Intraischemic Brain Temperature Research Articles

Keeping cool in acute liver failure: Rationale for the use of mild hypothermia

Encephalopathy, brain edema and intracranial hypertension are neurological complications responsible for substantial morbidity/mortality in patients with acute liver failure (ALF), where, aside from liver transplantation, there is currently a paucity of effective therapies. Mirroring its cerebro-protective effects in other clinical conditions, the induction of mild hypothermia may provide a potential therapeutic approach to the management of ALF. A solid mechanistic rationale for the use of mild hypothermia is provided by clinical and experimental studies showing its beneficial effects in relation to many of the key factors that determine the development of brain edema and intracranial hypertension in ALF, namely the delivery of ammonia to the brain, the disturbances of brain organic osmolytes and brain extracellular amino acids, cerebro-vascular haemodynamics, brain glucose metabolism, inflammation, subclinical seizure activity and alterations of gene expression. Initial uncontrolled clinical studies of mild hypothermia in patients with ALF suggest that it is an effective, feasible and safe approach. Randomized controlled clinical trials are now needed to adequately assess its efficacy, safety, clinical impact on global outcomes and to provide the guidelines for its use in ALF.

New Research in the Field of Stroke: Therapeutic Hypothermia after Cardiac Arrest

Therapeutic hypothermia as a potential treatment for stroke, cerebral ischemia, and other neurological diseases has gained momentum since the initial discovery that relatively small differences in intraischemic brain temperature critically determine ischemic neuronal vulnerability.1 Since that time, laboratories throughout the world have investigated the potential use of mild-to-moderate hypothermia in many ischemia models.2,3 Various studies have also investigated potential mechanisms contributing to hypothermic protection. Pathomechanisms sensitive to intra- and postischemic temperature reductions and elevations include glutamate release, stabilization of the blood-brain barrier, oxygen radical production, intracellular signal conduction, protein synthesis, ischemic depolarization, reduced cerebral metabolism, membrane stabilization, inflammation, activation of protein kinases, cytoskeletal breakdown, and early gene expression.2,4 Because the pathophysiology of ischemic brain injury is complex, the fact that many injury mechanisms have been reported to be temperature sensitive may account for the dramatic effects of temperature on ischemic outcome. Thus, therapeutic hypothermia has the necessary support from preclinical data to initiate well-designed clinical studies targeting various patient populations. In a recent issue of The New England Journal of Medicine , the results of 2 randomized clinical trials showed clearly that mild hypothermia improves neurologic outcome and reduces overall mortality in survivors of out-of-hospital–witnessed cardiac arrest.5,6 In the study from Australia, a total of 77 patients who remained comatose after the return of spontaneous circulation (ROSC) were randomized to receive 12 hours of hypothermia or standard normothermic temperature management.5 In that study, surface cooling was begun in the field and the target temperature of 32°C to 34°C was reached within 2 hours of ROSC. Forty-nine percent of those treated with hypothermia were discharged home or to a rehabilitation facility, as compared with 26% of those not treated with hypothermia ( P =0.046). In the second study from Europe, 9 centers in 5 countries participated, with …

Quantitative evaluation of extracellular glutamate concentration in postischemic glutamate re-uptake, dependent on brain temperature, in the rat following severe global brain ischemia

Changes in brain temperature are known to modulate the marked neuronal damage caused by an approximately 10-min intra-ischemic period. Numerous studies have suggested that the extracellular glutamate concentration ([Glu] e) in the intra-ischemic period and the initial postischemia period is strongly implicated in such damage. In this study, the effects of intra-ischemic brain temperature (32, 37, 39°C) on [Glu] e were investigated utilizing a dialysis electrode combined with ferrocene bovine serum albumin (BSA), which allows oxygen-independent real-time measurement of [Glu] e. This system allowed separate quantitative evaluation of intra-ischemic biphasic glutamate release from the neurotransmitter and metabolic pools, and of postischemic glutamate re-uptake in ischemia–reperfusion models. The biphasic [Glu] e elevation in the intra-ischemic period did not differ markedly among intra-ischemic brain temperatures ranging from 32 to 39°C. Intra-ischemic normothermia (37°C) and mild hyperthermia (39°C) markedly inhibited [Glu] e re-uptake during the postischemic period, although the intra-ischemic [Glu] e elevation did not differ from that during intra-ischemic hypothermia (32°C). It was assumed that normothermia or mild hyperthermia in the intra-ischemic period influences intracellular functional abnormalities other than the intra-ischemic [Glu] e elevation, thereby inhibiting glutamate re-uptake after reperfusion rather than directly modulating intra-ischemic [Glu] e dynamics.

