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(Stroke. 1996;27:2274-2281.)
© 1996 American Heart Association, Inc.

Articles

Delayed Postischemic Hyperthermia in Awake Rats Worsens the Histopathological Outcome of Transient Focal Cerebral Ischemia

Young Kim, MD; Raul Busto, BS; W. Dalton Dietrich, PhD; Susan Kraydieh, BS Myron D. Ginsberg, MD

the Cerebral Vascular Disease Research Center, Department of Neurology, University of Miami (Fla) School of Medicine.

	Abstract

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Background and Purpose Over the past several years, it has been demonstrated that mild intraischemic or immediate postischemic hyperthermia worsens ischemic outcome in models of global and focal ischemia. Periods of hyperthermia are commonly seen in patients after stroke and cardiac arrest. The hypothesis tested in this study was that a brief hyperthermic period, even when occurring days after an ischemic insult, has detrimental effects on the pathological outcome of focal ischemia.

Methods Rats were subjected to 60 minutes of transient middle cerebral artery occlusion by insertion of an intraluminal filament. Twenty-four hours after reperfusion, awake rats were subjected to temperature modulation for 3 hours in a heating chamber. The brain temperature was equilibrated to either 37°C to 38°C, 39°C, or 40°C. Changes in rectal temperature and blood glucose concentration were evaluated during and just after temperature modulation. Behavioral tests were also assessed. Three days after temperature modulation, brains were perfusion-fixed, and infarct volumes were determined.

Results In animals with 40°C hyperthermia, cortical and total infarct volumes were markedly greater (92.2±63.1 and 126.5±72.3 mm³ [mean±SD], respectively) than in normothermic rats (14.4±12.7 and 42.4±19.2 mm³) and in animals with 39°C hyperthermia (16.5±28.7 and 40.9±34.3 mm³) (P<.05), whereas there was no significant difference between normothermic and 39°C hyperthermic animals. In addition, animals with 40°C hyperthermia displayed worsened neurological scores compared with normothermic and 39°C hyperthermic rats. In the 39°C hyperthermia group, rectal temperatures were significantly lower (by 0.2°C to 0.5°C) than brain temperatures throughout the modulation period.

Conclusions The present findings provide evidence that, after a transient focal ischemic insult, the postischemic brain becomes abnormally sensitive to the effects of delayed temperature elevation, even of moderate degree. The threshold for aggravation of ischemic injury by delayed hyperthermia appears to be approximately 40°C. Body-temperature measurements, in both awake and anesthetized animals, may not accurately reflect brain temperature under these conditions. The present study stresses that fever of even moderate degree in the days following brain ischemia may markedly exacerbate brain injury.

Key Words: cerebral ischemia, focal • hyperthermia • middle cerebral artery occlusion • neuronal damage • rats

	Introduction

Top Abstract Introduction Materials and Methods Results Discussion References Introduction

 
It is not uncommon for stroke patients to present with elevated body temperature during the early postinfarction period. In most such cases, the fever is slight or moderate and may be due to either a variety of systemic complications (eg, respiratory or urinary tract infections, deep venous thrombosis) or central causes (eg, intracerebral hemorrhage or subarachnoid hemorrhage).^{1 2 3} It is known that the ischemic brain, particularly during the intraischemic and immediate postischemic periods, is so sensitive to temperature that small differences can critically influence neuropathological outcome. This robust effect of temperature on ischemic outcome has been well documented both experimentally^{4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21} and clinically.^{1 3 22} Studies from our laboratory have assessed the neuropathological consequences of global forebrain ischemia under normothermic (37°C) versus mild hyperthermic (39°C) conditions.^{13 21} Compared with normothermic rats, intraischemic hyperthermia increased the mortality and the severity of histopathological damage at 24 hours. The maturation rate of ischemic cell injury after intraischemic hyperthermia was also accelerated compared with normothermic ischemic rats. Finally, hyperthermia facilitated the transformation of ischemic neuronal injury into frank infarction and accelerated the evolution of ischemic necrosis in both cerebral cortex and striatum.

