio, and a decrease of more than 20% from baseline was noted in 24% of the patients. All patients were transported using a Drägerwerke (Lubëck, Germany) Oxylog transport ventilator. Forty percent of patients had head injury or intracerebral pathology, with another 28% having multiple traumas. In 71 patients, a pretransfer PaO2/FiO2 ratio greater than 250, age greater than 43 years, and FiO2 greater than 0.5 predicted deterioration of respiratory function after transport. In all, 55% of patients experienced a decline in respiratory function after the transport, five required up to 24 hours to recover, and in 18 patients the deterioration persisted for more than 1 day. Waydhas and co-workers23 found similar results with a decline in the PaO2/FiO2 ratio in nearly 83.7% of transported patients, and a greater than 20% decline from pretransport levels in 42.8%. Ventilation with positive end-expiratory pressure or continuous positive airway pressure (PEEP/CPAP) correlated significantly with a lower PaO2/FiO2 ratio after transport. In 20.4% of patients, the respiratory derangement lasted longer than 24 hours. Because removal of mechanically ventilated patients requiring PEEP from a ventilator often leads to desaturation, which may take considerable time to reverse, maintenance of pretransport

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ventilator setting during transport would appear to be the single most important measure to protect the neurosurgical patient from secondary insults.

Strategies to Ensure Safe Transport Link and associates24 constructed a transport unit allowing monitoring and treatment during transport. The unit was designed to be positioned at the head of the bed and to be moved with it. It contained a Siemens Servo 900A ventilator and a full complement of infusion pumps and monitors, including a capnometer and pulse oximeter. Swoboda and assoicates25 report on the use of a commercially available self-contained device (CarePorter, HillRom, Batesville, IN). They studied this device while it was under development and hypothesized that it would decrease the number of personnel and time required for transport without affecting ICU standards of care. The device was designed to allow both intensive care support and transport capability and attached to the head of the patient bed. The concept was to provide seamless care by managing the ventilator and infusion pumps in both the ICU and during transport, similar to that provided with neonatal transport units. The unit could be attached to power and gas supplies in the ICU and provide self-contained sources during transport. The ventilator, infusion pumps, and monitors were placed on the CarePorter throughout the patient’s stay in the ICU and thus were dedicated to and could be transported with the patient. Unfortunately, in practice, a CarePorter would be required at each ICU bed because it would be unlikely that one could predict beforehand which patients would require transport during their stay. Further, the CarePorter was only compatible with certain Hill-Rom beds. Patients transported with the CarePorter were compared to APACHE II matched cohorts transported in their ICU bed or on a stretcher. Use of the CarePorter reduced the number of personnel required for transports and the time to reestablish the patient’s pretransport status upon return to the ICU. There was no difference in preparation for transport or transit times, but it required 21 minutes longer to transfer patients to a stretcher when compared to transport with the CarePorter or the ICU bed. Unfortunately, this device is no longer available. With no commercial devices to choose from, those responsible for ICU patients must assemble the equipment and protocols necessary to ensure safe transport. Table 23-1 is a compilation of features a committee at my institution studying intrahospital transport identified as being essential, helpful, or unnecessary for five versions of a self-contained transport/treatment system. The concept was that all equipment would be modularized and could be connected directly to the bed, which would function as a self-contained ICU or other specialized treatment and transport system.

Components of a Safe Transport System While few studies have been directed specifically at evaluating complications that occur in neurosurgical patients, it is clear that maintenance of pretransport ventilatory status is key to preventing secondary cerebral insults. Variations in CO2 and O2 levels predispose to increased ICP and further insult. Hypotension and hypertension can have equally disastrous effects. All ICUs should have a system that can be transported along with the patient that contains all equipment and drugs needed to treat the broad range of problems and complications that can occur while the patients is outside the ICU. As documented in several previous studies, the complications that occur in the ICU will also occur during transport, assuring that the critically ill patient will require extensive care. Unfortunately, some compromises will have to be made. Transports can be broken down into two categories: those that originate from the ICU, and those that bring patients to the ICU (ED to ICU, ED to diagnostic studies to ICU, and ED to diagnostic studies to OR to ICU and OR to ICU). Clearly, with these patients, compromises must be made that would be unacceptable for other transports. Relatively little compromise must be made in terms of vital signs monitoring with the advent of many small transportable monitoring systems such as the Propaq monitor series (Welch Allyn, Beaverton, OR), which have monitoring capabilities similar to those of fixed ICU systems and the ability to operate for extended periods on battery power. Siemens, Phillips, and many other companies sell similar small transportable monitors. Likewise, most infusion pumps have battery life compatible with intrahospital transport, and several small multichannel infusion systems are available. The difficulty arises when the patient is transferred from fixed to transportable equipment. If the devices are from the same manufacturer, the connectors are likely compatible; if not, this may be a source of considerable redundancy and wasted time. Likewise, it is important to have compatible equipment in the diagnostic areas, particular CT. Diagnostic equipment for use in the MR scanner is a particular problem, usually requiring dedicated equipment for use in this area. Difficulties arise when there is no protocol for keeping devices charged between transports, and battery failure is one of the most frequent problems encountered in transport. While pulse oximetry is standard on almost all vital signs monitoring systems, capnometry is not. This is a worthwhile monitoring modality to consider because excessive hyperventilation or hypoventilation can quickly lead to cerebral compromise. The issue of an appropriate ventilator is a bigger problem. The preponderance of evidence favors the use of a mechanical ventilator over manual ventilation, especially in patients requiring PEEP/CPAP. There are several transport

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Table 23-1  A Wish List of Features for Five Versions of a Self-Contained Transportable Patient Care System

Intrahospital Transport

Ventilator General design Microprocessor controlled Ventilatory modes SIMV CPAP PSV PCV EIP HFJV (separate jet injector nozzle connector)

Conscious Sedation Station

Equipment Integrated smart patient alarms Fluid temp Battery charge Cylinder pressures Patient weight Bed temp (pediatrics only) Bear Hugger-like warmer (pediatrics) Bed position indicator Fluid balance monitor Individual Summated Pump alarms

Pre-hosp/Interfacility Transport

Monitors Patient EKG ST Analysis 2-lead upgradeable to 12-lead Print ability (rhythm strip) Defibrillator with/pacer internal/external capability Pulse oximetry with/plethysmography Gas analysis FiO2 FeO2 FiCO2 ETCO2 NO/NO2 Waveforms Anesthetic agents 4-channel pressure monitoring Cardiac output (in some form) Continuous pHI Noninvasive blood pressure Temp—1 to 2 channel Respiratory plethysmograph ICP Venous saturation unit 2 to 4 spare module slots Aspect 2000-type monitor

ICU on Wheels

Multi-use Care Provider Systems

Moveable OR/TIVA

Configuration

1 2 2 2 2 1

1 1 1 1 1 1

1 3 3 3 1 1

1 3 2 2 2 1

1 3 2 2 1 1

1 1 2 1 2 1 1 1 1 3 1 1 3 2 2 1 2

2 2 3 1 1 1 3 1 1 2 1 1 2 2 1 1 2

3 3 3 1 3 3 3 3 3 3 1 3 3 3 3 1 3

1 2 2 1 3 2 2 2 3 3 1 1 3 3 3 1 3

3 3 1 1 3 3 3 1 3 3 1 2 3 2 2 1 3

1 2 1 1 1 1 2 (1) 1 2 2 2 1

1 2 1 1 1 3 2 (1) 1 2 1 1 1

1 3 1 1 3 3 3 3 1 3 3 1

1 3 1 1 3 3 2 3 3 2 2 1

1 3 1 1 3 3 3 3 3 3 3 1

1

1

1

1

1

1 1 1 1 1 1

1 1 1 1 1 1

1 2 3 3 3 1

1 1 1 3 3 1

1 1 1 1 1 1 continued

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Table 23-1  A Wish List of Features for Five Versions of a Self-Contained Transportable Patient Care System (continued)

Pre-hosp/Interfacility Transport

Conscious Sedation Station

Intrahospital Transport

FiO2 control (0.21–1.0) Bilateral positive airway pressure Pressure range Peak inflation pressure (PIP) (up to 120 cm H2O) CPAP (1–40 cm H2O) PSV/PCV (1–60 cm H2O) Tidal volume range (0.1–1.5 L) Ventilator rate (2–60 per min) Inspiratory time (0.5–3 sec) Peak inspiratory flow rate (2–120 L/min) Inspiratory flow waveform Constant, decelerating Small nebulizer for aerosol therapy Integrated ETT cuff inflator system Display/controls CRT (graphics and alphanumeric data) Touch screen Monitoring capabilities Pressure PIP, Mean Paw, CPAP/PEEP Pressure measuring sites: Y piece of breathing circuit Carinal end of ETT Breathing frequency (spontaneous and mechanical) Flow/Volume measuring site Y piece of breathing circuit Flow rate VT (spontaneous and mechanical), VE (spontaneous and mechanical) Capnometer Single breath CO2 method (volume-based capnography) Pulse oximetry Pulmonary mechanics Compliance Resistance WOB PATIENT (via respiratory muscle pressure) WOB IMPOSED WOB VENTILATOR VD/VT ratio ETCO2 LCO2 Power source Pneumatic Oxygen (LOX system) Compressed air (self-contained turbine) Electric AC DC (battery) Size Weight Approx. 20 lbs. Dimensions Approx. 1 ft ¥ 1 ft ¥ 1 ft (cube) X-ray interface

ICU on Wheels

Multi-use Care Provider Systems

Moveable OR/TIVA

Configuration

1 2

1 1

1 2

1 3

1 2

1 1 1 1 1 1 1 1 1 1 1

1 1 1 1 1 1 1 1 1 1 1

1 (60) 1 (10) 1 1 1 1 1 1 1 1 1

1 1 1 1 1 1 1 1 1 1 1

1 1 1 1 1 1 1 1 1 1 1

1 1

1 1

1 1

1 1

1 1

1

1

1

1

1

1 1 1

1 1 1

1 1 1

1 1 1

1 1 1

1 1 1

1 1 1

1 1 1

1 1 1

1 1 1

1 1

1 1

1 1

1 1

1 1

1 1 1 1 1 1 1 1

1 1 1 1 1 1 1 1

1 1 1 1 1 1 1 1

1 1 1 1 1 1 1 1

1 1 1 1 1 1 1 1

1 1

1 1

1 1

1 1

1 1

1 1

1 1

1 1

1 1

1 1

1

1

1

1

1

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689

Multi-use Care Provider Systems

Moveable OR/TIVA

ICU on Wheels

Pre-hosp/Interfacility Transport

Conscious Sedation Station

Intrahospital Transport

Configuration

Pumps Number of pumps Number of 2-stage pumps Number of PCA programmable Bar code reader Umbilical cord system with/yoke Programmable from main monitor or distantly [Telemetry] Reversed-pump intermittent suction

4 1 1 1 1 1 1

8 1 1 1 1 1 1

4 1 0 1 1 1 1

4 1 1 1 1 1 1

4 1 1 1 1 1 1

Miscellaneous High-flow fluid warmer O2 concentrator Multiport, pressure regulated suction Pleurevac slot IABP holder bracket All data downloadable through USB or RS232 High-intensity light source for fiberoptic devices

1 3 1 1 3 1 1

1 3 1 1 3 1 1

1 3 1 1 1 1 1

1 3 1 1 3 1 1

1 3 1 1 1 1 1

Miscellaneous monitoring issues One monitor face “Picture-within-a-picture” capability for monitor Depth-type software so all data about equipment is on 1 screen. Slave screen All functions programmable from main screen or distant site. Screen-touch control Drug storage Drainage bags Self-propelled

1 1 1 1 1 1 1 1 1

1 1 1 1 1 1 1 1 1

1 1 1 1 1 1 1 1 1

1 1 1 1 1 1 1 1 1

1 1 1 1 1 1 1 1 1

Display/Communication Touch screen All features of all devices remotely controlled Recording of all data Display of vital signs including waveforms

1 1 1 1

1 1 1 1

1 1 1 1

1 1 1 1

1 1 1 1

1, a “must have” feature for the intended use; 2, a helpful, but not essential feature; 3, an unnecessary feature. AC, alternating current; CPAP, continuous positive airway pressure; CRT, cathode ray tube; DC, direct current; EIP, end-inspiratory pressure; ETCO2, endtidal carbon dioxide pressure; ETT, endotracheal tube; FeO2, fractional concentration of oxygen in expired gas; FiCO2, forced inspiratory carbon dioxide fraction of inspired oxygen; FiO2, fractional inspired oxygen concentration; HFJV, high-frequency jet ventilation; ICP, intracranial pressure; PSV, pressure supported ventilation; SIMV, synchronized intermittent mandatory ventilation; VE, respiratory minute volume; VT, tidal volume.

ventilators available with adequate sophistication to ventilate apneic patients, but in many cases it is advantageous to have the patient breathe spontaneously with an assist mode backup. Clearly, from the stability perspective it would be best to keep the patient on the same ventilator used in the ICU. Unfortunately, most of these ventilators are bulky, require large supplies of air and oxygen as well as electrical power and considerable expertise to use correctly, have no

battery backup, and in many hospitals are in short supply. Branson26,27 provides excellent reviews of the available ventilators, including those compatible with MRI, and their capabilities. For transports originating in the ED, a transport ventilator with PEEP/CPAP capability is probably a good compromise because many of these patients will be paralyzed and sedated. For institutions performing large numbers of OR to

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ICU and ICU-based transports, consideration should be given to having one or more dedicated ventilators. Fortunately, there are several compact turbine or gas-driven ventilators with sufficient sophistication to meet this need (e.g., LTV1000, Pulmonetics, Cotton, CA; Bird 8400 and TBird, Bird Products Corp., Palms Springs, CA). The turbinedriven devices have the advantage of needing only a compressed oxygen gas supply. While many authors state that it is acceptable to place patients on 100% oxygen during transport, this predisposes to absorption atelectasis and hypoxemia, and in general should be avoided unless oxygenation cannot be maintained at lower levels. A self-inflating bag must always be available in case of ventilator failure due to loss of electrical power or gas supply. Neurosurgical patients require several special considerations. For patients with an unstable spine injury, or a potential spine injury, adequate immobilization must be provided. This is best maintained until definitive stabilization by using the extrication and stabilization devices initiated by emergency medical services; such equipment should be available and applied in the ED in cases in which the patient is transported to the hospital without it. Cervical collars are not a definitive means of cervical spine immobilization. These immobilization devices allow the patient to be “log rolled” in case of regurgitation. The patient must not be fixed

to the bed or stretcher in a way that precludes turning them quickly as a unit. Likewise, patients with increased ICP or with ICP monitoring who have a stable spine should be ideally transported with the head elevated. In planning a transport system, consideration should be given to allowing adequate access to the head and airway. Placing equipment at the foot, rather than head, of the bed is preferable. Airway, drug, and IV administration kits should be readily available. Adequate suction for airway suctioning is a necessity. Suction for pulmonary drainage systems is a bigger problem. These systems should never be clamped during transport, even if they are removed from suction.

Conclusions Neurosurgical patients will continue to require transportation from ICUs to diagnostic areas of the hospital and to the OR. A properly outfitted transport system designed with the needs of the neurosurgical patient in mind will reduce the likelihood of secondary insults. These patients are likely to have significant derangement during transport, just as they do in the ICU. These must be anticipated and planned for. Meticulous attention to adequate ventilation, oxygenation, and blood pressure is required. For the most part, equipment

P earls 1. Waddell prospectively studied 55 transports of ICU patients over a 5-month period and reported one death per month, which he deemed directly related to the transport. 2. Time outside the ICU averaged 62 minutes, with some transports lasting longer than 7 hours. 3. Evans and Winslow found clinically important changes in arterial oxygen saturation (SaO2), heart rate, and blood pressure in 53% of transported patients, usually during the procedure. 4. . . . transported patients had a significantly (4 times) greater incidence of VAP compared to those not transported . . . 5. Most serious effects are related to disconnection of a ventilator or intravenous or intra-arterial lines, which may occur in as many as 8% of transports. 6. All ICUs should have a system that can be transported along with the patient that contains all equipment and drugs needed to treat the broad range of problems and complications that can occur while outside of the ICU. As documented in previous studies, the complications that occur in the ICU will also occur

7.

8.

9.

10.

during transport, assuring that the critically ill patient will require extensive care. The difficulty arises when the patient is transferred from fixed to transportable equipment. If the devices are from the same manufacturer, the connectors are likely compatible; if not this may be a source of considerable redundancy and wasted time. Likewise, it is important to have compatible equipment in the diagnostic areas, particularly CT. While pulse oximetry is standard on almost all vital signs monitoring systems, capnometry is not. This is a worthwhile monitoring modality to consider because excessive hyperventilation or hypoventilation can quickly lead to cerebral compromise. These immobilization devices allow the patient to be “log rolled” in case of regurgitation. The patient must not be fixed to the bed or stretcher in a way that precludes turning them quickly as a unit. In planning a transport system, consideration should be given to allowing adequate access to the head and airway. Placing equipment at the foot, rather than head, of the bed is preferable.

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is available for adequate vital signs monitoring during transport. On the other hand, particular attention should be paid to the choice of ventilator used during transport. Devices that provide a range of ventilation modes, including spontaneous ventilation, and a means to maintain PEEP/CPAP levels as they were in the ICU are preferable. If most patients are sedated and paralyzed, or for transports from the ED, a portable transport ventilator may be adequate if appropriate respiratory monitoring is available. In the absence of a commercially available self-contained transport system, each institution will have to individualize a transport system based on its specific needs. Careful planning and device selection can optimize care in the hostile transport environment.

References 1. Haupt MT, Rehm CG: Bedside procedures. Solutions to the pitfalls of intrahospital transport. Crit Care Clin 2000;16:1–6. 2. Braxton CC, Reilly PM, Schwab CW: The traveling intensive care unit patient. Road trips. Surg Clin North Am 2000;80:949–956. 3. Gunnarsson T, Theodorsson A, Karlsson P, et al: Mobile computerized tomography scanning in the neurosurgery intensive care unit: Increase in patient safety and reduction of staff workload. J Neurosurg 2000; 93:432–436. 4. Waddell G: Movement of critically ill patients within hospital. BMJ 1975;2:417–419. 5. Guidelines for the transfer of critically ill patients. Guidelines Committee of the American College of Critical Care Medicine; Society of Critical Care Medicine and American Association of Critical-Care Nurses Transfer Guidelines Task Force. Crit Care Med 1993;21:931–937. 6. AARC clinical practice guideline. Transport of the mechanically ventilated patient. American Association for Respiratory Care. Respir Care 1993;38:1169–1172. 7. Kalisch BJ, Kalisch PA, Burns SM, Kocan MJ, Prendergast V: Intrahospital transport of neuro ICU patients. J Neurosci Nurs 1995;27:69–77. 8. Hurst JM, Davis K Jr, Johnson DJ, Branson RD, Campbell RS, Branson PS: Cost and complications during in-hospital transport of critically ill patients: A prospective cohort study. J Trauma 1992;33:582–585. 9. Andrews PJ, Piper IR, Dearden NM, Miller JD: Secondary insults during intrahospital transport of head-injured patients. Lancet 1990; 335:327–330. 10. Smith I, Fleming S, Cernaianu A: Mishaps during transport from the intensive care unit. Crit Care Med 1990;18:278–281.

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11. Szem JW, Hydo LJ, Fischer E, Kapur S, Klemperer J, Barie PS: High-risk intrahospital transport of critically ill patients: Safety and outcome of the necessary “road trip.” Crit Care Med 1995;23:1660–1666. 12. Evans A, Winslow EH: Oxygen saturation and hemodynamic response in critically ill, mechanically ventilated adults during intrahospital transport. Am J Crit Care 1995;4:106–111. 13. Caruana M, Culp K: Intrahospital transport of the critically ill adult: A research review and implications. Dimens Crit Care Nurs 1998;17:146– 156. 14. Kollef MH, Von Harz B, Prentice D, et al: Patient transport from intensive care increases the risk of developing ventilator-associated pneumonia. Chest 1997;112:765–773. 15. Waydhas C: Intrahospital transport of critically ill patients. Crit Care 1999;3:R83–R89. 16. Lovell MA, Mudaliar MY, Klineberg PL: Intrahospital transport of critically ill patients: complications and difficulties. Anaesth Intensive Care 2001;29:400–405. 17. Gervais HW, Eberle B, Konietzke D, Hennes HJ, Dick W: Comparison of blood gases of ventilated patients during transport. Crit Care Med 1987;15:761–763. 18. Braman SS, Dunn SM, Amico CA, Millman RP: Complications of intrahospital transport in critically ill patients. Ann Intern Med 1987; 107:469–473. 19. Tobias JD, Lynch A, Garrett J: Alterations of end-tidal carbon dioxide during the intrahospital transport of children. Pediatr Emerg Care 1996;12:249–251. 20. Dockery WK, Futterman C, Keller SR, Sheridan MJ, Akl BF: A comparison of manual and mechanical ventilation during pediatric transport. Crit Care Med 1999;27:802–806. 21. Bekar A, Ipekoglu Z, Tureyen K, Bilgin H, Korfali G, Korfali E: Secondary insults during intrahospital transport of neurosurgical intensive care patients. Neurosurg Rev 1998;21:98–101. 22. Marx G, Vangerow B, Hecker H, Leuwer M, Jankowski M, Piepenbrock S, Rueckoldt H: Predictors of respiratory function deterioration after transfer of critically ill patients. Intensive Care Med 1998; 24:1157–1162. 23. Waydhas C, Schneck G, Duswald KH: Deterioration of respiratory function after intra-hospital transport of critically ill surgical patients. Intensive Care Med 1995;21:784–789. 24. Link J, Krause H, Wagner W, Papadopoulos G: Intrahospital transport of critically ill patients. Crit Care Med 1990;18:1427–1429. 25. Swoboda S, Castro JA, Earsing KA, Lipsett PA: Road trips and resources: There is a better way. Crit Care 1997;1:105–110. 26. Branson RD: Intrahospital transport of critically ill, mechanically ventilated patients. Respir Care 1992;37:775–793; discussion 793– 795. 27. Branson RD: Transport Ventilators. In Branson RD, Hess DR, Charburn RL (eds): Respiratory Care Equipment. Philadelphia, Lippincott, Williams and Wilkins, 1999.

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Chapter 24 Intraoperative and Immediate Postoperative Neuroanesthesia Dietrich Gravenstein, MD and Nikolaus Gravenstein, MD

Introduction Attempts to arrest or ameliorate the natural history of neurologic affliction or trauma will often play out in the operating theater. The physiologically dynamic course a surgical intervention represents can be quite challenging and requires an actively involved and informed anesthesiologist to assure the most favorable outcome. This chapter broadly describes considerations and objectives that are included in the formulation of a neuroanesthetic management plan and discusses the intraoperative issues confronting the anesthesiologist for a selection of representative clinical problems. On completion of surgery, the outcome and complications of the intraoperative anesthetic and surgical management become fully manifest in the intensive care unit (ICU) or postanesthesia care unit. Familiarity with anesthesia (and surgery) on the character of postoperative recovery can help the clinician distinguish findings that are related to anesthesia and are ephemeral from more ominous findings that require intervention.

Anesthesia and Basic Neuropathophysiology Defense and support of adequate cerebral and spinal cord oxygen delivery are the foremost objectives of every neuroanesthetic plan. These tasks are complicated because

agents used to accomplish surgical anesthesia also influence cerebral and spinal cord hemodynamics. The anesthetic agents and technique significantly affect cerebral oxygen consumption (CMRO2), cerebral oxygen delivery (CDO2), cerebral blood flow (CBF) and thereby apparent intracranial tissue volume, arterial oxygen content (CaO2), and the autoregulation of CBF. Recognition and treatment of concurrent acute and chronic maladies, optimization of the surgical exposure, and both avoidance and management of surgery-related events in the operating room and during the perioperative period broadly define secondary objectives of the anesthetic intervention. Cerebral Oxygen Consumption Approximately 40% of oxygen consumed by the brain is used to maintain the cellular integrity of its neural tissue. The remaining 60% of oxygen is consumed accomplishing cellular electrophysiologic functions.1 Potent inhalational anesthetic (PIA) agents, narcotics, and commonly used hypnotic agents all decrease CMRO2 by decreasing cortical electrical activity. Isoflurane is perhaps the PIA of choice for neurologic surgery. In addition to decreasing CMRO2, isoflurane uniquely lowers the critical CBF at which the electroencephalograph (EEG) begins to demonstrate cerebral ischemia from a baseline lower flow threshold of 20 mL/100 g brain tissue per minute to nearer 10 mL/100 g brain tissue per minute.2,3 This suggests isoflurane may provide some cerebral protection in low flow states and why the incidence 695

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of ischemia suggested by EEG during carotid endarterectomy (CEA) is lower with isoflurane than with other PIAs.4 Sodium thiopental and propofol, along with all other hypnotic agents (except ketamine), decrease CMRO2 and can, in sufficient doses, also produce an isoelectric EEG pattern. Cerebral oxygen consumption increases with cortical seizure and during hyperthermia. Conversely, cooling a patient slows all chemical reactions and lowers CMRO2 by slowing processes responsible for maintaining cellular integrity and those responsible for electrical function.5 Hence, cooling is one modality used to protect the brain from transient ischemic events. When autoregulation is intact, cooling the brain or spinal cord reduces CMRO2 and produces an approximate 7% decrease in CMRO2 per degree Celsius temperature drop. This decreases CBF and therefore cerebral blood volume (CBV) and, in turn, also decreases intracranial pressure (ICP). Induced hypothermia is not completely benign, however. It has associated risks of impaired coagulation, increased incidence of cardiac arrhythmia, leftward shift of the oxygen-hemoglobin dissociation curve, and slowed metabolism of administered drugs. A failure to rewarm adequately may prohibit extubation and occurrence of shivering may increase oxygen consumption (and its sequelae) by up to 400%.6 Cerebral Blood Flow Cerebral blood flow is normally under autoregulatory control and dependent on cerebral oxygen demand (CMRO2), cerebral perfusion pressure (CPP), arterial CO2 (PaCO2), and arterial O2 (PaO2). Oxygen given in sufficient quantity to increase the PaO2 above 300 mm Hg produces a mild (10%) reduction of CBF.7 Ventilation parameters affect PaCO2 and PaO2. Anesthetic agents simultaneously influence CMRO2, CPP [CPP = MAP - (the greater of CVP or ICP)], as well as diminishing in a dose-dependent fashion the CBF autoregulatory response itself.8 All PIAs (halothane, enflurane, isoflurane, desflurane, sevoflurane) are known “uncouplers” of CNS autoregulation, that is, cerebral perfusion pressure and cerebral blood flow. They decrease CMRO2 disproportionately to their effect on cerebrovascular resistance (CVR) and CBF, thereby causing a relatively increased CBF. Halothane, the most potent cerebral vasodilator among the PIAs, is seldom used during neurosurgery because of this attribute. When a PIA is used as part of a neuroanesthetic, it is often used only in low concentration and in conjunction with mild hypocapnia when concern over limited intracranial or intraspinal elasticity (i.e., elevated ICP or spinal cord injury) exists. A patient will be influenced by the general anesthesia and surgery for some time into the postanesthetic period. Cerebral hyperemia persisted for at least 30 minutes following extubation from an isoflurane-N2O-O2-fentanyl-atracurium or propofol-O2-air-fentanyl-atracurium–based anesthetic.9 Whether these prolonged effects result from trace anesthet-

ic induced impairment of autoregulation, hemodilution, recovery from prolonged hyperventilation, or a nonspecific response to stress is unknown.10 The intraoperative and postoperative management of blood pressure is further related to the incidence of postoperative intracranial hemorrhage (ICH).11 When intraoperative or postoperative blood pressure (within the first 12 hours of operation) remained above 160/90 mm Hg for two or more consecutive measurements made 5 minutes apart, the incidence of postoperative ICH after craniotomy was significantly higher (62% and 62%, respectively) than compared with nonhypertensive controls (34% and 25%, respectively). Generally, a functioning autoregulatory system in normal brain will produce an average regional CBF of approximately 50 mL/100 g per minute. The limits of autoregulation have conventionally been characterized as being between a CPP of 50 mm Hg and 150 mm Hg in normotensive patients but higher in chronically hypertensive patients (Fig. 24-1). When the CPP falls below the lower autoregulation limit the brain is considered at risk for hypoperfusion and ischemia, and when the CPP remains above the upper autoregulatory limit, hyperperfusion, hyperemia, and cerebral edema become a risk. Evidence now suggests that the cerebral blood flow autoregulatory response may not function properly at CPPs below 60 to 70 mm Hg in normotensive adults, fails at even higher levels in the uncontrolled chronically hypertensive patient and is slowed in adolescents.12–14 When autoregulation of regional CBF is compromised by injury, tumor associated factors, vascular malformation, ischemia, or deeper planes of general anesthesia, CBF becomes increasingly pressure dependent. Proper intraoperative and perioperative blood pressure management are thus even more critical. The effect of CPP on CBF, cerebral blood volume, and ICP is dependent on the volume of brain tissue under autoregulatory control. In situations where ICP is elevated but a substantial part of the brain remains under autoregu-

Cerebral Perfusion Pressure (mm Hg) Figure 24-1. Normal autoregulatory curve with right and left shifts depicted.

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latory control, elevation of blood pressure will augment CPP both by increasing mean arterial pressure and through autoregulatory arteriolar constriction causing lowered CBV thereby decreasing ICP. However, in the scenario where a more extensive cerebral insult has occurred and autoregulation is compromised, ICP changes will follow CPP and CBV changes. Because similar treatment can produce very different effects, multimodality monitoring (jugular venous bulb oximetry [SjvO2], transcranial Doppler, cerebral oximetry, EEG, tissue pO2, and invasive ICP monitoring) have all been used to guide therapy.13,15 Tissue pH, acutely influenced primarily by arterial PaCO2, and oxygenation also are prominent controllers of CBF. As PaCO2 decreases, CBF is reduced and consequently CBV and ICP are also decreased. Aggressive hyperventilation poses the risk of inducing cerebral ischemia through the powerful vasoconstrictive effect of hypocapnia and may, in the presence of respiratory alkalosis, even increase oxygen demand.16 During conditions of profound hypoxemia (PaO2 < 50 mm Hg), cerebral vasodilation will occur despite induced hypocapnia but this response is insufficient to resolve the ischemic state. Deep hyperventilation therapy to control ICP has now been associated with less favorable outcomes compared to normocapnic management. Intraoperatively, a mild hypocapnic state (PaCO2: 35 to 40 mm Hg) is the currently preferred goal. The brain can recover from brief episodes of ischemia but has little chance of return to normal after traumatic herniation. Therefore, when the potential for mechanical brain injury via herniation or surgical retractor pressure exists, severe hypocapnia (PaCO2: 20 to 25 mm Hg), even though it may risk cerebral ischemia and its associated morbidity can, in conjunction with other measures, be used to decrease cerebral volume. A PaCO2 as low as 20 mm Hg will decrease CBF to near 10 mL/100 g per minute. Although this blood flow normally produces profound cerebral ischemia, in the presence of isoflurane anesthesia it represents, in normal brain, the lowered threshold of where the EEG first demonstrates a pattern of ischemia.2 Several clinically simple maneuvers can further enhance CPP. These include recognition and correction of a pneumothorax, a non-neutral head position,17,18 and a tight tracheostomy tie or ECG lead stretched tightly across the neck with occlusion of a jugular vein. In addition, placing the patient into a head elevated position to augment venous drainage, judicious hyperventilation to produce mild hypocapnia with decreased CBV and lowered ICP, infusion of a vasopressor to maintain cerebral inflow, and institution of muscle relaxation to increase chest wall compliance can all improve CPP. With any head elevation all blood pressures should be zero-referenced to the head. Otherwise it is possible to produce the paradoxical and unintended effect of actually lowering the CPP, that is, the MAP referenced to the brain declines more than the CVP referenced to the brain. Admin-

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istration of diuretics, if not contra-indicated, will also lower CVP. Ventriculostomy drainage is another modality used to reduce CSF volume (Table 24-1). Arterial Oxygen Content Principal determinants of CDO2 include hemoglobin concentration, oxygen saturation, and cardiac output. Coexisting disease states, which can include chronic conditions or acute states such as pulmonary or cardiac contusion and aspiration, substantially influence transfusion, ventilation, and cardiovascular support limits. The need for transfusion is based on an estimate of probable cardiovascular reserve that is balanced against the current hemoglobin concentration, pulmonary function, available vascular access, and an estimate of the risk and severity of any additional bleeding. There are no data to suggest any cerebral or spinal cord benefit to increasing a patient’s hematocrit above 30%. Fluid and Electrolyte Management Fluid replacement during neurosurgical procedures differs from that used during non-CNS surgery. The tight-junctions found in the CNS and collectively referred to as the bloodbrain barrier, with an effective pore size of only 8 Å, are essentially impermeable to sodium, other ions, or proteins. They are, however, freely permeable to water.19 Hence, to avoid inducing or aggravating cerebral or spinal cord edema, intravenous solutions that are isotonic, such as 0.9% NaCl, or hypertonic (without glucose) are preferred over solutions like lactated Ringers (LR) that are hypotonic. Clinicians will observe that 0.9% NaCl solution has a calculated osmolality of 300 mOsm/kg water while LR solution has a calculated osmolality of 273 mOsm/kg water. These calculations are printed on the solution bags. They only represent the simple summation of the component electrolytes. These solutions are actually isotonic and hypotonic, respectively, because the calculated osmolalities do not account for the solute ion interactions that are responsible for a measured osmolality that is approximately 20 mOsm/kg water less than the calculated value (Table 24-2). The labeling on the solution bags is always of the calculated and never the measured osmolality. Solutions with glucose in water are generally avoided in neurosurgical patients for two reasons. First, although the glucosecontaining solution may be iso- or hypertonic (see Table 24-2), the glucose is rapidly metabolized. Thus, its osmotic contribution of 252 mOsm/kg water is lost and a net free water gain results. This free water will aggravate edema. Second, elevated serum glucose has been associated with worsened neurologic outcome. One theory for the mechanism of injury suggests that the presence of glucose increases neuronal metabolism and thereby decreases cellular viability during ischemia. Infants less than 5 kg are at some risk for intraoperative hypoglycemia and may therefore receive slightly hypertonic intravenous maintenance therapy with

698 Ø Ø Ø 0 0 0 ≠(?) Ø,?≠ Ø ≠ ≠ ≠ ≠ ≠ ≠ 0,≠ 0 0 0 0 0 ≠ ≠ 0 ≠ 0,≠ 0,≠

Ø Ø Ø 0 0 0 0 0 Ø ≠ ØD ØD,3≠‡ ØD ØD Ø 0 0 0 0 0 0 0 0 0 0 0 0,≠

Barbiturates (includes etomidate) Propofol Benzodiazepines Morphine Fentanyl Alfentanil Sufentanil Remifentanil Ketamine Nitrous oxide† Halothane Enflurane Isoflurane Desflurane Sevoflurane§ Succinylcholine Pancuronium Doxacurium, pipecuronium, vecuronium, rocuronium, rapacuronium (not studied yet) Atracurium Cisatracurium a- and b-blocking agents Sodium nitroprusside Nitroglycerine Trimethaphan Calcium channel blocking agents Phenylephrine Ephedrine 0 0 0 ≠ ≠ 0 ≠ 0,≠ 0,≠

0 0,?Ø 0 0 0 0 0 0 0,Ø 0 ≠ ≠ ≠ ≠ ≠ 0,≠ 0 0

CBF/CMRO2

0 0 0 ≠ ≠ 0

Ø Ø Ø ? Ø ? ? 0 Ø ≠ ≠ ≠ ≠ ≠ ≠ 0,≠ 0 0

CBV

N N N Ø Ø N N,Ø N N

N N N N N N N N ? N ØD ØD ØD ØD Ø N N N

Autoregulation

N N N Ø Ø Ø N N N

Ø N N N N N N N N N ØD N N N N N N N

CO2 Response

0,Ø 0 Ø Ø Ø Ø Ø ≠ ≠

Ø Ø Ø 0,Ø 0,Ø 0,Ø 0,Ø 0,Ø Ø 0,Ø Ø Ø Ø Ø Ø 0 0,≠ 0

BP

0,≠ 0 0 ≠ ≠ 0 0 0,≠ 0,≠

Ø Ø Ø 0,?≠ 0,?≠ 0,?≠ 0,?≠ 0,?≠ Ø 0,≠ 0,≠ 0,≠ 0,≠ 0,≠ 0,≠ 0,≠ 0 0

ICP

0,Ø 0 Ø Ø Ø Ø 0 0,≠ 0,≠

≠,Ø,0* ≠,Ø,0 ≠,Ø,0* Ø 0 Ø Ø 0,Ø Ø,≠,0* 0,Ø Ø Ø Ø Ø Ø 0,Ø 0 0

CPP

Ø ? Ø ? Ø ? ? ≠ 0 ≠ ≠ Ø 0 ? 0 0 Ø ≠ 0 Ø ?

Resistance to Absorption (Ra)

Ø ? ؇ ? 0 ? ?

Formation (Vf)

CSF

*Overall effect depends on what changes more—blood pressure or ICP. † In anesthetized patients or animals (i.e., when N2O is added to another agent, such as a barbiturate, the value will not exceed that in an awake subject). ‡ High dose, during seizure. § Some studies suggest effects seen with sevoflurane are less in both magnitude and in clinical significance than with the other inhaled agents. BP, blood pressure; CO2, vascular response to carbon dioxide; CPP, cerebral perfusion pressure; 0, no clinically important effect; ≠, increases parameter; Ø, decreases parameter; D, dose-related effect; N, preserves normal function in usual anesthetic dose range. If more than one effect is shown, effect varies, depending on patient pathology or if unresolved controversy exists.

CBF

CMRO2

Drug or Drug Class*

Table 24-1  Anesthetic Effects on Physiologic Variables

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Table 24-2  Calculated Osmolarity and Measured Osmolality of Common Intravenous Fluids Fluid Water D5W D5.2NS NS LR D5LR 3% Saline 6% Hetastarch 20% Mannitol Plasma protein fraction

Osmolarity

Osmolality

0 252 325 308 273 525 1,027 310 1,098 —

0 259 321 282 250 524 921 307 1,280 261

D5W, 5% dextrose in water; D5.2NS, 5% dextrose in 0.2 normal saline; D5NS, 5% dextrose in normal saline; D5LR, 5% dextrose in lactated Ringer’s solution.

D2.5% normal saline at our institution. This regimen addresses the CNS’ dependence on glucose as a metabolic substrate, the limitations of gluconeogenesis and the high metabolic rate observed in this population. It also yields an isotonic fluid after the glucose is consumed. However, when fluid boluses are needed, 0.9% NaCl solution, rather than D2.5% normal saline is used. Intravascular volume replacement therapy does not differ between neurosurgical and non-CNS procedures. Replacement of blood loss is a 3-to-1 (isotonic crystalloid : blood loss) volume ratio for 0.9% saline solutions and 1-to-1 for colloid, 3% NaCl, and blood products. Deficits calculated from fasting, insensible losses, urine output, and third-space losses are replaced 1 : 1. When blood or crystalloid replacement therapy exceeds a few liters (caused by hemorrhage, diabetes insipidus, or a pharmacologically induced diuresis) electrolytes, especially calcium, potassium, and sodium, must be followed serially and corrected. Blood transfusion during neurosurgical procedures may be viewed as somewhat more aggressive compared to other surgery but the management objective remains to keep hematocrit 25% to 30%. Anemia provokes increased cardiac output and cerebral vasodilatation. These responses tend to increase CBV, ICP, and edema and may aggravate blood loss in addition to the non-CNS ramifications that may exist.

Getting Started Preparation for a surgical intervention dictates that the anesthesiologist prepare an anesthetic management plan. This requires that the pathophysiology involved and any implications of the surgical approach or procedure be considered. Stable and controlled cerebral and cardiovascular hemodynamics are the goals prior to surgery. Induction of general anesthesia, laryngoscopy and intubation, positioning and

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application of the head pinioning apparatus, and eventually skin incision, are all profound yet transient interventions that make attainment of this goal challenging. Often a high dose of narcotic is administered slowly, with a relatively more modest dose of hypnotic agent and muscle relaxant to induce anesthesia. For intubation, additional narcotic, lidocaine, beta-blocker, or hypnotic is added, as needed. Careful timing and communication to allow coordination of drug effects with stimulus effects are essential to smoothly navigate the assorted surgical stimuli. Pinioning of the head, for example, can be safely accomplished in most adults with only a 5% to 10% variation of the vital signs. We like to administer 1 to 1.5 mg/kg esmolol and 100-mg sodium thiopental for pinioning when the patient has vital signs near preoperative values, sometimes with 1 mg/kg lidocaine, but less if the patient is frail. If the heart rate is lower than preoperative values, the dose of esmolol is reduced. Similarly, if the blood pressure has not recovered from induction, the thiopental dose is reduced. Once the drugs have been administered, we wait until the heart rate or the blood pressure shows a drug effect before proceeding to pinion the head. This coordination accomplishes matching the peak surgical stimulus with the peak drug effect, regardless of cardiac output. Other regimens, including pre-emptive local anesthetic infiltration of the pinion sites and titrated remifentanil infusion, have also been advocated for pinioning.20

Positioning Once a patient has been induced, the task of positioning is undertaken. The presence of anesthesia and muscle relaxation during patient transfer and positioning present conditions where the patient has been rendered insensible to pain, unable to protect himself and more susceptible to spinal injury through the removal of muscular tone. Hence, great care is taken to accomplish patient transfers and positioning on the operating room table. In large patients, the time taken to position may approach the actual surgical time. The different positions into which a patient may be placed for surgery are associated with various known risks. The supine position places pressure on the heels and occiput, reduces lumbar lordosis, and may cause flexion of the neck or pressure on an ulnar nerve. The ulnar nerve at the elbow is the most frequent place for position-related nerve injury. Injury of the brachial plexus can be caused by aggressive abduction and in the lateral position by a chest roll that slips into the axilla from its intended upper thorax location. The lateral position further risks lateral flexion of the cervical spine. Pressure from the surgical table on the “down arm” and the fibula may threaten either the brachial plexus or the superficial peroneal nerve. Regardless of body position, one must be cautious with rotation or extension of the head as it may cause venous congestion, is associated with elevated ICP, and could precipitate an intracranial hemorrhage.17,18

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The prone position requires the abdomen to be properly suspended, and knees, testicles, and breasts to be free from pressure. With the eyes facing downward a risk of ischemic optic neuropathy and central retinal artery thrombosis exists. The catastrophic outcome of blindness has been described when the head has been rested on a foam cushion with a cutout for the eyes, nose, and lips and even when the head has been suspended by a pinioning system. Young and old patients are at risk as are patients of any physical status. Speculation is that the pathogenesis involves low arterial perfusion pressure, elevated episcleral venous and intraocular pressures, anemia, embolic events, and the use of pressor agents.21,22 Periorbital edema is likely an important variable in the etiology. Hence, efforts are made empirically to defend perfusion, limit venous pressure to the eyes by assuming a position that elevates the head, and avoiding conditions promoting coagulation, such as vascular volume contraction. Venous air embolism (VAE) is most well known as a danger associated with the sitting position, but also is well described in association with the lateral, prone, and supine positions.23,24 The incidence of air detectable in neurosurgical cases (e.g., craniotomy, cervical laminectomy) using the sitting position is near 45% but can exceed 70%.24–26 Approximately 20% of VAE cases in adults produce clinically significant effects, while in children the significant effects are twice that of adults.27,28 Because the morbidity of VAE is significant, prevention and monitoring that allows early detection of intravascular gas are key elements of a successful management plan. Continuous positive end-expiratory pressure (PEEP) in the airway and adequate intravascular volume help to reduce VAE occurrence. Early detection is commonly accomplished with continuous precordial Doppler monitoring. Transesophageal echocardiography is more sensitive and specific but is used less frequently because the equipment is expensive and the patient’s position, with the head rotated or flexed, for example, may not allow the probe to be placed. The observance of acute changes during a stable anesthetic; in exhaled CO2; central venous, pulmonary artery or systemic blood pressures; or SpO2 are also suggestive of VAE. Successful management of VAE includes several maneuvers. The wound is flooded with irrigating fluid, the surgical site is lowered to a dependent position relative to the heart, and light manual jugular venous pressure is applied to arrest further entrainment of air and increase cerebral venous pressure. The elevated cerebral venous pressure from manual external jugular compression will, in many cases, demonstrate a new site of bleeding, that is, the site of air ingress before the artifactual elevation of venous pressure. All myocardial depressants (e.g., any PIA) are discontinued and ventilation switched to 100% oxygen. If nitrous oxide (N2O) was being used, it is eliminated at this time also. N2O poses a special risk because it has a low solubility coefficient. N2O can aggravate a VAE through its rapid diffusion into an intravascular gas collection, doubling its size in less than 15 minutes. The effectiveness of repositioning

the patient left-side down to sequester gas away from the right ventricular outflow track has been challenged,29 although experience confirms that some patients will benefit from this maneuver. In the face of an air-filled right ventricle, pulmonary hypertension, and diminishing systemic pressure, aggressive administration of volume to support preload, intravenous inotropic support, and even cardiopulmonary resuscitation are begun. Aspiration of air or foam from a multi-orifice central venous catheter, if present, may also be attempted. As many interventions may be necessary, early calls for assistance are advised. The addition of PEEP is not recommended for treatment of VAE, even though it may lessen the volume of additional air entrained. Application of PEEP after hemodynamic consequences are observed will increase intrathoracic pressure when air is already in the heart and pulmonary circulation. Consequently, addition of PEEP will compromise right ventricular preload just when it is most needed. Furthermore, with an approximately 25% incidence of patent foramen ovale in adults and a 35% incidence in children and adolescents, PEEP may increase the likelihood of causing a paradoxical air embolus, particularly on release when right atrial pressure is transiently higher than the left atrial pressure.26,30 Air traversing from the right atrium through a patent foramen ovale into the left atrium bypasses the lung, which normally filters out most air bubbles. Once in the left heart circulation, these air bubbles can travel to the brain or heart causing a stroke or myocardial infarction, respectively. Clinicians must remain vigilant especially if an intraoperative VAE occurred and PEEP was being used. Hemodynamically significant air embolism after intracranial or spinal surgery may also occur on moving the patient to a supine position.26 Air sequestered in the originally nondependent vertebral or splanchnic veins gains access to the heart when the previously sequestered air moves to a dependent location or is returned to the circulation on release of PEEP or when the patient is repositioned supine. It is easy to envision, because now the spine, paraspinal, and splanchnic venous complexes are relatively lower than the heart and the air simply floats up into the circulation.

Mass Lesions Tumors present risk to patients during and following anesthesia because of features related to size, vascularity, endocrine activity, and location. Rapidly growing tumors and those causing obstructive hydrocephalus can be associated with diminished intracranial elasticity and elevated ICP. When concerns over ICP exist, mild hyperventilation, reverse Trendelenburg position, diuretics, and decompression with CSF diversion are all ICP-decreasing options to consider. CPP and oxygenation are defended throughout induction and until the dura has been opened. Once resection of the tumor is underway, bleeding becomes a primary focus of concern. Anesthesia personnel will have secured

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intravenous access proportionate to the presumed risk of bleeding. When the arterial supply and venous drainage of a tumor are known to be high flow vessels, analogous to those in an arteriovenous malformation, the CPP will be adjusted downward as the tumor is excised. Failure to moderate CPP once the high flow–low resistance diversion is removed risks bleeding from the tumor bed and significant postoperative cerebral hyperemia and edema. The CPP may gradually be returned to normal over 24 to 72 hours as the cerebral vessels’ muscularis layer recovers its ability to modulate the vessels’ tone, that is, local cerebral vascular autoregulation normalizes. Surgery in the posterior fossa, especially when near the vestibular-cochlear nerves, is associated with a greater than 50% incidence of postoperative nausea. The nausea alone has been attributed to increasing the length of stay for some patients. Intraoperative anesthetic management can influence the incidence and the severity of postoperative nausea. We have used a multifaceted pharmacologic approach to reduce postoperative nausea. In addition to administration of intravenous ondansetron (4 mg) 30 minutes before the end of surgery, we also give dexamethasone (4 mg) and promethazine (6.25 mg) at the start of the procedure and run an infusion of propofol at 25 to 50 mg/kg per minute throughout the case. Anecdotally, this technique slightly slows the emergence from anesthesia, but dramatically decreases the incidence and severity of postoperative nausea. Other techniques, such as simply using higher doses of propofol, may demonstrate the same or better nausea prophylaxis. Resection of tumors in the brainstem can result in dramatic intraoperative and postoperative findings. When the tumor is located on the floor of the fourth ventricle and areas near the ventral medulla (vasomotor center) are manipulated, hypotension or profound hypertension and bradycardia or even asystole may be observed. Surgery in this vicinity may stimulate the dorsal motor nucleus of the vagus or the nucleus ambiguous, reducing cardiac contractility and blocking conduction through the atrioventricular (A-V) node. To address this possibility, a Zoll transthoracic pacer or a pacing pulmonary artery catheter (PAC) may be used in stand-by mode. A transesophageal atrial pacer probe that captures the atrium would not be indicated because the AV node is unlikely to transmit atrial impulses in this scenario. In the absence of a PAC with pacing capability or transthoracic pacer, pharmacologic treatment with anticholinergic medications will terminate episodes of bradycardia, but this approach eliminates the valuable surgical feedback that the episodes of bradycardia provide.

Vascular Neurovascular surgery inherently entails two major intraoperative risks: (1) inducing ischemic stroke and (2) hemorrhage. Strokes may originate from embolic sources, such as

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plaque loosened during carotid endarterectomy; during the time of temporary clip placement; or from misapplication or rotation of permanent clips during surgery for intracranial aneurysm. In recognition of these risks, CNS monitoring to alert the surgeon and anesthesia provider of such events is a priority. Patients who are operated on with only field block anesthesia, such as for carotid endarterectomy, serve as their own monitors. They are asked to respond verbally to questions and to complete simple tasks, such as squeezing a rubber toy, so their compliance with the request is unmistakable. When patients are under general anesthesia, CNS monitoring is accomplished with use of continual somatosensory-evoked potential (SSEP) or EEG monitoring. Transcranial electrical motor and visual evoked potential (TceMEP and VEP, respectively) and facial nerve monitoring are other modalities that have been utilized intraoperatively. TceMEP and VEP are quite difficult to obtain because they are exquisitely sensitive to conventional anesthetics and can limit the surgical field because of their physical setup. When any of these monitoring modalities are used, the anesthetic technique is biased toward using reduced concentration of PIA and increased, and preferably short acting, narcotic infusions. Most intracranial vascular pathology does not present with a significant mass effect–altering intracranial elasticity. Thus, the goal of intraoperative management is to maintain a stable transmural vessel pressure throughout surgery and avoid provoking rupture. Ventilation parameters are initially maintained near normal to prevent altering CBF or ICP, and maintaining a stable transmural pressure. For procedures requiring a craniotomy, it is common to gradually induce mild hypocapnia to decrease brain size after craniotomy, but before opening the dura, to facilitate a better surgical exposure. When the dura is taut, additional diuretic (mannitol, furosemide) may be requested, hypocapnia may be exaggerated, and the patient may be placed into a reverse Trendelenburg position. When additional steps are taken, plasma electrolytes, arterial CO2–end-tidal CO2 gradient, and urine output are followed closely. Electrolytes lost with diuresis are replaced. If the diuresis is brisk and sustained, and the urine dilute, the possibility of induced diabetes insipidus should be explored by checking the urine specific gravity and following serial serum sodiums. The hyperventilation is adjusted to an end-tidal CO2 that would produce an arterial CO2 of not less than 25 mm Hg. Blood pressure and heart rate are kept stable during clipping of simple aneurysms that present with a favorable orientation. Not infrequently, however, clipping an aneurysm will first require placement of temporary clips. In anticipation of this possibility and the implications for the regional cerebral ischemic insult, patients are cooled with a cooling blanket to approximately 34.5°C, the blood pressure gradually increased and an EEG-guided barbiturate coma instituted. Temperature can be measured from esophageal, rectal, or bladder probes, although the brain is likely to be cooler than measured core temperature because the surgical site is

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exposed to ambient room temperature. The barbiturate infusion is titrated to an EEG pattern showing at least 90% burst suppression. A deeper coma, that is, isoelectric EEG (100% burst suppression), has not been demonstrated to convey additional protection and may result in diminished hemodynamic stability, a slowed emergence, and an extended requirement for ventilatory support. The limit to which perfusion pressure during temporary clip times can be augmented is determined by the onset of, or worsening of, cardiac ischemia. Usually, a 20% increase above baseline blood pressure is sufficient additional pressure support to protect normal cerebral function. However, if cardiac ischemia develops, efforts must be made to improve oxygen delivery or decrease myocardial work. When the temporary or permanent clip application produces an alteration in the evoked potential, the mean arterial pressure is augmented further, usually with phenylephrine infusion. Placement of the clip may occlude one or more perforating vessels. The pressure necessary to perfuse via collateral vessels the ischemic and vasodilated tissues is near a mean pressure 10% to 30% above baseline.31 In these situations, once the perfusion pressure has been adjusted, a gradual recovery of evoked potential waves is often observed (Fig. 24-2). The usual loading and maintenance doses for barbiturate (sodium thiopental) coma are 10 mg/kg and 15 mg/kg per

Figure 24-2. Selected cortical evoked potentials from median nerve stimulation during clipping of a right middle cerebral artery aneurysm. Note that global events (temperature change and barbituates) affect the entire brain, but ischemia from temporary clip application affects only the surgical side. Once the perfusion pressure has been adjusted, a gradual recovery of evoked potential waves is observed.

hour, respectively. The probability of causing a delayed emergence and wake-up can be estimated by calculating the total dose of barbiturate delivered (induction, loading, and maintenance) during the case. Recovery from induction doses of barbiturate is typically less than five minutes despite an elimination half-life of 11 hours because the drug initially redistributes. As the total dose of barbiturate increases, the compartments for drug redistribution fill and recovery from the barbiturates becomes dependent on the rate of hepatic metabolism. Our observation has been that as the total thiopental dose delivered increases from 15mg/kg to 20mg/kg to 30mg/kg or higher, the probability of a postoperative extubation decreases from, respectively, near 100% to 50% to 10% and then becomes essentially zero. Emergence may occur from several hours to even days later, depending on total dose delivered, hepatic function, and condition of the brain. Vessel rupture and hemorrhage are major complications of neurovascular surgery. Ideally, the patient will be cooled and a small amount of barbiturate can be administered before a temporary clip is applied and the bleeding halted. When a rupture occurs during a time when no permanent or temporary clip can be placed, and the rate of bleeding does not allow for the time necessary to expose the aneurysm, profound but controlled hypotension is induced. Placement of the temporary clip defines the start of a regional ischemic event. The temperature of the brain and the total ischemic time will predict the likelihood of cerebral infarction. The longest “safe” ischemic time (approximately 60 minutes) is achieved in controlled situations when the patient is slowly cooled to 18°C and placed on low-flow cardiopulmonary bypass or circulatory arrest. Hypothermic circulatory arrest is predictably associated with a coagulopathy. It is not an option emergently. Management of the excision of an arteriovenous malformation (AVM) is similar to that of a vascular tumor. The need for intravenous access will be substantial in the event of significant bleeding during resection. Barbiturate coma is not employed in this disease because bleeding is not typically amenable to temporary clip placement. Patients are kept warm to avoid impairment of coagulation and the other risks of hypothermia (arrhythmias, shivering, slowed drug metabolism, shifted oxygen-hemoglobin dissociation curve). As the AVM is successfully removed, CBF can be expected to increase.32 Hence, CPP will be lowered to guard against hyperemia and cerebral edema. Strict avoidance of hypertension is a continued goal for at least 24 hours postoperatively. CEA differs from intracranial vascular surgery in its association with coronary and peripheral vascular disease and proximity to the carotid sinus. The patient undergoing CEA is not cooled for the operation. Effective cooling and complete rewarming would be difficult to accomplish in the time of surgery, which generally does not exceed 2 hours. Furthermore, the possibility of incomplete rewarming precipitating a shaking rigor and increased oxygen consumption

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would place the patient at considerable risk for perioperative cardiac ischemia, arrhythmia, and infarction. During carotid artery occlusion, the mean arterial pressure is augmented, just as it is for temporary clip application during cerebral aneurysm surgery. Blood pressure can be erratic with work near the carotid sinus. This intraoperative and postoperative liability may not be improved with the use of local anesthetic field blocks of the sinus.33,34 When exposure for carotid endarterectomy injures or denervates the carotid body, an altered chemoreceptor function and a diminished hypoxic response may result.35 The loss of the hypoxic response is a particularly relevant postoperative consideration in the patient with a prior CEA who has just begun to recover from a CEA on the contralateral side. Blood pressure and blood flow are reduced before removal of the carotid artery clamps to minimize hyperemia and the risk of postoperative bleeding. Arterial hemorrhage into the surgical site can be provoked or worsened during emergence by perioperative coughing, bucking, and hyperdynamic blood pressures. Hence, the target blood pressure is at the lowest end of the patient’s normal range. Because of their combined analgesic, sedative, and cough suppressant effects, narcotics are often used with emergence from anesthesia. Intravenous lidocaine, to reduce tracheal reactivity to the endotracheal tube that reduces bucking and coughing, is another common pharmacologic adjuvant. Perioperative hemorrhage following CEA represents a significant complication and usually first manifests as swelling in the neck. When the source is venous, the swelling typically is limited. An arterial bleeding source may continue to expand a hematoma to the point where the trachea is deviated and progresses to airway obstruction. This process may take several hours to become apparent and can be diagnosed in the recovery room, ICU, or ward. In addition to the observation of neck fullness or swelling, which may obscure the lateral shift of airway structures, patients with incipient airway obstruction will become progressively short of breath, tachypneic, hoarse, and either agitated or obtunded as they become more hypoxic and hypercarbic. Early detection requires a vigilant clinician. Aggressive management of pain with narcotics will blunt ventilatory drive. The addition of supplemental oxygen may obscure identification of hypoventilation by preserving arterial saturation, even as the patient becomes severely hypercarbic and acidotic. Treatment before respiratory compromise involves emergent return to surgery and intubation, followed with a decompression and re-exploration of the wound. If the airway has become compromised before arrival in the operating room, emergent airway management is facilitated by first effecting a surgical decompression at the bedside. Another concern in CEA is coronary artery disease and the associated increased risk of a perioperative myocardial infarction. It makes sense to monitor precordial V5 lead in the ICU. This is possible even if only a three-lead ECG system is used. In such a case, placing the left arm’s lead

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which is (+) in the V5 position (anterior axillary line, fifth intercostal space) and monitoring lead 1 is essentially equivalent in sensitivity to a true V5 lead.

Spine Surgery Spinal cord dynamics are similar to those of the brain. The cord responds to anesthetic agents, ventilation parameters, temperature, perfusion pressure, and ischemia in essentially the same fashion as the brain. Perioperative edema of the spinal cord presents with similar concerns of ischemia and infarction. The decompression, instrumentation, distraction, and fusion of vertebral elements are unique to surgery of the spine. Bleeding or the entrainment of air results most commonly from violations of the epidural veins. Intraoperative neurological injury, unless catastrophic, is not hemodynamically apparent but can usually be detected with ideally continuous neurologic monitoring (e.g., SEP or MEP) or less sensitively with an intraoperative wake-up test. In at-risk patients, these monitoring and exam modalities do not, unfortunately, guarantee functional outcomes. They demonstrate pathway integrity only of the monitored tracts and only during the period they are interrogated. The monitors will be removed at the conclusion of the case, often before turning the patient from a prone position to a supine position or emerging the patient. During these events and this unmonitored time, hardware or fusion grafts can dislocate, and ischemia or edema of the spinal cord may develop. Prolonged surgery in the prone position may produce generalized edema of the face and neck. This edema will be increased by large volume fluid administration, trauma (from a difficult intubation), and the head-down position as might be used for cervical spine surgery or as a result of positioning on a Wilson frame. Patients demonstrating significant facial and airway swelling must be carefully evaluated to establish their appropriateness for extubation. Generally, once the patient is supine and the head elevated, edema will resolve gradually over the same time course as it developed.

Extubation A clinical assessment of the airway and patient, taken in the context of the course of surgery, the anesthetic agents used, redosing intervals for drugs, and reversal or antagonizing agents given allow for a determination of the patient’s suitability for extubation. When a patient is left intubated, it is either at the surgeon’s request or in situations where the clinical assessment suggests extubation would be premature. The determination for leaving a patient intubated will also be influenced by a number of intraoperative scenarios. It may be difficult for a patient to predictably emerge from anesthesia after resection of a tumor using a surgical approach that necessitates prolonged frontal lobe retraction.

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These patients remain intubated until they are able to follow commands or demonstrate swallowing, coughing, or gagging. In other words, there must be evidence of an ability to protect the airway. Postoperatively, patients with surgical injury or edema to structures within the brainstem may also fail to “emerge from anesthesia” and not regain consciousness. When the reticular activating system, which resides in the upper pons and mesencephalon, has been disrupted consciousness can be affected. Similarly, spontaneous breathing can be impaired due to surgical or mass-effect related injury to respiration-related cells located low in the medulla or mid to caudal pons, as well as injury to suprapontine anatomy, most notably the limbic structures. Surgery in the posterior fossa may lead to dysfunction of cranial nerves IX, X, and XII. Impaired function of these cranial nerves can lead to difficulty swallowing, loss of a gag reflex, airway obstruction from vocal cord paresis, and increased risk of aspiration. When no evidence of a gag reflex, coughing, or swallowing can be elicited by manipulation of the endotracheal tube or with oropharyngeal suctioning, the patient will generally remain intubated. The conclusion of any operation on the cervical spine or surgery requiring a prone position always includes a reassessment of the airway for a determination of the suitability for extubation. Oropharyngeal or laryngeal edema, and macroglossia are recognized complications.36 Prolonged or vigorous lateral retraction of the trachea as can accompany anterior cervical spine approaches can provoke edema that may compromise the airway. Some clinicians will monitor tracheal pilot tube cuff pressure to assess the degree of retraction. The decision to extubate in the presence of edema, whether from local retractor associated trauma, neck flexion during posterior cervical approach, or from massive volume resuscitation can be aided by performing a few tests. The patient should be strong—with objectively verified recovery of neuromuscular function—warm, and following commands appropriately so that the only variable is the adequacy of the airway itself. In this situation, a positive pressure leak test will give a gauge of the airway edema present. It is performed by deflating the endotracheal tube cuff and then slowly increasing the airway pressure until gas leaking around the cuff is heard at the mouth. When the threshold leak pressure is less than 20 cm H2O, the airway can typically be safely extubated and maintained by the patient. If one is contemplating extubation of a patient in whom there was some difficulty placing the endotracheal tube, a more cautious approach is taken by also performing a negative pressure leak test. This test is performed by deflating the endotracheal tube cuff, disconnecting the breathing circuit from the endotracheal tube, and instructing the patient (after an exhalation) to breathe in while the endotracheal tube is occluded. With a stethoscope placed over the trachea, it is readily determined if the patient is successfully moving air into the lungs around the occluded endotracheal tube. If air movement is heard, this demonstrates that the

patient is able to stent open the airway despite the negative pressure in the oropharynx and the space-occupying endotracheal tube. Because posttraumatic swelling may continue to increase for several hours after surgery, the level of stimulation will decrease following removal of the tracheal tube, and the addition of any analgesics or sedatives, we will on occasion extubate these patients over a hollow tube changing device. The tube changer is taped in place just like an endotracheal tube; it is well tolerated and can be removed several hours later or, if necessary, used to jet ventilate or reintubate in the event worsening edema leads to evidence of obstruction.

Postoperative Hypothermia and Shivering Patient cooling occurs through the conduction, convection, radiation, and evaporation of heat. Patients may passively cool in the operating room when the surgical field does not allow them to be covered or actively warmed by a forced air warmer (e.g., a ventriculo-peritoneal shunt procedure exposes the head, chest, and abdomen). Patients are actively cooled when hypothermia is induced in anticipation of the need to temporarily clip a vessel or for performing circulatory arrest. Rewarming takes time and may not be completed before surgery has ended. Continued warming in the ICU will be necessary. The patient must be watched for “recurarization,” that is, the reappearance of neuromuscular blockade after demonstrating strength. This may occur because hypothermia decreases the sensitivity of neuromuscular junctions to the effects of nondepolarizing neuromuscular blocking (NMB) agents. Hence, a patient who is cold but strong may become warm and weak, especially if no reversal agents were given, as the warmed neuromuscular junctions become increasingly sensitive to residual NMB. Triggering and modulation mechanisms of shivering are complex and poorly understood.37 In the perioperative period, shivering can be observed as a reaction to hypothermia, anesthetic drug, and, mistakenly, as the tonic clonic movement of a seizure. Hypothermia almost immediately provokes vasoconstriction and release of norepinephrine. Hypothermia can induce shivering with a lowering of core temperature by only 1.5°C.38 If shaking rigors develop, oxygen consumption can increase 400% or more.6 Hypothermia also causes a leftward shift in the oxygen hemoglobin dissociation curve and is associated with cardiac arrhythmias, ranging from bradycardia, atrial fibrillation, ventricular tachycardia, to ventricular fibrillation and asystole (temperature 28°C, 25°C, 22°C, and 18°C, respectively). These factors, coupled with the presence of platelet-activating factors in the postoperative patient with pain, are speculated to contribute to a 2.2 relative risk of experiencing cardiac morbidity (unstable angina and ischemia, cardiac arrest, or myocardial infarction) in

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the hypothermic patient compared to the normothermic patient.39 Anesthetic agents are themselves associated with production of a shivering response, the so-called “halothane shakes,” which may be vigorous enough to be confused with seizure activity, during emergence. This has been attributed to the loss of spinal cord inhibition from cortical inputs that remain under the influence of anesthesia. Patients will not report being cold. Hypothermia and anesthetic induced shivering do not impair communication, cause loss of bowel or bladder control, are generally of brief duration, and have no post-ictal period. They are responsive to rewarming and small doses of intravenous meperidine (12.5 to 25 mg) or clonidine (25 to 50 mg). When the patient remains intubated and mechanically ventilated, it is tempting to use neuromuscular blockade to eliminate shivering; however, that will also mask the motor signs of a seizure.

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hyperkalemic event. Monitoring of neuromuscular blockade is also complicated when attempted on an affected limb of a patient with a previous CVA. Electrically stimulating the ulnar or posterior tibial nerve in an affected limb—where there is an increased neuromuscular junction density— produces exaggerated responses compared with the normal limb. Thus, well-intentioned titration of neuromuscular blocking agent to monitored twitches on a paretic or plegic limb can lead to significant overdosage of neuromuscular blocker and, subsequently, an inability to reverse the patient for extubation. Simply monitoring on a nonaffected side or following the activity of the levator palpebrae muscle with facial nerve stimulation or performance of a head lift for greater than 5 seconds will confirm suitable strength is recovered for extubation.

Delayed Emergence Patient with Previous Cerebrovascular Accident The patient who has recovered function from a cerebrovascular accident (CVA) either partially or wholly is at risk of awakening from anesthesia with some or all of the deficits that occurred at the time of the original CVA. This recapitulation phenomenon has been termed “differential awakening” of the brain and related to patients as a “reliving” of the CVA.40 It is postulated that the patient with a remote stroke has regained function by learning to use new pathways that require vastly more synapses than the original pathway. The normal brain recovers function with a certain low partial pressure of anesthetic agent along neurons and at receptors. One possible mechanism for explaining the phenomenon of differential awakening is that anesthetic agents are eliminated from injured or ischemic brains more slowly than from normal brains, perhaps because of differential blood flow. Another mechanism suggests that the cumulative amounts of the same low partial pressure anesthetic along the much longer neuronal pathways and vastly larger number of receptors used to overcome the CVA deficit are sufficient to keep those pathways nonfunctional. These anesthetic effects should dissipate within hours of discontinuation of anesthesia as the partial pressures and concentrations of drug continue to diminish. But if memory within the pathways has also been disturbed, full recovery to preoperative baseline may require days, weeks, and possibly even rehabilitation; however, full recovery is expected. The patient with preoperative paralysis of more than several days, whether from central or peripheral neural injury, poses other anesthetic and postoperative concerns. The paralyzed patient may have up-regulated the population of neuromuscular junctions to a degree that administration of a depolarizing muscle relaxant can precipitate an acute

Patients will occasionally fail to awaken immediately on conclusion of surgery. Residual anesthetic drugs whether given during surgery or taken before surgery are surely the most common culprits. Long-acting benzodiazepine drugs, narcotics, barbiturates, and residual muscle relaxants can prevent a patient from demonstrating wakefulness. Even caffeine withdrawal by a heavy coffee or soda drinker can manifest as an unarousable patient following surgery. It is crucial to maintain a broad differential diagnosis. In the context of the patient’s coexisting medical conditions, the surgical intervention, and intraoperative and postoperative management, less common causes of delayed emergence may be more plausible. For example, in the diabetic patient requiring intraoperative insulin and glucose management, one must consider hypoglycemia, along with other systemic metabolic derangements such as hypoxia, hypercapnia, and hyponatremia. Following surgery for brain injury, aneurysm (without barbiturates), or a difficult tumor resection, an intracranial event such as intracerebral hemorrhage or ischemia from a slipped clip are but two examples that can present as delayed awakening.41 Even uncomplicated neuroendoscopy performed with endoscope pressures that exceeded 30 mm Hg have been associated with delayed emergence.42 Although beyond the scope of this chapter’s objectives, a wellperformed neurologic examination to establish the presence or absence of new localized or global findings is fundamental to addressing the question of whether an anesthetic or metabolic derangement (global events) or surgery (focal event) is the more probable culprit in delayed awakening. In conclusion, a careful review and understanding of the intraoperative anesthetic management and surgical events will assist in forming differential diagnoses for clinical findings observed in the ICU. These insights can be used to help better guide postoperative care and the recovery expectations of family and health care staff, to everyone’s benefit.

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P earls 1. . . . isoflurane uniquely lowers the critical CBF at which the EEG begins to demonstrate cerebral ischemia from a baseline lower flow threshold of 20 mL/100 g brain tissue per minute to nearer 10 mL/ 100 g brain tissue per minute. This suggests isoflurane may provide some cerebral protection in low flow states and why the incidence of ischemia suggested by electroencephalography (EEG) during carotid endarterectomy (CEA) is lower with isoflurane than with other PIAs. 2. . . . cooling the brain or spinal cord reduces CMRO2 and produces an approximate 7% decrease in CMRO2 per degree Celsius temperature drop. 3. Oxygen given in sufficient quantity to elevate the PaO2 above 300 mm Hg produces a mild (10%) reduction of CBF. 4. . . . when the potential for mechanical brain injury via herniation or surgical retractor pressure exists, severe hypocapnia (PaCO2: 20 to 25 mm Hg), even though it may risk cerebral ischemia and its associated morbidity, can be used temporarily in conjunction with other measures to decrease cerebral volume. 5. In addition to administration of intravenous ondansetron (4 mg) 30 minutes before the end of surgery, we also give dexamethasone (4 mg) and promethazine (6.25 mg) at the start of the procedure and run an infusion of propofol at 25 to 50 mg/kg per minute throughout the case. 6. Our observation has been that as the total thiopental dose delivered increases from 15 mg/kg to 20 mg/ kg to 30 mg/kg or higher, the probability of a post-

References 1. Michenfelder JD: The interdependency of cerebral functional and metabolic effects following massive doses of thiopental in the dog. Anesthesiology 1974;41:231–236. 2. Jones TH, Morawetz RB, Crowell RM, et al: Thresholds of focal cerebral ischemia in awake monkeys. J Neurosurg 1981;54:773–782. 3. Messick JM Jr, Casement B, Sharbrough FW, et al: Correlation of regional cerebral blood flow (rCBF) with EEG changes during isoflurane anesthesia for carotid endarterectomy: Critical rCBF. Anesthesiology 1987;66:344–349. 4. Michenfelder JD, Sundt TM, Fode N, et al: Isoflurane, when compared to enflurane and halothane decreases the frequency of cerebral ischemia during carotid endarterectomy. Anesthesiology 1987;67:336–340. 5. Verhaegen M, Iaizzo PA, Todd MM: A comparison of the effects of hypothermia, pentobarbital, and isoflurane on cerebral energy stores at the time of ischemic depolarization. Anesthesiology 1995;82:1209– 1215. 6. MacIntyre PE, Pavlin EG, Dwersteg JF: Effect of meperidine on oxygen consumption, carbon dioxide production, and respiratory gas exchange in post anesthesia shivering. Anesth Analg 1987;66:751–755.

7.

8.

9.

10.

11.

operative extubation decreases from, respectively, near 100% to 50% to 10% and then becomes essentially zero. Emergence may occur from several hours to even days later, depending on total dose delivered, hepatic function, and condition of the brain. The longest “safe” ischemic time (approximately 60 minutes) is achieved in controlled situations when the patient is slowly cooled to 18°C and placed on lowflow cardiopulmonary bypass or circulatory arrest. . . . the possibility of incomplete rewarming precipitating a shaking rigor and increased oxygen consumption would place the patient at considerable risk for perioperative cardiac ischemia, arrhythmia, and infarction. In addition to the observation of neck fullness or swelling, which may obscure the lateral shift of airway structures, patients with incipient airway obstruction will become progressively short of breath, tachypneic, hoarse, and either agitated or obtunded as they become more hypoxic and hypercarbic. Spinal cord dynamics are similar to those of the brain. The cord responds to anesthetic agents, ventilation parameters, temperature, perfusion pressure, and ischemia in essentially the same fashion as the brain. The patient who has recovered function from a CVA either partially or wholly, is at risk of awakening from anesthesia with some or all of the deficits that occurred at the time of the original CVA. This recapitulation phenomenon has been termed “differential awakening” of the brain and related to patients as a “reliving” of the CVA; recovery is expected.

7. Rossi S, Stocchetti N, Longhi L, et al: Brain oxygen tension, oxygen supply, and oxygen consumption during arterial hyperoxia in a model of progressive ischemia. J Neurotrauma 2001;18;163–174. 8. Strebel S, Lam A, Matta B, et al: Dynamic and static cerebral autoregulation during isoflurane, desflurane, and propofol anesthesia. Anesthesiology 1995;83:66–76. 9. Bruder N, Pellissier D, Grillot P, et al: Cerebral hyperemia during recovery from general anesthesia in neurosurgical patients. Anesth Analg 2002;94:650–654. 10. Shubert A: Cerebral hyperemia, systemic hypertension, and perioperative intracranial morbidity: Is there a smoking gun? Anesthesia Analg 2002;94:485. 11. Basali A, Mascha E, Kalfas I, et al: Relation between perioperative hypertension and intracranial hemorrhage after craniotomy. Anesthesiology 2000;93:48–54. 12. Olsen KS, Svendsen LB, Larsen FS: Validation of transcranial nearinfrared spectroscopy for evaluation of cerebral blood flow autoregulation. J Neurosurg Anesthesiol 1996;8(4):280–285. 13. Unterberg AW, Kiening KL, Hartl R, et al: Multimodal monitoring in patients with head injury: Evaluation of the effects of treatment on cerebral oxygenation. J Trauma 1997;42(5 Suppl):S32– 37.

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14. Vavilala MS, Newell DW, Junger E, et al: Dynamic cerebral autoregulation in healthy adolescents. Acta Anaesthesiol Scand 2002;46(4):393– 397. 15. Meixensberger J, Jager A, Dings J, et al: Multimodal hemodynamic neuromonitoring—quality and consequences for therapy of severely head injured patients. Acta Neurochir Suppl (Wien) 1998;71:260–262. 16. Laffey JG, Kavanagh BP: Hypocapnia. N Engl J Med 2002;347(1):43– 53. 17. Mavrocordatos P, Bissonnette B, Ravussin P: Effects of neck position and head elevation on intracranial pressure in anesthetized neurosurgery patients. J Neurosurg Anesth 2000;12(1):10–14. 18. Seoane E, Rhoton AL: Compression of the internal jugular vein by the transverse process of the atlas as the cause of cerebral hemorrhage after supratentorial craniotomy. Surg Neurol 1999;51:500–505. 19. Fenstermacher JD, Johnson JA: Filtration and reflection coefficients of the rabbit blood-brain barrier. Am J Physiol 1966;211(2):341–346. 20. Agarwal A, Sinha PK, Pandey CM, et al: Effect of a subanesthetic dose of intravenous ketamine and/or local anesthetic infiltration on hemodynamic responses to skull-pin placement. J Neurosurg Anesth 2001; 13(3):189–194. 21. Nuttall GA, Garrity JA, Dearani JA, et al: Risk factors for ischemic optic neuropathy after cardiopulmonary bypass: A matched case/control study. Anesth Analg 2001;93(6):1410–1416. 22. Lee LA: ASA postoperative visual loss (POVL) registry. APSF Newsletter Winter 2001–02;16(4):56. 23. Albin MS, Carroll RG, Maroon JC: Clinical considerations concerning detection of venous air embolism. Neurosurgery 1978;3:380–384. 24. Black S, Ockert DB, Oliver WC Jr, et al: Outcome following posterior fossa craniectomy in patients in the sitting or horizontal positions. Anesthesiology 1988;69:49–56. 25. Papadopoulos G, Kuhly P, Brock M, et al: Venous and paradoxical air embolism in the sitting position: A prospective study with transesophageal echocardiography. Acta Neurochir (Wien) 1994;126(2– 4):140–143. 26. Schmitt HJ, Hemmerling TM: Venous air emboli occur during release of positive end-expiratory pressure and repositioning after sitting position surgery. Anesth Analg 2002;94:400–403. 27. Losasso TJ, Muzzi DA, Dietz NM, et al: Fifty percent nitrous oxide does not increase the risk of venous air embolism in neurosurgical patients operated upon in the sitting position. Anesthesiology 1992;77:21–30.

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28. Fuchs G, Schwartz G, Stein J, et al: Doppler color-flow imaging: Screening of a patent foramen ovale in children scheduled for neurosurgery in the sitting position. J Neurosurg Anesthesiol 1998;10:5. 29. Geissler HJ, Allen SJ, Mehlhorn U, et al: Effect of body repositioning after venous air embolism: An echocardiographic study. Anesthesiology 1997;86:710–717. 30. Hagen PT, Scholz DG, Edwards WD: Incidence and size of patent foramen ovale during the first 10 decades of life: An autopsy study of 965 normal hearts. Mayo Clin Proc 1984;59:17–20. 31. Taylor CL, Selman WR, Kiefer SP, et al: Temporary vessel occlusion during intracranial aneurysm repair. Neurosurgery 1996;39:893–905. 32. Hashimoto T, Young WL, Prohovnik I, et al: Increased cerebral blood flow after brain arteriovenous malformation resection is substantially independent of changes in cardiac output. J Neurosurg Anesth 2002;14:204–208. 33. Fardo DJ, Hankins WT, Houskamp W, et al: The hemodynamic effects of local anesthetic injection into the carotid body during carotid endarterectomy. Am Surg 1999;65:648–651; discussion 651–652. 34. Maher CO, Wetjen NM, Friedman JA, et al: Intraoperative lidocaine injection into the carotid sinus during endarterectomy. J Neurosurg 2002;97:80–83. 35. Vanmaele RG, De Backer WA, Willemen MJ, et al: Hypoxic ventilatory response and carotid endarterectomy. Eur J Vasc Surg 1992;6:241–244. 36. Sinha A, Agarwal A, Gaur A, et al: Pharyngeal swelling and macroglossia after cervical spine surgery in the prone position. J Neurosurg Anesth 2001;13:237–239. 37. De Witte J, Sessler DI: Perioperative shivering: Physiology and pharmacology. Anesthesiology 2002;96:467–484. 38. Xiong J, Kurz A, Sessler DI, et al: Isoflurane produces marked and nonlinear decreases in the vasoconstriction and shivering thresholds. Anesthesiology 1996;85:240–245. 39. Frank SM, Fleisher LA, Breslow MJ, et al: Perioperative maintenance of normothermia reduces the incidence of morbid cardiac events: A randomized clinical trial. JAMA1997;277:1127–1134. 40. Cucchiara RF: Differential awakening. Anesth Analg (Letter) 1992;75:467. 41. Black S, Enneking FK, Cucchiara RF: Failure to awaken after general anesthesia due to cerebrovascular events. J Neurosurg Anesth 1998; 10:10–15. 42. Fábregas N, López A, Valero R, et al: Anesthetic management of surgical neuroendoscopies: Usefulness of monitoring the pressure inside the neuroendoscope. J Neurosurg Anesth 2000;12:21–28.

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Chapter 25 Elevated Intracranial Pressure A. Joseph Layon, MD and Andrea Gabrielli, MD

Introduction To appropriately discuss elevated intracranial pressure (ICP), we must first refresh our recollection of the intracranial compartment. The skull is, essentially, a solid box with only one outlet, the foramen magnum. Within this solid structure are the intracranial contents: brain, cerebrospinal fluid (CSF), and blood. If one of the components within the cranium increases in volume, one of the others must decrease. Thus, a small amount of cerebral edema will displace CSF out of the cranial vault and into the subarachnoid space of the spinal cord. If the cerebral edema becomes more severe, more of the CSF will be displaced; thereafter the cerebral blood volume (CBV) will decrease as cerebral blood flow (CBF) decreases. If the cerebral edema continues to worsen, at some point CBF will critically decrease and cerebral ischemia will ensue. Brain tissue meets most of its energy requirements from the oxidation of glucose in the presence of oxygen. The cerebral metabolic rate for oxygen (CMRO2) is between 3.1 and 3.7 mL/100 g of brain tissue/min1; this decreases during coma and increases during seizures. The CMRO2 may be measured, or at least conceptually considered, using the following equation: CMRO 2 = CBF ¥ AVDO 2 The arteriovenous oxygen difference is kept at a relatively constant 6.5 mL of O2 per 100 mL of blood; thus, the CBF must change to meet the changing demands of the CMRO2. Normally, autoregulation of the cerebral vasculature maintains adequate perfusion (CBF = 50 [46 to 63 at normal

PaCO2 in Ketty and Schmidt’s work1] mL/100 g/min) at mean blood pressures ranging from 50 to 150 mm Hg.1–3 Regional alterations in CBF are known to occur. Thus, when an area of the brain performs “work,” its metabolic needs, and hence regional CBF, may increase.3 The ability to measure regional cerebral blood flows (rCBF) has made possible the evaluation for thresholds for cerebral dysfunction. For example, Morawetz and colleagues,4 using an awake Macaca irus monkey model with surgically placed ligatures allowing reversible middle cerebral artery occlusion, showed that at 20 mL/100 g/min, electroencephalography (EEG) and evoked potential abnormalities are seen, and paralysis is noted; at 15 mL/100 g/min, EEG and evoked potentials are lost. CBF at approximately 12 mL/100 g/min for longer than 120 minutes results in cerebral infarction; at 6 mL/100 g/min, cell membrane integrity is lost. While mean arterial blood pressure of approximately 60 mm Hg is usually adequate to ensure adequate brain perfusion, patients with a history of arterial hypertension shift their cerebral autoregulatory curve to the right, so that a higher pressure is required to maintain adequate perfusion of brain parenchyma. The implication is that in chronically hypertensive individuals, the lower limit of autoregulation may be as high as 110 to 130 mm Hg.2 In clinical practice, however, CBF is only conceptually useful, because it is not easily measured at the bedside. Of more clinical interest is the cerebral perfusion pressure (CPP). Although not without controversy, a cerebral perfusion pressure (CPP = mean arterial pressure [MAP] - ICP) of 55 mm Hg or greater is usually adequate in an awake patient as long as clinical signs of cerebral dysfunction are absent or 709

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electrophysiologically measured parameters give no indication for concern. Patients with head injury—whether a result of surgery or other trauma—resulting in elevated ICP, are maintained at a higher CPP, usually between 65 and 75 mm Hg. Comatose patients as a result of severe head trauma with ICP greater than 20 mm Hg, Glasgow Coma Scale (GCS) score less than 7, in whom the CPP was maximized to greater than 70 mm Hg were noted to have a mortality of 29%; 80% of survivors had no or minimal neurologic residua [Glasgow Outcome Scale (GOS) score 4 to 5].5 Of note, CPP was maintained at no less than 70 mm Hg. When needed to maintain this level of perfusion, aggressive CSF drainage was used; early use of vasopressors—phenylephrine (to a maximum of 4 mg/kg/min), norepinephrine (to a maximum of 0.2 to 0.4 mg/kg/min), and low-dose dopamine (at a so-called renal protection dose of 1.5 to 3 mg/kg/min)—was carried out if CSF drainage did not result in an adequately maintained CPP. Barbiturates, hypothermia, and continuous hyperventilation were not used in this series. Intermittent hyperventilation using a bag-valve-endotracheal tube device—titrated against CPP—was carried out during periods of acutely increased ICP. Success of this approach has been attributed to prevention of cerebral ischemia. The authors comment that there was no tendency for high CPP to potentiate intracranial hypertension (Fig. 25-1). The “maximal CPP school” has been challenged, however. Clinicians from Lund University Hospital in Sweden6 have considered that keeping CPP >70 to 80 mm Hg may result in

vasogenic edema through the transudation of fluid from the vasculature into the tissue of the brain. They comment that this transcapillary leakage, as well as inotropic (b2) stimulation resulting in vasodilation, may result in an elevated ICP that counteracts the elevated CPP. The Lund group bases their therapeutic rationale on the principle that the bloodbrain barrier is compromised in head injury and that this results in the necessity to maintain normal intravascular colloidal oncotic forces, reduce transcapillary pressure, and moderately constrict precapillary resistance vessels. This therapy ought to minimize cerebral edema by decreasing blood flow and extravasation through the injured bloodbrain barrier. Reduction of the ICP is achieved with a combination of low-dose thiopental (0.5 to 3 mg/kg/hour) and fentanyl (2 to 5 mg/kg/hour) infusions, and dihydroergotamine (0.1 to 0.9 mg/kg/hour intravenously [IV]), a precapillary and large vein vasoconstrictor. The b1-antagonist metoprolol (0.2 to 0.3 mg/kg/24 hours IV) and the a2agonist clonidine (0.4 to 0.8 mg/kg every 4 to 6 hours IV) are added to reduce MAP to age-indexed normal values. Fluid balance is kept even or moderately negative. Albumin and blood are used to maintain their respective values within normal limits and to ensure normovolemia and optimal oxygen supply. While the Lund therapy seems to achieve excellent survival (49/53, 92%) and recovery (42/49, 85% had a GOS of 4 to 5) in head trauma patients with ventriculostomy, there are no prospective randomized studies comparing this strategy with that of maintaining CPP of 70 mm Hg or greater.7

Monitoring Intracranial Pressure Who Requires Intracranial Pressure Monitoring?

Figure 25-1. Scatter-plot showing the relationship between ICP and CPP. The lowest ICP occurs with a CPP of approximately 112 mm Hg; high CPP does not potentiate intracranial hypertension. (From Rosner MJ, Rosner SD, Johnson AH: Cerebral perfusion pressure—Management protocol and clinical results. J Neurosurgery 1995;83:949–962, with permission.)

In the context of concern for elevated ICP, the most important initial question we must deal with is: Which patients will require monitoring of their ICP? After cardiopulmonary resuscitation from cardiac arrest, patients with head injury with an abnormal computed tomography (CT) scan result will require monitoring because they have between a 53% and 63% risk for elevated ICP.8 CT abnormalities noted included epidural and subdural hematomata, and evidence of diffuse edema. A normal CT scan of the head in a comatose patient carries an approximate 13% risk for elevated ICP. In the patient who is older than 40 years of age, hypotensive to a systolic blood pressure (BP) of less than 90 mm Hg, with evidence of posturing, the risk of having elevated ICP is approximately 60%.7 In the at-risk patient to whom we have administered sedative agents such that we are unable to evaluate neurologic status, or in whom neuromuscular blocking agents have been used as treatment for suspected elevated ICP, monitoring of ICP is mandatory. While patients having suffered only mild to moderate head injury (GCS score 9 to 15) do not usually undergo ICP

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monitoring, if there are other injuries requiring operative correction, the physicians caring for the patient may utilize such monitoring during a surgical intervention or if there is a traumatic mass lesion. Compared to patients with mild (GCS score 13 to 15) or moderate (GCS score 9 to 12) head injury, patients with severe head injury (GCS score 3 to 8) are at significant risk for intracranial hypertension (3%, 10% to 20 %, and 53% to 63%, respectively).9 In an abstract presentation, Gopinath and colleagues showed, in a large uniformly treated patient population, an adverse outcome when ICP was greater than 25 mm Hg, mean arterial blood pressure was less than 80 mm Hg, and CPP was less than 60 mm Hg. How Is Intracranial Pressure Monitoring Accomplished? ICP may be monitored both noninvasively as well as invasively. However, the former methods, such as transcranial Doppler (TCD), visual-evoked responses (VERs), and brainstem auditory-evoked responses (BAERs) are somewhat less commonly used in our institution than are the invasive methods. Regardless, each of these modalities is useful as a noninvasive technique for ICP monitoring. TCD examines variations in systolic and diastolic peak flows. When ICP increases, there is an increase in pulse pressure with higher peak systolic flows and lower diastolic flows. If the ICP becomes higher than diastolic pressure, then diastolic flow velocity disappears. When the ICP exceeds normal arterial flow, then retrograde flow may appear; this tends to be associated with brain death. Chan and colleagues10 studied middle cerebral artery blood flow velocity and SjvO2 in 41 patients with severe TBI. These clinicians noted that as CPP decreased below a critical value of 70 mm Hg, the TCD pulsatility index increased significantly; this relationship appeared to hold for both focal and diffuse injuries, and irrespective of whether the decreased CPP was due to an increase in ICP or a decrease in blood pressure. Major problems of TCD monitoring are that it is most often performed intermittently, which may result in clinically significant changes being missed, and that is operator-dependent (i.e., it is more reliable if repeated evaluations are performed by the same operator). Regardless, TCD is frequently used in the monitoring and treatment of patients with subarachnoid hemorrhage at risk for or having exhibited cerebral vasospasm,11 as well as for other pathologies. With VERs, one notes an N2 waveform at 20 msec associated with cortical phenomena. Ischemia or increases in ICP alter this waveform latency. (See Chapter 21 for a full discussion of noninvasive monitoring techniques.) The primary methods for direct ICP monitoring are ventriculostomy, which remains the gold standard, subdural bolt, and fiberoptic catheter. The ventriculostomy is an effective ICP monitor that is easily re-zeroed at the level of the patient’s ear (circle of Willis), and in addition, allows removal of CSF from the ventricle to control the ICP if it has

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increased to a level considered dangerous. There may well be major difficulty with the “free-hand” placement of a ventriculostomy in a patient with distorted anatomy or severe brain swelling. In such a situation, stereotactic placement may likely be required; this technology is not available in all institutions. The skill required to properly and safely place a ventriculostomy is greater than that with other devices. Further, there has been some controversy of increased infection risk if the ventriculostomy is left in place for a prolonged period. Mayhall and colleagues noted that the cumulative risk of infection at 5 days after placement of the ventriculostomy catheter was 9%, and this increased by days 8, 10, and 11 to 21%, 37%, and 42%, respectively.12 The organisms noted to cause the infections are detailed in Table 25-1. In a letter to the editor, Kanter and Weiner noted that in their practice, the risk of infection peaks at about day 6, diminishing thereafter.13 This suggests that the inoculation of the CSF occurs at the time of insertion of the ventriculostomy catheter. Thus, if the catheters are replaced every 5 days, as suggested by Mayhall,11 the risk of infection may actually increase. Öhrström and colleagues, retrospectively studying 256 patients who underwent ventriculostomy as their first neurosurgical procedure, found 27 (11%) in whom CSF infection developed.14 These authors also noted that there was a relatively even distribution of infection between days 2 and 7; they do not support routinely changing ventriculostomies. This ICP monitor is the technique of choice in our intensive care unit (ICU) practice. Using the subarachnoid screw, ICP is measured by creating fluid coupling between the CSF and the fluid-filled catheter. A larger burr hole is required for this technique, and the dura is opened to expose the CSF. Advantages of this

Table 25-1  Bacteria Associated with Cerebrospinal Fluid Infection in Patients with Ventriculostomies Bacteria Gram positive Coagulase-negative staphylococci Staphylococcus aureus Streptococcus faecalis Streptococcus mitis Gram negative Enterobacter aerogenes Enterobacter cloacae Escherichia coli Klebsiella pneumoniae Serratia marcescens Providencia stuartii Acinetobacter calcoaceticus

Frequency N (%) 21 (44.7%) 10 (21.3%) 1 (2.1%) 1 (2.1%) 2 (4.2%) 2 (4.2%) 1 (2.1%) 3 (6.4%) 1 (2.1%) 1 (2.1%) 4 (8.5%)

Adapted from Mayhall CG, Archer NH, Lamb VA, et al: Ventriculostomyrelated infections—A prospective epidemiologic study. N Engl J Med 1984;310:553–559; and Öhrström JK, Skou JK, Ejlertsen T, Kosteljanetz M: Infected ventriculostomy—Bacteriology and treatment. Acta Neurochir (Wien) 1989;100:67–69.

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system include its simplicity and ease of use. Bolts do not require the skill needed for placing a ventriculostomy catheter and, in fact, may be used when cerebral edema causes ventricular collapse. Disadvantages of the system include artifact from tube movement, obstruction by swollen brain, and the need to keep the transducer at a fixed point relative to the patient’s head to ensure fidelity of measurement.15 The rate of bacterial colonization of this device approximates 5%. Significant bleeding or hematomata do not seem to be a problem with the subarachnoid screw. However, malfunction or obstruction is noted to occur in approximately 16% of the devices, significantly higher than in ventricular catheters (6.3%) or subdural catheters (10.5%).15 The subarachnoid device is the least expensive of the commonly used devices (Table 25-2). Fiberoptic catheters, including the Camino catheter, have become quite popular, are relatively easy to insert, and may be placed in the subdural, intraparenchymal, or intraventricular spaces; intraventricular placement is considered the most accurate. The disadvantage of the fiberoptic device is that it is calibrated before insertion and cannot be recalibrated after being placed. Thus, there is the possibility for inaccurate measurement with this device reported from 9% to 40% of the cases. More significantly, one is unable to

withdraw CSF through the fiberoptic catheter. Bacterial colonization is noted in about 5% of ventricular or subdural placed catheters, but as high as 14% in parenchymally placed devices. Hematomas are noted 0% to 2.8% of the time.15 While not an ICP monitor, continuous monitoring of jugular venous bulb oxyhemoglobin saturation (SjvO2) is being used to assess the physiologic response of the traumatized brain to pharmacologic manipulation administered to treat elevated ICP. Although this technique is best applied in global ischemia and vasogenic edema, it may be used in comatose patients with focal lesions as well. The catheter is placed percutaneously into one of the internal jugular veins (IJV)—preferably the right because it is generally thought to be the dominant side16—and advanced cephalad into the jugular venous bulb. Blood in the jugular bulb is a mix of both hemispheres, with approximately 70% coming from the ipsilateral side, and approximately 30% from the contralateral hemisphere. Fiberoptic continuous oxygen saturation monitoring, or frequent jugular venous blood sampling, is used to compute cerebral oxygen consumption: CMRO 2 = CBF ¥ (CaO 2 - CjvO 2 ). Because the cerebral blood flow may be somewhat of a problem to obtain at the bedside, cerebral oxygen consump-

Table 25-2  Cost of Intracranial Pressure Monitoring Devices (1998 Prices) Device Location

Pressure Transduction

Transducer Cost

Display/Calibration Device Cost

Ventricle FC External Gauge (Abbott) FC Strain Gauge Catheter Tip (Codman) FC Fiberoptic Catheter Tip (Draeger) FC Fiberoptic Catheter Tip (Camino)

$212

—

$420

$820

$375

$820

$433

$6,250

$305

$820

$345

$6,250

Parenchymal Strain Gauge Catheter Tip (Codman) Fiberoptic Catheter Tip (Camino) Subarachnoid FC External Strain Gauge (Codman, Abbott)

$91

—

Subdural Strain Gauge Catheter Tip (Codman) (Gaeltec) Fiberoptic Catheter Tip (Camino) FC External Strain Gauge (Abbott)

$305 $355

$820 $1,705

~$355

$6,250

$101

—

Modified from Bullock MR (for the Task Force): Recommendations for intracranial pressure monitoring technology in management and prognosis of severe traumatic brain injury—Part 1: Guidelines for the management of severe traumatic brain injury. J Neurotrauma 2000;17:497–506.

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tion may be approximated via the following simplified equation: VO 2 = CI ¥ (CaO 2 - CjvO 2 ) Oxygen extraction may be approximated from the equation: (CaO 2 - CjvO 2 ) = VO 2 ∏ CI.

Lactate may also be measured in jugular venous blood. Use of SjvO2 and the previously calculated approximations allows assessment of both brain hemodynamic reserve and its metabolic regulation, limiting potentially deleterious side effects of therapeutic interventions aimed at ICP control. SjvO2 is normally between approximately 55% and 75%; a value less than 50% suggests that therapy aimed at increasing oxygen delivery (increased cardiac index, increased hematocrit, increased FIO2) or decreasing consumption be initiated. Side effects that may be prevented include cerebral hypoxia from vasoconstriction (hyperventilation or barbiturates) or a low flow state (mannitol). Another potential clinical application of jugular venous bulb saturation monitoring is that as long as the jugular venous oxygen saturation remains in the normal range, this potentially allows a decrease in the cerebral profusion pressure, traditionally set at 70 to 80 mm Hg, to a lower level. This may result in less vasogenic edema and transudation of fluid from the vasculature into brain tissue.6 No prospective randomized studies exist to prove or disprove this hypothesis. Cruz17 studied a group of severely head-injured patients, titrating therapy to minimize cerebral O2 consumption and decrease the CaO2–CjvO2 difference. This prospective, controlled study evaluated outcome both as mortality (9% vs. 30%) and functionality (using the GOS). Both were significantly better at 6 months using the previous strategy as compared to management only of CPP (mortality 9% vs. 30%, respectively). In a study of patients having suffered a closed head injury with a GCS score of 8 or less and requiring craniotomy, the failure of the cerebral A-VDO2 to narrow by more than 1 volume per 100 mL postoperatively was associated with delayed cerebral infarction and may be a predictor of poor outcome.18 A-VDO2 greater than 9 volumes per 100 mL likely implies cerebral ischemia. Despite these interesting studies, and our interest in this modality of monitoring, the use of SjvO2 measurement in severely head-injured, comatose patients or in patients with mass effect from any cause is limited, because SjvO2 as an indicator of regional ischemia is relatively insensitive19,20 Another interesting technique available to monitor cerebral tissue oxygenation is near-infrared light spectroscopy (NILS). This modality is, again, not a monitor of ICP per se but, using a noninvasive percutaneous probe that is placed on the frontal or temporo-partietal cranium, measures relative cerebral tissue oxygenation.21 The monitoring modality relies on the fact that at the near-infrared spectrum (700 to 900 nm), where hemoglobin and cytochrome a3 absorb light, there is relative tissue transparency. NILS is rel-

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atively uncommonly used because sources of artifact— inconsistency of optical path length and light scattering in the tissue field—are not controllable. Additionally, at least with the commonly available continuous-wave or timedomain technologies, there is no manner to determine the error of measurement because of a lack of a standard to which it may be compared; the less commonly available frequency-domain technology is said to be quantitative. Wide variability between arterial values and background artifact from venous blood—partly dependent upon the device used—generally limits the use of this device to a trend analysis of O2 saturation and correlation with brain ischemia threshold.22 Nevertheless, NILS offers an unprecedented opportunity to quickly and noninvasively monitor cerebral circulation and the “global effect” of therapeutic measures on CBF. Kampfl and colleagues23 studied patients with severe head injury (GCS score less than 6) in a prospective, nonrandomized fashion, using NILS to assess changes in regional cerebral oxygenation (rSO2). Patients (n = 8) were divided into two groups, four patients had an ICP greater than 25 mm Hg and four had an ICP less than 25 mm Hg. While the NILS determined rSO2 was significantly lower in the high ICP group, as compared to the low ICP group, values from arterial PO2, CO2, pulse oximetric saturation (SpO2), and TCD were similar in both groups. Additionally, rSO2 values after three minutes of ventilation with a forced inspiratory oxygen fraction of inspired oxygen (FIO2) of 0.5—as compared to a baseline FIO2 of 0.21—were significantly increased in patients with the lower, as compared to the higher, ICP values (Fig. 25-2). Using prototype frequency-domain NILS technology, Watzman and colleagues studied 20 anesthetized children with congenital heart disease, finding that rSO2 closely correlated with arterial and jugular bulb saturation (rSO2 = 0.46 SaO2 + 0.56 SjO2 - 17, r = 0.71, P < .03).24 While outcome studies using this monitor as an ischemia threshold alarm are not yet available, a recent nonblinded, nonrandomized study evaluating cerebral ischemia via cerebral oximetry versus the patient’s ability to respond to command has been reported.25 Patients were anesthetized via cervical plexus block, and although minimal sedation was used as needed, no intravenous sedatives or analgesics were administered for at least 10 minutes before or during the period of carotid occlusion. During carotid occlusion, neurologic status was evaluated every 5 minutes by determining the patient’s ability to respond to verbal commands and exhibit normal contralateral upper extremity strength. Deterioration of neurologic status resulted in the placement of a shunt. Surgeons were not aware of the rSO2, and alterations in therapy were not made based on this value. After the study was completed, patients were stratified into two groups: those who had neurologic symptoms (n = 10), and those who did not (n = 90). Change in the rSO2 was normalized by calculating a percentage change in the rSO2 in each patient during the cross-clamp. Analysis showed that compared to patients with

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Figure 25-2. A and B, Regional oxygen saturation in head injured patients with an ICP greater than (open bars) or less than (hatched bars) 25 mm Hg. rSO2 values were significantly lower in patients with higher ICP as compared to those with the lower ICP both at baseline (with an FIO2 of 0.21) and after oxygenation with an FIO2 of 0.5 for 3 minutes. Patients with a lower ICP had a significantly higher rSO2 after 3 minutes of an FIO2 of 0.5 than did patients with higher ICP. Note in Panel B that PaO2 is not different in either group. (From Kampfl A, Pfausler B, Denchev D, Jaring HP, Schmutzhard E: Near infrared spectroscopy [NIRS] in patients with severe brain injury and elevated intracranial pressure. Acta Neurochir, 1997;70 (Suppl):112–114, with permission.)

no neurologic deterioration, patients with deterioration had an approximate 2.5-times decrease in the ipsilateral rSO2 reading when the pre-clamp value was compared to the cross-clamped value. Using a 20% decrease in rSO2 during the cross-clamp—as compared to the pre-clamp—period as a predictor of neurologic deterioration resulted in a sensitivity of 80%, specificity of 82.2%, a false-positive rate of 66.7%, false-negative rate of 2.6%, a positive predictive value of 33.3%, and a negative predictive value of 97.4%. Although of great interest, the technology is not developed to a level that NILS will find common clinical use in the near future. Recently, the ICP waveform obtained from a ventriculostomy has been compared to a simultaneous arterial blood pressure waveform and subjected to a sophisticated spectral-electronic analysis. The theory is that the pulsatile increase in blood volume occurring with each heartbeat may be thought of as analogous to a small intracranial injection of volume. Thus the resultant ICP pulse ought to be related to cerebral elastance [ICP change with volume]. A linear response has been noted between ICP pulse amplitude and ICP until an ICP level of approximately 60 mm Hg is reached. A slightly different approach to this problem is the use of mathematically modified blood pressure-ICP waveform pairs. The analyzed signals are resolved into component frequencies and these are used to look at how much pressure is transmitted through the system and how the pressure signal is phase shifted as it is transmitted through the cerebrovascular bed. The interdependence of ICP with the arterial line waveforms has been highly predictive of reduced intracranial compliance, demanding earlier intervention to minimize ICP surges. This technique is being studied clinically.26 Finally, and again although not precisely a monitor of ICP, the utilization of a Clark-type polarographic electrode inserted into brain tissue has been noted to be useful in the management of severe brain injury.27–30 In small series and

case reports, whether traumatic brain injury or vasospasm after aneurysmal subarachnoid hemorrhage, this modality of monitoring has been useful in providing an early detection system of decreased oxygen delivery to the brain. Our experience with this technology in severe traumatic brain injury mirrors that in the published literature. This device, along with a ventriculostomy, is part of our standard of care after traumatic brain injury. We have ongoing protocols for its use in the detection and monitoring of vasospasm after aneurysmal subarachnoid hemorrhage. Regional Intracranial Pressures One normally assumes that the brain—surrounded by CSF—behaves as if it were fluid. Hence, ICP measured in one portion of the intracranial space will accurately reflect ICP throughout the intracranial space.31 However, clinical experience informs us that this is not always the case. We have cared for patients with significantly elevated ICP whose mental status—in the presence of properly functioning ICP monitors—would never alert one to the elevated pressure. Others have noted this as well. Chambers and colleagues31 studied 10 patients with severe head injury resulting in cerebral contusions, subdural hematomata (SDH), and intracerebral hemorrhage (ICH). Bilateral Camino ICP transducers were placed in the frontal area. Volumes of the mass lesions were calculated using CT scanning and specialized software. Differences in the bilateral ICP measurements were noted. The “delta” ICP readings were as high as 30 mm Hg when ipsilateral and contralateral readings were compared. This was particularly noted in patients with SDH; delta P values in patients with ICH and contusions showed close agreement. Mindermann and Gratzl32 studied six patients with severe head trauma; all patients had GCS score

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less than 9, normal coagulation parameters, and no spaceoccupying lesions requiring surgery. Patients had bifrontal ICP monitors placed. Three of the six patients had intrahemispheric pressure gradients of between 6 and 10 mm Hg that equilibrated over 6 to 7 hours. These data suggest that regional ICPs may exist and should be considered at least in patients having suffered severe head injury. While we do not routinely place bilateral ICP monitoring devices, some consideration ought to be given to formally studying this in the future. The treatment implications are intuitive but unproven.