Nicergoline enhances glutamate re-uptake and protects against brain damage in rat global brain ischemia

Whereas a 2–3°C decrease in intraischemic brain temperature can be neuroprotective, mild brain hyperthermia significantly worsens outcome. Our previous study suggested that an ischemic injury mechanism which is sensitive to temperature may not actually increase the extracellular glutamate concentration ([Glu] e) during the intraischemic period, but rather impairs the Glu re-uptake system, which has been suggested to be involved in the reversed uptake of Glu. We speculated that enhancing Glu re-uptake, pharmacologically or hypothermically, may shorten exposure to high [Glu] e in the postischemic period and thereby decrease its deleterious excitotoxic effect on neuronal cells. In the present study, rats treated with nicergoline (32 mg/kg, i.p.), an ergot alkaloid derivative, showed minimal inhibition of the [Glu] e elevation which characteristically occurs during the 10-min intraischemic period, while Glu re-uptake was dramatically improved in the postischemic period, when severe transient global ischemia was caused by mild hyperthermia. Moreover, the nicergoline (32 mg/kg, i.p.) treated rats showed reduced cell death morphologically and clearly had a far lower mortality. The present study suggests that the development of therapeutic strategies aimed at inhibition or prevention of the reversed uptake of glutamate release during ischemia, i.e., activation of the glutamate uptake mechanism, is a promising approach to reduce neural damage occurring in response to brain ischemia.

Minimal effect of brain temperature changes on glutamate release in rat following severe global brain ischemia: a dialysis electrode study.

Using a dialysis electrode, we recently developed an oxygen-independent system for real-time measurement of the glutamate concentration in the extracellular space ([Glu]e) during ischemia. This system allows separate evaluation of intra-ischemic biphase [Glu]e elevation, i.e. release from synaptic vesicles (1st phase), reversed uptake of glutamate from metabolic pools in neuronal cells (2nd phase), and post-ischemic glutamate re-uptake in ischemia-reperfusion models. Using the system, we attempted to clarify the relationship between biphase glutamate release and brain temperature in a model of acute global ischemia produced by transecting both carotid arteries. Our results showed that, in contrast to mild hyperthermia, hypothermia did not inhibit the 1st phase of [Glu]e release, and changes in intra-ischemic brain temperature had a minimal effect on the 2nd phase of [Glu]e elevation during severe acute ischemia. These findings, together with our previous data, indicate that brain temperature change in the intra-ischemic period plays an important role in disturbance of the glutamate re-uptake system during ischemia.

Combating hyperthermia in acute stroke: a significant clinical concern.

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. In standardized models of transient forebrain ischemia, intraischemic brain temperature elevations to 39 degrees 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. 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 combatted 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 degrees C to 37.0 degrees C [98.0 degrees F to 98.6 degrees F]) for at least the first several days after acute stroke or head injury.

Cerebral hyperthermia during cardiopulmonary bypass in adults

Accepted for publication June 7, 1995 In this report, we document that cerebral hyperthermia occurs regularly during rewarming from hypothermic cardiopulmonary bypass (CPB). These high brain temperatures are not adequately reflected by nasopharyngeal (NP) temperature and may contribute to neurologic morbidity. Stroke and neurocognitive injury remain significant components of perioperative morbidity associated with cardiac surgery. Hypothermic CPB is used in part for its cerebral protective effects. Recent reports, however, have indicated that the rewarming phase of hypothermic CPB is associated with a significant incidence of decreased cerebral venous oxygen saturation (Sjvo2; 50%). 1,2 Sjvo2 is thought to be a general index of the adequacy of the matching of cerebral oxygen supply with demand.

