1113
The Importance of Brain Temperature
in Cerebral Ischemic Injury
Raul Busto, BS, W. Dalton Dietrich, PhD,
Mordecai Y-T. Globus, MD, and Myron D. Ginsberg, MD
Cerebral Vascular Disease Research Center Investigative Group
University of Miami School of Medicine
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A verting the injurious consequences of brain
/ \
ischemia, long sought by cerebrovascular
A. \ - investigators, remains a tantalizing though
often elusive goal. Current advances in the neurosciences have raised the hope that pathophysiological approaches directed at specific mechanisms of
tissue injury may find eventual clinical application.1
In this brief survey, we call attention to another
avenue that, in our view, may hold promise and
deserves careful scrutiny: the therapeutic modification of brain temperature.
Observations of cerebroprotection by hypothermia are not new, though traditional approaches
have tended to employ overall reductions of wholebody temperature of rather sizable magnitude. In
contrast, our laboratory first suspected several years
ago that small fluctuations of brain temperature
might account in part for variability in the extent of
tissue injury encountered in animal models of reversible ischemia. (For example, we observed less histologic injury in animals whose heads may have
been inadvertently cooled by scalp tissue removal
for electroencephalographic monitoring.2) These
casual observations provided the impetus for a large
controlled study employing reversible forebrain ischemia in rats, in which 1) brain temperature was
directly monitored by an implanted thermocouple;
2) brain temperature was allowed to vary independently of rectal (core) temperature, which was held
constant at 37° C: and 3) careful histopathologic end
points of ischemic injury were blindly assessed.3
From the Cerebral Vascular Disease Research Center, Department of Neurology, University of Miami School of Medicine,
Miami, Florida.
Supported by United States Public Health Service Grants
NS-05820 and NS-22603. M.D.G. is the recipient of a Jacob
Javits Neuroscience Investigator Award. W.D.D. and M.Y-T.G.
are Established Investigators of the American Heart Association.
Address for correspondence: Myron D. Ginsberg, MD, Department of Neurology (D4-5), University of Miami School of
Medicine, PO Box 016960, Miami, FL 33101.
Received January 6, 1989; accepted April 4, 1989.
When no effort was made to control it, brain temperature tended to fall gradually by 5-6° C during
high-grade forebrain ischemia. By regulating brain
temperature at various levels (by means of a fan and
warming lamp), we observed that the histological
consequences of ischemia were markedly influenced by the level of intraischemic brain temperature. For example, hippocampal pyramidal neurons
of the CA1 layer showed grades 2-3 histologic
damage (many or all neurons affected) in 100% of
hemispheres held at 36° C during ischemia but in
only 20% of those held at 34° C, in 0% of those held
at 33° C, and in 0% of those held at 30° C. Similarly,
ischemic injury to the dorsolateral striatum, another
selectively vulnerable zone, was reduced by approximately 80% at 33-34° C and was completely eliminated when intraischemic brain temperature was
30° C.3 This marked dependence of iscnemic injury
on intraischemic brain temperature clearly suggests
that the failure to monitor or control brain temperature, or allowing body temperature to change
during ischemia and/or administration of therapeutic agents, might be expected to introduce unacceptable variability into the outcome of experimental
ischemia studies.
We have shown that this pronounced protective
effect of mild-to-moderate brain hypothermia is not
explicable on the basis of alterations in cerebral
blood flow, energy metabolites, or free fatty acids
during ischemia.34 Further studies employing intracerebral microdialysis, however, have shown that
as intraischemic brain temperature is lowered from
36° to 33° C, the (normally expected) sevenfold
increase in the release of the excitatory neurotransmitter glutamate into the brain's extracellular space
is almost totally suppressed, and the extracellular
release of dopamine is reduced by 60%.5 Furthermore, moderate intraischemic hypothermia has been
shown in autoradiographic studies to enhance early
postischemic glucose utilization and blood flow.6
The therapeutically relevant issue is whether postischemic induction of moderate brain hypothermia
1114
Stroke Vol 20, No 8, August 1989
TABLE 1. Number of Normal-Appearing Neurons per Standardized Microscopic Area7
CA1 subregion
Group
Nonischemic controls
Ischemia
36-36-36
36-36-30
n
4
6
6
Medial
131±5
3±1*
71±19tt
Middle
126±6
Lateral
135 ±7
7±3*
89±20t
20±8*
110±14*
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Halothane-anesthetized Wistar rats were subjected to 10 minutes of forebrain ischemia by bilateral common carotid artery
occlusion plus systemic hypotension (45-55 mm Hg). In the
36-36-36 ischemic group, brain temperature was maintained at
36° C throughout the preischemic, ischemic, and postischemic
periods. In the 36-36-30 group, postischemic brain temperature
was lowered to 30° C for 3 hours, beginning 5 minutes into the
recirculation period. Three days later, brains were perfusionfixed for histology, and numbers of normal-appearing neurons
were counted at lOOx magnification from standardized zones of
the hippocampal CA1 sector. Cell counts represent mean±SEM.
