Combating Hyperthermia in Acute Stroke
A Significant Clinical Concern
Myron D. Ginsberg, MD; Raul Busto, BS
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Background—Moderate elevations of brain temperature, when present during or after ischemia or trauma, may markedly
worsen the resulting injury. We review these provocative findings, which form the rationale for our recommendation that
physicians treating acute cerebral ischemia or traumatic brain injury diligently monitor their patients for incipient fever and
take prompt measures to maintain core-body temperature at normothermic levels.
Summary of Review—In standardized models of transient forebrain ischemia, intraischemic brain temperature elevations to
39°C enhance and accelerate severe neuropathological alterations in vulnerable brain regions and induce damage to
structures not ordinarily affected. Conversely, the blunting of even mild spontaneous postischemic hyperthermia confers
neuroprotection. Mild hyperthermia is also deleterious in focal ischemia, particularly in reversible vascular occlusion. The
action of otherwise neuroprotective drugs in ischemia may be nullified by mild hyperthermia. Even when delayed by 24
hours after an acute insult, moderate hyperthermia can still worsen the pathological and neurobehavioral outcome.
Hyperthermia acts through several mechanisms to worsen cerebral ischemia. These include (1) enhanced release of
neurotransmitters; (2) exaggerated oxygen radical production; (3) more extensive blood-brain barrier breakdown; (4)
increased numbers of potentially damaging ischemic depolarizations in the focal ischemic penumbra; (5) impaired recovery
of energy metabolism and enhanced inhibition of protein kinases; and (6) worsening of cytoskeletal proteolysis. Recent
studies demonstrate the feasibility of direct brain temperature monitoring in patients with traumatic and ischemic injury.
Moderate to severe brain temperature elevations, exceeding core-body temperature, may occur in the injured brain.
Cerebral hyperthermia also occurs during rewarming after hypothermic cardiopulmonary bypass procedures. Several
studies have now shown that elevated temperature is associated with poor outcome in patients with acute stroke. Finally,
recent clinical trials in severe closed head injury have shown a beneficial effect of moderate therapeutic hypothermia.
Conclusions—The acutely ischemic or traumatized brain is inordinately susceptible to the damaging influence of even modest brain
temperature elevations. While controlled clinical investigations will be required to establish the therapeutic efficacy and safety of
frank hypothermia in patients with acute stroke, the available evidence is sufficiently compelling to justify the recommendation,
at this time, that fever be combated assiduously in acute stroke and trauma patients, even if “minor” in degree and even when
delayed in onset. We suggest that body temperature be maintained in a safe normothermic range (eg, 36.7°C to 37.0°C [98.0°F
to 98.6°F]) for at least the first several days after acute stroke or head injury. (Stroke. 1998;29:529-534.)
Key Words: fever n ischemia n hypothermia n neuroprotection
W
ithin recent years, strikingly consistent and persuasive
evidence has accrued demonstrating that moderate hyperthermia, when present during or after a period of brain
ischemia or trauma, markedly exacerbates the degree of resulting neural injury. These initially unanticipated findings, which
emerged in the course of studies of therapeutic hypothermia,
now constitute a body of evidence so overwhelming as to
compel clinical neurologists, neurosurgeons, critical-care physicians, and internists to vigilantly monitor their acutely braininjured patients for incipient fever and to maintain core
temperature at normothermic levels for several days after the
onset of an acute ischemic or traumatic event. The intent of
this article is to present the rationale and supporting evidence
for this recommendation.
(The abundant experimental investigations which have established conclusively that brain hypothermia of mild to
moderate degree confers marked neuroprotection in cerebral
ischemia will not themselves be reviewed here, but several
detailed summaries of hypothermic neuroprotection in ischemia may be recommended.1– 6)
The Evidence
Hyperthermia Worsens Outcome in Studies of
Global and Focal Cerebral Ischemia
Global Ischemia
In a standardized rat model of transient (20-minute) forebrain
ischemia produced by temporary bilateral carotid artery occlu-
Received August 27, 1997; final revision received November 10, 1997; accepted November 10, 1997.
The opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.