In regard to the importance of postischemic temperature manipulations to ischemic outcome, studies published since our laboratory's first report that immediate postischemic hypothermia reduced the degree of hippocampal CA1 damage after transient global ischemia²³ have focused mainly on the effects of hypothermia^{23 24 25 26 27} and hyperthermia^{12 15 16 28} instituted during the immediate postischemic periods. More recent studies have shown neuroprotection with extended periods of hypothermia introduced from 1 hour up to several hours after the ischemic insult.^{17 29 30 31 32} These hypothermic data are important with reference to the present study because they clearly indicate that the progression of ischemic damage can be altered by temperature manipulations induced at relatively delayed periods after recirculation. In addition, fever following ischemic stroke has been shown to occur more commonly after some delay (eg, on days 1 or 2) than in the immediate period after stroke onset.³ These considerations thus establish the rationale for studying whether delayed postischemic temperature variations affect ischemic outcome. To our knowledge, experiments designed to determine whether induced episodes of delayed postischemic hyperthermia influence ischemic outcome have not been undertaken. In this study, we determined the relationship between delayed brain-temperature elevations and ischemic outcome after transient focal cerebral ischemia.

In the vast majority of previous studies of experimental cerebral hypoxia and ischemia in which hyperthermia was used, the procedures for eliciting hyperthermia have been performed under anesthesia and by the use of direct local heating lamps. However, anesthesia might seriously influence thermal effects on ischemic outcome^{12 16 33 34} and might eliminate the potentially harmful effects of stress capable of affecting stroke outcome.^{35 36} In addition, the use of direct local heating lamps might possibly distort temperature gradients between superficial and deeper parenchymal structures by physiological evaporative heat loss.⁷ To make the experimental design closely relevant to clinical febrile stroke, we elicited hyperthermia in awake rats exposed to 60 minutes of transient focal cerebral ischemia. The brain temperature during these modulations was adjusted to either 37°C to 38°C, 39°C, or 40°C. We used a humidified heating chamber that allowed the animal to move freely during heating. The purpose of these procedures was to avoid the risk of local overheating or intraparenchymal temperature gradients.

	Materials and Methods

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Animal Preparation
Male Sprague-Dawley rats (Charles River Laboratories, Wilmington, Mass) weighing 270 to 330 g were used in this study. Animals were fasted overnight but were allowed free access to water. All experimental protocols were approved by the Animal Research Committee of the University of Miami School of Medicine. Anesthesia was induced initially with 3% halothane, 70% nitrous oxide, and a balance of oxygen and was maintained with 1% halothane. Atropine sulfate (0.3 mg) was injected intraperitoneally. Polyethylene catheters were inserted into the right femoral artery and vein to monitor arterial blood pressure and blood gases and to permit drug injections. Rats were intubated endotracheally and were ventilated mechanically with 0.75% halothane, 70% nitrous oxide, and a balance of oxygen. Animals were then stabilized for a period of 50 minutes, during which arterial blood gases were measured and controlled at normal levels by adjusting the respirator. Temporalis muscle temperature was monitored as an indirect measure of brain temperature^{5 33} and controlled at 37.5°C throughout the surgical preparation for cerebral ischemia by a small high-intensity lamp placed above the head. Rectal temperature was also monitored and controlled independently between 37°C and 37.5°C by a heating lamp positioned above the body.

Middle Cerebral Artery Occlusion
The middle cerebral artery (MCA) was occluded with the intraluminal suture technique described by Zea Longa et al.³⁷ In brief, the right common carotid artery was exposed, and the external carotid artery and its branches and the pterygopalatine artery were occluded. After 0.1 mL heparin (150 IU/mL) was administered, a 3-0 monofilament nylon suture, its tip rounded by heating, was threaded into the internal carotid artery through the external carotid artery stump up to the origin of the MCA. After 60 minutes of MCA occlusion, animals were reanesthetized, and the intraluminal filament was withdrawn from the internal carotid artery to allow reperfusion. After these procedures, rats were returned to their cages and allowed to recover with free access to food and water. Sham-operated rats (n=12) underwent all surgical procedures, except that cerebral ischemia was not produced.