Brain Temperature Modulations During Global Ischemia Fail to Influence Extracellular Lactate Levels in Rats

While brain tissue lactate increases during cerebral ischemia and is known to be important in the pathogenesis of ischemic brain injury, patterns of extracellular lactate accumulation have been less well characterized, and the influence of brain temperature has not been previously investigated. Mild brain temperature modulations are known to affect the outcome of ischemia dramatically. This study examined changes of extracellular lactate during and after global cerebral ischemia, in which intraischemic brain temperature was held at either 30 degrees C, 37 degrees C, or 39 degrees C. Halothane-anesthetized fasted male Wistar rats underwent 20 minutes of global cerebral ischemia produced by bilateral carotid artery occlusions plus systemic hypotension (40 to 50 mm Hg). Rectal temperature was maintained at 37 degrees C throughout, and intraischemic brain temperature was held at either 30 degrees C (n = 6), 37 degrees C (n = 5), or 39 degrees C (n = 5). Before and after the ischemic insult, brain temperature was maintained at 37 degrees C in all groups. A microdialysis cannula was implanted in the right dorsolateral striatum and perfused with Ringer's solution. Dialysate samples were collected at 10-minute intervals before, during, and after ischemia and were analyzed for lactate by enzymatic-fluorometric techniques. In all groups, extracellular lactate rose during ischemia and peaked at 10 to 30 minutes of recirculation. Maximal extracellular lactate elevations were sevenfold, eightfold, and eightfold above control in the 30 degrees C, 37 degrees C, 39 degrees C groups, respectively. Significant elevations with respect to control were observed in all groups at 10 to 30 minutes of recirculation. In the 30 degrees C group, these elevations above control were also significant at the 10- and 20-minute ischemic time points (P = .001). At 30 minutes of recirculation, however, lactate levels were lower in the 30 degrees C rats than in the other groups. These data provide evidence that extracellular lactate accumulation is not a crucial determinant of ischemic brain injury. Our results suggest that the increased lactate release during ischemia and the accelerated clearance of lactate during recirculation might contribute in part to the neuroprotection of intraischemic hypothermia.

Detection of free radical activity during transient global ischemia and recirculation: effects of intraischemic brain temperature modulation.

To obtain direct evidence of oxygen radical activity in the course of cerebral ischemia under different intraischemic temperatures, we used a method based on the chemical trapping of hydroxyl radical in the form of the stable adducts 2,3- and 2,5-dihydroxybenzoic acid (DHBA) following salicylate administration. Wistar rats were subjected to 20 min of global forebrain ischemia by two-vessel occlusion plus systemic hypotension (50 mm Hg). Intraischemic striatal temperature was maintained as normothermic (37 degrees C), hypothermic (30 degrees C), or hyperthermic (39 degrees C) but was held at 37 degrees C before and following ischemia. Salicylate was administered either systemically (200 mg/kg, i.p.) or by continuous infusion (5 mM) through a microdialysis probe implanted in the striatum. Striatal extracellular fluid was sampled at regular intervals before, during, and after ischemia, and levels of 2,3- and 2,5-DHBA were assayed by HPLC with electrochemical detection. Following systemic administration of salicylate, stable baseline levels of 2,3- and 2,5-DHBA were observed before ischemia. During 20 min of normothermic ischemia, a 50% reduction in mean levels of both DHBAs was documented, suggesting a baseline level of hydroxyl radical that was diminished during ischemia, presumably owing to oxygen restriction to tissue at that time. During recirculation, 2,3- and 2,5-DHBA levels increased by 2.5- and 2.8-fold, respectively. Levels of 2,3-DHBA remained elevated during 1 h of reperfusion, whereas the increase in 2,5-DHBA persisted for 2 h. The increases in 2,3- and 2,5-DHBA levels observed following hyperthermic ischemia were significantly higher (3.8- and fivefold, respectively). In contrast, no significant changes in DHBA levels were observed following hypothermic ischemia.(ABSTRACT TRUNCATED AT 250 WORDS)

Regional alterations of protein kinase C activity following transient cerebral ischemia: effects of intraischemic brain temperature modulation.