Therapy of Elevated Intracranial Pressure ABCs As with any therapy related to critically ill patients, first things must come first. In this context, a thorough evaluation must be performed by the neurointensivist in the emergency department (ED) or upon the patient’s arrival to the ICU. Significant injuries are occasionally missed in the chaos that is sometimes seen in the ED. Particular attention must be paid to the “ABCs” of resuscitation (emergency and elective management of the airway is discussed in detail in Chapter 16). The airway should be reassessed to determine stability; the endotracheal tube may be found hanging precariously on the patient’s arrival to the ICU. If the patient’s airway is adequate, ventilatory status should be assessed with a visual observation for rate, synchrony, and evidence of flail chest. Arterial blood should be sent for gas analysis. The cardiac rhythm, rate, and evidence of hemodynamic adequacy should be re-evaluated and, if appropriate, treated. The patient may have been receiving intravenous fluids at a high hourly rate; the intensivist must be mindful of iatrogenically worsened cerebral edema after traumatic brain injury. A detailed general physical examination should be performed to confirm injuries noted in the ED and to ensure none were missed. A thorough neurologic examination should be performed to determine if the patient’s neurologic status has changed since initial ED evaluation. If the patient is determined to be at risk for elevated ICP, management should commence immediately. Positioning Treatment of elevated ICP begins with simple modes of intervention. For many years, it was uncontested dogma that elevation of the head was the best initial treatment for elevated ICP. While head elevation clearly decreases ICP, not until recently did researchers consider the negative impact on perfusion of the brain. For example, over 50 years ago, Scheinberg and Stead noted that in going from the supine to the erect (65 degrees to horizontal) positions in a group of

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20 healthy male volunteers, CBF—measured via the nitrous oxide technique—decreased from 65 to 51 mL/100 g/min, a decrement of approximately 21%.33 Durward and colleagues34 showed, in a group of 11 patients with GCS scores less than 8 who had either suffered a severe closed head injury or near-drowning, that ICP was minimized and CPP remained unchanged with the head elevated at between 15 and 30 degrees to horizontal; flexion occurred at the hips. CPP was significantly decreased (-7.9 ± 9.3 mm Hg) when the head was elevated to 60 degrees from horizontal. In this patient population, there were no significant changes in heart rate, central venous pressure (CVP), pulmonary artery pressure (PAP), or pulmonary capillary wedge pressure (PCWP), suggesting that the patients were adequately volume resuscitated (Table 25-3). More recently, Rosner and Coley35 studied 18 patients with various disorders (tumor, head injury, hemorrhage, metabolic abnormality) and found that while ICP did not significantly decrease with elevation of head from 10 to 50 degrees from horizontal, CPP, CVP, and systolic blood pressure did. These investigators suggested that the best treatment for ICP was to keep the head flat, as this was where CPP was optimized. Feldman and colleagues36 examined the effect of head position on CBF, CPP, and ICP, suggesting that adequate CBF is the sine qua non with which we ought to evaluate the issue of head position in patients with elevated ICP. These investigators studied 22 patients with head injury; the pathology included open and closed head injury, and in 17/22 patients the GCS score was 8 or less. In the summated data, going from 0 to 30 degrees resulted in no change in CBF or CPP, although the ICP significantly decreased. In six patients with an ICP greater than 25 mm Hg, going from 0 to 30 degrees resulted in a significant drop in ICP, with insignificant changes in CPP, CBF, and mean carotid pressure (Table 25-4). Table 25-3  Positional Changes Affecting Cerebral and Hemodynamic Parameters in Patients with Elevated Intracranial Pressure due to Closed Head Injury or Near Drowning: Compared to 0 Degrees Head Position (from Horizontal)

15 Degrees

30 Degrees

60 Degrees

ICP (mm Hg) CVP PAP PCWP HR

-4.5 ± 1.6* 1±1 1±2 0.5 ± 1.6 0±6

-6.1 ± 3.3* 0±1 0±2 -0.2 ± 1.5 0±8

-3.8 ± 9.3 0±3 1±2 1.4 ± 2.4 1±4

Values are deltas, compared to those at 0 degrees. *P < .001. CVP, central venous pressure; HR, heart rate; ICP, intracranial pressure; PAP, pulmonary artery pressure; PCWP, pulmonary capillary wedge pressure. Modified from Durward QJ, Amacher AL, Del Maestro RF, Sibbald WJ: Cerebral and cardiovascular responses to changes in head elevation in patients with intracranial hypertension. J Neurosurg 1983;59:938–944.

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Table 25-4  Positional Change Alterations in Cerebral and Hemodynamic Parameters in Patients with Intracranial Pressure Greater than 25 mm Hg Head Elevation Parameter

0 degrees

30 degrees

P

Mean carotid pressure (mm Hg) ICP (mm Hg) CPP (mm Hg) CBF (mL/100 g/min) Cerebrovascular resistance (CPP/CBF)

83.7 ± 15.1

74.7 ± 15.1

.085

30.7 ± 3.3 53 ± 17.1 59.8 ± 26.4 0.992 ± 0.226

20.3 ± 3.9 54.2 ± 12.8 55.9 ± 9.6 0.976 ± 0.398

.008 .53 .6 .86

CBF, cerebral blood flow; CPP, cerebral perfusion pressure; ICP, intracranial pressure. Modified from Feldman Z, Kanter MJ, Robertson CS, et al: Effect of head elevation on intracranial pressure, cerebral perfusion pressure, and cerebral blood flow in head-injured patients. J Neurosurg 1992;76:207–211.

The best data seem to suggest, and this is what we incorporate in our practice, that mild head elevation of from 15 to 30 degrees has beneficial effects on ICP with no significant detrimental effects on CPP or CBF. The head must be kept in a neutral position (i.e., not turned to the left or right) to minimize decreased jugular venous outflow, which could have the effect of further elevating ICP. Hyperventilation For some decades, treatment for elevated ICP has traditionally begun with hyperventilation. This represents a relatively easy mode of intervention, which can be initiated in the field or the ED. Hyperventilation decreasing PaCO2 to the range of 25 to 30 mm Hg causes cerebral vasoconstriction and has been considered a safe and effective initial means for treatment of elevated ICP.37 Therapy is based on the tenet that elevated ICP is associated with poor outcome, and that hyperventilation can decrease ICP.38 Cerebral lactic acidosis is also associated with poor outcome, and hyperventilation may transiently raise cerebral pH.39 Supporting the concept that hyperventilation is an important therapeutic tool for use in caring for patients with elevated ICP is the retrospective review of Marshall and colleagues.40 One hundred patients with severe head injury—defined in the paper as unable to follow commands and verbally unresponsive, suggesting a GCS score of 8 or less—were studied. ICP monitors were placed and ICP was considered normal if less than 15 mm Hg for 3 consecutive days from admission. Patients with ICP greater than this value were hyperventilated to a PaCO2 of 25 ± 3 mm Hg, neuromuscularly blocked, and administered mannitol and dexamethasone. Systolic blood pressure was kept below 160 mm Hg using antihypertensive agents. Barbiturates were used in patients with ICP elevated to greater than 40 mm Hg. Using this therapeutic regimen, 60% of patients were reported to have recovered with little

or moderate disability, 12% were severely disabled or vegetative, and 28% died. The authors thought that aggressive monitoring—especially of ICP—and treatment resulted in the reasonably good outcomes. They commented, in fact, that their use of barbiturates for only for ICP greater than 40 mm Hg was likely too conservative. Muizelaar and colleagues41 presented a randomized clinical trial examining hyperventilation versus normoventilation in 113 patients having suffered severe closed head injury (GCS score 8 or less) treated in one of three ways: 1. Normoventilation (PaCO2 35 ± 2 mm Hg, n = 41) 2. Hyperventilation (PaCO2 25 ± 2 mm Hg, n = 36) and 3. Hyperventilation with THAM (tris[hydroxymethyl]aminomethane, n = 36). The results showed that at 3 and 6 months in the patient subgroup with a motor score of 4 to 5, controls or hyperventilation with THAM had better outcome than hyperventilation alone; this difference was not maintained at 12 months after injury. The basis suggested for this difference was related to CMRO2 and CBF. When CBF decreases to such an extent that the CMRO2 is not met, the hypoperfused region of the brain becomes ischemic. While none of the CBF values from any group was suggestive of ischemia, the hyperventilation without THAM group had the highest lactate levels and also had abnormal phosphocreatine– inorganic phosphate ratio, indicative of insufficient oxidative metabolism. Another prospective randomized clinical study was performed in patients having suffered severe CHI (GCS score 8 or less). In this clinical study, 155 patients were randomized to either control or study group treatment (Table 25-5).42 The trial specifically excluded sustained hyperventilation, instead using a stepped therapeutic regimen with, in the study group, THAM to resolve CSF acidosis. Although there were no significant differences in acute outcome, or that at 3, 6, and 12 months after injury, between the control and THAM groups, the THAM group had lower ICP in the first 48 hours after injury. Further, the THAM group had a higher PaCO2 from day 4 after injury forward, and fewer of the THAM treated patients needed barbiturates to manage ICP. Again, however, there were no outcome differences tied to these ICP differences. The clinical introduction of SjvO2 offers new insights into the potential harm of indiscriminate or exaggerated hyperventilation.17 When increased ICP is associated with increased cerebral extraction of oxygen, hyperventilation can decrease CBF and dangerously reduce cerebral oxygenation. Judicious use of mannitol or therapeutic maneuvers aimed at reducing CMRO2 (i.e., barbiturates) is always preferred to hyperventilation. However, brief use of hyperventilation can still be helpful as a “bridge” intervention in herniation syndrome. Darby and colleagues presented the case of a 20-month-old patient with severe closed head injury (CHI) after a motor vehicular crash.43 He was initially hyperventilated, and was found to have, on repeated study,

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Table 25-5  Treatment Protocol after Severe Closed Head Injury Parameter Intubation Mechanical Ventilation PaO2 ≥ 80 mm Hg PEEP 0-20 cm H2O PRN FIO2 0.3-1.0 PRN NMB PRN “Normal” electrolytes and glucose Hematocrit 30% to 40% Fluids to keep PCWP 10-15 mm Hg PaCO2 33 ± 2 mm Hg ICP monitor ICP < 20 mm Hg NMB Morphine sedation IV Mannitol PaCO2 28-30 mm Hg CSF drainage Barbiturate coma THAM to elevate serum pH to 7.6

Control Group

Study Group

+ + + + + + +

+ + + + + + +

+ +

+ +

+ + + + + + + + + -

+ + + + + + + + + +

CSF, cerebrospinal fluid; ICP, intracranial pressure; NMB, neuromuscular blocking agent; PCWP, pulmonary capillary wedge pressure. From Wolf AL, Levi L, Marmarou A, et al: Effect of THAM upon outcome in severe head injury—A randomized prospective clinical trial. J Neurosurg 1993;78:54–59, with permission.

a hyperventilation-induced inverse steal phenomenon. Xenon-CT CBF studies showed that in the traumatized areas of the brain, hyperventilation from a PaCO2 of 34 to 20 mm Hg resulted in an ICP decrease from 25 to 18 mm Hg. The CBF went from a clearly decreased level at a PaCO2 of 34 mm Hg to a level that was 30% to 40% increased in the traumatized area at a PaCO2 of 20 mm Hg, despite a decrease in the ICP and blood pressure that was unchanged. This increase in CBF to the traumatized areas was clearly in the hyperemic range. The inverse steal phenomenon is thought to result from redistribution of blood, during hyperventilation, from normal to traumatized brain. The result may be a worsening in cerebral edema to the traumatized area, resultant from trauma-associated vasoparalysis. A more recent clinical study evaluated patients with severe CHI (GCS score 8 or less) in whom continuous brain tissue O2 tension (PbrO2) was measured using a polarographic Clarktype electrode.44 The electrode was placed contralateral to the area of injury, along with a fiberoptic ICP catheter. Effective hyperventilation, defined as a decrease in the PaCO2 by 2 mm Hg or greater, resulted in a decrease of the PbrO2 from 26.5 ± 11.6 to 23.6 ± 10.6 mm Hg, a significant change (P < .001). The adverse effect of hyperventilation on PbrO2 increased significantly over time (day 1 after injury to day 5 after injury). The authors of this study suggest that while there are uncertainties regarding the interpretation of their data, hyperventilation has the potential to result in decreased

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brain tissue O2, with potential secondary ischemic damage. Because alteration of cerebral blood flow and brain tissue O2 cannot be easily predicted at the bedside, hyperventilation should be, most often, used as a short-term therapeutic intervention as a means of controlling acute increase of the ICP after the first 24 hours after injury.45,46 We most commonly maintain the PaCO2 between 35 and 40 mm Hg unless acutely elevated ICP demands immediate therapy. Sedation/Neuromuscular Blockade Patients with CHI or those who are postcraniotomy for tumor resection frequently have diminished mental status and commonly thrash about in their beds, or “fight” the ventilator. These actions may increase ICP, especially if the patient is at the steep (or elbow) portion of the intracranial volume-pressure curve. Sedation or neuromuscular blockade may be an effective adjunct in the treatment of elevated ICP. Usually, sedation is preferred to neuromuscular blockade, because the former can usually be quickly and completely reversed, and still allows for sequential neurologic examinations. Propofol, from 10 to 100 mg/kg/min, is an excellent agent for this purpose because it is a short-acting and powerful sedative.47,48 After the redistribution “sinks” (fat) have been saturated, the drug has a longer effective duration of action as the half-life (T1/2b) is long. If the drug dose is progressively titrated down, the ability to rapidly arouse the patient for neurologic evaluation is maintained when the agent is discontinued. Arousability with gentle stimulation is our titration end-point (sedation score of 2); using the drug in this manner, equilibrium is achieved between the triad: drug input-redistribution-metabolism. Other sedatives may be used, including the short acting benzodiazepine midazolam, and the longer acting lorazepam, and indeed, their costs may be less than that of propofol. Nonetheless, propofol has a very secure place in the neuroICU, related to its fast-off properties that allow a patient to be properly sedated and yet be “awakened” hourly for neurologic evaluation. Propofol is the sedative agent of choice for neurosurgical or neurologic patients in our ICU. Since the introduction of propofol, the use of neuromuscular blocking (NMB) agents has become uncommon in our surgical intensive care unit. However, if sedatives are not capable of controlling the patient, use of a NMB agent, in addition to the sedative, may be indicated.49 As long as drug dose is titrated to neuromuscular function as measured by train-of-four response to a supramaximal impulse,50,51 any of the commonly used NMB agents (pancuronium, atracurium, vecuronium) may be used.40–42 The NMB agent infusion is titrated so that one twitch of the train-of-four (1/4) stimulus is always present. Minimization of Stimulation Along with sedation, there should be an overall decrease in “elective” interventions that will be painful or excessively stimulating. This means that suctioning of the endotracheal

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tube should be minimized if possible. Kerr and colleagues,52 studying 19 predominantly male (74%) victims of a motor vehicle crash (MVC), with GCS score of 3.5 ± 1.7 (SD), and an APACHE II score of 24.1 ± 3.1, found that when endotracheal suctioning was preceded by four supratidal volume breaths (135% of ventilator VT), ICP increased only transiently. Cerebral perfusion pressure was 70 mm Hg or greater and PjvO2 40 mm Hg or greater throughout the experiment. They suggested that endotracheal suctioning using their protocol did not appear to result in impaired cerebral oxygenation. Use of intratracheal lidocaine before suctioning to minimize coughing with resultant elevation in ICP is sometimes carried out; however, it is our experience that coughing upon instillation obviates its usefulness in this scenario. Therefore, our preference is to nebulize a solution of 2 mg/kg lidocaine (usually 4% lidocaine mixed in 0.9% saline solution to a total of 10 mL volume) a few minutes before suctioning. As an alternative, we use lidocaine intravenously approximately 90 seconds before stimulation or suctioning at a dose of 1 to 2 mg/kg ideal body weight, usually as a 1% solution. Control of Serum Glucose While it may not be intuitively obvious how a discussion of glucose control works into a section on elevated intracranial pressure, there is a link. It is widely known and generally accepted that hypoglycemia—blood glucose less than 50 mg/dL (less than 2.8 mM/L) in adults and less than 30 mg/dL (less than 1.7 mM/L) in neonates—may cause neuronal injury.53 Hypoglycemia induces a systemic stress response, and causes disturbances in CBF, increasing regional CBF by as much as 300% in severe hypoglycemia. Finally, hypoglycemia alters cerebral metabolism, ultimately resulting in permanent neuronal injury. Not so well understood or accepted is that hyperglycemia may, in the appropriate clinical setting, result in neuronal damage as well. In ischemic brain injury, hyperglycemia—defined for this purpose as a blood glucose greater than 150 mg/dL (greater than 8.4 mM/L) in nondiabetics and greater than 200 to 250 mg/dL (greater than 11.2 to 14 mM/L) in poorly controlled diabetics—has been noted to worsen outcome.53,54 Ischemic brain injury results in decreased oxidative metabolism, an increase in glycolysis with increased lactate production, with resultant intracellular acidosis. The decrement in intracellular pH leads to cellular dysfunction, including glycolysis, protein synthesis and activity, ion homeostasis (such as regulation of calcium gradients), neurotransmitter release and uptake (such as glutamate and aspartate), enzyme function (such as adenylate cyclase, xanthine oxidase, phospholipase), free radical production and scavenging, and stimulus response coupling. Some years ago, Lanier and colleagues55 showed that postischemic neurologic deterioration was related to high pre-insult blood glucose level, in a primate animal model of focal ischemia. In this study of 15 pigtail monkeys (Macaca

nemestrina), subjects were infused, before the ischemic insult, with either 5% dextrose in 0.45 saline solution, or lactated Ringer solution. The animals then underwent a 17-minute period of total cerebral ischemia, followed by 24 hours of intensive care, and then neurologic follow-up for an additional 72 hours. The animals to whom the glucose solution was infused before the ischemic insult had a worse outcome in all respects. They had a significantly prolonged extubation time, significantly worse neurologic outcome at 96 hours, and overall worse histopathologic scores. The authors recommended that patients at risk of cerebral ischemia avoid glucose-containing intravenous solutions. Huang and colleagues,56 using male Sprague-Dawley rats weighing between 300 and 350 g, reported that pre-ischemic hyperglycemia worsened ischemic damage in both permanent and transient middle cerebral artery occlusion models. Further, they noted that reperfusion in the presence of preischemic hyperglycemia accelerated the development of vasogenic edema and the decline of the apparent diffusion coefficient (ADC), normally correlating with tissue energy metabolism. Severe intracellular acidosis, and perhaps oxygen free radicals, may cause such damage to the cellular membrane so that the ADC is irreversibly altered. The authors question the wisdom of using thrombolytic therapy in stroke patients with elevated glucose values, as might be seen in diabetics. They worry that in the presence of preischemic hyperglycemia, significant reperfusion damage might occur. Cherian and colleagues,57,58 studying secondary ischemic injury after a cortical impact (closed head) injury in rats, found that hyperglycemia worsened brain damage when traumatic brain injury was complicated by secondary ischemia. The glucose-infused animals had higher blood glucose and lactate levels (Fig. 25-3), a larger contusion volume and fewer viable neurons (Fig. 25-4), and fewer successful beamwalking trials (Fig. 25-5). The authors suggest that patients with head injuries who suffer a secondary ischemic injury in the presence of hyperglycemia may have a worsened neurologic outcome. Finally, Bruno and colleagues,59 in an analysis of TOAST (Trial of ORG 10172 in Acute Stroke Treatment, designed to test the efficacy of a low-molecular weight heparinoid vs. placebo in ischemic stroke) results, found that a higher admission glucose was associated with a worse outcome at three months in all strokes combined and in nonlacunar strokes. The authors suggest that lowering elevated blood glucose levels during a nonlacunar ischemic stroke might be beneficial. The findings of the previously cited studies suggest that tight control of the blood glucose concentration in a patient at risk for a cerebral ischemic event is necessary to maximize neurologic outcome. Tight control of the blood glucose concentration after a neurosurgical procedure is recommended. A history of diabetes mellitus, as well as the diabetogenic effect of stress-induced endogenous catecholamines release and exogenous steroids represents a challenge to the intensivist. In these cases, the perioperative use of an intravenous

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Figure 25-3. Changes in blood glucose and lactate concentrations during the experiment were examined by repeated measures ANOVA. The P values for the treatment group effect, the time effect, and the treatment ¥ time interaction are displayed on each graph. Asterisks mark values that are significantly different (P < .05) from the saline infusion control group when adjusted for multiple comparisons by Dunnett’s method. (From Cherian L, Hannay HJ, Vagner G, et al: Hyperglycemia increases neurological damage and behavioral deficits from post-traumatic secondary ischemic insults. J Neurotrauma 1998;15:307–321, with permission.)

regular insulin infusion and hourly blood glucose level checks is our practice. A good rule, when beginning the insulin infusion, is to divide the blood glucose by 150 (or by 100 if steroids or catecholamines are in use or other diabetogenic conditions are present) and set the hourly regular insulin infusion rate at the value so obtained. Insulin resistance often develops in patients with preexisting diabetes mellitus when exposed to physiologic stresses or steroid therapy; these patients may require a much higher rate of insulin infusion. It is our practice to keep the perioperative or peri-event glucose level between 80 and 120 mg/dL (4.5 and 6.7 mM/L) in the nondiabetic patient with elevated ICP. In the diabetic patient with elevated ICP whose serum glucose has been poorly controlled, we will allow the high end of our control regimen to reach approximately 180 mg/dL (10.1 mM/L). Enteral or parenteral nutrition is held for a few days postoperatively to facilitate blood glucose control. An infusion of 5% dextrose in 0.9% saline solution is available if the blood glucose level drops below 80 mg/dL. This level of glucose control continues until the patient begins to improve and is unlikely to suffer additional ischemic brain injury. Mannitol Mannitol is an important therapeutic agent used in the treatment of elevated ICP. While the effects of mannitol on cere-

bral edema are generally ascribed to its hyperosmolality, creating an osmolar gradient between the vascular space and the brain tissue “space” that results in net water movement out of the brain, there are other mechanisms involved as well. Pappius and Dayes point out that hypertonic materials such as mannitol remove brain water from areas of normal brain60; mannitol is also thought to prevent movement of water from the vascular to the intracellular space during membrane pump failure.61,62 Furthermore, mannitol decreases blood viscosity and microcirculatory vascular resistance; additionally, it likely acts as an oxygen free-radical scavenger.63 Mannitol is also helpful in reestablishing perfusion after global ischemia.64 Despite the widespread acceptance of mannitol in the treatment of elevated ICP, there are some significant disadvantages to its use, essentially related to the hyperosmolality of the agent as, with continued use, patients may develop rebound cerebral edema, neuronal damage, or renal failure.65 Severe dehydration of the brain may result in clinically significant subdural and subarachnoid hemorrhage.60 Because of these problems, serum osmolality should not be allowed to increase above approximately 320 mOsm/kg H2O. The institution of mannitol usually begins with a bolus of 0.25 to 0.5 g/kg ideal body weight. An initial increase in CBF and oxygen delivery is often noted after a bolus dose of mannitol; these effects last between 3 and 15 minutes and

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Neurointensive Care: Specific Problems needed for increased ICP, the mean ICP was lower. This did not translate into an outcome difference in this relatively small study. When mannitol is used, measured serum osmolality should be kept below 320 mOsm/kg H2O; osmolality and serum sodium levels are serially checked, respectively, every 8 and 4 hours, and the free water deficit slowly corrected to a serum sodium level of 145 to 150 mEq/L. Hypovolemia must be avoided to help prevent renal damage. The use of invasive intravascular monitoring (CVP or pulmonary artery catheter) should be considered early. Use of mannitol in the presence of widespread disruption of the BBB, or for prolonged periods, may result in aggravation of cerebral edema due to penetration of the drug into the brain.65,68 Hypertonic Fluid Therapy

Figure 25-4. Histologic measures of injury at two weeks after injury. The p value in each graph is for the comparison of median values by the Kruskal-Wallis test. The asterisk identifies values that are significantly different (P < .05) from the saline control group when adjusted for multiple comparisons by the Dunn’s method. All animals studied are included in this analysis, but the animals that survived the entire 2-week study are shown by the open circles. Animals that died earlier are shown as closed circles. (From Cherian L, Hannay HJ, Vagner G, et al: Hyperglycemia increases neurological damage and behavioral deficits from post-traumatic secondary ischemic insults. J Neurotrauma 1998;15:307–321, with permission.)

are thought to be related to the immediate expansion of plasma volume after a mannitol bolus that decreases the blood viscosity. This is followed by a decrease in the ICP and CBV, with maintenance of CBF for 30 to 360 minutes. Animal studies have suggested that the decrease in the ICP after administration of mannitol is due to a decrease in the CSF formation rate (Vf) and a decrease in the brain tissue water content (BTWC).66 The use of small intermittent boluses, rather than a continuous intravenous infusion, decreases the total daily dose of mannitol administered and may be more effective in controlling ICP. Smith and colleagues67 showed that when mannitol was administered at regular intervals (0.25 mg/kg every 2 hours unless the serum osmolality is greater than 310 mOsm/kg) rather than as

Isovolemic hemodilution—decreasing the hematocrit from 40% to 20% while keeping the right atrial and arterial pressures stable—using both hypertonic Ringer lactate (HRL; Na+ = 252 mEq/L, osmolarity = 480 mOsm/kg H2O) and 0.9% saline (Na+ = 155 mEq/L, osmolarity = 310 mOsm/kg H2O) solutions has been carried out in a healthy rabbit model to evaluate the effects on cerebral physiology.69 Animals were hemodiluted over 1 hour, then data were collected over a second hour. The investigators found that while CBF significantly increased from baseline in both groups, ICP was also significantly increased with 0.9% saline solution group, as compared to the HRL group. The percentage water content in brain and muscle was significantly less in the HRL group as compared to either control or the 0.9% saline solution group. While this experiment was carried out in healthy animals, the investigators—rightly in our opinion —point out that the use of HRL for resuscitation in a headinjured patient may be beneficial. Nonetheless, there is concern that the hypernatremia and hyperosmolarity might result in cerebral dysfunction. Wisner and colleagues evaluated cerebral metabolism with hypertonic resuscitation, using phosphorus nuclear magnetic resonance spectroscopy.70 After instrumentation, which included placement of a 2-cm single turn circular radio frequency surface coil over the frontoparietal skull, the male Sprague-Dawley rats were bled to a MAP of 45 mm Hg; further blood was removed over 1 hour to keep the MAP at this level. The animals were then resuscitated, using either LR (osmolarity = 270 mOsm/kg H2O) or 7.2% saline solution (osmolarity = 2400 mOsm/kg H2O). Resuscitation volumes to return MAP to the end point of 75 mm Hg were significantly different. The LR group required approximately 25 mL/kg body weight, whereas the 7.3% saline solution group required only 2 to 3 mL/kg. There were no differences between the groups in the ratio of phosphocreatinine to inorganic phosphate (Pi), or adenosine triphosphate (ATP) total to Pi. Intracellular H+ concentration was higher in the hypertonic saline group, likely related to the high chloride load. The clear implications of this experiment are that the use of

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Figure 25-5. The number of successful beam-walking trials tended to increase over time and the overall success rate was significantly related to the experimental group. Chi squared = 78.21, P < .0001. Follow-up pairwise Chi-square tests of the overall success rate using a Bonferroni correction were significant for all of the following comparisons: glucose infusion and temperature control groups (P = .0007), glucose infusion and saline control groups (P < .0001), and temperature control and saline control groups (P = .0001). (From Cherian L, Hannay HJ, Vagner G, et al: Hyperglycemia increases neurological damage and behavioral deficits from post-traumatic secondary ischemic insults. J Neurotrauma 1998;15:307–321, with permission.)

hypertonic saline solutions do not adversely impact cerebral metabolism. Hypertonic saline (HS) is used in the treatment of patients with hemorrhagic shock. Both animal71,72 and human studies73,74 have shown that HS can decrease ICP and improve CPP even in cases refractory to more common therapy; in humans, ICP control does not always lead to improved ultimate outcome. Interestingly, in a canine model of normal preshock ICP, even though HS resuscitation results in decreased ICP and improved CPP after hemorrhagic shock as compared to LR, both solutions failed to restore cerebral oxygen transport to preshock levels (Fig. 25-6).75 However, in the presence of prehemorrhagic shock elevated ICP, the use of HS for resuscitation reduces ICP,

improves regional CBF, and improves cerebral oxygen delivery—although not to preshock levels—when compared to isotonic saline solution.76 HS, when used for acute control of the ICP, increases blood osmolarity, creating the driving force that pulls water out of neurons and the interstitium. Effective restoration of blood pressure and cardiac output contributes to the increase of CPP. While there are data to recommend HS therapy for traumatic or postoperative cerebral edema, the efficacy of HS in patients with nontraumatic intracranial hemorrhage or infarction was unable to be demonstrated in one study.77 Patients with traumatic brain injury (TBI) who have elevated ICP that has become unresponsive to mannitol have been successfully treated with 20 to 50 mL boluses of hyper-

Figure 25-6. Effect of lactated Ringer’s solution and hypertonic saline solution on intracranial pressure (ICP; left panel) and cerebral oxygen transport (CO2T; right panel). Values are means + SEM for six dogs in each group. (From Prough DS, Johnson JC, Stump DA, et al: Effects of hypertonic saline versus lactated Ringer’s solution on cerebral oxygen transport during resuscitation from hemorrhagic shock. J Neurosurg, 1986;64:627–632, with permission.)

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tonic saline (5 mM/mL, 30% saline solution).78 HS has been used as a solution whose concentration ranges from 3% to 23.4% and has been mixed with hydroxyethylstarch and dextran to improve cerebral microcirculatory flow. Schwartz and colleagues79 evaluated 30 instances of elevated ICP in nine patients having suffered either a space-occupying hemispheric stroke (n = 8) or a hypertensive putaminal hemorrhage with massive perifocal edema (n = 1). Patients were kept euvolemic by CVP readings. When ICP increased to 25 mm Hg or greater for longer than 5 minutes, or if new pupillary findings appeared, the patients were randomized to either 200 mL of 20% mannitol solution (osmolarity = 1100 mOsm/kg H2O) or 100 mL of 6% hetastarch in 7.5% saline solution (2570 mOsm/kg H2O). The drugs were infused for 15 minutes; therapy was assessed beginning at 10 minutes after the infusion had terminated, and was considered successful if ICP fell greater than 10% below the pretreatment value or pupillary abnormalities returned to normal. Mannitol was used in 14 episodes, hetastarchhypertonic saline (HES-HS) in the other 16. Therapy was effective in 10 of the 14 mannitol-treated episodes and in all of the HES-HS–treated episodes. Both therapies increased CPP transiently. Three of the patients died of uncontrolled intracranial hypertension and the other six were severely disabled. Again, control of ICP does not always translate to improved outcome. Härtl and colleagues80 studied rabbits with chronic cranial windows who had suffered a fluid-percussion injury to the brain. The animals were observed for 6 hours after injury. Intravital fluorescent microscopy was used to visualize white cell trafficking, to measure pial vessel diameter, and to evaluate venous shear rates. Resuscitation with hypertonic saline plus dextran (HS-DEX, 7.2% saline solution plus 10% dextran 60), dosed at 4 mL/kg body weight in study animals, but not controls, showed significantly less “sticking” of white blood cells to vessel walls, and less vasodilation. Because migrating neutrophils actively increase their volume by 30% to 60%, the apparent anti-inflammatory effect of HS-DEX may be related to an inhibition of migration caused by hyperosmolar shrinking of the neutrophil. Our experience is limited to the use of between 1.8% and 3% hypertonic saline solution. We prepare the solution as a balanced mixture of 1.8% sodium chloride (154 mEq/L sodium as the chloride) and sodium acetate (154 mEq/L of sodium as acetate, total of 308 mEq/L sodium), to reduce the incidence of hyperchloremic metabolic acidosis and maintain acid-base balance within normal limits. While the previously cited literature uses HS for ICP control, our practice is to combine HS with intermittent mannitol, as described previously. The 1.8% HS is administered as an infusion at roughly 1/2 the rate calculated for maintenance fluids. The serum sodium is not allowed to climb above approximately 155 to 160 mEq/L, nor the measured serum osmolarity above 320 mOsm/kg H2O. Invasive monitoring of central venous pressure or pulmonary artery pressure is

recommended. Finally, we point out, again, that there are no conclusive outcome data that would make HS the first-line agent for elevated ICP. Two recent reviews81,82 point this out and make clear the need for prospective, randomized studies to evaluate the questions raised by the animal and small human studies, some of which we have reviewed herein. Steroids French and Galicich,83 in a nonrandomized, nonblinded study, reported on 147 patients treated with dexamethasone who suffered cerebral edema secondary to various etiologies, including cerebral neoplasm, postoperative edema, CHI, subarachnoid hemorrhage, cerebral irradiation, intracerebral hematoma, and pseudotumor cerebri. Patients with cerebral neoplasm and postoperative patients accounted for the preponderance of cases (114/144, 79%). Dexamethasone was administered, in most patients, as a 10-mg intravenous dose, followed by 4 mg intramuscularly every 6 hours for 2 to 4 days. Thereafter, the dose was gradually decreased over 5 to 7 days; it is not stated how the other patients were dosed. Patients were followed on average for 12 days. Therapeutic response was evaluated by serial neurologic examinations. Neurologic improvement was seen in 80/89 (90%) tumor, 19/23 (83%) postoperative, 5/11 (45%) closed head injury, 7/8 (88%) SAH, 4/4 (100%) postcerebral irradiation, 0/1 pseudotumor cerebri patients. Side effects such as “moon facies,” electrolyte abnormalities, salt and water retention, delayed wound healing, infection, acute gastrointestinal bleed, and psychological disturbances were uncommon. The authors did comment on the presence of rebound cerebral edema in patients in whom steroids were rapidly discontinued. This early paper suggesting beneficial effects of steroids in patients with cerebral edema, while interesting and provocative, is flawed in the manner patients were selected, the lack of blinding, and the unclear dosage regimen. Renaudin and colleagues84 evaluated 20 patients with either primary or metastatic brain tumors. These patients were clinically deteriorating on standard doses (16 to 24 mg per day) of dexamethasone, and were thus treated with doses ranging from 32 to 96 mg per day. The investigators noted clinical improvement in 11/20 (55%) patients. No gastrointestinal bleeding or significant electrolyte abnormalities were noted; all patients did develop “moon facies”. Once clinical response had been established at a higher dose of dexamethasone, that dose could not be lowered without clinical compromise. Faupel and colleagues reported, in 1976, on 100 cases of closed head injury in adults.85 Patients were randomized to either placebo, low-dose (12 mg IV bolus followed by 16 mg intramuscularly per day for 8 days), or high-dose (200 mg IV in two doses 6 hours apart, followed by 16 mg IM per day for 8 days) dexamethasone. Five of the cases were excluded due to brain death (n = 3), pulmonary problems (n = 1), or medication error (n = 1). Mortality in the 95 patients who

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completed the study was significantly lower in the pooled steroid group compared to the placebo group (27% vs. 57%, P < .001). There appeared to be a dose-dependent effect because the low-dose dexamethasone group had a higher mortality than did the high dose group (30% vs. 18%, P < .05). While survival was better in the pooled dexamethasone group, quality of survival, as determined on discharge, was not better. In fact, it appeared that there was a larger group of “unconscious but stabilized” patients in the steroid group (Table 25-6). Although interesting, the study is flawed by its patient selection techniques, in which it appears that no patient with a GCS score of less than 7 was enrolled. The outcome data raise significant questions about the use of steroids in this group of selected patients. The preponderance of data suggest that in the headinjured patient, routine steroids have no role. This class of drug does not decrease ICP or positively alter outcome.86–88 One major reason why the steroids may be of such little use is that traumatic brain injury patients who die often have diffuse brain injury with gross anatomic disruption and/or parenchymal hemorrhage.87 Use of dexamethasone in TBI has fallen out of favor with most clinicians. The 21-aminosteroid nonglucocorticoid analog of methylprednisolone, tirilazad mesylate, is thought to inhibit post-traumatic CNS tissue lipid peroxidation. Hall and colleagues89 traumatized 1385 male CF-1 mice, weighing 17 to 22 g each, using a CHI-inducing system that dropped a 50-g weight 18 cm. This resulted in a concussive injury, resulting in immediate unconsciousness in all mice and death in 30% of the mice. Within 5 minutes of injury, survivors were injected with either tirilazad or vehicle, in a dose ranging from 0.001 to 30 mg/kg. Neurologic status was evaluated using a “grip test” 1 hour after the tail injection of the drug or vehicle. The grip test is a measure of whether, and for how long, a mouse will hold onto a string with which its front paws come into contact; 30 seconds was the maximum grip time allowed in those animals that achieved a grip using one to four paws, tail, or paws plus tail. The grip test results were superior over a wide range of tirilazad doses (0.003 to Table 25-6  Quality of Survival in Patients after Severe Closed Head Injury Treated with Placebo versus Dexamethasone

From Faupel G, Reulen HJ, Müller D, Schürmann K: Double-blind study on the effects of steroids on severe closed head injury. In Pappius HM, Feindel W (eds): Dynamics of Brain Edema. New York, Springer-Verlag, New York, 1976, pp 337–343, with permission.

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30 mg/kg) compared to vehicle (placebo). One-week survival rate in these animals was significantly increased in the tirilazad compared to vehicle group (78.6% vs. 27.3%, P < .02). A multinational, multicenter trial of tirilazad in 1120 patients with severe (GCS score 4 to 8, 85%) or moderate (GCS score 9 to 12, 15%) CHI found that there were no outcome differences between study and control patients.90 Striking problems were noted in the randomization procedure, however, such as significantly more hypotension and hypoxia in the study group, which may have altered the results. Future studies will have to ensure these factors are considered when randomization and analysis are performed. Steroids are not without their place, however. As stated previously, severe vasogenic edema from a rapidly expanding tumor mass may respond dramatically to doses of dexamethasone up to 10 mg IV every 4 hours. Dexamethasone is preferred to other steroids because of its minimal mineralocorticoid effects. Additionally, the use of methylprednisolone in acute spinal cord injury is thought to have beneficial effect, when given early, on motor function, and sensation to touch and pinprick.91 Barbiturates The penultimate option in the medical armamentarium involves the much-debated barbiturate coma. Barbiturates appear to exert their ICP lowering and cerebral-protective effects via several mechanisms: alterations in vascular tone, decreasing metabolism, and inhibition of free radical peroxidation of cerebral lipids.92 The metabolic reductions noted in barbiturate-treated patients with elevated ICP include an observable decrement in brain extracellular-space lactate, aspartate, and glutamate. While pentobarbital is the agent most studied, other agents—for example, thiopental—have been used. One of the first multicenter randomized trials of barbiturate coma in severe head injury was published in 1988. In this study, Eisenberg and colleagues93 evaluated the use of high-dose barbiturates in 73 patients with severe head injury (GCS 4 to 7) and elevated ICP. Pentobarbital was added to the standard regimen only when conventional therapy was inadequate in controlling the ICP; conventional therapy included the modalities noted in Table 25-7. Patients receiving pentobarbital at a dose of 10 mg/kg IV over 30 minutes, 5 mg per kg IV every hour for 3 hours, and then a maintenance dose of 1 mg per kg per hour to keep the serum pentobarbital level in the range of 3 to 4 mg per 100 mL, had significantly improved control of their ICP when compared to those randomized to continued conventional therapy. Follow-up at a median of 6 months after injury showed that 36% of barbiturate responders, but 90% of nonresponders, were vegetative or had died. This study suggests that barbiturates are an effective means of controlling ICP in patients refractory to other therapy. Studies that did not control conventional therapy carefully94 (mannitol or barbiturates in

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Table 25-7  Conventional Treatment Regimen in Severe Closed Head Injury 1. 2. 3. 4. 5. 6.

Elevation of head of bed to 30 degrees Hyperventilation to a PaCO2 of <30 mm Hg Morphine sulfate, 1 mg per hour Neuromuscular blocking agent (Pancuronium) Mannitol bolus, ≥0.25 g per kg body weight Ventricular drainage when possible

From Eisenberg HM, Frankowski RF, Contant CF, Marshall LF, Walker MD, and the Comprehensive Central Nervous System Trauma Centers: Highdose barbiturate control of elevated intracranial pressure in patients with severe head injury. J Neurosurg 1988;69:15–23, with permission.

patients with ICP of 25 mm Hg or greater for longer than 15 minutes), or that used prophylactic barbiturates regardless of ICP,95 showed no benefit of the barbiturates. Patients being placed in barbiturate coma require adequate volume resuscitation, and frequently a pulmonary artery catheter before initiation of therapy to monitor volume status, and the vasodilatory and myocardial depressant actions of the drug. Even if volume replacement is adequate, inotropic support with dopamine, epinephrine, or norepinephrine may be required to maintain hemodynamic stability. The use of barbiturates has been associated with an increased incidence of pneumonia, hepatic dysfunction, and sepsis syndrome.96 It is unlikely that each of these is related to the barbiturate. Rather the severity of illness may play a significant role in the nonhemodynamic complications. The loading dose of pentobarbital is 5 to 10 mg/kg, followed by 1 to 2 mg/kg/hour as a maintenance infusion. In addition to continued use of an ICP monitor, the drug is titrated to 90% burst suppression on a portable EEG monitor (two to six bursts per minute). A bolus dose of 2 to 3 mg per kg, in our experience, may still achieve EEG burst suppression in a timely fashion without causing severe vasodilatation and hypotension. Ninety-percent burst suppression is the most effective means for monitoring barbiturate therapy, while ICP monitoring informs us as to the effectiveness of the treatment. We have also used sodium thiopental for this purpose, although it is generally less satisfactory due to the high doses required. Usually within three to five days after the event that resulted in elevated ICP, the barbiturate infusion can be tapered, and the patient reassessed for further aggressive ICP control. Hypothermia Therapy Induced hypothermia is THE final weapon in our armory. In a 1959 review,97 Vandam and Burnap pointed out the two central issues that are still important to us: (1) cooling is a means to decrease cerebral metabolism; (2) there are downsides to the technique, including coagulation abnormalities, that make it imperative the technique not be mishandled. How do we define hypothermia and what, precisely, is the relationship between brain temperature and core body temperature? Normothermia has been defined as core body

temperature between approximately 36.5 to 38.5°C.98,99 As Sessler has commented, the body “jealously” guards core body temperature.100 So tightly is core temperature guarded, that the interthreshold range—the core temperatures between the sweating and vasoconstriction thresholds—is just 0.2°C in nonanesthetized humans. Anesthesia and surgery alter this delicate balance, so that intraoperative core body temperature may be 1 to 3°C below normal in a patient undergoing a surgical intervention in our operating rooms. While there appears to be some agreement on the definitions of hypothermia—mild hypothermia is defined as core body temperature between approximately 34 and 36°C,101 moderate hypothermia is core body temperature from 32 to 33°C,102 and core body temperatures less than 32°C is considered severe (or deep) hypothermia—this does not completely inform us. The core body temperature that we commonly measure—via a probe in the urinary bladder, the esophagus, or the rectum—may be significantly lower than that measured in the cerebral ventricles. Swedish investigators studied 15 patients with CHI, SAH, intracerebral hemorrhage, cerebral tumor, and hydrocephalus secondary to a shunt infection.103 Commercially available thermocouples were used to simultaneously measure rectal and ventricular temperatures in this patient population; there was no change in treatment based on the findings, this was an observational study. The investigators found that the ventricular temperature was higher than that measured rectally: in almost 400 observations, the mean difference was 0.33°C ± 0.18°C, with a range of 0.1 to 2.3°C. These findings were corroborated by Rumana and colleagues104 studying 30 patients with severe head injury who found, in addition, that the jugular venous and rectal temperatures tracked closely, but the intraparenchymal brain temperature was 1.1°C ± 0.6°C higher. Henker and associates105 noted a similar under-representation of bladder and rectal temperatures as compared to brain temperature in patients having suffered TBI. Our experience with continuous brain tissue temperature and core temperature measurements has shown a similar, but inconsistent, pattern. The significance of higher brain temperature is notable. In experimental brain injury, higher brain temperatures are associated with increased neuronal injury.105,106 Several relatively small human studies have suggested that the use of mild-to-moderate hypothermia in TBI patients may improve control of ICP and neurologic outcome.99,102,107 Preliminary reports in patients with TBI suggest that hypothermia to 32°C to 33°C was associated with rapid and effective control of the ICP, decreased CMRO2, and decreased CBF with no increase in complications.102 In another study, core temperature decrease to 34°C was tested as a therapeutic measure in a small group of patients with severe TBI monitored with ventriculostomy, SjvO2 and pulmonary artery catheters.108 Hypothermia was achieved via surface cooling (water blanket) and iced water nasogastric irrigation, and was maintained for from 1 to 5 days. Mild hypothermia was associated with decreased ICP, decreased CMRO2, and better coupling between CBF and CMRO2.

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Despite a 44% infection rate, this small group (n = 9) of patients had good-to-moderate recovery (7/9, 78%), suggesting a promising role of hypothermia in patients with severe head injury. More recently, Clifton and colleagues109 studied 392 patients with severe (GCS score 3 to 8 after resuscitation) CHI randomized into standard therapy (n = 193) and standard therapy plus hypothermia to 33°C (n = 199). This was a controlled, randomized, blinded study. The primary outcome measure was the 6-month GOS. Patients were randomized within approximately 4 hours of injury (standard group 4.1 ± 1.2 hours, hypothermia group 4.3 ± 1.1 hours) and cooling in the hypothermia group was achieved within 8.4 ± 3 hours; the mean temperature in the first 48 hours in the treatment group was 33.2°C ± 1°C. Nine patients in the hypothermia group did not achieve the desired temperature. The mean temperature in the normothermia group was 37.2°C ± 0.8°C, but 35% of the normothermia patients had a temperature of 35°C or less at some time during the first 16 hours after injury. Three hundred and sixty-eight patients were analyzable. All patients were treated as noted in Table 25-8. In the first 96 hours, the hypothermia group had fewer patients with ICP greater than 30 mm Hg than did the control group (P = .02). More complications were noted in the hypothermia than control group, although these were not surprising: critical hypotension (10% vs. 3%, P = .01), bradycardia with hypotension (16% vs. 4%, P = .04), and percentage of hospital days that any complication was noted (78% vs. 70%, P = .005). There were no reported outcome differences. Poor outcomes (severe disability, vegetative state, or death) were Table 25-8  Treatment Regimen in Severe Closed Head Injury Parameter ICP Monitor Continuous bladder temperature Arterial line Indwelling bladder catheter Central line (optional) Morphine sulfate, 5 to 10 mg IV per hour X ≥ 72 hours Vecuronium* Pressors/fluids to maintain CPP ≥70 mm Hg Mannitol, hyperventilation, CSF removal for ICP > 20 mm Hg Barbiturate coma for intractable ICP Phenytoin ¥ 7 days Minimize IV fluids with glucose Cooling to 33°C

Control

Hypothermia

+ + + + + +

+ + + + + +

+ +

+ +

+

+

+ + + -

+ + + +

*Vecuronium was administered to all control patients requiring mechanical ventilation and to all hypothermia patients for 72 hours to prevent shivering. CPP, cerebral perfusion pressure; CSF, cerebrospinal fluid; ICP, intracranial pressure; +, done; -, not done. From Clifton GL, Miller ER, Choi SC, et al: Lack of effect of induction of hypothermia after acute brain injury. N Engl J Med 2001;344:556–563, with permission.

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seen in 57% of both groups. Death was the same in both groups. However, in subgroup analysis, patients younger than 45 years of age who were admitted with a temperature 35°C or less and were randomized to the hypothermia group had fewer poor outcomes than did like patients randomized to normothermia (52% vs. 76%, P = .02). Irrespective of this subgroup with improved outcome, the authors comment that moderate hypothermia does not lead to improved outcome after severe CHI, despite, interestingly enough, lower ICP in the study group. The study was somewhat flawed, however, in that 35% of the control group had temperatures of 35°C or less, and nine (approximately 5%) of the study patients never achieved hypothermia. Both because of concern about an increased incidence of postoperative infection in hypothermic patients98 and the less than gratifying results in Clifton’s study,109 the technique of hypothermia has not yet been widely accepted. Our standard practice is to maintain euthermia and to aggressively cool a core temperature that rises to higher than 37°C. Nonetheless, recent positive results with mild hypothermia after cardiac arrest suggest that further evaluation of hypothermia after severe CHI is warranted.101,111 Surgical Therapy On rare occasions and in desperate situations, surgical therapies such as decompressive craniectomy112 or temporal lobe resection may be required to save a patient’s life. Our experience with this is relatively limited. However, most often the need for this therapy follows severe closed head injury rather than postcraniotomy for tumor resection. Outcome may be improved when the craniectomy is performed before the ICP exceeds 40 mm Hg for a prolonged period and within 48 hours of injury.112 Interestingly, during the rehabilitation phase of a patient’s course, decompressive craniotomy can be associated with low cerebrospinal fluid pressure symptoms, when the bone flap is removed and the skull vault is left open. These symptoms consist of severe postural headaches with cognitive and functional neurological decline. It has been hypothesized that the complete loss of hydrostatic pressure may be responsible for the clinical picture. In fact, all of the symptoms completely subsided in one case, in which the bone flap was replaced after aggressive hydration.113

Summary Control of elevated ICP is sometimes quite difficult. Using the techniques we have described previously, there is a reasonable chance that optimal control will be achieved. However, while uncontrolled ICP control most assuredly is not associated with a good neurologic outcome, ICP control alone is not sufficient for the desired neurologic outcome either. Optimal treatment of elevated ICP is best performed—in our opinion—using a protocol. The University of Florida TBI protocol, from prehospital care to that in the operating room is noted in Figure 25-7. Our emphasis is

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Neurointensive Care: Specific Problems Phase I: Field to Emergency Department

• Dispatch GCS ≤8 alert TBI team for neurosurgery on-call resident, critical care medicine fellow, and emergency department attending • Intubation in field for GCS ≤ 8 (or significant chest, facial injury) • O2 100% non-rebreathing mask or bag-valve-mask ventilation

Observations Every 5–10 Minutes • GCS • Therapy

Managment • Two large-bore IV femoral venous line optional • Keep SBP ≥100 mm Hg (CPR drugs, pressors [epinephrine, norepinephrine, neosynephrine] as required) • 500 mL boluses of 0.9% saline X 4 to keep SBP ≥100 mm Hg • Blood glucose check every hour • 0.9% saline if >80 mg/dL • D5 w 0.9% saline if <65 mg/dL • Sedatives: Benzodiazepine (Lorazepam or Midazolam only for severe agitaion) • Long back board • Rigid cervical collar • Head strap

A

Phase II: Emergency Department ATLS Trauma Evaluation • Emergency department attending • Critical care medicine fellow (anesthesiology) • Senior general surgery resident (unless isolated TBI) • Neurosurgery resident

Airway • ET intubation for all GCS ≤8, or as needed for O2 sat <93% unresponsive to stimulation/O2, or cyanosis, or apnea Inability to maintain the airway • Recommended drugs Etomidate, lidocaine, succinylcholine, rocuronium, propofol • Ventilation to PaCO2 35 mm Hg by ABG or ET CO2 35–40 mm Hg • Oxygenation SpO2 >95% (PEEP limited at 10 cm H2O) Investigations • Type and cross X 2 units • Hct, electrolytes, LFTs, PT/PTT/INR, platelets, urine toxicology • Hct ≥25% • Blood sugar 80–120 mg/dL (regular insulin IV) • Chest X-ray, lateral C-spine • Thoracic and lumbar spine (in stable pts) • CT head and neck

Blood Pressure • Fluid resuscitation 0.9% saline 500 mL or 3% saline 100 mL boluses High flow fluid warmer (temp. 36–37 ∞C) • Titrate to SBP ≥100 mm Hg • Refractory hypotension Neosynephrine (titrate to SBP ≥100 mm Hg) • Arterial line

General Measures • Sedation (propofol or etomidate [single dose]) • Pharmacologic paralysis if necessary (rocuronium/atracurium, titrate to 11/2 train of 4) • Head elevated 30 degrees (unless C-spine injury) • Temperature 36 ∞ to 37 ∞C • GCS, pupillary response every 5 minutes

B Figure 25-7A–F, The Shands Hospital at the University of Florida Traumatic Brain Injury Program, which deals with the acute and subacute treatment of elevated ICP.

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Phase III: Intensive Care Unit Monitoring • Arterial line • Intracranial pressure (ventricular catheter) • CVP or PA catheter • Pulse oximetry • End tidal CO2 • Temperature (core vs. brain) • PbtO2 probe, (SjvO2 catheter, transcranial Doppler) • Microdialysis probe • Data acquisition system

Defining Baseline Therapeutic Targets • Hct 25% to 35% • CPP >70 mm Hg • RAP 5–10 mm Hg • SpO2 >95% • PaCO2 35 mm Hg (ET CO2 35–40 mm Hg) • Temp 36 ∞ to 37 ∞C • Osmolality <320 mOsmoles/L • PbtO2 20–25 mm Hg, (SjvO2 50–70%, MCA TCD mFV 45–70 cm/sec or PI <1) Clinical Rehabilitation medicine consults on ICU admission C

Phase IIIa ICP >20mm Hg for more than 5 minutes

Is the monitor working properly (good waveform)?

Check • Patient position (IJ vein kinked or compressed) • Sedation (adequate or not) • Intravascular volume/blood pressure/electrolytes • CO2 level • Core/brain temperature • Special circumstances (recent patient care/seizures)

Action • Regain control of cerebral perfusion Ø ICP by CSF drainage to ICP 10 mm Hg If no CSF access—sedation bolus

CPP maintained, ICP reduced

• Maintain therapeutic targets • No additional action D Figure 25-7A–F, continued.

Action fails or >2 drainage required within 10 mins Action Phase lllb

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Phase lllb Persistent ICP >20 mm Hg despite previous measures

Is a head CT required to exclude a surgical lesion?

Yes • Regain control of cerebral perfusion Ø ICP (CSF drain, 3% saline, mannitol, hyperventilation) • CT scan

Surgical lesion

No Is the underlying cause vascular or nonvascular?

No surgical lesion

Operating Room

Vascular—Hyperemia, Vasospasm • Confirm Dx by perfusion indices Nonvascular—Cerebral Edema (cellular, BBB breakdown, etc.) • If hyperemia (high PbtO2, SjvO2, TCD) Augment blood pressure (phenylephrine) until: Is sedation adequate? CPP >70 mm Hg Is CPP appropriate? Perfusion indices (PbtO2, SjvO2, TCD) normalize Titrate CO2 against perfusion indices • If vasospasm (low Pbto2, hi SjvO2, TCD) Achievable Ensure RAP >10 mm Hg Accept ICP level to 30 mm Hg* Augment BP to MAP >100 mm Hg Unachievable (or if ICP >30 mm Hg) ICP remains elevated and perfusion • Drain CSF inadequate • 3% saline • Drain CSF • Mannitol 0.5 gm/kg every 6 h (keep osmolarity <320 mOsm/L) • 3% saline • Mannitol 0.5 gm/kg every 6 h (keep osmolarity <320 mOsmL)

E

Phase IIIc: Intensive Care Unit Refactory Intracranial Hypertension ICP >30 and CPP <70 despite previous measures

Check Is the patient salvageable? Mechanism of injury Best GCS Pupil response Age CT scan

Action • EEG single channel • Hypothermia (35 to 36 degrees C) • Barbiturates (pentobarbital 2–5 mg/kg for 30 min, then 1 mg/kg/hr (titrate to 90% burst suppression) • Maintain baseline therapeutic targets F

Figure 25-7A–F, continued. * Caveats to this include temporal lobe contusions.

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early and aggressive monitoring, with careful control of glucose, hydration, and position. There is, as yet, no “magic bullet” that ensures a good outcome in patients with elevated ICP, only vigilance, careful attention to detail, and hard,

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persistent work. This is what we have emphasized in this chapter. We cannot overemphasize the need for continuing laboratory research to help us understand how to limit primary and secondary CNS damage.

P earls 1. While the Lund therapy seems to achieve excellent survival (49/53, 92%) and recovery (42/49, 85% had a GOS of 4 to 5) in head trauma patients with ventriculostomy, there are no prospective randomized studies comparing this strategy with that of achieving CPP greater than 70 torr. 2. In the patient who is older than 40 years of age, hypotensive to a systolic BP of less than 90 torr, with evidence of posturing, the risk of having elevated ICP is approximately 60%. 3. SjvO2 is normally between about 55% and 75%; a value less than 50% suggests that therapy aimed at increasing oxygen delivery (increased cardiac index, increased hematocrit, increased FIO2) or decreasing consumption be initiated. 4. NILS is relatively uncommonly used because sources of artifact—inconsistency of optical path length and light scattering in the tissue field—are not controllable. 5. One normally assumes that the brain—surrounded by CSF—behaves as if it were fluid. Hence, ICP measured in one portion of the intracranial space will accurately reflect ICP throughout the intracranial space. However, clinical experience informs us that this is not

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6.

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always the case. We have cared for patients with significantly elevated ICP whose mental status—in the presence of properly functioning ICP monitors— would never alert one to the elevated pressure. When increased ICP is associated with increased cerebral extraction of oxygen, hyperventilation can decrease CBF and dangerously reduce cerebral oxygenation. Propofol is the sedative agent of choice for neurosurgical or neurologic patients in our ICU. It is our practice to keep the perioperative or perievent glucose level between 80 and 120 mg/dL (4.5 and 6.7 mM/L) in the nondiabetic patient with elevated ICP. Induced hypothermia is THE final weapon in our armory. There is, as yet, no “magic bullet” that ensures a good outcome in patients with elevated ICP, only vigilance, careful attention to detail, and hard, persistent work. This is what we have emphasized in this chapter. We cannot overemphasize the need for continuing laboratory research to help us understand how to limit primary and secondary CNS damage.

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80. Härtl R, Medary MB, Ruge M, et al: Hypertonic / hyperoncotic saline attenuates microcirculatory disturbances after traumatic brain injury. J Trauma 1997;42:S41–S47. 81. Peterson B, Khanna S, Fisher B, Marshall L: Prolonged hypernatremia controls elevated intracranial pressure in head-injured pediatric patients. Crit Care Med 2000;28:1136–1143. 82. Qureshi AI, Suarez JI: Use of hypertonic saline solutions in treatment of cerebral edema and intracranial hypertension. Crit Care Med 2000;28:3301–3313. 83. French LA, Galicich JH: The use of steroids for control of cerebral edema. Clin Neurosurg 1964;10:212–223. 84. Renaudin J, Fewer D, Wilson CB, et al: Dose dependency of Decadron in patients with partially excised brain tumors. J Neurosurg 1973; 39:302–305. 85. Faupel G, Reulen HJ, Müller D, Schürmann K: Double-blind study on the effects of steroids on severe closed head injury. In Pappius HM, Feindel W (Eds): Dynamics of Brain Edema. New York, SpringerVerlag, 1976, pp 337–343. 86. Bullock MR (for the Task Force): Role of steroids. In: Management and prognosis of severe traumatic brain injury—Part 1: Guidelines for the management of severe traumatic brain injury. J Neurotrauma 2000;17:531–535. 87. Cooper PR, Moody S, Clark WK, et al: Dexamethasone and severe head injury—A prospective double-blind study. J Neurosurg 1979;51: 307–316. 88. Saul TG, Ducker TB, Salcman M, Carro E: Steroids in head injury— A prospective, randomized clinical trial. J Neurosurg 1981;54:596– 600. 89. Hall ED, Yonkers PA, McCall JM, Braughler JM: Effects of the 21– animosteroid U74006F on experimental head injury in mice. J Neurosurg 1988:68:456–461. 90. Marshall MF, Maas AIR, Marshall SB, et al: A multicenter trial on the efficacy of using tirilazad mesylate in cases of head injury. J Neurosurg 1998;89:519–525. 91. Bracken MB, Shepard MJ, Collins WF, et al: A randomized, controlled trial of methylprednisolone or naloxone in the treatment of acute spinal-cord injury. N Engl J Med 1990;322:1405–1411. 92. Bullock MR (for the Task Force): Use of barbiturates in the control of intracranial hypertension. In Management and prognosis of severe traumatic brain injury—Part 1: Guidelines for the management of severe traumatic brain injury. J Neurotrauma 2000;17:527–530. 93. Eisenberg HM, Frankowski RF, Contant CF, Marshall LF, Walker MD, and the Comprehensive Central Nervous System Trauma Centers: High-dose barbiturate control of elevated intracranial pressure in patients with severe head injury. J Neurosurg 1988;69:15–23. 94. Schwartz ML, Tator CH, Rowed DW, et al: The University of Toronto head injury treatment study—A prospective, randomized comparison of pentobarbital and mannitol. Can J Neurol Sci 1984;11:434–440. 95. Ward JD, Becker DP, Miller JD, et al: Failure of prophylactic barbiturate coma in the treatment of severe head injury. J Neurosurg 1985;62:383–388. 96. Schwab S, Spranger M, Schwarz S, Hacke W: Barbiturate coma in severe hemispheric stroke—Useful or obsolete? Neurology 1997; 48:1608–1613. 97. Vandam LD, Burnap TK: Hypothermia. N Engl J Med 1959;261:546– 553 and 595–603. 98. Kurz A, Sessler DI, Lenhardt R (for the Study of Wound infection and Temperature Group): Perioperative normothermia to reduce the incidence of surgical wound infection and shorten hospitalization. N Engl J Med 1996;334:1209–1215. 99. Marion DW, Penrod LE, Kelsey SF, et al: Treatment of traumatic brain injury with moderate hypothermia. N Engl J Med 1997;336:540– 546. 100. Sessler DI: Deliberate mild hypothermia. J Neurosurg Anesthesiol 1995;7:38–46.

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101. Sessler DI: Complications and treatment of mild hypothermia. Anesthesiology 2001;95:531–543. 102. Marion DW, Obrist WD, Carlier PM, Penrod LE, Darby JM: The use of moderate therapeutic hypothermia for patients with severe head injuries—A preliminary report. J Neurosurg 1993;79:354–362. 103. Mellergård P, Nordström C-H: intracerebral temperature in neurosurgical patients. Neurosurgery 1991;28:709–713. 104. Rumana CS, Gopinath SP, Uzura M, Valadka AB, Robertson CS: Brain temperature exceeds systemic temperature in head-injured patients. Crit Care Med 1998;26:562–567. 105. Henker RA, Brown SD, Marion DW: Comparison of brain temperature with bladder and rectal temperatures in adults with severe head injury. Neurosurgery 1998;42:1071–1075. 106. Albrecht RF, Wass CT, Lanier WL: Occurrence of potentially detrimental temperature alterations in hospitalized patients at risk for brain injury. Mayo Clin Proc 1998;73:629–635. 107. Shiozaki T, Sugimoto H, Taneda M, et al: Selection of severely head injured patients for mild hypothermia therapy. J Neurosurg 1998; 89:206–211.

108. Tateishi A, Soejima Y, Taira Y, et al: Feasibility of the titration method of mild hypothermia in severely head-injured patients with intracranial hypertension. Neurosurgery 1998;42:1065–1070. 109. Clifton GL, Miller ER, Choi SC, et al: Lack of effect of induction of hypothermia after acute brain injury. N Engl J Med 2001;344:556–563. 110. The Hypothermia after Cardiac Arrest Study Group: Mild therapeutic hypothermia to improve the neurologic outcome after cardiac arrest. N Engl J Med 2002;346:549–556. 111. Bernard SA, Gray TW, Buist MD, et al: Treatment of comatose survivors of out-of-hospital cardiac arrest with induced hypothermia. N Engl J Med 2002;346:557–563. 112. Polin RS, Shaffrey ME, Bogaev CA, et al: Decompressive bifrontal craniectomy in the treatment of severe refractory posttraumatic cerebral edema. Neurosurgery 1997;41:84–94. 113. Ellis K, Speed J, Balbierz JM: Postcraniectomy intracranial hypotension—Potential impact on rehabilitation. Brain Injury 1998;12:895– 899.

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Chapter 26 Seizures Robin L. Gilmore, MD

Identifying and Treating Seizures Because seizures are a symptom of central nervous system (CNS) dysfunction, seizures are frequently encountered in the critically ill patient in the neurointensive care unit (neuro-ICU). Yet seizures may be so subtle as to be unrecognized or so dramatic as to shake the patient’s bed and instrumentation. A first problem then, is the identification of seizures. When a patient has an unexpected or unexplained change in level of consciousness, one should always consider the possibilities of sporadic, brief seizures or nonconvulsive status epilepticus. While other possibilities, such as an expanding mass, or complicating, secondary conditions, such as vasospasm, must also be considered, the possibility of a seizure should always be considered even when other conditions are “ruled in.” This is because a seizure may be considered a symptom of CNS dysfunction, and not just a complication in and of itself.

is the detection, treatment, and prevention of secondary brain injury. One of the cornerstones of the management of secondary brain injury is the adequate delivery of substrate (oxygen and glucose) to the injured brain, thereby avoiding further insult to vulnerable, but salvageable, tissue.

How to Suspect Seizures When a patient has an unexpected or unexplained change in level of consciousness or ability to interact with nursing and medical personnel, one should always consider the possibilities of sporadic, brief seizures with a prolonged postictal or interictal state, or nonconvulsive status epilepticus. An electroencephalogram (EEG) is an extremely useful diagnostic tool, and should be immediately available for clinicians caring for the critically ill patient with neurologic impairment. After experienced clinical personnel, the EEG is the best diagnostic tool for the diagnosis of seizures in the critically ill patient.

Mechanisms of Brain Injury Mechanisms of brain injury are divided into primary and secondary components. Secondary brain injury results when brain tissue, made vulnerable by an initial and primary injury, is exposed to secondary brain insults that then lead to ischemia. Examples of mechanisms of secondary insults include systemic hypotension, hypoxia, fever, and seizures. Seizures increase cerebral metabolic demand. An important focus of treatment of the patient with traumatic brain injury

The Electroencephalogram: When to Get It and What to Do with It While intensive care units are hostile recording environments, the experienced EEG technologist will almost always be able to record a clinically useful study. The technologist is able to record the relevant activity occurring at the patient’s bedside and note those activities that produce arti733

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fact that might interfere with accurate interpretation of the study. The technologist is the “eyes, ears, and hands” of the interpreting physician, and makes those observations relevant to record interpretation that cannot be done by the physician because he or she is not continuously at the bedside. When the EEG technologist cannot obtain an interpretable record due to patient movement, spasms, agitation, or other artifact-inducing activity at the patient’s bedside, the technologist will undertake those measures necessary to reduce artifact. This may even include asking the patient’s nurse or physician to consider obtaining an order to paralyze (with neuromuscular blockers) the patient (if already on a ventilator). Movement or electromyographic artifact can produce discharges, which resemble epileptiform activity. These discharges, in turn, can lead to false-positive interpretation of an EEG. The well-trained technologist will call the interpreting physician when there is a question of ongoing electrographic seizure activity. Once an interpretable record is obtained, the technologist alerts the physician for the necessity of interpreting the emergent or urgent EEG so that necessary treatments can be undertaken. Electroencephalogram Patterns The EEG may show several patterns. A normal EEG is rarely seen in the neuro-ICU. The EEG with focal or lateralized slowing (theta 4 to 8 Hz, and delta < 4 Hz) implies a destructive process ipsilateral to the slowing. The lower the frequency of slowing, the more severely abnormal is the EEG. The destructive process may be structural or functional. A cerebral contusion, hemorrhage, and tumor are examples of structural destructive processes. Functional destructive processes include the postictal state, or regional ischemia as in vasospasm. Epileptiform transients or paroxysmal activity include spikes, sharp waves, and repetitive, rhythmic, or periodic activity. Spikes are discharges lasting less than 80 msec; sharp waves last less than 200 msec. Epileptiform periodic activity usually has a frequency of 1 to 2 Hz or faster, and may last less than 5 seconds. Epileptiform activity may be focal, lateralized or generalized. When it occurs between seizures, it is called interictal activity and suggests a predilection for seizures. When repetitive epileptiform activity is present continuously for longer than 5 seconds at a frequency of greater than 1.5 to 2 Hz, a seizure is occurring and the EEG is referred to as ictal. The ictal EEG may be associated with clinical manifestations or may not. When no simultaneous clinical activity is recognized during the ictal EEG, the seizure is referred to as a subclinical seizure, or an electrographic seizure. The significance of subclinical seizures is varied. It depends on the underlying condition giving rise to seizures, and may also depend on the period of time the patient has been having subclinical seizures.

Subclinical seizures may contribute to the patient’s altered mental status.1 Appropriate treatment may lead to quick and significant improvement in the patient’s neurologic status. However, for other patients with severe CNS disease, this may not be the case. Usually such determinations can be made clinically, but this is not always so. On some occasions it may be necessary to treat recurrent or continuous electrographic seizures empirically. When the electrographic seizures become continuous (at some arbitrary time limit— usually several minutes), nonconvulsive status epilepticus is said to exist (Fig. 26-1). A similar issue comes up frequently in the evaluation of patients with nonconvulsive status epilepticus (NCSE).2–5 The clinical significance and management of NCSE is a controversial issue. There are some authorities who regard this condition as almost equivalent to convulsive status epilepticus, and advocate its emergent treatment. Other clinicians are less aggressive. They consider NCSE an epiphenomenon of the irreversibly injured brain. Because they do not consider the seizures as contributing to the ongoing injury but only as a marker of irreversible injury, they do not believe it warrants aggressive treatment. The answer is likely in between, and likely highly individualized, depending on the underlying etiologies of the NCSE.

What to Consider The physician should consider the seizure a symptom of CNS dysfunction. The urgency to find the cause is determined by the patient’s vital signs, level of consciousness, focality on examination, and other physical examination findings. The health care provider should also remember that there are certain drug-related syndromes that produce seizures or paroxysmal events that resemble seizures. They may be provoked by the addition or withdrawal of certain drugs or substances. These types of syndromes are summarized in Table 26-1. The need for emergent neuro-imaging studies and lumbar puncture will obviously depend on the likelihood of the diagnosis of a new or expanding intracranial lesion, infection (CNS or systemic), and metabolic state. Several factors predispose patients to seizures. These include (1) changes in bloodbrain barrier permeability due to infection, hypoxia, loss of or dysfunctional autoregulation of cerebral blood flow, or microdeposition of hemorrhage or edema secondary to vascular endothelial damage; (2) alteration of neuronal excitability by exogenous or endogenous substances including excitatory and inhibitory neurotransmitters; (3) inability of glial cells to regulate the neuronal extracellular environment; (4) electrolyte imbalances; or (5) hypoxiaischemia. Some patients without a history of epilepsy may be genetically prone to have seizures secondary to systemic factors.

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Figure 26-1. EEG of a patient in nonconvulsive status epilepticus (NCSE). She had had a right parietal infarct. Note the sharply contoured sharp waves in the right parietal derivations. She eventually recovered without significant neurologic residua.

Post-traumatic Seizures Post-traumatic seizures (PTS) can be a serious complication of head injury. These seizures can cause secondary brain damage through increased metabolic requirements, raised intracranial pressure, cerebral hypoxia, and/or excessive release of neurotransmitters. The occurrence of an

immediate seizure and post-traumatic status epilepticus may thus complicate the patient’s treatment.6 Additionally, the patient and his or her family will have questions regarding the likelihood of continued risk for seizures. Damage to the hippocampus, especially the CA1 regions, occurs in a high proportion of fatal head injuries,7,8 and may be important to the development of epilepsy in survivors.9

Table 26-1  Syndromes Producing Seizures or Seizure-like Events Syndromes

Clinical Findings CNS Effects

Peripheral Effects

Central anticholinergic Cholinergic

Hallucinations, confusion, sedation, seizures, mydriasis, hyperthermia Confusion, lethargy, seizures

Sympathomimetics

Agitation, seizures

Serotonin

Confusion, agitation, myoclonus, hypomania, dysarthria, orobuccal dyskinesias, tremor, rigidity with cog-wheeling, hyperreflexia, incoordination Marked rigidity, consciousness disturbance

Decreased gut motility, dry skin and oral mucosa, tachycardia, urinary retention Salivation, lacrimation, urination, diarrhea, increased gut motility, emesis, bradycardia, bronchorrhea, bronchospasm Diaphoresis, hypertension, hyperthermia, tachycardia, cardiac dysrhythmias Dysautonomia, hyperthermia, diaphoresis, diarrhea, mydriasis, tachycardia

Malignant hyperthermia CNS, central nervous system.

Hyperthermia, dysautonomia, rhabdomyolysis

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Fluctuating changes in the patient’s level of consciousness, intermittent behavioral changes, and changes in staffing may lead to diagnostic problems, especially in the first 1 to 2 weeks after injury. Determining which changes are really related to the patient, which are related to posttraumatic syndrome, and which may be caused by seizure activity may be difficult but are very important for management. For this reason video-EEG monitoring may be necessary for definitive diagnosis in some cases.9 These patients, having suffered significant trauma to the brain, and perhaps other organ systems, are often unstable and particularly vulnerable to the consequences of seizures. Phenytoin and its prodrug fosphenytoin are the drugs of choice for preventing and treating early seizures because of demonstrated efficacy and the availability of a formulation for intravenous administration. Recommended concentration of the unbound or free phenytoin is less than 2.0 mg/mL.

Seizures and Vascular Lesions Seizures and Subarachnoid Hemorrhage Subarachnoid hemorrhage is a common condition in the neuro-ICU. It may be seen following trauma, or in association with aneurysmal or arteriovenous malformation (AVM) rupture. Convulsive seizures may occur in 10% to 25% of aneurysms that rupture or rebleed.10,11 In approximately one-third of patients with AVMs, the presenting and only manifestation is a seizure. Cavernous malformations or cavernous angiomas may also present with seizures; the incidence of this presentation is not known. Seizures that present at onset are an independent risk factor for later seizures and a predictor of poor outcome.11 Natriuresis is a common systemic manifestation of aneurysmal subarachnoid hemorrhage (SAH). Natriuresis and its accompanying hypovolemia may be a major contributing factor in the pathophysiology of symptomatic cerebral vasospasm. This may also contribute to seizures. See the following paragraphs for management of seizures related to hyponatremia. Vasculitis Seizures as a manifestation of vasculitis may occur as a feature of encephalopathy, or as a focal neurologic deficit. The incidence of seizures increases with duration and severity of the underlying vasculitis,12 ranging from 24% to 45%. The relationship of the seizure disorder to the underlying disease may not always be clear, however. A confounding feature of antiepileptic drug treatment is the occurrence of drug-induced systemic lupus erythematosus.13 Antiphospholipid antibody syndrome is also associated with seizures; most are associated with focal brain infarction.14 Systemic necrotizing vasculitis and granulomatous vasculitis rarely present with seizures. Among patients with

giant-cell arteritis with nonocular signs, seizures occur in 1.5%.15 Bechet’s disease has neurologic involvement in 10% to 25% of patients. The onset is more often acute and is occasionally associated with seizures.16

Malignancy Mechanisms for seizures in patients with cancer include direct invasion of cortex or leptomeninges, metabolic derangements, opportunistic infection, and chemotherapeutic agents.17 Seizures may be an early symptom of CNS malignancy or may appear after surgical procedures for diagnosis or treatment. Following biopsy for diagnosis or resection single seizures may occur, or a first seizure of an epileptic disorder may occur. The occurrence of focal or generalized seizures is a major manifestation, occurring in 20% to 50% of all patients with cerebral tumors. Seizures are quite common among patients with low grade astrocytomas. In approximately 50% of patients a focal or generalized seizure is the first symptom. Over the course of the illness 60% to 75% of patients will experience seizures. More than one-half of patients with oligodendrogliomas present with partial or generalized seizures; seizures may persist for years before other symptoms or signs develop. Other tumor types are associated with seizures as well. Glioblastomas, ependymomas, and meningiomas are all well represented among patients with tumors and seizures. Metastatic carcinoma frequently presents with seizures. Remote effects of malignancy or paraneoplastic syndromes are much less common than direct effects of malignancy. Seizures associated with these syndromes are therefore less commonly seen, but do occur. Limbic encephalitis is a paraneoplastic syndrome seen in patients with small cell carcinoma or, less commonly, Hodgkin’s disease. Patients usually present with amnestic dementia, affective disturbance, and sometimes a personality change. During the course of the illness, both complex, partial, and generalized seizures may occur. Paraneoplastic limbic encephalitis associated with anti-Hu antibodies may present with seizures and precede the diagnosis of cancer.18 Opsoclonus myoclonus occurs most frequently in young children (mean age, 18 months). Approximately half of the cases have been reported in neuroblastoma, but only about 3% of all the cases of neuroblastoma have this complication. Opsoclonus myoclonus occurs in adults as well. The syndrome has been reported with carcinoma, but also occurs on an idiopathic basis. Since the idiopathic and paraneoplastic syndromes are indistinguishable clinically, the appearance of opsoclonus myoclonus should always lead to a search for neuroblastoma or other occult neoplasm. In the adult, these neoplasms tend to be small cell lung cancer or breast cancer. Symptoms are responsive to steroids or corticotropin.19 Intravenous immunoglobulin has also been used.20

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Other Causes of Seizures Hyperbaric oxygenation precipitates seizures, possibly as a toxic effect of oxygen itself. Some antineoplastic drugs, such as chlorambucil and methotrexate, also precipitate seizures. Other drugs reported to precipitate seizures are seen in Table 26-2. Obstructive sleep apnea is also common in medically refractory epilepsy patients.21 It may also be seen in patients with malformations and trauma of anterior cranial structures.22 Gastrointestinal disease is occasionally associated with seizures. Approximately 7% to 10% of patients with nontropical sprue have seizure disorders.23 Deficiencies of calcium, magnesium, and vitamins; genetic factors24; and isolated CNS vasculitis25 are potential mechanisms. Inflammatory bowel disease (ulcerative colitis and Crohn’s disease) is associated with a low incidence of focal or generalized seizures. Whipple’s disease is a multi-system granulomatous disease caused by Tropheryma whippellii.26 Approximately 10% of patients with Whipple’s disease have neurologic involvement; as many as 25% of these patients have seizures.27 Sawka and colleagues28 described four patients with tension pneumocranium who presented with seizures or impaired mental status after transsphenoidal pituitary surgery. Heavy metal intoxication, especially with lead and mercury, is a well-known seizure precipitant. Ingestion of lead from paint and inhalation of lead oxide are especially hazardous for young children.

Transplantation and Seizures Transplantation of organs has led to newly recognized CNS disorders and new manifestations of old disorders. Seizures in patients anticipating or having undergone transplantation may be difficult to manage for several reasons: (1) these patients are frequently metabolically stressed; (2) pre-

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existing diseases and preceding therapies may have affected the CNS (e.g., bone marrow transplant patients may have received L-asparaginase, which is associated with acute intracerebral hemorrhage and infarction, and ischemic seizures); and (3) immunosuppressive drugs, especially cyclosporine and tacrolimus (FK506), may provoke seizures. Certain populations of transplant patients appear to have higher risks for seizures. Liver In one large series, Widjicks and associates29 concluded that the majority of new onset seizures in liver transplant patients was secondary to immunosuppressant neurotoxicity (cyclosporin and FK506). They also concluded that new onset seizures were not indicative of poor outcome. Lung Vaughn and co-workers30 found that of 85 lung transplant cases, 22 patients had seizures (including 15 of 18 patients with cystic fibrosis). Further, patients younger than 25 years old, particularly those on intravenous methylprednisolone for rejection, may be at increased risk for seizures. Bone Marrow In patients undergoing bone marrow transplantation, it has been noted that the risk of seizures from cyclosporin neurotoxicity increases in patients with HLA-mismatched and unrelated donor transplant.31 Foscarnet, used to treat cytomegalovirus hepatitis following bone marrow transplantation,32 may also precipitate seizures.33 Treatment For acute management of prolonged seizures, benzodiazepines are least likely to induce the enzyme system

Table 26-2  Medications That May Cause Seizures Analgesics Antibiotics Antidepressants Antineoplastic drugs Antipsychotics Bronchodi ators General anesthetics Local anesthetics Sympathomimetics Others

Fentanyl, meperidine, mefenamic acid, pentazocine, propoxyphene, tramadol Ampicillin, carbenicillin, cephalosporins, imipenem, isoniazid, lindane, metronidazole, nalidixic acid, oxacillin, penicillin, pyrimethamine, ticarcillin Amitriptyline, bupropion, citalopram, doxepin, fluoxetine, maprotiline, mianserine, nomifesine, nortriptyline, paroxetine, sertraline BCNU, busulfan, chlorambucil, cytosine arabinoside, methotrexate, vincristine Chlorpromazine, haloperidol, olanzapine, perphenazine, prochlorperazine, thioridazine, trifluoperazine, ziprasidone Aminophylline, theophylline Enflurane, ketamine Bupivacaine, lidocaine, procaine Ephedrine, phenylpropanolamine, terbutaline Alcohol, amphetamines, anticholinergics, antihistamine, atenolol, baclofen, cyclosporin A, domperidone, ergonovine, FK506, flumazenil, folic acid, foscarnet, hyperbaric oxygen, insulin, aqueous iodinated contrast, lithium, methylphenidate, methylxanthines, oxytocin, phencyclidine

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responsible for metabolizing immunosuppressant drugs.34 Long-term management is determined after the etiology has been ascertained. Because allograft survival is decreased in patients treated with phenytoin or phenobarbital and steroids, the use of these older antiepileptic drugs has been discouraged.35 The half-lives of prednisolone,36 and probably cyclosporine,34 are decreased when phenobarbital, phenytoin, and carbamazepine are used for treatment of seizures. In patients other than those having undergone hepatic transplantation and bone marrow transplantation during engraftment, valproic acid is a reasonable antiepileptic choice. Newer antiepileptic drugs, with fewer drug interactions, such as leviteracetam and gabapentin, should also be considered. Leviteracetam and gabapentin may be useful for hepatic transplantation and bone marrow transplantation patients. These drugs are eliminated from systemic circulation by renal excretion as unchanged drug. Very little gabapentin (<3%) and leviteracetam (<10%) are protein-bound. Obviously, use among patients in renal failure must be modified. Phenytoin might be considered for partial seizures, except during bone marrow engraftment, when carbamazepine is also relatively contraindicated. Both of these drugs may have toxic hematologic side effects. During the 2- to 6-week period of engraftment, phenobarbital is acceptable. When antiepileptic drugs other than valproic acid, gabapentin or leviteracetam are used, the doses of immunosuppressive drugs should be increased to ensure therapeutic immunosuppression. Cyclosporine levels should be periodically assessed. Experience with other antiepileptic drugs such as lamotrigine and topiramate in these settings is limited. Topiramate dosing must be adjusted for renal insufficiency.

Management of Seizures Patients in the neuro-ICU may have co-existing conditions making management of antiepileptic drug regimens challenging. For instance, a CNS trauma patient may also have liver lacerations or contusions with consequent acute hepatic failure. Understanding the interaction of other organ systems is therefore necessary for appropriate management of seizures. In hepatic and renal dysfunction, treatment with antiepileptic drugs will be altered secondary to changes in pharmacokinetics induced by metabolic dysfunction. In cases of hepatic dysfunction, plasma concentrations must be correlated with serum albumin and protein levels, and free (unbound) levels measured, if possible. Additionally, patients with hepatic and renal failure may have normal serum and albumin levels, but altered protein binding that results in elevated free drug level.37 Changes in temperature also may be associated with increased protein binding by phenytoin.38 Metabolic disorders are considered in this chapter because the management of seizures is intricately related to the patient’s metabolic state.

Metabolic Disorders Hyponatremia In the hospital setting, disorders of electrolytes and fluid balance are some of the more common metabolic disorders noted. Hyponatremia is defined as a serum sodium level less than 135 mEq/L, and is one of the most frequent metabolic abnormalities, occurring in 2.5% of hospitalized patients.39 Acute hyponatremia is a frequent event in neurosurgery practice and is usually associated with subarachnoid hemorrhage, head trauma, infections, and neoplasms.40 The two common clinical manifestations are the syndrome of inappropriate antidiuretic hormone (SIADH) secretion, and the cerebral salt wasting syndrome (CSWS), which have previously been attributed to each other due to identical clinical presentation. When the serum sodium acutely decreases to 125 mEq/L or less, neurologic symptoms, including seizures, are seen more frequently in acute rather than chronic hyponatremia.41–43 The critical difference between SIADH and CSWS is that CSWS involves renal salt loss leading to hyponatremia and volume loss, whereas SIADH is a euvolemic/hypervolemic condition.44 Attention to volume status in patients with hyponatremia is essential. The primary treatment for CSWS is water and salt replacement. Urgent, but not immediate, correction to serum sodium levels greater than 120 mEq/L is essential when hypovolemia is absent. Obviously when hypovolemia is present, more rapid correction is necessary. The critical difference between SIADH and CSWS is that CSWS involves renal salt loss leading to hyponatremia and volume loss, whereas SIADH is a euvolemic/hypervolemic condition. Serum sodium is commonly reduced as a result of sodium depletion,45 resulting in hypo-osmolar hyponatremia. Hyponatremia with normal osmolality is rare, but may be seen in patients with hyperlipidemia or hyperproteinemia. Hyperosmolar hyponatremia occurs in hyperosmolar states such as hyperglycemia. Hypo-osmolar hyponatremia may be associated with normal extracellular fluid volume, hypovolemia, or hypervolemia.46 Hypo-osmolar hyponatremia with hypovolemia may be seen from renal (diuretic use, Addison’s disease) or extrarenal loss (vomiting, diarrhea, or “third-spacing”), and CSWS. SIADH, hypothyroidism, and certain drugs including the antiepileptic drugs carbamazepine and oxcarbazepine, and psychotropic agents may cause hypo-osmolar hyponatremia with normal volume. Hypo-osmolar hyponatremia associated with hypervolemia, frequently noted in patients with clinical edema, occurs in cardiac failure, nephrotic syndrome, and acute or chronic renal failure. The therapeutic implications of these conditions are great because appropriate therapy for normovolemic or hypervolemic hyperosmolar hyponatremia is water restriction. Hypovolemic hyponatremia is managed by replacement of water and sodium.46 Because these distur-

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bances are usually secondary processes, management of associated seizures requires identification and treatment of the primary disorder in conjunction with correction of the fluid or electrolyte disturbance. However, the rapidity with which a low serum sodium is corrected may be controversial when hypovolemia is absent. Rapid correction of hyponatremia has been associated with central pontine myelinolysis (CPM), manifested clinically by pseudobulbar palsy and spastic quadriparesis. Norenberg and colleagues47 noted that in each of 12 patients with CPM, there had been a recent rapid increase in serum sodium (see Chapter 18). Disturbances of Glucose Metabolism Hypoglycemia and nonketotic hyperglycemia may be associated with focal seizures, but these do not occur with ketotic hyperglycemia48 possibly secondary to the anticonvulsant action of ketosis. Ketosis also involves intracellular acidosis with augmented activity of glutamic acid decarboxylase increasing gamma-aminobutyric acid (GABA) levels, which increases seizure threshold. Nonketotic hyperglycemia with or without hyperosmolarity may be associated with seizures. Hyperglycemia increases the frequency of seizures through brain dehydration in animal models with cortical lesions.49 Focal motor seizures and epilepsia partialis continua are a well-known complication of nonketotic hyperglycemia, occurring in approximately 20% of cases.50 Hypocalcemia Seizures due to severe hypocalcemia (<6 mg/dL) are relatively infrequent, but do occur. Severe acute hypocalcemia most frequently follows thyroid or parathyroid surgery. Although not well understood, late-onset hypocalcemia with seizures rarely may develop years after extensive thyroid surgery.51 Hypocalcemia frequently complicates renal failure and acute pancreatitis.45 Tetany is the most frequent neuromuscular symptom in patients with hypocalcemia52 and can be mistaken for seizure activity. Tetany is the clinical manifestation of spontaneous, irregular, repetitive action potentials originating in peripheral nerves. Latent tetany may be unmasked by hyperventilation or regional ischemia (Trousseau test). In the average adult, a slow intravenous (IV) bolus of 15 mL of 10% calcium gluconate solution (9 mg calcium/mL) with careful cardiac monitoring followed by slow infusion of the equivalent of 10 mL/hr of 10% calcium gluconate solution should alleviate seizures.53 Hypomagnesemia Hypomagnesemia is associated with seizures most often when serum levels are less than 0.8 mEq/L. Because secondary hypocalcemia may be produced by a decrease in circulating levels of or end-organ resistance to parathyroid

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hormone in the presence of hypomagnesemia, magnesium levels should be measured in the hypocalcemic patient who does not respond to calcium supplementation. Treatment requires administration of intramuscular 50% magnesium sulfate every 6 hours or intravenous infusion. Because precipitation of respiratory muscle paralysis may be induced by transient hypermagnesemia,54 intravenous calcium gluconate should be administered concurrently. Hypophosphatemia Profound hypophosphatemia may accompany alcohol withdrawal, diabetic ketoacidosis, chronic intake of phosphate binding antacids, recovery from extensive burns, hyperalimentation, and severe respiratory alkalosis. A sequence of symptoms consistent with metabolic encephalopathy occurs, involving irritability, apprehension, muscle weakness, numbness, paresthesias, dysarthria, confusion, obtundation, convulsive seizures, and coma.55 Generalized tonic-clonic seizures may occur with levels less than 1.0 mg/dL, and may not be controlled with antiepileptic drugs.56 Hypoparathyroidism Thirty percent to 70% of patients with hypoparathyroidism experience seizures, usually in association with tetany and hypocalcemia. These seizures may be generalized tonicclonic, focal motor, and, less frequently, atypical absence and akinetic attacks. Restoration of normal calcium levels is necessary for control. Because antiepileptic drugs may partially suppress seizures as well as tetany and Trousseau’s sign, hypocalcemia must be considered. Uremia Mental status changes are the hallmark of uremic encephalopathy involving simultaneous neural depression (obtundation) and neural excitation (twitching, myoclonus, generalized seizures). Phenytoin is a typical antiepileptic drug utilized to treat seizures in nontransplanted uremic patients. However, the physician should remember that critical changes in antiepileptic drug pharmacokinetics occur including (1) increased volume of distribution, producing lowered plasma drug levels; (2) decreased protein binding, creating higher free drug levels; and (3) increased hepatic enzyme oxidation, yielding increased plasma elimination.37 Because uremic patients have plasma proteinbinding abnormalities, and because phenytoin is highly plasma bound, administration is different from that in nonuremic patients. In nonuremic patients, up to 10% of phenytoin is not protein-bound. In uremic patients, as much as 75% may not be protein-bound, and therefore it is necessary to use free phenytoin levels (between 1 and 2 mg/mL) instead of total phenytoin levels to assess therapeutic efficacy.57 Because fosphenytoin is preferred over phenytoin for parenteral administration, the neuro-ICU physician should

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be familiar with its use as well. For drugs such as gabapentin,58 leviteracetam, and zonisamide that are eliminated largely via renal excretion, the usual total dose should be reduced equivalently to the reduction in creatinine clearance. Hepatic Encephalopathy Hepatic encephalopathy is classified into four stages; those of interest to us here are stage III, associated with focal or generalized seizures and stage IV, marked by coma and decerebrate posturing. The incidence of seizures varies widely, from 2% to 33%.59,60 Hypoglycemia, complicating liver failure, may be responsible for some seizures. Therapy should be directed at the underlying etiology of the hepatic failure with intervention focused on reduction of gastrointestinal protein and administration of lactulose. Antiepileptic drug treatment of hepatic encephalopathy does not usually require chronic treatment unless there is a known predisposition to seizures (e.g., previous cerebral injury). Little experience with the use of antiepileptic drugs has been reported. Antiepileptic drugs with sedative effects may precipitate coma60 and are generally contraindicated. Antiepileptic drugs not metabolized by the liver, such as gabapentin or levetiracetam, should be considered if parenteral drugs are judged unnecessary. However, when a parenteral drug is needed, fosphenytoin and phenytoin are less sedating than phenobarbital. Oral or parenteral valproate derivatives should be avoided.

Intoxication This section is not to be used as a guide to the management of drug intoxication, but rather to deal with specific instances of intoxication that may arise in the neuro-ICU setting. Recreational Drug-Induced Seizures Alcohol and recreational drugs are often involved in cerebral trauma. For this reason it is important for the clinician to recognize the occurrence of substance-induced and substance withdrawal-induced seizures. Alldredge and associates61 retrospectively identified 49 cases of recreational drug-induced seizures in 47 patients. Most patients experienced a single generalized tonic-clonic seizure associated with acute drug intoxication, but seven patients had multiple seizures and status epilepticus developed in two patients. The recreational drugs implicated were cocaine (32 cases), amphetamine (11), heroin (7), and phencyclidine; combinations of agents account for the discrepancy in case numbers. Marijuana is unlikely to alter seizure threshold.62 However, seizures occurring in patients with toxicology screens positive for marijuana should be tested for additional illicit drug use and alcohol.

Cocaine Cocaine, a biologic compound, is one of the most abused recreational drugs in the United States. Common neurologic complications include tremors and generalized seizures.63 Cocaine can provoke seizures, exacerbate a preexisting seizure disorder, or cause an ischemic or hemorrhagic stroke that leads to seizures.64 Seizures can occur immediately after drug administration, without other signs of toxicity. Convulsions and death may occur within minutes of overdose. The majority of seizures are single and generalized, induced by intravenous or crack cocaine, and not associated with any lasting neurologic deficits. Most focal or repetitive events are associated with an acute intracerebral complication or concurrent use of other drugs.65 The treatment of choice is diazepam or lorazepam. Bicarbonate for acidosis, artificial ventilation, and cardiac monitoring are also useful, depending on the duration of the seizures. Urinary acidification accelerates excretion of the drug. Chlorpromazine use has also been recommended because it increased rather than decreased the seizure threshold in cocaine-intoxicated primates.66 Tricyclic antidepressants may also be useful by decreasing vasoconstrictor and cardiac action.67 Methamphetamine Methamphetamine is a synthetic drug similar to cocaine with toxic effects, including seizures, similar to those of amphetamine and cocaine.68 The amphetamine derivative 3,4-methylenedioxymethamphetamine (MDMA) is also known as “ecstasy”; it has become a frequently abused substance in the United States, especially popular at “raves.” It may cause seizures with rhabdomyolysis and hepatic dysfunction.69 Treatment of methamphetamine-induced seizures is similar to cocaine-induced seizures. Hyperthermia is a life-threatening complication of MDMA use.70 While protracted seizure activity may be associated with hyperthermia, the degree of hyperthermia is lower than that associated with MDMA use. Very high temperatures (>104°F) should raise the suspicion of MDMA intoxication. Nonrecreational Drug-Induced Seizures Many medications have been associated with provocation of seizures in both epileptic and nonepileptic patients (see Table 26-2). Predisposing factors include family history of seizures, concurrent illness, and high dose intrathecal and intravenous administration. More commonly, these are generalized convulsions with or without focal features, and status epilepticus may occur. Because multiple medical conditions are associated with polypharmacy, drug-induced seizures may be even more common in the elderly patient.71,72 The prescribing information should be consulted to determine the seizure potential of drugs for specific conditions.

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Serotonin Syndrome The “serotonin syndrome,” which consists of delirium, tremors, and occasionally seizures,73 is increasingly recognized. In part, it is occurring more frequently because of the increasing use of selective serotonin reuptake inhibitor (SSRI) antidepressant agents. The syndrome is characterized by confusion, agitation, diaphoresis, tachycardia, myoclonus, and hyperreflexia. Sometimes the myoclonus may be confused with seizures. Seizures are less frequent with this condition than previously reported. The EEGs recorded from patients with serotonin syndrome may be quite disorganized with slowing of the background, both generalized and lateralized. The increased use of serotonergic agents (alone and in combination) across multiple medical disciplines presents the possibility that the prevalence and clinical significance of this condition will increase in the future. The syndrome of inappropriate antidiuretic hormone (SIADH) has been reported with most antidepressant drugs but appears to be more common with serotonergic agents and in elderly patients. Thus, while the nature of the patient’s surgery may suggest SIADH as a reasonable complication, be sure to check the patient’s medication list for possible contributing factors! Central Anticholinergic Syndrome Many drugs used in anesthesia and in the ICU can precipitate seizures. Although listing of each drug is not possible, we will review the central anticholinergic syndrome,74 a common disorder associated with blockade of the central cholinergic neurotransmission. Acetylcholine modulates many interactions among most other central transmitters. The clinical picture of central cholinergic blockade is identical with the central symptoms of atropine intoxication, including seizures, agitation, hallucinations, disorientation, stupor, coma, and respiratory depression. Such disturbances may be induced by opiates, ketamine, etomidate, propofol, nitrous oxide, and halogenated inhalation anesthetics, as well as by H2-blocking agents such as cimetidine. While there is an individual predisposition for central anticholinergic syndrome, it is unpredictable from laboratory findings or other signs. The postanesthetic syndrome can be prevented by administration of physostigmine during anesthesia. Analgesics Meperidine, pentazocine, and propoxyphene, among other analgesic drugs, infrequently cause seizures.75 Nonetheless, caution should be used in critically ill and postsurgical patients. Tramadol is a centrally acting synthetic analgesic whose mechanism is unknown. It has been associated with seizures even when taken within the recommended dosage range. Seizure risk is increased with doses above the recommended range. Simultaneous use with certain drugs also

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increases the risk of seizures. These drugs include the SSRI antidepressants and anorectics, tricyclic antidepressants, and opioids. Other drugs that may increase the seizure risk include the MAO inhibitors and neuroleptics. Antidepressants Intoxication from tricyclic antidepressants has caused generalized tonic-clonic seizures. In fact, seizures may occur at therapeutic levels in approximately 1% of patients.76 Because desipramine is believed to have a lower risk of precipitating seizures than other drugs of this class, it is preferred in patients with known seizure disorders77 when this class of antidepressant is needed. Since amitriptyline and imipramine depress the level of consciousness, use of barbiturates is relatively contraindicated to treat seizures, and diazepam or paraldehyde is recommended. Physostigmine may reverse the neurologic manifestations of tricyclic antidepressant toxicity; however, because it may also cause asystole, hypotension, hypersalivation, and convulsions, it should not be used to treat tricyclic-induced seizures. Fluoxetine and sertraline are SSRIs. These drugs may have an associated seizure risk of approximately 0.2%. The SSRIs may have an antiepileptic effect at therapeutic doses.78 However, when combined with other serotonergic agents or MAO inhibitors, the “serotonin syndrome” may occur. Antipsychotics Antipsychotic drugs have long been known to precipitate seizures.79,80 Both phenothiazines and haloperidol have been implicated, but the potential for seizures is greater with phenothiazines, and seizures occur more frequently with increasing dosage.81 Clozapine is an atypical antipsychotic drug (dibenzodiazepine class) for treatment in patients with intractable schizophrenia. Like other antipsychotic agents, the incidence of seizures increases with increasing dosage.82 Seizures rarely occur with newer antipsychotic agents such as ziprasidone and olanzapine. Methylxanthines Theophylline and other methylxanthines may lead to generalized tonic-clonic seizures. In rare patients, theophylline at nontoxic concentration may provoke seizures. When seizures are a result of overdosage, they are best treated acutely with intravenous diazepam. Massive over dosage may produce hypocalcemia and other electrolyte abnormalities.83 Anesthetics Lidocaine may precipitate seizures, usually in the setting of congestive heart failure, shock, or hepatic insufficiency.

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General anesthetics such as ketamine and enflurane are also implicated in precipitating seizures.84 (See also Central Anticholinergic Syndrome.) Antibiotics Many antiparasitic drugs and antimicrobials, particularly penicillins and cephalosporins in high concentrations, precipitate seizures. Lindane, an antiparasitic shampoo against head lice (Pediculosis capitis), has a rare association with self-limited, generalized seizures. However, it is best to use another agent if reinfestation occurs. Seizures have not been reported with permethrin, another antipediculosis agent. Isoniazid Isoniazid (INH) combines with pyridoxine inhibiting pyridoxine kinase that forms the active cofactor for the enzyme glutamic acid decarboxylase, required for the synthesis of GABA. Therefore, INH depletes GABA and alters seizure threshold.85 Severe INH intoxication involves coma, severe intractable seizures, and metabolic acidosis. Ingestion of more than 80 mg/kg body weight produces severe CNS symptoms that are rapidly reversed with intravenous administration of pyridoxine86 at 1 mg for every 1 mg of isoniazid. Conventional doses of short-acting barbiturates, phenytoin, or diazepam are also recommended to potentiate the effect of pyridoxine.87

Treatment: How to Use the Antiepileptic Drugs: Old and New Benzodiazepines Benzodiazepines remain the antiepileptic drug (AED) of choice in the initial treatment of acute seizures. Either lorazepam or diazepam may be used. The dose for lorazepam is 0.1 to 0.2 mg/kg over 2 to 4 minutes. Maximum dose is 8 mg. For diazepam the dose is 0.1 to 0.3 mg/kg over 2 to 4 minutes. Maximum dose is 20 mg. Rectal diazepam gel (Diastat, Extek) can be used when IV access is delayed or difficult, but this formulation is unlikely to be used in the ICU setting. Lorazepam and diazepam are available for oral administration but are uncommonly used for maintenance antiepileptic treatment. When an oral benzodiazepine is used in chronic seizure disorders maintenance, a more useful drug is clonazepam. Dosage ranges from 0.25 to 5 mg/day in the drug non-naive patient. Phenytoin and Fosphenytoin Although several newer antiepileptic drugs have been released in the last five years, there are still only a few AEDs for acute and chronic seizure treatment that are available for

parenteral use. Phenytoin is still used extensively in ICUs. Fosphenytoin is the phosphate ester prodrug of phenytoin. It has several advantages over phenytoin that are detailed in the following section. Phenytoin is soluble in saline and only at high pH. It is quite toxic to tissue when inadvertently extravasated. For acute seizure management it should only be administered intravenously. It should never be used via the intramuscular route. Fosphenytoin can be safely administered intramuscularly (IM). Phenytoin is administered parenterally at a maximum rate of 50 mg/min. The typical loading dose for the treatment of status epilepticus is 18 to 20 mg/kg. Fosphenytoin can be administered intravenously at a higher maximum rate than phenytoin88 150 mg PE/min. All fosphenytoin doses are expressed as the amount of phenytoin delivered. The “PE” in the dosage means phenytoin equivalent. When administering phenytoin or fosphenytoin using the intravenous route, cardiac and blood pressure monitoring are necessary. Never use phenytoin IM; when treating status epilepticus, always use the IV route. For chronic phenytoin use, the typical dose is 300 to 400 mg/day. Obviously, levels should be followed (see the preceding discussion for details regarding serum free and bound phenytoin levels). Barbiturates and Primidone Phenobarbital is used in the treatment of status epilepticus, acute seizures, and for chronic seizure management. For treatment of status, the loading dose is 20 mg/kg over 10 minutes. Thereafter it is delivered at 0.75 mg/minute. Usually it is administered after benzodiazepines and phenytoin (or fosphenytoin) have not controlled the seizures. Because of the risk of respiratory compromise, it is essential to be prepared for endotracheal intubation of the patient. When treating refractory status epilepticus, EEG monitoring is desirable. One titrates the barbiturate to burst suppression on the EEG. Some clinicians prefer pentobarbital when it appears that the patient may be entering refractory status epilepticus. From the standpoint of sedation, respiratory compromise, and duration of sedating effects, there is little difference. However, it is believed that for long-term use, pentobarbital has fewer adverse effects on myocardial contractility. Nonetheless, hypotension is an adverse effect with both drugs. When using pentobarbital in the treatment of refractory status epilepticus, the dosage is 5 to 15 mg/kg followed by a continuous infusion of 1 to 3 mg/kg/hour titrating to burst suppression on the EEG. When managing chronic seizures with phenobarbital, the usual dose is 100 to 240 mg/day. For primidone, the usual daily maintenance dose is 500 to 1,500 mg. Primidone is metabolized to PEMA and phenobarbital. When ordering levels, be sure to obtain a “primidone battery,” which

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measures both. Primidone is not available for parenteral use. If a patient is unable to take oral primidone, one can substitute phenobarbital. Other Drugs for Treating Refractory Status Epilepticus Other drugs are being studied for the treatment of refractory status epilepticus.89 Another possibly useful drug is midazolam. It is loaded IV in a 0.15- to 0.3-mg/kg bolus, and followed with a continuous infusion of 2 to 6 mg/kg per minute. Propofol is also being used for managing refractory status epilepticus. The loading dose is a 1- to 2-mg/kg bolus followed by a continuous infusion of 3 to 10 mg/kg per hour. Valproate/Depacon Parenteral formulation of valproate is a recent addition to the armamentarium of AEDs. It has been used at doses of 15 to 44 mg/kg using infusion rates of 0.25 to 0.73 mg/kg per minute to achieve a serum concentration ranging from 71 to 277 mg/mL.90 Although studies of its use in status epilepticus are preliminary, it may well be useful in that setting.91 Carbamazepine Carbamazepine remains one of the most widely prescribed AEDs. The usual daily dose ranges from 400 to 2,400 mg. There is no parenteral formulation available. Carbamazepine is marketed with several names and formulations. Tegretol, marketed by Novartis, is available as a suspension, as chewtabs, or as tablets. Carbamazepine has recently become available as extended release formulations: Tegretol XR (Novartis) and Carbatrol (Shire Richwood). For patients with dysphagia the Carbatrol capsule may be opened, and sprinkled on food. The Tegretol XR tablet should not be opened. The adverse effects of carbamazepine are well known. They include drowsiness, blurred vision, and double vision. Some of these side effects are attenuated with the extended release formulation; some however, including leukopenia and, infrequently, hyponatremia are not. Other Antiepileptic Drugs The drugs in this category have become available in the past decade and are only available for oral administration. However, the neuro-intensivist will have some patients taking these drugs and so they are, therefore, briefly discussed. Oxcarbazepine Oxcarbazepine is chemically and structurally similar to carbamazepine, but has a completely different biotransformation. It is considered a separate AED. Oxcarbazepine is reduced to form its 10-monhyodroxy metabolite (MHD),

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which is the active metabolite and accounts for its antiepileptic activity. It is unaffected by induction or inhibition of the cytochrome P-450 system, which reduces the potential for interactions with other drugs, including AEDs. Hepatic impairment has no apparent effect on the pharmacokinetics of oxcarbazepine or MHD. However, MHD concentrations are significantly increased in patients with a creatinine clearance under 30 mL/minute. Hyponatremia occurs more commonly with oxcarbazepine than with carbamazepine. Gabapentin Despite its structural similarity to GABA, gabapentin does not bind to GABA receptors in the CNS. Gabapentin is not metabolized, and not plasma protein bound. It neither induces nor inhibits hepatic metabolism. It is eliminated by the kidney. Thus, drug-drug interactions are not an issue with gabapentin. The gabapentin T1/2 in otherwise healthy patients is 4 to 9 hours, and is dosed three to four times per day. The usual daily dose as an antiepileptic is 3,600 mg. Patients with renal insufficiency need lower dosages and less frequent dosing. Adverse effects are usually mild and transient.92 Lamotrigine Lamotrigine is an effective adjunctive therapy for the treatment of partial seizures.93,94 It also is effective for the partial and generalized seizures associated with Lennox-Gastaut syndrome in children. Because it takes several weeks to titrate the drug to the appropriate dosage, it is unlikely to be initiated in the neuro-ICU setting. However, patients with epileptic or psychiatric disorders may be taking it already when admitted to the neuro-ICU. It is metabolized by the liver. Its half-life fluctuates according to concomitant therapy: when the patient is taking enzyme-inducing AEDs its T1/2 is 14 hours; when the patient is taking valproate, the T1/2 is approximately 70 hours. A typical daily dose is 300 to 500 mg when the patient is not concurrently taking valproate. The neurotoxic side effects of lamotrigine include insomnia, drowsiness, dizziness, headache, somnolence, diplopia, and ataxia. The primary systemic side effects are rash and nausea. A benign rash may develop in up to 10% of patients. The risk of severe dermatologic reaction is 0.3% to 1%. The prompt evaluation of any rash is crucial. Topiramate Topiramate is a relatively effective antiepileptic drug. It is effective as adjunctive therapy for the treatment of adults with partial seizures, and may have efficacy for other seizure types. It has multiple mechanisms of action that include blocking sodium channels and enhancing GABA activity. Its metabolism is dependent on hepatic P450 microsomal enzymes. The half-life of topiramate is approximately 21 hours with normal renal function. Nearly 70% to 80% is

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excreted unchanged in the urine. Tablets and sprinkles are available. A typical daily dose is 200 to 400 mg. Side effects include a peculiar psychomotor slowing, difficulty with concentration, speech and language problems, somnolence, or fatigue. Additional side effects can include decreased appetite, weight loss, and kidney stones.

Tiagabine Tiagabine is an AED affecting the GABAergic system by interfering with GABA metabolism. The usual daily dosage is 32 to 56 mg. Its metabolism is primarily hepatic. It may reduce concentration of concurrently administered valproate. Side effects include dizziness and somnolence.

Levetiracetam Levetiracetam is a very good antiepileptic drug with few adverse effects. It is rapidly and almost completely absorbed after oral administration. It is not protein bound (<10%) and the major metabolic pathway is hydrolysis of the acetamide group to the inactive carboxylic derivative. Because urinary excretion of the unchanged drug accounts for approximately 50% of the administered dose, dosage adjustment may be necessary in patients with moderate and severe renal impairment. Its metabolism is independent of the hepatic cytochrome P450 system. There is little potential for pharmacokinetic interactions with other drugs, including oral contraceptives.95 Usual daily dosing is 1,000 to 3,000 mg.

Zonisamide Zonisamide is a sulfonamide derivative that is rapidly and nearly completely absorbed following oral administration with negligible first-pass metabolism. Protein binding is between 40% and 60%, and is unaffected by other tightly protein bound drugs. It does not affect the protein binding of other drugs. It has a high affinity for red blood cell carbonic anhydrase (like other sulfonamide derivatives). It should be avoided in patients with allergies to sulfa drugs. Steady state is reached in 7 to 10 days. A typical maintenance dose is 400 to 600 mg/day in adults.