From the Cerebral Vascular Disease Research Center, Department of Neurology, University of Miami School of Medicine (Fla).
Reprint requests to Myron D. Ginsberg, MD, Department of Neurology (D4 –5), University of Miami School of Medicine, PO Box 016960, Miami,
FL 33101. E-mail [email protected]
© 1998 American Heart Association, Inc.
529
530
Combating Hyperthermia in Acute Stroke
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sions with prior bilateral vertebral artery coagulation,7 we
showed that intraischemic elevations of brain temperature to
39°C enhanced and accelerated the appearance of severe
neuropathological alterations in the hippocampus and striatum.
In contrast to normothermic ischemia, hyperthermic ischemia
also led to marked damage to the superficial layers of neocortex
and to foci of frank infarction in cortex, thalamus, cerebellum,
and substantia nigra.8,9 Hyperthermic ischemic rats tended to
remain unresponsive and to die soon after ischemia.9 Transient
hyperthermia in the absence of ischemia produced no pathological changes.
These findings have been strongly supported and extended
by other laboratories in rodent and canine models of transient
forebrain ischemia.10 –15 In one study, the marked loss of
hippocampal CA1 pyramidal neurons produced by 5 minutes
of high-grade forebrain ischemia in gerbils was dramatically
attenuated merely by counteracting the mild core-temperature
elevation (approximately 1.5°C) that tended otherwise to
occur during the first 90 minutes of postischemic recirculation.11 Other workers14,15 have called attention to a prolonged
period of spontaneous hyperthermia after a 10-minute forebrain ischemic insult in rats, which could be abolished by the
administration of dipyrone, an anti-inflammatory/antipyretic
drug, resulting in partial neuroprotection. In dogs subjected to
12.5 minutes of complete cerebral ischemia (by arterial hypotension plus intracranial hypertension) with central-arterial and
cranial temperature monitoring, those animals maintained at
37°C were behaviorally normal or near normal, while dogs
maintained at 39°C either remained comatose or died, and
animals held at 38°C had an intermediate outcome.13
Focal Ischemia
Studies in focal ischemia are also unequivocal in showing a
deleterious effect of mild hyperthermia. In a model of reversible proximal middle cerebral artery (MCA) occlusion in rats,
the elevation of brain temperature from 36°C to 39°C during
a 2-hour period of MCA occlusion resulted in a 3-fold increase
in infarction volume as measured histologically.16 (In the same
study, lowering the brain temperature to 30°C reduced infarct
volume by approximately 70% compared with normothermia.)
By contrast, the infarct resulting from permanent MCA
occlusion in that study was not significantly affected by
hyperthermia.16 Other investigators, however, using a rat
model of permanent MCA and ipsilateral carotid artery occlusions, reported that moderate hyperthermia (39.9°C) for 1
hour or more in the immediate peri-infarct period produced a
1.5- to 1.6-fold increase in the volume of infarction compared
with normothermic (37°C) animals.17
Other studies in focal ischemia have shown that mild
hyperthermia may nullify the effect of an otherwise neuroprotective drug. Rats receiving 2 hours of MCA occlusion were
treated before and after ischemia with MK-801,18 an extensively studied N-methyl-D-aspartate antagonist known to be
protective in focal ischemia.19 In one group of rats, temperature
was allowed to rise spontaneously (to 39°C to 39.5°C) during
ischemia, while in another group it was controlled at nearnormal levels. MK 801 reduced infarct volume markedly in the
temperature-controlled group but failed to have a therapeutic
effect in rats with mild spontaneous hyperthermia.18
Hyperthermia has also been shown to have a detrimental
effect in focal ischemia when combined with thrombolytic
therapy. In a rat model of blood clot embolization to the
carotid artery territory, hyperthermia alone (39°C for 2 hours)
increased the mean infarct volume by 1.4-fold and enhanced
mortality.20 In animals treated with tissue plasminogen activator 2 hours after embolization, hyperthermic rats, despite
showing the most complete recanalization by angiography,
now had 2.8-fold larger infarct volumes than treated normothermic animals (P,.02). The results of this study take on
added meaning in the context of the recent clinical approval of