Statistical significance was assessed by a one-way analysis of
variance followed by the Scheffe and Dunn tests.
*t/><0.01, 0.05, respectively, significantly different from nonischemic controls.
ip<0.01 significantly different from 36-36-36 ischemic group.
might also protect. Recent evidence suggests that
this may be the case.7 In rats subjected to 10
minutes of bilateral carotid artery occlusion and
systemic hypotension, an insult resulting in consistent injury to hippocampal pyramidal neurons of the
CA1 layer, a reduction of brain temperature to
30° C for 3 hours, beginning 5 minutes after resumption of circulation, conferred a marked protective
effect (Table 1). If the institution of hypothermia
was delayed for 30 minutes, however, protection
was less pronounced, suggesting the possibility that
a narrow postischemic "therapeutic window" may
exist in this setting.
Can selective brain cooling be accomplished feasibly and safely in humans? Studies bearing on this
point are lacking. Nonetheless, the experimental
evidence is now compelling that moderate degrees
of selective brain cooling, if instituted promptly,
may markedly protect against ischemic neuronal
injury of the type that occurs commonly following
cardiac arrest in humans.8 Whether selective cerebral hypothermia might also protect against focal
brain infarction remains an important but as yet
uninvestigated question. As concerned investigators and clinicians, we should begin promptly to
design and implement the studies needed to resolve
these important issues.
References
1. Rothman SM, Olney JW: Glutamate and the pathophysiology
of hypoxic-ischemic brain damage. Ann Neurol 1986;
19:105-111
2. Vibulsresth S, Dietrich WD, Busto R, Ginsberg MD: Failure
of nimodipine to prevent ischemic neuronal damage in rats.
Stroke 1987;18:210-216
3. Busto R, Dietrich WD, Globus MY-T, Valdes I, Scheinberg
P, Ginsberg MD: Small differences in intraischemic brain
temperature critically determine the extent of ischemic neuronal injury. / Cereb Blood Flow Metab 1987;7:729-738
4. Busto R, Globus MY-T, Dietrich WD, Martinez E, Valdes I,
Ginsberg MD: Effect of mild hypothermia on ischemiainduced release of neurotransmitters and free fatty acids in rat
brain. Stroke 1989;20:904-910
5. Globus MY-T, Busto R, Dietrich WD, Martinez E, Valdes I,
Ginsberg MD: Intra-ischemic extracellular release of dopamine and glutamate is associated with striatal vulnerability to
ischemia. Neurosci Lett 1988;91:36-40
6. Ginsberg MD, Busto R, Castella Y, Valdes I, Loor J: The
protective effect of moderate intra-ischemic brain hypothermia is associated with improved postischemic glucose utilization and blood flow. J Cereb Blood Flow Metab 1989;S380
7. Busto R, Dietrich WD, Globus MY-T, Ginsberg MD: Postischemic moderate hypothermia inhibits CA1 hippocampal
ischemic neuronal injury. Neurosci Lett (in press)
8. Petito CK, Feldmann E, Pulsinelli WA, Plum F: Delayed
hippocampal damage in humans following cardiorespiratory
arrest. Neurology 1987;37:1281-1286
KEY WORDS • cerebral ischemia • hypothermia
The importance of brain temperature in cerebral ischemic injury.
R Busto, W D Dietrich, M Y Globus and M D Ginsberg
Stroke. 1989;20:1113-1114
doi: 10.1161/01.STR.20.8.1113
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