P earls 1. . . . seizures may be so subtle as to be unrecognized or so dramatic as to shake the patient’s bed and instrumentation. 2. When a patient has an unexpected or unexplained change in level of consciousness or ability to interact with nursing and medical personnel, one should always consider the possibilities of sporadic, brief seizures with a prolonged postictal or interictal state, or nonconvulsive status epilepticus. 3. After experienced clinical personnel, the EEG is the best diagnostic tool for the diagnosis of seizures in the critically ill patient. 4. Natriuresis is a common systemic manifestation of aneurysmal subarachnoid hemorrhage (SAH). Natriuresis and its accompanying hypovolemia may be a major contributing factor in the pathophysiology of symptomatic cerebral vasospasm. This may also contribute to seizures. 5. Seizures may be an early symptom of CNS malignancy or may appear after surgical procedures for diagnosis or treatment.

6. Because the idiopathic and paraneoplastic syndromes are indistinguishable clinically, the appearance of opsoclonus myoclonus should always lead to a search for neuroblastoma or other occult neoplasm. 7. Obstructive sleep apnea is also common in medically refractory epilepsy patients. 8. For acute management of prolonged seizures, benzodiazepines are least likely to induce the enzyme system responsible for metabolizing immunosuppressant drugs. 9. In cases of hepatic dysfunction, plasma concentrations must be correlated with serum albumin and protein levels, and free (unbound) levels measured if possible. 10. Rapid correction of hyponatremia has been associated with central pontine myelinolysis (CPM), manifested clinically by pseudobulbar palsy and spastic quadriparesis.

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48. Singh BM, Strobos R: Epilepsia partialis continua associated with nonketotic hyperglycemia: clinical and biochemical profile of 21 patients. Ann Neurol 1980;8:155–160. 49. Vastola EF, Maccario M, Homan RO: Activation of epileptogenic foci by hyperosmolality. Neurology 1967;17:520–526. 50. Singh BM, Gupta DR, Strobos RJ: Nonketotic hyperglycemia and epilepsia partialis continua. Arch Neurol 1973;29:189–190. 51. Halperin I, Nubiola A, Vendrell J, Vilardell E: Late–onset hypocalcemia appearing years after thyroid surgery. J Endocrinol Invest 1989;12(6):419–422. 52. Layzer RB: Neuromuscular Manifestations of Systemic Disease. Philadelphia, FA Davis, 1985, pp 58–62. 53. Reber PM, Heath H: Hypocalcemic emergencies. Med Clin North Am 1995;79:93–106. 54. Whang R: Clinical disorders of magnesium metabolism. Compr Ther 1997;23(3):168–173. 55. Silvis SE, Paragas PD: Paresthesias, weakness, seizures, and hypophosphatemia in patients receiving hyperalimentation. Gastroenterology 1972;62:513–520. 56. Knochel JP: The pathophysiology and clinical characteristics of severe hypophosphatemia. Arch Intern Med 1977;137:203–220. 57. Lockwood AH: Neurologic complications of renal disease. Neurol Clin 1989;7(3):617–627. 58. Beydoun VA, Uthman BM, Sackellares JC: Gabapentin: pharmacokinetics, efficacy, and safety. Clin Neuropharmacol 1995;18(6):469–481. 59. Adams RD, Foley JM: The neurological disorder associated with liver disease. In: Metabolic and Toxic Diseases of the Nervous System. New York, Publishing Association for Research and Nervous and Mental Disease, 1952, pp 198–231. 60. Plum F, Posner JB: Diagnosis of Stupor and Coma. Philadelphia, FA Davis, 1984, pp 222–225. 61. Alldredge BK, Lowenstein DH, Simon RP: Seizures associated with recreational drug abuse. Neurology 1989;39:1037–1039. 62. Brust JCM, Ng SKC, Hauser AW, Susser M: Marijuana use and the risk of new onset seizures. Trans Am Clin Climatol Assoc 1992;103:176– 181. 63. Jeri FR, Sanchez CC, Del Pozo T, Fernandez M, Carbajal C: Further experience with the syndromes produced by coco paste smoking. Bull Narc 1978;30:1–7. 64. Koppel BS, Samkoff L, Daras M: Relation of cocaine use to seizures and epilepsy. Epilepsia 1996;37:875. 65. PascualLeone A, Dhuna A, Altafullah I, Anderson DC: Cocaine–induced seizures. Neurology 1990;40(pt. 1):404–407. 66. Johnson S, O’Meara M, Young JB: Acute cocaine poisoning. Importance of treating seizures and acidosis. Am J Med 1983;75:1061–1064. 67. Antelman SM, Kocan D, Rowland N, de Giovanni L, Chiodo LA: Amitriptyline provides long-lasting immunization against sudden cardiac death from cocaine. Eur J Pharmacol 1981;69:119–120. 68. Jaffe JH: Drug addiction and drug abuse. In Gilman AG, Goodman LS, Rall TW, Murrad F (eds): Goodman and Gilman’s The Pharmacologic Basis of Therapeutics. New York, Macmillan, 1985, pp 550–554. 69. Henry JA, Jeffreys KJ, Dawling S: Toxicity and death from 3,4methylenedioxymethamphetamine (“ecstasy”). Lancet 1992;340: 384–387. 70. Burgess C, O’Donohoe A, Gill M: Agony and ecstasy: A review of MDMA effects and toxicity. Eur Psychiatry 2000;15:287. 71. Eisenschenk S, Gilmore RL: Current concepts of seizures in the elderly. Part I: Etiologies and differential diagnosis. Geriatrics, in press.

72. Bodner RA, Lynch T, Lewis L, Kahn D: Serotonin syndrome. Neurology 1995;45:219–223. 73. Schneck HJ, Rupreht J: Central anticholinergic syndrome (CAS) in anesthesia and intensive care. Acta Anaesthesiol Belg 1989;40:219–228. 74. Blain PG, Stewart-Wynne E: Neurologic disorders. In Davies DM (ed): Textbook of Adverse Drug Reactions, 3rd ed. New York, Oxford University Press, 1985, p 494. 75. Lowry MR, Dunner FJ: Seizures during tricyclic therapy. Am J Psychiatry 1980;137:1461–1462. 76. Richardson JW III, Richelson R: Antidepressants: Clinical update for medical practitioners. Mayo Clin Proc 1984;59:330–337. 77. Favale E, Rubino V, Mainardi P, Lunardi G, Albano C: Anticonvulsant effect of fluoxetine in humans. Neurology 1995;45:1926–1927. 78. Kurtzke JF: Seizures with promazine. J Nerv Ment Dis 1957;125:119– 125. 79. Messing RO, Simon RP: Seizures as a manifestation of systemic disease. Neurol Clin 1986;4:563–584. 80. Logothetis J: Spontaneous epileptic seizures and electroencephalographic changes in the course of phenothiazine therapy. Neurology 1967;17:869–877. 81. Devinsky O, Honigfeld G, Patin J: Clozapine–related seizures. Neurology 1991;41:369–371. 82. Eshleman SH, Shaw LM: Massive theophylline overdose with atypical metabolic abnormalities. Clin Chem 1990;36:398–399. 83. Steen PA, Michelfelder JD: Neurotoxicity of anesthetics. Anesthesiology 1979;50:437–453. 84. Wood JD, Peesker SJ: The effect of GABA metabolism in brain of isonicotinic acid hydrazide and pyridoxine as a function of time after administration. J Neurochem 1972;19:1527–1537. 85. Watkins RC, Hambrick EL, Benjamin G, Chavda SN: Isoniazid toxicity presenting as seizures and metabolic acidosis. J Natl Med Assoc 1990;2:57–64. 86. Chin L, Sievers ML, Herrier RN, Pichionni AL: Potentiation of pyridoxine by depressants and anticonvulsants in the treatment of acute isoniazid intoxication in dogs. Toxicol Appl Pharmacol 1981;58:504– 509. 87. Fierro LS, Savulich DH, Benerza DA: Safety of fosphenytoin sodium. Am J Health Syst Pharmacol 1996;53:2707–2712. 88. Prasad A, Worrall BB, Bertram EH, Bleck TP: Propofol and midazolam in the treatment of refractory status epilepticus. Epilepsia 2001;42:380– 386. 89. Wheless JW, Venkataraman V: Safety of high dose intravenous valproate loading doses in epilepsy patients. J Epilepsy 1998;11:319–324. 90. Hovinga CA, Chicella MF, Rose DF, Eades SK, Dalton JT, Phelps SJ: Use of intravenous valproate in three pediatric patients with nonconvulsive or convulsive status epilepticu. Ann Pharmacother 1999;33:579–584. 91. Morris GL: Efficacy and tolerability of gabapentin in clinical practice. Clin Ther 1995;17:891. 92. Schachter SC: Efficacy and safety of lamotrigine, a new anticonvulsant. Today’s Ther Trends 1995;12:135. 93. Gilliam F, Vazquez B, Sackellares JC, et al: An active-control trial of lamotrigine monotherapy for partial seizures. Neurology 1998;51: 1018. 94. Nicolas JM, Collart P, Gerin B, et al: In vitro evaluation of potential drug interactions with levetiracetam, a new antiepileptic agent. Drug Metab Disp 1999;27:250–254. 95. Mason PJ, Morris VA, Balcezak TJ: Serotonin syndrome. Presentation of 2 cases and review of the literature. Medicine 2000;79:201–209.

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Chapter 27 Altered Mental Status Eric H. Gluck, MD, FCCP, FCCM, Jacob Samuel, MD, Andreas Sarrigiannidis, MD, FCCP, and Cory M. Franklin, MD

Definitions According to estimates, more than 5% of admissions to the emergency departments of large municipal hospitals are due to diseases causing disorders of consciousness. Clouding of consciousness (confusion) cannot easily be separated from a diminished level of consciousness (drowsiness, stupor, and coma) and the two are produced by many of the same medical disorders. Although the interpretation of consciousness is a psychological and philosophical matter, the distinction between level of consciousness (wakefulness) and content of consciousness (awareness) has neurologic significance. A system of upper brainstem and thalamic neurons, the reticular activating system (RAS) and its broad connections to the cerebral hemispheres maintain wakefulnessalertness (Fig. 27-1). Reduced wakefulness results from depression of the neuronal activity in either the cerebral hemispheres or in the RAS. Awareness and thinking are dependent on integrated and organized thoughts, subjective experiences, emotions, and mental processes, each of which reside in anatomically defined regions of the brain. Self-awareness requires that the organism senses this personal stream of thoughts and emotional experiences. The inability to maintain a coherent sequence of thoughts, usually accompanied by inattention and disorientation, is the best definition of confusion and is a disorder of the content of consciousness. Drowsiness is a disorder that simulates light sleep from which the patient can be easily aroused by touch or noise and can maintain alertness for some time. Stupor defines a state in which the patient can be awakened only by vigorous and repeated stimuli.

Coma indicates a state from which the patient cannot be aroused by stimulation, and no purposeful attempt is made to avoid painful stimuli.

The Confusional State Confusion is a behavioral state of reduced mental clarity, coherence, comprehension, and reasoning. Inattention and disorientation are the main early signs; however, as an acute confusional state worsens there is deterioration in memory, perception, comprehension, problem solving, language, praxis, visuospatial function, and various aspects of emotional behavior that are each identified with particular regions of the brain. Early in the process, it is difficult to know if these complex mental functions are reduced solely as a result of the pervasive defect in attention, but global cortical dysfunction is expected from the metabolic diseases and pharmacologic agents that are the most common sources of the acute confusional state. A patient is said to have an encephalopathy when confusion is accompanied by an element of drowsiness. Confusion may be a feature of a dementing illness, in which case the chronicity of the process and often a disproportionate effect on memory distinguish the former from acute confusion. The confused patient is usually subdued, not inclined to speak, and is inactive physically. In certain cases, illusions (misperceptions of environmental sight, sound, or touch) or hallucinations (spontaneous endogenous perceptions) accompany confusion. While psychiatrists use the term delirium interchangeably with confusion, neurologists prefer 747

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Figure 27-1. The broad connections of the reticular activating system. Note projection into the thalamus and cerebral hemispheres. (From Aminoff M, Greenberg D, Simon R: Clinical Neurology, 3rd ed. Stamford, Appleton-Lange, 1996, p 289, with permission.)

to reserve the former term as a description for an agitated, hypersympathicotonic, and hallucinatory state most often due to alcohol or drug withdrawal or to hallucinogenic drugs.

Pathophysiology of Coma and Confusion Coma of metabolic origin is produced by interruption of energy substrate delivery (hypoxia, ischemia, hypoglycemia) or by alteration of the neurophysiologic responses of neuronal membranes (drug or alcohol intoxication, toxic endogenous metabolites, anesthesia, or epilepsy). These same metabolic abnormalities can cause widespread neuronal dysfunction in the cortex that reduces all aspects of mentation and results in an acute confusional state. In this way, acute confusion and coma can be viewed as a continuum in metabolic encephalopathy. Abnormalities of osmolarity are involved in the coma and seizures caused by several systemic medical disorders, including diabetic ketoacidosis, the nonketotic hyperosmolar state, and hyponatremia. Brain water volume correlates best with level of consciousness in hyponatremic-hyposmolar states, but other factors probably also play a role. Sodium levels below 125 mmol/L cause acute or subacute confusion and below 115 mmol/L are associated with coma and con-

vulsions, depending on the rapidity with which the hyponatremia develops (Fig. 27-2). Serum osmolarity is generally above 350 mOsmol/L in hyperosmolar coma. Hypercapnia produces a diminished level of consciousness proportional to the PaCO2 and the rapidity of onset. A relationship between cerebrospinal fluid (CSF) acidosis and the severity of symptoms has been established. The pathophysiology of other metabolic encephalopathies such as hypercalcemia, hypothyroidism, vitamin B12 deficiency, and hypothermia are incompletely understood but must also reflect derangements of central nervous system (CNS) biochemistry and membrane functioning. The large group of drugs that depress the CNS, anesthetics, and some endogenous toxins appear to produce coma by suppression of both the RAS and the cerebral cortex. For this reason, combinations of cortical and brainstem signs occur in drug overdose and some other metabolic comas, which may lead to a specious diagnosis of structural brainstem damage. Although all metabolic derangements alter neuronal electrophysiology, the only primary disturbance of brain electrical activity encountered in clinical practice is epilepsy. Continuous, generalized electrical discharges of the cortex (seizures) are associated with coma even in the absence of epileptic motor activity (convulsions). Coma following seizures, termed the postictal state, may be due to exhaustion of energy metabolites or secondary to locally toxic molecules produced during the seizures. Recovery from postictal unresponsiveness occurs when neuronal metabolic balance is restored. The postictal state produces a pattern of continuous, generalized slowing of the background electroencephalography (EEG) activity similar to that of metabolic encephalopathy. The diagnosis and acute management of coma depend on knowledge of its main causes in clinical practice, an interpretation of certain clinical signs, notably the brainstem reflexes, and the efficient use of diagnostic tests. It is common knowledge that acute respiratory and cardiovascular

Figure 27-2. Levels of serum sodium correlating with alterations in mental status, from least to most severe. Of particular note, there is significant overlap in the serum sodium level of an alert patient, and that of one who is comatose or seizing. (From Arieff AL, Llach F, Massry SG: Neurologic manifestations and morbidity of hyponatremia. Medicine 1976;55:121–129, with permission.)

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problems should be attended to before neurologic diagnosis. A complete medical evaluation, except for the vital signs, fundoscopy, and examination for nuchal rigidity, may be deferred until the neurologic evaluation has established the severity and nature of coma.1

Initial Evaluation of the Comatose Patient Ordinarily, treatment follows accurate diagnosis, but coma is an exception to this rule. It is helpful to follow an algorithm to guide the evaluation. In this way, jumping to conclusions is avoided and potentially curable processes are not overlooked. For example, the head-injured patient may have an injury caused by a fall provoked by hypoglycemia. The postsurgical patient may suffer from nonconvulsive status epilepticus or alcohol withdrawal and not postoperative delirium. The management should ensure that the basic steps are not neglected. The causes of stupor and coma can be broadly grouped into three categories: 1. Structural intracranial disorders (33%), 2. Toxic or metabolic disorders (66%), and 3. Psychiatric disorders (1%). Three common and, treatable major threats to life are 1. Herniation syndromes, 2. Increased intracranial pressure, and 3. Meningitis or encephalitis. If there is no diagnosis after the initial evaluation, the most likely cause of coma is a metabolic or toxic etiology or a brainstem stroke.

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presence of a basal skull fracture, nasotracheal intubation is unwise2 (see Chapter 16). Breathing After the airway is secured, adequate oxygenation and ventilation should be provided. The rate and rhythm of the initial spontaneous respirations should be documented in the chart. The respiratory rate provides an important diagnostic aid to the anatomic diagnosis of coma (see following section). Circulation The cardiac rhythm and arterial blood pressure should be recorded and documented in the chart. An electrocardiogram should be obtained. All patients should have at least one good peripheral intravenous (IV) line. At the time of initial IV placement, blood should be sent for complete blood cell count, electrolytes, renal and liver function studies, and toxicology screen. Rapid evaluation of glucose serum should be done and, if the glucose is low, 50 cc of D50W should be infused. The longer the hypoglycemia lasts, the more likely it is to create irreversible loss of neurons. If there is any hint of opiate overdose from history or physical examination, 0.4 to 2.0 mg of naloxone should be given intravenously.2 If there is no improvement following 1 to 2 mg of IV naloxone, coma is unlikely to be due to opiate overdose. Use of flumazenil is controversial, outside of known benzodiazepine overdose. It may induce seizures, particularly in patients who have overdosed on tricyclic antidepressants, in patients with chronic dependence on benzodiazepines, or in patients with a history of epilepsy.3 Drugs.

General Physical Examination The Basics: The ABCs It is often necessary to administer emergency treatment before obtaining an accurate history and performing a detailed examination. Airway The top priority is that the airway must be secured. Comatose patients are frequently intubated for one of three reasons: oxygenation or ventilatory failure, airway protection, or hyperventilation to lower intracranial pressure. Airway protective reflexes, gagging and coughing, may be lost in coma, increasing the risk of aspiration. Also, the oropharynx and tongue relax, increasing the risk of airway obstruction. Aspiration risk is increased if gastric lavage is used for suspected toxic ingestion without a cuffed endotracheal tube in place. A patient in a hard cervical collar may be difficult to intubate orally as neck extension cannot, and indeed should not, be attempted. In such a case, nasotracheal or another method of intubation can be attempted; in the

History In many cases, the cause of coma is immediately evident (e.g., trauma, cardiac arrest, or known drug ingestion). In the remainder, historical information about the onset of coma may be sparse. General physical examination may reveal a systemic illness associated with coma (e.g., cirrhosis, hemodialysis shunt, rash consistent with meningococcemia) or signs of head trauma. The patient must be examined in a systematic fashion. A rapid search should be made for fractures and, especially, for signs of cranial trauma. Neurologic Examination The neurologic examination is focused on determining the patient’s level of consciousness, location of the lesion, and whether herniation is occurring. Repeated examinations are necessary to detect and intervene if clinical deterioration occurs. By evaluating five important physical findings (state of consciousness, pupillary responses, oculocephalic

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Figure 27-3. Characterization of pupillary size and response to light with lesions at varying levels of the brain. (From Brazis P, Mosdeau J, Billen J: Localization in Clinical Neurology. Boston, Little Brown, 1985, p 390, with permission.)

responses, motor responses and respiratory pattern), it is usually possible to determine which pathophysiologic type of coma the patient is experiencing. The goal of the neurologic examination is to determine whether there is a bihemispheric process or a RAS problem. Particular attention should be paid to the signs of herniation.4 The neurologic examination of the comatose patient is largely based on the pupillary size and the light reflexes (Fig. 27-3). Focal findings, i.e., dissimilar movement of the right and left sides of the body, are critical pieces of information, suggesting a structural lesion. Nonfocal findings increase the likelihood of a metabolic cause of coma. An exact description of spontaneous and elicited movements is of great value in establishing the level of neurologic dysfunction. The patient’s state should be observed first without examiner intervention. The nature of respirations and spontaneous

movements are noted. Patients who toss about, reach up toward the face, cross their legs, yawn, swallow, cough, or moan are closest to being awake. The only sign of seizures may be small excursion twitching of a foot, finger, or facial muscle. An out turned leg at rest or lack of restless movements on one side suggests a hemiparesis. The terms decorticate and decerebrate rigidity, or “posturing,” describe stereotyped arm and leg movements occurring spontaneously or elicited by sensory stimulation (Fig. 27-4). Flexion of the elbows and wrists, arm supination, and extension of the legs and feet (decortication) suggest severe bilateral damage in the hemispheres above the superior colliculi or the decussation of the rubrospinal pathway in the midbrain. Extension of the elbows and wrists with pronation, extension of the legs and feet, and opisthotonos (decerebration) suggest damage to the corticospinal tracts

Figure 27-4. Neurologic signs in coma. Note the fourth column (motor response to pain), panels 2 and 3, which show—respectively—decorticate and decerebrate posturing. (From Aminoff M, Greenberg D, Simon R: Clinical Neurology, 3rd ed. Stamford, Appleton-Lange, 1996, p 291, with permission.)

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between the superior colliculi or the decussation of the rubrospinal pathway, and the rostral vestibular nuclei. The response is abolished with involvement of the vestibular nuclei.5,6 If the patient is not arousable by conversational voice, a sequence of increasingly intense stimuli is used to determine the patient’s best level of arousal and the optimal motor response of each limb. It should be recognized that the results of this testing may vary from minute to minute and that serial examinations are most useful. Nasal tickle with a cotton wisp is a strong arousal stimulus. Pressure on the knuckles or bony prominences is the preferred and humane form of noxious stimulus. Pinching the skin over the face, chest, or limbs causes unsightly ecchymoses and is unnecessary. Responses to noxious stimuli should be appraised critically. Abduction avoidance movement of a limb is usually purposeful and denotes an intact corticospinal system to that limb. Stereotyped posturing following stimulation of a limb indicates severe dysfunction of the corticospinal system. Adduction and flexion of the stimulated limbs may be reflex movements and imply corticospinal system damage. Brief clonic or twitching limb movements occur at the end of extensor posturing excursions and should not be mistaken for convulsions. Finally, care must be taken not to confuse reflex activity with other responses. In particular triple flexion of the lower extremity is a reflex signaling upper motor dysfunction. It may look like spontaneous movement of the leg away from painful stimuli, but it is a reflex—the important finding is that the reflex response is very rapid and stereotyped. A stiff neck may indicate bacterial meningitis or subarachnoid hemorrhage, but in the latter case there is often a delay of up to 12 hours before blood in the subarachnoid cerebrospinal fluid has produced enough chemical meningeal irritation to be detected by neck flexion. Neck stiffness as an index of meningitis may be masked in coma because patients do not feel the pain of meningismus. Neck rigidity occurs in meningeal irritation of any cause, in inflammatory and destructive disease of the cervical spine, in cervical fusion, occasionally in cervical spondylosis and in Parkinsonism, and in high intracranial pressure when tonsillar herniation is present. It is important to remember that neck rigidity may result from cerebellar tonsillar herniation at the level of the foramen magnum because it would contraindicate lumbar puncture.7 If convulsions are known to be limited to one part of the body, this suggests structural disease of the opposite hemisphere. Repeated focal convulsions involving more of the limb each time are suggestive of spreading cortical thrombophlebitis or encephalitis. Minor twitching of the unilateral extremity has localizing value. If bilateral, this merely indicates diffuse cerebral disorder. Asterixis is the flapping tremor that can be elicited in patients with metabolic encephalopathy, particularly

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impending hepatic coma (“liver flap”). In hepatic failure, asterixis carries prognostic significance, as its presence is associated with increased mortality. It is due to an inability to maintain voluntary muscular contraction. Thus, it requires patient cooperation and cannot be elicited in coma. Asterixis consists of involuntary jerking movements, characterized by a sequence of flexions and extensions. It is nonspecific, and can be seen in uremia, hypercapnia, poisoning, or electrolyte imbalances. Myoclonic seizures are minor motor seizures characterized by sudden muscle contractions of the face and upper extremities. The eyelids and forearms are commonly affected. There is no detectable loss of consciousness. Myoclonic jerks occur after hypoxic injury and as a result of metabolic encephalopathy.8 The Eye Examination Pupillary abnormality is one of the cardinal features differentiating surgical disorders from medical disorders. Pupillary abnormalities in coma generally herald structural changes in the brain, whereas in metabolic coma such abnormalities are not present. In patients who are on a ventilator and have received paralytic agents, pupillary examination may be the only objective neurologic test possible.9 In the critical care setting, the pupils should not be pharmacologically dilated for funduscopy, because this eliminates a prime means to assess brain stem integrity. One should check for orbital or direct ocular trauma, including injury to the iris that could cause pupillary dilatation with no neurologic significance. Previous cataract surgery will impair mobility of the iris and pupillary reaction. The use of mydriatic eye drops by a previous examiner or the patient may cause misleading pupillary enlargement. A significant pupillary abnormality in neurosurgical practice is the unilaterally dilated and fixed pupil, which generally indicates uncal herniation. If the pupils are unequal, it is important to decide which is abnormal. A frequent mistake is to investigate the cause of a dilated pupil on one side, because the larger pupil is more impressive, when the patient actually has a constricted pupil on the other side (Horner’s syndrome). Accompanying signs can be of aid— ptosis on the side of the small pupil implies Horner’s syndrome, where ptosis on the side of the large pupil implies a partial third cranial nerve lesion.10 The unilaterally small pupil of Horner’s syndrome is detected by failure of the pupil to enlarge in the dark. It is rare in coma but may occur ipsilaterally in large cerebral hemorrhage affecting the thalamus. The poorly reactive and dilated pupil observed in coma is often thought to represent an acute third cranial nerve palsy due to brain herniation or aneurysm. In the well patient, however, the isolated dilated pupil is unlikely to be due to third cranial nerve palsy. It is more commonly due to benign causes such as local iris sphincter abnormalities, pharmacologic dilation, tonic pupil syndrome, or sympathetic irritation.11

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Pupillary dilatation can also occur with sudden expansion or rupture of an internal carotid artery aneurysm, or lesion of the midbrain. In extreme midbrain compression, both pupils become fixed and dilated. Fixed and dilated pupils also characterize the terminal stages of brain death. Specific pupillary reactions may suggest lesions at different levels of the CNS.12 Reactive and bilaterally small, but not pinpoint pupils (1 to 2.5 mm) are most commonly seen in metabolic encephalopathy or after deep bilateral hemispheric lesions such as hydrocephalus or thalamic hemorrhage. This has been attributed to dysfunction of sympathetic nervous system efferents emerging from the posterior hypothalamus. Pinpoint pupils (less than 1 mm) characterize narcotic or barbiturate overdose but also occur with acute, extensive bilateral pontine damage, usually from hemorrhage. The response to naloxone and the presence of reflex eye movements is the distinguishing characteristic. Light shining in one eye causes that pupil and the contralateral pupil of the other eye to simultaneously constrict. The latter is named consensual light reflex. An absent pupillary light response increases the possibility that the coma is due to a structural cause. An exception to this rule is certain intoxications (e.g., atropine) that result in bilaterally dilated and nonreactive pupils. Although the corneal reflexes are rarely useful alone, they may corroborate eye movement abnormalities because they also depend on the integrity of pontine pathways. By touching the cornea with a wisp of cotton, a response consisting of brief bilateral lid closure may be observed. The corneal response may be lost if the reflex connections between the fifth and seventh cranial nerves within the pons are damaged. The normal efferent response is bilateral, with closure of both eyelids. CNS depressant drugs diminish or eliminate the corneal responses soon after the reflex eye movements become paralyzed, but before the pupils become nonreactive to light. In examining for the corneal response,

care should be taken to observe contralateral as well as ipsilateral eyelids. Ipsilateral weakness of the orbicularis oculi may cause an apparent loss of the reflex. A unilateral absent corneal response, considered in association with other findings, may have localizing value.5,13 Third cranial nerve paralysis results in paralysis of inferior oblique, medial, inferior, and superior rectus muscles (Fig. 27-5). The result is an eye turned down and out. The lid is drooped and the pupil is dilated (because additional muscles innervated by third cranial nerve are the levator palpebral muscle and the pupillary constrictor muscle). If paresis is due to diabetes mellitus, it usually spares the pupil. The nerve courses parallel to the course of the posterior communicating artery intracranially. Ruptured aneurysms in that area can cause paralysis. The nerve also passes under the tentorial ridge and therefore is highly susceptible to uncal herniation. Spontaneous eye movements are generated by the cerebral cortex. Each hemisphere initiates conjugate horizontal gaze to the opposite side. Closed eyelids in coma mean that the lower pons is intact. Blinking means that reticular activity is taking place; however, blinking can occur with or without purposeful eye movement. Eyes that conjugately deviate away from hemiparetic limbs indicate a destructive cerebral lesion on the side toward which the eyes are directed. Eyes turned toward paretic limbs may mean a pontine lesion, an adversive seizure, or “the wrong way gaze paresis of thalamic hemorrhage.”14 Fundoscopy Fundoscopic examination is used to detect subarachnoid hemorrhage (subhyaloid hemorrhages), hypertensive encephalopathy (exudates, hemorrhages, vessel-crossing changes), and increased intracranial pressure (papilledema). The fundus should be examined for evidence of arterial emboli, which appear as luminescent, highly refractile yellow, or white plaque–like material, occluding vessels.

Figure 27-5. Eye movement abnormalities seen with lesions at different levels of the brain. (From Brazis P, Mosdeau J, Billen J: Localization in Clinical Neurology. Boston, Little Brown, 1985, p 391, with permission.)

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There are numerous causes of a swollen optic nerve head, with the term “papilledema” reserved for cases where swelling is due to raised intracranial pressure. It is uncommon to see papilledema immediately after the acute onset of coma in an otherwise healthy individual. The presence of papilledema suggests a subacute or chronic process. Papilledema occurs frequently in patients with brain tumors, especially in childhood tumors of the cerebellum and fourth ventricle. An acute form of papilledema is found with subarachnoid hemorrhage (Fig. 27-6). It is uncommon in acute meningitis but is a feature in subacute and chronic meningitis as well as in patients with brain abscesses. Papilledema developing within 12 to 24 hours of a neurologic event frequently indicates increased intracranial pressure due to intracranial mass lesions, such as brain trauma or hemorrhage. Pronounced papilledema at the onset of symptoms usually indicates lesions of longer duration (e.g. brain tumor or abscess) (Fig. 27-7). Papilledema may appear as early as four to five hours after elevation of the intracranial pressure. After relief of the intracranial pressure, papilledema takes six to eight weeks to resolve. Ventilatory Pattern Most comatose patients with neurosurgical disorders and a Glasgow Coma Score less than 9 (Table 27-1) are intubated to ensure adequate oxygenation of the brain. Because these patients are intubated, paralyzed, and ventilated, classic ventilatory patterns (Figs. 27-8 and 27-9) cannot be observed.9 When spontaneous breathing is present, ventilatory patterns should be observed before stimuli are applied by the examiner. These patterns have received much attention in coma diagnosis but are of inconsistent localizing value. Apneustic, cluster, and ataxic breathing are patterns associated with lesions of the mid lower pons, upper medulla, and caudal medulla, respectively, and all provide inadequate ventilation

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Figure 27-7. Chronic papilledema, left eye. (From Sautter H, Straub W, Turss R, Rossmann H: Der Photographierte Augenhintergrund. München, Urban and Schwanzerberg, 1984, p 62, with permission.)

so that mechanical ventilatory support is needed. With apneusis, the patient has a prolonged inspiratory phase or respiration may consist of cycles of quick inhalationpause-exhalation-pause. Cluster breathing consists of several rapid shallow breaths followed by pauses, while ataxic breathing is irregular brief respirations of small random tidal

Table 27-1  The Glasgow Coma Score Neurologic Parameter

Figure 27-6. Early papilledema, right eye. (From Sautter H, Straub W, Turss R, Rossmann H: Der Photographierte Augenhintergrund. München, Urban and Schwanzerberg, 1984, p 60, with permission.)

Eye opening Spontaneous To sound To pain None Motor response Obeys commands Localizes pain Normal flexion (withdrawal) Abnormal flexion (decorticate) Extension None Verbal response Oriented Confused conversation Inappropriate words Incomprehensible sounds None

4 3 2 1 6 5 4 3 2 1 5 4 3 2 1

From Teasdale G, Jennett B: Assessment of coma and impaired consciousness. A practical scale. Lancet 1974;2:81-84, with permission.

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Figure 27-8. Respiratory patterns seen with lesions at different levels of the brain. (From Brazis P, Mosdeau J, Billen J: Localization in Clinical Neurology. Boston, Little Brown, 1985, p 386, with permission.)

volumes. Apnea is of poor localizing value and may be seen secondary to cardiac arrest, multifocal brain lesions, drug overdose, spinal cord transection, or primary pulmonary processes. Respiration that is variably irregular in rate and amplitude (ataxic or Biot breathing) indicates medullary damage and can occur in patients with meningitis. Ataxic breathing may progress to apnea, which may also occur abruptly in acute posterior fossa lesions. Ataxic breathing is a variant of Cheyne-Stokes respiration in the sense that it is a sequence of hyperpneas and apneas. However, the ataxic pattern lacks the typical abrupt beginning, crescendo-decrescendo pattern, and regularity of Cheyne-Stokes breathing. Stertorous breathing (heavy, snoring sounds especially during inspiration), accompanied by stridor and cyanosis if respiratory obstruction, is common in epileptic fits and cerebrovascular accidents. Shallow, slow, but well-timed regular breathing suggests metabolic or drug depression. Rapid, deep (Kussmaul) breathing usually implies metabolic acidosis but also may occur with pontomesencephalic lesions. Cheyne-Stokes respiration, in its classic crescendodecrescendo form, ending with a brief apneic period, signifies mild bihemispheral damage or metabolic suppression, and commonly accompanies stupor. Cheyne-Stokes breathing is a “stable” breathing pattern, in that it does not imply impending respiratory arrest. This pattern is important to recognize because the associated apnea may be quite frightening to inexperienced staff.15 Although classic CheyneStokes respiration may sometimes be a benign respiratory pattern,6 it may also be an early sign of transtentorial herniation.1 Agonal gasps reflect bilateral lower brainstem damage and are well known as the terminal respiratory pattern of severe brain damage. In brain-dead patients, shallow

respiratory-like movements with irregular, nonrepetitive back arching may be produced by hypoxia and are probably generated by the surviving cervical spinal cord and lower medullary elements. Other cyclic breathing variations are not usually diagnostic of specific local lesions. Ominous respiratory signs are end-expiratory pushing (coughing), and fish mouthing (lower jaw depression with inspiration). Hiccup is usually a trivial breathing aberrance, but in a comatose patient, hiccup is an ominous sign indicating severe damage to the brainstem. A change of pulse rate combined with hyperventilation and hypertension may signal an increase in intracranial pressure. Brainstem Reflexes Brainstem signs are a key to localization of lesions in coma. As a rule, coma associated with normal brainstem function indicates widespread and bilateral hemispheric disease or dysfunction. Skew deviation (a vertical misalignment of the eyes) usually signifies a structural brainstem lesion with the higher eye ipsilateral to the side of the lesion.8 “Doll’s-eye,” or oculocephalic, responses are reflex movements tested by moving the head from side to side or vertically, first slowly then briskly; eye movements are evoked in the opposite direction to head movement (Fig. 27-10). These responses are generated by brainstem mechanisms originating in the labyrinths and cervical proprioceptors. They are normally suppressed by visual fixation mediated by the cerebral hemispheres in conscious patients but appear as the hemispheres become suppressed or inactive. The neuronal pathways for reflex horizontal eye movements require integrity of the region surrounding the sixth nerve nucleus and are yoked to the contralateral third nerve via the medial longitudinal fasciculus (MLF). Two disparate pieces of information are obtained from the reflex eye movements. First, in coma

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Figure 27-9. Ventilatory patterns seen with lesions at different levels in the brain. Note that both structural lesions and metabolic disturbances may exhibit either Cheyne-Stokes respiration or central hyperventilation, thus making them less useful for anatomic localization. Pontomedullary lesions most often show either ataxic or gasping respiratory patterns. (From Aminoff M, Greenberg D, Simon R: Clinical Neurology, 3rd ed. Stamford, Appleton-Lange, 1996, p 294, with permission.)

resulting from bihemispheral disease or metabolic or drug depression, the eyes move easily or “loosely” from side to side in a direction opposite to the direction of head turning. The ease with which the globes move toward the opposite side is a reflection of disinhibition of brainstem reflexes by damaged cerebral hemispheres. Second, conjugate oculocephalic movements demonstrate the integrity of brainstem pathways extending from the high cervical spinal cord and medulla, where vestibular and proprioceptive input from head turning originates, to the midbrain, at the level of

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the third nerve. Thus, full and conjugate eye movements induced by the oculocephalic maneuver demonstrate the intactness of a large segment of brainstem and virtually exclude a primary lesion of the brainstem as the cause of coma. Caloric stimulation of the vestibular apparatus (oculovestibular response) is an adjunct to the oculocephalic test, acting as a stronger stimulus to reflex eye movements but giving fundamentally the same information. It is also used to test eye movements in individuals with suspicion of an unstable cervical spine. Irrigation should be preceded by confirmation of integrity of the tympanic membrane by otoscopy. The condition of the tympanic membrane should be recorded in detail as irrigation may cause trauma to the tympanic membrane. The patient should be placed with the head flexed at 30 degrees. This orients the semicircular canal in a horizontal position. A large bore syringe is filled with 20 to 30 mL of ice water, which is used to irrigate the external auditory canal. The normal response is the development of nystagmus. The eyes move slowly to the irrigated side, followed by rapid movement of the eyes to the midline. Because nystagmus is named from its rapid phase, the use of cold water causes nystagmus to the opposite side. If instead warm water is used, the eyes will show the rapid component toward the side irrigated; the mnemonic COWS, which stands for “cold opposite, warm same” can be used to remember the response.16 Irrigation of the external auditory canal with cool water causes convection currents in the endolymph of the labyrinths of the inner ear. An intact brainstem pathway from the labyrinths to the oculomotor nuclei of the midbrain is indicated, with brief latency, by tonic deviation of both eyes (lasting 30 to 120 seconds) to the side of cool-water irrigation. Bilateral conjugate eye movements therefore have similar significance as full oculocephalic responses. If the cerebral hemispheres are functioning properly, as in hysterical coma, an obligate rapid corrective movement is generated away from the side of tonic deviation. The absence of this nystagmus-like quick phase signifies that the cerebral hemispheres are damaged or suppressed. The caloric test is also helpful for differentiating organic coma from hysterical coma. Hysterical patients will develop nystagmus from caloric testing. Caloric testing may also reveal gaze paralysis, individual muscle paresis, or internuclear ophthalmoplegia. In metabolic encephalopathy in the early stages, the oculocephalic reflexes are intact.17 The Glasgow Coma Scale The Glasgow Coma Scale (GCS) (see Table 27-1) grades three neurologic parameters. Patients who open their eyes spontaneously, obey commands, and are oriented score a total of 15 points, the highest possible score, whereas flaccid patients who neither open their eyes nor talk score the minimum of 3 points. A GCS score of 8 or less is the generally accepted definition of coma. Head-injured patients with

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Figure 27-10. Pathways mediating conjugate horizontal eye movements. In a comatose patient with an intact brain stem, head rotation causes eye deviation away from the direction of the rotation. Irrigation of the tympanic membrane with iced water results in rotation of the eyes toward the stimulated side, due to inhibition of the vestibulo-ocular pathways. (From Aminoff M, Greenberg D, Simon R: Clinical Neurology, 3rd ed. Stamford, AppletonLange, 1996, p 292, with permission.)

a GCS score of 8 or less are categorized as having a severe head injury; those with a GCS score of 9 to 12 are categorized as having a moderate head injury; and those with a GCS score of 13 to 15 are categorized as having a mild head injury.18,19

Laboratory Examination for Acute Confusion and Coma Chemical blood determinations are made routinely to investigate metabolic, toxic, or drug-induced encephalopathies. The major metabolic aberrations encountered in clinical practice are those of electrolytes, calcium, blood urea nitrogen (BUN), glucose, plasma osmolarity, and hepatic dysfunction (NH3). Toxicologic analysis is of great value in any case of coma where the diagnosis is not immediately clear. However, the presence of exogenous drugs or toxins, especially alcohol, does not ensure that other factors, particularly head trauma, may not also contribute to the clinical state. This point cannot be overstated: The presence of alcohol does not ensure that alcohol is the cause of the altered mental status. Other, life-threatening, causes MUST be ruled out. Ethanol levels in nonhabituated patients of 200 mg/dL generally cause confusion and impaired mental activity and above 300 mg/dL are associated with stupor. The development of tolerance may allow the chronic alcoholic to remain awake at levels over 400 mg/dL.

Imaging The increased availability of computed tomography (CT) and magnetic resonance imaging (MRI) has focused attention on causes of coma that are radiologically detectable (e.g., hemorrhage, tumor, or hydrocephalus). This approach, although at times expedient, is imprudent because most cases of confusion and coma are metabolic or toxic in origin. The notion that a normal CT scan excludes anatomic lesions as the cause of coma is also erroneous. Early bilateral hemisphere infarction, small brainstem lesions, encephalitis, meningitis, mechanical shearing of axons as a result of closed head trauma, absent cerebral perfusion associated with brain death, sagittal sinus thrombosis, and subdural hematomas isodense to adjacent brain are some of the lesions that may be undiagnosed with CT. Even MRI may fail to demonstrate these processes early in their evolution. Nevertheless, in coma of unknown etiology, CT or MRI should be performed. In those cases in which the etiology is clinically apparent, these tests provide verification and define the extent of the lesion.

Electroencephalography The EEG is abnormal in almost all conditions of impaired consciousness but may point to otherwise unsuspected diagnoses. Some conditions, such as hepatic encephalopathy, herpes encephalitis, and barbiturate or other anesthetic

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intoxications, have characteristic, although not necessarily diagnostic EEG findings. The EEG is useful in metabolic or drug-induced confusional states but is rarely diagnostic in coma, with the exception of comas due to clinically unrecognized seizures, herpes virus encephalitis, and CreutzfeldtJakob disease. The amount of background slowing of the EEG is a useful gauge of the severity of any diffuse encephalopathy. Predominant high-voltage slowing (delta waves) in the frontal regions is typical of metabolic coma, as from hepatic failure, whereas widespread fast (beta) activity implicates the effects of sedative drugs. A pattern of “alpha coma” is defined by widespread, invariant 8- to 12-Hz activity superficially resembling the normal alpha rhythm of waking but unresponsive to environmental stimuli. Alpha coma results from either high pontine or diffuse cortical damage and is associated with a poor prognosis. Coma due to persistent epileptic discharges not clinically manifested may be revealed by EEG recordings. Normal alpha activity on the EEG also may alert the clinician to the locked-in syndrome or a hysterical case. Computed on-line EEG analysis and evoked potential recordings (auditory and somatosensory) are useful additional methods for coma diagnosis and monitoring. The EEG is less often used now to assess for focal cerebral disease but remains useful to demonstrate focal dysfunction before pathology is visible on CT (e.g., focal temporal lobe EEG abnormalities in HSV encephalitis).

Lumbar Puncture Lumbar puncture is now used more judiciously in cases of coma or confusion because the CT scan excludes intracerebral hemorrhage and most cases of subarachnoid hemorrhage. The use of lumbar puncture in coma is limited to diagnosis of meningitis or encephalitis, and instances of suspected subarachnoid hemorrhage in which the CT is normal. Lumbar puncture should not be deferred if meningitis is a strong clinical possibility. Xanthochromia is documented by spinning the CSF in a large tube and comparing the supernatant to water. This yellow coloration indicates preexisting blood in the CSF (or very high protein levels) and permits exclusion of a traumatic puncture. Initial and final tubes should be inspected for a decrement in the number of erythrocytes, the presence of which indicates traumatic puncture. Knowing the pressure within the subarachnoid space is of further help in interpreting the cell count and protein content of the CSF. The primary contraindication to lumbar puncture is the presence of increased intracranial pressure (ICP) caused by cerebral edema or a mass lesion (e.g., brain abscess). A lumbar puncture in the presence of increased ICP can lead to a continued CSF leak, precipitating herniation of a temporal lobe over the tentorium cerebelli or a cerebellar tonsil through the foramen magnum, leading to neurologic deterioration and death. The risk of

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herniation is low (<2%) in patients with meningitis alone. The risk increases substantially (10% to 20%) in patients with mass lesions. In most situations, patients with papilledema or focal neurologic signs should have a CT scan to rule out a mass lesion before lumbar puncture is performed.

Neurologic Diagnoses Common to the Intensive Care Unit Overview of Severe Stroke Severe stroke is an emergency, requiring rapid neurologic assessment and diagnosis. After history and physical examination, CT is the first diagnostic step with the aim of determining the extent, localization, and possible pathophysiology of ischemia to direct specific diagnostic and therapeutic options. Early CT signs, including the size of the hypodensity and brain swelling, are important prognostic markers. Cerebral angiography should be performed if acute occlusion of the basilar artery or middle cerebral artery trunk is suspected, and intra-arterial thrombolysis is a potential therapy. Intravenous thrombolysis has been proven to be effective in improving outcome in severe stroke; it is safe if the exclusion criteria are strictly applied. Ventricular drainage should be performed when there is marked ventricular dilatation due to obstruction or blood in the ventricles. Most patients with cerebellar hemorrhage of more than 3 cm in diameter should undergo surgery to avoid brainstem compression and hydrocephalus. In suitable operative candidates, nondominant hemisphere putaminal and lobar hemorrhages with lateral displacement of midline structures and extensive edema should be evacuated if the patient’s level of consciousness deteriorates rapidly, or if elevation of ICP cannot be controlled pharmacologically, and herniation is impending. Patient selection for surgery must be carefully performed, considering age, clinical status, and possible contraindications such as cerebral amyloid angiopathy and coagulation disorders.20 Ischemic Stroke Ischemic stroke may result from either embolic or thrombotic occlusion of an intracerebral artery, a distinction often difficult to make on clinical grounds. Nearly 50% of patients with stroke have had one or more premonitory transient ischemic attacks (TIAs). The diagnosis of cardioembolic stroke is strongly supported by the presence of conditions that predispose to embolus formation, such as mitral stenosis, atrial fibrillation, endocarditis, or myxomatous mitral valve prolapse. In addition to dislodged thrombi, emboli may also consist of fat, tumor cells, and air or nitrogen bubbles. Stroke symptoms generally evolve rapidly, often becoming maximal within seconds to minutes (see Chapter 13).21

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Cerebral Hemorrhage The onset of symptoms is usually less abrupt than it is when an embolism occurs—symptom evolution over several hours is characteristic. Headache, vomiting, and altered states of consciousness are common symptoms. Stupor, coma, and decerebrate rigidity may result from large shifts or extension of blood into the ventricles. In pontine hemorrhage, there is paralysis of conjugate gaze, marked pupillary myosis, and flaccid quadriplegia with bilateral long tract signs. Decerebration is often present. Hemorrhage into the pons produces a fulminant syndrome in which coma occurs within seconds to minutes, and death follows within 48 hours. Hyperthermia often occurs because muscular rigidity and shivering increase body heat, while interruption of sympathetic pathways in the brain stem prevents sweating. Direct hemorrhage into the fourth ventricle is the rule.22 Cerebellar hemorrhage leads to headache, vomiting, unsteadiness of gait, and collapse. Examination may reveal nuchal rigidity, ipsilateral paresis of conjugate gaze or skew deviation, dysarthria, reduced corneal reflex, and peripheral facial weakness. Plantar reflexes are initially flexor but become extensor as the patient deteriorates. Cerebellar hemorrhage is very important to diagnose, because it can lead to rapid death via brainstem compression. Patients with cerebellar hematomas may appear stable but may worsen suddenly. Cerebellar hemorrhage is regarded as a neurosurgical emergency. Controversy remains concerning the management of patients with cerebellar hemorrhage. However, patients with deteriorating consciousness are very likely to die irrespective of the choice of therapy, and it is not clear if surgical intervention will benefit patients in a deeply comatose state (see Chapter 13).23,24 Subarachnoid Hemorrhage While an intracranial aneurysm may occur at any age; middle age is the most common time for rupture. The probability of rupture is small when the aneurysm is less than 1 cm in diameter. In those that rupture, approximately 50% will experience a warning leak before aneurysm rupture. The leak generally occurs a few days to one month before the catastrophic event, and produces abrupt-onset headache, nausea and vomiting, photophobia, meningismus, and, occasionally, focal neurologic signs that depend on the location of the aneurysm. The diagnosis is rarely made until frank rupture of the aneurysm, when the patient presents with a sudden violent headache (the worst ever experienced “like being hit over the head by a hammer”), followed rapidly by confusion and agitation, collapse, and coma. There may be no focal neurologic signs. Nuchal rigidity and other signs of meningeal irritation will be present, and the finding of grossly bloody spinal fluid under increased pressure will confirm the diagnosis. The initial diagnostic test of choice is a CT scan. Subarachnoid hemorrhage requires emergent neurosurgical consultation (see Chapter 6).8

Table 27-2  The Hunt and Hess Classification of Subarachnoid Hemorrhage Grade I: Grade II: Grade III: Grade IV: Grade V:

Asymptomatic or minimal headache and slight nuchal rigidity. Moderate-to-severe headache, nuchal rigidity, and no neurologic deficit other than cranial nerve palsy. Drowsiness, confusion, or mild focal deficit Stupor, moderate-to-severe hemiparesis, possible early decerebrate rigidity, and vegetative disturbances Moribund appearance

From Hunt WE, Hess RM: Surgical risk as related to time of intervention in the repair of intracranial aneurysms. J Neurosurg 1968;28:14–20, with permission.

According to the Hunt and Hess classification (Table 27-2), five grades are used for classification and decision making in subarachnoid hemorrhage.25 Hypertensive Encephalopathy Hypertensive encephalopathy generally develops in response to rapid elevation of systemic blood pressure and is thought to result from autoregulatory failure of cerebral blood flow. The syndrome is most commonly encountered in patients with chronic hypertension. In this situation, a diastolic blood pressure of 150 mm Hg is often required to produce symptoms, whereas patients with acute hypertension (e.g., from eclampsia, glomerulonephritis, or drugs) may become symptomatic with a diastolic pressure of 100 mm Hg. There is rapid development of confusion and toxic delirium, often accompanied by myoclonic twitching or convulsion, which may progress to a stuporous or coma state. Focal neurologic signs, such as aphasia, hemiparesis, or cortical blindness, may be present. A prodrome may be seen of increasingly severe headaches, characteristically occipital and worse in the early morning. These features resemble those of headaches caused by increased intracranial pressure. Various visual symptoms, such as blurring, scintillating scotoma, or cortical blindness may appear. Examination reveals elevation of diastolic blood pressure, retinal hemorrhages and exudates, papilledema, and focal neurologic signs.26 Intracranial Lesions Intracranial lesions may be classified as focal or diffuse, although both forms of injury frequently coexist. Focal lesions include epidural hematomas, subdural hematomas, contusions, and intracerebral hematomas. Patients with diffuse brain injury may have a normal CT scan but demonstrate altered mental sensorium or even deep coma. Diffuse brain injury is the most common type of injury. The pathophysiology of diffuse injury is not completely understood, but diffuse axonal injury is thought to be one of the major mechanisms of injury.27,28 Postconcussive symptoms, which

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include headache, dizziness, fatigue, and documented deficits in cognition, are seen even after mild injuries without loss of consciousness. In general, the prognosis for recovery is very good, with most cognitive and somatic sequelae improving markedly by 3 months, and 85% of patients experience no disabling symptoms at 1 year of follow-up.29,30 In chronic subdural hematoma, a history of injury, occasionally slight, is present in about 75% of cases. The symptoms usually manifest at 2 to 3 months. Headache is a prominent symptom. A progressive fluctuating disturbance of consciousness is typical leading to a deep somnolence with few, if any, neurologic signs. CT scanning confirms the diagnosis, the lesion being shown as a biconvex, hypodense zone displacing the surface of the brain from the cranium. A stage occurs during which the hematoma is isodense with the brain substance and therefore not visible. An acute subdural hematoma cannot be differentiated clinically from an acute epidural hematoma. Extensive work from the Traumatic Coma Data Bank has provided data on the outcome in severe head injury. Verbal output, eye opening, and the best motor response are important predictors of ultimate outcome. Eighty-five percent of patients with aggregate GCS scores of three or four die 24 hours after injury. Yet a number of patients with a poor initial findings, including absent pupillary light responses, survive, suggesting that aggressive management is justified in virtually all patients. Patients younger than approximately 20 years, particularly children, may make remarkable recoveries after having grave early neurologic signs. Increased intracranial pressure, older age, and signs of cisternal compression and midline shift on CT scan are all poor prognostic signs (see Chapters 8 and 28).31 Increased Intracranial Pressure Signs and symptoms of increased intracranial pressure (ICP) include headache, nausea and vomiting, lethargy, diplopia, transient visual disturbances, and papilledema. As intracranial pressure continues to rise there is brain stem distortion, causing bradycardia, elevation of blood pressure, and slowing of respiratory rate, termed the Cushing reflex. The most common symptom of increased ICP is headache, usually described as diffuse or bifrontal, worse at night and sometimes awakening the patient from sleep. It can be aggravated by coughing, sneezing, or straining. The site and quality of headache are less helpful, but any severe or unusual headache should be taken seriously. When ICP rises quickly, there is depression of the level of consciousness. The most important physical sign of increased ICP is drowsiness. This is much more important than papilledema. Papilledema may not occur if the rise in ICP is very recent. Many older people do not develop papilledema, even with great elevations of ICP. Patients may lapse into coma and die from increased ICP before papilledema has time to develop.

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The treatment of cerebral edema involves increasing serum osmolality as well as inducing hyperventilation and volume depletion. The normal serum osmolality is 275 to 290 mOsm/kg. An increase in serum osmolality of as little as 10 mOsm/kg is enough to have a significant effect on cerebral edema. Mannitol is generally given in small boluses rather than as a continuous infusion. In addition to the osmotic effect, mannitol decreases CSF production, increases cerebral blood flow and cerebral oxygen delivery, and decreases blood viscosity, thereby improving perfusion. Mannitol is generally effective for 48 to 72 hours. Its use beyond 72 hours is ineffective because mannitol slowly leaks out of the blood vessel, especially in areas of blood-brain barrier breakdown, with resulting loss of the osmotic gradient. Serum electrolytes and osmolality should be carefully monitored. Hyperventilation is generally initiated for acute management of increased ICP, but sustained hyperventilation as a mode of therapy has not been found to be beneficial, as compensatory mechanisms come into play.32 Further, recent studies show that some patients with increased ICP, such as those with acute head trauma, may have low blood flow to begin with. Hyperventilation in these individuals may actually worsen the clinical condition.33 When undertaken, hyperventilation should be moderate, bringing the PaCO2 down to 28 to 32 mm Hg. Furosemide has been used as an adjunct to mannitol, although it should not be used alone (see Chapter 25).

Brain Herniation Syndromes Herniation refers to displacement of brain tissue away from a mass, past a less mobile structure such as the dura, and into a space that it normally does not occupy. The common herniations seen at postmortem examinations are trans falcial (displacement of the cingulate gyrus under the falx in the anterior midline), transtentorial (medial temporal lobe displacement into the tentorial opening), and foraminal (the cerebellar tonsils forced into the foramen magnum). Effective and quick relief of brain compression depends on recognition of the site of the primary expanding lesion. Accurate localization depends on interpretation of neurologic symptoms and signs and the results of the imaging studies. The brain herniates as a consequence of increased intracranial pressure. It can herniate in five locations (Figs. 27-11 and 27-12):

1. Mesial temporal uncus through the tentorium (transtentorial or uncal herniation). 2. Midline thalamus through the tentorium (central herniation). 3. Medulla and cerebellar tonsils through the foramen magnum (tonsillar herniation) (Fig. 27-13). 4. Out of a craniotomy defect, and

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Figure 27-11. Site of intracranial herniation. 1—cingulate herniation; 2—tentorial (uncal) herniation; 3—central herniation;4—tonsillar herniation. (From Rengachary S, Wilkins R: Principles of Neurosurgery. London, Wolfe, 1994, pp 2.8 and 2.9, with permission.)

Figure 27-13. A different view of the cerebellar tonsils on the medulla. (From: Jennett B, Galbraith S: An Introduction to Neurosurgery, 4th ed. Boston, Heinemann, 1983, with permisison.)

5. Cingulate gyrus under the falx in the midline (see Fig. 27-12). Uncal, central, and tonsillar herniation syndromes can be fatal unless recognized and treated promptly.

Figure 27-12. Site of intracranial herniation. 1—cingulate herniation; 2—tentorial (uncal) herniation; 3—central herniation; 4—tonsillar herniation. (From Rengachary S, Wilkins R: Principles of Neurosurgery. London, Wolfe, 1994, pp 2.8 and 2.9, with permission.)

Craniotomy and cingulate herniation are very serious, but not necessarily fatal. The major causes of brain herniation are examples of acute mass lesions or decompensated hydrocephalus. A lesion with anatomic asymmetry and rapid onset is more likely to produce herniation than is a slow onset, symmetric lesion. Herniation has been reported after lumbar puncture (LP) in cases of high ICP. However, tonsillar herniation is rarely ever reported after an LP in patients suspected of having idiopathic intracranial hypertension (IIH). On the other hand, tonsillar herniation may occur as a late complication following lumbo-peritoneal shunt insertion (occasionally used in the treatment of patients with IIH). This may be due to the decrease in brain stiffness, that is, an increase in brain compliance as the condition improves following shunt insertion.34 Nonspecific signs and symptoms of increased

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ICP include headache, nausea, vomiting, hypertension, bradycardia, papilledema, sixth cranial nerve palsy, transient visual disturbances, and alteration in consciousness. Although it has been recognized that aggressive medical management can reverse transtentorial herniation, it is believed that overall outcome in such patients is poor.35 Descending tentorial herniation (DTH) can be diagnosed with computed tomography. Early signs of uncal herniation include encroachment on the suprasellar cistern, displacement of the brain stem, enlargement of the ipsilateral crural subarachnoid space, and compression of the contralateral cerebral peduncle. Increasingly severe combined uncal and hippocampal DTH results in progressive obliteration of the suprasellar and interpeduncular cisterns, elongation or compression of the brainstem, and inferior or posterior displacement of the basilar artery. Effacement of the tentorial cisterns, depression of the pineal body, and contralateral hydrocephalus have been described.36,37

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Figure 27-14. Time course of signs and symptoms of ethanol withdrawal. (From Victor M, Adams RD: The effect of alcohol on the nervous system. Res Publ Assoc Res Nerv Ment Dis 1952;32:526–573, with permission.)

Seizures Approximately ten persons per 1000 population have epilepsy, and five times as many have had a seizure at one time or another. Epileptic seizures also may be caused or exacerbated by underlying systemic diseases, the ingestion of drugs, and noncompliance with medications. Generalized tonic clonic (grand mal) seizures are typically followed by a transient confusional postictal state that resolves within 1 to 2 hours. If there are no witnesses to the seizure itself, patients may present with a confusional state or agitated delirium with no apparent cause (see Chapter 26). Status Epilepticus Status epilepticus is a condition in which seizures continue uninterruptedly for at least 30 minutes or occur so frequently that consciousness is not regained between attacks. The most dangerous form of status epilepticus is convulsive status epilepticus, but nonconvulsive status or epileptic twilight states resulting from either continuous or rapidly repetitive temporal lobe seizures or absence attacks may also occur. Status epilepticus is defined as seizures lasting longer than 30 minutes or repetitive seizures over 30 minutes between which the patient does not return to a baseline neurologic level. A patient may have a decreased level of consciousness if the seizure is still occurring (nonconvulsive status epilepticus) or if the patient is postictal. The two states can be difficult to differentiate without an EEG. Anticonvulsant levels need to be checked for any seizure patient on medication presenting in status epilepticus, as many anticonvulsants are epileptogenic at toxic levels. Additional elements need to be considered in the differential diagnosis for immunocompromised patients, particularly tubercular or fungal meningitis, and toxoplasmosis. Ethanol withdrawal seizures occur within 48 hours after the beginning of abstinence; in about 66% of cases they occur within 7 to 24 hours (Fig. 27-14). About 33% of patients with withdrawal seizures develops delirium tremens (see Chapter 26).

Anoxic, Infectious, Metabolic, and Toxic Encephalopathies The term encephalopathy is generally used to designate diffuse cerebral dysfunction. Such dysfunction is typically manifested by alterations in cortical function and disturbances of consciousness, ranging from mild confusional states to coma. Abnormalities of consciousness reflect dysfunction of both cerebral hemispheres or of the reticular activating system in the brain stem. Encephalopathies may also be characterized by focal deficits, reflecting more localized cerebral dysfunction. In general, the cause is a systemic disorder that affects the brain diffusely, though some regions are more severely involved than others. Metabolic encephalopathies are common among patients in the critical care unit. Septic, hypoxic-ischemic, hepatic, and uremic encephalopathies are the most frequently seen. Neurologic manifestations are often present in the early stages of systemic illness and may be the first symptom. The severity of encephalopathy generally correlates with that of the systemic illness. Electroencephalogram is useful to grade the severity of encephalopathy. With some exceptions, such as hypoxic-ischemic encephalopathy, most metabolic encephalopathies are reversible unless secondary complications such as brain herniation occur.38 Metabolic and toxic encephalopathies cannot be distinguished with confidence from those caused by mass lesions, but certain general points can be made. Onset is often insidious except when an acute event, such as cardiac arrest or drug overdose, is responsible. In general, neurologic findings are symmetric or multifocal in distribution, and tremor, asterixis, and myoclonus are common. Asterixis (flapping tremor) consists of brief periods of a sustained muscular contraction, as when the arms are held outstretched against gravity. Focal or lateralizing signs are absent or inconsistent;

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when present, they sometimes alternate from one side to the other. Preserved pupillary responses in the context of impaired brain stem function are strongly suggestive of metabolic or toxic disorders. Further evaluation of the encephalopathic patient is directed by the history and physical examination. Imaging usually shows no pertinent abnormalities, but may reveal preexisting abnormalities (e.g., chronic subdural hematoma or previous brain damage), the effects of which can mimic or accentuate metabolic delirium. Because focal neurologic abnormalities indicate focal pathology, patients with focal findings should undergo CT or MRI. Patients with signs of meningeal irritation must undergo lumbar puncture for cerebrospinal fluid examination. Because of the risk of herniation in patients with spaceoccupying CNS lesions, a CT scan should be performed before lumbar puncture in any obtunded patient with a focal neurologic abnormality. In the encephalopathic patient with nonfocal neurologic examination results and lacking meningeal signs, the underlying etiology is likely to be metabolic. Laboratory evaluation may define the nature of the underlying problem. Electroencephalography is a valuable tool for arriving at a correct diagnosis of hepatic encephalopathy or inconvulsive status epilepticus. In unresponsive patients with no evidence of metabolic disarray, focal neurologic abnormalities, or meningeal irritation, consideration should be given to an underlying psychiatric disorder. Intoxications Stupor or coma caused by depressant drug poisoning usually presents the characteristic picture of acute general anesthesia. CNS depression tends to be bilateral and symmetric. Respiratory and circulatory control mechanisms in the lower brainstem usually are not affected unless very high dosages of drug are present. Except with the seldom-used sedative glutethimide and very high-dose barbiturates, the pupillary light reflexes are preserved.39 Ethanol Even though “legal intoxication” requires a blood alcohol concentration of at least 80 to 100 mg/dL, behavioral, psychomotor, and cognitive changes are seen at levels as low as 20 to 30 mg/dL (i.e., after one to two drinks). Narcosis, or deep sleep, is induced at twice the legal intoxication level, and even in the absence of concomitant medications, death can occur at levels between 300 and 400 mg/dL. Ethanol, either alone or in combination with agents such as benzodiazepines, may be responsible for more toxic overdose deaths than any other agent. Phencyclidine Phencyclidine, a cyclohexylamine derivative related to ketamine, is widely used in veterinary medicine to immobilize large animals and is sometimes described as a dissociative

anesthetic. Phencyclidine is taken orally, by smoking, or by intravenous injection. It is also used as an adulterant in illicitly sold tetrahydrocannabinol (THC), lysergic acid diethylamide (LSD), amphetamine, and cocaine. The most common street preparation, “angel dust,” is a white granular powder that contains 50% to 100% of the drug. Low doses produce agitation, excitement, impaired motor coordination, dysarthria, and analgesia. Users may have horizontal or vertical nystagmus, flushing, diaphoresis, and hyperacusis. Behavioral changes include distortions of body image, disorganization of thinking, and feelings of estrangement. Higher doses may produce hypersalivation, vomiting, myoclonus, fever, stupor, or coma. Extremely high doses cause convulsions, opisthotonus, and decerebrate posturing, which may be followed by prolonged coma. Lysergic Acid Diethylamide LSD is a very potent drug; oral doses as low as 20 mg may induce profound psychological and physiologic effects. Tachycardia, hypertension, pupillary dilation, tremor, and hyperpyrexia occur within minutes following oral LSD ingestion in doses of 0.5 to 2 mg/kg. A variety of bizarre and often conflicting perceptual and mood changes, including visual illusions, synesthesias, and extreme lability of mood, usually occur within 30 minutes after LSD intake. The action of LSD may persist for 12 to 18 hours, even though the halflife of the drug is only three hours. Opioids High doses of opiates taken intentionally (e.g., suicide attempt) or by a user who has misjudged the potency of the substance can result in a toxic reaction or lethal overdose. While toxic reactions are seen with all opiates, more potent drugs such as fentanyl (80 to 100 times more powerful than morphine) are especially dangerous. The typical syndrome, which occurs immediately with intravenous overdose, includes shallow respirations at a rate of two to four per minute, pupillary myosis (with mydriasis once brain anoxia develops), bradycardia, decrease in body temperature, and general absence of responsiveness to external stimulation. If left untreated, symptoms can progress to cyanosis, and death can ensue from respiratory depression and cardiorespiratory arrest. An “allergic-like” reaction to intravenous heroin, apparently at least in part related to adulterants, can also occur and is characterized by decreased alertness, a frothy pulmonary edema, and an elevation in the blood eosinophil count. Sympathomimetics Characteristically, overdose is characterized by a confusional state with hallucinations, hyperactivity, stereotyped behavior, and schizophreniform paranoid psychosis. Physical examination shows tachycardia, hypertension, and dilated pupils. Hyperthermia, tremors, and seizures may occur. Cocaine and amphetamine use have been associated with

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thrombotic, embolic, and hemorrhagic strokes. Because the actions of amphetamine last longer than those of cocaine, amphetamine intoxication is more likely to require treatment.

Infections Brain Abscess Approximately 85% of abscesses are in the cerebrum. Of these, 80% are frontal and temporal, 18% are parietal, and 2% are occipital. Infections commonly arise from distant sources. The more common primary sources are middle ear infections, sinusitis, bronchiectasis, endocarditis, and congenital heart disease. Brain abscess often presents more like a tumor than an infection. Many patients do not appear toxic. Fewer than 50% have fever or the combination of fever, headache, and focal neurologic deficits. Most patients present subacutely, with a two week or longer history of headache, mild-to-moderate alteration in mental status, and focal neurologic abnormality.40 Nausea and vomiting occur in 20% to 50% of cases. Stiff neck or papilledema occurs in fewer than 25%. Important focal neurologic signs are hemiplegia, aphasia, and hemianopia. Seizures occur early in 30% to 40% of cases. Approximately 15% of abscesses occur in the cerebellar hemispheres and present with signs of ataxia, nystagmus, and dysmetria. The untreated patient will become progressively obtunded, and fatal brain herniation will occur. Diagnosis hinges on the demonstration of a ring-enhancing lesion (or lesions) or cerebritis. MR imaging is more sensitive, but CT detects more than 95% of abscesses. Viral Meningitis Fever, photophobia, headache, stiff neck, Kernig’s (strong passive resistance to attempts to extend the knee from the flexed thigh position) or Brudzinski’s (involuntary flexion of hips and knees after attempting to flex neck of a supine patient) signs, and a CSF that is sterile by conventional culture techniques for bacteria and fungi are the hallmarks of aseptic meningitis. Usually, the disease is the result of viral infection. Nonviral causes include drug-associated chemical meningitis, leptospirosis, Mycoplasma pneumoniae infection, and Rickettsia rickettsii infection. The presence of seizures, neurologic findings other than meningismus, or a depressed level of consciousness indicate a meningoencephalitis. Encephalitis tends to occur in a pre-existing illness not, initially, involving the CNS with either characteristic signs and symptoms (e.g., typhus, measles) or nonspecific ones (e.g., influenza) along with disturbances of the sleep rhythm and signs of cerebral irritation (e.g., epileptic seizures, myoclonus, and choreoform disturbances of movement).

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Herpes simplex encephalitis (HSE) is a serious disease that has a 70% mortality rate when untreated. Most other viral causes of encephalitis are more benign. The availability of antiviral therapy for HSE makes it imperative to distinguish HSE from other viral encephalitides and other diseases that mimic HSE. Herpes simplex encephalitis is a medical emergency requiring rapid diagnosis and treatment if major morbidity and death are to be avoided. Fever, headache, and focal neurologic signs, such as focal seizures, visual field disturbances, aphasia, and hemiparesis, evolve over several days. Altered behavior is also common. Memory loss, said to be classic, is found in only 25% of patients.41–45 Nonherpetic viral encephalitis presents with fever, headache, a depressed level of consciousness, and, occasionally, seizures. It usually does not have the temporal and frontal lobe predilections of herpes simplex; behavioral change and focal aphasia and hemiplegia are rare. Only rarely do other viruses mimic the focality of HSE. EpsteinBarr virus infection, St. Louis encephalitis, and enterovirus infections have been proven by biopsy to mimic HSE. The main clue to herpes, versus other causes of viral encephalitis, is its focal nature, especially the involvement of the temporal lobe.46 Bacterial Meningitis Because the meninges are pain sensitive, the cardinal symptom of meningitis is headache; some patients also report neck ache and backache. More than 85% of patients with bacterial meningitis classically present with fever, headache, meningismus, and signs of cerebral dysfunction (confusion, delirium, or declining level of consciousness). Meningismus may be subtle, marked, or accompanied by Kernig’s or Brudzinski’s signs. However, these signs are elicited in half of adult patients with bacterial meningitis and their absence does not exclude the diagnosis. Many of the signs of bacterial meningitis, including alteration in consciousness, are present in patients following neurosurgery or head trauma. Meningitis is difficult to diagnose in this situation, and the physician should have a low threshold for performing CSF examination if any clinical deterioration occurs in these settings. Some conditions can lead to white cells in the CSF and can be misdiagnosed as meningitis; these disorders include cerebral infarcts, both bland and hemorrhagic, seizures, migraine headaches, and hypoglycemia. The pleocytosis in these conditions is acute and transient. The typical CSF findings in acute bacterial meningitis consist of an elevated opening pressure, neutrophilic pleocytosis, elevated protein concentration, and hypoglycorrhachia. The opening pressure is elevated in virtually all cases. Values exceeding 600 mm H2O (600/13.5 = mm Hg) suggest cerebral edema, communicating hydrocephalus, or the presence of intracranial suppurative foci. The gross appearance of the fluid may be cloudy or turbid if the white

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cell count is elevated. Occasionally, the fluid may appear turbid owing to the presence of microorganisms in the absence of significant CSF pleocytosis; this is an ominous prognostic sign. If the lumbar puncture is traumatic, the CSF may be bloody at first, but it should clear as flow continues. Although xanthochromia can occur in meningitis, this finding should suggest the possibility of subarachnoid hemorrhage, and in patients with valvular heart disease, it raises the possibility of ruptured mycotic aneurysm. The leukocyte concentration in CSF usually is elevated in untreated bacterial meningitis, with counts ranging from 103 to greater than 106 cells/mL. Values in the latter range are found in 60% to 70% of cases. The leukocytosis shows a neutrophilic predominance. A very low CSF white cell concentration in bacterial meningitis has been associated with a poor outcome. Therefore, Gram stain and culture should be performed on all CSF specimens, even in the absence of CSF pleocytosis. The CSF protein concentration is elevated in virtually all cases of bacterial meningitis, sometimes to an extreme degree when spinal block is present, presumably owing to disruption of the blood-brain barrier and/or generation of protein by leukocytes and/or microorganisms in the subarachnoid space. The CSF glucose concentration is less than 2.2 mM/L (40 mg/dL) in approximately 60% of patients with bacterial meningitis, and the CSF-to-serum ratio of glucose concentrations is less than 0.31 in approximately 70% of patients. The CSF glucose concentration must be compared with a simultaneous serum glucose concentration for proper evaluation. In the case of meningitis, treatment must not be delayed to obtain a CT or lumbar puncture. Lumbar puncture results will not be significantly compromised even if obtained immediately after antibiotic administration. If cultures are negative, bacterial antigens will remain positive. Human immunodeficiency virus (HIV) meningitis should be suspected in any patient with known or identified risk factors for HIV infection. Aseptic meningitis is a common manifestation of primary infection with HIV and occurs in 5% to 10% of cases. In some patients, seroconversion may be delayed for several months, and in seronegative patients, serology should be repeated after 3- and 6-month intervals. HIV can be cultured from CSF in some patients. Cranial nerve palsies are more common in HIV meningitis than in other viral infections, most commonly involving cranial nerves V, VII, or VIII (see Chapter 12). Cerebral Venous Thrombosis Cerebral venous thrombosis usually occurs after severe diseases, after furuncles in the region of the upper lip, in diseases of the middle ear, or postpartum. If the sinus cavernosus is affected, the diagnosis is obvious from the stasis in the eyelids. If the sinus longitudinalis sagittalis is affected, congestion in the hemisphere surfaces, especially

the parasagittal areas, gives symptoms of paraparesis with progression to disordered consciousness. Seizures also can occur. The CSF is usually xanthochromic.47

Encephalopathies Delirium Delirium is characterized by the acute onset of impairment of cognitive functions resulting from diffuse cerebral dysfunction. The course is usually fluctuating, brief and most often reversible. Delirium is multifactorial, involving interrelationships between patient vulnerability, predisposing factors at admission, and noxious insults or precipitating factors during hospitalization. A delirium episode is often the first sign of dementia requiring attention from medical and social service professionals. Ten percent of all hospital inpatients manifest some degree of delirium. It reaches 30% in surgical intensive care units (SICU) and coronary care units (CCU). It occurs most commonly in children and the aged. Preexisting brain damage, a history of substance abuse including alcohol, and a history of preexisting delirium increase the risk of developing the syndrome. Medications are often implicated and the list of implicated drugs is long. Delirium is characterized by severe attentional deficits in a patient with relatively preserved alertness. Although onset is usually acute, sometimes premonitory symptoms, such as daytime restlessness, anxiety, fearfulness, or hypersensitivity to light and sounds may occur. The patient is confused and disoriented, and has impaired reality testing. The patient is unable to distinguish between dreams, illusions, and true hallucinations, or between sleep and wakefulness, thus contributing to a disturbance of the sleep-wake cycle. The patient is easily distracted by irrelevant stimuli. The ability to think coherently is impaired and thought processes become slowly disorganized. Diurnal variability in behavior is a sign of delirium; it is usually more severe and incapacitating during the night and early morning hours (“sundowning”). EEG characteristics of delirium include slowing or dropout of the posterior dominant rhythm, generalized theta or delta slow-wave activity, poor organization of the background rhythm, and loss of reactivity of the EEG to eye opening and closing.48 The main differential diagnosis is with dementia. Dementia (an enduring or permanent decline in mental processes owing to an organic process not accompanied by a reduction in arousal) has a slower onset and the demented patient is alert. The sleepwake cycle is intact in dementia but is always disrupted in delirium. Delirium is reversible if the underlying cause is treated successfully. Untreated delirium may clear spontaneously or may progress to dementia or another organic mental syndrome. In general, the older the patient and the longer the

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period of delirium, the longer it takes to clear. Approximately 10% to 30% of delirious patients progress to coma or death. Proper electrolyte balance should be addressed. Optimal sensory, social, and nursing support should be provided. Dimmed light at night, frequent visits by staff and family, and explanations and reassurance should be given. Haloperidol is the drug of choice. Insomnia is best treated with a short acting benzodiazepine. Targeting preventive strategies toward identified risk factors (e.g., physical restraint use, malnutrition, adding more than three drugs, bladder catheter use, iatrogenic events) can be successful in the primary prevention of delirium.49 Postoperative Delirium Delirium is one of the most frequent symptoms of disease in elderly surgical patients. A large variation of incidence and prevalence data is reported probably due to different patient populations and inconsistent diagnostic criteria. In elderly medical and surgical inpatients, delirium has a prevalence rate of approximately 15% in postoperative patients; the prevalence rates vary greatly, ranging between 7% and 52%, depending on patient population and clinical setting. In nursing homes, the prevalence is even higher and delirium is often combined with dementia. Data support the statement that delirium is most often found in hospitalized somatically ill elderly patients.50 After surgical intervention, delirium can occur as a serious and possible lethal complication in approximately 5% to 15% of patients. After openheart and orthopedic surgery more than half of the patients are affected.51,52 Cerebral infarction, bleeding, long-lasting hypoperfusion, and profound hypoxia are well-known factors behind CNS dysfunction after anesthesia. Other explanations are the metabolic-endocrine stress response, anesthetic agents, and psychological factors related to changes in the environment. The clinical presentations can be obvious, as in cerebral death or stroke, but delirium also may be readily recognized. A more subtle and long-lasting deterioration in cognitive function is called postoperative cognitive dysfunction. This condition can only be detected with the use of neuropsychologic testing and recently, postoperative cognitive dysfunction has been detected as the most common cerebral complication after noncardiac surgery in elderly patients.53 Hypoxia after hip surgery, particularly after femoral neck fracture, is a common problem. A noted decreased incidence of delirium is thought due to supplemental oxygen, when indicated and monitored by pulse oximetry.51,54 Cognitive impairment caused by medication is more likely in the elderly than in younger patients. This reflects age- and disease-associated changes in brain neurochemistry and drug handling. Delirium (acute confusional state) is the cognitive disturbance most clearly associated with drug toxicity, but dementia has also been reported. The etiology

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of cognitive impairment is commonly multifactorial, and it may be difficult to firmly establish a causal role for an individual medication. In studies of elderly hospital patients, drugs have been reported as the cause of delirium in 11% to 30% of cases. Medication toxicity occurs in 2% to 12% of patients presenting with suspected dementia. In some cases, CNS toxicity occurs in a dose-dependent manner, often as a result of interference with neurotransmitter function. Druginduced delirium can also occur as an idiosyncratic complication. Finally, delirium may occur secondary to iatrogenic complications of drug use. Almost any drug can cause delirium, especially in a vulnerable patient.55 Delirium in the elderly after coronary artery bypass graft surgery is common. A history of a stroke and a longer duration of cardiopulmonary bypass may be a predisposing factor. A tendency to have experienced low cardiac output postoperatively has also been noted.56–58 Psychogenic Unresponsiveness In psychogenic unresponsiveness, the patient, although apparently unconscious, usually shows some response to external stimuli. Attempts to elicit the corneal reflex may cause a vigorous contraction of the orbicularis oculi. Marked resistance to passive movements of the limbs may be present, and signs of organic disease are absent. The caloric optokinetic responses, and EEG are all normal. It is not possible to mimic the roving eye movements of coma, nor it is possible to mimic the slow closure seen after the examiner raises the eyelids. The diagnosis of catatonic stupor as a cause of psychogenic unresponsiveness is more difficult. In such cases, the EEG may be abnormal. Catatonia This is most frequently a symptom of a psychotic state in which the patient, otherwise entirely normal, lies mute, immobile and unresponsive. The patient does not follow movements, does not appear to be paying any attention to the surroundings, and will often have rigidity of the limbs, which may remain in any position in which they are placed.7 Anoxic Encephalopathy Under normal conditions, 90% of the cerebral energy needed to transmit nervous impulses and to maintain ionic gradients across cell membranes derives from oxidation of glucose. The brain normally consumes 3.5 mL of O2/100 g of brain tissue/minute. When this rate declines to 2.5 mL, delirium supervenes; rates of cerebral oxygen metabolism below 2 mL/100g/min are incompatible with alertness. The brain can survive for only a few minutes if oxygen is reduced below critical levels. During total anoxia, consciousness is lost within 15 seconds. In humans, electroencephalographic changes may be noted with PO2 less than 35 mm Hg.

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Electrocerebral silence occurs after approximately 18 seconds of total anoxia. Transient circulatory arrest may lead to global cerebral ischemia and syncope, preceded by nonspecific premonitory symptoms such as paresthesias, light-headedness, palpitations, and “graying-out” of vision. Syncope is associated with pallor and loss of muscle tone. With prolonged ischemia, tonic posturing occurs, accompanied by irregular jerking movements resembling seizures. Depending on the duration, ventricular fibrillation or asystole may cause irreversible anoxic-ischemic brain damage. The prognosis varies according to the patient’s age, duration of circulatory arrest, and interval before resuscitation is undertaken. Circulatory arrest from ventricular fibrillation has a better prognosis than that from asystole. Neurologic consequences of circulatory arrest relate to the accumulation of intracellular calcium, increased extracellular concentrations of glutamate and aspartate, and increased levels of free radicals. In the mature nervous system, gray matter is more vulnerable to ischemia than white matter, and the cerebral cortex is more sensitive than the brain stem. Watershed areas bordering zones supplied by major arteries are especially vulnerable to circulatory arrest of less than five minutes duration. Generalized ischemia causes one of three types of anatomic brain injury: a limited hypoxic state presenting as a Korsakoff ’s type of memory loss with sparing of other mental performance; a more severe widespread neuronal damage with the corresponding clinical state varying from dementia with apathy to a virtually vegetative or “apallic state” presenting as neocortical death in which only brain stem function persists and, finally, a more brief and predominantly ischemic insult that produces infarction in the watershed or low-flow border-zone regions resulting in shoulder and proximal arm weakness or cortical blindness and related visual difficulties. In this last type of injury, complete recovery is usual. However, in rare patients, the circulatory arrest is followed, after 7 to 10 days, by a demyelinating encephalopathy, with increasing cognitive dysfunction and pyramidal or extrapyramidal deficits that may have a fatal outcome.59 Circulatory arrest of longer than 5 minutes’ duration may cause widespread and irreversible brain damage, resulting in prolonged coma. Prognosis for survival or useful recovery is poor, especially when brainstem reflexes (most notably the pupillary responses to light) are lost. Loss of pupillary reactivity for more than 24 hours, or persistence of coma for more than 4 days indicates a poor outcome. In one study of comatose survivors of cardiac arrest, those who continued to have nonreactive pupils, failed to open their eyes in response to pain, or had absent or reflex motor responses three days after onset of coma generally failed to survive or to regain useful independent function.60 Even if consciousness is regained, focal or multifocal neurologic signs may lead to significant disability from focal motor deficits, extrapyramidal disturbances (e.g.,

parkinsonism), sensory loss, seizures, myoclonus, and disturbances of higher cortical function from which recovery is usually delayed and incomplete. Intention (action) myoclonus is particularly characteristic in such circumstances; it is often activated by startle or various sensory stimuli and is only occasionally responsive to clonazepam, valproate, piracetam, or 5-hydroxytryptophan. Some patients never fully regain consciousness after circulatory arrest but remain in a persistent vegetative state or show evidence of brain death. The persistent vegetative state is characterized by the return of sleep-wake cycles and various reflex activities. Wakefulness is, however, without awareness.61,62 Jorgensen et al. found that the time to recovery of individual neurologic functions seemed to be the key to prognostication. Testing for caloric vestibular reflex or stereotypic reactivity differentiated patients regaining consciousness from those remaining unconscious at 24 hours. The presence of speech at 24 hours or the ability to cope with personal necessities at 72 hours predicted complete recovery.63 Locked-In Syndrome This syndrome occurs in patients with bilateral ventral pontine lesions. The most common etiology is pontine infarction; other etiologies include pontine hemorrhage, trauma, central pontine myelinolysis, tumors, and encephalitis. In pontine lesions with tetraplegia and cranial-nerve disturbances, loss of responsiveness may be misinterpreted as coma. “Pseudocoma” of this kind may be associated with normal consciousness or relatively mild psychological disorders. This explains the discrepancy between a normal EEG (only minor abnormalities) and presumed unconsciousness. The term “locked-in” expresses the patient’s inability to communicate. In typical cases there may be only vertical eye movements and blinking. Using these remaining innervated muscles, the examining and treating physician must try to communicate with the patient. The locked-in state may be mistaken for coma particularly if there had been a preceding episode of unconsciousness. Moreover, the “locked-in” syndrome (LIS) often passes into a state of unconsciousness or coma. The degree of communication may change on an hourly basis. Most of the cases of this syndrome are caused by basilar artery thrombosis.64 Clinically, the “locked-in” patient is quadriplegic due to bilateral damage of the corticospinal tracts in the ventral pons. Such lesions spare both the somatosensory pathways and the ascending neuronal systems responsible for arousal and wakefulness, but interrupt the corticobulbar and corticospinal pathways. The patient is unable to speak and incapable of facial movement because of involvement of corticobulbar tracts. Horizontal eye movements also are limited by bilateral involvement of nuclei and fibers of cranial nerve VI. Consciousness is preserved as the reticular activating system is not damaged. The patient is able to communicate by movement of the eyelids, although otherwise he

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or she is completely immobile.65 The EEG is either normal or minimally slow, and shows reactivity to various stimuli.66 It is the preservation of alertness and the presence of reactivity of the EEG that distinguish the patients with LIS from those who are comatose due to an extensive brainstem lesion. There are reports of patients with LIS who recover.67 Although late neurologic recovery uncommonly occurs in chronic LIS, survival may, nonetheless, be prolonged with adequate supportive care. Modern computerized technology offers patients with LIS the ability to interact with their environment. This information may assist physicians in making ethical and long-term care decisions with the patient rather than for the patient with LIS.68,69

Brain Death In 1950s, European neurologists called attention to a state of coma where the brain was irreversibly damaged and had ceased to function, but cardiopulmonary function was preserved. Mollaret and Goulon referred to this condition as coma depasse (a state beyond coma). The whole-brain criterion of death was first formally published in a “Special Communication” in the Journal of the American Medical Association in 1968.70 Since then, all states in the United States and many western countries have endorsed this definition of death (see Chapter 30). The strongest defense of the concept of “brain death” was provided by Bernat, who emphasized the important distinctions between the definition and the criteria of death and the tests for death. Analysis demonstrates that brain-related criteria for the presence of death are inconsistent with traditional concepts of death. Thus, although death is properly understood as a biological phenomenon, “brain death” is a social construct created for utilitarian purposes, primarily to permit organ transplantation. The best definition of death is “the event that separates the process of dying from the process of disintegration” and the proper criterion of death in human beings is “the permanent cessation of the circulation of blood.” Because brain-related criteria of death have been widely accepted, and because our society has demonstrated a strong commitment to organ transplantation, abandoning the concept of brain death would create serious political problems. Abandoning the “dead donor rule” would solve the problem of obtaining organs for transplantation, but would create different, equally serious, political problems. Preserving the concept of brain death as a social construct, as a “legal definition of death,” but distinct from biologic death, is also problematic, but may be our most acceptable alternative.71 Brain death is defined as the loss of all cerebral activity, including activity of the cerebral cortex and brain stem, for at least 6 hours if confirmed by electroencephalographic

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evidence of electrocerebral inactivity, or 24 hours without a confirmatory electroencephalogram. Brain death may be simulated clinically by extreme hypothermia, sedative overdose, and neuromuscular blockade. Such conditions must always be excluded, especially when no clear history of circulatory arrest can be obtained. Brain death is a state of total cessation of cerebral blood flow and global infarction of the brain at a time when respiration is preserved by artificial support and the heart continues to function. Confirmatory diagnostic criteria are simple, conducted at the bedside, and allow no chance of diagnostic error. There are three essential elements: 1. Widespread cortical destruction shown by deep coma; 2. Global brainstem damage demonstrated by absent pupillary light reaction, absent oculovestibular and corneal reflexes; and 3. Medullary destruction indicated by complete apnea. The pulse rate is also invariant and unresponsive to atropine. Most patients have diabetes insipidus, but in some it develops after clinical signs of brain death. The pupils need not be enlarged but should not be constricted. The absence of deep tendon reflexes is not required because the spinal cord may remain functional. There are certain reflexes that can persist in the presence of brainstem death. These include the stretch reflexes, plantar responses or withdrawal, and flexion of the upper or lower limb triggered by neck flexion. In brain death, the arterial blood pressure falls without support and the body temperature sinks below 35°C. Spinal reflexes may remain or reappear.72 These spinal reflexes and automatisms may result in doubt about the diagnosis.73 Approximately 30% of brain-dead patients retain normal plantar responses. Most patients who are brain dead experience somatic death from cardiovascular collapse within 48 to 72 hours despite supportive treatment; in contrast to patients in the persistent vegetative state, prolonged somatic survival is rare. Unusual movements of the extremities can occur for 15 to 30 minutes after ventilatory assistance is withdrawn in brain-dead patients and are presumably a manifestation of terminal spinal cord ischemia.74 These movements may be commonly underreported, but do not preclude the diagnosis of brain death.75 On occasion, a brain-dead patient may trigger the mechanical ventilator or demonstrate symmetric upper limb movements resembling decerebrate posturing.76,77 The possibility of profound drug-induced or hypothermic CNS depression should always be excluded. Some period of observation, usually no less than 12 to 24 hours is desirable, during which this state is shown to be sustained. It is often advisable to delay clinical testing for up to 24 hours if a cardiac arrest has caused brain death or if the inciting disease is not known. There is no explicit reason to make the diagnosis of brain death except when organ transplantation

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or difficult resource-allocation (intensive care) issues are involved. Although it is commonly accepted that the respirator can be disconnected from a brain-dead patient, most problems arise because of inadequate explanation and preparation of the family by the physician. An isoelectric EEG is often used as a confirmatory test for total cortical damage, but is not absolutely necessary. Radionuclide brain scanning, cerebral angiography, or transcranial Doppler measurements may also be used to demonstrate the absence of cerebral blood flow, but with the exception of Doppler, they are cumbersome and have not been correlated extensively with pathologic material. An isoelectric EEG is not synonymous with brain death, but only reflects electrical silence of the cerebral cortex. Drug intoxication, hypothermia and viral encephalitis have been documented to produce an isoelectric EEG, and each is associated with a high probability of complete or partial neurologic recovery. An isoelectric EEG is a necessary, but not sufficient, requirement for brain death in many of the published criteria, although some criteria do not require EEG testing. Multimodality evoked potentials (MEPs), which can be rapidly performed at the patient’s bedside, assess the brain stem as well as the cerebral cortex, and are innocuous for the patient. Moreover, their insensitivity to a number of misleading factors (hypothermia, drugs, and metabolic disturbances) is usually sufficient to distinguish brain death. MEPs are a safe, accurate, and reliable tool for confirming the diagnosis of brain death, and their use can improve the organ donation rate while preserving the safety of the patient.78 A necessary clinical study in patients with suspected brain death is the apnea test. This test involves evaluation of the respiratory response of the brain stem by allowing PaCO2 to

rise to greater than 60 mm Hg while 100% oxygen is given through the endotracheal tube. Brain-dead patients have no ventilatory response to the apnea test.79 Demonstration of apnea generally requires that the PaCO2 be high enough to stimulate respiration. This can be accomplished safely in most patients by removal of the respirator and use of diffusion (apneic) oxygenation sustained by a tracheal cannula connected to an oxygen supply. In brain-dead patients, CO2 tension increases approximately 0.3 to 0.4 kPa/minute (2 to 3 mm Hg/minute) during apnea. At the end of an appropriate interval, which may be approximated by calculating the number of minutes required to increase the PaCO2 to at least 60 mm Hg from a measured starting point, the PaCO2 should be at or above this value for the test to be valid. It is generally accepted that a positive apnea test result requires a PaCO2 of 60 mm Hg or greater. It seems clear that this aspect is more important than the duration of the test.80 In the presence of acute lung injury, using CPAP with apneic oxygenation will prevent, most often, desaturation. Hadani and colleagues81 found that transcranial Doppler (TCD) ultrasonography is a highly specific (100%) and sensitive (96.5%) confirmatory test and can be included as an additional test in the protocol for the assessment of brain death. Braum82 found that cessation of blood flow within the internal carotid arteries and its branches as evaluated by cerebral intravenous digital subtraction angiography (IV DSA) was consistently found in brain death. In sedated patients in whom EEG and evoked brain-stem responses are nondiagnostic, or in order to shorten the observation time, TCD should be performed to determine the timing for IV DSA, which is a reliable method of confirming brain death. New fast techniques, such as diffusion-weighted imaging MRI, sensitive to cerebral ischemia, can also demonstrate ultrastructural changes secondary to brain death.81–83

P earls 1. Clouding of consciousness (confusion) cannot easily be separated from a diminished level of consciousness (drowsiness, stupor, and coma) and the two are produced by many of the same medical disorders. 2. The inability to maintain a coherent sequence of thoughts, accompanied usually by inattention and disorientation, is the best definition of confusion and is a disorder of the content of consciousness. 3. Stupor defines a state in which the patient can be awakened only by vigorous and repeated stimuli. Coma indicates a state from which the patient cannot be aroused by stimulation, and no purposeful attempt is made to avoid painful stimuli. Confusion is a behav-

ioral state of reduced mental clarity, coherence, comprehension, and reasoning. Inattention and disorientation are the main early signs. When there is, in addition to confusion, an element of drowsiness, the patient is said to have an encephalopathy. 4. Use of flumazenil is controversial, outside of known benzodiazepine overdose. It may induce seizures, particularly in patients who have overdosed on tricyclic antidepressants, in patients with chronic dependence on benzodiazepines, or in patients with a history of epilepsy. 5. By evaluating five important physical findings (state of consciousness, pupillary responses, oculocephalic

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Chapter 27  responses, motor responses and respiratory pattern), it is usually possible to determine which pathophysiologic type of coma the patient is experiencing. 6. Hiccup is usually a trivial breathing aberrance, but in a comatose patient, hiccup is an ominous sign indicating severe damage to the brainstem. 7. Lumbar puncture should not be deferred if meningitis is a strong clinical possibility. 8. Status epilepticus is defined as seizures lasting longer than 30 minutes or repetitive seizures for longer than

References 1. Plum F, Posner JB: The Diagnosis of Stupor and Coma. Philadelphia, FA Davis, 1980. 2. Hoffman RS, Goldfrank LR: The poisoned patient with altered consciousness. Controversies in the use of a “coma cocktail”. JAMA 1995;274:562–569. 3. Gueye PN, Hoffman JR, Taboulet P, Vicaut E, Baud FJ: Empiric use of flumazenil in comatose patients: Limited applicability of criteria to define low risk. Ann Emerg Med 1996;27:730–735. 4. Brock DG, Bleck TP: Coma: A practical approach. In Bone R (ed): Pulmonary and Critical Care Medicine. Chicago: Mosby-Year Book, 1995. 5. Goldstein L, Roses A: Initial evaluation and treatment of the comatose patient. In Rengachary S, Wilkins R (eds): Principles of Neurosurgery. London: Wolfe Medical, 1994. 6. Fisher CM: The neurological examination of the comatose patient. Acta Neurol Scand 1969;45:1–56. 7. Bickerstaff ER: Neurological Examination in Clinical Practice. Oxford, Blackwell, 1968. 8. Wiebers D, Feigin V, Brown R Jr: Handbook of Stroke. Philadelphia: Lippincott-Raven, 1997. 9. Rengachary S, Duke D: Impaired consciousness. In Rengachary S, Wilkins R (eds): Principles of Neurosurgery. London, Wolfe, 1994. 10. Patten J: Neurological Differential Diagnosis. London, Springer-Verlag, 1996. 11. Lee AG, Taber KH, Hayman LA, Tang RA: A guide to the isolated dilated pupil. Arch Fam Med 1997;6:385–388. 12. Aminoff M, Greenberg D, Simon R: Clinical Neurology. Stamford, CT: Appleton Lange, 1996. 13. Bozza-Marubini M: Coma. In Tinker J (ed): Care of the Critically Ill Patient. New York, Springer Verlag, 1983. 14. Brust J: Coma. In Rowland L (ed): Merritt’s Textbook of Neurology, 9 th ed. Baltimore, Williams & Wilkins, 1995. 15. Cherniack NS, Longobardo GS: Cheyne-Stokes breathing. An instability in physiologic control. N Engl J Med 1973;288:952–957. 16. Schwartz M: Textbook of Physical Diagnosis. History and examination. Philadelphia,WB Saunders, 1994. 17. Nathanson M, Bergman PS: The evaluation of the unconscious patient including oculo-cephalic and vestibulo-ocular testing. J Mt Sinai Hosp NY 1966;33:252–264. 18. Teasdale G, Jennett B: Assessment of coma and impaired consciousness. A practical scale. Lancet 1974;2:81–84. 19. Teasdale G, Jennett B: Assessment of coma and severity of brain damage [letter]. Anesthesiology 1978;49:225–226. 20. Brandt T, Grau AJ, Hacke W: Severe stroke. Baillieres Clin Neurol 1996;5:515–541. 21. Mumenthaler M: Neurologie, 9th ed. Auflage, Stuttgart, Georg Thieme Verlag, 1990. 22. Broderick JP, Brott TG, Tomsick T, Barsan W, Spilker J: Ultra-early evaluation of intracerebral hemorrhage. J Neurosurg 1990;72:195–199.

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30 minutes between which the patient does not return to a baseline neurologic level. 9. Ten percent of all hospital inpatients manifest some degree of delirium. It reaches 30% in surgical intensive care units (SICU) and coronary care units (CCU). 10. . . . although death is properly understood as a biologic phenomenon, “brain death” is a social construct created for utilitarian purposes, primarily to permit organ transplantation.

23. Yanaka K, Meguro K, Fujita K, Narushima K, Nose T: Immediate surgery reduces mortality in deeply comatose patients with spontaneous cerebellar hemorrhage. Neurol Med Chir (Tokyo) 2000;40:295299; discussion 299–300. 24. St. Louis EK, Wijdicks EF, Li H: Predicting neurologic deterioration in patients with cerebellar hematomas. Neurology 1998;51:1364–1369. 25. Hunt WE, Hess RM: Surgical risk as related to time of intervention in the repair of intracranial aneurysms. J Neurosurg 1968;28:14–20. 26. Healton EB, Brust JC, Feinfeld DA, Thomson GE: Hypertensive encephalopathy and the neurologic manifestations of malignant hypertension. Neurology 1982;32:127–132. 27. Sahuquillo J, Vilalta J, Lamarca J, Rubio E, Rodriguez-Pazos M, Salva JA: Diffuse axonal injury after severe head trauma. A clinicopathological study. Acta Neurochir 1989;101:149–158. 28. Gennarelli TA, Thibault LE, Adams JH, Graham DI, Thompson CJ, Marcincin RP: Diffuse axonal injury and traumatic coma in the primate. Ann Neurol 1982;12:564–574. 29. Alexander MP: Mild traumatic brain injury: Pathophysiology, natural history, and clinical management [see comments]. Neurology 1995;45:1253–1260. 30. Levin HS, Mattis S, Ruff RM, et al: Neurobehavioral outcome following minor head injury: a three-center study. J Neurosurg 1987;66:234–243. 31. The Brain Trauma Foundation: The American Association of Neurological Surgeons. The Joint Section on Neurotrauma and Critical Care. Initial management [In Process Citation]. J Neurotrauma 2000;17:463–469. 32. Raichle ME, Plum F: Hyperventilation and cerebral blood flow. Stroke 1972;3:566–575. 33. Bouma GJ, Muizelaar JP, Choi SC, Newlon PG, Young HF: Cerebral circulation and metabolism after severe traumatic brain injury: The elusive role of ischemia. J Neurosurg 1991;75:685–693. 34. Salman M: Why does tonsillar herniation not occur in idiopathic intracranial hypertension? Med Hypoth 1999;53:270–271. 35. Qureshi AI, Geocadin RG, Suarez JI, Ulatowski JA: Long-term outcome after medical reversal of transtentorial herniation in patients with supratentorial mass lesions. Crit Care Med 2000;28:1556–1564. 36. Hahn FJ, Gurney J: CT signs of central descending transtentorial herniation [letter]. AJNR 1985;6:844–845. 37. Osborn AG: Diagnosis of descending transtentorial herniation by cranial computed tomography. Radiology 1977;123:93–96. 38. Chen R, Young GB: Metabolic encephalopathies. Baillieres Clin Neurol 1996;5:577–598. 39. Plum F: Sustained impairments of consciousness. In Bennet and Plum (eds): Cecil Textbook of Medicine, 20th ed. Philadelphia, WB Saunders, 1996. 40. Mampalam TJ, Rosenblum ML: Trends in the management of bacterial brain abscesses: A review of 102 cases over 17 years. Neurosurgery 1988;23:451–458. 41. Whitley RJ, Soong SJ, Linneman C Jr, Liu C, Pazin G, Alford CA: Herpes simplex encephalitis. Clinical Assessment. JAMA 1982;247:317–320.

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42. Nahmias AJ, Whitley RJ, Visintine AN, Takei Y, Alford CA Jr: Herpes simplex virus encephalitis: Laboratory evaluations and their diagnostic significance. J Infect Dis 1982;145:829–836. 43. McKendall RR: Herpes simplex diseases. In McKendall RR (ed): Handbook of Clinical Neurology. Amsterdam, Elsevier, 1989, pp 207–227. 44. Pohl-Koppe A, Dahm C, Elgas M, Kuhn JE, Braun RW, ter Meulen V: The diagnostic significance of the polymerase chain reaction and isoelectric focusing in herpes simplex virus encephalitis. J Med Virol 1992;36:147–154. 45. Whitley RJ, Cobbs CG, Alford CA Jr, et al: Diseases that mimic herpes simplex encephalitis. Diagnosis, presentation, and outcome. NIAD Collaborative Antiviral Study Group. JAMA 1989;262:234–239. 46. Whitley RJ: Viral encephalitis. N Engl J Med 1990;323:242–250. 47. Baumagartner G: Koma by zerebralen Affectionen. In Siegenthaler W (Hrsg): Differentialdiagnose innerer Krankheiten,16 Auflage. Stuttgart, Georg Thieme Verlag, 1988. 48. Jacobson S, Jerrier H: EEG in delirium. Semin Clin Neuropsychiatry 2000;5:86–92. 49. Inouye SK: Prevention of delirium in hospitalized older patients: Risk factors and targeted intervention strategies. Ann Med 2000;32:257–263. 50. Bucht G, Gustafson Y, Sandberg O: Epidemiology of delirium. Dement Geriatr Cogn Disord 1999;10:315–318. 51. Gallinat J, Moller H, Moser RL, Hegerl U: [Postoperative delirium: risk factors, prophylaxis and treatment (see comments)]. Anaesthesist 1999;48:507–518. 52. Edlund A, Lundstrom M, Lundstrom G, Hedqvist B, Gustafson Y: Clinical profile of delirium in patients treated for femoral neck fractures. Dement Geriatr Cogn Disord 1999;10:325–329. 53. Rasmussen LS, Moller JT: Central nervous system dysfunction after anesthesia in the geriatric patient. Anesthesiol Clin North Am 2000;18:59–70, vi. 54. Clayer M, Bruckner J: Occult hypoxia after femoral neck fracture and elective hip surgery. Clin Orthop 2000;265–271. 55. Moore AR, O’Keeffe ST: Drug-induced cognitive impairment in the elderly. Drugs Aging 1999;15:15–28. 56. Rolfson DB, McElhaney JE, Rockwood K, Finnegan BA, Entwistle LM, Wong JF, Suarez-Almazor ME: Incidence and risk factors for delirium and other adverse outcomes in older adults after coronary artery bypass graft surgery. Can J Cardiol 1999;15:771–776. 57. Owens JF, Hutelmyer CM: The effect of preoperative intervention on delirium in cardiac surgical patients. Nurs Res 1982;31:60–62. 58. Chan D, Brennan NJ: Delirium: Making the diagnosis, improving the prognosis. Geriatrics 1999;54:28-30, 36, 39–42. 59. Ginsberg MD: Delayed neurological deterioration following hypoxia. Adv Neurol 1979;26:21–44. 60. Edgren E, Hedstrand U, Kelsey S, Sutton-Tyrrell K, Safar P: Assessment of neurological prognosis in comatose survivors of cardiac arrest. BRCT I Study Group [see comments]. Lancet 1994;343:1055–1059. 61. Medical aspects of the persistent vegetative state (1). The Multi-Society Task Force on PVS [see comments]. N Engl J Med 1994;330:1499–1508. 62. Medical aspects of the persistent vegetative state (2). The Multi-Society

63. 64.

65. 66. 67. 68. 69. 70.

71. 72. 73.

74. 75. 76. 77.

78. 79. 80. 81.

82.

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Task Force on PVS [see comments] [published erratum appears in N Engl J Med 1995;333(2):130]. N Engl J Med 1994;330:1572–1579. Jorgensen EO, Holm S: Prediction of neurological outcome after cardiopulmonary resuscitation. Resuscitation 1999;41:145–152. Flugel KA, Fuchs HH, Druschky KF: [The “locked-in” syndrome: pseudocoma in thrombosis of the basilar artery (author’s transl)]. Dtsch Med Wochenschr 1977;102:465–470. Patterson JR, Grabois M: Locked-in syndrome: a review of 139 cases. Stroke 1986;17:758–764. Markand ON: Eectroencephalogram in “locked-in” syndrome. Electroencephalogr Clin Neurophysiol 1976;40:529–534. Khurana RK, Genut AA, Yannakakis GD: Locked-in syndrome with recovery. Ann Neurol 1980;8:439–441. Haig AJ, Katz RT, Sahgal V: Mortality and complications of the lockedin syndrome. Arch Phys Med Rehabil 1987;68:24–27. de Graaf AS, Rybnikar MD: “Locked-in” but not “locked-out”. A case report. S Afr Med J 1986;69:839–840. A definition of irreversible coma. Report of the Ad Hoc Committee of the Harvard Medical School to Examine the Definition of Brain Death. JAMA 1968;205:337–340. Taylor RM: Reexamining the definition and criteria of death. Semin Neurol 1997;17:265–270. Robert F, Mumenthaler M: [Criteria of brain death. Spinal reflexes in 45 personal studies]. Schweiz Med Wochenschr 1977;107:335–341. Spittler JF, Wortmann D, von During M, Gehlen W: Phenomenological diversity of spinal reflexes in brain death. Eur J Neurol 2000;7:315– 321. Samules M: Coma and related disorders. In Stein JH (ed): Internal Medicine, 5th ed. St. Louis, Mosby, 1988. Saposnik G, Bueri JA, Maurino J, Saizar R, Garretto NS: Spontaneous and reflex movements in brain death. Neurology 2000;54:221–223. Willatts SM, Drummond G: Brainstem death and ventilator trigger settings. Anaesthesia 2000;55:676–677. Marti-Fabregas J, Lopez-Navidad A, Caballero F, Otermin P: Decerebrate-like posturing with mechanical ventilation in brain death. Neurology 2000;54:224–227. de Tourtchaninoff M, Hantson P, Mahieu P, Guerit JM: Brain death diagnosis in misleading conditions. QJM 1999;92:407–414. Schafer JA, Caronna JJ: Duration of apnea needed to confirm brain death. Neurology 1978;28:661–666. Telleria-Diaz A: [Apnea testing to establish death based on brain criteria]. Rev Neurol 1998;27:108–110. Hadani M, Bruk B, Ram Z, Knoller N, Spiegelmann R, Segal E: Application of transcranial doppler ultrasonography for the diagnosis of brain death. Intensive Care Med 1999;25:822–828. Braum M, Ducrocq X, Huot JC, Audibert G, Anxionnat R, Picard L: Intravenous angiography in brain death: Report of 140 patients. Neuroradiology 1997;39:400–405. Lovblad KO, Bassetti C, Basssetti C: Diffusion-weighted magnetic resonance imaging in brain death [see comments] [published erratum appears in Stroke 2000 Apr;31(4):992]. Stroke 2000;31:539–542.

