Table Of ContentHypothermia and Cerebra! Ischemia
Hypothermia
and Cerebral Ischemia
Mechanisms and Clinical Applications
Edited by
Carolina M. Maier,
PhD
Department of Neurosurgery,
Stanford University School of Medicine, Stanford, CA
and
Gary K. Steinberg,
MD, PhD
Departments of Neurosurgery and Neurology,
Stanford University School of Medicine, Stanford, CA
*-
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Artwork Description: Top Left Panel: Neuronal Immunocytochemistry Composite. Top Right Panel: Magnetic
Resonance Image of an Adult Human Brain. Bottom Left Panel: Cerebral Angiogram Highlighting an Aneu
rysm. Bottom Right Panel: Immunocytochemistry Highlighting Blood Vessels and Inflammatory Cells in an
Ischemic Brain. Created by Elizabeth Hoyte and Carolina Maier.
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10987654321
ISBN 978-1-61737-120-2 ISBN 978-1-59259-653-9 (eBook)
DOI 10.1007/978-1-59259-653-9
Library of Congress Cataloging-in-Publication Data
Hypothermia and cerebral isehemia : mechanisms and elinieal applications I edited by Carolina M. Maier and
Gary K. Steinberg.
p.; cm.
Includes bibliographieal referenees and index.
1. Cerebra 1 ischemia--Treatment. 2. Brain damage--Treatment. 3. Brain--Effect of cold on. 4. Cold-
Therapeutic use. I. Maier, Carolina M. 11. Steinberg, Gary K.
[DNLM: 1. Brain Ischemia--therapy. 2. Hypothermia, Induced. 3. Brain Injuries--therapy.
4. Cerebrovascular Accident--therapy. WL 355 H9988 20041
RC388.5 H97 2004
616.8'1--dc21
2003049949
Preface
Stroke is aglobai health problem affecting approximately 750,000
people annually in the United States alone and ranks as the third leading
cause of death and the most common cause of disability in most devel
oped countries. Traumatie brain injury (TB I) accounts for an estimated
34% of all injury-related deaths in the United States. Stroke and TBI can
produce both focal and widespread damage to the brain, whieh can yield
acute and chronic impairments of sensory, motor, and cognitive func
tions. Because of their enormous medical and socioeconomie impact,
a tremendous research investment is being made in the treatment and
prevention of stroke and TBI.
Strategies for reducing adverse neurologie outcomes after ischemic or
TBI have led to the development of a wide range of neuroprotective
agents. However, despite promising results in animal models of stroke
and TBI, and extensive testing in randomized clinical trials, no
neuroprotective drug has yet proven effective in humans.
In recent years, there has been a resurgence of interest in mild hypo
thermia as a method of cerebral protection. Although deep hypothermia
(below 30°C) is known to be neuroprotective, c1inically the benefit is
offset by the risks of cardiac arrhythmias and coagulopathies, and by the
extensive resources necessary to achieve deep hypothermia, inc1uding
cardiopulmonary bypass. Alternatively, small decreases in brain tem
perature (2-5°C below normal brain temperature) are well-tolerated
and confer signifieant neuroprotection in animal models of cerebral
ischemia. Indeed, mild hypothermia is one of the most effective
neuroprotective therapies in experimental ischemia models, and the
feasibility of using mild hypothermia to treat stroke and TBI patients is
currently being evaluated in c1inical trials. Recently, two prospective,
randomized controlled studies demonstrated improved neurologic out
come with mild hypothermic treatment for patients with cardiac arrest
from ventrieular fibrillation.
Increased understanding of the mechanisms by which mild hypoth
ermia exerts its neuroprotective effects has allowed basic scientists and
c1inicians to optimize the use of mild hypothermia as a therapeutic
strategy. New technological advances are now facilitating the imple-
v
VI Preface
mentation of mild hypothermia in the clinical setting. Knowledge and
experience gained from clinical trials around the world have helped
develop guidelines for the intraoperative and intensive care manage
ment of patients undergoing mild hypothermie treatment.
There is also interest in combining hypothermia with other thera
peutic strategies. The rationale for this combination approach is that
mild hypothermia could prolong the therapeutic window for
neuroprotective agents. Using hypothermia in conjunction with other
pharmacological agents for the treatment of acute cerebral ischemia is
also discussed in this book, along with future directions in both basic
and clinical research.
Hypothermia and Cerebral Ischemia: Mechanisms and Clinical
Applications is intended to provide a comprehensive review of mild
hypothermia' s therapeutic potential, its limitations, and recent develop
ments in both basic and clinical research. We hope that this volume
serves to educate clinicians, other health professionals, and basic scien
tists, as weIl as promote interest in the study and implementation of mild
hypothermia for the treatment of stroke and TBI.