thrombolytic therapy in the management of hyperacute ischemic stroke.21,22
Hyperthermia May Act Through Several
Mechanisms to Worsen Cerebral Ischemia
Neurotransmitter Release
Release of neurotransmitters in both global and focal ischemia
is accentuated by hyperthermia and diminished by hypothermia. In a microdialysis study of 20-minute forebrain ischemia
(produced by bilateral carotid artery occlusions plus hypotension), normothermic rats showed a 21-fold increase in basalganglionic glutamate levels during ischemia, which returned to
normal by 20 to 30 minutes of recirculation. By contrast,
glutamate levels in hyperthermic (39°C) brains increased by
37-fold during ischemia (P5.02) and tended to persist longer
during the recirculation period.23 Intraischemic hyperthermia
also accentuated the release of g-aminobutyric acid and doubled the release of glycine. Importantly, the excitotoxic index,
a composite measure of neurotransmitter release,24 rose by only
2-fold in normothermic rats but showed a 20-fold elevation
after hyperthermic ischemia—implying that the potential for
greatly enhanced excitotoxicity may exist under hyperthermic
conditions.23
In focal ischemia, we studied this problem in a model of
2-hour temporary MCA clip-occlusion in rats monitored for
cortical blood flow (by laser-Doppler flowmetry) and for
glutamate release (by intracortical microdialysis).25 In hyperthermic (39°C) rats, peak glutamate release in the penumbral
cortex during MCA occlusion averaged 31-fold above baseline
compared with 6.5-fold elevations in normothermic (37°C)
rats. Furthermore, this glutamate release occurred at a substantially higher blood flow threshold in hyperthermic rats (61% of
control flow) than in normothermic animals (33% of control
flow).
Oxygen Radical Production
We used in vivo microdialysis to sample the brain’s extracellular fluid for evidence of hydroxyl radical production (as
reflected in the formation of the stable adducts 2,3- and
2,5-dihydroxybenzoic acid after salicylate administration).26
We showed that cortical oxygen radical production during the
early recirculation period after a global ischemic insult is
markedly influenced by intraischemic brain temperature: while
no elevation of these radical adducts occurred after moderately
hypothermic (30°C) ischemia, 2- to 3-fold elevations were
observed after a normothermic (36°C) period of global ischemia, and 4- to 5-fold elevations were observed after mildly
Ginsberg and Busto
hyperthermic (39°C) ischemia.26 These results have been
strongly confirmed in a recent study by another group.27
Blood-Brain Barrier Changes
Ischemia-induced blood-brain barrier opening is remarkably
sensitive to brain temperature. The mild extravasation of
protein tracers across the barrier observed after periods of
normothermic global ischemia is attenuated by mild to moderate (30°C to 33°C) intraischemic hypothermia but is markedly exaggerated by mild intraischemic hyperthermia
(39°C).28,29
Ischemic Depolarizations
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Focal vascular occlusion is known to trigger repetitive episodes
of ischemic depolarization (so-called peri-infarct depolarizations) within the cortical penumbra. These events are associated with severe transmembrane ionic dyshomeostasis (elevations of extracellular potassium ion and of intracellular calcium
ion), and they obligate an inordinate energy expenditure to
restore ion gradients in ischemically threatened cortex,30 –32
resulting in the eventual irreversible deterioration of the
penumbra and expansion of the zone of infarction.33–35 Intraischemic hyperthermia (40°C) both increases the numbers of
these depolarizing shifts and, pari passu, enlarges the size of the
resulting infarct.36 (Conversely, hypothermia diminishes both.)
Brain Metabolism and Second Messengers
In cats subjected to 16 minutes of global cerebral ischemia,
metabolic recovery was assessed with 31P MR spectroscopy.
Hyperthermia (mean, 40.6°C) induced 1 hour or more before
ischemia and maintained for 1.5 to 2 hours after recirculation
enhanced the degree of intracellular acidosis and impaired the
recovery of cerebral ATP and phosphocreatine levels compared with normothermic cats.37 We obtained similar findings
in a study in which we directly assayed regional brain energy
metabolites in rats recovering from 20 minutes of high-grade
global ischemia performed at different cranial temperatures.