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Chapter 28 Traumatic Brain Injury: Management and Complications Bizhan Aarabi, MD, Howard M. Eisenberg, MD, Katrina Murphy, MD, PhD, Chet Morrison, MD, and Max Weinmann, MD

Introduction

Background

Because severe head injury is a heterogeneous disorder, the degree of salvageability, outcome, and social integration of a victim of such an injury ultimately depends on the patient’s age, genetic background, injury severity, and the events that transpire during the prehospital, emergency department (ED), intensive care unit (ICU), and rehabilitation periods.1–9 Over the past 30 years, however, we have come to better understand the pathophysiology of traumatic brain injury (TBI), the dynamics of intracranial hypertension, and brain ischemia, but we are still unable to predict outcome within the first 24 hours of injury using a fixed set of variables such as age, injury severity, and computed tomography.10–12 We manage secondary injury better than 10 to 20 years ago, but are unable to define the extent of primary injury.13–21 The traditional management of TBI has been to decompress the brain as soon as possible and observe the patient in ICU using the critical care pathways. Between 1994 and 1996, a group of neurosurgeons tried to set the guidelines for management of TBI based on scientific evidence (class I, II, and III papers). In 1996 the first edition of evidence-based guidelines for management of TBI was released and was updated in 2000.3,22 Uniform application of the recommended practice parameters in the guidelines, which are supported by the American Association of Neurological Surgeons and Brain Trauma Foundation, could improve outcome and help us in future well-designed prospective randomized controlled trials.23,24

Fascination with the unfolding processes inside the cranium following TBI probably goes back to the Stone Age. Centuries ago trephination was used in management of head injury, perhaps in some cases for release of pressure or hematoma. In mass graves of ancient battlefields, skulls have been discovered with trephination across fracture lines.25 In the 18th century, Percival Pott, Henry Francois Le Dran, and Lorenz Heister related the altered mental status and seriousness of head injury to pressure on the brain rather than damage to the skull (1750s).26 By the turn of the twentieth century, it was known that intracranial pressure increased in head injury and Jabouley reiterated the need for trephines in head injury to release the intracranial pressure.27 Jefferson, in 1938, described the syndrome of uncal herniation, giving credence to the consequences of intractable intracranial hypertension.25,26,28–30 With the introduction of coma scoring, computed tomography, and intracranial pressure (ICP) monitoring, the stage was set for a better appreciation of the dynamics of increased intracranial pressure.16,17,31–35 Clinical studies from 1970 to the 1990s made it clear that there were two components to TBI: (1) primary injury, and (2) secondary insults incurred upon the brain during the prehospital triage, ED evaluation, and hospital course.1,5,7,17,36–40 It was realized that while we could do very little to the primary injury, the fundamental issue at stake was how to prevent secondary cerebral ischemia, which was prevalent in the victims of closed head injury.6,7,18,28,29 To improve patient 771

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outcome, a number of neurosurgeons banded together in the early 1990s and put together the guidelines for the management of severe TBI.

Pathogenesis Translation of kinetic energy into passive parenchymal damage and secondary brain insults are considered TBI. Compressive, tensile, and shearing strains heavily contribute to tissue damage in form of contusion, laceration, or diffuse axonal injury. While passive damage is instantaneous, secondary brain insults occur from hours to several days after TBI and significantly alter the prognosis.7,28,29 Transient mechanical microporation, cell rupture, activation of voltage- and ligand-gated N-methyl-d-aspartate (NMDA) channels, and ischemia result in cellular entry of Ca2+ and Na+, and egress of potassium ions and in an altered state of consciousness.41,42 Even in concussive states, the concentration of extracellular K+ is increased 50-fold. There is a direct relationship between extracellular potassium and mortality. Excess potassium in ECF is sequestered by the glial cells leading to swelling of the astrocytic footplates, cytotoxic edema, increased ICP, and secondary ischemia.18,24 Disturbance of calcium homeostasis through inward movement of Ca2+ results in metabolic cascades with dire consequences.21,43,44 Elevated levels of calcium in the cytosol result in multimeric transformation of proteins in the mitochondrial outer membrane and formation of mitochondrial permeability transition pore (MPTP). MPTP allows abnormally high concentrations of calcium in the mitochondrial matrix, compromises electron transport and formation of reactive oxygen species, and allows for the activation of lipases, proteases, and endonucleases with resultant enhanced cell necrosis. Release of apoptogenic protein from mitochondria along with intrinsic pathways signal activation of apoptotic processes that terminate in programmed cell death.45 Abnormal concentrations of Ca2+ into the axons activate calpainmediated cytoskeletal damage and compromises axonal transport. The long-term effect of cytoskeletal damage is axotomy and Wallerian degeneration.45 Primary Injury Following translation of the kinetic energy into tissue damage, the primary injury is produced. It is very difficult to ascertain how much of the clinical picture of a patient with TBI is related to the primary injury and how much due to secondary injury. It is not always easy to visualize the primary injury with diagnostic studies. Injury to the blood vessels is obvious by tissue tear hemorrhages, intracerebral, subdural, or epidural hematomas, all of which can result in turn in secondary injury.16,28,29,35,36,46 Coronal translational forces are more apt to produce widespread axonal injuries. Patients with diffuse axonal injury are less likely to have

increased intracranial pressure and lucid intervals.36,47 Amyloid precursor protein topography shows that axons in the corpus callosum and fornices are most susceptible to injury.2 Secondary Injury Mechanical loading of the brain not only results in primary injury but also ignites a set of biochemical reactions and cascades that may take several hours to days to manifest. Chemical Axotomy Transmission of inertial energy in the form of angular acceleration or deceleration results in axonal disruption and immediate coma.36 Computed tomography in such cases is usually without significant intracranial injury. Penetration of axolemma by Ca2+ may activate the calpain cascade and disrupt the cytoskeleton and cause chemical axotomy.45 Microdialysis studies have shown that the concentration of extracellular fluid glutamate in patients with diffuse axonal injury is less than that encountered in cortical injury underneath the subdural hematomas and contusions.21 Focal Contusions Focal contusions are usually in the form of high or mixed density lesions. Focal contusions do not occupy much space in the beginning but may blossom within days and cause significant intracranial hypertension. The extracellular concentration of glutamate is higher in patients with focal cortical damage than in patients with diffuse axonal injury, and cerebral blood flow is decreased around focal contusions.46 Intracerebral Hematomas Intracerebral hematomas are usually in the form of parenchymal contusions. Delayed intracerebral hematomas could have traumatic aneurysms as the main source of bleeding. Subdural Hematomas Up to 35% to 40% of patients with severe TBI have subdural hematomas (SDH). Translational shifts of the hemispheres inside the cranium will result in rupture of cortical veins or arteries and bleeding in the subdural space. SDH could be considered as epiphenomena of underlying cortical injuries. Epidural Hematomas Depending on the type of the patient population studied, between 1% and 10% of patients with head injury will have epidural hematomata (EDH). Epidural hematoma is abnormal collection of blood between the dura and the cranium, usually from a torn middle meningeal artery. Cerebral Ischemia, Blood Flow, and Metabolism after Traumatic Brain Injury Cerebral ischemia is at the core of the secondary injuries to the brain.48 Ischemia may have peripheral causes (such as

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anemia, shock, or low SaO2) or central pathogenetic mechanisms (such as low microcirculatory flow, high ICP, diffusion difficulties, or problems with electron transfer at the mitochondrial level).4,7 More than 90% of patients who die from head trauma have evidence of hypoxic brain damage at autopsy, and up to 36% of patients in the neurointensive care unit (NICU) will have, at one point during their hospitalization, global desaturation as evident by jugular venous oxygen saturation (SjvO2) or brain tissue oxygen monitoring.28,29,46,49–52 Application of advanced trauma life support prehospital and ED pathways, plus refraining from excessive dehydration and hyperventilation of patients with multiple traumatic injuries or TBI, have all contributed to the prevention of ischemic episodes. There is still evidence that a good proportion of patients sustain episodes of hypoxia and hypotension during transfer and resuscitation, as well as in the operating room and during intensive care management.4,7 During the first 24 hours after TBI, cerebral blood flow is decreased; this is especially so in the first 6 hours, which contributes to poor outcome.46,53–60 After the first day and for the next 3 to 5 days thereafter, CBF will increase to go down again within the next 2 weeks.57,58,61 Cerebral metabolism is generally depressed during the postinjury course of TBI.62 Hyperglycolysis and increased cerebral blood flow (CBF) immediately after TBI could be part of the restorative mechanisms of membrane instability and may have a relationship with good outcome.60,63

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facilitate the transfer of the patients directly to a trauma center.6,7,10,11,13,39,40,48,64–78 Guidelines for treatment stem from an evidence-based analysis of extant clinical and nonclinical studies.3,22 Initial Management Every patient with TBI and a Glasgow Coma Scale (GCS) score of 8 or less should have immediate airway support, oxygenation, and ventilation. Following hemodynamic resuscitation, the victim of TBI should undergo computed tomography (CT) followed by ICP control and perfusion pressure management according to the pathway presented in Figure 28-1.73,75,78–80 In this category, recommendations are at the level of options.3,22 Resuscitation of Blood Pressure and Oxygenation The recommendations of the Guidelines Committee in this category are at the level of guidelines.3,22 Hypotension (systolic blood pressure [SBP] less than 90 mm Hg) or hypoxia (apnea, cyanosis, or an O2 saturation less than 90% in the field or a PaO2 less than 60 mm Hg) must be monitored for and scrupulously avoided, or corrected immediately in severe TBI.5–7,10,14,38–40,64–69,71,81–86 Indications for Intracranial Pressure Monitoring

Cerebral Swelling Mechanical microporation and a massive surge in extracellular fluid glutamate result in accumulation of excessive amounts of potassium ions in the extracellular space and subsequent sequestration into the astrocytes. Oxidative distress and dysfunction of mitochondria contribute to dysfunction of Na+/K+ pump and further cell swelling. The latter may cause massive intracranial hypertension, depending on the severity of TBI. Ischemic swelling of the brain is more pronounced underneath the subdural hematomas. Ischemic episodes during prehospital, ED, intraoperative, and ICU management accentuate cytotoxic edema.16,46

ICP monitoring is appropriate in patients with severe head injury with an abnormal admission CT scan (Table 28-1).20 Severe head injury is defined as a GCS score of 3 through 8 after cardiopulmonary resuscitation. An abnormal CT scan of the head is one that reveals hematomas, contusions, edema, or compressed cisterns. ICP monitoring is appropriate in patients with severe head injury and a normal CT scan if two or more of the following features are noted at admission: age over 40 years, unilateral or bilateral motor posturing, SBP less than 90 mm Hg.17,18,20,35,87–95 Intracranial Pressure Treatment Threshold

Guidelines for Management of Traumatic Brain Injury Trauma Systems The introduction of Trauma Systems in any community will guarantee early resuscitation and transport for the trauma victim to prevent secondary brain injury. The National Institutes of Health-supported studies of the 1980s and 1990s, based on patients entered into the Traumatic Coma Data Bank, proved the deleterious effects of hypotension (systolic blood pressure less than 90 mm Hg) and hypoxia (PO2 less than 60 mm Hg) on outcome following TBI. Trauma systems

Guidelines: ICP treatment should be initiated at an upper threshold of 20 to 25 mm Hg. Studies have shown increased mortality and morbidity when intracranial pressure is beyond 20.3,20,89–94 Recommendations for Intracranial Pressure Monitoring Technology Generally speaking, intraventricular catheters (IVCs) are more accurate and economical. Parenchymal fiberoptic systems are similar to IVCs but they have potential for measurement drift. Subarachnoid, subdural, and epidural monitors are less accurate.3,22,96–111

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Figure 28-1. Initial resuscitation of the severe head injury patient (treatment option). (Modified from 1998 Brain Trauma Foundation,3 p 26, with permission.)

Table 28-1  Head CT Findings and Classification after Severe Traumatic Brain Injury Category

Initial CT Findings

Diffuse injury I Diffuse injury II

No visible pathology Cisterns are present; midline shift <5 mm and/or lesion densities present, no high- or mixed density >25 mL, may include bone fragments and foreign bodies Cisterns are compressed or absent; midline shift is 0–5 mm; no high or mixed-density lesion >25 ml Midline shift >5 mm, no high- or mixed-density lesion >25 mL Any lesion surgically evacuated High- or mixed-density lesion >25 mL, not surgically evacuated

Diffuse injury III (swelling) Diffuse injury IV (shift) Evacuated mass Nonevacuated mass

From Marshall LT, Gautille T, Klauber MR, et al: The outcome of severe closed head injury. J Neurosurg 1991; 75:S14-S20, with permission.

Guidelines for Cerebral Perfusion Pressure The strength of the recommendations for the level of perfusion pressure is at the level of options. Cerebral perfusion pressure (CPP) should be maintained at a minimum of 70 mm Hg. Most trauma centers in the United States surveyed by Ghajar prefer CPP of 60 to 70 mm Hg. However, one must take care not to let the CPP fall below 60 mm Hg as the chances of ischemia, stroke, and poor outcome increase precipitously below this level.5,6,22,82,87,88,90,112–122 Increasing perfusion pressure beyond 70 mm Hg may be less beneficial because it could cause complications such as brain swelling and adult respiratory distress syndrome.86,119,122,123

Hyperventilation In the absence of intracranial hypertension, chronic prolonged hyperventilation (PaCO2 less than 25 mm Hg) should be avoided as it may cause ischemic damage to an already compromised brain. The strength of evidence against

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chronic prolonged hyperventilation is at the level of standards.3,22,63 Because CBF is reduced during the first 24 hours after head trauma, prophylactic hyperventilation (PCO2 less than 35 mm Hg) also should be avoided during this period. In the presence of paralysis deterioration of neurologic status and refractory intracranial hypertension not responsive to sedation, CSF drainage, and osmotherapy, hyperventilation for brief periods may be used as an option.124–126 The Use of Mannitol Evidence-based data support the use of mannitol for reduction of intracranial pressure at the level of guidelines. It is effective for control of increased intracranial pressure following severe head injury. The dose ranges from 0.25 to 1 g/kg body weight.3,22,127–135 Barbiturates in the Control of Intracranial Hypertension Patients with intractable intracranial hypertension, resistant to all medical and surgical means and who seem salvageable and are hemodynamically stable, may be considered for high dose pentobarbital therapy. The supporting evidence is at the level of guidelines.22,136,137 The Role of Steroids Steroids are not recommended for improving outcome or decreasing intracranial pressure after severe head injury.22,138–140 Critical Pathway for the Treatment of Established Intracranial Hypertension The following pathway (Fig. 28-2) is a guideline committee consensus (class III) on treatment of intracranial hypertension. The treatment threshold is between 20 and 25 mm Hg.22,138 Nutrition The recommendation of the guidelines is to replace 140% of resting metabolic rate in nonparalyzed patients and 100% of resting metabolic rate in paralyzed patients using enteral or parenteral formulas containing at least 15% of calories as protein by the seventh day after TBI.3,22 The Role of Antiseizure Prophylaxis Following Head Injury Antiseizure medications (phenytoin, carbamazepine, phenobarbital, or valproate) are not indicated to prevent late

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post-traumatic seizures (standards); however, they may be used as an option to control early post-traumatic seizures.22 Hypertonic Saline, Decompressive Craniectomy There is increasing preclinical and clinical evidence that hypertonic saline (3%, 5%, 7.5%) could be used as a low volume resuscitation fluid or as a rescue solution to decrease intracranial pressure when mannitol is ineffective.141–150 Decompressive craniectomy is again gaining momentum for intractable intracranial hypertension as a valid option. It could be used early after evacuation of a subdural hematoma or later in the face of swelling of the brain not responsive to conventional measures. When done early in young patients, it is an effective measure to reduce the intracranial pressure but still not known is whether it really improves outcome.151–157

Spinal Cord Injury Introduction In the field of neurotrauma, few conditions have stimulated the imagination, interest, desire, and passion of researchers and clinicians as much as spinal cord injury. Although a rich and ever increasing valuable and optimistic literature details the pathophysiologic mechanisms of traumatic spinal cord injury in subhuman species,158–161 an immense cloud of uncertainty and controversy surrounds prehospital, ED, surgical, and medical management of spinal cord injury in humans.162–175 Even the effectiveness of steroids (NASCIS II and NASCIS III) in enhancing motor recovery is questioned.168 Does surgical decompression of the spinal cord help with the functional recovery? What is the best timing for surgical decompression? How can we interrupt secondary spinal cord insults, which begin immediately after an acute episode of mechanical loading of the spinal cord? In a sympathectomized quadriplegic, how high should we maintain the mean arterial blood pressure (MAP). Even if the logistics and time constrains of prehospital, ED, and operative management of spinal cord damage are solved, the technologic difficulties with availability of a timely CT and MRI could rob us of the golden window of opportunity in saving valuable parenchyma from secondary ischemic and biochemical insults. As we continue to teach the public and enforce the current community laws of spinal cord injury prevention (i.e., the Think First outreach organization), certain common sense issues need to be stressed. Examples include spinal cord perfusion pressure management, prevention of medical and pulmonary difficulties, nutrition, and prophylaxis against deep venous thrombosis (DVT). Early alignment and fixation of the spinal column and aggressive rehabilitation and ultimately integration of the victim of the spinal cord injury into society, as is

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Figure 28-2. Critical pathway for treatment of intracranial hypertension in the patient with severe head injury (treatment option). (Modified from Brain Trauma Foundation,3 p 141, with permission.)

practiced in an advanced Model Spinal Cord Injury System, is our objective. Pathogenesis Primary Injury Without any question, the most important functional prognostic factor after spinal cord injury is the extent of the original mechanical loading of the spinal cord. This could result in spinal cord contusion, transection, deformation, or compression. Many of the experimental attempts to reproduce exactly the same type of mechanical loading of the spinal cord have not been successful. For example, the clip compression of the spinal cord will produce a continued sustained pressure on the spinal cord, which is not true in dynamic loading of the cord in the human being. Balloon compression of the cord is too slow. Graded compression may finally answer these issues.160,176–180

Secondary Injury Over the past 90 years, Allen’s concept of secondary spinal cord damage after mechanical compression has been expanded and has increased our molecular knowledge of this dynamic phenomenon. After a transient and abrupt translation of energy into the spinal cord by passive forces during fracture or subluxation, a series of systemic and biochemical events ultimately determine the degree of parenchymal injury. These biochemical cascades may last several hours to days and will result in central myelomalacia. 1. Systemic and local vascular changes: There is a transient hypertension and tachycardia followed by prolonged bradycardia and hypotension. Hypotension is usually due to an abrupt loss of the sympathetic tone and unopposed vagal response. Local vascular changes include decreased spinal cord blood flow and perfusion, concomitant with loss of autoregulation and vasospasm of

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the sulcal arterioles. The final effect is persistent ischemia of the spinal cord which spreads rostrally and caudally.181–186 Ionic flux: Mechanoporation of the cell membrane results in opening of the ionic channels, which results in inward rush of calcium and sodium ions and flux of potassium ions into the extracellular fluid. This process will trigger swelling, massive discharge, and initiation of biochemical cascades that result in, for example, damage to the mitochondria. Ionic fluxes start in minutes and continue for several hours.187–197 Excitotoxicity: Accumulation of glutamate into the extracellular fluid will bind to NMDA and non-NMDA receptors and further ionic flux. In experimental animals, administration of MK801, which blocks NMDA receptors, and NBQX, which blocks AMPA receptors, helps alleviate some of the far reaching effects of glutamate on the spinal cord.198,199 Vasoactive agents: Evidence indicates that after spinal cord injury there is accumulation of the vasoactive agents in the extracellular fluid and further reduction of spinal cord blood flow. These vasoactive agents include dopamine, norepinephrine, and serotonin.200–202 Opiates: Release of dynorphins has been confirmed in spinal cord injury, but antagonists such as naloxone and TRH (thyrotropin release hormone) have not been effective in functional recovery in human being spinal cord injury.203–207 Lipid peroxidation: Oxidative stress after spinal cord injury results in excess free radical species release, with subsequent lipid peroxidation. Free radical scavengers have not been able to promote improved functional outcome following spinal cord injury. Lipid peroxidation goes on for up to 8 hours after injury.208–212 Oxygen species: Oxygen free radicals, which have an isolated electron in their outer orbits, result from oxidative stress at the level of mitochondria.188,208,211,212 Inflammatory changes: Activation of the complement pathway immediately following spinal cord injury results in signaling that triggers local and distant inflammatory cell movement. Within 24 hours, polymorphonuclear cells appear at the site of spinal cord injury. This is also noted to be true within 3 days for microglia, and within 1 week for lymphocytes and macrophages. Finally, within three weeks, reactive astrocytes begin to cover the walls of the necrotic encephalomalacic cavity.213–217 Apoptosis: Programmed cell death is a well-proved process following spinal cord injury and could be due to release of cytochrome C following oxidative stress and activation of caspases. Apoptosis is clearly evident at seven days and may last for months.218–227 Calpain: Activation of calpain following entrance of calcium ions into the axons will result in neurofila-

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ment impaction, spectrin proteolysis, and finally axotomy.223,228–230 Pathology Different variables contribute to spinal cord injury (SCI) across single or multiple vertebral motion segments. The degree of laxity of the joints, ligaments, and other soft tissues; presence of spinal stenosis; and the extent of fracture or subluxation play a significant role in the extent of damage. Sustained compression and deformation of the spinal cord following the primary insult may contribute to an aggravated pathologic process and outcome. The majority of patients with spinal cord injury do not have mechanical disruption of the cord itself. The kinetic thrust of the mechanical forces at the time of injury, the extent and direction of forces applied, and mechanical deformation determine the degree of damage to the spinal cord. Attempts have been made to reproduce spinal cord pathologies with different experimental models. Weight drop technique, which originally was introduced by Allen, has been extensively used in different laboratories. To simulate sustained pressure on the spinal cord, vascular clips have been applied directly to the spinal cord for different time periods. Using micropressure transducers and controlled contusion techniques, Carlson and colleagues were able to monitor translation of kinetic energy across the spinal cord. These studies indicated that within 30 minutes of spinal cord compression, the interface pressure across the spinal cord decreased to 13% of baseline pressure.231 Pathologic profile of spinal compression varies depending on the extent of compression. Presence of symptoms may be noted with a normal magnetic resonance image (MRI). On the other hand, extensive hemorrhagic necrosis could be noted as myelomalacia on MRI. In the latter situation, within 5 minutes of spinal cord compression, there is congestion of the gray matter followed by extravasation of the erythrocytes within 15 to 30 minutes. By approximately 60 minutes, there is the beginning of ischemic type chromatolysis and, by 4 hours, hemorrhagic necrosis is seen in the cord substance. After invasion of the phagocytic cells and digestion of the necrotic spinal cord, a small cavity will be seen on MRI, lined by reactive astrocytes.189,202,231–233 Presentation 1. Radiculopathy: A significant number of patients with apparent spinal cord injury actually have radicular symptoms. These cases either have disk or spondylotic radicular irritation or unilateral facet subluxation. Fractures of articulating processes may also irritate the related nerve root and cause weakness of the muscles innervated by that specific nerve root. 2. Myelopathy: The overwhelming majority of the patients with spinal cord injury present with myelopathy. This

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could be in the form of either partial or complete myelopathy. The clinical syndromes are usually in the form of a. Quadriparesis or quadriplegia. b. Cauda equina syndrome. c. Conus medullaris syndrome. d. Central cord syndrome. e. Brown Sequard syndrome. f. Anterior spinal artery syndrome. g. Posterior spinal artery syndrome. To evaluate the degree of functional loss, we can apply either Frankel or ASIA (American Spinal Cord Injury Association) classification.234 ASIA classification is as follows: ASIA Grade A, complete injury: No motor or sensory function is preserved in the sacral segments S4 through S5. ASIA Grade B, incomplete injury: Sensory but not motor function is preserved below the neurological level and extends through the sacral segments S4 through S5. ASIA Grade C, incomplete injury: Motor function is preserved below the neurological level, and the majority of key muscles below the neurological level have a muscle grade less than three. ASIA Grade D, incomplete injury: Motor function is preserved below the neurological level, and the majority of key muscles below the neurological level have a muscle grade three or greater. ASIA E, Normal: Motor and sensory function are normal.

processes of spinal cord injury. It is crucial to keep the blood pressure of the patient up. It is recommended that the MAP be kept at approximately 85 mm Hg for at least 7 days. The arterial saturation should not be allowed to fall below approximately 95%.174,182,238,239 2. Medical management: Medical interruption of secondary injury is the objective of any medication used after spinal cord injury. The use of methylprednisolone is now considered an option. GM-1 ganglioside as a restorative medication has not attracted too much attention despite the well-designed randomized studies.240–244 3. Traction: Traction is used for a speedy closed reduction of the fracture subluxations in order to relieve the pressure on the spinal cord. There is some controversy with regard to the amount of weight that should be used for this (Fig. 28-3).170,236,245,246

Evaluation The optimal diagnostic tool in spinal cord injury should be able to tell us about the degree of ligamentous and bony damage, instability, cord compression, and severity of spinal cord injury. Plain radiographs are good for screening but are weak in depicting the bony damage at the craniocervical and cervicothoracic junctions. CT covers some of the deficit but can not tell us about the degree, significance, and severity of spinal cord injury. MRI is by far the superior tool to tell us about the bony and ligamentous damage, herniated disk, cord compression, and the severity of spinal cord damage. We should make every effort to obtain MR images before or after application of traction.235–237 Management Management of spinal cord injury must include early immobilization, application of the principles of advanced trauma life support (ATLS), stabilization, rehabilitation, and reintegration into society. 1. Systemic resuscitation: There is evidence to suggest that hypotension and hypoxia could worsen the pathologic

Figure 28-3. Sagittal T2-weighted images of an MRI scan from a 20-year-old man following a motor vehicle accident and C6 tetraplegia, indicating C6 / C7 flexion distraction injury resulting in bilateral facet subluxation and grade three listhesis. There are signal changes in the cord indicating evidence of primary and secondary injuries.

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4. Surgical management: There is universal agreement that patients with unstable spinous injuries should undergo operative intervention to re-establish stability. The rationale behind stabilization is to interrupt further injury to the spinal cord, produce an optimum environment for the spinal cord to interrupt ischemia, and reduce the possibility of future tethering and syrinx formation. The question of whether an operation should be based on the rationale of decompressing the spinal cord to gain functional improvement is less easy to answer. Experimental data in all subhuman species show early decompression leads to a better functional outcome. This situation has not been reproduced in human beings. There is a substantial body of literature indicating conservative management is followed by functional improvement in a significant number of patients. Thus, the next question is when to operate? This question has also not been settled by well-designed randomized studies. Anecdotal clinical cases show a better result with early decompression, but late surgeries have also been reported with improved functional outcome. If a decision is made to operate, the nature of fracture subluxation dictates the technique of stabilization. If the posterior column or tension band is involved (facet fracture or subluxations), corrective surgery should involve the posterior column (Fig. 28-4). If the patient has involvement of the anterior column (burst fractures, disk herniations, kyphotic deformity), one should concentrate on the anterior spine. In case of combined anterior supportive column and posterior tension band involvement (compression fractures with subluxation) the anterior and posterior approach is perhaps the answer (Figs. 28-5–28-7).163,165,166,169,172,173,175,245,247–258

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Multiple Organ Dysfunction Syndrome Introduction The clinical entity of multiple organ failure (MOF), the simultaneous dysfunction of several organ systems, was first described almost 30 years ago, and despite significant improvements in the management of critically ill patients, it continues to be a major cause of death in ICUs. In 1973, Tilney et al. reported failure of initially intact organ systems postoperatively after massive acute blood loss in 18 patients with ruptured abdominal aortic aneurysms.259 Four years later, Eisman et al. coined the term “multiple organ failure” to describe their series of 42 patients with progressive MOF, half of whom had intra-abdominal abscesses.260 Thus, during the 1980s, MOF was thought to be caused by infection and subsequent sepsis. This theory was further supported by Fry and associates who presented a paper entitled “Multiple System Organ Failure: The Role of Uncontrolled Infection” that reviewed 553 patients admitted to an ICU and found that MOF developed in 7%, and 90% of those with MOF were septic.261 However, with time, it became evident that MOF could develop in the absence of infection. Although we still do not completely understand the pathophysiology of MOF, we now recognize it as a consequence of secondary insults such as hypotension, hypoxia, hypoxemia, or hypercarbia, and as a major cause of death in all critically ill patients. These secondary insults are particularly devastating in patients with serious head injuries. In 1982, Miller and Becker reported a mortality of 24% to 50% related to secondary insults in patients with serious head injuries.39 Today, MOF remains the leading cause of death after severe trauma and is the cause of 50% to 80% of deaths in surgical ICUs.262 Moreover, it has been characterized as the major therapeutic challenge facing intensive care physicians treating critically ill or injured patients.

Incidence

Figure 28-4. Sagittal reformatted computed tomography of cervical spine indicating unilateral C4 / C5 facet subluxation.

The Acute Physiologic and Chronic Health Evaluation III (APACHE III) database, comprised of 17,440 randomly selected ICU admissions from 13 US medical centers, found the incidence of two or more organ system failures to be 14%.263 Other groups have reported similar figures.264,265 Interestingly, the prevalence of multiple organ dysfunction syndrome (MODS) does not differ markedly among medical, surgical, and trauma patients. For example, in a series of 1171 severe trauma patients, Regel et al. found an 11.4% incidence of MOF with a 61.5% mortality.266 Despite advances in the care of critically ill patients, the incidence and outcome of MOF has not improved.267 For the past decade, MODS has also been the leading cause of patient

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B A Figure 28-5. A and B, Plain lateral views of the cervical spine from a 70-year-old woman following a fall and sustaining right deltoid and biceps weakness due to perched C4-C5 facets. Closed reduction was followed by short segment lateral mass screw fixation with interspinous Songer cable to reconstruct her tension band.

death in intensive care units, and is currently the cause of approximately 60% of patient deaths in this setting.268 As one would predict from the preceding figures, MOF is a significant cause of morbidity and mortality in trauma patients. Gullo and co-workers divided mortality in patients with major trauma temporally, and found that 50% die at the scene, 30% die within 4 hours, and the remaining 20% of deaths occur in the ICU, often weeks to months after injury, frequently due to MOF.269 In a series of 900 consecutive deaths related to trauma over an 11-year period, Acosta and colleagues found that 72 hours after admission, acute inflammatory processes, including MOF, were the leading causes of death, with 10% of all trauma deaths caused by organ failure.270 The high frequency of head injury in the severe trauma patient admitted to the intensive care unit suggests that the clinician managing patients with head injury will frequently encounter MOF. Our group analyzed data from 476 patients admitted over a one-year period with acute head injury. The goal was to discern patterns of MOF in these patients, and to determine the relationship between neurotrauma and the development of this disease process. We found that MOF occurred in 25% (95) of these patients, with a mortality of 39%. In contrast, the mortality of the patients without organ failure was 6%. One similarity among the

neurotrauma patients who developed MOF was the prevalence of significant extracranial injury in addition to their acute head injury. Thus, MOF is a particularly grave threat to the multi-injured trauma patient.

Etiology There is significant overlap among the many theories and pathophysiologies regarding MOF. A common theme, however, is the disruption of normal homeostasis leading to an adverse cycle of events. There are multiple varied hypotheses for the etiology of MOF including infection, cytokine excess, microcirculatory compromise, excess NO production, and cellular transcription failure. Clinically, there is a close relationship between sepsis, acute respiratory distress syndrome (ARDS), systemic inflammatory response syndrome (SIRS), and MOF. There are two accepted paradigms that explain the initiation of MOF from a clinical standpoint—the “one-hit” model and the “two-hit” model. In the one-hit model, a massive traumatic insult can precipitate MOF. Alternatively, the “two-hit” model involves multiple sequential insults. Each insult may not be clinically significant, but it is believed to prime the host immune system such that subsequent

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B Figure 28-6. A, Diving accident in a 28-year-old man followed by C5 tetraplegia and C5 burst fracture with intact facets. B, Sagittally reformatted computed tomography shows burst fracture of C5 followed by corpectomy and fusion.

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Figure 28-7. Diving accident in a 20-year-old man followed by C5 tetraplegia and C5 burst fracture with C5-C6 facet joint damage. Sagittally reformatted computed tomography shows burst fracture of C5 followed by corpectomy and 360-degree fusion.

inflammatory responses to the following insults are exaggerated. Secondary insults in the patient with severe head injury were described by Wald et al.271 In their review of 170 patients with head injuries, the most common secondary insults were hypotension and hypoxia, and these were associated with a mortality rate twice that of patients with a singular insult. Although infection is one of the causes of MOF, it is documented in less than 50% of MOF cases. Gram-negative rods are the most common pathogens, others include enterococci, Bacteroides fragilis, and Candida.262 When infection does trigger MOF, it is usually from a pulmonary or intraabdominal source. One theory regarding the role of specific pathogens in MOF is the “gut” hypothesis. This theory is based on data showing the gastrointestinal system to be a frequent source of bacteria implicated in the pathogenesis of pneumonia in ventilated patients.272 Clinically, in patients with sepsis and in volunteers given endotoxin, gut permeability is increased.273 This may be due to the sensitivity of the gastrointestinal mucosa to hypoxia and ischemicreperfusion injury.274 Disrupted epithelial lining may then lead to the escape of bacteria and bacterial-derived

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substances into the bloodstream. Alternatively, bacteria may also be disseminated through the mesenteric lymph.275 One hypothesis for MOF in those without infection is centered on macrophages and excess cytokine production. Macrophages activate synthesis of cytokines and other inflammatory products. Pro-inflammatory cytokines— tumor necrosis factor (TNF) alpha, interleukin-1b (IL-1b), and IL-6—are associated with sepsis and there is substantial data to suggest they are associated with MOF as well.276 Elevated levels of circulating cytokines—G-CSF, GM-CSF, IL-8, IL-6—are seen in both ARDS and MOF. Using autopsy data, Nuytinck et al. linked ARDS and MOF to histologic changes of generalized organ inflammation that are consistent with the effects of cytokines.277 Additional evidence to support the role of cytokines in MOF is that TNF, given to volunteers, causes microvascular injury and symptoms similar to MOF. The initiation of MOF is frequently described as a cascade of multiple events that are postulated to begin on the microvascular level. One such scenario for the development of MOF is circulatory shock, which causes inadequate global oxygen delivery and leads to ischemic-reperfusion injury of the microvasculature.278 This endothelial damage initiates microvascular plugging by platelets, leukocytes, and cellular debris that in turn results in impaired peripheral vasoregulation and increased vascular permeability.269 Tissue edema as a result of this increased permeability causes inadequate tissue oxygenation. Prolonged tissue hypoxia prompts decreased adenosine triphosphate (ATP) production and the remaining ATP in ischemic tissue is converted to hypoxanthine, which forms toxic oxygen free radicals upon reperfusion and culminates in irreversible cell damage.278 In addition, cytokines and oxidants are known to injure endothelial cells by converting them to proinflammatory, procoagulant cells that have increased production of tissue factor and adhesion molecule surface expression.279 This stimulates leukocyte adherence leading to neutrophilmediated microvascular injury. Thus, there are several mechanisms for microvascular damage in MOF. Another effect of injured tissue is the upregulation of inducible nitric oxide synthase (iNOS), an enzyme that converts arginine to nitric oxide (NO). Excessive NO production has also been implicated in the cascade of events leading to MOF.280 NO can combine with superoxide anion to form peroxynitrite, a long-lasting potent oxidant that causes direct cellular injury by multiple mechanisms. One mechanism of injury is by disrupting lipids and proteins through lipid peroxidation. In addition, peroxynitrite inactivates mitochondrial electron transport impairing cellular respiration. Furthermore, peroxynitrite induces deoxyribonucleic acid single-strand breakage that stimulates the repair enzyme poly-adenosine diphosphate ribosyl synthetase (PARS). This enzyme cleaves NAD, leading to depletion of cellular NAD and ATP causing cell dysfunction and death. Clearly, there are many possible mechanisms for the development of MOF.

Pathophysiology The current consensus is that MOF is a continuum of progressive organ injury starting with a severe local or systemic disruption that leads to global overexpression of the immune response. Once this response is initiated, multiple cytokines propagate the progressive impairment seen with MOF. For example, gram-negative rods can produce an endotoxin that binds to lipopolysaccharide (LPS)-binding protein.281 This complex then adheres to a macrophage surface receptor inducing production of specific cytokines including TNF, platelet activating factor (PAF), interleukins, nitric oxide, and arachidonic acid derivatives. An important interleukin is IL-1b, which is predominant during advanced phases of sepsis and induces production of TNF and IL-2. Another important pro-inflammatory cytokine is TNF-a. This cytokine has similar effects as IL-1b; both initiate the release of other cytokines and stimulate neutrophil activation. In animal models, these two pro-inflammatory cytokines cause sepsis-like symptoms: hypotension, tachycardia, tachypnea, lactic acidosis, hemoconcentration, hyperkalemia, and hyperglycemia followed by hypoglycemia.282 Activation of pro-inflammatory cytokines is the final common pathway between both infectious and noninfectious etiologies leading to MOF. Inflammatory responses seen in MOF are also associated with other interleukins. For example, IL-6 production is stimulated by TNF-a and IL-1. IL-6 is secreted from numerous cells: monocytes, macrophages, neutrophils, T and B cells, endothelial cell, fibroblasts, smooth muscle cells, and mast cells.283 There is strong evidence that serum IL-6 levels reflect injury and it is considered the most reliable prognostic indicator of outcome of all the cytokines. However, in animal models, IL-6 does not produce signs of sepsis like TNF-a and IL-1b, making the exact role of IL-6 in MOF unclear.283 IL-8 is another inflammatory interleukin that is significantly elevated in the sera of injured patients who develop MOF.284 This interleukin is synthesized by monocytes, macrophages, neutrophils, and endothelial cells and recruits inflammatory cells to sites of injury. In addition, IL8 enhances neutrophil function, stimulates chemotaxis and expression of adhesion molecules. Not all cytokines are pro-inflammatory; there are two main anti-inflammatory agents—IL-4 and IL-10. These interleukins inhibit the synthesis of TNF-a, IL-1, IL-6, and IL-8. IL-10 is frequently elevated in sera of trauma patients and, in animal models, IL-10 improves survival after sepsis.285 TNF-a and IL-1b also stimulate the synthesis of acute-phase reactants, compounds that are synthesized in the liver and function to maintain homeostasis.285,286 They are anti-inflammatory agents and act as opsonins, protease inhibitors, hemostatic agents, and transporters. Another important mediator of MOF is free radical oxygen. This is produced as a result of aberrant ATP degradation during hypoxia. Under normal conditions, ATP is

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degraded to hypoxanthine, which is converted to xanthine and uric acid by xanthine dehydrogenase. However, during ischemia, xanthine dehydrogenase is converted to xanthine oxidase. When reperfusion occurs, oxygen causes xanthine oxidase to convert hypoxanthine to xanthine, oxygen, and hydrogen peroxide. This oxygen then releases iron from ferritin leading to the production of hydroxide ion, a very reactive free radical oxygen. This free radical oxygen is the main cause of ischemia-reperfusion tissue injury and it is released from endothelial cells, neutrophils, and monocytes.269 Definition For many years there was not a singular accepted definition of MOF. There are two main reasons for this delay in classification: (1) understanding of this complex syndrome evolved over time and (2) early definitions were subjective and varied among investigators.287 For almost two decades after the first recognition of serial organ dysfunction in 1973,259 differing measures of the degree of organ dysfunction were used to determine MOF. In 1992, the Society of Critical Care Medicine and American College of Chest Physicians,288 coined the term “multiple organ dysfunction syndrome (MODS)” during a consensus conference and recognized it as a result of an inflammatory response.289 This definition made MOF a continuum of ARDS and SIRS. At that time, SIRS was clearly defined as including at least two of the following clinical features: (1) body temperature greater than 38°C or less than 36°C; (2) heart rate greater than 90 beats per minute; (3) tachypnea with a respiratory rate greater than 20/minute or hyperventilation with a PaCO2 less than 32 mm Hg; and (4) a white blood cell count greater than 12,000 or less than 4,000 WBC/mL or the presence of >10% band neutrophils. Similarly, ARDS was also clearly defined: bilateral diffuse pulmonary infiltrate on chest radiograph with a pulmonary capillary wedge pressure of 18 mm Hg or less, pulmonary compliance less than 50 mL/cm H2O, and an arterial to alveolar partial pressure of oxygen less than 0.25.289 When MOF was initially defined, it incorporated specific functional parameters for eight organ systems and used a scale of 0 to 3 to describe severity of organ dysfunction. Eventually, it was condensed to four organ systems. In addition, MOF cannot be diagnosed until 48 hours after primary injury to avoid any ambiguity between dysfunction as a result of the primary injury and dysfunction as the result of an inflammatory response.287 Diagnosis For many years, multiple systems were proposed and utilized to quantify and score MODS. This plurality led to difficulties when attempting to compare clinical studies or to establish a standard of care. The basic differences among these scoring systems were determining when an organ system was failing, and how many organ systems should be followed. For

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example, Goris proposed a scale based on seven organ systems in 1985290; this was followed in 1988 by a system proposed by Marshall based on six organ systems291; and this was subsequently followed in 1991 by a system proposed by Moore based on four organ systems.292 The most recent scoring system was devised in 1995, a revision of the Marshall score, has been shown to correlate well with outcome.291 Two other scores occasionally used in clinical trial are the sequential organ failure assessment (SOFA) and the logistic organ dysfunction system (LODS). These scoring systems have been well summarized in a recent review of organ dysfunction scoring systems.293 Risk Factors Multiple risk factors that have been associated, to varying degrees, with the development of MOF include sepsis,294 infection,295 prolonged hypotension and shock,296 severe trauma,297 intra-abdominal abscess,298 severe burns,299 increased intra-abdominal pressure,300 and massive fluid resuscitation. Regel and associates reviewed 1171 severe trauma patients admitted to their institution between 1986 and 1995 to reveal factors associated with the development of MOF.266 They found that the average age of those patients that developed MOF was only slightly older than those who did not (37.7 +/- 15.5 years vs. 34.2 +/- 14.3). Other studies have also found advanced age, specifically 65 years or older, to be a risk factor for the development of MOF.295,297,301 Regel et al. also assessed the relationship between MOF and initial injury. They noted an increased risk with thoracic abdominal and pelvic injury; however, no significant difference in the incidence of MOF in patients with head or extremity injuries. The severity of initial injury was also directly correlated with the risk of developing MOF; this has been validated by other studies that have shown high arterial base deficits and lactate levels to be predictive of MOF.262 Blood transfusions have also been found to be an independent predictor of MOF, with the incidence rising almost linearly with the amount of units transfused.302 In the review by Regel et al., other factors correlated to MOF development included coexistence of chronic disease and intercurrent cardiac arrest. Other less reliable indicators include gastric intramucosal pH less than 7.35 (indicating splanchnic hypoperfusion), anaphylatoxin C5a, and endotoxin titers. Factors not significantly correlated to MOF development were prehospital treatment, rescue time, operative care, and hypothermia.266 The role of neurologic injury in the development of MOF is not well defined. The GCS is a reliable indicator of postinjury death; however, its relation to the development of MOF is controversial. Regel et al. found a slightly higher incidence of head injury as the primary insult in the patients who developed MOF compared to those who did not (83.8% vs. 77.8%); however this difference was not statistically

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significant.266 Hebert and co-workers found a GCS < 8 to be an independent predictor of postinjury MOF.303 However, Sauaia and colleagues did not find a correlation between GCS score less than 8 and MOF, neither univariately nor after adjustment for confounders.304 One of the difficulties in using GCS as a predictor of MOF is that there are many non-neurologic factors that can confound GCS such as sedation, intubation, paralytics, and shock. Originally, neurologic failure was part of the MOF score; however, it was deleted after a multicenter trial showed that it did not predictably contribute to the diagnosis of MOF.287 Typical Onset MOF has a variable time of onset depending upon the initial injury; MOF may occur within hours after an abdominal aortic aneurysm rupture; however, it may not occur until days after the onset of intraperitoneal sepsis.269 In the series of Regel and associates, MOF developed in 11.4% cases of severe trauma.266 The pulmonary system was the first to fail in over 80% of the patients with a mean day of onset of 3.7 +/- 2.8 days. The cardiovascular system failed less frequently, but when it did, it was usually the second system to fail when the mean day of onset was 5.6 +/- 3.2 days. The hepatic system was the second most frequent system to fail and it was usually the last to fail at 7.2 +/- 3.2 days. In half the patients, the sequence of organ system failure was lung then liver. This was associated with 53.9% mortality. The cardiovascular system failed less frequently than the lung and liver, however it was associated with a higher mortality. In 23.1% of patients, the sequence of failure was lung then heart, and this was associated with 66.7% mortality. Liver failure occurring before lung failure happened in only 11.5% and was associated with 33.3% mortality. Renal failure was rare and usually was the last to fail. The predominance of respiratory failure in MOF has resulted in its being described as the “pacemaker” of MOF.266 There are several explanations for its prevalence in MOF. In trauma patients, there is often associated pulmonary injury such as contusion that makes the respiratory system more susceptible to failure. In addition, the pulmonary capillary bed acts as a filter for toxins and cytokines leading to increased permeability and edema. The frequencies of these primary and secondary insults make the respiratory system more vulnerable to failure. Prevention Prevention of MOF is considered the best cure. Appropriate organ-specific support, source control, prevention of infection, drainage of intra-abdominal infection and careful antimicrobial therapy are required in care of MODS. Prevention of hypotension, which has been shown to double adverse outcome in severe brain injury, and hypoxia is critical, as is prevention of secondary brain injury which could hasten progression to MODS. Deitch et al. have targeted

three phases of prevention: the resuscitative phase, the operative phase, and the ICU phase.262 Adequate resuscitation is imperative and requires aggressive volume repletion in the early stages of treatment. The goal is to maintain optimal tissue perfusion and oxygenation. Good indicators of volume restoration include serum lactate and base deficit.305 Gastric tonometry to measure mesenteric perfusion has also been found useful.306 Timely operative management of soft tissue injuries is the aim of the next phase. Debriding nonviable tissue will decrease the risk of infection. The goal is to minimize the excess activation of the immune/inflammatory response of the host to injury. Early fracture fixation, although controversial in the management of head-injured patients, may benefit the patient at risk from MODS by decreasing the incidence of the fat emboli syndrome.307 The ICU phase has multiple components including early nutritional support, appropriate use of antibiotics and continued debridement of tissue necrosis and infection. Early nutrition is consistently cited as important in critically ill patients for several reasons. Enteral feeding may have a role in decreasing the incidence of MODS by limiting bacterial translocation and by preventing overexpression of the gut-derived inflammatory mediators.308 In addition, many ICU patients have increased caloric requirements because they are in a hypermetabolic state.286 Management The current treatment for MOF is supportive care and organ specific support. This includes mechanical ventilation, renal replacement therapy, blood transfusions, and antibiotics. Prevention of hypotension and hypoxia is critical in that these are significant causes of secondary injury and have been shown to double adverse outcome. Possible etiologies for the onset of MOF should be examined with special attention to potential sources of infection. A CT scan of the abdomen is appropriate to rule out intraabdominal abscess. In addition, early fracture fixation has been advocated to decrease infection risk as well as reduce the risk of fat emboli. Diligent debridement of wounds will also lower infection risk. Early nutritional support is a fundamental component in treating MOF. Patients with MOF are hypermetabolic and hypercatabolic and early nutrition has been associated with improved outcome. Reduction of infection has been seen in patients fed with enteral formulas that were enriched with nucleotides, glutamine, arginine, omega-3, and fatty acids.269,308 Possible reasons for this decrease in infections are improved gut-associated immunologic properties and limited translocation of gut-related bacteria. Administration of exogenous glutamine has been shown to increase the height of gastrointestinal villi and thus provide improved protection from ulceration and translocation.308 In addition, enteral feeding may prevent over-expression of gut-derived inflammatory mediators that propagate MOF. If enteral

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feeding is not tolerated, total parental nutrition is indicated. Patients not receiving enteral feeding are at increased risk low gastric pH and gastrointestinal bleeding. Several exogenous factors have also been shown to affect gastric pH: blood transfusions have lowered gastric pH and adrenergic agents, including dobutamine and dopamine, have elevated low gastric pH. However, in septic and postoperative cardiac patients, dobutamine has also been shown to decrease gastric pH.269 H2 blockers have been used to increase gastric pH; however, they are controversial because by increasing gastric pH, they may increase bacterial growth. Sucralfate is a good alternative in those patients who will tolerate it. Respiratory failure in the ICU patient is often unavoidable. Neither mechanical ventilation nor positive endexpiratory pressure (PEEP) prevents respiratory failure. However, maintaining an optimal level of PEEP and avoiding fluid overload may delay its progression. Measures to reduce the complications associated with mechanical ventilation include avoiding excess airway pressures, even if the patient becomes hypercapnic, and keeping the FIO2 less than 50% to avoid oxygen toxicity.308 Adequate oxygenation is essential in managing respiratory failure. At our institution, we frequently use prone positioning and inverse-ratio pressure-controlled ventilation to optimize oxygenation. Inhalation of nitric oxide has also been effective in improving blood oxygenation. Hepatic failure is a frequent component of MOF and elevated bilirubin is associated with poor prognosis. Unfortunately, little can be done to prevent or treat this condition. Ultrasound of the liver will rule out possible surgical conditions such as biliary obstruction. Acalculous cholecystitis has been reported in association with MOF. Kidney failure can frequently be avoided by maintaining adequate blood volume. Caution should be used with “renaldose” dopamine because it may compromise microcirculation. Hemodialysis or continuous hemofiltration should be used sparingly because it requires anti-coagulation. Some have advocated the use of hemodialysis to remove harmful cytokines from the blood; however, theoretically, it would also remove any protective compounds. Patients with MOF are at increased risk for developing hematologic complications. These should be treated aggressively with appropriate blood component replacements. Disseminated intravascular coagulation is not uncommon and requires fresh-frozen plasma. Thrombocytopenia is also frequently seen and platelets should be transfused as needed. Neurologic compromise may present as agitation or decreased level of consciousness. Midazolam and propofol should be used for sedation as they are short acting and will allow neurologic function to be assessed and followed. If a patient becomes comatose, an EEG is useful in determining cerebral function, particularly when the CT scan does not show evidence of injury. Other interventions that have been used to treat MOF include selective digestive tract decontamination (SDD)309

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and continuous arteriovenous hemofiltration (CAVH).310 SDD has been advocated to reduce bacterial translocation and is achieved by oral antibiotics, or on occasion, intravenous antibiotics. A reduced rate of pneumonia has been correlated with SDD; however, no significant change in overall mortality has been demonstrated. CAVH has been shown to improve respiration and hemodynamics; however, it is not an established treatment at this time. Prognostic Indicators Several prognostic factors have been correlated with outcome in patients who develop MOF. The most predictive parameter is the number of organ systems involved. Deitch and co-workers found 20% mortality with single organ system failure and 100% mortality with four or more failed organ systems.262 Similarly, Regel and colleagues reported 26.2% mortality with one organ system involved, 42.9% mortality with two systems involved, and 100% mortality with three or more failed systems.267 The duration of organ failure has also been found to be prognostic; in patients with single organ system failure, Knaus and associates found an increase in mortality from 22% to 41% in failure that lasted 1 day compared to 7 days.311 Several authors have found age to relate to outcome. Regel and co-workers found a slight increase in age in severely injured patients who died from MOF compared to survivors, 38.6 years compared to 36.2 years. Other indicators are varied. Sauaia and colleagues found patients with MOF and head injuries have worse outcomes than patients with MOF and torso injuries.268 As mentioned previously, mortality rates are higher with respiratory failure than with other organ systems, the combination of respiratory failure and cardiovascular failure being associated with the highest mortality. Some laboratory tests have been found to correlate with outcome. Deitch and associates reported serum lactate levels directly correlate with circulatory failure in ICU patients. Abramson and co-workers found 75% of patients with normal lactate level 48 hours post injury survived compared to 13% with elevated lactate levels.312 Pastores and colleagues found intramucosal gastric pH less than 7.32 to be associated with 37% mortality in ICU patients and pH greater than 7.32 to be associated with 100% survival.313 Blood levels of endotoxin have also been shown to correlate with outcome. Interestingly, preinjury comorbidities have not been shown to predict MOF course.

Future Endotoxin, one of the first recognized triggers of MOF, was an early target of experimental therapies and anti-endotoxins continue to be a compelling area of investigation. In 1982, Ziegler and associates reported the administration of human polyclonal antibodies against lipid A (from endotoxin) to septic patients was associated with a decrease in

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mortality.314 Subsequent studies confirmed the efficacy of polyclonal anti-endotoxin sera in septic patients. However, there were two problems with using human sera; one was the risk of infection because it was derived from pooled sera, and the other was the instability of this compound. Fortunately, genetic advances in the 1990s addressed these issues. Two large multicenter, double blind, placebo controlled trials using two monoclonal anti-endotoxin monoclonal antibodies showed mixed results. The first trial involved 486 patients with suspected gram-negative sepsis.315 Each patient received either E5, a murine immunoglobulin (IgM) anti-lipid A monoclonal antibody or placebo. This study did not show a significant difference between the two groups. A second trial using human IgM anti-endotoxin monoclonal antibody showed an improved survival in patients with gram-negative bacteremia and septic shock; however, there was increased mortality in nonbacteremic and nonshock patients.316 Another experimental agent aimed at endotoxin is polymixin, an endotoxin binding substance. However, its use has been limited due to toxicity. Thus, an effective method for sequestering endotoxin has not yet been found. Targeting the systemic mediators of the inflammatory response has been similarly disappointing. Anti-TNF antibody in animal studies showed possible benefit, but no improvement in outcome was seen in Phase III trials. The North American Sepsis Trial (NORASEPT)317 was a prospective, multi-center, randomized, double-blind trial that showed no improvement in 28-day mortality with a TNFalpha antibody. Similarly the International Sepsis Trial (INTERSEPT),318 with 533 patients, tested a different TNFa antibody and showed no improvement. IL-1 receptor antagonists showed improved sepsis control in animals, but in a large clinical trial did not show significant effect. Several phase II trials with IL-1Ra, an IL-1 inhibitor, have shown no significant improvement.319 Similarly, platelet activating factor receptor antagonist, BN 52021, decreased mortality in

patients with gram negative sepsis but did not change the overall outcome in patients without gram negative sepsis.320 Discouraging results were also seen in a human trial of a potent PAF antagonist, lexipafant, showing no reduction in the development of MOF compared to placebo.321 Another area of recent interest is the attenuation of vasodilatation as a result of nitric oxide formation. Inducible nitric oxide synthase (iNOS) has been shown to play a pivotal role in vasodilation associated with sepsis. However, human trials of compounds targeting iNOS have been unsuccessful in preventing MOF.322 Bernard and colleagues recently reported the results of a randomized double blind international study in which patients were given recombinant activated protein C, (drotrecogin alfa) as a 96-hour infusion.323 It had previously been noted that activated protein C levels were diminished in the majority of septic patients. Furthermore, activated protein C was known to have potent anti-inflammatory effects. The study found that absolute mortality was decreased from 30.8% to 24.7%, giving a reduction of the relative risk of death in the treatment group of 20%. This effect persisted even when controlling for age, severity of illness, number of dysfunctional organ systems, the site of infection, or the type of infecting organism. Furthermore, 70% of the patients enrolled in the study were already in shock, and 75% were being mechanically ventilated, which makes the reduction in mortality even more striking. Of note, there was a trend of increased bleeding in the treated group, and patients who were at an increased risk of bleeding were excluded, including patients who had undergone recent surgery. It is thus questionable how many patients with acute head injury— particularly patients who are postoperative—would benefit from activated protein C. The results are nevertheless important, as this is the first well controlled clinical trial that shows an absolute reduction in the mortality of MOF effected by administration of a single drug.

P earls 1. There is a direct relationship between extracellular potassium and mortality. 2. Release of apoptogenic protein from mitochondria along with intrinsic pathways signal activation of apoptotic processes terminate in programmed cell death. 3. The extracellular concentration of glutamate is higher in patients with focal cortical damage than in patients with diffuse axonal injury and cerebral blood flow is decreased around focal contusions. 4. Ischemic episodes during prehospital, ED, intraoperative, and ICU management accentuate cytotoxic edema.

5. However, one must take care not to let the CPP fall below 60 mm Hg because the chances of ischemia, stroke, and poor outcome increase precipitously below this level. 6. Steroids are not recommended for improving outcome or decreasing intracranial pressure after severe head injury. 7. Without any question, the most important functional prognostic factor after spinal cord injury is the extent of the original mechanical loading of the spinal cord. This could result in spinal cord contusion, transection, deformation, or compression. 8. After a transient and abrupt translation of energy into

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10.

11.

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the spinal cord by passive forces during fracture or subluxation, a series of systemic and biochemical events ultimately determine the degree of parenchymal injury. These biochemical cascades may last several hours to days and will result in central myelomalacia. Mechanoporation of the cell membrane results in opening of the ionic channels, which results in inward rush of calcium and sodium ions and flux of potassium ions into the extracellular fluid. This process will trigger swelling, massive discharge, and initiation of biochemical cascades that result in, for example, damage to the mitochondria. Evidence indicates that after spinal cord injury there is accumulation of the vasoactive agents in the extracellular fluid and further reduction of spinal cord blood flow. These vasoactive agents include dopamine, norepinephrine, and serotonin. Oxidative stress after spinal cord injury results in excess free radical species release, with subsequent lipid peroxidation. MRI is by far the superior tool to tell us about the bony and ligamentous damage, herniated disk, cord compression, and the severity of spinal cord damage. We should make every effort to obtain MR images before or after application of traction.

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13. There is evidence to suggest that hypotension and hypoxia could worsen the pathologic processes of spinal cord injury. 14. Secondary insults in the patient with severe head injury were described by Wald and colleagues.64 In their review of 170 patients with head injuries, the most common secondary insults were hypotension and hypoxia, and these were associated with a mortality rate twice that of patients with a singular insult. 15. The initiation of MOF is frequently described as a cascade of multiple events that are postulated to begin on the microvascular level. One such scenario for the development of MOF is circulatory shock, which causes inadequate global oxygen delivery and leads to ischemic-reperfusion injury of the microvasculature. 16. There is strong evidence that serum IL-6 levels reflect injury and it is considered the most reliable prognostic indicator of outcome of all the cytokines. 17. The predominance of respiratory failure in MOF has resulted in it being described as the “pacemaker” of MOF. 18. Early fracture fixation, though controversial in the management of patients with head injuries, may benefit the patient at risk from MODS by decreasing the incidence of the fat emboli syndrome.

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222. Liu XZ, Xu XM, Hu R, et al: Neuronal and glial apoptosis after traumatic spinal cord injury. J Neurosci 1997;17(14):5395–5406. 223. Ray SK, Fidan M, Nowak MW, Wilford GG, Hogan EL, Banik NL: Oxidative stress and Ca2+ influx upregulate calpain and induce apoptosis in PC12 cells. Brain Res 2000;852(2):326–334. 224. Rosenblum WI: Histopathologic clues to the pathways of neuronal death following ischemia/hypoxia. J Neurotrauma 1997;14(5):313– 326. 225. Saito N, Yamamoto T, Watanabe T, Abe Y, Kumagai T: Implications of p53 protein expression in experimental spinal cord injury. J Neurotrauma 2000;17(2):173–182. 226. Springer JE, Azbill RD, Knapp PE: Activation of the caspase-3 apoptotic cascade in traumatic spinal cord injury. Nat Med 1999;5(8):943– 946. 227. Wada S, Yone K, Ishidou Y, et al: Apoptosis following spinal cord injury in rats and preventative effect of N-methyl-D-aspartate receptor antagonist. J Neurosurg 1999;91(Suppl 1):98–104. 228. Banik NL, Shields DC, Ray S, et al: Role of calpain in spinal cord injury: effects of calpain and free radical inhibitors. Ann NY Acad Sci 1998;844:131–137. 229. Schumacher PA, Eubanks JH, Fehlings MG: Increased calpain Imediated proteolysis, and preferential loss of dephosphorylated NF200, following traumatic spinal cord injury. Neuroscience 1999;91(2):733–744. 230. Schumacher PA, Siman RG, Fehlings MG: Pretreatment with calpain inhibitor CEP-4143 inhibits calpain I activation and cytoskeletal degradation, improves neurological function, and enhances axonal survival after traumatic spinal cord injury. J Neurochem 2000; 74(4):1646–1655. 231. Carlson GD, Warden KE, Barbeau JM, et al: Viscoelastic relaxation and regional blood flow response to spinal cord compression and decompression. Spine 1997;22(12):1285–1291. 232. Bunge RP, Puckett WR, Becerra JL, Marcillo A, Quencer RM: Observations on the pathology of human spinal cord injury. A review and classification of 22 new cases with details from a case of chronic cord compression with extensive focal demyelination. Adv Neurol 1993;59:75–89. 233. Ducker TB, Kindt GW, Kempe LG: Pathological findings in acute experimental spinal cord trauma. J Neurosurg 1971;35:700–708. 234. Waters RL, Adkins RH, Yakura JS: Definition of complete spinal cord injury. Paraplegia 1991;29(9):573–581. 235. Rao SC, Fehlings MG: The optimal radiologic method for assessing spinal canal compromise and cord compression in patients with cervical spinal cord injury. Part I: An evidence-based analysis of the published literature. Spine 1999;24(6):598–604. 236. Rizzolo SJ, Vaccaro AR, Cotler JM: Cervical spine trauma. Spine 1994;19(20):2288–2298. 237. Schaefer DM, Flanders AE, Osterholm JL, et al: Prognostic significance of magnetic resonance imaging in the acute phase of cervical spine injury. J Neurosurg 1992;76:218–223. 238. Levi L, Wolf A, Belzberg H: Hemodynamic parameters in patients with acute cervical cord trauma: Description, intervention, and prediction of outcome. Neurosurgery 1993;33(6):1007–1016. 239. Wallace MC, Tator CH: Successful improvement of blood pressure, cardiac output, and spinal cord blood flow after experimental spinal cord injury. Neurosurgery 2002;20:710–715. 240. Bracken MB, Shepard MJ, Collins WF Jr, et al: A randomized, controlled trial of methylprednisolone or naloxone in the treatment of acute spinal-cord injury. Results of the Second National Acute Spinal Cord Injury Study. J Neurosurg 1992;76:23–31. 241. Bracken MB, Shepard MJ, Holford TR, et al: Administration of methylprednisolone for 24 or 48 hours or tirilazad mesylate for 48 hours in the treatment of acute spinal cord injury. Results of the Third National Acute Spinal Cord Injury Randomized Controlled Trial. National Acute Spinal Cord Injury Study. JAMA 1997;277:1597– 1604.

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Traumatic Brain Injury: Management and Complications

242. Bracken MB, Shepard MJ, Collins WF Jr, et al: Methylprednisolone or naloxone treatment after acute spinal cord injury: 1-year follow-up data. Results of the Second National Acute Spinal Cord Injury Study. J Neurosurg 1992;76:23–31. 243. Constantini S, Young W: The effects of methylprednisolone and the ganglioside GM1 on acute spinal cord injury in rats. J Neurosurg 1994;80:97–111. 244. Geisler FH, Dorsey FC, Coleman WP: Recovery of motor function after spinal-cord injury—a randomized, placebo-controlled trial with GM-1 ganglioside. N Engl J Med 1991;324(26):1829–1838. 245. Hadley M, Fitzpatrick B, Sonntag V, Browner C: Facet fracturedislocation injuries of the cervical spine. Neurosurgery 1992;30:661– 666. 246. Star AM, Jones AA, Cotler JM, Balderston RA, Sinha R: Immediate closed reduction of cervical spine dislocations using traction. Spine 1990;15(10):1068–1072. 247. Anderson PA, Bohlman HH: Anterior decompression and arthrodesis of the cervical spine: Long-term motor improvement. Part II. Improvement in complete traumatic quadriplegia. J Bone Joint Surg [Am] 1992;74:683–692. 248. Benzel EC, Larson SJ: Functional recovery after decompressive spine opertion for cervical spine fractures. Neurosurgery 1987;20:742–746. 249. Bohlman HH, Anderson PA: Anterior decompression and arthrodesis of the cervical spine: Long-term motor improvement. Part I: Improvement in incomplete traumatic quadriparesis. J Bone Joint Surg [Am] 1992;74(5):671–682. 250. Bohlman HH, Kirkpatrick JS, Delamarter RB, Leventhal M: Anterior decompression for late pain and paralysis after fractures of the thoracolumbar spine. Clin Orthop 1994;300:24–29. 251. Bohlman HH: Acute fractures and dislocations of the cervical spine. An analysis of three hundred hospitalized patients and review of the literature. J Bone Joint Surg [Am] 1979;61(8):1119–1142. 252. Dall DM: Injuries of the cervical spine. II. Does anatomical reduction of the bony injuries improve the prognosis for spinal cord recovery? S Afr Med J 1972;46(3):1083–1090. 253. Levi L, Wolf A, Rigamonti D, Ragheb J, Mirvis S, Robinson WL: Anterior decompression in cervical spine trauma: Does the timing of surgery affect the outcome? Neurosurgery 1991;29:216–222. 254. McAfee PC, Bohlman HH: One-stage anterior cervical decompression and posterior stabilization with circumferential arthrodesis. A study of twenty-four patients who had a traumatic or a neoplastic lesion. J Bone Joint Surg [Am] 1989;71(1):78–88. 255. McAfee PC, Bohlman HH, Ducker TB, Zeidman SM, Goldstein JA: One-stage anterior cervical decompression and posterior stabilization. A study of one hundred patients with a minimum of two years of follow-up. J Bone Joint Surg [Am] 1995;77(12):1791–1800. 256. Mirza SK, Krengel WF 3rd, Chapman JR, et al: Early versus delayed surgery for acute cervical spinal cord injury. Clin Orthop 1999;359:104–114. 257. Schlegel J, Bayley J, Yuan H, Fredricksen B: Timing of surgical decompression and fixation of acute spinal fractures. J Orthop Trauma 1996;10(5):323–330. 258. Tator CH, Fehlings MG, Thorpe K, Taylor W: Current use and timing of spinal surgery for management of acute spinal surgery for management of acute spinal cord injury in North America: Results of a retrospective multicenter study. J Neurosurg 1999;91(1 Suppl):12– 18. 259. Tilney NL, Bailey GL, Morgan AP: Sequential system failure after rupture of abdominal aortic aneurysms: An unsolved problem in postoperative care. Ann Surg 1973;178:117–122. 260. Eiseman B, Beart R, Norton L: Multiple organ failure. Surg Gynecol Obstet 1977;144:323–326. 261. Fry DE, Pearlstein L, Fulton RL, et al: Multiple system organ failure. The role of uncontrolled infection. Arch Surg 1980;115:136–140. 262. Deitch EA, Goodman ER: Prevention of multiple organ failure. Surg Clin North Am 1999;79:1471–1488.

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263. Zimmerman JE, Wagner DP, Draper EA, et al: Evaluation of acute physiology and chronic health evaluation III predictions of hospital mortality in an independent database. Crit Care Med 1998;26:1317– 1326. 264. Moore FA, Sauaia A, Moore EE, et al: Post-injury multiple organ failure: A bimodal phenomenon. J Trauma 1996;40:501–510. 265. Spanier TB, Klein RD, Nasraway SA, et al: Multiple organ failure after liver transplantation. Crit Care Med 1995;23:466–473. 266. Regel G, Grotz M, Weltner T, et al: Pattern of organ failure following severe trauma. World J Surg 1996;20:422–429. 267. Regel G, Lobenhoffer P, Grotz M, et al: Treatment results of patients with multiple trauma: An analysis of 3406 cases treated between 1972 and 1991 at a German Level I Trauma Center. J Trauma 1995;38:70– 78. 268. Sauaia A, Moore FA, Moore EE, et al: Epidemiology of trauma deaths: A reassessment. J Trauma 1995;38:185–193. 269. Gullo A, Berlot G: Ingredients of organ dysfunction or failure. World J Surg 1996;20:430–436. 270. Acosta JA, Yang JC, Winchell RJ, et al: Lethal injuries and time to death in a level I trauma center. J Am Coll Surg 1998;186:528–533. 271. Wald SL, Shackford SR, Fenwick J: The effect of secondary insults on mortality and long-term disability after severe head injury in a rural region without a trauma system. J Trauma 1993;34:377–381. 272. Niederman MS: Gram-negative colonization of the respiratory tract: Pathogenesis and clinical consequences. Semin Respir Infect 1990;5:173–184. 273. O’Dwyer ST, Michie HR, Ziegler TR, et al: A single dose of endotoxin increases intestinal permeability in healthy humans. Arch Surg 1988;123:1459–1464. 274. Fink MP: Gastrointestinal mucosal injury in experimental models of shock, trauma, and sepsis. Crit Care Med 1991;19:627–641. 275. Magnotti LJ, Upperman JS, Xu DZ, et al: Gut-derived mesenteric lymph but not portal blood increases endothelial cell permeability and promotes lung injury after hemorrhagic shock. Ann Surg 1998;228:518–527. 276. Kim PK, Deutschman CS: Inflammatory responses and mediators. Surg Clin North Am 2000;80:885–894. 277. Nuytinck HK, Offermans XJ, Kubat K, et al: Whole-body inflammation in trauma patients. An autopsy study. Arch Surg 1988;123:1519– 1524. 278. Granger DN: Role of xanthine oxidase and granulocytes in ischemiareperfusion injury. Am J Physiol 1988;255:H1269–H1275. 279. Cotran RS, Pober JS: Cytokine-endothelial interactions in inflammation, immunity, and vascular injury. J Am Soc Nephrol 1990;1:225– 235. 280. Groeneveld PH, Kwappenberg KM, Langermans JA, et al: Nitric oxide (NO) production correlates with renal insufficiency and multiple organ dysfunction syndrome in severe sepsis. Intensive Care Med 1996;22:1197–1202. 281. Birkenmaier C, Hong YS, Horn JK: Modulation of the endotoxin receptor (CD14) in septic patients. J Trauma 1992;32:473–478. 282. Tracey KJ, Beutler B, Lowry SF, et al: Shock and tissue injury induced by recombinant human cachectin. Science 1986;234:470–474. 283. Hack CE, Aarden LA, Thijs LG: Role of cytokines in sepsis. Adv Immunol 1997;66:101–195. 284. Partrick DA, Moore FA, Moore EE, et al: Jack A. Barney Resident Research Award winner. The inflammatory profile of interleukin-6, interleukin-8, and soluble intercellular adhesion molecule-1 in postinjury multiple organ failure. Am J Surg 1996;172:425–429. 285. Kato T, Murata A, Ishida H, et al: Interleukin 10 reduces mortality from severe peritonitis in mice. Antimicrob Agents Chemother 1995;39:1336–1340. 286. Moshage H: Cytokines and the hepatic acute phase response. J Pathol 1997;181:257–266. 287. Moore FA, Moore EE: Evolving concepts in the pathogenesis of postinjury multiple organ failure. Surg Clin North Am 1995;75:257–277.

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288. Parsons PE, Moore FA, Moore EE, et al: Studies on the role of tumor necrosis factor in adult respiratory distress syndrome. Am Rev Respir Dis 1992;146:694–700. 289. Bone RC, Balk RA, Cerra FB, et al: Definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis. The ACCP/SCCM Consensus Conference Committee. American College of Chest Physicians/Society of Critical Care Medicine. Chest 1992;101:1644–1655. 290. Goris RJ, Boekhorst TP, Nuytinck JK, et al: Multiple-organ failure. Generalized autodestructive inflammation? Arch Surg 1985;120: 1109–1115. 291. Marshall JC, Cook DJ, Christou NV, et al: Multiple organ dysfunction score: A reliable descriptor of a complex clinical outcome. Crit Care Med 1995;23:1638–1652. 292. Moore FA, Moore EE, Read RA: Post-injury multiple organ failure: role of extrathoracic injury and sepsis in adult respiratory distress syndrome. New Horizons 1993;1:538–549. 293. Vincent JL, Ferreira F, Moreno R: Scoring systems for assessing organ dysfunction and survival. Crit Care Clin 2000;16:353–366. 294. Brun-Buisson C, Doyon F, Carlet J, et al: Incidence, risk factors, and outcome of severe sepsis and septic shock in adults. A multicenter prospective study in intensive care units. French ICU Group for Severe Sepsis. JAMA 1995;274:968–974. 295. Bell RC, Coalson JJ, Smith JD, et al: Multiple organ system failure and infection in adult respiratory distress syndrome. Ann Intern Med 1983;99:293–298. 296. Balk RA: Pathogenesis and management of multiple organ dysfunction or failure in severe sepsis and septic shock. Crit Care Clin 2000;16:337–352, vii. 297. Baker CC, Oppenheimer L, Stephens B, et al: Epidemiology of trauma deaths. Am J Surg 1980;140:144–150. 298. Fry DE: Occupational risks of infection in the surgical management of trauma patients. Am J Surg 1993;165:26S–33S. 299. Marshall WG Jr, Dimick AR: The natural history of major burns with multiple subsystem failure. J Trauma 1983;23:102–105. 300. Sugerman HJ, Bloomfield GL, Saggi BW: Multisystem organ failure secondary to increased intraabdominal pressure. Infection 1999;27:61–66. 301. Beal AL, Cerra FB: Multiple organ failure syndrome in the 1990s. Systemic inflammatory response and organ dysfunction. JAMA 1994;271:226–233. 302. Moore FA, Moore EE, Sauaia A: Blood transfusion. An independent risk factor for postinjury multiple organ failure. Arch Surg 1997;132:620–624. 303. Hebert PC, Drummond AJ, Singer J, et al: A simple multiple system organ failure scoring system predicts mortality of patients who have sepsis syndrome. Chest 1993;104:230–235. 304. Sauaia A, Moore FA, Moore EE, et al: Early risk factors for postinjury multiple organ failure. World J Surg 1996;20:392–400. 305. Davis JW, Shackford SR, Mackersie RC, et al: Base deficit as a guide to volume resuscitation. J Trauma 1988;28:1464–1467. 306. Ivatury RR, Simon RJ, Havriliak D, et al: Gastric mucosal pH and oxygen delivery and oxygen consumption indices in the assessment of adequacy of resuscitation after trauma: A prospective, randomized study. J Trauma 1995;39:128–134.

307. Velmahos GC, Arroyo H, Ramicone E, et al: Timing of fracture fixation in blunt trauma patients with severe head injuries. Am J Surg 1998;176:324–329. 308. Vincent JL: Prevention and therapy of multiple organ failure. World J Surg 1996;20:465–470. 309. van Saene HK, Stoutenbeek CP, Zandstra DF: Selective decontamination of the digestive tract (SDD) in multiple trauma patients. J Trauma 1998;44:570–572. 310. Bellomo R, Tipping P, Boyce N: Continuous veno-venous hemofiltration with dialysis removes cytokines from the circulation of septic patients. Crit Care Med 1993;21:522–526. 311. Knaus WA, Wagner DP: Multiple systems organ failure: Epidemiology and prognosis. Crit Care Clin 1989;5:221–232. 312. Abramson D, Scalea TM, Hitchcock R, et al: Lactate clearance and survival following injury. J Trauma 1993;35:584–588. 313. Pastores SM, Katz DP, Kvetan V: Splanchnic ischemia and gut mucosal injury in sepsis and the multiple organ dysfunction syndrome. Am J Gastroenterol 1996;91:1697–1710. 314. Ziegler EJ, McCutchan JA, Fierer J, et al: Treatment of gram-negative bacteremia and shock with human antiserum to a mutant Escherichia coli. N Engl J Med 1982;307:1225–1230. 315. Greenman RL, Schein RM, Martin MA, et al: A controlled clinical trial of E5 murine monoclonal IgM antibody to endotoxin in the treatment of gram-negative sepsis. The XOMA Sepsis Study Group. JAMA 1991;266:1097–1102. 316. Cunnion RE: Clinical trials of immunotherapy for sepsis. Crit Care Med 1992;20:721–723. 317. Abraham E, Wunderink R, Silverman H, et al: Efficacy and safety of monoclonal antibody to human tumor necrosis factor alpha in patients with sepsis syndrome. A randomized, controlled, doubleblind, multicenter clinical trial. TNF-alpha MAb Sepsis Study Group. JAMA 1995;273:934–941. 318. Cohen J, Carlet J: INTERSEPT: An international, multicenter, placebo-controlled trial of monoclonal antibody to human tumor necrosis factor-alpha in patients with sepsis. International Sepsis Trial Study Group. Crit Care Med 1996;24:1431–1440. 319. Fisher CJ Jr, Dhainaut JF, Opal SM, et al: Recombinant human interleukin 1 receptor antagonist in the treatment of patients with sepsis syndrome. Results from a randomized, double-blind, placebocontrolled trial. Phase III rhIL-1ra Sepsis Syndrome Study Group. JAMA 1994;271:1836–1843. 320. Dhainaut JF, Tenaillon A, Le Tulzo Y, et al: Platelet-activating factor receptor antagonist BN 52021 in the treatment of severe sepsis: A randomized, double-blind, placebo-controlled, multicenter clinical trial. BN 52021 Sepsis Study Group. Crit Care Med 1994;22:1720–1728. 321. Johnson CD, Kingsnorth AN, Imrie CW, et al: Double blind, randomised, placebo controlled study of a platelet activating factor antagonist, lexipafant, in the treatment and prevention of organ failure in predicted severe acute pancreatitis. Gut 2001;48:62–69. 322. Schoonover LL, Stewart AS, Clifton GD: Hemodynamic and cardiovascular effects of nitric oxide modulation in the therapy of septic shock. Pharmacotherapy 2000;20:1184–1197. 323. Bernard GR, Vincent JL, Laterre PF, et al: Efficacy and safety of recombinant human activated protein C for severe sepsis. N Engl J Med 2001;344:699–709.

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Chapter 29 Neurorehabilitation Joella Beard, MD

Introduction The purpose of this chapter is to familiarize the reader with the rehabilitative management of the patient with neurologic injuries. The following text addresses the main elements of the rehabilitative medical care of the intensive care unit (ICU) patient by presenting issues specific to three major categories of neurologic injury: spinal cord injury, stroke, and traumatic brain injury. Rehabilitation for each of these populations is complex; this chapter presents the most common features of patient care and minimally overlaps the concepts addressed throughout the remainder of this textbook. The basic goal of rehabilitation is to restore physical and cognitive functional abilities to improve quality of life. In the ICU, this includes minimizing the sequelae of injury or illness through use of medical interventions, patient mobilization, and rehabilitative therapies. One must keep in mind that the intensive care period is truly critical not only in treating the life-threatening conditions but also in minimizing disability to achieve the ultimate goal of returning the patient to his or her home and community life.

relies on effective communication between all involved team members. A physiatrist (a physician who specializes in physical medicine and rehabilitation) is usually consulted to supervise the overall medical management of the rehabilitation process and to prescribe the appropriate therapies in an efficient and cost-effective manner. Occasionally clinical pathways are used to assure that patients’ needs are addressed in a systematic manner.

The Multitrauma Patient Many patients with neurologic trauma have other injuries including chest trauma, long bone fractures, or pelvic fractures, in addition to traumatic brain injury (TBI) or spinal cord injury (SCI). Obviously, these complex cases require coordinated care to schedule concurrent surgeries such as tracheostomy, serial irrigation and debridement, and gastrostomy or jejunostomy tube placements. Individuals on different treatment teams should coordinate their care, and even routine medications should be reviewed frequently to minimize sedation and the need for intubation to facilitate transfer to the next level of care as early as feasible.

The Rehabilitative Team The rehabilitative team for the critically ill patient is comprised of all treating health care providers including the physicians, nurses, respiratory therapists, physical and occupational therapists, nutritionists, speech-language pathologists, psychologists, and social workers. An interdisciplinary approach to patient care allows for coordinated services and

General Survey for Concomitant Injuries The standard Advanced Trauma Life Support and Advanced Cardiac Life Support measures address the initial management of the patient with neurologic injuries. Hemodynamic and cardiopulmonary resuscitation issues are described elsewhere (see Chapters 8 and 14–16). 795

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Whether patients are admitted after trauma or secondary to a stroke, they may be obtunded, sedated, or intubated on arrival in the ICU. Although most concomitant injuries are identified in the initial emergency department examinations, one should perform a careful repeat survey to look for occult injuries unidentified in the process of treating the more critical conditions. During an ICU consultation, it is common for the physiatrist to identify an occult fracture or other musculoskeletal injury sustained from a fall due to the stroke or during the precipitating trauma. Such injuries may declare themselves by late joint effusions, ecchymoses, or an increased pain response to palpation or movement of the involved body part. There may be concomitant neurologic injuries as well. If the demonstrated paralysis is not fully explained by a known intracranial lesion, one might suspect other neurologic injury. For example, a patient with a head injury involved in a motorcycle accident may demonstrate unilateral upper extremity paralysis and one should suspect injury to the brachial plexus or cervical nerve root avulsions. If a patient has paradoxical respiration or priapism, one might suspect a concomitant spinal cord injury. This is particularly true in pediatric patients who may sustain a spinal cord injury without radiographic abnormality (SCIWORA). Subtle injuries may declare themselves as the patient begins to awaken from coma and therefore subsequent evaluations should be performed serially during the ICU period.

Spinal Cord Injury General Approach The goal of rehabilitation is to maximize medical, surgical, and other therapeutic management from the onset of injury to improve quality of life regardless of residual impairments or disabilities. For the patient with spinal cord injury (SCI), an early physiatric consultation is strongly recommended. Although the timing of this may vary between practitioners and facilities, it is usually appropriate to request physiatric evaluation within 72 hours of admission, although some physiatrists prefer to be consulted on admission.

Spinal Shock Neurogenic spinal shock refers to the time after injury when the spinal cord reflexes are blunted or absent. While neurogenic spinal shock usually resolves within hours, it may persist for weeks.1 The neurologic lesion is not considered complete until resolution of spinal shock, which is signaled by the return of spinal reflexes, the first of which is often the bulbocavernosus reflex. Incidentally, if the injury is to the conus medullaris, the bulbocavernosus reflex may not recover even after spinal shock ends. Once spinal shock is

resolved, the neurologic level of injury can be defined as a complete or incomplete lesion. Classification of Neurologic Injury The neurologic examination should include a comprehensive evaluation of intracranial function as addressed elsewhere (see Chapter 4). The neurologic examination of spinal cord involvement should use the American Spinal Injury Association’s International Standards for Neurological Classification of Spinal Cord Injury (Fig. 29-1).2 With this examination, motor strength is evaluated using the standard manual motor testing and sensory function is evaluated for light touch and pin prick sensation. The examination should include a digital rectal examination to test for the bulbocavernosus reflex, which if present, signals the resolution of spinal shock. Deep tendon reflexes, pathologic reflexes, presence of spasticity and proprioceptive sensation are assessed. Tetraplegia (previously quadriplegia) is the term used for spinal cord injury affecting both the lower and upper extremities (i.e., a lesion affecting the spinal cord from C1 through T1). Paraplegia is the term used for injury to the thoracolumbar spinal levels or sacral roots. A neurologically complete spinal cord injury can be determined after spinal shock resolves and is evidenced by no sacral sparing; that is, sensation and motor function are absent in the perianal (S4/5) dermatome. The American Spinal Injury Association Impairment Scale (Table 29-1) describes the criteria for complete and incomplete injuries.2 Significant SCI (such as a complete transection) will produce a distinct level of injury, although some asymmetry between either side is common. Several incomplete spinal cord injury syndromes have been described. In clinical practice, most injuries are not “classic” due to irregular insult to the spinal cord tissue. Despite this, a thorough examination will reveal patterns that are generally recognizable as one of these classic syndromes. As cord edema or

Table 29-1  ASIA Impairment Scale

From International Standards for Neurologic Classification of Spinal Cord Injury, Revised 2000. Reprinted with permission of American Spinal Injury Association, Chicago, 2000.

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Figure 29-1. Standard neurologic classification of spinal cord injury. (From International Standards for Neurological Classification of Spinal Cord Injury, Revised 2000. Reprinted with permission of American Spinal Injury Association, Chicago, 2000.)

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hemorrhage resolves, the syndrome patterns may become more apparent. Central cord syndrome3 notably demonstrates greater weakness in the upper extremities than the lower extremities and there is sacral sparing. This usually has a good prognosis for ambulation potential, for recovery of bladder, bowel, and sexual function and proximal greater than distal upper extremity function. Anterior cord syndrome involves injury to the anterior two thirds of the spinal cord and spares the posterior columns. There is loss of motor function below the injury level, and loss of pinprick sensation but intact deep pressure and proprioception. This syndrome has a less optimistic prognosis for functional recovery of approximately 10% to 20%.4 The Brown-Sequard syndrome is associated with ipsilateral paralysis and proprioceptive loss with contralateral sensory loss for pain and temperature. The majority of patients have a good functional prognosis for ambulation and bladder and bowel recovery.5 A lesion to the conus medullaris or to the cauda equina is characterized by lower extremity weakness and bladder and bowel dysfunction to variable degrees; both have a good prognosis for functional ambulation.6 Pulmonary Considerations Pulmonary complications following SCI are the leading cause of death in survivors after the first 6 months from injury.7 The patient with spinal cord injury is at increased risk for atelectasis, decreased inspiratory capacity, impaired cough, and retention of secretions; these abnormalities increase the risk of pneumonia and respiratory failure. Additionally, sleep-disordered breathing, hypoventilation, and hypoxia may be seen.8 Essentially, the higher the level of cervical cord injury, the less neuromuscular control of respiratory function remains. Tetraplegics with C1 to C3 lesions require ventilatory support. Individuals with C4 to C5 lesions may be able to resume independent respiration but often require ventilatory support in the ICU setting. Patients with lesions at C6 to T5 should be considered at risk for pulmonary complications due to intercostal and abdominal musculature weakness. The lower thoracic level lesions may cause respiratory weakness but, if ventilatory support is needed at all, patients are usually easily weaned in the ICU. Numerous studies have emphasized the importance of a systematic approach to pulmonary management in the patient with SCI and describe specific techniques to this end.9 The reader is directed to works such as those by McMichan10 or Ragnarsson.11 Mentioned here will be some specific rehabilitative concepts of pulmonary care regarding the SCI patient. General Concepts Some tetraplegic patients have a decreased vital capacity in the sitting position due to phrenic nerve denervation result-

ing in a lower position of the diaphragm. An abdominal binder or corset can alleviate some of this problem in the sitting position. They often have improved diaphragmatic excursion in the supine position, the theory being that the diaphragm is in better position for compliance and improved contractility in the supine position. Assisted coughing can help with secretion management. Bradycardia often occurs with suctioning and prophylactic atropine may be needed before suction. One ought to also consider using a rotating bed or mattress to help decrease pulmonary stasis. The patient should be given preventative immunizations for pneumococcus and influenza in the subacute phase of care. Alternative Ventilatory Support Techniques Individuals who can be managed with bilevel positive airway pressure or continuous positive airway pressure are discussed elsewhere. Other considerations include the use of pneumobelts or, in select patients, electrophrenic respiration (phrenic nerve stimulation). A pneumobelt is essentially an external abdominal corset with an inflatable air bladder connected to a positive-pressure ventilator; it is used in the sitting position. When inflated, the externally applied pressure compresses the abdominal viscera, which passively elevates the diaphragm for exhalation; with the bladder deflated, the diaphragm lowers to assist in passive inhalation. Phrenic nerve stimulation requires intact phrenic nerves and is typically used in injuries at or above C3. These alternative techniques are usually assessed after the acute period as some patients recover a neurologic level (or more) as cord edema resolves. Glossopharyngeal breathing, affectionately termed “frog breathing,” is an alternative to assisted ventilation that should be taught to a high cervical SCI individual for use in the event of ventilator failure. This technique can be used emergently or electively. “Frog breathing” uses the tongue to “gulp” small boluses of air (60 to 100 cc) at an approximate rate of twelve times per minute and propels the bolus into the lungs with successive thrusts to achieve adequate tidal volumes and minute volumes for minutes to hours of unassisted ventilation.12,13 Tracheostomy and Phonation Patients with injuries at or above C3 can anticipate longterm ventilation and early tracheostomy placement should be considered. Patients with a good prognosis for weaning but who will require prolonged intubation should also be considered for early tracheostomy. Not only will this decrease the risk of paranasal sinusitis,14 but it will increase the patient’s options to achieve early phonation. Long-term ventilation can also cause mucosal ulceration and bleeding, trachiectasis, and the formation of granulation tissue. If possible, maintaining the cuff pressure below 25 cm H2O (optimally below 15 cm H2O) is helpful.

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There are numerous ways to achieve phonation while intubated or cannulated.15 Once the pulmonary status is stable and the patient is at decreased risk of aspiration, one can either deflate the cuff or change to a cuffless fenestrated tube. Alternatively, while still on ventilatory support, a double-lumen ventilatory tube may be used. Speaking valves such as the Passy-Muir valve allows tracheostomy patients to communicate while maintaining access to their airway. A trial period of capping the tracheostomy may be useful to determine if the patient can tolerate airway closure and secretion management before decannulation. To assist in the communication needs of the SCI patient, one should consult the respiratory therapist and the speech-language pathologist. Cardiovascular Considerations Autonomic Dysreflexia The most profound cardiovascular changes in SCI are a result of loss of sympathetic regulation in patients injured at or above T6. Once patients are out of spinal shock, they are at risk for autonomic dysreflexia. This is a life-threatening condition initiated by a noxious stimulus below the level of injury and is usually precipitated by visceral distention (likely bladder or bowel), but may be due to less obvious stimuli such as tight clothing, an acute abdomen, occult fracture, and postural changes.16 Due to impaired regulatory control of the autonomic outflow, it is characterized by hypertension (with pressures up to 300/180 mm Hg), cephalgia, nasal congestion, flushing above the injury level, diaphoresis, and bradycardia or occasionally tachycardia. Even in the acute phase of injury in the ICU, the SCI patient may tolerate relatively lower blood pressures (about 90 mm Hg systolic). If the patient is symptomatic according to the preceding description, and blood pressure is elevated— perhaps only 20 to 40 mm Hg above baseline in adults, and over 15 mm Hg in children and adolescents—he or she should be evaluated for autonomic dysreflexia (AD). The Consortium for Spinal Cord Medicine has published Clinical Practice Guidelines with a treatment algorithm for AD.17 Patients showing any signs of AD should have their blood pressure measured and if elevated, should be placed in the sitting position, if possible. The bladder should be drained and if this does not resolve the hypertension, the bowel should be evacuated. Lidocaine gel is used for urinary catheter placement and for the rectal examination to avoid increasing noxious stimulation. If this does not resolve the hypertension, antihypertensive medications should be used according to the algorithm. Such medications include nitrates, nifedipine, hydralazine, and diazoxide among others. Although autonomic dysreflexia is not usually seen in the ICU patient, staff should be able to recognize precipitating events and be familiar with the treatment protocol as published. Additionally, patients and their caregivers should be educated about this condition and the treatment algorithm.

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Thromboembolic Events Deep vein thrombosis (DVT) occurs in up to 80% of SCI patients. The reported incidence varies depending on the diagnostic methods used, but positive venograms have been found 6 to 8 days after injury in 62% of patients.18–20 Notably, the clinical examination is not very useful, but duplex ultrasound is a reliable diagnostic tool. A high index of clinical suspicion is indicated and, more importantly, attempted prevention of thromboembolism is standard of care. Heparinoids should be used according to standard protocols. Mechanico-humoral attempts to prevent DVT often include pneumatic compression devices, gradient elastic hosiery, and performance of active ankle plantar and dorsiflexion (when possible). The combination of pneumatic compression, elastic stockings, and subcutaneous heparin (5000 U twice daily) has reportedly reduced the risk of DVT to 5%.21 Despite aggressive attempts at prevention, pulmonary embolism (PE) has an early incidence of about 5%.22–24 One should consider inferior vena caval filter placement if the patient has significant risk for pulmonary embolism. The American College of Chest Physicians has published their consensus guidelines for prevention and treatment of thromboembolism, as has the Consortium for Spinal Cord Medicine.25,26 Orthostatic Hypotension Due to the impaired sympathetic tone and vasodilation with venous pooling, the patient with acute SCI is subject to orthostatic hypotension upon first trials at sitting, or when feasible, standing. Appropriate hydration is still fundamental, so intake and output should be monitored. Gradually elevating the head of the bed, early mobilization by the therapy and nursing staffs, and using lower extremity elastic stockings and an abdominal binder are helpful. Some promising, but highly individualized, medications for potential prevention of orthostasis include fludrocortisone and midodrine. Midodrine, which has an active metabolite that works as an alpha-1-agonist and has a half-life of approximately 3 to 4 hours, requires caution because the patient should not be supine for 4 hours after the dose due to risk of hypertension.27

Gastrointestinal Considerations During the period of spinal shock, traditional signs of acute abdomen may be absent or blunted. Clinical suspicion and serial examinations should be followed with appropriate diagnostic studies, especially in the acute period after SCI.28 Abdominal trauma occurs in 6.8% of SCI patients and diagnostic peritoneal lavage as well as computed tomography may be useful.29 Nasogastric tube decompression is usually indicated due to the risk of gastric atony and ileus. Ileus can be expected within 48 hours after SCI, usually resolving within a few days to nearly a week. Abdominal distention,

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absence of bowel sounds, and a typical bowel distention pattern on radiographs indicate ileus is present. Hydration, electrolyte imbalance, and nutritional deficiency may be managed with intravenous fluids and total parenteral nutritional support during the early postinjury period in the presence of ileus.30 Once bowel sounds have returned, one can begin enteral feeds either orally or via feeding tube, as the case allows. Especially in patients with injuries above T6, there is decreased sympathetic tone and unopposed vagal stimulation, which may increase gastric acid secretion. If upper gastrointestinal bleeding occurs, it often is within the first 10 days of injury and carries significant mortality.29 Because “stress” ulcers are found in up to 22% of patients during the first month after SCI,31 ulcer prophylaxis (type 2 histamine blockers; proton pump inhibitors; sucralfate; enteral feeding, if possible) should be initiated and continued for the early months after injury.32,33 Patients can begin a bowel management program while in the ICU if bowel function returns. Gastrointestinal transit time is expected to be longer in spinal cord injury than in those with a neurologically intact gut (80.7 hours compared to 39 hours).34 A bowel management program should consist of timing bowel care to about 30 minutes after feeding to maximize the gastrocolic reflex and should occur once every 2 days. If the patient is out of spinal shock and has a bulbocavernosus reflex or anocutaneous reflex (anal wink), a reflexic bowel is likely present and one can use a colonic stimulant such as a bisacodyl suppository or digital stimulation. Caution is mandated because this may elicit an episode of autonomic dysreflexia. If this occurs, either topical 2% lidocaine gel is used before rectal stimulation or prophylaxis with nifedipine (10 mg by mouth) may be used approximately 30 minutes before rectal stimulation. If an areflexic bowel is present, manual evacuation of a somewhat firmer stool is the preferred program with a goal of daily evacuation. Both bowel programs will likely need adjustment over time and the physiatrist and rehabilitation nurse will manage this after discharge from the ICU. The essential features of bowel management are consistent scheduling of the bowel program, a relatively high fiber diet (no less than 15 g daily), adequate hydration, and manual or stimulant evacuation. Stool softeners and stimulants can be added as needed. Rectal tubes should be avoided due to risk of perianal skin breakdown. Superior mesenteric artery syndrome can be seen even in the acute period.35 This is a syndrome of postprandial nausea, emesis, and abdominal discomfort or pain, often worse in the supine position, and is caused by the superior mesenteric artery compressing the duodenum. Genitourinary Considerations During the ICU period, when intravenous fluid management is required and an initial diuresis occurs (due to sym-

pathetic changes), strict evaluation of intake and output is needed. Continuous bladder drainage via an indwelling catheter is recommended to assure adequate hydration and bladder management. Indwelling catheters can be secured to the suprapubic region in males and to the medial thigh in females to decrease the risk of skin breakdown from irritation at pressure-sensitive areas. The meatus should be examined routinely to assure no breakdown occurs. Historically, sterile intermittent catheterization significantly reduced mortality in the SCI population36; therefore, after hemodynamic stabilization, sterile intermittent catheterization should be initiated every 4 to 6 hours. The urine volumes with each catheterization should be approximately 300 to 600 cc depending on the general habitus of the individual; if greater than this, catheterization schedules or fluid intake should be adjusted as appropriate. Urinary tract infections should be treated with appropriate antibiotics, especially during this acute period, to prevent risk of colonization or sepsis. Sexuality is seldom a practical issue in the ICU phase of care, but the patient’s concerns should be addressed and prognosis of functional recovery given by the urologist, physiatrist, or other knowledgeable health care provider. Dermatologic Considerations Appropriate attention to skin care is required in the ICU to prevent pressure ulcerations and their long-term sequelae. Due to immobility and paresthesias, there is risk for pressure ulcerations that occur in up to 85% of SCI patients. Aggravating factors are primarily external pressure at bony prominences, shearing, and maceration. The patient in the ICU phase of care is at risk for pressure sores especially at the coccyx, sacrum, heels, malleoli, trochanters, and occiput, with the elbows and scapula involved less often. Ischial ulcers occur later in the patient’s course when seated for prolonged periods. Prevention is preferred to treatment. Nursing orders should include positioning to relieve pressure on bony prominences, padding or splinting as needed, frequent turning of the patient (every 2 hours) and meticulous skin care. One should prevent shearing during transfers or positioning. If the patient is seated in a chair at bedside, he or she should have an appropriate cushion and weight shift maneuvers should be employed every twenty minutes to prevent breakdown. Adequate nutrition, hydration, skin cleansing, moisturizing, and resolution of anemia or hypoalbuminemia are essential elements to prevention. Rectal tubes are not preferred and skin around catheters should be examined routinely. Scapular skin ulcers can be found inside a halo vest despite the soft inner liner. Rotating beds and low air-loss mattresses are helpful. Classification of pressure ulcerations has been described by grades or stages depending on the text reviewed.37–39 A stage I ulceration is characterized by nonblanching erythema of intact epidermis that does not resolve after 30 minutes of

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pressure relief. A stage II ulcer has dermal violation and may blister (partial-thickness skin loss). A stage III ulcer has fullthickness injury into subcutaneous tissue. A stage IV ulcer protrudes into the fascia to the muscles, bone, or joint. Stages I and II sores respond well to pressure relief and skin hygiene or hydrocolloids. Stage III and IV sores require to wet-to-damp packing with sterile saline, hydrocolloids, or calcium alginate dressings, depending on the nature of the wound. Whirlpool, pulsatile lavage, or surgical intervention may be needed. Dakin’s solution may be used if signs of infection are present. Typically, an enterostomy nurse will assist in the treatment of the wounds at any stage; at Shands Hospital at the University of Florida, a physician-run wound team assists in management of these problems. The morbidity of pressure sores cannot be emphasized enough when length of stay, health care risks, and surgeries are considered in light of the nearly preventable nature of the condition. The Consortium for Spinal Cord Medicine has published practice guidelines for prevention and treatment.40

Musculoskeletal Considerations As previously mentioned, a general survey should be performed for occult injuries even after admission to the ICU. Commonly, ligamentous injuries, subluxed shoulders, nondisplaced fractures, retroperitoneal hematomas, to name but a few, have declared themselves or been discovered on serial examination of the ICU patient with spinal cord injury. One should assure that joint injuries are identified before initiating rehabilitative therapy in order to prevent aggravating the injury. In the ICU phase, the various physician teams will need to coordinate management if there are multiple injuries. For example, treatment of concomitant brain injury, abdominal injuries, and/or fractures will necessitate coordination of surgical scheduling. Some physicians choose particular treatment options (e.g., early or delayed surgical fixation of an extremity fracture) based on the prognosis for functional recovery such as ambulation. The physiatrist will assist the primary team in determining the patient’s prognosis for overall functional recovery. In this acute phase, the treatment that will maximize later outcomes should the patient eventually regain function is the treatment of choice. Another condition seen in the SCI patient is spasticity. Spasticity is the term used for velocity-dependent resistance to passive stretch. Spasticity in SCI is seen once spinal shock resolves but most often is not clinically significant in the acute period. Occasionally, noxious stimulation, such as from a urinary tract infection or pressure sore, contributes to increased spasticity. If it becomes a problem, there are several therapeutic options available (such as baclofen, tizanidine, dantrolene, diazepam, splinting, or positional therapies); one should consult the physiatrist for treatment.

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Soft tissue contractures are usually not problematic in the acute phase of SCI care, but early intervention during the ICU stay is necessary to decrease contracture formation. Appropriately applied range of motion to the extremities should occur at least twice daily. The position of comfort is usually the position predisposing to contracture formation. Barring contraindications to joint mobilization due to fracture, sprain, or other position-sensitive condition (e.g., arterial lines), a physical or occupational therapist may perform passive range of motion exercises to paralyzed limbs or assist the patient in active range of motion exercises. The nursing staff should incorporate range of motion activities into their daily patient care and family members can be trained to perform these activities during visits to the bedside. A final condition that may be identified during the ICU period is heterotopic ossification (HO). HO is a pathologic response to injury found not only in SCI, but also associated with burns, head injuries, hip joint replacements and, rarely, in neurologic events such as stroke. The etiology is poorly understood and is thought to be a metaplastic conversion of pluripotent connective tissue cells.41,42 In some cases, direct soft tissue injury can contribute to the entity,43 but in this and other neurogenic causes, it is localized at joints. The initial signs of HO are warmth, minimal erythema, painful range of motion, and later edema or effusion as the inflammatory process progresses.44,45 In SCI, the most common sites for HO are the hips and knees and, less commonly, the shoulder and elbow. It may be found in the paralyzed regions as early as 19 days after injury. Often the first evidence of HO is an increased pain response or soft tissue resistance at a joint noted by the therapist during range of motion activity. If HO is considered, one may follow the alkaline phosphatase and phosphorous levels; when both elevate, and clinical suspicion indicates, one should consider treatment. Clinical suspicion and early diagnosis is the key to treatment, but once HO forms it is often difficult to contain. Radiographs reveal ossification only after calcification but, since matrix formation occurs first, a positive triple phase of a 99m-technetium–labeled bone scan can precede the radiographic findings by up to two weeks. Passive range of motion should continue as comfort allows and strict adherence to proper technique is critical to minimize risk of peripheral nerve injury, although this can occur from the HO alone. Disodium etidronate can minimize calcification of the matrix. The regimen recommended is a single daily dose of 20 mg/kg for 2 weeks followed by 10 mg/kg per day for 10 weeks. If gastrointestinal side effects are noted, the dose may be divided. Renal function should be followed and adequate hydration ensured to decrease the risk of nephrolithiasis. Indomethacin is alternatively used, but may be poorly tolerated in the acute phase of SCI due to risk of gastric bleeding. Rarely, direct radiation therapy may be used to minimize HO formation. Once the HO “bone” matures, best determined by bone scan and usually seen after

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approximately 18 months, surgical resection may be performed.

a treatment on a general ward.50 Consideration should be given to the creation and use of such a unit.

Rehabilitative Issues

Pulmonary Considerations

The rehabilitative goal of the entire treatment team is to restore functional recovery to achieve maximum quality of life. Even if ventilator-dependent, an active and productive lifestyle can be attained and all efforts to minimize disability should be considered throughout the acute period. The physiatrist will guide the efforts for restoring function and maximize medical treatment for the long-term care of the patient. Rehabilitation therapy should be initiated once the patient is hemodynamically and skeletally stable. Physical therapy may include pulmonary exercise; bed mobility training; transfer training; and strengthening, range of motion, and endurance exercises. Occupational therapy may include the preceding therapies to facilitate activities of daily living (e.g., dressing, hygiene, toileting). Either may apply orthotics for positioning, spasticity, or to improve functional movements. Physical modalities used in the ICU seldom go beyond ice or heat packs. A speech-language pathologist should be consulted to evaluate swallowing or communication function and will initiate adaptive equipment for communication as approved by the medical staff. A psychologist should be consulted early in the patient’s ICU stay to assist with adjustment to disability for both the patient and the family.

Pneumonia is the cause of 25% to 30% of stroke deaths and usually is due to pulmonary aspiration of oral or gastric secretions or food substances.51,52 Obviously, the patient who is intubated or cannulated is considered to have some degree of swallowing dysfunction (dysphagia). Reduced consciousness, dysarthria, a weak or “wet” cough, or an impaired gag reflex should indicate the need for nothing-by-mouth (NPO) status. A speech-language pathologist should assess alert stroke patients for aspiration risk before initiating oral feeding. Often, well-meaning family or staff has offered liquids to the patient only to find thin liquids are grossly aspirated on a radiologic swallow evaluation. The speech therapist should identify aspiration risk at the bedside and recommend fluoroscopic evaluation with a modified barium swallow (MBS) or a flexible endoscopic evaluation to further delineate the aspiration risk. I prefer the MBS, because it allows the speech therapist to trial different postural methods (chin-tuck, head tilt, etc.) to alleviate the aspiration. Further detailed discussion of how dysphagia evaluations may be incorporated into the stroke pathway, with resultant decreased risk of aspiration pneumonia, and reduced length of stay may be found in the cited literature.49,53,54 Enteral or parenteral feeds are recommended if the NPO status is prolonged.

Stroke Rehabilitation

Cardiovascular Considerations

General Approach The occurrence of medical complications after stroke is associated with worse functional outcome and reduced discharge to home even if controlled for similar impairment and disability.46,47 Minimizing morbidity in the ICU is thus particularly important. Initial patient evaluations are likely performed in the emergency department and include cardiopulmonary and neurologic assessments. Cardiac monitoring should continue to aid in detection of associated cardiovascular events. Other underlying illnesses should be monitored and treated appropriately to decrease overall morbidity and mortality. Treating the patient in a designated stroke unit has decreased length of stay, decreased morbidity and mortality, and improved functional outcomes.48,49 An “acute stroke center” where a patient is triaged, admitted, treated with clinical pathways of coordinated care, and outcomes routinely assessed, is considered to improve functional outcomes in a cost-effective manner. One study demonstrated a 50% decrease in mortality, a 40% decrease in nursing home placement, and a 30% decreased length of stay compared to

The American Heart Association published guidelines for the management of acute ischemic stroke55 that are discussed elsewhere (see Chapters 6 and 13). Some items are of significant mention regarding the rehabilitative care. Among intensivists and neurologists acute blood pressure management is controversial, but most agree that one should avoid significant and rapid decreases in elevated blood pressure. On admission, the patient with a hypertensive urgency needs bed rest. Mobilization begins gradually as the patient improves; most begin to increase activity on day 2 of the hospitalization. Because cardiac events are common among stroke patients, physical and occupational therapists are trained to watch for hypertension, orthostatic hypotension, evidence of cardiac insufficiency, or neurologic changes during their treatment sessions. Thromboembolism In the absence of prophylaxis, deep vein thrombosis (DVT) has an incidence in stroke of between 40% and 60%, depending on the diagnostic technique used. Clinical suspicion and Doppler ultrasound are combined for effective

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diagnosis; stroke patients generally show clinical signs or communicate their discomfort more often than the other populations discussed in this chapter. DVT and PE prevention with heparin (5000 units twice-daily subcutaneously) improve outcomes. It is common to use sequential compression stockings in patients for whom heparin is contraindicated; in high-risk patients these stockings are used in addition to heparin.56,57 Patients considered at higher risk for DVT are older, have had a large stroke with severe paralysis, have an infection, prolonged hospitalization, recent surgery, or previous DVT. Compression devices are best used continuously but once the patient is transferred to the rehabilitation unit this may not be practical. The American College of Chest Physicians publishes guidelines on recommendations for thromboembolism prophylaxis and treatment (Table 29-2).25 Once patients are walking at least 50 ft per day, they may be considered at lower risk.58 As noted elsewhere, caution should be used when considering heparin in a patient having suffered an intracranial hemorrhage, especially if associated with hypertension; some clinicians recommend heparin only if the hematoma is unchanged for 1 week and the blood pressure is well controlled. Most avoid heparinoids in the presence of an arteriovenous malformation, and after clipping of an aneurysm, although some use these agents once the patient is stable (personal communications, Kralick, 2001). Musculoskeletal Considerations Preventative care in the ICU is necessary to avoid the musculoskeletal complications of immobility. The patient should be positioned appropriately in bed to avoid edema or malalignment of the paretic limbs. Range of motion exercises may begin once the patient is off strict bed rest, that is, when activity will not increase the risk of intracranial pressure elevations or compromise hemodynamic stability. Staff and family members should be trained to appropriately perform range of motion and positioning. Splints may be provided to prevent contracture formation, but skin must be

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evaluated frequently for the presence of potential pressure damage and, if erythema occurs, they should be revised for better fit. Spasticity is not usually a problem for stroke patients during their early ICU stay. As described by Twitchell, poststroke motor recovery usually starts progressing from the flaccid state (absence of tendon reflexes) within 48 hours.59 Proximal function often returns before distal in a synergy pattern; that is, a voluntarily induced, but gross, composite motor movements such as flexion in the upper extremity and extension in the lower extremity. Voluntary movement usually returns but recovery may halt at any phase. Poor prognosis for functional recovery is related to a prolonged flaccid period, late onset of motor return (2 to 4 weeks), absence of voluntary hand motion (4 to 6 weeks), and severe proximal spasticity. Spasticity should be treated to decrease pain and the formation of contractures or pressure sores, and to improve function, but the treatment options are limited by comorbid factors or side effect profiles (Table 29-3).