Carolina M. Maier, PhD
Gary K. Steinberg,
MD, PhD
Contents
Preface .................................................................................................. v
Contributors ...................................................................................... ix
1 Resurgenee of Hypothermia as a Treatment
for Brain Injury
Carolina M. Maier and Gary K. Steinberg .............................. 1
2 The Effeets of Hypothermia and Hyperthermia
in Global Cerebral Isehemia
Myron D. Ginsberg and Ludmila Belayev .............................. 17
3 Mild Hypothermia in Experimental Foeal
Cerebral Isehemia
Carolina M. Maier .................................................................. 39
4 Hypothermie Protection in Traumatie Brain Injury
W. Dalton Dietrich and Miguel A. Perez-Pinzon ................... 65
5 Postisehemic Hypothermia Provides Long-Term
Neuroprotection in Rodents
Frederick Colboume and Dale Corbett ................................. 79
6 Combination Therapy With Hypothermia
and Pharmaeeutieals for the Treatment
of Aeute Cerebral Isehemia
David C. Tong and Midori A. Yenari ..................................... 93
7 Intraoperative and Intensive Care Management
of the Patient Undergoing Mild Hypothermia
Teresa E. Bell-Stephens, Richard A. laffe,
and Gary K. Steinberg .................................................... 103
8 Management of Traumatic Brain Injury
With Moderate Hypothermia
Elad I. Levy and Donald W. Marion .................................... 119
Vll
Vlll Contents
9 Hypothermia: Clinical Experience in Stroke Patients
Stefan Schwab and Werner Hacke ........................................ 145
10 Hypothermia Therapy: Future Directions
in Research and Clinical Practice
Wataru Kakuda, Takao Shimizu, and Hiroaki Naritomi ...... 161
Index ................................................................................................ 179
Contributors
LUOMILA BELAYEV, MD· Cerebral Vascular Disease Research Center,
Department of Neurology, University of Miami School of Medicine,
Miami, FL
TERESA E. BELL-STEPHENS, RN • Department of Neurosurgery,
Stanford Stroke Center, Stanford University School of Medicine,
Stanford, CA
FREOERICK COLBOURNE, PhO • Department of Psychology, University
of Alberta, Edmonton, Canada
DALE CORBETT, PhO • Faculty of Medicine, Memorial University
of New Foundland, St. John 's, Canada
W. DALTON DIETRICH, PhO • Miami Project to Cure Paralysis,
Neurotrauma Research Center, Departments of Neurological
Surgery and Neurology, University of Miami School of Medicine,
Miami, FL
MYRON D. GINSBERG, MD· Cerebral Vascular Disease Research
Center, Department of Neurology, University of Miami School
of Medicine, Miami, FL
WERNER HACKE, MD • Department of Neurology, University
of Heidelberg, Heidelberg, Germany
RICHARO A. lAFFE, MD, PhO • Department of Anesthesiology, Stanford
University School of Medicine, Stanford, CA
WATARU KAKUOA, MD· Stroke Division, Department of Internal
Medicine, Hoshigaoka Koseinenkin Hospital, Osaka, Japan
ELAO I. LEVY, MD· Department of Neurosurgery and Toshiba Stroke
Research Center, School of Medicine and Biomedical Sciences,
University of Buffalo, The State University of New York, Buffalo, NY
CAROLINA M. MAlER, PhO • Department of Neurosurgery, Stanford
Stroke Center, Stanford University School of Medicine, Stanford, CA
DONALO W. MARION, MD • Department of Neurosurgery,
Boston University School of Medicine, Boston, MA
ix
x Contributors
HIROAKI NARITOMI, MD • Cerebrovascular Division, Department
of Medicine, National Cardiovascular Center, Osaka, Japan
MIGUEL A. PEREZ-PINZÖN, PhD· Neurotrauma Research Center,
Department of Neurology, University of Miami School of Miami
School of Medicine, Miami, FL
STEFAN SCHWAB, MD· Department of Neurology, University
of Heidelberg, Heidelberg, Germany
T AKAO SHIMIZU, MD • Department of Medicine, Aino Hospital, Osaka,
Japan
GARY K. STEINBERG, MD, PhD • Departments of Neurosurgery
and Neurology, Stanford Stroke Center, Stanford University
School of Medicine, Stanford, CA
DA VID C. TONG, MD • Department of Neurology, Stanford Stroke
Center, Stanford University School of Medicine, Stanford, CA
MIDORI A. YENARI, MD • Departments of Neurosurgery and Neurology,
Stanford Stroke Center, Stanford University School of Medicine,
Stanford, CA
1
Resurgence of Hypothermia
as a Treatment for Brain Injury
Carolina M Maier,
PHD,
and Gary K Steinberg,
MD, PHD
INTRODUCTION
Like all homeothermie animals, humans maintain their thermal core
temperature within a narrow range despite variations in environmental
conditions and endogenous heat production. Thermoregulation is under
central nervous system (CNS) control, mainly in the hypothalamus, and
body functions are impaired if brain temperature deviates from the
normothermic range. With prolonged exposure to an extreme cold chal
lenge in whieh the thermoregulatory system is overwhelmed, core body
temperature falls below the desired temperature range (i.e., hypother
mia) and, unless reversed, can lead to death (1). On the other hand,
temperature can be modulated in a therapeutie manner to achieve organ
protection. Hypothermia-induced protection of tissue has interested
scientists and clinicians since the 19th century, when hypothermia was
first utilized in the clinical setting as a local anesthetic during surgieal
procedures.
The use of induced hypothermia as a therapeutie strategy in neuro
logie emergency care dates back to the early 1940s, when Dr. Temple
Fay cooled 124 patients with severe head injury (2). A decade later,
Bigelow et al. (3) introduced the concept of using hypothermia during
cardiac surgieal procedures that required circulatory arrest and thus
global cerebral ischemia. These studies led to the notion that hypother
mia could be used to protect the brain by reducing cerebral metabolism,
and nonrandomized trials of induced hypothermia in various neurosur
gieal subspecialties followed. However, complications such as ven
trieular fibrillation, acidosis, coagulation disorders, ischemie sensory
From: Hypothermia and Cerebrallschemia: Mechanisms and Clinical Applications
Edited by: C. M. Maier and G. K. Steinberg © Humana Press Inc., Totowa, NJ
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