Again, there was less complete recovery of ATP levels and
adenylate energy charge in both cortex and subcortical regions
of rats with intraischemic hyperthermia (39°C).38
Hyperthermia also appears to affect the manner in which
various protein kinases are influenced by ischemia. Calcium/
calmodulin-dependent protein kinase II is a mediator of many
of the second-messenger actions of calcium, including neurotransmitter release, synaptic transmission, and cytoskeletal
function. Hyperthermia (39°C) during ischemia was found to
exacerbate the degree of inhibition of calcium/calmodulindependent protein kinase II induced by a brief period of global
ischemia.12 Similarly, hyperthermia significantly influenced
patterns of protein kinase C alteration induced by global
ischemia.39
Cytoskeletal Degradation
Calpain is a calcium-sensitive cysteine protease that, when
activated, degrades neuronal cytoskeletal proteins such as
spectrin and microtubule-associated protein 2 (MAP2). Calpain activation and spectrin proteolysis have been implicated in
neuronal injury produced by hypoxia and ischemia. In a study
of 1-hour transient proximal MCA occlusion, hyperthermia
(39°C) during the period of focal ischemia led to spectrin
531
proteolysis in cortical pyramidal neurons soon after the onset of
reperfusion, which became marked by 4 and 24 hours, in
association with morphological evidence of irreversible neuronal injury. 40 By contrast, after normothermic MCA occlusion, only occasional neurons showed spectrin proteolysis, and
this subsided by 24 hours.
In a related study, three groups of gerbils received 5 minutes
of global forebrain ischemia (by bilateral carotid artery occlusions) while scalp temperatures were maintained at either
33.3°C, 36.7°C, or 39.7°C; brains were subsequently studied
by immunochemistry for calmodulin and MAP2. The marked
decrease in calmodulin and MAP2 immunoreactivity induced
in the vulnerable hippocampal CA1 sector at 48 hours in
normothermic animals and the subsequent delayed death of
these neurons were both aggravated by mild intraischemic
hyperthermia.41
Hyperthermia, Even If Delayed, Worsens
Ischemic and Traumatic Injury
In recent studies from our laboratory, the core-body temperature of rats receiving mild to moderate focal or global
ischemic insults was increased by external warming 1 day after
the initial ischemic insult. In each case, a dramatic accentuation
of neural injury resulted. In the first of these studies,42 the
MCA of normothermic rats was occluded for 60 minutes with
an intraluminal suture. A focal ischemic insult of this duration
normally gives rise only to restricted basal ganglionic infarction
with a very small cortical component. However, when brain
temperature was elevated to 40°C for a 3-hour period 24 hours
after the MCA occlusion, the resulting cortical infarct volume
enlarged dramatically (on average, by 6.4-fold), as did the total
infarct volume (by 3-fold), and neurobehavioral scores worsened. Since postischemic hyperthermia of 39°C failed to
produce significant worsening, the threshold for this effect thus
appears to be 40°C. This study established that the postischemic brain is abnormally sensitive to the effects of delayed
temperature elevation, which is capable of greatly enlarging an
otherwise modest histopathological lesion resulting from a
short period of focal vascular occlusion.42
We conducted a similar study in a model of global forebrain
ischemia produced by bilateral carotid artery occlusions and
hypotension for either 5 or 7 minutes in the rat.43 Twenty-four
hours later, rats were placed into a warming chamber in which
rectal temperature was elevated to 39°C to 40°C for 3 hours.
Hippocampal histopathology was quantitated after an 8-day
survival. In rats with the 7-minute ischemic insult, delayed
hyperthermia resulted in a 2.5- to 3-fold increase in numbers
of ischemic neurons throughout the vulnerable CA1 sector of
hippocampus; a similar (but nonsignificant) trend was noted in
rats with a 5-minute ischemic insult. These results support the
highly deleterious effect of delayed temperature elevations in
the context of a brief global ischemic insult, such as might
occur in patients with cardiac arrest followed by resuscitation.43
Delayed hyperthermia also worsens outcome after experimental traumatic injury. Twenty-four hours after undergoing
moderate fluid-percussion brain injury, rats received a 3-hour
period of either brain hyperthermia (39°C) or normothermia
(36.5°C). Compared with normothermic rats, delayed hyperthermia resulted in a 2.6-fold increase in mortality rate, a
532
Combating Hyperthermia in Acute Stroke
13-fold enlargement of cortical contusion volume, a 6-fold
increase in the area of early hemorrhage and blood-brain
barrier breakdown (to horseradish peroxidase), and increased
numbers of abnormally swollen axons.44
surface). These conclusions are consistent with the observations described above in patients with traumatic brain injury.