Dermatologic Considerations Due to immobility, edema, insensate regions, and/or impaired consciousness, the stroke patient is at risk for pressure ulcer formation. Preventive care is imperative; staff should avoid skin maceration from soiling, and shear forces during positioning or transfers. Bony prominences should be padded and edematous extremities elevated. The stages of pressure sores are described in the spinal cord injury section.

Rehabilitation Considerations The goal of stroke rehabilitation is to minimize complications of the neurologic injury and subsequent immobility, and to improve functional recovery. Recall that a left hemiparetic patient (due to a right cortical stroke) when com-

Table 29-2  Prevention of DVT in Patients with MI and Ischemic Stroke Condition

Regimen

MI

Control Low-dose unfractionated heparin High-dose heparin

Ischemic stroke

Control Low-dose unfractionated heparin Low-molecular-weight heparin

No. of Trial

No. of Patients

No. of DVT

Incidence (%)

95% Cl

4

214

51

24

18–30

4

165

11

7

3–11

71

2

70

3

4

0–8

86

4

257

161

63

57–69

2

202

47

23

17–29

63

4

167

27

16

10–22

75

Modified from Geerts WH, Heit JA, Clagett PG, et al: Prevention of venous thromboembolism. Chest 2001;119:132S–175S.

Relative Risk Reduction (%)

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Table 29-3  Common Enteral Antispasmodic Medications Used in Neurorehabilitation Medication

Enteral Dose

Notable Feature

Side Effects

Lioresal

Initial: 5 mg TID Maximal: 20 mg TID-QID. Some have used higher doses

Generally tolerated

Sedation, dizziness, ataxia, hypotonia, lowered seizure threshold, especially if discontinued abruptly

Clonidine

Initial: 0.1 mg BID Maximal: 0.1 mg BID

Generally less tolerated

Cardiac dysrhythmias, orthostatic hypotension, dry mouth, drowsiness, ankle edema

Dantrolene Sodium

Initial: 25 mg QID Maximal: 100 mg QID

Generally tolerated in divided doses; works peripherally, so often preferred in patients with head injury

Dizziness, weakness, diarrhea, hepatotoxicity, nausea, and vomiting

Diazepam

Initial: 2 mg BID Maximal: 20 mg TID

Not usually preferred as a first-line agent except for painful spasms

Sedation, depression, confusion, potential for dependency

Tizanidine

Initial: 2 mg qhs Maximal: 36 mg in 3–4 divided doses

Generally tolerated if tapered upward

Hypotension, drowsiness, dry mouth, hallucinations, abnormal liver function tests

Cardenas DD. In Chapman JR (ed.): Spinal Cord Injuries State of the Art Reviews. Philadelphia, Hanley & Belfus, 1999, pp 13, 583. Reproduced with permission of Hanley & Belfus, Inc.

pared to a right hemiparetic patient will usually have more verbal fluency, visuomotor perceptual impairment, loss of visual memory, and left neglect. These patients generally will be more impulsive, have less insight and therefore impaired safety judgment, so may appear less cooperative early in their hospital course. On the other hand, a right hemiparetic patient (due to a left cortical stroke) will likely be aphasic and thus lack verbal comprehension or expression, making it difficult to communicate effectively. Especially in the ICU, it is apparent that the hemorrhagic stroke patient has a higher risk of mortality compared to those with ischemic events. However, the Oxfordshire Community Stroke Project showed that survivors had good functional outcomes.60 Although there are published prognostic indicators both for mortality and rehabilitation outcomes, each patient should be evaluated on an individual basis. Family or caregiver support for a given patient is often the major factor in successful return to the community after stroke, regardless of residual functional deficits. Some known poor prognostic indicators for successful rehabilitation are prior stroke, older age, urinary or bowel incontinence, and visuospatial deficits. Some of these features suggest bilateral stroke involvement and therefore more severe debility.61 Elevated temperature, even by one degree, is an independent predictor of poor outcome.62 During rehabilitative therapies common sense would thus suggest that one minimize exercise during hyperthermic episodes. Hyperglycemia at admission is predictive of poor outcome.63 The team should be aware of how the blood glucose values and medication needs may change with increasing activity in these patients.

Therapy Because depression is common after stroke and may impair functional recovery, psychology services should be initiated early for mood disorders and cognitive remediation. The choice of antidepressants or the short-term use of psychostimulants is dictated by medical comorbidities and desirable or undesirable side effect profiles (Table 29-4). Physical therapy emphasizes early mobilization to minimize the sequelae of immobility, including thromboembolic events, pressure ulcers, contractures, depression, and functional loss. The initial therapy may begin with range of motion activities and progress to edge of bed sitting, transfers, and standing or ambulating as possible. Resistive exercises are not usually the focus of the ICU treatment phase due to the tenuous hemodynamic or neurologic status. Occupational therapy also may begin in the ICU initially with range of motion activities, and as the patient becomes more stable, they may progress to feeding, basic grooming, or functional transfer activities. The occupational therapist will also help remediate visuospatial and cognitive deficits. As discussed previously, early evaluation by a speechlanguage pathologist is recommended, followed by videofluoroscopic swallowing examination if indicated.64 Some of the swallowing issues addressed by the speech pathologist are the level of alertness, impaired attention or mood dysfunction, posture and positioning during meals, the rate and amount of bolus attempted per bite, cognitive deficits, visual field deficits, upper extremity weakness, and poor dentition.

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Table 29-4  Common Antidepressants for Subacute Stroke Depressive Disorders Medication

Dose

Side Effects

Tricyclics (e.g., Amitriptyline, Doxepin, Imipramine, Desipramine)

Initially prefer lowest dose in elderly patients with gradual increase to effective dose if tolerated. Initial: 10 mg at bedtime Maximal: 300 mg/day if tolerated

Cardiac dysrhythmias, weight gain, delirium, common anticholinergic effects (sedation, dry mouth, constipation, urinary retention)

Tricyclics: Nortriptyline

Initial: 25 mg daily Maximal: 100 mg daily

As with other tricyclics, but often less cardiac effects

Methylphenidate

Initial: 5 mg every morning Maximal: 15 mg twice daily

Agitation, lowers seizure threshold

Selective serotonin reuptake inhibitors Fluoxetine Paroxetine Setraline

Initial: lowest dose (20–25 mg daily). Increase by taper if needed Maximal: 80 mg 50 mg 200 mg

Confusion, agitation/anxiety, headache, anorexia, impotence, rash, hypoglycemia, tremor

Trazadone

Initial: 50 mg daily Maximal: 600 mg daily in divided doses

The diet may need to be modified for consistency and the patient may need physical assistance or direct supervision due to pocketing of food or impulsiveness, which is especially noted in patients with right cortical strokes.

Traumatic Brain Injury General Approach The rehabilitative management of the patient with traumatic brain injury (TBI) begins early in the hospital course. The physiatrist will perform a comprehensive examination to help define the extent of brain injury along with other concomitant injuries, and will suggest specific medications and therapies based on the patient’s status and anticipated recovery. Expect the rehabilitative course to be revised as the patient shows spontaneous recovery and responds to medications, or based on intercurrent medical conditions (e.g., respiratory insufficiency, altered mental status, or agitation). In the ICU, the general rehabilitative management for an individual with brain injury is similar to that for other patients with respect to preventing the sequelae of immobility and loss of functional capacity. The nature of the injury usually does not direct major variations for care. However, the nature of the injury often does direct the pharmacologic management of the patient and the anticipated response to rehabilitative treatments. These management and treatment options are discussed in the following sections. Classification of Injury The terms used in rehabilitation to categorize brain injuries and the patient with brain injury will be defined for use in

Sedation, priapism (rare)

this chapter specifically. The term brain injury will be used for all intracranial events other than stroke or neoplasms that lead to various stages of morbidity or mortality. Although anoxic events (e.g., from near drowning or cardiopulmonary arrest states) are often initially treated similarly, the long-term outcomes can vary greatly. Toxic-metabolic events will not be discussed in this chapter, although basic principles discussed herein do apply. Brain injuries that involve skull fractures or open head injury, are managed similarly to craniotomies for trauma, for tumor excision, or for hematoma evacuation (whether due to trauma or hypertensive hemorrhage). TBI may include penetrating or blunt trauma, and therefore includes both open or closed head injuries. The Unconscious Patient The Glasgow Coma Scale (GCS),65 as discussed elsewhere (see Chapters 8 and 28), is descriptive for the level of consciousness. Patient response is observed for eye opening and motor and verbal functioning. The GCS score may initially be low due to factors other than brain injury (e.g., hemorrhagic shock, intoxication, or concomitant spinal cord injury); therefore, most clinicians consider the lowest GCS score after resuscitation to be the most reliable indicator of the TBI severity. The GCS is helpful as a standardized description of the patient’s level of consciousness and is usually recorded at the scene, upon hospital admission, and on serial neurologic examinations. Grading the brain injury as mild, moderate, or severe helps anticipate rehabilitative planning. Mild TBI is defined with a GCS score of 13 to 15 and a normal computed tomography scan image. A moderate TBI is defined as a GCS score of 9 to 12, and a severe TBI as a GCS score of 3 to 8.

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Initially, most patients requiring the neurointensive care unit will be comatose or intubated after brain injury. It is generally preferred to minimize sedation for these patients. To prevent self-injury once the patient starts to arouse, loose restraints with close monitoring by the nursing staff may suffice to help limit chemical sedation. Because this is not always possible, close communication between the various teams is important to coordinate examinations under minimal (or no) sedation for accurate documentation of the level of consciousness. Medications should be chosen judiciously to avoid blunting responsiveness and alternatives with less sedating side effects should be chosen as much as feasible. Some medications, such as propofol, are chosen specifically for the rapid onset and offset of their sedative properties. In our institution, patients with TBI requiring sedation are medicated with propofol at a dose that ranges between 5 and 100 mg/kg/min, titrated to a sedation score of 2 to 3. Prevention of Secondary Sequelae Pulmonary Considerations The basic guidelines of extubation or tracheotomy apply to these patients as to others. Recall that aphasia (impaired ability to receive or express communication) may inhibit the patient’s ability to follow a command such as “lift your head” in assessing readiness for extubation. Motor apraxia (the inability to process a desired action) may also impede their ability to respond appropriately to some commands. Therefore, the examiner should adapt his or her technique to obtain an adequate examination and assess understanding/alertness/readiness for extubation. Similar risks of aspiration pneumonia are found in TBI patients as in stroke patients. While the patient is intubated, comatose, and after consciousness begins to return, appropriate oral hygiene is important to minimize risk of infection. After tracheal extubation and before oral feeding, a speech-language pathologist should be consulted to evaluate for dysphagia and aspiration risk. Bedside swallowing evaluations can determine the need for further examinations such as videofluoroscopic or flexible endoscopic swallowing evaluations. The presence of a gag response does not ensure absence of dysphagia and its consequent aspiration risk. Post-traumatic Epilepsy Most patients with brain injury are treated prophylactically with anticonvulsants on admission to the ICU. The incidence of post-traumatic epilepsy (PTE) is approximately 5% in nonpenetrating injuries and nearly 50% in penetrating injuries. Post-traumatic seizures are divided into three categories based on timing of occurrence from injury as follows: immediate—within the first 24 hours; early—within the first 7 days; and late—after the first week. Some patients may have seizure activity at the time of injury, often referred to as a “contact seizure.” Over half of seizures are immediate and of

those, 50% occur within the first hour. Many of the immediate seizures occur in those with depressed skull fractures. Early PTE is often due to correctable causes such as intracranial hemorrhage or metabolic disturbances such as hyponatremia. The noted risk factors for PTE66 are brain contusion with subdural hematoma, skull fracture, loss of consciousness or amnesia for more than 1 day, and age of 65 or older. Generally, the more severe the head injury, the higher the risk of PTE.67 Predictors for late PTE are acute intracranial hematoma, early epilepsy, and depressed fracture. Phenytoin is beneficial as prophylaxis against early, but not late, PTE68,69; therefore, current practice is to discontinue prophylaxis if no seizure has occurred within the first week; I prefer to taper the anticonvulsants to discontinuance over the subsequent week. Should late seizure activity occur, standard treatment and dosing is instituted. During phenytoin prophylaxis, patients often demonstrate fluctuations in cognitive ability due to sedation especially with the standard dose of 100 mg three times daily given via gastric tube. Once the patient is able to take oral medications it is preferred to give the dose at bedtime to decrease daytime sedation. Post-traumatic hydrocephalus is usually normal pressure hydrocephalus, and the classic triad of incontinence, ataxia, and dementia may not be obvious in the TBI patient. The patient may, however, demonstrate a decline or arrest in his or her recovery, seizures, or prolonged coma.70,71 Vascular Considerations Venous thromboembolism prophylaxis after brain injury is individualized. Mechanico-humoral methods using compressive stockings or intermittent pneumatic compression are usually employed, but lower extremity wounds or external fixation of fractures may prevent their use. Subcutaneous, low-dose unfractionated heparin is usually individually evaluated for benefit versus risk. Studies of heparin in general trauma patients and elective neurosurgical patients have found it to be effective and associated with minimal risk.72,73 At present, if coagulation factors are normal and imaging studies demonstrate stable hemorrhagic lesions, a dose of 5000 units every 8 or 12 hours administered subcutaneously is typically used. Lowmolecular-weight heparin and warfarin have not typically been used in the early ICU period after TBI due to concern about hemorrhage, although one noted study favorably compares heparin and low molecular weight heparin use in trauma patients.74 Heparins may induce thrombocytopenia. Neurologic Considerations Central dysautonomia occurs during coma states, especially in patients with severe TBI. Hyperhydrosis, hypertension, and fever are classically seen and, as discussed elsewhere, a

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beta-blocker is often effective in decreasing the symptoms. Central fevers often respond to dopamine agonists or morphine but one should always be suspicious of treatable causes of fever including aspiration pneumonia, sinusitis, or even an abscessed tooth. If the hyperhydrosis is seen unilaterally on the face or chest in a paralyzed or comatose patient, occult spinal cord injury should be considered. Spasticity may be more problematic in this population than the others presented previously because the duration of coma may produce a longer length of stay in the ICU. That is, SCI and stroke patients will likely be transferred from the ICU before the development of significant spasticity, compared to the TBI patient who likely will still be in the ICU when spasticity develops. Noxious stimuli may contribute to increased spasticity; therefore, treatment of infection, prevention of pressure ulcers, and management of dysautonomia may decrease episodic spasticity. For longterm management, less sedating medications are preferred and therefore lioresal and benzodiazepines are not typically first-line choices. Clonidine, when used for antihypertensive management, may produce improvement in spasticity but the sedative effects are quite problematic for this population.75 Subsequent orthostatic hypotension impairs its use in some patients, which is also the case for tizanidine, an alphaadrenergic agonist. Dantrolene sodium is a good initial choice because it works at the skeletal muscle level but cautious use is recommended, as it is not selective to only spastic musculature; liver function tests should be followed.76 The occupational or physical therapist may be requested to make resting splints for appropriate positioning of flaccid joints or anti-spasticity splints for those with more tone.77 Maintaining adequate range of motion will limit future impairment if the patient recovers functional use of the involved extremity. Typically, later in the rehabilitative course, nerve blocks or botulinum toxin injections may be considered by the consulting physiatrist to reduce localized spasticity.78,79 The patient should be examined for neurologic injury unrelated to the brain injury. For example, the presence of a unilateral upper extremity weakness which is not directly explained by the location of the brain lesion(s) should result in evaluation for brachial plexus injury or cervical nerve root avulsion as early as possible, especially in a motorcycle injury. The physiatrist or neurologist may perform an electrodiagnostic examination to assess this issue. Dermatologic Management As with other immobilized patients, pressure relief, avoidance of friction, skin hygiene, hydration, nutrition, and positioning are all important issues to prevent pressure sore formation. Once patients are more mobile, having the nursing and therapy staff position them to a bedside cardiac chair is appropriate; adequate cushioning in the chair is mandatory to prevent ischial breakdown. Standard aggressive wound care is used if pressure sores develop.

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Musculoskeletal Management Due to the increased risk of prolonged immobilization and increased spasticity, range of motion therapy and proper positioning is vital to prevent soft-tissue contractures. The patients should be examined thoroughly to exclude undiscovered injuries before initiating therapy activities. Fractures, severe sprains, and such injuries that require orthopedic splinting and immobilization preclude range of motion as usual. Hemodynamically unstable patients should be at bed rest, but once stabilized, therapists, nurses, and trained family members can initiate passive range of motion to the comatose patient’s joints. Patients requiring intracranial pressure monitoring should be closely evaluated before and during range of motion therapy as it may cause a pressure elevation above the threshold value for treatment (usually about 18 to 20 mm Hg). At that point, the therapist is expected to stop treatment and notify the nurse, as would be done with any significant change in vital signs or status change. HO is a problem in this population. Reported incidence varies depending on the methods of detection, but up to three fourths of patients in comatose states for longer than 1 month have shown HO.80 The “typical” traumatic brain injury patient is a young adult male and textbooks often cite this as the population considered at risk for HO. However, in my experience (due to tertiary referral patterns), a high index of suspicion of HO is prudent for all patients. Again, once clinical signs occur treatment is not as effective, yet generalized prophylaxis in all TBI patients is not the norm. Those who are anticipated to remain in coma for longer than 2 to 4 weeks and those showing increased tone (spasticity) would be ones more likely to develop HO. HO may be anticipated in the spastic elbow, shoulders, knees, or hips. Often the first sign of HO formation is increased resistance to passive range of motion noted by the therapist and if patients are more alert, they may complain of pain. Erythema, warmth, and edema are noted. Range of motion may be continued within neutral positions, but aggressive activity should not be forced. Disodium etidronate may be used as discussed previously with SCI patients to prevent calcification of the matrix.81 Nonsteroidal anti-inflammatory agents are not known to prevent neurogenic HO but may relieve the associated discomfort in the more alert patient. Especially with unresponsive or less communicative patients, one should watch for signs of gastrointestinal intolerance of the drug. Further research would be helpful in the prevention and treatment of heterotopic ossification. Pharmacotherapy in Traumatic Brain Injury As noted previously, medications chosen for use in the patient with brain injury should minimize sedation and cognitive impairment. While the patient is intubated this is not usually problematic, but as the patient arouses, his or her

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alertness may be directly affected by medications used for management of other issues. Gastric ulcer prophylaxis with H2 blockers (e.g., ranitidine), motility agents/antiemetics (e.g., metoclopramide), or antihypertensives (e.g., clonidine) all have side effect profiles that may blunt alertness, particularly in those with brain injury. Analgesics should be neither over- nor underutilized, and vital signs may indicate pain responses not obvious to the examiner. Medications used for affective disorders, agitation, or cognitive enhancement after brain injury are often studied in clinical trials, but there is a significant need for multicenter, controlled studies to determine optimal dosage and choice of these agents. The trend in rehabilitation is to extrapolate such information from the larger stroke literature or more recent rehabilitation studies, and use appropriate clinical judgment on an individual basis. For example, a tricyclic antidepressant such as desipramine may be selected not only for its antidepressant effect, but also for its reported attention-enhancing effect.82,83 Selective serotonin re-uptake inhibitors may be preferred for a given individual due to the decreased risk of lowering the seizure threshold or due to comorbid cardiac conditions. Aphasias have been treated with dopamine agonists.84,85 Clonidine has been suggested to have a negative influence on motor recovery in stroke and likely in TBI as well.86 Haloperidol has also been implicated in impaired motor recovery in animals87 and a small study of TBI patients showed an increased duration of post-traumatic amnesia.88 Additionally, clinical management is often extrapolated from chronic TBI studies. Methylphenidate reportedly has variable effectiveness for enhancing cognition89,90; it is used on an individual basis in rehabilitation centers. The main goal of medication management in early TBI is to choose medications that have the least undesirable side effects but maximize cognitive responsiveness. Because the literature is replete with mixed results for many of these medications, and because patients have unique clinical conditions, the treating physicians must have a global approach to their treatment plans and add each medication in light of the long-term effects of the drug (Table 29-5). Medical management of the agitated patient with brain injury during the ICU period is one such area in which the global picture must be considered. The ICU staff frequently encounters the postoperative patient who “fights the tube” and has physical or chemical restraints prescribed. The patient with brain injury who begins to awaken would not be expected to have a similarly short duration of agitation and the frequent use of short-acting chemical restraints on an “as-needed” basis may not be as practical as medications that have longer half lives. The physiatrist will often recommend individualized medications to minimize restraints or will facilitate transfer to a rehabilitation unit as early as possible to manage the patient’s care environmentally or behaviorally.

Some methods used to decrease agitation in the ICU are to first assure no physical problems are causing the agitation (e.g., hypoxia or pain), to minimize stimulation (both iatrogenic and from visitors), and provide light/dark periods to facilitate sleep/wake cycles. Longer-term medications, such as beta-blockers, antidepressants, or low-dose antihistamines rather than short-term medications, such as haloperidol, may be prescribed. In adults, I prefer to initiate buspirone at 5 mg per gastric tube three times daily at the earliest sign of agitation. This dose is successfully tapered upward to produce an effect (often 10 mg three times daily) by the time of early discharge from the ICU to the rehabilitation unit. The use of lorazepam is reserved for those patients who are uncontrollably a danger to themselves or violent to staff; 2 milligrams intramuscularly will likely work in an emergency and may need to be repeated. Although recommendations for agitation management can be found in many articles, I suggest beginning with Sandel 1996 and Mysiw 1997 in the references provided.91,92 Rehabilitation Issues The appropriate approach toward family members of a comatose patient is sometimes elusive to the treating physician. Family members often report that the patient demonstrates meaningful responses, but the clinician recognizes these activities as posturing, spasticity, or reflexive movement. When the patient is in a comatose state, most clinicians can readily explain these reflex activities to the family but once the patient begins spontaneous eye opening physicians are often less comfortable in their explanations. The following paragraphs are meant to provide some definitions used in rehabilitation to help clarify the level of consciousness from a neurobehavioral perspective. The nomenclature for various states of consciousness was described in a position paper of the American Congress of Rehabilitation Medicine (ACRM) published in the Archives of Physical Medicine and Rehabilitation.93 Coma refers to the unconscious state with no eye opening, no command following, no verbalizations, no intentional movements, and the inability to sustain visual pursuit when the examiner attempts to elicit such with head turning. Vegetative state refers to that condition of impaired consciousness like coma except that the presence of spontaneous or stimulated eye opening and spontaneous roving eye movements (often called “the coma vigil”) may be noted. During this state, distinct sleep/wake cycles may be noted and the patient may no longer require ventilatory support. This vegetative state becomes persistent according to the American Academy of Neurology94 at 1 month after injury. The term permanent is used at 3 months after nontraumatic and 12 months after traumatic injuries. However, this term does not clarify the diagnosis or prognosis for a given patient and the term permanent connotes absolute certainty, which is not supported scientifically or clinically. Although the term persistent

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Table 29-5  Common Medications for Brain Injury Management Medication Options

Indications or (Desired Effect)

Enteral Dose

Side Effects

Amantadine

(Arousal from low level) (Attention/concentration) (Verbal initiation)

Initial: 100 mg daily Maximal: 200 mg twice daily

Confusion, hallucinations, seizures, constipation, lethargy, livedo reticularis

Amitriptyline

Insomnia (sedation) Drooling (dry mouth and desired anticholinergic effects) Anxiety

Initial: 10 mg at bedtime Maximal: 100 mg at bedtime

Cardiac dysrhythmia, anticholinergic changes, delirium, fatigue, weight gain, hypotension, sedation, seizures

Anticonvulsants Carbamazepine Valproic acid

Agitation with combativeness Seizures

Initial: 100–125 mg twice daily Maximal: 200–250 twice daily (Typical doses for agitation, not seizure management)

Sedation, aplastic anemia, hepatotoxicity

Buspirone

Agitation Anxiety

Initial: 5 mg twice daily Maximal: 20 mg three times daily

Headache, dizziness

Desipramine

(Arousal from low level) (Verbal initiation) Hyperphagia

Initial: 25 mg daily Maximal: 75–100 mg daily

Tachyarrythmias, lowers seizure threshold, confusion, less anticholinergic than amitriptyline

Diphenhydramine

(Sedation)

Initial: 25 mg at bedtime Maximal: 50 mg twice daily

Sedation, hypotension, constipation, hangover effect, anticholinergic effects, increased agitation

Lorazepam

Agitation with risk of injury to self or others

Urgent need: 0.5–2 mg IM/IV every 6 hours Maximal: 10 mg daily

Sedation, withdrawal

Methylphenidate

(Attention/concentration)

Initial: 5 mg every morning Maximal: 10 mg three time daily Extended release may be used daily

Increased agitation, lowers seizure threshold Sustained release form may be used

Propranolol

Agitation, especially if sympathetic signs (tachycardia)

Initial: 10 mg daily b1b2 blockade, hyperglycemia, Maximal: 40 mg four times daily CNS depression Usual maximal effective dose: 10 mg three times daily as needed prn

Serotonin dopamine receptor antagonists Risperidone Olanzapine

Agitation with combativeness Psychosis

Risperidone Initial: 0.5 mg at bedtime Maximal: 10 mg in divided doses Olanzapine Initial: 2.5 mg at bedtime Maximal: 10 mg daily

Usually respond to very low doses with significant sedation, increased risk for extrapyramidal side effects

Trazadone

Insomnia (sedation) Depression

Initial: 25 mg at bedtime Maximal: 300 mg twice daily

Low doses for sedation Priapism (rare)

describes the tenacity of the condition, certainly enough patients have disproven the term permanent vegetative state to merit its disuse. Minimally responsive is the state in which the patient responds meaningfully to some prompt (a command, stimulation, or question); such response is noted significantly less often when the prompt is not presented and has been observed during formal assessment at least once. The term locked-in refers to the patient who is cognitively aware of the environment, capable of eye movement, but has

quadriplegia and is incapable of speech due to disruption of corticospinal and corticobulbar tracts.93 The other major category of definitions useful in the rehabilitation of patients with brain injuries is the Rancho Levels of Cognitive Functioning (Table 29-6).95 This is a ten level tool to describe responsiveness. The levels seen in the intensive care period typically are Levels I through IV depending upon length of stay. Level I is an unresponsive coma state. Level II shows pain responses, generalized

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Table 29-6  Rancho Levels of Cognitive Functioning (Summarized) Level of Function 1 2 3 4 5 6 7 8 9 10

Behavioral Characteristics

Assistance Needed

No response Generalized response Localized response Confused—agitated Confused—inappropriate—nonagitated Confused—appropriate Automatic—appropriate Purposeful and appropriate Purposeful and appropriate Purposeful and appropriate

Total Total Total Maximal Maximal Moderate Minimal for routine daily living skills Stand-by Stand-by on request Modified independent

Reproduced with permission from Hagen CC: The Rancho Levels of Cognitive Functioning. A Clinical Case Management Tool. The Revised Levels, 3rd ed. Downey, CA: Professional Staff Association of Rancho Los Amigos Hospital, 1998.

physiologic responses, and may include moaning or other vocalization. Level III is typified by inconsistent localized responses, which include withdrawing from or localizing a stimulus. The eyes may focus on presented objects and patients may be able to follow simple commands inconsistently. Because the responses are so inconsistent, it is common for staff to document variations between one examination and the next. The morning notes may document “follows simple commands” but on afternoon rounds, there may be little to no responsiveness. The patient with brain injury may have fluctuations in alertness, in responsiveness, in the ability to follow commands, and will have frequent periods of somnolence. There may be overlap between the levels depending on the timing of the examination. If possible, one should adjust medications to decrease daytime sedation. This level is also when tracheal extubation is often successful as somnolence diminishes and the patient is able to maintain the airway more consistently. The physiatrist may begin medications to enhance arousal. Level IV deserves particular mention. It is often the most frustrating level for the ICU staff, yet the most encouraging for the rehabilitationist. This level is characterized by increased physical activity, confusion, agitation, inappropriate verbalizations without typical social constraints, and possibly aggressive behavior. This state, as others, can be variable in duration but often patients are transferred to rehabilitation before, or soon after, this stage occurs. While in the ICU the tendency is to use physical restraints to prevent harmful self-removal of tubes or to prevent falls because these patients try to climb out of bed. Level IV patients are not aware of physical disabilities that impede their independence. The positive thing about this stage is that patients seldom recall their actions and families can be assured that inappropriate behavior is not intentional. The medications preferred for decreasing agitation vary by practitioner, and the reader is strongly encouraged to discuss this with the physiatrist to determine what medications may be used to abate agitation while improving cognitive function. At this time and if there are no contraindications, I prefer to

begin buspirone at 5 mg three times daily at the onset of agitation and taper upward every 5 to 7 days as needed. To provide sedation at night, low dose trazodone is initiated at 25 mg and increased if needed. Trazodone has a reported 1% risk of priapism, presumably at higher doses. Antihistamines can be effective for sedation. Propranolol may decrease agitation in the patient with tachycardia if the tachycardia is unrelated to hemodynamic causes or pain, and if the patient has no pulmonary or cardiac contraindications to its use. Lorazepam is used as indicated for risk of harm. The remaining six Rancho Los Amigos levels are typically encountered in the rehabilitation unit and the reader is directed to the literature for further description. Therapy for the Patient with Brain Injury Rehabilitation of the patient with brain injury in the ICU will be individualized based on the medical status, the comorbid illnesses/injuries, and the premorbid functional level. Generally, the physical or occupational therapists will begin passive range of motion activity to the extremities and will work within the medical parameters ordered by the physiatrist or primary physician. They may provide splints for contraction prevention, and will educate visiting family about the exercise and positioning regimens. As the patient becomes more alert, the therapists will begin mobility and functional skills for daily activities. The speech-language pathologist should begin cognitive, communicative, and swallowing assessments while the patient is in the ICU but there will be little involvement from this discipline until the patient begins to regain consciousness. While the patient is emerging from a coma, the main focus of this therapy will be on stimulus/response and documentation of consciousness levels. Once the patient regains consciousness, more emphasis will be directed to assessing visual perception and cognition. Formal dysphagia assessments along with communicative skills and adaptive devices are evaluated as needed. The entire rehabilitative team will coordinate treatments to progress the patients along toward recovery; there

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is great overlap in the preceding treatments and often cotreatment sessions occur for the patient with brain injury. The other discipline in the rehabilitative team is neuropsychology. The psychologist with specific training for neurorehabilitation of patients with brain injuries should be introduced to the patient once he or she begins to regain consciousness. Before this, psychology services will help the family members cope with this frequently painful emotional situation. They can also begin the evaluation of the social situation, to determine if substance abuse or domestic abuse counseling will be needed, and to educate the family in the expected recovery process. There can be overlap with social services in addressing some of these issues, but the psychologist needs to be involved early in the case. More formal cognitive testing performed by the neuropsychologist is usually deferred until the patient is able to attend to a task for prolonged periods but he or she may document the duration of post-traumatic amnesia by various tests. The appropriate time for transfer of the patient from the ICU to the rehabilitation unit is determined on an individual basis. The determining factor will be the receiving facility’s ability to safely manage the intubated patient, the extubated but somnolent patient, or the confused and agitated patient. Because of the complexity of rehabilitative needs, I highly recommend referring the patient with brain

Neurorehabilitation

injury to an acute rehabilitation facility rather than attempting early transfer to a nursing home facility.

Closing Comments Neurorehabilitation during the intensive care period is individualized, but the general principles for treating the patient remain similar among the diagnostic categories. Adequate evaluation of comorbid illnesses and injuries helps determine the overall plan of care. Focusing attention on each body system will help prevent problems due to secondary conditions. Preventing the sequelae of immobility and deconditioning while enhancing functional recovery is a key goal of rehabilitation in the ICU. Common sense indicates this will decrease morbidity, length of hospital stay, and overall costs. The physiatrist will prescribe the rehabilitation therapies and related medical interventions as indicated and thereby direct the physical and functional recovery on a dynamic basis. To improve the potential for returning patients with neurologic injuries to their homes, their communities, and enjoyment of life, rehabilitation should be part of every clinicians’ daily treatment plan.

P earls 1. The rehabilitative team for the critically ill patient is comprised of all treating health care providers including the physicians, nurses, respiratory therapists, physical and occupational therapists, nutritionists, speech-language pathologists, psychologists, and social workers. 2. Neurogenic spinal shock refers to the time after injury when the spinal cord reflexes are blunted or absent. While neurogenic spinal shock usually resolves within hours, it may persist for weeks. 3. A neurologically complete spinal cord injury can be determined after spinal shock resolves and is evidenced by no sacral sparing; that is, sensation and motor function are absent in the perianal (S4/5) dermatome. 4. Central cord syndrome notably demonstrates greater weakness in the upper extremities than the lower extremities and there is sacral sparing. This usually has a good prognosis for ambulation potential, for recovery of bladder, bowel, and sexual function, and for proximal greater than distal upper extremity function. 5. The Brown-Sequard syndrome is associated with ipsilateral paralysis and proprioceptive loss with contralateral sensory loss for pain and temperature. The

811

6. 7.

8.

9.

10.

majority of patients have a good functional prognosis for ambulation and bladder and bowel recovery. Bradycardia often occurs with suctioning and prophylactic atropine may be needed before suction. The most profound cardiovascular changes in SCI are a result of loss of sympathetic regulation in patients injured at or above T6. Once the patient is out of spinal shock, he or she is at risk for autonomic dysreflexia. Deep vein thrombosis (DVT) occurs in up to 80% of SCI patients. The combination of pneumatic compression, elastic stockings, and subcutaneous heparin (5000 U twice daily) has reportedly reduced the risk of DVT to 5%. Especially in patients with injuries above T6, there is decreased sympathetic tone and unopposed vagal stimulation, which may increase gastric acid secretion. If upper gastrointestinal bleeding occurs, it often is within the first ten days of injury and carries significant mortality. Due to immobility and paresthesias, there is risk for pressure ulcerations that occur in up to 85% of SCI patients.

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References 1. Atkinson PP, Atkinson JLD: Spinal shock. Mayo Clinic Proc 1996;71:384. 2. Marino RJ (ed): International Standards for Neurological Classification of Spinal Cord Injury, Revised 2000. American Spinal Cord Injury Association, Chicago, 2000. 3. Merriam WF, Taylor TKF, Ruff SJ, McPhail MJ: A reappraisal of acute traumatic central cord syndrome. J Bone Joint Surg 1986;68B:708. 4. Stauffer ES: Neurologic recovery following injuries to the cervical spinal cord and nerve roots. Spine 1984;9:532. 5. Roth EJ, Park T, Pang T, et al: Traumatic cervical Brown-Sequard and Brown-Sequard plus syndromes; the spectrum of presentations and outcomes. Paraplegia 1991;29:582. 6. Finkelstein JA: Evaluation of spinal cord injury patients. In Chapman JR (ed): State of the Art Reviews Spinal Cord Injuries. Philadelphia, Hanley & Belfus, 1999, p 469. 7. Jackson AB, Groomes TE: Incidence of respiratory complications following spinal cord injury. Arch Phys Med Rehabil 1994;75:270. 8. Lanig IS, Peterson WP: The respiratory system in spinal cord injury. In: Kraft GH, Hammond MC (eds): Physical Medicine Rehabilitation Clinics of North America; Topics in Spinal Cord Injury Medicine. Philadelphia, WB Saunders, 2000, p 29. 9. Peterson WP, Charlifue S, Gerhart K, et al: Two methods of weaning persons with quadriplegia from mechanical ventilators. Paraplegia 1994;32:98. 10. McMichan JC, Michel L, Westbrook P: Pulmonary function following traumatic quadriplegia. JAMA 1980;243:528. 11. Ragnarsson KT, Hall KM, Wilmot CB, et al: Management of pulmonary, cardiovascular, and metabolic conditions after spinal cord injury. In Stover SL, DeLisa JA, Whiteneck GG (eds): Spinal Cord Injury: Clinical Outcomes from the Model Systems. Gaithersburg, Aspen Publishers, 1995, pp 79–99. 12. Dail CW, Affeldt JE, Collier CR: Clinical aspects of glossopharyngeal breathing: Report of use by one hundred post-poliomyelitis patients. JAMA 1953;158:445. 13. Dail C, Rodgers M, Guess V, Adkins HV: Glossopharyngeal breathing manual. Downey, CA, Professional Staff Association of Rancho Los Amigos Hospital, 1979. 14. Deutschman CS, Wilton P, Snow J, et al: Paranasal sinusitis associated with nasotracheal intubation: A frequently unrecognized and treatable source of sepsis. Crit Care Med 1986;14:111. 15. Mason M: Speech Pathology for Tracheostomized and Ventilator Dependent Patients. Newport Beach, CA, Voicing, 1993. 16. Beard JP, Wade WH, Barber DB: Sacral insufficiency stress fracture as etiology of positional autonomic dysreflexia: Case report. Paraplegia 1996;34:173. 17. Consortium for Spinal Cord Medicine: Acute management of autonomic dysreflexia: Adults with spinal cord injury presenting to healthcare facilities. Clinical Practice Guidelines. Washington, DC, Paralyzed Veterans of America, 2001. 18. Merli GJ, Herbison GJ, Ditunno JF: Deep vein thrombosis in acute spinal cord-injured patients. Arch Phys Med Rehabil 1990;71:566. 19. Myllynen P, Kammonen M, Rokkanen P, et al: DVT and pulmonary embolism in patients with acute spinal cord injury: A comparison with nonparalyzed patients immobilized due to spinal fractures. J Trauma 1985;25:541. 20. Rossi E, Green D, Rosen J, et al: Sequential changes in factor VIII and platelets preceding deep vein thrombosis in patients with spinal cord injury. Br J Haematol 1980;45:143. 21. Merli GJ, Crabbe S, Doyle L: Mechanical plus pharmacological prophylaxis for deep vein thrombosis in acute spinal cord injury. Paraplegia 1992;30:558. 22. Waring WP, Karunas RS: Acute spinal cord injuries and the incidence of clinically occurring thromboembolic disease. Paraplegia 1991;29:8.

23. Lim AC, Roth EJ, Green D: Lower limb paralysis: Its effect on the recanalization of deep-vein thrombosis. Arch Phys Med Rehabil 1992;73:331. 24. Green D: Deep vein thrombosis in spinal cord injury: Summary and recommendation. Chest 1992;102(Suppl):S633. 25. Clagett GP, Anderson, FA, Geerts W, et al: Prevention of venous thromboembolism. Fifth ACCP Consensus Conference on Antithrombotic Therapy. Chest 1998;114:531S–560S. 26. Consortium for Spinal Cord Medicine: Prevention of Thromboembolism in Spinal Cord Injury. Clinical Practice Guidelines. Washington, DC, Paralyzed Veterans of America, 1998. 27. Barber DB, Rogers SJ, Fredrickson MD, Able AC: Midodrine Hydrochloride and the treatment of orthostatic hypotension in tetraplegia: Two cases and a review of the literature. Spinal Cord 2000;38(2):9. 28. Berlly MH, Wilmot CB: Acute abdominal emergencies during the first four weeks after spinal cord injury. Arch Phys Med Rehabil 1984;65:687. 29. Halm MA: Elimination concerns with acute spinal cord trauma. Crit Care Nursing Clin North Am 1990;2:385. 30. Kuric J, Lucas CE, Ledgerwood AM: Nutritional support: A prophylaxis against stress bleeding after spinal cord injury. Paraplegia 1989;27:140. 31. Kewalramani LS: Neurogenic gastroduodenal ulcerationa and bleeding associated with spinal cord injuries. J Trauma 1979;19(4):259. 32. Epstein N, Hood DC, Ransohoff J: Gastrointestinal bleeding in patients with spinal cord trauma. J Neurosurg 1981;54:16. 33. Gore RM, Mintzer RA, Calenoff L: Gastrointestinal complications of spinal cord injury. Spine 1981;6:538. 34. Nino-Murcia M, Stone JM, Chang PJ, et al: Colonic transit in spinal cord-injured patients. Invest Radiol 1990;25:109. 35. Roth EJ, Fenton LL, Gaebler-Spira DJ, et al: Superior mesenteric artery syndrome in acute traumatic quadriplegia: Case reports and literature review. Arch Phys Med Rehabil 1991;72:417. 36. Guttmann L, Frankel H: The value of intermittent catheterization in the early management of traumatic paraplegia and tetraplegia. Paraplegia 1966;4:63. 37. Enis JE, Sarmiento A: The pathophysiology and management of pressure sores. Orthop Rev 1973;2:25. 38. Bergstrom N, Bennett MA, Carlson CE, et al: Treatment of Pressure Ulcers. Clinical Practice Guideline Number 14. AHCPR Publication No. 95-0642. Rockville, MD, Agency for Health Care Policy and Research, Public Health Service, US Department of Health and Human Services, 1994. 39. National Pressure Ulcer Advisory Panel: Pressure Ulcers: Incidence, Economics, Risk Assessment. Consensus Development Conference Statement. West Dundee, IL, S-N Publications, 1989. 40. Consortium for Spinal Cord Medicine. Pressure Ulcer Prevention and Treatment Following Spinal Cord Injury. Clinical Practice Guideline. Washington, DC, Paralyzed Veterans of America, 2000. 41. Ostrowski K, Wlodanski K: Induction of heterotopic bone formation. In Bourne G (ed): Biochemistry and Physiology of Bone, vol 3. New York, Academic Press, 1971, p 299. 42. Buring K: On the origin of cells in heterotopic bone formation. Clin Orthop 1975;110:293. 43. Silver JR: Heterotopic ossification: A clinical study of its possible relationship to trauma. Paraplegia 1969;7:220. 44. Venier LH, Ditunno JF Jr: Heterotopic ossification in the paraplegic patient. Arch Phys Med Rehabil 1971;52:475. 45. Stover Sl, Hataway CG, Zerger HE: Heterotopic ossification in spinal cord impaired patients. Arch Phys Med Rehabil 1975;56:199. 46. Brousseau L, Potvin L, Phillippe P, et al: Post-stroke inpatient rehabilitation II. Predicting discharge disposition. Am J Phys Med Rehabil 1996;75:431. 47. Johnston K, Li J, Lyden P, et al: Medical and neurological complications of ischemic stroke: Experience from the RANTTAS Trial. Stroke 1998;29:447. 48. Lyden PD, Rapp K, Babcock T, et al: Ultra-rapid identification, triage,

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51. 52. 53.

54. 55.

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61. 62. 63.

64. 65. 66. 67.

68.

69. 70. 71. 72.

and enrollment of stroke patients into clinical trials. J Stroke Cardiovasc Dis 1994;4:106. Odderson IR, Keaton JC, McKenna BS: Swallow management in patients on an acute stroke pathway: Quality is cost effective. Arch Phys Med Rehabil 1995;76:1130. Jorgensen HS, Nakayama H, Raaschou HO, et al: The effect of a stroke unit: Reduces mortality, discharge to nursing home, length of hospital stay and cost. A community-based study. Stroke 1995;26:1178. Smithard DG, O’Neill PA, Park C, et al: Complications and outcome after acute stroke. Stroke 1996;27:1200. Daniels SK, Brailey K, Priestly DH, et al: Aspiration in patients with acute stroke. Arch Phys Med Rehabil 1998;79:14. Martens L, Cameron T, Simonsen M: Effects of a multidisciplinary management program on neurologically impaired patients with dysphagia. Dysphagia 1990;5:147. Veis Sl, Logemann JA: Swallowing disorders in persons with cerebrovascular accident. Arch Phys Med Rehabil 1985;66:372. Adams HP, Brott TG, Crowell RM, et al: Guidelines for the management of patients with acute ischemic stroke. A statement for healthcare professionals from a special writing group of the stroke council, American Heart Association. Stroke 1994;25:1901. Kamran SI, Downey D, Ruff RL: Pneumatic sequential compression reduces the risk of deep vein thrombosis in stroke patients. Neurology 1998;50:1683. International Stroke Trial Collaborative Group: The international stroke trial (IST): A randomized trial of aspirin, subcutaneous heparin, both, or neither among 19435 patients with acute ischaemic stroke. Lancet 1997;349:1569. Bromfield E, Reding M: Relative risk of deep venous thrombosis or pulmonary embolism post-stroke based on ambulatory status. Neurorehabilitation 1988;2:51. Twitchell TE. The restoration of motor function following hemiplegia. Brain 1951;74:443. Bamford J, Sandercock P, Dennis M, et al: A prospective study of acute cerebrovascular disease in the community: The Oxfordshire Community Stroke Project 1981-86. 2. Incidence, case fatality rates and overall outcome at one year of cerebral infarction, primary intracerebral and subarachnoid haemorrhage. J Neurol Neurosurg Psychiatry 1990;53:16. Jongblood L: Prediction of function after stroke: A critical review. Stroke 1986;17:765. Azzimondi G, Bassein L, Nonino F, et al: Fever in acute stroke worsens prognosis. A prospective study. Stroke 1995;26:2040. Kushner M: Relation of hyperglycemia early in ischemic brain infarction to cerebral anatomy, metabolism, and clinical outcome. Ann Neurol 1990;28:129. Teasell RW, Bach D, McRae M: Prevalence and recovery of aspiration poststroke: A retrospective analysis. Dysphagia 1994;9:35. Jennett B, Teasdale G: Management of Head Injuries. Philadelphia, FA Davis, 1981. Annegers JF, Hauser WA, Coan SP: A population-based study of seizures after traumatic brain injuries. New Engl J Med 1998;338:20. Jennett B: Post-traumatic epilepsy. In Rosenthal M, Griffith ER, Bond MR, Miller JD (eds): Rehabilitation of the Head Injured Adult. Philadelphia, FA Davis, 1983. Temkin NR, Dikmen SS, Wilensky AJ, et al: A randomized double-blind study of phenytoin for the prevention of post-traumatic seizures. New Engl J Med 1990;338:20. Yablon SA: Post-traumatic seizures. Arch Phys Med Rehabil 1993;74:983. Beyerl B, Black PM: Post-traumatic hydrocephalus. Neurosurgery 1984;15:257. Katz RT, Brander V, Sahgal V: Update on the diagnosis and management of post-traumatic hydrocephalus. Am J Phys Med Rehabil 1989;68:91. Geerts W, Code K, Jay R, et al: A prospective study of venous thromboembolism after major trauma. N Engl J Med 1994;331:1601.

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73. Frim D, Barker F, Poletti C, et al: Postoperative low-dose heparin decreases thromboembolic complications in neurosurgical patients. Neurosurgery 1992;30:830. 74. Geerts, W Jay R, Code K, et al: A comparison of low-dose heparin with low molecular weight heparin as prophylaxis against venous thromboembolism after major trauma. N Engl J Med 1996;335:701. 75. Dall JT, Harmon RL, Quinn CM: Use of clonidine for treatment of spasticity arising from various forms of brain injury: A case series. Brain Injury 1996;10:453. 76. Joynt RL: Dantrolene sodium: Long-term effects in patients with muscle spasticity. Arch Phys Med Rehabil 1976;69:254. 77. Conine TA, Sullivan T, Mackie T, Goodman M: Effect of serial casting for the prevention of equines in patients with acute head injury. Arch Phys Med Rehabil 1990;71:310. 78. Yablon SA, Sipski ML: Transdermal clonidine effect on spinal spasticity: A case series. Am J Phys Med Rehabil 1993;72:154. 79. Moore T, Anderson R: The use of open phenol blocks to the motor branches of the synaptic transmission block. Am J Phys Med 1980;59:184. 80. Varghese G, Williams K, Desmet A, et al: Nonarticular complication of heterotopic ossification: A clinical review. Arch Phys Med Rehabil 1991;72:1009. 81. Spielman G, Gennarelli TA, Rogers CR: Disodium etidronate in the prevention of heterotopic ossification following spinal cord injury (preliminary report). Paraplegia 1976;14:146. 82. Mysiw WJ, Jackson RD: Tricyclic antidepressant therapy after traumatic brain injury. J Head Trauma Rehabil 1987;2:34. 83. Reinhard Dl, Whyte J, Sandel ME: Improved arousal and initiation following tricyclic anti-depressant use in severe brain injury. Arch Phys Med Rehabil 1996;77:80. 84. Small SL: Pharmacotherapy of aphasia: A critical review. Stroke 1994;25:1282. 85. Haig AJ, Ruess JM: Recovery from vegetative state of six months’ duration associated with Sinemet (levodopa/carbidopa). Arch Phys Med Rehabil 1990;71:1081. 86. Goldstein LB: Common drugs may influence motor recovery after stroke. The Sygen in Acute Stroke Study Investigators. Neurology 1995;45:865. 87. Feeney DM, Gonzalez A, Law WA: Amphetamine, haloperidol and experience interact to affect rate of recovery after motor cortex injury. Science 1982;217:855. 88. Rao N, Jellinek H, Woolston D: Agitation in closed head injury: Haloperidol effects on rehabilitation outcome. Arch Phys Med Rehabil 1985;66:30. 89. Gualtier CT, Evans RW: Stimulant treatment for the neurobehavioral sequelae of traumatic brain injury. Brain Injury 1988;2:273. 90. Speech TJ, Rao SM, Osmon DC, et al: A double-blind placebo controlled study of methylphenidate treatment in closed head injury. Brain Injury 1993;7:333. 91. Sandel ME, Mysiw WJ: The agitated brain injured patient. Part I: definitions, differential diagnosis, and assessment. Arch Phys Med Rehabil 1996;77:617. 92. Mysiw WJ and Sandel ME. The agitated brain injured patient. Part II: pathophysiology and treatment. Arch Phys Med Rehabil 1997;78:213. 93. American Congress of Rehabilitation Medicine Position Paper: Recommendations for use of uniform nomenclature pertinent to patients with severe alterations in consciousness. Arch Phys Med Rehabil 1995;75:205. 94. Multi-Society Task Force on PVS: Medical aspects of the persistent vegetative state: Statement of a multi-society task force. New Engl J Med 1994;330:1499. 95. Hagen CC, et al: The Rancho Levels of Cognitive Functioning. A Clinical Case Management Tool. The Revised Levels—Third Edition. Downey, Calif, Professional Staff Association of Rancho Los Amigos Hospital, 1998.

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Chapter 30 Ethical Issues in the Neurointensive Care Unit A. Joseph Layon, MD and Andrea Gabrielli, MD, with a contribution on Brain Death, David M. Greer, MD

Some elements of this chapter have appeared previously.*

What Are “Ethics” Related to the Intensive Care Unit? What are ethics not? If it feels good, it must be right. If it feels bad—or is difficult—it must be wrong. What my “gut” tells me. What my “superiors” say is correct. What “everyone” says is right. Ethics is defined as “the discipline dealing with what is good and bad and with moral duty and obligation.”1 Patients present to us daily with illnesses that require the physician to consider not only diagnostic and therapeutic questions, but ethical ones as well. While these ethical concerns are often asked and answered on only an intuitive level, physicians and nurses in the intensive care unit face an increasingly complex set of ethical and medicolegal concerns and *Layon AJ, D’Amico, R, Caton D, Mollet CJ: And the patient chose— Medical ethics and the case of the Jehovah’s Witness. Anesthesiology, 1990;73:1258–1262. Biedermann CL, Layon AJ, D’Amico R: Ethics in the intensive care unit. Anesth Clinics NA, 1991;9:423. Layon AJ: To care for the dying—Resuscitation and DNR in the operating room and ICU. Ethical Issues for anaesthesiologists, intensivists, and surgeons. J Anasth Intensiv, 1998;5:43–47. Layon AJ, Dirk L: Resuscitation and DNR—Ethical aspects for anaesthetists. Can J Anaesth, 1995;42:34–140.

questions. Issues such as the rationing of health care resources, futility of care, withdrawing or withholding of care, disagreements between the patient or the patient’s family and the physician, “informed” consent, physicianassisted suicide, and euthanasia make it important that we reflect on the ethical aspects of our decisions. The fact that such complex issues confront us suggests that a critical, instead of simply an intuitive, approach to ethical problems be used. This will be discussed later in some detail; we use adherents to the Jehovah Witness religion for case examples because their religious-moral–based refusal to accept blood and blood products often creates a conflict between the patient and the health care team (meaning, in the context of this chapter, physicians and nurses).

Principles of Medical Ethics The four pillars of ethical behavior in medicine are autonomy, beneficence, nonmaleficence, and justice. Autonomy, or patient self-determination, has become more important in recent years. Individuals are generally more aware of medical issues than they were in the past, and are more willing— indeed anxious—to take part in health care decisions. That this change has been relatively widely accepted is illustrated by the reactions of medical professionals to the Jehovah’s Witness (JW) decision not to receive blood or blood products due to their religious beliefs. Health care workers generally respect the decision of JWs, even though such a decision limits the therapeutic options of the health care team. Acceptance of this decision results from our general 815

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belief in the patient’s circumscribed right to determine his or her fate. The concepts of informed consent and informed refusal require that the health care professional acknowledge this point. A legal parallel for this principle is Supreme Court Justice Benjamin Cardozo’s statement in 1914 that “Every human being of adult years and of sound mind has a right to determine what shall be done with his body.”2 On the other hand, beneficence and nonmaleficence direct health care workers, respectively, to help their patients and to do no harm. Beneficence demands of health care workers that we do all within our power to aid our patient. In this context, the physician caring for a patient must not be concerned about the cost to society, either financial or otherwise, of a set of therapies that the patient requires. The physician’s duty, in this context, is simply to do all that is necessary for the sick human under his or her care. Concerns about how the care provided will impact Medicare, the hospital’s bottom line, the national deficit, or the generalized physician-patient relationship are irrelevant while the physician is functioning as a “front-line” care giver. Obviously, these other issues are significant, but are best considered as generalities rather than when dealing with a specific patient. Nonmaleficence, related to the principle of beneficence, demands that, not only do we do something, but that the “something” we do cause no harm, or at least less harm than good. In this time of modern, invasive medicine, almost any therapy we prescribe for a patient has the potential to cause harm. Thus, we must weigh carefully the risks and benefits of a therapeutic intervention before administering it to our patient. Finally, the concept of justice directs health care workers to provide medical care equitably to all who are in need. Any rationing of health care must be impartial and consider the ramifications to persons of different socioeconomic and age groups. These principles form the basis of trust in the physician-patient relationship.

The Need for Ethical Thinking A physician provides treatment for the patient’s benefit; in most instances, this benefit is clear. For example, a person with a fractured femur clearly benefits from having the fracture reduced in order to ensure healing and return of normal function. The principle of beneficence—that the physician intervenes medically to help the patient—is thus fulfilled. But what does the physician do when the “best” interest of the patient is unclear or when the interests of the patient and physician conflict? In these cases, the study of moral theory may aid the physician. Physicians are trained specifically and intensively to make decisions about diagnoses, therapy, and outcome. An example of such training is the calculations of the risk-benefit ratio of diagnostic and therapeutic interventions in a patient who is 48 hours status post placement of a ventriculoperitoneal shunt who becomes suddenly short of

breath and tachypneic. The risk of a pulmonary embolus is relatively low, about 10% to 15%, the risk of the commonest diagnostic procedures—a ventilation-perfusion scan with radio-nuclear venogram or spiral volumetric computed tomography (CT) scan of the chest—are low, but the risk of bleeding with the use of heparin is not inconsiderable. These are the types of calculations and decisions we make frequently and, most often, well. However, medical decisions may be influenced by nonmedical considerations. For example, legal worries have often been a factor in medical decisions because of the medicolegal climate in the United States; this is currently perceived as an issue that is building to a threatening state. Ethical considerations also influence physicians’ decisions. Because physicians usually have little or no formal training in this area, our tendency is to make ethical decisions intuitively (i.e., without conscious reasoning) rather than critically (i.e., with conscious reasoning). Although it will not improve diagnostic or therapeutic acumen, moral theory may help the physician to evaluate the moral implications of medical decisions and may shed light on concepts that are taken for granted, such as health, normalcy, and harm. Using the following case involving a JW, the ethical and legal considerations involved when the interests of the patient and the physician, as a preserver of life, are in conflict will be reviewed. During bowel resection and abscess drainage in a mentally competent, 37-year-old woman with a 10-year history of Crohn disease, a problem arose from acute, unplanned hemodilution. A Jehovah’s Witness, this woman had clearly stated during the preoperative workup that she did not want, under any circumstances, to be transfused with blood products. With the exception of a hematocrit of 30%, her preoperative studies, including coagulation parameters, were normal. Upon opening of the abdominal abscess cavity, she lost approximately 3,000 mL of blood, a loss that ultimately resulted in a hematocrit nadir of 4%. Her physicians obtained, with permission of the family, a court order, and despite the patient’s expressed desire, administered blood. She was discharged from the intensive care unit after 24 hours and recovered without further medical problems.

This case contains facets of several classic problems in the definition of health and healing—the relative priorities of temporal and spiritual well-being; the autonomy of the patient; the responsibility of the physician; and conflicts among values held by the patient, the physician, the patient’s family, and at least one social organization, the court, whose judge granted the order. The Position of the Physician The position of the physician is one that is familiar to most of us: Blood transfusion is an accepted treatment used in a

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variety of situations to preserve life and promote healing. However, less familiar is the situation in which administration of blood against a patient’s expressed will may result in a civil damage suit.3 Because the physicians caring for the woman were concerned with her survival, they transfused blood against her expressed wishes. Was their action justified? Because the woman is alive and with her family, is it even relevant that blood was transfused against her wishes? Should she actually be grateful for the transfusion after she recovered? Indeed, a physician could argue that a person’s religious beliefs, however rational or irrational, should not result in that person’s death. On the other hand, a mentally competent adult may want to sacrifice his or her life for a belief in a Supreme Being. Should a physician ignore this wish because it does not appear to be in the patient’s best medical interest? Perhaps the physicians in the previous case believed that they would be abetting suicide if they allowed the patient to die. Legal precedent, however, suggests that permitting death to occur from a cause that is not self-inflicted is not abetting suicide.4–6 In addition, other examples of self-sacrifice for a belief (e.g., a soldier’s sacrifice in war) are not considered, by most people, to be suicide and even are encouraged in most cultures of our present world. The Position of the Jehovah’s Witness The belief of JWs that prevents them from accepting transfused blood originates in scriptural passages suggesting that “life” or the “life force” resides in blood and therefore must be treated respectfully.7,8 Whereas the biblical passage specifically forbids the eating of blood, the interpretation accepted generally by JWs also precludes the receipt of banked blood products, but, at the believer’s discretion, not the receipt of plasma protein factor, clotting factors or albumin.9 Also, intraoperative, preblood-loss hemodilution with a continuously flowing circuit may be deemed acceptable by the JW. Parenthetically, the exact definition of a “continuous flowing” circuit is left rather vague. Collection of shed blood into a citrated blood bag on a rocker, with continuity of the tubing with the patient, seems to fulfill the definition. Followers of this faith interpret the pertinent Biblical passages literally. They also consider life on earth a temporary period that will be followed by eternal life after death and resurrection. Therefore, a JW who knowingly allows transfusion of blood or selected blood products risks losing “eternal life” and risks suffering damnation on earth.10 There are no religion-based consequences for a JW who has been “forced” to receive blood, but the loss of “innocence” is considered so serious that the JW might take legal action against the health care team.3,11 Conversely, we are aware of no legal decisions that have been made against physicians for withholding blood or blood products under clearly defined preoperative conditions.10

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Society’s Position It seems to be clearly established that the First Amendment of the United States Constitution, as extended to the individual States by the Fourteenth Amendment . . . protects the absolute right of every individual to freedom in his religious belief and the exercise thereof may properly be limited by governmental action where such exercise endangers, clearly and presently, the public health, welfare or morals. . . . Even though we may consider (an individual’s) beliefs unwise, foolish or ridiculous, in the absence of an overriding danger to society we may not permit interference therewith . . . for the sole purpose of compelling (an individual) to accept medical treatment forbidden by (his or her) religious principles, and previously refused by (him or her) with full knowledge of the probable consequences.3

In this widely recognized decision, an Illinois Appellate Court held that a competent JW—who was a married adult woman with no minor children and who, aware of the probable consequences, had refused recommended blood transfusions—had a federal constitutional right to refuse medical treatment based on her religious convictions.3 As we write in the United States, it is of significance to review fundamental principles of the legal system of our country. Adults in the United States have a common-law right (i.e., nonstatutory and by virtue of court decisions) to refuse medical treatment, even if it is life-sustaining.12 Adults also have a constitutionally based right to refuse lifesaving medical treatment3; this right is grounded in the provisions of the first amendment to the U.S. Constitution: “Congress shall make no law respecting an establishment of religion, or prohibiting the free exercise thereof. . . .” Further, “the commands of the First Amendment to the United States Constitution relating to religious freedom are embraced within the Fourteenth Amendment and by it extended to the States.”13 There is, however, a legally significant distinction between religious belief, which is a constitutionally guaranteed freedom, and the way in which people practice their religion, which is not an absolutely guaranteed legal protection. Thus, in the face of constitutionally based assertions of a right to engage in certain religious practices, courts have upheld a variety of laws on the theory that society has an overriding interest in protecting its citizen’s lives. Laws requiring compulsory vaccinations,14 laws against polygamy,15 and laws prohibiting the handling of snakes during religious rituals fall into this category.16 In cases in which JWs have refused life-saving blood transfusions, the distinction between the protections that are accorded to such individuals and their religious beliefs, and the restrictions that are constitutionally sanctioned against certain conduct, has manifested itself in a variety of ways. Most notable have been those cases involving JW parents who refuse to consent to life-saving blood transfusions for

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their minor children. Courts in these cases have consistently approved the appointment of temporary guardians to consent to blood transfusions where it has been evident that the risk associated with the transfusion was low and that without this procedure significant harm would result. The theory underlying these decisions is that society has a serious interest in protecting the rights of immature children, who are considered incapable of making a knowing and informed decision with respect to such matters.17* While we have no doubt that the state has an interest in protecting the lives— and hence the rights—of minor children, some clarification is required at this juncture. Our experience with the minor children of JWs, some 20 cases ranging in age from approximately 3 to 17 years of age, suggests that court orders are often unnecessary. Many of the children presented to one of our institutions (Shands Hospital at the University of Florida in Gainesville, Florida) after being removed by their parents from other hospitals. Querying the parents about why they left the other institutions always brought the same story, in different guises: “The physicians and social workers were rude and threatening. They were disrespectful.” When the parents attempted to express their heartfelt wishes related to the care of their children, in the context of the religious beliefs they held dear, these adults thought that the medical system let them down. The ideological-philosophical framework by which they led their lives was not only questioned, it was ridiculed and dismissed. These parents felt they could not connect with the health care workers, as the latter seemed to see them (the parents) as religious fanatic cardboard cutouts. How could the JW adults, then, entrust their children to these physicians and nurses? Our position has been to allow the parents to tell us what they want for their children. The parent’s desire that the children not receive blood is met with respectful compromise. We inform the parents that we will do everything in our power to remain true to the beliefs of the family. If in our best opinion, however, the child is going to die without transfusion, we tell the parent that we will give blood. We do not get a court order. We do not leave the operating room and demand that the parents give their permission. We simply do what is, in our best estimation, optimal for the child while trying aggressively to keep faith with the family’s wishes. Using this approach, which the JW families as well as the Church Elders seem to accept and appreciate, we have had no family members walk out of the hospital, nor have we had a lawsuit. As one might expect, transfusion is very

rarely required. In our series, blood has been given once or twice for major procedures in which significant blood loss occurred. Adolescents are allowed to make their own decision about blood. Most often, the adolescent will have his or her preoperative evaluation with the parents, and perhaps one or another of the Church Elders, present. It is our policy, and the Church Elders approve of this, to ask the parents and Elders to leave toward the end of the preoperative evaluation interview. Then, alone with the adolescent, we ask what he or she wants. Usually, the young adult will say, as they did when their parents were present, that they wish to receive no blood. On several occasions, however, the adolescent has very emotionally and emphatically asked that they not be allowed to die if transfusion becomes necessary. Rather, they wish to have the blood administered. These are not individuals whom we treat as victims of “brain washing.” Rather, we respectfully query them as to their desires related to blood and the Church. Many are firm in their religious convictions; those who are not have blood used, if needed. Again, the permission is not requested of the parents if significant blood loss occurs. The courts have considered as legally significant certain facts—such as whether the JW refusing life-saving blood transfusions is married or has minor children who might become wards of the state in the event that the parent died— in determining whether societal interests should prevail over an individual’s choice of religious conduct.11 Nevertheless, it is relatively clear that single adult JW patients with no minor children have a constitutionally protected right to refuse blood transfusions. Thus, it appears that respect for the patient’s autonomy may require the physician to forgo transfusion and, perhaps as a consequence, allow the patient to die. Does respecting the patient’s decision put the physician in conflict with both the principles of beneficence and nonmaleficence? Such conflicts occur within the realm of critical care medicine, and are all too often seen in the neurointensive care unit. Because physicians frequently do not have formal training in ethical reasoning to help resolve these conflicts, merely attempting to enforce one or another of these principles, or using intuitive analyses may lead to inadequate or controversial solutions or to an ethical dilemma. Understanding moral reasoning may help us in these situations.

Moral Theory Facts versus Values

*But see also the case of In re EG, a Minor, 133 Illinois 2d 98, 549 N.E. 2d 292 (1989), in which the Illinois Supreme Court held that a mature Jehovah’s Witness minor, who was within 6 months of her eighteenth birthday and who had been shown by clear and convincing evidence to appreciate the consequences of her refusal to accept medical treatment, had a common-law right to consent to or refuse medical care.

Given correctly gathered empirical data, a statement of fact is either true or false. This is not so in regard to values or evaluative principles. While “values” are supposed to promote that which is good and discourage that which is bad, they are neither true nor false. Although it seems simple

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to distinguish a fact from a value, in many situations the two may be confused. In the case of the JW who hemorrhages to a hematocrit of 4%, a value incompatible with life, it is a fact that the patient has a low hematocrit. The patient’s need for enhanced oxygen-carrying capacity to sustain life is also a fact. It is a fact, we suspect, in the minds of most physicians that the patient needs a red blood cell transfusion to sustain life, and further, that the correct response to the hematocrit of 4% is to transfuse blood. However, some of these facts also presuppose a value judgment that the physician makes because he or she values life above all else. The JW, although agreeing that the hematocrit is 4% and that death will occur if oxygen-carrying capacity is not enhanced, would still refuse transfusion of blood cells regardless of the hematocrit or the probability of dying. The suggestion to JWs that a transfusion of blood is needed to preserve life involves a violation of principles concerning their temporal life, which they consider to be but a transitory preparative stage for an everlasting one. If the JW were to accept transfusion of red cells, a central religious rule would have been violated, as a result of which the JW would lose the chance of everlasting spiritual life.18 The ability to distinguish between disputes about facts and those about values is important to the physician-patient relationship and may have a significant impact on patient well-being. Of course, some patients may hold beliefs due to incorrect information. When educated about their disease and treatment, this latter group of patients may agree to follow the physician’s recommendations. This change does not come about because of a change in the patient’s morals, but because of medical education. It is the health care worker’s responsibility to determine whether lack of education about a disease, as opposed to a different set of values, is the cause of patient noncompliance. It is not acceptable, however, to simply dismiss the patient’s values or preferences because they differ from the physician’s. Consequential versus Nonconsequential Ethical Theories Two commonly used ethical theories in Western culture are utilitarianism and the idea of rights; moral philosophers have worked to unify these two theories.19 Classical utilitarianism is often associated with David Hume, Jeremy Bentham, and John Stuart Mill, all of whom wrote in the late 18th and early 19th centuries. The idea of human rights originated in social contract theories of the 17th and 18th centuries. Utilitarianism is a moral theory that holds that “there is one and only one basic principle in ethics, the principle of utility, which asserts that we ought always to produce the greatest possible balance of value over disvalue.”20 The utilitarian thus looks at the consequences of an action and determines the overall good—the value—that it brings to

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the persons involved. The “goodness” of a principle or action is thus related to the positive net effect it has on the greatest number of concerned persons. The notion of rights, also called a deontologic ethic as it emphasizes the principle of duty over utility, is a nonconsequential approach to ethics. The notion of rights in ethics stresses that certain actions are wrong even if the consequences are beneficial. Thus, a theory of rights would stress justice over utility, or assert limits on actions no matter how attractive, desirable, or beneficial. The difference between these two theories can be shown through the example of euthanasia, if considered from the perspective of the physician. When applied to the physician’s situation, the utilitarian approach does not begin with the principle that killing is wrong, but only with the simple principle of utility plus the empirical knowledge that has been gained about various situations. Normally, killing is wrong because it clearly harms individuals. However, when confronted with a patient who has a widely metastatic neoplasm causing unremitting and untreatable pain, and who has requested that his or her life be ended quickly, the utilitarian would hold that euthanasia might serve that patient’s interests and thus be justified. In this specific situation, the greater utility for any other patient in a similar situation would be in allowing the patient a quick, painless death. An ethical theorist who stressed rights and obligations, however, would hold that the act of a physician killing a patient is wrong no matter what the results and no matter what the patient requests. The purpose of insisting that a right or principle is at stake is to establish a constraint on decision making. The argument made by a “rights” theorist is that without such a definite restriction on euthanasia, physicians will find themselves on a “slippery slope,” ultimately resulting in a willingness to kill patients for convenience or prejudice. In the previous case, the argument was made from principle specified from the physician’s perspective. It is possible, if the principle is taken from that of the patient, for a theory of rights to defend a patient’s right to suicide based upon an unqualified right to one’s own existence and control of one’s body. Thus, the bare statement of these two theories of ethics does not obviate further reflection on moral reasoning. Critical versus Intuitive Thinking In critical reflection, as the term is used in philosophy, an individual takes the time, and has the freedom, to analyze moral assumptions. In doing so, the thinker can speculate about moral decisions and experiment with moral reasoning. Health care workers are often called upon to act in situations in which there are conflicts of values. By having considered such conflicting and conflictive issues ahead of time, whether they be related to JWs, withdrawal of therapy, physician-assisted suicide, or any other issue of our time, the

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physician can better prepare his or her moral intuitions for times of crisis.19 Drawing further on the euthanasia example, alluded to in the patient with widely metastatic cancer and untreatable— and unremitting—pain, what should the physician do for this patient, assuming that the patient-physician relationship is a strong one? If the relationship is not strong, or if the patient and physician do not know one another, the options are severely limited, and one would not—indeed could not—act on a patient’s request for aid in dying in such a situation. However, assuming a strong physician-patient bond, should the physician assist in the demise of this patient? The principle of respecting the patient’s autonomy and always stressing beneficence would suggest that the answer is “yes.” If the physician-patient relationship is strong, the physician, patient, and patient’s family members will have discussed, at some point during the patient’s illness, the options for dying. Some individuals want to watch every sunrise possible, no matter what pain is involved. Others, faced with the promise of a painful and humiliating death, want to pass from this world as soon and as comfortably as possible. Thus, if euthanasia were ever to be justifiable, it would have to be responsive wholly to the patient’s preferences. What should be done when the patient requests help with his or her death, but the physician feels morally compromised if this aid were to be provided? If the case is unfolding in the emergency department, in an individual whose premorbid wishes are unknown to any of the health care team, the only option is to make every attempt to save life and limb and relieve pain. On the other hand if, over time, the patient had made his or her fundamental preference known to the physician, if that preference is to opt for an assisted death, and if the physician feels—during the process that makes up these discussions—that he or she would be personally compromised in following the patient’s wishes, the physi-cian ought to withdraw early and leave the patient in the care of a designated colleague who feels no such moral compromise. In a nonemergency situation, where there has been time to discuss the issues and make clear the fundamental moral preferences, the patient who finds that his or her physician will not carry out the patient’s fundamental moral preference is left in a position in which paternalism allows physicians to substitute their values for those of the patient. This position is, as has been argued elsewhere,18 unacceptable from a practical and moral standpoint, and would lead to the destruction of the bond of trust that links physician and patient. Physicians have the duty to argue with and confront their patients on these issues. Attempting to dissuade another person from a choice is yet another aspect of the use of critical, as opposed to intuitive, thinking. The assertion that all fundamental moral preferences should be treated as equal is itself an ethical principle, but one that is not acceptable to us. Everything, every choice, is not equal in some universal

schema of “truth.” Preferences can and perhaps should be criticized, challenged. Indeed, one way to challenge a patient’s intuitive moral preference is to begin by assuming the equality of all preferences and then to analyze the justification for the patient’s choice. One need not agree with the patient’s specific moral preferences to acknowledge them. However, and this is a particularly important point in a critically ill patient or for a family member of such a patient attempting to make surrogate decisions for their loved-one, questioning a patient’s basic moral choices should not lead to coercion.

Limiting Access to Health Care Resources Rationing Health Care Access Health care spending in the United States is said to be increasingly burdensome to the economy. In 1987, 11.4% of the gross national product or $511 billion was spent on health care,21 almost three times the proportion of the gross national product spent in 1950.22 Of these monies, 15% was used for intensive care services.23 More recent figures show that 13.5% of the gross national product, or $1.092 trillion, was spent on health care services in 1997,24 an increase of 4.8% compared to 1996, and apparently the smallest increase in 35 years.24 Yet despite the prodigious sums of money thrown at the “problem”of health care, the number of people without insurance coverage for an entire year increased to 43.4 million, 16.1% of the population of the United States, up from 30 to 37 million people, 11.5% to 14.2% of the 1990 population who were without access to health care.24,25 Many of these uncovered individuals work minimum wage jobs, do not qualify for Medicare or Medicaid, do not have private insurance, and, therefore, cannot afford medical care. Even these dismal figures do not yield a complete picture, as the U.S. Census Bureau calculated, in a study done between 1993 through 1995, that 71.5 million people, approximately one-third of our population, lacked insurance for at least part of the year.26 Several factors have been associated with the rise in health care expenditures, including technologic imperatives, inefficiency of supportive services, and an aging population.27 The cost spiral may be unsustainable. Multiple cost containment measures have been attempted and are currently in place. The most destructive of these, in our opinion, is that form of rationing termed managed care. In its worst incarnation, managed care is merely a manner by which for-profit insurance companies force hospitals and physicians to subsidize the cost of caring for patients who have paid premiums, but get little in return. One solution to the cost spiral, advocated by some, is a more explicit form of rationing.27 The United States has experienced, and continues to experience, rationing by lack of access. As noted previously, 30 to

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37 million people in our country had no access to health care in 1987, today that number hovers at 43 million, and this after a decade of “economic expansion.” While many of these individuals without access are the working poor, even those with better paying jobs and “access” to health care may find themselves in trouble. A 50-year-old female professor of comparative literature had a managed care plan through her university; care was provided by what is considered one of the best university medical centers in the country, although access was through a primary care physician (PCP) not affiliated with the university. The woman, previously healthy except for uterine fibroids, presented to her PCP complaining of lethargy, forgetfulness, and a very severe headache. The PCP diagnosed a urinary tract infection, and sent her home with antibiotics. Several days later she presented to the PCP with the same complaints; further antibiotics were given. During a serendipitous telephone call, she described her symptoms to a physician not involved with the health maintenance organization (HMO) to which she belonged. The physician insisted that there were very few problems that could be causing the symptoms she was exhibiting, and they required an aggressive workup that did not include a urinalysis. He insisted that she return to the PCP, demand a CT scan of the head, pointing out to the PCP that the top three items in the differential were tumor, subarachnoid hemorrhage, and meningitis or encephalitis. The CT was performed 14 days later, and an aggressive tumor was diagnosed. The patient refused to be cared for further by the Managed Care Organization (MCO) that had misdiagnosed her for nearly a month. Her tumor was removed at the University of Florida–Shands Hospital. The MCO refused to pay for any of her care, despite the fact that their misdiagnosis could have cost her life.

This patient had access, insurance, and was well eductated. But it did her little good because the physicians involved had felt a higher loyalty to the MCO and their finances than to the patient. How might this system be rectified? In our view, a single payor national health insurance program serving as the base beneath which no one slips, but on which other levels of service could be added for those with the wealth to purchase them, seems at least one proper response; others might view the options differently. There are, however, strong moral objections to any system that rations purely on the basis of socioeconomic status and disregards equity. Aaron and Schwartz define another type of rationing, a system in which “not all care expected to be beneficial is provided to all patients.”28 The National Health Service of England is often cited as an example of this type of rationing. Because of inadequate levels of funding, British physicians are placed in a position in which they decide who is to receive a specific treatment that exists in limited supply.27-29 These physicians perform the difficult and ethically complex function of “gatekeeping.” This gatekeeping function appears to be the

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action that resulted in the problem for the patient in the previous example. The physician as gatekeeper is a relatively recently described concept.25 We believe that it is not an appropriate role for physicians performing “front-line” care to patients. When a physician agrees to care for a patient, the physician-patient relationship requires—what is more, demands—that the physician do everything in his or her patient’s best interest without regard to cost, convenience, hospital profits, managed care profits, or personal lucre.30 This principle of advocacy is an understood, if often unstated, part of the physician-patient relationship. If patients thought that the decisions made by their physicians were colored by economic considerations, the physicianpatient relationship, fragile to begin with, would be irreversibly undermined. Advocacy does not mean that the physician must access all services and techniques for the patient, only that he or she strive to provide the ill individual with all of the services that are in the patient’s best interest. And while the definition of the patient’s “best interest” may be, on occasion, difficult to determine, we would rather see the determination made upon physiological principles, rather than economic ones. To maintain the integrity of the physician-patient relationship, the gatekeepers, if they must exist and if they are physicians, should only be those individuals who do not function as direct patient caregivers. This is, unfortunately for all, most often not the case.

Intensive Care Services With a relatively fixed number of intensive care unit (ICU) beds currently available, ICU nurses and physicians must decide who will and who will not be admitted to this specialty area.31,32 There are several ways to make such decisions. Medical facts decide many of the conflicts, but the scientific data are often inadequate, and, thus, ethical decisions must frequently be made. Because intensive care consumes a significant portion of the health care budget, more efficient ways to utilize ICU resources are continuously sought. Keeping the terminally ill out of the ICU, or arguing that individuals with selected diseases or those above a certain age ought not be admitted to the ICU are only some of the ways that “efficiency” is sought. The issue of age and health resource limitations has been argued by many prominent medical ethicists. They suggest that if each person has a limited amount of health care “assets” at his or her disposal, the individual would be wise to direct the use of those assets over the early years of life to receive the most benefit. On the other hand, Levinsky33 argues that care should be allocated according to expected benefit to the patient regardless of age. He uses the example of a productive 85-year-old artist with pneumococcal pneumonia and no other life-threatening disease. By what convoluted logic would it be right to deny the artist ICU care because he is 85 years old when there is

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a good chance of recovery to a productive life? Indeed, leaving aside what appears to us to be a cultural bias against the elderly, we find data indicating that age, in and of itself, is not a predictor of poor outcome. Chalfin and Carlon,34 for example, found that older critically ill cancer patients in the ICU had a lower mortality rate than that of younger patients. These authors reviewed the records of all cancer patients admitted to the ICU over a 1-year period. Patients younger than 65 years of age had a higher proportion of systemic malignancies, whereas those 65 years of age and older had primarily solid tumors. The length of stay was the same for the two groups, but the average severity of illness was less for the 65-and-older group and, as mentioned previously, the mortality was lower. Work by our group at the University of Florida also suggests that chronologic age is an inadequate indicator by which ICU resources might be rationed.35-37 Thus, age by itself is not an adequate parameter for exclusion from ICU care. While, in selected instances, age may be one of several physiologic factors considered when admission to the ICU is contemplated, it should never be the only criterion. Furthermore, the principles of patient autonomy and the physician’s duty of beneficence, no less than justice, must have major roles in any contemplated rationing plan.

Withdrawing or Withholding Therapy, and Living Wills Terminal care decisions in the ICU are commonly made. Such decisions are often wrought with moral, ethical, and legal implications. The ethical principles discussed previously may help physicians, patients, and families to arrive at appropriate care decisions. We next discuss some of the ethical ramifications of withholding or terminating life support. The first step in resolving any end-of-life issue in the ICU involves considering the type of patient being cared for. Veatch38 described four classifications of patients involved in terminal care decisions. The first group encompasses patients who are competent. Courts have consistently permitted these patients to decide their own course. One example is the JW refusing life-saving blood transfusions. These patients are exercising their right of autonomy. While the physician has a moral obligation to educate these individuals about the temporal consequences of their decision, he or she cannot force them to accept a treatment they do not want. The patient may ethically refuse treatment, in the case of the JW, because of religious beliefs that make the treatment overly burdensome. Patients may also refuse on the grounds that the treatment is useless. The second group of patients includes those who are incompetent but who hold, and had expressed when they were competent, preferences concerning life and its termination. This group may contain individuals in a persistent

vegetative state who have previously expressed their wishes not to have life supported artificially should they ever reach such a state. The ethical principle affecting decisions for these patients is also autonomy. For example, the Massachusetts Supreme Judicial Court ruled in 1986 that the feeding tube could be removed in the case of a 49-year-old man who, after unsuccessful surgery for a ruptured basilar artery aneurysm, was in a persistent vegetative state. The Court ruled in this manner because the patient had indicated, while he was competent, a wish never to be kept alive by artificial means. The court ruled on three concepts.39 The first of these was that the patient had a right to refuse artificial feeding because he would have refused such lifesustaining treatment had he been able to express himself. The second was that by upholding the patient’s right to refuse treatment, the court would not be allowing suicide but would, rather, be letting the underlying disease take its natural course. The third was that the physicians involved would not be forced to stop the artificial feeding if they felt morally compromised in doing so, but they would be obliged to facilitate transfer to another institution or to another physician’s care in which the patient’s preferences would be honored. The court stated that withholding and withdrawing artificial life support should be considered the same. This understanding has found an echo in the literature.40 The rationale for this involves the consideration that the reasons for withdrawing treatment are often the same as those for withholding it and, therefore, should not be treated as morally different. A potential problem here is that some physicians may be uncomfortable withdrawing therapy and, hence, may hesitate starting a therapy with the knowledge they may have to face the decision to withdraw it at a later time. In our experience, this concern is an issue for some of our colleagues, although usually one that can be worked through with discussion. A third group of patients includes those who have never been competent and have no one to speak for them because of lack of interested family members. In this situation, the course of action must follow the principle of beneficence. Usually, a court-appointed guardian must be designated to make decisions in the best interest of the patient. The Saikewicz case is an example of this situation.41 Mr. Saikewicz was a 67-year-old, severely mentally retarded man who had lived in a state institution most of his life. Although physically strong, he had no communication skills except for gestures and physical contact. Mr. Saikewicz became ill with an acute leukemia. His guardians at the state institution debated whether to allow him to be treated with a chemotherapeutic regimen that might prolong his life for as much as 1 year. After discussions with the patient’s physicians, they believed that the course of chemotherapy would cause Mr. Saikewicz considerable suffering and that he would probably require multiple transfusions, none of which he would understand. They were concerned that he might need to be restrained or sedated to complete the

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chemotherapy. Although the patient had two sisters, they declined to become involved. The institution then sought a court-appointed guardian to make decisions regarding his case because they were unsure as to the correct course of action. The court-appointed guardian reviewed the case and decided against treatment. The court agreed, basing its decision on the ethical principle that extraordinary measures should not be used when, after careful medical scrutiny, death is determined to be the only expected outcome. Patients in Veatch’s fourth group are incompetent, but have an interested and loving family. This group includes those patients who, if previously competent, had never expressed any wishes pertaining to therapy before incompetency. Veatch40 argues that in this situation, the family need not necessarily do what is most objectively in the patient’s best interest, but may choose what they believe is in the patient’s best interest. If the family is believed to be going far beyond what is reasonable, a surrogate may be appointed. What becomes abundantly clear with this classification system is that the physician is never the person making the final decision. The patient, or his or her surrogate, is the true source of authority for decision making. The physician acts as an educator for the individual making the decisions, presenting the options for and against treatment, and facilitating the decision. Directives for initiating or withdrawing treatment may be provided in a living will. Most states have passed legislation recognizing living wills and natural death directives as legal documents. Honoring the living will is an extension of the principle of respecting patient autonomy. The document speaks for the patient when the latter is unable to express his or her wishes, which can occur after the onset of dementia, a debilitating stroke, an accident resulting in a persistent vegetative state, and other situations. Living wills help in many instances, but they may also become very problematic by using terms such as “extraordinary,”“heroic,” or “imminent,” each of which are difficult to precisely define. What is considered “extraordinary”? What is “heroic”? How “imminent” does death have to be to be imminent? These issues are all too frequently made more opaque by well-intentioned, but poorly written living wills. The Society for Critical Care Medicine has a template for an advanced directive that we have found useful (Box 30-1). Eisendrath and Jonsen42 presented a case in which a very active elderly woman completed a living will indicating that if she should be left without reasonable expectation of recovery from a grave physical or mental disability, no artificial means or extraordinary measures should be used to keep her alive. The woman underwent a carotid endarterectomy and, although initially doing well, postoperatively suffered a massive cerebrovascular accident that left her paraplegic and aphasic. Aspiration pneumonia developed, ultimately requiring nonemergent tracheostomy for continued care. Knowing the content of her living will and considering the extent of her debilitation, the patient’s brother questioned

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the care being provided his sister. Because of the brother’s persistent questioning, the case was taken to the hospital’s ethics committee. They recommended that treatment be continued because they were unsure exactly what the patient wanted. Because of the ambiguity, they believed they should err on the side of treatment. Over the next several months, the patient recovered a significant portion of her previous health and expressed her satisfaction with the ethics committee’s decision. Despite some confusion as to the patient’s moral preference, the committee opted to invoke the principle of beneficence in choosing life-sustaining treatment. This should, of course, be done whenever significant doubt exists as to the patient’s desires. Exceptions to choosing treatment are when the burden of treatment outweighs the benefits, or when there is no hope of recovery. The latter is the basis for the court ruling in the Saikewicz case.41

When Patients and Physicians Disagree Another problem that occasionally arises within the critical care setting is a disagreement between patient and physician with respect to treatment. Patients may refuse life-sustaining treatment or they or their families may request withdrawal of treatment. Less frequently, patients or their families may request therapy that is potentially inappropriate. Health care workers involved with the patient, physicians as well as nurses, may disagree with the patient’s decision based on moral grounds. Hospital policy may not allow withdrawal of certain forms of life-sustaining treatment. The ethical principles involved in all of these cases are patient autonomy, beneficence, and justice. On what moral grounds can patients refuse life-sustaining treatment? When do the state’s rights take precedent over those of an individual? When does the principle of beneficence attain greater importance than the patient’s right to autonomy? Veatch40 argues that in the case of the competent patient, there are several morally defensible positions for refusal of therapy by the physician. If the treatment has no benefit, it is useless and may be refused. This principle also applies to the situation in which a patient, or a patient’s family, requests a useless therapy. The other ground for refusal is if the treatment presents a great and overwhelming burden for the patient. The same treatment can be a grave burden for one patient but not for another, depending on that person’s frame of reference. These positions also may be extended to the group of always incompetent patients who have caring and loving families, and to the group of incompetent patients who have previously made known that they do not want artificial life support. When health care workers or institutions disagree with the patient’s request or refusal, the courts may become involved. The courts have considered the individual’s right to autonomy, but have also described at

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Box 30-1  Advance Directive to My Physicians I, , have a right to life-prolonging procedures including food and water (nutrition and hydration). I also have a right to have life-prolonging procedures stopped or no new ones started. I can choose someone to do this for me if I am unconscious, in a coma, incompetent, or otherwise mentally or physically incapable of making my wishes known. I understand that treatments or medications that take away pain, suffering, anxiety, or other forms of distress will not be withheld or withdrawn, even if they hasten my death. By signing below, I hereby choose , my , whose telephone numbers are: and whose address is: as my designee. I would like my designee, my health care or residential facility, physician, or other health care provider, to read my answers to the following questions and use my answers to help them carry out my wishes if I am unable to do that myself. 1. If I have a terminal condition from which I will probably not recover or survive and my death will likely occur within weeks: a. I want life-prolonging procedures to be: withdrawn continued b. I would want artificially administered food and water such as tube or intravenous feedings to be: withheld/withdrawn continued c. If my heart or breathing stopped, I would want my physician to try to restart it through CPR (cardiopulmonary resuscitation) or other means: yes no 2. If I have a medical condition that is steadily getting worse and my physician has told me (or my designee) that there is no reasonable chance of recovery, but I could survive this condition for weeks or even months: a. I want life-prolonging procedures to be: withdrawn continued b. I would want artificially administered food and water such as tube or intravenous feedings to be: withheld/withdrawn continued c. If my heart or breathing stopped, I would want my physician to try to restart it through CPR (cardiopulmonary resuscitation) or other means: yes no 3. If I am in an irreversible coma, persistent vegetative state, or other condition where my physician has determined that there is no reasonable medical likelihood I will ever be awake or able to make medical decisions for myself again: a. I want life-prolonging procedures to be: withdrawn continued b. I would want artificially administered food and water such as tube or intravenous feedings to be: withheld/withdrawn continued c. If my heart or breathing stopped, I would want my physician to try to restart it through CPR (cardiopulmonary resuscitation) or other means: yes no

4. If I must live in a hospital or nursing home for the rest of my life because I am unable to feed or groom myself or take care of my other bodily functions such as responding to my toilet needs: a. I want life-prolonging procedures to be: withdrawn continued b. I would want artificially administered food and water such as tube or intravenous feedings to be: withheld/withdrawn continued c. If my heart or breathing stopped, I would want my physician to try to restart it through CPR (cardiopulmonary resuscitation) or other means: yes no 5. If I have progressive or permanent memory loss such that I am no longer able to recognize my family and friends or communicate my thoughts to others: a. I want life-prolonging procedures to be: withdrawn continued b. I would want artificially administered food and water such as tube or intravenous feedings to be: withheld/withdrawn continued c. If my heart or breathing stopped, I would want my physician to try to restart it through CPR (cardiopulmonary resuscitation) or other means: yes no 6. If I am in the hospital with a serious condition and my physician and I have decided to continue treatment because we believe it may be effective and treatment seems to be going well, if my heart or breathing unexpectedly stopped, I would want my physician to try to restart it through CPR (cardiopulmonary resuscitation) or other means: yes no 7. In my current state of health, if my heart or breathing unexpectedly stopped I would want my physician to try to restart it through CPR (cardiopulmonary resuscitation) or other means: yes no I understand that I can make quality of life choices. I am not asking anyone else to make quality of life choices for me. This document merely directs others to carry out the quality of life choices I have made. If, in the course of making decisions for me, my designee is dissatisfied with any determination of my attending physician, my designee may substitute another attending physician. If I can not make medical decisions for myself, I want the directions in this Declaration to be accepted and fulfilled as the final expression of my legal right to accept or refuse medical or surgical treatment and to accept the consequences of my decisions. I understand the full import of this directive and I am emotionally and mentally competent to make this Declaration. By executing this Declaration, I am revoking all prior Declarations. Signed Of the City of

Date and State of

.

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Box 30-1  Advance Directive to My Physicians—continued In signing this Declaration on the date noted above, I state that the Declarant is known to me and I believe the Declarant to be of sound mind. I certify that I am not the Declarant’s designee named in this document. Witness: Current residence of First Witness:

In signing this Declaration on the date noted above, I state that the Declarant is known to me and I believe the Declarant to be of sound mind. I certify that I am not the Declarant’s spouse, blood relative, or designee named in this document. Witness: Current residence of Second Witness:

From the Society for Critical Care Medicine.

least four reasons for the state to enforce treatment. These are as follows: 1. It would be upholding the standards and values of the medical profession to do so; 2. It is preserving life; 3. It is preventing suicide; and 4. It is protecting dependents.43 The first three have frequently not been considered compelling reasons. In several cases, the courts have found that the patient’s wish should be honored over the objections of the physician and the institution, which were required to provide continuous care even though they requested to have the patients transferred to the care of others not ethically opposed to the patient’s preference.44 In the feeding tube case, discussed previously, the physicians were directed to facilitate transfer so that they would not have to carry out orders conflicting with their central moral beliefs. In all of these cases, the courts determined that the principle of patient autonomy outweighed the principle of beneficence. Although the preservation of life is believed to be crucial, in many cases the courts have cited the criterion of “uselessness of further treatment” and “grave burden” to the patient to allow withdrawal of life support. In the Conroy case,45 the New Jersey Supreme Court rejected the argument that terminating life support was tantamount to suicide by differentiating between self-destruction and self-determination. The court stated that individuals have the right to terminate life support and thereby allow the underlying disease to take its natural course. They recognized that termination of life support fulfilled the patient’s preference to live free from medical support and pain. One situation in which the courts have ruled that the patient must undergo treatment is in cases in which there are dependents who may, upon the death of the patient, become wards of the state. Such situations may arise when a JW single parent of minor children refuses life-saving blood transfusions. All instances of disagreement do not go to the courts, nor should they. Although there are many disagreements in

medicine, these should, under ideal circumstances, rarely progress to the courts because of the trust within the patient-physician relationship. When disagreements arise, careful consideration needs to be given to the possible causes of the dispute, such as whether it stems from a lack of patient education or a misunderstanding concerning what is in the patient’s best interest. These questions need to be addressed in all patient-physician interactions. The type of disagreements noted previously, as between a JW who refuses blood and a medical team that wishes to transfuse, are relatively easy to bring to a successful conclusion. More difficult are disagreements occasioned by loss of faith or confidence by the family or patient in the medical team caring for them. In our experience, this situation most often results from inadequate communication between the physicians and the patient or family. In the cases with which we have been involved, either directly or indirectly, compromised communication set the stage for a problem that a medical-nursing misadventure consummated. The misadventure need not be serious, it may be as minor as a patient being left on the bed pan for what appears to be “too long”; as serious as a failed attempt at weaning from the ventilator or a pneumothorax after central line placement. The experienced physician will note that these events are not uncommon in the ICU. They become problems when we have been too busy to give a family the time they need to understand what we are doing to their loved one. As difficult as it often is to find the time needed to do all that is required of us, we must—if we are to remain true to our common humanity and the principles that guide us—give the families of our patients the time for questions and explanations they need. While we claim no special expertise in this area, we have, as fathers and sons, watched our loved ones become ill and die. We have watched colleagues who are simply “too busy” to speak with us or our families. How can this be? We are the same as they. We do the same work they do. We are these colleagues. Yet it is true, such behavior is not uncommon among us. Some physicians and nurses deal with the difficulty of dying, or at least not improving, patients by withdrawing emotionally from the patient and family. While this is perhaps understandable, it is also flies in the face of the

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principles of medical ethics that we detail at the outset of this work. Medicine is an art and a science; it is in fact a “humane science.” If the humanity is stripped from our practice of medicine, we lessen ourselves and our patients.

Euthanasia and Physician-Assisted Suicide While euthanasia and physician-assisted suicide (PAS) are not the same entities, we will discuss them together in this section. Euthanasia and PAS may be considered as extensions of the principle of autonomy. Emanuel46 reminds us that the discussions being had in our society regarding euthanasia are neither new, nor specifically related to advanced medical technology. The same debate was joined, between 1870 and 1936, both in Britain and the United States. Thus the genesis of these discussions—including significant opposition—predate the rise of fascism and the crimes of the Nazi regime, and appear related to the desire of patients to manage the method and timing of their demise, as much as limiting health system control of this last “great journey.” Euthanasia is the delivery of an agent or agents to a patient by a physician so that the patient dies. Euthanasia is often parsed into passive and active, with active being further subdivided into voluntary and involuntary. Passive euthanasia is a shorthand term for withdrawal or withholding of therapy. In a situation in which the patient, family, or health surrogate has determined, with the physicians and nurses caring for the individual, that there is no longer any hope for an outcome that is acceptable to the patient (hope for recovery is outweighed by the burden of further treatment47), a decision to discontinue or not initiate a potentially beneficial therapy is considered appropriate. That which is “acceptable” will, of course, vary based upon individual desires, histories, and the presence or absence of religious beliefs. Irrespective of how “acceptable” is defined, when a patient or family has determined that the battle for a cure is terminated, that further therapy is not desired, and that death is not an option they any longer wish to forgo, therapy may be withdrawn. While it is possible that families and the physicians and nurses caring for the patient may disagree on these issues, it is our experience that, when lines of communication are kept open throughout the patient’s hospital stay, disagreements are slowly worked out in the process of discussions about outcome possibilities. We have had many cases in which disagreements as to acceptable outcome were had. The very act of discussing these issues makes it possible to determine, for all those concerned about the patient, a strategy that is in keeping with the closely held moral beliefs of the patient and family. The act of continued discussion also makes it possible for the family to understand the position of the health care team in this, final, stage of the patient’s life.

When the decision is ultimately made to withdraw/withhold further therapy, the roles of the physicians and nurses change. We shift from using all resources at our disposal to effect a cure, to using whatever resources are needed to ensure, as much as is possible, that the human under our care does not die a death punctuated with needless suffering and pain. The role we play is to ensure that the patient and family are as comfortable as possible. We eliminate, to the extent possible, any restrictions on visitation. We ensure that there are no obvious signs of pain; a patient who has a ventilator and pressors discontinued is given intravenous narcotics if there are signs of distress such as diaphoresis, tachypnea, or grunting, among others. As the intent is to make the patient comfortable, rather than speed death, this is not termed active, but passive, euthanasia. The “double-effect” of Thomas Aquinas is used to justify narcotic administration in this situation.48 There is a significant literature that supports the termination of therapy in this manner.2,3,12,13, 38–41 Active euthanasia is a process by which the patient’s death is the desired result of an administration of drugs. Active euthanasia may be subdivided into voluntary and involuntary processes. As one might expect, involuntary euthanasia is the killing of a patient who has not asked—either directly or through a surrogate—for his or her life to be shortened. There is no acceptance of involuntary euthanasia among most physicians. There have been, however, reports in which it is clear that active, involuntary euthanasia has been carried out. For example, in neonates, withdrawal of therapy is often made in the context of severe congenital diseases. A recent Dutch study in which physicians were queried as to their use of potentially life-shortening drugs suggests that in the neonatal ICU, drugs that might shorten life were administered in 37% of all deaths.49 In greater than 70% of the cases, the physician’s best estimate was that the use of these drugs—primarily but not exclusively morphine or other opioids—shortened the patient’s life by less than 1 week. Of particular interest, these authors found that, in the context of withdrawal or withholding of therapy—including the administration of drugs meant to alleviate pain and suffering—neuromuscular blocking agents were used in 6% of the 108 neonates administered potentially life-shortening drugs. Additionally, hastening death was an explicit desire in 48% of the neonates to whom drugs were administered; in 54% of neonates to whom neuromuscular blocking agents were administered, the intent was to hasten death. Whether or not the administration of drugs was intended to hasten death, the physician’s decision was discussed with parents only in 88% of cases. In 1995 in the Netherlands, 2.7% of deaths involved euthanasia–physician-assisted suicide (EAS).50 Adult cases of EAS were studied to determine if the criteria set by the Royal Dutch Medical Association (RDMA) were being met.50 These criteria mandate that for the prudent consideration of EAS, the patient must fulfill specific criteria (Table 30-1), and

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Table 30-1  Euthanasia–Physician-Assisted Suicide Prudent Practice Guidelines

From the Board of the Royal Dutch Medical Association, 1996.

a colleague consultant must confirm the criteria. While, overall, consultation took place in 63% to 79% of deaths, 99% of cases reported to the Public Prosecutor had consultants. However, in those cases that were not reported, even though reporting is required by law, only 21% had consultations. This suggests that a portion of cases of EAS are performed without fulfilling the RDMA criteria to ensure the aversion of abuse. Other series of deaths in neonatal and pediatric intensive care units51,52 report difficulties and significant debate,53 from the use of neuromuscular blocking agents when mechanical ventilation was to be withdrawn, to possibly inadequate doses of analgesics or amnestics, to cultural differences that result in limitation of drug use whose aim is the shortening of life. We support the ability of a physician and his or her patient to determine the course of therapy that will be taken. Although some—perhaps many—physicians would disagree, we extend this support to EAS as defined by the RDMA, as well as decisions made between physicians and parents of children with incurable disorders. However we and others54 worry that the two papers referenced previously suggest that at least some of our Dutch colleagues are stretching “prudent practice” beyond recognizable bounds. This suggests an arrogance, a paternalistic view, about what is “best” for the patient that is concerning. The consequences of such paternalism impact primarily—but not only—the patient. The physicians behaving in this manner take upon

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themselves a heavy and unnecessary responsibility to adjudicate a patient’s preferences and moral beliefs, and to determine for each one not only the appropriate treatment, but also the patient’s ultimate interests. Besides mistaken medical judgments that can result from not knowing a patient’s preferences, the physician would be unlikely to know what would constitute a patient’s best interest, and yet the physician would bear the burden of responsibility for any error that occurs. Communication between patient and physician, already difficult, becomes even more complicated when decisions about deeply held precepts are adjudicated privately by the physician.55 Indeed, such arrogance brings to mind the most worrying aspects of Kevorkian’s euthanasia cases.56 The principles of medical ethics require us to provide all appropriate therapy to a patient, and we strive to do so. We have been often faced, however, with very serious questions as to whether the addition of further therapy would provide any benefit to our patient. This usually comes up in the case of a very seriously ill individual with whose family or surrogate there is no agreement as to an endpoint. A 60-year-old with a metastatic lesion to the brain, of unknown primary, suffers a stroke after resection of the brain lesion. The stroke is not an obvious direct complication of the surgical intervention. The procedure was performed to give the patient time with her family; now there is a complication with results for outcome that are unclear. As the left middle cerebral artery territory lesion progresses through its natural history, the patient is unable to express her wishes, and the family wants “everything” done. At what point does “everything” become inappropriate? When the cerebral edema is not better by day 3? When it is worse at day 5? When there is impending herniation on CT scan? When the herniation has been resolved medically but the patient is left vegetative? Is it our place to make the judgment as to whether therapy should continue to be added or is it only the family’s decision? Our best, and most respectful, judgment is that there are times when, despite daily discussions with the family, they are in hope of a miracle that we can not provide. In this situation, we will not withdraw any therapy, but rather will write a note in the chart that, in our best judgment, further aggressive therapy would be futile, so none will be added. If the patient deteriorates, we allow that to occur. In most cases, this is note is accompanied by a “Do Not Resuscitate” order, in which we state that cardiac compressions are not to be performed and cardioactive agents are not to be given, but all other therapy is to be continued. This judgment is never carried out without a second consenting opinion from a colleague involved in the care of the patient. As the issue of futility is a medical decision in line with the principle of nonmaleficence rather than one related to autonomy, we do not seek the family’s permission for this. We do ensure that the issue has been discussed and laid out as clearly as possible. We do not hesitate to let the family

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know when we have reached the end of the therapeutic tether. PAS is a version of voluntary, active euthanasia requiring the assistance of a physician to prescribe medications that the patient may take at a time he / she determines is appropriate. The central issue with PAS is to give the terminally ill patient control over the timing, if not the manner, of death. There has been significant controversy about PAS, although not only in the medical literature. Recently, the Attorney General of the United States threatened physicians in the state of Oregon with the loss of their Drug Enforcement Administration (DEA) number, used to prescribe narcotics, if they assist in legally allowed (under the laws of the State of Oregon) PAS (see Amednews.com at ama-assn.org/scipubs/amnews/pick_01/prsb1126.htm and ama-assn.org/.../ pick_02/prsc0506.htm). Willems and colleagues evaluated attitudes and practices at the end of life, comparing physicians in the Netherlands and the United States.57 Physicians (oncologists, internists, family practitioners in Oregon, and internists in the Netherlands) were enrolled and had four clinical vignettes posed to them (Table 30-2); they were then asked whether they would increase morphine, perform euthanasia or PAS. The results suggest that the Oregonian physicians were as likely to increase morphine or provide drugs for PAS as were their Dutch colleagues. The Americans, however, were less likely to be supportive of euthanasia (Table 30-3). Interestingly, when the Burden vignette (see Table 30-2) was posed, the American physicians significantly more frequently were willing to prescribe drugs to allow PAS than were their Dutch Table 30-2  Clinical Vignettes 1. Pain: A patient develops metastatic cancer that invades the bones, resulting in excruciating pain. Current levels of morphine, nerve blocks, and other treatments are failing to completely control the pain. 2. Debility: A competent patient has terminal cancer with a few months to live. The patient has no pain but is debilitated and cannot get out of bed or provide self-care. The patient has seen a psychiatrist and is not clinically depressed, but repeatedly asks for a life-ending injection. 3. Burden: A competent patient has a terminal cancer with a few months to live. The patient has well-controlled pain and can continue self-care but is increasingly concerned over the burden that deterioration and death will place on his or her family. The patient has seen a psychiatrist and is not clinically depressed, but repeatedly asks for a life-ending injection. 4. Meaningless: A competent patient has a terminal cancer with a few months to live. The patient has well-controlled pain and can continue self-care but finds life meaningless and purposeless. The patient has seen a psychiatrist and is not clinically depressed, but repeatedly asks for a life-ending injection because he sees no point in a drawn-out death process. From Willems DL, Daniels ER, van der Wal G, van der Maas PJ, Emanuel EJ: Attitudes and practices concerning the end of life—A comparison between physicians from the United States and from the Netherlands. Arch Intern Med 2000;160:63–68, with permission.

Table 30-3  Attitudes Concerning Physician-Assisted Suicide and Euthanasia Vignette

United States

Dutch

P

Pain Increase morphine PAS Euthanasia

97% 53% 24%

96% 56% 59%

.67 .71 <.001

Debility Increase morphine PAS Euthanasia

36% 37% 14%

43% 52% 49%

.32 .03 <.001

Burden Increase morphine PAS Euthanasia

24% 24% 7%

6% 9% 4%

.007 .01 .44

Meaningless Increase morphine PAS Euthanasia

20% 22% 7%

15% 18% 14%

.42 .56 .14

From Willems DL, Daniels ER, van der Wal G, van der Maas PJ, Emanuel EJ: Attitudes and practices concerning the end of life—A comparison between physicians from the United States and from the Netherlands. Arch Intern Med 2000;160:63–68, with permission.

colleagues. Physicians who considered themselves religious were less likely to be supportive of either PAS or euthanasia, irrespective of nationality. Sullivan and colleagues’ review of PAS in Oregon58 noted that the frequency of patients ingesting lethal medications increased between 1998 (n = 16) and 1999 (n = 27); respectively the proportion of total deaths went from six to nine per 10,000. The underlying illnesses in 1998 were cancer (88%) and other diseases (12%, AIDS, ALS, CHF, COPD, MSOF); in 1999, cancer accounted for 63% and other diseases 37%. College graduates were 12 times more likely to use PAS than were individuals without a high-school education. Reasons patients gave to their physicians for requesting assisted suicide included loss of autonomy, inability to participate in activities that make life enjoyable, and loss of control of bodily functions; pain control was less commonly an issue for the patients in 1998 (12%) and 1999 (26%, P = .30). No patient cited concerns about cost of treating the illness or of prolonging life. Interestingly, when family members were queried as to the reasons that their loved ones would have requested assisted suicide, the responses were similar to the ones given by the physicians from whom assistance was requested. A difference was noted in that family members of a subgroup of four of 19 patients who had died stated that the patient was fearful of ending life in a coma or, despite an advanced directive, on a mechanical ventilator. The authors note that control over how one died was the central unifying rationale which led patients to request PAS. Euthanasia and PAS are not without difficulties of a technical type, however. Groenewoud and colleagues59 reviewed

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649 cases in which euthanasia (n = 535) or PAS (n = 114) were intended. Seventy-five percent of the patients had cancer, the mean age was 63.9 years (range, 21 to 96 years), and 55% were men. In 69% (367/535) of euthanasia cases, the agent administered was a neuromuscular blocking agent, usually—but not always (data not given)—after the administration of a barbiturate. In 71% (81/114) of the PAS cases, a barbiturate was used; in 14% of cases, a neuromuscular blocking agent was administered after a barbiturate. In the cases in which euthanasia was intended, drugs were administered by a physician or nurse 95% of the time; a person other than the physician or nurse, but not the patient, administered the agents in 5% of cases. Where PAS was intended, the patient self-administered drugs in 75% of cases, but a physician or other person had to administer some or all of the agent 25% of the time. Technical problems were seen in 5% of cases, complications in 4%, and difficulties with completion (death taking either more or less time than expected) in 7%; there was a significant difference in each of these three categories between euthanasia and PAS groups, with the PAS group having a higher incidence of each (Table 30-4). An accompanying editorial by Nuland60 notes that, given the complication rates in the Dutch series, it would be remarkable if PAS were to be complication-free in the United States, even though no such series have been Table 30-4  Technical Problems, Complications, and Difficulties with Completion Problem Area

Euthanasia (n = 535)

Physician-assisted Suicide (n = 114)

Technical* Finding vein With IV catheter Administering oral drug Other Not specified

1.9% 0.7% 0.7% 0.6% 0.6%

0.9% 0 6.1% 2.6% 0

Complications† Spasm/myoclonus Cyanosis Nausea/vomiting Other Not specified

1.1% 0.7% 0.4% 1.3% 0.2%

0.9% 0.9% 3.5% 3.5% 0

Completion Time to death longer than expected/no coma Patient awoke from coma

4.3% 0.9%

12.3% 1.8%

*Other technical problems included inappropriate equipment, drugs that were unpleasant to swallow or irritated the throat. † Other complications included patient’s eyes remaining open, the patient sitting-up, tachycardia, excessive mucus production, hiccups, perspiration, extreme gasping, a feeling of drunkenness. Modified from Groenewoud JH, van der Heide A, Onwuteaka-Philipsen BD, Willems DL, et al: Clinical problems with the performance of euthanasia and physician-assisted suicide in the Netherlands. N Engl J Med 2000;342:551–556.