Procedures for Temperature Modulation
After MCA occlusion and recirculation, rats were fasted for 12 hours before heating but were allowed free access to water. Animals were not further studied if their rectal temperatures had already risen to above 38.5°C before the heating procedure 1 day after ischemia. Twenty-four hours after transient focal ischemia, rats were reanesthetized, intubated, and connected to a ventilator for the insertion of temperature probes into the brain and rectum. The head was secured in a stereotaxic apparatus. A 33-gauge thermocouple probe (CN9000, Omega), which had been calibrated against a mercury thermometer in a water bath before each experiment, was introduced stereotaxically through a small burr hole (drilled 1 mm anterior and 2.5 mm lateral to the bregma) into the striatum to a depth of 5 mm from the cortex ipsilateral to MCA occlusion. This probe was attached firmly to the surface of the skull with glue and dental cement to avoid parenchymal injury due to the animal's movement. The rectal probe was inserted to a depth of 7 cm. After blood glucose was measured, rats were allowed to awaken and were then placed into the heating chamber for the temperature modulation. The cable of the brain-temperature probe was connected to a hanging device (CMA/120 System for freely moving rats, Carnegie Medicin AB) installed above the heating chamber. The heating chamber, which measured 70x45x50 cm (lengthxwidthxheight), was equipped with a heating lamp, humidifier, and oxygen supplier and had a small window for probe cables. The heating lamp elevating ambient temperature was controlled by a servo-regulated temperature controller (CN76000 Autotune, Omega) to maintain the target brain temperature of each animal group. The chamber also contained a shady area so that the animal could avoid direct lamp heat. The animals in each experimental group were left in the chamber for 3 hours from the time their brain temperatures reached the target temperature. They received humidified oxygen during that period. After the 3-hour hyperthermic or normothermic period, rats were returned to their cages after their blood glucose levels were remeasured under light anesthesia. Three animal groups with prior ischemia were studied, which differed with respect to their brain temperatures. The normothermic group was maintained at 37°C to 38°C (group 1, n=8) during the 3-hour period, while the hyperthermic groups were maintained at either 39°C (group 2, n=8) or 40°C (group 3, n=8). Sham-operated nonischemic animals underwent similar manipulations, including a 3-hour heating period to determine whether this duration of hyperthermia by itself would result in any histopathological damage (group C1: normothermia, n=4; group C2: 39°C, n=4; and group C3: 40°C, n=4).

Neurological Evaluation
The neurological status of each rat was evaluated daily after surgery by an observer who was blinded to the experimental procedure. The animal's neurological level was graded and recorded 2 days after ischemia, ie, 1 day after temperature modulation, with a score of 0 to 3, in which 0=no observable deficit; 1=forelimb flexion present; 2=decreased resistance to lateral push without circling; and 3=same behavior as 2, but with circling.³⁸

Histopathological Evaluation
Four days after MCA occlusion (ie, 3 days after hyperthermia or normothermia), animals were deeply anesthetized with 3% halothane and perfused transcardially with a mixture of 40% formaldehyde, glacial acetic acid, and methanol (FAM, 1:1:8 by volume). The head was immersed in FAM for 24 hours. The brain was then removed and paraffin-embedded. Coronal sections 10 µm thick were prepared throughout the extent of the infarct and were stained with hematoxylin and eosin. Twelve standardized coronal levels with easily identifiable anatomic landmarks were chosen from each brain for morphometric study.³⁹ Each section was viewed at low power (x10), and the area of complete infarction (defined as a zone of microscopic pallor containing necrotic eosinophilic neurons, pallor and homogenization of the neuropil, and incipient macrophage infiltration) was traced onto paper with the use of a camera lucida microscope attachment.³⁹ Each drawing was then retraced onto a digitizing tablet interfaced to a DEC VAX minicomputer, which computed infarcted areas at each coronal level. The infarct volume was calculated by numeric integration of sequential infarct areas. Intergroup differences in infarct volume were analyzed by ANOVA; the Bonferroni procedure was used to correct for multiple comparisons. Differences were regarded statistically significant at the P<.05 level.