Importantly, the success of external cooling in lowering brain
temperature was convincingly established.52
Brain Temperature Monitoring Is Feasible in
Patients With Traumatic and Ischemic Injury;
Cerebral Hyperthermia Is Common in the
Injured Brain
Elevated Temperature Is Associated With Poor
Outcome in Patients With Acute Stroke
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Several groups have independently reported direct measurements of brain temperature in patients with head injury or
other neurological conditions. In 15 neurosurgical patients
(with brain tumors, head trauma, subarachnoid or intracerebral
hemorrhage, or hydrocephalus), intracerebroventricular temperatures were monitored by means of a thermocouple introduced through an intracranial pressure-monitoring catheter.
Intraventricular temperature exceeded rectal temperature in
approximately 90% of measurements, with the maximal gradient being 2.3°C.45 In another, smaller series, the intracranial
temperature of acutely head-injured patients exceeded body
temperature by 0.5°C to 2.5°C, and a gradient of temperature
was present within the brain, with ventricular temperatures
1°C to 1.5°C higher than the superficial cortex.46 Other groups
have also documented that moderate to severe elevations of
brain temperature47 and intracerebral temperature gradients48
may be present in head-injured patients. Hyperthermia has also
been described after cardiopulmonary resuscitation.49 Cardiopulmonary bypass procedures (CPB) are associated with a
substantial incidence of neuropsychological sequelae.50 In this
context, it may be relevant that a recent report has called
attention to the regular occurrence of cerebral hyperthermia in
patients during the rewarming phase after hypothermic CPB:
In 10 adults undergoing hypothermic (27°C) CPB for cardiac
surgery, jugular venous and nasopharyngeal temperatures were
monitored.51 Cerebral temperature (as reflected in jugular
venous temperature) was found to rise very quickly during
rewarming, and all 10 patients had peak cerebral venous
temperatures of at least 39°C, for an average duration of 15
minutes. These authors rightly hypothesize that hyperthermia
may accentuate an ischemia-related injury cascade, and they
urge that rewarming procedures be modified to avoid cerebral
hyperthermia.51
The feasibility of brain temperature monitoring and modulation has recently been demonstrated in patients with severe
ischemic infarction. In 15 patients with large MCA territory
ischemic strokes, measurements were made of intracerebroventricular, epidural, or parenchymal brain temperature (measured by means of an implanted thermistor or thermocouple
over a 3- to 7-day period, in conjunction with the monitoring
of core-body (bladder) and jugular venous temperatures.52 In
all patients of that series, brain temperature exceeded corebody temperature by 1.0°C to 2.1°C, and ventricular temperature exceeded epidural temperature by 0.6°C to 2.0°C.