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published. He further notes that we must rethink our reluctance to participate in, or even be present for, assisted suicide; we have suggested such a position in the past61 and continue to agree that this issue must be reconsidered in our United States. Easy answers do not exist, but responses to our patient’s well-considered needs must be sought. While the Supreme Court of the United States has ruled that there is no constitutional right to PAS, they seem to have come down on the side of palliative care.62,63 How this will play out in future is presently uncertain, but it does appear that the principle of the palliative use of narcotics and other drugs at the end of life is supported by the Supreme Court. Orentlicher, while noting that intolerable and refractory symptoms exist in between 15% and 50% of dying patients, has termed the use of palliative pharmacologic agents “terminal sedation” and a kind of “slow euthanasia.”64 He notes that there is a dubious distinction between terminal sedation and euthanasia, and that, by rejecting PAS, the Court has left open the possibility of a therapeutic mode that is no less at risk of abuse than is PAS. The position of the American College of PhysiciansAmerican Society of Internal Medicine65 (ACP-ASIM) on this issue is that physicians ought to use their skills to eliminate conditions that cause suffering, but that the medicine can not arrogate to itself the task of relieving all human suffering; the ACP-ASIM rejects the legalization of PAS. In doing so, they suggest that the physician caring for the dying patient who has requested PAS ensure that pain and depression are adequately treated, that hospice is utilized where needed, and that the physician should “explore the reasons for the request, try to understand its meaning, keep dialogue open and affirm that he or she will not abandon the patient”. ACP-ASIM claims that embracing PAS might compromise the patient-physician bond or be discriminatorily applied, with the poor, the elderly, ethnic minorities, or other vulnerable persons placed at risk of arbitrariness in decision making. Nonetheless, and not without appreciation and respect for colleagues who have taken differing positions, we feel that it is simply not the place of organized medicine, the Supreme Court, or others to decide what happens between a physician and his or her patient. If the patient or family and the physician determine that the best course of events will be attained if the physician assists the patient in his/her death, based upon knowledge of the patient’s condition, and premorbid deeply held beliefs, we believe it is within the realm of the moral and ethical to so assist the patient. We make no demand that such behavior be legalized; indeed, legalization well might lead to abuse. Our fellow human beings who, as they die, ask us not for understanding or open lines of communication, but help, should receive no less than that. To respond with bromides about the possible ill-effects for society as a whole, while this human suffers, seems to us unconscionable.

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Do Not Resuscitate in the Operating Room History of the Do Not Resuscitate Order Although the right of patient autonomy was articulated in 1914 and the phrase “informed consent” was coined in 1957,66 it was not until 1985 that open discussion of explicit policies to limit medical care began,67 in part as a result of data that began to accumulate on the outcome of cardiopulmonary resuscitation (CPR). CPR originated as a means to treat sudden cardiac or respiratory arrest, usually in patients with acute illness under the care of an anesthesiologist, cardiologist, neurologist, or surgeon.68 Discharge from the hospital (the definition of long term survival) after CPR was initially reported to be about 70%,69 but this figure rapidly gave way to 24% for all patients suffering cardiac or respiratory arrest.70 While the percentage of intraoperative or recovery room arrests was not reported in the first study,69 in the later one70 64% of arrests occurred in operating and recovery rooms, and only 7% elsewhere. In 1988, a 7-month study encompassing medical, as opposed to surgical, patients reported that, in 71 patients, cardiac arrest was followed by CPR (70% from acute myocardial infarction or acute pulmonary edema). While 29 (41%) were successfully resuscitated, only 13 (18%) were discharged from the hospital.67 In 1989, a retrospective study of 503 elderly patients reported that 17 of 259 (6.5%) patients who suffered in-hospital cardiac arrest survived to hospital discharge, while only two of 244 (0.8%) of those who suffered out-of-hospital cardiac arrest survived to discharge.71 Of the total 19 who survived, five were transferred to rehabilitation hospitals and six to a nursing home or chronic-care hospital; only eight returned home. Thus, the rate of long-term survival after CPR ranges from about 70% to less than 1%, the highest rate being reported three decades ago in a select group of patients and the lowest in elderly patients who underwent out-ofhospital resuscitation attempts. Up to 38% of hospitalized patients with Do Not Resuscitate (DNR) orders on their charts do not suffer cardiorespiratory arrest and are discharged from the hospital.72 One study recently showed the number of deaths preceded by CPR in similarly ill patients decreased significantly from 73% to 39% between 1981 and 1983, and between 1987 and 1988, likely because a stable medical staff and clear, objective criteria have made it possible to identify hopelessly ill patients and thus to avoid futile therapy. This strategy takes into account the wishes of patient/surrogate, as well as medical prognosis.73 Regardless of any criticism of this retrospective study, the central issue—limiting care when all involved agree this is appropriate—is significant. Finally, the issue of DNR does not disappear when the patient is discharged from the hospital.74 Individuals sent from hospital to either their home or a chronic nursing facility require clarity as to their resuscitation status because, if

the Emergency Medical System (EMS) is at some point called to respond due to the patient’s having suffered a cardiac arrest, the paramedics are required, in the absence of a formal order or declaration of DNR, to perform CPR until either the physician responsible for the paramedics gives permission to stop in the field or, having arrived at the hospital, the patient is declared dead by the Emergency Department physician. This is a major issue of controversy for us today. Policies Guiding the Do Not Resuscitate Order: Formalization of Patient Autonomy Because CPR is a measure that literally brings a person back to life, it is, unlike other therapies, automatically instituted by nurses or emergency medical technicians unless the patient’s medical chart specifically contains a DNR order. To prevent the inappropriate use of CPR, policies concerning DNR orders have been established by hospitals and groups such as the American Society of Anesthesiologists. Generally, a DNR order is placed on a patient’s medical record as specific instructions signed by the attending physician stating that CPR should be withheld; also included are orders clearly designating the therapies that should not be discontinued. DNR orders can apply to a specific therapy, such as CPR, even while other therapies are continued, because patients may continue to benefit from other interventions and may even improve such that the DNR status is no longer appropriate. Thus, DNR orders need frequent, often daily, reevaluation. Even though the DNR order arose ostensibly out of the medical concern that drastic therapy was not always effective, the most significant aspect of this order may be that it formalizes the influence of the patient’s autonomy. Unfortunately, institution of the DNR order, while implying the patient’s involvement, has, in some circumstances, actually circumvented autonomy. In one retrospective study reported in 1986,72 389 of 521 (75%) patients who died without CPR had a DNR order on their charts. Written documentation that the patient was involved in this decision, however, was evident in only 86 of 389 (22%) of cases, the reason for this in most cases being that the patient was “incompetent.” While appropriate documentation of DNR status in the medical record tended to increase from 50% to 82% between 1980 and 1983, patient input into this decision was considered inadequate. Indeed, according to the investigators, discussion between physician and patient / surrogate of DNR status did not begin until approximately 1 week after admission, by which time a majority of patients had become incompetent. Others have documented this phenomenon as well.75 Everhart and Pearlman’s prospective study suggests both that patients want to take part in decision-making about their resuscitative status and their choices tend to remain stable over time.76 Assuming a decision to invoke DNR status ought to represent both the autonomous choice of a patient

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and the physician’s medical decision, how are we to ensure that placing such an order in the medical record chart actually involved the patient? Do Not Resuscitate and Quality of Life: The Patient’s Conditions Generally, patients who request a DNR order have an irreversible illness whose suffering will continue and likely increase until death ensues.77 The focus is as often on suffering, which the patient must identify, as on the imminence of death, which a physician identifies. Thus, quality of life can be as strong a rationale for a DNR order as futility of therapy. Distinguishing between rationales for a DNR order may be the best approach to answering DNR-related questions,77 especially for determining whether a patient may want to be involved in the decision, as well as for determining whether limited care means no care. CPR is just one of many options that may or may not be chosen or agreed to by a critically ill patient.78 Patients may benefit medically from treatment options but may, nonetheless, reject them, based on quality of life. Quality-of-life issues demand more of the physicianpatient relationship—that physicians communicate more than their knowledge of pathophysiology and pharmacology, and that patients communicate more than their symptoms. Social values about life and death make communication difficult. A medical journal report about a television documentary that showed the discussions about these decisions as they were taking place79 noted that the discussions varied widely in their nature and were highly emotional, both for medical staff, who continue to struggle with the call of beneficence and nonmaleficence, and for patients or surrogates, who must contend with their own personal struggles. Even though patients may want to take part in the decision, they may hesitate to openly express a preference for death or ambivalence about medical treatment as life in our society is considered sacrosanct, to the point that preservation of life is a state,80 as well as a medical, interest. This value permeates our thinking in subtle ways. For example, refusing treatment can be construed as suicide. Physicians may hesitate to address the issue for the same reason or because of different moral values.81 Furthermore, physicians may not discern subtle signals from a hesitant patient simply because there is not enough time “to just talk.”82 This aspect of the problem was strikingly portrayed in a recent study of these decisions.83 The average time between first considering a DNR order for a patient and finally writing it on the patient’s chart was approximately 5 days. For a medical decision, the efficacy of which usually depends on the speed with which a treatment is administered, this is indeed a “prolonged” period. For a person attempting to decide whether life is worth continuing, 5 days may seem too brief. The need for time to fully consider what could be called a “life-shaking”

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decision may make patients appear to physicians passive and unwilling to make such decisions.66 Care in the Presence of a Do Not Resuscitate Order: Conditional Treatment The problems surrounding communication about DNR orders can become even more complex if, once a DNR order is established, the patient could benefit from anesthesia and surgery. Nevertheless, until techniques such as decision analogs84 are more widely used, communication should enable most problems to be resolved. To illustrate, we analyze a case that is synthesized from and encompasses experience with many different patients. A patient may require one of any number of surgical interventions, depending on the pathophysiology that initially led to the DNR order, for example, exploratory laparotomy for lysis of adhesions in the face of a small bowel obstruction in a cancer patient, or tracheostomy, gastrostomy, and jejunostomy in a patient in a persistent vegetative state. Again, although DNR patients undergoing anesthesia and surgery seem to place both surgeon and anesthesiologist in a difficult position,85-90 the difficulty is only an apparent contradiction resulting from the different goals of beneficence, nonmaleficence, and autonomy, which in turn reflect whether the rationale for the DNR order is lack of medical benefit or quality of life. The principle of autonomy would imply that a patient with a DNR order should be able to undergo anesthesia and surgery, yet not have CPR administered if a cardiopulmonary arrest occurs. For the physician, however, beneficence and nonmaleficence indicate that the physician should try to preserve the patient’s life and thus should perform CPR if an intraoperative cardiopulmonary arrest occurred. The resolution of this apparent quandary lies within open and frequent communication with the patient or surrogate to clearly understand the rationale for the DNR order when it is not based on lack of medical benefit. For example, a DNR order may be based on the patient’s perception of quality of life after CPR as opposed to quality of life before CPR, when the patient considers quality of life before CPR marginal. It is, after all, the patient77 who lives with the results of our medical decisions. Consider the possibilities in the case of a 50-year-old man with widely metastatic adenocarcinoma of the colon. Mental status changes, resultant from the effects of both the tumour and tumor-related hypercalcemia, have impaired airway reflexes, but the patient had earlier refused endotracheal intubation to prevent aspiration of oral secretions. Hence, the risk of pulmonary complications is increased. Additionally, pain requires morphine in quantities that further depress the patient’s mental status. Before becoming incompetent and after several in-depth discussions, the physician and patient agreed that his chart would contain a DNR order and a note that endotracheal intubation would

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be excluded from his treatment options. The DNR order states that no CPR will be administered if the patient suffers cardiac or respiratory arrest, that already initiated therapies will be continued but no new ones will be added, except for analgesics as needed, and possibly palliative chemotherapy. In keeping with the patient’s autonomous request that his dying not be delayed or interrupted indefinitely, neither CPR, vasopressors, nor fluid boluses to keep blood pressure elevated will be administered. Morphine sulfate will be administered intravenously to prevent, as much as possible, unacceptable discomfort. Any consequent respiratory depression due to the morphine is accepted as less objectionable than pain. This plan is clearly in harmony with the preceding ethical principles. The patient then undergoes palliative chemotherapy and a complication occurs: sclerosis of peripheral veins, a problem that would normally lead to the alternative of central venous access. In this case, however, how should the physician proceed? The subclavian approach to the central vasculature is easiest for this physician but is associated with an approximate 1% to 3% risk of pneumothorax.29 Before attempting the central access, the physician considers what is to be done if a pneumothorax occurs: Place a chest tube? Allow events to unfold as they will without further corrective intervention? Give 100% oxygen by nonrebreathing mask in the hope the pneumothorax will slowly resolve spontaneously? A pneumothorax after placing a central venous line by the infraclavicular subclavian approach would clearly qualify as an iatrogenic complication; it will not occur if the physician does not intervene. On the other hand, the central venous line would not have been necessary absent the selected option for chemotherapy. How is a complication like this handled? Arguably, because the rationale for the DNR order is centrally concerned with quality of life, any life-threatening event falls under the DNR order, and thus nothing need be done. This course of action would fulfill the principle of autonomy. Also arguably, because it resulted directly from the intervention, not the underlying pathophysiology, the complication should be treated. Doing so would likely fulfill the principles of nonmaleficence and beneficence.

The only way out of this dilemma would have begun before the situation developed. Recognizing the risk of pneumothorax postcentral line placement, the physician would have discussed it with the patient or surrogate in the process of obtaining informed consent. The question to the patient/surrogate would have been: If a complication occurs during placement of the central line, it can be treated. Do you want treatment initiated, even though it might cause some discomfort and will not alter the ultimate outcome? If the patient or surrogate wanted no treatment of a pneumothorax, even if that meant, or because that meant, a more rapid death, the physician would have to decide, based on his or her own autonomous position or beliefs, whether following the wishes of the patient/surrogate would be ethically compromising. If the answer were yes, the physician would be obliged either to assist the patient in finding another

physician who would not be so compromised, or to find an alternative to central access by infraclavicular subclavian approach (perhaps the femoral vein or a PICC [peripherally inserted central] line). In such cases, there is not one correct ethical response to the question of how to handle a complication resulting from central line insertion. However, the best ethical response can only be known by talking with the patient or surrogate. In doing so the allowable options range from rescinding the DNR order to withdrawing from the patient’s care. Only through frank discussion can we know which of these to choose in order to maintain faith with the central principles of medical ethics. Because in this specific case, medical intervention has the potential for adverse effects without a hope of medically altering the patient’s ultimate outcome, the patient’s autonomous concern for quality of life, whether based on pain or moral beliefs, becomes the primary consideration. Only by discussing with the patient / surrogate the options of intervention and the consequences of choosing, or not choosing, an intervention can we arrive at an ethically sound decision. The same rationale would hold if our patient needed to be taken to the operating room for a small bowel obstruction. The patient or surrogate will be approached for informed consent. The physician explains what will occur in the operating room, including the potential for complications, and also points out the therapeutic options if problems occur. Once again, it is only through careful and empathic discussion that this issue can be resolved.77,91,92 As best as possible, the patient/surrogate must understand the nature of the physiologic insult entailed by the procedure, as well as the possible surgical and anesthetic complications involved. These would range from hypotension upon induction of anesthesia to cardiac arrest. If considered appropriate by the surgeon and anesthesiologist, a request could be made to rescind the DNR order for 24 to 48 hours. This would allow the surgical team access to all modalities of therapy for that period of time, after which the DNR order would be reinvoked. It would be made clear to the patient or surrogate that any therapy would be discontinued when no longer necessary or when it was no longer effective in reversing the acute physiologic abnormalities induced by surgery. Thus, the patient/surrogate could consent to the procedure with three options:86 1. Rescind the DNR order. 2. Stipulate which therapies are acceptable for the surgical team’s use. 3. Leave the DNR order in effect. The surgical team would weigh the moral risk of proceeding with the intervention if the second or third option is chosen by the patient or surrogate. If they opt not to proceed, they are obliged to refer the patient to others who will. Finally, what are we to do if, after the patient or surrogate agrees to the procedure and allows any therapy deemed

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necessary intraoperatively and for the first 24 to 48 hours after operation, the patient undergoes tracheal intubation and mechanical ventilation but does not improve to the point that the trachea can be decannulated after 48 hours? As this scenario would have been discussed with the patient / surrogate prior to the operative intervention, life support could be withdrawn.85,86,88,89,93

A Further Word about the Team While we have spoken in some detail about the “patientphysician” relationship, it is necessary to point out that, in the modern day hospital setting to which we refer, a team of physicians, more often that not, is involved in the care of a patient. While one of the team is usually the patient’s “own” doctor, the others involved are, as well, the attending physicians for that patient. For example, in our surgical intensive care unit and burn center, there are, at any one time, two attending physicians: the surgical attending and the critical care attending. Neither of these is a consultant; for both, the patient is their “private” patient. While, in the experience at our institution, this works well, there is the possibility that disagreement between the physicians on the team will result in confusion and, thus, fear on the part of the patient. It is critical, therefore, prior to any one of the physicians discussing the issue of DNR with the patient, for the physician team to come to some general agreement as to the most appropriate medical plan of action for that patient. In our experience at Shands Hospital at the University of Florida, the physicians collective agreement that DNR is appropriate must precede physician discussion with the patient (but, of course, not patient discussion with one of the physicians or nurses) about this issue. While a certain tension ensues when there is disagreement, the strength of our team has, over the past 20 years—with minor exceptions—resulted in a decision acceptable to all members of the physician team.

What Else Needs to Be Done While data on CPR outcome suggest patients should be concerned about their resuscitation status, the information, although dated, suggests physicians and patients discuss this issue only rarely (4% to 19%),71,94 even though many patients want to discuss such therapeutic options with their physician.94 The reasons for this may go beyond the social attitudes toward life mentioned earlier, which affect both physician and patient. For physicians specifically, reasons may also include discomfort when such discussions throw their own mortality into bold relief; inadequate training in this type of communication during medical school; and inability or unwillingness to make time, as mentioned previously, because of the constraints of the medical system. A further obstacle is the view that DNR orders and death represent “defeat” and thus failure. This view derives from the

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very goal of medicine, the seeking to heal or cure that beneficence conveys, and from the competitiveness in American society, wherein failure is often considered “a fate worse than death”—to be avoided at all costs. DNR orders should only placed on a patient’s chart after discussion with the patient/surrogate and among all pertinent medical and nursing staff. Further, the status of the order should be reevaluated regularly through a continuing dialog with patient / surrogate. Patients do want to both discuss these issues and be involved in the decision making that leads up to the choice of a DNR order—they want control over their death, life’s last important milestone. Discussions of advanced directives, living wills, and DNR orders are simply a means to ensure that this control is not unjustly taken from those under medical care. In the operating room too, the issue of control exists. A partial solution to this problem is to ensure that each hospital, and departments of anesthesiology and surgery, have policies mandating the reconsideration of DNR orders that predate the planned operative intervention. DNR orders should not simply be canceled, nor should they lead to surgeon or anesthesiologist refusal to undertake a palliative procedure. Those of us working in this area need to heed our patients’ concerns that their deaths be as dignified and humane as possible. In doing so physicians remain true to all the principles of medical ethics, most especially to the one that demands we treat each person under our care as if he or she were a loved member of our family.

Brain Death What Is Brain Death? Mollaret and Goulon originally introduced the concept of brain death in 1959, when they described “irreversible coma” in 23 patients with unresponsiveness, loss of brainstem reflexes, and an absence of spontaneous respiration, who additionally had flat electroencephalograms.95 With the advent of mechanical ventilators to ensure adequate ventilation in patients with a complete absence of respiratory drive or capacity, many patients who otherwise would have succumbed to terminal neurologic disorders can be sustained temporarily with careful attention to cardiovascular and endocrine dysfunction that subsequently arise. Others have pointed particularly to devastating brainstem damage as the essential component of brain death96; indeed, most of the clinical features examined in brain death determination specifically assess brainstem function. The correct determination of brain death is essential in medical care for a number of reasons, among which are to ensure that inappropriate measures are not undertaken, to provide finality for families concerned for potential prognoses, and to provide an opportunity for organ donation.

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Pathology of Brain Death The most common causes of brain death in adults are traumatic brain injury (TBI), hypoxic/anoxic brain injury, and subarachnoid hemorrhage.97 In children, the most common causes are abuse, motor vehicle accidents, and asphyxia.98 The underlying pathology reflects the mechanism of injury. For TBI, the devastation can relate either directly from localized injuries, or indirectly due to secondary injury related to hypoxia or edema formation (Figs. 30-1A and B). Near a large subdural hematoma, for example, there may be effacement of sulci, and there may be secondary brainstem (Duret) hemorrhages due to shearing effect or with rapid herniation. Duret hemorrhages typically occur in the pons and midbrain. On a cortical level, separate from locations of injury, there may be early edema formation due to secondary hypoxic-ischemic injury from hypoperfusion due to increased intracranial pressure (ICP). With hypoxic-ischemic injury, the degree of injury and the clinical outcome are directly related to duration and extent of impaired oxygenation and circulation.99,100 In the acute period following a hypoxic-ischemic arrest, there may be very few neuropathologic changes, which consist mainly of cerebral edema (Figs. 30-2A and B). However, if patients

are resuscitated to the point at which they can be maintained on a ventilator, "respirator brain” may develop. This is a process in which the complete lack of intracranial blood flow leads to progressive liquefaction of brain matter. The earliest portions of brain to undergo this process are the upper brainstem, diencephalon, and cerebellum, followed by the cerebral hemispheres. The medulla may be involved to a lesser degree, accounting for the frequently preserved cardiovascular homeostasis. There is typically widespread cerebral venous engorgement and thrombosis. There are often hemorrhages secondary to the congestion and due to the breakdown of endothelium. There are typically widespread infarcts that affect the watershed regions first. In the initial hours following a hypoxic-ischemic event there may be little change on a microscopic level, restricted mostly to “cloudy swelling” of the nuclear region of neurons with loss of basophilia. The classic “red neurons,” with progressive eosinophilia of the cytoplasm, do not typically occur until 8 to 12 hours after the event.101 Clinical Diagnosis and Confirmatory Testing The clinical determination of brain death requires that certain specific conditions are met, eliminating the possibil-

B A Figure 30-1. Gradient-recalled (GRE), axial MR images obtained at the level of the low convexity and incisura, respectively. This type of MR sequence is particularly sensitive to the presence of microscopic amounts of blood products. Microhemorrhage creates a susceptibility artifact producing punctate areas of hypointensity (i.e., dark spots relative to brain). A, A left PCA infarction related to advanced downward transtentorial herniation (arrow). B, Evidence of the actual herniation of the right parahippocampal gyrus (P) and obliteration of the incisural cisterns. Small dark areas (arrows) within the rostral brainstem are indicative of microhemorrhage. Although subtle, the hypointense mesencephalic signal alterations evident along the outer margins of the rostral brainstem are consistent with early hemorrhagic necrosis secondary to severe downward transtentorial herniation. Once such microhemorrhages coalesce they become more easily seen and are known as a Duret hemorrhage.

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B

Figure 30-2. Axial, noncontrast, CT sections in the low-convexity and incisural levels demonstrate the CT features of global cytogenic edema and advanced downward transtentorial herniation. In cases of global events with generalized cerebral swelling these features may be difficult to appreciate, unless some reasonably normal brain density can be used for comparison. In most cases cerebellar and vermic CT density is less affected even in advanced states of hypoxic-hypoperfusion states (or any other cause of global brain injury). Therefore, it is important to compare cerebral density with cerebellar density in order to detect globally altered CT hypodensity, which is illustrated in this case. A, Both the right and left hemisphere have similar CT appearance. B, Portions of the cerebellum (single arrow) are visualized and more accurately define normal CT brain density. Now, the diffuse cytogenic edema is better appreciated. Since the cerebral and cerebellar density should be close to the same, the full extent of brain swelling is evident; edema to this extent in the face of advanced downward transtentorial herniation (double arrows) predicts a very low probability for survival.

ity of a falsely positive test (Table 30-5). The cause of the neurologic state must be known unequivocally, and it must be devastating to the degree that there is irreversible damage to both cerebral hemispheres, the brainstem, or both. There must be no confounding medical conditions that may influence the clinical examination, such as severe electrolyte disturbances; acid-base disorders; or endocrine disorders, in Table 30-5  Prerequisites Before Determination of Brain Death Definitive, acute, irreversible catastrophic event involving both hemispheres and brainstem Exclusion of complicating medical conditions that may confound clinical assessment, particularly severe electrolyte, acid base, or endocrine disturbances Core temperature of ≥32° C No documented evidence of drug intoxication, poisoning, or neuromuscular blocking agents From Wijdicks E: Brain Death. Philadelphia, Lippincott Williams & Wilkins, 2001, p 62, with permission.

particular profound hypo- or hyperthyroidism and severe cortisol deficiency. The patient must have a core temperature of at least 32º C. The systolic blood pressure must be maintained above 90 mm Hg. There must be no evidence of drug intoxication, poisoning, or use of neuromuscular blocking agents. A noncontrast CT scan can elucidate an underlying cause, such as an intracerebral hemorrhage, mass lesion, or profound edema following a hypoxic arrest. However, the CT scan may be normal in the early hours following an arrest, or with fulminant meningitis or encephalitis. In the latter case, lumbar puncture may provide the diagnosis. The key features of the clinical brain death evaluation (Table 30-6) involve establishing that the patient is in a comatose state, and performing a thorough evaluation of the cranial nerves and other brainstem functions. By definition, patients should have no response, including eye opening or motor response, to noxious stimuli. Noxious stimuli include a loud voice, vigorous shaking (provided the concomitant injuries, specifically to the cervical spine, do not preclude shaking the patient), and pain, as elicited by pressing on the

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Table 30-6  Clinical Criteria for Brain Death in Adults and Children Coma Absence of motor responses (except spinally mediated) Absence of pupillary responses to light Absence of corneal reflexes Absence of oculocephalic response Absence of oculovestibular response (“cold calorics”) Absence of gag reflex Absence of coughing in response to tracheal suctioning Absence of sucking and rooting reflexes Absence of respiratory drive at a PaCO2 that is 60 mm Hg or 20 mm Hg above normal base-line values* Interval between two evaluations, according to patient’s age Term to 2 mo old, 48 hr >2 mo to 1 yr old, 24 hr >1 yr to <18 yr old, 12 hr ≥18 yr old, interval optional Confirmatory tests† Term to 2 mo old, 2 confirmatory tests >2 mo to 1 yr old, 1 confirmatory test >1 yr to <18 yr old, optional ≥18 yr old, optional *PaCO2 denotes the partial pressure of arterial carbon dioxide. † See Table 30-8 for descriptions of the available confirmatory tests. Tests may be required by law outside the United States. Modified from Wijdicks E: The diagnosis of brain death. N Engl J Med 2001;344:1216, with permission.

supraorbital nerve, the nail bed, or at the temporomandibular joint.102 Pupillary response is tested by shining a bright light into each eye, which should not elicit any response. A magnifying glass may be necessary to evaluate for minimal pupillary movement. The pupillary shape may be round or irregularly shaped, and most often is in the mid position (4 to 6 mm).103 Pre-existing confounding factors to pupillary abnormalities must be sought, such as prior cataract surgery or glaucoma. Next, ocular movement should be evaluated with the eyes held open. There should be no spontaneous movement, including nystagmus. If there are no concerns of cervical spine injury or abnormality, an oculocephalic reflex should be sought, performed by rapid turning of the head from the midposition to 90° bilaterally. If this is absent, a more powerful stimulus, namely oculovestibular testing, should be performed. With an intact tympanic membrane cleared of cerumen or blood, the patient’s head is elevated to 30°. The tympanic membrane is then irrigated with 30 mL of ice water for 60 seconds, and observed for one additional minute. There should be five minutes between testing the opposite ear. With an intact brainstem, the eyes should tonically deviate toward the cold irrigated ear, but there should be no movement with brain death. Additional confounding factors for this test include prior exposure to certain ototoxic drugs (including aminoglycosides, vancomycin, certain antiepileptic drugs, tricyclic antidepressants, chemotherapeutic agents, and anticholinergics),104 as well as trauma to the globes, orbits, or petrous bone.

The corneal response is tested using a cotton swab on the edge of the cornea. There should be no blink response with brain death. Facial myokymias may be a result of denervation of the facial muscles, and are permissible. These are spontaneous movements, and should not appear in response to noxious stimuli. The facial musculature should also be observed for grimacing while stimulating other parts of the body. The gag and cough response may be tested by manipulating the endotracheal tube, but in older patients this reflex may be absent without brain death, and thus a more potent stimulus should be used in its absence. The reflex can be said to be truly absent if there is no coughing on deep bronchial suctioning. Movement in the extremities is assessed by providing noxious stimuli, typically by nail bed pressure. The presence of abnormal posturing of the extremities, decorticate or decerebrate, precludes the diagnosis of brain death. Deep tendon reflexes are spinally mediated, and thus allowable, as are a Babinski response and triple flexion response in the lower extremity. A number of other spinally mediated movements (Table 30-7) have also been reported in patients with brain death confirmed by ancillary testing, such as an isoTable 30-7  Spinal Movements and Reflexes in Brain Death Cervical spine Tonic neck reflexes (neck flexion) Neck-abdominal muscle contraction Neck-hip flexion Neck-arm flexion Neck-shoulder protrusion Head turning to side Upper extremity Isolated finger jerks Flexion elevation of arm; joining of hands possible Trunk Asymmetric opisthotonic posturing of trunk Flexion of trunk, causing partial sitting movements Abdominal reflexes Lower extremity Plantar flexion of toes after percussion Triple flexion, Babinski sign Modified from Goulon M, Nouailhat F, Babinet P: Irreversible coma [French]. Ann Med Interne 1971;122:479–486; Hanna JP, Frank JI: Automatic stepping in the pontomedullary stage of central herniation. Neurology 1995;45:985– 986; Bueri JA, Saposnik G, Maurino J, et al: Lazarus’ sign in brain death. Movement Disorders 2000;15:583–586; Christie JM, O’Lenic TD, Cane RD: Head turning in brain death. J Clin Anesth 1996;8:141–143; Saposnik G, Bueri JA, Maurino J et al: Spontaneous and reflex movements in brain death. Neurology 2000;54:221–223; Ropper AH: Unusual spontaneous movements in brain-dead patients. Neurology 1984;34:1089–1092; Martí-Fàbregas J, López-Navidad A, Caballero F, et al: Decerebrate-like posturing with mechanical ventilation in brain death. Neurology 2000;54: 224–227; Fujimoto K, Yamauchi Y, Yoshida M: Spinal myoclonus in association with brain death [Japanese]. Rinsho ShinKeigaku 1989;29:1417–1419; and Wijdicks E: Brain Death. Philadelphia, Lippincott Williams & Wilkins, 2001, p 76, with permission.

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electric EEG or an angiogram with absence of intracranial flow. These include the so-called “Lazarus signs”: slight spontaneous abduction or adduction of an extremity, raising of the torso to a 40° to 60° angle, head turning to one side,105 arm raising, and back arching. In some patients this may be seen in synchrony with ventilator-delivered breaths.106 The apnea test evaluates for medullary function, which is the final brainstem structure to be affected in the rostral-tocaudal progression of herniation. The purpose of this test is to demonstrate the absence of respiratory efforts despite the potent stimuli of acidosis and hypercapnea. Efforts should be made to ensure normocarbia (35 to 45) and a normal pH (7.35 to 7.45) prior to the test. The patient is preoxygenated with 100% oxygen for five minutes prior to the test. Preoxygenation eliminates nitrogen within the lungs and thus maintains adequate oxygenation during the test. The endotracheal tube should be connected to a source of 100% oxygen. This can be accomplished either with a T-piece device with continuous 100% oxygen flowing, or by placing a lengthy catheter within the endotracheal tube to approximately the level of the carina, with continuous 8 to 10 liter per minute oxygen flow. The patient should be removed from the ventilator and observed closely for signs of spontaneous respirations, including by palpating the chest wall. The patient should also be monitored for significant changes in oxygenation (including the presence of cyanosis), heart rate, or blood pressure, any of which indicate that the test should be aborted and ancillary tests pursued. Otherwise, the period of observation is eight to ten minutes, which typically is ample time to see significant changes in the pCO2 and pH to fulfill brain death criteria. The pCO2 should rise 20 mm Hg or more from baseline, or to a total of 60 mm Hg or higher. The pH should decrease by at least 0.02 units per minute of apnea, to less than 7.30. The apnea test is generally safe, but its most common complication is hypotension,107 which typically occurs when there is inadequate preoxygenation. Cardiac arrest during apnea testing is thought to be quite rare.107 After a patient has reached death according to clinical brain death criteria, it is optional, but customary, to have a six-hour observation period, followed by repeat testing of brainstem function. This period was set forth by the American Academy of Neurology Practice Parameters,108 and has been greatly shortened from the original 24-hour observation period. It is not necessary to repeat the formal apnea testing, as no patient has ever been reported to regain spontaneous respirations after appropriate performance of an apnea test. The observation period may be shortened if a confirmatory test has been performed, or if there is a transplant recipient waiting. Confirmatory tests (Table 30-8) include cerebral angiography, electroencephalography, transcranial Doppler, MRI, SPECT, evoked potentials, and CT angiography. Cerebral angiography should show an absence of flow in the intracranial arteries. Contrast will typically fill the external carotid circulation, also supplying the meningeal arterial system;

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Table 30-8  Confirmatory Testing for a Determination of Brain Death Cerebral angiography The contrast medium should be injected under high pressure in both the anterior and posterior circulation. No intracerebral filling should be detected at the level of entry of the carotid or vertebral artery to the skull. The external carotid circulation should be patent. The filling of the superior longitudinal sinus may be delayed. Electroencephalography A minimum of eight scalp electrodes should be used. Interelectrode impedance should be between 100 and 10,000 W The integrity of the entire recording system should be tested. The distance between electrodes should be at least 10 cm. The sensitivity should be increased to at least 2 mV for 30 minutes with inclusion of appropriate calibrations. The high-frequency filter setting should not be set below 30 Hz, and the low-frequency setting should not be above 1 Hz. Electroencephalography should demonstrate a lack of reactivity to intense somatosensory or audiovisual stimuli. Transcranial Doppler ultrasonography There should be bilateral insonation. The probe should be placed at the temporal bone above the zygomatic arch or the vertebrobasilar arteries through the suboccipital transcranial window. The abnormalities should include a lack of diastolic or reverberating flow and documentation of small systolic peaks in early systole. A finding of a complete absence of flow may not be reliable owing to inadequate transtemporal windows for insonation. Cerebral scintigraphy (technetium Tc 99m hexametazime) The isotope should be injected within 30 minutes after its reconstitution. A static image of 500,000 counts should be obtained at several time points: immediately, between 30 and 60 minutes later, and at 2 hours. A correct intravenous injection may be confirmed with additional images of the liver demonstrating uptake (optional). From Wijdicks E: The diagnosis of brain death. N Engl J Med 2001;344: 1218, with permission.

internal carotid flow, however, is arrested at the petrous portion.109,110 Contrast is injected under high pressure in the carotid system, and the flow in the vertebral arteries typically is observed via an aortic arch injection. Contrast typically arrests at the atlanto-occipital junction. EEG determination of brain death typically employs a 16or 18-channel recording for at least 30 minutes. A minimum of eight channels is required. The interelectrode impedance should be between 100 and 10,000 ohms, and the distance between electrodes at least 10 cm. The sensitivity should be increased to at least 2 uV. The high-frequency filter setting should be set above 30 Hz, and the low-frequency setting below 1 Hz. There should be no response to auditory, visual, or tactile stimuli.111,112 Given the high sensitivity settings, artifacts are quite common, especially in the intensive care unit. There are multiple reports of EEG activity continuing in patients who otherwise clinically met brain death criteria.

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In patients with a cause of brain death that primarily affects the brainstem prior to affecting the cerebral hemispheres this is quite possible, and activity has been documented for several days.113 Overall, the sensitivity and specificity of EEG in the determination of brain death approximates 90%.114 Transcranial Doppler (TCD) sonography has more recently been validated as an ancillary test in brain death determination. Via the temporal bone above the zygomatic arch, the middle cerebral arteries (MCAs) are insonated. The typical pattern seen with brain death, given the high intracranial pressures and lack of sufficient intracranial flow, is oscillating flow with reversal of flow during diastole. Small peaks are seen during systole, consistent with high intracranial pressures. Further requirements were set forth by the task force group on cerebral death of the Neurosonology Research Group of the World Federation of Neurology in 1998.115 These include 1. Confirmation of cerebral circulatory arrest with extraand intracranial Doppler sonography, bilaterally, on two examinations 30 minutes apart. 2. Systolic spikes or oscillating flow in any cerebral artery (anterior or posterior). 3. Diagnosis established by intracranial examination must be confirmed by the extracranial bilateral recording of the common carotid, internal carotid, and vertebral arteries. 4. Disappearance of intracranial flow signals together with typical extracranial signs can be accepted as proof of circulatory arrest when no intracranial signal is found. 5. Exclusion of patients with ventricular drains or large craniotomy.

The sensitivity of TCD for determining brain death ranges from 91% to 99%, with a specificity of 100%.116,117 TCD has the added advantage of being portable, and many neurointensivists are familiar with its use. Single photon emission computed tomography (SPECT) has been a useful ancillary test in determining brain death. 99m Tc-HMPAO is injected 15 to 30 minutes before scanning. Again, there should be an absence of intracranial perfusion, seen as a lack of tracer uptake. Given the persistent extracranial circulation, there is flow to the meningeal and skull vessels, giving rise to such signs as the “hollow skull,” “empty light bulb,” and “hot nose” signs (Figs. 30-3A and B).118,119 SPECT studies are more cumbersome, and require patient transport. They also require a specialist trained in nuclear medicine for interpretation. Newer modalities used in the evaluation of brain death include magnetic resonance (MR) imaging (Fig. 30-4) and angiography (MRA; Fig. 30-5), and computed tomography angiography (CTA). Numerous reports have surfaced regarding the utility of MRI, with such findings as herniation, lack of intracranial flow, poor gray-white differentiation,120,121 and contrast enhancement of the nose (MRI “hot nose” sign).122 CTA uses a bolus intravenous injection of iodinated contrast, and can be used to track any arterial flow intracranially. Unlike in conventional cerebral angiography, contrast is obviously not injected under high pressure into the arterial system.123 Neither MRI nor CTA have been validated in a prospective study for brain death determination. Finally, evoked potentials have been studied extensively in brain death, but their value has been questioned based on their relatively poor predictive value.124

A

B Figure 30-3. Two studies on the same patient showing the lack of value of the "hot nose" sign and the significance of flow. A, Intact intracerebral flow. The flow is abnormal but is present above the tentorium. Sagittal sinus seen on static image. Although the patient has a "hot nose," he is not yet brain dead. B, A second study one day later. There is no flow and no sagittal sinus visualized. This patient is now brain dead.

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Figure 30-4. Sagittal projection, T1-weighted, MR sequence demonstrates features of advanced downward transtentorial herniation. The downward displacement of the hypothalamus, parahippocampal gyri, and even splenium of the corpus callosum result in obliteration of the incisural cisterns and compression of the rostral brainstem. Secondarily, there is also downward tonsillar herniation. Expected flow voids in the proximal extradural carotid and intradural basilar artery. However, there is no evidence of intradural carotid flow (double arrow) nor of filling of distal basilar branches beyond the basilar tip (single thin arrow). These changes indicate no significant afferent arterial circulation. There is abnormal, increased signal within the superior sagittal sinus (i.e., absence of the usual flow-void) indicating dural sinus thrombosis (solid large point arrow). This indicates lack of functional venous egress from the brain. Lack of both afferent and efferent circulation, plus advanced parenchymal cytogenic edema and advanced downward herniation represent MR features of virtually irreversible brain injury.

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guidelines in 1987.125 In particular, these guidelines called for a mandatory confirmatory ancillary test in patients under the age of one, as well as observation periods based on the patient’s age. The Task Force called for an observation period of 48 hours for patients aged seven days to two months, with a repetition of the clinical examination and an EEG. For patients aged two months to one year, the Task Force recommended clinical examinations and EEGs separated by 24 hours, unless an angiogram documented absence of intracerebral flow. For patients over one year of age, an observation period of 12 hours is recommended, but no ancillary testing is required. The exception to this is in cases of hypoxic-ischemic injury, in which a 24-hour observation period is recommended, unless there is a confirmatory EEG or angiogram. Although patients fewer than seven days of age with brain death were initially omitted from Task Force recommendations due to uncertainty regarding the examination, recommendations for this age group have been provided more recently, and an observation period of 48 hours is currently recommended to confirm the diagnosis.126 Anencephalic newborns pose a particular problem, given that brainstem function is often preserved. In the absence of brainstem function, including an apnea test, the diagnosis of brain death can be made, but an observation period of 24 to 48 hours is recommended. Walters and colleagues discussed the difficulty of performing a brain death evaluation in anencephalic infants.127

Brain Death Evaluation in Children Establishing brain death in the pediatric population poses special challenges, given that there are often underlying pathophysiologic differences in young children with open fontanelles, pediatric patients are often hypothermic following a traumatic brain injury, and multiple cranial nerve reflexes may not be fully developed, depending on the age of the patient (see Table 30-6). For these reasons, there are several distinct differences from the procedure performed in adults. As with adults, there must be a proximate cause of the patient’s neurologic state, and this must be irreversible. Again, there can be no confounding factors, such as hypothermia, intoxication with medications or poisons, recent use of paralytics, or hypotension. A Task Force for Determination of Brain Death in Children published their

Figure 30-5. Lateral projection MR angiography (MRA) demonstrates opacification of the main portion of the basilar artery (arrow), but nonopacification of any distal branches. Additionally, there is no opacification of the intradural portion of the internal carotid artery; only its extradural portion opacifies (double arrow). However, given the persistant opacification of the basilar artery proximally, this ancillary study is not supportive of brain death.

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Neurologic States Mimicking Brain Death The clinician must be acutely aware of certain conditions that can mimic brain death, remembering that the first rule of brain death determination is establishing the underlying cause, and assuring that it is irreversible. A neurologist or neurosurgeon should be involved in the determination of brain death. A study by Youngner and associates found a high rate of misdiagnosis among intensivists, anesthesiologists, ICU nurses, OR nurses, and medical students.128 As stated previously, hypothermia must be sought out, and a core temperature of at least 32° C is essential for performing the clinical exam. Such severe hypothermia can result from exposure to low ambient temperature, severe hypoglycemia, or severe hypothyroidism. Active rewarming with aggressive resuscitation efforts should be made, as a good cognitive outcome was reported in a patient who was resuscitated after nine hours with a temperature of 13.7° C.129 Poisoning or toxic levels of medications can also cause a clinical state of brain death (Table 30-9). A toxicology screen should be performed in patients who have an unknown cause of coma with suspected medication or poison ingestion. In patients who have recently been treated with barbiTable 30-9  Drugs That May Confound Neurologic Examination in Brain Death Drugs

Plasma t1/2 (h)

Therapeutic Range

Lorazepam Clonazepam Midazolam Flurazepam Diazepam Phenytoin Chlordiazepoxide Carbamazepine Valproic acid Phenobarbital Thiopental Pentobarbital Primidone Morphine Fentanyl Ketamine Amitriptyline Pancuronium* Vecuronium* Pipecuronium* Alcohol† Cocaine Codeine

10–20 20–30 2–5 70–100 40 ≥140 10–12 10–60 15–20 100 10 10 15–20 2–3 18–60 2–4 10–24 2–3 2–3 2–3 10 mL/h 1 3

0.1–0.3 mg/mL 10–50 ng/mL 50–150 ng/mL 100–500 ng/mL 0.2–0.8 mg/mL 10–20 mg/mL 1–3 mg/mL 2–10 mg/mL 40–100 mg/mL 20–40 mg/mL 6–35 mg/mL 1–5 mg/mL 9–12 mg/mL 70–450 ng/mL NA NA 75–200 ng/mL NA NA NA 800–1500 mg/L 150–300 ng/mL 200–350 ng/mL

NA, not available. *Peripheral nerve stimulation may be helpful. When all twitches in a train of four stimuli are present, it is unlikely that neuromuscular junction blockers are major confounders. † Plasma t 1/2 may easily change as a result of interacting drugs and organ failure. Use legal alcohol limit for determination of brain death. From Wijdicks E: Brain Death. Philadelphia, Lippincott Williams & Wilkins, 2001, p 121, with permission.

turates in an effort to control ICP, a barbiturate level should be checked as well. The typical level at which pentobarbital is not thought to alter the clinical examination is 5 μg/mL or lower. Severe metabolic disturbances, such as hypo- or hypernatremia, hypo- or hyperglycemia, hypothyroidism, and hypocortisolemia can cause a comatose state, but do not cause a complete loss of brainstem reflexes. Patients with a primary brainstem process, such as a basilar thrombosis or pontine hemorrhage, may have complete tetraplegia and loss of multiple brainstem reflexes. With the “locked-in syndrome,” there is often preservation of consciousness, with retained vertical eye movements and blinking ability.130,131 Obviously, with a careful clinical examination, these patients would not be considered for brain death evaluation. Two primary neuromuscular disorders can mimic brain death as well. Usually, the clinical presentation and history point to a progressive neurologic deterioration with neuromuscular failure, precluding a diagnosis of brain death. Guillain-Barré syndrome can mimic brain death, especially in the setting where the patient has received neuromuscular blocking agents.132 We recently observed a woman with documented amyotrophic lateral sclerosis (ALS), who, at the family’s insistence, progressed to such a profound late stage that she was completely dependent on full ventilatory support, with absent brainstem reflexes. This should be considered an extreme deafferented state, which is unusual in modern medical treatment of ALS. Other conditions, such as a persistent/permanent vegetative state or akinetic mutism, can be rapidly distinguished from brain death on the basis of preserved consciousness and intact brainstem reflexes, but in the study by Youngner and co-workers this was a common area of misconception.128 Special Considerations: Isolated Brainstem Death In patients with a primary brainstem process, such as an isolated brainstem hemorrhage, infarction, neoplastic process, or traumatic injury (e.g., gunshot wound), there may be complete loss of brainstem function with preservation of blood flow and electrical activity in the cerebral hemispheres. Based on clinical criteria, the patient is brain dead, with loss of brainstem reflexes and positive apnea test. However, there is considerable debate regarding the determination of brain death with known preserved cortical tissue, and ancillary tests, including angiography and electroencephalograpy, may well show preserved intracerebral flow and EEG activity, respectively. The United Kingdom has validated the concept of brainstem death to fulfill the official criteria for brain death, stating “if the brainstem is dead, the brain is dead, and if the brain is dead, the person is dead.”133–135 Ancillary tests are not required in the instance of brainstem death in the United Kingdom. In the United States, the concept of isolated brainstem death equating to brain death has not reached unanimity, and there is no

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formal position at present. The clinical diagnosis of brain death is based on the knowledge of an irreversible neurologic cause with absent brainstem activity, including apnea. No survivor has ever been reported with complete loss of brainstem function who otherwise met brain death criteria, but one could postulate that some specific neurologic causes, such as a primary brainstem hemorrhage, may warrant a longer period of observation.136 Ethical, Religious, and Legal Issues The concept of defining death of the individual with irreversible loss of all brain function has gained widespread acceptance over the past 30 years.137,138 Subsequently, in the United States, the President’s Commission for the Study of Ethical Problems in Medicine and Biomedical and Behavioral Research defined brain death as equating to death,139 and other countries soon followed.134,140 Korein expanded on the concept that when there is complete loss of brain functioning, the organism as an individual, coherent, functioning entity no longer exists.141 The death of the brain inevitably leads to the death of the whole individual; it is only with the advent of modern technology, intensive care technology in particular, that the issue of temporizing the death of other organs has surfaced. Indeed, human cells may be kept alive and multiply in culture for years, long after the person as an entity has ceased to exist. Without the brain, the organism can no longer function as a whole, and is thus no longer vital. Difficulties may arise when there is family resistance to the concept of brain death. Great care must be taken to carefully explain the difference between coma, which is of varied and sometimes reversible causes, and brain death, which is irreversible and final. Some advocate that it is prudent in these cases to continue treatment for one to two days, allowing the family sufficient time to adjust to the concept of brain death, although there is no legal obligation. James Bernat provides an eloquent discussion of these and other important ethical issues in brain death.142 At this time, most major Western religions are supportive of organ donation, but most do not have formal positions or teachings regarding brain death.143 The major religions of the United States (Christianity, Islam, and

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Judaism) are all accepting of the concept of brain death equating to death, with the notable exception of some of the Orthodox Jewish community, who feel that death can only occur with the cessation of the heart beat. In the state of New York, there is a specific set of regulations mandating that brain death determination be withheld when there are “religious or moral objections.”144 In practice, when there are conflicts regarding end-of-life care secondary to religious concerns, it is wise and helpful to include the clergy to facilitate discussions, and when possible include the personal clergy of the family. As previously stated, most religions are supportive in principle of organ donation in the setting of neurologic catastrophe, but there are notable exceptions. For example, Shinto is a Japanese folk religion, in which the dead body is considered impure and dangerous, and “injuring a dead body is a serious crime.”145,146 Gallagher and Wijdicks provide an excellent summary of different religious points of view on brain death and organ donation.147 Most of the legal problems surrounding brain death involve either an erroneous clinical determination or an unsophisticated interaction with the family of the brain dead patient. The legal basis for brain death in the United States is the Uniform Determination of Death Act, which stipulates that a person is dead if they have sustained either “(1) irreversible cessation of circulatory and respiratory functions, or (2) irreversible cessation of all functions of the entire brain, including the brainstem. . . . A determination of death must be made in accordance with accepted medical standards.”148 New Jersey has a notable addendum, which mandates that brain death criteria may not be applied if a physician has “reason to believe. . . . that such a declaration would violate the personal religious beliefs of the individual.”149 New York also recognizes potential religious influences, but is more ambiguous in their statutes, calling for “reasonable accommodation” in cases of religion-based objections.144 The key underlying legal issue is that brain death is an irreversible state, equal to death. It requires technical expertise in its determination, and compassion and understanding when informing families. For an indepth discussion of numerous legal cases and issues concerning brain death, please see J. Richard Beresford’s excellent discussion in Wijdicks’ Brain Death.150

P earls 1. The four pillars of ethical behavior in medicine are autonomy, beneficence, nonmaleficence, and justice. 2. The belief of JWs that prevents them from accepting transfused blood originates in scriptural passages suggesting that “life” or the “life force” resides in blood, and therefore must be treated respectfully. Whereas the biblical passage specifically forbids the

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eating of blood, the interpretation accepted generally by JWs also precludes the receipt of blood bank products, but, at the believer’s discretion, not the receipt of plasma protein factor clotting factors, or albumin. Also, intraoperative, preblood-loss hemodilution with a continuously flowing circuit may be deemed acceptable by the Witness. Continued

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3. Adults in the United States have a common-law right (i.e., nonstatutory and by virtue of court decisions) to refuse medical treatment, even if it is life sustaining. Adults also have a constitutionally based right to refuse lifesaving medical treatment; this right is grounded in the provisions of the first amendment to the U.S. Constitution. 4. If in our best opinion a child of JW parents is going to die without transfusion, we tell the parent that we will give blood. We do not get a court order. We do not leave the operating room and demand that the parents give their permission. We do what is, in our best estimation, optimal for the child, while trying aggressively to keep faith with the family’s wishes. 5. The ability to distinguish between disputes about facts and those about values is important to the physicianpatient relationship and may have significant impact on patient well-being. 6. Utilitarianism is a moral theory which holds that “there is one and only one basic principle in ethics, the principle of utility, which asserts that we ought always to produce the greatest possible balance of value over disvalue.” 7. The notion of rights, also called a deontologic ethic because it emphasizes the principle of duty over utility, is a nonconsequential approach to ethics. The notion of rights in ethics stresses that certain actions are wrong even if the consequences are beneficial. Thus, a theory of rights would stress justice over utility or assert limits on actions no matter how attractive, desirable, or beneficial. 8. In critical reflection, as the term is used in philosophy, an individual takes the time, and has the freedom, to analyze moral assumptions. In doing so, the thinker can speculate about moral decisions and experiment with moral reasoning. Healthcare workers are often called on to act in situations in which there are conflicts of values. By having considered such conflicting and conflictive issues ahead of time, whether they be related to JWs, withdrawal of therapy, physicianassisted suicide, or any other issue of our time, the physician can better prepare his/her moral intuitions for times of crisis. 9. Euthanasia is the delivery of an agent or agents to a patient by a physician so that the patient dies. Euthanasia is often parsed into passive and active, with active being further subdivided into voluntary and involuntary. Passive euthanasia is a shorthand term for withdrawal/withholding of therapy. 10. Active euthanasia is a process by which the patient’s death is the desired result of an administration of drugs. 11. Physician-Assisted Suicide (PAS) is a version of voluntary, active euthanasia requiring the assistance of a physician to prescribe medications that the patient may take at a time he or she determines is appropriate. The central issue with PAS is to give terminally ill patients control over the timing, if not the manner, of their deaths.

12. Up to 38% of hospitalized patients with DNR orders on their charts do not suffer cardiorespiratory arrest and are discharged from the hospital. 13. The problems surrounding communication about DNR orders can become even more complex if, once a DNR order is established, the patient could benefit from anesthesia and surgery. 14. With the advent of mechanical ventilators to ensure adequate ventilation in patients with a complete absence of respiratory drive or capacity, many patients who otherwise would have succumbed to terminal neurologic disorders can be sustained temporarily with careful attention to cardiovascular and endocrine dysfunction that subsequently arise. 15. The most common causes of brain death in adults are traumatic brain injury, hypoxic/anoxic brain injury, and subarachnoid hemorrhage. In children, the most common causes are abuse, motor vehicle accidents, and asphyxia. 16. The earliest portions of the brain to undergo liquefactive necrosis are the upper brainstem, diencephalon, and cerebellum, followed by the cerebral hemispheres. The medulla may be involved to a lesser degree, accounting for the frequently preserved cardiovascular homeostasis. 17. The key features of the clinical brain death evaluation involve establishing that the patient is in a comatose state, and performing a thorough evaluation of the cranial nerves and other brainstem functions. By definition, patients should have no response, including eye opening or motor response, to noxious stimuli. Noxious stimuli include a loud voice, vigorous shaking (provided the concomitant injuries, specifically to the cervical spine, do not preclude shaking the patient), and pain, as elicited by pressing on the supraorbital nerve, the nail bed, or at the temporomandibular joint. 18. Facial myokymias may be a result of denervation of the facial muscles, and are permissible. These are spontaneous movements, and should not appear in response to noxious stimuli. The facial musculature should also be observed for grimacing while stimulating other parts of the body. 19. Deep tendon reflexes are spinally mediated, and thus allowable, as are a Babinski response and triple flexion response in the lower extremity. A number of other spinally mediated movements have also been reported in patients with brain death confirmed by ancillary testing, such as an isoelectric EEG or an angiogram with absence of intracranial flow. These include the so-called “Lazarus signs”: slight spontaneous abduction or adduction of an extremity, raising of the torso to a 40° to 60° angle, head turning to one side, arm raising, and back arching. In some patients this may be seen in synchrony with ventilator-delivered breaths. 20. The apnea test evaluates for medullary function, which is the final brainstem structure to be affected in the rostral-to-caudal progression of herniation. The

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purpose of this test is to demonstrate the absence of respiratory efforts despite the potent stimuli of acidosis and hypercapnea. 21. Single photon emission computed tomography (SPECT) has been a useful ancillary test in determining brain death. 99mTc-HMPAO is injected 15 to 30 minutes before scanning. Again, there should be an absence of intracranial perfusion, seen as a lack of tracer uptake. Given the persistent extracranial circulation, there is flow to the meningeal and skull vessels, giving rise to such signs as the “hollow skull,” “empty light bulb” and “hot nose” signs. SPECT studies are more cumbersome, and require patient transport. They also require a specialist trained in nuclear medicine for interpretation. 22. Establishing brain death in the pediatric population poses special challenges, given that there are often

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underlying pathophysiologic differences in young children with open fontanelles, in pediatric patients who are often hypothermic following a traumatic brain injury, and that multiple cranial nerve reflexes may not be fully developed, depending on the age of the patient. For these reasons, there are several distinct differences from the procedure performed on adults. 23. The death of the brain inevitably leads to death of the whole individual; it is only with the advent of modern technology, intensive care technology in particular, that the issue of temporizing the death of other organs has surfaced. Indeed, human cells may be kept alive and multiply in culture for years, long after the person as an entity has passed. Without the brain, the organism can no longer function as a whole, and is thus no longer vital.

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44. Miles SH, Singer PA, Siegler M: Conflicts between patient’s wishes to forgo treatment and policies of health care facilities. N Engl J Med 1989;321:48. 45. In the Matter of Conroy, 464 A2d 303 (NJ Supr Ct 1985). 46. Emanuel EJ: The history of euthanasia debates in the United States and Britain. Ann Intern Med 1994;121:793–802. 47. Prendergast TJ: Withholding or withdrawal of life-sustaining therapy. Hosp Pract 2000;91–102. 48. Gillon R: The principle of double effect and medical ethics. BMJ 1986;292:193–194. 49. van der Heide A, van der Maas PJ, van der Wal G, Kollee LAA, de Leeuw R: Using potentially life-shortening drugs in neonates and infants. Crit Care Med 2000;28:2595–2599. 50. Onwuteaka-Philipsen BD, van der Wal G, Kostense PJ, van der Maas PJ: Consultation with another physician on euthanasia and assisted suicide in the Netherlands. Soc Sci Med 2000;51:429–438. 51. Cuttini M, Nadai M, Kaminski M, et al: End-of-life decisions in neonatal intensive care—Physicians’ self-reported practices in seven European countries. Lancet 2000;355:2112–2118. 52. Burns JP, Mitchell C, Outwater KM, et al: End-of-life care in the pediatric intensive care unit after the forgoing of life-sustaining treatment. Crit Care Med 2000;28:3060–3066. 53. Goldstein B, Merkens M: End-of-life in the pediatric intensive care unit—Seeking the family’s decision of when and how, not if. Crit Care Med 2000;28:3122–3123. 54. Schmitz ML, Taylor BJ, Anand KJS: End-of-life decisions in the neonatal intensive care unit—Medical infanticide or palliative terminal care? Crit Care Med 2000;28:2668–2671. 55. Biedermann CL, Layon AJ, D’Amico R: Ethics in the intensive care unit. Anesth Clinics North Am 1991;9:423. 56. Kevorkian Jack: Prescription—Medicide. Buffalo, NY: Prometheus Books, 1991. 57. Willems DL, Daniels ER, van der Wal G, van der Maas PJ, Emanuel EJ: Attitudes and practices concerning the end of life—A comparison between physicians from the United States and from the Netherlands. Arch Intern Med 2000;160:63–68. 58. Sullivan AD, Hedberg K, Fleming DW: Legalized physician-assisted suicide in Oregon—The second year. N Engl J Med 2000;342:598– 604. 59. Groenewoud JH, van der Heide A, Onwuteaka-Philipsen BD, et al: Clinical problems with the performance of euthanasia and physicianassisted suicide in the Netherlands. N Engl J Med 2000;342:551– 556. 60. Nuland SB: Physician-assisted suicide and euthanasia in practice. N Engl J Med 2000;342:583–584. 61 Sobel RM, Layon AJ: Physician-assisted suicide—Compassionate care or brave new world? Arch Intern Med 1997;157:1638–1640. 62. Burt RA: The supreme court speaks—Not assisted suicide but a constitutional right to palliative care. N Engl J Med 1997;337:1234– 1236. 63. Washington v. Glucksberg, 117 S.Ct. 2258 (1997), and Vacco v. Quill, 117 S.Ct. 2293 (1997), cited in Burt RA: The supreme court speaks— Not assisted suicide but a constitutional right to palliative care. N Engl J Med 1997;337:1234–1236. 64. Orentlicher D: The supreme court and physician-assisted suicide— Rejecting assisted suicide but embracing euthanasia. N Engl J Med 1997;337:1236–1239. 65. Snyder L, Sulmasy DP: Physician-assisted suicide (Position paper of the ACP-ASIM). Ann Intern Med 2001;135:209–216. 66. Sprung CL, Winick BJ: Informed consent in theory and practice— Legal and medical perspectives on the informed consent doctrine and a proposed reconceptualization. Crit Care Med 1989;17:1346– 1354. 67. Rozenbaum EA, Shenkman L: Predicting outcome of in-hospital cardiopulmonary resuscitation. Crit Care Med 1988;16:583–586.

68. Blackhall LJ: Must we always use CPR? N Engl J Med 1987;317:1281– 1285. 69. Kouwenhoven WB, Jude JR, Knickerbocker GG: Closed-chest cardiac massage. JAMA 1960;173:1064–1067. 70. Jude JR, Kouwenhoven WB, Knickerbocker GG: Cardiac arrest— Report of application of external cardiac massage on 118 patients. JAMA 1961;178:1063–1070. 71. Murphy DJ, Murray AM, Robinson BE, Campion EW: Outcomes of cardiopulmonary resuscitation in the elderly. Ann Intern Med 1989;111:199–205. 72. Bedell SE, Pelle D, Maher PL, Cleary PD: Do-not-resuscitate orders for critically ill patients in the hospital—How are they used and what is their impact? JAMA 1986;256:233–237. 73. Stern SG, Orlowski JP: DNR or CPR—The choice is ours. Crit Care Med 1992;20:1263–1272. 74. Sachs GA, Miles SH, Levin RA: Limiting resuscitation—Emerging policy in the emergency medical system. Ann Intern Med 1991;114:151–154. 75. Schafer A: Implementing a DNR policy—Promise and perils (Editorial). Can J Anaesth 1991;38:549–550. 76. Everhart MA, Pearlman RA: Stability of patient preferences regarding life-sustaining treatments. Chest 1990;97:159–164. 77. Tomlinson T, Brody H: Ethics and communication in do-notresuscitate orders. N Engl J Med 1988;318:43–46. 78. Youngner SJ: Do-not-resuscitate orders—No longer secret but still a problem. Hastings Center Report 1987;17:24–33. 79. Wolf SM: “Near death”—In the moment of decision. N Engl J Med 1990;322:208–209. 80. Peters PG: The state’s interest in the preservation of life—From Quinlan to Cruzan. Ohio St Law J 1989;50:891–910. 81. Pellegrino ED: Compassion needs reason too. JAMA 1993;270:874– 875. 82. Caine ED: Self-determined death, the physician, and medical priorities. Is there time to talk? JAMA 1993;270:875–876. 83. Lee DKP, Swinburne AJ, Fedullo AJ, Wahl GW: Withdrawing care— Experience in a medical intensive care unit. JAMA 1994;271:1358– 1361. 84. O’Meara JJ, McNutt RA, Evans AT, Moore SW, Downs SM: A decision analysis of streptokinase plus heparin as compared with heparin alone for deep-vein thrombosis. N Engl J Med 1994;330:1864–1869. 85. Keffer MJ, Keffer HL: Do-not-resuscitate in the operating room— Moral obligations of anesthesiologists. Anesth Analg 1992;74:901–905. 86. Franklin CM, Rothenberg DM: Do-not-resuscitate orders in the presurgical patient. J Clin Anesth 1992;4:181–184. 87. Cohen CB, Cohen PJ: Do-not-resuscitate orders in the operating room. N Engl J Med 1991;325:1879–1882. 88. Walker RM: DNR in the OR—Resuscitation as an operative risk. JAMA 1991;266:2407–2412. 89. Truog RD: “Do-not-resuscitate” orders during anesthesia and surgery. Anesthesiology 1991;74:606–608. 90. Reeder JM: Do-not-resuscitate orders in the operating room. AORNJ 1993;57:947–951. 91. Quill TE: Doctor, I want to die. Will you help me? JAMA 1993;270: 870–873. 92. Bellet PS, Maloney MJ: The importance of empathy as an interviewing skill in medicine, commentary. JAMA 1991;266:1831– 1832. 93. Martin RL, Soifer BE, Stevens WC: Ethical issues in anesthesia— Management of the do-not-resuscitate patient. Anesth Analg l991;73: 221–225. 94. Bedell SE, Delbanco TL: Choices about cardiopulmonary resuscitation in the hospital—When do physicians talk to patients? N Engl J Med 1984;310:1089–1093. 95. Mollaret P, Goulon M: Le coma dépassé (mémoire préliminaire). Rev Neurol 1959;101:3–5.

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Chapter 30  96. Diagnosis of brain death: Statement issued by the honorary secretary of the Conference of Medical Royal Colleges and their Faculties in the United Kingdom on 11 October 1976. BMJ 1976;2: 1187–1888. 97. Wijdicks EF: Determining brain death in adults. Neurology 1995;45: 1003–1111. 98. Ashwal S, Schneider S: Brain death in children. Pediatr Neurol 1987;3:5–11, 69–77. 99. Denny-Brown D, Russell WR: Experimental cerebral concussion. Brain 1941;64:93–164. 100. Walker AE, Kollros JJ, Case TJ: Physiological basis of concussion. J Neurosurg 1944;1:103–116. 101. Graham DI: Hypoxia and vascular disorders. In Adams JH, Duchen LW (eds): Greenfield’s Neuropathology, 5th ed. New York, Oxford University Press, 1992, pp 154–268. 102. Wijdicks EFM: Temporomandibular joint compression in coma. Neurology 1996;45:1003–1011. 103. Sims JK, Bickford RG: Non-mydriatic pupils occurring in human brain death. Bull LA Neurol Soc 1973;38:24–32. 104. Snavely SR, Hodges GR: The neurotoxicity of antibacterial agents. Ann Intern Med 1984;101:92–104. 105. Christie JM, O’Lenic TD, Cane RD: Head turning in brain death. J Clin Anesth 1996;8:141–143. 106. Marti-Fàbregas J, López-Navidad A, Caballero F, et al: Decerebrate-like posturing with mechanical ventilation in brain death. Neurology 2000;54:224–227. 107. Goudreau JL, Wijdicks EFM, Emery SF: Complications during apnea testing in the determination of brain death: Predisposing factors. Neurology 2000;55:1045–1048. 108. The Quality Standards Subcommittee of the American Academy of Neurology: Practice parameters for determining brain death in adults (summary statement). Neurology 1995;45:1012–1014. 109. Cantu RC: Brain death as determined by cerebral angiography. Lancet 1973;1:1391–1392. 110. Kricheff II, Pinto RS, George AE, et al: Angiographic findings in brain death. Ann NY Acad Sci 1978;315:168–183. 111. Jorgensen EO: Technical contribution. Requirements for recording the EEG at high sensitivity in suspected brain death. Electroencephalogr Clin Neurophysiol 1974;36:65–69. 112. American Electroencephalographic Society. Guideline three: Minimal technical standards for EEG recording in suspected cerebral death. J Clin Neurophysiol 1994;11:10–13. 113. Grigg MM, Kelly MA, Celesia GG, et al: Electroencephalographic activity after brain death. Arch Neurol 1987;44:948–954. 114. Buchner H, Schuchardt V: Reliability of electroencephalogram in the diagnosis of brain death. Eur Neurol 1990;30:138–141. 115. DuCrocq X, Braun M, Debouverie M, et al: Consensus opinion on diagnosis of cerebral circulatory arrest using Doppler-sonography: Task Force Group on Cerebral Death of the Neurosonology Research Group of the World Federation of Neurology. J Neurol Sci 1998;159: 145–150. 116. Report of the American Academy of Neurology, Therapeutics and Technology Assessment Subcommittee: Assessment: Transcranial Doppler. Neurology 1990;40:680–681. 117. Hadani M, Bruk B, Ram Z, et al: Application of transcranial Doppler ultrasonography for the diagnosis of brain death. Intensive Care Med 1999;25:822–828. 118. Facco E, Zucchetta P, Munari M, et al: 99mTc-HMPAO SPECT in the diagnosis of brain death. Intensive Care Med 1998;24:911– 917. 119. Mishkin FS, Dyken ML: Increased early radionuclide activity in the nasopharyngeal area in patients with internal carotid artery obstruction: “Hot nose.” Radiology 1970;96:77–80. 120. Ishii K, Onuma T, Kinoshita T, et al: Brain death: MR and MR angiography. Am J Neuroradiol 1996;17:731–735.

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121. Matsumura A, Mequero K, Tsurushima H, et al: Magnetic resonance imaging of brain death. Neurol Med Clin Chir 1996; 6:166–171. 122. Orrison WW Jr, Champlin AM, Kesterson OL, et al: MR “hot nose sign” and “intravascular enhancement sign” in brain death. Am J Neuroradiol 1994;15:913–916. 123. Dupas B, Gayet-Delacroix M, Villers D, et al: Diagnosis of brain death using two-phase spiral CT. Am J Neuroradiol 1998;19:641–647. 124. Machado C, Valdés P, Garcia-Tigera J, et al: Brain-stem auditory evoked potentials in brain death. Electroencephalogr Clin Neurophysiol 1991;80:392–398. 125. Guidelines for the determination of brain death in children. Pediatrics 1987;80:298–300. 126. Ashwal S: Brain death in the newborn. Current perspectives. Clin Perinatol 1997;24:859–882. 127. Walters J, Ashwal S, Masek T: Anencephaly: Where do we now stand? Semin Neurol 1997;17:249–255. 128. Youngner SJ, Landefeld CS, Coulton CJ, et al: “Brain death” and organ retrieval. A cross sectional survey of knowledge and concepts among health professionals. JAMA 1989;261:2205–2210. 129. Gilbert M, Busund R, Skagseth A, et al: Resuscitation from accidental hypothermia of 13.7 degrees C with circulatory arrest. Lancet 2000;355:375-376. 130. Patterson JR, Grabois M: Locked-in syndrome: A review of 139 cases. Stroke 1986;17:758–764. 131. Dollfus P, Milos PL, Chapuis A, et al: The locked-in syndrome: A review and presentation of two chronic cases. Paraplegia 1990;28: 5–16. 132. Vargas F, Hilbert G, Gruson D, et al: Fulminant Guillain-Barré syndrome mimicking cerebral death: Case report and review of the literature. Intensive Care Med 2000;26:623–627. 133. Pallis C: ABCs of brain death. From brain death to brainstem death. BMJ 1982;285:1487–1490. 134. Criteria for the diagnosis of brainstem death: Review by a working group convened by the Royal College of Physicians and endorsed by the Conference of Medical Royal Colleges and Their Faculties in the United Kingdom. J R Coll Phys Lond 1995;29:381– 382. 135. Pallis C, Harley DH: The ABCs of Brainstem Death, 2nd ed. London, British Medical Journal Publishing Group, 1996. 136. Becker KJ, Baxter AB, Cohen WA, et al: Withdrawal of support in intracerebral hemorrhage may lead to self-fulfilling prophesies. Neurology 2001;56:766–772. 137. A definition of irreversible coma: Report of the Ad Hoc Committee of the Harvard Medical School to Examine the Definition of Brain Death. JAMA 1968;205:337–340. 138. Pernick MS: Brain death in a cultural context: The reconstruction of death 1967–1981. In Youngner SJ, Arnold RM, Schapiro R (eds): The Definition of Death: Contemporary Controversies. Baltimore, Johns Hopkins University Press, 1999, pp 3–33. 139. Guidelines for the determination of death: Report of the Medical Consultants on the Diagnosis of Death to the President’s Commission for the Study of Ethical Problems in Medicine and Biomedical and Behavioral Research. Neurology 1982;32:395–399. 140. Canadian Neurocritical Care Group: Guidelines for the diagnosis of brain death. Can J Neurol Sci 1999;26:64–66. 141. Korein, J: The problem of brain death: Development and history. Ann NY Acad Sci 1978;315:19–38. 142. Bernat JL: Philosophical and ethical aspects of brain death. In Wijdicks EFM (ed): Brain Death. Philadelphia. Lippincott Williams & Wilkins, 2001, pp 171–187. 143. De Long WR: Organ Transplantation in Religious, Ethical and Social Context—No Room for Death. New York, Haworth Pastoral Press, 1993. 144. NY COMP CODES, RULES 7 REGS, Title 10, sec 400.16(d),(e)(3) (1992)

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145. Hardacre H: Response of Buddhism and Shinto to the issue of brain death and organ transplant. Camb Q Healthcare Ethics 1994;3:585– 601. 146. Namihira E: Shinto concept concerning the dead human body. Transplant Proc 1990;22:940–941. 147. Gallagher CM, Wijdicks EFM: Religious and cultural aspects of brain death. In Wijdicks EFM (ed): Brain Death. Philadelphia, Lippincott, Williams & Wilkins, 2001, pp 135–149.

148. Uniform Determination of Death Act, 12 Uniform Laws Annotated 589 (West 1993 and West Suppl 1997). 149. NJ STAT ANN 26-6A-5 (1987, suppl 1994). 150. Beresford HR: Legal aspects of brain death. In Wijdicks EFM (ed): Brain Death. Philadelphia, Lippincott, Williams & Wilkins, 2001, pp 151–169.

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Chapter 31 Novel Strategies for Neuroprotection against Acute Brain Injury Shao-Hua Yang, MD, Jian Wang, PhD, and James W. Simpkins PhD

Introduction There are more than 750,000 new strokes per year in the United States alone and the prospect of debilitating outcomes from stroke are great. Unfortunately, there are few available options for the treatment of stroke-related brain damage. Currently, only clot dissolving drugs are available for treatment of an ongoing stroke. These compounds have proven to be of limited benefit for a variety of reasons, among which are their innate toxicity and the need for their administration within a limited time after the onset of a nonbleeding stroke. A variety of novel strategies are under investigation to protect brain tissue during a stroke. The rapid explosion of our knowledge of the mechanisms by which neurons die has led to investigations into interventions to preserve structure and function of neurons during ischemic and traumatic events. Additionally, recent discoveries indicate that brain structure and function are plastic. Neurons can respond to traumatic damage through growth and replacement of lost axons and dendrites as well as through the replacement of neurons with re-initiation of cell division. Indeed, it now appears that in several areas of the brain, production of new neurons through cell division is a process that occurs throughout life. This chapter considers in detail the mechanisms by which neurons die during ischemic trauma, how they respond in an attempt to survive the insult, and how we can use this knowledge to target treatment to enhance their ability to survive acute trauma. We focus on ischemic brain damage because much more is known about mechanisms during

ischemia than with other brain insults. Finally, we will demonstrate that the knowledge obtained from a variety of approaches can be applied to the development of new drugs for the protection of brain tissue from injury. We begin with a detailed consideration of types of neuronal cell death during ischemia, followed by a description of the mechanisms of neurons cell death derived largely from in vitro models using molecular biologic techniques, and then consider the mechanisms of brain damage from cerebral ischemia discovered using animal models. Finally, we consider interventions that have resulted from this new knowledge and assess their potential role as therapies for neuroprotection during traumatic brain damage.

Types of Neuronal Cell Death Under ischemic conditions, brain cells die mainly from a lack of oxygen and glucose supply. The outcome of an ischemic insult is different in the ischemic core and in the penumbra. It is widely accepted that cells in the ischemic core usually die with typical signs of necrosis,1–3 in which cells and their organelles swell and rupture in an uncontrolled manner, and the cellular contents are released, causing an inflammatory response in the surrounding tissue. Necrosis is primarily the result of massive cellular influx of calcium and other ions from activation of voltage-dependent and ligand-dependent ion channels that trigger permanent opening of the mitochondrial transition pore, resulting in production of reactive oxygen species (ROS), uncoupling of mitochondrial respiration, and the termination of active transport processes.4 849

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Calcium overload also can overactivate degradative enzyme activities, including phospholipase, protease, and endonuclease activities, which ultimately cause widespread destruction of membranes and macromolecules, resulting in relatively rapid necrosis. Apoptosis, also called programmed cell death, is the type of cell death in the penumbra. Cells dying from apoptosis share many morphologic features that are distinct from the features observed in cells undergoing pathologic, necrotic cell death. These shared morphologic features might be a result of common conserved, specialized cellular machinery.5 Typical hallmarks of apoptosis have been identified, including cell shrinkage, membrane blebbing, chromatin condensation, deoxyribonucleic acid (DNA) fragmentation, and protein degradation. Depending on the type and strength of the insult and the type of the affected tissue, not all classical hallmarks of necrosis or apoptosis are displayed in a given cell. Furthermore, apoptosis and necrosis might represent the two opposing ends of a spectrum of intermediate forms of cell death.6

In Vitro Mechanisms for Neuronal Death and Survival Mitochondria Mitochondria appear to play a central role in neuronal cell death decisions (Fig. 31-1). Consequences of mitochondrial injury after cerebral ischemia and reperfusion include collapse of the mitochondrial transmembrane potential, uncoupling of the respiratory chain, increased production of ROS, disruption of mitochondrial biogenesis, outflow of glutathione, exacerbation of excitotoxicity through impaired intracellular calcium buffering, and releasing of proapoptotic factors such as cytochrome c, Apaf-1, and procaspases-9. These events lead to the disruption of plasma membrane integrity (necrosis) or the activation of apoptogenic proteases with secondary endonuclease activation and consequent oligonucleosomal DNA fragmentation (apoptosis). Calcium It is widely believed that disturbances of calcium homeostasis play a central role in the pathologic process culminating in neuronal injury induced by ischemia/reperfusion.7–10 Neuronal cell injury has been found to be associated with both increases and decreases of cytoplasmic calcium activity, mitochondrial calcium overload, and depleted endoplasmic reticulum calcium stores.11 The traditional calcium hypothesis is based on the observation that ischemia induces a massive rise in neuronal cytoplasmic calcium due to an influx of calcium ions through voltage-gated and ligand-activated calcium channels and release of calcium from intracellular stores such as the

Figure 31-1. Mitochondria play a central role in cell death signaling. (From Green DR, Reed JC: Mitochondria and apoptosis. Science 1998;281:1309–1312, with permission.)

endoplasmic reticulum and mitochondria.12 However, therapeutic interventions designed to suppress the ischemiainduced rise in cytoplasmic calcium activity failed to produce a clear neuroprotective effect unless these drugs had a vasoactive component.11 A calcium set-point hypothesis has been proposed: high intracellular calcium levels promote cell death through necrosis, whereas low intracellular calcium levels promote cell death through apoptosis, and modestly raising Ca2- may inhibit apoptosis13 (Fig. 31-2). One possible mechanism underlying neuronal cell injury induced by low intracellular calcium activity is a depleted endoplasmic reticulum calcium store under this circumstance. Intracellular calcium mobilization is based on the interplay between three calcium stores in the cell: the endoplasmic reticulum, mitochondria, and cytosolic proteins. The majority (about 80%) of calcium influxed from extracellular space or released from the endoplasmic reticulum during reperfusion is very quickly sequestered by mitochondria. Thereafter, a much slower release of calcium from the mitochondria serves as the calcium supply for the intermediate

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Figure 31-2. Relationship between cellular calcium concentrations and necrotic versus apoptotic cell death. (From Yu SP, Canzoniero LM, Choi DW: Ion homeostasis and apoptosis. Curr Opin Cell Biol 2001;13:405–411, with permission.)

calcium exchanges between the endoplasmic reticulum and the cytosolic proteins.14 During reperfusion, there is a massive influx of calcium ions into mitochondria leading to mitochondrial calcium overload.8 Mitochondrial calcium overload may cause an increase in the production of free radicals, and together with oxidative stress, it may further induce disturbances of oxidative phosphorylation and the permeability transition after several hours of reperfusion. The openings of the mitochondrial permeability transition pore (PTP) cause the release of large quantities of matrix calcium and activate the release of cytochrome c and other proapoptotic factors from the mitochondria matrix into the cytosol.15 The endoplasmic reticulum is a subcellular calcium storage compartment and plays a pivotal role in the folding, processing and excretion of membrane and secretory proteins.16–18 Endoplasmic reticulum calcium homeostasis is controlled by the IP3- and the ryanodine receptors which, upon stimulation, release calcium from the endoplasmic reticulum, and a calcium pump (sarcoplasmic/endoplasmic reticulum Ca2+ ATPase) that pumps calcium ions back into the endoplasmic reticulum against a steep concentration gradient. Endoplasmic reticulum calcium stores are depleted and endoplasmic reticulum function is disturbed after transient ischemia. Depletion of endoplasmic reticulum calcium stores blocks the folding and processing of membrane proteins.19,20 Two downstream responses are triggered: an activation of the expression of genes coding for transcription factors and endoplasmic reticulum-resident stress proteins, and an activation of kinases that specifically phosphorylate the eukaryotic initiation factor resulting in the suppression of global protein synthesis.21 It has been proposed that the antiapopotic protein, Bcl2, could act on Ca2+ signaling by affecting ion fluxes across the organelle membranes.14 Bcl-2 protein alters Ca2+ handling in the cytosol, in the mitochondrial matrix and in the lumen of the endoplasmic reticulum and the Golgi

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apparatus.22–24 On stress stimulation, the amount of Ca2+ released from the endoplasmic reticulum (and that accumulated in the mitochondria) is significantly reduced, a process regulated by Bcl-2. Also, the mitochondrial Ca2+ response is reduced, caused by a global reduction of the cellular Ca2+ signal rather than an intrinsic limitation of the capacity of mitochondria to accumulate Ca2+.25 The alteration in Ca2+ signaling in the mitochondria is related to cell survival inasmuch as Ca2+ overload has been proposed to be a major apoptotic signal.26 Ischemic and postischemic mitochondrial alterations may significantly influence intracellular Ca2+ homeostasis. Mitochondrial Ca2+ uptake occurs when the cytosolic Ca2+ concentration rises above the mitochondrial “set point.”27 Rapid uptake of Ca2+ by mitochondria into the matrix from a wide range of sources is mediated by a uniporter that permits transport of the ion down its electrochemical gradient, DY. Calcium efflux may be mediated by Ca2+/2H+ antiporter and the Na+/H+ antiporter; the latter is driven by DpH.28 Under physiologic stimuli, relatively low levels of mitochondrial Ca2+ sequestration stimulate matrix Ca2+-sensitive dehydrogenase activity to enhance adenosine triphosphate (ATP) synthesis to meet the increased cellular energy demand.29 Mitochondrial Ca2+ sequestration also occurs during reperfusion. Higher levels of Ca2+ sequestration may promote Ca2+ release, which may play an important role in the propagation of Ca2+ signals.30 Above a certain level, Ca2+ sequestration can begin to compromise mitochondrial function, resulting in respiratory inhibition, uncoupling of oxidative phosphorylation, formation of nonspecific pores, free radical production, injury to the inner mitochondrial membrane, cytochrome c release, and osmotic lysis.31 Thus, mitochondrial Ca2+ loading is a critical event in the determination of neuronal viability after ischemia. Therapeutic strategies designed to block disturbances of calcium homeostasis induced by ischemia should be selected according to the subcellular compartment targeted. Mitochondria need to be protected from the stress induced by high calcium levels while the endoplasmic reticulum needs to be protected from depletion of calcium stores. Because both high and low cytoplasmic calcium levels can lead to neuronal cell death, drugs designed to suppress neuronal cell injury by blocking voltage-gated calcium channels may be toxic because a decrease of cytoplasmic calcium may be sufficient to cause neuronal apoptosis.11 Mitochondrial Permeability Transition The mitochondrial permeability transition is a phenomenon first characterized by Hunter and Haworth.32 Ca2+, Pi, and ROS induce onset of the mitochondrial permeability transition, whereas Mg2+, adenosine diphosphate (ADP), low pH, and high membrane potential oppose the onset. The consequence of this event is an increased permeability of the inner membrane to small molecular weight solutes (less than 1500

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Daltons). This rapid change of permeability causes membrane depolarization, uncoupling of oxidative phosphorylation, release of intramitochondrial ions, loss of metabolic intermediates, and large amplitude mitochondrial swelling. The recovery of extracellular pH from acidotic to physiologic pH during reperfusion can actually precipitate lethal cell injury and pH-dependent onset of the mitochondrial permeability transition may contribute to pH-dependent reperfusion injury.33 Release of Caspase-Activating Proteins Mitochondria sequester a potent cocktail of pro-apoptotic proteins.34 Most prominent among these is cytochrome c, an electron carrier involved in mitochondrial oxidative phosphorylation. It is also one of the components (in addition to the adaptor protein Apaf-1) required for activation of caspase-9 in the cytosol.35 The release of the caspase-activating protein, cytochrome c, through mitochondrial PTP results in rapid loss of membrane potential and organellar swelling, thus committing the cell to die.36 The mitochondrial PTP is composed of both inner membrane proteins, such as the adenine nucleotide translocator (ANT), and outer membrane proteins, such as porin (voltage-dependent anion channel; VDAC), which form a channel though which solutes with a molecular weight of 1.5 kD or less pass.37 Opening of this channel is followed by equilibration of ions and of solutes within the matrix and intermembrane space of mitochondria, thus collapsing the H+ gradient across the inner membrane and uncoupling the respiratory chain.38 PTP opening results in entry of water and solutes into the matrix, causes the matrix space to expand, which can eventually cause outer membrane rupture, and releases caspase-activating proteins located within the intermembrane space into the cytosol.36 Bcl-2 family is involved in the regulation of mitochondrial activity. Many Bcl-2 family proteins reside in the outer mitochondrial membrane and form channels or large holes by changing conformation.39 It has been shown that Bcl-2 and Bcl-xL increase mitochondrial Ca2+ buffering capacity and suppress release of sequestered matrix Ca2+ induced by respiration uncouplers.40 Pro-apoptotic family members interact with other mitochondrial outer membrane proteins to form a large pore channel. Several Bcl-2 family members can bind to VDAC and regulate its activity.41 Other apoptosis mediators, such as AIF, Smac/DIABLO, and several procaspases, including procaspase-2, -3, -9, are also present in mitochondria and are released upon induction of apoptosis.39 Reactive Oxygen Species and Cellular Redox State Reactive oxygen species (ROS) include hydroxyl radicals, superoxide anion, hydrogen peroxide and nitric oxide. The majority of intracellular ROS production is derived from the mitochondria and mitochondria are a primary source of

ROS in ischemia/reperfusion injury.42,43 Excessive Ca2+ accumulation can potentiate neuronal mitochondrial superoxide production.44 Mitochondrial lipids are subject to oxidative modifications during cerebral ischemia/reperfusion and certain mitochondrial proteins may be subject to oxidative injury.45–47 Evidence has accumulated, showing that ROS are involved in brain injury after ischemic stroke.48 During ischemia-reoxygenation, cells are under oxidative stress. Mitochondria produce superoxide, which in turn is converted to hydrogen peroxide and the potent reactive species, hydroxyl radical. Alternatively, mitochondrial superoxide may react with nitric oxide to form a potent oxidant, peroxynitrite, and as a consequence, mitochondrial function is altered. On the other hand, an increase in the release of calcium from mitochondria induced by ROS stimulates calcium-dependent enzymes such as calcium-dependent proteases, nucleases, and phospholipases, which subsequently trigger apoptosis of the cells.49 A rise in intracellular ROS levels has two potentially important effects: (1) damage to various cell components by oxidizing nucleic acids, proteins, and membrane lipids and (2) triggering of the activation of specific signaling pathways. The major aspects of cellular and molecular responses include alterations in the gene expression of antioxidant enzymes, stress-response genes, and cytokines. The regulatory mechanisms that control this genetic response are complex, involving stimulation of signal transduction components such as Ca2+-signaling and protein phosphorylation, and activation of transcription factors.50,51 Oxidants such as superoxide, hydrogen peroxide, hydroxyl radicals, nitric oxide and lipid hydroperoxides are now recognized as signaling molecules under subtoxic conditions. The main signaling pathways in response to oxidative stress include the extracellular signal-regulated kinase (ERK), c-Jun aminoterminal kinase (JNK) and p38 mitogen-activated protein kinase (MAPK) signaling cascades, the phosphoinositide 3kinase (PI(3)K)/Akt pathway, the nuclear factor NF-kB, the AP-1 signaling system, p53 activation, and the heat shock response.43 In general, the heat shock response, ERK, PI(3)K/Akt and NF-kB signaling pathways exert a pro-survival influence during oxidant injury, whereas activation of p53, JNK and p38 are more commonly linked to apoptosis. Consequences of oxidative stress include modification to cellular proteins, lipids and DNA. Carbonyl formation can occur through a variety of mechanisms including direct oxidation of certain amino acid side chains and oxidationinduced peptide cleavage. Mitochondrial DNA is generally considered to be even more sensitive than nuclear DNA to oxidative damage because of its proximity to the main source of oxidant generation or because of a limited DNA repair system.43 Cellular antioxidant defense system includes the enzymatic scavengers, superoxide dismutase (SOD), catalase, and

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glutathione peroxidase. SOD promotes the conversion of superoxide to hydrogen peroxide, whereas catalase and glutathione peroxidase convert hydrogen peroxide to water. In addition to these well-characterized antioxidant enzymes, at least five members of a new family of peroxide scavengers termed peroxiredoxins have recently been isolated. A variety of other nonenzymatic, low molecular mass molecules are important in scavenging ROS. These include ascorbate, pyruvate, flavinoids, carotenoids, and perhaps most importantly, glutathione, which is present in millimolar concentrations within cells.

metabolism, repair, messenger ribonucleic acid (mRNA) splicing, and DNA replication.67,68 Cellular survival factors, such as Bcl-2 and Bcl-xL, are also cleaved by caspases, as are the proapoptotic proteins Bid and Bax, producing a fragment that promotes apoptosis.69–71 At least 13 protein kinases are known to be cleaved during apoptosis, including PAK2, PRK2, PKC, MEKK1, Raf1, and Akt1. Caspases also cleave other types of proteins involved in signal transduction pathway including the proinflammatory cytokines, prointerleukin-1b, pro-interleukin-16, NFkB, and steroid response element-binding protein.72

Caspases

Bcl-2 Family Proteins

Activation of proteases of the caspase family is one of the common mechanisms that mediates apoptotic cell death.52 Caspases belong to the cysteine protease family and specifically cleave their substrates immediately after aspartic acid residues. Caspases are normally expressed as proenzymes that are proteolytically processed to their active form upon appropriate stimulation. Three general mechanisms of caspase activation have been described. First, they are processed by an upstream caspase. A proapoptotic signal culminates in activation of an initiator caspase that, in turn, activates effector caspases, resulting in cellular disassembly. The three short prodomain caspases, caspase-3, -6, and -7 are the downstream effector caspases more abundant and active than other long prodomain caspases.39 Second, caspase-8 is the key initiator caspase in the death-receptor pathway. Upon ligand binding, death receptors such as CD95 aggregate and form membrane-bound signaling complexes, which then recruit several molecules of procaspase-8 to further activate several other caspases.53–55 Third, Apaf-1/ caspase-9 are activated by cytochrome c.35,56–58 Apoptotic events include DNA fragmentation, chromatin condensation, protein degradation, membrane blebbing, cell shrinkage, and disassembly into membrane-enclosed vesicles, followed by the engulfment of apoptotic bodies by other cells. A subset of caspases is responsible for the cellular changes that occur during apoptosis. Activation of the nuclease by caspases is responsible for the nucleosomal ladder.59 In nonapoptotic cells, the nuclease responsible for DNA fragmentation, CAD (caspase-activated deoxyribonuclease) is present as an inactive complex with ICAD. Caspases can cleave ICAD/DFF45, an inhibitor of CAD, leaving CAD free to function as a nuclease and thereby initiating endonucleolytic chromosome degradation.60–62 During apoptosis, nuclear lamins are cleaved by caspases, causing lamina, a structure that underlies the nuclear membrane, to collapse and contributing to chromatin condensation, nuclear shrinking, and budding.63,64 Disassembly of overall cell structure is caused by the cleavage of some cytoskeletal proteins such as fodrin and gelsolin,65 actin, keratin 18, and p21-activated kinase2 (PAK2).66 Caspases inactivate or deregulate proteins involved in DNA

Bcl-2 family proteins are key regulators of apoptosis, acting to either inhibit or promote cell death. There are at least 15 Bcl-2 family members that have been identified. All members possess one or more conserved Bcl-2 homology domains (BH1-4), which control the ability of these proteins to dimerize and function as regulators of apoptosis.73,74 Some members (Bcl-2 and Bcl-xL) possess anti-apoptotic activity, whereas others (Bax, Bak, and Bok) promote cell death.39 The major anti-apoptotic members of the Bcl-2 family, Bcl2 and Bcl-xL, reside on the mitochondrial outer membrane, the endoplasmic reticulum and perinuclear membrane.75 Bax is cytosolic before an apoptotic stimulus and plays a crucial role for neuronal cell death induced by trophic factor withdrawal as well as injury.76 Many Bcl-2 family members can homodimerize, but more importantly, pro- and anti-apoptotic members can heterodimerize and their ratio determines survival or death following an apoptotic stimulus.77 For example, Bcl-2 and Bcl-xL inhibit the activities of pro-apoptotic members of the Bcl-2 family through heterodimerization.73 Bcl-2 directly or indirectly prevents the release of cytochrome c from mitochondria. The binding of cytochrome c to Apaf-1 may facilitate a change in Apaf-1 structure, an event that triggers procaspase-9 recruitment and processing, leading to apoptosis.56,78 Bcl-2 can also protect cells after cytochrome c has been released.36 Bcl-xL may inhibit the association of Apaf-1 with procaspase-9 and thereby attenuate its ability to promote caspase-9 activation. Pro-apoptotic relatives like Bik may free CED-4/Apaf-1 from the death inhibitor.79,80 Bax- and Bax-like proteins’ effects on mitochondrial function and subsequent cell death may be caspase-independent. However, in response to a death signal, their translocation, mitochondrial membrane insertion, and homodimerization can result in cell death.52

Introduction to Ischemia Injury Although the human brain represents only about 2.5% of body weight, it accounts for 25% of basal metabolism. In

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addition, brain neurons have a near exclusive dependence on glucose as energy substrate, and brain stores of glucose or glycogen are limited. The high metabolic rate and low energy reserve of the human brain contribute to the vulnerability of brain tissue to ischemic damage. Complete interruption of blood flow to the brain for only 5 minutes triggers the death of vulnerable neurons in several brain regions, whereas 20 to 40 minutes of ischemia are required to kill cardiac myocytes or kidney cells. Cerebral ischemia may either be transient, followed by reperfusion, or essentially permanent. Both types of focal ischemia can occur in patients. In the transient occlusion, reperfusion injury also adds to brain damage. A region of the brain may be affected, as occurs during an arterial occlusion, or the entire brain may become globally ischemic, as occurs during a cardiac arrest. In addition to such settings, where ischemia is the primary insult, ischemia may also contribute secondarily to brain damage in the setting of mass lesions, hemorrhage, or trauma. Many experimental models are used to study ischemic damage, with most of them using rodents. In vitro ischemia models that include exposure of neuronal, glial, or freshly isolated brain sections to anoxia or to anoxia in the absence of glucose have provided important insight into events in vivo. Two types of rodent brain ischemia models are available, global ischemia models, which simulate cardiac arrest, and focal ischemia models, which pathophysiologically are more similar to stroke in human subject. These models provide indispensable tools for the study of the mechanism of ischemia/reperfusion injury and for evaluation of the neuroprotective effects of new and known compounds, which have been tested in vitro. On the other hand, animal models will never mimic the clinical situation, regarding the heterogeneity of the stroke in patients.81 These models should be regarded as a method to screen whether a particular compound has the ability to rescue neurons. Brain ischemia and reperfusion engage multiple independently fatal terminal pathways involving loss of membrane integrity in partitioning ions, progressive proteolysis, and inability to check these processes because of loss of general translational competence and reduced survival signal-transduction. Within seconds of cerebral insult, ischemia results in rapid loss of high-energy phosphate compounds, and cortical activity, as detected by electroencephalography, ceases. This shutdown of neural activity is induced by an abrupt and dramatic redistribution of ions across the plasma membrane, associated with membrane depolarization: efflux of K+ and influx of Na+, Cl-, and Ca2+. This anoxic depolarization results in the excessive release of neurotransmitters, in particular glutamate, promoting further spatial spread of cellular depolarization, depletion of energy stores, and advancement of injury cascades. Major events in the cascade triggered by hypoxiaischemia include calcium entry into cells, activation of a

variety of calcium-sensitive enzymes, production of oxygen free radicals, and injury to mitochondria, all leading in turn to either necrosis or apoptosis of neurons.82

Excitotoxicity, Calcium, and Oxidant Stress Excitotoxicity refers to a process of neuronal death caused by excessive or prolonged activation of receptors for the excitatory amino acid neurotransmitter. Glutamic acid is the major excitatory transmitter within the mammalian central nervous system. Aspartic acid is also a potent neuronal excitant, activating the same receptors as glutamic acid.83 Excitotoxicity appears to involve sustained elevations of intracellular calcium levels. The calcium-induced excitotoxicity occurring after ischemia has been widely accepted as a key event after cerebral ischemia. Ischemia-induced energy failure causes membrane depolarization and release of excitatory amino acids such as glutamate into the extracellular space. A massive rise in extracellular concentrations of glutamic acid following cerebral ischemia has been demonstrated by microdialysis techniques in rats subjected to a transient global cerebral ischemia.84,85 The increase in extracellular glutamic acid has also been shown in a rat model of focal ischemia.86 Glutamate receptors become activated, resulting in calcium overload of neurons.8 Water, sodium, and chloride move intracellularly via ion channels into the cell causing so-called cytotoxic edema. The entry of water causes an increase in cell volume and a dilution of the cytoplasmic contents, leading to disruption of organelles and osmotic swelling. The final consequence of this process is cell lysis and release of cell contents into the extracellular milieu.87,88 Free radicals play an important role in the excitotoxic process, with the resulting damage to intracellular organelles playing a major role in cell death. Release of excitatory transmitters, depolarization, and an increase in calcium trigger enhanced production of the traditional ROS as well as of nitric oxide (NO).89,90 Calcium also activates phospholipase A2 and cyclooxygenase, producing ROS. Nitric oxide (NO) is synthesized from l-arginine and molecular oxygen by calcium-dependent NO synthase (NOS), and NO reacts with superoxide to form peroxynitrite.91,92 The ROS release promotes further membrane damage, and subsequently mitochondrial dysfunction. The increase in the ROS level during reperfusion causes some secondary effects that make the situation even worse.93–95 In particular, the appearance of oxidized phosphatidylserine on the surface of the ROS-producing cell attracts phagocytes that start to bombard this cell with O2- generated by NADPH oxidase in their plasma membrane. This results in further increase in ROS in the target cell and in the region surrounding the cell. Moreover, ROS are known to initiate the formation and release of proinflammatory agents, such as cytokines, that subsequently attract and activate

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neutrophils (polymorphonuclear leukocytes) and carry out phagocytosis.

Novel Therapies for Brain Protection During Stroke

Inflammation

Introduction

Cerebral ischemia-reperfusion injury is associated with an inflammatory response with pathologic contributions from vascular leukocytes and endogenous microglia. Expression of pro-inflammatory genes is induced by the synthesis of transcription factors and release of mediators of inflammation, such as NF-kB, platelet-activating factor, tumor necrosis factor and interferon regulatory Factor I.96–98 Consequently, expression of the adhesion molecules such as intercellular adhesion molecule-1 (ICAM-1), P-selectins, and E-selectins occurs on the endothelial surface.99–101 After binding to adhesion molecules, neutrophils adhere to the endothelium, cause microvascular obstruction, cross the vascular wall, and enter the brain parenchyma followed by macrophages and monocytes.102,103 Postischemic inflammation could contribute to ischemic damage by many mechanisms. Activated inflammatory cells and injured neurons produce a number of toxic mediators such as inducible NOS that may worsen ischemia.104 It is noteworthy that the proinflammatory gene expression commences early after insult and lasts up to 5 days, which provide a new opportunity for novel therapeutics.102

The effort to develop effective therapies for acute ischemic stroke achieved several important successes during the past decade. The greatest successes were related to thrombolysis. However, with the restrictive three hour therapeutic window for recombinant tissue plasminogen activator (rtPA) in stroke therapy,108 only a small number of acute stroke patients are estimated to receive this intervention.109 Even with the patient educational efforts, institutional initiatives, and the advanced techniques of diffusion and perfusion magnetic resonance imaging, only 10% of the acute stroke patients are candidates for the intervention.110,111 During the past decade, tremendous effort has been made to develop new neuroprotective agents that can rescue neurons after ischemic and traumatic brain injury. Neuroprotective agents have been developed and tested for nearly all components of the ischemic cascade (Fig. 31-3). Various strategies include free radical scavengers, anti-excitotoxic

Apoptosis Ischemic injury-induced cell death has traditionally been characterized as necrosis, in which cells and their organelles swell and rupture. However, morphological and biochemical evidence of apoptosis have now been well documented in experimental animal models of ischemic brain injury.105,106 Apoptosis can be triggered by a number of pathophysiological processes, including excitotoxicity, free radicals, the inflammatory reaction, and mitochondrial and DNA damage. Apoptosis can occur after severe ischemiareperfusion injury because the entire process of apoptosis may take only 15 minutes. Apoptosis can also occur after milder ischemic injury, particularly within the ischemic penumbra, which results in delayed neuronal death. The processes take much longer in the latter situation. So, antiapoptosis therapies are important in both acute and chronic stages of stroke. For many years, it was considered that apoptotic and necrotic cell death were two mutually exclusive alternative pathways that dying neurons could take and that toxic insults triggered either apoptosis or necrosis. However, these two processes are complementary and the dying neurons may switch from one to the other.107 Mammalian apoptosis is regulated by the Bcl-2 family of proteins, the adaptor protein Apaf-1 (apoptotic protease-activating Factor I) and the cysteine protease caspase family.75 Modulating the expression of key molecular components of the cell death machinery is an attractive and obvious strategy.

Figure 31-3. Potential therapeutic target for anti-stroke drug discovery. (Modified from Fisher M, Schaebitz W: An overview of acuted stroke therapy. Arch Int Med 2000;160:3196–3206, with permission.)