	Results

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Physiological Variables
Physiological values in the normothermic and hyperthermic groups are shown in Table 1. The preischemic and intraischemic values for arterial blood gases and pH, mean arterial pressure, and intraischemic plasma glucose were similar between the groups.

View this table: [in this window] [in a new window]   Table 1. Physiological Variables

Temperature Modulations
Fig 1 shows typical recordings of rectal and brain (intrastriatal) temperatures during the animals' 3-hour period in the heating chamber. In normothermic groups, mean brain temperatures tended to be 0.1°C to 0.2°C lower than mean rectal temperatures throughout this entire period, and this was statistically significant at times 0 and 3 hours (Fig 1). In the animals heated to a brain temperature of 39°C, brain temperatures were significantly higher (range, 0.2°C to 0.5°C; between-subjects effect P=.0001 by repeated measures ANOVA) than rectal temperatures throughout the 3-hour hyperthermic period. In animals with brain temperatures of 40°C, mean brain temperatures were higher than mean rectal temperatures during the first hour of hyperthermia. Subsequently, rectal temperature tended to increase and become higher than brain temperature toward the end of the heating period (Fig 1). Rectal temperatures increased significantly throughout the 3-hour temperature modulation period (P<.05, repeated measures ANOVA by ranks). No significant temperature differences were noted between sham-operated nonischemic groups versus ischemic groups during the temperature modulation period.

View larger version (30K): [in this window] [in a new window]   Figure 1. Time course of changes in rectal and brain temperatures in rats exposed to 3 hours of temperature modulation based on target brain temperature in each animal group. Data points represent the mean temperature (±SD). Repeated measures ANOVA with post hoc Bonferroni procedures revealed significant differences (P<.05) between brain and rectal temperatures during hyperthermic modulations (denoted by *). During temperature modulation of 40°C, rectal temperature increased significantly (P<.05 in repeated measures ANOVA). BT indicates brain temperature; RT, rectal temperature.

Effect of Temperature Modulation on Blood Glucose
In the 40°C groups, blood glucose concentration tended to increase after heating, but this did not reach statistical significance (Table 2). The other groups failed to show any blood glucose increment after temperature modulation.

View this table: [in this window] [in a new window]   Table 2. Changes in Blood Glucose

Mortality and Neurological Status
In group 1 (normothermia after ischemia) and group 2 (39°C hyperthermia after ischemia), there were no deaths related to the surgical and temperature-modulation procedures. However, postischemic heating led to a 27% mortality rate (3 of 11) in group 3 (40°C hyperthermia after ischemia). Two of these rats developed seizures during heating, and severe hypothermia (30°C) was discovered in the third rat 1 day after heating. None of the sham-operated nonischemic rats showed any problem related to heating even though they developed brain temperatures of 40°C, and all of these animals survived throughout the study period.

On neurological evaluation 1 day after temperature modulation, group 3 animals had significantly worse neurological scores than groups 1 or 2, whereas there was no significant difference between groups 1 and 2 (Fig 2). None of the sham-operated nonischemic rats displayed a neurological deficit.

View larger version (12K): [in this window] [in a new window]   Figure 2. Neurological scores 1 day after temperature modulation (each animal's score is represented as ). Kruskal-Wallis one-way ANOVA by ranks showed significant differences (denoted in the bar by ) between the normothermic vs 40°C hyperthermic groups (P=.01) and between the 39°C hyperthermic vs 40°C hyperthermic groups (P=.02) but not between the normothermic vs 39°C hyperthermic groups.