Systemic cooling by means of cooling blankets and alcohol
washing was effective in achieving sustained brain hypothermia
(33°C to 34°C).52 Thus, this important study established both
the disparity between brain and body temperature in patients
with acute neural injury, as well as a temperature gradient
within regions of the brain (ventricles warmer than the cortical
In a retrospective analysis of 110 patients admitted within 24
hours of stroke, fever and “subfebrility” (temperatures between
37.5°C and 38.0°C) were associated with more severe symptoms.53 A similar conclusion was reached in a second small
prospective study54 and in two more recent, larger studies of
this problem. In the first of the latter reports,183 patients with
acute ischemic or hemorrhagic stroke (excluding subarachnoid
hemorrhage) were followed prospectively; fever occurred in
43% of this cohort during the first week of hospitalization
(mean value of maximum temperature, 38.3°C).55 High fever
($37.9°C) proved to be an independent factor predicting a
worse prognosis (odds ratio, 3.4). Patients with high fever were
far more likely to die within the first 10 days than those with
lower temperatures.55
In a second recent prospective study of this problem in 390
consecutive cases of acute stroke, Reith et al56 classified patients
into three admission-temperature groups: hypothermic
(#36.5°C), normothermic (.36.5°C to 37.5°C), and hyperthermic (.37.5°C). By multiple regression analysis, admission
body temperature proved to be highly correlated with initial
stroke severity (P5.009), infarct size (P,.0001), mortality
(P5.01), and poor outcome (P5.001). For a 1°C difference in
body temperature, the relative risk of poor outcome (death or
Scandinavian Stroke Scale score ,30 on discharge) increased
by 2.2-fold (95% confidence interval, 1.4 to 3.5). The relationship between body temperature and poor outcome was
independent of stroke severity on admission.56
A recent report studying the antecedents of brain infarction
has called attention to an increased prevalence of “infection/
inflammation” in patients with acute stroke during the 1 week
preceding stroke onset compared with community control
subjects or hospitalized neurological patient controls.57
Moderate Brain Cooling Appears to be
Neuroprotective in Clinical Head Injury
While no randomized clinical trials of therapeutic hypothermia
in acute ischemic stroke have yet been announced, encouraging results have been recently reported in the setting of acute
traumatic brain injury,58 and a National Institutes of Health–
funded phase III clinical trial is presently in progress, based on
improved neurological outcome with minimal toxicity observed in a phase II study.59 In the former report,58 82 patients
with severe closed head injury (Glasgow Coma Scale score 3 to
7) were randomized to normothermia or hypothermia (cooling
to 33°C within 10 hours of injury, maintenance at 32°C to
33°C for 24 hours, then gradual rewarming). In the patient
subgroup with somewhat less severe initial injuries (Glasgow
Coma Scale score 5 to 7), hypothermia significantly improved
outcome at 3 and 6 (but not at 12) months. Physiological
observations of severely head-injured patients treated with
hypothermia (32°C to 33°C) have described a normalization of
Ginsberg and Busto
elevated cerebral lactate production (denoting brain ischemia),
together with marked declines in intracranial hypertension.60
Conclusions and Recommendations
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The considerable evidence reviewed above leaves little doubt
that the acutely ischemic or traumatized brain is inordinately
susceptible to the damaging influence of even relatively modest
degrees of brain temperature elevation, such as commonly
occurs in the setting of fever in patients with acute stroke and
head injury. Even temperature elevations occurring many
hours after an acute stroke are capable, in experimental studies,
of engendering secondary injury. Fever occurs very commonly
in patients with acute stroke and head injury. Direct measurements of brain temperature in such patients have substantiated
that systemic fever is associated with even higher degrees of
brain temperature elevation—indeed, to levels known from
experimental studies to be capable of inflicting substantial
secondary injury.
The message, therefore, is clear: Fever may aggravate the
outcome of brain ischemia and should be combated assiduously
in stroke patients. It is obvious that the therapeutic application
of frank hypothermia in acute stroke patients must await the
completion of controlled clinical investigations establishing the
efficacy and safety of this therapy; one hopes that such trials
will be expeditiously undertaken. In the meantime, however,
we believe that the available evidence is sufficiently compelling
to justify the recommendation, at this time, that clinicians
institute measures, as part of their routine acute stroke care, to
counteract incipient fever, even if ostensibly “minor” in
degree, and even when it arises many hours after stroke onset,
in order to avert secondary hyperthermic brain injury. We
suggest that body temperature be maintained in a safe normothermic range (eg,36.7°C to 37.0°C, [98.0°F to 98.6°F]) for at
least the first several days after acute stroke or head injury.
Similarly, steps should be taken in CPB patients to avoid
hyperthermia during the rewarming phase.51
Acknowledgment
Our studies were supported by US Public Health Service grants NS
05820 and NS 30291.
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Combating Hyperthermia in Acute Stroke: A Significant Clinical Concern
Myron D. Ginsberg and Raul Busto
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Stroke. 1998;29:529-534
doi: 10.1161/01.STR.29.2.529
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