It is well established that ischemia-induced release of glutamate and the subsequent activation of post-synaptic glutamate receptors are important processes involved in the development of ischemic neuronal damage. Moderate intraischemic hypothermia attenuates glutamate release and confers protection from ischemic damage, whereas mild intraischemic hyperthermia increases glutamate release and augments ischemic pathology. As protein kinase C (PKC) is implicated in neurotransmitter release and glutamate receptor-mediated events, we evaluated the relationship between intraischemic brain temperature and PKC activity in brain regions known to be vulnerable or nonvulnerable to transient global ischemia. Twenty minutes of bilateral carotid artery occlusion plus hypotension were induced in rats in which intraischemic brain temperature was maintained at 30 degrees C, 37 degrees C, or 39 degrees C. Prior to and following ischemia, brain temperature was 37 degrees C in all groups. Cytosolic, membrane-bound, and total PKC activities were determined in hippocampal, striatal, cortical, and thalamic homogenates at the end of ischemia and at 0.25-24 h of recirculation. PKC activity of control rats varied by region and were affected by altered brain temperature. For both membrane-bound and cytosolic PKC, there was a significant temperature effect, and for membrane-bound PKC there was also a significant effect of region. Rats with normothermic ischemia (37 degrees C) showed extensive depressions of all PKC fractions. Hippocampus and striatum were noteworthy for depressions in PKC activity extending from the earliest (15 min) to the latest (24 h) recirculation times studied, whereas cortex showed PKC depressions chiefly during the first hour of recirculation, and the thalamic pattern was inconsistent.(ABSTRACT TRUNCATED AT 250 WORDS)

Temperature changes associated with forebrain ischemia in the gerbil

Changes in brain temperature during and following ischemia have not been systematically examined in the gerbil. In this study, gerbils were subjected to a 5-min bilateral carotid artery occlusion. During surgery, skull and body temperatures were maintained with a heated water blanket and a homeothermic blanket unit, respectively. Rectal, skull and brain temperatures were monitored throughout ischemia and for up to 3 h in the post-ischemic period. Intra-ischemic brain temperature fell by approximately 1.5°C even though skull and rectal temperatures remained at normal values. Since brain temperature modulates the extent of ischemic injury it may not be sufficient to rely on skull and/or rectal temperature readings, especially during periods of anesthesia.

Interrelationships between increased vascular permeability and acute neuronal damage following temperature-controlled brain ischemia in rats

This study examined regional patterns of increased vascular permeability and morphological indicators of acute neuronal injury following normothermic and mildly hyperthermic forebrain ischemia. Rats underwent 20 min of four-vessel occlusion during which intraischemic brain temperature was maintained at either 37 degrees C or 39 degrees C. At 45-min recirculation, the blood-brain barrier (BBB)-tracer horseradish peroxidase was injected and rats were perfusion-fixed at 1-h recirculation for light and electron microscopic analysis. In normothermic and hyperthermic rats, sites of increased vascular permeability were spatially correlated with dark shrunken type IV neurons. Neuronal alterations within cortical, hippocampal, striatal, and thalamic areas ranged from mild cytoplasmic vacuolation and mitochondrial swelling to severe cytoplasmic shrinkage and increased density. Although dark shrunken neurons were routinely associated with permeable blood vessels in both temperature groups, dark neurons were not detected in regions demonstrating an intact BBB. Following normothermic brain ischemia, the appearance of dark shrunken neurons was restricted to the cerebral cortex and striatum. In both temperature groups, luminal leukocytes were detected within otherwise well-perfused forebrain microvascular beds. Our studies suggest a close interrelationship between postischemic microvascular abnormalities, including increased vascular permeability, and morphological indicators of acute neuronal injury following brain ischemia.