Histopathological Results
In ischemic groups with 60-minute transient MCA occlusion, histological examination of the brain after a 4-day survival showed a consistent pattern of ischemic brain damage, characterized by a mixture of infarction and selective ischemic neuronal changes (Fig 3). The infarcted zones were well demarcated and displayed pancellular necrosis as well as dense areas of eosinophilic, shrunken neurons along the edges of the infarct. All ischemic animals had infarcts of the caudoputamen. The dorsolateral cortex was the predominant site of cortical involvement. In normothermic and 39°C hyperthermic ischemic rats, only small patchy areas of neocortical infarction were noted, which in several instances were contiguous with the inferior striatal infarct (Fig 3A and 3B). By contrast, 40°C hyperthermic ischemic brains showed, in seven of eight cases, extensive zones of neocortical infarction (Figs 3C and 4). Four rats showed small regions of hemorrhagic infarction, all belonging to the 40°C hyperthermic ischemic group. In one instance this involved the neocortex (Fig 3D), in two cases the striatum, and in one brain the cortical-striatal interface.

View larger version (154K): [in this window] [in a new window]   Figure 3. Hematoxylin and eosin–stained paraffin-embedded coronal sections illustrating pathological features. A, B, C, Low-power views of middle cerebral artery–occluded hemisphere in rats with postischemic normothermia (A), 39°C hyperthermia (B), and 40°C hyperthermia (C). In the normothermic brain (A) and the 39°C hyperthermic brain (B), infarction involves the central and inferior portions of striatum and a small area of overlying inferolateral neocortex. By contrast, the zone of infarction in the 40°C hyperthermic brain (C) involves the entire caudoputamen and extensive areas of the dorsolateral, lateral, and inferior neocortex. Panel D shows a small zone of hemorrhagic infarction in the neocortex of a 40°C hyperthermic rat.

View larger version (58K): [in this window] [in a new window]   Figure 4. Topographical diagrams of infarcted regions at the level of premotor cortex, caudoputamen, and hippocampus in all ischemic rats exposed to 3-hour temperature modulation. Infarcted regions are represented in black.

Volumes of cortical infarction and total infarction were significantly greater (by sixfold and threefold, respectively) in group 3 (40°C hyperthermic group) than in groups 1 or 2 (P<.05, one-way ANOVA) (Table 3, Fig 4), whereas there was no significant difference between groups 1 and 2. In addition, values for striatal infarct volume did not show any significant difference among the groups. None of the sham-operated nonischemic rats (groups C1, C2, and C3) showed any pathological alterations of the brain except for a fine linear area of parenchymal destruction extending from the cortex to the caudoputamen, produced by the brain-temperature probe.

View this table: [in this window] [in a new window]   Table 3. Volume of Infarction of Ischemic Groups

	Discussion

Top Abstract Introduction Materials and Methods Results Discussion References Introduction

 
In this study we induced a period of delayed hyperthermia in awake rats 24 hours after transient MCA occlusion. The salient finding of our study is the marked aggravation of ischemic neuronal damage produced by this delayed postischemic brain-temperature elevation. Delayed hyperthermia caused the zone of ischemic injury to extend from the caudoputamen to involve the overlying cortex in most of the animals with brain temperatures of 40°C. The degree and pattern of increased ischemic damage seen in these animals was similar to that previously observed with intraischemic hyperthermia.^{5 8 13 14 15 21} Thus, in addition to affecting intraischemic events, hyperthermia also appears capable of altering postischemic processes so as to aggravate ischemic damage. Our results showing no histopathological damage in nonischemic animals with delayed hyperthermia indicate that hyperthermia alone is not responsible for the pathological alterations observed. In addition, mildly hyperthermic ischemic animals (brain temperature 39°C) did not show a significant difference from the normothermic ischemic animals in either their neurological or neuropathological evaluation.