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agents, apoptosis inhibitors, anti-inflammatory agents, metal ion chelators, ion channel modulators, antisense oligonucleotides, gene therapy, and stem cell transplantation. These various agents aim to prevent progression of the ischemic cascade, thereby reducing brain damage. Some of these intervene at more than one point in the ischemic cascade. Neuroprotection is also considered as an adjunct to therapies designed to improve cerebral circulation, such as thrombolytic agents for arterial thrombosis. The prospects for the introduction of an effective neuroprotective agent in the near future are encouraging. In addition to their prevention of brain damage during acute cerebrovascular disease, neuroprotective therapy has a role in preventing cerebral ischemia during high-risk cardiovascular procedures, as well as in neuronal protection from neurodegenerative diseases. Anti-Excitotoxicity Therapy The importance of free radicals in mediating excitotoxicity is underlined by the ability of antioxidants, free radical scavengers, and inhibitors of nitric oxide synthase to attenuate excitotoxic damage both in cell culture and animal models. Currently available anti-excitotoxic drugs have played a role in exploring the factors responsible for neuronal death. This has led to the initiation of several clinical trials of antiexcitotoxic drugs, principally NMDA receptor antagonist. However, clinical experience has been disappointing. It is not clear whether the failure to demonstrate efficacy with the many anti-excitotoxic drugs that have been evaluated in stroke is due to the unacceptable safety profile of these drugs, to insensitive clinical trial methodology, or to a lack of understanding of underlying pathogenesis during stroke. In this respect, the outcome of ongoing clinical trials of stroke with the better tolerated glycine site antagonists and AMPA/kainate receptor antagonists may be informative.83 Anti-Inflammation Therapy Interference with inflammatory cascades is another general approach likely to aid neuronal survival. One of the key events amenable to therapeutic intervention may be the adherence of leukocytes to blood vessels in the ischemic region shortly after the insult. Inhibition of this step may not only limit the release of proinflammatory cytokines, but also reduce the ischemic insult itself by limiting microvascular occlusion.112 Therapies aimed at preventing inflammatory response have demonstrated neuroprotective efficacy in experimental models of stroke. Pharmacological blockade of iNOS reduces ischemic brain injury.113 Ischemic neurons also express cyclooxygenase 2, an enzyme that contributes to ischemic injury by producing superoxide and toxic prostanoids. Cyclooxygenase 2–blockers significantly reduce ischemic brain damage.114,115 Furthermore, injured neurons produce the proinflammatory cytokine, IL-1b, that can be

blocked by IL-1b inhibitors to reduce infarct size after ischemia. Inhibition of the release or action of proinflammatory cytokines could be another approach for neuroprotection. The inflammation reaction is an attractive pharmacologic opportunity, considering its rapid initiation and progression over many hours after stroke and its contribution to evolution of tissue injury. Anti-Apoptosis Therapy Caspases are important therapeutic targets for modulating apoptosis. The two major caspases involved in neuronal cell death are caspase-3 and caspase-9. Although a caspase inhibitor for the inhibition of apoptosis, has yet to reach the clinic, preclinical studies are compelling. In animal models of ischemia-reperfusion injury, caspase inhibition has shown remarkable efficacy.116,117 In addition to decreased apoptosis, caspase inhibition improved survival, decreased infarct volumes, and markedly improved function. Importantly, when caspase inhibitors are administrated after ischemic insult, they retain their efficacy. This is likely due to the natural delay in the apoptotic response, an important practical issue that distinguishes this therapeutic strategy from many that have preceded it. Drugs are under development for various caspase family members, with the most attention being paid to caspase-3 as a major contributor to the apoptotic machinery.118 Other agents that may counteract apoptosis after focal cerebral ischemia via Bcl-2/Bax–dependent mechanisms are growth factors such as brain-derived neurotrophic growth factor. Other Therapeutic Approaches Recovery and reorganization of the brain after focal ischemic injury occurs over weeks and may have a major impact on the outcome after stroke. The underlying mechanisms of recovery include neuronal sprouting and synaptogenesis, which are part of the spontaneous recovery process particularly after smaller focal lesions. Enhancement of recovery followed by improvement of behavioral outcome can be achieved in animals with drugs such as growth factors and amphetamines. Stem Cell Therapy Stem cell biology has generated considerable optimism that it will be possible to direct the differentiation of progenitor cells along predefined and therapeutically relevant pathways of differentiation. It is now clear that embryonic progenitor cells can differentiate into postmitotic neurons in an adult environment. In addition, the mature mammalian CNS also appears to contain progenitor cells, which while normally relatively quiescent, can be goaded into proliferative activity by insult in vivo or by exposure to mitogenic factors in vitro. Moreover, some of these cells can even differentiate into neurons when reintroduced into the adult CNS.119 New

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neurons can be generated in the cerebral cortex of adult rats after transient focal cerebral ischemia. Cortical neurogenesis may be a potential pathway for brain repair after stroke.120 Clinical stem cell transplantation could greatly add to the physician’s armamentarium against stroke. Although these advances are exciting, many key issues remain unresolved. First, the location of the adult stem cells and the brain regions to which their progeny migrate in order to differentiate remain unresolved. Second, the functions of the newly generated neurons after ischemia are still unclear. Third, for ischemia involving projection neurons, it is not clear how reintroduction of a newly generated neuron will solve the problem of long-distance axonal growth and selective synapse formation in an adult environment. Polypharmacy Most of the neuroprotective agents studied to date target a specific pathway of the ischemic cascade. It is evident that the administration of either an NMDA-receptor antagonist or a voltage-dependent Ca2+–channel blocker will not be able to completely control excessive neuronal Ca2+ accumulation. Although these compounds can reduce infarct size in animal models, we should not expect that any single drug that interferes with a specific event in the ischemic cascade will have a large clinical impact. Combination strategies that use multiple drugs that work on different ischemia pathways or a single drug that works on multiple ischemia pathways seem rational because cerebral ischemia triggers a multitude of pathophysiologic events that affect the evolution of ischemia. Treatments using a combination of reperfusion enhancing agents with neuroprotection or a cocktail of carefully selected neuroprotective drugs could improve the outcome of stroke. The potential approach to prolonging the therapeutic time window for successful thrombolysis would be to give neuroprotective therapy before, during, or after the infusion of IV rtPA. It is likely that combination therapy with tPA to restore blood flow, and neuroprotective agents to halt or reverse the cascade of neuronal damage, will dominate the future of stroke care. Compared with thrombolysis, the neuroprotective approach for stroke treatment is more complex and reflects the diversity of the ischemic cascade. Estrogen Replacement Therapy We first demonstrated that estrogens are potent neuroprotectants121 and are very effective against ischemia-induced brain damage.122 Also, gender differences in the incidence and outcome of stroke suggest that hormonal factors may influence the development and outcome of this process.123,124 Recently, estrogens have been found to be associated with a decreased risk and delayed onset and progression of stroke, and enhanced recovery from numerous traumatic and chronic neurologic and mental diseases.122,125–127 Various lines of clinical and experimental evidence have shown that both endogenous and exogenous estrogens exert

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neuroprotective effects.125–128 Protective effects of estrogen have been widely reported in different types of neuronal cell against different toxicities including serum deprivation, oxidative stress, amyloid b peptide (Ab)–induced toxicity and excitotoxicity.128 Estrogens are multifaceted hormones modulating many aspects of neuronal function and no single mechanism of action has yet to be elucidated for the neuroprotective effects of estrogens. Antioxidant effects of the steroid,129 estrogen receptor (ER) activation, activation of the MAP kinase pathway,130,131 attenuation of NMDA receptor activation,132 and increased expression of anti-apoptotic Bcl-2 family proteins have been implicated as mechanisms for the neuroprotective effects of estrogens.133 The phosphatidylinositol 3-kinase pathway, which includes the downstream effector, Akt, is well characterized as being able to mediate inhibition of apoptosis and supports neuronal survival. Estrogens have been also shown to activate Akt in vitro.134,135 Additionally, estrogen exposure results in activation of the cAMP/PKA/CREB pathway and modulation of intracellular calcium concentrations.128 Currently it is not known to what extent estrogen neuroprotection is dependent on any of these particular mechanisms.136 There is now abundant evidence for neuroprotection by estrogen in different experimental models in vivo. Both focal and global experimental forebrain ischemia models have been commonly used to test the neuroprotective effects of estrogens on ischemia-reperfusion injury in vivo. The protective effects of estrogens in this model have been documented in rats, mice, and gerbils.122,137,138 Estrogens’ neuroprotective effects have been suggested in both females and males, in both pretreatment and post-treatment studies.139 The therapeutic window of estrogens could last up to three hours after insult (Fig. 31-4).140 In an MRI study, serial images show that estradiol treatment dramatically decreases ischemic lesion sizes and intensities, as demonstrated by both DWI (Fig. 31-5) and T2WI (Fig. 31-6).141 The effects of estrogens are exerted both during ischemia and reperfusion. Another study shows that post-treatment during early reperfusion can attenuate lesion volume.139 The protective effects of estrogens during reperfusion made them the candidate for neuroprotection. Additionally, it could be possible to prolong the therapeutic time window for successful thrombolysis by administration of estrogens or analogues before, during, or after the infusion of IV rt-PA. Although estrogens are neuroprotective, feminizing effects limit their clinical application, especially considering high pharmacological dose or application in males. From the clinical perspective, estrogen analogues with neuroprotective activity but lacking feminizing effects on peripheral estrogen responsive tissues could be applied in both males and females for whom estrogen therapy is contraindicated. Many biologic effects of estrogens are mediated by ERs within the nuclei of target cells. The ERs exist in two known forms, estrogen receptor a (ERa) and estrogen receptor b (ERb),

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Figure 31-4. Protective effects of delayed estrogen treatment in a permanent middle cerebral artery occlusion model. (From Yang SH, Shi J, Day AL, Simpkins JW: Estradiol exerts neuroprotective effects when administered after ischemic insult. Stroke 2000;31:745–750, with permission.)

both of which are thought to act as ligand inducible transcription factors. However, it has not been demonstrated that the neuroprotective effects of estrogens are ERs mediated.133,142 Encouragingly, numerous nonreceptor binding estrogen analogues have been shown to exert potent neuroprotective effects that are equivalent to or greater than that of estradiol.129,143,144 Although the application of estrogens for treatment of acute neuronal death and neurodegeneration disease requires further clinical study, a plethora of data supports a direct neuroprotective role for estrogens. Given the proven clinical safety of this steroid, estrogen therapy may be useful in treating acute neurotrauma such as cerebral ischemia and head injury. Further, the efficacy of nonfeminizing estrogen analogues suggest that these compounds may be clinically useful for treating neuronal death in men or women for whom estrogen therapy is contraindicated.

Conclusions Over the last decade, tremendous progress has been made in the discovery of molecular mechanisms of neuronal cell death. This knowledge allows us to develop new strategies for the protection of neurons during and following an ischemic event or traumatic brain injury. It appears that an agent that targets a single neurotoxic mechanism alone will not be sufficient to prevent brain cell death. A case in point

is the complexity of Ca2+ regulation during ischemia and reperfusion and the apparent ineffectiveness of therapies aimed at blocking influx of Ca2+. Protection of neurons during ischemia/reperfusion will require a polypharmacy approach or use of a compound, such as an estrogen, that has pleotrophic actions and appears to affect multiple neurotoxic processes. This strategy should be effective over the short term in producing pharmacotherapies that can reduce ischemic or traumatic brain damage and the resulting neurologic deficits. Over the long term, strategies for the restoration of the number of neurons, or for their regrowth, are needed to improve function in brain damaged subjects. This will require a vast increase in our knowledge of the biology of stem cells as well as improved ability to direct these cells to specific areas of the brain and to encourage them to make functional synaptic connections. Despite these challenges, progress in the therapy of acute brain damage will be made through the pursuit of basic knowledge and its clinical application.

Acknowledgments Work described herein was supported in part by the following grants: National Institute on Aging grant AG 10485, U.S. Army grant DAMA 17-99-1-9473, and a grant from Apollo BioPharmaceutics, Inc.

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Figure 31-5. Effects of estrogen pretreatment on diffusion weighted image (DWI) in a transient middle cerebral artery occlusion model. (From Shi J, Bui JD, Yang SH, et al: Estrogens decrease reperfusion-associated cortical ischemic damage: An MRI analysis in a transient focal ischemia model. Stroke 2001;32:987–992, with permission.)

Figure 31-6. Effects of estrogen pretreatment on T2-weighted image (T2WI) in a transient middle cerebral artery occlusion model. (From Shi J, Bui JD, Yang SH, et al: Estrogens decrease reperfusion-associated cortical ischemic damage: An MRI analysis in a transient focal ischemia model. Stroke 2001;32:987–992, with permission.)

P earls 1. The rapid explosion of our knowledge of the mechanisms by which neurons die has led to investigations into interventions to preserve structure and function of neurons during ischemic and traumatic events. 2. The outcome of an ischemic insult is different in the ischemic core and in the penumbra. 3. Mitochondria appear to play a central role in neuronal cell death decisions. 4. . . . mitochondrial Ca2+ loading is a critical event in the determination of neuronal viability after ischemia. 5. The majority of intracellular ROS production is derived from the mitochondria and mitochondria are a primary source of ROS in ischemia-reperfusion injury. 6. Activation of proteases of the caspase family is one of the common mechanisms that mediates apoptotic cell death.

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7. Bcl-2 family proteins are key regulators of apoptosis, acting to either inhibit or promote cell death. 8. Free radicals play an important role in the excitotoxic process, with the resulting damage to intracellular organelles playing a major role in cell death. 9. Cerebral ischemia-reperfusion injury is associated with an inflammatory response with pathologic contributions from vascular leukocytes and endogenous microglia. 10. Drugs are under development for various caspase family members, with the most attention being paid to caspase-3 as a major contributor to the apoptotic machinery. 11. Estrogens are multifaceted hormones modulating many aspects of neuronal function and no single mechanism of action has yet to be elucidated for the neuroprotective effects of estrogens.

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93. Carney JM, Floyd RA: Protection against oxidative damage to CNS by alpha-phenyl-tert-butyl nitrone (PBN) and other spin-trapping agents: A novel series of nonlipid free radical scavengers. J Mol Neurosci 1991;3:47–57. 94. Christensen T, Bruhn T, Balchen T, Diemer NH: Evidence for formation of hydroxyl radicals during reperfusion after global cerebral ischaemia in rats using salicylate trapping and microdialysis. Neurobiol Dis 1994;1:131–138. 95. Zini I, Tomasi A, Grimaldi R, Vannini V, Agnati LF: Detection of free radicals during brain ischemia and reperfusion by spin trapping and microdialysis. Neurosci Lett 1992;138:279–282. 96. Dirnagl U, Iadecola C, Moskowitz MA: Pathobiology of ischaemic stroke: an integrated view. Trends Neurosci 1999;22:391–397. 97. O’Neill LA, Kaltschmidt C: NF-kappa B: A crucial transcription factor for glial and neuronal cell function. Trends Neurosci 1997;20:252– 258. 98. Ruscher K, Isaev N, Trendelenburg G, et al: Induction of hypoxia inducible factor I by oxygen glucose deprivation is attenuated by hypoxic preconditioning in rat cultured neurons. Neurosci Lett 1998;254:117–120. 99. Haring HP, Berg EL, Tsurushita N, Tagaya M, del Zoppo GJ: E-selectin appears in nonischemic tissue during experimental focal cerebral ischemia. Stroke 1996;27:1386–1392. 100. Lindsberg PJ, Carpen O, Paetau A, Karjalainen-Lindsberg ML, Kaste M: Endothelial ICAM-1 expression associated with inflammatory cell response in human ischemic stroke. Circulation 1996;94:939–945. 101. Zhang R, Chopp M, Zhang Z, Jiang N, Powers C: The expression of P- and E-selectins in three models of middle cerebral artery occlusion. Brain Res 1998;785:207–214. 102. Barone FC, Feuerstein GZ: Inflammatory mediators and stroke: New opportunities for novel therapeutics. J Cereb Blood Flow Metab 1999;19:819–834. 103. Sun A, Cheng J: Novel targets for therapeutic intervention against ischemic brain injury. Clin Neuropharmacol 1999;22:164–171. 104. Forster C, Clark HB, Ross ME, Iadecola C: Inducible nitric oxide synthase expression in human cerebral infarcts. Acta Neuropathol (Berl) 1999;97:215–220. 105. Charriaut-Marlangue C, Margaill I, Represa A, Popovici T, Plotkine M, Ben-Ari Y: Apoptosis and necrosis after reversible focal ischemia: An in situ DNA fragmentation analysis. J Cereb Blood Flow Metab 1996;16:186–194. 106. Li Y, Chopp M, Jiang N, Zhang ZG, Zaloga C: Induction of DNA fragmentation after 10 to 120 minutes of focal cerebral ischemia in rats. Stroke 1995;26:1252–1257; discussion 1257–1258. 107. Choi DW: Ischemia-induced neuronal apoptosis. Curr Opin Neurobiol 1996;6:667–672. 108. Tissue plasminogen activator for acute ischemic stroke. The National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group. N Engl J Med 1995;333:1581–1587. 109. Clark WM, Albers GW, Madden KP, Hamilton S: The rtPA (alteplase) 0- to 6-hour acute stroke trial, part A (A0276g) : Results of a doubleblind, placebo-controlled, multicenter study. Thromblytic therapy in acute ischemic stroke study investigators. Stroke 2000;31: 811– 816. 110. Hacke W, Brott T, Caplan L, et al: Thrombolysis in acute ischemic stroke: Controlled trials and clinical experience. Neurology 1999;53:S3–S14. 111. Fisher M, Albers GW: Applications of diffusion-perfusion magnetic resonance imaging in acute ischemic stroke. Neurology 1999;52:1750– 1756. 112. Lee JM, Grabb MC, Zipfel GJ, Choi DW: Brain tissue responses to ischemia. J Clin Invest 2000;106:723–731. 113. Iadecola C, Zhang F, Casey R, Nagayama M, Ross ME: Delayed reduction of ischemic brain injury and neurological deficits in mice lacking the inducible nitric oxide synthase gene. J Neurosci 1997;17:9157– 9164.

114. Iadecola C, Forster C, Nogawa S, Clark HB, Ross ME: Cyclooxygenase2 immunoreactivity in the human brain following cerebral ischemia. Acta Neuropathol (Berl) 1999;98:9–14. 115. Nogawa S, Zhang F, Ross ME, Iadecola C: Cyclo-oxygenase-2 gene expression in neurons contributes to ischemic brain damage. J Neurosci 1997;17:2746–2755. 116. Cursio R, Gugenheim J, Ricci JE, et al: A caspase inhibitor fully protects rats against lethal normothermic liver ischemia by inhibition of liver apoptosis. Faseb J 1999;13:253–261. 117. Endres M, Namura S, Shimizu-Sasamata M, et al: Attenuation of delayed neuronal death after mild focal ischemia in mice by inhibition of the caspase family. J Cereb Blood Flow Metab 1998;18:238– 247. 118. Nicholson DW: From bench to clinic with apoptosis-based therapeutic agents. Nature 2000;407:810–816. 119. Gage FH: “Mammalian neural stem cells.” Science 2000;287:1433– 1438. 120. Jiang W, Gu W, Brannstrom T, Rosqvist R, Wester P: Cortical neurogenesis in adult rats after transient middle cerebral artery occlusion. Stroke 2001;32:1201–1207. 121. Bishop J, Simpkins JW: Estradiol treatment increases viability of glioma and neuroblastoma cells in vitro. Mol Cell Neurosci 1994;5:303–308. 122. Simpkins JW, Rajakumar G, Zhang YQ, et al: Estrogens may reduce mortality and ischemic damage caused by middle cerebral artery occlusion in the female rat. J Neurosurg 1997;87:724–730. 123. Stegmayr B, Asplund K, Kuulasmaa K, et al: Stroke incidence and mortality correlated to stroke risk factors in the WHO MONICA Project. An ecological study of 18 populations. Stroke 1997;28:1367–1374. 124. Thorvaldsen P, Asplund K, Kuulasmaa K, Rajakangas AM, Schroll M: Stroke incidence, case fatality, and mortality in the WHO MONICA project. World Health Organization Monitoring Trends and Determinants in Cardiovascular Disease. Stroke 1995;26:361–367. 125. Garcia-Segura LM, Azcoitia I, DonCarlos LL: Neuroprotection by estradiol. Prog Neurobiol 2001;63:29–60. 126. Honjo H, Kikuchi N, Hosoda T, et al: Alzheimer’s disease and estrogen. J Steroid Biochem Mol Biol 2001;76:227–230. 127. Panidis DK, Matalliotakis IM, Rousso DH, Kourtis AI, Koumantakis EE: The role of estrogen replacement therapy in Alzheimer’s disease. Eur J Obstet Gynecol Reprod Biol 2001;95:86–91. 128. Green PS, Simpkins JW: Neuroprotective effects of estrogens: Potential mechanisms of action. Int J Dev Neurosci 2000;18:347–358. 129. Behl C, Skutella T, Lezoualc’h F, et al: Neuroprotection against oxidative stress by estrogens: structure-activity relationship. Mol Pharmacol 1997;51:535–541. 130. Singh M, Setalo G Jr, Guan X, Frail DE, Toran-Allerand CD: Estrogen-induced activation of the mitogen-activated protein kinase cascade in the cerebral cortex of estrogen receptor-alpha knock-out mice. J Neurosci 2000;20:1694–1700. 131. Singh M, Setalo G Jr, Guan X, Warren M, Toran-Allerand CD: Estrogen-induced activation of mitogen-activated protein kinase in cerebral cortical explants: convergence of estrogen and neurotrophin signaling pathways. J Neurosci 1999;19:1179–1188. 132. Weaver CE Jr, Park-Chung M, Gibbs TT, Farb DH: 17beta-Estradiol protects against NMDA-induced excitotoxicity by direct inhibition of NMDA receptors. Brain Res 1997;761:338–341. 133. Dubal DB, Shughrue PJ, Wilson ME, Merchenthaler I, Wise PM: Estradiol modulates bcl-2 in cerebral ischemia: A potential role for estrogen receptors. J Neurosci 1999;19:6385–6393. 134. Honda K, Sawada H, Kihara T, Urushitani M, Nakamizo T, Akaike A, Shimohama S: Phosphatidylinositol 3-kinase mediates neuroprotection by estrogen in cultured cortical neurons. J Neurosci Res 2000;60:321–327. 135. Singh M: Ovarian hormones elicit phosphorylation of Akt and extracellular-signal regulated kinase in explants of the cerebral cortex. Endocrine 2001;14:407–415.

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136. Honda K, Shimohama S, Sawada H, et al: Nongenomic antiapoptotic signal transduction by estrogen in cultured cortical neurons. J Neurosci Res 2001;64:466–475. 137. Chen J, Xu W, Jiang H: 17 beta-Estradiol protects neurons from ischemic damage and attenuates accumulation of extracellular excitatory amino acids. Anesth Analg 2001;92:1520–1523. 138. Culmsee C, Vedder H, Ravati A, et al: Neuroprotection by estrogens in a mouse model of focal cerebral ischemia and in cultured neurons: evidence for a receptor-independent antioxidative mechanism. J Cereb Blood Flow Metab 1999;19:1263–1269. 139. McCullough LD, Alkayed NJ, Traystman RJ, Williams MJ, Hurn PD: Postischemic estrogen reduces hypoperfusion and secondary ischemia after experimental stroke. Stroke 2001;32:796–802. 140. Yang SH, Shi J, Day AL, Simpkins JW: Estradiol exerts neuroprotec-

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Chapter 32 Gene Therapy for Disorders of the Central Nervous System Ronald J. Mandel, PhD, Margaret J. Velardo, PhD, Sean Michael Sullivan, PhD, Edgardo Rodriguez, PhD, Emily Piercefield, MD, Jie Deng, MD, Carmen E. S. Peden, BS, Paul J. Reier, PhD, and Corinna Burger, PhD

Introduction Gene therapy refers to transferring genes for the de novo synthesis of proteins or various peptides capable of inhibiting protein expression such as messenger ribonucleic acid (mRNA) antisense or ribozymes. As it is currently conceived, gene therapy for central nervous system (CNS) disorders can be viewed as a relatively noninvasive method for continuously delivering large molecules inside the blood-brain barrier (BBB) as compared to indwelling mechanical devices such as pumps or reservoirs. Although many investigators are attempting to develop non-neurosurgical methods to deliver genes to the CNS, at least in the near term, CNS gene therapy will require a neurosurgical procedure to deliver the gene therapy vector. Therefore, at our current stage of technology, gene therapy for CNS disorders is best suited to localized delivery of a given molecule. In particular, disorders where it is advantageous to deliver a transgene or reduce expression of a gene in a particular anatomical region to the exclusion of global delivery are especially attractive targets. Other disorders that will require transduction (permanent genetic engineering) of 100% of a given neural cell population will have to await future advances in technology. Several factors regarding recent developments in both understanding the pathogenesis of CNS diseases and advances in gene therapy vectors suggest that gene therapies aimed at the human CNS will become a reality sooner rather than later. The present chapter will review avenues of gene transfer that are closest to clinical testing along with discussing the most relevant advances in understanding the pathogenesis of disorders that help define other such

strategies. However, detailed discussions of either topic are beyond the scope of the current review, and readers are referred to the most comprehensive reviews available for each topic. Thus, the present chapter is designed as an introduction to a wide range of gene therapies that are potentially on the horizon and that will require the participation and active aid of clinicians to bring these experimental treatments to the clinic.

Ex Vivo Gene Therapy There are two different methods to deliver foreign genes to the CNS termed ex vivo or in vivo gene transfer. Ex vivo gene transfer refers to the implantation of cells that have been transduced to express a foreign gene while the cells are in culture. One of the conceptual and practical advantages of this approach is that it can provide localized delivery of a transgene product. Virtually any type of cell can be considered as a candidate for use in CNS transplantation. Each cell type displays advantages and disadvantages, both regarding ease of culture and properties that they assume after transplantation. Currently, much attention is focused on neural stem cells and genetically modified fibroblasts as promising candidates for ex vivo gene therapy. While this approach was the first type of gene therapy originally proposed for the CNS, the implementation of this strategy has proved to be more complicated than originally thought. For example, while vectors capable of delivering genes to cultured cells that support unlimited duration of transgene expression have been available for many years, demonstrating 865

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long-term gene expression in vivo after transplantation has been elusive.1,2 Thus, there are several technical hurdles to consider when dealing with ex vivo gene therapy. First, the cells must be cultured and, in the best case, well characterized in terms of purity and the ultimate fate of the cell after transplantation. The requirement for consistent or clonal cells alone, disregarding the genetic engineering of the cells, especially with regard to stem or progenitor cells, is a challenge for ex vivo gene therapy. Second, either very efficient gene transfer vectors (see following discussion) or cells that can be subcloned must be used in order to obtain suspensions of cells that are nearly 100% transduced for transplantation. Therefore, while there are certainly conceptual advantages associated with ex vivo gene therapy, major technical hurdles remain prior to this strategy becoming a therapeutic reality. These experimental data obtained in the CNS using ex vivo gene therapy have been recently reviewed in detail.1 One ex vivo gene therapeutic strategy that might simplify many of these issues is the use of encapsulated cells. This strategy would allow for any type of cell, even dividing cells and xenogenic cells, to be genetically engineered, encapsulated in a permeable biocompatible membrane and transplanted into the CNS.3 Indeed, this strategy has progressed into the clinic for both encapsulated unmodified bovine adrenal medulla cells4,5 for pain management and genetically engineered baby hamster kidney cells in amyotrophic lateral sclerosis.6

In Vivo Gene Therapy In vivo gene delivery involves delivery of deoxyribonucleic acid (DNA) directly into cells via viral or nonviral vectors. Viral vectors take advantage of the fact that viruses have evolved the ability to transfer and express their DNA in foreign cells over millions of years. As described in the following sections for each individual vector, engineering different viruses to be used as vectors results in unique advantages and disadvantages for each viral platform. Several factors must be taken into account when considering the relative merits of viral vectors for direct in vivo gene transfer. First, the binding and entry of the engineered virus into the cell, which is rarely altered at present, may be relatively toxic. Second, the ability of different vectors to deliver their DNA to the nucleus or to form functional episomes in the nucleus is variable and is important for the ultimate expression of the transgene of interest. Third, the size of the transgene payload of each virus depends both on the original size of the wild-type viral genome and the proportion of wild-type genes that can be removed without totally crippling the virus. Nonviral vectors include naked DNA or DNA surrounded by cationic lipids (liposomes) to facilitate crossing the cell membrane. At present, the forms of these vectors that have

been used in in vivo research have resulted in limited duration and magnitude of transgene expression. However, nonviral, synthetic vectors will ultimately replace viral vectors in clinical practice when our state of knowledge of all the variables regarding successful transduction of a target cell is much greater. It is clear, however, that the strategy of entering the first phase of clinical gene therapy requires the use of viral vectors that are vastly more efficient than currently available synthetic vectors.

Viral Vectors Viral vectors are the most advantageous gene delivery vehicles currently available because their wild-type counterparts have evolved to deliver genetic material to the cell. Advances in the characterization of the life cycle of wild-type viruses have allowed the engineering of recombinant viral vectors that are deficient in replication functions but are capable of infecting the cell to introduce foreign genes. Because the majority of cells in the CNS are postmitotic, vectors that are capable of gene delivery to quiescent cells are of the most interest for this application. Adenoviruses (Ad), adenoassociated viruses (rAAV), herpes simplex viruses (HSV), and lentiviruses (Lv) are currently most common viral vectors that have been demonstrated to reliably transfer DNA in animal models of CNS disorders (Table 32-1). To amplify the ability to transduce large areas of the CNS, the idea of intracarotid, intraventricular, or intrathecal vector injection of the vector with or without hyperosmolar disruptions of the BBB have been attempted.7–11 However, these types of injections invariably result in low efficiency transduction of the parenchyma, due most likely to (1) inability to pass the ependymal wall of ventricle due to the size of the vector, (2) existence of viral receptors in the ependymal lining, and/or (3) dilution of the vector by either blood or CSF to unacceptably low multiplicities of infection. Recombinant Adenovirus Wild-type Ad (wt-Ad) is associated with respiratory infections, conjunctivitis, and gastroenteritis in humans, and most people have been exposed to wt-Ad. Ad is a relatively large virus (d = 80 nm) with a 36-kb genome of linear doublestranded DNA.12 Adenovirus binds to a specific receptor, the coxsackie and adenovirus receptor (CAR)13 and alphaV-beta5 or alphaV-beta3 integrin co-receptors. The recombinant version of Ad can transduce both mitotic and postmitotic cells. In the CNS, Ad transduces both neurons and glia,14 leading to high levels of transgene expression. The wild-type viral genome is composed of two inverted terminal repeats that are required for replication, a packaging signal, early genes, and late genes. First-generation recombinant Ad vectors have a deletion of the E1 early gene that is responsible for viral growth and induction of late genes. For pro-

vif, vpr, vpu, nef tat, rev All above and 5¢ LTR inactivation

3rd generation rLV

Self-inactivating

Neurons

Neurons

Neurons

Neurons

Neurons, glia

Integrated

Integrated

Integrated

Integrated

Episomal/latent

Episomal/latent

Episomal/latent

Episomal/integrated

Episomal

Episomal

Molecular Fate

~9 kb

~9 kb

~9 kb

~9 kb

~20 kb

~20 kb

~20 kb

Low antigenicity

Moderate antigenicity

Low

Low

High antigenicity Moderate antigenicity Low antigenicity

No antigenicity

Moderate antigenicity

<37 kb

~4.7 kb

High antigenicity

Immune Response in the CNS

~8 kb

Transgene Capacity

High protein production long term

High protein production long term

High protein production long term

High protein production long term

High protein production short term High protein production short term Low protein production short term

High protein production long term

High protein production; variable durability pending promoter and immune response Variable protein production long term

In Vivo Transgene Expression

Potential problem from VSV-G, pseudotyped envelope, possible HIV seroconversion, possible recombination Potential problems from VSV-G, pseudotyped envelope, possible HIV seroconversion, possible recombination VSV-G, seroconversion, recombination VSV-G, seroconversion

Low toxicity

Moderate toxicity

High toxicity

Insertional mutagenesis?

Moderate toxicity

High toxicity

Safety Concerns

Each vector has advantages and disadvantages. The ratings given in the individual cells are generalizations and may not apply to every vector version ever published, but in general the listed characteristics fit the general picture.

vif, vpr, vpu, nef

gag, pol, env

2nd generation rLV

rLV 1st generation rLV

Amplicon

Neurons, glia

ICP4, ICP22, ICP27, ICP47 All except oris and pac

Replication-defective

Neurons

Neurons, glia

rep, cap

rAAV rAAV-2

Neurons, glia

Neurons, glia

Cell Specificity

rHSV Replication-competent

All structural

Ela, Elb, E3

Deletions

Gutless

rAd r-Ad

Viral Vector

Table 32-1  Comparison of the Properties of the Different Recombinant Viral Vectors

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duction of the recombinant form of Ad, the E1 gene product can be provided in trans in another separate plasmid.15 This allows for the deletion of the E1 gene, which renders the virus replication deficient and allows introduction of therapeutic genes in place of the E1 gene. However, in this firstgeneration version of the Ad vector, most of the wt-viral genes remain in the vector. While expression of these viral genes may be impaired due to the deletion of E1, they are not ablated. Thus, in vivo, expression of these wt Ad genes leads to a host inflammatory response which hinders the use of this vector for clinical purposes.16–21 The inflammatory response of the brain to rAd injections has been the subject of extensive and detailed research.16–21 Indeed, it is this first generation rAd vector that was used in an ill-fated clinical trial that used hepatic delivery of rAd for ornithine transcarbamylase deficiency.22,23 Newer Ad vectors, the so-called gutless vectors, have been designed that retain only the inverted terminal repeats, that is, with all viral genes removed. The production of this vector requires the use of helper first-generation Ad.24–26 While the gutless Ad has been demonstrated to transduce cells in the CNS with reduced toxicity, there also seems to be some loss of transduction efficiency.21 In addition, at this time, removing all helper Ad from the final gutless Ad preparation is difficult and incomplete. Thus, problems dealing with longterm expression and antigenicity of the recombinant vector remain to be resolved before its use in gene therapies requiring permanent CNS transduction. Applications for brain tumors are, however, realistic at this time.27,28 Adeno-Associated Virus Wild-type adeno-associated virus (wt-AAV) is a small virus (approximately 20 nm) that is a nonpathologic member of the parvovirus family. When wt-AAV infects a cell, it normally integrates into the host cell genome and goes into latency. To enter a lytic cycle in which progeny are produced, wt-AAV requires adenovirus or herpes simplex virus to provide helper functions for replication.29 Combined with its lack of pathogenicity and its natural proclivity for latency, replication incompetent AAV makes an excellent candidate for a gene therapy vector. Wt-AAV is a single stranded DNA virus with a genome size of 4.7 kb that contains two genes, rep and cap, both of which are necessary for its life cycle. These two genes are flanked by two inverted terminal DNA repeats (ITR). Recombinant AAV has been stripped of both rep and cap genes and includes the ITRs that are necessary for second strand synthesis and integration in the cell. The genes necessary for vector production are provided in trans by a helper transfection system.30,31 Genetic sequences of up to approximately 4.7 kb can be inserted between the two ITRs in the viral vector for delivery into the target cell. Six different serotypes of wt-AAV exist, termed AAV1-6, but AAV2 is the most commonly used

virus vector for gene therapy, although others have recently been used.32 The recombinant version of AAV (rAAV) transduces virtually exclusively neurons in the CNS.33–37 The receptor for AAV2 has been characterized and is composed of the heparan sulfate proteoglycan receptor, and at least one co-receptor, FGF- receptor-1 (FGFr1) (Fig. 32-1).38,39 Herpes Simplex Virus Wild-type herpes simplex virus is a large linear doublestranded DNA virus that encodes over 80 genes spanning a genome of about 150 kb. The wild type virus is the pathogen that is associated with cold sores, as well as corneal blindness and encephalitis. Wt-HSV can infect a wide variety of cells due to the envelope binding to heparan sulfate and herpes virus entry mediators. After endocytosis, the wt-HSV virus is retrogradely transported to the cell body and eventually to the nucleus where it replicates. Wt-HSV can infect cells lytically or establish latency.40 HSV-1 can infect both neurons and glia.41 There are two types of HSV-1 vectors: recombinant virus and amplicon vectors. The recombinant HSV virus contains almost the entire genome, and the gene of interest is inserted in this vector by homologous recombination. Potentially, up to 150 kb could be inserted in this vector if all viral genes could be removed.42 The amplicon vector system is produced similarly to other recombinant vector systems and contains a viral origin of replication and a packaging signal, while the genes necessary for virus production and replication are provided in trans by a helper virus/transfection system.43–45 One of the problems of the HSV-1 vectors is their inherent cytotoxicity and their inability to support long-term expression in vivo. Work regarding production methods that allow more viral genes that mediate toxicity to be removed is being continued. In addition, the factors controlling longterm in vivo expression are also being elucidated.41,46–48 Therefore, there is no reason to doubt that HSV vectors will become useful for gene transfer to the CNS.49 Indeed, HSV’s inherent neural tropism, retrograde transport, and large transgene capacity are attractive features to be exploited in the future. Lentivirus Lentiviruses belong to the retrovirus family of RNA viruses. In contrast to more commonly studied oncoretroviruses, they can infect both mitotic and postmitotic cells.50 Human immunodeficiency virus (HIV) type I is classified as a lentivirus. Because HIV is one of the most studied wild-type viruses and production of recombinant retroviruses has the longest history in gene therapy, it was natural to study HIV as a potential viral vector for gene transfer.51 Similar to all retroviruses, the lentivirus genome consists of the gag, pol, and env coding regions that encode the core proteins; the virion-associated enzymes; and the envelope glycoprotein,

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Figure 32-1. Striatal transduction of neurons after a single 2.0-mL injection of rAAV expressing enhanced gfp driven by the CBA promoter in a rat. The survival time of the sample shown here was 3 weeks after vector injection. The vector was injected over 2 minutes. The 40-mm sections were immunostained using an anti-gfp antibody and developed using the diaminobenzidine chromogen. The arrow indicates the site of the injection. We estimate that approximately 400,000 neurons were transduced after injection of 8 ¥ 108 infectious particles. cc, corpus callosum; GP, globus pallidus; LV, lateral ventrical; str, striatum.

flanked by the long terminal repeats (LTR). The LTRs are important for integration, transcription, and polyadenylation. Lentiviruses are more complex than other retroviruses because they contain other regulatory genes such as tat and rev, as well as other accessory genes including vif, vpr, vpu, and nef. The tropism and stability of the virion of the recombinant version of the HIV virus have been extended by pseudotyping the envelope glycoproteins with the envelope of the vesicular stomatitis virus glycoprotein (VSV-G).52 A number of nonreplicating vectors have been developed that involve three viral transfection constructs: a packaging construct, the vector containing the LTRs, and a plasmid encoding the VSV-G.53,54 Because of the concern about HIV vector biosafety, two new generations of lentivirus vectors have been developed. The first consisted of vector production

plasmids with removal of all of the accessory HIV genes from the plasmid that are unnecessary for vector propogation (vif, vpr, vpu, and nef) and supplying the essential tat gene in a separate plasmid to produce the tat protein in trans.55 The third-generation version of lentiviral vector, termed the self-inactivating lentivirus, was produced by inactivating the 5¢ LTR to vastly reduce the probability of a recombination event after the vector genome has integrated into the host.56 These self-inactivating viral vectors lack the promoter and enhancer sequences in the LTR to prevent possible replication of the virus during vector production. Recently, a packaging cell line containing VSV-G has been developed that may allow high titer production of the virus.57,58 Lv vectors have been extensively used in the nervous system and show a tropism toward neurons, though it does show expression in a minority of glia as well.53,59

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Nonviral Vectors Nonviral gene therapy delivers genes to cells in the form of a circular DNA, termed plasmid DNA, which is propagated in bacteria. The plasmid contains the following features: a prokaryotic origin of replication sequence to amplify the number of plasmids per bacteria, a drug resistance gene to selectively grow only those bacteria containing the plasmid, and a eukaryotic expression cassette to express the therapeutic gene in eukaryotic cells. The expression cassette is composed of a promoter sequence that signals RNA polymerase II to initiate transcription, a cap sequence to yield a G-methyl capped RNA, an intron/exon for correct post transcriptional processing, a Kozak sequence to identify the correct translational start codon, a stop codon to halt translation, a 5¢ and 3¢ untranslated region for intracellular trafficking and transcript stability, and a poly A signal for polyadenylation of the transcript. The plasmids can be manufactured in large scale, currently at tens of grams scale, under the U.S. Food and Drug Administration’s (FDA) Good Manufacturing Procedures (GMPs). Surprisingly, even though plasmid DNA is highly negatively charged and has a molecular weight greater than 106 daltons, the plasmid can be administered by itself into tumors or muscle yielding gene expression,60 although the expression levels are lower than those obtained with formulated plasmid or application of external stimuli. Plasmids also can be formulated with polymers or lipids to facilitate gene transfer by increasing cell uptake of the plasmid. The polymers can either be a neutral, noninteractive molecule, such as polyvinylpyrolidone or poloxamer,61 or positively charged polymers, such as poly-L-lysine, chitosan, or polyethyleneimine. The neutral polymers are effective for local administration to the muscle or tumors, although the mechanism by which gene transfer is increased is unknown. Similar to the positively charged polymers are the positively charged lipids, first discovered in the late 1980s.62 The lipids are composed of a positively charged head group attached to hydrophobic acyl chains. The head group either ion pairs with the phosphate backbone or hydrogen bonds to the DNA. The lipids are formulated in the form of liposomes and added to the plasmid. On binding of the cationic liposomes to the DNA, a transfection complex is formed. These complexes are effective for systemic delivery and yield gene transfer to the lungs, liver, and spleen.63,64 Nonviral vectors have been used in CNS, although duration of expression and expression levels have not reached those reported for viral vectors. However, as stated previously, continued development of nonviral vectors will eventually lead to the most characterized and consistent vectors for gene therapy in the future.

Transcriptional Regulation The ability to regulate the levels of transgene expression of a gene that is successfully expressed via ex vivo or in vivo

gene transfer in the CNS will ultimately be an important issue for this field of study. Although other schemes exist, the main focus of transgene regulation has been at the transcriptional level by engineering internal promoters that are dependent upon binding some external prodrug, either for onset or cessation of promoter activity (Table 32-2). The most highly developed version of this regulation concept is the tetracycline-regulated promoter system.65 This system, which now includes both an inducer and a repressor system,66 has been used successfully in both viral vectors67,68 and transgenic animals.69–71 Other promising transciptional regulation candidate systems that are amenable to gene transfer vectors also exist, one of which uses a progestininducible system72–75 and another which uses a rapamycindimerizing system.76–78 The further development of these gene regulation systems is important for the future clinical progression of gene therapy. It is obvious that, with the exception of gene therapy strategies designed to destroy tumors or in cases where the transgene is completely nontoxic, virtually all gene therapy applications will require the ability to externally regulate protein levels in the CNS for individual dosing and as a safety net in the event of side effects.

Target Central Nervous System Disorders Parkinson’s Disease Parkinson’s disease (PD) is a progressive neurologic disorder of the CNS characterized by degeneration of dopamine (DA)-producing neurons of the substantia nigra that causes motor impairment manifested as rigidity, bradykinesia, and tremor.79 Due to the relative clinical success obtained with transplantation of fetal ventral mesencephalic tissue in PD but the lack of a consistent or sufficient supply of tissue, and the existence of good animal models, gene therapy for PD has been well studied.80 The following sections discuss the two main strategies, transmitter replacement and protective strategy, that are currently being pursued for PD gene therapy. Transmitter Replacement A broad gene therapy approach is striatal dopamine (DA) replacement, which might provide local striatal delivery of DA in a pharmacokinetically advantageous manner. In theory, local delivery of l-dopa via gene transfer would reduce side effects due to extrastriatal conversion of l-dopa to DA and continuous delivery of l-dopa would reduce motor fluctuations. Thus, to deliver l-dopa, the gene for the rate-limiting enzyme for DA production, tyrosine hydroxylase (TH), must be expressed. Moreover, tetrahydrobiopterin (BH4) is a cofactor necessary for the reaction catalyzed by TH, and the primary enzyme required for BH4 production is GTP-cyclohydrolase 1 (GTPCH1). Given this biosynthetic

Dimerizing activity of immunosupresssants such as Rp, FK506, and cyclosporin A Human progesterone-receptor

Rapamycin (Rp)

Mifepristone

Rapamycin

Ec or analogs (e.g., muristerone A)

Gal4/PR-LADD/VP16 fusion protein§

Heterodimer of retinoid X receptor and Ec receptor/VP16 fusion protein Herterodimer of ZFHD1/FKBP12‡ and NfKBp65/FRAP‡

Reverse Tet repressor-VP16 fusion protein

Tet repressor-VP16* fusion protein

Activator

Presence of Te induces binding of activator to Tet O Ec induces dimerization of activator and binding to Ec-DNA responsive element.† Rp mediates dimerization of activator and binding to ZFHD1 DNA-responsive sites Presence of RU486 mediates activator binding to GAL4 DNA sites

Absence of Tet releases repression in Tet O

Activation

~3.5K fold

~5 K fold

~3 K fold

Same

~4 K fold

Levels

Pleiotropic effects on mammalian systems due to retinoid X receptor Immunosuppressive effects could prove detrimental in long-term therapies Anti-progesterone, anti-glucocorticoid activity must be suppressed

Cytotoxic effects and high doses of Tet or analogs can potentially cause bone and liver abnormalities

Safety

*VP 16 is a transcription-activating domain. † Ec-DNA responsive element is a hybrid binding site consisting of both Ec-binding sites and glucocorticoid-responsive elements. ‡ ZFHD1/FKBP12 is a fusion protein consisting of DNA binding domains (ZFHD1) and Rp binding domains. NFkBp65 is a transcription-activating domain fused to the Rp binding domain of FRAP. § Gal4 is a DNA-binding domain. PR-LBDD is a truncated form of the human progesterone receptor incapable of binding to progesterone but able to interact with mifepristone.

Mifepristone (RU486)

Steroid hormone in D. melanogaster

Eckysone (Ec)

Same

Reversible

Same

Tet and analogs (e.g., doxicycline)

Tet resistant operator (Tet O) of E. coli

Tetracycline (Tet)

Inducer

Original

Biological Origin

System

Induction

Table 32-2  Comparison of the Four Most Developed Transcriptional Regulation Systems for Use in Gene Transfer Vectors

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pathway, one strategy for increased production of DA is vector-mediated over-expression of both TH and GTPCH1 in target tissues of the neostriatum. The advantages and disadvantages of this strategy have been reviewed in detail.81 Another transmitter replacement approach involves improving the effectiveness of oral l-dopa by supplying the DA-depleted neostriatum with an overabundance of the enzyme aromatic amino-acid decarboxylase (AADC) to convert oral l-dopa to DA more efficiently, specifically in striatum. In culture, rat and monkey models of PD, rAAV delivered AADC has been shown to increase striatal DA production in response to systemic l-dopa administration.82,83 The conceptual advantage of this approach for PD patients might be that enhanced AADC expression specifically in striatum could allow lower doses of Sinimet (carbidopalevodopa) to produce a greater clinical effect while reducing extrastriatally mediated side effects. Another major advantage of this approach is that Sinimet treatment would become a pro-drug approach for the transgene where no effect of the transgene would be seen without Sinimet treatment, thus obviating transcription regulation of the transgene product. Protection of Dopamine Neurons via Trophic Factor Delivery While gene therapy using transmitter replacement in PD is a symptomatic therapy that does not address the underlying ongoing death of nigrostriatal DA neurons, viral delivery of neuronal growth factors is considered a potential method to halt the ongoing progressive cell death in PD. The most potent DA-ergic neuronal growth factor studied to date is glial cell line—derived neurotrophic factor (GDNF).84 Gene therapy for PD using vector-delivered GDNF has been recently reviewed in detail.85 This field has progressed rapidly in the past 3 years. Initially, the focus of gene transfer was the substantia nigra; however, it became clear that even though these strategies protected all the nigral DA neurons from neurotoxin-induced cell death, there was no functional impact of the GDNF treatment because striatal DA innervation is necessary for motoric recovery.84,85 Thus, it was subsequently demonstrated that striatal viral derived GDNF was most effective in inducing behavioral recovery in both rats86–88 and monkeys.89 Therefore, this strategy is being seriously considered for eventual clinical trials.90 However, effective transcriptional regulation of the transgene66 will have to be first developed and characterized because of the potential for side effects associated with GDNF administration.91 Finally, strategies aimed at inhibition of apoptosis are beginning to appear. The interest in these approaches is based on data that indicate that nigral cell death in PD may be apoptotic.92 To our knowledge the first report using an anti-apoptotic gene in an in vivo gene therapy setting for PD showed nigral HSV-mediated bcl-2 expression substantially blocked 6-hydroxydopamine-induced cell death.93 However, as discussed previously, this strategy would not be expected to produce symptomatic relief because the nigrostriatal DA

terminal field is not protected. This was confirmed in a recent publication by Eberhart and associates, who reported protection of nigral cell bodies in the 1-methyl-4-phenyl1,2,3,6-tetrahydropyridine (MPTP) mouse model by nigral Ad-mediated expression of an X-chromosome–linked inhibitor of apoptosis but not striatal DA terminals. However, when these authors also delivered GDNF to the striatum, both the nigral DA neurons and their terminals were spared.94 Alzheimer’s Disease Alzheimer’s disease (AD) is a severe neurodegenerative disorder characterized by progressive memory loss with concomitant underlying neuropathology in most cortical structures.95 This widespread pathology is the greatest challenge for gene therapy because, under current technology, it is not feasible to transduce a great proportion of cells in the cerebral cortex. On the other hand, if some releasable factor is identified that can impact the underlying pathology of AD, then a gene therapeutic strategy may become more plausible for the treatment of AD. For many years, the field of AD research has been dominated by the hypothesis that the memory deficits characteristic of this neurodegenerative disease were caused by the specific loss of a small group of cells in the basal forebrain that use acetylcholine (ACh) as their neurotransmitter and which have widely diffuse projections to the cerebral cortex.96 Indeed, this hypothesis was strongly supported by both early neuropathological findings of reduced cortical choline acetyltransferase activity and ACh in AD, and animal model studies that showed that cholinergic depletions cause memory problems in rodents.97 The only currently approved drugs for treatment of memory problems in AD function by blocking ACh metabolism in the synaptic cleft by inhibiting acetylcholinesterase.97 However, this class of drugs is only partially effective in a subset of patients with early symptoms and the cholinergic hypothesis has been called into question.98 The first identified neurotrophic factor, nerve growth factor (NGF),99 was conclusively demonstrated to be a trophic factor for the cholinergic neurons of the basal forebrain. Injections of NGF protein into the lateral ventricles can maintain basal forebrain cholinergic neurons even after a normally lethal axotomy.100,101 Moreover, in aged rodents and primates that have been demonstrated to be deficient in cortical ACh signaling, NGF has been shown both to increase ACh synthesis and improve memory deficits.102–105 Based on the cholinergic hypothesis of learning and memory, and, given that gene transfer can be viewed as a relatively noninvasive protein delivery system, it was natural to focus on NGF delivery as a gene therapy for AD. This strategy has been taken the farthest by genetically modifying primary dermal fibroblasts to express NGF and then transplanting these retrovirally transduced cells to the basal

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forebrain.106–110 A phase I clinical trial has recently started to test this strategy in AD. Successful gene transfer of NGF also has been achieved using rLv and rAAV.111,112 However, because this strategy only affects one neuronal phenotype in a disease characterized by widespread pathology, highly significant clinical benefit in response to basal forebrain NGF delivery is unlikely. Huntington’s Disease Huntington’s disease (HD) is a rare autosomally dominant inherited progressive neurologic disorder characterized by the selective loss of GABA-ergic medium spiny neurons in the striatum.113,114 Symptoms, which usually commence during midlife, include cognitive deficits, psychiatric manifestations, and violent uncontrollable chorea. Although striatal degeneration is evident in sections of brains from patients, neuronal dysfunction in striatum before actual cell death may be responsible for the neurologic symptoms.115–119 This view agrees with recent data obtained from newly available transgenic mouse models.120–124 The discovery of the HD gene revealed that the mutation responsible for the disease consists of a trinucleotide CAG expansion within exon 1 of the HD gene.125 While the pathogenic event that leads to cellular pathology as a result of the expression of expanded polyglutamine tracts in the huntingtin (htt) protein is currently unknown, abnormal folding of the htt protein causing the propensity to form toxic aggregates has been previously predicted126–128 and recent evidence supports this idea.129 Moreover, research is ongoing with regard to whether HD pathology is due to a gain of abnormal function, a loss of normal function, or both a gain of toxic function combined with reduced function of the wildtype gene.130 Unfortunately, the powerful new transgenic mouse models of HD have not been available long enough for gene therapy strategies to have been tested under more clinically relevant, experimental conditions. However, data from “old fashioned” striatal excitotoxin models131,132 and inhibition of complex II using 3-nitropropionic,133 as well as in vitro models with fragments of htt with expanded polyglutamines suggest that neurotrophins or ciliary neurotrophic factor (CNTF) might be effective against the pathological processes in HD.134,135 It is worth noting that gene transfer technology has added to the study of the toxicity of expanded polyglutamine tracts. Senut and colleagues used rAAV for direct striatal delivery of a fusion protein consisting of expanded polyglutamine and GFP.136 They demonstrated increased apoptosis in the striatum in the area of transduction suggesting a toxic role for polyglutamine tracts themselves. Trophic Factor Delivery The use of trophic factors, such as CNTF and brain-derived neurotrophic factor (BDNF), in the treatment of neurode-

873

generative diseases has been well documented.135 Trophic factor delivery has been most effectively explored using the encapsulated cell method of ex vivo gene therapy. Clinical trials based on the transplantation of polymerencapsulated cell lines engineered to secrete CNTF in the striatum of HD patients are under way.6 This clinical trial was supported by preclinical data from excitotoxin based models in rats137 and monkeys.138,139 The neurotrophins, NGF and BDNF, have been shown to protect striatal neurons from excitotoxic injury in some experimental gene therapy settings but not universally.140–143 In one study, NGF delivered via transplanted syngeneic primary fibroblasts protected 80% of the cells destined to die from excitotoxic damage,144 but BDNF was ineffective in this experiment. Similar success was obtained using progenitor cells retrovirally engineered to produce NGF in the rat quinolinic acid model of HD.145 In contrast to the ex vivo NGF delivery data, one group has recently shown that by using rAd vectors carrying the BDNF gene, they are able to prevent degeneration in the quinolinic acid model of HD.142 The biologic basis for the actions of these trophic factors on striatal neurons is unclear. For example, striatal Trk-A expression, the high affinity receptor for NGF, is limited to the small population of cholinergic interneurons in the adult striatum.146 Similarly, in adulthood, a truncated, nonsignalling version of the Trk-B (BDNF) receptor is the predominant isoform expressed in adult striatum.147,148 In contrast, a specific depletion of BDNF in the striatum of HD brains suggests that reduction of BDNF protein is diseasedependent.141 Coupled with Saudou’s data134 indicating that BDNF can prevent cell death in cells with polyglutamineinduced intranuclear inclusions, these data suggest that BDNF delivery in mouse models of HD would be interesting to pursue. Similar to the neurotrophins, the biological action of CNTF is uncertain as CNTF does not contain a signal sequence and therefore is not normally released from the cell.149 In addition, HD patients that are homozygous for a common null allele mutation on the CNTF gene do not show earlier onset of symptoms compared to wild-type and the severity of the disease is dependent only on the polyglutamine expansion length.150 However, as previously reviewed, CNTF delivery showed promise in preclinical experiments and is currently in clinical trials using the encapsulation technology to treat HD. Glioblastoma In 1998, there were 17,400 new cases of brain and other CNS tumors reported in the United States, along with 13,300 deaths.151 Brain tumors are classified into nine different categories. Of these, glioblastoma multiforme is the most common malignant brain tumor and the cause of the majority of deaths.152 Standard therapy is surgical resection and postoperative radiation. There is an orally active

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chemotherapeutic agent, temozolomide, which has demonstrated meaningful efficacy and an acceptable safety profile.152 Efficacy is based on increase in survival time rather than complete remission. Hence, the prognosis for malignant forms of brain cancer is poor, thus justifying a need for the development of an effective therapy. Gene therapy for treatment of brain cancer was first initiated with the delivery of a herpes virus–derived thymidine kinase gene to brain tumors using a replication incompetent retrovirus.153,154 De novo expression of thymidine kinase in dividing cells leads to the production of a toxic nucleoside when the drug gancyclovir is administered after gene transfer. This leads to the death of any cell actively producing DNA (dividing) and simultaneously harboring the thymidine kinase gene. Excitement for this strategy was greatly enhanced by the observation that incomplete transduction of the tumor was still sufficient to support removal of the tumor by gancyclovir treatment, an effect termed “the bystander effect.”155,156 As this is the most mature effort in gene therapy for glioblastoma, the HSV thymidine kinase strategy has moved into the clinical trial stage with varying success.157 Moreover, research into improving the success of this strategy has continued.158 However, since the advent of the initial thymidine kinase gene transfer strategy, there has been an explosion of new strategic avenues in gene therapy for glioma. Moreover, because of the prognosis for survival after diagnosis is poor, highly experimental therapies such as gene therapy are even more attractive from an FDA regulatory point of view as could be the case for ALS, as noted following. A cursory search in Pubmed yields 493 publications on this topic; 148 only regard the thymidine kinase strategy. Therefore, a full review of the literature is beyond the scope of this chapter. Interested readers are referred to several recent reviews of this important field.158–161 Currently, there are many new genes, such as antiangiogenesis factors162–164 to block angiogenesis, Fas ligand for cell killing,165,166 pro-apoptotic genes,167,168 cytokines such as IL4169,170 or GM-CSF171 as immuno-amplifiers that are realistic for use in gene therapeutic strategies for glioma. In addition, new gene delivery vehicles such as VSV pseudotyped retrovirus to increase viral tropism,172 and combination therapies, such as expression of angiostatin and in combination with radiation173 or p53 expression and radiation174 are being developed for the treatment of brain cancer. All of these therapies focus on local administration directly into the tumor. The preceding approaches rely on viral gene delivery, using either a retrovirus or adenovirus. The retroviruses have been shown in the clinic to be extremely inefficient or nearly incapable of infecting human tumor cells.175 On the contrary, adenovirus can infect tumor cells. However, expression of the CAR receptor and an integrin are required for infection. In addition, adenovirus has immune implications associated with it that can lead to unwanted inflammation.20,21 Recently, a combination of lipofectamine transfection

complexes immediately after bradykinin administration showed transfection of brain tumor endothelium and tumor cells.176 Thus, nonviral vectors will also likely play a significant role in this field in the near future. Another related approach that has received recent attention is the use of wild type oncolytic viruses such as reoviruses and polioviruses to treat experimental gliomas.177–180 With regard to the poliovirus version of this strategy, sequences within the polio virus are engineered to reduce virulence in normal neural tissue but cytotoxicity is retained in cell lines derived from glioblastomas.178 In the case of the reovirus strategy, available data suggest that this virus is nonpathogenic in its normal latent peripheral respiratory or enteric location.177,179,180 However, on exposure to cells with activated ras pathways, this virus becomes cytolytic. Advocates of the reovirus strategy contend that activated Ras is a very common feature of idiopathic gliomas.179 As is the case with research into gene therapy for glioma, the fact that the currently available tumor models may not be as invasive as the idiopathic human versions hinder the interpretation of the strongly positive data obtained using the wild-type oncolytic virus strategy.177 Amyotrophic Lateral Sclerosis Amyotrophic lateral sclerosis (ALS) is a neuromuscular disorder characterized by loss of motoneurons in the brain and spinal cord. The hallmark symptoms of this progressively debilitating disease are muscle weakness and spasticity that eventually lead to respiratory failure and death within 4 years of disease onset. At the cellular level, muscle denervation, cytoskeletal abnormalities in motoneurons,181 vacuolar degeneration,182,183 and cellular aggregates are observed.184–186 The cause of the disease is uncertain, but several theories have been proposed.187–189 The fact that motoneurons show selective vulnerability in ALS has been discussed in several reviews.188,190–192 The best targets for gene therapy regard a subset of hypothesized potential cellular defects in ALS, for example, superoxide dismutase-1 (SOD1) mutations, glutamate excitotoxicity, and cytoskeletal defects. SOD-1 Mutations Approximately 1% of ALS cases have been shown to have a mutation in the Cu2+/Zn2+ SOD-1 gene.193 The ubiquitously expressed SOD-1 protein converts superoxide to water and hydrogen peroxide to regulate oxidative stress in the cellular cytoplasm. Interestingly, there is no alteration in SOD-1 enzyme activity in familial ALS.194,195 Furthermore, transgenic mice overexpressing wild-type SOD-1 do not display motoneuron pathology,186 and SOD-1 knock-out mice only display a mild phenotype.196,197 These findings suggest that the mutant SOD-1 protein obtains a gain of toxic function.187,188 A number of transgenics have been generated that express different SOD-1 mutations identical to a subset of those seen

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in familial ALS, and these mutant mice develop ALS-like symptoms.197–200 Several trophic factors have been identified in various assays that might be active in ALS. Indeed, an illfated ALS clinical trial using peripheral injection of CNTF was undertaken.201 However, the toxicity observed in that trial was probably related to the systemically delivered protein crossing the BBB and affecting the hypothalamus.202 Therefore, site directed delivery via gene therapy would seem to be more ideally suited to this task. This has raised interest in gene therapy for ALS. As mentioned previously, CNTF is currently being delivered via intrathecal encapsulated genetically modified cells in ALS in a phase I trial, and side effects have not been reported.6 General technical issues related to gene therapy in the spinal cord will be discussed following. In a model of facial nerve axotomy both GDNF and BDNF have been demonstrated to rescue motorneurons.203,204 In an ex vivo gene therapy setting, myoblasts were retrovirally transduced to produce GDNF and transplanted into two hindlimb muscles.205 This ex vivo treatment resulted in reduced motoneuron shrinkage and improved performance in motor tests.205 In contrast, ex vivo gene GDNF delivery via encapsulated cells had an effect on neuron survival but did not prevent axonal degeneration in mice with progressive motoneuron degeneration (pmn).206 In contrast, similar mice using an identical CNTF delivery approach displayed a retardation of neuronal degeneration in this model.207 Intramuscular adenoviral transduction of another neurotrophin, NT-3, has shown significant activity in pmn mice resulting in an actual increase in life-span.208,209 More recently, lentiviral delivered GDNF was found to increase neuronal survival and proximal axon degeneration in a facial nerve axotomy model.210 In this case, the vector was injected directly into the facial nucleus. One possibility raised by these data is that GDNF is more efficient when delivered in or proximal to the cell body. This, in turn, raises an important problem for gene therapeutic strategies in ALS. All upper and lower motoneurons are affected by the ALS disease process. Therefore, if in vivo GDNF delivery must occur at the level of the cell soma, then the motoneuron pools of the entire spinal cord, not to mention motoneurons at various suprasegmental levels, will require transduction for a successful therapy in ALS. This is obviously a daunting and currently unrealistic consideration that will need to be resolved or somehow circumvented. Regional rescue of motoneurons (e.g., phrenic motoneurons) has been entertained and might be more feasible; however, what that would mean in terms of an individual’s quality of life would still require serious consideration. Spinal Cord Pathobiology Obviously injury to the spinal cord, irrespective of the etiology of the damage, is devastating to the victim, and, in most cases, there is no consistently successful treatment available for the bulk of spinal maladies. Therefore, the use of gene

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transfer to deliver protective or regenerative proteins either as a monotherapy or in combination with other approaches is an attractive proposition. At a minimum, gene transfer techniques offer the opportunity to study individual factors in a site-directed manner to tease out molecular mechanisms of regeneration of injured spinal cord. Various approaches to the treatment of spinal-related disorders are discussed in the following sections in terms of in vivo and ex vivo strategies. In Vivo Gene Delivery and Potential Applications in Motor Degenerative Disease and Spinal Trauma Peripheral Delivery and Retrograde Transport of Vector As discussed with regard to ALS, a major emphasis of experimental in vivo gene delivery to the spinal cord has been focused on motoneuron transduction.211 One of the first approaches to accomplish motoneuron transduction has involved intramuscular injections with viral constructs or plasmids that are retrogradely transported to the motoneuron innervating the muscle injected.212 Because wt-HSV-1 is neurotropic and is transported in a retrograde manner up peripheral nerves, HSV-1 vectors were among the first developed for the purpose of motoneuron transduction.213,214 A complication of HSV-1 is the host immune response to the vector which limits transgene expression.213 More recently, attenuated live HSV vectors have been similarly used with less reported vector-induced pathology of the spinal cord.215 Adenoviral vectors are also transported in a retrograde manner in the CNS.17,216,217 Thus, successful transduction of motoneurons after intramuscular injection of rAd has been demonstrated.217–219 Intraspinal Delivery via Intraparenchymal or Intrathecal Injection Direct injection of adenovirus into the spinal cord also results in efficient transduction of neurons and glia at the site of injection, and of neurons that project to the injection site via retrograde transport.219,220 As is the case with first generation rAd, transgene expression can be transient, either due to promoter shut-off or immune response, and this phenomenon has been reported after intraspinal rAd transduction.219 However, rAd-mediated transgene expression does not appear to affect normal neuronal neurophysiologic properties.221,222 Indeed, consistent with these neurophysiologic findings, behavior in an operant runway task was not affected by rAd transgene expression in the spinal cord.219 However, consistent with findings based on Ad gene transfer to the brain, intraspinal injections of earlier generations of this vector were associated with inflammatory and/or immune responses and gliosis.219,223 As indicated previously, rAAV has not been associated with an inflammatory response in the CNS. This lack of host response to rAAV transduction was confirmed in the spinal

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cord by Peel and co-workers.34 This first report of the use of rAAV in the spinal cord demonstrated 15 weeks of marker gene expression in the absence of any overt sign of inflammation.34 Moreover, the study by Peel and associates included a comparison between a neuron-specific internal promoter, neuron-specific enolase (NSE), and the platelet-derived growth factor (PDGF) promoter.34 This comparison yielded interesting results that indicated neuron-specific transgene expression from both promoters.34 It was subsequently found, however, that rAAV-mediated neuronal transduction could be achieved even when using the glial fibrillary acid protein (GFAP) promoter.224 These data are in agreement with the notion that rAAV only infects neurons.33,37 These studies of rAAV-mediated spinal cord transduction have since been extended with improved vector preparations of higher titer and purity.225 These new studies demonstrate that rAAV gene delivery to the adult rat spinal cord results in a persistence of transgene expression extending beyond 1 year with no evidence of overt pathology of transduced neurons or their neighbors (Reier, Velardo, Williams, Burger, and Muzyczka, unpublished observations). Functional in Vivo Gene Transfer and Treatment of Spinal Cord Disorders While several basic issues related to in vivo gene delivery to the spinal cord have been addressed in the normal spinal cord, very few experiments have been thus far carried out in the diseased or injured spinal cord. Nevertheless, there are several plausible strategies to study the effect of gene transfer in the injured spinal cord, of which neuronal rescue and axonal regeneration and/or induced-sprouting will be reviewed (Fig. 32-2A and B). Neuronal Rescue Using peripheral injections of rAd encoding either BDNF, CNTF, or GDNF alone or in combination, several groups have shown significant rescue of facial and spinal motoneurons that were at risk of imminent death following axotomy.223 Investigations also have begun in which rAAV is delivered before or after spinal cord injury. These studies indicate that neurons transduced with rAAV-gfp expressing vectors (alone or downstream of genes encoding NT3, BDNF, or LIF) prior to spinal injury will continue to express the marker transgene following axotomy even in cells (e.g., dorsal nucleus of Clarke) that will undergo progressive retrograde death after axotomy. A similar finding has been reported for gene transfer via injections of naked plasmids into the injured spinal cord.226 It is currently being investigated whether and for how long after axotomy cells that are susceptible to imminent cell death can be successfully transduced and express transgenes of interest. Apoptosis, or programmed cell death, is the final common pathway following many different kinds of CNS damage. Transfer of the anti-apoptotic gene, Bcl-2, has been

Figure 32-2. A, Transduction of neurons in the ventral gray matter of the adult rat spinal cord using rAAV expressing enhanced gfp driven by the CBA promoter. Transduction was achieved by multiple site, stereotaxically guided micropipette injections of a total of 1.0 mL of the rAAV construct using a picospritzer. Survival time after infection is 8 weeks. Longitudinally oriented dendritic bundles are also seen. B, The same specimen as illustrated in (A), but two spinal segments rostral to the nearest injection site. This longitudinal section shows the extensive degree of anterograde gfp expression that accompanies neuronal transduction with rAAV. Tightly bundled axons in lateral white matter (WM) are seen at the upper edge of the figure. The remainder of the illustration demonstrates numerous neuritic processes in gray matter. This is not an accurate representation of the appearance of native GFP fluorescence which, of course, is normally green, not white as shown.

attempted using rAd or nonviral plasmid cDNA.226,227 In both cases, some increased survival of neurons otherwise destined to die was reported.226,227 Similar success has also been reported after rAd-mediated expression of GDNF in the rabbit spinal cord model of ischemia produced by infrarenal aortic occlusion.228 Thus, motoneurons in the lumbar cord were spared relative to controls when rAd-GDNF was injected in the spinal cord 2 days before the ischemic event.228 Axonal Regeneration and Sprouting To date, there are few examples of the capacity of in vivo gene delivery to promote axonal regrowth. One model for

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addressing axonal regeneration builds on the fact that when dorsal root sensory axons are cut, they are unable to grow back through the dorsal root entry zone (DREZ) and into the spinal cord parenchyma.229–233 Thus, Zhang and associates234 transected the fourth, fifth, and sixth lumbar spinal nerves of adult rats and then reanastomosed them. Then, to determine whether a vector-delivered neurotrophin could be used to encourage regeneration of primary afferents through the DREZ, an adenoviral vector containing the NT-3 gene was injected into the ventral horn of the lumbar spinal cord 14 to 19 days after transection. Strong expression of the transgene was observed both in glial cells and in motoneurons for up to 40 days after injection. They report increased fiber invasion through the DREZ to Lamina V. Others also have reported modest success using an rAd-delivered transgene that affects transcription factors involved in neurite outgrowth.235 As a cautionary note, unintended axonal growth or sprouting also can be induced in the spinal cord setting. For example, injection of an rAd encoding NGF into the normal gray matter of the spinal cord resulted in sprouting of painmediating primary afferent fibers.236 Animals treated in this manner demonstrated hyperalgesia in a pattern consistent with the site of injection. This type of result clearly illustrates the need for regulated transgene expression in almost any therapeutic target. In Vivo Gene Delivery and Modulation of Allodynia Gene therapy for the treatment of neuropathic pain is a promising clinical avenue for development of this novel technology. Traditional analgesic treatments, which focus upon peripherally administered, centrally acting pharmacologic agents (e.g., opiates), have multiple shortcomings when used for the control of chronic pain syndromes. These drawbacks include the need for repetitive administration, general CNS and respiratory drive depression, and desensitization or addictive properties. The complications might be obviated by an in vivo gene transfer approach that includes the de novo genetic expression of analgesic peptides, such as endorphins and enkephalins.237 Recombinant HSV-1 encoding rat preproenkephalin A has been engineered to drive the production of enkephalin in rat dorsal ganglia.238 Three weeks after infecting the hindlimb footpads, met-enkephalin levels were increased 40% to 160% in the dorsal spinal cord and dorsal ganglia. Moreover, when the vector was applied to the abraded skin of the mouse dorsal hindpaw, it selectively blocked hyperalgesia (responses to radiant heat, capsaicin, and dimethylsulfoxide) mediated by C and A delta fibers without disrupting normal sensory neurotransmission.238 This analgesic effect lasted at least seven weeks postinfection.238 Finegold and colleagues239 transferred the gene for a potent form of endogenous beta-endorphin to the meninges surrounding the spinal cord using rAd. The vector transduced pia mater cells

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and ameliorated hyperalgesia in an inflammatory model of chronic pain, without having an effect on baseline nociceptive responses.239 Applications of ex Vivo Gene Delivery to Spinal Cord Pathology To date, the most extensive experience with gene delivery to the spinal cord has involved ex vivo transfer via genetically modified cells such as fibroblasts,240–246 Schwann cells246,247 or neural stem cells.248,249 As in the case of in vivo gene transfer, studies of spinal cord injury and regeneration have mainly started to explore the effects of different neurotrophins, secreted by grafts of transduced cells, on neuronal survival and axonal regrowth and/or sprouting. An appealing feature of the ex vivo approach is that gene delivery can be coupled with a complementary transplantation approach in a single procedure. This becomes attractive because it is likely that the transplanted cells also provide factors or favorable substrates that amplify the positive biologic response in these systems. Neuronal/Tissue Rescue Genetically modified fibroblasts expressing NGF or BDNF were placed directly into thoracic contusion injuries.250 Tests of locomotor recovery showed faster functional improvements in grafted animals as compared to those receiving transplant controls; however, the functional benefits seemed to wane over time. Neuropathologic analyses at 6 weeks after injury/transplantation also suggested a greater degree of tissue sparing in the animals that had growth factorexpressing grafts. Other more recent lines of evidence251 suggest that BDNF secretion by modified fibroblasts can rescue magnocellular rubrospinal neurons, which either die or undergo severe atrophy after spinal injury. Axonal Growth and Functional Responses An impressive degree of axonal growth has been elicited in the normal or injured spinal cord in experiments involving the transplantation of syngeneic, genetically modified fibroblasts expressing various neurotrophic factors or cell adhesion molecules. As seen with in vivo delivery approaches,236 both injured and uninjured neurons are responsive to these molecules.107,249,252–254 In some cases, axons show robust ingrowth into the fibroblast grafts. With one notable exception,248 axons that enter these grafts usually fail to exit,255 much like what has been described with grafts of peripheral nerve. There is some evidence that similarly modified Schwann cells may perform even better in this regard.256,257 Neuronal populations are differentially stimulated by genetically modified cells depending on the neurotrophin being secreted and which neurotrophin tyrosine kinase receptors are expressed.258 Accordingly, very robust regeneration can be promoted by grafts of NGF-producing

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fibroblasts into acute or chronically injured spinal cords.243,255 Similarly, fibroblast grafts engineered to secrete NT-3 or BDNF in the contused spinal cord can stimulate ingrowth of local choline acetyltransferase-immunoreactive axons, whereas this was not the case with similar grafts expressing NGF, CNTF, or bFGF.254 In addition to local responses, lesioned corticospinal tract (CST) fibers can be induced to sprout after administration of exogenous NT-3 after spinal cord injury (SCI).259 Consistent with this, Grill and co-workers244 reported that continuous cellular delivery of NT-3 over a 3-month interval led to the regrowth of lesioned CST fibers, which was observed primarily in host gray matter at and below the lesion site. In a shorter term version of this experiment (2 weeks) from the same group, leukemia inhibitory factor (LIF)-producing fibroblasts also were reported to attract CST axons.243 In this study, the LIF fibroblasts appeared to induce endogenous production of NT-3 with no effect on other neurotrophic molecules. This effect of LIF in SCI was investigated in an in vivo setting using rAAV with no discernable effects on CST ingrowth to the lesion site (Williams, Velardo, and Reier, unpublished observations). These data underscore the suggestion that the cellular component of the ex vivo approach can be an important variable to consider. Augmentation of Intrinsic Repair Processes In addition to promoting axonal regeneration, gene therapy also appears to offer potential for modulating intrinsic repair mechanisms, particularly with regard to demyelination and remyelination after spinal trauma. Using an ex vivo approach involving fibroblasts expressing PDGF, Ijichi and associates260 reported that they were able to increase the number of O2-A oligodendrocyte progenitor cells in the spinal cord. McTigue and colleagues demonstrated similar effects expressing NT-3 and BDNF in fibroblast grafts.254 This is presumably due to the fact that oligodendroctyes and their progenitors express all three neurotrophin tyrosine kinase receptors.261 These data suggest that oligodendroglia or their precursors may be recruited to an injury site in the presence of ex vivo-delivered neurotrophins. Thus, it remains to be explored whether an ex vivo or another gene delivery approach can be effectively used to recruit oligodendrocytes or their precursors for remyelination of denuded, but spared, axons in the clinically relevant spinal contusion injury paradigm. Ex Vivo Gene Delivery and Modulation of Pain Neuropathic pain often occurs following peripheral nerve damage and can be modeled in the rat by virtue of a chronic constriction injury (CCI) whereby the sciatic nerve is exposed and four loose ligatures are tied around it.262 In this model, mild thermal or tactile stimulation of the affected hindlimb subsequently elicits abnormal behavioral responses. Thus, hyperalgesia and allodynia are associated with the CCI model and manifested within 1 week after

surgery. Serotonin (5HT) projections to the dorsal spinal gray matter from the brainstem raphé and neighboring reticular formation have been shown to exert an antinociceptive effect on the spinal cord by way of descending inhibition of dorsal horn neurons and primary afferent fibers.263 Along these lines, a neuronal cell line has been developed264 to release neurotrophic molecules or specific neurotransmitters such as serotonin (5-HT).265,266 These cells have been demonstrated to synthesize and secrete 5-HT due to their endogenous phenotype but only when exposed to BDNF either in vitro or in vivo. Therefore, to permit serotonergic differentiation of this RN46A line, the cells were transfected with the rat BDNF gene. The resulting RN46-A-B14 cell line can subsequently survive for at least 7 weeks after grafting to the lumbar spinal subarachnoid space. When grafted 1 week after sciatic CCI, these cells were able to alleviate chronic neuropathic pain in terms of a reduction in tactile and cold allodynia and thermal hyperalgesia that is induced by CCI.265,266 Similar effects were obtained with grafts of another immortalized cell line (RN33B) which was transduced to express galanin267,268 or GABA.266 Because BDNF can induce intrinsic serotonergic systems as well and play other significant roles in central pain modulation,269 the results obtained with the RN46-A-B14 cell line cannot be fully attributed to 5-HT being produced by the grafted cells. In agreement with this possibility, a more recent study showed that a BDNF-secreting cell, derived from the RN33B rat neuronal cell line, could reverse the same chronic pain manifestation after CCI as did the 5HTproducing grafts.270 Gene transfer is also suitable for ex vivo methodologies, in which transplanted cells also can be engineered to deliver antinociceptive molecules.271 Along these lines, Eaton and coworkers267 created temperature-sensitive galanin-secreting cells by transfecting the RN343b rat neuronal cell line with the gene for rat preprogalanin. After inducing a neuropathic pain syndrome in rats by unilateral chronic constriction of the sciatic nerve, they grafted galanin or control cells into the lumbar arachnoid space. Both tactile and cold allodynia and tactile and thermal hyperalgesia were significantly reduced or eliminated during the 2- to 7-week post-transplantation interval. In a similar ex vivo study, Hagihara and associates272 implanted mouse neuroblastoma cells capable of secreting beta endorphin into the subarachnoic space of the spinal cord. These authors engineered the construct so that a tetracycline-sensitive promoter was linked to the POMC gene, thus, they were able to induce expression of gene product by administering intraperitoneal injections of tetracycline. Gene Therapy for Spinal Cord Disorders: Conclusions and Comments Applications of gene therapy to various spinal cord disorders related to either disease or trauma are still very limited and are mostly phenomenologic in principle by virtue of the still evolving nature of in vivo and ex vivo approaches and their

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underlying technologies. Many of the unresolved technical and conceptual issues confronting gene transfer to the spinal cord are similar to those that also weigh heavily on the use of various vectors or cellular platforms for treating neurologic disorders affecting the brain and brainstem. For example, highly directed gene delivery to specific neuronal or glial populations still represents a major challenge to in vivo gene delivery in most regions of the CNS, and this is no less the case when considering gene therapy for the treatment of various spinal disorders. Gene delivery to spinal gray matter often entails a rather nonselective infection of neurons within the immediate vicinity of the injection site.8,34,273 In the case of ALS or after spinal cord injury spasticity, an obvious approach would be to selectively target motoneurons or specific interneuron phenotypes, respectively. Furthermore, in the case of trauma, gray matter surrounding the primary lesion is in immediate jeopardy and may demand one type of neuroprotection directed at neurons, whereas oligodendrocytes, which often die later in the postinsult period, would be another cellular target requiring a different gene product, as well as a potentially different viral platform with high affinity for glial cell types. Lastly, optimal treatment of neuropathic pain syndromes could necessitate infection of specific dorsal horn neurons. These and several other issues that relate to the temporal and spatial distribution of gene products, controlled durations and levels of expression notwithstanding, it is encouraging that powerful trophic and tropic effects can be obtained with gene transfer. As indicated by this overview, these approaches can augment regeneration and plasticity in the injured spinal cord or modulate neural circuits as in the case of chronic pain management. Furthermore, it is conceivable that in vivo and ex vivo strategies can be used in tandem, not to mention in conjunction with other therapeutic approaches for spinal injury and other spinal disorders.

Lysosomal Storage Disorders The deficiency of any lysosomal enzyme results in accumulation of its substrate in lysosomes. Because of specific expression patterns of specific lysosomal enzymes, accumulations of glycoproteins tend to occur in regional tissues creating a characteristic clinical picture. Some of these diseases include Hurler syndrome, Hunter syndrome, I-cell disease, Niemann-Pick disease, Gaucher disease, and Krabbe disease. Lysosomal storage diseases (LSDs) are classified as mucopolysaccharidoses (MPS), lipidoses, or mucolipidoses depending on the nature of the stored material. More than 40 LSDs are known and they have a collective incidence of approximately 1 in 7000 to 8000 live births.274–276 Most of the genes for these lysosomal proteins have been cloned, permitting mutation analysis in individual cases. This information can be used for genotype/phenotype correlations,

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genetic counseling, and the selection of patients for novel forms of therapy, such as substrate deprivation or dispersal, enzyme replacement, bone-marrow transplantation, and gene transfer. Mucopolysaccharidoses The MPS disorders are specifically characterized by an inherited deficiency of one of the lysosomal acid hydrolases catalyzing degradation of glycosaminoglycans.276 Patients with MPS usually have less than 10% and often less than 1% of residual enzyme activity.276 These enzymatic defects lead to the accumulation of mucopolysaccharides and chemically similar substrates within the lysosome.276 Because mucopolysaccharides are found throughout the body, it is understandable that these diseases affect most organ systems.276 The clinical symptoms of MPS include coarse facies, dysostosis multiplex, joint abnormalities, hepatosplenomegaly, corneal clouding, varying degrees of CNS abnormalities, and premature death. The MPS disorders are divided into seven distinct subgroups, based on the specific enzyme deficiency.276 Mucopolysaccharidose VII In the case of MPS VII (Sly syndrome), b-glucuronidase activity is deficient, which leads to storage and urinary excretion of heparan sulfate and dermatan sulfate. Patients with this disorder show widely differing clinical features, ranging from severe storage disease, with coarse features, skeletal deformities, hepatosplenomegaly, and delayed development, to involvement of the aorta with dissecting aneurysm. This variety of clinical severity is probably due to differing genetic backgrounds of the individuals.277 Prospective treatments for MPS VII have been evaluated through the use of an excellent mouse model.278–282 The MPS VII mice have clinical, phenotypic, and pathological features similar to those of human MPS VII. This similarity, their uniform genetic constitution, their relatively short life span, and the availability of b-glucuronidase with the mannose 6-phosphate (man-6-P) moiety necessary for endocytosis make this a useful model for evaluating experimental therapies for LSD. Thus, the combination of poor blood-brain barrier penetrance of the enzyme and the existence of an excellent mouse model, have led to a concentration of gene therapy studies in the brain of MPS VII mice. These studies are thought of as “proof of principle” studies because there are less than 20 MPS VII patients currently alive in the United States, making clinical development of this strategy nearly impossible (Sands, personal communication).277,281 Enzyme Replacement Given that the technology exists to manufacture large quantities of recombinant proteins, enzyme replacement strategies for LSDs are always a primary treatment consideration.

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As little as 20% of normal enzyme activity may be enough to allow normal metabolic homeostasis, which bodes well for replacement strategy or gene transfer. For example in Gaucher disease, previous attempts at enzyme infusion therapy in humans have been successful. Enzyme replacement therapy has also been successful through the use of recombinant mouse b-glucuronidase with the mannose-6-P moiety,282 necessary for receptor-mediated endocytosis and lysosomal targeting of exogenous enzyme. b-glucuronidase levels in injected MPS VII mouse pups were equal to or greater than those of normal mice in every tissue examined except for the brain, where 31% of normal activity was present.282 The reduced levels in the brain are due to the difficulty in passing the BBB. MPS VII mice treated with weekly b-glucuronidase injections from birth to five weeks of age had an improved phenotype and increased b-glucuronidase activity in the liver, spleen, kidney, and brain at 6 weeks of age.283 Bone Marrow Transplantation Since the early 1980s, a variety of attempts to use bone marrow transplantation (BMT) as a therapeutic modality have been reported. BMT has been demonstrated to increase survival and improve biochemical and pathologic markers of disease when performed on adult animals but with notable lack of effect in the CNS.284 When the BMT procedure was performed on neonates, however, the neuronal response was undetectable except in animals which had received the highest level of conditioning radiation.285 These levels of radiation are currently unacceptable for use in children because of the inherent toxicity of radiation during development.285 BMT has also been attempted without conditioning radiation using very high doses of cells with good success except in brain.286 In an attempt to improve the efficacy of BMT, bone marrow cells have also been transduced with a retroviral vector encoding b-glucuronidase prior to transplantation.287,288 This ex vivo gene therapy resulted in low levels of b-glucuronidase activity with correction of excess lysosomal storage in spleen and liver. However, this strategy has been followed up in a larger dog model with less success.289 In a similar strategy designed to obviate the need for bone marrow cells, immortalized neural-derived stem cells were placed into the lateral ventricles of newborn MPS VII mice, and these cells engrafted throughout the neuraxis. The donorderived stem cells intermingled with host cells, increased brain b-glucuronidase activity and decreased neuronal and glial lysosomal storage.290 Likewise, purified macrophages from wild-type mice or retrovirally transduced macrophages were transplanted into nonablated MPS VII mice resulting in correction in the liver and spleen.291 Skin fibroblasts292,293 or myoblasts294 have also been transduced using retrovirus and transplanted as a neo-organ. Consistent with the other peripherally oriented studies, lysosomal storage correction

was seen depending on the organ closest to the transplant.292,293 In Vivo Gene Therapy Theoretically, gene therapy represents a specific and longterm solution for LSDs that would require minimal invasiveness. One of the key advantages of gene therapy in this field as compared to a transplantation approach is because the patient’s own cells would be engineered to produce the missing enzyme, graft rejection would be eliminated. However, it should be pointed out that in patients who have a total knockout of gene expression, de novo enzyme expression may induce an immune response. Because of the nature of the preceding systemic treatments, the LSD-induced neuropathology was rarely affected by either enzyme replacement or BMT. Therefore, gene therapy may fill a niche in this field by being used in combination with one of the described systemic treatments (see later discussion). Recombinant Adenovirus Ghodsi and colleagues295 reported that intrastriatal injection of rAd encoding b-glucuronidase results in focal, intense expression near the injection site. More importantly, however, enzyme activity was observed throughout the ipsilateral striatum, in the corpus callosum, ventricles, and bilateral neocortex. This study thus established the fact that b-glucuronidase is secreted from transduced cells which ultimately results in cross-correction of un-transduced cell populations in the vicinity of the injection. Stein and coworkers have gone on to both systemically and intracerebrally inject rAd encoding b-glucuronidase.293 Using methods to suppress the immune-response to rAd, this study demonstrated correction of lysosomal storage in both the periphery and brain.296 This same group has also shown that they can spread the vector further, thus obtaining a larger area of lysosomal storage reduction, by using mannitol to create hyperosmolarity just before the intracerebral rAd injection.297 Herpes Simplex Virus Gene transfer to the CNS using a herpesvirus vector encoding the b-glucuronidase cDNA has been reported,298 but the vector’s CNS toxicity and the low level of expression of the gene limited the area of gene expression. Recombinant Adeno-Associated Virus Several investigators have used rAAV to successfully deliver b-glucuronidase to both the periphery and the brain.299–302 In probably the most significant report, therapeutic levels of b-glucuronidase were achieved 1 week after neonatal IV injection of rAAV-b-glucuronidase in the liver, heart, lung, spleen, kidney, brain, and retina.301 These levels were persistent and therapeutic for the duration of the study (16

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weeks). By using neonatal mice whose BBB integrity was still lacking, these investigators gained access to the CNS intravenously, thus avoiding a more invasive procedure later in life.302 In addition, adult mice have also benefited from AAV therapy. After a single intracerebral injection of rAAV encoding b-glucuronidase, continuous high levels of expression were found along the sites of injection as well as secreted enzyme extending along most of the neuraxis.299 This resulted in widespread reversal of the hallmark pathology. Similarly, a complete reversion of lysosomal storage lesions in the enzymatically active areas, and in most neurons, in surrounding negative areas, and in the noninjected hemisphere has been reported. Thus, treatment of LSDs in older patients may entail BMT, transplantation of neo-organs, or enzyme replacement for correction of peripheral enzyme deficients combined with intracerebral gene therapy to correct the devastating neuropathology.281,283

Stroke In Western countries, stroke is the third most common cause of death and the second most common cause of neurologic disability after Alzheimer’s disease. Its incidence has decreased in recent decades, but the declining frequency of stroke now appears to have leveled off, and cerebrovascular disease (CVD) remains the leading cause of institutional placement for loss of independence among adults. Therefore, treatment of cerebral ischemia is an important target for any commercial drug development entity. Intuitively, prevention of stroke is preferable to treatment after stroke has occurred. Well-defined, at-risk populations are those with atherosclerosis (specifically symptomatic high-grade carotid stenoses), hypercoagualable states, multiple strokes, peripheral vascular disease, chronic atrial fibrillation, and/or dilated cardiomyopathy. However, even with identifying who is at risk, it is impossible to foresee stroke location, or even narrowly anticipate the onset of the stroke. In a protective gene therapy, at-risk patients would have to be treated with the vector prior to a major ischemic event. In this scenario, the duration of transgene expression prior to the time when it would be actually needed is unpredictable. Along these lines, glucocorticoid activated promoters, designed to respond to an ischemic event and therefore, express transgene only during an ongoing response to ischemia have recently been developed.303 Several recent reviews have summarized the field of gene therapy for cerebral ishcemia.304–307 These reviews all indicate that gene transfer, both to the brain and to the cerebral vasculature, can result in transgene expression. Therefore, each review indicates optimism that as mechanisms of neural cell death in ischemia are elucidated, appropriate transgenes can be expressed to reduce infarct size after a stroke. The conclusions of these reviews are a testament to the fact that

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research in gene therapy for cerebral ischemia is in its infancy. The Sapolsky group at Stanford has been using HSV amplicon vectors in rat models of stroke.308–310 They have reported success in using gene transfer of calbindin d28K to buffer intracellular calcium to inhibit focal ischemic cell death in striatum.309 They have then followed this study up with a characterization of the time window of treatment that is effective, demonstrating that the vector can be somewhat efficacious when delivered after the onset of ischemia.308 These authors also are interested in the therapeutic potential of the 72-Kd heat shock protein in reversing the effects of middle cerebral artery occlusion.310 Modulation of the inflammatory response via interleukin-1 receptor antagonist-based adenoviral gene transfer has been reported to reduce infarct volume when delivered 5 days before middle cerebral artery occlusion.311 The authors assert that diminished inflammatory response evidently facilitated reperfusion through the capillaries. Studies of rAAV expressing GDNF have been investigated in rats undergoing transient bilateral common carotid ligation and right middle cerebral artery occlusion for 90 minutes.312 The rAAV was injected during the ischemic procedure. These authors examined the brains 48 hours later, revealing smaller infarct volumes in the GDNF treated group.312 However, short-term survival periods after ischemic episodes have often led to incorrect conclusions in this field.313 Finally, remarkable data have been reported using an ex vivo approach for NGF delivery to the striatum.314 In this study, neuronal progenitor cells retrovirally transduced to produce NGF were implanted in striatum 1 week before a 30-minute occlusion of the middle cerebral artery. Careful histologic analysis showed a remarkable level of sparing of striatal neurons. There was some significant sparing in a control group transplanted with untransduced progenitor cells as well, indicating that the cells alone contributed some beneficial factor.

Conclusion Obviously, from a research perspective, the field of gene therapy for CNS disorders is burgeoning. A strong argument can be put forth that, in situations where continuous sitespecific protein delivery is required for therapeutic efficacy, gene transfer is probably the least invasive delivery method for the CNS. However, because the technology involved is unproven in the clinical arena and many of the transgenes that may be of clinical interest are of uncertain efficacy, few gene therapy trials have been carried out (although many have been proposed). Indeed, only in the case of glioblastoma has a gene therapy trial been conducted, although an ex vivo gene therapy trial to deliver NGF in AD is on the immediate horizon.

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This chapter has reviewed many, but not all, of the potential CNS applications of gene transfer with clinical implications. Notably missing is the use of gene transfer to treat obesity202 and leukodystrophies such as Canavan disease.315,316 However, this chapter provides a guide for the

interested reader to learn more about a particular topic for greater focus. It is clear that gene therapy will probably play a role in the treatment of multiple CNS disorders at some point; however, it is presently impossible to predict which strategy or which disorder.

P earls 1. As it is currently conceived, gene therapy for CNS disorders can be viewed as a relatively noninvasive method for continuously delivering large molecules inside the BBB as compared to indwelling mechanical devices such as pumps or reservoirs. 2. In vivo gene delivery involves delivery of DNA directly into cells via viral or nonviral vectors. Viral vectors take advantage of the fact that viruses have evolved the ability to transfer and express their DNA in foreign cells over millions of years. 3. Because the majority of cells in the CNS are postmitotic, vectors that are capable of gene delivery to quiescent cells are of the most interest for this application. Ad, rAAV, HSV, and Lv are currently the most common viral vectors that have been demonstrated to reliably transfer DNA in animal models of CNS disorders. 4. Nonviral gene therapy delivers genes to cells in the form of a circular DNA, termed plasmid DNA, which is propagated in bacteria. The plasmid contains the following features: a prokaryotic origin of replication sequence to amplify the number of plasmids per bacteria, a drug resistance gene to selectively grow only those bacteria containing the plasmid, and a eukaryotic expression cassette to express the therapeutic gene in eukaryotic cells. 5. Although other schemes exist, the main focus of transgene regulation has been at the transcriptional level by engineering internal promoters that are dependent on binding some external prodrug, either for onset or cessation of promoter activity. The most highly developed version of this regulation concept is the tetracycline-regulated promoter system. This system, which now includes both an inducer and a repressor system, has been used successfully in both viral vectors and transgenic animals. 6. To deliver L-dopa, the gene for the rate-limiting enzyme for DA production, TH must be expressed.

References 1. Lundberg C: Engineered cells and ex vivo gene transfer. In Dunnett SB, Boulton AA, Baker GB (eds): Neuromethods: Neural Transplantation Methods. Totowa, NJ, Humana, 2000, pp. 89–102. 2. Leff SE, Rendahl KG, Spratt SK, Kang UJ, Mandel RJ: In vivo L-dopa production by genetically modified primary rat fibroblast or 9L

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Moreover, tetrahydrobiopterin (BH4) is a cofactor necessary for the reaction catalyzed by TH, and the primary enzyme required for BH4 production is GTPcyclohydrolase 1 (GTPCH1). Given this biosynthetic pathway, one strategy for increased production of DA is vector-mediated over-expression of both TH and GTPCH1 in target tissues of the neostriatum. AD is a severe neurodegenerative disorder characterized by progressive memory loss with concomitant underlying neuropathology in most cortical structures. This widespread pathology is the greatest challenge for gene therapy because, under current technology, it is not feasible to transduce a great proportion of cells in the cerebral cortex. Because this is the most mature effort in gene therapy for glioblastoma, the HSV thymidine kinase strategy has moved into the clinical trial stage with varying success. Direct injection of adenovirus into the spinal cord also results in efficient transduction of neurons and glia at the site of injection, and in neurons that project to the injection site via retrograde transport. Neuronal populations are differentially stimulated by genetically modified cells depending on the neurotrophin being secreted and which neurotrophin tyrosine kinase receptors are expressed. Accordingly, very robust regeneration can be promoted by grafts of NGF-producing fibroblasts into acute or chronically injured spinal cords. Similarly, fibroblast grafts engineered to secrete NT-3 or BDNF in the contused spinal cord can stimulate ingrowth of local choline acetyltransferase (ChAT)-immunoreactive axons, whereas this was not the case with similar grafts expressing NGF, CNTF, or bFGF. Glucocorticoid activated promoters, designed to respond to an ischemic event and, therefore, express transgene only during an ongoing response to ischemia, have recently been developed.

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256.

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266.

267.

268.

269. 270.

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Gene Therapy for Disorders of the Central Nervous System

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273. Bledsoe AW, Gillespie GY, Morrow CD: Targeted foreign gene expression in spinal cord neurons using poliovirus replicons. J Neurovirol 2000;6:95–105. 274. Poorthuis BJ, Wevers RA, Kleijer WJ, et al: The frequency of lysosomal storage diseases in The Netherlands. Hum Genet 1999;105:151– 156. 275. Meikle PJ, Hopwood JJ, Clague AE, Carey WF: Prevalence of lysosomal storage disorders. JAMA 1999;281:249–254. 276. Winchester B, Vellodi A, Young E: The molecular basis of lysosomal storage diseases and their treatment. Biochem Soc Trans 2000;28:150– 154. 277. Vogler C, Sands MS, Galvin N, et al: Murine mucopolysaccharidosis type VII: The impact of therapies on the clinical course and pathology in a murine model of lysosomal storage disease. J Inherit Metab Dis 1998;21:575–586. 278. Birkenmeier EH, Davisson MT, Beamer WG, et al: Murine mucopolysaccharidosis type VII. Characterization of a mouse with beta-glucuronidase deficiency. J Clin Invest 1989;83:1258–1260. 279. Levy B, Galvin N, Vogler C, Birkenmeier EH, Sly WS: Neuropathology of murine mucopolysaccharidosis type VII. Acta Neuropathol (Berl) 1996;92:562–568. 280. Sands MS, Birkenmeier EH: A single-base-pair deletion in the betaglucuronidase gene accounts for the phenotype of murine mucopolysaccharidosis type VII. Proc Natl Acad Sci USA 1993;90:6567–6571. 281. Sands MS, Wolfe JH, Birkenmeier EH, et al: Gene therapy for murine mucopolysaccharidosis type VII. Neuromuscul Disord 1997;7:352– 360. 282. Vogler C, Sands M, Higgins A, et al: Enzyme replacement with recombinant beta-glucuronidase in the newborn mucopolysaccharidosis type VII mouse. Pediatr Res 1993;34:837–840. 283. Sands MS, Vogler C, Kyle JW, et al: Enzyme replacement therapy for murine mucopolysaccharidosis type VII. J Clin Invest 1994;93:2324– 2331. 284. Birkenmeier EH, Barker JE, Vogler CA, et al: Increased life span and correction of metabolic defects in murine mucopolysaccharidosis type VII after syngeneic bone marrow transplantation. Blood 1991; 78:3081–3092. 285. Sands MS, Barker JE, Vogler C, et al: Treatment of murine mucopolysaccharidosis type VII by syngeneic bone marrow transplantation in neonates. Lab Invest 1993;68:676–686. 286. Soper BW, Lessard MD, Vogler CA, et al: Nonablative neonatal marrow transplantation attenuates functional and physical defects of beta-glucuronidase deficiency. Blood 2001;97:1498–1504. 287. Wolfe JH, Sands MS, Barker JE, et al: Reversal of pathology in murine mucopolysaccaridosis type VII by somatic cell gene transfer. Nature 1992;360:749–752. 288. Marechal V, Naffakh N, Danos O, Heard JM: Disappearance of lysosomal storage in spleen and liver of mucopolysaccharidosis VII mice after transplantation of genetically modified bone marrow cells. Blood 1993;82:1358–1365. 289. Wolfe JH, Sands MS, Harel N, et al: Gene transfer of low levels of beta-glucuronidase corrects hepatic lysosomal storage in a large animal model of mucopolysaccharidosis VII. Mol Ther 2000;2: 552–561. 290. Snyder EY, Taylor RM, Wolfe JH: Neural progenitor cell engraftment corrects lysosomal storage throughout the MPS VII mouse brain. Nature 1995;374:367–370. 291. Ohashi T, Yokoo T, Iizuka S, Kobayashi H, Sly WS, Eto Y: Reduction of lysosomal storage in murine mucopolysaccharidosis type VII by transplantation of normal and genetically modified macrophages. Blood 2000;95:3631–3633. 292. Moullier P, Bohl D, Heard JM, Danos O: Correction of lysosomal storage in the liver and spleen of MPS VII mice by implantation of genetically modified skin fibroblasts. Nat Genet 1993;4:154– 159.

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293. Moullier P, Marechal V, Danos O, Heard JM: Continuous systemic secretion of a lysosomal enzyme by genetically modified mouse skin fibroblasts. Transplantation 1993;56:427–432. 294. Naffakh N, Pinset C, Montarras D, Li Z, Paulin D, Danos O, Heard J: M. Long-term secretion of therapeutic proteins from genetically modified skeletal muscles. Hum Gene Ther 1996;7:11–21. 295. Ghodsi A, Stein C, Derksen T, Yang G, Anderson RD, Davidson BL: Extensive beta-glucuronidase activity in murine central nervous system after adenovirus-mediated gene transfer to brain. Hum Gene Ther 1998;9:2331–2340. 296. Stein CS, Ghodsi A, Derksen T, Davidson BL: Systemic and central nervous system correction of lysosomal storage in mucopolysaccharidosis type VII mice. J Virol 1999;73:3424–3429. 297. Ghodsi A, Stein C, Derksen T, Martins I, Anderson RD, Davidson B: L. Systemic hyperosmolality improves beta-glucuronidase distribution and pathology in murine MPS VII brain following intraventricular gene transfer. Exp Neurol 1999;160:109–116. 298. Wolfe JH, Deshmane SL, Fraser NW: Herpesvirus vector gene transfer and expression of beta-glucuronidase in the central nervous system of MPS VII mice. Nat Genet 1992;1:379–384. 299. Skorupa AF, Fisher KJ, Wilson JM, Parente MK, Wolfe JH: Sustained production of beta-glucuronidase from localized sites after AAV vector gene transfer results in widespread distribution of enzyme and reversal of lysosomal storage lesions in a large volume of brain in mucopolysaccharidosis VII mice. Exp Neurol 1999;160:17–27. 300. Sferra TJ, Qu G, McNeely D, et al: Recombinant adeno-associated virus-mediated correction of lysosomal storage within the central nervous system of the adult mucopolysaccharidosis type VII mouse. Hum Gene Ther 2000;11:507–519. 301. Daly TM, Okuyama T, Vogler C, Haskins ME, Muzyczka N, Sands MS: Neonatal intramuscular injection with recombinant adeno-associated virus results in prolonged beta-glucuronidase expression in situ and correction of liver pathology in mucopolysaccharidosis type VII mice. Hum Gene Ther 1999;10:85–94. 302. Daly TM, Vogler C, Levy B, Haskins ME, Sands MS: Neonatal gene transfer leads to widespread correction of pathology in a murine model of lysosomal storage disease. Proc Natl Acad Sci USA 1999;96:2296–2300. 303. Ozawa CR, Ho JJ, Tsai DJ, Ho DY, Sapolsky RM: Neuroprotective potential of a viral vector system induced by a neurological insult. Proc Natl Acad Sci USA 2000;97:9270–9275.

304. Papadopoulos MC, Giffard RG, Bell BA: Principles of gene therapy: potential applications in the treatment of cerebral ischaemia. Br J Neurosurg 2000;14:407–414. 305. Gunnett CA, Heistad DD: The future of gene therapy for stroke. Curr Hypertens Rep 2001;3:36–40. 306. Weihl C, Macdonald RL, Stoodley M, Luders J, Lin G: Gene therapy for cerebrovascular disease. Neurosurgery 1999;44:239–252; discussion 253. 307. Heistad DD, Faraci FM: Gene therapy for cerebral vascular disease. Stroke 1996;27:1688–1693. 308. Phillips RG, Monje ML, Giuli LC, et al: Gene therapy effectiveness differs for neuronal survival and behavioral performance. Gene Ther 2001;8:579–585. 309. Yenari MA, Minami M, Sun GH, et al: Calbindin d28k overexpression protects striatal neurons from transient focal cerebral ischemia. Stroke 2001;32:1028–1035. 310. Yenari MA, Fink SL, Sun GH, et al: Gene therapy with HSP72 is neuroprotective in rat models of stroke and epilepsy. Ann Neurol 1998;44:584–591. 311. Alexander MY, Brosnan MJ, Hamilton CA, et al: Gene transfer of endothelial nitric oxide synthase but not Cu/Zn superoxide dismutase restores nitric oxide availability in the SHRSP. Cardiovasc Res 2000;47:609–617. 312. Tsai TH, Chen SL, Chiang YH, et al: Recombinant adeno-associated virus vector expressing glial cell line-derived neurotrophic factor reduces ischemia-induced damage. Exp Neurol 2000;166:266–275. 313. Corbett D, Nurse S: The problem of assessing effective neuroprotection in experimental cerebral ischemia. Prog Neurobiol 1998;54:531– 548. 314. Andsberg G, Kokaia Z, Björklund A, Lindvall O, Martinez-Serrano A: Amelioration of ischaemia-induced neuronal death in the rat striatum by NGF-secreting neural stem cells. Eur J Neurosci 1998;10:2026– 2036. 315. Leone P, Janson CG, Bilaniuk L, et al: Aspartoacylase gene transfer to the mammalian central nervous system with therapeutic implications for Canavan disease. Ann Neurol 2000;48:27–38. 316. Matalon R, Michals-Matalon K: Biochemistry and molecular biology of Canavan disease. Neurochem Res 1999;24:507–513.