The Importance of Brain Temperature in Alterations of the Blood-Brain Barrier Following Cerebral Ischemia

We studied whether small variations in intraischemic brain temperature influence the response of the blood-brain barrier (BBB) to transient forebrain global ischemia. Six animal subgroups included rats whose brain temperature was maintained at 30, 33, 36 or 39 degrees C during 20 minutes (min) of 4-vessel occlusion. Control rats without ischemia had brain temperature maintained between 30 and 39 degrees C for a 20 min period. After a 45 min postischemic recirculation period, rats were injected with the protein tracer, horseradish peroxidase (HRP), and perfusion fixed 5 or 15 min later. Control rats showed no leakage of the tracer protein. Postischemic rats in which brain temperature was controlled at either 30 or 33 degrees C failed to demonstrate consistent BBB alterations. In contrast, foci of cortical HRP extravasation were consistently documented in rats whose intraischemic brain temperature was 36 degrees C. Permeability alterations were more widespread in the 39 degrees C ischemic group and occurred in cortical, thalamic, hippocampal and striatal regions. The HRP extravasation frequently involved arterioles surrounded by perivascular spaces. Routes of increased permeability to HRP included endothelial pinocytosis, opening of the interendothelial tight junctions and diffuse leakage through damaged endothelial cells. These results demonstrate that brain temperature is a critical factor in determining whether BBB dysfunction is an acute consequence of a transient cerebral ischemic insult.

Effect of mild hypothermia on ischemia-induced release of neurotransmitters and free fatty acids in rat brain.

We have demonstrated previously that mild intraischemic hypothermia confers a marked protective effect on the final histopathological outcome. The present study was carried out to evaluate whether this protective effect involves changes in the degree of local cerebral blood flow reductions, tissue accumulation of free fatty acids, or alterations in the extracellular release of glutamate and dopamine. Rats whose intraischemic brain temperature was maintained at 36 degrees C, 33 degrees C, or 30 degrees C were subjected to 20 minutes of ischemia by four-vessel occlusion combined with systemic hypotension. Levels of local cerebral blood flow, as measured autoradiographically, were reduced uniformly in all experimental animals at the end of ischemia by gas chromatography after tissue extraction and separation by thin layer chromatography. A massive ischemia-induced accumulation of individual free fatty acids was observed in animal groups whose intraischemic brain temperature was maintained at either 36 degrees C or 30 degrees C. Extracellular neurotransmitter levels were measured by microdialysis; the perfusate was collected before, during, and after ischemia. In rats whose intraischemic brain temperature was maintained at 36 degrees C, dopamine and glutamate increased significantly during ischemia and the early period of recirculation (by 500-fold and sevenfold, respectively). In animals whose brain temperature was maintained at 33 degrees C and 30 degrees C, the release of glutamate was completely inhibited, and the release of dopamine was significantly attenuated (by 60%). These results suggest that mild intraischemic hypothermia does not affect the ischemia-induced local cerebral blood flow reduction or free fatty acid accumulation.(ABSTRACT TRUNCATED AT 250 WORDS)

Postischemic moderate hypothermia inhibits CA1 hippocampal ischemic neuronal injury

We have determined whether lowering brain temperature during the acute recirculation period following transient cerebral ischemia would influence the extent of ischemic neuronal injury. Anesthetized rats underwent 10 min of bilateral carotid artery occlusion combined with systemic hypotension (50 mmHg). Four animal subgroups were investigated, including non-ischemic controls; rats whose postischemic brain temperature was maintained at 36 or 30°C starting 5 min into the recirculation period; and rats in which postischemic hypothermia was begun 30 min into the recirculation period. In all cases, intra-ischemic brain temperature was 36°C and body temperature was held at 36–37°C throughout. Three days following the ischemic insult, the CA1 sector of the hippocampus was severely damaged in normothermic rats (36°C). In contrast, when postischemic brain temperature was decreased to 30°C starting 5 min into the recirculation period, normal-appearing pyramidal neurons were present throughout the CA1 hippocampus. A beneficial effect of postischemic hypothermia was not demonstrated when brain cooling was initiatied 30 min into the recirculation period. These results demonstrate that postischemic hypothermia can markedly protect CA1 pyramidal neurons from injury following transient ischemia. The ‘therapeutic window’ for postischemic hypothermia was found to be narrow under the present experimental conditions.