A unique aspect of this study was that we performed temperature modulation in awake rats that were freely moving except for mild restraint related to the temperature cables. The present method thus allowed for continuous measurement and control of brain and rectal temperatures in freely moving rats. Even though some studies have suggested that the use of restraint might increase temperature in awake animals,^{12 40} none of the animals of the normothermic groups of our study developed fever during their stay in the chamber. This suggests that the present method alone, in the absence of heating, does not induce significant stress. Although brain-temperature monitoring induced restricted brain injury along the probe track, neuropathological study confirmed that there were no intracranial hemorrhages or other pathological changes related to probe movement. In addition, these awake rats appeared to tolerate the implanted probes well. Consequently, in the present study we produced hyperthermia in awake rats safely and reliably using a heating chamber and brain-temperature monitoring.

Brain Temperature Thresholds for Worsening Produced by Delayed Hyperthermia
In the present study an obvious aggravation of ischemic damage by delayed hyperthermia was noted exclusively at a brain temperature of 40°C. Our results thus suggest that delayed temperature elevations elicit an "all-or-none" threshold response rather than a graded worsening of injury in proportion to the change of temperature. The threshold for hyperthermic aggravation of ischemic brain injury in the present study appears to be at approximately 40°C in the postischemic period, since milder delayed hyperthermia was unable to exacerbate injury. These results thus suggest that the ischemic brain may become insensitive to postischemic temperature elevations of milder degree when induced in a delayed fashion. This stands in marked contrast to the results of several recent studies in which hyperthermia was present in the intraischemic or immediate postischemic periods; in the latter studies, even mild increments in brain temperature enhanced ischemic neuronal damage.^{5 8 12 13 14 15 16 21 41 42 43} In fact, the insensitivity of postischemic brain to delayed temperature alterations has also been noted in several hypothermia studies. These reports demonstrated that no protection was found when hypothermia was induced 40 minutes⁴⁴ or 60 minutes^{17 45} after the onset of ischemia. In addition, Dietrich et al⁴⁶ have shown that, in contrast to intraischemic hypothermia, a restricted 3-hour period of moderate postischemic hypothermia does not chronically protect the ischemic brain but rather merely delays the eventual onset of ischemic cell death. Furthermore, in the study of Baker et al,¹⁷ who assessed the influence of hypothermia on ischemic outcome as a function of time of onset after ischemia, the protective effect of hypothermia on the ischemic lesion gradually diminished with increasing time after the onset of ischemia.

The mechanisms underlying the relative resistance of the postischemic brain to delayed temperature elevations are not clear. The peripheral zone of a focally ischemic region—the so-called ischemic penumbra⁴⁷ —is known to be a temperature-sensitive area,^{15 43} and it has been demonstrated to become reduced in size at increasing reperfusion times.^{48 49 50 51} Thus, a reduction in the size of the temperature-sensitive ischemic penumbra may be a possible explanation for the delayed decrease in temperature sensitivity of the postischemic brain. In addition, while hyperthermia is known to exacerbate acidosis and high-energy phosphate depletion,^{52 53 54} one report has suggested that such effects become insignificant in the postischemic period: Chopp et al⁴¹ demonstrated that preischemic hyperthermia significantly lowers intracellular pH and disturbs the recovery of high-energy phosphates during recirculation, whereas postischemic hyperthermia has no significant effect.

Deleterious Effect of Delayed Postischemic Hyperthermia on Outcome
The aggravated ischemic injury produced by delayed postischemic hyperthermia in this study is likely to involve multiple cytotoxic events. In addition to an increase in cellular metabolism long regarded as being a primary mechanism underlying hyperthermic aggravation, recent evidence indicates that hyperthermia may affect various ischemia-induced pathophysiological events, in particular, those related to reperfusion injury. During this period, ischemia-induced excitotoxic processes with subsequent activation of second messenger systems may be prominent, as well as other ischemic events.⁵⁵ Many studies have demonstrated that increased temperature might accentuate cytotoxic events during the reperfusion period. For example, hyperthermia has been reported to accentuate postischemic blood-brain barrier disruption,^{21 56 57} postischemic free radical formation,^{58 59} intravascular leukocyte accumulation,²¹ and glutamate release into the extracellular space.⁴³