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Note: Page numbers followed by b indicate boxed material; those followed by f indicate figures; those followed by t indicate tables. ABCs of multisystem support, for hemorrhagic stroke, 157–158, 159t Abducent nerve anatomy of, 34f, 35 examination of, 121, 123f Abscesses epidural pediatric, 317, 318f spinal, 384–385 of brain. See Brain abscesses. of thoracic spine, 252–253 Accessory nerve anatomy of, 37 examination of, 122, 126f Acid-base balance, potassium balance and, 568, 569 Acidosis, potassium balance and, 568, 569 Acromegaly, airway management with, 523 Acyclovir, for viral encephalitis, 355 Adeno-associated virus, as gene therapy viral vectors, 868, 869f, 880–881 Adenomas, pituitary, 152, 152f Adenosine, for arrhythmias, 539t Adenovirus, recombinant, as gene therapy viral vector, 866, 868, 880 Adrenergic agents, 671, 672t–673t, 674 Adrenomedullin, 566 Adult advanced life support, guidelines for, 469–470 Adult basic life support, guidelines for, 468–469 Advance directives, 823, 824b–825b Advanced cardiac life support, 441–442 pediatric, 442 Agonal gasps, 754 Air embolism, venous, risk of, during surgery, 700 Airway, closure of, distribution of ventilation and, 581 Airway management, 499–528 consequences of hypoxia and hypercapnia and, 499–500, 500t difficult airway algorithm for, 508–519, 508f “cannot intubate” patient when bag-valvemask ventilation is still possible, 509 Combitube in, 517–518, 518f confirming endotracheal intubation and, 514–515, 515f endotracheal tube management after esophageal misplacement and, 515 for “cannot ventilate, cannot intubate” scenario, 509–514, 511f–514f laryngeal mask airway management in, 515–517, 516f

predictable difficult airway and, 508–509 ventilation after transtracheal airway placement and, 518–519 difficult airway cart for, 526, 527t extubation of difficult airway and, 524–526, 525t accidental, 525 criteria for and timing of, 525–526 exchanging tubes and, 526 for comatose patients, 749 in acromegalic patients, 524 in neuromuscular disease, 524 in pediatric patients, 524 in prehospital care, 441 intracranial pressure control and, 715 intubation for, patient preparation for, 503–504, 505f laryngoscopy in blade for, 506–507 unsuccessful, alternatives for, 507–508 view for, 506, 507f mask ventilation for, 504–505 obstruction due to soft tissue collapse and, overcoming, 505–506, 505t, 506f organized approach to, 500–503 aspiration of gastric contents and difficult airway and, 500–501, 503 predicting difficult airway and, 500, 501f–503f, 501t, 502t pearls for, 528 spinal cord injury and, 521–523, 522f strategy for, 503–508, 503f, 504f training issues in, 526–527 with carotid endarterectomy, 523–524 with central nervous system trauma, 519–521 with head frames, 524 with intracranial vascular procedures, 523 Airway pressure, 587 Airway resistance, 587–588 increased, with mechanical ventilation, 595–596 Akinetic mutism, diagnosis of, 621t Albendazole, for cysticercosis, 374 Alcohol, toxic levels of, clinical state of brain death caused by, 840t Alcohol intoxication, head injury and, 446 Alfentanil (Alfenta), 666 physiologic effects of, 698t Alkalosis, potassium balance and, 568, 569 Alkylating agents, for tumors, 147 Allodynia, gene therapy for, 877

Alpha2 agonists, 668–669, 668t Alpha antagonists for myocardial ischemia, 543 physiologic effects of, 698t Alteplase, for ischemic stroke, 408 Altered mental status. See also Coma; Confusion; Unconsciousness encephalopathies and, 764–767 infections associated with, 763–764 neurologic diagnoses associated with, 757–763 pearls for, 768–769 terminology for, 808–809 with intracerebral hemorrhage, 174 with subarachnoid hemorrhage, 165, 165t Alzheimer’s disease, gene therapy for, 872–873 Amantadine, for head injury, 809t Ambulance transport, 439 Amebic encephalitis, 382–383 Aminocaproic acid, for ischemic stroke, 404 Amiodarone, for arrhythmias, 539t Amitriptyline for head injury, 809t toxic levels of, clinical state of brain death caused by, 840t Amoxicillin, for Lyme disease, 381 Amphotericin B Blastomyces meningitis, 367 for coccidioidal meningitis, 366 for cryptococcal meningitis, 363, 364 for histoplasma meningitis, 365 for zygomycotic meningitis, 367, 368f Ampicillin, for bacterial meningitis, 346, 347t Amrinone, 673t, 674 for congestive heart failure, 546, 548t Amygdala, anatomy of, 9, 11, 12f Amyloid angiopathy, intracerebral hemorrhage associated with, 171 Amyotrophic lateral sclerosis gene therapy for, 874–875 mimicking brain death, 840 Analgesics, seizures induced by, 741 Anastomotic vein, inferior and superior, 13, 14f Anemia, with myocardial ischemia, 544 Anesthesia, 695–706 arterial oxygen content and, 697 cerebral blood flow and, 696–697, 696f, 698t cerebral oxygen consumption and, 695–696 delayed emergence from, 705 extubation and, 703–704 fluid and electrolyte management and, 697, 699, 699t

891

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Anesthesia (Continued) for neurovascular surgery, 701–703, 702f for spine surgery, 703 induction and, 699 pearls for, 706 positioning and, 699–700 postoperative hypothermia and shivering and, 704–705 with mass lesions, 700–701 with previous stroke, 705 Anesthetics, seizures induced by, 741–742 Aneurysms cerebral, subarachnoid hemorrhage and, 162–163 fusiform, subarachnoid hemorrhage and, 162 intracerebral hemorrhage associated with, 173 intracranial endovascular surgery for, 186–188, 187f approaches for, 187–188 complications of, 188, 189f, 190f rupture of, following endovascular treatment, 188, 189f saccular occlusion with platinum coils, 167 subarachnoid hemorrhage and, 162–163 Angiography cerebral, to confirm brain death, 837t computed tomography, 62, 63f, 67, 70f brain death confirmation and, 837t, 838 of intracerebral hemorrhage, 174 in subarachnoid hemorrhage, 156, 157f, 158f four-vessel, in subarachnoid hemorrhage, 156, 157f magnetic resonance, 52–53, 54f brain death confirmation and, 837t, 838 of intracerebral hemorrhage, 174 in subarachnoid hemorrhage, 156, 157f of subarachnoid hemorrhage, 166 Angioplasty, endovascular for extracranial stenosis, 203–208, 205f–207f approaches for, 206, 208 complications of, 208 for intracranial stenosis, 208–209 approaches for, 209, 210f complications of, 209, 211f Ankylosing spondylitis, of cervical spine, 248, 248f Anosognosia, 134 Anoxic encephalopathy, altered mental status with, 761, 765–766 Anterior cingulate syndrome, 23 Anterior perforated surface, anatomy of, 16 Anterior spinal artery syndrome, 135 Anterolateral sulcus, anatomy of, 24, 25f Antibiotics. See also specific drugs seizures induced by, 742 Anticholinergic agents, for myasthenia gravis, 426 Anticholinergic syndrome, central, seizures and, 741 Antidepressants for depression, following stroke, 804, 805t seizures induced by, 741 Antidiuretic hormone potassium balance and, 569 sodium balance and, 557, 557f Antiendotoxin therapy, for multiple organ failure, 785–786 Antiepileptic drugs, 677–678, 742–744 Antihypertensive agents, 674–677 Antiplatelet therapy, for myocardial infarction, 545 Antipsychotics, seizures induced by, 741

Anxiolytic drugs, 653 Aortic flush, for suspended animation, 480 Aortic regurgitation, 549 Aortic stenosis, 547–548 Apert’s syndrome, 297 Aphasia Broca’s, 118, 118f, 119f, 134 Wernicke’s, 118, 118f, 119f, 134 Apnea, with head injury, 215–219, 216f, 217t therapeutic options for, 222 Apnea test, for brain death, 837 Apneustic breathing, 754 Apoptosis, 850 anti-apoptosis and, 856 necrosis vs., 113–114 neuroprotection and, 855 with spinal cord injury, 777 Arachnoid cysts, intracranial, 298–300, 299f Arbovirus infections, laboratory diagnosis of, 352t Arousal, determining level of, 751 Arrhythmias in Guillain-Barré syndrome, management of, 422 in patient without preexisting cardiac disease, 535–536 with spinal surgery, 262 Arterial dissection ischemic stroke due to, 399 subarachnoid hemorrhage and, 163, 164f Arterial oxygen content, anesthesia and, 697 Arterial rupture, following balloon angioplasty, for cerebral vasospasm, 192 Arteriovenous fistulas, dural, endovascular surgery for, 197–200, 197t approaches for, 198, 199f, 200f complications of, 199–200 Arteriovenous malformations endovascular surgery for, 192–197, 193t, 195f, 196f approaches for, 194 complications of, 194, 196–197 excision of, anesthesia for, 702 intracerebral hemorrhage associated with, 173, 173f of thoracic spine, 254–255, 256f pediatric, 313–314, 313t subarachnoid hemorrhage and, 163, 163f Aseptic meningitis, 348–355 altered mental status with, 763 clinical manifestations of, 351, 352t, 353–355, 353f, 354f, 354t epidemiology of, 349–350 pathogenesis of, 350–351 pearls for, 389 treatment of, 355 Aspergillosis brain abscess in, 356 meningitis in, 367–368 Aspiration, of gastric contents, difficult airway and, 500–501, 503 Aspirin for ischemic stroke, 409t, 410 for myocardial infarction, 545 Assist-controlled ventilation, 589 Asterixis, 751 Astrocytomas cerebellar, pediatric, 306–307, 307f thoracic, 252, 254f Ataxic breathing, 754 Atlas assimilation of, 241 fractures of, 235–237, 236f management of, 236–237

Atovaquone for malaria, 373 for toxoplasmosis, with HIV infections, 370 Atracurium, 671t physiologic effects of, 698t Atropine, for arrhythmias, 539t Auditory-evoked potentials, 631–633 auditory pathway and, 632–633 theoretical basis for, 631–632, 632f Automatic tube compensation mode, for mechanical ventilation, 594 Autonomic dysreflexia, with spinal cord injury, 799 Auto-positive end-expiratory pressure, 593 prevention or reversal of, 595 Autopropagnosia, 134 Awareness, 747 Axis fractures, 237–240, 237f, 238f complications of, 238, 240 management of, 238, 239f Axonal regeneration and sprouting, gene therapy and, 876–878 Axotomy, chemical, 772 Backward, upward, rightward laryngeal displacement, 506, 507f Baclofen, intrathecal for dystonia, pediatric, 321 for spasticity, pediatric, 320 Bacterial meningitis, 337–348 altered mental status with, 763–764 clinical manifestations of, 341 complications of, 346, 348 diagnosis of, 341–344 cerebrospinal fluid analysis in, 342–344, 343t radiologic studies in, 344, 344f, 345f epidemiology of, 337–339, 338t etiology of gram-negative bacilli in, 339 group B Streptococcus in, 339 Haemophilus influenzae in, 338 Listeria monocytogenes in, 338–339 Neisseria meningitidis in, 337–338 Streptococcus pneumoniae in, 337 Haemophilus influenzae, 347t Listeria monocytogenes, 347t Neisseria meningitidis, 347t pathogenesis of meningeal invasion in, 339–341 pearls for, 388 Streptococcus agalactiae, 347t Streptococcus pneumoniae, 347t treatment of, 345–346, 347t tuberculous. See Tuberculous meningitis. vaccination for, 348 Bag-valve-mask ventilation, 439, 441, 504–505 Balloon angioplasty for vasospasm, 169, 170f, 171f transluminal, for cerebral vasospasm, 192, 193f Balloon migration, following carotid-cavernous fistula occlusion, 202 Barbiturate(s), 653–655, 654t for intracranial pressure control, with head injury, 775 for seizures, 742–743 in cerebral resuscitation, 474 pharmacodynamics of, 654 physicochemical properties and pharmacokinetics of, 654 physiologic effects of, 698t Barbiturate coma for intracranial pressure control, 723–724, 724t for neurovascular surgery, 701–702

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Index Basal forebrain syndrome, 23 Basal ganglia anatomy of, 9 vascularization of, 21f, 23 Basal vein of Rosenthal, anatomy of, 14f, 16–17 Basic life support, 440–441 Basilar artery, anatomy of, 41f, 42 Basilar impression, of craniovertebral junction, 240–241 Basilar invagination, of craniovertebral junction, 240, 242f Basilar sulcus, anatomy of, 24, 25f Bcl-2 family proteins, neuronal death and survival and, 843 Benedikt’s syndrome, 43f, 44 Beneficence, principle of, 816 Benzodiazepines, 655–662, 655t for seizures, 742 mechanism of action of, 656 pharmacodynamics of, 656 physicochemical properties and pharmacokinetics of, 656, 656t physiologic effects of, 698t Beta blockers, 676–677, 677t for arrhythmias, 539t for myocardial infarction, 544 for myocardial ischemia, 542–543, 543t physiologic effects of, 698t Biopsy, stereotactic, 276–277, 278f Biot breathing, 754 Bladder, distention of, after spinal surgery, 262 Blastomycosis, meningitis in, 366–367 Blood, in endotracheal tube or tracheostomy tube, 596 Blood pressure. See also Hypertension; Hypotension endotracheal intubation and, with intracranial vascular procedures, 523 following head injury, 445 management of, in intracerebral hemorrhage, 415, 415t resuscitation of, with head injury, 773 Body water. See Water balance. Bone marrow transplantation for lysosomal storage disorders, 880 seizures following, 737 Botulinum toxin for dystonia, pediatric, 321 for spasticity, pediatric, 320 Bowel, distention of, after spinal surgery, 262 Bowel management, with spinal cord injury, 800 Brain abscesses, 355–358 altered mental status with, 763 clinical manifestations of, 357 diagnosis of, 357–358, 357f microbiology of, 356–357 pathogenesis of, 356 pearls for, 389 pediatric, 317–319 treatment of, 358 Brain death, 833 algorithm for determination of, 647 confirmation of, tests for, 837, 837t determination of, 767–768, 834–838, 835t, 836t, 838f, 839f in children, 839 electroencephalography and, 628 ethical issues concerning, 841 evoked potentials for confirmation of, 634–635 isolated brainstem death as, 840–841 legal issues concerning, 841 neurologic examination for, 621–622, 621t, 622t

neurologic states resembling, 621, 621t, 840, 840t pathology of, 834, 834f, 835f religious issues concerning, 841 Brain herniation altered mental status with, 759–761, 760f imaging of, 73, 74f, 75, 75f of downward cerebellar tonsillar herniation, 73, 74f, 75, 75f of downward transtentorial herniation of parahippocampal gyrus, 70, 71f–72f, 73 of subfalcine herniations, 70, 70f of upward transtentorial herniation, 73, 73f Brain injury. See also Head injury mechanisms of, 733 Brain ischemia global, 457 with head injury, 222 Brain perfusion computed tomography, 63, 64f, 69 in dural sinus thrombosis, imaging of, 76, 82f in oligemia, imaging of, 75–76, 76f–78f in stroke, imaging of, 75–76, 78, 79f, 80, 80f magnetic resonance imaging, 52 Brain resection, for tumefactive lesions, postoperative imaging and, 95–96, 97f Brain tumors imaging of, 87, 89–98 of dyshistiogenetic lesions, 91, 91f of inflammatory or infective lesions, 87, 89, 90f of tumors masquerading as other lesions, 91, 93f, 94f of vascular lesions, 91, 92f post-treatment, 95–98, 97f, 98f predicting biologic tumor behavior and, 93–95, 94f–96f neurosurgery for, hyponatremia with, 566 seizures and, 736 Brainstem anatomy of, 24–26, 25f functions of, 134–135 lesions of, mimicking brain death, 840–841 surgery in, anesthetic risk with, 701 Brainstem reflexes, with altered mental status, 754–755, 756f Brainstem syndromes, 41f, 42, 43f, 44 Breathing coma and, 749 control of, 586–587 “frog,” for spinal cord injury, 798 glossopharyngeal, for spinal cord injury, 798 intracranial pressure control and, 715 synchronous and asynchronous, 588 work of, 588 pressure-supported ventilation and, 591 Broca’s aphasia, 118, 134 Brodmann’s cytoarchitectonic map, 118f Bromocriptine, for neuroleptic malignant syndrome, 428 Bronchodilators, 598–599 Brown-Sequard syndrome, 135 Bumetamide, for congestive heart failure, 548t Buprenorphine (Buprenex), 667 Buspirone, for head injury, 809t Butorphanol tartrate (Stadol), 667 Calcarine artery, anatomy of, 19 Calcarine sulcus, anatomy of, 20, 21f Calcarine veins anterior, anatomy of, 22 posterior, anatomy of, 22

893

Calcium neuronal death and survival and, 850–851, 851f neuroprotection and, 844–845 Calcium balance, disorders of, 571–572, 571t. See also Hypercalcemia; Hypocalcemia Calcium chloride, 672t Calcium gluconate, 672t Calcium-channel blockers, 676, 676t for myocardial ischemia, 543 in cerebral resuscitation, 474–475 physiologic effects of, 698t Callosal syndrome, 23 Calories, sources of, 611–613, 613t Calpain, with spinal cord injury, 777 Candidiasis meningitis in, 367 of brain, 356 Carbamazepine for head injury, 809t toxic levels of, clinical state of brain death caused by, 840t Carbohydrates, requirements for, 611–612, 613t Carbon dioxide transport, 586 Cardiac arrest cerebral resuscitation after. See Cerebral resuscitation encephalopathy following, pathophysiology of, 465–467 Cardiac disease, 533–550 heart-brain interaction and, 533, 534f, 535f in patient without previous cardiac disease, 533–540 arrhythmias and, 535–536 cardiac enzyme concentration increases and, 536 cardiac testing and, 536–537 clinical presentation of, 538 differential diagnosis of, 538 electrocardiographic abnormalities and, 534–535, 536f mechanism of injury and, 537 postmortem data for, 537 treatment of, 538–540, 539t pearls for, 550 preexisting, 540–549 congestive heart failure as, 545–547, 545t, 546t, 547f, 548t coronary artery disease as. See Coronary artery disease valvular, 547–549 Cardiac dysrhythmias in Guillain-Barré syndrome, management of, 422 in patient without preexisting cardiac disease, 535–536 with spinal surgery, 262 Cardiac enzymes, increase in, in patient without preexisting cardiac disease, 536 Cardiopulmonary bypass, emergency, 473–474 Cardiopulmonary resuscitation, 441. See also Do not resuscitate orders guidelines for, 467–470 historical background of, 463, 465 open-chest, 473 Cardiopulmonary-cerebral resuscitation, 457, 459. See also Cerebral resuscitation guidelines for, 467–470 historical background of, 465 Cardiovascular disorders with spinal cord injury, rehabilitation and, 799 with stroke, rehabilitation and, 802 CarePorter, 686

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Index

Carotid artery, internal, anatomy of, 17, 18f Carotid artery-jugular vein compression, for dural arteriovenous fistulas, 198 Carotid endarterectomy airway management during, 523–524 anesthesia for, 702–703 for carotid stenosis, 204, 205f Carotid stenosis, endovascular surgery for, 203–208, 205f–207f approaches for, 206, 208 complications of, 208 Carotid-cavernous fistulas, endovascular surgery for, 200–203, 201f approaches for, 202, 203f complications of, 202–203 Cartesian coordinate system, for stereotactic surgery, 269, 271 Caspase(s), neuronal death and survival and, 853 Caspase-activating proteins, release of, 852 Cat scratch disease, 382 Catatonia, 765 Catecholamine(s), potassium balance and, 568 Catecholamine surge, with head injury, 215, 216f, 217t, 219–220 Cauda equina syndrome, 259 Cavernous malformations, pediatric, 314–315 Cefotaxime, for bacterial meningitis, 345, 347t Ceftazidime, for brain abscesses, 358 Ceftriaxone for bacterial meningitis, 345, 347t for brain abscesses, 358 for Lyme disease, 381 for syphilis, 378 for Whipple’s disease, 382 Central nervous system. See also Brain; Spinal cord entries components of, 3 Cephalocele, 298 Cerebellar artery inferior anterior, anatomy of, 38, 40 posterior, anatomy of, 38, 39f, 40 superior, anatomy of, 40, 41f, 42 Cerebellar hemorrhage, 758 Cerebellar incisurae, anatomy of, 28–29, 30f Cerebellar peduncles, middle, anatomy of, 24, 25f Cerebellar tonsillar herniation, downward, imaging of, 73, 74f, 75, 75f Cerebellopontine angle, anatomy of, 27, 28f Cerebellopontine fissure, anatomy of, 27, 28f Cerebellum, anatomy of, 25f, 26–31, 28f of petrosal surface and fourth ventricle, 25f, 26–28, 28f of suboccipital surface and fourth ventricle, 29, 30f, 31, 32f of tentorial surface and fourth ventricle, 28–29, 30f Cerebral aneurysms, subarachnoid hemorrhage and, 162–163 Cerebral angiitis, ischemic stroke due to, 399 Cerebral arteries anterior, anatomy of, 21f, 22–23 middle, 13, 14f, 15 posterior, anatomy of, 17, 18f, 19 Cerebral blood flow anesthesia and, 696–697, 696f, 698t electroencephalography and, 626–627, 627f monitoring of, 635–641, 635t cerebral oximetry for, 641, 641f

cerebral oxygen supply and demand balance and, 639–641, 641f direct cerebral blood flow measurement for, 635–636, 636f jugular bulb oxygen saturation and, 640–641 transcranial Doppler ultrasonography for, 636–638, 637f–640f promotion of, in cerebral resuscitation, 472–473 with head injury, 773 Cerebral cavernous malformations intracerebral hemorrhage and, 163 subarachnoid hemorrhage and, 163 Cerebral embolism, ischemic stroke due to, 399 Cerebral hemorrhage, 758 Cerebral ischemia electroencephalography and, 626–627, 627f neuroprotection and, 853–855 apoptosis and, 855 excitotoxicity, calcium, and oxidant stress and, 854–855 inflammation and, 855 with head injury, 772–773 Cerebral metabolism, with head injury, 773 Cerebral oximetry, 641, 641f Cerebral oxygen consumption, anesthesia and, 695–696 Cerebral oxygen supply/demand balance, assessment of, 639–641 cerebral oximetry for, 641, 641f jugular bulb oxygen saturation for, 640–641 Cerebral peduncles, anatomy of, 24, 25f Cerebral perfusion pressure intracranial pressure related to, 709–710, 710f with head injury, guidelines for, 774 Cerebral resuscitation, 440–443, 457–483 advanced cardiac life support and, 441–442 antireperfusion injury therapy in, 444 basic life support and, 440–441 cardiopulmonary bypass and, 473–474 cardiopulmonary resuscitation and, 441, 463, 465 open-chest, 473 cerebral blood-flow promotion in, 472–473 circulatory adjuncts for, 443 cold aortic flush in, 480 definitions related to, 457, 458f, 459 deleterious chemical cascades and, 467 ethical issues in, 440, 480–481 guidelines for, 467–470 for adult advanced life support, 469–470 for adult basic life support, 468–469 historical background of, 463, 465 hypothermia in, 443, 444t, 475–479, 475t importance of, 459–460, 460f–462f, 463, 464f medicated aortic flush in, 480 neonatal, 442–443 new indexes of long-term neurologic prognosis for, 443–444 pearls for, 483 pediatric advanced life support and, 442 pharmacologic strategies for, 474–475 postischemic encephalopathy and, 465–466 postischemic hypoperfusion and, 466–467 postresuscitation-induced hypertension and, 444 standard brain-oriented life support and, 470–472, 470t–472t suspended animation in, 479–480 Cerebral salt wasting syndrome, hyponatremia due to, 563–565, 565t

Cerebral swelling, with head injury, 773 Cerebral vasospasm, endovascular surgery for, 190–192 approaches for, 191–192, 192f, 193f complications of, 192 Cerebral vein, middle, deep, 13, 14f Cerebral venous thrombosis, 417–419, 417t, 418f, 419f altered mental status with, 764 causal factors in, 417–418, 417t clinical presentation of, 418 imaging of, 418, 418f, 419f treatment of, 418–419 Cerebrospinal fluid analysis, in bacterial meningitis, 342–344, 343t Cerebrospinal fluid flow studies, magnetic resonance imaging, 55, 57f, 67–68 Cerebrum, anatomy of, 3–23 of basal surface arterial, 17, 18f, 19 neural, 14f, 15–16 venous, 14f, 16–17 of lateral surface arterial, 13, 14f, 15 neural, 3–13, 5f, 7f, 10f, 12f venous, 13, 14f of medial surface arterial, 21f, 22–23 neural, 19–22, 21f venous, 22 Cervical diskectomy, anterior, with interbody fusion, 243–245, 245f Cervical spine disorders, 235–248 ankylosing spondylitis as, 248, 248f atlas fractures as, 235–237, 236f axis fractures as, 237–240, 237f–239f congenital craniovertebral junction abnormalities as, 240–241, 242f degenerative, 241–243, 242f nonsurgical management of, 243 Paget’s disease as, 247 posterior longitudinal ligament ossification as, 247, 247f rheumatoid arthritis as, 248, 248f subaxial fractures as, 240, 241f surgical management of, 243–247, 244f anterior cervical diskectomy with interbody fusion as, 243–245, 245f corpectomy as, 245–246, 245f for cervical disk disease, posterior approach for, 246 laminectomy for spondylotic myelopathy as, 247 posterior lateral mass plate fixation of subaxial spine as, 246–247, 246f Chemical axotomy, 772 Chemical synapses, 108 Chemotherapy for tumefactive lesions, imaging following, 98, 98f for tumors, 147–148 Cheyne-Stokes respiratory, 754 Chiari 1 malformations, 294–296 Child abuse, head injury caused by, 303 Children. See Pediatric patients. Chloramphenicol for bacterial meningitis, 345, 347t for rickettsial infections, 381 Chlordiazepoxide, toxic levels of, clinical state of brain death caused by, 840t Chloroquine phosphate, for malaria, 373 Chondrosarcomas, of thoracic spine, 252 Chordomas, of thoracic spine, 252

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Index Choroid plexus, anatomy of, 27–28, 28f Choroidal arteries anterior, anatomy of, 17, 18f posterior, lateral, anatomy of, 19 posterior, medial, anatomy of, 19 Choroidal fissure, anatomy of, 11 Cincinnati Prehospital Stroke Scale, 450t, 451 Cingulate gyrus, anatomy of, 19, 20, 21f Circulation. See also Cerebral blood flow coma and, 749 intracranial pressure control and, 715 pulmonary distribution of ventilation and, 581–583, 582f metabolic functions of, 584 Circulatory shock, multiple organ failure and, 782 Circumflex arteries, anatomy of, 19 Circumfundibular anastomosis, anatomy of, 17, 18f Cisatracurium, 671t physiologic effects of, 698t Clarithromycin, for toxoplasmosis, with HIV infections, 370 Claude’s syndrome, 43f, 44 Claustrophobia, magnetic resonance imaging limitation by, 58 Clayshoveler’s fracture, 240, 241f Clearance, of drugs, 650, 650f, 650t Clindamycin for malaria, 373 Clonazepam, toxic levels of, clinical state of brain death caused by, 840t Clonidine for intracranial pressure control, 710 for spasticity, following stroke, 804t Cluster breathing, 754 Coagulopathy, intracerebral hemorrhage associated with, 171, 173 Cocaine seizures induced by, 740 toxic levels of, clinical state of brain death caused by, 840t Coccidioidosis, meningitis in, 365–366 Codeine, toxic levels of, clinical state of brain death caused by, 840t Collateral sulcus, 14f, 16 Colliculi, inferior and superior, anatomy of, 24, 25f Coma assessment of, evoked potentials for, 634 barbiturate for intracranial pressure control, 723–724, 724t for neurovascular surgery, 701–702 brain death and, 767–768 differential diagnosis of, 117–118 drug overdose and, 749 electroencephalography and, 628 initial evaluation of, 749–756 ABCs in, 749 brainstem reflexes in, 754–755, 756f eye examination in, 751–752, 752f fundoscopy in, 752–753, 753f Glasgow Coma Scale in, 755–756 history in, 749 neurologic examination in, 749–751, 750f ventilatory pattern in, 753–754, 753t, 754f, 755f laboratory examination for, 756–757 pathophysiology of, 748f, 748–749 Combitube for difficult airway management, 510, 511f, 517–518, 518f with spinal cord injury, 522–523

Communicating artery, posterior, anatomy of, 17, 18f Computed tomography, 60–63 contrast media for, 60–62, 61f, 68 iodinated, restrictions on use of, 61–62 filters for, 60 image segmentation and, 60 in ischemic stroke, 399–401 in stereotactic surgery, 271, 272–273, 274f, 275, 276 intracranial hemorrhage on, 83, 84, 84f of intracerebral hemorrhage, 174 postprocessing and, 60 sequences for, 62–63 brain perfusion and, 63, 64f, 69 CT angiography as, 62, 62f, 67, 69f helical CT scanning as, 62 image reformations and, 62 Computed tomography angiography, 62, 62f, 67, 69f brain death confirmation and, 837t, 838 in subarachnoid hemorrhage, 156, 157f, 158f of intracerebral hemorrhage, 174 Confusion, 747–748 laboratory examination for, 756–757 pathophysiology of, 748, 748f Congestive heart failure, 545–547 diagnosis of, 545–546, 545t exacerbating factors for, 546, 546t pharmacologic management of, 546–547, 547f, 548t Consciousness, alteration of. See Altered mental status; Coma; Confusion Consensual light reflex, 752 Continuous drug infusions, 652–653, 653t Continuous positive airway pressure, 592–593 contraindications to, 593 Contractures with head injury, rehabilitation and, 807 with spinal cord injury, rehabilitation and, 801 Contrast media. See specific imaging techniques and media Controlled ventilation, 589 Contusions, of brain, focal, 772 Cooling methods, for hypothermia induction, 478 Corneal reflexes, 752 brain death and, 836 in neurologic examination, 622t Coronal synostosis, unilateral, 296–297, 296t Coronary artery disease, neurosurgery with, 540–545 management strategies for, 542–545, 543t, 544t risk stratification for, 540–541 surveillance and, 541–542, 541t, 542f Corpectomy, of cervical spine, 245–246, 245f Corpus callosum, anatomy of, 8–9 Corticosteroids, 669–670, 669t, 670t. See also specific corticosteroids contrast enhancement effects of, in magnetic resonance imaging, 58, 59f for Guillain-Barré syndrome, 423 for myasthenia gravis, 425 Cortisol, 669t Cortisone, 669t Cough reflex, in neurologic examination, 622t Cranial nerves I (olfactory) anatomy of, 31 examination of, 119, 120f

895

II (optic) anatomy of, 31, 32f, 33 examination of, 119, 120f, 121f III (oculomotor) anatomy of, 32f, 33, 34f examination of, 119, 121f IV (trochlear) anatomy of, 33, 34f examination of, 119, 121, 122f V (trigeminal) anatomy of, 33, 34f, 35 examination of, 121, 123f VI (abducent) anatomy of, 34f, 35 examination of, 121, 123f VII (facial) anatomy of, 35–36 examination of, 122, 124f VIII (vestibulocochlear) anatomy of, 36 examination of, 122 IX (glossopharyngeal) anatomy of, 36 examination of, 122, 124f X (vagus) anatomy of, 36–37 examination of, 122, 125f XI (accessory) anatomy of, 37 examination of, 122, 126f XII (hypoglossal) anatomy of, 37 examination of, 122 examination of, 119–122, 120f–126f injuries of, following transarterial embolization, for dural arteriovenous fistulas, 199 Craniectomy decompressive, for head injury, 775 for intracranial pressure control, 725 Craniopharyngiomas, pediatric, 310–311 Craniosynostosis, 296–298, 296t Craniotomy for intracranial pressure control, 160 for tumors, 142, 143f, 144f, 144–145 Craniovertebral junction abnormalities, congenital, 240–241, 242f Cricothyroidotomy, emergency, 511–512, 512f needle, 512, 514f percutaneous, 512, 512f, 513f Critical thinking, intuitive thinking vs., 819–820 Crouzon’s syndrome, 297 Cryoprecipitate, for ischemic stroke, 404 Cryptococcal meningitis, 363–364 Cryptococcomas, 356 Cuffed pharyngeal airway, 510–511 Cuneus, anatomy of, 20, 21f Cushing response, 219 Cyst(s) arachnoid, intracranial, 298–300, 299f neurenteric, 293t Cysticercosis, 374–375, 374f Cytokines, multiple organ failure and, 782 Cytomegalovirus infections, with HIV infections, 370–371 Dandy-Walker complex, 300–301, 301f Dantrolene for neuroleptic malignant syndrome, 428 for spasticity, following stroke, 804t Dapsone, for toxoplasmosis, with HIV infections, 370 Decerebrate rigidity, 750–751, 750f

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Index

Deconditioning syndrome, in critical illness, 427 Decorticate rigidity, 750, 750f Deep brain stimulation, 278–279, 279f Deep vein thrombosis with head injury, rehabilitation and, 806 with spinal cord injury, 799 with stroke, rehabilitation and, 802–803, 803t Degenerative disorders, of cervical spine, 241–243, 242f Delirium, 747–748, 764–765 postoperative, 765 Dentate gyrus, anatomy of, 21–22, 21f Dentate nucleus, anatomy of, 29, 30f Deontologic ethics, 819 Depacon, for seizures, 743 Dermal sinus tract, 293t Dermatologic disorders with head injury, rehabilitation and, 807 with spinal cord injury, rehabilitation and, 800–801 with stroke, rehabilitation and, 803 Desflurane, physiologic effects of, 698t Desipramine, for head injury, 809t Dexamethasone, 669t for bacterial meningitis, 346, 347t for intracranial pressure control, 722–723, 723t for reducing postoperative nausea, 701 for tuberculous meningitis, 362 Dexmedetomidine (Precedex), 668–669 Dezocine (Dalgan), 667 Diabetes insipidus, 560 Diaphragmatic weakness, in Guillain-Barré syndrome, management of, 422 Diazepam (Valium), 656–657 for spasticity, following stroke, 804t toxic levels of, clinical state of brain death caused by, 840t Difficult airway. See Airway management Diffusion, of neurotransmitters, 110 Digoxin, for arrhythmias, 539t Dihydroergotamine, for intracranial pressure control, 710 Diltiazem (Cardizem), 676t for arrhythmias, 539t Diphenhydramine, for head injury, 809t Disk herniation cervical, 242 lumbar, 257–259, 258f thoracic, 250, 250f Diskectomy, cervical, anterior, with interbody fusion, 243–245, 245f Disodium etidronate, for heterotopic ossification, 801 Disorientation, 747 Do not resuscitate orders, 830–833 care under, 831–833 historical background of, 830 issues involving, 831–833 physician team and, 833 policies guiding, 830–831 quality of life and, 831 Dobutamine, 671, 673t for congestive heart failure, 548t Dopamine, 671, 673t, 674 for blood pressure elevation, in intracerebral hemorrhage, 415t for congestive heart failure, 548t for intracranial pressure control, 710 Dopexamine, for congestive heart failure, 548t Doppler ultrasound, transcranial, for cerebral blood flow measurement, 636–638 brain death confirmation and, 638, 640f, 837t, 838

in head injury, 638, 639f intracranial pressure assessment and, 638, 639f theoretical basis for, 636–637, 637f vasospasm detection and, 638, 638f Dorsal column syndrome, 135 Doxacurium, physiologic effects of, 698t Doxycycline for Lyme disease, 381 for malaria, 373 for rickettsial infections, 381 for syphilis, 378 Drowsiness, 747 Drug(s). See also specific drugs and drug types consciousness level and, 748 Drug interactions, 651 Drug overdose, treatment of, 749 Drug use/abuse, intracerebral hemorrhage associated with, 173 Drug-induced seizures, 737, 737t, 740–742 Dural sinus thrombosis, imaging of, 78, 80, 81f Dysautonomia central, with head injury, rehabilitation and, 806–807 in Guillain-Barré syndrome, management of, 422 Dyshistiogenetic brain lesions, imaging of, 91, 91f Dysrhythmias in Guillain-Barré syndrome, management of, 422 in patient without preexisting cardiac disease, 535–536 with spinal surgery, 262 Dystonia, pediatric, 319–321 Eastern equine encephalitis, 349 Echinococcosis, 375 Ehrlichiosis, 382 Electrical synapses, 108 Electrocardiography, abnormalities on, in patient without preexisting cardiac disease, 534–535, 536f Electrochemical gradients, 103, 105f Electroencephalography, 622–628 brain death and, 628, 837–838, 837t coma and, 628 regional ischemia and, 626–627, 627f seizures and, 627–628, 628f, 733–734 patterns in, 734, 735f theoretical basis for, 622–626, 622f–626f, 625t, 626t with altered mental status, 756–757 Elimination, of drugs, 650, 650f, 650t Embolization of arteriovenous malformations approaches for, 194 complications of, 194, 196–197 endovascular, 193–194, 195f, 196f transarterial, for dural arteriovenous fistulas, 198, 199f, 200f Emergency medical service systems, 439–440 response for head injury, 222–223, 223f Empyema, pediatric, 316–317 Enalapril, for blood pressure elevation, in intracerebral hemorrhage, 415t Enalaprilat for congestive heart failure, 548t for hypertension, 544t Encephalitis amebic, 382–383 viral, 348–355 clinical manifestations of, 351, 352t, 353–355, 353f, 354f, 354t

epidemiology of, 349–350 pathogenesis of, 350–351 treatment of, 355 Encephalocele, 298 Encephalopathy, 747 anoxic, altered mental status with, 761, 765–766 hepatic, seizures and, 740 HIV, 371–372, 372f pearls for, 388 hypertensive, 758 infectious, altered mental status with, 761 metabolic altered mental status with, 761–762 diagnosis of, 621t postischemic, 465–466 toxic, altered mental status with, 761–763 Endosaccular coiling, 167 Endoscopic surgery, spinal, 261, 261f Endoscopic third ventriculostomy, for hydrocephalus, 291 Endotracheal intubation confirming, 514–515, 515f esophageal misplacement and, 515 following head injury, 445–446 hypertension following, with head injury, 521 laryngeal mask airway and, 509, 509f, 510f placement of, 510 patient preparation for, 503–504, 505f retrograde, 519, 520f with penetrating neck injuries, 523 Endotracheal tubes. See also Extubation blood in, 596 complications related to, 595 exchanging, 526 Endovascular interventions for subarachnoid hemorrhage, 167 for vasospasm, 169, 170f, 171f Endovascular surgery for acute thromboembolic stroke, 183–186 approaches for, 184–185, 185f, 186f complications of, 186 for arteriovenous malformations, 192–197, 193t, 195f, 196f approaches for, 194 complications of, 194, 196–197 for carotid-cavernous fistulas, 200–203, 201f approaches for, 202, 203f complications of, 202–203 for cerebral vasospasm, 190–192 approaches for, 191–192, 192f, 193f complications of, 192 for dural arteriovenous fistulas, 197–200, 197t approaches for, 198, 199f, 200f complications of, 199–200 for extracranial stenosis, 203–208, 205f–207f approaches for, 206, 208 complications of, 208 for intracranial aneurysms, 186–188, 187f approaches for, 187–188 complications of, 188, 189f, 190f for intracranial stenosis, 208–209 approaches for, 209, 210f complications of, 209, 211f pearls for, 212 Enflurane, physiologic effects of, 698t Enteral nutrition, 614 parenteral nutrition vs., 614–615 Enterovirus infections, laboratory diagnosis of, 352t Enzymatic degradation, of neurotransmitters, 110 Enzyme replacement, for lysosomal storage disorders, gene therapy for, 879–880

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Index Ependymomas, 149–150, 150f posterior fossa, 307–308, 307f Ephedrine, 673t physiologic effects of, 698t Epidural abscesses pediatric, 317 spinal, 384–385 Epidural hematomas, cerebral, 772 Epinephrine, 671, 672t, 674 for arrhythmias, 539t for congestive heart failure, 548t for pediatric advanced life support, 442 Equilibrium, of drugs, 649–650 Erythromycin, for Lyme disease, 381 Esmolol, 677t for blood pressure elevation, in intracerebral hemorrhage, 415t for hypertension, 544t Estrogen replacement therapy, for neuroprotection, 857–858, 858f, 859f Ethambutol, for tuberculous meningitis, 361 Ethanol, altered mental status with, 762 Ethical issues, 815–833 advance directives and, 823, 824b–825b do not resuscitate orders as, 830–833 euthanasia as, 826–829, 827t–829t importance of, 816–818 for Jehovah’s Witnesses, 816–817 for physicians, 816–817 for society, 817–818 in brain death, 841 in cerebral resuscitation, 480–481 in resuscitation, 440 moral theory and, 818–820 consequential vs. nonconsequential, 819 critical vs. intuitive thinking and, 819–820 facts vs. values and, 818–819 patient-physician disagreement and, 823, 825–826 physician-assisted suicide as, 826–829, 827t–829t principles of, 815–816 rationing health care resources as access and, 820–821 intensive care services and, 821–823 withdrawing/withholding therapy as, 822–823 Etomidate (Amidate), 659–661, 660t for airway management, with head injury, 521 Euthanasia, 826–829, 827t–829t Evoked potentials, 628–635 applications in neurointensive care unit, 634–635 auditory, 631–633, 632f motor, 633–634 signal averaging and, 629, 629f somatosensory, 629–631, 630f, 632t terms describing, 629, 629f, 630t theoretical basis for, 628–629 visual, 633 Excitatory postsynaptic potentials, 110–112 Excitotoxicity antiexcitotoxicity therapy and, 856 neuroprotection and, 854–855 with spinal cord injury, 777 External ventricular drains, 387–388 Extracranial stenosis, endovascular surgery for, 203–208, 205f–207f approaches for, 206, 208 complications of, 208 Extravasation, of contrast media, for computed tomography, 61–62 Extubation of difficult airway, 524–526, 525t

accidental, 525 criteria for and timing of, 525–526 postoperative, 703–704 weaning from mechanical ventilation and, 601 Eye examination, with altered mental status, 751–752, 752f Eye movements, in neurologic examination, 752, 752f Facial nerve anatomy of, 35–36 examination of, 122, 124f Facts, values vs., 818–819 Fast spin-echo imaging, 50–51 Fastigium, anatomy of, 27, 28f Fat suppression, for magnetic resonance imaging, 56, 56f Fenoldopam for congestive heart failure, 548t for hypertension, 544t Fentanyl (Sublimaze), 665 for intracranial pressure control, 710 physiologic effects of, 698t toxic levels of, clinical state of brain death caused by, 840t Fever, following hemorrhagic stroke, 161–162 Filum terminale, tight, 293t Flocconodular nodule, anatomy of, 26 Flocculus, peduncle of, anatomy of, 27, 28f Fluconazole for coccidioidal meningitis, 366 for cryptococcal meningitis, 363, 364 Flucytosine, for cryptococcal meningitis, 363–364 Fluid and electrolyte management, anesthesia and, 697, 699, 699t Fluid attenuating with strong T2-weighted imaging, 51, 52f Flumazenil (Romazicon), 657–658 for drug overdose, 749 Fluoxetine, for depression, following stroke, 805t Flurazepam, toxic levels of, clinical state of brain death caused by, 840t Folinic acid, for toxoplasmosis, with HIV infections, 370 Foramen of Monro, anatomy of, 8, 10f Foscarnet, for cytomegalovirus infections, with HIV infections, 371 Fosphenytoin (Cerebyx), 678 for seizures, 742 Foville’s syndrome, 42, 43f Fractures. See specific site or bone Frameless stereotaxis, 275 Free oxygen radicals, multiple organ failure and, 782–783 “Frog” breathing, for spinal cord injury, 798 Frontal gyrus, medial, anatomy of, 20, 21f Frontal horn, anatomy of, 6 Frontal lobe anatomy of, 4 functions of, 124 Frontal veins inferior, anatomy of, 14f, 16 medial, anatomy of, 22 Functional magnetic resonance imaging, 54 Fundoscopy, with altered mental status, 752–753, 753f Fungal meningitis, 362–368 cryptococcal, 363–364 in aspergillosis, 367–368 in blastomycosis, 366–367 in candidiasis, 367 in coccidioidosis, 365–366

897

in histoplasmosis, 364–365 in zygomycosis, 367, 368f pearls for, 389 Furosemide, for congestive heart failure, 548t Fusiform aneurysms, subarachnoid hemorrhage and, 162 GABA receptors, 105–106 Gabapentin, for seizures, 743 Gadolinium, restriction of usage of, 58 Gag reflex, in neurologic examination, 622t Gamma knife system, 280 Ganciclovir, for cytomegalovirus infections, with HIV infections, 371 Gas exchange, 584–585 diffusion limitation and, 584–585 hypoventilation and, 584, 584t shunt and, 585 ventilation-perfusion mismatch and, 585 Gastric contents, aspiration of, difficult airway and, 500–501, 503 Gastric mucosal ulceration, with head injury, 220–221 Gastroduodenal erosions, following hemorrhagic stroke, 161 Gastrointestinal disorders seizures and, 737 with spinal cord injury, rehabilitation and, 799–800 Gene therapy, 865–882 ex vivo, 865–866 in vivo, 866, 875–877 for lysosomal storage disorders, 880–881 intraspinal, via intraparenchymal or intrathecal injection, 875–876 nonviral vectors for, 870 target central nervous system disorders for, 870, 872–881 Alzheimer’s disease as, 872–873 amyotrophic lateral sclerosis as, 874–875 glioblastoma as, 872–873 Huntington’s disease as, 873 lysosomal storage disorders as, 879–881 motor degenerative disease as, 875–876 Parkinson’s disease as, 870, 872 spinal cord pathobiology as, 875 spinal trauma as, 876–879 stroke as, 881 transcriptional regulation and, 870, 871t viral vectors for, 866, 867t, 868–869 adeno-associated virus as, 868, 869f, 880–881 herpes simplex virus as, 868, 880 lentivirus as, 868–869 recombinant adenovirus as, 866, 868, 880 Genitourinary disorders after spinal surgery, 262 with spinal cord injury, rehabilitation and, 800 Gentamicin, for bacterial meningitis, 347t Geometric coordinate system, for stereotactic surgery, 269, 271 Gerstmann’s syndrome, 119, 134 Glasgow Coma Scale, 117, 118f in head injury, pediatric, 302 with altered mental status, 753, 753t, 755–756 with head injury, 805 Glioblastomas, gene therapy for, 873–874 Gliomas, 139, 148–149 low-grade, 148, 148f malignant, 149, 149f pediatric, 311–312 brainstem, 309–310

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Index

Global brain ischemia, 457 Glossopharyngeal breathing, for spinal cord injury, 798 Glossopharyngeal nerve anatomy of, 36 examination of, 122, 124f Glucose, serum, control of, for intracranial pressure control, 718–719, 719f–721f Glutamate receptors, 104–105, 107f Glycine receptors, 105–106 Gram-negative bacilli, meningitis due to, 339 Guglielmi detachable coils, for intracranial aneurysms, 186–187, 187f Guillain-Barré syndrome, 419–428 management of, 421t, 421–423 mimicking brain death, 840 pearls for, 429 presentation and diagnosis of, 419–421, 420t, 421t Haemophilus influenzae meningitis, 338, 347t Half-lives, of drugs, 650, 652 Halothane, physiologic effects of, 698t Hangman’s fractures, 235, 236, 236f Head frames, airway management with, 523 Head injury, 215–223, 771–775 airway management with, 519–521 apnea associated with, 215–219, 216f, 217t, 218f therapeutic options for, 222 catecholamine surge associated with, 215, 216f, 217t, 219–220 cerebral blood flow monitoring in, transcranial Doppler ultrasonography and, 638, 639f emergency medical service response for, 222–223, 223f gastric mucosal ulceration associated with, 220–221 hyperglycemia associated with, 220 hyponatremia with, 566 intracranial pressure elevation and. See Intracranial pressure management guidelines for, 773–775 for antiseizure prophylaxis, 775 for barbiturates, 775 for blood pressure and oxygenation, 773 for cerebral perfusion pressure, 774 for decompressive craniectomy, 775 for hypertonic saline, 775 for hyperventilation, 774–775 for initial management, 773, 774f for intracranial pressure monitoring, 773, 774t for intracranial pressure treatment, 773, 775, 776f for mannitol, 775 for steroids, 775 for trauma systems, 773 nutritional, 775 myocardial injury associated with, 221 neurogenic pulmonary edema, associated with, 221, 221f pathogenesis of, 772–773 pearls for, 786–787 pediatric, 301–303 prehospital care for, 444–448 for closed head injuries, 444–447 for pediatric patients, 447 for penetrating injuries, 447–448 primary injury and, 772 rehabilitation for. See Rehabilitation, for head injury

secondary injury and, 772–773 seizures following, 735–736 target therapy for, 223 University of Florida TBI protocol for, 725, 726f–728f, 729 Headache with brain abscess, 357 with intracerebral hemorrhage, 174 with subarachnoid hemorrhage, 165 Health care rationing access and, 820–821 intensive care services and, 821–822 Heart. See also Cardiac starvation and, 607–608 Helical computed tomography, 62 Heliox, to improve oxygenation, 597 Hematomas epidural, cerebral, 772 evacuation of, for intracerebral hemorrhage, 175–176, 176t intracerebral, 772 subdural, cerebral, 772 Hemiplegia alternans syndrome, 140 Hemodilution for intracranial pressure control, 720–722, 721f for vasospasm management, 169 Hemorrhage cerebellar, 758 cerebral, 758 following hemorrhagic stroke, 160 intracerebral. See Intracerebral hemorrhage perimesencephalic, benign, 164 postoperative, intracerebral hemorrhage associated with, 173 risk of, with neurovascular surgery, 701 subarachnoid. See Subarachnoid hemorrhage Hemorrhagic stroke, 155–178 acute evaluation of, 155 diagnosis and etiology of, 156–157, 156f–159f epidemiology and significance of, 155 intracerebral hemorrhage causing, 155, 156f. See also Intracerebral hemorrhage management strategy for, 157–162 ABCs of multisystem support and, 157–158, 159t for delayed sequelae, 160 for systematic complications, 160–162 intracranial pressure and cerebral perfusion and, 158–159, 161f timing and management of underlying cause and, 162 mobilization and rehabilitation following, 162 pearls for, 177–178 psychosocial support and, 162 subarachnoid hemorrhage causing, 162–170. See also Subarachnoid hemorrhage Heparin for cerebral venous thrombosis, 418–419 for ischemic stroke, 404, 409–410, 409t for myocardial infarction, 545 Hepatic encephalopathy, seizures and, 740 Herpes simplex virus, as gene therapy viral vectors, 868, 880 Herpes virus infections, laboratory diagnosis of, 352t, 353–354 Heterotopic ossification with head injury, 807 with spinal cord injury, 801–802 Hiccup, 754 High-frequency ventilation, 592 Hippocampus, anatomy of, 9, 10f Histoplasmosis, meningitis in, 364–365 HIV encephalopathy, 371–372, 372f

Hormones, vasopressor, 557, 557f Hughlings-Jackson syndrome, 135 Human immunodeficiency virus (HIV) infection CNS infections associated with, 368–371 pearls for, 388 encephalopathy and, 371–372, 372f pearls for, 388 laboratory diagnosis of, 352t Huntington’s disease, gene therapy for, 873 Hydralazine (Apresoline), 677, 677t for blood pressure elevation, in intracerebral hemorrhage, 415t Hydrocephalus, 286–291, 287t clinical and radiographic features of, 287–288 myelomeningocele and, 289 posthemorrhagic, 288–289, 288t treatment and complications of, 289–291 with subarachnoid hemorrhage, 168 Hydrocortisone, for myasthenia gravis, 426 Hyperbaric oxygen therapy in cerebral resuscitation, 474 seizures and, 737 Hypercalcemia, 571–572, 571t Hypercapnia consciousness level and, 748 consequences of, 499 respiratory responses to, 586 Hypercoagulable states, ischemic stroke due to, 399 Hyperdynamic state, following neurologic injury, 609 Hyperglycemia intracranial pressure control and, 718 prevention of, 612, 613t seizures and, 739 with head injury, 220 Hyperinflation, dynamic, prevention or reversal of, 595 Hyperkalemia, 569–570, 569t clinical manifestations of, 569–570 management of, 570 Hypermagnesemia, 572–573, 573t Hypernatremia, 558–562, 559f, 559t causes of, in neurointensive care unit, 560 clinical manifestations of, 558–559 following hemorrhagic stroke, 161 management of, 560–562, 561t Hyperphosphatemia, 572, 572t Hypertension following endotracheal intubation, with head injury, 521 following stroke, rehabilitation and, 802 in Guillain-Barré syndrome, management of, 422 induced, for vasospasm management, 169 intracerebral hemorrhage associated with, 171, 172f postresuscitation-induced, in cerebral resuscitation, 444 with myocardial ischemia, management of, 544, 544t Hypertensive encephalopathy, 758 Hypertonic fluid therapy, for intracranial pressure control, 720–722, 721f Hyperventilation for head injury, guidelines for, 774–775 for intracranial pressure control, 716–717, 716t Hypervolemia, for vasospasm management, 169 Hypnotic drugs, 653 Hypocalcemia, 571t, 572 seizures and, 739

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Index Hypocarbia, for intracranial pressure elevation, 160 Hypoglossal nerve anatomy of, 37 examination of, 122 Hypoglycemia intracranial pressure control and, 718 seizures and, 739 Hypokalemia, 570–571, 570t clinical manifestations of, 570 management of, 570–571 Hypomagnesemia, 573, 573t seizures and, 739 Hyponatremia, 562–568 causes of, in neurointensive care unit, 563–567, 564t clinical manifestations of, 562–563, 563f following hemorrhagic stroke, 160–161 in meningitis, 567 in neurosurgery for brain tumors, 566 initial evaluation of, 562 management of, 567–568 seizures and, 738–739 with head injury, 566 with subarachnoid hemorrhage, 565–566 management of, 568 Hypoparathyroidism, seizures and, 739 Hypoperfusion, postischemic, 466–467 Hypophosphatemia, 572, 572t seizures and, 739 Hypophyseal arteries, superior, anatomy of, 17, 18f Hypophysectomy, airway management during, 523 Hypotension orthostatic, with spinal cord injury, 799 with mechanical ventilation, 595 with myocardial ischemia, management of, 544 with spinal cord injury, 449 Hypothermia diagnosis of, 621t for head injury prehospital care, 447 for intracranial pressure control, 724–725, 725t in cerebral resuscitation, 443, 444t, 475t, 475–479 mimicking brain death by, 840 postoperative, 704–705 rewarming following, with myocardial ischemia, 543–544 Hypoventilation, gas exchange and, 584, 584t Hypoxia consequences of, 499–500, 500t imaging of, 81–82, 82f, 83f respiratory responses to, 586 with head injury, 520 with mechanical ventilation, 596 Hypoxic pulmonary vasoconstriction, 583–584 Ibutilide, for arrhythmias, 539t Ilanzapine, for head injury, 809t Imaging, 47–99. See also specific modalities for evaluation of ventricular size, 85–87, 87f–89f in bacterial meningitis, 344, 344f, 345f in ischemic stroke, 399–401 in tuberculous meningitis, 361, 361f in verbal osteomyelitis, 386–387 of brain abscesses, 357–358, 357f of brain herniations, 68–74 of downward cerebellar tonsillar herniation, 73, 74f, 75, 75f

of downward transtentorial herniation of parahippocampal gyrus, 70, 71f–72f, 73 of subfalcine herniations, 70, 70f of upward transtentorial herniation, 73, 73f of brain masses. See Brain tumors, imaging of of dural sinus thrombosis, 78, 80, 81f of intracerebral hemorrhage, 414–415 of oligemia, 75–76, 76f–78f of stroke, 75–76, 78, 79f, 80, 80f of tumors, 140–141 pearls for, 99 with altered mental status, 756 Immobilization, for cervical spine disorders, 243 Immune function, starvation and, 608 Implanted devices, magnetic resonance imaging limitation by, 59 Inattention, 747 Infants neurologic examination of, 286 newborn, resuscitation of, 442–443 Infection. See also specific infections multiple organ failure and, 781–782 of thoracic spine, 252–254, 255f starvation and, 608 Infectious encephalopathy, altered mental status with, 761 Infectious tumefactive brain lesions, imaging of, 87, 90f, 99 Inflammation anti-inflammation therapy and, 856 injury due to, 114 multiple organ failure and, 782 neuroprotection and, 855 with spinal cord injury, 777 Inflammatory tumefactive brain lesions, imaging of, 87, 90f, 99 Infundibular arteries, anatomy of, 17, 18f Inhibitory postsynaptic potentials, 110–112 Injury, response to starvation and, 609 Inotropic agents, 671–674 Inotropic receptors, 104 Insula of Reil, anatomy of, 6 Insulin, potassium balance and, 568 Integrilin, for ischemic stroke, 407 Interbrachial sulcus, anatomy of, 29, 30f Intermittent mandatory ventilation, 589 synchronized, 589 Internal capsule, anatomy of, 8, 10f Interpeduncular fossa, anatomy of, 14f, 16 Interpeduncular sulcus, anatomy of, 29, 30f Intervertebral disks, herniation of. See Disk herniation Intestinal barrier function, starvation and, 609 Intracerebral hematomas, 772 Intracerebral hemorrhage, 155, 156, 157f, 171–176, 411–417 clinical presentation of, 174 critical care management of, 174–175 diagnostic evaluation of, 174 etiology of, 171–174 amyloid angiopathy in, 171 coagulopathy in, 171, 173 drug use in, 173 hypertensive small vessel disease in, 171, 172f intracranial aneurysm in, 173 postoperative hemorrhage in, 173 vascular malformations in, 173, 173f venous occlusive disease in, 173 following arteriovenous malformation embolization, 194, 196–197

899

following endovascular surgery for stroke, 186 imaging of, 77, 82–85, 84f intraventricular, 412, 413f lobar, 412, 412f, 413f medical therapy for, 175 outcome after, 176 outcomes with, 413–414, 413f, 414t risk factors for, 411–412, 412t surgical therapy for, 175–176, 176t treatment of, 414–417, 415t, 416t with endovascular cervical carotid revascularization, 208 Intracranial lesions, altered mental status with, 758–759 Intracranial pressure, 709–729 assessment of, transcranial Doppler ultrasonography and, 638, 639f cerebral perfusion pressure related to, 709–710, 710f elevated altered mental status with, 759 control of, 775 critical pathway for treatment of, 775, 776f following head injury, 219, 220 therapy of, 715–725, 726f–728f barbiturates in, 723–724, 724t hypertonic fluid therapy in, 720–722, 721f hyperventilation in, 716–717, 716t hypothermia in, 724–725, 725t mannitol in, 719–720 minimization of stimulation and, 717–718 neuromuscular blockade in, 717 positioning in, 715, 715t, 716t resuscitation and, 715 sedation in, 717 serum glucose control and, 718–719, 719f–721f steroids in, 722–723, 723t surgical, 725 University of Florida TBI protocol for, 725, 726f–728f, 729 treatment threshold for, 773 with neoplastic disease, 139–140 in hemorrhagic stroke, 158–159, 161f lowering of, for intracerebral hemorrhage, 174–175 monitoring of, 710–715 in intracerebral hemorrhage, 416 indications for, 710–711, 773, 774t methods for, 711–714, 711t, 712t, 714f regional, 714–715 technology for, 773 pearls for, 729 regional, 714–715 Intracranial stenosis, endovascular surgery for, 208–209 approaches for, 209, 210f complications of, 209, 211f Intrahospital transport, 683–691 complications encountered during, 684–685 pearls for, 690 reasons for, 683 safe components of transport system for, 686, 689–690 strategies for ensuring, 686, 687t–689t ventilation during, 685–686 Intravenous gamma globulin for Guillain-Barré syndrome, 423 for myasthenia gravis, 425 Intuitive thinking, critical thinking vs., 819–820

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Index

Invisible targets, for stereotactic surgery, 273, 276f, 277f Ion channels, 103, 106f Ionic flux, with spinal cord injury, 777 Ionization, of drugs, 650, 651t Ipratropium bromide, to improve oxygenation, 598 Ischemia neurotransmission disruptions due to, 112–113 subendocardial, following hemorrhagic stroke, 160 Ischemic stroke, 397–411, 757 evaluation in, 399–401 following arteriovenous malformation embolization, 197 management of, 400, 401t–403t, 402–411, 403f for specific stroke emergencies, 410–411, 410f, 411f future directions for, 408, 409f in patients not eligible for thrombolysis, 408–410, 409t intra-arterial thrombolysis for, 404–408, 405f–407f, 407t pathophysiology of, 397–399, 398f, 398t with endovascular cervical carotid revascularization, 208 Isoflurane, physiologic effects of, 698t Isoniazid for tuberculous meningitis, 361 seizures induced by, 742 Isoproterenol, 671, 673t, 674 for arrhythmias, 539t for congestive heart failure, 548t Itraconazole, Blastomyces meningitis, 367 JC virus infections, laboratory diagnosis of, 352t Jehovah’s Witnesses, ethical issues and, 816–818 Jugular bulb oxygen saturation, assessment of, 640–641, 712–713 Ketamine, 661–662, 661t physiologic effects of, 698t toxic levels of, clinical state of brain death caused by, 840t Ketorolac (Toradol), 669 Klûver-Bucy syndrome, 134 Kyphosis, 249–250, 249f La Crosse encephalitis, 349 Labetalol (Tomodyne, Trandate), 676–677, 677t for blood pressure elevation, in intracerebral hemorrhage, 415t for hypertension, 544t Lambdoid synostosis, 296t, 297 Laminectomy, cervical, for spondylotic myelopathy, 247 Lamotrigine, for seizures, 743 Language function, disorders of, 118–119, 118f, 119f Laryngeal mask airway, 509, 509f, 510f, 515–517, 516f contraindications to, 516–517 endotracheal intubation following, 517 placement of, 510 prehospital role of, 517 with spinal cord injury, 522 Laryngoscopy achieving best view for, 506, 507f blade choice for, 506–507 rigid fiberoptic laryngoscopes for, 519 unsuccessful, alternatives for, 507–508

Lateral mass plate fixation, posterior, of subaxial spine, 246–247, 246f, “Lazarus sign,” brain death and, 837 Legal issues, in brain death, 841 Length constant, in synaptic transmission, 111 Lentivirus, as gene therapy viral vector, 868–869 Leukoencephalopathy, multifocal, progressive, 383, 384f Levetiracetam, for seizures, 744 Lidocaine, for arrhythmias, 539t Life support, discontinuation of, 481 Limen insulae, anatomy of, 6 Linear accelerators, 281, 282f Lingula, anatomy of, 27, 28f Lioresal, for spasticity, following stroke, 804t Lipid(s), requirements for, 612 Lipid peroxidation, with spinal cord injury, 777 Lipomyelomeningocele, 293–294, 293t Liquid ventilation, 595 Listeria monocytogenes meningitis, 338–339, 347t Liver transplantation, seizures following, 737 Living wills, 823, 824t–825t Locked-facets, 240, 241f Locked-in, definition of, 809 Locked-in syndrome, 766–767 diagnosis of, 621t Lorazepam (Ativan), 657 for head injury, 809t for seizures, in bacterial meningitis, 348 toxic levels of, clinical state of brain death caused by, 840t Los Angeles Prehospital Stroke Screen, 450t, 451 Low back pain, epidemiology of of, 256–257 Low molecular weight heparin, for myocardial infarction, 545 Lumbar puncture, with altered mental status, 757 Lumbosacral spine disorders, 255–261 cauda equina syndrome as, 259 congenital, 255 disk herniation as, 257–259, 258f endoscopic procedures for, 261, 261f fractures as, 259 low back pain and, epidemiology of, 256–257 spinal fusion procedures for, 260–261, 260f spondylolisthesis as, 255–256, 257f stenotic, 259, 259f Lung transplantation, seizures following, 737 Lung volumes, 580, 581f pulmonary mechanics and, 587 Lyme disease, 379–381 pearls for, 388 Lymphocytic choriomeningitis virus infections, laboratory diagnosis of, 352t Lymphoma, with HIV infections, 370 Lysergic acid diethylamide, altered mental status with, 762 Lysosomal storage disorders, gene therapy for, 879–881 Macrophages, multiple organ failure and, 782 Magnesium balance disorders of, 571, 572–573, 573t. See also Hypermagnesemia; Hypomagnesemia pearls for, 573 Magnetic resonance angiography, 52–53, 54f, 66f, 67, 67f brain death, confirmation and, 837t, 838 in subarachnoid hemorrhage, 156, 157f of intracerebral hemorrhage, 174 Magnetic resonance diffusion imaging, 52, 53f, 67 Magnetic resonance imaging, 47–59 brain death, confirmation and, 837t, 838

for stereotactic surgery, 271, 273, 275 localization using, 273, 275f imaging sequences for, 48–51, 52–55, 63–66 cerebrospinal fluid flow studies as, 55, 57f, 67–68 contrast medium and abnormal contrast enhancement and, 49–50, 50f, 64 fast spin-echo (RARE) techniques as, 50–51 fat suppression as, 56, 56f, 64 fluid attenuating inversion recovery imaging with strong T2 weighting as, 51, 52f functional MRI as, 54 gradient-recalled echo (GRE) as, 51, 51f, 65, 65f high-detail inversion recovery (STIR), 64f, 65 magnetic resonance angiography as, 52–53, 54f, 56, 56f, 67f magnetic resonance diffusion imaging as, 52, 53f, 67 magnetic resonance spectroscopy as, 54–55, 55f, 68, 69f magnetic resonance venography as, 52–54, 54f, 67, 67f relative brain perfusion imaging as, 52 spin-echo with T1 weighting as, 48, 49f, 65 spin-echo with T2 weighting as, 48, 49f, 65 in ischemic stroke, 399–401 in subarachnoid hemorrhage, 156–157, 158f, 159f intracranial hemorrhage on, 84, 85, 86f of intracerebral hemorrhage, 174 physical basis for, 47 restrictions on use of, 55, 57–59 claustrophobia as, 58 corticosteroids and, 58, 59f gadolinium-related, 58 implanted devices as, 59 metal implants as, 58–59 obesity as, 55 pacemakers as, 59 pregnancy as, 55 uncooperativeness as, 58 Magnetic resonance spectroscopy, 54–55, 55f, 68, 68f Magnetic resonance venography, 52–54, 54f, 67, 67f Malaria, 372–373 pearls for, 388 Malignancy, seizures and, 736 Mandibular nerve, anatomy of, 35 Mannitol for head injury, guidelines for, 775 for intracranial pressure control, 719–720 hypernatremia due to, 560 Maxillary nerve, anatomy of, 35 Mechanical ventilation, 518–519, 588–593 assist-controlled, 589 automatic tube compensation mode for, 594 complications of, 595–597 during initiation of positive-pressure ventilation, 595–596 with PEEP, 596–597 controlled, 589 during intrahospital transport, 685–686 for Guillain-Barré syndrome, 421–422 for multiple organ failure, 785 for myasthenia gravis, 425 high-frequency, 592 intermittent mandatory, 589 liquid, 595 negative pressure, 588

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Index Mechanical ventilation (Continued) pearls for, 602–603 PEEP or CPAP and, 592–593 positive pressure, 588–589 noninvasive, 593 pressure limit, volume-guaranteed, 594 pressure-controlled, 589–590 pressure-regulated, 594 pressure-supported, 590–592 volume-assured, 594 weaning from, 599 proportional assisted ventilation as, 594–595 switching modes of, 592 synchronized intermittent mandatory, 589 synchronized mandatory intermittent, weaning from, 599 volume-controlled, 589 volume-supported, 593–594 weaning from, 599–601 extubation and, 601 failure of, 599–600 from pressure-supported ventilation, 599 from synchronized mandatory intermittent ventilation, 599 strategies to improve, 600–601 T-piece wean and, 599 with spinal cord injury, 798 Medications, toxic levels of, clinical state of brain death caused by, 840, 840t Medulla, anatomy of, 24, 25f Medullary syndromes lateral (Wallenberg’s), 42, 43f, 44 medial, 42, 43f Medullary velum, inferior, anatomy of, 27, 28f Medulloblastomas, 150 pediatric, 305–306, 306f Mefloquine, for malaria, 373 Meningiomas, 139, 151–152, 151f thoracic, 252, 254f Meningitis bacterial. See Bacterial meningitis fungal. See Fungal meningitis hyponatremia with, 567 viral. See Viral meningitis Meningoencephalitis, 348–355 clinical manifestations of, 351, 352t, 353–355, 353f, 354f, 354t epidemiology of, 349–350 pathogenesis of, 350–351 treatment of, 355 Mental status altered. See Altered mental status; Coma; Confusion; Unconsciousness in examination, 117–119, 118f, 119f Meperidine hydrochloride, 665 Mesocortical fusiform, 14f, 16 Metabolic encephalopathy, altered mental status with, 761–762 Metabolic insufficiency, imaging of, 81–82, 82f, 83f Metabolism of drugs, 651 starvation and, 607 Metabotropic receptors, 106–107 Metallic implants, magnetic resonance imaging limitation by, 58–59 Metastases cerebral, 152f, 153 to thoracic spine, 250–251 Metered dose inhalers, 598–599 Methamphetamine, seizures induced by, 740 Methohexital sodium (Brevital), 654–655 Methoxamine (Vasoxyl), 674

N-Methyl-D-aspartate receptors, 104–105, 107f Methylphenidate for depression, following stroke, 805t for head injury, 809t Methylprednisolone (Depo-Medrol, Medrol, Methylone, Solu-Medrol), 669–670, 669t Methylxanthines, seizures induced by, 741 Metopic synostosis, 296t, 297 Metoprolol, 677t for intracranial pressure control, 710 Metronidazole, for brain abscesses, 358 Micronutrients, requirements for, 613 Microvascular changes, injury due to, 114 Midazolam (Versed), 657 for seizures, 743 toxic levels of, clinical state of brain death caused by, 840t Midbrain, anatomy of, 24, 25f Midbrain syndromes combined ventral and tegmental (Benedikt’s), 43f, 44 tectal (Parinaud’s), 43f, 44 tegmental (Claude’s), 43f, 44 ventral (Weber’s), 43f, 44 Millard-Gubler syndrome, 42, 43f, 135 Milrinone, for congestive heart failure, 548t Mineralocorticoids, potassium balance and, 569 Minimally responsive, definition of, 809 Mitochondria, neuronal death and survival and, 850–852, 850f, 851f Mitochondrial permeability transition, 851–852 Mitral regurgitation, 549 Mitral stenosis, 549 Mivacurium (Mivacron), 671, 671t Mobilization, following hemorrhagic stroke, 162 Monitoring, of intracranial pressure, 710–715 indications for, 710–711 methods for, 711–714, 711t, 712t, 714f regional, 714–715 Monkey B virus encephalitis, 355 Morphine physiologic effects of, 698t toxic levels of, clinical state of brain death caused by, 840t Morphine sulfate, 665 for congestive heart failure, 548t Motor degenerative disease, gene therapy for, 875–876 Motor examination, 126–127, 127f, 128f Motor function, assessment of, evoked potentials for, 634 Motor-evoked potentials, 633–634 Movement disorders deep brain stimulation for, 278–279, 279f pediatric, 319–321 Moyamoya disease, pediatric, 315–316 Mucopolysaccharidoses, gene therapy for, 879 Multiple myeloma, of thoracic spine, 251–252, 253f Multiple organ dysfunction syndrome, 779–785 diagnosis of, 783 etiology of, 780–782 future therapies for, 785–786 incidence of, 779–780 management of, 784–785 pathophysiology of, 782–783 pearls for, 787 prevention of, 784 prognostic indicators in, 785 risk factors for, 783–784 typical onset of, 784 Muscle, functions of, 135

901

Muscle mass, starvation and, 607 Musculoskeletal disorders with head injury, rehabilitation and, 807 with spinal cord injury, rehabilitation and, 801–802 with stroke, rehabilitation and, 803, 804t Mutism akinetic, diagnosis of, 621t cerebellar, 309 Myasthenia gravis, 423–426 management of, 425–426 pearls for, 430 presentation and diagnosis of, 423–425 Mycobacterium tuberculosis infection, of brain, 356 Mydriasis, 425–426 Myelinosis, pontine, central, acute, 427 Myelocystocele, terminal, 293t Myelomeningocele, 291–293 diagnosis and management of, 291–293 epidemiology and etiology of, 291 hydrocephalus and, 289 Myelopathy spondylotic, cervical laminectomy for, 247 with spinal cord injury, 777–778 Myocardial infarction diagnosis of, 542, 542f management of, 544–545 Myocardial injury, with head injury, 221 Myocardial ischemia diagnosis of, 541, 541t management of, 542–544, 543t, 544t Myoclonic seizures, 751 Myopathy, 135 critical illness, 426–427 thick filament, in critical illness, 426–427 Nalbuphine hydrochloride (Nubain), 667 Naloxone (Narcan), 667 for opiate overdose, 749 Naltrexone (Revia), 667 Neck injuries, penetrating, airway management with, 523 Necrosis, apoptosis vs., 113–114 Negative pressure ventilation, 588 Neisseria meningitidis meningitis, 337–338, 347t Neonates, resuscitation of, 442–443 Neoplastic disease, 139–153. See also specific tumors anesthetic risk with, 700–701 epidemiology of, 139, 140t metastatic, 152f, 153 of spinal cord, pediatric, 312–313 pearls for, 153 radiographic evaluation of, 140–141 signs and symptoms of, 139–140, 140t treatment of, 141–148 chemotherapy in, 147–148 radiation surgery in, 145–147, 146f, 147f radiation therapy in, 145, 145f surgical, 141–145, 141f–144f Nesiritide, for congestive heart failure, 548t Neurenteric cyst, 293t Neuroanatomy, 3–45. See also specific structures pearls for, 45 Neuroectodermal tumors, primitive, posterior fossa, 150 pediatric, 305–306, 306f Neurofibromatosis, type 1, 311–312 Neuroleptic malignant syndrome, 427–428 Neurologic disease major categories of, 136, 136t pearls for, 137

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Neurologic examination, 117–134, 620–622, 621t, 622t mental status in, 117–119, 118f, 119f motor, 126–127, 127f, 128f of cranial nerves, 119–122, 120f–126f reflexes in, 127, 128f, 129f sensory, 127, 129f–133f, 134 with altered mental status, 749–751, 750f Neurologic monitoring, 619–642 central nervous system electrical activity and. See Auditory-evoked potentials; Electroencephalography; Evoked potentials; Motor-evoked potentials; Somatosensory-evoked potentials; Visual-evoked potentials neurologic examination in, 620–622, 621t, 622t of cerebral blood flow. See Cerebral blood flow pearls for, 643 Neuromuscular blockers, 670–671 depolarizing, 670, 670t for head injury prehospital care, 447–448 for intracranial pressure control, 717 nondepolarizing, 670–671, 671t Neuromuscular disease, airway management in, 523 Neuromuscular junction, functions of, 135 Neuromuscular weakness. See also GuillainBarré syndrome; Myasthenia gravis in intensive care unit, 426–427 pearls for, 430 Neuron(s), 103, 104f Neuronal cell death in vitro mechanisms for, 850–853 Bcl-2 family proteins and, 853 caspases and, 850–852, 850f, 851f mitochondria and, 850–852, 850f, 851f reactive oxygen species and cellular redox state and, 852–853 types of, 849–850 Neuronal rescue, gene therapy for, 876, 877 Neurophysiology, 103–115 pearls for, 115 Neuroprotection, 849–859 during stroke, 855–858, 855f anti-apoptosis therapy and, 856 anti-excitotoxicity therapy and, 856 anti-inflammation therapy and, 856 estrogen replacement therapy and, 857–858, 858f, 859f polypharmacy and, 857 stem cell therapy and, 856–857 in vitro mechanisms for neuronal death and survival and, 850–853 Bcl-2 family proteins and, 853 caspases and, 853 mitochondria and, 850–852, 850f, 851f reactive oxygen species and cellular redox state and, 852–853 ischemia injury and, 853–855 apoptosis and, 855 excitotoxicity, calcium, and oxidant stress and, 854–855 inflammation and, 855 of dopamine neurons, via trophic factor delivery, 872 types of neuronal cell death and, 849–850 Neuroreceptors, control of breathing by, 586 Neurotransmission, disruption of, 112–114, 112f Neurotransmitters, 108–110, 109f, 109t Neurovascular surgery, anesthesia for, 701–703, 702f

Nicardipine, for hypertension, 544t Nifedipine (Procardia), 676t Nimodipine, for vasospasm in cerebral arteries, following hemorrhagic stroke, 160 Nitric oxide, to improve oxygenation, 597 Nitric oxide synthase, inducible, multiple organ failure and, 782 Nitroglycerin (Nitro-Bid, Nitrostat), 674–675, 676, 676t for congestive heart failure, 548t for hypertension, 544t for myocardial infarction, 545 for myocardial ischemia, 543 physiologic effects of, 698t Nitroprusside for blood pressure elevation, in intracerebral hemorrhage, 415t for congestive heart failure, 548t for hypertension, 544t Nitrous oxide, physiologic effects of, 698t Nocardial infection, of brain, 356 Nonmaleficence, principle of, 816 Nonsteroidal anti-inflammatory drugs, 669 Norepinephrine, 671, 672t for blood pressure elevation, in intracerebral hemorrhage, 415t for congestive heart failure, 548t sodium balance and, 557, 557f Nortriptyline, for depression, following stroke, 805t Noxious stimuli, responses to, 751 Nutrition, 607–626 pearls for, 616 starvation and, 607–609 with head injury, 775 Nutritional assessment, 609–610, 609b, 610b Nutritional status, monitoring of, 615, 615b Nutritional support administration route for, 614–615 for multiple organ failure, 784–785 nutritional requirements for, 611–613, 613t special formulations for, 615 timing of, 610–611 Obesity, magnetic resonance imaging limitation by, 55 Occipital lobe anatomy of, 4, 5f functions of, 124 Occipital plagiocephaly, 297 Occipitobasal vein, anatomy of, 14f, 16 Occipitotemporal sulcus, 14f, 16 Ocular movements, in neurologic examination, 622t Oculomotor nerve anatomy of, 14f, 16, 24, 25f, 32, 33, 34f examination of, 119, 121f Oculovestibular response, 755 Odontoid fractures, 237–238, 237f Olfactory nerve anatomy of, 31 examination of, 119, 120f Olgivie’s syndrome, after spinal surgery, 262 Oligemia, imaging of, 75–76, 76f–78f Olives, anatomy of, 24, 25f Ondansetron, for reducing postoperative nausea, 701 Operculoinsular compartment, of sylvian fissure, anatomy of, 6, 7f Ophthalmic artery, anatomy of, 17, 18f Ophthalmic nerve, anatomy of, 33, 35 Opiates, with spinal cord injury, 777 Opioid(s), 662–667, 663t agonist/antagonists and, 667

agonists of, 664–665 altered mental status with, 762 elimination of, 666, 666t induction of anesthesia using, 664 pharmacodynamics of, 664 physicochemical properties and pharmacokinetics of, 663–664 receptor activation and mechanism of action of, 663 Opioid antagonists, 667 Opsoclonus myoclonus, 736 Optic nerve anatomy of, 31, 32f, 33 examination of, 119, 120f, 121f Optimal external laryngeal manipulation, 506, 507f Orbital gyri, 14f, 15–16 Orbital sulcus, 15 Organ function, starvation and, 607–608 Organ transplantation, seizures and, 737–738 Orthostatic hypotension, with spinal cord injury, 799 Osmolarity, coma and, 748, 748f Osteomyelitis, vertebral, 386–387 of thoracic spine, 253–254, 255f Oxcarbazepine, for seizures, 743 Oxidant stress, neuroprotection and, 854–855 Oxygen free radicals neuronal death and survival and, 852–853 with spinal cord injury, 777 Oxygen transport, 585 Oxygenation resuscitation of, with head injury, 773 strategies to improve, 597–599 pulmonary bronchodilators as, 598–599 pulmonary vasodilators as, 597–598 Pacemakers, magnetic resonance imaging limitation by, 59 Paget’s disease, of cervical spine, 247 Pain, modulation of, gene therapy for, 878 Pallidotomy, stereotactic, 278, 279f Pancuronium physiologic effects of, 698t toxic levels of, clinical state of brain death caused by, 840t Papaverine, for cerebral vasospasm, 191–192, 192f Papilledema, with altered mental status, 753, 753f Paracentral lobule syndrome, 23 Parahippocampal gyrus, 14f, 16 anatomy of, 20, 21f downward transtentorial herniation of, imaging of, 70, 71f–72f Paraneoplastic syndromes, seizures and, 736 Parasitic infections, 372–373 brain abscess in, 356–357 cysticercosis as, 374–375, 374f echinococcal, 375 malaria as, 372–373 Strongyloides, 375 Toxocara, 376 Paraterminal gyrus, anatomy of, 20, 21f Parenteral nutrition, 614 enteral nutrition vs., 614–615 Parietal lobe anatomy of, 4, 5f functions of, 124 Parietal veins, medial, anatomy of, 22 Parieto-occipital arteries, anatomy of, 19 Parieto-occipital sulcus, anatomy of, 20, 21f Parinaud’s syndrome, 43f, 44, 135, 140 Parkinson’s disease, gene therapy for, 870, 872 Parolfactory gyrus, anatomy of, 20, 21f Parolfactory sulcus, anterior, anatomy of, 20, 21f

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Index Paroxetine, for depression, following stroke, 805t Pars orbitalis, 15 Particle accelerator systems, 280–281 Patient(s), physician disagreement with, 823, 825–826 Patient positioning for intracranial pressure control, 715, 715t, 716t for surgery, 699–700 Patient transport. See Intrahospital transport Patient-physician disagreement, ethical issues related to, 823, 825–826 Pediatric patients. See also Infants advanced life support for, 442 airway management in, 523 brain death evaluation in, 839 difficult airway cart for, 526, 527t head injury in, prehospital care for, 447 neurologic examination of, 286 neurosurgery in. See Surgery, pediatric Penicillin, for brain abscesses, 358 Penicillin G for bacterial meningitis, 347t for Lyme disease, 381 for syphilis, 378 for Whipple’s disease, 382 Pentazocine (Talwin), 667 Pentobarbital for intracranial pressure control, 723–724 toxic levels of, clinical state of brain death caused by, 840t Perforating arteries anatomy of, 17, 18f direct, anatomy of, 19 Pericallosal artery, splenic (posterior), anatomy of, 19 Perimesencephalic hemorrhage, benign, 164 Peripheral nerves, functions of, 135 Persistent vegetative state, 481, 808–809 Petrosal fissure, anatomy of, 27, 28f Phakomatoses, 139 Pharmacokinetics, 649–653 continuous infusions and, 652–653, 653t drug half-lives and, 650, 652 drug interactions and, 651 elimination and, 650, 650f, 650t factors affecting amount of drug and, 653 ionization and, 650, 651t metabolism and, 651 offset of action and, 652 protein binding and, 649 redistribution and equilibrium and, 649–650 saturable effects and, 651–652 therapeutic index and, 651, 651f Pharmacotherapy, 649–679 alpha2 agonists in, 668–669, 668t antiepileptic drugs in, 677–678 antihypertensive agents in, 674–677 anxiolytic drugs in, 653 barbiturates in, 653–655, 654t benzodiazepines in, 655–662, 655t corticosteroids in, 669–670, 669t, 670t for head injury, 807–808, 809t hypnotic drugs in, 653 inotropic agents in, 671–674 neuromuscular blockers in, 670–671 nonsteroidal anti-inflammatory drugs in, 669 opioid antagonists in, 667 opioids in, 662–667, 663t pearls for, 678–679 pharmacokinetics and. See Pharmacokinetics vasodilators in, 674–677

Phencyclidine, altered mental status with, 762 Phenobarbital for bacterial meningitis, 348 for seizures, 742–743 in bacterial meningitis, 348 toxic levels of, clinical state of brain death caused by, 840t Phenylephrine (Neosynephrine), 674 for blood pressure elevation, in intracerebral hemorrhage, 415t for intracranial pressure control, 710 physiologic effects of, 698t Phenytoin (Dilantin), 677–678, 677t for seizures, 742 in bacterial meningitis, 348 Phonation, tracheostomy and, 798–799 Phosphodiesterase inhibitors, for congestive heart failure, 546 Phosphorus balance disorders of, 571, 572, 572t. See also Hyperphosphatemia; Hypophosphatemia pearls for, 573 Phrenic nerve stimulation, for spinal cord injury, 798 Physician(s) ethical issues and, 816–817 on team, do not resuscitate orders and, 833 patient disagreement with, 823, 825–826 Physician-assisted suicide, 826–829, 827t–829t Pinioning, 699 Pipecuronium physiologic effects of, 698t toxic levels of, clinical state of brain death caused by, 840t Pittsburgh Brain Stem Scale, 470, 470t Pituitary adenomas, 152, 152f Plagiocephaly, occipital, 297 Plant alkaloids, for tumors, 147–148 Plasma exchange for Guillain-Barré syndrome, 423 for myasthenia gravis, 425 Plasma tonicity, regulation of, 556–557 Plasmacytomas, of thoracic spine, 251–252, 253f Plasmid DNA, as gene therapy vector, 870 Pneumobelts, for spinal cord injury, 798 Pneumonia, following stroke, rehabilitation and, 802 Poisoning acute, diagnosis of, 621t clinical state of brain death caused by, 840, 840t Polyneuropathy, critical illness, 426 Pons, anatomy of, 24, 25f Pontine syndromes lateral (Foville’s), 42, 43f medial, (Millard-Gubler), 42, 43f Pontomedullary sulcus, anatomy of, 24, 25f Pontomesencephalic sulcus, anatomy of, 24, 25f Positive end-expiratory pressure, 592–593 complications of, 596–597 contraindications to, 593 Positive-pressure ventilation, 588–589 complications during initiation of, 595–596 noninvasive, 593 Posterior fossa anatomy of, 23–24 arteries of, anatomy of, 38, 39f, 40, 41f, 42 surgery in, anesthetic risk with, 701 veins of, anatomy of, 34f, 37–38, 39f Posterior longitudinal ligament, ossification of, 247, 247f Postolivary sulcus, anatomy of, 24, 25f

903

Postsynaptic potentials, 110 Potassium, dietary, potassium balance and, 569 Potassium balance, 568–571 disorders of. See Hyperkalemia; Hypokalemia pearls for, 574 Pott’s disease, of thoracic spine, 254, 255f Praziquantel, for cysticercosis, 374 Prednisolone, 669t Prednisone, for tuberculous meningitis, 362 Pregnancy contrast media during, for computed tomography, 62 magnetic resonance imaging restriction during, 56–57 Prehospital care, 439–454 cerebral resuscitation in. See Cerebral resuscitation for head injury, 444–448 closed, 444–447 in pediatric patients, 447 penetrating, 447–448 for spinal cord injury, 448–449 for stroke, 449–453, 450t, 451f, 452f, 452t organization of, 439–440 pearls for, 453–454 Preolivary sulcus, anatomy of, 24, 25f Pressure limit ventilation, volumeguaranteed, 594 Pressure ulcers following stroke, rehabilitation and, 803 with spinal cord injury, 800–801 Pressure-controlled ventilation, 589–590 switching to volume-controlled ventilation, 592 Pressure-regulated ventilation, 594 Pressure-supported ventilation, 590–592 hazards of, 591–592 volume-assured, 594 weaning from, 599 work of breathing and, 591 Primaquine phosphate, for malaria, 373 Primidone for seizures, 743 toxic levels of, clinical state of brain death caused by, 840t Probenecid for Lyme disease, 381 for syphilis, 378 Procainamide, for arrhythmias, 539t Progressive multifocal leukoencephalopathy, 383, 384f Proguanil, for malaria, 373 Promethazine, for reducing postoperative nausea, 701 Prone position, for surgery, 700 Propofol (Diprivan), 658–659, 658t, 659f for intracranial pressure control, 717 for seizures, 743 physiologic effects of, 698t Proportional assisted ventilation, 594–595 Propranolol, 677t for head injury, 809t Prostaglandins, to improve oxygenation, 597–598 Protamine sulfate, for ischemic stroke, 404 Protein, requirements for, 612–613 Protein binding, of drugs, 649 Protein C, activated, for multiple organ failure, 786 Pro-urokinase, for ischemic stroke, 408 Psychogenic unresponsiveness, 765 Psychosocial support, with hemorrhagic stroke, 162

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Pulmonary barotrauma, with PEEP, 596–597 Pulmonary circulation distribution of ventilation and, 581–583, 582f metabolic functions of, 584 Pulmonary disorders with head injury, rehabilitation and, 806 with spinal cord injury, rehabilitation and, 798–799 with stroke, rehabilitation and, 802 Pulmonary edema following hemorrhagic stroke, 160 neurogenic, with head injury, 221, 221f Pulmonary embolism, with spinal cord injury, 799 Pulmonary failure, with spinal surgery, 262 Pulmonary mechanics, 587–588 Pulmonary vascular resistance, 583–584, 583f Pupil(s), in neurologic examination, 751–752, 752f Pupillary light reaction, in neurologic examination, 622t Pupillary reflexes, 31, 33 Pyrazinamide, for tuberculous meningitis, 361 Pyrimethamine, for toxoplasmosis, with HIV infections, 370 Quadrigeminal plate, anatomy of, 24, 25f Quality of life, do not resuscitate orders and, 831 Quinidine gluconate, for malaria, 373 Quinine sulfate, for malaria, 373 Rabies, 349–351 clinical manifestations of, 354–355 laboratory diagnosis of, 352t Radiation surgery, 279–281, 280f for arteriovenous malformations, 193–194 for tumors, 145–147, 146f, 147f gamma-knife system for, 280 linear accelerator systems for, 281, 282f paradigm for, 281, 282f particle accelerator systems for, 280–281 Radiation therapy for tumefactive lesions, imaging following, 95, 98f for tumors, 145, 145f Radiculopathy cervical, 242, 243 with spinal cord injury, 777 Rancho Levels of Cognitive Functioning, 809–810, 810t Rapacuronium, physiologic effects of, 698t Rationing of health care resources access and, 820–821 intensive care services and, 821–823 Reactive oxygen species neuronal death and survival and, 852–853 with spinal cord injury, 777 Rebleeding, in hemorrhagic stroke, 160 Recombinant tissue plasminogen activator for ischemic stroke, 401, 403–405, 404t for thromboembolic stroke, acute, 183, 184 Recreational drugs, seizures induced by, 740 Redistribution, of drugs, 649–650 Redox state, neuronal death and survival and, 852–853 Reference points, for stereotactic surgery, 271, 272f Reflex(es) brainstem, with altered mental status, 754–755, 756f consensual light, 752 corneal, 752 in neurologic examination, 622t

cough, in neurologic examination, 622t examination of, 127, 128f, 129f gag, in neurologic examination, 622t pupillary, 31, 33 Reflex activity, consciousness level and, 751 Rehabilitation, 795–811 following hemorrhagic stroke, 162 for head injury, 805–811 classification of injuries and, 805 dermatologic disorders and, 807 general approach for, 805 in unconscious patient, 805–806 musculoskeletal disorders and, 807 neurologic disorders and, 806–807 pharmacotherapy in, 807–808, 809t prevention of secondary sequelae and, 806–807 pulmonary disorders and, 806 rehabilitative issues in, 808–810, 810t seizures and, 806 therapy in, 810–811 vascular disorders and, 806 for spinal cord injury, 796–802 cardiovascular disorders and, 799 classification of injuries and, 796, 796t, 797f, 798 dermatologic disorders and, 800–801 gastrointestinal disorders and, 799–800 general approach for, 796 genitourinary disorders and, 800 musculoskeletal disorders and, 801–802 pulmonary disorders and, 798–799 rehabilitative issues in, 802 for stroke, 802–805 cardiovascular disorders and, 802 dermatologic disorders and, 803 general approach for, 802 musculoskeletal disorders and, 803, 804t pulmonary disorders and, 802 rehabilitative issues in, 803–804 therapy in, 804–805, 805t thromboembolism and, 802–803, 803t general survey for concomitant injuries and, 795–796 multitrauma patients and, 795 pearls for, 811 team and, 795 Relative brain perfusion imaging, 52 Religious issues, in brain death, 841 Remifentanil (Ultiva), 666, 666t physiologic effects of, 698t Renal toxicity, of contrast media, for computed tomography, 61 Renal tubular flow, potassium balance and, 569 Renin, sodium balance and, 557 Repair mechanisms, intrinsic, augmentation by gene therapy, 878 Reperfusion injury, prevention of, 444 Respiratory failure, following head injury, 446 Respiratory function. See also Breathing; Lung; Pulmonary; Ventilation pearls for, 601–602 physiology of, 579–586, 580f carbon dioxide transport and, 586 distribution of ventilation and, 580–583, 582f gas exchange and, 584–585, 584t lung volumes and, 580, 581f metabolic functions of pulmonary circulation and, 584 oxygen transport and, 585 pulmonary vascular resistance and, 583–584, 583f Respiratory muscles, fatigue of, 586–587

Respiratory virus infections, laboratory diagnosis of, 352t Resuscitation. See also Cardiopulmonary resuscitation; Cardiopulmonarycerebral resuscitation; Cerebral resuscitation; Do not resuscitate orders for spinal cord injury, 778 Retavase, for ischemic stroke, 408 Reticular activating system, wakefulnessalertness and, 747, 748f Reticular formation, anatomy of, 25 Reuptake, of neurotransmitters, 110 Rewarming, 478 Rhabdomyolysis, acute, in critical illness, 427 Rheumatoid arthritis, of cervical spine, 248, 248f Rhinal sulcus, 14f, 16 Rhizotomy, dorsal, for spasticity, pediatric, 320 Rickettsia, 381 Risperidone, for head injury, 809t Rocky Mountain spotted fever, 381 Rocuronium, 671t physiologic effects of, 698t Rostral sulci, anatomy of, 20, 21f Saccular aneurysms occlusion with platinum coils, 167 subarachnoid hemorrhage and, 162–163 Sagittal synostosis, 296, 296t St. Louis encephalitis, 349 Saline, hypertonic for head injury, 775 for intracranial pressure control, 721–722, 721f Saturable effects, of drugs, 651–652 Scheuermann’s disease, 249–250, 249f Schwannomas thoracic, 252, 254f vestibular, 150–151, 150f Scoliosis, 249, 249f Sedation, for intracranial pressure control, 160, 717 Seizures, 733–744 altered mental status with, 761, 761f antiseizure prophylaxis for, with head injury, 775 drug-induced, 737, 737t, 740–742 electroencephalography and, 627–628, 628f, 733–734 patterns on, 734, 735f evaluation of, 751 factors predisposing to, 734, 735t following hemorrhagic stroke, 160 glucose metabolism disturbances and, 739 hepatic encephalopathy and, 740 hypocalcemia and, 739 hypomagnesemia and, 739 hyponatremia and, 738–739 hypoparathyroidism and, 739 hypophosphatemia and, 739 identifying, 733 in bacterial meningitis, 348 malignancy and, 736 management of, 738 mechanisms of brain injury and, 733 organ transplantation and, 737–738 pearls for, 744 post-traumatic, 735–736 signs of, 733 treatment of, 733, 742–744 uremia and, 739–740 vascular lesions and, 736 with gastrointestinal disease, 737 with head injury, rehabilitation and, 806 with hyperbaric oxygen therapy, 737 with neoplastic disease, 140, 140t

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Index Selective serotonin reuptake inhibitors, for depression, following stroke, 805t Sensory examination, 127, 129f–133f, 134 Serotonin syndrome, seizures and, 741 Sertraline, for depression, following stroke, 805t Sevoflurane, physiologic effects of, 698t “Shaken impact syndrome,” 303 Shivering, postoperative, 704–705 Shock circulatory, multiple organ failure and, 782 spinal, 796 with spinal surgery, 262 with spinal surgery, 262 Shunt, gas exchange and, 585 Signal averaging, evoked potentials and, 629, 629f Signal transduction, postsynaptic, 110–112 Signal transmission, 107–108 Single photon emission computed tomography, brain death confirmation and, 837t, 838, 838f Sitting position, for surgery, 700 Skeletal mass, starvation and, 607 Sniffing position, 506, 507f Sodium balance, 555–556, 556f, 557f disorders of. See Hypernatremia; Hyponatremia mechanisms of, 557–558, 557f, 558f pearls for, 573–574 Sodium nitroprusside (Nitropress), 674–676, 675t physiologic effects of, 698t Sodium thiopental (Pentothal), 655 Somatosensory function, assessment of, evoked potentials for, 634 Somatosensory-evoked potentials, 629–631 somatosensory pathway and, 631, 632t theoretical basis for, 629–631, 630f Spasticity following stroke, rehabilitation and, 803, 804t pediatric, 319–320 with head injury, rehabilitation and, 807 with spinal cord injury, 801 Spatial summation, 111 Speech, tracheostomy and, 798–799 Sphenoidal compartment, of sylvian fissure, anatomy of, 6, 7f Spina bifida occulta, 293–294, 293t Spinal cord anatomy of, 44 functions of, 135 pathobiology of, gene therapy for, 875 in vivo, 876, 876t split, 293t tethering of, 294 tumors of pediatric, 312–313 thoracic, 252, 254f Spinal cord injury, 775–779 airway management with, 521–523, 522f complications of, 262 evaluation of, 778 management of, 778–779, 778f–781f pathogenesis of, 776–777 primary injury and, 776 pathology of, 777 pearls for, 786–787 pediatric, 303–305 prehospital care for, 448–449 presentation of, 777–778 rehabilitation for. See Rehabilitation, for spinal cord injury secondary injury and, 776–777

Spinal disorders, 235–264 Spinal dysraphism, occult, 293–294, 293t Spinal epidural abscesses, 384–385 Spinal fusion procedures, 260–261 anterior lumbar interbody procedures as, 260–261 posterior lumbar interbody procedures as, 260, 260f Spinal injuries gene therapy for, 876–879 pediatric, 303–305 Spinal meningitis, tuberculous, 362 Spinal movements, brain death and, 836–837, 836t Spinal reflexes, brain death and, 836–837, 836t Spinal shock, 796 with spinal surgery, 262 Spinal surgery, 235–264 anesthesia for, 703 complications of, 261–262 endoscopic, 261, 261f medical complications of of, 261–262 pearls for, 263–264 Spondylolisthesis, lumbar, 255–256, 257f Spondylosis, cervical, 242, 242f, 243 Starvation, 607–609 immune function and, 608 intestinal barrier function and, 609 metabolic effects of, 607 organ function and, 607–608 stress or injury and, 609 wound healing and, 608–609 Status epilepticus, treatment of, 743 Stem cell therapy, for neuroprotection, 846–847 Stenting, endovascular for extracranial stenosis, 203–208, 205f–207f approaches for, 206, 208 complications of, 208 for intracranial stenosis, 208–209 approaches for, 209, 210f complications of, 209, 211f Stereotactic biopsy, of tumors, 141–142, 141f, 142f Stereotactic frame, 271–272, 272f Stereotactic surgery, 269–283, 270f biopsy using, 276–277, 278f brain in geometric coordinate system and, 269, 271 deep brain stimulation and, 278–279, 279f frameless stereotaxis and, 275 functional stereotactic lesions and, 277–278, 279f magnetic resonance imaging localization for, 273, 275f past and future of, 281 pearls for, 283 points and volume and, 273, 275 radiation, 279–281, 280f for arteriovenous malformations, 193–194 for tumors, 145–147, 146f, 147f gamma-knife system for, 280 linear accelerator systems for, 281, 282f paradigm for, 281, 282f particle accelerator systems for, 280–281 reference points and, 271, 272f stereotactic frame and, 271–272, 273f vertical coordinate problem and, 272–273, 274f visible and invisible targets in, 273, 276f, 277f Steroids. See also Corticosteroids; Mineralocorticoids; specific steroids

905

for head injury, 775 for intracranial pressure control, 722–723, 723t Stimulation, minimization of, for intracranial pressure control, 717–718 Streptococcus agalactiae meningitis, 339, 347t Streptococcus pneumoniae meningitis, 337, 347t Streptomycin for tuberculous meningitis, 361 for Whipple’s disease, 382 Stress, response to starvation and, 609 Stroke, 397–419 brain perfusion in, imaging of, 74, 76, 80f, 81f gene therapy for, 871 hemorrhagic. See Hemorrhagic stroke; Intracerebral hemorrhage; Subarachnoid hemorrhage ischemic. See Ischemic stroke neuroprotection during. See Neuroprotection, during stroke pearls for, 429 prehospital care for, 449–453, 450t, 451f, 452f, 452t previous, anesthesia with, 705 rehabilitation for. See Rehabilitation, for stroke risk of, with neurovascular surgery, 701 severe, 757–758 signs and symptoms of, 450–451, 450t thromboembolic, acute, endovascular surgery for, 183–186 approaches for, 184–185, 185f, 186f complications of, 186 Strongyloidosis, 375 Stupor, 747 Subarachnoid hemorrhage, 155, 156f, 162–170, 452–453, 452t, 758, 758t aneurysmal, hyponatremia with, 565–566, 568 cardiac disease with, 534–540 clinical presentation of, 534–537, 536f, 538 differential diagnosis of, 538 mechanism of injury and, 537 postmortem data on, 537 treatment of, 538–540, 539t cerebral vasospasm following, endovascular surgery for, 190–192 approaches for, 191–192, 192f, 193f complications of, 192 clinical presentation of, 165, 165f, 165t diagnostic evaluation of, 166, 166t etiology of, 162–165 arterial dissection as, 163, 164f idiopathic subarachnoid hemorrhage and, 163–164, 164f intracranial aneurysm as, 162–163 vascular malformations as, 163, 163f hydrocephalus with, 168 management of complications of therapy and, 167 critical care, 166 endovascular treatment for, 167 surgical treatment for, 167 timing of intervention and, 166 outcome after, 170 seizures following, 736 vasospasm with, 168–169 monitoring and prophylaxis of, 168–169, 168f treatment of, 169, 170f, 171f Subaxial fractures, 240, 241f Subcallosal area, anatomy of, 20, 21f Subclavian steal, 204, 206, 207f Subdural hematomas, cerebral, 772

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Index

Subfalcine herniations, imaging of, 70, 70f Succinylcholine (Anectine), 670, 670t physiologic effects of, 698t Suction bulb, for confirming endotracheal intubation, 514–515, 515f Sufentanil (Sufenta), 666 physiologic effects of, 698t Suicide, physician-assisted, 826–829, 827t–829t Sulcus limitans, anatomy of, 30–31, 32f Sulfadiazine, for toxoplasmosis, with HIV infections, 370 Summation, in synaptic transmission, 111 Supine position, for surgery, 699 Supplementary motor area syndrome, 23 Supraolivary fossette, anatomy of, 24–25, 25f Surgery anesthesia for. See Anesthesia for arteriovenous malformations, 193, 193t for brain tumors, hyponatremia with, 566 for cervical spine disorders, 243–247, 244f anterior cervical diskectomy with interbody fusion as, 243–245, 245f corpectomy as, 245–246, 245f for cervical disk disease, posterior approach for, 246 laminectomy for spondylotic myelopathy as, 247 posterior lateral mass plate fixation of subaxial spine as, 246–247, 246f for intracerebral hemorrhage, 175–176, 416–417 for intracranial aneurysms, 186–188 for intracranial pressure control, 725 for spinal cord injury, 778–779, 779f–781f for subarachnoid hemorrhage, 167 hyponatremia with, 567 patient positioning for, 699–700 pediatric, 285–321 cerebellar mutism and, 309 for arachnoid cysts, 299–300 for arteriovenous malformations, 314 for brain abscess, 319 for brainstem gliomas, 309–310 for cavernous malformations, 315 for cerebellar astrocytoma, 307 for Chiari 1 malformations, 295–296 for craniopharyngioma, 310–311 for craniosynostosis, 297–298 for Dandy-Walker complex, 300–301, 301f for empyema, 317 for encephalocele, 298 for ependymoma, 308 for epidural infection, 317 for head injury, 302–303 for hydrocephalus, 289–291 for medulloblastoma, 306 for movement disorders, 319–321 for moyamoya disease, 316 for myelomeningocele, 291–293 for neurofibromatosis type 1, 311–312 for occult spinal dysraphism, 294 for spinal cord tumors, 312–313 for spinal injuries, 304–305 for vein of Galen malformations, 314 neurologic evaluation for, 285–286 pearls for, 321 radiation. See Stereotactic surgery, radiation stereotactic. See Stereotactic surgery Suspended animation, in cerebral resuscitation, 479–480 Swallowing, abnormalities of, with PEEP, 597 Sylvian fissure, anatomy of, 4, 6, 7f Sylvian point, 14f, 15

Sylvian vein deep, tributaries of, 13, 14f superficial, anatomy of, 13, 14f Sympathomimetics, altered mental status with, 762–763 Synapses chemical, 108 electrical, 108 Synaptic transmission, 108–110, 109f, 109t Synaptobrevin, 110 Synchronized intermittent mandatory ventilation, 589 weaning from, 599 Syndrome of inappropriate antidiuretic hormone, hyponatremia due to, 563–565, 565t Syphilis, 376–379 pearls for, 388 serologic testing for, 377–378 treatment of, 378–379 Syringomyelia, 294–296 Teardrop fractures, 240, 241f Tela choroidea, anatomy of, 27, 28f Temporal arteries, anatomy of, 19 Temporal lobe anatomy of, 4, 5f functions of, 124 Temporal lobe resection, for intracranial pressure control, 725 Temporal summation, 111 Temporal veins, inferior, anatomy of, 14f, 16 Thalamogeniculate arteries, anatomy of, 19 Thalamoperforating arteries, posterior, anatomy of, 19 Thalamotomy deep brain stimulation with, 278–279, 279f stereotactic, 277–278 Thalamus anatomy of, 9 vascularization of, 21f, 23 Therapeutic index, 651, 651f Thiabendazole, for strongyloidiasis, 375 Thiopental for airway management, with head injury, 521 for intracranial pressure control, 710 in cerebral resuscitation, 474 toxic levels of, clinical state of brain death caused by, 840t Third cranial nerve paralysis, 752, 752f Third ventriculostomy, endoscopic, for hydrocephalus, 291 Thoracic spine disorders, 248–255 anatomic considerations related to, 248–249 congenital, 249–250, 249f disk herniation as, 250, 250f infection as, 252–254, 255f metastatic, 250–251 pathologic processes and, 250 primary tumors as, 251–252, 253f spinal cord tumors tumors as, 252, 254f traumatic, 250, 251f, 252f vascular malformations as, 254–255, 256f Thromboembolism. See also Deep vein thrombosis; Pulmonary embolism following endovascular treatment, for intracranial aneurysms, 188, 189f, 190f with spinal surgery, 261 Thrombolytic therapy for cerebral venous thrombosis, 419 for intracerebral hemorrhage, 175 for ischemic stroke, 404f–407f, 405–408

for myocardial infarction, 544 for thromboembolic stroke, 183–184 Thunderclap headache with intracerebral hemorrhage, 174 with subarachnoid hemorrhage, 165 Thymectomy, for myasthenia gravis, 426 Tiagabine, for seizures, 744 Time constants distribution of ventilation and, 581 pulmonary mechanics and, 588 Tizanidine, for spasticity, following stroke, 804t Toddlers, See Pediatric patients Tonicity, potassium balance and, 568 Topiramate, for seizures, 743–744 Torsemide, for congestive heart failure, 548t Total ACA area infarction, 23 Toxic encephalopathy, altered mental status with, 761–763 Toxocariasis, 376 Toxoplasmosis brain abscess in, 356 with HIV infections, 368–370, 369f clinical manifestations of, 369 diagnosis of, 369–370, 369f lymphoma and, 370 treatment of, 370 T-piece wean, 599 Tracheostomy emergency, 511 for spinal cord injury, phonation and, 798–799 Tracheostomy tubes blood in, 596 complications related to, 595 Traction, for spinal cord injury, 778, 778f Transcranial Doppler ultrasound, for cerebral blood flow measurement, 636–638 brain death confirmation and, 638, 640f, 837t, 838 in head injury, 638, 639f intracranial pressure assessment and, 638, 639f theoretical basis for, 636–637, 637f vasospasm detection and, 638, 638f Transcriptional regulation, gene therapy and, 870, 871t Transient ischemic attacks, signs and symptoms of, 450–451, 450t Transport. See Intrahospital transport Transtentorial herniation downward, of parahippocampal gyrus, imaging of, 70, 71f–72f, 73 upward, imaging of, 73, 73f Transtracheal catheter ventilation, 513–514 Transtracheal jet ventilation, 518–519 Trauma, neurotransmission disruptions due to, 112–113 Trauma systems, 773 Traumatic brain injury. See Brain injury; Head injury Trazodone for depression, following stroke, 805t for head injury, 809t Tricyclic antidepressants. See also specific drugs for depression, following stroke, 805t Trigeminal nerve anatomy of, 33, 34f, 35 examination of, 121, 123f Trimethaphan, physiologic effects of, 698t Trimethoprim-sulfamethoxazole for bacterial meningitis, 347t for brain abscesses, 358 for toxoplasmosis, with HIV infections, 370 for Whipple’s disease, 382

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Index Trochlear nerve anatomy of, 33, 34f examination of, 119, 121, 122f Tromethamine, as alternative to mannitol, 560 Tuberculomas, 356, 362 Tuberculous meningitis, 358–362 clinical presentation of, 359–360, 360t diagnosis of, 360–361, 361f epidemiology of, 358–359 pathogenesis of, 359 prognosis and sequelae of, 362 spinal, 362 treatment of, 361–362 tuberculoma in, 362 Tuberous sclerosis, 139 Two-person mask ventilation, 506, 506f Ultrasound, Doppler, transcranial, for cerebral blood flow measurement, 636–638 brain death confirmation and, 638, 640f, 837, 838 in head injury, 638, 639f intracranial pressure assessment and, 638, 639f theoretical basis for, 636–637, 637f vasospasm detection and, 638, 638f Unconsciousness. See also Altered mental status; Coma head injury rehabilitation and, 805–806 Uncooperativeness, magnetic resonance imaging limitation by, 58 Uncus, anatomy of, 20–21, 21f, 22 University of Florida TBI protocol, 725, 726f–728f, 729 Uremia, seizures and, 739–740 Urokinase, for ischemic stroke, 404–406, 405f, 406f Utilitarianism, 819 Vaccination, for bacterial meningitis, 348 Vagus nerve anatomy of, 36–37 examination of, 122, 125f Valproate, for seizures, 743 Valproic acid for head injury, 809t toxic levels of, clinical state of brain death caused by, 840t Values, facts vs., 818–819 Valvular heart disease, 547–549 VAMP, 110 Vancomycin, for bacterial meningitis, 345, 347t Vascular lesions imaging of, 91, 92f seizures and, 736 Vascular malformations. See also Arteriovenous malformations intracerebral hemorrhage associated with, 173, 173f

of thoracic spine, 254–255, 256f subarachnoid hemorrhage and, 163, 163f Vascular surgery, intracranial, airway management during, 523 Vasculitis, seizures and, 736 Vasoactive agents, 674 for cerebral vasospasm, 191–192, 192f pulmonary, 597–598 with spinal cord injury, 777 Vasodilators, 674–677 for cerebral vasospasm, 191–192, 192f pulmonary, 597–598 Vasopressors, 674 Vasospasm cerebral, detection by transcranial Doppler ultrasonography, 638, 638f in cerebral arteries, following hemorrhagic stroke, 160 with subarachnoid hemorrhage, 168–169 monitoring and prophylaxis of, 168–169, 168f treatment of, 169, 170f, 171f Vecuronium, 671t physiologic effects of, 698t toxic levels of, clinical state of brain death caused by, 840t Vegetative state, 808–809 Vein of Galen anatomy of, 34f, 37 malformations of, pediatric, 314 Vein of Labbé, 13, 14f Vein of Trolard, 13, 14f Venous air embolism, risk of, during surgery, 700 Venous occlusion following transarterial embolization, for dural arteriovenous fistulas, 199–200 intracerebral hemorrhage associated with, 173 Ventilation distribution of, 580–583, 582f mechanical. See Mechanical ventilation pattern of, with altered mental status, 753–754, 754f, 755f Ventilation-perfusion mismatch, gas exchange and, 585 Ventilatory support, in prehospital care, 441 Ventral, meaning of, 3 Ventricles fourth, anatomy of, 25f, 26, 28f lateral, anatomy of, 6, 7f, 8–11 size of, evaluation of, imaging for, 85, 87, 87f–89f third, anatomy of, 11, 12f, 13 Ventricular drainage, for intracerebral hemorrhage, 175 Ventriculoperitoneal shunts, for hydrocephalus, 289 infection of, 290–291 obstruction of, 289–290

907

Ventriculostomy, 387–388 Verapamil (Calan), 676t for arrhythmias, 539t Vermis, anatomy of, 26 Vertebral osteomyelitis, 386–387 of thoracic spine, 253–254, 255f Vertical coordinates, for stereotactic surgery, 272–273, 274f Vesicular-SNAREs, 110 Vestibular schwannomas, 150–151, 150f Vestibulocochlear nerve anatomy of, 36 examination of, 122 Viral encephalitis, 348–355 clinical manifestations of, 351, 352t, 353–355, 353f, 354f, 354t epidemiology of, 349–350 pathogenesis of, 350–351 treatment of, 355 Viral meningitis, 348–355 altered mental status with, 763 clinical manifestations of, 351, 352t, 353–355, 353f, 354f, 354t epidemiology of, 349–350 pathogenesis of, 350–351 pearls for, 388, 389 treatment of, 355 Viral vectors, for gene therapy, 866, 867t, 868–869 adeno-associated virus as, 868, 869f, 880–881 herpes simplex virus as, 868, 880 lentivirus as, 868–869 recombinant adenovirus as, 866, 868, 880 Visible targets, for stereotactic surgery, 273 Visual-evoked potentials, 633 Volume-controlled ventilation, 589 switching to pressure-controlled ventilation, 592 Volume-supported ventilation, 593–594 von Hippel-Lindau disease, 139 Von Recklinghausen’s disease, 139 Wallenberg’s syndrome, 42, 43f, 44, 135 Water balance, 555–556, 556f, 557f mechanisms of, 556–557 pearls for, 573 Weakness, with neoplastic disease, 140 Weber’s syndrome, 43f, 44, 135 Wernicke’s aphasia, 118, 134 West Nile virus, 349 Whipple’s disorder, 382 Withdrawing/withholding therapy, 822–823 Witzelsucht, 134 Wound healing, starvation and, 608–609 Zinc, injury due to, 114 Zonisamide, for seizures, 744 Zygomycoses brain abscess in, 356 meningitis in, 367, 368f