Intra-ischemic extracellular release of dopamine and glutamate is associated with striatal vulnerability to ischemia

We have previously described a marked attenuation of postischemic striatal neuronal death by prior substantia nigra (SN) lesion, and have shown that lowering the brain temperature by only a few degrees during ischemia also confers a marked protective effect. The present study was carried out to evaluate whether the protective effect of these manipulations involves changes in extracellular release of striatal dopamine (DA) and glutamate (Glu) during ischemia. Four animal subgroups were investigated, including unilateral SN-lesioned rats whose intra-ischemic brain temperature was maintained at 36°C, and non-lesioned animals whose brain temperature was not regulated, or was maintained at 33 or 36°C during ischemia. Striatal extracellular sampling was performed by a microdialysis probe in rats subjected to 20 min of ischemia by 4-vessel occlusion. In rats whose intra-ischemic brain temperature was 36°C, both DA and Glu increased significantly. In SN-lesioned rats no changes were found in extracellular levels of DA. However, significant increases in Glu were measured. In animals whose brain temperature was not regulated (the intra-ischemic brain temperature fell to 30°C) or maintained at 33°C there was a significant increase of DA release, but no changes were found in extracellular levels of Glu. These results, taken together with the neuropathological findings, suggest that release of both DA and Glu during ischemia is necessary for the development of postischemic striatal damage.

Small differences in intraischemic brain temperature critically determine the extent of ischemic neuronal injury.

We have tested whether small intraischemic variations in brain temperature influence the outcome of transient ischemia. To measure brain temperature, a thermocouple probe was placed stereotaxically into the left dorsolateral striatum of rats prior to 20 min of four-vessel occlusion. Rectal temperature was maintained at 36-37 degrees C by a heating lamp, and striatal temperature prior to ischemia was 36 degrees C in all animals. Six animal subgroups were investigated, including rats whose intraischemic striatal brain temperature was not regulated, or was maintained at 33, 34, 36, or 39 degrees C. Postischemic brain temperature was regulated at 36 degrees C, except for one group in which brain temperature was lowered from 36 degrees C to 33 degrees C during the first hour of recirculation. Energy metabolites were measured at the end of the ischemic insult, and histopathological evaluation was carried out at 3 days after ischemia. Intraischemic variations in brain temperature had no significant influence on energy metabolite levels measured at the conclusion of ischemia: Severe depletion of brain ATP, phosphocreatine, glucose, and glycogen and elevation of lactate were observed to a similar degree in all experimental groups. The histopathological consequences of ischemia, however, were markedly influenced by variations in intraischemic brain temperature. In the hippocampus, CA1 neurons were consistently damaged at 36 degrees C, but not at 34 degrees C. Within the dorsolateral striatum, ischemic cell change was present in 100% of the hemispheres at 36 degrees C, but in only 50% at 34 degrees C. Ischemic neurons within the central zone of striatum were not observed in any rats at 34 degrees C, but in all rats at 36 degrees C. In rats whose striatal temperature was not controlled, brain temperature fell from 36 to 30-31 degrees C during the ischemic insult. In this group, no ischemic cell change was seen within striatal areas and was only inconsistently documented within the CA1 hippocampal region. These results demonstrate that (a) rectal temperature unreliably reflects brain temperature during ischemia; (b) despite severe depletion of brain energy metabolites during ischemia at all temperatures, small increments of intraischemic brain temperature markedly accentuate histopathological changes following 3-day survival; and (c) brain temperature must be controlled above 33 degrees C in order to ensure a consistent histopathological outcome. Lowering of the brain temperature by only a few degrees during ischemia confers a marked protective effect.