In addition to these ischemia-induced excitotoxic events, hyperthermia may also affect the reactivity of intracerebral arterioles. According to one study in rats,⁶⁰ normal intracerebral arterioles significantly constricted (by 72% of control) within 3 minutes of ambient temperature elevation to 40°C and then dilated gradually over the subsequent 15 minutes. Furthermore, when temperature was returned to 37.5°C after exposure to hyperthermia, vessels exhibited further transient dilations (to 138% of control). These events might seriously affect the hemodynamics of the ischemic region. Under conditions of defective autoregulation in ischemic brain tissue, constriction of normal vessels may impair collateral blood supply to the ischemic territory and facilitate the formation of cerebral edema due to luxury perfusion. In addition, cerebral blood flow in the ischemic area may be further reduced as a result of steal phenomena.^{61 62} These hemodynamic disturbances may contribute to the delayed hyperthermic aggravation of ischemic injury.

Another salient finding of the present study was that hyperthermia affected blood glucose concentration in these awake animals. Physiological stresses such as fever may elevate the blood glucose concentration to a level that could augment ischemic brain damage.^{63 64 65}

In summary, the present results demonstrate that hyperthermia of moderate degree (40°C), even if delayed, leads to an aggravation of ischemic neuronal damage during the postischemic period, whereas hyperthermia of slightly milder degree (39°C) fails to affect the severity of the ischemic lesion. These findings indicate that both the timing and the degree of temperature modulation are important factors in influencing the thermal effect on ischemic outcome. In the clinical arena, fever is a common complication after stroke. The present results stress that, in patients with moderate fever after cerebral ischemia, aggressive temperature normalization should be instituted to protect the ischemic brain from secondary cytotoxic events accentuated by fever, even in the delayed period after stroke onset.

	Acknowledgments

 
This study was supported by US Public Health Service grant NS 05820. We are grateful to Ofelia F. Alonso for expert technical assistance and to Helen Valkowitz for preparation of the typescript.

	Footnotes

 
Reprint requests to Myron D. Ginsberg, MD, Department of Neurology (D4-5), University of Miami School of Medicine, PO Box 016960, Miami, FL 33101.

Received May 10, 1996; revision received July 3, 1996; accepted September 17, 1996.

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Editorial Comment

William I. Rosenblum, MD, Guest Editor

Division of NeuropathologyMedical College of VirginiaVirginia Commonwealth UniversityRichmond, Va

	Introduction

Top Abstract Introduction Materials and Methods Results Discussion References Introduction

 
The authors provide good evidence that in a rodent model of ischemic stroke, mild hyperthermia is detrimental even when the hyperthermia is brief and does not begin until 24 hours after the onset of reperfusion. Reports like this one focus our attention on the events that must occur in the brain after the event that initiates the stroke. A tremendously large literature has developed concerning various pathogenic cascades that are initiated by ischemia and/or reperfusion. Many scientists are trying to develop interventions that can be begun after patients present with their strokes. The hypothesis that such interventions will be beneficial is based on the evidence that these cascades exist and can be successfully interrupted after the onset of ischemia or reperfusion. The accompanying article suggests that hyperthermia developing 1 day later than the stroke and lasting for periods of time as short as 3 hours may exacerbate the bad effects of one or more noxious cascades. The data do not permit a guess as to which pathway is involved. If data from the small rodent brain can be extrapolated to human brains, the data may suggest that mild fever, starting after the stroke and lasting for only a short period of time, may be detrimental to the victim. Since fever, for one reason or another, often occurs in patients with stroke, it is important to examine the possibility that it can indeed make the stroke worse. If so, one might wonder whether antipyretic therapy would be warranted as prophylaxis in all stroke victims as soon as they arrive at the hospital.

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